{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-0-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 0, "text": "Center for Drug Evaluation and Research - Compliance Central with FDA Center Compliance Directors: Part 1 Donald D. Ashley, JD 2017 FDLI Enforcement, Litigation, and Compliance Conference: For the Drug, Device, Food, and Tobacco Industries December 6, 2017\n\nwww.fda.gov", "n_tokens": 55, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-1-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 1, "text": "CDER Office of Compliance\nOverview\n\n>—_ High Quality?\n\nwww.fda.gov", "n_tokens": 17, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-2-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 2, "text": "Office of Drug Security, Integrity and Response (ODSIR)\n\nwww.fda.gov\n\nOffice of Compliance Structure\n\nOffice of Compliance\n\nOffice of Unapproved Drugs and Labeling Compliance (OUDLC)\n\nOffice of Manufacturing Quality (OMQ)\n\nOffice of Program and Regulatory Operations (OPRO)\n\nOffice of Scientific Investigations (OSI)\n\n3", "n_tokens": 66, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-3-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 3, "text": "Responsibility Throughout Lifecycle\n\nPREAPPROVAL : APPROVAL\nI\n\nPOSTMARKET CUSTOMER DISTRIBUTION\n\nOutside the Normal Lifecycle\n\n+ Internet Pr\n- Marketed t\n\nwww.fda.gov", "n_tokens": 31, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-4-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 4, "text": "Office of Scientific Investigations\n\nBIMO Warning Letters issued from FY14-FY17\n\n18\n\n16\n\n14\n\nPostmarketing Adverse Drug Experience\n\n12\n\nSponsor Investigator\n\n10\n\nGood Laboratory Practice\n\n8\n\n6\n\nInstitutional Review Board\n\nSponsor\n\n4\n\n2\n\nClinical Investigator\n\n0\n\nwww.fda.gov\n\nFY14\n\nFY15\n\nFY16\n\nFY17\n\n5 5", "n_tokens": 63, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-5-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 5, "text": "Office of Unapproved Drugs and Labeling Compliance: FY17 Compounding Activities\n\nConducted 141 compounding inspections • 62 warning letters have been issued to compounders\n\nBrought 2 injunctions against\n\ncompounders\n\nOversaw 41 recall events • Held 2 Pharmacy Compounding Advisory Committee meetings Issued 6 guidance documents Issued 3 rules\n\n•\n\nwww.fda.gov\n\n6", "n_tokens": 65, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-6-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 6, "text": "Office of Drug Security, Integrity and Response\n\nDrug Supply Chain Security Act Goals\n\nDevelop an electronic, interoperable system by 2023 to identify and trace certain prescription drugs as they move through the U.S. supply chain to:\n\nFacilitate the exchange of information by trading partners at the individual package level\n\nImprove efficiency of recalls – Enable prompt response to suspect and illegitimate products when found\n\nCreate transparency and accountability in the drug supply chain\n\nEstablish national standards for licensure for wholesale distributors and third-party logistics providers www.fda.gov\n\n7", "n_tokens": 104, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-7-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 7, "text": "Office of Manufacturing Quality Concept of Operations (“Con Ops”)\n\nThe Program Alignment initiative created a program-based management structure that aligns staff by FDA-regulated product. CDER and ORA developed a Con Ops that outlines how OMQ, Office of Pharmaceutical Quality and ORA will work within this programmatically-aligned environment, and applies to the following types of human drug facility inspections: – Pre- and post-approval inspections – For-cause inspections – Surveillance inspections\n\nCon Ops supports GDUFA II FY19 commitment to communicate final inspection classifications that do not negatively impact approvability of any pending application within 90 days of the end of the inspection – Creates 90-day decisional letters for surveillance inspection outcome\n\n6 month goal date for issuing Warning Letters • CDER and ORA have begun to operationalize Con Ops\n\nInternal policies and procedural documents will be updated as needed\n\nwww.fda.gov\n\n8", "n_tokens": 181, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-8-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 8, "text": "Concept of Operations (“ConOps”)\n\nEnsures consistency, efficiency and transparency\n\nAdvances strategic alignment by creating\n\nclear roles and responsibilities Improves operational capacity by enhancing collaboration\n\nMeets User Fee commitments Improves timeline for actions •\n\nwww.fda.gov\n\n9", "n_tokens": 45, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-9-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 9, "text": "Enforcement and Advisory Tools\n\nJan. 1 – Nov. 1, 2017\n\nRegulatory Meetings\n\nInjunctions\n\nRegulatory Discretion, 36\n\nImport Alerts, 47\n\nConsent Decrees\n\nImport Alerts\n\nWarning Letters, 57\n\nOther Warning Letters, 2*\n\nSeizures\n\nWarning Letters\n\nUntitled Letters, 5\n\nUntitled Letters\n\nOthers\n\nImport Alerts, 47\n\nUntitled Letters, 5\n\nRegulatory Discretion, 36\n\nOther Warning Letters, 2*\n\nWarning Letters, 57\n\nExcludes compounding-related actions * Warning letters from another office within CDER Compliance with OMQ CGMP violations\n\nwww.fda.gov\n\n1010", "n_tokens": 105, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-10-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 10, "text": "Office of Manufacturing Quality Warning Letters by Calendar Years\n\n60\n\n50\n\ns r e t t e\n\n40\n\nl g n n r a w Q M O\n\ni\n\n30\n\n20\n\nOther\n\nIndia\n\nChina\n\nUS\n\n10\n\n0\n\n2015\n\n2016 Year\n\n2017*\n\nThrough November 1, 2017. Does not include compounding warning letters or warning letters from another office within CDER Compliance with OMQ CGMP violations. 1111\n\nThrough November 1, 2017. Does not include compounding warning letters or warning letters from another office within CDER Compliance with OMQ CGMP violations. 1111", "n_tokens": 108, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-11-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 11, "text": "Office of Manufacturing Quality FY17 Activities\n\nEpiPen Warning Letter (September 2017) • First combination product WL that includes charges from\n\nCDER and CDRH\n\nCDER considered compliance with all drug CGMP violations and FDA’s Center for Devices and Radiological Health (CDRH) considered compliance with specified provisions under 21 CFR part 4\n\nFacility was considered violative separately by each FDA center under the applicable regulations – Firm was not appropriately investigating failures and\n\ncomplaints\n\nFirm did not reopen and broaden the investigation, or recall products until FDA inspection\n\nwww.fda.gov\n\n1212", "n_tokens": 116, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-12-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 12, "text": "Office of Manufacturing Quality FY17 Activities\n\nContract Manufacturing: From Bad to Worse\n\n“Drugs Made for You by Firm B\n\nYou have engaged Firm B to manufacture Firm A Perox-A-Mint, (b)(4). These products […]are adulterated as enumerated in the preceding violations. They are also adulterated for the reasons set forth in Warning Letter 515029, issued by FDA to Firm B on June 29, 2017. Among other things, Firm B manufactured your oral solution drugs using the same equipment in which Firm B manufactured toxic industrial-grade car washes and waxes. You are responsible for ensuring that all of your products are manufactured in accordance with CGMP, including oversight of the manufacturing operations conducted by your contractor, Firm B, on your behalf. Contractors are extensions of the manufacturer, and you are required to ensure that your drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity…”\n\n-WL July 2017\n\nwww.fda.gov\n\n1313", "n_tokens": 225, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-13-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 13, "text": "www.fda.gov\n\nOffice of Manufacturing Quality FY17 Activities\n\nFinal Guidance on Quality Agreements: Quality agreements can be used to define expectations and responsibilities in a contract manufacturing arrangement up front.\n\nhttps://www.fda.gov/downloads/Drugs/Guida nceComplianceRegulatoryInformation/Guidanc es/UCM353925.pdf\n\n1414", "n_tokens": 78, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-14-0", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 14, "text": "THANK YOU\n\n15\n\nwww.fda.gov", "n_tokens": 8, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-0-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 0, "text": "W\n\nOGD UPDATE: elcome to much more than GDUFA II\n\nKathleen Uhl, MD Director, Office of Generic Drugs CDER/FDA\n\nAAM GRx+Biosims Conference September 7, 2017\n\n1", "n_tokens": 45, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-1-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 1, "text": "Disclaimer\n\nThis presentation reflects the views of the speaker and do not reflect official FDA, HHS, or other government opinion or policy.\n\nI have nothing to disclose.\n\n2", "n_tokens": 35, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-2-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 2, "text": "OFFICE OF GENERIC DRUGS (OGD) UPDATE\n\nTypically “Year in Review” • But September is too early for FY2018 report out • FY2018 data closeout/validation will not occur for several months • Please refer to numerous reporting requirements:\n\nMonthly, quarterly, annually – GDUFA II\n\nMonthly Performance Report\n\nhttps://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplication s/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm\n\nQuarterly Performance Report\n\nhttps://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/ucm600678.htm\n\nFDARA (unfunded mandates)\n\nSection 807 Quarterly Report of Priority Review and CGTs\n\nhttps://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/ucm596532.htm\n\nSection 903 Quarterly Report of Guidances and Public Meetings\n\nhttps://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FD ARA/UCM606015.pdf\n\n3", "n_tokens": 284, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-3-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 3, "text": "OUTLINE\n\n1. Status of Generic Drug Program 2. OGD Accomplishments 3. GDUFA II 4. Non-GDUFA activities 5. Closing Comments\n\n4", "n_tokens": 32, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-4-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 4, "text": "ww U.S. FOOD & DRUG\n\nADMINISTRATION\n\nSTATUS OF GENERIC DRUG PROGRAM", "n_tokens": 15, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-5-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 5, "text": "GENERIC DRUG PROGRAM Current State\n\nFDA’s generic drug program and OGD are in excellent shape • FDA is meeting or exceeding the GDUFA goals • Numerous significant accomplishments • Standing up/implementing GDUFA II • Evaluating and implementing FDARA • Performing a variety of non-GDUFA activities\n\n6", "n_tokens": 60, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-6-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 6, "text": "FDA’s GENERIC DRUG PROGRAM\n\nOGD is not “THE” generic drug program • OGD interfaces with applicants to coordinate the review of ANDAs\n\nOGD is not “THE” generic drug program • OGD interfaces with applicants to coordinate the review of ANDAs\n\nOM\n\nOGD issues regulatory action on ANDAs • OPQ and OGD work very closely to evaluate Pharmaceutical Quality, Filing, Bioequivalence, Labeling, and other review activities\n\nOSP\n\nFDA’s Generic Drug Program involves: • All CDER offices • ORA • Office of the Commissioner, esp. Office of Chief Counsel (OC • CDRH • CBER\n\nC)\n\nOCOMM\n\nOMP\n\nCompliance\n\nOGD\n\nORA OCC Others\n\nOTS\n\nOND\n\nOSE\n\n7", "n_tokens": 151, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-7-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 7, "text": "GENERIC DRUG PROGRAM Program Data/Analytics\n\nFDA’s generic drug program is in “Steady State” • All ANDA submissions have GDUFA goals, as of 8/1/18 – “Bridging” of GDUFA I pre-Year 3 ANDAs - COMPLETE\n\nThis Photo by Unknown Author is licensed under CC BY-SA\n\n8", "n_tokens": 69, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-8-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 8, "text": "GENERIC DRUG PROGRAM Program Data/Analytics\n\nRegulatory action “OUT” reflects number of submissions “IN” – True, but not for the same month\n\nMonthly statistics will show variability in FDA output\n\nTrue, and as expected - Number of regulatory actions (TA/AP, CR letters) issued (OUTPUT) in any given month are the direct result of the types of submissions (INPUT) in previous months and their GDUFA goal dates\n\nMisstatements about program output:\n\n“OGD's full approval total also exceeded the submission total for the fourth time in FY 2018, an indication of an overall workload reduction.”\n\nActions (OUTPUT) in any given month are not related to submissions (INPUT) for the same month • No sign of workload reduction • (848 ANDAs, 1,887 Amendments, 5,434 CBEs, 933 PAS, 2,460 controls – for first 10 months of FY2018)*\n\n“FDA can only remove ANDAs from its books if they are approved…”\n\nOnce regulatory action is issued, i.e., AP, TA, CR, or RTR, the ANDA is off FDA’s books and the GDUFA clock stops\n\nActivities Report of the Generic Drugs Program (FY 2018) Monthly Performance. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm\n\n- Generic Approvals: https://www.raps.org/news-and-articles/news-articles/2018/7/generic-approvals-rebound-as-first-generics-dont - Generic Drug Snapshot: http://www.lachmanconsultants.com/2018/06/ogd-releases-2nd-quarter-generic-drug-snapshot-on-its-dashboard/ - https://pink.pharmaintelligence.informa.com/PS123675/Generic-Review-At-US-FDA-Record-Month-Completes-Approval-Volume-Recovery\n\n9", "n_tokens": 453, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-9-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 9, "text": "250\n\n225\n\n200\n\n175\n\n150 s t p e c e 125 R A D N A 100\n\ni\n\n75\n\n50\n\n25\n\n0\n\nGENERIC DRUG PROGRAM Variable Submission Volume (New Originals)\n\n235\n\n216\n\n197 Simplified version: September 2017 ANDA submission + 10 month GDUFA review clock = July 2018 regulatory actions\n\n131\n\n108\n\n91\n\n78\n\n69\n\n60\n\n59\n\n81\n\n57\n\n58\n\n75\n\n66\n\n67\n\n73\n\n73\n\n65\n\n50\n\n6 1 0 2\n\n6 1 0 2\n\n6 1 0 2\n\n6 1 0 2\n\n6 1 0 2\n\n6 1 0 2\n\n6 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n7 1 0 2\n\n8 1 0 2\n\n,\n\nn u J\n\n, l\n\nu J\n\n, g u A\n\n,\n\np e S\n\n, t c O\n\n, v o N\n\n, c e D\n\n,\n\nn a J\n\n,\n\nb e F\n\n, r a M\n\n, r p A\n\n, y a M\n\n,\n\nn u J\n\n, l\n\nu J\n\n, g u A\n\n,\n\np e S\n\n, t c O\n\n, v o N\n\n, c e D\n\n,\n\nn a J\n\n* Updated 7/1/2018. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n56\n\n8 1 0 2\n\n,\n\nb e F\n\n139\n\n8 1 0 2\n\n, r a M\n\n83\n\n8 1 0 2\n\n, r p A\n\n57\n\n8 1 0 2\n\n, y a M\n\n85\n\n8 1 0 2\n\n,\n\nn u J\n\n10", "n_tokens": 306, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-10-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 10, "text": "Variable Submission Volume & GDUFA Goal Dates\n\nAmendment, Major\n\nOUTPUT: Approval (AP) Tentative Approval (TA) Complete Response (CR) Refuse to Receive (RTR)*\n\nt – 10 months\n\nt – 8 months\n\nt – 6 months\n\nt – 3 months\n\nt=0\n\nNew Original ANDA\n\nPre-Facility Correspondence (PFC)/ANDA\n\nAmendment, Minor\n\nNew Original ANDA\n\n*RTR output is closely linked to time of original ANDA submission, e.g., within 60 days of submission.\n\n11", "n_tokens": 104, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-11-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 11, "text": "GENERIC DRUG PROGRAM Ongoing Challenges\n\n1. Large number of RTRs 2. Low first cycle approvals 3.\n\nIn general, multiple review cycles to AP/TA\n\nInefficient and leads to a huge amount of re-work for FDA and applicants alike\n\n12", "n_tokens": 52, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-12-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 12, "text": "REFUSE TO RECEIVE (RTR) • During GDUFA I, many ANDAs submitted received RTR • ~1% due to fees not paid and this continues to occur • OGD has a robust, high quality process for filing review\n\n% ANDAs RTR-ed*\n\nFY2015 (GDUFA I Year 3)\n\n19\n\nFY2016 (GDUFA I Year 4)\n\n25\n\nFY2017 (GDUFA I Year 5)\n\n13\n\nOverall for GDUFA I\n\n~20¥\n\nFY2018** (GDUFA II)\n\n~9\n\nUpdated 7/31/2018. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. ¥ - During GDUFA I, the RTR percentage decreased slightly after RTR Guidance was revised and certain deficiencies (e.g., environmental impact analysis statement, English translation) were classified as minor deficiencies. **FY2018 – Partial year data, reflects ANDAs submitted up to May 2018. 13", "n_tokens": 209, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-13-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 13, "text": "TOP 3 REASONS* FOR RTR\n\nDEFICIENCY\n\n1. Inadequate Stability\n\n2. Inadequate Dissolution\n\n3. Impurities\n\n* Analysis of FY2017 Year 5 cohort: 168 RTRs on 1,320 ANDAs.\n\n14", "n_tokens": 43, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-14-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 14, "text": "FILING DEFICIENCIES ANDAs with Clinical Endpoint Studies\n\n9%\n\n6%\n\nMissing information related to the clinical studies other than datasets (38%)\n\nMissing datasets (35%)\n\n12%\n\n12%\n\n38%\n\n45%\n\nFormulation issue (12%)\n\n25%\n\n35%\n\nBioequivalence and clinical deficiencies (9%)\n\n18%\n\nOrganization/format issue (6%)\n\nBOTTOM LINE: • Submit FULL clinical study reports including all data sets. • Majority of RTRs due to missing data sets and missing\n\ninformation related to the clinical studies.\n\nFermaglich LJ et al. DIA Therapeutic Innovation & Regulatory Science, 2018.\n\nThe clinical endpoint BE study failed to show bioequivalence (12%)\n\nThe clinical endpoint BE study did not demonstrate superiority of the generic and/or reference products over placebo (25%)\n\nSkin irritation, sensitization, and adhesion studies failed to meet the non-inferiority limit (18%)\n\nMissing clinical studies (45%)\n\n15", "n_tokens": 205, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-15-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 15, "text": "“RTR” is a lifetime blemish on an ANDA AND Indicator of poor application quality\n\nIf ANDA received RTR…. – Fewer 1st cycle AP or TA – More deficiencies in Complete Response Letter(s) – Worse (“major”) deficiencies – Quick turnaround of RTR with re-submission results in even lower likelihood for AP or TA\n\nNOTE TO INDUSTRY: Slow down and QA/QC the entire ANDA before submitting/re-submitting\n\n16", "n_tokens": 99, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-16-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 16, "text": "OGD EFFORTS Preventing an RTR\n\nGUIDANCES\n\nRTR Standards Revision 2 (GDUFA I Required Guidance)\n\nhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM578368.pdf (Final 12/21/16)\n\nRTR Standards Q&A Draft Guidance\n\nhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM578368.pdf (Draft 10/2/17)\n\nLack of Justification of Impurity Limits Guidance\n\nhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM414598.pdf (Final 8/24/16)\n\nContent and Format of ANDA Draft Guidance\n\nhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM400630.pdf (Draft 6/11/14)\n\nGood ANDA Submission Practices Draft Guidance\n\nhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM591134.pdf (Draft 1/3/18)\n\nMAPPs\n\nFiling Review of ANDAs (MAPP 5200.14; essentially an ANDA Filing Checklist)\n\nhttps://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProced ures/UCM574493.pdf (September 2017)\n\nCommunicating Certain Deficiencies Identified During Filing Review of ANDAs (MAPP 5220.3)\n\nhttps://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProced ures/UCM578093.pdf (September 2017)\n\nGood ANDA Assessment Practices (MAPP 5241.3)\n\nhttps://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProced ures/UCM591143.pdf (January 2018)\n\n17", "n_tokens": 497, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-17-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 17, "text": "FIRST CYCLE ANDA APPROVALS¥\n\nPrior to GDUFA\n\n< 1%\n\nFY2015\n\n11.6%\n\nFY2016\n\n14.7%\n\nFY2017*\n\n~10%\n\nFY2018**\n\nTBD\n\nDOSAGE FORM: Injectables > solid oral > others\n\nUpdated 5/1/2018. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. Some FY2017 ANDAs are under review and within goal. **FY2018 – ANDAs are under review and within goal; the majority of FY2018 ANDAs have not reached their GDUFA goal date. ¥ DEFINITION: The percentage of AP and TA original and original-response to RTR ANDAs that were received for extensive review AND were given a regulatory decision (excluding ANDAs under review). 18", "n_tokens": 174, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-18-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 18, "text": "OGD review disciplines First-cycle approvability\n\nBioequivalence\n\nLabeling\n\n>70% “adequate” decisions in the first cycle\n\nLarge % are “adequate” at end of first full review cycle\n\nHigh rate of adequate\n\nbioequivalence reviews due to availability of product-specific guidances\n\nHOWEVER, almost all have deficiencies that require correction as communicated to applicant with IRs and/or DRLs\n\nRLD/USP/Patent & Exclusivity constantly changing resulting in additional labeling deficiencies and cycles\n\n19", "n_tokens": 103, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-19-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 19, "text": "GDUFA I ANDAs*\n\n“Off FDA’s Books”\n\n*Data as of 5/31/2018, Data Source: ANDAs originally submitted during GDUFA I, internal FDA database. Data generated by CDER/OTS/OB, Jingyu (Julia) Luan, PhD, Jing Han, PhD, and Stella Grosser, PhD.\n\nAP = 1550\n\n20", "n_tokens": 78, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-20-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 20, "text": "REVIEW EFFICIENCIES Reduce Cycles to Approval\n\nUnder FDA control\n\nUnder Industry control\n\nFormat - Data requirements - Product Specific Guidances (PSGs) - Streamlining processes - Ancillary assistance (consults/other disciplines)\n\nMissing data - Deviation from PSG without adequate justification - Data integrity - Non-standard statistical/analytical methods - Incorrect Formulation development - Facility problems\n\n21", "n_tokens": 73, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-21-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 21, "text": "UNDER INDUSTRY CONTROL Tell the “story” of your ANDA • Use ANDA to demonstrate you know your product and all critical aspects of the\n\nRLD; capture that knowledge in your application\n\nOrganize information to tell the story\n\nUse clear labels and figures; make data easy to read and compare\n\nQA/QC application before submission\n\nCorrect omissions, minimize duplication, proofread – OGD Filing review is NOT a QA/QC function for industry but rather a regulatory\n\ndecision, “acceptable for filing”, i.e., that the ANDA is sufficiently complete to allow for scientific review • Know your audience\n\nFDA reviewers/assessors are very detail-oriented – Don’t make them hunt for information/data\n\n22", "n_tokens": 145, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-22-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 22, "text": "UNDER INDUSTRY CONTROL Completeness of Submissions\n\n“Right the First Time” • Timely and complete responses to FDA Information Requests, DRLs, other communications – Timely is important, but getting it correct and providing the right data to\n\nFDA is most critical\n\nAll legal documents and relevant updates related to court findings (e.g., patent/exclusivity) have been submitted to ANDA\n\n23", "n_tokens": 77, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-23-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 23, "text": "24\n\nGDUFA\n\nTRANSFORM THE PROGRAM and PERFORM WHILE TRANSFORM\n\nNEED TO BUILD A QUALITY SYSTEM\n\nSlide from Uhl Presentation October 2014, GPhA Fall Technical Conference\n\n24", "n_tokens": 31, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-24-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 24, "text": "GDUFA\n\nTRANSFORM THE PROGRAM and PERFORM WHILE TRANSFORM\n\nFDA BUILT A QUALITY SYSTEM Exemplary drug regulatory program\n\n25", "n_tokens": 20, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-25-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 25, "text": "ww U.S. FOOD & DRUG\n\nADMINISTRATION\n\nOGD ACCOMPLISHMENTS", "n_tokens": 13, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-26-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 26, "text": "DATE\n\n10/2017\n\n2/2018\n\n3/2018\n\n4/2018\n\n4/2018\n\n5/2018\n\n6/2018\n\n8/2018\n\nNOTABLE ANDA APPROVALS\n\nGeneric Name\n\nRLD\n\nSodium acetate injection\n\nSodium Acetate\n\nGlatiramer acetate injection pre-filled syringe\n\nCopaxone\n\nCinacalcet HCl tablets\n\nSensipar\n\nEverolimus tablets\n\nZotress\n\nColesevelam HCl tablets\n\nWelchol\n\nTadalafil tablets\n\nCialis\n\nBuprenorphine HCL and Naloxone sublingual film\n\nSuboxone\n\nEpinephrine autoinjector\n\nEpiPen\n\n*Indication is truncated from full product labeling\n\nIndication*\n\nHyponatremia\n\nMultiple sclerosis\n\nHyperparathyroidism\n\nTransplant rejection\n\nHypercholesterolemia\n\nErectile dysfunction\n\nOpioid dependence\n\nAllergic reactions and anaphylaxis\n\n27", "n_tokens": 167, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-27-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 27, "text": "NOTABLE ANDA APPROVALS\n\n1st new, original ANDA submitted in GDUFA II was approved; a 1st cycle approval (August 2018)\n\n1st Competitive Generic Therapy (CGT) designated approval (August 2018)\n\nJuly 2018 – largest output in single month ever\n\n96 AP, 30 TA, 357 CRs – Result of:\n\nLarge number of September 2017 original ANDA submissions • GDUFA II bridging goal date for pre-Year 3 GDUFA I ANDAs • Other submissions with July 2018 GDUFA goal dates • (see slides 9-11)\n\n28", "n_tokens": 114, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-28-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 28, "text": "OGD ACCOMPLISHMENTS\n\nImplemented new pre-ANDA program for complex generic drug products per GDUFA II\n\n68 pre-ANDA meeting requests* • Double the pre-GDUFA II number • 100% grant/deny within 30 days • 100% granted meetings within 120 days\n\n* Data as of 8/8/18\n\n29", "n_tokens": 65, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-29-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 29, "text": "OGD ACCOMPLISHMENTS Guidances for Industry* • ANDA Submissions – Amendments (final 7/3/18)\n\nhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM404440.pdf\n\nGood ANDA Submission Practices (draft 1/3/18) https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM591134.pdf\n\nDetermining Whether to Submit an ANDA or 505(b)(2) application (draft 10/11/17)\n\nhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM579751.pdf\n\nGeneral Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products (final 11/21/17)\n\nhttps://www.fda.gov/downloads/Drugs/.../Guidances/UCM492172.pdf\n\nANDAs for Certain Highly Purified Synthetic Peptide Drug Products that Refer to Listed Drugs of rDNA Origin (draft 10/2/17)\n\nhttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM578365.pdf\n\nProduct Specific Guidances**: 89 new and 59 revised, including 22 for inhalation drug products\n\n* This does not represent a complete list of Guidances for Industry published by OGD in FY2018. ** Data as of 8/8/18.\n\n30", "n_tokens": 339, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-30-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 30, "text": "OGD ACCOMPLISHMENTS\n\nOrange Book Updates\n\nAddition of patent submission date – Receiving/processing one-time marketing status updates for products in the active section (FDARA requirement)\n\n31", "n_tokens": 33, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-31-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 31, "text": "OGD ACCOMPLISHMENTS Communication\n\nREQUIRED: • GDUFA Performance Reports • GDUFA Financial Reports • GDUFA Quarterly Performance Report • •\n\nFDARA Quarterly Report of Priority Review and CGTs FDARA Quarterly Report of Guidances and Public\n\nENHANCED: • Updated web presence www.fda.gov/genericdrugs • GDUFA Annual Regulatory Science Research Report • Monthly Activities Report of the Generic Drug Program • Quarterly Meeting Minutes Between FDA and Industry • Quarterly Generic Drug Review Dashboard (last published\n\nApril 2018) ANDA First Generic Drug Approvals • • Office of Generic Drugs Annual Reports • Generic Drugs Updates and GDUFA listservs • Generic Drugs Patient and Prescriber Education\n\nCampaigns\n\nMeetings • Webinars (in collaboration with DIA) • 2018 Generic Drugs Forum\n\n32", "n_tokens": 154, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-32-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 32, "text": "OGD ACCOMPLISHMENTS GDUFA II Outreach Videos\n\nBrief videos by FDA staff highlighting new features in GDUFA II on FDA.gov:\n\nGDUFA Overview • Pre-ANDA Program for Complex Products • Type II Drug Master Files (DMF) Update • Performance Goals • Goals Integration • Review Status Updates • Post Complete Response Letter (CRL) Meeting • Requests for Reconsideration • Review Classification\n\n33", "n_tokens": 83, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-33-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 33, "text": "OGD ACCOMPLISHMENTS DIA Podcasts/Webinars “Innovation in Generics”\n\nOGD Speaker\n\nMaryll Toufanian, JD\n\nAn Introduction to Generic Drugs – Hatch Waxman Overview\n\nXiaohui (Jeff) Jiang, PhD An Overview of Challenges and Opportunities in the\n\nDevelopment of Complex Generic Drug Products\n\nKim Witzmann, MD\n\nOvercoming Barriers to Entry for Complex Generic Oral Inhalation Drug Products\n\nSam Raney, PhD\n\nFDA Champions Research to Make Complex Generic Transdermal Products Available to Patients*\n\nLiang Zhao, PhD\n\nPioneering Modeling Methodologies in Generic Drug Development\n\nhttps://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/ucm585393.htm\n\nPodcast- Recorded\n\nMarch 6, 2018 2:00 pm\n\nMarch 15, 2018 3:00 pm\n\nApril 25, 2018 2:00 pm\n\nMay 17, 2018 1:00 pm\n\n34", "n_tokens": 185, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-34-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 34, "text": "OGD COMMUNICATIONS CDER Small Business and Industry Assistance (SBIA) Newly issued Guidance Webinars\n\nWebinar Topic\n\nOGD Speaker Elizabeth Giaquinto Friedman, JD, LLM ANDA Submissions – Amendments to Abbreviated New Drug\n\nPhilip Bonforte, JD\n\nLisa Bercu, JD\n\nApplications under GDUFA final guidance Information Requests and Discipline Review Letters under GDUFA draft guidance Controlled Correspondence Related to Generic Drug Development draft guidance\n\nTamara Coley, JD\n\nPost-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA draft guidance\n\nElizabeth Giaquinto Friedman, JD, LLM Determining Whether to Submit an ANDA or 505(b)(2) Application\n\ndraft guidance\n\nElizabeth Giaquinto Friedman, JD, LLM Formal Meetings Between FDA and ANDA Applicants of Complex\n\nProducts Under GDUFA draft guidance\n\nChinese translations for SBIA resources are located here - https://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm559631.htm\n\nDate July 2018\n\nDecember 2017\n\nNovember 2017\n\nNovember 2017\n\nOctober 2017\n\nOctober 2017\n\n35", "n_tokens": 224, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-35-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 35, "text": "OGD ACCOMPLISHMENTS Scientific Publications\n\nNumerous OGD scientific publications found at: Science & Research “Publications and Resources” page\n\nEffects of Formulation Variables on Lung Dosimetry of Albuterol Sulfate Suspension and Beclomethasone Dipropionate Solution Metered Dose Inhalers (AAPS PharmSciTech, June 2018) • Overview of the Generic Drug Program and Surveillance, DIA Journal, May 2018\n\nhttp://journals.sagepub.com/doi/abs/10.1177/2168479018774557\n\nNanotechnology Characterization Laboratory Unveils New Technical Services for Drug Developers (National Cancer Institute, March 2018)\n\nModeling to Speed Tricky Generic Development (AAPS News, February 2018) • Paying it Forward: A kidney transplant patient shares how joining a clinical trial helped her family — and\n\nothers (University of Cincinnati Health, December 2017) Lamotrigine Generics Equal to Brand—Single-dose study of generic antiepileptic drug finds minimal differences (MedPage Today, June 2017)\n\nUS FDA Pushing For Generic Alternatives To Long-Acting Injectables, Implants (The Pink Sheet, March 2017)\n\n36", "n_tokens": 237, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-36-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 36, "text": "OGD ACCOMPLISHMENTS Workshops on Complex Generic Drug Products\n\nOct. 2-3, 2017: Leveraging Quantitative Methods and Modeling to Modernize Generic Drug Development and Review – https://www.fda.gov/Drugs/NewsEvents/ucm554182.htm\n\nOct. 6, 2017: Demonstrating Equivalence of Generic Complex Drug Substances and Formulations\n\nhttps://www.fda.gov/Drugs/NewsEvents/ucm552461.htm\n\nOct. 20, 2017: Topical Dermatological Generic Drug Products: Overcoming Barriers to Development and Improving Patient Access – https://www.fda.gov/Drugs/NewsEvents/ucm557252.htm\n\nJan. 9, 2018: New Insights for Product Development and Bioequivalence Assessments of Generic Orally Inhaled and Nasal Drug Products – https://www.fda.gov/Drugs/NewsEvents/ucm576064.htm\n\nSept. 12-13, 2018: Complex Generic Drug Product Development Workshop\n\nhttps://events-\n\nna12.adobeconnect.com/content/connect/c1/1315899612/en/events/event/shared/1956258287/event_landing.html?sco- id=1956288436&_charset_=utf-8\n\n37", "n_tokens": 282, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-37-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 37, "text": "OGD COMMUNICATIONS Workshops for Industry\n\nFDA/CDER Small Business and Industry Assistance (SBIA) Regulatory Education for Industry (REdI): Generic Drugs Forum 2018 https://www.fda.gov/drugs/developmentapprovalprocess/smallbusinessassistance/ucm598753.htm\n\nApril 11-12, 2018 – Up-to-date information on program progress and current initiatives – Over 1,000 participants from around the world – Opportunity to interact with FDA subject matter experts involved in the Generic Drug Review Program\n\nFREE, open to the public, streamed live and with enduring materials on the internet\n\n38", "n_tokens": 130, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-38-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 38, "text": "OGD ACCOMPLISHMENTS Science, Research & Communication\n\nPlease see: • “Generic Drug Science and Research”\n\nhttps://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicine safely/genericdrugs/ucm567695.htm\n\n“Generic Drugs Priorities and Projects”\n\nhttps://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedici neSafely/GenericDrugs/ucm585132.htm\n\n39", "n_tokens": 106, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-39-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 39, "text": "ww U.S. FOOD & DRUG\n\nADMINISTRATION\n\nGDUFA II\n\n(clarifications)", "n_tokens": 20, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-40-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 40, "text": "GDUFA II\n\n–Numerous review program enhancements\n\nMid-cycle & post CR t-cons, ability to dispute a variety of CDER actions • More touch points with industry pre-, during, and post-submission\n\n–Pre-ANDA program for complex products\n\nMeetings, timeframes for Product-Specific Guidances, updates to Inactive Ingredients Database (IID) https://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/ucm578012.htm\n\n“PFC” – Pre-submission Facility Correspondence\n\nPriority Submission with PFC - 8 month goal\n\nDMF enhancements – Accountability and reporting enhancements –Small business relief\n\n41", "n_tokens": 149, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-41-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 41, "text": "REVIEW PROGRAM ENHANCEMENTS\n\nFDA committed to:\n\nInformation requests (IRs) and/or mid-cycle discipline review letters (DRLs) from disciplines assessing/reviewing ANDAs at or about mid- cycle\n\nThis applies ONLY to GDUFA II new original ANDAs, i.e., those new original ANDAs submitted on or after October 1, 2017\n\n(If resources permit, IRs and/or DRLs may be issued for other submission types, but this is not a GDUFA II commitment)\n\n42", "n_tokens": 101, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-42-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 42, "text": "PRE-ANDA PROGRAM FOR COMPLEX GENERIC DRUG PRODUCTS\n\nResearch, PSGs, meetings • Three types of meetings • Not PDUFA style Type “A” meetings • Guidance for Industry – Formal Meetings Between FDA and ANDA https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM578366.pdf (Draft 10/2/17)\n\nSee What’s Important to Consider When Developing a Complex\n\nGeneric Drug? on Wednesday 9/4/18 Presentation by Rob Lionberger (OGD ORS)\n\n43", "n_tokens": 121, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-43-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 43, "text": "SMALL BUSINESS RELIEF\n\nAltered fee structure\n\nAnnual facility fee on approved ANDAs only – Lower program fees for smaller companies commensurate with the number of approved ANDAs\n\nNo per-ANDA submission fee\n\nCMOs pay 1/3 the annual fee paid by firms that manufacture under ANDAs they own\n\nNOTE: All companies, regardless of size, must meet all the regulatory standards for ANDA approval\n\n See Update on GDUFA and BsUFA User Fees on Thursday 9/5/18 (numerous\n\nFDA speakers)\n\n44", "n_tokens": 102, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-44-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 44, "text": "GDUFA II\n\n“Goals” or “Commitment” letter:\n\nhttp://www.fda.gov/downloads/forindustry/userfees/genericdruguserfees/ucm525234.pdf\n\nPLEASE READ!\n\n45", "n_tokens": 52, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-45-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 45, "text": "ww U.S. FOOD & DRUG\n\nADMINISTRATION\n\nNON-GDUFA ACTIVITIES", "n_tokens": 16, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-46-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 46, "text": "Commissioner’s Drug Competition Action Plan (DCAP)\n\n1. Streamline ANDA review process to increase efficiency, effectiveness, and output of approvals\n\n2. Enhance development and review of complex generic drug products 3. Reduce “gaming” that delays generic drug approval and extends monopoly beyond what Congress intended\n\nAligns with GDUFA II main objectives See Presentations by Ann Abram (FDA Keynote) and Maryll Toufanian\n\n(OGD Policy)\n\n47", "n_tokens": 90, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-47-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 47, "text": "HARMONIZATION EFFORTS • FDA is focusing efforts that harmonize on scientific and technical aspects while respecting and\n\nacknowledging regulatory and legal differences\n\nVenues of activity:\n\nICH - “Q” documents applicable to both brand and generic drug products – Mutual Recognition Agreement (MRA)\n\nFDA and EU regulators able to utilize each other’s GMP inspections of pharmaceutical manufacturing facilities\n\nIPRP member (consolidation of IGDRP & IPRF) – Engagement with other Regulatory Bodies (e.g., EMA-FDA bilateral) ICH efforts will succeed for generics only if both regulators AND industry dedicate adequate resources to efforts\n\n See Harmonization Opportunities for the Generic Industry through ICH – Topic on Wednesday\n\n9/4/18  Theresa Mullin, CDER Associate Director for Strategic Initiatives\n\n48", "n_tokens": 150, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-48-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 48, "text": "Non-GDUFA activities*\n\nFDARA implementation • Suitability Petitions • Bio-INDs • CBEs • Safety Labeling Changes • FTC requests • ANDA consolidation requests • ANDA withdrawals • S/E Determinations • Postmarket safety activities (FAERS, surveillance, Sentinel)\n\nNon-GDUFA mandated process\n\ncontrol documents (SOPs, MAPPs, Guidances) • PET product review • Citizen Petitions • Non-action letters\n\n(acknowledgement, withdrawal, Dunners)\n\nTriaging administrative\n\namendments • Annual Reports • Orange Book\n\n* Does not represent a complete inventory of OGD activities that are not associated with GDUFA goals.\n\n49", "n_tokens": 131, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-49-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 49, "text": "Non-GDUFA activities*\n\nGuidance documents\n\nGeneral – Many Product-Specific Guidances (PSGs)\n\nRequired staff training • Presentations (Internal and External)\n\nProgram analytics • Media requests • Congressional requests • OIG audits/reports • GAO studies/reports • Legislative Proposal Technical Assistance\n\nPeer-reviewed publications\n\n* Does not represent a complete inventory of OGD activities that are not associated with GDUFA goals.\n\n50", "n_tokens": 82, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-50-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 50, "text": "ww U.S. FOOD & DRUG\n\nADMINISTRATION\n\nCLOSING COMMENTS", "n_tokens": 12, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-51-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 51, "text": "OGD is a high functioning, high performing office\n\nOGD and the FDA’s generic drug program are in excellent shape – Historically probably in the BEST place ever\n\nReproducibly high volume and high quality output\n\nRobust processes allow for transparency to\n\nand predictability for industry • Robust generic drug pipeline • OGD Leadership at the Office and Division\n\nlevels are fully capable to continue: – The momentum of this program – OGD’s mission and vision – Accomplishment of great things Incredibly talented, knowledgeable and dedicated staff\n\n52", "n_tokens": 102, "kind": "text"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-52-0", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 52, "text": "mY U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-0-0", "doc_id": "AAMkeynoteChoe2021", "page": 0, "text": "Association for Accessible Medicines GRx+Biosims 2021\n\nOFFICE OF GENERIC DRUGS KEYNOTE\n\nSally Choe, Ph.D. Director, Office of Generic Drugs\n\nCenter for Drug Evaluation and Research U.S. Food and Drug Administration\n\nNovember 9, 2021\n\n1LL", "n_tokens": 50, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-1-0", "doc_id": "AAMkeynoteChoe2021", "page": 1, "text": "Generic Drug Access\n\nCOVID-19\n\nComplex Generics\n\nGDUFA II Successes\n\nFDA Partnerships\n\n2", "n_tokens": 18, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-2-0", "doc_id": "AAMkeynoteChoe2021", "page": 2, "text": "Addressing COVID-19*\n\nApprovals that improved access to critical COVID-19 treatments:\n\n69 COVID-related original ANDAs • 1000+ COVID-related supplements\n\nGuidance\n\nDevelopment of ANDAs During the COVID-19 Pandemic – Questions and Answers • Protecting Participants in Bioequivalence Studies for ANDAs During the COVID-19 Public Health Emergency\n\nReview Timelines for Applicant Responses to Complete Response Letters When a Facility Assessment Is Needed During the COVID-19 Public Health Emergency\n\nPublic Presentations\n\nCOVID-19 Impact on Generic Drug Regulation and Evaluation • Addressing Common Challenges in Bioequivalence Studies Due to COVID-19 * 2020-10/15/2021\n\nCOVID-19 Impact on Generic Drug Regulation and Evaluation • Addressing Common Challenges in Bioequivalence Studies Due to COVID-19 * 2020-10/15/2021\n\n3", "n_tokens": 175, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-3-0", "doc_id": "AAMkeynoteChoe2021", "page": 3, "text": "www.fda.gov\n\nGDUFA II Commitments\n\nANDA original applications\n\nANDA prior approval supplements\n\nControlled Correspondence\n\nProduct-Specific Guidance\n\n4", "n_tokens": 26, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-4-0", "doc_id": "AAMkeynoteChoe2021", "page": 4, "text": "www.fda.gov\n\nIncreasing Generic Drug Access\n\n670+ full approvals\n\n90+ first generics\n\nMilestone 100+ cumulative Competitive Generic Therapy (CGT) approvals\n\n5", "n_tokens": 33, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-5-0", "doc_id": "AAMkeynoteChoe2021", "page": 5, "text": "Notable Generic Approvals in FY2021\n\nGeneric Name\n\nBrand Name\n\nIndication\n\nGlucagon for Injection packaged in an emergency kit\n\nGlucagon for Injection packaged in an emergency kit\n\nSevere hypoglycemia\n\nLinaclotide Capsules\n\nLinzess Capsules\n\nIrritable bowel syndrome with constipation and chronic idiopathic constipation\n\nApremilast Tablets\n\nOtezla Tablets\n\nModerate to severe plaque psoriasis\n\nHydrocodone Bitartrate Extended-Release Tablets\n\nHysingla ER Tablets\n\nSevere pain\n\nIbrutinib Capsules\n\nImbruvica Capsules\n\nMantle cell lymphoma (MCL)\n\nEnzalutamide Capsules\n\nXtandi Capsules\n\nProstate cancer\n\nLenalidomide Capsules\n\nRevlimid Capsules\n\nMultiple myeloma, anemia, and certain lymphomas\n\nTofacitinib Tablets\n\nXeljanz Tablets\n\nCertain types of arthritis and ulcerative colitis\n\nVarenicline Tablets\n\nChantix Tablets\n\nSmoking cessation\n\nLinagliptin Tablets\n\nTradjentaTablets\n\nType 2 Diabetes Mellitus\n\nwww.fda.gov\n\nApproval Date\n\n12/28/2020\n\n2/9/2021\n\n2/18/2021\n\n3/1/2021\n\n3/31/2021\n\n5/14/2021\n\n5/21/2021\n\n6/1/2021\n\n8/11/2021\n\n8/31/2021\n\n6", "n_tokens": 278, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-6-0", "doc_id": "AAMkeynoteChoe2021", "page": 6, "text": "Product-Specific Guidances (PSGs)\n\nScientific advice to assist generic drug product development\n\nRevisions driven by science and research\n\n135 PSGs in FY21\n\n53 (39%) PSGs for complex products\n\n20 PSGs provided a more efficient BE approach\n\nNew PSG snapshot infographic\n\nwww.fda.gov\n\n7", "n_tokens": 62, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-7-0", "doc_id": "AAMkeynoteChoe2021", "page": 7, "text": ". FDA\nComplex Generics fe)\n\nwww.fda.gov 8", "n_tokens": 13, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-8-0", "doc_id": "AAMkeynoteChoe2021", "page": 8, "text": "FDA’s Pre-ANDA Program\n\nReduce time from development to market\n\nAddress complex scientific issues\n\nCommunicate with prospective applicants\n\nHelp applicants develop more complete submissions\n\nClarify regulatory expectations\n\nwww.fda.gov\n\n9", "n_tokens": 37, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-9-0", "doc_id": "AAMkeynoteChoe2021", "page": 9, "text": "research and training\n\nwww.fda.gov\n\nThe Center for Research on Complex Generics\n\nwebinars\n\nworkshops\n\nlaboratory projects\n\nScholars program\n\n10", "n_tokens": 25, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-10-0", "doc_id": "AAMkeynoteChoe2021", "page": 10, "text": "April 2021\n\nGeneric Drug Forum 2021: Lifecycle of a Generic Drug\n\nwww.fda.gov\n\nRecent Workshops\n\nJune 2021\n\nGeneric Drug Regulatory Science Initiatives Public Workshop\n\nAug. 2021 IVRT and IVPT Methods: Best Practices and Scientific Considerations for ANDA Submission\n\nSept. 2021\n\nAdvancing\n\nGeneric Drug Development: Translating Science to Approval\n\nRegulatory Utility of Mechanistic Modeling to Support Alternative BE Approaches\n\n11", "n_tokens": 73, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-11-0", "doc_id": "AAMkeynoteChoe2021", "page": 11, "text": "Parallel Scientific Advice with European Medicines Agency\n\nwww.fda.gov\n\nGlobal Engagement\n\nICH Generic Drug Discussion Group and ICH M13 Expert Working Group\n\nGeneric Drug Global Cluster\n\nInternational Pharmaceutical Regulators Programme Working Groups\n\n12", "n_tokens": 37, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-12-0", "doc_id": "AAMkeynoteChoe2021", "page": 12, "text": "Upcoming Events\n\nGDUFA III Public Meeting\n\nwww.fda.gov\n\n13", "n_tokens": 14, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-13-0", "doc_id": "AAMkeynoteChoe2021", "page": 13, "text": "www.fda.gov\n\nStay Informed\n\nFDA’s GDUFA and Generic Drugs Updates listservs: https://public.govdelivery.com/accounts/USFDA/subscriber/new\n\nWebinars\n\nFDA Product-SpecificGuidances: Lighting the Development Pathway for Generic Drugs\n\nCommon Labeling Deficiencies and Tips for Generic Drug Applications\n\nGDUFA Science and Research\n\nActivities Metrics, such as:\n\nFirst Generic Drug Approvals •Report of the Generic Drugs Program (Monthly Performance)\n\n14", "n_tokens": 103, "kind": "text"}
{"chunk_id": "AAMkeynoteChoe2021-14-0", "doc_id": "AAMkeynoteChoe2021", "page": 14, "text": "PAW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-0-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 0, "text": "Biosimilar Regulatory Policy: Understanding the Landscape and Relevance to Medical Practice\n\nSue Lim, M.D., Director of the Scientific Staff, Therapeutic Biologics and Biosimilars Staff/CDER/FDA", "n_tokens": 44, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-1-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 1, "text": "Disclosure Information\n\nI have no financial relationships to disclose.\n\nI will not discuss off label use and/or investigational use in my presentation.\n\n2\n\n2", "n_tokens": 29, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-2-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 2, "text": "Overview of Presentation\n\nBiosimilars\n\nData supporting approval – Clinical studies and extrapolation\n\nInterchangeable Products – Data supporting approval – Switching study design\n\nKey Points and Practical aspects\n\n“Substitution” vs “Switch” vs. “Switches”\n\nSummary\n\n3\n\n3", "n_tokens": 48, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-3-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 3, "text": "ew U.S. FOOD & DRUG\n\nADMINISTRATION\n\nBiosimilars:\nData to Support Approval", "n_tokens": 19, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-4-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 4, "text": "General Requirements: 351(k) application\n\nA 351(k) application must include information demonstrating that the biological product:\n\n Is biosimilar to a reference product;  Utilizes the same mechanism(s) of action for the proposed condition(s) of use -- but only to the extent the mechanism(s) are known for the reference product;\n\n Condition(s) of use proposed in labeling have been previously\n\napproved for the reference product;\n\n Has the same route of administration, dosage form, and strength\n\nas the reference product; and\n\n Is manufactured, processed, packed, or held in a facility that meets standards designed to assure that the biological product continues to be safe, pure, and potent.\n\n5\n\n5", "n_tokens": 141, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-5-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 5, "text": "General Requirements: 351(k) application\n\nThe PHS Act requires that a 351(k) application include, among other things, information demonstrating biosimilarity based upon data derived from:\n\nAnalytical studies demonstrating that the biological product is “highly similar” to the reference product notwithstanding minor differences in clinically inactive components;\n\nAnimal studies (including the assessment of toxicity); and\n\nA clinical study or studies (including the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD)) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product\n\nFDA may determine, in its discretion, that an element described above is unnecessary in a 351(k) application.\n\n6\n\n6", "n_tokens": 178, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-6-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 6, "text": "Biosimilar Product: Data for Approval Adequate data in the 351(k) application to support that the proposed product is biosimilar to the US-licensed reference product •\n\nProposed product must be highly similar to the US-licensed reference product notwithstanding minor differences in clinically inactive components – Comparative analytical data - the foundation – Analytical data is more sensitive than clinical data in detecting differences\n\nbetween products, should differences exist\n\nA biosimilar product with highly similar structure and function to the reference product should behave like the reference product (i.e., have similar efficacy and safety as the reference product) in a clinical setting.\n\nThere are no clinically meaningful differences between the proposed product and US-licensed reference product in terms of safety, purity and potency • pharmacology, additional clinical studies)\n\nComparative clinical data (clinical\n\n7\n\n7", "n_tokens": 169, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-7-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 7, "text": "Biosimilar Product: Data for Approval\n\nGoals of “standalone“ biological product vs. biosimilar product development differ – Standalone: de novo safety and efficacy\n\nBiosimilar: biosimilarity (highly similar, no clinically meaningful differences)\n\nUse a totality-of-the-evidence approach in consideration all the data and information in a 351(k) application\n\nNo “pivotal” study in biosimilar development\n\nAdditional clinical studies are not “pivotal” in the way Phase 3 clinical trials are for standalone development\n\n8\n\n8", "n_tokens": 110, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-8-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 8, "text": "Biosimilar: Comparative Clinical Study • A comparative clinical study should be designed to investigate whether\n\nthere are clinically meaningful differences in safety and efficacy between the proposed product and the reference product. – Not establishing de novo safety and efficacy\n\nPopulation, endpoint, sample size and study duration should be adequately sensitive to detect differences between products, should they exist. – Population can be novel/unapproved but justifiable to use as a test assay because of sensitivity, e.g., neoadjuvant breast cancer for biosimilar to Herceptin – biosimilar does not subsequently receive approval for that novel population/indication\n\nEndpoint can be novel/unapproved if it reflects activity of the product, e.g., VEGF for biosimilar to Avastin (anti-VEGF MAb)\n\nSample size and duration generally similar or less than in the original clinical trials; no need to re-establish efficacy (e.g, mortality) or long term safety\n\nTypically, an equivalence design would be used, but other designs may be justified depending on product-specific and program-specific considerations.\n\n• Assessment of immunogenicity\n\n9\n\n9", "n_tokens": 239, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-9-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 9, "text": "Extrapolation\n\nThe potential exists for a biosimilar product to be approved for one or more conditions of use for which the reference product is licensed based on extrapolation\n\nSufficient scientific justification for extrapolation is necessary\n\nDifferences between conditions of use (e.g., indications) do not necessarily preclude extrapolation\n\nFDA guidance outlines factors to consider, including:\n\nMoA in each condition of use – PK and biodistribution in different patient populations – Immunogenicity in different patient populations – Differences in expected toxicities in each condition of use and patient population\n\n10", "n_tokens": 118, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-10-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 10, "text": "Extrapolation Considerations: “Stand-alone” Drug Development\n\nClinical Safety & Efficacy\n\nClinical Safety & Efficacy\n\nClinical Safety & Efficacy\n\nClinical Pharmacology\n\nIndication 2\n\nIndication 3\n\nAnimal\n\nAnalytical\n\nIndication 1\n\nClinical Safety & Efficacy\n\nIndication 4\n\n11\n\n11", "n_tokens": 45, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-11-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 11, "text": "Extrapolation Considerations: Standalone vs. Biosimilar Development\n\nClinical Safety & Efficacy\n\nClinical Safety & Efficacy\n\nClinical Safety & Efficacy\n\nClinical Pharmacology\n\nIndication 2\n\nIndication 3\n\nAnimal\n\nAnalytical\n\nBiosimilar extrapolation is based on all available data in the 351(k) BLA and FDA’s finding for the reference product, not from the indication(s) studied for the biosimilar to other non-studied indications\n\nClinical Safety & Efficacy\n\nIndication 4\n\n12", "n_tokens": 94, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-12-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 12, "text": "Interchangeable Products: Data to Support Approval", "n_tokens": 8, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-13-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 13, "text": "Interchangeability\n\nInterchangeable or Interchangeability:\n\n the biological product is biosimilar to the reference product;  it can be expected to produce the same clinical result as the\n\nreference product in any given patient; and\n\n for a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.\n\nAn interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.\n\n14", "n_tokens": 120, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-14-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 14, "text": "General Requirements: 351(k) application\n\nA 351(k) application must include information demonstrating that the biological product:\n\n Is biosimilar to a reference product;  Utilizes the same mechanism(s) of action for the proposed condition(s) of use -- but only to the extent the mechanism(s) are known for the reference product;\n\n Condition(s) of use proposed in labeling have been previously\n\napproved for the reference product;\n\n Has the same route of administration, dosage form, and strength\n\nas the reference product; and\n\n Is manufactured, processed, packed, or held in a facility that meets standards designed to assure that the biological product continues to be safe, pure, and potent.\n\n15\n\n15", "n_tokens": 141, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-15-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 15, "text": "Interchangeability\n\nInterchangeable or Interchangeability:\n\n the biological product is biosimilar to the reference product;  it can be expected to produce the same clinical result as the\n\nreference product in any given patient; and\n\n for a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch.\n\nAn interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.\n\n16", "n_tokens": 120, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-16-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 16, "text": "Interchangeability: General Principles\n\nWhen a product is first licensed as a biosimilar, that licensure may be referenced to support a showing for this statutory criterion for demonstrating interchangeability\n\nFDA expects that sponsors will submit data and information to support a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in all of the reference product’s licensed conditions of use – The data and information may vary depending on the nature of the\n\nproposed interchangeable product.\n\nThe data and information should include a scientific justification as to why any differences that exist between the reference product and the proposed interchangeable product, with respect to the factors described in the guidance, do not preclude a showing that the proposed interchangeable product can be expected to produce the same clinical result as the reference product in any given patient.\n\n17", "n_tokens": 168, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-17-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 17, "text": "Interchangeability: General Principles\n\nFDA expects that applications for a product administered more than once to an individual generally will include data from a switching study or studies in one or more appropriate conditions of use\n\nSwitching Study to demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such alternation or switch.\n\n18", "n_tokens": 86, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-18-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 18, "text": "Design of a Switching Study Considerations will be product-specific and should generally consider the scenario of switching where there is the most clinical concern for patients. Sponsors should consider:\n\nStudy Endpoints- primary endpoint should assess the impact of switching on clinical PK, and PD if available as these endpoints are generally most likely to be sensitive to changes in immunogenicity and/or exposure that may arise as a result of alternating or switching; immunogenicity and safety should be descriptively analyzed as secondary endpoints – Study Population- adequately sensitive to allow for detection of differences in PK and PD, common AEs, and immunogenicity\n\nCondition of Use to be Studied- should be one for which the reference product is already licensed and should support extrapolation for other conditions of use\n\nRoute of Administration- should study the route that will best assess how a patient’s immune response will impact clinical performance\n\nA switching study should evaluate changes in treatment that result in two or more alternating exposures (switch intervals)\n\n• Sufficient scientific justification for extrapolation is necessary.\n\n19", "n_tokens": 215, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-19-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 19, "text": "Example of Switching Study Design\n\nRP\n\nSafety follow-up\n\nRP\n\nRandomization\n\nIC\n\nRP\n\nIC\n\nTrough PK sampling after each switch\n\nIntensive PK sampling\n\nEndpoint for Intensive PK sampling AUCtau, Cmax (3 half lives)\n\nSafety and immunogenicity assessed throughout Switching period based on appropriate sampling\n\nschedule\n\nEnd of Study\n\n20\n\n20", "n_tokens": 68, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-20-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 20, "text": "Biosimilar and Interchangeable products: Key Points •\n\nThere isn’t a different analytical standard for biosimilar vs. interchangeable (IC) products – highly similar – Analytical similarity data in a 351(k) application to support approval of an IC\n\nproduct is not more, better or different than the analytical similarity data needed to support a biosimilar product\n\nA product that is first approved as a biosimilar is not expected to be manipulated or changed in some manner to “become” an IC product\n\nRegardless of whether an Applicant is developing a biosimilar or IC product, extended characterization through additional methods and orthogonal testing reduces uncertainty about potential clinical impact stemming from differences between the biosimilar/IC and the reference product (RP)\n\nBiosimilar and IC products (and RPs) must be manufactured, processed, packed or held in a facility that meets the same standards\n\nBiosimilar and IC products can be used for the same conditions of use (indications) as previously approved for the RP – Treatment naïve and treatment experienced patients\n\n21", "n_tokens": 217, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-21-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 21, "text": "Biosimilar and Interchangeable products: Key Points • Different and distinct statutory approval requirements for biosimilar vs. IC\n\nproducts – IC product is biosimilar, and has additional data requirements\n\n“Expected to produce the same clinical result… any given patient” • “Risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch”\n\nThese additional data elements allow FDA to evaluate whether the product is one that may be substituted for the reference product without consulting the prescriber\n\nFDA has described its thinking in guidance as to how the IC standards could be addressed though certain showings, data and information – Onus is on the Applicant to choose their approach, and provide adequate support for their approach in addressing these additional requirements\n\n22", "n_tokens": 171, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-22-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 22, "text": "Biosimilar and Interchangeable products: Key Points\n\nBy definition, the showings, data and information needed to support approval of a biosimilar differ from that needed to support approval of an IC product – What the Applicant submits differs between a biosimilar and an IC product – What the FDA evaluates differs between a biosimilar and an IC product\n\nA product approved as an interchangeable product means that FDA has concluded it may be substituted for the reference product without consulting the prescriber – Some states may permit pharmacy-level substitution; laws vary from state to state – Prescription and substitution laws overseen by the state pharmacy board\n\nWhen FDA carries out a scientific review of a proposed biosimilar, the evaluation does not include a determination of whether the biosimilar is interchangeable with the reference product and whether the biosimilar can be substituted for the reference product at the pharmacy – Substitution of a biosimilar for a reference product is a matter of state pharmacy law and is a decision that is generally outside of FDA’s regulatory role\n\nAlthough there are distinct approval requirements for reference products, biosimilars, and interchangeable products, the approval standards that apply to each type of biological product assure prescribers of the safety and effectiveness of each type of product 23", "n_tokens": 262, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-23-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 23, "text": "Terminology Matters\n\nHealth care providers should make the prescribing decision that is appropriate for\n\ntheir patient. In the context of evaluating whether a product can be licensed as a biosimilar product, depending on the clinical experience of the reference and proposed products (taking into consideration the conditions of use and patient population), FDA may evaluate data from the evaluation of a subset of patients which provides a substantive descriptive assessment of whether a single cross-over from the reference product to the proposed biosimilar would result in a major risk in terms of hypersensitivity, immunogenicity, or other reactions.\n\nAt this time, FDA-approved labeling for biosimilar products does not specifically reference a “one-time switch” or “transition” from the reference product to the biosimilar, nor is there a statement recommending that biosimilar products be used only in treatment-naïve patients.\n\nAs part of the demonstration of interchangeability, for a product that is administered more than once to an individual, an applicant must demonstrate the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch. – A switching study intended to support a demonstration of interchangeability should evaluate changes in treatment that result in two or more alternating exposures (switch intervals) to the proposed interchangeable product and to the reference product.\n\n– An interchangeable product may be substituted for the reference product without the\n\nintervention of the health care provider who prescribed the reference product.\n\n24", "n_tokens": 319, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-24-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 24, "text": "Using Reference Products, Biosimilar and Interchangeable Products\n\nPatients and their physicians can expect that there will be no clinically meaningful differences between taking a reference product and a biosimilar when these products are used as intended\n\nPatients and their physicians can expect that the interchangeable product will have the same clinical result as the reference product\n\nThe FDA’s high standard for approval of biosimilar and interchangeable products means that patients and health care professionals can be confident of the safety and effectiveness of a biosimilar or interchangeable product, just as they would for the reference product.\n\n25", "n_tokens": 119, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-25-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 25, "text": "Summary • Data to support approval of a biosimilar is a demonstration of\n\nbiosimilarity – Highly similar and no clinically meaningful differences\n\nData to support approval of an interchangeable product includes demonstrating biosimilarity, and additional requirements as outlined by the statute – Data and information to support a showing that the proposed\n\ninterchangeable product can be expected to produce the same clinical result as the reference product in all of the reference product’s licensed conditions of use\n\nGenerally data from a switching study will also be needed – These data are evaluated by FDA and, if adequate, can allow FDA to approve a proposed product as an interchangeable product to the reference product. Some states may permit a pharmacist to substitute an interchangeable product for the reference product without consulting the prescriber (pharmacy-level substitution)\n\nLack of clarity around terminology can be confusing\n\nBiosimilar and interch products are safe and effective when used as intended\n\n26\n\n26", "n_tokens": 191, "kind": "text"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-26-0", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 26, "text": "Thank you for your attention.\n\nFor more information, go to www.fda.gov/biosimilars", "n_tokens": 22, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-0-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 0, "text": "Biosimilar and Interchangeable Products: The U.S. FDA Perspective\n\nJoe Franklin, J.D., Ph.D., Director of the Policy Staff, TBBS/OND/CDER/FDA.", "n_tokens": 46, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-1-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 1, "text": "Disclosure Information AACR 2018 Joe Franklin\n\nI have no financial relationships to disclose.\n\nand -\n\nI will not discuss off label use and/or investigational use in my presentation.", "n_tokens": 34, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-2-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 2, "text": "Overview of Presentation\n\nBackground and key concepts\n\n–BPCI Act –Terminology –351(k) Biologics License Application –Interchangeability –Biological product naming\n\nBiosimilars program at FDA\n\n3", "n_tokens": 38, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-3-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 3, "text": "BACKGROUND AND KEY CONCEPTS", "n_tokens": 4, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-4-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 4, "text": "Background: BPCI Act\n\nThe Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was enacted on March 23, 2010.\n\nThe BPCI Act created an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA- licensed reference product.\n\nOther provisions of the BPCI Act include: – An amended “biological product” definition – Exclusivities – Procedures for identifying and resolving patent disputes involving 351(k) BLAs\n\n5", "n_tokens": 101, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-5-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 5, "text": "“Biological Product”\n\nThe term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.\n\nSection 351(i)(1) of the PHS Act.\n\n6", "n_tokens": 110, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-6-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 6, "text": "“Reference Product” Reference Product:\n\n the single biological product licensed under section\n\n351(a) of the PHS Act against which a biological product is evaluated in an application submitted under section 351(k). Section 351(i)(4).\n\nAn application submitted under section 351(a) of the PHS Act is a “stand-alone” application that must contain all information and data necessary to demonstrate that the proposed product is safe, pure and potent.\n\nIn contrast, an application submitted under section 351(k) needs to demonstrate that the proposed product is biosimilar to, or interchangeable with, the reference product.\n\n7", "n_tokens": 129, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-7-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 7, "text": "“Biosimilar” or “Biosimilarity”\n\nBiosimilar or Biosimilarity means:  that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and\n\n there are no clinically\n\nmeaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.\n\nSection 351(i)(2).\n\n8", "n_tokens": 87, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-8-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 8, "text": "351(k) BLA: General Requirements\n\nA 351(k) BLA must include information demonstrating that:\n\n The proposed product is biosimilar to a reference product;  The proposed product and the reference product utilize the same mechanism(s) of action for the proposed condition(s) of use -- but only to the extent the mechanism(s) are known for the reference product;\n\n The condition(s) of use in labeling for the proposed product have\n\nbeen previously approved for the reference product;\n\n the route of administration, dosage form, and strength of the\n\nproposed product are the same as those of the reference product; and\n\n The facility in which the proposed product is manufactured,\n\nprocessed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.\n\n9", "n_tokens": 163, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-9-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 9, "text": "“Interchangeable” or “interchangeability”\n\nStatutory definition: The term “interchangeable” or “interchangeability”— —in reference to a biological product that is shown to meet the standards described in section 351(k)(4), means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.\n\nSection 351(i)(3).\n\n10", "n_tokens": 85, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-10-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 10, "text": "Interchangeability standards\n\nStandards under section 351(k)(4):\n\n the biological product is biosimilar to the reference\n\nproduct;\n\n it can be expected to produce the same clinical result as\n\nthe reference product in any given patient; and\n\n for a product that is administered more than once to an\n\nindividual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and the reference product is not greater than the risk of using the reference product without such alternation or switch.\n\n11", "n_tokens": 101, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-11-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 11, "text": "Nonproprietary Naming of Biological Products: Four-letter suffix\n\nNonproprietary names (i.e. proper names) for biological products should include—\n\n—a core name attached by a hyphen to an FDA-designated suffix.\n\nHypothetical example: replicamab-cznm\n\nFDA Guidance: Nonproprietary Naming of Biological Products\n\n12", "n_tokens": 75, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-12-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 12, "text": "Nonproprietary Naming of Biological Products: Four-letter suffix\n\nA unique suffix should be designated for each originator biological product, related biological product and biosimilar product.\n\nFDA is continuing to consider the format of the suffix for interchangeable biological products.\n\nFDA Guidance: Nonproprietary Naming of Biological Products\n\n13", "n_tokens": 66, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-13-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 13, "text": "Nonproprietary Naming of Biological Products: Four-letter suffix\n\nExample: for hypothetical products sharing the fictitious core name replicamab, the proper names would include a unique suffix:\n\nOriginator biological product : replicamab-cznm • Related biological product: replicamab-rzbh • Biosimilar product: replicamab-hixf FDA Guidance: Nonproprietary Naming of Biological Products\n\n14", "n_tokens": 89, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-14-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 14, "text": "BIOSIMILARS PROGRAM AT FDA\n\n15", "n_tokens": 8, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-15-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 15, "text": "Biosimilars Approved by FDA\n\nSince program inception and as of April 1, 2018, 12 companies have publicly announced submission of 23 351(k) BLAs to FDA. • Nine 351(k) BLAs for biosimilar products have been approved.\n\nZarxio (filgrastim-sndz) – Inflectra (infliximab-dyyb) – Erelzi (etanercept-szzs) – Amjetiva (adalimumab-atto) – Renflexis (infliximab-abda) – Cyltezo (adalimumab-adbm) – Mvasi (bevacizumab-awwb) – Ogivri (trastuzumab-dkst) – Ixifi (infliximab-qbtx)\n\n16", "n_tokens": 186, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-16-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 16, "text": "Development-Stage Advice to Sponsors\n\nAs of April 1, 2018, • 63 programs were enrolled in the Biosimilar\n\nProduct Development (BPD) Program to discuss development of proposed biosimilar products or proposed interchangeable products\n\nCDER has received meeting requests to discuss the development of biosimilar or interchangeable products for 31 different reference products.\n\n17", "n_tokens": 72, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-17-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 17, "text": "FDA Biosimilars Guidance Development 1.\n\nScientific Considerations in Demonstrating Biosimilarity to a Reference Product (final, 2015)\n\n2. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (final, 2015)\n\n3. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (final, 2015) Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (final, 2015) 4.\n\n5. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (final, 2016)\n\n6. Nonproprietary Naming of Biological Products (final, 2017) 7. Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (draft, 2015) Labeling for Biosimilar Products (draft, 2016)\n\n8. 9. Considerations in Demonstrating Interchangeability With a Reference Product (draft, 2017)\n\n10. Statistical Approaches to Evaluate Analytical Similarity (draft, 2017)\n\nhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm\n\n18", "n_tokens": 252, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-18-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 18, "text": "FDA’s Education and Outreach Campaign for Biosimilars\n\nLaunched by FDA in October 2017 • Goals of this initiative are to increase:\n\nUnderstanding of biologics, reference products, biosimilars and interchangeable products.\n\nAwareness of FDA’s role in the biosimilar approval process.\n\nKnowledge of the data and information FDA reviews/requires to determine biosimilarity.\n\n19", "n_tokens": 79, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-19-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 19, "text": "Biosimilars: FDA Strategic Priority\n\nFDA’s 2018 Strategic Policy Roadmap announced FDA’s plan to launch a comprehensive program to encourage biosimilar competition.\n\nGoal: to help address the high cost of medicines through the development of science-based policies that can improve competition, access, and the opportunity for patients to benefit from safe and effective, and lower cost biosimilar alternatives.\n\n20", "n_tokens": 82, "kind": "text"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-20-0", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 20, "text": "Thank you for your attention.\n\nFor more information, go to www.fda.gov/biosimilars", "n_tokens": 22, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-0-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 0, "text": "CDER New Drugs Program: 2017 Update\n\nPatrick Frey Chief of Staff Office of New Drugs, CDER/FDA\n\nFDA/CMS Summit December 5th, 2017", "n_tokens": 31, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-1-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 1, "text": "Introduction\n\nHousekeeping\n\n Data and analyses presented reflect latest information,\n\nalthough usual QC for official FDA reports has not occurred. Presentation content should be considered preliminary.\n\n Pay close attention to fiscal year (FY), calendar year (CY),\n\nor academic year (AY) and cut-off dates on data presentations; denominators are important too!\n\n Talented staff at FDA provide the data and analyses for this talk each year. Special thanks and acknowledgement to: – Nader Qassim, Nancy Maizel, and Reza Kazemi-Tabriz in CDER’s\n\nOffice of Program and Strategic Analysis\n\nMike Lanthier in the Office of the Commissioner\n\n2", "n_tokens": 133, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-2-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 2, "text": "Introduction\n\nTopics to be covered\n\n New drug review process efficiency: a historical look and changes in PDUFA VI  New drug activity in 2017: approvals,\n\nworkload, international comparisons, and profiling the 2017 class of NMEs/BLAs\n\n Development phase activity: IND workload,\n\nthe breakthrough program, meeting workload and changes in PDUFA VI\n\n A look ahead to 2018\n\n3\n\n•3", "n_tokens": 78, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-3-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 3, "text": "New Drug Review Process Efficiency\n\nCDER New Molecular Entity Approval Rates by PDUFA Cohort\n\n100%\n\n90%\n\nPDUFA V\n\n80%\n\nl\n\na v o r p p A g n i v i e c e R s E M N %\n\n70%\n\n60%\n\n50%\n\n40%\n\nPDUFA IV\n\nPDUFA I-III\n\n30%\n\n20%\n\nPre-PDUFA\n\n10%\n\n0%\n\n6\n\n12\n\n18\n\n24\n\n30 Elapsed Time (months)\n\n36\n\n42\n\n48\n\n54\n\nPre-PDUFA (1988-1992)\n\nPDUFA I-III\n\nPDUFA IV\n\nPDUFA V (receipts through 3/31/2016)\n\nPDUFA V estimates based on 77 NMEs submitted in FY 2013 – mid FY 2015 (it is too early to estimate performance for later submissions)\n\nProjection estimates account for actions to date and elapsed time to date for non-approvals *\n\nData as of 9/30/16\n\n4", "n_tokens": 191, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-4-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 4, "text": "New Drug Review Process Efficiency\n\nNME Review Program\n\n PDUFA V established a new review model for NME NDAs and original BLAs\n\nthat had three main features: − Specified touchpoints during review for FDA-applicant communication [i.e., mid-\n\ncycle communication, late-cycle meeting (LCM)]\n\n− Additional time for FDA review\n\n− Independent contractor (Eastern Research Group) evaluations\n\n Highly successful program – a conclusion shared by industry, FDA, and ERG  Changes in PDUFA VI\n\n− Flexibility: FDA and applicant may agree on a Formal Communication Plan;\n\ncodified treatment of expedited reviews; LCMs may be held by phone rather than F2F\n\n− Application orientation meetings are envisioned as part of a communication plan\n\n− Advisory committee meetings may be scheduled slightly later in the review\n\nprocess; FDA and applicant have option for informal teleconference to debrief on AC feedback\n\n Review Program is now applied to biosimilar applications in BsUFA II\n\n5", "n_tokens": 195, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-5-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 5, "text": "New Drug Activity in 2017\n\nNew Drug Activity in 2017\n\n In CY 2017 so far*, CDER has approved 40 NMEs, including\n\n17 orphan drugs – Record number of orphan indications approved across all NDAs\n\nand BLAs (not just NMEs and BLAs)\n\nUS continues to lead the world in first approval of NMEs\n\n In FY 2017, new applications increased across the board for\n\nCDER compared to five year averages: – 48 NMEs and original BLAs (14% increase) – 106 non-NME NDAs (28% increase) – 231 efficacy supplements (43% increase)\n\nThis information is accurate as of November 30th, 2017. designation or the status of its application as a new biologics license application (BLA). This note applies to all references to NME/Original BLAs in this presentation. In rare instances, it may be necessary for FDA to change a drug’s new molecular entity (NME)\n\n6\n\n•6", "n_tokens": 190, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-6-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 6, "text": "New Drug Activity in 2017\n\nCDER NME NDAs/BLAs† Filings and Approvals by CY as of 11/30/17\n\n60\n\n50\n\n50\n\n45\n\n41\n\n43\n\n41\n\n41\n\n41\n\ns l a v o r p p A / s g n\n\n40\n\n30\n\n28\n\n26\n\n47\n\n36\n\n26\n\n30\n\n22\n\n26\n\n32\n\n38\n\n26\n\n35\n\n34\n\n36\n\n23\n\n36\n\n30\n\n35\n\n33\n\ni l i F\n\n20\n\n10\n\n23\n\n19\n\n28\n\n34\n\n25\n\n33\n\n25\n\n19\n\n11\n\n15\n\n31\n\n18\n\n18\n\n16\n\n21\n\n20\n\n15\n\n24\n\n33\n\n25\n\n11\n\n12\n\n0\n\n2 3 9 9 1\n\n2 4 9 9 1\n\n1\n\n5 9 9 1\n\n6\n\n6 9 9 1\n\n5\n\n7 9 9 1\n\n5\n\n8 9 9 1\n\n2 9 9 9 1\n\n2 0 0 0 2\n\n5\n\n1 0 0 2\n\n6\n\n2 0 0 2\n\n6\n\n3 0 0 2\n\n5\n\n4 0 0 2\n\n2 5 0 0 2\n\n4\n\n6 0 0 2\n\n2 7 0 0 2\n\n3\n\n8 0 0 2\n\n6\n\n9 0 0 2\n\n6\n\n0 1 0 2\n\n6\n\n1 1 0 2\n\n6\n\n2 1 0 2\n\n2 3 1 0 2\n\n4 1 0 2\n\n5 1 0 2\n\nCalendar Year\n\nBLA Approvals\n\nNDA Approvals\n\nFilings\n\n† Multiple applications pertaining to a single new molecular/biologic entity are only counted once. Original BLAs that do not contain a new active ingredient are excluded. * This information is accurate as of November 30th , 2017. of its application as a new biologics license application (BLA). This note applies to all references to NME/Original BLAs in this presentation. Since applications are received and filed throughout a calendar year, the filed applications in a given calendar year do not necessarily correspond to an approval in the same calendar year. Certain applications are within their 60-day filing review period and may not be filed upon completion of the review.\n\nIn rare instances, it may be necessary for FDA to change a drug’s new molecular entity (NME) designation or the status\n\n43\n\n15\n\n7\n\n6 1 0 2\n\n43\n\n28\n\n12\n\n7 1 0 2\n\n7\n\n•7", "n_tokens": 398, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-7-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 7, "text": "New Drug Activity in 2017\n\nNME Actions and Approvals by CY\n\n100\n\n90\n\n82%\n\n80\n\n70\n\ns n o i t c A E M N #\n\n60\n\n50\n\n40\n\n30\n\n20\n\n10\n\n0\n\n0 0 0 2\n\n1 0 0 2\n\n2 0 0 2\n\n3 0 0 2\n\n4 0 0 2\n\n5 0 0 2\n\n6 0 0 2\n\n7 0 0 2\n\n8 0 0 2\n\n9 0 0 2\n\n0 1 0 2\n\n1 1 0 2\n\n2 1 0 2\n\n3 1 0 2\n\n4 1 0 2\n\n5 1 0 2\n\n6 1 0 2\n\n7 1 0 2\n\nCalendar Year\n\nApproval\n\nNon-Approval\n\nApproval Action Rate\n\nData as of 11/30/2017 Includes discrete actions on a given date for an active ingredient which, if approved, would constitute a new molecular entity. Actions for original submissions and resubmissions as well as actions for new BLAs are included. Multiple actions which occur on the same date for multiple dosage forms or indications are counted as a single regulatory action. 8\n\nData as of 11/30/2017 Includes discrete actions on a given date for an active ingredient which, if approved, would constitute a new molecular entity. Actions for original submissions and resubmissions as well as actions for new BLAs are included. Multiple actions which occur on the same date for multiple dosage forms or indications are counted as a single regulatory action. 8\n\n100%\n\n90%\n\n80%\n\n70%\n\n60%\n\n50%\n\n40%\n\n30%\n\n20%\n\n10%", "n_tokens": 287, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-8-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 8, "text": "New Drug Activity in 2017\n\nCDER NME NDAs/BLAs† First Action Approval Rate by FY\n\n100%\n\n90%\n\n89%\n\n80%\n\n78%\n\n70%\n\n70%\n\n72%\n\n60%\n\n50%\n\n40%\n\n50%\n\n54%\n\n50%\n\n48%\n\n42%\n\n45%\n\n52% 52%\n\n46%\n\n43%\n\n56%\n\n30%\n\n36%\n\n30%\n\n35%\n\n31%\n\n20%\n\n23%\n\n25%\n\n25%\n\n10%\n\n0%\n\n1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016\n\nFiscal Year of Receipt\n\nData as of 11/30/2017 † Multiple applications pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers represented here for filings are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded. Percentages exclude pending applications from the denominator.\n\n77%\n\n71%\n\n9\n\n•9", "n_tokens": 207, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-9-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 9, "text": "New Drug Activity in 2017\n\nApproved Orphan Indicationsfor all NDAs and BLAs† by CY\n\n60\n\n50\n\n40\n\n30\n\n20\n\n25\n\n24\n\n18\n\n20 20\n\n20\n\n16 17\n\n20\n\n10\n\n11 10\n\n13 14 13\n\n10 11\n\n14\n\n14\n\n12\n\n14\n\n0\n\n2 3 8 9 1\n\n3 4 8 9 1\n\n4\n\n5 8 9 1\n\n7\n\n6 8 9 1\n\n8\n\n7 8 9 1\n\n8\n\n8 8 9 1\n\n9 8 9 1\n\n0 9 9 1\n\n1 9 9 1\n\n2 9 9 1\n\n3 9 9 1\n\n4 9 9 1\n\n5 9 9 1\n\n6 9 9 1\n\n7 9 9 1\n\n8 9 9 1\n\n9 9 9 1\n\n0 0 0 2\n\n6\n\n1 0 0 2\n\n2 0 0 2\n\n3 0 0 2\n\n4 0 0 2\n\n5 0 0 2\n\n6 0 0 2\n\n7 0 0 2\n\n8 0 0 2\n\n9 0 0 2\n\nCalendar Year\n\n† Includes Efficacy Supplements * Data as of 11/30/2017\n\n15\n\n0 1 0 2\n\n26 26\n\n1 1 0 2\n\n2 1 0 2\n\n33\n\n3 1 0 2\n\n49 48\n\n4 1 0 2\n\n5 1 0 2\n\n39\n\n6 1 0 2\n\n56\n\n7 1 0 2\n\n10", "n_tokens": 216, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-10-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 10, "text": "New Drug Activity in 2017\n\nUSA Share of New Active Substances Launched on World Market Remains High\n\nData as of 11/30/2017\n\nSource: Scrip Magazine (1982 - 2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007 - 2016)\n\n11", "n_tokens": 59, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-11-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 11, "text": "New Drug Activity in 2017\n\nSnapshot of CY 2017 NME NDAs/BLAs† Drug Approvals (1/2)\n\nTrade Name\n\nMet PDUFA Goal Date*\n\nApproved on First Cycle\n\nFirst in Class\n\nApproved First in the U.S.\n\nBreakthrough Therapy\n\nPriority Approval\n\nFast Track\n\nAccelerated Approval Orphan Drug\n\nTRULANCE\n\nPARSABIV\n\nEMFLAZA\n\nSILIQ\n\nXERMELO\n\nKISQALI\n\n 70% of CY 2017 NME NDA/BLA approvals (28/40) designated and reviewed under priority review\n\nXADAGO\n\nSYMPROIC\n\n 17 breakthrough therapies approved, highest annual\n\nBAVENCIO\n\nZEJULA\n\napproval count to date for program\n\nOCREVUS\n\n 18 fast track designated products approved, also\n\nDUPIXENT\n\nAUSTEDO\n\nhighest number approved in a given year\n\nINGREZZA\n\nBRINEURA\n\nRYDAPT**\n\nTYMLOS\n\nALUNBRIG\n\nIMFINZI\n\nData as of 11/30/2017 † Multiple submissions pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded. * A PDUFA Goal Date is marked as met if the application is acted on within its first cycle due date. ** RYDAPT was submitted with two indications, of which one of the indications was granted Breakthrough Therapy designation and the other granted Fast Track designation. QIDP - Qualified Infectious Disease Product\n\nQIDP\n\n12", "n_tokens": 312, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-12-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 12, "text": "New Drug Activity in 2017\n\nSnapshot of CY 2017 NME NDAs/BLAs† Drug Approvals (2/2)\n\nTrade Name\n\nMet PDUFA Goal Date*\n\nApproved on First Cycle\n\nFirst in Class\n\nApproved First in the U.S.\n\nBreakthrough Therapy\n\nPriority Approval\n\nFast Track\n\nAccelerated Approval\n\nRADICAVA\n\nKEVZARA\n\nBAXDELA\n\nBEVYXXA\n\nTREMFYA\n\nNERLYNX\n\nVOSEVI\n\nIDHIFA\n\nMAVYRET\n\nBESPONSA\n\nBENZNIDAZOLE\n\nVABOMERE\n\nOver ⅔ of 2017 NME NDA/BLA approvals used more than one expedited development or review program\n\nALIQOPA\n\nSOLOSEC\n\nVERZENIO\n\nCALQUENCE\n\nVYZULTA\n\nPREVYMIS\n\nFASENRA\n\nMEPSEVII\n\nHEMLIBRA\n\nData as of 11/30/2017 † Multiple submissions pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded. * A PDUFA Goal Date is marked as met if the application is acted on within its first cycle due date. QIDP - Qualified Infectious Disease Product\n\nOrphan Drug\n\nQIDP\n\n13", "n_tokens": 257, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-13-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 13, "text": "New Drug Activity in 2017\n\nIn CY 2017, CDER Continued To Ensure The Efficiency Of First Cycle Review\n\nMet PDUFA Goal Date\n\n All of the (100%) NMEs/BLAs approved to date in 2017 met their PDUFA goal dates\n\n100%\n\n Almost nine out of 10 (88%) of the drugs approved to date in 2017 were approved in the first review cycle\n\nApproved on First Cycle\n\n88%\n\n14\n\n•14", "n_tokens": 85, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-14-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 14, "text": "New Drug Activity in 2017\n\nUtilization of Expedited Development and Review Programs Remained High in 2017\n\n More than two – thirds (70%) of the drugs approved to date in 2017 were approved under Priority Review\n\nBreakthrough Therapy\n\n About four out of ten (43%) of the drugs approved to date in 2017 received Breakthrough Therapy designation\n\n43%\n\n Almost half (45%) of the drugs\n\napproved to date in 2017 received Fast Track designation\n\nPriority Review\n\n70%\n\nFast Track\n\n45%\n\n15\n\n•15", "n_tokens": 94, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-15-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 15, "text": "New Drug Activity in 2017\n\n2017 Continues A Strong Track Record For Drug Innovation\n\n About four out of ten (43%)\n\nof the drugs approved to date in 2017 are orphan drugs\n\n Almost a third (30%) of the drugs approved to date in 2017 are the first in their class\n\n Over three – quarters (78%)\n\nof the drugs approved to date in 2017 were first approved in the U.S.\n\nFirst in Class\n\n30%\n\nOrphan Drugs\n\n43%\n\nApproved First in the United States\n\n78%\n\n16\n\n•16", "n_tokens": 100, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-16-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 16, "text": "Development Phase Work\n\nDevelopment Phase Work Continued to Grow in 2017\n\nCommercial INDs With Activity\n\n7000\n\n6000\n\n5000\n\n695\n\n672\n\n713\n\n726\n\n732\n\n808\n\n824\n\n879\n\n4000\n\n588\n\n586\n\n3000\n\n2000\n\n3773\n\n4023\n\n4281\n\n4516\n\n4808\n\n5002\n\n5026\n\n5067\n\n5278\n\n5258\n\n1000\n\n0\n\n2004\n\n2005\n\n2006\n\n2007\n\n2008\n\n2009\n\n2010\n\n2011\n\n2012\n\n2013\n\nAcademic Year\n\nDrug INDs\n\nBiologic INDs\n\nData are from the PDUFA Workload Adjuster and represent a 12 month period of July 1st - June 30th\n\n1218\n\n5186\n\n2014\n\n1367\n\n5412\n\n2015\n\n1480\n\n5261\n\n2016\n\n1662\n\n5358\n\n2017\n\n17\n\n•17", "n_tokens": 134, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-17-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 17, "text": "Development Phase Work\n\nCDER Breakthrough Therapy Requests by Division 2% 1% 1% 1%\n\n4%\n\n4%\n\n25%\n\n4%\n\n5%\n\n5%\n\n6%\n\n8%\n\n8%\n\n10%\n\nData as of 11/30/2017\n\n16%\n\nOncology\n\nHematology\n\nNeurology\n\nAntiviral\n\nPulmonary / Allergy / Rheumatology Psychiatry\n\nGastroenterology / Inborn Errors\n\nCardiovascular / Renal\n\nTransplant / Ophthalmology\n\nDermatology / Dental\n\nAnesthesia / Analgesia / Addiction Anti-Infective\n\nBone / Reproductive / Urologic\n\nMetabolic / Endocrinology\n\n18\n\n18", "n_tokens": 119, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-18-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 18, "text": "Development Phase Work\n\nCDER Has Granted 192 Breakthrough Therapy Designations Since Inception\n\n5%\n\n3%\n\n2%\n\n2% 2% 1% 1%\n\n12%\n\n3%\n\n36%\n\n4%\n\n5%\n\n529 Requests\n\n6%\n\n192 Granted\n\n8%\n\n47%\n\n12%\n\nGranted\n\nDenied\n\nWithdrawn\n\nPending\n\nData as of 11/30/2017\n\n29%\n\n22%\n\nOncology\n\nHematology\n\nAntiviral\n\nPulmonary / Allergy / Rheumatology\n\nPsychiatry\n\nGastroenterology / Inborn Errors\n\nDermatology / Dental\n\nAnti-Infective\n\nNeurology\n\nAnesthesia / Analgesia / Addiction\n\nTransplant / Ophthalmology\n\nCardiovascular / Renal\n\nMetabolic / Endocrinology\n\nBone / Reproductive / Urologic\n\n19\n\n19", "n_tokens": 137, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-19-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 19, "text": "Development Phase Work\n\nCDER Number of Breakthrough-Designated Development Programs Continues to Grow\n\n100\n\nt n e m p o l e v e D e v i t c A n\n\n90\n\n80\n\n70\n\nReview Phase\n\ni s t c u d o r P d e t a n g i s e d - h g u o r h t k a e r B\n\n60\n\n50\n\n40\n\n30\n\nIND Phase\n\n20\n\nf o r e b m u N\n\n10\n\nl\n\na t o T\n\n0\n\n2 1 - c e D - 1\n\n3 1 - b e F - 1\n\n3 1 - r p A - 1\n\n3 1 - n u J - 1\n\n3 1 - g u A - 1\n\n3 1 - t c O - 1\n\n3 1 - c e D - 1\n\n4 1 - b e F - 1\n\n4 1 - r p A - 1\n\n4 1 - n u J - 1\n\n4 1 - g u A - 1\n\n4 1 - t c O - 1\n\n4 1 - c e D - 1\n\n5 1 - b e F - 1\n\n5 1 - r p A - 1\n\n5 1 - n u J - 1\n\n5 1 - g u A - 1\n\n5 1 - t c O - 1\n\n5 1 - c e D - 1\n\n6 1 - b e F - 1\n\n6 1 - r p A - 1\n\n6 1 - n u J - 1\n\n6 1 - g u A - 1\n\n6 1 - t c O - 1\n\n6 1 - c e D - 1\n\n7 1 - b e F - 1\n\n7 1 - r p A - 1\n\nIND Phase\n\nReview Phase\n\n* Data as of 11/30/17 .Figures includes total # of granted breakthrough designations for drug/indications under active IND development but have not yet received marketing approval or rescission decision.\n\n7 1 - n u J - 1\n\n7 1 - g u A - 1\n\n7 1 - t c O - 1\n\n20", "n_tokens": 377, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-20-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 20, "text": "Development Phase Work\n\nCDER PDUFA Formal Meeting Requests by FY\n\n3500\n\n3000\n\n2500\n\n2000\n\n2015\n\n2236\n\n2256\n\n2209\n\n2027\n\n1969\n\n2008\n\n1500\n\n1464\n\n1000\n\n500\n\n0\n\n2003\n\n2004\n\n2005\n\n2006\n\n2007\n\n2008\n\n2009\n\n2010\n\nFiscal Year\n\nData as of 9/30/2017 BLAs were transferred to CDER in FY2004\n\n2010\n\n2011\n\n2073\n\n2012\n\n2221\n\n2013\n\n2360\n\n2014\n\n2732\n\n2015\n\n2885\n\n2016\n\n3059\n\n2017\n\n21\n\n•21", "n_tokens": 89, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-21-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 21, "text": "Development Phase Work\n\nMeeting Management Changes in PDUFA VI\n\n\n\nEnd-of-Phase 2* meetings are now in a new category, Type B (EOP) meetings with unique parameters – Earlier notification that meeting is granted\n\nEarlier submission of background package\n\nFDA commits to send preliminary comments\n\nIndustry commits to respond to prelim comments\n\n\n\n70-day scheduling goal Type C meetings also changed – Earlier submission of background package\n\nFDA commits to send preliminary comments\n\nIndustry commits to respond to prelim comments\n\n Written Response Only meetings: Sponsors may request this option for any\n\nmeeting category\n\nCertain EOP1 meetings (e.g., 21 CFR Part 312 Subpart E or 21 CFR Part 314 Subpart H) are also included in this category\n\n*\n\n22", "n_tokens": 145, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-22-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 22, "text": "Development Phase Work\n\nNew Meeting in PDUFA VI: Early Consultations on New Surrogate Endpoints\n\n Early consultation can be important when a sponsor intends to\n\nuse a biomarker as a new surrogate endpoint\n\n Consultation is intended to discuss feasibility of the surrogate as a primary endpoint, any knowledge gaps, and how these gaps should be addressed\n\n Consultations will be a Type C meeting with the following\n\nmodifications: – Meeting background package is due at time of request and must include preliminary human data indicating the impact of drug on biomarker\n\nMeeting preparation will involve CDER’s Medical Policy Council – Meetings will be F2F; they will not be converted to a Written Response Only meeting\n\n23", "n_tokens": 138, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-23-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 23, "text": "Looking ahead to 2018\n\n Ensure that recruitment and hiring of new drugs program\n\nstaff continues to be a priority – 1108 FTEs on-board January 1, 2017 – 1198 FTEs projected to be on-board by December 31, 2017 – Net addition of 90 FTEs in 2017\n\n Continued implementation of new PDUFA VI and BsUFA II\n\nagreements, other aspects of FDARA and 21st Century Cures  Continued ongoing critical evaluation of new drug regulatory program operations to ensure that we can meet program demands and our public health obligations to the American people\n\n24", "n_tokens": 109, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-24-0", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 24, "text": "PAY U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-0-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 0, "text": "CDER New Drugs Program: 2019 Update\n\nKhushboo Sharma, MBA, RAC Deputy Director for Operations Office of New Drugs, CDER/FDA\n\nFDA/CMS Summit December 3rd, 2019", "n_tokens": 41, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-1-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 1, "text": "Housekeeping\n\n Data and analyses presented to reflect latest information,\n\nalthough usual QC for official FDA reports has not occurred. Presentation content should be considered preliminary.\n\n Pay close attention to fiscal year (FY), academic year (AY)\n\nand cut-off dates on data presentations; denominators are important too!\n\n Talented staff at FDA provide the data and analyses for this talk each year. Special thanks and acknowledgement to: – Nader Qassim, Nancy Maizel, and Reza Kazemi-Tabriz in CDER’s\n\nOffice of Program and Strategic Analysis\n\nMike Lanthier in the Office of the Commissioner\n\n2", "n_tokens": 126, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-2-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 2, "text": "Topics to be covered\n\n New drug review process efficiency: a historical look and on-\n\ngoing changes in PDUFA VI\n\n New drug activity in 2019: approvals, workload, international\n\ncomparisons, and profiling the 2019 class of NMEs/BLAs\n\n Development phase activity: IND workload, the breakthrough\n\nprogram, meeting workload and continued changes in PDUFA VI\n\n A look ahead to 2020: New Drugs Regulatory Program\n\nModernization efforts\n\n3\n\n•3", "n_tokens": 88, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-3-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 3, "text": "CDER New Molecular Entity Approval Rates by PDUFA Cohort\n\nProjection estimates account for actions to date and elapsed time to date for non-approvals\n\nData as of 9/30/19\n\n4", "n_tokens": 41, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-4-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 4, "text": "New Drug Activity in 2019\n\n\n\nIn FY 2019*, CDER has approved 45 NMEs, including 23 orphan drugs\n\n32 Priority Reviewed NME approvals\n\nRoughly half of the NMEs approved are orphan drugs to treat rare diseases\n\nMore than half of the orphans (12 of 23) are for cancer/cancer imaging\n\n4 for neuropsychiatric drugs for: LEMS, polyneuropathy of hereditary transthyretin-mediated amyloidosis, and two for excessive daytime sleepiness (EDS) in adult patients with narcolepsy\n\n3 orphans are for inherited genetic conditions: polyneuropathy of hereditary transthyretin- mediated amyloidosis, primary hemophagocytic lymphohistiocytosis (HLH), Adenosine Deaminase- Severe Combined Immunodeficiency (ADA-SCID)\n\n\n\n2019 has a unique blend of therapeutic areas\n\n\n\nU.S. continues to lead the world in first approval of NMEs\n\n\n\nSeveral Notable Approvals, including:\n\nTrikafta\n\nRecarbrio and Fetroja\n\nSpravato\n\nScenesse\n\nThis information is accurate as of September 30th, 2019. In rare instances, it may be necessary for FDA to change a drug’s new molecular entity (NME) designation or the status of its application as a new biologics license application (BLA). This note applies to all references to NME/Original BLAs in this presentation. 5\n\n•5", "n_tokens": 292, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-5-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 5, "text": "Notable Approvals: Not Only Quantity but Quality for 2019\n\n\n\nTrikafta - the first triple combination therapy to treat patients with Cystic Fibrosis (CF) who have the most common form of the CF gene mutation, which is estimated to represent 90 percent of the cystic fibrosis population for some patients with CF, but many patients have mutations that are ineligible for treatment.\n\n\n\nRecarbrio and Fetroja - two new antibiotics effective against certain Gram-negative infections --- important advances because Gram-negative bacteria represent a growing danger of serious and potentially life-threatening infections.\n\n\n\nSpravato - closely related chemically to the drug ketamine, originally approved in 1970 under the trade name Ketalar as an injectable anesthetic for certain diagnostic and surgical procedures. Esketamine was approved in 2019 as a nasal spray, to be used in conjunction with an oral antidepressant, for the treatment of depression in adults who have tried other antidepressant medicines but have not benefited from them (treatment-resistant depression).\n\n\n\nScenesse - to increase pain-free light exposure in patients with phototoxic reactions (sensitivity to sunlight) due to erythropoietic protoporphyria, a rare condition resulting from excess accumulation of a chemical that normally helps red blood cells deliver oxygen to the body\n\n6\n\n•6", "n_tokens": 276, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-6-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 6, "text": "CDER NME NDAs/BLAs† Filings and Approvals by FY as of 9/30/19\n\n† Multiple applications pertaining to a single new molecular/biologic entity are only counted once. Original BLAs that do not contain a new active ingredient are excluded. * This information is accurate as of September 30th, 2019. of its application as a new biologics license application (BLA). This note applies to all references to NME/Original BLAs in this presentation. Since applications are received and filed throughout a calendar year, the filed applications in a given calendar year do not necessarily correspond to an approval in the same calendar year. Certain applications are within their 60-day filing review period and may not be filed upon completion of the review.\n\nIn rare instances, it may be necessary for FDA to change a drug’s new molecular entity (NME) designation or the status\n\n7\n\n•7", "n_tokens": 183, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-7-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 7, "text": "NME Actions and Approvals by FY\n\n*Data as of 9/30/2019 Includes discrete actions on a given date for an active ingredient which, if approved, would constitute a new molecular entity. Actions for original submissions and resubmissions as well as actions for new BLAs are included. Multiple actions which occur on the same date for multiple dosage forms or indications are counted as a single regulatory action.\n\n8", "n_tokens": 84, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-8-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 8, "text": "NME FILINGS BY FISCAL YEAR AND THERAPEUTIC AREA\n\n* Data as of 9/30/2019\n\n•9", "n_tokens": 20, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-9-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 9, "text": "CDER NME NDAs/BLAs† First Action Approval Rate by FY\n\n89%\n\n78%\n\n77%\n\n74% 74%\n\n71%\n\n54%\n\n56%\n\n50%\n\n50%\n\n48%\n\n42%\n\n45%\n\n50%\n\n52%\n\n46%\n\n43%\n\n36%\n\n35%\n\n30%\n\n31%\n\n23%\n\n25%\n\n25%\n\n1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018*\n\nFiscal Year of Receipt\n\nData as of 9/30/2019 * There are 3 Pending FY 18 applications as of 9/30/19 † Multiple applications pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers represented here for filings are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded.\n\n91%\n\n84%\n\n10", "n_tokens": 190, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-10-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 10, "text": "CDER Orphan Drug Approvals by FY\n\n* Data as of 9/30/2019\n\n•11", "n_tokens": 20, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-11-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 11, "text": "USA Share of New Active Substances Launched on World Market Remains High\n\nData as of 9/30/2019\n\nSource: Scrip Magazine (1982 - 2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007 - 2018)\n\n12", "n_tokens": 54, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-12-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 12, "text": "Snapshot of FY 2019 NME NDAs/BLAs† Drug Approvals (1/2)\n\nData as of 9/30/2019 † Multiple submissions pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded. * A PDUFA Goal Date is marked as met if the NME is acted upon within its approval cycle due date.\n\n13", "n_tokens": 115, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-13-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 13, "text": "Snapshot of FY 2019 NME NDAs/BLAs† Drug Approvals (2/2)\n\nData as of 9/30/2019 † Multiple submissions pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded. * A PDUFA Goal Date is marked as met if the NME is acted upon within its approval cycle due date.\n\n14", "n_tokens": 115, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-14-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 14, "text": "In FY 2019, CDER Continued To Ensure The Efficiency Of First Cycle Review\n\n All of the (100%) NMEs/BLAs approve FY 2019 met their PDUFA goal dates\n\nd in\n\n All but three (93%) of the drugs appro in FY 2019 were approved in the first review cycle\n\nved\n\n15\n\n•15", "n_tokens": 69, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-15-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 15, "text": "Utilization of Expedited Development and Review Programs Remained High in 2019\n\n Almost three – quarters (71% drugs approved in FY 2019 w approved under Priority Rev\n\n) of the ere iew\n\n About one out of four (24%) drugs approved in FY 2019 re Breakthrough Therapy desig\n\nof the ceived nation\n\n About three out of ten (31% drugs approved in FY 2019 re Fast Track designation\n\n) of the ceived\n\n16\n\n•16", "n_tokens": 91, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-16-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 16, "text": "2019 Continues A S t rong Track Record For Drug In n o vation\n\n Just over half (51%) of drugs approved in FY 2 are orphan drugs\n\nth e 0 1 9\n\n Four out of ten (40%) o t f drugs approved in FY 2 0 1 are the first in their cla ss\n\nhe 9\n\n Almost two-thirds (64% ) o the drugs approved in FY 2019 were first approv ed the U.S.\n\nf\n\nin\n\n17\n\n•17", "n_tokens": 98, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-17-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 17, "text": "Snapshot of FY 2020 NME NDAs/BLAs† Drug Approvals\n\nData as of 11/21/2019 † Multiple submissions pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded.\n\n18", "n_tokens": 86, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-18-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 18, "text": "Development Phase Work Continued to Grow in 2019\n\nData are from the PDUFA Workload Adjuster and represent an Academic Year (12 month period of July 1st - June 30th)\n\n19\n\n•19", "n_tokens": 38, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-19-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 19, "text": "CDER Breakthrough Therapy Requests by Division Oncology, Hematology, and Neurology account for over 50% of Breakthrough Requests.\n\nData as of 9/30/2019\n\n20\n\n20", "n_tokens": 37, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-20-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 20, "text": "CDER Breakthrough Therapy Grants by Division\n\nData as of 9/30/2019\n\n21\n\n21", "n_tokens": 17, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-21-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 21, "text": "CDER Breakthrough Therapy Approvals by FY\n\n* Data as of 9/30/2019\n\n•22", "n_tokens": 20, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-22-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 22, "text": "CDER Active Breakthrough Development Programs\n\n* Data as of 9/30/19 .Figures includes total # of granted breakthrough designations for drug/indications under active IND development but have not yet received marketing approval or rescission decision.\n\n23", "n_tokens": 46, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-23-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 23, "text": "CDER PDUFA Formal Meeting Requests by FY\n\nData as of 9/30/2019 BLAs were transferred to CDER in FY2004 *2019 Data is preliminary\n\n24\n\n•24", "n_tokens": 39, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-24-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 24, "text": "CDER Denied Meeting Requests By FY\n\nData as of 9/30/2019\n\n25\n\n•25", "n_tokens": 19, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-25-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 25, "text": "New Drugs Regulatory Program Modernization\n\nObjectives\n\nGuiding principles for modernizing the new drugs regulatory program\n\nScientific Leadership\n\nWe will grow our scientific expertise and clarify pathways to regulatory approval. • •\n\nExpanding the armamentarium to address unmet medical needs is an important part of our public health mission. Towards that end, we will proactively collaborate with academic medical scientists and patient/disease advocates, evaluate scientific gaps, and strategically foster drug development.\n\nIntegrated Assessment\n\nWe will critically, collaboratively and consistently assess whether information in submissions meets statutory and regulatory requirements. •\n\nWe will take a new approach to document our assessments, developing a more integrated, cross-disciplinary document to foster collaboration and reduce redundant information. Our assessments will be rigorous, risk-based, and clinically relevant; focus on the key issues; and incorporate the patient perspective.\n\nBenefit-Risk Monitoring\n\nWe will establish a unified post-market safety surveillance framework. •\n\nTo effectively protect the American public, we will systematically monitor the benefits and risks of approved drugs across their lifecycles.\n\nManaging Talent\n\nWe will attract, develop, and retain outstanding people. •\n\nWe will use 21st Century Cures Act authorities to recruit and retain technical, scientific and professional experts, and eliminate our backlog of vacant positions.\n\nOperational Excellence\n\nWe will have a dedicated focus on operational excellence. •\n\nWe will enhance our ability to address OND’s large volume workload through greater process standardization and better defined roles and responsibilities. This will improve operational efficiency and enable our scientists to focus on science, not ancillary tasks.\n\nKnowledge Management\n\nWe will facilitate knowledge management. • • •\n\nVast and diverse information is submitted to and generated by the New Drugs Regulatory Program. We will make it easy for our staff to find and use scientific and regulatory precedents. This will reduce manual work time, increase the speed and efficiency of submission assessment, and increase the consistency and predictability of regulatory decision-making.\n\n26\n\n26", "n_tokens": 379, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-26-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 26, "text": "The New Drugs Regulatory Program has 6 active initiatives\n\nIntegrated Review for Marketing Applications\n\nDeveloping a streamlined interdisciplinary review process and template to support the new integrated review for assessing NDA/BLAs\n\nIND Review Management\n\nStreamlining the IND scientific review processes for managing IND applications, beginning with 30-Day Safety Reviews and Protocols\n\nPost-Market Safety Management\n\nCreating a standardized, consistent, and effective approach to post-market drug safety\n\nAssessing Talent\n\nDeveloping an effective and consistent process for hiring, onboarding, developing and evaluating new Clinical and Pharm/Tox reviewers\n\nReorganization and Transition Management\n\nPlanning, coordinating, and implementing modernization and organization changes at the future Office and Division levels across the New Drugs Program\n\nAdministrative Operations\n\nOptimize administrative and clerical staff roles, structure, and functions to enhance customer focus and employee engagement\n\n27", "n_tokens": 154, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-27-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 27, "text": "Re-org will therapeutically align offices and divisions to support scientific exchange and improve consistency across OND\n\nApproved\n\nDetails to follow\n\nOND Immediate Office\n\nOND Director\n\nDeputy Director (Clinical)\n\nDeputy Director (Operations)\n\nPharm/ Tox ADs\n\nOffice of Drug Evaluation Sciences\n\nOffice of New Drug Policy\n\nOffice of Therapeutic Biologics and Biosimilars\n\nOffice of Program Operations\n\nOffice of Admin. Operations\n\nOffice of Regulatory Operations\n\nClinical Outcomes Assessment\n\nClinical offices (x8) Division 1 Division 1 Division 1 Division 1 Division 1\n\nClinical Policy Division\n\nScientific Review and Policy Staffs (x2)\n\nExecutive Operations Staff\n\nFinancial Services Staff\n\nDivisions of Regulatory Division 1 Division 1 Operations1 (x8) Division 1 Division 1 Division 1\n\nRegulatory Policy Division\n\nBusiness Process Operations Staff\n\nAdmin. Analysis Staff\n\nBiomedical Informatics, Biomarker Qualification and Research\n\nTherapeutically aligned to support scientific exchange\n\nProgram Development, Implementation and Mgmt Staff\n\nAdmin. Operations Staff (x5)\n\nLearning and Talent Development Staff\n\nEnsures “unit” size optimizes leaders ability for detailed supervision and involvement in regulatory work, as well as external development\n\n1 Regulatory Operations Divisions align to each clinical office\n\n28", "n_tokens": 224, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-28-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 28, "text": "Clinical Office and Division Names\n\nApproved\n\nOffice of Regulatory Operation: Divisions of Regulatory Operations\n\nOffice of Infectious Diseases (OID)\n\nOffice of Oncologic Diseases (OOD)\n\nOffice of Nonprescription Drugs (ONPD)1\n\nOffice of Neuroscience (ON)\n\nOffice of Cardiology, Hematology, Endocrinology and Nephrology (OCHEN)\n\nOffice of Immunology and Inflammation (OII)\n\nOffice of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (ORPURM)\n\nOffice of Specialty Medicine (OSM)\n\nDivision of Anti- infectives (DAI)\n\nDivision of Oncology I (DO I)\n\nDivision of Nonprescription Drugs I (DNPD I)\n\nDivision of Neurology I (DN I)\n\n Division of Cardiology and Nephrology (DCN)\n\nDivision of Rheumatology and Transplant Medicine (DRTM)\n\n Division of Pediatrics and Maternal Health (DPMH)\n\nDivision of Ophthalmology (DO)\n\n Division of Antivirals (DAV)\n\nDivision of Oncology II (DO II)\n\n Division of Nonprescription Drugs II (DNPD II)\n\nDivision of Neurology II (DN II)\n\nDivision of Non-Malignant Hematology (DNH)\n\n Division of Pulmo- nology, Allergy, and Critical Care (DPACC)\n\nDiv. of Rare Diseases and Medical Genetics (DRDMG)\n\nDivision of Medical Imaging and Radiation Medicine (DMIRM)\n\nDiv. Of Pharm/Tox for Infectious Diseases (DPT-ID)\n\nDivision of Oncology III (DO III)\n\nDivision of Psychiatry (DP)\n\nDivision of Diabetes, Lipid Disorders, and Obesity (DDLO)\n\nDivision of Gastro- enterology (DG)\n\nDivision of Urology, Obstetrics, and Gynecology (DUOG)\n\n Division of Hematologic Malignancies I (DHM I)\n\n Division of Hematologic Malignancies II (DHM II)\n\nDiv. of Anesthesio- logy, Addiction Medicine, and Pain Medicine (DAAP)\n\nDivision of Pharm/Tox for Neuroscience (DPT-N)\n\n", "n_tokens": 446, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-28-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 28, "text": "Division of General Endocrinology (DGE)\n\nDiv. of Pharm/Tox for Cardiology, Hematology, Endocrinology, and Nephrology (DRO- CHEN)\n\nDivision of Hepatology and Nutrition (DHN)\n\nDivision of Dermatology and Dentistry (DDD)\n\nDiv. of Pharm/Tox of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (DPT- RPURM)2\n\nShared P/T support to OSM\n\nDivision of Heme / Onc Toxicology (DHOT)\n\nDiv. of Pharm/Tox for Immunoogy and Inflammation (DPT- II)\n\n1 ONPD P/T staff in the ONPD IO given the small current size of P/T staff. P/T staff will grow into a division from OMUFA; 2 Single P/T division with staff supporting both ORPURM and OSM; PT DD will have dotted line reporting to ORPURM and OSM for P/T issues, and solid line to ORPURM Office Director for 29\n\nPMAP, etc.\n\n•29", "n_tokens": 232, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-29-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 29, "text": "Integrated Review of Marketing Applications\n\n▪ Effort attempts to design a streamlined issue-based integrated review process and template\n\nthat reduces silo reviews, by\n\nCreating a template and a process that are issue-based, foster interdisciplinary collaboration, reduce redundancy and low-value work, and enable better knowledge management\n\nDeveloping a tracking tool to be utilized from pre-NDA through end of review cycle, allowing for systematic tracking of review issues for the entire review team\n\nAdding new roles to allow reviewers to focus on the science and regulatory aspects of the application: (1) Clinical Data Scientists to support safety analysis and (2) Medical Editors to provide editing and formatting services\n\nIncorporating purposeful scoping working meetings with early involvement of leadership to discuss known benefit and risk issues; and joint assessment meetings focused on specific review issues\n\nCurrently in Phased Implementation. All divisions to begin using the new process and template in 2020.\n\n30\n\n•30", "n_tokens": 179, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-30-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 30, "text": "IND Review Management\n\n▪ Effort attempts to address variable practices across divisions and reduce\n\nredundant documentation practices\n\n▪ Creating templates that are issue-based, foster interdisciplinary collaboration,\n\nreduce redundancy and low-value work, and enable better knowledge management\n\n▪ Establishing procedures that standardize the review process, clearly define roles and responsibilities and improve our ability to provide high-quality feedback to sponsors in a timely manner\n\n▪ Developing a risk based approach to categorize incoming protocols and\n\namendments and identify the protocols that should follow a higher priority process to review more expeditiously\n\nCurrently in Phased Implementation. All divisions to begin using the new process and template in 2020.\n\n31\n\n•31", "n_tokens": 130, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-31-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 31, "text": "Post-Market Safety Management\n\nCreate a standardized post-market drug safety framework that will include:\n\n▪ Cross-disciplinary, collaborative, science-focused assessments ▪ Clear roles, responsibilities, and governance ▪ IT-enabled processes to enhance knowledge management and fit-for-purpose\n\nanalytic tools to promote optimal evaluations\n\n▪ Policies and processes (i.e., via SOPs, charters, templates) that support this framework\n\nAnticipate beginning implementation in 2020\n\n32\n\n•32", "n_tokens": 92, "kind": "text"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-32-0", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 32, "text": "PAY U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-0-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 0, "text": "CDER Office of Surveillance and Epidemiology: 2017 Update\n\nGerald J. Dal Pan, MD, MHS Director Office of Surveillance and Epidemiology Center for Drug Evaluation and Research\n\nFDA/CMS Summit December 5, 2017", "n_tokens": 47, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-1-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 1, "text": "PN U.S. FOOD & DRUG\n\nADMINISTRATION\n\nAdverse Event Data", "n_tokens": 13, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-2-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 2, "text": "FDA Adverse Event Reporting System lis\n(FAERS)\n\n1,800,000\n\nNumber of Adverse Event Reports\n\n1,600,000\n@ Non-Expedited\n1,400,000 mo Day\n@ Direct\n1,200,000\n$1,000,000\na\ns\ni\n2\n= 800,000\nSs\n2\n\nE\n8\n\nE\n8\n\n200,000\n\n2004 =2005 2006 2007 2008 2009 2010 2011 2012-2013, 2014S 2015S. 2016", "n_tokens": 88, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-3-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 3, "text": "Best Practices for Pharmacovigilance FDAAA 2007 establishes requirement for 18-month/10,000 patient safety review.\n\nImpact analysis show that these reviews have little value.\n\n21st Century Cures Act 2016 removes this requirement\n\n4", "n_tokens": 46, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-4-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 4, "text": "Best Practices for Pharmacovigilance\n\nPN U.S. FOOD & DRUG\n\nADMINISTRATION\n\nDrugs\n\nHome | Food | Drugs | Medical Devices\n\nHome > Drugs > Drug Safety and Availability > Postmarket Drug Safety Information for Patients and Providers\n\nPostmarket Drug Safety\n\nInformation for Patients and\nProviders\n\nIndex to Drug-Specific Information\n\nResources for You\n\n* REMS@FDA Approved Risk\nEvaluation and Mitigation\nStrategies (REMS)\n\nPostmarket Drug Safety\nInformation for Patients and\nProviders\n\nf SHARE OW TWEET Im UNKEDIN @ PINT Mewar SG PRINT\n\nIn accordance with Section 915 of the Food and Drug Administration\nAmendments Act of 2007 (FDAAA), this website contains links to\npostmarket drug safety information to improve transparency and\ncommunication to patients and healthcare providers\n\nRadiation-Emitting Products | Vaccines, Blood & Biologics | Animal & Veterinary | Cosmetics | Tobacco Products\n\nNotice: Drug and Biologics\nSafety Surveillance Best\n\nPractice Statement (PDF -\n79KB\n\nidance Outlines Hoy\nCommunicates, Priontizes Drug\nSafety Issues\n\nRecalls & Alerts", "n_tokens": 206, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-5-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 5, "text": "Best Practices for Pharmacovigilance\n\nDrug and Biologics Safety Surveillance Best Practice Statement\nCenter for Drug Evaluation and Research (CDER)\nCenter for Biologics Evaluation and Research (CBER)\n\nUS Food and Drug Administration\n\nThe 21st Century Cures Act (the “Cures Act”), enacted on December 13, 2016, has the goal of advancing\nmedical product innovation as well as ensuring patient access to safe and effective treatments as soon\nas possible. One of the provisions of the Cures Act includes a revision to a previous statutory\nrequirement that generally required FDA to undertake routine safety analyses of drugs 18 months\nfollowing approval or after 10,000 individuals have used the drug, whichever occurs later. See section\n505(r)(2)(D) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) before and after it was amended by\nthe Cures Act. These assessments were largely redundant to our current surveillance practices at the\nFood and Drug Administration (FDA), were not an efficient use of FDA resources, and did not provide", "n_tokens": 213, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-6-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 6, "text": "Improved Access to\nAdverse Event Reports\n\nipyN U.S. FOOD & DRUG\n\nADMINISTRATION\n\nHome | Food | Drugs | Medical Devices | Radiation-Emitting Products | Vaccines, Blood & Biologics | Animal & Veterinary | Cosmetics | Tobacco Products\nNews & Events\n\nHome > News & Events > Newsroom > Press Announcements\n\nFDA News Release\n\nInquiries\nFDA improves access to reports of adverse drug\nreactions Mesie\nNew online tool makes it easier for users to search the FDA Adverse Event Reporting System Ceo\nfF SHARE OW TWEET Im LINKEDIN @PINIT | MB EMAL & PRINT\nConsumers\n\n{ 888-INFO-FDA\n\nFor Immediate September 28, 2017\nRelease\nFollow FDA\nRelease The U.S. Food and Drug Administration today launched a new user-friendly search\ntool that improves access to data on adverse events associated with drug and Follow @US_FDA®\nbiologic products through the FDA’s Adverse Event Reporting System (FAERS). The G Follow FOA®\n\ntool is designed to make it easier for consumers, providers, and researchers to\n\n\" ¥ Follow @FDAmedia\naccess this information. S\n\n“Tools like the FDA Adverse Event Reporting System are critical to the FDA's ability\nto help ensure the greatest level of transparency and help patients and providers\nmake safe use of drug and biologic products after they are approved by the FDA,”\nsaid FDA Commissioner Scott Gottlieb, M.D. “The FDA is committed to fully informing\npatients and providers of adverse events reported with medical products and this\nenhanced portal now provides patients, doctors and others with easier access to the\ndata they are interested in.”\n\n‘The new dashboard enables users to search for and organize data by criteria such as\ndrug/biological product, age of the patient, type of adverse event, year the adverse\n\nevent occurred, or within a specific timeframe. In addition to making it easier for\n\nconsumers to search for adverse events reported with drug or biologic products, the\n\nFDA hopes the increased transparency will spur the submission of more detailed and\n\ncomplete reports from consumers, health care professionals and others, by making it\n\neasier for people to see other reports that the FDA receives, and search the 7\ndatabase for similar observations.", "n_tokens": 430, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-7-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 7, "text": "Sample Dashboard Search\n\nents Reporting System (FAERS) Pubic Dashbar\n\nEXONDYS 51 0 at a on\n\nomni r\nseas oma et nn concn Bret ew we\ninte + ete 7 ~\neee\nee ow onne\n\ni\n{\ni\n\ncwmocnmcneac®. mene. won Noman\n\nFDA Adverse Et\n\nERS) Pubic Dashboard\n\ns Reporting Syste\n\n“SPINRAZA 0 wn\n\na oy on\ncom 9 haters Peco\nos 7] ba\n\nSr a Te Saad\n\nNACI? toad teat one mes.", "n_tokens": 119, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-8-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 8, "text": "Media Articl\n\n@DcCcnBc\n\nHOME U.S.\n\nNEWS MARKETS INVESTING\n\nTECH MAKE IT\n\nVIDEO SHOWS MORE\n\nBIOTECH AND PHARMACEUTICALS\n\nHEALTHCARE | HOSPITALS | PHARMA | HEALTHINSURANCE | MODERN MEDICINE\n\nBiotech stocks drop after FDA\nmakes it easier for public to search\nfor drug side effects\n\n* Biotech stocks fell Friday, a day after the U.S. Food and Drug Administration made its\ndatabase of side effects for medicines searchable.\n\n+ Sarepta Therapeutics, Ionis Pharmaceuticals, Biogen and Acadia Pharmaceuticals all\ntraded lower after investors found reports on their drugs on the FDA's Adverse Events\nReporting System.\n\n+ It is not clear whether the adverse events were caused by the medicines themselves, or\n\nwere incidental, an analyst said.\n\nFDA\n\ne\n\nSarepta's Exondys 51, approved last year for certain patients with\nDuchenne muscular dystrophy, or DMD, had 11 reports of serious cases,\nincluding three deaths, according to FAERS.\n\n(Spinaza, a treatement from Biogen and lonis for spinal muscular atrophy,\nor SMA, had 101 reports of serious cases, including 12 deaths.\n\nAnd Acadia's ‘Nuplazid, for patients with Parkinson's, had 1,343 serious\ncase reports, including 493 deaths, FAERS reveals", "n_tokens": 267, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-9-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 9, "text": "NLP and Machine Learning in FAERS\n\nthe i 2017, Vol.0, No. 0\n\nJournal of the American Medical informatics Association, (0), 2017, 1-8\ndoi: 10.1 083famia/ocxtZ2 N MZ I N\n\nResearch and Applicatons OXFORD\n\nResearch and Applications\n\nDevelopment of an automated assessment tool for\nMedWatch reports in the FDA adverse event reporting\nsystem\n\nLichy Han, ' Robert Ball,” Carol A Pamer,” Russ B Altman,** and Scott Proeste!*\n\n\"Biomedical Informatics Training Program, Stanford University, Stanford, CA, USA, *Office of Surveillance and Epidemiclogy,\nCenter for Drug Evaluation and Research, Food and Drug Administraton, Siver Spring MD, USA, \"Department of Genetcs,\n‘Stanford of Bioeng ‘Stanford\n\nCorresponding Author: Scott Proestel, Division of Epidemiology, Office of Biostatistics and Epidemiology, FDA Center for\nBiologics Evaluation and Research, White Oak Building 71, Room 1260, 10913 New Hampshire Avenue, Silver Spring, MD\n20883, USA. Phone: {240} 402-0396. E-mail Scott ProasteN@fda hhs.gov\n\nReceived 1 September 208 Revised 3) Jensery 2017; Accepted 0 Fabry 217\n\nABSTRACT\n\nObjective: As the US Food and Drug Administration (FDA) receives over 8 million adverse event reports assock\n‘sted with medication use every yesr, 8 system is needed w aid FDA safety evalustors in identifying reports\nmost likely to causal to the suspect ‘We combined text mining with ma-\nchine learning to construct and evaluate suche system to identify medication<elated adverse event reports.\n\n FDA safety 326 reports for We features\nfrom these reports and constructed random forest, L1 regularized logistic regression, and support vector ma-\nchine models. model and further utility by g 19 report rankings that rep-\nresented @ prioritized report review process.\n Results: Our random forest model showed the best performance in report ranking and accurscy, with an ares\nunder the receiver curve of 0.66. The report ordering assigns reports with\nhigher probe bility of medicstion-relsted causality ¢ higher rank ands significantly correlated to. perfect report\nordering, with a Kendalf stau of028(F— 002).\n\n", "n_tokens": 489, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-9-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 9, "text": "‘Our models pr report\n\nthat enable FDA safety evaluators to focus on re-\n\nports that are more Ikely to contain v licati adverse event our mod-\nels to ll FDA adverse event reports has the potential to streamline the manual review process and gresty\nreduce reviewer workload.\n\n Key words: drug-related side effect iverse reactions, supervised machine learning\n\nBACKGROUND AND SIGNIFICANCE\n\nThe US Food and Drug Administration (FDA) receives more than\n4000 medication safety reports every day, and the numberof reports\nreceived each year has been increasing exponentially over the last\ndecade. These reports are stored in a database known as the FDA\nAdverse Event Reporting System (FAERS}, which has collected over\n11 million repos since its inception in 1969.\" In the United States,\n\nreporting these adverse events, medication errors, and product qual-\nity issues by health care professionals and consumers via the Med-\nWatch program is voluntary, but it is mandatory for drug\nmanufacturers.’ The FDA wes these reports to detect safety issues\nthat may not have been identified during pre-market dlinical trials\nused a the basis for medication approval, Among the reasons for\n‘not detecting safety issues during pre-market evaluation are thatthe\n\nPablahed by Oxford Universdy Press on behalf ofthe American Medical lf omatics Associaton 217.\n ‘This wos is written by US Gow mment employees tnd isthe public domain in the Urited States.\n\n == L1 Reguiarized Logistic Regression\n\nod — Random Forest\nom > ev\nos os obo os ie\nFalse Positive Rate\npire 2. ROC carve fora danteaton moda\nA By Date B Rendom Forest\n\nFigure. c: o intra nei (A) dane and (8) random of Certain, Probatie. or assem\nments of Uniikelyor Unassesaabie.\n\nsystems, the FDA Adverse Event Sys- ‘The succes of text classification in the Vaccine Adverse Event\n\ntem. Over the last decade, the number of adverse event reportshas System and previous of new\n\niy, resubing in a for re related in FAERS**\"” have generated sig-\n\nviewers. Delays in detecting drug adverse events can have costly and\ndetrimental effects on public health, and thus a system to identify re\nports most likely to contain information demonstrating causal drug\n‘events would be highly beneficial.", "n_tokens": 491, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-9-2", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 9, "text": "Researchers have investigated\nsuch approaches using the US Vaccine Adverse Event Reporting Sys-\ntem, in which extracted text features'*\"” were used with mukiple\nasification algorithms to create an effective report classification\nmodel.\n\n nificant interest in developing a classification system for FAERS. To\naccomplish this, we built models to classify and rank adverse event\n‘reports based on the likelihood of medication-related causality. In\naddition, we showed the potential utility of our models to assist\nmanual adjudicators by shifting reports with 2 higher probability of\nmedication related causality to a higher priority in rank order.\n\n For the first phase of this study, we chose to focus om reports\nwith of Certain to Us 2, as they\n\n10", "n_tokens": 146, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-10-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 10, "text": "Can Social Media Generate Signals?\n\nEnglish-language Twitter posts\n\nAuthor’s conclusion:\n\nmentioning 23 medical products Identified posts resembling adverse events (proto-AEs) • Vernacular internet terms translated to MedDRA\n\nTerms aggregated by MedDRA SOC • 4,401 proto-AEs identified • High correlation with FAERS at SCO level\n\n“Patients reporting AEs on Twitter showed a range of sophistication when describing their experience. Despite the public availability of these data, their appropriate role in pharmacovigilance has not been established. Additional work is needed to improve data acquisition and automation.”\n\nSource: Freifeld et al. Drug Saf 2014; 37:343-350\n\n11", "n_tokens": 139, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-11-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 11, "text": "Methods Development\n\nSource: Nikfarjam et al. J Am Med Inform Assoc c 2015;22:671–681; Tricco et al. BMJ Open l (http://dx.doi.org/ 10.1136/bmjopen-2016- 013474); Pierce et al. Drug Saf 2017;40:317–331\n\n12", "n_tokens": 83, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-12-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 12, "text": "PAY U.S. FOOD & DRUG\n\nADMINISTRATION\n\nSentinel", "n_tokens": 10, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-13-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 13, "text": "FDA Sentinel System\n\nNational medical product monitoring system • 17 data partners with 178 million members with pharmacy and medical coverage\n\nDistributed system where data partners retain physical control of data to protect privacy and security\n\nwww.sentinelinitiative.org/\n\n14", "n_tokens": 46, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-14-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 14, "text": "https://www.sentinelinitiative.org/background\n\nTimeline\n\n15", "n_tokens": 16, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-15-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 15, "text": "Requirement to Consider Sufficiency of ARIA before PMR\n\nSection 905 Mandates creation of ARIA\n\nLinked\n\nSection 901 New FDAAA PMR authority\n\n“The Secretary may not require the responsible person to conduct a study under this paragraph, unless the Secretary makes a determination that the reports under subsection (k)(1) and the active postmarket risk identification and analysis system as available under subsection (k)(3) will not be sufficient to meet the purposes set forth in subparagraph (B).”\n\nFDAAA = FDA Amendments Act 2007\n\nhttps://www.gpo.gov/fdsys/pkg/PLAW-110publ85/pdf/PLAW-110publ85.pdf\n\n16", "n_tokens": 149, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-16-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 16, "text": "Active Risk Identification and Analysis\n\nLevel 2 (L2) Inferential analyses\n\nLevel 1 (L1) Complex descriptive analyses\n\nSummary Table (ST) Simple counts\n\nModular Programs: Validated, re-usable analytic tools that facilitate rapid safety analyses to be run on high quality electronic healthcare data\n\n17", "n_tokens": 57, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-17-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 17, "text": "Sentinel ARIA Analyses (N=233)\n\n70\n\n60\n\nST\n\nL1\n\nL2\n\nL3\n\n1 6\n\n50\n\n40\n\n30\n\n20\n\n1 1 5\n\n3\n\n15\n\n1\n\n14\n\n2\n\n12\n\n1 3 4\n\n2\n\n12\n\n56\n\n10\n\n16\n\n15\n\n16\n\n10\n\n16\n\n16\n\n0\n\nQTR1\n\nQTR2\n\nQTR3\n\nQTR4\n\nQTR1\n\nQTR2\n\nQTR3\n\n2016\n\n2017\n\nFrom all FDA Centers, by date of distribution to Data Partners\n\n5\n\nQTR4\n\n18", "n_tokens": 86, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-18-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 18, "text": "10th Annual Public Workshop\n\nhttps://healthpolicy.duke.edu/events/2018-sentinel-initiative-annual-public-workshop\n\n19", "n_tokens": 32, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-19-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 19, "text": "Sentinel and PDUFA\n\nPDUFA V Commitments\n\nPublic stakeholder meeting\n\nFund 4 – 6 activities\n\nInterim Sentinel Assessment\n\nFinal Sentinel Assessment\n\nPDUFA VI Commitments\n\nExpand data sources and core capabilities • Enhance communications with sponsors and public • Evaluate additional ways to facilitate public and sponsor access to Sentinel • Hold public stakeholder meeting • Establish MAPPS and SOPPs for sponsor communication • • Develop a comprehensive training program for review staff • Report impact of Sentinel expansion and integration by FY2022 20", "n_tokens": 95, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-20-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 20, "text": "New Base Contract for Sentinel Coordinating Center\n\nhttps://www.fbo.gov/index?s=opportunity&mode=form&id=ec59b8dbb36970e2912801aa2cfdd87d&tab=core&_cview=0\n\n21", "n_tokens": 64, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-21-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 21, "text": "Making Sentinel Available to Others\n\nIMEDS shares the same analytic center at Harvard Pilgrim Healthcare as Sentinel IMEDS has the same analytic tools and similar database available to FDA IMEDS is publicly accessible\n\n• Currently active with multiple analyses ongoing\n\nhttps://www.sentinelinitiative.org/sentinel/reagan-udall-foundation-and-imeds\n\n22", "n_tokens": 74, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-22-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 22, "text": "Real-world Evidence\n\nThe NEW ENGLAND JOURNAL of MEDICINE\n\nSOUNDING BOARD\n\nReal-World Evidence — What Is It and What Can It Tell Us?\n\nRachel E. Sherman, M.D., M.P.H., Steven A. Anderson, Ph.D., M.P.P.,\n\nGerald J. Dal Pan, M.D., M.H.S., Gerry W. Gray, Ph.D., Thomas Gross, M.D., M.P.H.,\nNina L. Hunter, Ph.D., Lisa LaVange, Ph.D., Danica Marinac-Dabic, M.D., Ph.D.,\nPeter W. Marks, M.D., Ph.D., Melissa A. Robb, B.S.N., M.S., Jeffrey Shuren, M.D., J.D.,\nRobert Temple, M.D., Janet Woodcock, M.D., Lilly Q. Yue, Ph.D., and Robert M. Califf, M.D.\n\n23", "n_tokens": 226, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-23-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 23, "text": "PN U.S. FOOD & DRUG\n\nADMINISTRATION\n\nRisk Evaluation and Mitigation\nStrategies", "n_tokens": 17, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-24-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 24, "text": "Format and Content of REMS Document\n\nFormat and Content of a REMS Document – Revised draft guidance • Includes a section for each participant – Who – What – When – With what\n\n25", "n_tokens": 36, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-25-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 25, "text": "Use of a Drug Master File for Shared System REMS Submissions\n\nDraft guidance issued November 2017\n\nIntended to improve efficiency\n\n26", "n_tokens": 22, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-26-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 26, "text": "REMS Document and Structured Product Labeling\n\nREMS into SPL format\n\nDraft guidance\n\nMake REMS\n\ninformation available within existing healthcare systems and workflows – Easier sharing of information and incorporation in health information technology\n\n27", "n_tokens": 40, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-27-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 27, "text": "REMS Website\n\nf\n\nyy U.S. FOOD & DR'\n\nADMINISTRATION\n\nRadiation-Emating Products | Vaccines, Blood & Biologics | Anmai & Veternary Tobacco Products\n\nHome > Drug Databases > REMS\n\nApproved Risk Evaluation and Mitigation Strategies (REMS)\n\nf ounce | w in eceon\n\nREMSSFDA\n\nContact Us | REMS Basics | (5 Get REMS Email Alerts | Reports & Data Files\nThe Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug or biological product outweigh its\n1Sks\n\nThe table below provides links to currently approved individual and shared system REMS\n\ninformation on historical and released REMS ts available in downloadat\n\nREMS Approved ¢ Last Updated ¢ MedGuide (MG)\"\n\nAdasuve (loxapine), aerosol, powder\n\n12/21/2012 ETASL IS\nAcer ssemcigiipe ha 06/16/2017 ETASU S\nAdempes (inciquat, lth, Sim costed 10/08/2013 011772017 MG ETASL s\nAtrezza (nsuin human), powder, metered onorpot owonmors\nAcecwon 11/22/2016 ETASU\n\n05/11\n\nAndrogel 1% (testosterone), get\n\nAndroge! 1.62% (testosterone), gel\n\n04/29/2011\n\nAveed (testosterone undecanoate), injection\n\n03/05/2014 12/09/2016", "n_tokens": 322, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-28-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 28, "text": "Stakeholder Sections\n\nADMINISTRATION\n\nFood | Drugs | Medical Devices | Radiation-Emitting Products | Vaccines, Blood & Biologics | Animal & Veterinary | Cosmetics | Tobacco Products\n\nHome > Drug Databases > REMS\n\nApproved Risk Evaluation and Mitigation Strategies (REMS)\n\nin UNKEDIN @ PINT BEMAL B PRINT\n\nREMSSFDA\n\nContact Us | REMS Basics | ©) Get REMS Email Alerts | Reports & Data Files\n\nClozapine\nShared System REMS\n\nREMS last update: 09/15/2015\n\nWhat do participants need to know?\n\nBelow is a general overview of the REMS for all REMS participants (e.g., patients, pharmacies, and healthcare providers). See the application holder(s) REMS Website or the\napproved REMS materials for more information.\n\nView application holder(s) REMS Website #\n\nView additional drug-specific postmarket safety information from the FDA\n\nDisclaimer: This webpage provides general information sbout REMS programs to various REMS participants (@.g.. patients, pharmacies, and healthcare providers). The summary information provided herein is not comprehensive and may not include all ofthe information relevant to REMS participants. This,\nwebpage does not constitute a replacement modification, or revision of the approved REMS document, including any appended REMS materials. Refer to the approved REMS document for complete information on the REMS requirements for each approved application\n\n29\n\nNote: If you need help accessing information in different file formats, see Instructions for Downloading Viewers and Players.\nLanguage Assistance Available: Espafiol | #88473 | Tiéng Viét | +20} | Tagalog | Pyccxuit | 4+. | Kreydl Ayisyen | Francais | Polski | Portugués | Italiano | Deutsch | 8235 | .~J4| English", "n_tokens": 384, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-29-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 29, "text": "Stakeholder Sections\n\nClozapine\nShared System REMS\nREMS last update: 09/15/2015\n\nWhat do participants need to know?\n\n Below is a general overview of the REMS for all REMS participants (e.g., patients, pharmacies, and healthcare providers). See the application holder(s) REMS Website or the\napproved REMS materials for more information.\n\n View application holder(s) REMS Website @\n\nHealthcare Providers who prescribe clozapine products must\n\n+ Review the drug's prescribing information.\n\n + Review Clozapine and Risk of penia: A Guide for fe Providers. | Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers |\nTo be able to prescribe = the Kn igs for Healthcare Providers and submit the lly knowledge to the tion holder. |\nKnowledge Assessment for Healthcare Providers |\n+ Enroll in the REMS by fing and submitting the Prescriber E: Form. | Prescriber Enrollment Form |\n\nCounsel the patient on the risks associated with clozapine including severe neutropenia and the REMS program requirements using What You Need to Know\nabout Clozapine and Neutropenia: A Guide for Patients and Caregivers. | What You Need to Know about Clozapine and Neutropenia: A Guide for Patients and\n\nCaregivers |\n+ Unless clinical j indicates that the patient's 2 to the regimen will be negatively impacted: provide the patient with What You Need to\nBefore the first prescription Know about Clozapine and A Guide for Patients and Caregivers. | What You Need to Know about Clozapine and Neutropenia: A Guide for Pa-\ntients and Caregivers |\n\n+ Assess the patient's absolute neutrop\ncontact center.\n\n count (ANC). Document and submit the results to the REMS program via the online system, by fax, or calling the\n\nEnroll the patient by completing and submitting the Patient Enrollment Form. Retain a completed copy in the patient's record. | Patient Enrollment Form |\n\n+ Assess the patient's ANC. Document and submit the results to the REMS program via the online system, by fax, or calling the contact center.\n\n", "n_tokens": 458, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-29-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 29, "text": "For patients with an ANC that falls below the range in the Pr tion: assess the patient's benefits of conti\nwith the risks of developing severe neutropenia\n\nAt specified intervals, according to the Prescribing jing treatment\n\nInformation for a clozapine product, during treatment\n\nFor patients whose continuing\ntreatment to the REMS program\n\nbenefit the risk of developing severe i and submit the authorization to continue\n\nView additional drug-specific postmarket safety information from the FDA 30", "n_tokens": 95, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-30-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 30, "text": "Framework for Benefit-Risk Counseling to Patients About Drug with a REMS\n\nPart of REMS Integration\n\nInitiative • Four Es:\n\nEvaluate – Educate – Engage – Ensure\n\n31", "n_tokens": 32, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-31-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 31, "text": "PN U.S. FOOD & DRUG\n\nADMINISTRATION\n\nPrescription Opioid Abuse", "n_tokens": 15, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-32-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 32, "text": "Deaths per 100,000 population\n\n11\n\n10\n\n>\n\nw\n\n2\n\n1\n\n0\n\n2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015\n\nOverdose Deaths Involving Opioids, by Type of Opioid,\nUnited States, 2000-2015\n\nAny Opioid\n\nHeroin\n\nNatural & Semi-Synthetic\nOpioids...\n\nOther Synthetic Opioids\n(e.g., fentanyl, tramadol)\n\nSe\n——_ Methadone\n\nwww.cdc.gov\n\nSOURCE: CDC/NCHS, National Vital Statistics System, Mortality. COC WONDER, Atlanta, GA: US Department of Health\nand Human Services, CDC; 2016. https://wonder.cdc.gov/.\n\nredible Health Info\n\n33", "n_tokens": 146, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-33-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 33, "text": "Opioids\n\nA busy year! • Six of seven Drug Safety and Risk Management Advisory Committee meetings 2017 concerned opioids\n\nThree public meetings:\n\nPackaging, Storage, and Disposal Options To Enhance Opioid Safety--Exploring the Path Forward, December 11-12, 2017\n\nData and Methods for Evaluating the Impact of Opioid Formulations with Properties Designed to Deter Abuse in the Postmarket Setting: A Scientific Discussion of Present and Future Capabilities, July 10, 2017\n\nTraining for Opioid Analgesic Prescribers, May 9-10, 2017\n\n34", "n_tokens": 111, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-34-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 34, "text": "Opana ER\n\nepartment of Health and Human Services\n\nAtoZ index | FollowFDA | En\n\nU.S. FOOD & DRUG :\nADMINISTRATION fsearcnroas\n\nHome | Food | Drugs | Medical Devices | Radiation-Emitting Products | Vaccines, Blood & Biologics | Animal & Veterinary | Cosmetics | Tobacco Products\n\nNews & Events\n\nHome > News & Events > Newsroom > Press Announcements\n\nFDA News Release\n\nInquiries\nFDA requests removal of Opana ER for risks\nrelated to abuse Media\n\n®& Sarah Peddicord\nf SHARE WTWEET in UNKEDIN @PiINT MBemMAL @ PRINT \\% 301-796-2805\n\n® Michael Felberbaum\n\\% 240-402-9548\n\nFor Immediate June 8, 2017\nRelease Consumers\n\nX33 INFOFDA\n\n35", "n_tokens": 159, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-35-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 35, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-0-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 0, "text": "CDER Office of Surveillance and Epidemiology: 2018 Update\n\nGerald J. Dal Pan, MD, MHS Director Office of Surveillance and Epidemiology Center for Drug Evaluation and Research\n\nFDA/CMS Summit December 11, 2018", "n_tokens": 47, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-1-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 1, "text": "Label Changes Study\n\nSource: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]\n\n2", "n_tokens": 41, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-2-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 2, "text": "Data Source - Issues\n\nIssue were identified by reviewing label and approval letter\n\nIssues were recorded as stated in the label text • A second reviewer independently reviewed the abstracted individual safety issues\n\nEnumerated the number of issues incorporated into:\n\nEach relevant section of the label – Issues per labeling update\n\nSource: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]\n\n3", "n_tokens": 93, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-3-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 3, "text": "Results\n\n278 NMEs approved between October 1, 2002 and December 31, 2014.\n\n1 safety withdrawal • 195 (70.1%) with ≥ 1 safety outcome • 83 (29.9%) no safety related label change or withdrawal\n\nSource: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]\n\n4", "n_tokens": 85, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-4-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 4, "text": "Results\n\nSource: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]\n\n5", "n_tokens": 39, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-5-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 5, "text": "Hierarchical presentation of time to drug label updates for NMEs by section of the label updated as of December 31, 2015\n\n13 12\n\n) s r a e y n i ( p u - w o\n\n11 10\n\n9\n\n8\n\n7\n\nl l\n\no f\n\n6\n\nf o h t g n e L\n\n5\n\n4\n\n3 2\n\n1\n\n2014\n\n2013\n\n2012\n\n2011\n\n2010\n\n2009\n\n2008\n\n2007\n\n2006\n\n2005\n\n2004\n\nYear of approval (CY)\n\nSource: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]\n\n2003\n\n2002\n\n6", "n_tokens": 119, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-6-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 6, "text": "Average number of label updates per year of follow-up\n\n1 r 4\n\na e y\n\nr e p s e t a d p u\n\nl\n\ne b a\n\nl\n\nf o r e b m u N\n\n3 0.5\n\n2 0\n\n~ ~\n\n1.1 1 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 -0.1 Range 0 n\n\n0- 1 2\n\n0-4 2 248\n\n0- 3 3\n\n0-3 0-2 0-2 4 7 10 190 76 Follow-up period (in years)\n\n0-4 5 166\n\n0- 6 3\n\n0-4 8\n\n0- 9 3\n\n0-2 11 57\n\nMean Median Upper IQR Lower IQR Range (Low-High)\n\n0- 12 2\n\n0-1 13 6\n\nRange n\n\n0-4 0-4 109 248 Source: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]\n\n0-2 278\n\n0-3 221\n\n0-3 190\n\n0-2 131\n\n0-4 166\n\n0-3 147\n\n0-3 93\n\n0-2 76\n\n0-2 57\n\n0-2 27\n\n0-1 6\n\n7", "n_tokens": 261, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-7-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 7, "text": "Average number of issues per year of follow-up\n\nSource: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]\n\n8", "n_tokens": 48, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-8-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 8, "text": "ew U.S. FOOD & DRUG\n\nADMINISTRATION\n\nAdverse Event Data", "n_tokens": 13, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-9-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 9, "text": "FDA Adverse Event Reporting System (FAERS)\n\n*2018 data through 20 November 2018\n\n10", "n_tokens": 17, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-10-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 10, "text": "ew U.S. FOOD & DRUG\n\nADMINISTRATION\n\nSentinel", "n_tokens": 11, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-11-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 11, "text": "FDA Sentinel System\n\nNational medical product monitoring system • 17 data partners with 178 million members with pharmacy and medical coverage\n\nDistributed system where data partners retain physical control of data to protect privacy and security\n\nwww.sentinelinitiative.org/\n\n12", "n_tokens": 46, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-12-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 12, "text": "Analysis in Sentinel’s Distributed Data Network\n\n1- User creates and submits query (a computer program)\n\n2- Data partners retrieve query\n\n3- Data partners review and run query against their local data\n\n4- Data partners review results\n\n2\n\n5\n\n5- Data partners return results via secure network\n\n6- Results are aggregated\n\n13", "n_tokens": 63, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-13-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 13, "text": "ARIA is Comprised of Modular Programs\n\nLevel 1 Descriptive Analyses, Unadjusted Rates\n\nLevel 2 Adjusted Analyses with Sophisticated Confounding Control\n\nLevel 3 Sequential Adjusted Analyses with Sophisticated Confounding Control\n\n14", "n_tokens": 40, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-14-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 14, "text": "https://www.nejm.org/doi/full/10.1056/NEJMp1809643\n\n15", "n_tokens": 29, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-15-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 15, "text": "Just as the Sentinel Initiative looks very different today than it looked 5 years ago, in 5 to 10 years the system will have improved capabilities and will use new data sources and methods.\n\nhttps://www.nejm.org/doi/full/10.1056/NEJMp1809643\n\nThe Sentinel Initiative can become a critical component of the FDA’s implementation of its mandates under the 21st Century Cures Act by providing data and expertise to support the incorporation of real- world data into regulatory decision making in other areas in addition to safety assessments.\n\n16", "n_tokens": 116, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-16-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 16, "text": "Sentinel Strategic Plan\n\nVISION\n\nA sustainable national resource to monitor the safety of marketed medical products, and expand Real- World Data sources used to capture medical product performance\n\nSTRATEGIC OBJECTIVES\n\nAccelerate use of the Sentinel System within FDA and scale capabilities to meet needs\n\nIncrease the utility of Real- World Data to accelerate drug development and assess medical product performance\n\nMeet legislative mandates regarding medical product safety and effectiveness\n\nFacilitate use by other stakeholders and foster innovation & development\n\nSTRATEGIC AIMS\n\nEnhance the foundation of the Sentinel System (data, infrastructure, operations, technology)\n\nFurther enhance safety capabilities by leveraging advances in data science and signal detection\n\nAccelerate access to and broader use of Real-World Data\n\nCreate a national resource and further open the Sentinel System by broadening the Sentinel user base\n\nDisseminate knowledge and advance regulatory science to meet Agency scientific needs\n\n17", "n_tokens": 156, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-17-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 17, "text": "70\n\nSentinel ARIA Analyses (N=256)\n\n60\n\n1 6\n\n50\n\n40\n\n30\n\n1\n\n3\n\n1\n\n2\n\n56\n\n20\n\n10\n\n15\n\n15\n\n2\n\n12\n\n3 4\n\n12\n\n10\n\n16\n\n15\n\n16\n\n16\n\n16\n\n10\n\n0\n\nQ1\n\nQ2\n\nQ3\n\nQ4\n\nQ1\n\nQ2\n\nQ3\n\n2016\n\n2016\n\n2016\n\n2016\n\n2017\n\n2017\n\n2017\n\nSummary Table\n\nLevel 1\n\nLevel 2\n\nLevel 3\n\nFrom all FDA Centers, by date of distribution to Data Partners\n\n3\n\n19\n\n0 Q4\n\n2017\n\n18", "n_tokens": 85, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-18-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 18, "text": "1\n\nDanijela Stojanovic\n\n2\n\nLiz Suarez\n\n3\n\nSusan Andrade\n\nNew Mother- Infant Linkage\n\nNew ICD-10 Gestational Age Algorithm\n\nValidation of ICD-10 Stillbirth Algorithm\n\nhttps://www.sentinelinitiative.org/communications/sentinel-initiative-events/drug-safety-pregnancy-large-multisite-database-advances\n\n4\n\nDavid Martin\n\nOpen Source Mobile App for Data Collection\n\n19", "n_tokens": 88, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-19-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 19, "text": "https://www.fda.gov/NewsEvents/Newsroom/FDAInBrief/ucm625228.htm https://www.fda.gov/Drugs/ScienceResearch/ucm624785.htm https://github.com/PopMedNet-Team/FDA-My-Studies-Mobile-Application-System\n\n20", "n_tokens": 85, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-20-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 20, "text": "www.fda.gov\n\nFDA My Studies\n\nMobile App\n\nStandard frameworks - ResearchKit (iOS), ResearchStack (Android)\n\nGateway capability\n\nWeb-based configuration portal Secure Storage Environment • – FISMA complaint – Partitioned for distributed research – Responses can be downloaded in broadly compatible formats (e.g., for use in SAS, Excel, etc.)\n\n21", "n_tokens": 73, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-21-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 21, "text": "Signal Detection Approaches Available in Sentinel\n\nPre-Specified Panel of Select Outcomes Prospective sequential surveillance tool (Level 3)\n\nOne Product, All Outcomes TreeScan\n\nOne Outcome, All Products DrugScan\n\nAll Products, All Outcomes No existing tool in Sentinel\n\n22", "n_tokens": 46, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-22-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 22, "text": "Proposed Sentinel Signal Identification Process\n\nIntegrated Safety Summary\n\nClinical Trial Data\n\nPrescribing Information\n\nSignal identification led by Divisions of Pharmacovigilance and Sentinel Program Team\n\nFollow up investigations to be conducted by Divisions of Epidemiology\n\n1 2 3 4 5\n\nSelect 1 product\n\nChoose study design(s) or tool\n\nConduct analysis\n\nReview and classify statistical alerts\n\nIntegrate results with other sources of information\n\nIdentify Outcome for Further Evaluation (if any)\n\n23", "n_tokens": 86, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-23-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 23, "text": "Advancing the Sentinel System\n\n• •\n\nExplore opportunities to leverage advances in machine learning, natural language processing, artificial intelligence Expand the Sentinel Common Data Model Enhance existing data sources, particularly with electronic health records\n\nhttps://healthpolicy.duke.edu/events/improving-efficiency-outcome-validation-sentinel-system https://healthpolicy.duke.edu/events/public-webinar-planned-next-steps-advance-sentinel-system\n\n24", "n_tokens": 98, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-24-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 24, "text": "FDA's Sentinel Initiative - News and Events\n\nf SHARE = WOTWEET) in LINKEDIN @ PINIT) S% EMAL & PRINT\n\nFDA is committed to an open public process that will enable information to be disseminated and stakeholder\ncontributions to be gathered as it explores the scientific, technical, and policy issues that will affect the Sentinel\n\nSystem's development.\nSign up for E-mail Updates\n\nUpcoming Events\nEleventh Annual Sentinel Initiative Public Workshop\n\nThe Sentinel Initiative was launched in response to the Food and Drug Administration Amendments Act of\n2007 (FDAAA) and is comprised of several components including the Sentinel Systeme, the Active Risk\nIdentification and Analysisg, the Biologics Effectiveness and Safety System (BEST IDIQ #1, BEST IDIQ #2)\nand FDA Catalystg. The Food and Drug Administration (FDA) is committed to facilitating stakeholder\nengagement on approaches to modernize the Sentinel Initiative’s capabilities. The Annual Public Workshop\nis a gathering of the Sentinel community and leading experts to share recent developments within the\nSentinel Initiative, provide training on Sentinel System’s tools and data infrastructure, and promote\nengagement and collaboration with patients, industry, academia, and consumers. This year marks the\nEleventh Annual Sentinel Initiative Public Workshop and will be a two-day event. Please note that there are\nseparate registrations for each day of the meeting and there are two different locations for Days 1 and 2.\nDay 3 is by invitation only for international regulators.\n\nhttps://www.fda.gov/Safety/ucm149341.htm\n\n25", "n_tokens": 311, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-25-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 25, "text": "Sentinel Annual Meeting | Day 1\n\nDAY 1 | Sentinel Initiative Public Workshop, April 3, 2019\n\nRegistration: Open to everyone. Please register through this Duke Margolis linkgp.\nLocation: Hyatt Regency Bethesda\n\n1 Bethesda Metro Center\n\nBethesda, MD 20814\n\nAgenda and Details: Day 1 will be convened by the Robert J. Margolis, MD, Center for Health Policy at\nDuke University under a cooperative agreement with FDA. The workshop will feature updates on how the\nSentinel Initiative is being used by FDA as a core safety surveillance program from leaders at FDA and from\ninvestigators within the Sentinel Initiative. Discussion will also highlight strategic initiatives and potential\nfuture directions for continued improvements to the distributed data infrastructure. There will be opportunities\nthroughout the day’s discussion for stakeholders to provide input and ask questions.\n\n26", "n_tokens": 163, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-26-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 26, "text": "Sentinel Annual Meeting | Day 2\n\nDAY 2 | Sentinel System Analysis Tools Training: Hands-On Workshop, April 4, 2019\n\nLocation: FDA White Oak Campus\n\n10903 New Hampshire Avenue\n\nBuilding 31, Room 1503 A (the Great Room)\nSilver Spring, MD 20993\n\nAgenda and Details: Day 2 will be the third public training sponsored by FDA and the Sentinel Operations\nCenter targeting researchers who have prior experience executing epidemiologic analyses with claims data\nusing SAS statistical packages and programming. Registrants are expected to have either attended the prior\nSentinel Public Training Events held in July 2017 (Part 1)@ and February 2018 (Part 2) or viewed the\nrecorded contents online prior to attending. This workshop will build on these prior trainings using a hands-\non laboratory format. Attendees should bring a laptop to the training to participate. Due to the interactive\nnature of the training, no online participation will be available.\n\n27", "n_tokens": 184, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-27-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 27, "text": "ew U.S. FOOD & DRUG\n\nADMINISTRATION\n\nRisk Evaluation and Mitigation Strategies", "n_tokens": 17, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-28-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 28, "text": "Development of a Shared System REMS\n\nThis draft guidance is meant to enhance clarity and transparency of the development process for shared system REMS, specifically it:\n\nProvides recommendations for industry on the development of a shared system REMS for multiple prescription drug products, including biological products\n\nProvides information about the benefits of shared system REMS\n\nDescribes situations in which a shared system is not required under the statute, but the Agency may encourage manufacturers to develop one to reduce burden on the healthcare system\n\n29", "n_tokens": 93, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-29-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 29, "text": "Waivers of the Single, Shared System REMS Requirement\n\nThis guidance is meant to provide clarity to help alleviate the delays in ANDA approvals that can be caused by prolonged negotiations over the development of a single, shared system REMS, specifically it:\n\ndescribes the factors FDA will consider in evaluating a request for a waiver of the single, shared system requirement\n\nprovides recommendations to ANDA applicants regarding the submission and content of waiver requests\n\naddresses the requirement that any separate system use a different, comparable aspect of the ETASU\n\n30", "n_tokens": 103, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-30-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 30, "text": "FDA issued its report on the use of accredited CE as a method to implement HCP education under a REMS\n\nPart of the REMS Integration Initiative\n\nFDA looked at the feasibility of using Continuing Education for individual REMS\n\nReport concluded that CE can be a useful too to implement HCP education: – Will likely require FDA to provide a blueprint which serves as the basis for the content of the education – More practically implemented in the postapproval setting\n\n31", "n_tokens": 90, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-31-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 31, "text": "FDA REMS Resources Portal\n\nLaunched in 2018 in response to stakeholder requests for easier access and to improve their understanding of REMS\n\n32", "n_tokens": 26, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-32-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 32, "text": "Navigating Within the Portal\n\n“Landing page”\n\n“Navigation Bar”\n\n“Key HCP Pages”\n\n33", "n_tokens": 21, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-33-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 33, "text": "ew U.S. FOOD & DRUG\n\nADMINISTRATION\n\nMedication Error Prevention Program", "n_tokens": 14, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-34-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 34, "text": "Contents of a Complete Submission for Threshold Analyses and Human Factors Submissions\n\nDraft issued in September 2018\n\nDescribes to industry and FDA staff the contents of and submission procedures for threshold analyses and human factors submissions that will support efficient Agency review, and presents timelines for FDA’s review of such submissions.\n\n35", "n_tokens": 57, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-35-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 35, "text": "Phonetic Orthographic Computerized Analysis (POCA) Database Update\n\nFirst released to public in Spring 2009 as a search tool to identify similar drug names – Assigns similarity scores – Searches databases listing approved product names and internal databases\n\nlisting proposed proprietary names*\n\nFDA has adapted the POCA tool to include a database of suffixes that are incorporated within the nonproprietary name of approved biological products.\n\nThe new features of the POCA enable reviewers to\n\ncompare a suffix candidate to drug names (brand or established names) to avoid the suffix candidates that are too similar to other drug names, or – conduct target comparisons of suffix candidates to the suffix component of biological nonproprietary names.\n\n*proposed proprietary name and biological product suffix listings are only available to FDA - not the public\n\n36", "n_tokens": 155, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-36-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 36, "text": "ew U.S. FOOD & DRUG\n\nADMINISTRATION\n\nPrescription Opioid Abuse", "n_tokens": 15, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-37-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 37, "text": "Source: https://www.cdc.gov/drugoverdose/pdf/pubs/2018-cdc-drug-surveillance-report.pdf\n\n38", "n_tokens": 33, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-38-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 38, "text": "Opioids\n\nAnother busy year! • Seven of nine Drug Safety and Risk Management Advisory Committee meetings 2018 concerned opioids\n\nIncreasing public health focus\n\n39", "n_tokens": 29, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-39-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 39, "text": "pioids REMS\n\nU.S. Department of Health and Human Services\n\nyy U.S. FOOD & DRUG\n\nADMINISTRATION\n\nMedical Devices\n\nFood | Drugs\nNews & Events\n\nHome > News & Events > Newsroom > Press Announcements\nFDA News Release\n\nFDA takes important steps to encourage\nappropriate and rational prescribing of opioids\nthrough final approval of new safety measures\ngoverning the use of immediate-release opioid\nanalgesic medications\n\nToday’s action places immediate-release opioid analgesic drugs intended for use in an outpatient\nsetting into agency’s Opioid Analgesic Risk Evaluation and Mitigation Strategy\n\nfisware TWEET im UNKEDIN, @ PINT BB EMAL |B PRINT\n\nFor Immediate September 18, 2018\nRelease\n\nAtoZ index\n\nRadiation-Emitting Products | Vaccines, Blood & Biologics | Animal & Veterinary | Cosmetics\n\nFollow FDA | En Espafol\n\nTobacco Products\n\nInquiries\n\nMedia\n\n© Lyndsay Meyer\n240-402-5345\n\n© Michael Felberbaum\n240-402-9548\n\nDepartment of Health and Human Services\n\nPayl U.S. FOOD & DRU dex | Flom FDA | En Espa\n\nADMINISTRATION\n\nMedical Devices\n\nRadiation-Emiting Products | Vaccines, Blood & Biologics | Animal & Veterinary | Cosmetics | Tobacco Products\n\nDrugs\n\nHome > Drugs > Drug Safety and Availabilty > Information by Drug Class\n\nOpioid Analgesic Risk Evaluation and Mitigation\nStrategy (REMS)\n\nf sure | WoTWeET im UNKEOIN @ PIT BBEWAL & PRINT\n\nExtended-release. long-acting (ER/LA). and immediate-\nrelease (IR) opioid analgesics, such as hydrocodone,\noxycodone, and morphine, are powerful pain-reducing\nmedications that have both benefits as well as potentially\nserious risks. The FDA has determined that a REMS is,\nnecessary for all opioid analgesics intended for outpatient use\nto ensure that the benefits of these drugs continue to\noutweigh the risks. The Opioid Analgesic REMS, approved on\nSeptember 18, 2018, is one strategy among multiple national\nand state efforts to reduce the risk of abuse, misuse,\naddiction, overdose, and deaths due to prescription opioid\nanalgesics\n\n40", "n_tokens": 462, "kind": "text"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-40-0", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 40, "text": "mY U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-0-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 0, "text": "CDISC-SEND COMMON ISSUES AND CDER POLICY UPDATES\n\nJesse Anderson, MPH Program Manager, OCS\n\nStephanie Leuenroth-Quinn, PhD Pharmacologist, OND\n\nJennifer Feldmann Contractor, OCS\n\nPatricia Brundage, PhD Pharmacologist, OND\n\nJune 15, 2020\n\n1", "n_tokens": 62, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-1-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 1, "text": "PART I: COMMON ISSUES WITH CDISC-SEND DATA\n\nJesse Anderson, MPH Program Manager, KickStart Service Office of Computational Science Center for Drug Evaluation and Research U.S. Food and Drug Administration\n\nJen Feldmann SEND Subject Matter Expert IBM Contractor for the Office of Computational Science\n\nwww.fda.gov\n\n2", "n_tokens": 62, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-2-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 2, "text": "Today’s Topics\n\nSEND at the FDA\n\nCommon SEND Data Fitness Issues\n\nFDA Communication on SEND\n\n3", "n_tokens": 18, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-3-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 3, "text": "It All Starts with SEND\n\nKey Concepts\n\n1. Carcinogenicity, single-dose and repeat-dose toxicity, and cardiovascular and respiratory safety pharmacology currently covered by SENDIGv3.0 and SENDIGv3.1 in the FDA Data Standards Catalog.\n\n2. SEND should present nonclinical data in a consistent and predictable manner.\n\n3. SEND allows exploration of study data and automated creation of tables and graphs.\n\n4. Use of SEND electronic data is a process change for the reviewer community within a short timeline for many submissions.\n\n5. OCS KickStart service and resources support reviewer use of SEND electronic data.\n\n4", "n_tokens": 130, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-4-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 4, "text": "Nonclinical Regulatory Review\n\nGero\n\nidation Rules\neCTD Submission\n\nStudy Data Validation Rules\n\nBetter Data | Better Tools | Better Decisions\n\nwww.fda.gov 5", "n_tokens": 33, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-5-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 5, "text": "Applications Received with SEND\n\nIND\n\nNDA/BLA\n\n600\n\n500\n\n493\n\n400\n\n300\n\n200\n\n151\n\n100\n\n0\n\n21\n\n4\n\n22\n\n46\n\n2017\n\n2018\n\n2019\n\nNumber of Applications Per Calendar Year\n\nThe types of studies included Repeat-Dose Toxicity, Single-Dose Toxicity, and Carcinogenicity. FDA has received 735 applications with SEND data during this time period.\n\n6", "n_tokens": 69, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-6-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 6, "text": "Janus Nonclinical\n\nKey Concepts\n\n1. Janus Nonclinical is a database and system that allows reviewers to use SEND datasets for their reviews\n\n2. Every SEND study received in an application goes through Janus loading process automatically\n\n3. More than 1,740 studies loaded as of Dec. 2019\n\n4. Reviewers may request a Kickstart Service to help them with their application in Janus Nonclinical consisting of:\n\nOne-on-one training\n\nData Fitness Analysis\n\nHelp with study data exploration and analysis\n\n5. Reviewers may also receive support from the Office of Computational Science (OCS) Service Desk\n\n7", "n_tokens": 125, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-7-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 7, "text": "SEND Studies in Janus Nonclinical\n\n225\n\ns u n a J n\n\ni\n\nd e d a o L\n\ns e d u t S\n\ni\n\nl\n\na c n\n\ni\n\ni l\n\nc n o N\n\n200\n\n175\n\n150\n\n125\n\n100\n\n75\n\n50\n\n25\n\n0\n\nStudies Loaded\n\n2017 33\n\n+\n\n2018 354\n\n+\n\n2019 1359\n\n=\n\nTotal in Janus 1740+\n\nApplications Loaded\n\n25\n\n+\n\n173\n\n+\n\n539\n\n=\n\n735+\n\n8", "n_tokens": 81, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-8-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 8, "text": "The KickStart Service\n\nKey Concepts\n\n1. KickStart is offered by OCS to all Pharm/Tox reviewers for their applications.\n\n2. Pre-KickStart Training includes overviews of:\n\nThe SEND Standard\n\nNonclinical Study Data Reviewers Guide (nSDRG)\n\nDefine.xml\n\nJanus Nonclinical features\n\n3. The KickStart Service covers:\n\nA data fitness assessment with sponsor report and details to reviewer for issues that impact use of data\n\nShows reviewers how to explore study data using Janus Nonclinical and how to produce tables and graphs that can be used in review documents\n\nPrepare graphs and tables for key analyses using Janus Nonclinical\n\n9", "n_tokens": 138, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-9-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 9, "text": "KickStart Services for Nonclinical Review Applications Through End of December 2019\n\nIND\n\nNDA/BLA\n\n40\n\n38\n\n30\n\n22\n\n20\n\n10\n\n6\n\n7\n\n7\n\n0\n\n0\n\n2017\n\n2018\n\n2019\n\nwww.fda.gov\n\nCalendar Year Counts Kickstart service provided when: • Study loaded into Janus Nonclinical • Reviewer requests service One or two studies per application generally reviewed\n\n10", "n_tokens": 74, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-10-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 10, "text": "Studies Included in KickStart Applications Through End of December 2019\n\nStudy Type\n\nSpecies\n\n5\n\n3 2\n\n12\n\n11\n\nRepeat Dose Tox\n\nSingle Dose Tox\n\n26\n\nCarcinogenicity\n\n107\n\n33\n\nTest Facility Countries\n\nTest Facility Organizations\n\n2 1\n\n6\n\n8\n\n5\n\nUS\n\n6\n\nCanada\n\n9\n\nChina\n\nJapan\n\nUK\n\n21\n\n74\n\nGermany\n\nDemark\n\nItaly\n\nwww.fda.gov\n\n116\n\n49\n\nRat\n\nMonkey\n\nDog\n\nMouse\n\nMinipig\n\nRabbit\n\nCRO\n\nSponsor\n\n11", "n_tokens": 78, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-11-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 11, "text": "Pre-KickStart Training\n\nFor first KickStart service, the KickStart team provides reviewers with general training on the SEND topics, including: – Domains – Controlled Terminology – Overview of the nSDRG – Introduction to the define file – Introduction to Janus Nonclinical\n\nTraining\n\nData Fitness\n\nTraining and Resources\n\nwww.fda.gov\n\n12", "n_tokens": 69, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-12-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 12, "text": "KickStart Data Fitness Assessment\n\nAutomated and manual review of SEND datasets and associated nSDRG and define.xml files – Verify compliance with standards and FDA rules/recommendations – Confirm and document data not submitted – Check consistency across study files and documents – Ensure summarizations included in study report can be reproduced Issues that affect data analysis are discussed with reviewer\n\n• Sponsor data fitness report details all issues identified\n\nTraining\n\nData Fitness\n\nTraining and Resources\n\nwww.fda.gov\n\n13", "n_tokens": 92, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-13-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 13, "text": "KickStart Data Exploration Session\n\nInteractive look at the best way to interact with application study data using Janus Nonclinical\n\nShow tables and graphs from key domains with findings aligned with study report when possible\n\nProvide outputs may be used as part of application review documents\n\nTraining\n\nData Fitness\n\nStudy Data Exploration\n\nwww.fda.gov\n\n14", "n_tokens": 63, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-14-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 14, "text": "KickStart Timeline Overview\n\nDay 0\n\nApplication received,\nuploaded to Janus\nNonclinical. Reviewer\nrequests service.\n\nData Quality Assessment\nDays 0 to5\n\nSafety\n\nSEND and Janus Nonclinical Training\n\nScheduled between Days 3 and 5\n\nwww.fda.gov\n\nFDA\n\nDay5\n\nData Fitness Service\nRepeat customers\n\nDay 6\nFull KickStart Service\n\nFirst-time customers\n\nMaterials delivered: Materials delivered:\n\n=> Consult Response =» Consult Response\n\n=» Data Fitness Summaries =» Data Fitness Summaries\n\n=> Sample Safety Analysis Outputs\n\nAnalysis Outputs\nDays 4 to 6\n\nPre-KickStart Training\n\nFirst-time customers\n\nMaterials delivered:\n\n@> Janus Nonclinical User Guide\n=> SEND Terminology Guide\n\n=» Link to OCS Learning Catalog\n\n15", "n_tokens": 147, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-15-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 15, "text": "SEND Study Package Issues for Discussion\n\nDefine.xml\n\nSubmission Files, File Naming, StudyName Attribute\n\nISO8601 Values\n\nDates, Date/Times, Durations\n\nStandardization of Timing Variables\n\nVISITDY/--NOMDY, timing relative to dose, unscheduled tests\n\nCategorical Results\n\nLBSTRESN and the FDA Study Data Technical Conformance Guide\n\nReplacement Values for Results Outside Limit of Quantitation\n\nSubmission of --CALCN\n\nCodes and Abbreviations\n\nImpact on reviewers when these are undefined", "n_tokens": 97, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-16-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 16, "text": "File Naming – define.xml\n\nUse “define.xml” • Required stylesheet name is included in the define.xml file: xml-stylesheet type=\"text/xsl\" href=\"define2-0-0.xsl”\n\nSome incorrect naming seen….\n\nSome older stylesheets also reference define.css\n\nSubmit the files in the study tabulation/send folder with the datasets\n\ndefine.xml enables loading of data into Janus Nonclinical\n\n17", "n_tokens": 102, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-17-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 17, "text": "Example SEND Package • define.xml and\n\nreferenced stylesheet\n\nSEND dataset files follow naming convention in SENDIG\n\nnsdrg.pdf\n\nAll files in the same folder\n\n18", "n_tokens": 34, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-18-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 18, "text": "Define.xml StudyName\n\nStudy Data Technical Conformance Guide\n\nStudyName at FDA In 44% of studies reviewed by Kickstart in calendar 2019, StudyName does not conform to the Technical Conformance Guide\n\nStudyName identifies the study in the SEND files to Janus Nonclinical\n\nStudyName, when aligned with the eCTD submission study identifier, gives a reviewer a consistent identifier for the study\n\n• StudyName may need to be updated by sponsor prior to submission\n\n19", "n_tokens": 97, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-19-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 19, "text": "ISO 8601 Values\n\nISO 8601 format in SEND – Dates and/or Times – Intervals and Durations of Time\n\nCertain domain variables use ISO 8601 format • Some TS/TX Parameters use ISO 8601 format for –VAL • SENDIG indicates when ISO 8601 format is used\n\nInclude only ISO 8601 formatted text when the SENDIG indicates that this format is used and no other formats.\n\n20", "n_tokens": 80, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-20-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 20, "text": "Common Data Fitness Issues\n\nAnalysis of Kickstart Data Fitness Results for 68 studies in 45 applications in calendar 2019 identified a number of key themes:\n\nIncorrect reporting of timing variables needed for summarization and analysis of results • Incorrect reporting of categorical data • Omission of the numeric value to use in calculations as\n\na replacement for a text result\n\nUndefined codes/abbreviations included in datasets\n\nwww.fda.gov\n\n21", "n_tokens": 86, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-21-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 21, "text": "Common Issues with Standardization of Timing Variables\n\nPlanned/nominal day does not align data with the study report summary\n\nIncorrect reporting of timing for tests or observations scheduled relative to dose\n\nIncorrect reporting of result from unscheduled tests or observations.\n\nwww.fda.gov\n\n22", "n_tokens": 51, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-22-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 22, "text": "VISITDY/--NOMDY Used for Analysis\n\nExample: Study Schedule indicates each animal has two sample collections: One pretest and one at the conclusion of dosing. Sponsor reported actual collection day in VISITDY. Reviewer must adjust days prior to use of data in summary analyses.\n\nPretest\n\nPost Dose\n\n23", "n_tokens": 62, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-23-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 23, "text": "VISITDY/--NOMDY and –ELTM Use for Analysis\n\nExample: Sponsor reported sample collection day in VISITDY when samples collected at times relative to dose. Tabular data is therefore mislabeled; graphs of results relative to dose do not include data for timepoints > 24 hrs post dose\n\nDay 1 24hr\n\n24", "n_tokens": 68, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-24-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 24, "text": "Timing Relative to Dose\n\nElapsed Time --ELTM\n\nuses ISO8601 duration format – describes amount of time relative to the dose event\n\nTime Point Reference --TPTREF\n\nDescription of the dose event that the elapsed time –ELTM is relative to\n\nConsider the dosing regimen for the study in --TPTREF\n\nFor timed infusion, inhalation, or other dosing over time, include whether elapsed time is relative to start or end of the dose\n\nFor multiple doses per day, include which dose the elapsed time is relative to\n\nFrom the SENDIG: It is recommended that --TPTREF be as descriptive as possible so the reference time point can be inferred without looking at other variables.\n\n25", "n_tokens": 155, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-25-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 25, "text": "Timing Relative to Dose\n\nExample: 1 hr infusion, twice per day. Sample collection 2 hrs after start of 1st infusion day 1 and 2 hrs after start of 2nd infusion day 28.\n\nUse --ELTM=PT2H to represent 2 hours post dose\n\nCommon issue: --TPTREF is not specific to the specific dose during the day or to the start/end of the dose .\n\nFor example if --TPTREF is “Day 1 Dose” and “Day 28 dose” --ELTM and --TPTREF together would not match the study report: “2 hours after Day 1 Dose” and “2 hours after Day 28 Dose”\n\nBe specific in --TPTREF: “Start of 1st Day 1 Dose” and “Start of 2nd Day 28 Dose”\n\nFrom the SENDIG: It is recommended that --TPTREF be as descriptive as possible so the reference time point can be inferred without looking at other variables.\n\n26", "n_tokens": 206, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-26-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 26, "text": "Unscheduled Tests/Observations • Results from unscheduled tests or observations are generally\n\ntabulated separately in the study report tables. In SEND, for an unscheduled test result or observation: – SENDIG 3.0, VISITDY with no value identifies an unscheduled result – In SENDIG 3.1, --USCHFL=“Y” identifies an unscheduled result\n\nCorrect flagging of unscheduled results in SEND allows reviewer to align results with study report. – Unscheduled data can be included/excluded – Using only text variables to label unscheduled results is not sufficient\n\n27", "n_tokens": 132, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-27-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 27, "text": "Data Fitness Issues with Reporting of Categorical Test Results\n\nSeen in the Laboratory Test Results (LB) dataset • Issue with including LBSTRESN for categorical results – Refer to the FDA Technical Conformance Guide, section 4.1.3.3\n\nSEND has no specific flag for categorical results – Define-xml value-level metadata inconsistently reported – Janus attempts to identify non-numeric tests using LBSTRESN\n\nwww.fda.gov\n\n28", "n_tokens": 91, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-28-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 28, "text": "Example Incidence Counts for LB in Janus\n\nTests with no LBSTRESN reported with summary incidence counts in Janus Nonclinical\n\nwww.fda.gov\n\n29", "n_tokens": 32, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-29-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 29, "text": "Example of Incorrect Standardization\n\nSemi-quantitative urine protein test are in SEND with the result range in LBSTRESC and with values incorrectly in LBSTRESN. This causes Janus Nonclinical to report means and standard deviations on those numeric results rather than incidence counts.\n\n30", "n_tokens": 56, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-30-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 30, "text": "Data Fitness Issues with Character Replacement Values\n\nSponsor omitted character replacement values for use in PC or LB summary calculations in approximately half the studies reviewed: – Most commonly missing for plasma concentration results reported in the PC dataset.\n\nShould be reported in SUPP-- dataset, with --CALCN in the\n\nQNAM variable and the replacement value in QVAL. • For example SUPPPC would have entries with PCCALCN. • Use of group mean results supplied in study report is impaired when replacement values are not submitted.\n\nwww.fda.gov\n\n31", "n_tokens": 112, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-31-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 31, "text": "Example: LBCALCN Not Supplied\n\nStudy Report indicates that half of LLOQ is used for results <1.0. LBCALCN not supplied so results <1.0 eliminated from mean in FDA Tools\n\n32", "n_tokens": 45, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-32-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 32, "text": "Undefined Code/Abbreviations included in the Dataset\n\nAlmost 50% of studies have codes/abbreviations in the SEND datasets in variables where they are not expected. – Frequently without a definition – For some studies, the nSDRG notes generally that abbreviations are defined in the study report.\n\nCodes and abbreviations have been seen as result values, in reason fields, as finding modifiers and in comments.\n\nUndefined unit abbreviations (not part of the published UNIT codelist) have also been submitted.\n\nwww.fda.gov\n\n33", "n_tokens": 110, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-33-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 33, "text": "www.fda.gov\n\nExamples of Undefined Code/Abbreviations\n\n34", "n_tokens": 14, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-34-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 34, "text": "Feb 2018\n\nSEND Data Quality Assessment\n\nRelative Number of Issues in SEND Datasets Per Study, Normalized, All Kickstart Studies\n\nJan 2019\n\nRelative Number of Issues in SEND Datasets Per Study, Calendar 2019 Only\n\nDec 2019\n\n35", "n_tokens": 46, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-35-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 35, "text": "Key Points\n\nFDA saw significant increase in number of studies containing SEND datasets in the past year\n\nFDA Pharm/Tox Reviewers transitioning to utilize SEND datasets alongside the study report\n\nComplete and correct SEND datasets are critical for seamless, confident use of SEND datasets by FDA reviewers\n\nSome common issues in a SEND dataset can complicate or even prevent FDA reviewers use of those SEND datasets\n\nThe FDA KickStart team identifies issues in SEND data to communicate with industry, identify trends, and help reviewers maximize use of their SEND datasets\n\n36", "n_tokens": 116, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-36-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 36, "text": "FDA SEND Communications\n\nHow We Communicate\n\n1. Responses to questions sent to eData@fda.hhs.gov\n\n2. Technical Conformance Guide Updates\n\n3. FDA Business Rule Updates\n\n4. Sponsor-Specific Study Data Fitness Reports\n\n5. PhUSE Presentations, Papers, and Posters\n\n•\n\nPhUSE US Connect PhUSE Computational Science Symposium (CSS)\n\n6. CDISC Collaborations\n\nCDISC-SEND Face-to-Face (F2F) Public Forums\n\n37", "n_tokens": 92, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-37-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 37, "text": "OND Responses to Common SEND Questions\n\nPatricia Brundage, PhD Pharmacologist\n\nStephanie Leuenroth-Quinn, PhD Pharmacologist\n\nU.S. Food and Drug Administration Center for Drug Evaluation and Research Office of New Drugs\n\nSBIA Webinar/ June 15, 2020", "n_tokens": 58, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-38-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 38, "text": "Purpose\n\nBased on feedback the Agency is receiving from industry (e.g., eData mailbox, conferences), responses to commonly asked questions have been prepared to increase communication and disseminate this information across a larger audience. Additional information has also been included to facilitate the understanding of SEND requirements for nonclinical submission to the Office of New Drugs (OND) and the Office of Biostatistics (OB).\n\n2", "n_tokens": 88, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-39-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 39, "text": "Outline\n\nCommonly asked Questions about SEND • SEND Requirements versus the Technical Rejection Criteria (including the simplified ts.xpt)\n\nwww.fda.gov\n\n3", "n_tokens": 29, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-40-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 40, "text": "COMMONLY ASKED QUESTIONS ABOUT SEND\n\nedata@fda.hhs.gov\n\n4", "n_tokens": 15, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-41-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 41, "text": "Q: Draft Versus Final Study Reports?\n\nA: SEND datasets are required when submitting a draft or final study report for study types modeled in an FDA supported SEND Implementation Guide (SENDIG) version.\n\nDRAFT REPORT\n\nRegulatory Decisions for Clinical Development\n\nFINAL REPORT\n\nREVIEW\n\n5", "n_tokens": 53, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-42-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 42, "text": "Q: SEND for Safety Pharmacology & SENDIG v3.1?\n\nA: For cardiovascular and respiratory test results collected during safety pharmacology studies or other study types that are modeled in SENDIG version 3.1, SEND datasets are required for studies initiated after March 15, 2019 for NDA/BLAs or after March 15, 2020 for commercial INDs. In vitro cardiovascular studies are not currently modelled in SEND.\n\nIn Vivo Cardiovascular Safety Pharmacology Study\n\nRespiratory Safety Pharmacology Study\n\nRepeat Dose Study with Cardiovascular and/or Respiratory Data\n\n6", "n_tokens": 117, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-43-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 43, "text": "Q: FDA Support for SENDIG-DART?\n\nA: SENDIG-DART (Developmental and Reproductive Toxicology) version 1.1, which models embryo-fetal development studies, is NOT currently on the FDA Data Standards Catalog. New study data standards (e.g., SENDIG-DART v1.1 ) will be required for studies started 24 months after the publication of a Federal Register notice (FRN) announcing FDA support of the standard and placement on the FDA Data Standards Catalog.\n\n7", "n_tokens": 101, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-44-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 44, "text": "Q: SEND for Juvenile Animal Studies?\n\nA: Although dedicated juvenile studies are out of scope for SENDIG v3.0 and v3.1, SEND is required for repeat dose toxicology studies using standard toxicity endpoints in juvenile animals (reflected in the age of the animal at study initiation).\n\n26-Week Toxicity Study in Juvenile Rats\n\n4.2.3.2\n\nDedicated Juvenile Toxicity Study in Rats\n\n4.2.3.5.4\n\nSEND Required\n\nREPEAT-DOSE TOXICITY\n\nSTUDIES IN WHICH THE OFFSPRING [JUVENILE ANIMALS] ARE DOSED AND/OR FURTHER EVALUATED\n\n8", "n_tokens": 115, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-45-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 45, "text": "Q: SEND for Animal Rule Studies?\n\nA: The Federal Register Notice was published announcing FDA support of the CDISC SDTM v1.8 & CDISC SENDIG-AR v1.0 on March 15, 2020. These new standards will be required in submissions to FDA effective March 15, 2022.\n\n9", "n_tokens": 66, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-46-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 46, "text": "Q: Study Data Standardization Plan (SDSP) Use?\n\nA: The SDSP is used during development to communicate the intent to submit SEND datasets for completed, ongoing, and planned studies. It allows for the identification of potential data standardization issues and timely discussion with the review division, if needed.\n\nIdeally it is provided in the early stages of the application and may be updated as clinical development progresses.\n\nIt can also be used to communicate the intended use of simplified ts.xpt files.\n\n10", "n_tokens": 100, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-47-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 47, "text": "Q: SEND for Non-GLP Studies? Non-GLP studies can be highly variable in content, study design, and purpose.\n\nExploratory\n\nThorough,\n\nwell-designed studies with standard toxicity endpoints and\n\nFew animals, multiple endpoints, information from higher dosing\n\nstudies,\n\nno control group, single or few endpoints\n\ngroup sizes\n\n(e.g., 2000-page study report)\n\nNot all non-GLP studies\n\nare the same\n\n11", "n_tokens": 92, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-48-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 48, "text": "Q: SEND for Non-GLP Studies?\n\nA: SEND facilitates the review process for any study report submitted. At this time, and as previously stated, for studies that are modeled in a supported SENDIG on the FDA Data Standards Catalog, SEND is required for GLP and non-GLP studies.\n\nCDER/OND is currently evaluating if certain non-GLP studies can be excluded from this requirement. Any future decision on this topic will be communicated in the Study Data Technical Conformance Guide (TCG).\n\n12", "n_tokens": 107, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-49-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 49, "text": "SEND REQUIREMENTS VERSUS THE TECHNICAL REJECTION CRITERIA\n\n13", "n_tokens": 8, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-50-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 50, "text": "745A (a) Binding Guidance\n\nRequires that submissions under section 505(b), (i), or (j) of the FD&C Act and submissions under section 351(a) or (k) of the Public Health Service Act (PHS Act) be submitted in electronic format specified by the Food and Drug Administration\n\nStandardized Study Data\n\nBinding Guidance: FDA policy on requirements for submission of standardized study data\n\nPublished December 17, 2014\n\nLists data standards supported and required by FDA in electronic submissions\n\nUpdated as needed\n\nDescribes how industry should submit\n\nstandardized study data in NDAs, BLAs, INDs and ANDAs\n\nUpdated twice per year\n\n14", "n_tokens": 128, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-51-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 51, "text": "Electronic Study Data Requirements\n\nFor CDER/OND, the following nonclinical study types are required to have SEND datasets as defined by study initiation date:\n\nSEND Requirement Dates for Nonclinical Studies Modelled in SEND (Studies started after these dates require SEND datasets) NDAs/BLAs December 17, 2016 (SENDIG v3.0)\n\nCommercial INDs December 17, 2017 (SENDIG v3.0)\n\nStudy Types Modelled in SEND\n\nSingle Dose Toxicity,\n\nRepeat Dose Toxicity, and Carcinogenicity Studies\n\nMarch 15, 2019 (SENDIG v3.1)\n\nMarch 15, 2020 (SENDIG v3.1)\n\nCardiovascular and Respiratory Safety Pharmacology Studies\n\nMarch 15, 2019 (SENDIG v3.1)\n\nMarch 15, 2020 (SENDIG v3.1)\n\nThe table reflects current SEND requirements on the date of this presentation (June 15, 2020).\n\n15", "n_tokens": 186, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-52-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 52, "text": "SEND Requirements, eCTD Structure, and the TRC\n\nSeq. 0001\n\nSEND Requirement (FDA Data Standards Catalog)\n\neCTD Structure (ICH M2)\n\nTRC Check (Initial Activation)*\n\nIND\n\nNonclinical Studies\n\n✓\n\nCNS Safety Pharm SSD = 3-19-2020\n\nCV Safety Pharm SSD = 3-19-2020\n\n4.2.1.3\n\nSafety Pharmacology\n\nX No\n\n✓\n\n1-Month Rat Toxicity SSD = 2-15-2015\n\n1-Month Dog Toxicity SSD = 5-10-2019\n\n4.2.3.2\n\nRepeat-Dose Toxicity\n\n✓ Yes Use simplified ts.xpt when appropriate\n\nRat Fertility and Early Embryonic Development SSD = 2-15-2015\n\n4.2.3.5.1\n\nFertility and Early Embryonic Development\n\nX No\n\n✓ = SEND required\n\nSSD = Study Start Date\n\n*Any future updates will be communicated in the TRC for Study Data and the sdTCG\n\n16", "n_tokens": 197, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-53-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 53, "text": "Enforcement of SEND Requirements: The Technical Rejection Criteria (TRC)\n\nAutomated Validation Process\n\nAdded to the existing eCTD validation criteria to enforce compliance with the SEND requirements for study types modeled in an FDA- supported SEND Implementation Guide (SENDIG) version.\n\nIndustry will be given a 90-Day notice prior to activation\n\nFor nonclinical studies, the Technical Rejection Criteria (TRC) will only apply to eCTD Modules 4.2.3.1 (single- dose toxicity), 4.2.3.2 (repeat-dose toxicity), and 4.2.3.4 (carcinogenicity) when initially activated.\n\n17", "n_tokens": 132, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-54-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 54, "text": "SEND Requirements and the TRC\n\nSEND Requirement timelines are SEPARATE from TRC activation and implementation timelines\n\nFDA Data Standards Catalog - Electronic Standardized Data Requirements - Lists Dates of Implementation\n\nTechnical Rejection Criteria Internal System for Study Validation - - Enforcement of the Data Requirements - Will check relevant eCTD Modules\n\n1-Month Rat Toxicity Study Study Start Date = 1-1-2019 REQUIRES SEND\n\nModule 4.2.3.2 Repeat Dose Toxicity\n\nTRC checks all studies submitted to a specific Module as outlined in the TRC for Study Data\n\nWhat is the SEND requirement based on study type and initiation date?\n\nWhere is this study submitted in eCTD format?\n\nIs a simplified ts.xpt needed based on TRC?\n\n18", "n_tokens": 142, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-55-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 55, "text": "Submission to Appropriate eCTD Modules\n\nRat Juvenile Animal Toxicity STF = pre-clinical-study-report At this time, there is NO SEND Requirement (Based on the FDA Data Standards Catalog)\n\nModule 4.2.3.5.4 (Studies in which the offspring (juvenile animals) are dosed and/or further evaluated) ✓ CORRECT eCTD Folder ✓ Not currently checked by Technical Rejection Criteria ✓ No need to include simplified ts.xpt\n\nModule 4.2.3.2 (Repeat-Dose Toxicity)\n\n! Incorrect eCTD Folder Would be subject to the Technical Rejection Criteria Validation Would require simplified ts.xpt or would not be accepted at the electronic gateway\n\nRefer to ICH M2 and ICH M4 for further information on eCTD structure\n\n19", "n_tokens": 154, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-56-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 56, "text": "USING THE SIMPLIFIED TS.XPT\n\n20", "n_tokens": 8, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-57-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 57, "text": "Nonclinical Submissions, eCTD Structure and SEND Requirements\n\n✓ = SEND required\n\n✓\n\n✓\n\n✓\n\nIND\n\nNonclinical Studies\n\nStudies that don’t require SEND What are these study reports?\n\nModule 4.2.3.2 Repeat Dose Toxicity (Subject to TRC Validation)\n\n14-Day Rat Toxicity Study Initiated 10-7-2016 (SEND not required by Study Initiation Date)\n\nExpert Pathologist Report (Text Based Document: No study initiation date)\n\nDraft Study Protocol (for Chronic Tox Study) (Text Based Document: No study initiation date)\n\n21", "n_tokens": 113, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-58-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 58, "text": "How will the TRC Identify Studies not Requiring SEND?\n\n28-Day Rat Toxicity SSD = Dec. 12, 2018 SEND Required ✓ Full ts.xpt ✓\n\n28-Day Rat Toxicity SSD = Feb. 2, 2015 SEND NOT Required SSD Prior to requirement\n\n4.2.3.2 Toxicology\n\nNeed Additional Machine Readable Information\n\nExpert Pathologist Report SSD = NA SEND NOT Required Text Based Document\n\nSimplified ts.xpt Explained in Study Data TCG & TRC for Study Data\n\nSSD = Study Start Date NA = Not Applicable\n\n22", "n_tokens": 111, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-59-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 59, "text": "Full and Simplified ts.xpt files\n\nFull ts.xpt\n\nAccompanies SEND datasets\n\nFollows published CDISC Standard\n\nIf a Full ts.xpt is submitted, a Simplified ts.xpt is not needed.\n\nSimplified ts.xpt • Used when SEND datasets are not required for\n\nsubmissions in Modules 4.2.3.1, 4.2.3.2 or 4.2.3.4\n\nNeeded when using a STF file tag of: o pre-clinical-study-report o legacy-clinical-study-report\n\nNeeded when using a STF file tag of: o pre-clinical-study-report o legacy-clinical-study-report\n\nSTUDYID\n\nTSPARMCD TSVAL\n\nStudy ID in STF STSTDTC\n\nyyyy-mm-dd\n\nTSVALNF\n\nSTUDYID\n\nTSPARMCD TSVAL\n\nTSVALNF\n\no study-report-body\n\nStudy ID in STF STSTDTC\n\n(Leave blank) NA\n\n23", "n_tokens": 202, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-60-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 60, "text": "Using the Simplified ts.xpt\n\nThe Agency encourages the use of simplified ts.xpt prior to the activation of Technical Rejection Criteria (TRC).\n\nInitial TRC activation will only include Modules 4.2.3.1, 4.2.3.2, and 4.2.3.4 (single-dose toxicity, repeat-dose toxicity and carcinogenicity)\n\nIf sponsors submit a simplified ts.xpt with safety pharmacology studies (Module 4.2.1.3) to accommodate internal practices or processes, it will not interfere with the submission. [Note: Upon initial activation, Module 4.2.1.3 will not be subject to the TRC.]\n\n24", "n_tokens": 146, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-61-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 61, "text": "Study Data TCG and TRC\n\nStudy Data Technical Conformance Guide (TCG) provides additional information on the TRC and the nonclinical use of the simplified ts.xpt\n\nSection 8.2.2: Support on Data Validation Rules\n\nExplains when and how to use the simplified ts.xpt for nonclinical submissions Provides link to free and open- source software for creating Simplified ts.xpt files\n\n25", "n_tokens": 86, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-62-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 62, "text": "Resources\n\nFor questions about submitting study data please contact: edata@fda.hhs.gov • Study Data Technical Conformance Guide (March 2020): https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources\n\nTechnical Rejection Criteria:\n\nhttps://www.fda.gov/industry/study-data-standards-resources/study-data-submission-cder- and-cber\n\nElectronic Common Technical Document (eCTD):\n\nhttps://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common- technical-document-ectd\n\nStandardized Study Data Guidance:\n\nGuidance for Industry, Providing Regulatory Submissions in Electronic Format — Standardized Study Data (PDF - 131 KB)\n\nWebinar: Most Common Issues with CDISC-SEND Data in FDA Toxicology Review (September 12, 2019): https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/kickstart\n\nWebinar: The FDA Study Data Technical Conformance Guide v4.4 (November 22, 2019): https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/sbia-webinars\n\n26", "n_tokens": 276, "kind": "text"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-63-0", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 63, "text": "That concludes the SBIA presentations. We are going to take a quick break to review the submitted questions and will begin answering them in a few minutes.\n\n27", "n_tokens": 31, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-0-0", "doc_id": "CDER_Update_Presentation", "page": 0, "text": "CDER Update\n\nJanet Woodcock MD Director, CDER, FDA December 5, 2017", "n_tokens": 17, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-1-0", "doc_id": "CDER_Update_Presentation", "page": 1, "text": "2017: Busy Year\n\nHigh levels of applications and approvals in many premarket programs\n\nImplementation of cures and reauthorized UFs • Ongoing opioid crisis • Increased emphasis on competition • Drug shortage exacerbation by hurricane activity\n\nContinuing implementation of DQSA", "n_tokens": 54, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-2-0", "doc_id": "CDER_Update_Presentation", "page": 2, "text": "2018 CDER Priorities (Preliminary)\n\nCenter-wide informatics implementation • Implement CURES legislation • Carry out reauthorized BSUFA, GDUFA, PDUFA and meet goals\n\nImprove hiring process (with OC) • Take multiple actions regarding opioid crisis • Further progress in regulating compounding • New drug regulatory program modernization • OTC monograph reform", "n_tokens": 74, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-3-0", "doc_id": "CDER_Update_Presentation", "page": 3, "text": "Center-wide Informatics\n\nReview platform fully operational in generics program\n\nWorking to implement for new drug review program this year\n\nHave put in place formal Center governance of informatics activities\n\nChallenging area: hope for improvements in work management, understanding capacity, knowledge management, data standardization\n\nMulti-year project, $$$", "n_tokens": 60, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-4-0", "doc_id": "CDER_Update_Presentation", "page": 4, "text": "21st Century Cures Implementation\n\nReal world evidence policy development • Patient-focused drug development • Drug development tools program • New hiring authorities • Antimicrobial drugs breakpoint information • Novel trial designs • Model-based drug development", "n_tokens": 44, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-5-0", "doc_id": "CDER_Update_Presentation", "page": 5, "text": "Real World Evidence\n\nIntend to publish Real-World Evidence framework as stipulated in legislation. Framework will describe the steps towards common understanding/utilization of such data • Working on harmonization of common data models and open standards for evidence development (with NIH and HHS/ONC); also collaboration with UCSF of source data capture from EHRs using standardized clinical research data\n\nOngoing demonstration projects\n\nIMPACT Afib – Study comparing outcomes of randomized clinical trials to RWE collected from claims databases", "n_tokens": 95, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-6-0", "doc_id": "CDER_Update_Presentation", "page": 6, "text": "Patient-focused Drug Development\n\nSection 3001, Patient Experience Data\n\nClinical reviewers will be filling out a new section in the benefit/risk section to include a statement on any patient experience data submitted or utilized during a review\n\nSection 3002\n\nPublic workshop on Dec 18 for feedback on\n\nStandardized nomenclature and terminologies for PFDD • Methods to collect meaningful patient input throughout the drug development process\n\nMethodologic considerations for data collection, reporting, management and analysis of patient input\n\nFDA will publish a discussion document prior to the workshop", "n_tokens": 101, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-7-0", "doc_id": "CDER_Update_Presentation", "page": 7, "text": "Patient-focused Drug Development\n\nWill put up a web site to pull together various patient-related activities\n\nWill start a centralized process for non- application-related meeting requests\n\nPRO qualification process has been converted to CURES-mandated DD tools procedures\n\nWill have standardized processes to receive and respond to externally-developed “Voice of the Patient” reports and draft guidances\n\nWorking with CTTI on patient engagement projects", "n_tokens": 77, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-8-0", "doc_id": "CDER_Update_Presentation", "page": 8, "text": "Drug Development Tools\n\nHave adopted Cures-stipulated process for qualification of DDTs including PROs, biomarkers and clinical outcome assessments\n\nResponsibility placed in OND • Set up senior management committee to oversee precedential decision-making processes (similar to breakthrough designation) • C-Path Institute to be an independent body to provide advice and\n\nconsultation to tool developers\n\nWorkshop on evidence generation for qualification will be held; CDER working with FNIH on describing evidentiary criteria for surrogate endpoints\n\nCPIMs (Critical Path Innovation Meetings) continue to be a great vehicle for non-regulatory brainstorming on innovative ideas, including tools, trial design, and novel development programs", "n_tokens": 131, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-9-0", "doc_id": "CDER_Update_Presentation", "page": 9, "text": "Hiring and Retention\n\nNew hiring authorities in CURES currently being explored; expect implementation in 2018; Melanie Keller, CDER’s exec officer, currently on detail to OC to work on this\n\nNew process and authorities should bring some relief and improved hiring and retention to medical product Centers\n\nRecent independent evaluation and public meeting on FDA HR process (stipulated in PDUFA) revealed many of the ongoing problems FDA is facing", "n_tokens": 82, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-10-0", "doc_id": "CDER_Update_Presentation", "page": 10, "text": "Implement Re-Authorized PDUFA, GDUFA and BsUFA Programs • PDUDFA and BsUFA goals don’t have major\n\nalterations from prior program\n\nFDA has initiated various projects laid out in the goals letters for these projects\n\nGDUFA goals are challenging AND application rate continuously increasing\n\nFDA’s Drug Competition Action Plan adds a number of projects to the OGD portfolio\n\nCDER expects to meet or exceed GDUFA goals", "n_tokens": 87, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-11-0", "doc_id": "CDER_Update_Presentation", "page": 11, "text": "Facility Assessment\n\nFacility problems continue to plague GDUFA, PDUFA and BsUFA programs—a major reason for more application cycling\n\nCDER’s OPQ/OC is currently implementing with ORA the new “concept of operations” for facility assessment based on the ORA reorganization.\n\nThis comes with clear roles and responsibilities and timelines for completing actions after facility inspections and notifying firms of final classification of facility status.\n\nStill need better clarity about cGMP standards and expectations. NIPP project (new inspection protocol) has been slow due to multiple other obligations of staff.", "n_tokens": 117, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-12-0", "doc_id": "CDER_Update_Presentation", "page": 12, "text": "Opioid Crisis\n\nTreating opioid use disorder: CDER just approved a once monthly depot form of bupenophine • Preventing new OUD: ongoing expansion of\n\nopioid REMS; education about appropriate pain management\n\nOngoing evaluation of B/R of currently approved opioids\n\nEvaluation of additional methods to improve prescribing practices\n\nNaloxone: developing information needed for OTC use", "n_tokens": 80, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-13-0", "doc_id": "CDER_Update_Presentation", "page": 13, "text": "Regulation of Pharmacy Compounding\n\nContinue to build framework to implement statute: – Pharmacy Compounding Advisory Committee – Multiple guidances to be issued – Rulemaking to follow\n\nFollow-up on outbreaks, reports of patient harm; issuing compounding risk alerts • Working extensively with states and state\n\nBoards of Pharmacy", "n_tokens": 59, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-14-0", "doc_id": "CDER_Update_Presentation", "page": 14, "text": "New Drug Regulatory Program Modernization • FDA’s new drug program a global leader: some\n\nsay “the gold standard”\n\nKnown both for rigor of assessment and timeliness\n\nComprised of both pre-market review (IND and market application) and post-market regulatory oversight\n\nJust achieved successful re-authorization of PDUFA", "n_tokens": 62, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-15-0", "doc_id": "CDER_Update_Presentation", "page": 15, "text": "New Drug Regulatory Program Modernization\n\nMultiple factors drive the need for change:\n\nNew, rapidly-evolving science\n\nTargeted therapies and precision medicine raise new challenges\n\nChanging societal expectations\n\nPatient involvement in drug development • Expectation of transparency – Digital revolution and rise of RWE – Globalization of drug development and maturation of multiple drug regulatory authorities around the world\n\nPressures on society from rising drug spend and consequent new scrutiny of regulatory authorities’ standards\n\nCall for new structures at FDA, e.g. OCE – Multiple unfunded or partially-funded Congressional mandates", "n_tokens": 107, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-16-0", "doc_id": "CDER_Update_Presentation", "page": 16, "text": "New Drug Program Modernization\n\nChanges not about speed of review (“faster” or “slower”) or about approval standards (“higher” or “lower”)\n\nWill work out more efficient and effective ways to accomplish the review work in order to: – Collaborate with the community to address unmet medical needs – Oversee the approved armamentarium—both for safety and for\n\nappropriateness\n\nEnsure policy consistency in regulatory decisions across units – Work with international regulatory community on harmonizing standards\n\nKeep up with the fast moving science – Improve the transparency of our work – Increase currency and number of disease-specific drug development guidances", "n_tokens": 119, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-17-0", "doc_id": "CDER_Update_Presentation", "page": 17, "text": "OTC Monograph Reform\n\nCurrent OTC monograph system is outdated and almost unworkable\n\nFDA has little ability to respond to safety issues arising with monographed products\n\nNo possibility of innovation—stopped at 1972 • Staffing (approx 18 FTE in division) not adequate for the many tens of thousands of products on the market\n\nFDA has been working with other stakeholders on a reform proposal", "n_tokens": 73, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-18-0", "doc_id": "CDER_Update_Presentation", "page": 18, "text": "Additional Activities\n\nRegulation reform: ORP working on evaluating existing regulations for currency\n\nContinuing to implement provisions of Supply Chain Security Act\n\nIntend to issue further guidance on sponsor\n\ncommunications with payers, and on communications consistent with FDA-approved labelling\n\nIssue guidance on identifying subpopulations for targeted therapies\n\nKeep ahead of emerging drug shortages as possible • And many more", "n_tokens": 70, "kind": "text"}
{"chunk_id": "CDER_Update_Presentation-19-0", "doc_id": "CDER_Update_Presentation", "page": 19, "text": "Conclusions\n\nCDER continues to have a robust number of ongoing initiatives to complete in addition to our regulatory workload\n\nRecent focus has been on generic drug and drug quality programs\n\nNow most urgent focus is IT governance and new drug regulatory program\n\nLikely other crises will happen over FY 18 • Program must rise to the various challenges and continue to serve the public in multiple ways", "n_tokens": 70, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-0-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 0, "text": "www.fda.gov\n\nState of CDER FDLI Annual Conference October 8, 2020\n\nPatrizia Cavazzoni, MD Acting Center Director Center for Drug Evaluation and Research U.S. Food and Drug Administration", "n_tokens": 44, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-1-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 1, "text": "CDER’s All Hands on Deck Approach to COVID-19\n\nCDER’s 3 key priorities during the COVID public health emergency include:\n\n1. Working with drug companies and investigators to bring safe and effective drugs for COVID-19 to the public as soon as possible\n\n2. Monitoring the nation’s supply of medicines and taking action to mitigate or prevent drug shortages\n\n3. Working to help ensure the health of all patients\n\nConsistent stakeholder engagement and collaboration are foundational to these priorities\n\n2", "n_tokens": 100, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-2-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 2, "text": "CDER Stands Ready to Assist\n\nCDER is facing a number of challenges, but we are also trying to address them via innovative approaches.\n\nWe know industry is facing challenges such as:\n\nConducting clinical trials\n\nReduced ability to conduct on-site inspections\n\nMeeting regulatory requirements\n\nWe’re able to reduce impact by providing guidance to help our stakeholders navigate\n\nthis uncharted territory\n\n3", "n_tokens": 71, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-3-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 3, "text": "CTAP Treatment Acceleration Program\n\nAs of August 31:\n\nOver 590 drug\n\ndevelopment programs in planning stages*\n\nOver 310 trials reviewed by FDA**\n\n5 treatments authorized for Emergency Use\n\nActive Pre-INDs excluding vaccines\n\n**Safe to proceed IND excluding vaccines\n\n4", "n_tokens": 49, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-4-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 4, "text": "Preserving supply and access to medications\n\nCDER has been monitoring the drug supply chain to prevent or mitigate drug shortages\n\nExpediting new guidance to bolster drug supply (including manufacturing and inspections1)\n\nProactively working with manufacturers to evaluate supply chains and exercise regulatory flexibility and discretion when appropriate, without compromising safety\n\nOutreach to hospitals, pharmacists, and clinicians – Leveraging real-world data to understand drug usage and demand\n\n1 Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers\n\n5", "n_tokens": 111, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-5-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 5, "text": "Drug Supply and Access: Key Measures\n\nAppropriate regulatory flexibility and discretion to meet critical needs\n\nGuidance on compounding by outsourcing facilities and pharmacies not registered as outsourcing facilities for certain drugs used for hospitalized patients with COVID-19\n\nEmergency Use Authorization to address shortages – propofol, dialysate fluid – Expedited review and approval of generic drugs – Assisting new and established manufacturers to produce alcohol-based hand sanitizer and ethanol for use in hand sanitizers during the COVID-19 pandemic\n\nSince March 1, 2020, more than 3,500 new hand sanitizersmanufacturers have registered with FDA\n\n6", "n_tokens": 132, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-6-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 6, "text": "Regulatory Action to Protect Public Health\n\nFDA has taken action against sellers of fraudulent products for the treatment or prevention of COVID-19, including issuing more than 90 warning letters. FDA has also warned consumers of contaminated and subpotenthand sanitizer that the Agency advises consumers not use.\n\n7", "n_tokens": 58, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-7-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 7, "text": "Maintaining Focus on Other Critical CDER Activities\n\no\n\nContinuous work to support development of safe, effective, high quality therapies for rare diseases, cancer, diabetes, heart disease, autoimmune conditions, neurological conditions, substance use disorders, and many other diseases and conditions\n\no Ongoing assessment, surveillance, compliance, and pharmaceutical quality\n\nefforts across all regulated products\n\no Helping to ensure access to affordable, life-saving drugs and other needed\n\nmedications\n\no UFA Reauthorization\n\no\n\nImplementing FDA’s new OTC monograph reform authorities\n\no\n\nEstablishment of Compounding Quality Center of Excellence\n\no\n\nContinued collaboration with industry to encourage and facilitate the adoption of Advanced Manufacturing\n\n8", "n_tokens": 128, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-8-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 8, "text": "Drug Review Programs: Key Measures\n\nNovel Drug Approvals\n\nSince January 1, FDA has approved more than 40 novel drugs and therapeutic biological products (i.e., those never before approved or marketed in the U.S.), including many innovative therapies to treat a variety of cancers and other conditions\n\nGeneric Drug Approvals\n\nSince January 1, FDA has approved more than 488 generic drug applications, including at least 42 first generics, such as the first generic of a widely used inhaler to treat patients with breathing conditions\n\n9", "n_tokens": 107, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-9-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 9, "text": "It’s Important for CDER to Stay Connected\n\nFrom January 1 to September 30, CDER fielded more than 49,909 inquiries from the general public, including health care providers, consumers and manufacturers, regarding medications; this total included more than 15,600 inquiries specifically related to COVID-19\n\nCDER will continue our work to advance treatments related to COVID-19, while also\n\nstaying focused on other critical areas that are non-COVID-19 related\n\nWe will maintain communications with stakeholders to keep you updated on recent\n\nitems of possible interest, such as regulatory actions, guidances, and webinars\n\nPlease reach out to us with questions at druginfo@fda.hhs.govor (855) 543-3784\n\n10", "n_tokens": 152, "kind": "text"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-10-0", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 10, "text": "QUESTIONS?", "n_tokens": 2, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-0-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 0, "text": "FDA Drug Topics: ROLE OF FDA AND ISMP IN PREVENTING MEDICATION ERRORS\n\nMishale Mistry, PharmD, MPH Associate Director, FDA, CDER, OSE, OMEPRM, Division of Medication Error Prevention and Analysis (DMEPA)\n\nMichael R. Cohen RPh, MS, ScD (hon), DPS (hon) President, Institute of Safe Medication Practices (ISMP)\n\n1", "n_tokens": 83, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-1-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 1, "text": "Learning Objectives\n\nDescribe FDA’s role in pre-marketing and post-marketing activities to prevent and address medication errors.\n\nOutline strategies aimed to increase the safe use of drug products by minimizing use error that is related to the design, naming, labeling, and/or packaging of drug products.\n\nReview examples of recent medication error reports. • Summarize how healthcare providers can help identify, prevent, and mitigate medication errors.\n\n2", "n_tokens": 87, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-2-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 2, "text": "DMEPA’s Premarket and Postmarket Activities in Preventing Medication Errors\n\nMishale Mistry, PharmD, MPH Associate Director, FDA, CDER, OSE, OMEPRM, Division of Medication Error Prevention and Analysis (DMEPA)\n\n3", "n_tokens": 54, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-3-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 3, "text": "Center for Drug Evaluation and Research (CDER)\n\nOffice of Surveillance and Epidemiology (OSE)\n\nOffice of Pharmacovigilance and Epidemiology (OPE)\n\nOffice of Medication Error Prevention and Risk Management (OMEPRM)\n\nDivision of Pharmacovigilance I, II (DPV I, DPV II)\n\nDivision of Epidemiology I, II (DEPI I, DEPI II)\n\nDivision of Medication Error Prevention and Analysis (DMEPA)\n\nDivision of Risk Management (DRM)\n\n4", "n_tokens": 113, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-4-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 4, "text": "Overview of DMEPA\n\nDivision of Medication Error Prevention and Analysis\n\nCDER lead for medication error prevention and analysis for drug and therapeutic biological products\n\nScientists and healthcare professionals with varied backgrounds\n\nMission: To increase the safe use of drug products by minimizing use error that is related to the naming, labeling, packaging, or design of drug products\n\n5", "n_tokens": 67, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-5-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 5, "text": "Definition: Medication Error\n\n“A medication error is any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer” – National Coordinating Council for Medication Error Reporting and Prevention (NCC\n\nMERP)\n\nIntentional or deliberate uses (e.g., abuse, misuse, off label use) are generally not considered medication errors\n\n6 FDA Medication Errors Related to CDER-Regulated Drug Products: https://www.fda.gov/drugs/drug-safety-and-availability/medication-errors-related-cder-regulated-drug-products", "n_tokens": 131, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-6-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 6, "text": "Medication Errors are a Global Public Health Burden Estimated annual cost of U.S. outpatient and inpatient preventable medication errors\n\n$21\n\nBILLION\n\n52%\n\nAmong adult outpatients…52% (95% CI: 42–62%) of adverse drug reactions were preventable\n\n45%\n\nAmong inpatients…45% (95% CI: 33– 58%) of adverse drug reactions were preventable [errors]\n\nNetwork for Excellence in Health Innovation. Dec 2011. Available from: http://www.nehi.net/bendthecurve/sup/documents/Medication_Errors_%20Brief.pdf Hakkarainen KM, et. al., Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions – a meta-analysis. PLoS One. 2012.\n\n7", "n_tokens": 169, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-7-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 7, "text": "Medication Errors and Product Life Cycle\n\nDiscovery & development\n\nPreclinical research\n\nClinical research\n\nFDA review\n\nMarket approval\n\nPostmarket safety monitoring\n\nPremarket (pre-approval)\n\nPostmarket (post-approval)\n\n8", "n_tokens": 40, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-8-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 8, "text": "WHAT DO WE DO?\n\nDMEPA Review Activities Reviews take into account current federal regulations, applicable Guidance for Industry, USP Standards, and relevant postmarket experience.\n\nPROPRIETARY NAMES Primary/signatory authority on review of proprietary names.\n\nNONPROPRIETARY NAME SUFFIX\n\nPRODUCT LABELING\n\nPRODUCT PACKAGING\n\nHUMAN FACTORS/ PRODUCT DESIGN Primary/signatory authority on human factors protocols.\n\nPOSTMARKET PHARMACOVIGILANCE\n\n9", "n_tokens": 81, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-9-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 9, "text": "BEST PRACTICES IN DEVELOPING PROPRIETARY NAMES FOR DRUGS\n\nDRAFT GUIDANCE FOR INDUSTRY MAY 2014\n\nSafety assessment of proposed proprietary name for risk of drug name confusion that may lead to medication errors.\n\nConsiderations: • spelling of the name • pronunciation of the name when spoken • appearance of the\n\nname when scripted throughout the medication use system\n\n10", "n_tokens": 60, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-10-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 10, "text": "BEST PRACTICES IN DEVELOPING PROPRIETARY NAMES FOR DRUGS\n\nDRAFT GUIDANCE FOR INDUSTRY MAY 2014\n\nLook-Alike Sound-Alike Safety Assessment\n\nInstitute for Safe Medication Practices. Durasal-Durezol mix-up illustrates how dangerous product problems persist long after recognition. ISMP Med Saf Alert Acute Care. 2011;16(19):1-3.\n\n11", "n_tokens": 70, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-11-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 11, "text": "BEST PRACTICES IN DEVELOPING PROPRIETARY NAMES FOR DRUGS\n\nDRAFT GUIDANCE FOR INDUSTRY MAY 2014\n\nProprietary Name Review\n\nOPDP*\n\nConducts misbranding assessment of the proposed proprietary name\n\nFor OTC products, the misbranding review is conducted by the Office of Nonprescription Drugs (ONPD)\n\nOND\n\nProvides misbranding and safety concerns with the proposed proprietary name based on clinical, chemistry, and/or pharmacology data that may impact acceptability\n\nDMEPA\n\nConducts safety assessment of the proposed proprietary name for risk of drug name confusion that may lead to medication errors.\n\n12", "n_tokens": 113, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-12-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 12, "text": "BEST PRACTICES IN DEVELOPING PROPRIETARY NAMES FOR DRUGS\n\nDRAFT GUIDANCE FOR INDUSTRY MAY 2014\n\nProprietary Name Review Misbranding Assessment\n\nDMEPA will object to a proposed name if it may misbrand the product for the following reasons: • The proprietary name suggests that the drug\n\nis safer or more effective than has been demonstrated by scientific evidence. • The proprietary name is “fanciful” and suggests that it has some unique effectiveness or composition when it does not. (21 CFR 201.10(c)(3)).\n\n13", "n_tokens": 103, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-13-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 13, "text": "BEST PRACTICES IN DEVELOPING PROPRIETARY NAMES FOR DRUGS\n\nDRAFT GUIDANCE FOR INDUSTRY MAY 2014\n\nProprietary Name Review Safety Assessment\n\nFocus: Prevent medication errors due to drug name confusion 21 CFR 201.10 (c.) The labeling of a drug may be misleading by reason (among other reasons) of: (5) Designation of a drug or ingredient by a proprietary name that, because of similarity in spelling or pronunciation, may be confused with the proprietary name or the established name of a different drug or ingredient.\n\nDraft Guidance: Best Practices in Developing Proprietary Names for Drugs http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm398997.pdf\n\n14", "n_tokens": 146, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-14-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 14, "text": "BEST PRACTICES IN DEVELOPING PROPRIETARY NAMES FOR DRUGS\n\nDRAFT GUIDANCE FOR INDUSTRY MAY 2014\n\nProprietary Name Review Safety Assessment\n\nPreliminary safety assessment:\n\n— United States Adopted Names (USAN) stems — other characteristics that when incorporated into a\n\nproprietary name may cause or contribute to medication errors\n\nSimilarity in printing, writing, and speech • FDA Prescription Simulation Studies — handwritten prescriptions — verbal pronunciation of the drug name — computerized provider order entry\n\nSimilarity of names by using FDA’s Phonetic and Orthographic Computer Analysis (POCA) program and assessment of POCA scores\n\nPhonetic and Orthographic Computer Analysis (POCA) Program. http://www.fda.gov/Drugs/ResourcesForYou/Industry/ucm400127.htm\n\n15", "n_tokens": 147, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-15-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 15, "text": "BEST PRACTICES IN DEVELOPING PROPRIETARY NAMES FOR DRUGS\n\nDRAFT GUIDANCE FOR INDUSTRY MAY 2014\n\nProprietary Name Review Safety Assessment\n\nRole of product characteristics in proprietary name review\n\nCoumadin 4 mg or Avandia 4 mg?\n\n• Strength • Dose • Dosage form • Unit of measure, typical quantity or volume • Route of administration • Frequency of administration\n\nIndications\n\nInstructions for Use • Patient population • Prescriber population • Product Packaging • Physical attributes • Storage conditions • Setting of use 16", "n_tokens": 90, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-16-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 16, "text": "BEST PRACTICES IN DEVELOPING PROPRIETARY NAMES FOR DRUGS\n\nDRAFT GUIDANCE FOR INDUSTRY MAY 2014\n\nProprietary Name Review Safety Assessment\n\nConsiderations for Computerized Provider Order Entry\n\n”Starts with” Provides choices after typing only a few letters\n\n”Contains” Provides all options that contain what was typed\n\nBrintellix Brilinta\n\nRanexa Tranexamic acid\n\n17\n\nBrintellix name changed to Trintellix in May 2016 http://www.fda.gov/Drugs/DrugSafety/ucm497942.htm", "n_tokens": 104, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-17-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 17, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nProduct container labels and carton labeling should communicate information that is critical to the safe use of a medication throughout the medication use system.\n\n18", "n_tokens": 46, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-18-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 18, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nCritical product information should appear the most prominent on the Principal Display Panel (PDP)\n\nEstablished name or proper name\n\nRx only NDC 12345-6789-30\n\nMydrug (drugozide) Injection\n\nProduct strength\n\n50 mg/10 mL\n\n(5 mg/mL)\n\nRoute of administration\n\nFor continuous infusion after dilution Single-dose vial – Discard unused portion.\n\n10 mL single dose vial\n\nThe Principal Display Panel is the portion of the container label or carton labeling that is most likely to be displayed, presented, shown, or examined by the user when the product is on a shelf\n\nProprietary name\n\nDosage form\n\nWarnings or cautionary statements\n\n19", "n_tokens": 151, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-19-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 19, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nProduct information on side and back panels\n\nSide Panel\n\nUsual Dosage • Product strength equivalency statement\n\nPrincipal Display Panel Rx only NDC 12345-6789-30\n\nMydrug (drugozide) Injection\n\nSide Panel\n\nManufacturer name and logo\n\nReconstitution instructions\n\nStorage\n\n50 mg/10 mL\n\nXXXX XX/XX\n\n(5 mg/mL)\n\nFor continuous infusion after dilution Single-dose vial – Discard unused portion.\n\n10 mL single dose vial\n\nSpecial storage requirements Special preparation instructions\n\nGuidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors. 2013. 20 Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM349009.pdf\n\nLot Number Expiration Date\n\nBarcode", "n_tokens": 188, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-20-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 20, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nText Size, Font Style, and Color on the Principal Display Panel\n\nUse at least a 12- point sans-serif font (e.g., Arial)\n\nProprietary Name (Established name)\n\nChoose text and\n\nbackground color to afford adequate legibility of text\n\nProprietary Name (Established name)\n\nAvoid color\n\ncombinations that do not afford maximum legibility of text\n\nProprietary Name (Established name)\n\n21", "n_tokens": 96, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-21-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 21, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nProduct Name\n\nThe proprietary and established or proper name should be the most prominent information on the label\n\nThe established name should be at least ½ the size of the proprietary name\n\nThe established name should include the dosage form\n\n22", "n_tokens": 61, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-22-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 22, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nProduct Strength Expression\n\nUse metric units of measure (e.g., mg, mcg, mL)\n\nThe strength should match the units of measure in the Dosage and Administration section of the Prescribing Information\n\nSmall volume parenteral products: Express strength as the quantity per total volume followed in close proximity by quantity per milliliter enclosed by parentheses\n\nDry powder parenteral products: Express strength as the amount per container\n\nBlister packs: Express strength per unit; may also display the dose in certain instances\n\n23", "n_tokens": 121, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-23-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 23, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nProduct Strength and Net Quantity Statements\n\nNote prominence of strength\n\nNote the placement of strength and net quantity\n\n24", "n_tokens": 38, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-24-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 24, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nProduct Strength Differentiation\n\nEnsure the product strength stands out on the container label and carton labeling\n\nTechniques include: • Boxing • Prominent typeface or type\n\nweight\n\nColor differentiation\n\n10 mg\n\n20 mg\n\n30 mg\n\n40 mg\n\n50 mg\n\n60 mg\n\n70 mg\n\n80 mg\n\n25", "n_tokens": 67, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-25-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 25, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nRoute of Administration\n\nMust be present on the PDP for non-oral products per 21 CFR 201.100 (b)(3) • Avoid abbreviations • Use affirmative statements (e.g., use “for irrigation” instead of “not for injection”) because “not” can be obscured or overlooked\n\n26", "n_tokens": 84, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-26-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 26, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nWarnings for Critical Information\n\nUse affirmative statements —For intravenous infusion —Fatal if given by any other —Must dilute before use\n\nConsider whether the statement is helpful to ensure safe use Patient: Took 1 mg orally once daily. Patient stated she was following directions on the bottle\n\nInstitute for Safe Medication Practices. Safety Briefs: Positive change, negative consequence. ISMP Med Saf Alert Acute Care. July 2014;19(15):1.\n\nAstagraf XL\n\nTake 6 mg orally once daily\n\n27", "n_tokens": 121, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-27-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 27, "text": "SAFETY CONSIDERATIONS FOR CONTAINER LABELS and CARTON LABELING TO MINIMIZE MEDICATION ERRORS\n\nDRAFT GUIDANCE FOR INDUSTRY APRIL 2013\n\nAvoid Crowding, Visual Clutter, Dangerous Abbreviations, and Acronyms • Crowded labels/labeling may make important\n\ninformation difficult to read and/or easily overlooked\n\nSafety considerations:\n\n— Separate lines or blocks of text with sufficient blank space — Place non-critical information on side/back panels — Refer to ISMP’s “List of Error Prone Abbreviations, Symbols, and\n\nDose Designations”\n\n— Don’t superimpose text over images or logos\n\n28", "n_tokens": 110, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-28-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 28, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nFDA EXPECTS MANUFACTURERS TO:\n\n1.\n\nInvestigate, understand and correct identified risks Use analytical methods to develop drug products\n\n2. Build safety into the product design Apply these methods early in drug development and throughout the drug product’s life cycle\n\n3. Enable safe and correct use Eliminate or reduce design elements that can cause use-related hazards\n\n29", "n_tokens": 79, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-29-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 29, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nDrug product user interface refers to all parts of a product a user interacts (e.g., sees and touches)\n\nPackaging\n\nInstructions for Use\n\nProduct labels\n\nDelivery device constituent part, and any associated controls and displays\n\n30", "n_tokens": 57, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-30-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 30, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nMost effective strategies focus on improvements to design of drug product user interface.\n\nConsider effect of each design choice on end user\n\nEvaluate using proactive risk assessments before finalizing design\n\nEvaluate how and why problems have occurred with similar products\n\nIdentify error prone features and eliminate them from design\n\nPrevent same errors from occurring\n\nSponsors should consider lessons learned to minimize risks associated with their designs 31", "n_tokens": 84, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-31-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 31, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nContainer Closure Design\n\nIs the container closure design:\n\nsafe for the route of administration? – appropriate for the intended users?\n\nAvoid use of a container closure that implies a route of administration other than the route intended, unless there are no other options available\n\n32", "n_tokens": 63, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-32-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 32, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nProduct Strength\n\nReview for\n\ninconsistency between drug product strength and dosing – Multiple units (e.g.\n\ntablets, capsules, vials, syringes) required to achieve a usual single dose?\n\nDosing errors due to:\n\nmiscalculations – forgetting how much has already been administered\n\n33\n\nThis Photo by Unknown Author is licensed under CC BY-NC-ND", "n_tokens": 91, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-33-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 33, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nProduct Strength\n\nCo-packaged dosage\n\ndelivery device should be consistent with recommended dosing regimen/directions for use • Printed matter appearing on dosage delivery device is considered labeling – Dose markings must be easy\n\nto read\n\nDosing devices for oral solutions should use metric unit markings\n\n34", "n_tokens": 68, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-34-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 34, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nHuman Factors? “…the application of knowledge about human capabilities (physical, sensory, emotional, and intellectual) and limitations to the design and development of tools, devices, systems, environments, and organizations….”\n\nHuman factors engineering – Design of medical devices. American National Standards Institute / Association for the Advancement of Medical Instrumentation (ANSI/AAMI) HE75:2009, Introduction. http://my.aami.org/aamiresources/previewfiles/HE75_1311_preview.pdf\n\n35", "n_tokens": 123, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-35-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 35, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nHuman Factors Considerations\n\n36\n\n36", "n_tokens": 19, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-36-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 36, "text": "SAFETY CONSIDERATIONS FOR PRODUCT DESIGN TO MINIMIZE MEDICATION ERRORS\n\nGUIDANCE FOR INDUSTRY APRIL 2016\n\nHuman Factors Validation Studies • Systematic collection of data from representative\n\nparticipants in realistic situations\n\nHelp determine whether users can safely and correctly perform critical tasks involved in using the product • Results can be used to update the Failure Mode and Effects Analysis (FMEA)\n\nShould be conducted before product is submitted for approval, before any product modifications or additions to a product line\n\nRecommend that sponsors conduct human factors studies to characterize risks as well as develop mitigation strategies – Studies are generally small in size and short in duration (as compared to clinical studies that support drug approval) – Relatively small investment of resources early in product development can avoid the need to resolve issues post- approval 37", "n_tokens": 144, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-37-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 37, "text": "Postmarket Surveillance of\n\nMedication Errors", "n_tokens": 6, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-38-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 38, "text": "Why is postmarket surveillance necessary?\n\nLimitations of premarket clinical trials\n\nTrials are conducted under controlled conditions, and may not use the final approved name, labels, labeling, and packaging\n\nNumbers of patients tested is too small to detect serious but rare problems, and some errors may fall into this category\n\nTrials are often of short duration\n\nFDA has a robust program to identify potential errors and address them prior to approval. However, medications errors remain a significant burden on public health*\n\nAllows us to monitor error reports and address those causes of errors that may be related to a drug’s name, label and labeling, or packaging (before a product is widely distributed).\n\n*Preventing Mediation Errors: A $21 Billion Opportunity. Network for Excellence in Health Innovation (NEHI); 2011. https://www.nehi.net/bendthecurve/sup/documents/Medication_Errors_%20Brief.pdf\n\n39", "n_tokens": 187, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-39-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 39, "text": "Medication error case reports\n\nFDA has Memorandum of\n\nUnderstanding (MOU) agreements with ISMP and other organizations to share publicly available medication error information\n\nThe FDA Adverse Event Reporting System (FAERS) is FDA’s primary source for monitoring medication errors, but we surveil other sources, including ISMP newsletters\n\n*Preventing Mediation Errors: A $21 Billion Opportunity. Network for Excellence in Health Innovation (NEHI); 2011. https://www.nehi.net/bendthecurve/sup/documents/Medication_Errors_%20Brief.pdf\n\n40", "n_tokens": 118, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-40-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 40, "text": "Medication errors are underreported\n\nExtent of underreporting is unknown\n\nElliott, et.al., “estimated that 237 million medication errors occur at some point in the medication process in England per year”\n\nPrevalence and Economic Burden of Medication Errors in The NHS in England. 2018 (http://www.eepru.org.uk/wp- content/uploads/2018/02/eepru-report-medication-error-feb-2018.pdf)\n\nNo U.S. requirement to report medication errors to FDA\n\nLikelihood of reporting medication errors versus adverse events\n\n41\n\nThis Photo by Unknown Author is licensed under CC BY", "n_tokens": 131, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-41-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 41, "text": "Barriers for reporting medication errors\n\nFear of punishment or litigation\n\nEmbarrassment of having been involved a medication error\n\nDifferent definitions for medication error\n\nNot knowing where, why, or what to report\n\nNo allowance for anonymous reporting\n\nOrganizational culture\n\nWorkload/amount of time required for reporting\n\n42", "n_tokens": 50, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-42-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 42, "text": "Example of Progression from Nonserious Event to SERIOUS\n\nReport warning of potential look-alike container and cartons\n\nDMEPA performs risk assessment, notifies FDA review division and company\n\nMultiple reports of “near miss”\n\nCompany issues safety alert, distributes stickers, prepares to revise labeling\n\nFirst serious report received (patient received wrong drug)\n\nLabels and labeling urgently revised\n\n43", "n_tokens": 73, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-43-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 43, "text": "Summary\n\nWe encourage healthcare providers to report all medication errors to MedWatch.\n\nIf we are aware of potential problems, we can work to provide effective interventions that may help minimize further errors.\n\nPost marketing experience also helps us anticipate potential errors.\n\nWe aim to identify and address the risk prior to marketing to help prevent medication errors.\n\n44", "n_tokens": 66, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-44-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 44, "text": "Resources\n\nGuidances for Industry:est Practices in Developing Proprietary Names for Drugs (Draft) – May • Best Practices in Developing Proprietary Names for Drugs (Draft) – May 2014 • Safety Considerations for Container Labels and Carton Labeling Design to Minimize\n\nMedication Errors (Draft) – April 2013\n\nSafety Considerations for Product Design to Minimize Medication Errors – April 2016 • Applying Human Factors and Usability Engineering to Medical Devices – February 2016\n\nWe update guidances periodically. For the most recent version of a guidance, check the FDA Guidance Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.\n\nRegulations*: • 21 CFR 200s, 300s and 600s\n\n*http://www.ecfr.gov/cgi-bin/text- idx?SID=c8497935ae0f040dfcfe06c6251ba507&mc=true&tpl=/ecfrbrowse/Title21/21tab_02.tpl\n\n45", "n_tokens": 214, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-45-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 45, "text": "A Lot Happens When You Report A Medication Error or Hazard to FDA and ISMP\n\nMichael R. Cohen RPh, MS, ScD (hon), DPS (hon) President, Institute of Safe Medication Practices (ISMP) (www.ismp.org)\n\nwww.ismp.org | 46", "n_tokens": 63, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-46-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 46, "text": "ISMP National Medication Error Reporting System\n\n— Early warning system\n\nIssue nationwide hazard alerts and press\n\nreleases — Learning\n\nDissemination of information and tools\n\n— Change\n\nProduct nomenclature, labeling, and packaging changes, device design, practice issues\n\n— Standards and Guidelines\n\nAdvocates for national standards and guidelines\n\nwww.ismp.org | 47", "n_tokens": 60, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-47-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 47, "text": "ABOUT CONTACT NEWS SUPPORT\n\nme g ae\n\nISMP and ECRI Institute Join Forces\n\nBy joining together, ECRI Institute and. ISMP create one of the largest\n\nhealthcare quality and safety institutions in the world, driving greater value\nto the healthcare organizations they serve with unrivaled expertise,\n\nresources, and solutions.\n\nLEARN MORE\n\nwww.ismp.org 48", "n_tokens": 70, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-48-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 48, "text": "Institute for Safe Medication Practices\n\nAn ECRI institute Affiliate\n\nABOUT\n\nOur Reporting Programs\n\nWhat We Do with Your Reports\nYour Reports at Work\nWho We Work With\n\nData Analysis and Coaching\n\nReport an Error\n\nError Reporting for Practitioners\nError Reporting for Consumers\n\nReport a Vaccine Error\n\nBy joining together, ECRI Institute and ISMP create one of the largest\n\nhealthcare quality and safety institutions in the world, driving greater value\n\nto the healthcare organizations they serve with unrivaled expertise,\n\nresources, and solutions.\n\nLEARN MORE\n\nCONTACT\n\nNEWS\n\nSUPPORT\n\nwww.ismp.org\n\n49", "n_tokens": 104, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-49-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 49, "text": "MP\n\nAn ECRI Affiliate\n\nSMP) ABOUT NEWS EVENTS SUPPORT ISMP\n\nInstitute for Safe Medication Practices Information for consumers >\n\nISMP National\nMedication Errors Reporting Program\n\nThank you for for submitting a report to the ISMP National Medication Errors Reporting Program (MERP).\n\n© Please provide as much detail as possible when telling us the story of what went wrong or could go wrong, the causes or\ncontributing factors, how the event or condition was discovered or intercepted, and the actual or potential outcome of the\ninvolved patient(s).\n\n© Be sure to include the names, dosage forms, and dose/strength of all involved products. For product-specific concerns (e.g.,\nlabeling and packaging risks), please include the manufacturer.\n\ne Share your recommendations for error prevention.\n\n¢ If possible, submit associated materials (e.g., photographs of products, containers, labels, de-identified prescription orders) that\nhelp support the report being submitted.\n\nPlease complete the form below and click on the “Submit” button to report the error or hazard to the ISMP National\nMedication Errors Reporting Program.\n\nName: [ | (optional)\nEmail: | ]\n\nConfirm email: | ]\n\nError Please describe the incident as best you can. This information will be handled in\nDescription: confidence.\n\n(optional)\n\nUp to three images can be uploaded, Input area will appear after each image is selected up to 3.\n\n| Submit |\n\nwww.ismp.org,\n\n150", "n_tokens": 290, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-50-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 50, "text": "UKSMP) CHEERS ABOUT CONTACT NEWS SUPPORT\n\nInstitute for Safe Medication Practices Information for consumers @\n\nConsulting and Education Tools and Resources Publications and Alerts Error Reporting LOGIN\n\nReporting to ISMP as a PSO\n\nPatient Safety\n\nOrganization\n\nSMP) www.ismp.org [51\n\nAn ECRI Affiliate", "n_tokens": 58, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-51-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 51, "text": "Where does ISMP get its information? Where does it go?\n\nwww.ismp.org | 52", "n_tokens": 21, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-52-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 52, "text": "Process when you report a hazard or error to ISMP – Every report is indispensable!\n\nReport received and entered into ISMP database\n\nISMP professional staff review every report and gather additional information if necessary\n\nReport identified as requiring further investigation for sharing the lessons learned\n\nFurther investigation conducted, with additional resources accessed\n\nRealistic, measurable and attainable recommendations identified along with ambitious recommendations to drive further improvements\n\nHazard/error story & recommendations shared via newsletters and direct conversations with FDA, manufacturers, vendors, other regulatory agencies & other key stakeholders\n\nAggregate data from error databases analyzed and published periodically\n\nwww.ismp.org |53", "n_tokens": 121, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-53-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 53, "text": "Report received and entered into ISMP database\n\nReport entered into one of our\n\ndatabases and initially reviewed by ISMP nurse or pharmacy technician analyst\n\nISMP sends an email to reporter to confirm receipt of the report and thank him or her for reporting\n\nwww.ismp.org |54", "n_tokens": 54, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-54-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 54, "text": "ISMP professional staff review every report and gather additional information if necessary\n\nReport redacted of identifying provider and/or facility information\n\nNurse or analyst distributes reports and accompanying photographs, screen shots or attachments through secure portal to ISMP interdisciplinary professional staff\n\nProfessional staff reviews every report, shares comments on topic with one another via the portal\n\nwww.ismp.org |55", "n_tokens": 73, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-55-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 55, "text": "ISMP professional staff review every report and gather additional information if necessary\n\nSimilar hazards, errors identified • Suggest questions to ask reporter to better understand the report, make recommendations for mitigating the risk\n\nReports incite conversation among professional staff\n\nGain understanding of the reported risks and underlying causes\n\nwww.ismp.org | 56", "n_tokens": 62, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-56-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 56, "text": "Report identified as requiring further investigation for sharing the lessons learned\n\nSignificant factor - is report actionable? Leads to further investigation and sharing of lessons learned\n\nCan patients, vendors, standards organizations and regulators take specific actions to prevent or reduce risk of similar error, or mitigate potential patient harm?\n\nIs hazard or error new? Has it caused or could it cause harm? Does it require action by FDA or manufacturer, state professional board, standards organizations such as USP or The Joint Commission?\n\nwww.ismp.org |57", "n_tokens": 103, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-57-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 57, "text": "Further investigation conducted, with additional resources accessed\n\nSteps ISMP may take to investigate hazards or errors: • Reach out to reporter to ask clarifying questions, seek out additional information, graphics or examples\n\nConduct professional literature, drug information and error-reporting database searches\n\nSeek out expert advice from established advisory groups or organizations with extensive knowledge in key subject areas\n\nwww.ismp.org |58", "n_tokens": 75, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-58-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 58, "text": "Further investigation conducted, with additional resources accessed\n\nInteract with other federally listed patient safety organizations (PSOs), such as our ECRI affiliate\n\nInteract with FDA Division of Medication Error Prevention and Analysis and others within the agency.\n\nMemorandum of Understanding with CDER\n\nwww.ismp.org | 59", "n_tokens": 57, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-59-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 59, "text": "Further investigation conducted, with additional resources accessed\n\nFormal monthly calls and two face to face meetings annually\n\nContact the pharmaceutical product manufacturer, device and technology vendors, drug information vendors and other service providers\n\nConduct surveys to learn more about specific types of errors\n\nwww.ismp.org | 60", "n_tokens": 54, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-60-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 60, "text": "Recommendations identified to drive further improvements\n\nPrimary focus is on a few well-thought-out, high- leverage, long-term recommendations that are realistic, measurable, and attainable with reasonable resources\n\nBecause ISMP is not a standards-setting organization, we sometimes make ambitious recommendations to drive practice, process, and technology improvements\n\nMany reports trigger FDA, manufacturer,\n\ndevice/technology vendors to further investigate and respond\n\nwww.ismp.org |61", "n_tokens": 88, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-61-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 61, "text": "Aggregate data from error databases analyzed and published periodically\n\nhttps://www.ismp.org/resources/2017-2018-vaccine-bi-annual-report\n\nhttps://www.ismp.org/node/14240\n\nwww.ismp.org |62", "n_tokens": 56, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-62-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 62, "text": "Hazard/error story & recommendations shared with FDA and via newsletters, interaction with manufacturers, vendors, other key stakeholders\n\nISMP’s primary vehicles are publication in one or more of our 5 subscription-based newsletters\n\nUrgent medication advisories requiring immediate notification of healthcare providers published first in a National Alert Network (NAN) bulletin to both ISMP email lists, ASHP members, ISMP website and member organizations of National Coordinating Council Medication Error Reporting and Prevention (NCCMERP)\n\nError information contextually deidentified as necessary. Stories make information memorable\n\nwww.ismp.org |63", "n_tokens": 118, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-63-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 63, "text": "INFORM\n\nAn ECRI Affiliate\n\nJanuary/February 2020 . Volume 8 Issue 1\n\nLong-Term Care\n\nAdviseERR | il\n\nAlot happens vunon you roort haz you report a hazard or error to\n\nISMP—there’s,\nn 2018, ISMP colobrat\nzation devoted entire\n‘ocomplishments ove}\n\nto our successes bocau:\n\nbringing attention to sign\nand wo want to assure\n\n‘aver fall into a “blackhd\n\nbbe seen again. To demor-——\n\nYou all that happens wh\n\nISMP (summarized in Fig\n\nvia email ora phone cil\n\nreporting programs thd\n\nReporting Program (is|\n\nVaccine Errors Report\n\nISMP Consumor Medic\n\n(SMP CMERP).\n\n initial Review of Repot\n‘When [SMP receives a\nInto one of our databased\n\nASMP)\n\n sy 0 ne MP\n\nNurse AdviseERR: __\n\n Educating the Heskncare Community About Safe Medication Practices ==\n\nAlot happens when you report a hazard or errorto - SAFETY wires\nISMP—there’s no “black hole” here! Abbreviations to avoid. Angiot\n\nJanuary 2020 . Volume 19 Issue 1\n\nNovember/December 2019 . Volume 17 Issue 6\n\nSAFEMedicine’\n\n Educating the Healthcare Community About Safe Medication Practices\n\nSpeaking up about patient safety requires an\nobservant questioner and a high index of suspicion\n\nCommunity/Ambulatory Care\n__ ISMPMedication Safety Alert\neee\n\nSAFETY’ briefs —\n\nMixcups between Almavig strengths\n\nASMP)\n\nnt and commu-\ne aware thatthe\n\nBI antibody indi-\nprophylaxis. The\nfo mg or 140mg\n\nmu Protect Yourself from h lication Errors\n\nAs approval of medical marijuana spreads state by\nstate, labeling problems have led to errors\n\n(GIAPREZA) injection for intr\n12018, ISMP. its 250 38 the nation’s oF\nzation devoted entirely to medication error prevention. Aq\n‘accomplishments over the years, we recognize that you, tod\nto our successes because you have reported medication hazar|\nbringing attention to significant medication safety issues. Ever]\n\nJanuary 30, 2020 , Volume 25 Issue 2\n\nbittorent than the street product. With medical\n\n‘Columbia (Washington, DC) have legalizad\n\nplus DC have legalized recreational use of\n\nSidebar:\nLaboling issue with modical marijuana\n‘A patint in the hospital told a nurse she\n\n‘takes medical mariana at home for pain\n‘are tohelp her sloop. She showed the bots\n\n‘once monthly.\n", "n_tokens": 508, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-63-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 63, "text": "ple-dose profiled\nr patient self-\n\nloducts’ contents, so this can be\nHowever, each state has its own regulations\n\nble to us, and we want to assure you that the reports you\n‘submit never fall into a “black hole” iretriovably lost and\n‘over to be soon again. To demonstrato this, we want to\n‘share with you all that happens when you raport a hazard\nor error to ISMP (summarized in Figure 1), whether itis\nface-to-face, via email or @ phone call, or through one of\n‘our three errorreporting programs—the ISMP National\nMediation Emors Reporting Program USMP_MEBP), the\nISMP National Vaccine Errors Raporting Program (I\n\nERP), and the ISMP Consumer Medication Errors oper.\n jing Program (ISMP C-MERP),\n\nInitial Review of Reports\nWhen ISMP receives a hazard or error repor, itis entered\ninto one of our databases and intially raviowed by an SMP\n‘nurse or pharmacy technician analyst. Since most reports\n‘submitted to ISMP include the reporter's email address,\nISMP sends an email to the reportar to confirm receipt of\nthe report and to thank thm for reporting.\n\n ‘nurse or pharmacy tachi]\nsubmitted to ISMP incl\nISMP sends an email to\nthe report and to thank’\n\n‘Aftor redacting any ido\nfacility information, ou\n\nreports and any accom}\nthrough 2 secure port}\nprofessional staff. The prq\nand often share commel\nthrough the portal; ide|\nrelated resources; sugge|\nbetter understand the roy\n{for mitigating the risk.\n\n among ISMP profession]\nthe reported risks and ur\n\nDepending on the level\nreport, our nurse or analy\nsonds specific questions}\n‘much as possible abot\naddition, each report iss\nAdministration (FDA)\n° %\n\n‘After redacting any identitying patient andior faciity infor.\n ‘mation, our nurse or analyst distributes all reports and any\n‘accompanying pictures or attachments through @ secure\nportal to all ISMP interdisciplinary professional staff. The\nprofessional staff review every report and often share\n‘comments on the topic with each other through the portal;\nIdentity similar hazards, errors, or related resources; suggest\n‘questions to ask the reporter to better understand the report;\n‘Suppd ‘and make recommendations for mitigating the risk.", "n_tokens": 500, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-63-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 63, "text": "Many\n\n‘ports incite conversation among ISMP professional staff\n\nAcute Care\n\nISMPMedication Safety Alert I\nty Alert\n\nEducating the Healthcare Community About Safe Medication Practices\n\nMedical abbreviations that have\ncontradictory or ambiguous meanings\n\n{SMP woud Ik fo hank Nall M. Dav, Pham) MS, FASHP fr suring th ala\n‘The author can be reached at:\n\n [SAFETY briefs —\nAx Wisse and enor risk tied to Stvarga\n\n£2 packaging. The oral kinase inhibitor\nSTIVARGA ) is approved for\n\nIntroduction )\n‘Abbreviations are a conveniance, a time saver, and a way of fting a word\n\nCr phraso into a restricted space or avoiding the possibilty of misspalling\n\nwords. However, @ high price can be paid for their use. Abbraviations ara\n\nnot misread, or Thoit uso\n\nthe time needed to train ‘wastes timo\n\nCe een ee\noccasionally results in patient harm.\n\n ‘raatment of metastatic colorectal cancer,\nmetastatic gastrointestinal stromal tumor,\nand hepatocellular carcinoma. The drug,\n\\hichisevellablo through spacial phar-\nmacias, is formulated as 40 mg tablets and\nsupplied in a carton containing three 28-\ncount bottles, totaling 8 tablets (Figure 1),\nCurrentlabeling state, “Store tablets inthe\noriginal bot,” and “Discard any unused\n{able 7 woke ser pein the bet”\n\n| published my first book of medical Modical, 1700 Con.\nvenionces at the Expense of Communication and Safety in 1983. To expand the list of\n‘abbreviations, | contacted hospitals and requested lists of abbreviations that were used\nat their facility, soarched the litaratura, and solicited readers to send me abbreviations.\n ‘Sinca thon, | have published 16 editions of the book, which now contains 55,000 abbra-\nvations.’ A web version ofthe bookis updated with more than 20 naw entries per wack?\n\n ‘80 we can all the reported risks and:\n\ncauses.\n\n Depending on the level of detail provided in the original\nreport, our nurse or analyst (or another ISMP professional)\n‘sends specific questions to the reporter so we can learn as\n‘much a possible about the event and its causes.", "n_tokens": 483, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-63-3", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 63, "text": "In addi-\ntion, each report is shared with the US Food and Drug\n‘Administration (FDA) and, if known, the manufacturor(s)\n\n‘continued on page 2—No “black hole” >\n\n‘Supported by educational grants from\nNovartis and Fresenius Kabl\n\nOne oft that one:\ndictory or yeanings, which can craato collected\nthoee reonings ands paral tis of medcal abbroviatone wih contraeory or mblgu-\n‘ous meanings is shown in Table 1 (pages 25). Itis obvious from an examination ofthis\nlist that these abbreviations should not be used, as they fall to communicate with any\ncertainty their intended meaning and present possible dangers to the health of pationts,\n\ncould have two or\n\n‘The Joint Commission directs medical failties to publish a Do Not Use List’ of abbrevia-\ntons that must not be used (soe ISMP¢ list at wwwismp.orginada/). This lit is @ vary\nimportant stp inte right rection but coos notctve wy tami problem ofan sre,\nviation with ings? The Joint standards\n\nalso state if multiple: the\n‘id ens wb wed line emblguyTis sap ecvemely eto acl\n\n‘Two Possible Solutions That May Not Be Feasible )\n © Create a national list of standard abbreviations. A simplistic approach to this,\n\ndose is 160 mg daily\n(tx a0 mo asf th fet 21 doy of\neach 2-day cycle, which totals 84 tblots\npor cycle. Treetmontis continued until ds-\n80 progression or unacceptable taxcity\n\nProduct labeling mentions various drug-\n3d toxicities that require reduced\ncontinued on page 2 — SAFETY wists >\n\nFigure 1. Svar carton hls ree 2c\nbots. =\n\nin a wide variety of medical marijuana prod-\nth the laboling of these products.\n\n4 )\nha is Cannabis sative. Much like the different\n/marijuana comes in many different strains\nled cannabinoids. These cannabinoids are\n\nThedrop-\nper bots hed a wrap-around label ont\n(Figure 1). The label said it was a 330mg\n‘tincture and lst the contents 3s a “hybrid”\n‘with a 1:10 rato, Instructions for use were\n‘noton ha labo.", "n_tokens": 506, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-63-4", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 63, "text": "The patent statadtha bot\ncontained a 30-day supply and that she\n‘akas half dropperful at bedtime, The drop-\nporhad 05mL and 1 mL markings on it.\n\n ton the growing\n\njnodical marijuana are tetrahydrocannabinol\nts the mind, behavior, and coordination,\n‘such as euphoria (happiness), relaxation,\nIntensity of these effects tends to be dose-\nbrijuana with high lavols of THC may make\nIEven when taken in small doses, symptoms\n{neadedness, increasing the risk of falls. THC\n [pannabis uso disorder)\n\ntudes suggest it may help reduce inflamma.\n | and seizures from epilepsy. Unfortunately,\nal the effects of CBD, they may take higher\njects include headache, diarrhea, restlessness,\n‘to marijuana addiction.\n continued on page 2—Medical marijuana >\n\nBrand X\nMedical Marijuana\n\n330 MG Hybrid\nTINCTURE | 1:10\n\n‘Tha a a iia\nsane rplcad with\n\n‘Sohow much = and! oa did the pationt\n‘take with each dose? The labol does not\nhowhowmuch iquid (mL) oquals 330mg.\n Since the botle contained a 30-day supply,\n‘the nurse calculatad that the full bottle\nlikaly contained 15 mL (90 daystimes each\ndaily dose of 05 mL}. Thus, the strength of\ntha product might have boon 330 mg por\n1SmL. But this is an unreliable way to\ndetermine the product strength\n\nThe labol also doas not say if the ratio of\n1140s THC:CBD or CBD:THC. So how much\nTHC and CBD are in each dose?", "n_tokens": 361, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-63-5", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 63, "text": "When the\npationts husband brought in the box that\nhold the botlo, the labo said thore was no\n(CBD at all in tho product, even though tha\nlabel said twas 0 1:10ratio of « “hybrid”\n\nplan 140 mg/mL\n\npved in May 2018,\nfons containing\ninjector (for the\nwo 70 moi\n140 mg monthly\njts to administer\n40 mg dose, the\nda 140 mg/mL\n3S approved in\nwaver, until the\neoeaiing two\ndepleted, there:\njckages on the\ning one 10 mg\n[carers\n\nSAE leetips ca lab yi gow Yor\nmed-\n\nproblem is to create @ national list of approved , with each\nhaving only one meaning. The problem with this approach is that all medical specialties,\n\nication safety word, (SMP ls ow\n\nallied heath ‘and forthres\nhhave to agree on one meaning for each abbreviation. ‘gramsthatbogin this surumorfll—the ISMP\n\n‘Safo Matication Manegemant Followship,\n‘A recognized health-related organization, such as USP the American Medical Association, | tha ISMP Intarational Madication Sefoty\nthe Council of Science Editors, ISMP or ECA! Institute, would have to be funded to take | ‘Management Fallowship, and the FDA(US\n\nfor creating and such a list-The ‘would have to\n\n‘each out to all the health-related organizations to suggest abbreviations that should be\n\n(on this list-Then, arbitration would be required botween organizations if thera is conflict\n\nwho mxgoded tereveton tettee mare en one mime’ meaning. sch 8 PT\ncontinued on pape 2—\n\nFood and Drug Administration)ISMP Safe\nMedication Management Falowstip. The\n‘doadina for appications is March 31,2020\n For information, program descriptions, and\n\nvist: mn.\n\nwww.ismp.org,\n\n64", "n_tokens": 407, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-64-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 64, "text": "May 14, 2020 , Volume 25 Issue 9 (Supplement) Ss PEC IAL\nEDITION\nAcute Care os\n\nISMPMedication Safety Alert J*\n\nEducating the Healthcare Community About Safe Medication Practices\n\nCOVID-19-related medication errors\nIn our April 9, 2020 newsletter (www.ismp.or,\n\n5489), we shared\n\nan idea to add a question, “Is this event related to COVID-19 (corona\nvirus)?” to reporting systems to categorize COVID-19-related events,\nallow rapid analysis of quickly emerging risks, and reduce leadership's\n\nRemdesivir investigational drug labeling confusion\n\nreaction time in knowing about and addressing some of these issues.\n Since then, we have received several COVID-19-related medicati:\nerrors each week and wanted to update you on a few important issues.\n\n ISMP received a report last week\nabout a hospital compounding\nissue due in part to label confusion\nwith the investigational drug\nremdesivir. Some facilities have\n\nTce ale\nPerma 24a oe\n\nCoton: er Ora = irc —_\nreceived this drug, manufactured eerste aro eesonioal ae -\nby Gilead Sciences, under a |sstssmorrercmcamoim “TO\n\nta stoma mae come ozvcey reas\n\ncompassionate use program\nduring a period of expanded\n\naccess and through an emergency Seth omtain 10mg.\n\n Figure 1. Label on vial of remdasivir lyophilized powder ni\n\nuse authorization (EUA) program\nissued by the US Food and Drug\nAdministration (FDA).The hospital\nhad implemented an investiga-\ntional study using intravenous\n\nnd oy Feet\n\nPer Cont Trt ee Qnty\nae ey\n\n(IV) doses of remdesivir to treat\npatients with severe COVID-19.The\nadult protocol called for an initial\nloading dose of 200 mg, followed\n\nCRO EROENET ES cane J GILEAD\n\n2. Label on vial of ramdesivir injectable solution does not\nindicate the total amount (100 mg) of drug in each vial; instead,\nit lists a per mL amount (5 mg/mL} and balow that, the total\n\nby subsequent 100 mg doses. Each cattents of the vial, 21.2 mL, which can be easily missed.\n\nvial of ramdesivir contains a total of 100 mg.", "n_tokens": 487, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-64-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 64, "text": "Instead of using\n1 vial to prapare each 100 mg subsequent dose, 2 vials were\nused, thus providing 200 mg for each subsequent dose\ninstead of the intanded 100 mg.\n\n Remdesivir is available for use in clinical trials in at least two\ndifferent dosage forms: a lyophilized powder for injection\nand a solution for injection. Like many investigational drug\ncontainer labels, the vials are not clearly labeled, and the\ninformation presented is crowded and in a small font (see\nour 2-part article about problems with investigational drug\nlabeling: www. ismp.org/noda/i048; www. ismp.org/noda/ 1068).\n The vials of lyophilized powder have a label listing the total\namount (100 mg) of drug in the vial (Figure 1). The vials of\nremdesivir injectable solution have a label that lists the per\nmL strength, “Remdesivir (GS-5734) Injection, 5 mg/ml”\n(Figure 2). Below the 5 mg/mL listing, the vial label notes\nthe total volume in the vial, “Contents: 21.2 mL,” which may\n\ncontinued on page 2 —COVID-15 errors >\n\nra) Toney\n\nremdesivir\ninjection\n100 mg/20 mt\n(S mg/ml)\n\nGausrd\n\nFigure 3 Anne bel rm\nremdesivir injectable solution,\nwhich prominently lists the\ntotal amount of drug in each\nvial (100 mg/20 mL), with the\nper mL amount (5 mg/mL} in\nparentheses below it.\n\nASMP)\n\n‘An BCR Affliate\n\n,- COVID-19 Collaboration\n\n® Double concentration (2%) propofol\nproduct becoming available\nFrasenius Kabi received an emergency\nuse authorization (EUA) on May 8, 2020,\nfrom the US Food and Drug Administra ~\n\n- COVID-19 Col\n\nDouble concentration (2%) propofol\nproduct becoming available\n\nFrasenius Kabi received an emergency\nuse authorization (EUA) on May 8, 2020,\n\nfrom the US Food and Drug Administra -\n\nwho require mechanical ventilation in an\nintensive care unit (ICU) during the\nCOVID-19 pandemic. Propoven 2% is\nexpected to be available by mid-June.\n This will help address the unprecedented\ndemand for propofol used to treat\nhospitalized patients with COVID-19,\nparticularly given pending propofol\nshortages.\n\n", "n_tokens": 510, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-64-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 64, "text": "There is an obvious concem with\nPropoven 2% given its double concen-\ntration. Use of the product may lead to\noverdoses if practitioners are unaware\nof the differant concentration. Propoven\n2% should be carefully reviewed by an\nintardisciplinary committee including\npharmacy, nursing, medical, anesthesia,\ncritical care, and ambulatory care repre-\nsentatives. Prior to use, all critical care\nprescribers (including those redeployed\nto COVID-19 critical care units), nurses\nworking in critical care units, and\nanesthesia providers should be alerted\nto the double concentration. Frasenius\nKabi will be providing stickers that wam\nabout the 2% concentration, which should\nbe applied immediately upon raceipt of\nthe productin the pharmacy sothat each\n\ncontinued on page 2— Codlaboration >\n\nJune 4, 2020 = Volume 25 Issue 11\n\nAcute Care\n\nISMPMedication Safety Alert !-\n\nity About Safe\n\nEducation is “predictably disappointing” and\n\nshould never be relied upon alone to improve safety\nA recent editorial in the May 2020 issue of BMJ Quality & Safety provides\na noteworthy description of why education alone is a weak, low-value\nimprovement intervention.’ The editorial examines the impact of a\nnational education program in Australia aimed at reducing outpatien:\n\nproton-pump inhibitor\nZa changes in discontinua\n\nof the intervention. The|\n\nalone are unlikely to m|\nof PPis. They offer several salient rd\nproduce results. They first reviewed\nno improvements when examining tf\nand clinical outcomes. Despite healthy\nthe authors conclude that educatio\nment efforts,” earning it a “necessa\ninterventions.\"\n\nASMP)\n\n‘An ECS AarBiate\n\nSpecial Alert!\n\nto the increase in demand for neuro-\nmuscular blocking agents for critically ill\nCOVID-19 (coronavirus) patients on\n\nshortage has occurred\n\npducts, including vecuro-\n\nSpecial Alert! Imari Tossa\n\n. lability of these two criti-\n\nPrepare for vials of neuromuscular fanaa Us Fond ead\nblocking agents without cap warnings —§ btion(FDA) has no objec-\nP P Lest for the abbreviated\n\nDue to the increase in demand for meuro- § Jication (ANDA) holder,\nmuscular blocks ants for critically ill & | Limited, to temporarily\nJune until July/August\n\nISMP agrees that education alone is 2 weak Improvement strategy.", "n_tokens": 495, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-64-3", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 64, "text": "cat\n\nplace as a basic prerequisite—it provides healthcare practitioners with the required\nknowledge (what they know) needed to develop the skills (applying that knowledge) to\ndo their job well. For example, education about new medications, devices, automation,\nprocesses, and known risks is fundamental to forming a well-qualified complement of\npractitioners to manage medication safety. But while knowledge and skills are a necessary\nfirst step, education ranks among the least effective interventions in ISMP's hierarchy of\neffectiveness of risk-reduction strategies (Figure 1), right below rules and policies, and\nfar below more effective system-focused strategies such as forcing functions, barriers\nand fail-safes, and automation. ISMP has long noted that improvement strategies\n\nwith the greatest impact\non patient safety and\nthe ability to sustain\nimprovement are those\nthat make it hard for\npractitioners to do their\ncont'd on pg 2— Education >\n\nFigure 1. ISMPs hierarchy of\neffectiveness of risk-reduction\n‘strategies. High-leverage strate-\nQies are mast effective because\n‘they can eliminate the risk of\n\n“designing out’ hazards; how-\never, they oftan raquire complex\nimplementation plans. Medium-\nleverage strategies, which are\ngasier to implament, reduce the\nlikelihood of errors or minimize\nharm; however, they may nead\nperiodic updating and reinforce-\nment. Low-leverage strategies,\nwhich aim to improve human\nperformance, are easy and\nquick to implement; however,\n‘they are the least effective\n‘strategies for error prevention\nalthough frequently relied upon.\n\nabesan3] yoy\n\naberana] uipayy\n\nafe10n3] Mo }\n\nForcing functions\n\nBarriers and fail-safes\n\nAutomation and\ncomputerization\n\nStandardization\nand protocols\n\nRedundancies\n\nWarnings, alerts,\nreminders, checklists\n\nRules and policies\nEducational programs\n\nAvailable information\n\nSuggestions to “be\nmore careful”\n\nMost.\n\n Effective\nHardest to\nImplement\n\nLeast\nEffective\n\nEasiest to\nImplement\n\n@isMP\n\n2020) these drugs without the vial cap\n(seal) incorporating the usual statement,\n“Warning: Paralyzing Agent,” required\nby USP and FDA (Figure 1). Supply\nconstraints prevent Gland from obtaining\nthe products with the usual warning\n‘statements on the vial cap in time to\naddress the shortage.\n\n This temporary situation has obvious\nsafety implications since the absence of\nthe warning may make the vials look\nmore like other medications in similar\nsize vials and cap colors. Neuromuscular\n\nFigure 1.", "n_tokens": 485, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-64-4", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 64, "text": "Images of curently approved cap (left and\n‘temporary cap (right) for vecuronium bromide injec-\n‘tion 10 mg vial and 20 mg vial.\n blocking agents are high-alert madica-\ntions because of their well-documented\nhistory of causing catastrophic injuries\nor death when used in error. Staff aware-\nness about the absence of the usual\n‘warning statement is critically important,\n8s will be safe handling, as noted below.\ncontinued on page 2 — Special Alert! >\n(<<< ee eee", "n_tokens": 110, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-65-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 65, "text": "ISMP Publications\n\n— Regular Journal and Newsletter Features:\n\nPharmacy Practice News\n\nNursing 2020\n\nHospital Pharmacy\n\nPharmacy Times\n\nPharmacy Today\n\nUS Pharmacist\n\nJournal of Emergency Nursing\n\nHome Healthcare Now\n\n©2020 ISMP | www.ismp.org |66", "n_tokens": 47, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-66-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 66, "text": "Error reporting outcomes\n\nASMP)\n\nAn ECRI Affiliate", "n_tokens": 10, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-67-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 67, "text": "Reporter’s Event Description\n\n— “81 y.o. male admitted to hospital with slurred speech and gait change to R/O stroke. Blood glucose 57\n\nmg/dL (Hgb A1C was 13.9% upon admission).\n\n— It was discovered that the patient had not been removing the inner cap of his pen needle for his\n\ninsulin until the day prior to admission.\n\n— For over a year, the patient's physician was constantly increasing the patient’s insulin dose to 150 units in the\n\nmorning and 156 units at bedtime (plus 80 units insulin lispro before each meal).\n\n— The patient described that when he injected his insulin, he would use a napkin to soak up the excess insulin\n\nthat spilled when he injected himself.\n\n— He confirmed he would use an entire pen per day. On day PTA he realized he had not been removing the\n\npen needle inner cap as instructed during diabetes self-management education.\n\n— Patient took off the inner cap and injected the prescribed amount of insulin resulting in hypoglycemia.\n\n— The patient was treated and recovered. During hospital stay he required significantly less insulin (glargine 15\n\nunits subcutaneously hs and insulin lispro 4-6 units before meals).”\n\nwww.ismp.org | 68", "n_tokens": 264, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-68-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 68, "text": "Hazard/Error Story & Recommendations Shared\n\nwww.ismp.org | 69", "n_tokens": 15, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-69-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 69, "text": "ISMP Medication Safety Alert! January 31, 2019\n\nwww.ismp.org | 70", "n_tokens": 18, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-70-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 70, "text": "Working with industry to improve products\n\nwww.ismp.org | 71", "n_tokens": 14, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-71-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 71, "text": "Working with industry to improve products\n\nwww.ismp.org | 72", "n_tokens": 14, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-72-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 72, "text": "July 18, 2019 . Volume 24 Issue 14\n\nAcute Care\n\nISMPMedication Safety Alert I\n\nEducating the Healthcare Community About Safe Medication Practices\n\nNew recommendations to improve drug allergy\ncapture and clinical decision support\n\nThe Partnership for Health IT Patient Safety, a national collabor\nconvened by ECA! Institute, has released a new report on drug alle\ninteractions and how clinical decision support (CDS) and he\ninformation technology (IT) can be used to improve safety. 'The re\nSafe Practices for Drug Allergies—Using CDS and Health\nPresents the findings of a multistakeholder workgroup composed\nmembers from the Partnership, including healthcare providd\nmembers from professional and patient safety organizations, safety and qi\nadvocates, health IT developers, and academic researchers. The workgroup\nco-chaired by ISMP President Michael Cohen and ISMP Medication Safety Speci:\nChristina Michalek and funded in part by the Gordon and Betty Moore Foundatij\nThe report sets forth evi ‘based safe practices and jested implementat|\n‘strategies for using technology to standardize allergy documentation, enabling\ntools to provide more actionable allergy information, monitoring alerts\neffectiveness, and engaging patients. A summary of key highlights from the re\nfollows. \"\n\nImportance of Drug Allergy Information and CDS Tools\nTimely access to accurate, up-to-date drug allergy information is critical to\nPotentially life-threatening adverse drug reactions that can delay the delivery o\nappropriate treatment, necessitate additional treatments, increase care costs,\nnegatively impact patient outcomes. To facilitate the appropriate triggering of ale\nthe information must be documented using the correct allergy terminology,\nproperly, and captured in a standard location. Outdated allergy information\nalso be removed from the patient's list of active allergies.\n\n continued on page 2—Drug allar\n\n22\"¢ Annual ISMP Cheers Awards Nominations\n\nIn our ongoing effort to improve patient safety, ISMP takes great joy in recognizir\nothers who share this same vision for the future. Each year, ISMP celebrates individ ls\ninstitutions, and groups that have demonstrated exemplary commitmentto the continued\n‘science and study of medication safety through innovative and creative proje\n\neducational efforts, standard setting, and/or research. The celebrated winners\nreceive an ISMP Cheers Award, which will be presented during an evening ceremo\nin early December of each year—more to follow on the gala!\n\n", "n_tokens": 476, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-72-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 72, "text": "Nominations for this year's Choars Awards will be accepted through Saleiraalhd\nISMP accepts extemal nominations, including\n\n, SAFETY briefs —\n\n@ Prolia-Udenyca look-alike update. We\ncontinue to receive reports about potential\nlook-alike mix-ups between cartons of\nPROLIA (denosumab; Amgen), an osteo-\nporosis drug, and UDENYCA (pegfilgrastim-\ncbqv; Coherus BioSciences), a biosimilar\nleukocyte growth factor associated with the\nreference peghigrastim product, NEULASTA.\n The US Food and Drug Administration (FDA)\ninitially approved Prolia in 2010. Udenyca\nwas approved in November 2018, and since\nits launch in January, we have received 12\nreports of potential mix-ups. None of the\nreports have mentioned an actual error\ninvolving a patient. However, as reported in\nour May 23, 2019 issue, we have received\nreports of dispensing and drug storage\nerrors. In several cases, a Profia syringe car-\nton was stocked in place of Udenyca, and\n\n‘Figure 1. Package similarity has led to dispensing\nand storage errors.\n\n The reports all indicate that the similar\nappearance of the outer cartons of these\nmedications increases the risk of a med-\nication error (Figure 1). Each carton holds\na single syringe. Each outer carton has sim-\nilar green and white coloring, and the pack-\naging appears to be of similar size and\ndimension. Both medications are marked\n“for subcutaneous use.” The concentration\nfor each drug is listed in a green circle in\nthe same location. Both concentrations\n\ninclude the numbers 6 and 0, which one\ncontinued on page 2—SAFETY briefs >\n\n- Your Reports\nat Work\n\nThanks to your reporting,\n\nCoherus BioSciences sub-\n\nmitted a revised carton\n\nlabel to the US Food and\nDrug Administration (FDA) for its product,\nUDENYCA (pegfilgrastim-cbqv), a biosim-\nilar leukocyte growth factor associated\nwith the reference pegfilgrastim product,\nNEULASTA. The revision was recently\napproved. ISMP had received several\nreports last year about the potential for\nconfusion with PROLIA (denosumab;\nAmgen), an osteoporosis drug.", "n_tokens": 499, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-72-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 72, "text": "Two actual\nerrors were reported in which patients\nreceived the wrong drug. Figure 1 shows\nthe carton label similarities between\nand Prolia while Figure 2 shows\nthe revised carton label. While the com-\npany works to implement the new pack-\naging, cartons of Udenyca will be shipped\nwith a bright orange-red warning sticker\naffixed to the carton (Figure 3).\n\n nocrore tore % Onty\n\nont 0 GDENYCA\npegfilgrastim-cbqv\n\nInjection\n@ img in 0.5 ee Singte- Ouse Premmnes rihanna\nFor Subcutaneous Use Ce ecneae\nsneaker RePreeemne — |\n\nFigure 1. Former green carton label for Udenyca\n(bottom) led to confusion with Prolia cartons\n\n(top).\n\n NOC FON 1@80 % Only\n\n“a\ncv @ UDENYCA\npegfilgrastim-cbqv\n\nInjection\na == ee\n= =\nFor Subestaneous Use\n\nColompsStemahiting facioe\n‘Sarde Seton - Mo Preseraeve\n\niRoweevececs cred a\nfront ca\n\nFigure 2. Recently approved color change for\nUdenyca contrasts with Prolia carton label above.\n\n UDENYCA\nilgrastim-cbqv\n\npau\n@ =- = mre\n\nFor Subcutaneous Use ‘hry mtr\nStews ben. he earn -\n\nFigure 3. An orange-red sticker will be affixed to\nthe original Udenyca carton until the new packaging\nis available. The sticker reminds practitioners to\nverify the product name and strength before use.\n\n www.ismp.org | 73", "n_tokens": 344, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-73-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 73, "text": "Error reporting outcomes\n\n— Improvements in patient safety as a result of hundreds of specific product-related\n\nchanges\n\nDrug naming, labeling, packaging, medication-related device design, measuring devices, infusion pump safety issues.\n\n— Some products withdrawn from market due to medication error issues\n\n— Thousands of product label and labelling changes as a result of new FDA\n\nrequirements or changes in USP standards (USP <7>) due to reported medication errors.\n\nDangerous abbreviations and dose designations, ratio expression, expression of drug concentration, certain new drug packaging requirements, etc.\n\n— Practice-related standards (CMS, Joint Commission, etc.)\n\nwww.ismp.org | 74", "n_tokens": 133, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-74-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 74, "text": "USP Standards\n\nMP\n\nAn ECRI Affiliate\n\n [REVISION BUNETIT\nOfficial September 1, 2019\n\nFT\n\n(7) LABELING\n\nThis general Chapter provides definitions and standards for labeling of official articles. Labeling standards for an article\nin the article’s and tis in that all articles\ninhror Nw be sje othe ang egret spches in ths chapter by ie ra ‘As with\nare speci\ning, identity, strength city cad Create compensa rectiomente ior for labeling have a role in\nthe adulteration and misbranding provisions of federal law [see the Fi | Food, Drug, and Cosmetic Act (FDCA) sections\nS10, 50246K3}0),502(9), and 5020) Exceptions or addtional requirement speci o anima rug products and\n\nThe term “labeling” includes all labels and other written, printed, or graphic matter on an article’s immediate container or\non, oF in, any package or wr tin which itis enclosed, except any outer shipping container. The term “label” is that part\nthe labeling on\nA shipping’ sontainer that contains a single article, unless the container also is essentially the immediate container or the\noutside of the consumer package, must be labeled with a minimum of product identification {except for controlled\n\n\"Beyond vse dates (GUDs) and expiration dates are not the same, Ane\ndates (BUDs) and expiration dates are not the same. An expiration date identifies the time during which a\ncos if one exists, /ided it is kept under the prescribed storage conditions. The expiration date limits\nbe dispensed of used. Expiration dates are assigned by mes cf, active c raceubal gn (API), or may\n‘on\nand of the ‘chemical and\nanalytical Performance testing sterility, py aby, ond Packaging integrity of the Product.\n beyond-use date (BUD) is the date or time beyond which a ded pr ion must be The date or\n\ntime is determined from the date the preparation was compounded.\n\nLABELS AND LABELING FOR DRUG PRODUCTS AND COMPOUNDED PREPARATIONS\nEXPRESSED AS ACTIVE MOIETY IN NAME AND STRENGTH\n\nbe orp aterm ofthe active", "n_tokens": 455, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-74-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 74, "text": "he ihe bel relate 1121 raph Nomiog Poky fo Sal Drag\nterms active , it\net ne Psu ims of the act ‘moiety on (see »% yoph Policy ‘Drug\nLabeling\n\nThe states the salt form of the active that the because\ntha ptomnaton cat i useful to provtiioner ond Dalen The artes anid seni of bots the actos eee and and specific\nsalt form (when applicable) are provided in the labeling.\n\n Exceptions\nclinial perapective an exception to tis polity may be considered. In such gases when the monograph tlle contains the\nclinical perspective, an exception to this policy may be considered. In such cases, when the title contains the\nspecific salt form ofthe active moiety, the strength of the product or preparation is also terms of the specific salt\n\nLABELS AND LABELING FOR INJECTABLE PRODUCTS\n\nThe labels! and the labeling state the following information:\n * Name of the product\n° In the case of a liquid, the quantity or proportion of each active moiety or drug substance in a specified volume\n\nGintlons for Droper storage of tee conetiouted sokition. arvd s BUD {see Egnrotion Date ond Bopond-tise Be)\n © Route(s) of administration\n\nTil there are space limitations, see 21 CFR§ 201.10(i), 21 CFR§ 201.105(b), 21 CFR§ 610.60.\n\n © 2019 The United States ial Convention All Rights\n(C234255-M4908-NL2015, rev. 00 20190830\n\nwww.ismp.org\n\n75", "n_tokens": 343, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-75-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 75, "text": "FDA Guidance Statements\n\nASMP)\n\nAn ECRI Affiliate\n\nGuidance for Industry\n\nBest Practices in Developing\nProprietary Names for Drugs\n\nDRAFT GUIDANCE\nThis gui di is being distr for purposes only.\nCc and suggesti ing this draft doc should be d within 60 days of\n\npublication in the Federal Register ofthe notice announcing the availability ofthe draft\nguidance. Submit electronic comments to http:/www-regulations.gov/ Submit written\ncomments to the Division of Dockets Management (HFA-305), Food and Drug Administration,\n5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with\nthe docket number listed in the notice of availability that publishes in the Federal Register.\n\nFor questions regarding this draft document contact (CDER) Office of Surveillance and\nEpidemiology, Division of Medication Error Prevention and Analysis, Kellie Taylor at 301-796-\n0157, or (CBER) Office of Ci Oo and Development at 800-835-4709 or\n240-402-7800.\n\nU.S. Department of Health and Human Services\nFood and Drug Administration\nCenter for Drug Evaluation and Research (CDER)\nCenter for Biologics Evaluation and Research (CBER)\n\nMay 2014\nDrug Safety\n\nSafety Considerations\nfor Product Design to\nMinimize Medication\nErrors\nGuidance for Industry\n\nU.S. Department of Health and Human Services\nFood and Drug Administration\nCenter for Drug Evaluation and Research (CDER)\n\nApril 2016\nDrug Safety\n\nwww.ismp.org | 76", "n_tokens": 298, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-76-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 76, "text": "Public Health Advi\n\nASMP)\n\nAn ECRI Affiliate\n\nsories\n\nthe New Year and our continued service to\nyou as we work together to protect patients\nfrom medication errors.\n\nFDA Public Health\n\nAdvisory.\nThanks to your reports, FDA\npublished a Public Health\nAdvisory late Wednesday to wam\nUS citizens traveling abroad or\nbuying prescription drugs via the\nInternet about risks when\nobtaining medications from\nforeign sources (www.fda.gov/\noc/opacom/re; confusi\nnames.html). The advisory noted\nthat some FDA-approved\nproducts have the same brand\nnames as foreign drug products with\ncompletely different ingredients. They also\nfound that 105 US brand names are danger-\nously close to foreign brand names used for\ndifferent products; patients who fill prescrip-\ntions abroad may get the wrong drugs. FDA\nnoted that the advisory builds on recognition\nof the problem as published in our January\n13, 2005 newsletter. The advisory was accom-\npanied by tables to identify the involved\nproducts. continued on page 2 >\n\nprrooues oan,\nunsteady fii\nreported ma:\nof the type c\n\nTo further ir\nwe asked ou\nknow if the\nHf\nit\nn\na\ntl\n\ntl\n\n——\npl\n\nlong, causin\nsame mann\nkey might r\nlater, when\ncould not re\n\nHer inability\ncase may be\nfirst report\nDuring an\n\nfound that «\nbe directly n\n\nwww.ismp.org\n\n77", "n_tokens": 280, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-77-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 77, "text": "FDA drug safety communications\n\nFDA Drug Safety Communications for Drug Products\nAssociated with Medication Errors\n\ne FDA Drug Safety Communication: FDA approves brand name change for\nantidepressant drug Brintellix (vortioxetine) to avoid confusion with antiplatelet drug\nBrilinta (ticagrelor)\n\ne FDA Drug Safety Communication: FDA cautions about dosing errors when switching\n\nbetween different oral formulations of antifungal Noxafil (posaconazole); label\nchanges approved\n\ne FDA Drug Safety Communication: FDA cautions about dose confusion and\nmedication error with antibacterial drug Avycaz (ceftazidime and avibactam)\n\ne FDA Drug Safety Communication: FDA cautions about dose confusion and\nmedication errors for antibacterial drug Zerbaxa (ceftolozane and tazobactam)\n\ne FDA Drug Safety Communication: FDA Alerts Pharmacists and Health Care\nProfessionals to Potential for Injury when Dispensing the Similar-Sounding Drugs\nDurezol and Durasal\n\ne FDA Drug Safety Communication: FDA requires label warnings to prohibit sharing of\nmulti-dose diabetes pen devices among patients\n\ne FDA Drug Safety Communication: FDA requiring color changes to Duragesic\n(fentanyl) pain patches to aid safetyaemphasizing that accidental exposure to used\npatches can cause death\n\ne FDA Drug Safety Communication: FDA warns about potential medication errors\n\nresulting from confusion regarding nonproprietary name for breast cancer drug\nM Pp Kadcyla (ado-trastuzumab emtansine)\n\nAn ECRI Affiliate\n\nwww.ismp.org | 78", "n_tokens": 330, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-78-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 78, "text": "FDA Advise-ERR in ISMP Medication Safety Alert! publications and FDA website\n\nwww.ismp.org | 79", "n_tokens": 24, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-79-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 79, "text": "ISMP educational programs\n\nAN EVENT CONDUCTED AT THE AMERICAN ORGANIZATION OF NURSE EXECUTIVES (AONE) 2019 ANNUAL CONFERENCE\n\nManage the Safety Risks Associated\nwith IV Push Medication Use\n\nJust Culture\n\nTraining for Managers\n\n: Judy Smetzer, RN, BSN, FISMP\nWorking Together to Address Institute for Safe Medication Practices\n\nGlobal Drug Safety Issues jsmetzer@ismp.org\nwith Packaging and Labeling\n\nMichael R. Cohen, RPh, MS, ScD (hon), DPS (hon) FASHP 3\nea President, Institute for Safe Medication Practices °\nChairperson, Internationlal Medication Safety Network\n\nwww.ismp.org |80\n\nAn ECRI Affiliate", "n_tokens": 129, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-80-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 80, "text": "Safety Tools/Lists\n\nISMP List of Confused Drug Names\n\nis is of conto ug rames, wich nudes lok ab and\ncanst ol hos amo pars that ha\n\n‘ut spore salaqunt orice the isk fers. This may inte\nstatis such as using both tho band and genres on presrp-\nreer era ial cy pe nadine\n\nsens 1 pret ok alto\n\nFDA and ISMP Lists of\n\nLook-Alike Drug Names with Recommended Tall Man Letters\n\n‘Sno 7008, SMP has mati a tf droga pats and res wth\n, etre to bop daw\natten to the dares ok alk cr panes. The fs cos\n\nlotrs was inftated i 2001 wah the agoncy’s Name Ditfereatiten\nPropet (omme /3-S.\n\n‘man ts dona cpt wh tr at necro ree\none prog ea  n s*se\n\n Mop pel neotenic a tse\n{hs te pss tn ng ei i\nape hat\n\nTable 1 proves an siptabtind st of FDA approved eth drug\n‘es wath ecard ta man ets\n\nTle 2 pros\n\n‘mendations from [SMP regarding the wn and placement of tall man\n‘ers. Ths 1 nt an oficial st approved by FDA. ttn for\nelutary ws by hoaicarepractionars, drag bfemuton vend, ad\nmediation techolgy venders. Any proc abl changes by manta,\n{urs equre FLA approval\n\n5 tanfardcati egardng wich rst preset upper,\nwhose\n\n‘mares ages fo ett rk of eras dot sear dry rae. Yo\nsciatic prot\n\n‘ho stat apts\nsah,\n\ncata part\n\nor he po a ee\nSeog elt eee\ntw ad bad on a alate opt scored.\n\n", "n_tokens": 416, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-80-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 80, "text": "‘Sefton arene\n\n{SMP suggests that ho bolded, tl man tg sche prov by\nOA and ISMP fr he drag mame pars std i Tables 1 and 2 bo\nfeo |\n\nAn ECRI Affiliate\n\n(C70 | FA and SP ints of ak Alt me wth comer Ta Man ots\n\nISMP List of High-Alert Medications in\nLong-Term Care (LTC) Settings\n\nISMP List of High-Alert Medications in\nCommunity/Ambulatory Healthcare\n\nISMP List of High-Alert Medications\n\nin Acute Care Settings\n\ngh alert maicatons a gs that ar a gh sk of causing spit ptt ham whon Hoya sd nen, Ao stats\nyea coe ih eu. nef a chy a sia ns Wo\nws iss red the isk of ors.\n tt aig, sean, poprton and admins tesa pacino css iomsn ca ths gs ity acs\nalot medications sng aur aol amp nica decison suport an automa lors and sig rokrdans sch 2 automata or\n\n‘nt atways the optimal aor raducton statugy and may nat b practical fo alo ha\n‘madication on tho Hist)\n\nanasthtic pons, gon kd and Va, propal ttn ry)\n =e 109. idocaina, arson)\nagonts, including\n. eh -wartann, low molecular weight heparin,\n\n‘opanin)\n1 rt oral antcoagutants and actor Xaintbitos fa, datigaran, raraxatan,\n© rect thrombin ints og. agarban, bv, dabigatran)\n © ghenpotain ata nititrs fg. ptt)\n\n1» thrombolytics (a. alteplase, retopkase, |\nade tons\nr=\ndesigne) -doxtroso,typortorec, 20% or graator\ncan\n(ta nratocal medications\nome ~ rae modesto Wg. dox ny\n(we iocsomeal ‘Based on error reports submitted to the\nway ergs 09. (SMP Naboral Medication Erors\n™ Us —— Setar Sa\nWi midagctam, ones | Ws\n", "n_tokens": 494, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-80-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 80, "text": "fos oi poh ‘otal bya, ta ry he ups wos an\nia sidan. ‘nent a hm\nia nd lay eer SM\n= “opoxds, ncluding created and penidically updates a list of\nHt 1” vl gh tet meter\n' — Ses pt\n| tend on BMP ne gd\nbeck aps op. since, cero. wen) «hewn matte et\n[Barontoral nutnhan proparabons: ‘tions, Further, to assure relevance and\n‘njachon.typertanc. rotor than -concantration _completonoss, the clinical staff at [SMP\nwater — colina ‘ao rons of he ISP advey bead\nof 100 mi oF more, were asked to rewew the potential list\nTh lato modeatnt at waten\nsora oral. iii, lcs felt king\nlin. TOLBUT rico) Salone peal tee\nion dates: Warman: Wham\nap) oar —\n\nRecommendations for the Safe Management of Patients\n\nwith an External Subcutaneous Insulin Pump During Hospitalization\nPeas note\n‘suet\n| Initial Assessment Process.\n\n0\n1 Ast ofan intial patient anision assent russ sleet specially atl pins if thy ing an iin ap.\n 21 Neptune ni ey, acing tn ine pet mmr ed ty tig in\n\nin pices\nSit egeontn ang\n\nPaint Selection Cita\n\n\"A \" ou a oon inion\nscr nba te C ‘wn be et\nCao\nUlenie, he psn ab stil |\nTancditnpeseaiea”\n\nPi teetia teeriise amen e eed ones eons heceaee inven\n\nISMP Guidelines for\nSafe Electronic Communication\nof Medication Information\n\nPEE Sore Presentation of Drug Names\n\n© Winen expressing » ener tener aries using in te 5)\n", "n_tokens": 398, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-80-3", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 80, "text": "‘tne praryexpronon of org nomecioture,eosureg Mat ex mans he US Food and Ong Ramseaton\n{FOS approved nomenclature so that eictronic medication records agree Wt a carton and container bets.\n\n® wonen expressing a generic drug name, do not include the saft of the chemscal untess there are mulDple satts avatatHe\n(eg. hydeOXYeine HCI and IydrOXY.ine paenoate) or the salt alters the drug release (e.g. uPMENAZine HC! and\n\n‘and thus conveys 1 the sat ie used 25 Dart of the mame, disctay\nthe fll name ofthe sat unless an abbreviation has been approved by USP (Le, K [potassium Na (sedue), HBr fhy>\n‘crobromide|, and HC! Inydrocnionae)). The salt shousd follow tne drug name.\n\n Comment: The symbous Na and K are intended for use in dbreviging the names ofthe sats of organic sci, Dut these\n[Symbols should not be used when the word sodium) or potsksium appears atthe beginning ofan offcia drag name\n(ag. Na Dicarponate is not acceptable because t may be misread as “no Dcarbonste\"7.\n\n © wen exoresing 9 brand drug name, use an unpeRase fst ier Tradean meats (eg, TM 8) should nt be\ntad\n\n‘Comment amnough the use of i se lowercase\nisros ove more snoo aad catmgocte Bon $s bacco wnoecece Wire each ok Soni ba Se re\niticult to reed, especie in low Iighting.\" Also, using all wpercase letters fo express brand names dows net alow for\n{he use of ta man eters when Indlcated, o¢ mentioned i Rem #8.\n\n @ tnssuse he word “Mix” and any numeral values Bat are pan ofthe brand name for tee combination insu\nfraducts eg. NowoLOG", "n_tokens": 466, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-80-4", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 80, "text": "Mx 7020) together on te sme ine on compte screens, mesesBon administration\n‘cars MAG) and ete secon forms of ommuncaten\n\n© Ure bodes, UPPERCASE tat man eter eg. vNCRISNe, ROLASEN or specie oroupe ot simi n\nSocks anna arr wor ova vat om on aan nna Tha hap marin eo\nselecting he wrong produc, ‘ate ames appear enue and\n‘Sorcn rat To promote sansaraton Othe ers posted in UPPERCASE Bal or foo he recom\n‘mention on te FDA and ESM Lists of LooksAlike Drug Names wieh Recommedded Tal Man Lectors\n(oom. ore 7B,\n\nCrmment: FOX eceroom mented veuty twenty eee oh ite drug nares teed WE Re\nProject 7 using the al man lets on al packaging and is\nDeg mates\n\n© For arug names ending with the letter “I> capitalize the “E (e.g., propranciol 20 mg) to avoid confusion with the\n‘numeral 1 In the Gose that fosows the drug name. See item #27 fora recommendation to provice adequate space be-\n‘ween he crug name and dose.\n\n ‘Comment A lowercase ler “I” 3 the end of 2 dug name has been confused as the numerat “1° and mistaken a5 part\nofte dose, particulary # adequate space has not been provided between the drug Asme and dose e.g, proprancloc0\n‘mg nas been mistaken 2& proprancic! 120 mg). Almays Iaave 3 space betwwen the end of the dug name, te dose or\n‘strength. 300 the unit designation Ve 0. a\n\nisuromy ‘commend onpete? Gusdelnes\n\nwww.ismp.org |81", "n_tokens": 408, "kind": "text"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-81-0", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 81, "text": "ISMP Practice Guidelines\n\nISMP Targeted Medication ISMP Guidelines for\n\nSafety Best Practices Optimizing Safe Subcutaneous\nfor Hospitals Insulin Use in Adults\n\nGuidelines for Optimizing\n\nSafe Implementation and Use\nof Smart Infusion Pumps\n\nwww.ismp.org\n\nLESMP) Recommendations for the Sate Management of Patients\nMadiction Practices i with an External Subcutaneous Insulin Pump During Hospitalization\n\nwww.ismp.org\n\nPeene cate ee rennin eee comet tM ae pm ot et Nae he heed Prep ayerews ®\n\nSafe Use of Automated ————\n\n|) Re pet da eed pitert aimee avermmnwnt saree Cun! be pamgted t gerd aly wd ab putenm | fey ae img a cmd pay\n\nISMP Dispensing Cabinets\n\nAn ECRI Affiliate\n\nD tte pete camqoatend entogae foqgnentaty fo tnd priat enmt Galbaty to ptat | ing ce\n\nwww.ismp.org |82", "n_tokens": 213, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-0-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 0, "text": "Enhanced Drug Distribution Security in 2023 Under the Drug Supply Chain Security Act (DSCSA)\n\nAbha Kundi, JD, MPH Regulatory Counsel\n\nConnie Jung, RPh, PhD Senior Advisor for Policy\n\nOffice of Drug Security, Integrity, and Response​ Office of Compliance​ CDER | US FDA​ CDER SBIA Webinar – October 5, 2021", "n_tokens": 69, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-1-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 1, "text": "Learning Objectives\n\nDiscuss enhanced drug distribution security requirements that go into effect in 2023 under the Drug Supply Chain Security Act (DSCSA)\n\nExplain how enhanced drug distribution security will help protect patients from exposure to drugs that may be counterfeit, stolen, contaminated, or otherwise harmful • Summarize updates on implementation of supply chain security requirements under the DSCSA\n\nwww.fda.gov\n\n2", "n_tokens": 77, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-2-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 2, "text": "www.fda.gov\n\nPharmaceutical Supply Chain\n\nMaintaining integrity from manufacturer to patient(s) • Who touches the product? • Where are the vulnerabilities? • What are the threats?\n\nProtect the product\n\nProtect the patient\n\n3", "n_tokens": 45, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-3-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 3, "text": "Threats to the Pharmaceutical Supply Chain\n\nIllegitimate product Counterfeit, diverted, stolen, intentionally adulterated, subject to a fraudulent transaction, or otherwise unfit for distribution that would result in serious adverse health consequences or death to humans\n\nUnscrupulous players • • •\n\nDistribute illegitimate product Don’t maintain quality of the product Don’t maintain security or integrity of the supply chain (examples: are not authorized or do business with entities that are not authorized)\n\nWeakness in the drug supply chain can be anywhere\n\nwww.fda.gov\n\n4", "n_tokens": 103, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-4-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 4, "text": "Recent Counterfeits\n\nSymtuza tablets (Image from Janssen/Johnson & Johnson)\n\nBiktarvy tablets (Image from Gilead)\n\nDescovy tablets (Image from Gilead)\n\nProtecting the supply chain ultimately protects patients!\n\nwww.fda.gov\n\n5", "n_tokens": 54, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-5-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 5, "text": "Investigate and properly handle suspect and illegitimate products\n\nSuspect Product: reason to believe that product potentially is:\n\nIllegitimate Product: credible evidence shows that the product is:\n\ncounterfeit, diverted, stolen\n\ncounterfeit, diverted, stolen\n\nsubject of fraudulent transaction\n\nsubject of fraudulent transaction\n\nintentionally adulterated or appears otherwise unfit for distribution such that the product would result in serious adverse health consequences or death to humans\n\nintentionally adulterated or appears otherwise unfit for distribution such that the product would result in serious adverse health consequences or death to humans\n\nNotify FDA of Illegitmate Product within 24 hours (Form FDA 3911) and other trading partners within 24 hours\n\nwww.fda.gov\n\n6", "n_tokens": 129, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-6-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 6, "text": "The Drug Supply Chain Security Act DSCSA\n\nEnacted November 27, 2013\n\nOutlines steps to build an electronic, interoperable system to identify and trace certain prescription drugs as they are distributed in the U.S.\n\nEnhances ability to help protect consumers from exposure to drugs that may be counterfeit, stolen, contaminated, or otherwise harmful\n\nImproves detection and removal of potentially dangerous drugs from the drug supply chain\n\nwww.fda.gov\n\n7", "n_tokens": 85, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-7-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 7, "text": "www.fda.gov\n\nDSCSA Goals\n\n1. Implement interoperable, electronic tracing of products at the package level by 2023 that will:\n\nEnable secure tracing of product at the package level\n\nUse product identifiers to verify product at the package level\n\nEnable prompt response to suspect and illegitimate products when found\n\nImprove efficiency of recalls\n\n2. Establish national standards for licensure for wholesale distributors and third-party logistics providers (3PLs)\n\n8", "n_tokens": 89, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-8-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 8, "text": "www.fda.gov\n\nDSCSA Key Requirements\n\nProduct Tracing\n\nVerification\n\nProduct Identifier\n\nAuthorized Trading Partner\n\n9", "n_tokens": 21, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-9-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 9, "text": "www.fda.gov\n\nTrading Partners under DSCSA\n\nManufacturers\n\nRepackagers\n\nWholesale Distributors (WDDs)\n\nDispensers (primarily Pharmacies)\n\nThird-party logistics providers (3PLs)\n\n10", "n_tokens": 44, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-10-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 10, "text": "Products\n\nWhat’s covered:\n\nPrescription drug in finished dosage form for administration to a patient without further manufacturing (such as capsules, tablets, lyophilized products before reconstitution)\n\nWhat’s not covered:\n\n‒\n\nBlood or blood components intended for transfusion Radioactive drugs or biologics Imaging drugs Certain IV products\n\n‒ ‒ ‒ ‒ Medical gas ‒ Homeopathic drugs ‒\n\nLawfully compounded drugs\n\nRefer to the definition for “product” in section 581(13) of the FD&C Act for specific information regarding exceptions.\n\nwww.fda.gov\n\nTransactions\n\nInvolve transfers of product where a change of ownership occurs Excludes:\n\n– – – – – –\n\n– – – – – –\n\nIntracompany distributions Distribution among hospitals under common control Public health emergencies Dispensed pursuant to a prescription Product sample distribution Blood and blood components for transfusion Minimal quantities by a licensed pharmacy to a licensed practitioner Certain activities by charitable organizations Distributions pursuant to a merger or sale Certain combination products Certain medical kits Certain IV products Medical gas distribution Approved animal drugs\n\nRefer to the definition for “transaction” in section 581(24) of the FD&C Act for specific information regarding exclusions.\n\n11", "n_tokens": 242, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-11-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 11, "text": "Product Tracing Information\n\nTransaction Information (TI): •\n\nProprietary or established name or names of the product; Strength and dosage form of the product; National Drug Code number of the product; Container size; Number of containers; Lot number of the product; Date of the transaction; Date of the shipment, if more than 24 hours after the date of the transaction; and Business name and address of the person from whom and to whom ownership is being transferred.\n\n• • • • • •\n\nTransaction Statement (TS): A statement, in paper or electronic form, that the-- •\n\nEntity transferring ownership in a transaction is authorized as required under DSCSA; Received the product from a person that is authorized as required under DSCSA; Received transaction information and a transaction statement from the prior owner of the product, as required under the law; Did not knowingly ship a suspect or illegitimate product; Had systems and processes in place to comply with verification requirements under the law; Did not knowingly provide false transaction information; and Did not knowingly alter the transaction\n\nTransaction History (TH): A statement in paper or electronic form, including the transaction information for each prior transaction going back to the manufacturer of the product\n\nwww.fda.gov\n\n12", "n_tokens": 247, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-12-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 12, "text": "www.fda.gov\n\nDSCSA Implementation\n\n2015\n\nAuthorized Trading Partner Product Tracing • Verification\n\n2018+ •\n\nProduct Identifier • Verification (package- level)\n\n2023\n\nEnhanced Drug Distribution Security Requirements\n\n2023+\n\nEnhanced System\n\nThe requirements under section 582 of the FD&C Act apply to manufacturers, repackagers, wholesale distributors, and dispensers (pharmacies).\n\n13", "n_tokens": 80, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-13-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 13, "text": "DSCSA Implementation\n\n2015\n\n2015\n\n2015\n\nAuthorized Trading Partners • Manufacturers and\n\nRepackagers: valid registration with FDA\n\nWDDs & 3PLs: valid State or Federal license and compliance with reporting requirements • Dispensers: valid State license\n\nProduct Tracing\n\nLot-level • Provide and receive\n\ntransaction documentation with each sale\n\nRespond to request for information • Store records • Paper and electronic\n\nformats\n\nVerification\n\nQuarantine and investigate\n\nsuspect product Investigation illegitimate product\n\nNotify FDA and trading partners of illegitimate product\n\nResponse to verification requests • Store records\n\nwww.fda.gov\n\n14", "n_tokens": 109, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-14-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 14, "text": "DSCSA Implementation\n\n2018\n\n2018+\n\nProduct Identification (Serialization) •Manufacturers & repackagers encode product identifiers on prescription drug packages on the smallest individual saleable unit\n\nVerification •Serialized product can be verified\n\ndown to the package level using the product identifier\n\nSaleable returns •Compliance policies issued that provide additional time\n\nProduct Identifier: National Drug Code (NDC), Serial Number, Lot, Expiration Date)\n\nwww.fda.gov\n\n15", "n_tokens": 94, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-15-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 15, "text": "DSCSA Implementation\n\n2023\n\n2023 & Beyond\n\nEnhanced Drug Distribution Security Requirements • All electronic • Enhanced product tracing at\n\nthe package level (i.e., includes product identifier) • Enhanced verification\n\nEnhanced System\n\nEnhanced drug distribution security • Across the pharmaceutical supply chain • Improved inspections and investigations • Improved data analytics • Continued compliance and enforcement\n\nwww.fda.gov\n\n16", "n_tokens": 73, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-16-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 16, "text": "Challenge Question #1\n\nKey supply chain security requirements under DSCSA include which of the following? A. Product Tracing B. Verification C. Product Identifier D. Authorized Trading Partner E. All of the above\n\nwww.fda.gov\n\n17", "n_tokens": 49, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-17-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 17, "text": "www.fda.gov\n\nDSCSA Key Requirements\n\nProduct Tracing\n\nVerification\n\nProduct Identifier\n\nAuthorized Trading Partner\n\n18", "n_tokens": 21, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-18-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 18, "text": "2023 Enhanced Drug Distribution Security Effective 11/27/2023\n\nSection 582(g) Enhanced Drug Distribution Security -\n\n(1) In general.--On the date that is 10 years after the date of enactment of the Drug Supply Chain Security Act, the following interoperable, electronic tracing of product at the package level requirements shall go into effect:\n\n(A) The transaction information and the transaction statements as\n\n(D) The systems and processes necessary to promptly respond with the\n\ntransaction information and transaction statement for a product upon a request by the Secretary (or other appropriate Federal or State official) in the event of a recall or for the purposes of investigating a suspect product or an illegitimate product shall be required.\n\n required under this section shall be exchanged in a secure, interoperable, electronic manner in accordance with the standards established under the guidance issued pursuant to paragraphs (3) and (4) of subsection (h), including any revision of such guidance issued in accordance with paragraph (5) of such subsection.\n\n (B) The transaction information required under this section shall include the product identifier at the package level for each package included in the transaction.\n\n (C) Systems and processes for verification of product at the package level, including the standardized numerical identifier, shall be required in accordance with the standards established under the guidance issued pursuant to subsection (a)(2) and the guidances issued pursuant to paragraphs (2), (3), and (4) of subsection (h), including any revision of such guidances issued in accordance with paragraph (5) of such subsection, which may include the use of aggregation and inference as necessary.\n\n(E) The systems and processes necessary to promptly facilitate gathering the information necessary to produce the transaction information for each transaction going back to the manufacturer, as applicable, shall be required- (i) in the event of a request by the Secretary (or other appropriate Federal or State official), on account of a recall or for the purposes of I nvestigating a suspect product or an illegitimate product; or (ii) in the event of a request by an authorized trading partner, in a secure manner that ensures the protection of confidential commercial information and trade secrets, for purposes of investigating a suspect product or assisting the Secretary (or other appropriate Federal or State official) with a request described in clause (i).\n\n", "n_tokens": 484, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-18-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 18, "text": "(F) Each person accepting a saleable return shall have systems and\n\nprocesses in place to allow acceptance of such product and may accept saleable returns only if such person can associate the saleable return product with the transaction information and transaction statement associated with that product.\n\n www.fda.gov\n\n19", "n_tokens": 58, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-19-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 19, "text": "System Attributes\n\nTransaction Information (TI) and Transaction Statement (TS) will be exchanged in a secure, interoperable, electronic manner…\n\nTI will include the product identifier at the package level for each package included in the transaction.\n\nSystems and processes for verification of product at the package level, including the standardized numerical identifier…which may include the use of aggregation and inference as necessary.\n\nSystems and processes necessary to promptly respond with the TI and TS for a product upon a request by FDA (or other appropriate Federal or State official) in the event of a recall or for investigating a suspect product or an illegitimate product\n\nSystems and processes necessary to promptly facilitate gathering the information necessary to produce the TI for each transaction going back to the manufacturer, as applicable (upon a request by FDA…or an authorized trading partner…)\n\nSystems and processes in place to allow acceptance of saleable returns and only if such person can associate the saleable return product with the TI and TS associated with that product.\n\nwww.fda.gov\n\n20", "n_tokens": 204, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-20-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 20, "text": "Aggregation and Inference • Aggregation is the process of building a relationship between unique\n\nidentifiers assigned to packaging containers.\n\nPackages (bottles)\n\nCase\n\nPallet\n\nInference involves examining information for a higher level of packaging to infer information about the next level of packaging and its contents.\n\nwww.fda.gov\n\n21", "n_tokens": 59, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-21-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 21, "text": "www.fda.gov\n\nSystem Structure\n\nSemi - centralized Model\n\nCommunication hub\n\nFDA or other Federal or State Official\n\nCentralized • Trading partners provide data into a central\n\nrepository (database)\n\nProduct tracing and verification is performed by querying the central repository\n\nDatabase\n\nDatabase\n\nDatabase\n\nDatabase\n\nDecentralized • Trading partners maintain their data in their own\n\nlocal database or a data storage provider’s database\n\nManufacturer 1\n\nManufacturer 2\n\nWholesale Distributor 1\n\nWholesale Distributor 2\n\nDispenser 1 (Pharmacy)\n\nDispenser 2 (Pharmacy)\n\nProduct tracing and verification is performed by querying the multiple databases\n\nA communications hub (active or passive) connects different databases\n\nManufacturer 2\n\nWholesale Distributors 3\n\nDispenser 3 (Pharmacy)\n\nSemi – Centralized • Trading partners maintain data into a few centralized databases or data storage provider(s) database(s) • Product tracing and verification is performed by querying the each databases • A communications hub connects different databases\n\n22", "n_tokens": 178, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-22-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 22, "text": "Enhanced Product Tracing: Exchange of Transaction Information & Statement\n\nTH Sunsets\n\nSelling Trading Partner\n\nTI and TS\n\nPurchasing Trading Partner\n\nBeginning 11/27/2023 -\n\nExchange of transaction information and transaction statements must be in a secure, interoperable, electronic manner\n\nAdditional requirement to promptly facilitate the gathering of information necessary to produce the transaction information for each transaction going back to the manufacturer\n\nwww.fda.gov\n\n23", "n_tokens": 78, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-23-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 23, "text": "www.fda.gov\n\nProduct Identifier (Serialization)\n\nManufacturers/Repackagers (November 2018)\n\nEncode product identifiers on prescription drug packages • Determine smallest individual saleable unit • Verification requirements changes once products are serialized with product identifier\n\nProduct Identifier\n\nNDC: XXXX-XXXX-XX SERIAL: XXXXXXXX LOT: XXXXXXX EXP: YYYY-MM-DD\n\nNational Drug Code (NDC) • Serial Number • Lot Number • Expiration Date Human and machine readable formats Machine readable barcodes:\n\n2D data matrix for packages - Linear or 2D data matrix for homogenous cases\n\n24", "n_tokens": 136, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-24-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 24, "text": "Packages Without Product Identifiers\n\nExcluded Products\n\nNot all prescription drugs are required to have a product identifier and are excluded.\n\nGrandfathered\n\nSome products will be in the supply chain before the product identifier requirement took effect.\n\nWaiver, Exception or Exemption\n\nSome products were granted a waiver, exception or exemption from the product identifier requirement.\n\nIf you are unsure whether a product should have a product identifier, verify with the manufacturer or repackager.\n\nwww.fda.gov\n\n25", "n_tokens": 100, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-25-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 25, "text": "Enhanced Product Tracing: Serialized Transaction Information\n\nBeginning 11/27/2023, the exchange of transaction information (TI) shall include the product identifier at the package level.\n\nPre-November 2023\n\nTransaction Information: •\n\nProprietary or established name or names of the product Strength and dosage form of the product National Drug Code number of the product Container size Number of containers Lot number of the product Date of the transaction Date of the shipment, if more than 24 hours after the date of the transaction Business name and address of the person from whom and to whom ownership is being transferred\n\n• • • • • •\n\nNovember 2023+\n\nTransaction Information: •\n\nProprietary or established name or names of the product Strength and dosage form of the product National Drug Code number of the product Container size Number of containers Lot number of the product Date of the transaction Date of the shipment, if more than 24 hours after the date of the transaction Business name and address of the person from whom and to whom ownership is being transferred Serial number Expiration date\n\n• • • • • •\n\n•\n\nwww.fda.gov\n\n26", "n_tokens": 216, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-26-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 26, "text": "www.fda.gov\n\nEnhanced Product Tracing: Reconciliation of Data and Product\n\nSelling Trading Partner\n\nRead product identifier (barcode) on the outbound package(s) or homogenous case(s) to fulfill an order\n\nCapture this data for the product tracing information (TI/TS) to be sent to the purchasing trading partner\n\nProvide data (TI/TS) and product(s) to purchasing trading partner\n\nTI and TS\n\nPurchasing Trading Partner\n\nor\n\nReceive data (TI/TS) and product(s) from selling trading partner\n\nRead product identifier (barcode) on the inbound package(s) or homogenous case(s) received in an order\n\nCapture this data and reconcile with associated product tracing information (TI/TS) received from the selling trading partner\n\n27", "n_tokens": 157, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-27-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 27, "text": "Enhanced Product Tracing: Handling Aggregation Errors & Other Discrepancies\n\nProduct tracing information should be true, accurate, and complete.\n\nThere may be a clerical error or discrepancy in product tracing information that may not be indicative of a suspect product.\n\nIf a trading partner purchases product and identifies a potential clerical error or other discrepancy in product tracing information it received, that trading partner should resolve the error or discrepancy.\n\n➢ Immediately contact the trading partner that provided product tracing information\n\n➢ Do not sell product until the error or discrepancy has been resolved\n\n➢ If the error or discrepancy cannot be resolved and the product is determined to be a suspect or illegitimate product, follow steps for verification if applicable (e.g., quarantine and investigation)\n\nwww.fda.gov\n\n28", "n_tokens": 164, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-28-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 28, "text": "Examples: Aggregation Errors\n\nMissing product: Product tracing information reflects 10 bottles of product and purchasing trading partner only received 9 bottles\n\nExtra product: Product tracing information reflects 10 bottles of product and purchasing trading partner received 12 bottles\n\nDuplicate data: Product tracing information contains the same product listed twice (This should not be confused with duplicate serial numbers listed for two packages of a product; this scenario should be considered as suspect.)\n\nMissing data: Product identifier for the homogeneous case is missing so there is no other identifier to associate with product identifiers of the packages of product physically received within the case 29\n\nMissing data: Product identifier for the homogeneous case is missing so there is no other identifier to associate with product identifiers of the packages of product physically received within the case 29", "n_tokens": 158, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-29-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 29, "text": "Examples: Other Discrepancies\n\nOther discrepancies may occur during the ordering, shipment, or receipt of product. For example:\n\nThe transaction information is missing the address of the purchasing trading partner.\n\nThe transaction information misstates the address of the purchasing trading partner.\n\nThe transaction information is missing the quantity of product, but the purchasing trading partner received the quantity of product that it ordered.\n\nwww.fda.gov\n\n30", "n_tokens": 85, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-30-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 30, "text": "Recommendations: How to Resolve Errors & Discrepancies\n\nImmediately contact the selling trading partner that provided product tracing information ​and determine the reason for the error\n\nWork together to resolve the error and document through current business practices (e.g., nature of error, how error was resolved, names of persons involved, date of resolution)\n\nIf the product is determined to be a suspect or illegitimate, follow steps for applicable verification requirements (e.g., quarantine, investigation, and proper disposition)\n\nwww.fda.gov\n\n31", "n_tokens": 105, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-31-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 31, "text": "Challenge Question #2 Which of the following statements is NOT true about DSCSA requirements?\n\nA.\n\nVerification includes quarantine and investigation of suspect product and quarantine and disposition of illegitimate product.\n\nB. When a trading partner identifies illegitimate product, it must notify FDA and other immediate trading partners within 24 hours of making the determination.\n\nC.\n\nFor products under DSCSA, it is optional to encode packages with a product identifier that includes the NDC, serial number, lot number and expiration date.\n\nD.\n\nProduct tracing changes in 2023 and the transaction information will need to include the data elements of the product identifier at the package level for each package.\n\nwww.fda.gov\n\n32", "n_tokens": 145, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-32-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 32, "text": "www.fda.gov\n\nProduct Identifier (Serialization)\n\nManufacturers/Repackagers (November 2018)\n\nEncode product identifiers on prescription drug packages • Determine smallest individual saleable unit • Verification requirements changes once products are serialized with product identifier\n\nProduct Identifier\n\nNDC: XXXX-XXXX-XX SERIAL: XXXXXXXX LOT: XXXXXXX EXP: YYYY-MM-DD\n\nNational Drug Code (NDC) • Serial Number • Lot Number • Expiration Date Human and machine readable formats Machine readable barcodes:\n\n2D data matrix for packages - Linear or 2D data matrix for homogenous cases\n\n33", "n_tokens": 136, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-33-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 33, "text": "Key\n\nRequest for TI/TS\n\nResponse with TI/TS\n\nManufacturer\n\nwww.fda.gov\n\nGathering of Relevant Product Tracing Information\n\nRequestor: Regulator/Authorized Trading Partner\n\nUnder sections 582(g)(1)(D) and (E) of the FD&C Act: ...promptly respond with the TI and TS...upon a request by the Secretary (or other appropriate Federal or State official) in the event of a recall or for the purposes of investigating a suspect product or an illegitimate product shall be required...\n\nand\n\nWholesale Distributor\n\nDispenser\n\n...promptly facilitate gathering the information necessary to produce the TI for each transaction going back to the manufacturer... (i) in the event of a request by the Secretary (or other appropriate Federal or State official), on account of a recall or for the purposes of investigating a suspect product or an illegitimate product; or (ii) in the event of a request by an authorized trading partner, in a secure manner that ensures the protection of confidential commercialinformation and trade secrets, for purposes of investigating a suspect product or assistingthe Secretary (or other appropriate Federal or State official) with a request described in clause (i).\n\n34", "n_tokens": 246, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-34-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 34, "text": "Enhanced Verification: Package-Level\n\nor\n\nKey\n\nRequest for verification of the product identifier (including the NDC and serial number)\n\nRequestor: FDA/Authorized Trading Partner\n\nAuthorized Trading Partner\n\nUnder section 582(g)(1)(C) of the FD&C Act: systems and processes for verification of product at the package level, including the standardized numerical identifier shall be required in accordance with the standards established under the guidance issued pursuant to subsection (a)(2) and the guidances issued pursuant to paragraphs (2), (3), and (4) of subsection (h)...which may include the use of aggregation and inference as necessary.\n\nResponse to verification request\n\nwww.fda.gov\n\n35", "n_tokens": 152, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-35-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 35, "text": "Enhanced Verification: Saleable Returns\n\nReturned Product\n\nTI and TS\n\nAuthorized Trading Partner: who is accepting returned product\n\nUnder Section 582(g)(1)(F) of the FD&C Act: Each person accepting a saleable return shall have systems and processes in place to allow acceptance of such product and may accept saleable returns only if such person can associate the saleable return product with the transaction information and transaction statement associated with that product.\n\nwww.fda.gov\n\n36", "n_tokens": 96, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-36-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 36, "text": "Challenge Question #3 Is the following statement true or false?\n\nEnhanced drug distribution security requirements that go into effect in 2023 include the exchange of transaction information and transaction statements in a secure, interoperable, electronic manner.\n\nA. True\n\nB. False\n\nwww.fda.gov\n\n37", "n_tokens": 56, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-37-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 37, "text": "2023 Enhanced Drug Distribution Security Effective 11/27/2023\n\nUnder section 582(g)(1) of the FD&C Act requirements for interoperable, electronic tracing of product at the package level go into effect :\n\n(A) the exchange of transaction information and transaction statements in a secure, interoperable, electronic manner;\n\n(B) transaction information that includes the data elements of the product identifier at the package level for each package included in the transaction;\n\n(C) systems and processes for verification of product at the package level;\n\n(D) systems and processes necessary to promptly respond with the relevant transaction information and transaction statement for a product upon request by FDA or appropriate Federal or State official in the event of a recall or for the purposes of investigating a suspect product or an illegitimate product;\n\n(E) systems and processes necessary to promptly facilitate the gathering of the information necessary to produce the transaction information for each transaction going back to the manufacturer...upon request by FDA or other appropriate Federal or State official in the event of a recall or for the purposes of investigating a suspect product or an illegitimate product, or upon request of an authorized trading partner...for the purposes of investigating a suspect product or an illegitimate product or assisting FDA or other appropriate Federal or State official with a request; and\n\n(F) systems and processes to associate a saleable return product with its applicable transaction information and transaction statement to allow a trading partner to accept the returned product\n\nwww.fda.gov\n\n38", "n_tokens": 302, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-38-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 38, "text": "www.fda.gov\n\nwww.fda.gov\n\nEffective November 27, 2023\n\nEnhanced Drug Distribution Security\n\nElectronic\n\nInteroperable\n\nSystem across the pharmaceutical distribution supply chain\n\n39", "n_tokens": 32, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-39-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 39, "text": "www.fda.gov\n\nHow DSCSA Protects Patients\n\nPrevent harmful drugs from entering the supply chain.\n\nDetect harmful drugs if they enter the supply chain.\n\nRespond rapidly when harmful drugs are found.\n\n40", "n_tokens": 39, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-40-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 40, "text": "FDA Resources\n\nDSCSA main webpage\n\nhttps://www.fda.gov/Drugs/DrugSafety/DrugIntegrityandSupplyChainSecuri ty/DrugSupplyChainSecurityAct/default.htm\n\nDSCSA regulatory documents (i.e., regulations, guidances, federal register notices, pilot programs)\n\nhttps://www.fda.gov/Drugs/DrugSafety/DrugIntegrityandSupplyChainSecuri ty/DrugSupplyChainSecurityAct/ucm424963.htm\n\nwww.fda.gov\n\n41", "n_tokens": 126, "kind": "text"}
{"chunk_id": "DSCSA_Webinar_October_2021-41-0", "doc_id": "DSCSA_Webinar_October_2021", "page": 41, "text": "PY U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 10, "kind": "text"}
{"chunk_id": "DrThrockmorton1-0-0", "doc_id": "DrThrockmorton1", "page": 0, "text": "FDA Role in Regulation of Cannabis Products\n\nNIDA February 2019\n\nSharon Lindan Mayl, J.D. Senior Advisor for Policy Office of Foods and Veterinary Medicine Food and Drug Administration\n\nDouglas C. Throckmorton, M.D. Deputy Director for Regulatory Programs CDER, FDA", "n_tokens": 56, "kind": "text"}
{"chunk_id": "DrThrockmorton1-1-0", "doc_id": "DrThrockmorton1", "page": 1, "text": "FDA’s Policy Interests\n\nProtecting the public from harmful products • Protecting the public from fraudulent products with unproven disease claims (which could result in patients foregoing proven treatments) Incentivizing rigorous scientific research to support beneficial therapies (through requiring NDAs)\n\nProtecting human subjects involved in research (through requiring INDs)\n\nProtecting the integrity of the conventional food supply and dietary supplements\n\nRespecting the “right to try” unapproved drugs for seriously ill patients\n\n2", "n_tokens": 93, "kind": "text"}
{"chunk_id": "DrThrockmorton1-2-0", "doc_id": "DrThrockmorton1", "page": 2, "text": "FDA and Cannabis\n\nRegulatory roles under the Federal Food, Drug & Cosmetic Act (FDCA):\n\nScientific and regulatory support for research on potential therapeutic uses of cannabis\n\nRegulation of products (e.g., foods, drugs, cosmetics) from cannabis • Enforcement actions as necessary against products made from cannabis or containing compounds found in the cannabis plant, particularly those that present human health risks\n\nFDA roles under the Controlled Substances Act (CSA):\n\nAssisting the Drug Enforcement Administration (DEA) on protocol registration for Schedule I drug research (Under 21 CFR 1301.18 and 1301.32)\n\nConducts scientific and medical analysis (‘8-factor analysis’) to recommend appropriate controls under the CSA (working with NIDA)\n\nAt DEA request – Responding to citizen petitions – New approved drug products with need for scheduling action\n\n3", "n_tokens": 162, "kind": "text"}
{"chunk_id": "DrThrockmorton1-3-0", "doc_id": "DrThrockmorton1", "page": 3, "text": "Regulatory Landscape\n\nFederal/state coordination is necessary:\n\nStates – DEA – FDA – USDA – Others: SAMHSA, NIDA, ONDCP\n\n4", "n_tokens": 31, "kind": "text"}
{"chunk_id": "DrThrockmorton1-4-0", "doc_id": "DrThrockmorton1", "page": 4, "text": "Intra-Agency Team\n\nFDA has a cross-Agency team that works on cannabis issues:\n\nAll product divisions represented as well as field inspectorate\n\nPolicy • Enforcement • Outreach • Interagency coordination – Federal, state, international\n\n5", "n_tokens": 44, "kind": "text"}
{"chunk_id": "DrThrockmorton1-5-0", "doc_id": "DrThrockmorton1", "page": 5, "text": "The Farm Bill • Agriculture Improvement Act of 2018 (Farm Bill) changes some federal authorities related to the production and marketing of hemp. – Establishes a state-USDA process and gives USDA the authority to issue federal regulations and guidelines concerning hemp production\n\nHemp is defined as cannabis (Cannabis stativa L), and derivatives of cannabis, with extremely low (not more than 0.3 percent on a dry weight basis) concentrations of THC\n\nRemoved hemp from the definition of marijuana in the Controlled Substances Act (CSA)\n\nMarijuana is still regulated by DEA under Schedule 1 of the CSA\n\nNote: Epidiolex and certain future FDA approved CBD products have been classified as Schedule V\n\n6", "n_tokens": 139, "kind": "text"}
{"chunk_id": "DrThrockmorton1-6-0", "doc_id": "DrThrockmorton1", "page": 6, "text": "The Farm Bill - FDA\n\nFDA’s authorities under the FD&C Act and section 351 of the PHS Act were specifically preserved by the Farm Bill.\n\nCannabis and cannabis-derived products are subject to the same authorities and requirements as FDA-regulated products containing any other substance.\n\n7", "n_tokens": 57, "kind": "text"}
{"chunk_id": "DrThrockmorton1-7-0", "doc_id": "DrThrockmorton1", "page": 7, "text": "Overview of FDA Drug Authority\n\nUnder the FD&C Act, any product, including a cannabis product (hemp or otherwise), that is marketed with a claim of therapeutic benefit, or with any other disease claim, is considered to be a drug. A new drug must be approved by the FDA for its intended use before it may be introduced into interstate commerce.\n\n8", "n_tokens": 74, "kind": "text"}
{"chunk_id": "DrThrockmorton1-8-0", "doc_id": "DrThrockmorton1", "page": 8, "text": "Drug Development from Cannabis\n\nDevelopment of drugs has focused on using compounds in cannabis: CBD, THC\n\nFour products approved:\n\nMarinol (dronabinol) (1985): nausea from cancer chemotherapy. Schedule III\n\nCesamet (nabilone) (1985 (2006)): nausea & neuropathic pain. Schedule II\n\nSyndros (dronabinol) (2016): nausea from cancer chemotherapy. Schedule II\n\nEpidiolex (CBD) (2018): for childhood seizures. Schedule V\n\n9\n\n9", "n_tokens": 107, "kind": "text"}
{"chunk_id": "DrThrockmorton1-9-0", "doc_id": "DrThrockmorton1", "page": 9, "text": "FDA Support for Drug Development from the Cannabis Plant\n\nRegulatory programs and expediting pathways for important drug development\n\nPriority Review of NDAs, Fast Track Designation, Breakthrough Therapy Designation\n\n“FDA and Marijuana” web page includes links to Q&A page, guidance on initiating INDs or DMFs, contact points for Office of New Drugs’ review divisions, small business assistance, and links to NIDA Drug Supply Program and DEA registration site\n\nUpdated final guidance in 2016, Botanical Drug Development, on the use of botanicals (e.g., cannabis) as sources for drugs – Focus on quality manufacturing and controls during development\n\n10", "n_tokens": 123, "kind": "text"}
{"chunk_id": "DrThrockmorton1-10-0", "doc_id": "DrThrockmorton1", "page": 10, "text": "FDA Support for Drug Development (cont’d)\n\nBotanicals Team available to guide development of drugs from plants\n\nCan request Botanicals Team participation, to gain clarity on characterizing an investigational botanical drug to support proposed clinical study or NDA submission\n\nControlled Substances Staff available to help with FDA- DEA interactions\n\nE.g., issues around abuse potential assessment requirements to support an NDA submission\n\n11", "n_tokens": 78, "kind": "text"}
{"chunk_id": "DrThrockmorton1-11-0", "doc_id": "DrThrockmorton1", "page": 11, "text": "THC and CBD in Food: 301(ll)\n\nCBD and THC cannot be added to foods under the FD&C Act regardless of whether the substances are hemp-derived. – Under section 301(ll) of the FD&C Act, it is prohibited to introduce or deliver for introduction into interstate commerce any food (including animal food or feed) to which has been added a substance which is an active ingredient in a drug product that has been approved under 21 U.S.C. § 355 (section 505 of the Act) or a drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public.\n\nException: If article was marketed in food before the drug was approved or before the substantial clinical investigations involving the drug had been instituted or, in the case of animal feed, that the drug is a new animal drug approved for use in feed and used according to the approved labeling.\n\nFDA has no evidence that this exception applies\n\n12", "n_tokens": 201, "kind": "text"}
{"chunk_id": "DrThrockmorton1-12-0", "doc_id": "DrThrockmorton1", "page": 12, "text": "Other Applicable Regulatory Requirements for Foods\n\nAll foods are subject to a number of other regulatory requirements related to topics such as: – Safety of ingredients – Production controls – Labeling\n\n13", "n_tokens": 33, "kind": "text"}
{"chunk_id": "DrThrockmorton1-13-0", "doc_id": "DrThrockmorton1", "page": 13, "text": "Hemp Seed-Derived Ingredients • FDA completed the evaluation of three GRAS notices\n\nrelated to the use of hemp seed-derived food ingredients in December 2018. – Hulled hemp seed, hemp seed protein, hemp seed oil – Products have typical food uses\n\nFDA had no questions about the submitter’s conclusion that the ingredients were GRAS for the uses in the notice.\n\nThese products can be legally marketed in human foods for these uses without food additive approval, provided they comply with all other requirements and do not make disease claims.\n\n14", "n_tokens": 110, "kind": "text"}
{"chunk_id": "DrThrockmorton1-14-0", "doc_id": "DrThrockmorton1", "page": 14, "text": "THC and CBD in Dietary Supplements: 201(ff)(3)(B) It is unlawful to market CBD and THC products as, or in, dietary supplements, regardless of whether the substances are hemp- derived.\n\nCBD and THC products are excluded from the definition of dietary supplements under the FD&C Act – Under sections 201(ff)(3)(B)(i) and (ii) of the FD&C Act, if a substance (such\n\nas THC or CBD) is an active ingredient in a drug product that has been approved under 21 U.S.C. § 355 (section 505 of the FD&C Act), or has been authorized for investigation as a new drug for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, then products containing that substance are outside the definition of a dietary supplement.\n\nException: If the substance was \"marketed as\" a dietary supplement or as a conventional food before the drug was approved or before the new drug investigations were authorized, as applicable.\n\nFDA has no evidence that this exception applies\n\n15", "n_tokens": 233, "kind": "text"}
{"chunk_id": "DrThrockmorton1-15-0", "doc_id": "DrThrockmorton1", "page": 15, "text": "Cosmetics\n\nNo premarket approval for cosmetic products and ingredients, with the exception of color additives\n\nMust not be adulterated\n\nSafe for consumers when used according to the directions in labeling and under customary/usual conditions of use\n\nMust not be misbranded • If a topical product, including those that contain CBD, is intended to affect the structure or any function of the body, or to be used in the diagnosis, cure, mitigation, treatment, or prevention of disease, it is a drug, even if it is also a cosmetic (dual classification is common). New drugs must be approved 16", "n_tokens": 121, "kind": "text"}
{"chunk_id": "DrThrockmorton1-16-0", "doc_id": "DrThrockmorton1", "page": 16, "text": "Current FDA Warning Letters Related to CBD Products\n\nFDA has issued numerous WLs from 2015 to present – Unapproved new drugs [§§201(p), 301(d), and 505(a)] – Misbranded drugs [§§301(a) and 502(f)(1)] – Illegally marketed food [§301(ll)] – Illegally marketed supplements [§201(ff)(3)(B)]\n\nFDA posted lab results for dozens of CBD products cited in the warning letters. – In many cases, the CBD content did not match the labeled\n\nclaims and some products did not contain any CBD\n\n17", "n_tokens": 135, "kind": "text"}
{"chunk_id": "DrThrockmorton1-17-0", "doc_id": "DrThrockmorton1", "page": 17, "text": "Challenges\n\nChallenges include: • Rapidly-changing legal frameworks at the federal,\n\nstate, and local level\n\nContinually evolving market with many types of products\n\nNeed for more data (e.g., safety) • Need to support rigorous scientific research into therapeutic uses of products from cannabis • Impact of Farm Bill on CBD for research\n\nResources\n\n18", "n_tokens": 66, "kind": "text"}
{"chunk_id": "DrThrockmorton1-18-0", "doc_id": "DrThrockmorton1", "page": 18, "text": "Commissioner Gottlieb Statement December 20, 2018\n\nAffirming FDA’s commitment to protect and promote the public health with respect to these products, including enforcement action when needed\n\nConcern about unapproved drugs and about introduction into the food supply\n\nSoliciting input on how to make legal pathways for the lawful marketing of these products more efficient\n\nTaking steps to evaluate options for use in foods, including dietary supplements Intent to hold a public meeting for stakeholders to share experiences and challenges with these products – Including information related to safety\n\nhttps://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm628988.htm\n\n19", "n_tokens": 136, "kind": "text"}
{"chunk_id": "DrThrockmorton1-19-0", "doc_id": "DrThrockmorton1", "page": 19, "text": "FDA Website\n\nhttps://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168. htm\n\n20", "n_tokens": 32, "kind": "text"}
{"chunk_id": "DrThrockmorton1-20-0", "doc_id": "DrThrockmorton1", "page": 20, "text": "Summary and Conclusions\n\nFDA has a well-defined role to play in the regulation and development of products containing cannabis and cannabis-derived compounds\n\nFDA continues to focus on supporting scientifi rigorous testing and approval of drugs derive cannabis FDA will solicit input on how to make legal pa lawful marketing of these products more effic FDA will continue to protect and promote the with respect to these products\n\nc and d from\n\nthways for the ient public health\n\n21", "n_tokens": 91, "kind": "text"}
{"chunk_id": "DrThrockmorton1-21-0", "doc_id": "DrThrockmorton1", "page": 21, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-0-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 0, "text": "Federal Efforts to Prevent Drug Shortages\n\nAn FDA Perspective\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs Center for Drug Evaluation and Research FDA\n\nDuke Margolis Center for Health Policy\n\nNovember 27, 2018\n\n1", "n_tokens": 43, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-1-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 1, "text": "Definitions of Medical Product Shortage\n\nDrug Shortage (FDA): A drug shortage means a period when the demand or projected demand for the drug within the United States exceeds the supply of the drug.\n\nDrug Shortage (ASHP*): A drug product is in shortage: – once the shortage is verified with manufacturers – when supply issues affect how a pharmacy prepares or dispenses a drug product, or influence patient care requiring prescribers to use an alternative therapy\n\nASHP: American Society of Health-System Pharmacists\n\n2", "n_tokens": 105, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-2-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 2, "text": "Trends in New Drug Shortages 2010-2017\n\nFrom FDA Drug Shortage Report to Congress, 2017 https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/U CM610662.pdf\n\n3", "n_tokens": 48, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-3-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 3, "text": "Sources of Shortages: Manufacturing Challenges\n\nConsolidation in manufacturing of sterile injectables\n\nIn Fall of 2017, interruption of manufacturing by a single firm led to shortages of multiple critical drugs including injectable narcotics, “caines” and others drugs\n\nShortages of critical sterile injectable drugs from increased demand or manufacturing problems\n\nIV electrolyte salts, Magnesium Sulfate, Calcium Gluconate and Potassium Chloride\n\n4", "n_tokens": 79, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-4-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 4, "text": "Sources of Shortages: Natural Disasters\n\nHurricane Maria affected multiple manufacturers in Puerto Rico •\n\nIV fluid shortages which began in 2014 were worsened due to Baxter facility impact in PR\n\n5", "n_tokens": 32, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-5-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 5, "text": "What FDA Does to Address Drug Shortages\n\nDrug Shortage Staff focused on addressing drug shortages • Facilitate temporary and long-term strategies to address\n\nshortages\n\nCoordinate timely and comprehensive risk/benefit decisions within FDA\n\nPersonnel across multiple FDA Offices involved in shortage response\n\nDistribute information (web posting, professional organizations): • https://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm • Goal: Maintain availability while minimizing risk to patients\n\n6", "n_tokens": 93, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-6-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 6, "text": "What FDA Cannot Do to Address Drug Shortages\n\nFDA cannot require:\n\nA company to disclose details of why a shortage occurs\n\nA company to make a drug • A company to make more of a drug • How much and to whom the drug is distributed\n\n7", "n_tokens": 48, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-7-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 7, "text": "Lessons Learned\n\nAvailability of drugs for patients is critical for healthcare – Interruptions of drug manufacturing due to any reason can lead to drug shortages with devastating impact on public health\n\nSources of drug shortages include manufacturing challenges and natural disasters – FDA response tailored to address underlying cause(s) – Communications and information sharing are critical both to\n\npreventing and to mitigating shortages\n\nRecovery from shortages takes time. Prevention is critical to reducing the numbers of drug shortages\n\n8", "n_tokens": 86, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-8-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 8, "text": "Communication is Critical\n\nRequirements to Industry For Early Notification\n\nManufacturers are required to notify the FDA of a permanent discontinuance or interruption in manufacturing that is likely to lead to a meaningful disruption in the supply of a covered drug in the United States\n\nAt least 6 months in advance of but in no case later than 5 business days after the interruption in manufacturing occurs\n\nNot limited to medically necessary products\n\nRegardless of market share, or number of companies marketing, or wholesaler volumes\n\n9", "n_tokens": 93, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-9-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 9, "text": "Today’s Meeting\n\nDiscussion goals:\n\nRoot Causes of drug shortages • Economics of drug shortages\n\nMeasurement of shortages and their public health impact • Economic drivers underlying drug shortages\n\nManufacturing and Distribution\n\nAnticipating vulnerabilities, eliminating barriers to adequate drug supply\n\nPotential tools to address drug shortages\n\nMarket-driven actions • Governmental actions\n\nIncentives to encourage adequate drug supply and manufacturing redundancy and resiliency\n\n10", "n_tokens": 75, "kind": "text"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-10-0", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 10, "text": "Thank You\n\n11", "n_tokens": 3, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-0-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 0, "text": "FDA Office of Generic Drugs (OGD) Keynote Address\n\nGDUFA: Past, Present and Future\n\nKathleen Uhl, MD Director, Office of Generic Drug CDER/FDA\n\nGPhA Annual Meeting February 14, 2017\n\n1", "n_tokens": 44, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-1-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 1, "text": "Disclaimer\n\nThis presentation reflects the views of the speaker and do not reflect official FDA, HHS, or other government opinion or policy\n\nI have nothing to disclose\n\nSome data represent FY2016 while others are for CY2016. FY2017 data represent preliminary data that are being further reviewed and validated for official reporting purposes.\n\n2", "n_tokens": 69, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-2-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 2, "text": "Introductory Comments\n\nTHANK YOU • For working with us on GDUFA I implementation – Your engagement and feedback improved the program\n\nFor your patience and resilience during the past four years of tremendous change\n\nFor working with us on GDUFA II\n\nNumerous, major program enhancements to reduce cycles to approval (AP)\n\n3", "n_tokens": 62, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-3-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 3, "text": "GDUFA Overview\n\n1. Past 2. Present 3. Future 4. Closing Thoughts\n\n4", "n_tokens": 18, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-4-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 4, "text": "GDUFA Overview\n\n1. Past 2. Present 3. Future 4. Closing Thoughts\n\n5", "n_tokens": 18, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-5-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 5, "text": "GDUFA: Past\n\n•\n\nIn 2012, GDUFA was enacted as part of FDASIA In 2013-2014, FDA restructured ANDA review program to prepare for goal dates\n\nFDA also worked with GPhA to improve communications and transparency – e.g., agreed to TADs\n\n2015 to present: GDUFA goal dates, TADs, other formal and informal commitments 6", "n_tokens": 76, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-6-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 6, "text": "GDUFA Overview\n\n1. Past 2. Present 3. Future 4. Closing Thoughts\n\n7", "n_tokens": 18, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-7-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 7, "text": "GDUFA: Present\n\nFDA is meeting or exceeding the GDUFA goals • Numerous other significant accomplishments • Main outstanding challenge is multiple review cycles – Leads to a huge amount of re-work for FDA and\n\napplicants alike\n\n8", "n_tokens": 44, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-8-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 8, "text": "GDUFA Goal: Original ANDAs\n\nGDUFA goal: Review and act on 60% of FY2015 Original ANDAs within 15 months of submission\n\nFDA acted on 97% of FY2015 Original ANDAs within 15 months of submission\n\nFY2016 original submissions are just now starting to hit their GDUFA goal dates\n\n9", "n_tokens": 69, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-9-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 9, "text": "GDUFA Goal: PAS\n\n100%\n\n100%\n\n100%\n\n100%\n\n100%\n\n100%\n\n100%\n\n100%\n\n100%\n\n100%\n\n100%\n\n94%\n\n94%\n\n90%\n\ne c n a m r o f f r e P\n\n80%\n\n60%\n\nl\n\na u t c A A F U D G\n\n40%\n\n20%\n\n0%\n\nJan-2015 Feb-2015 Mar-2015 Apr-2015 May-2015 Jun-2015\n\nJul-2015 Aug-2015 Sep-2015 Oct-2015 Nov-2015 Dec-2015 Jan-2016 Feb-2016 Month-Year\n\nGDUFA PAS Goal\n\nGoal dates provided on submissions received through February 2016, as those are the goal dates that have actually occurred. The cohort data is not mature enough to report on whole year data\n\n*Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm\n\n100%\n\n10", "n_tokens": 231, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-10-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 10, "text": "GDUFA Goal: Controlled Correspondence\n\nControlled Correspondence FY 16 GDUFA Performance by FDA Receipt Date – All Disciplines\n\n100%\n\n96.84%\n\n90.10%\n\n90.68%\n\n92.06%\n\n98.09%\n\n98.04%\n\n97.76%\n\n96.77%\n\n97.26%\n\n98.81%\n\n94.16%\n\n98.10%\n\n80%\n\ne c n a m r o f r e P\n\n60%\n\nl\n\na u t c A A F U D G\n\n40%\n\n20%\n\n0%\n\nOct-2015 Nov-2015 Dec-2015 Jan-2016 Feb-2016 Mar-2016 Apr-2016 May-2016 Jun-2016\n\nJul-2016 Aug-2016 Sep-2016\n\nMonth-Year\n\nGDUFA Controlled Correspondence Goal\n\nGoal dates provided on submissions received in FY2016.\n\n*Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm\n\n11", "n_tokens": 239, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-11-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 11, "text": "Other Accomplishments: Approvals and Tentative Approvals\n\nApproval\n\nTentative Approval\n\n900\n\nGDUFA starts, 10/1/12\n\n800\n\n184\n\n700\n\n600\n\ns A D N A\n\n500\n\n400\n\n139\n\n139\n\n102\n\n95\n\n91\n\n120\n\n300\n\n651\n\n200\n\n426\n\n458\n\n517\n\n440\n\n409\n\n492\n\n100\n\n0\n\nFY2010\n\nFY2011\n\nFY2012\n\nFY2013\n\nFY2014\n\nFY2015\n\nFY2016\n\n*As of 1/1/17. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n47\n\n169\n\nFY2017*\n\n12", "n_tokens": 120, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-12-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 12, "text": "Other Accomplishments: Notable FY2016 “First Generic” Approvals\n\nGeneric Name\n\nReference Listed Drug\n\nBendamustine Hydrochloride for Injection, 25 mg/vial and 100 mg/vial\n\nTreanda for Injection\n\nDasatinib Tablets, 20 mg, 50 mg, 70 mg, and 100 mg\n\nSprycel Tablets\n\nDofetilide Capsules, 0.125 mg, 0.25 mg, and 0.5 mg.\n\nTikosyn Capsules\n\nEfavirenz Tablets USP, 600 mg\n\nSustiva Tablets\n\nImatinib Mesylate Tabelets, 100 and 400 mg\n\nGleevec Tablets\n\nLacosamide Tablets, 50 mg, 100 mg, 150 mg and 200 mg\n\nVimpat Tablets\n\nMometasone Furoate Nasal Spray, 50 mcg\n\nNasonex Nasal Spray\n\nOlopatadine Hydrochloride Ophthalmic Solution USP, 0.1%\n\nPatanol Ophthalmic solution\n\nOseltamivir Phosphate Capsules USP, 30 mg, 45 mg and 75 mg\n\nTamiflu\n\nRosuvastatin Calcium Tablets, 5 mg (base), 10 mg (base), 20 mg (base) and 40 mg (base)\n\nCrestor Tablets\n\nRufinamide Tablets USP, 200 mg and 400 mg\n\nBanzel tablets\n\nSildenafil Citrate Tablets, 25 mg, 50 mg and 100 mg**\n\nViagra Tablets\n\n*http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/drugandbiologicapprovalreports/andagenericdrugapprovals/default.htm **ANDA approved but listed in Discontinued section of Orange Book\n\n13", "n_tokens": 354, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-13-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 13, "text": "Other Accomplishments: Starting to See First Cycle Approvals (FY2015 cohort)\n\n1st cycle\n\nFirst Cycle RTR Rate\n\nFirst Cycle AP/TA Rate\n\nFirst Cycle CR Rate\n\n20%\n\n9% 71%\n\nN=523\n\n2nd cycle\n\nSecond Cycle AP/TA Rate\n\nSecond Cycle CR Rate\n\n42% 56%\n\nN=67**\n\nWithdrawn\n\n2%\n\n*As of 1/23/17. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. **Completed reviews of second submissions; most others are pending with industry or under review at FDA and within goal.\n\n14", "n_tokens": 120, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-14-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 14, "text": "Other Accomplishments: Expanded Communications with Industry\n\n800\n\n700\n\n600\n\nMore than 5,400 communications to industry in FY16 during ANDA review\n\n727\n\n585\n\n721\n\n570\n\n632\n\n500\n\n481\n\n497\n\n533\n\n466\n\n500\n\n470\n\n480\n\n450\n\n441\n\n400\n\n300\n\n324\n\n330\n\n424\n\n345\n\n358\n\n200\n\n259\n\nECD/IR*\n\n100\n\n84\n\n129\n\n66\n\n0\n\n*Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n288\n\n15", "n_tokens": 91, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-15-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 15, "text": "Other Accomplishments: Overall Actions\n\nPre-GDUFA\n\nGDUFA\n\nFY2012\n\nFY2013\n\nFY2014\n\nFY2015\n\nFY2016\n\nANDA approvals\n\n517\n\n440\n\n409\n\n492\n\n651\n\nPAS approvals\n\n275\n\n535\n\n659\n\n624\n\n496\n\nTentative Approval (TA)\n\n102\n\n95\n\n91\n\n120\n\n184\n\nComplete Response (CR) ¥\n\n84\n\n1251\n\n1254\n\n1180\n\n1725\n\nTOTAL **\n\n978\n\n2321\n\n2413\n\n2416\n\n3056\n\nDMF Completeness Assessment (CA)\n\n0\n\n1699\n\n1706\n\n901\n\n886\n\n* As of 1/1/17. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. ** FDA will aspire to the extent possible to maintain levels of productivity at least similar to pre-GDUFA levels, while hiring and training incremental staff necessary to achieve the program performance goals, building necessary systems and implementing outlined program changes in years 1 and 2 of the program (GDUFA Commitment Letter, page 3) http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm ¥ Complete Response both with and without inspections for ANDAs.\n\nFY2017*\n\n169\n\n115\n\n47\n\n446\n\n777\n\n102\n\n16", "n_tokens": 289, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-16-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 16, "text": "Received\n\nApproved\n\nCR Letter\n\nOther Accomplishments: PAS Actions\n\nFY2013\n\nFY2014\n\nFY2015\n\nFY2016\n\n482\n\n436\n\n563\n\n567\n\n532\n\n654\n\n616\n\n542\n\n8\n\n18\n\n185\n\n242\n\nFY2017\n\n(as of Jan 30, 2017)\n\n160\n\n145\n\n75\n\n17", "n_tokens": 61, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-17-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 17, "text": "Other Accomplishments: Filing\n\n> 900 original ANDAs, resubmissions, and PASs underwent filing review in FY2016\n\nAlso, OGD has eliminated large filing backlog\n\n18", "n_tokens": 36, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-18-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 18, "text": "Other Accomplishments: Filing\n\nRevised Refuse To Receive (RTR) Guidance published 12/21/16 • Implementing Good Review Practices on Filing Review: – Robust training and review practices for staff, including strong\n\ndocumentation\n\nIntense engagement with OGD Policy on regulatory and legal framework\n\nInternal procedures to ensure consistency with filing determinations – Resulting in very few rescissions of RTR in FY2016 and FY2017\n\nDFR heavily involved with Controlled Correspondence\n\nSuccess here should translate into industry submitting ANDAs that will less likely be RTR’ed for the question raised in the Control\n\n19", "n_tokens": 115, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-19-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 19, "text": "s e c n a d u G\n\ni\n\nf o r e b m u N\n\n250\n\n200\n\n150\n\n100\n\n50\n\n0\n\nOther Accomplishments: Product-Specific Guidances\n\nNew Guidance\n\n223\n\nRevised Guidance\n\n135\n\n134\n\n154\n\n102\n\n78\n\n94\n\n61\n\n41\n\n56\n\n69\n\n41\n\nFY 13\n\nFY 14\n\nFY 15\n\nFY 16\n\n115\n\n65\n\n50\n\nFY 17*\n\n20", "n_tokens": 67, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-20-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 20, "text": "Other Accomplishments: GDUFA Regulatory Science  FDA standards\n\n“Product-specific” guidances – ~200 per year – Developing more for complex products\n\n~15 for inhalation products\n\nNew “general” product or BE guidances\n\nEvaluating Abuse Deterrence of Generic Opioid Products (March 2016) – Assessing Adhesion for Generic TDS and Topical Patches (May 2016) – Comparative Analyses and Human Factors Studies for Drug-device Combinations submitted in an ANDA (January 2017) – rDNA peptides (on public guidance agenda, in progress)\n\n21", "n_tokens": 109, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-21-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 21, "text": "Other Accomplishments: GDUFA Reg. Science Access to Generics\n\nEach area in portfolio is a $billion/year market without generic competition\n\nCoordinated internal and external research drives progress – ~90 active contracts and grants\n\nHuge public health impact with small regulatory science investments -- leads to large return on investment (ROI) – Guidance on complex products – Internal CDER & FDA alignment on complex issues – Confidence in generic substitution – Review tool development and use – Faster and smarter generic drug development and review 22", "n_tokens": 97, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-22-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 22, "text": "Other Accomplishments: Policy Transparency & Predictability • REGULATIONS ISSUED\n\nMMA Final Rule (September 2016)\n\nGUIDANCES ISSUED\n\nRTR for Lack of Justification of Impurity Limits (August 2016) – Updated RTR Guidance (December 2016) – 180-Day Exclusivity Guidance (January 2017) – Referencing Products in ANDAs Guidance (January 2017)\n\nGUIDANCES IN DEVELOPMENT\n\nDetermining 505(b)(2) or 505(j) Pathway\n\n23", "n_tokens": 87, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-23-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 23, "text": "Other Accomplishments: OGD Communication Enhancements\n\nMonthly Activities Report of the Generic Drug Program • ANDA First Generic Drug Approvals • Quarterly Generic Drug Review Dashboard • Generic Drugs listserv\n\nOGD RPMs using in signature block – >800 signed up in first month\n\nGDUFA Regulatory Science Annual Report • Office of Generic Drugs 2015 Annual Report • GDUFA Annual Performance Report, 2015\n\n24", "n_tokens": 77, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-24-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 24, "text": "Notable Comms. Accomplishment: Generic Drug Review Dashboard Review productivity and current workload with FDA and with industry\n\nUpdated Quarterly Four reports available:\n\nTotal Original ANDA Workload Activity for Pre-GDUFA Year 3 Application Cohorts\n\nTotal Original ANDA Workload Activity for All Unapproved Applications – Original ANDAs - Total Agency Actions for the Most Recent 12 Months – ANDA Prior Approval Supplements - Total Agency Actions for the Most Recent 12 Months\n\nhttp://go.usa.gov/cunHT\n\n25", "n_tokens": 103, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-25-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 25, "text": "Outstanding Challenge: Multiple Review Cycles\n\nCMC Review Cycles to ANDA Approval 2009 through July 2014\n\n26", "n_tokens": 19, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-26-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 26, "text": "Outstanding Challenge: Multiple Review Cycles\n\nCDER NME NDAs/BLAs First Action Approval Rate\n\nLesson Learned from PDUFA: If submission is “right the first time,” FDA can approve in the first cycle.\n\n27", "n_tokens": 44, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-27-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 27, "text": "Outstanding Challenge: Multiple Review Cycles\n\nSubstantially all of the ANDA workload is: – At FDA and within the GDUFA goal, OR – With the applicant\n\nMany ANDAs are not lawfully approvable yet, because patent/exclusivity have not expired\n\nThe main challenge is: It usually takes several review cycles to get to approval\n\nWhile UFAs count actions, approval is the ultimate objective • The good news is: The older ANDAs are now on their second or third review cycle and therefore should be ripe for approval\n\n28", "n_tokens": 108, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-28-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 28, "text": "Outstanding Challenge: Multiple Review Cycles ANDAs Under FDA Review\n\n3,500\n\n3,000\n\n2,866\n\n2,500\n\n~2,950\n\ns A D N A\n\n2,000\n\n1,500\n\n1,000\n\n500\n\n0\n\nOct. 1, 2012\n\nJan. 1, 2016\n\n*Approximate Values, January 2017\n\n~2,350\n\nJan. 1, 2017\n\n29", "n_tokens": 70, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-29-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 29, "text": "Outstanding Challenge: Multiple Review Cycles Complete Response Letters (CRs) & TAs\n\ns A D N A\n\n2000 1800 1600 1400 1200 1000 800 600 400 200 0\n\n~1,150\n\n100\n\nOct. 1, 2012\n\nJan. 1, 2016\n\n*Approximate Values, January 2017\n\n~1,850\n\nJan. 1, 2017\n\n30", "n_tokens": 63, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-30-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 30, "text": "Outstanding Challenge: Multiple Review Cycles\n\nThe most common deficiencies are: • Inadequate CMC\n\n− Stability − Dissolution − Inactive ingredients • Inadequate facilities\n\n31", "n_tokens": 28, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-31-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 31, "text": "Outstanding Challenge: Multiple Review Cycles\n\nNext Steps -- • FDA and GPhA have a strong track record of working together to\n\novercome GDUFA challenges\n\nFor example, in 2013-14, we improved review communications and transparency, revised “Communications with Industry MAPP” Let’s work together to convert the CRs into Approvals (Aps)\n\n• Trade press has noted the challenge here -- applicants also need to respond to high volume of IRs/DRLs on ANDAs that are under active review and might be imminently approved\n\nFDA-GPhA quarterly meetings stopped during negotiations\n\nThese will resume soon icnluding GDUFA II negotiators and FDA\n\nGDUFA II will help a lot for new, incoming submissions • We can do this!\n\n32", "n_tokens": 152, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-32-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 32, "text": "GDUFA Overview\n\n1. Past 2. Present 3. Future 4. Closing Thoughts\n\n33", "n_tokens": 18, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-33-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 33, "text": "GDUFA II\n\nProposed agreement between FDA and industry stakeholders\n\nGeneric Pharmaceutical Association (GPhA) – Bulk Pharmaceutical Task Force (BPTF) – Pharma and Biopharma Outsourcing Association (PBOA) – European Fine Chemical Group (EFCG)\n\n34", "n_tokens": 55, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-34-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 34, "text": "GDUFA II\n\nWhile there is a proposed agreement between FDA and industry stakeholders, Congress needs to reauthorize by October 1, 2017 -- otherwise, GDUFA expires\n\n“Goals” or “Commitment” letter:\n\nhttp://www.fda.gov/downloads/forindustry/userfees/genericdruguserfees/ucm525234.pdf\n\n35", "n_tokens": 83, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-35-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 35, "text": "GDUFA II Highlights\n\nFaster review of priority submissions: 8 months “Priority” defined in MAPP – includes first generics, sole source, • shortages\n\nTo obtain priority review, applicants must submit Pre-submission Facility Correspondence (“PFC”) at least 2 months prior to submission\n\nWhy 8 months? So ANDA can be approved in the first review cycle. • FDA must plan and conduct facility inspections (many are overseas) and\n\nfacility often needs opportunity to correct deficiencies\n\nFDA review team must communicate – and applicant must address – deficiencies “Real time” communication to fix and approve ANDA now, not later\n\n36", "n_tokens": 124, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-36-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 36, "text": "GDUFA II Highlights\n\nANDA Review Program Enhancements • Refine and enhance efficiency of review process from\n\nstart to finish\n\nNew procedures for filing, review communications, review status communications, timely AP and TA, post- CRL t-cons, and dispute resolution\n\nMany concepts drawn from PDUFA: Create more opportunities for applicants to address deficiencies in current review cycle, instead of waiting to receive them in a later-issued CRL\n\nIncrease first cycle approvals • Reduce number of cycles to approval\n\n37", "n_tokens": 101, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-37-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 37, "text": "GDUFA II Highlights\n\n“No submission left behind” • GDUFA Goals for all ANDAs and\n\namendments\n\nGDUFA I “Bridging” – E.g., any pre-FY2015 ANDAs with missed/never assigned TADs as of Oct. 1, 2017 will get a GDUFA II goal date NLT July 31, 2018\n\n38", "n_tokens": 76, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-38-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 38, "text": "GDUFA II Highlights\n\nPre-ANDA Program • Clarify regulatory expectations early in product\n\ndevelopment, so ANDA can be “right the first time”\n\nIncrease odds of first cycle approval • Reduce number of cycles to approval • More efficient and effective review process\n\n39", "n_tokens": 51, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-39-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 39, "text": "GDUFA II Highlights\n\nFeatures of Pre-ANDA Program •\n\n“Complex Product” defined in the proposed GDUFA II Commitment Letter – Products with complex active ingredients, formulations, routes of delivery or dosage forms – Complex drug-device combinations – Other products where complexity or uncertainty concerning the approval pathway or other\n\nalternative approach would benefit from early scientific engagement\n\nMeetings\n\nProduct development, pre-submission, mid-review cycle -- FDA will issue guidance Product-Specific Guidance – Product-specific guidance for NCEs (not complex) – Identify the methodology for developing drugs and generating evidence needed to support generic approval\n\nOther enhancements include: – Controlled correspondence – Regulatory science – Inactive Ingredients Database (IID) – Safety Determination letters for REMS applications\n\n40", "n_tokens": 148, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-40-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 40, "text": "GDUFA II Highlights\n\nDMF Review Program Enhancements • DMF program enhancements were developed in\n\ncollaboration with API manufacturers\n\nNew efficiencies and better coordination with ANDA review will benefit ANDA sponsors\n\n41", "n_tokens": 44, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-41-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 41, "text": "GDUFA II Highlights\n\nFacility Assessment Enhancements\n\nFDASIA eliminated longstanding minimum inspection frequency requirements and directed FDA instead to inspect facilities globally on the basis of risk The transition to a new paradigm was disruptive -- over time Industry had developed expectations and business practices based on the old model\n\nTo mitigate ANDA sponsor concerns regarding the transparency and speed of facility assessment and its impact on ANDA approvability and product launch, FDA would: •\n\nCommunicate outstanding facility issues that could prevent approval of an ANDA or PAS through an IR, DRL or CRL Communicate to the facility owner final inspection classifications that do not negatively impact approvability of any pending application within 90 days of the end of the inspection Provide updates to and seek feedback from Industry stakeholders concerning facility assessment -- FDA understands strong GPhA concerns and looks forward to the dialogue To enhance transparency concerning the compliance status of GDUFA self-identified facilities and sites, FDA would update its existing, publicly available database\n\n42", "n_tokens": 194, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-42-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 42, "text": "GDUFA II Highlights\n\nAccountability and Reporting Enhancements Build internal capacity to enable improved productivity and performance through: • Transparent and efficient administration, allocation, and\n\nreporting of user fee resources • Resource management planning – Modernized time reporting\n\nIndependent third-party evaluations of program • Robust and expanded program performance reporting\n\nMonthly, quarterly, annually\n\n43", "n_tokens": 64, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-43-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 43, "text": "GDUFA II Highlights\n\nProgram Size Commensurate with ANDA Workload • ANDAs are the primary workload driver of the program • GDUFA I assumed that FDA would receive approximately\n\n750 ANDAs per year\n\nOver the first 4 years of GDUFA, ANDA receipts have averaged approximately 1,000 per year\n\nIn order to maintain current productivity and implement proposed GDUFA II improvements, FDA and Industry agreed that user fees should total $493.6 million annually, adjusted each year for inflation\n\n44", "n_tokens": 103, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-44-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 44, "text": "GDUFA II Highlights\n\nModifications to User Fees • To maintain a predictable fee base and better align\n\nfee responsibility with program costs and fee- paying ability, FDA and Industry propose to shift the burden more towards annual ANDA holder “Program Fees”\n\nSponsors with one or more approved ANDAs would pay an annual fee\n\nChanges to facility fees • Elimination of supplement (PAS) fees\n\n45", "n_tokens": 74, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-45-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 45, "text": "GDUFA II Highlights\n\nSmall Business Fee Considerations • No facility or ANDA sponsor would be charged an annual\n\nfee until an ANDA in which it is listed is approved • Annual program fee would have three tiers based on number of approved ANDAs owned by a firm and its affiliates: large (20+), medium (6 – 19), and small (1 – 5) • Contract Manufacturing Organizations (CMOs -- hired by ANDA sponsors to manufacture their generic drugs) would pay one-third of the annual facility fee paid by manufacturers that produce their own ANDAs\n\n46", "n_tokens": 117, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-46-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 46, "text": "GDUFA Overview\n\n1. Past 2. Present 3. Future 4. Closing Thoughts\n\n47", "n_tokens": 18, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-47-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 47, "text": "Closing Thoughts\n\nWe are on the right track: More approvals than ever before\n\nUnfinished business -- Convert CRs to APs, reduce cycles to approval\n\nTHANK YOU for your engagement, commitment, and support\n\nGenerics are more important than ever • GDUFA II will make a big difference • Together, we can do it!\n\n48", "n_tokens": 66, "kind": "text"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-48-0", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 48, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-0-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 0, "text": "FDA Role in Marijuana Regulation\n\nDouglas C. Throckmorton, M.D. Food and Drug Administration (FDA)\n\nFDLI July 19,2017", "n_tokens": 31, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-1-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 1, "text": "Disclosure Statement\n\nI have no financial relationships with proprietary entities that produce health care goods and services\n\nThe opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA\n\n2\n\n2", "n_tokens": 41, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-2-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 2, "text": "Central Messages\n\nFDA has clear role in supporting scientific and rigorous assessment of marijuana, including product development and regulation of marketing • The promise of safety, efficacy and reliability is not good enough However • FDA needs to do all it can to support the needed scientific research with marijuana to characterize its therapeutic promise\n\n3\n\n3", "n_tokens": 60, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-3-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 3, "text": "Status of MJ at the Federal Level\n\nControlled Substance Act of 1970:\n\n–Marijuana regulated under Schedule I\n\nHigh potential for abuse • No currently accepted medical use • Lack of accepted safety for use under medical supervision\n\nIn 2016 FDA completed review of published literature and recommended MJ remain in Schedule I 4\n\n4", "n_tokens": 58, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-4-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 4, "text": "Status of Marijuana Laws in the US\n\nSource: Marijuana Policy Project\n\n5", "n_tokens": 13, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-5-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 5, "text": "FDA Roles in MJ Regulation\n\nRegulatory role:\n\nFDA provides regulatory oversight for products containing\n\ncompounds from marijuana to encourage drug development •Scientific role: • FDA provides scientific assessment on the appropriate controls (‘schedule’) for marijuana to HHS and DEA\n\nFDA supports rigorous scientific research on marijuana •Enforcement role:\n\nTaking actions against products that present human health risks or that make egregious labeling claims\n\n6\n\n6", "n_tokens": 79, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-6-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 6, "text": "Center for Food Safety & Applied Nutrition\n\nFDA Work with Marijuana\n\nOffice of the Commissioner\n\nOffice of Regulatory Affairs\n\nCenter for Drug Evaluation & Research\n\nCenter for Biologics Evaluation & Research\n\nCenter for Devices & Radiological Health\n\nCenter for Veterinary Medicine\n\nNational Center for Toxicological Research\n\nCenter for Tobacco", "n_tokens": 53, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-7-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 7, "text": "FDA, State and Federal Coordination\n\nFDA has worked with 12 states to date on MJ issues\n\nFDA cooperation with DEA and NIDA extensive\n\nMOU between FDA and DEA facilitating data-sharing – FDA and NIDA cooperating to support study of abuse potential of CBD (trial ongoing)\n\nFDA interacts with multiple other Agencies across USG: – ONDCP, USDA, EPA, CBP, SAMHSA, NIDA\n\nwww.fda.gov\n\n8", "n_tokens": 92, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-8-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 8, "text": "FDA Support for Drug Development from MJ\n\nThree products approved:\n\nMarinol (dronabinol) (1985): nausea from cancer chemotherapy\n\nCesamet (nabilone) (1985 (2006)): nausea & neuropathic pain\n\nSyndros (dronabinol) (2017)\n\nwww.fda.gov\n\n9\n\n9", "n_tokens": 68, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-9-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 9, "text": "FDA Support for Drug Development from MJ\n\nFDA work to provide guidance and speed review\n\nFinal Guidance on the use of botanicals (e.g., marijuana) as sources for drugs – 2016\n\nFocus on measures to take to help assure quality manufacturing\n\nExpediting drug development using available tools: • Orphan Disease designation, Priority Review, Fast Track Designation\n\nBotanicals Team assistance\n\nhttp://www.fda.gov/newsevents/publichealthfocus/ucm421168.htm\n\nwww.fda.gov\n\n10", "n_tokens": 107, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-10-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 10, "text": "FDA Support for Drug Development from MJ\n\nFDA work to provide guidance and speed review (cont): – FDA actively maintains a website with Q and A section\n\naddressing common issues\n\nhttps://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168. htm\n\nExtensive communication between FDA, investigators and public about MJ and product development\n\nIn the past 12 months, CDER has responded to over 450 calls, emails, and letters about marijuana/CBD\n\nwww.fda.gov\n\n11", "n_tokens": 108, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-11-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 11, "text": "www.fda.gov\n\nFDA Supports Early Access to Investigations Products MJ\n\nFDA supports early access to\n\ninvestigational drugs from MJ: – Expanded Access (EA) programs allow access to investigational drugs during development under IND\n\nSet up by developer and investigator\n\nRequires safety data collection and human subjects protection\n\nExample: EA program for Epidiolex\n\nOver 400 children have received Epidiolex through EA\n\nhttp://www.fda.gov/newsevents/publichealthfocus/ucm421168.htm 12", "n_tokens": 107, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-12-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 12, "text": "FDA Enforcement Role in Regulating MJ\n\nCannabidiol Edibles\n\n13", "n_tokens": 14, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-13-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 13, "text": "CBD Warning Letters\n\nFDA has enforcement role to target nationally marketed products making egregious health claims – Includes products that allege to contain CBD\n\nFDA has issued two sets (Feb 2015 & Feb 2016) of warning letters (14 total) to those marketing unapproved drugs for the diagnosis, cure, mitigation, treatment, or prevention of diseases\n\nSome of these firms claim that their products contain cannabidiol (CBD)\n\nhttp://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421163.htm\n\n14\n\n14", "n_tokens": 120, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-14-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 14, "text": "Examples of Claims\n\n“[S]tudies have found CBD to possess the following medical properties: … Antipsychotic – combats psychosis disorders…combats neurodegenerative disorders … Anti-tumoral – combats tumor and cancer cells …combats…depression disorders”\n\nTreats rheumatoid arthritis • CBD helps with cancer, multiple sclerosis …diabetes, arthritis, dystonia, Crohn’s disease…\n\nhttp://www.fda.gov/NewsEvents/PublicHeal thFocus/ucm435591.htm\n\n15\n\n15", "n_tokens": 125, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-15-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 15, "text": "Results of Analytic Testing\n\nFDA has tested these products, and many were found to not contain the levels of CBD they claimed to contain. Consumers should beware purchasing and using any such products.\n\nhttp://www.fda.gov/newsevents/publich ealthfocus/ucm484109.htm\n\n16\n\n16", "n_tokens": 70, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-16-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 16, "text": "Summary\n\nFDA has a clear role with multiple activities ongoing around the regulation of marijuana\n\nOngoing FDA work includes:\n\nProviding scientific advice on the risks of marijuana and its constituents\n\nSupporting rigorous scientific research into\n\ntherapeutic value of marijuana and its constituents • Taking appropriate actions related to the marketing of\n\nproducts containing marijuana or its constituents\n\n17\n\n17", "n_tokens": 60, "kind": "text"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-17-0", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 17, "text": "Conclusions\n\nFDA will continue to support development of specific new drugs that are safe, effective, and manufactured to a high quality\n\nDrug development, grounded in rigorous scientific research is essential to determining the appropriate uses of marijuana and its constituents in the treatment of human disease\n\nFDA is committed to making this process as efficient as possible and looking for ways to speed the availability of new drugs from marijuana for the American public\n\n18\n\n18", "n_tokens": 79, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-0-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 0, "text": "FDA Role in Regulation of Cannabis Products\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs, CDER, FDA\n\nNew Jersey Association of County and City Health Officials (NJACCHO) Meeting\n\nSeptember 16, 2021", "n_tokens": 45, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-1-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 1, "text": "Disclaimer\n\nThis talk reflects the views of the author and should not be construed to represent FDA’s view or policies. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an implied endorsement of such products by the actual or Department of Health and Human Services.\n\n2", "n_tokens": 73, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-2-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 2, "text": "Biography\n\nAs Deputy Director for Regulatory Programs, in the Center for Drug Evaluation and Research at the FDA, Dr. Throckmorton shares the responsibility for overseeing the regulation of research, development, manufacture and marketing of prescription, over-the-counter, and generic drugs in the United States. He is committed to ensuring that the benefits of approved drugs outweigh their known risks. Among his responsibilities in CDER, Dr. Throckmorton works on issues related to controlled substances, including cannabis and cannabis-derived products.\n\nDr. Throckmorton received his medical degree from the University of Nebraska Medical School and completed his residency and fellowship at Case Western Reserve University and Yale University, respectively. Prior to coming to the FDA in 1997, he conducted basic science research and practiced medicine at the Medical College of Georgia, Augusta, Georgia and Augusta Veterans Administration Hospital.\n\n3", "n_tokens": 173, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-3-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 3, "text": "FDA Responsibilities\n\nRegulated Products include:\n\nHuman Foods (e.g., conventional foods, dietary supplements, food additives)\n\nDrugs (including prescription and non- prescription)\n\nBiologics (e.g., vaccines, blood and blood products)\n\nElectronic Products that give off radiation (e.g., microwave oven, X-ray equipment)\n\nCosmetics (e.g., skin moisturizers, lipsticks, eye and facial make-up, nail polish, cleansing shampoos)\n\nVeterinary Products (e.g., animal foods, animal drugs)\n\nPicture: https://pixabay.com/vectors/us-united-states-russia-map-1907526/\n\nMedical Devices (e.g., tongue depressors, pacemakers)\n\nTobacco Products (e.g., cigarettes, smokeless tobacco)\n\n4", "n_tokens": 172, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-4-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 4, "text": "FDA Authority\n\nFederal Food, Drug & Cosmetic Act (FD&C Act)\n\nFDA regulations\n\nFDA guidance\n\nFederal law enacted by Congress • Along with other federal laws it establishes legal framework within which FDA operates\n\nDevelops regulations based on law set forth in FD&C Act or other laws under which FDA operates\n\nFDA regulations can be found in Title 21 of the Code of Federal Regulations (21 CFR)\n\nFollows procedures required by its “Good Guidance Practice” regulation to issue FDA Guidance\n\nDescribe FDA’s current thinking on a regulatory issue\n\nFDA Basics: https://www.fda.gov/aboutfda/transparency/basics/ucm194909.htm\n\n5", "n_tokens": 134, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-5-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 5, "text": "FDA Role in Regulation of Cannabis Products\n\nCannabis-derived compounds\n\nCompounds occurring naturally in the\n\nplant – like CBD and THC\n\nThese compounds are extracted directly\n\nfrom the plant\n\nCan be used to manufacture drug\n\nproducts\n\nExample: highly-purified CBD extracted\n\nfrom the plant\n\nCANNABIS Cannabis sativa L. is a plant that contains over 80 different naturally occurring compounds called “cannabinoids” Two well-known cannabinoids: • Cannabidiol (CBD) • Tetrahydrocannabinol (THC) Plants are grown to produce varying concentrations of cannabinoids – THC or CBD These plant variations are called cultivars\n\nCannabis-related compounds • These synthetic compounds are created in\n\na laboratory\n\nCan be used to manufacture drug products • Some synthetic compounds may also occur naturally in the plant and some may not • Examples: Synthetically-derived dronabinol (also naturally occurring) and nabilone (not naturally occurring)\n\nAgency approved one cannabis-derived drug product: Epidiolex (cannabidiol)\n\nAgency approved 3 synthetic cannabis-\n\nrelated drug products: Marinol & Syndros (dronabinol), Cesamet (nabilone)\n\nFDA and Cannabis: Research and Drug Approval Process\n\n6", "n_tokens": 252, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-6-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 6, "text": "Regulatory Landscape : The Agriculture Improvement Act of 2018 (Farm Bill)\n\nGives US Department of Agriculture (USDA) authority to issue federal regulations and guidelines concerning hemp production. Individual States or tribes desiring primary regulatory authority over hemp production must submit a plan to USDA\n\nRemoved hemp from the definition of marijuana in the Controlled Substances Act (CSA)\n\nHemp: defined as cannabis (Cannabis sativa L.), and derivatives of cannabis, with extremely low (not more than 0.3 percent on a dry weight basis) concentrations of delta-9 THC\n\nMarijuana is still regulated by DEA under Schedule 1 of the CSA\n\n7", "n_tokens": 126, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-7-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 7, "text": "The Farm Bill’s Impact on FDA Authorities\n\nFDA’s authorities under the FDCA and section 351 of the PHS Act were specifically preserved by the Farm Bill\n\nCannabis and cannabis-derived products are subject to the same authorities and requirements as FDA-regulated products containing any other substance\n\nAllows hemp to serve as a source of cannabis and cannabis-derived compounds for drug development without CSA controls, if the investigational drug does not contain delta-9 THC at more than 0.3 percent by dry weight\n\n8", "n_tokens": 102, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-8-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 8, "text": "Overview of FDA Drug Authority\n\nUnder the FD&C Act:\n\nAny product, including a cannabis product (hemp or otherwise), that is marketed with a claim of therapeutic benefit, or with any other disease claim, is considered to be a drug\n\nGenerally, a new drug must be approved by the FDA for its intended use before it may be introduced into interstate commerce (limited exceptions, e.g., certain OTC drugs)\n\n9", "n_tokens": 88, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-9-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 9, "text": "THC and CBD: Active ingredients in approved drugs\n\nSec. 301(ll) of the FD&C Act (21 U.S.C. § 331)- paraphrased – It is prohibited to introduce into interstate commerce any food that contains an active ingredient (such as THC or CBD) in an approved drug product or in a potential drug for which substantial clinical investigations have been instituted and made public.\n\nCBD and THC cannot be added to foods under the FD&C Act – This prohibition applies regardless of whether the substances are hemp-derived\n\nCBD and THC products are excluded from the definition of dietary supplements under FD&C Act Section 201(ff)(3)(B)\n\n10", "n_tokens": 150, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-10-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 10, "text": "Cannabis Drug Development\n\nWhen used under clinical trial, cannabis and cannabis-derived compounds must meet all FDA requirements for IND applications, which includes 3 broad areas 1. Animal Pharmacology and Toxicology Studies 2. Manufacturing Information 3. Clinical Protocols and Investigator Information\n\nDevelopment of drugs has focused on using compounds in cannabis: CBD, THC\n\nFour products approved:\n\n1. Marinol (dronabinol) (1985): nausea from cancer chemotherapy Schedule III\n\n2. Cesamet (nabilone) (1985 (2006)): nausea & neuropathic pain  Schedule II\n\n3.\n\nSyndros (dronabinol) (2016): nausea from cancer chemotherapy  Schedule II\n\n4.\n\nEpidiolex (CBD) (2018): for childhood seizures & TSC  No longer controlled\n\n11 11", "n_tokens": 162, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-11-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 11, "text": "Cannabis Drug Development Draft Guidance •\t On July 21st, 2020 FDA published Draft Guidance Cannabis and Cannabis-Derived Compounds:\n\nQuality Considerations for Clinical Research\n\nCannabis and cannabis-derived compounds can be used in clinical research\n\nUnder an Investigational New Drug (IND) application to study a specific therapeutic indication\n\nSources of Cannabis\n\nResources for Information on Quality Considerations\n\nPercent Delta-9 THC Calculation\n\n12\n\n12", "n_tokens": 73, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-12-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 12, "text": "FDA Authority Over Foods for Humans and Animals & Food Additives Foods: •\t Exceptions to §301(ll):\n\nIf article was marketed in food before the drug was approved or before the substantial clinical investigations involving the drug had been authorized.\n\nNote: FDA has examined the available evidence and concluded that this exception does not apply to CBD\n\nFDA can also create an exception to 301(ll) through notice and comment rulemaking. •\t All ingredients in human and animal food must be approved food additives or GRAS for their intended use in the intended species.\n\nFood Additives: •\t At this time, there are no approved food additive uses for any substances derived from\n\nhemp and we are unaware of any basis to conclude that CBD is GRAS for its use in human or animal food. –\t This includes a lack of available safety data related to-food producing animal use (residues in\n\nmeat, milk, eggs).\n\n13", "n_tokens": 184, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-13-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 13, "text": "FDA Work on Cannabis\n\nFDA’s Cannabis Product Committee (CPC) - a cross- Agency collaboration\n\nOffice of the Commissioner\n\nOffice of Regulatory Affairs\n\nCenter for Food Safety & Applied Nutrition\n\nCenter for Drug Evaluation & Research\n\nCenter for Biologics Evaluation & Research\n\nCenter for Devices & Radiological Health\n\nCenter for Veterinary Medicine\n\nNational Center for Toxicological Research\n\nPictures: https://www.umassmed.edu/nutrition/Cardiovascular/ask-nutritionist/How-Can-I-Eat-More-Fruits-and-Veggies/ ; https://www.usatoday.com/story/news/nation/2018/07/25/prescription-drugs-industry-has-long-promised-cut-prices/830704002/ ; https://mymodernmet.com/fantastic-portraits-of-farm/ ; https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm624483.htm ; https://www.theatlantic.com/politics/archive/2016/05/low-tar-cigarettes/481116/ ; https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM611463.pdf ; https://www.fda.gov/aboutfda/centersoffices/oc/officeofscientificandmedicalprograms/nctr/whatwedo/researchdivisions/ucm078482.htm ; https://www.fda.gov/BiologicsBloodVaccines/ScienceResearch/ucm234680.htm\n\nCenter for Tobacco Products\n\n14", "n_tokens": 385, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-14-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 14, "text": "FDA’s CBD Work Plan\n\nDevelop a comprehensive research agenda that includes stakeholder input to address data gaps related to preclinical and clinical data needs identified based on scientific review of CBD safety data.\n\nEvaluate potential new pathways for CBD products, while evaluating issuance of an enforcement policy and continuing with WLs and enforcement as needed to address public health risks\n\nRespond to mandated Reports to Congress\n\nContinue to engage and communicate with consumers, federal and state regulators, as well as other stakeholders.\n\n15", "n_tokens": 99, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-15-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 15, "text": "Scientific Uncertainties for CBD\n\nEffects of cumulative and long-term human exposure •\t Effects in susceptible populations: children, pregnant/lactating mothers, elderly\n\nReversibility of adverse nonclinical effects (e.g., males, pediatric patients)\n\nDrug-drug interaction data •\t Pharmacology and toxicology of 7-COOH-CBD\n\nMetabolic profile across toxicology species (rabbit, nonhuman primate) •\t Impact of excipients in marketed consumer products on bioavailability (e.g., topicals/transdermals, smoking or vaping)\n\n16", "n_tokens": 123, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-16-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 16, "text": "Other FDA Activities: Warning Letters Related to CBD Products\n\nFDA issued numerous Warning Letters from 2015 to present, including after passage of the Farm Bill: –\t Unapproved new drugs [§§201(p), 301(d), and 505(a)] –\t Misbranded drugs [§§301(a) and 502(f)(1)] –\t Illegally marketed food [§301(ll), 402(a)(2)(C)(i), and 301(a)] –\t Illegally marketed supplements [§201(ff)(3)(B)] –\t Unapproved new animal drugs [§§301(a) and 501(a)(5)]\n\nFDA posted lab results for dozens of CBD products cited in the warning letters. – In many cases, the CBD content did not match the labeled claims and some products did not contain any CBD\n\n17", "n_tokens": 188, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-17-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 17, "text": "9/14/21 Consumer Update on delta-8 THC\n\nDelta-8 tetrahydrocannabinol, also known as delta-8 THC, is a psychoactive substance found in the Cannabis sativa plant, of which marijuana and hemp are two varieties.\n\n5 things you should know about delta-8 THC 1.\t Delta-8 THC products have not been evaluated or approved by the FDA for safe use\n\nand may be marketed in ways that put the public health at risk.\n\n2.\t The FDA has received adverse event reports involving delta-8 THC-containing products.\n\n3.\t Delta-8 THC has psychoactive and intoxicating effects. 4.\t Delta-8 THC products often involve use of potentially harmful chemicals to create the concentrations of delta-8 THC claimed in the marketplace.\n\n5.\t Delta-8 THC products should be kept out of the reach of children and pets.\n\n18", "n_tokens": 188, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-18-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 18, "text": "Adverse Event Reporting How to report complaints and cases of accidental exposure or adverse events •\n\nIf you think you are having a serious side effect that is an immediate danger to your health, call 9-1-1 or go to your local emergency room. Health care professionals and patients are encouraged to report complaints and cases of accidental exposure and adverse events to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program:\n\nCall an FDA Consumer Complaint Coordinator if you wish to speak directly to a person about your problem.\n\nComplete an electronic Voluntary MedWatch form online or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the form, or submit by fax to 1-800-FDA-0178.\n\nComplete a paper Voluntary MedWatch form and mail it to the FDA. • To report adverse events in animals to FDA’s Center for Veterinary Medicine, please download and submit Form FDA 1932a found at: www.fda.gov/ReportAnimalAE.\n\n19", "n_tokens": 205, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-19-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 19, "text": "Other FDA Activities: Real-World Data FDA Voices Blog: Better Data for a Better Understanding of the Use and Safety Profile of Cannabidiol (CBD) Products\n\n20", "n_tokens": 35, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-20-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 20, "text": "Other FDA Activities: Real-World Data\n\nFDA Voices Blog includes: –\t FDA ongoing work on CBD –\t Engagement with stakeholders on CBD issues –\t FDA’s CBD product sampling and testing activities –\t Additional work is needed to build data on CBD use and safety – Practical framework for robust, collaborative CBD data projects to inform public health decisions\n\nFDA thinks real-world data (RWD) on CBD use and safety has a crucial role alongside data from other types of studies to fill the current gaps 21", "n_tokens": 102, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-21-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 21, "text": "Summary and Conclusions • FDA has a well-defined role to play in the regulation and development of products containing cannabis and cannabis-derived compounds\n\nFDA continues to support scientific and rigorous testing and approval of drugs derived from cannabis and to support robust scientific research into understanding the therapeutic uses and safety of non-drug cannabis products\n\nFDA is actively exploring potential regulatory pathways for the lawful marketing of appropriate cannabis-derived products\n\nFDA is committed to protect and promote the public health with respect to products containing cannabis and cannabis-derived compounds, including enforcement action when needed\n\n22", "n_tokens": 106, "kind": "text"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-22-0", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 22, "text": "mW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-0-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 0, "text": "www.fda.gov\n\nFDA Update: 2018\n\nDouglas C. Throckmorton MD Deputy Director for Regulatory Programs CDER, FDA\n\nAmerican College of Surgeons May 21, 2018\n\n1LL", "n_tokens": 36, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-1-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 1, "text": "The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA", "n_tokens": 22, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-2-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 2, "text": "Drug Overdose Deaths\n\nhttps://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates\n\n3\n\n3", "n_tokens": 30, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-3-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 3, "text": "What does 53,000 people look like?\n\nhttp://www.espn.com/nfl/team/stadium/_/name/cin/cincinnati-bengals\n\n4\n\n4", "n_tokens": 37, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-4-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 4, "text": "Overdose Death Rates\n\n1999\n\n2014\n\nDesigned by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System\n\nScience = Solutions", "n_tokens": 35, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-5-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 5, "text": "FDA Response to this Crisis\n\n\"Unquestionably, our greatest immediate challenge is the problem of opioid abuse. This is a public health crisis of staggering human and economic proportion … we have an important role to play in reducing the rate of new abuse and in giving healthcare providers the tools to reduce exposure to opioids to only clearly appropriate patients, so we can also help reduce the new cases of addiction.\"\n\nScott Gottlieb, FDA Commissioner\n\nAddress to FDA staff, May 15, 2017", "n_tokens": 101, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-6-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 6, "text": "Available FDA Tools to Accomplish These Goals • Improving the safe use of drugs through careful\n\nand appropriate regulatory activities\n\nImproving the safe use of drugs through careful and appropriate policy development\n\nImproving product develoment through improved science\n\nImproving the safe use of drugs through communication, partnership and collaboration\n\n7", "n_tokens": 53, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-7-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 7, "text": "Responding to Challenges: Opioids", "n_tokens": 7, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-8-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 8, "text": "The Opioid Crisis: FDA’s Priorities & Strategies 1. Decreasing Exposure & Prevent New Addiction  Appropriate Dose/Duration Labeling  Appropriate Packaging, Storage, and Disposal  Health Care Provider 2. Supporting the Treatment of Those With Opioid Use Disorder\n\nEducation\n\n\n\nNaloxone Medication Assisted Treatment (MAT)\n\n3. Fostering the Development of Novel Pain Treatment Therapies  Partnerships & Meetings  Abuse Deterrent Formulations (ADFs)  Pain Treatment Alternatives\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\nImproving Enforcement Assessing Benefit-Risk", "n_tokens": 102, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-9-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 9, "text": "FDA Priorities align to HHS Strategic Priorities and other National Activities\n\nHHS STRATEGIC PRIORITIES Strengthening public health surveillance\n\nFDA PRIORITIES\n\nOTHER ACTIVITIES President’s Opioid Initiative\n\nTargeting availability and distribution of overdose- reversing drugs\n\nSupporting cutting- edge research\n\nImproving access to treatment and recovery services\n\nAdvancing the practice of pain management\n\n1. Decreasing Exposure & Prevent New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\nOffice of National Drug Control Policy Recommendations\n\nComprehensive Addiction and Recovery Act (CARA)\n\nNational Pain Strategy Recommendations\n\nNational Public Health Emergency", "n_tokens": 126, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-10-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 10, "text": "Summary and Conclusions\n\nFDA working to address opioid epidemic as a part of the larger HHS response – One of the FDA’s very highest priorities\n\nGoing forward, FDA is committed to taking decisive actions, grounded in the available science and appropriate public input to address this critical challenge to the US health and welfare\n\nCollaboration with professional societies an other stakeholders is essential to successfully meeting this challenge\n\nOur focus is addressing opioid abuse while assuring appropriate access to effective pain treatment\n\n11", "n_tokens": 93, "kind": "text"}
{"chunk_id": "FDA_Update_2018_May_21_2018-11-0", "doc_id": "FDA_Update_2018_May_21_2018", "page": 11, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-0-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 0, "text": "Some of CDER’s Top Issues, Priorities, and Goals\n\nPatrizia Cavazzoni, M.D. Director Center for Drug Evaluation and Research Food and Drug Administration U.S. Department of Health and Human Services\n\nPresented at Food and Drug Law Institute Annual Conference May 18, 2023", "n_tokens": 60, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-1-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 1, "text": "Areas We Will Cover Today\n\n Availability of medicines  Safety:\n\nSubstance use and misuse – Supply chain integrity\n\n Process enhancement and modernization", "n_tokens": 23, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-2-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 2, "text": "—_\n\nAvailability of Medicines:\nWhat CDER Can Do", "n_tokens": 11, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-3-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 3, "text": "Drug Shortages\n\n FDA’s Definition  Prevention: Early Notification is Key\n\nNumber of prevented shortages, CDER, 2021: 303 – Number of new shortages, CDER, 2021: 38\n\nWhat we CAN require:\n\nWhat we CANNOT require:\n\nNotification by manufacturers (FDASIA) of:  Supply disruptions  Delays  Discontinuations  Notification of certain manufacturing\n\nchanges\n\nA company to report an increase in demand\n\nthat might lead to shortage • A company to make a drug • A company to make more of a drug • A distributor to report on how much of a drug is distributed and which purchasers will be given priority", "n_tokens": 117, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-4-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 4, "text": "FDA’s Approach to Preventing & Mitigating Shortages\n\n Prioritize medically necessary products  Maintain availability while minimizing risk to patients  Work with firms to address problems by:\n\nPrompting firms to look at supply and demand\n\nExpediting review of company’s proposed plan to mitigate/resolve the shortage\n\nRegulatory discretion, e.g. on stability data for new manufacturing line\n\nTemporarily exercising regulatory flexibility and discretion regarding importation from other countries -- rare; contingencies apply\n\n In the event a shortage cannot be prevented, FDA and the manufacturer can\n\nwork together to encourage smart distribution, aka allocation", "n_tokens": 117, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-5-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 5, "text": "Regulatory Science – BSUFA III\n\n Pilot a BsUFA regulatory science program broadly applicable to biosimilar & interchangeable biological product development. Project goals should not be specific to a product or product class.\n\n Two demonstration projects:\n\nAdvancing the Development of Interchangeable Products\n\nImproving the Efficiency of Biosimilar Product Development\n\n Stakeholder Engagement\n\nIncludes public mtg on/before 10/2025 to review progress, solicit input on future priorities\n\nBefore meeting, FDA will issue interim report on project progress\n\nPublish final summary report on project outcomes in FY2027\n\n Deliverable: Publish comprehensive strategy within 12 mos of completing projects  For additional information, Biosimilars | Science and Research | FDA", "n_tokens": 138, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-6-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 6, "text": "Generic Drug User Fee Amendment (GDUFA III)\n\nResearch and Priority Initiatives for 2023  Develop methods for generics to address impurities, e.g., nitrosamines  Improve efficiency of BE approaches for oral and parenteral generics  Facilitate utility of model-integrated evidence to support demonstrations of BE  Enhance Approval of Complex Generics\n\nEnhance efficiency of BE approaches for complex active ingredients, routes of delivery, dosage forms and formulations, drug-device combination products\n\nFocus pre-submission meetings on key issues; option for enhanced mid-cycle mtg to resolve issues; new post-CRL mtg to facilitate subsequent cycle approval", "n_tokens": 126, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-7-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 7, "text": "GDUFA III (cont’d)\n\nANDA Communications and Review Enhancements  Imminent approval, goal date extensions  reduction in number of review cycles  Revisions to Pre-submission Facility Correspondence pathway requirements  Expansion of options for advice after a CRL  New goals around responses to suitability petitions to facilitate development of new ANDAs for different route of administration, strength, dosage form, or one different active ingredient\n\n Opportunities for telecons, correspondence, scientific mtgs when there are changes\n\nin product-specific guidances impacting ongoing BE studies", "n_tokens": 105, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-8-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 8, "text": "U.S. Drug and Biological Approval Pathways\n\nApproval of Drugs & Biologics\n\nAWC Trials\n\nClinical endpoint or validated surrogate\n\nReasonably likely surrogate/ Intermediate clinical endpoint\n\nSubstantial Evidence\n\nAWC – Adequate and Well Controlled Trials\n\n21 CFR 312.126\n\nTraditional approval\n\nAccelerated approval*\n\n21 CFR Part 314, Subpart H (for drugs) 21 CFR Part 601, Subpart E (for biologics) Food and Drug Administration Safety and Innovation Act 506(c)", "n_tokens": 101, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-9-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 9, "text": "Accelerated Approval Tradeoff: Speed to Meet Unmet Need vs. Certainty About Clinical Benefit p\n\n Serious and life-threatening diseases without adequate therapies  Challenges:\n\nAbility to identify a surrogate or intermediate clinical endpoint that predicts a clinically meaningful outcome\n\nRequires sufficient understanding of pathogenesis – Limitations of animal models\n\n Potential advantages:\n\nStreamlined development – Greater access as/if benefit is confirmed\n\n Confirmatory trials:\n\nPostmarketing trials required to verify and describe drug’s clinical benefit – Address remaining uncertainty of surrogate endpoint’s relation to clinical benefit", "n_tokens": 108, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-10-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 10, "text": "Consolidated Appropriations Act, 2023 Section 3210 Modernizing AA\n\n‘‘(D) STUDIES BEGUN BEFORE APPROVAL—The Secretary may require, as appropriate, a study or studies to be underway prior to approval, or within a specified time period after the date of approval, of the applicable product.’’\n\n Confirmatory: specify conditions for post-approval studies; sponsor reporting\n\non progress of such studies\n\n Accelerated Approval Council: Engages with product review team on policy development, training, e.g., best practices for communication between sponsors & FDA; product-specific development, review, withdrawal under AA\n\n Expedited withdrawal: codifies the expedited withdrawal procedures if\n\nsponsors fail to conduct required post approval study with due diligence", "n_tokens": 144, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-11-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 11, "text": "FDORA: Accelerated Approval Withdrawal\n\n The Food and Drug Omnibus Reform Act of 2022 (FDORA)’s revisions to the accelerated approval pathway include new streamlined withdrawal procedures\n\n Prior to the changes, the sponsor could elect to require FDA to hold an informal\n\nhearing that included an advisory committee (AC) prior to withdrawal\n\n As revised by FDORA, section 506(c)(3)(B) of the FD&C Act now provides the\n\nopportunity for a written appeal to the Commissioner (or Commissioner’s designee) on the proposed withdrawal\n\nSponsor is entitled to a meeting with the appellate decision-maker, but not a hearing. – Sponsor can request an AC, but is not entitled to one if an AC has previously advised FDA on the issues related to the proposed withdrawal\n\nFDA must provide for public comment on the proposed withdrawal, publish a summary of such comments, and provide FDA’s response to such comments", "n_tokens": 182, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-12-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 12, "text": "Prescription to Nonprescription Switch Updates\n\n FDA approved non-prescription Narcan, rapidly reverses effects of opioid overdose\n\nWorking to ensure all forms of naloxone remain available during and after the switch – Marketing status: Approved generic 4 mg naloxone nasal spray products with Narcan as RLD “misbranded” if labeled as prescription-only\n\nAny branded 4 mg naloxone nasal spray product that does not have a clinically meaningful difference from nonprescription Narcan misbranded\n\n Timing TBD for approval of other nonprescription naloxone products, including switch of\n\nother prescription naloxone products to nonprescription\n\n FDA issued (4/28) final guidance for industry, Smoking Cessation and Related Indications: Developing Nicotine Replacement Therapy Drug Products to assist sponsors in clinical development of NRT drug products to help cigarette smokers stop smoking\n\n Proposed Rule: Nonprescription Drug Product with An Additional Condition for\n\nNonprescription Use (ACNU) Published in FR, 6/28/22 (87 FR 38313)", "n_tokens": 223, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-13-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 13, "text": "OTC Monograph Updates\n\n FRN (March 2023), Over-The-Counter Monograph Drug User Fee Rates for Fiscal Year 2023 includes fee calculations and applicability of OMUFA fees\n\n Draft guidance for industry, Over-the-Counter Monograph Order Requests\n\n(OMORs): Format and Content (April 2023)\n\n Posted five final administrative orders (April 2023). Section 505G of the\n\nFederal Food, Drug, and Cosmetic (FD&C Act), as added by the CARES Act, deemed final monographs and tentative final monographs to be final orders. FDA is issuing a notice to withdraw regulations establishing final monographs in title 21 of the CFR", "n_tokens": 136, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-14-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 14, "text": "Safety: Substance Use and Misuse Supply Chain Integrity", "n_tokens": 10, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-15-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 15, "text": "1\n\n2\n\n3\n\n4\n\nFDA Overdose Prevention Framework\n\nSupport primary prevention by eliminating unnecessary initial prescription drug exposure and\n\ninappropriate prolonged prescribing\n\nEncourage harm reduction through innovation and education\n\nAdvance development of evidence-based substance use disorder treatments\n\nProtect the public from unapproved, diverted or counterfeit drugs presenting overdose risks", "n_tokens": 58, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-16-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 16, "text": "CDER’s “Opioid Policy Refresh” in Action\n\nSeptember 23, 2022\n\nApril 3, 2023\n\nJune 26-27, 2023\n\nMarch 29, 2023\n\nApril 13, 2023", "n_tokens": 41, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-17-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 17, "text": "Appropriate Opioid Prescribing -- Safety Labeling Change\n\n Part of FDA’s comprehensive work to support safer opioid analgesic use and shared decision making between HCPs and patients regarding balanced pain management\n\n FDA is requiring several updates to the prescribing information for immediate- release (IR) and extended-release/long-acting (ER/LA) opioid analgesics\n\n Key updates:\n\nInclude statement that many acute pain conditions, including surgical procedures, treated in the outpatient setting require no more than a few days of an opioid pain medicine\n\nClarify that ER/LA opioid pain medicines should be reserved for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate\n\nInclude new warning about opioid-induced hyperalgesia and allodynia", "n_tokens": 174, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-18-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 18, "text": "Saving Lives by Making Naloxone More Accessible\n\n Approval of nonprescription naloxone (Narcan 4 mg Nasal Spray)​\n\nPrescription products will still be available – Any generic products affected by the switch of the Narcan nasal spray must switch their products to nonprescription status\n\nFDA will continue to work with stakeholders during this period of transition to ensure continued access to naloxone\n\nThe DSCSA guidance, issued September 2022, will still be in effect to help harm reduction programs continue to purchase naloxone\n\n FDA will continue to gather information from stakeholders, such as at recently held public workshop, as part of our proactive approach to manage overdoses – Speakers and panelists from harm reduction groups did not ask for higher dose\n\nnaloxone; they called for lower dose or more titratable formulations", "n_tokens": 169, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-19-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 19, "text": "Safer Disposal of Unused Opioids: REMS Modification for Mail-Back Envelopes\n\n FDA is requiring a modification to the Opioid Analgesic REMS  Manufacturers must make prepaid mail-back envelopes available to\n\noutpatient pharmacies and other dispensers\n\n Part of FDA’s comprehensive approach to address the overdose crisis by\n\nproviding patients an option to safely and securely dispose of unused opioid medicines – FDA is also exploring in-home disposal options\n\nFDA will participate in NASEM workshop (June 2023) for stakeholders to examine in- home drug disposal systems\n\nFDA opened a docket to collect public comments to help determine whether in-home disposal products can mitigate risk of nonmedical use or overdose through a REMS", "n_tokens": 148, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-20-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 20, "text": "November 8, 2022\n\nXylazine Activities\n\nFebruary 28, 2023", "n_tokens": 14, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-21-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 21, "text": "Increased Prescription C-II Stimulant Use Years 2010-2021\n\nEstimated prescriptions for scheduled (C-II) stimulants dispensed from U.S. outpatient pharmacies, annually 2010-2021. Source: Symphony Health Metys™. Study period 2010-2021, data extracted March 2022. Outpatient pharmacies include retail and mail-order pharmacies. Data include all dosage formulations.CII stimulants include amphetamine, dexmethylphenidate, dextroamphetamine, dextroamphetamine/amphetamine, lisdexamfetamine, methamphetamine , methylphenidate, and serdexmethylphenidate/dexmethylphenidate. C-II = schedule II, M = millions", "n_tokens": 171, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-22-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 22, "text": "FDA Updating Warnings to Improve Safe Use of Prescription Stimulants for Treating ADHD & Other Conditions\n\n Key updates: boxed warning & prescribing info for CII\n\nstimulants (amphetamines & methylphenidate)\n\nDescribes risks of misuse, abuse, addiction, overdose consistently across CII stimulants, including that use of CII stimulants can lead to misuse or abuse even when prescribed to treat a specific condition\n\nIncludes language that patients should never share prescription stimulants or use differently than directed by health care professionals\n\nFor details, see the Drug Safety Communication", "n_tokens": 124, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-23-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 23, "text": "Drug Supply Chain Security Act (DSCSA)\n\n Enacted November 27, 2013\n\n Outlines steps to achieve interoperable, electronic tracing of product at the package level to identify and trace certain prescription drugs as they are distributed in the U.S.\n\n Establishes national licensure standards for wholesale drug distributors and\n\nthird-party logistics providers (3PLs)\n\n Improves detection and removal of potentially dangerous drugs from the drug\n\nsupply chain\n\n Enhances ability to help protect consumers from exposure to drugs that may\n\nbe counterfeit, stolen, contaminated, or otherwise harmful", "n_tokens": 106, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-24-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 24, "text": "DSCSA Implementation\n\n Stakeholder Readiness and Challenges for November 2023 – Industry has shown progress -> there is still work to do before the\n\n11/27/2023 deadline (e.g., including industry testing)\n\nWhile most data exchange will be standardized, flexible methods may be needed for small entities (e.g., web portals or email)\n\nContinue outreach to trading partners and other stakeholders, as lack of understanding of complexities and needs may still exist, particularly with small entities or State regulators\n\nVariety of Implementation Challenges", "n_tokens": 105, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-25-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 25, "text": "DSCSA Implementation (cont’d)\n\n What’s Next  2023 and Beyond\n\nGuidances for Industry – Small Dispenser Assessment – Stakeholder Engagement (e.g., public private partnership, public meeting)\n\nFinalize Wholesale Distributor/Third-party Logistics Provider (3PL) proposed regulations – Compliance and enforcement", "n_tokens": 66, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-26-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 26, "text": "Nitrosamine Impurities Overview\n\nNitrosamine Issues\n\nRegulatory Activity\n\nRisk Assessments\n\nN-nitrosodimethylamine (NDMA) • FDA became aware of the\n\npresence of NDMA in valsartan, an angiotensin II receptor blocker (ARB) in 2018\n\nFDA learned that common synthetic pathways could introduce NDMA and other types of nitrosamine impurities\n\nNitrosamine Drug Substance- Related Impurities (NDSRIs) • FDA alerted the public in\n\nNovember 2021 regarding the presence of NDSRIs\n\nNDSRIs share structural similarity to the active pharmaceutical ingredient (API) and present unique challenges\n\nFDA issued guidance in September 2020, “Control of Nitrosamine Impurities in Human Drugs” • Provides recommendations on\n\ndetecting and preventing unacceptable levels of nitrosamines Identifies acceptable intake (AI) limits for six nitrosamine impurities\n\nFDA updated guidance in February 2021 • Extended timeframe for\n\ncompletion of risk assessments\n\nFDA issued a statement on NDSRIs in November 2021 • Provides possible mitigation strategies and additional information on how NDSRIs are formed\n\nAmes Testing • Ames tests are typically used to assess mutagenicity. However, Ames tests have been shown to be inadequate in characterizing mutagenic potential in nitrosamines\n\nFDA’s National Center for\n\nToxicological Research (NCTR) has been testing different conditions to develop an enhanced Ames test\n\nComputational Toxicology •\n\n(Q)SAR can be used to predict the outcome of an Ames test and can be used to classify an impurity • Can be done more rapidly than in vitro or in vivo testing and can be an efficient means to assess nitrosamine toxicity in the absence of experimental data\n\n• Encourages manufacturers to consider mitigation strategies\n\nMitigation\n\nFDA identified on its webpage two examples of mitigation strategies to reduce levels of NDSRIs in drug products • Addition of an antioxidant to\n\ninhibit formation of nitrosamines • Formulation in a neutral or basic\n\nenvironment", "n_tokens": 402, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-27-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 27, "text": "Nitrosamines: Federal Register Notice and Collaborative Efforts\n\n Federal Register Notice related to nitrosamine impurities\n\npublished May 4, 2023 – FDA is requesting comments from the public regarding the identification, assessment, and control of NDSRIs including scientific and regulatory considerations and areas that may benefit from collaborative efforts\n\n Collaborative efforts\n\nFDA has collaborated with international regulators since 2018 and other groups such as the Health and Environmental Sciences Institute (HESI) to address various issues related to nitrosamine impurities\n\nFDA is interested in the feasibility of collaborative efforts within industry to avoid potentially duplicative in vitro or in vivo testing of NDSRIs", "n_tokens": 125, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-28-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 28, "text": "—_\n\nProcess Enhancement and\nModernization", "n_tokens": 6, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-29-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 29, "text": "Prescription Drug User Fee Act (PDUFA VII) Fiscal Years 2023-2027\n\n Provides FDA with resources needed to maintain predictable, efficient review process for human drug and biologic products. Ensures stable, consistent funding that will allow FDA to fulfill its mission to protect and promote public health by helping to bring to market critical new medicines for patients.\n\n FDA developed proposed enhancements for PDUFA VII in consultation with drug industry\n\nrepresentatives, patient/consumer advocates, health care professionals, and other public stakeholders.\n\nTwo new formal meeting types: Type D and INTERACT​\n\nExpanded definition of face-to-face formal meetings with industry: includes in-person and virtual on IT platforms with audio and visual communication\n\nPILOT PROGRAMS\n\nSplit Real-Time Application Review (STAR) for priority efficacy supplements for unmet medical need​\n\nRare Disease Endpoint Advancement (RDEA) to address developing appropriate efficacy endpoint(s) for CTs evaluating effectiveness of rare disease therapies​\n\nAdvancing Real-World Evidence (RWE) to identify approaches for generating RWE that meet regulatory requirements in support of labeling for effectiveness or for meeting post-approval study requirements; annual reporting", "n_tokens": 224, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-30-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 30, "text": "PDUFA VII (cont’d)\n\nEnhanced overall CMC-related communications during drug development and application review\n\nPMRs\n\nIncludes pilot: 2 additional CMC meetings for development of products for unmet medical needs, accelerated clinical timelines​\n\nNew process, timelines, performance goals to ensure timely availability for public of safety and efficacy information\n\nNew process for sponsors to request review of existing PMRs\n\nTraining for FDA staff on updated processes for communication with sponsors ​\n\nWill update corresponding MAPPs, SOPs, guidances\n\nFDA to host public workshop on using innovative manufacturing technologies to facilitate their adoption\n\nFDA reporting quarterly on hiring goals", "n_tokens": 119, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-31-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 31, "text": "Decentralized Clinical Trials for Drugs, Biological Products, and Devices\n\n Bringing the trial to the patient\n\nVideo and telemedicine visits – Digital health technologies – Direct distribution of products – Electronic informed consent – Home visits – Use of local health care providers and facilities\n\n Guidance issued May 2\n\nhttps://www.fda.gov/media/167696/download", "n_tokens": 73, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-32-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 32, "text": "Guidance to Support Use of DCTs\n\n The DCT guidance includes recommendations on:\n\nDesign considerations – Conduct of remote CT visits and CT-related activities – Use of digital technologies to remotely acquire data – Roles and responsibilities of sponsor and investigators – Obtaining informed consent; IRB oversight of informed consent process – Appropriateness of investigational products for use in a DCT – Product packaging and shipping – Safety monitoring of participants", "n_tokens": 80, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-33-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 33, "text": "Advisory Committee Modernization\n\n CDER is modernizing its Advisory Committee processes to ensure we\n\ncontinue to have access to world-class experts to advise us on scientific, policy and technical matters. To this end, we will:\n\nRefine the selection of AC members, so that their expertise applies precisely to the matters under consideration\n\nOptimize our internal business processes for planning and managing AC meetings\n\nDevelop communication strategies to ensure that our stakeholders understand the role of the AC versus the role of the Agency. Committees provide advice; FDA has decision-making authority", "n_tokens": 105, "kind": "text"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-34-0", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 34, "text": "Looking Forward\n\n There is much more, for example:\n\nRWD/RWE: do we need an “Operation Warp Speed”?\n\nQuantitative medicine: expand use of modeling in drug development through a multidisciplinary approach\n\nClinical trial innovation: need end-to-end, multimodal framework\n\nDrug supply chain disruption: what should CDER do and not do, and how can we bring others to the table?\n\nWorkforce: retention, hiring, hybrid work environment, all in a fiercely competitive labor environment", "n_tokens": 100, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-0-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 0, "text": "2023 PDA/FDA JOINT REGULATORY CONFERENCE\n\nCGMP: Quality Through Science and Innovation\n\n18-20 SEPTEMBER | WASHINGTON, DC #PDAFDA\n\npda.org/2023PDAFDA\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 54, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-1-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 1, "text": "Call to Action: Assuring Quality through Sustainable Compliance, Vigilant Quality Management and Modern Manufacturing\n\nPatrizia Cavazzoni, M.D. Director Center for Drug Evaluation and Research Food and Drug Administration U.S. Department of Health and Human Services September 18, 2023\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 71, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-2-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 2, "text": "Areas We Will Cover Today\n\nManufacturing Issues Leading to Drug Shortages • Inspections • Achieving Sustainable Compliance • Call to Action\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 35, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-3-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 3, "text": "Reasons for New Shortages in CY2022\n\nAvailability of API\n\n8%\n\ns e g a t r o h S r o f\n\nIncrease in demand\n\nNatural disaster/PHE\n\n8%\n\n29%\n\ns n o s a e R\n\nProduction discontinuation\n\n8%\n\nQuality issues/Manufacturing Delays\n\n46%\n\n0\n\n5\n\n10 15 Number of Shortages\n\n20\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER\n\n25\n\n4", "n_tokens": 82, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-4-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 4, "text": "Early Notification is Key to Prevention\n\nThrough ongoing dialogue/work with industry the number of prevented shortages continues to grow, while new drug shortages remain flat\n\nDepending on the precipitating events, some drug shortages can endure for months to years (e.g., due to the need for plant remediations)\n\nThe earlier this work begins the greater the likelihood a shortage can be prevented, or the most severe impacts mitigated\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER\n\n1. Ninth Annual Report on Drug Shortages for Calendar Year 2021", "n_tokens": 111, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-5-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 5, "text": "Manufacturing Capacity Shortfall\n\nFor critical drugs, there exists a U.S. and global production capacity shortfall  This is particularly true for sterile injectable drugs  There are no current incentives for generic drug manufacturers to produce\n\nexcess over market demand (unlike other commodities)\n\nThis can lead to disruptions in supply which can ultimately result in shortages  Disruptions can be caused by significant events:\n\no Hurricane Maria in Puerto Rico o Necessary compliance remediations o Geopolitical concerns\n\n Or financial pressures can lead to: o Manufacturing site closures o Firm bankruptcies\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 121, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-6-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 6, "text": "Oncology Drug Shortages\n\n16 drugs in shortage (as of August 2023)\n\namifostine injection, – azacitadine injection, – capecitabine tablets, – carboplatin injection, – cisplatin injection, – cytarabine injection, – dacarbazine injection, – dexamethasone injection\n\nfludarabine injection – hydrocortisone injection – leucovorin injection – lutetium lu 177 vipovotide textraxeta injection – methotrexate injection – methotrexate tablets – palifermin injection – streptozocin injection\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 140, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-7-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 7, "text": "Current US Shortage of Critical Oncology Drugs\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 22, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-8-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 8, "text": "Critical Shortage of Cisplatin and Carboplatin\n\n1.8 million Americans are diagnosed with some form of cancer every year\n\nThere are estimates that up to\n\n500,000 patients possibly could have a stage and a diagnosis that would rely on a platinum agent\n\nThe current shortages of cisplatin and carboplatin followed an inspection and identification of quality issues at one company’s facility\n\nShortages posted on FDA website in 2/23 and 4/23. respectively\n\nThe company shut down production leading to the current shortage. In addition, the shortage of cisplatin led to a ripple effect as demand for the second line treatment, carboplatin, increased but the manufacturers were not able to meet demand\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 153, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-9-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 9, "text": "Critical Shortage of Cisplatin and Carboplatin\n\nCisplatin and Carboplatin shortage\n\nInspection at one company’s facility found quality issues  company temporarily shut down production\n\nDemand for carboplatin (second-line therapy) then increased  manufacturers could not meet demand\n\nFDA is taking steps to help increase supply. For example:\n\nNot objecting to temporary importation of unapproved cisplatin and temporary exclusion of drugs from import alert\n\nAsking manufacturers to submit data to support extended expiration dating for lots in distribution approaching labeled expiration date\n\nThe most up to date information is on the FDA drug shortage website\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 135, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-10-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 10, "text": "Compliance and Inspections\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 17, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-11-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 11, "text": "Inspections\n\nFDA continued mission-critical inspections throughout the public health emergency\n\nFDA has conducted domestic inspections at standard operational levels since October 2021​\n\nFDA resumed foreign facility surveillance inspections in March 2022, and resumed inspections in China with U.S.-based staff in April 2023​\n\nFDA continues to leverage a variety\n\nof tools for facility assessment, including remote assessments\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 81, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-12-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 12, "text": "Enforcement and Advisory Tools\n\nShift in Source of Information for Drug Adulteration Advisory Actions Warning Letters FY18-23**\n\n** Warning Letters through July 31, 2023\n\nExcludes compounding-related actions\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 55, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-13-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 13, "text": "Recurring Issues in Drug Manufacturing Compliance • Microbial contamination\n\nLack of data integrity, transparency,\n\nOphthalmic product contaminated with multi- drug resistant bacteria\n\nand record retention – Information must be accurate, reliable, and\n\nBurkholderia cepacia complex in non-sterile, water-based drug products\n\nPoor excipient quality and manufacturing controls – Diethylene glycol/ethylene glycol testing – Benzene contamination (warning letter) – First CGMP Warning letter issued to excipient\n\nmanufacturer\n\nRefusal of inspection; failure to respond to requests for records\n\ncomplete\n\nAppropriate remediation strategy and suitable timeframes are important\n\nInadequate controls related to: • Aseptic manufacturing • Cleaning and cross-contamination • Supply chain globalization & contract\n\nmanufacturing\n\nFacility design and maintenance • Out-of-specification result investigations\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 178, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-14-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 14, "text": "What is Compliance?\n\nCompliance is:\n\nThe act or process of complying with a regimen.\n\nThe degree of constancy and accuracy with which a prescribed regimen is followed.\n\nExamples:\n\nExample 1: Patient adherence to prescription\n\nQ: What is the result of patient non-compliance with taking a drug as directed (e.g., antiseizure, heart failure, antibiotic)? A: Patient non-compliance leads to a higher probability of failure of the therapy and unfavorable health outcomes.\n\nExample 2: Manufacturing\n\nQ: What happens if a manufacturer doesn’t follow CGMP requirements? A: There is less assurance of product quality and a higher probability of defects and failures.\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER\n\nAmerican Heritage Stedman Medical Dictionary and Merriam Webster Dictionary", "n_tokens": 167, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-15-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 15, "text": "Sustainable Compliance\n\nFDA’s Current Good Manufacturing Practice (CGMP) requirements provide the foundation for a robust state of control and drug quality\n\nMaintaining ongoing CGMP compliance requires a proactive and prevention-focused quality system • If the quality system at a facility is slow to address operations with excessive variability, this reactive approach is a recipe for lapses in compliance and inconsistent pharmaceutical quality which increases the risk of product quality failures\n\nFigure A: This facility experiences lapses in control due to inconsistent adherence to CGMP and vacillates between acceptable and substandard compliance.\n\nFigure B: This prevention-focused, facility results in consistent CGMP compliance.\n\nCompliant\n\nCompliant\n\ntime\n\ntime\n\nNon-Compliant\n\nNon-Compliant\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 155, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-16-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 16, "text": "Critical Factors Associated with Sustainable Compliance\n\nSenior Management Oversight of Facilities\n\nTechnological capability directly impacts quality of outputs and is central to sustainable compliance.\n\nEnsure ongoing suitability of operational design, control, and maintenance.\n\nAllocate resources for production infrastructure upgrades when operations are deficient.\n\nLifecycle Quality Signals and Root Cause Analysis\n\nImplement effective systems for detecting emerging issues – Use structured approach for investigations to determine root cause, in order to accurately define the needed Corrective Action and Preventive Action (CAPA)\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 110, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-17-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 17, "text": "Senior Management Oversight and Opportunities for Manufacturing Modernization • Digitization • Digitalization • Automation (e.g., robotics) • Semi-Continuous or Continuous Manufacturing • Building Management Systems • 100% Inspection Technologies • Containment Advances (e.g., isolators) • Rapid Testing and Monitoring Technologies • Optimization of Quality Management System\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER\n\n18", "n_tokens": 80, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-18-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 18, "text": "Example of Recidivism and Lack of Sustainable Compliance\n\nLarge, multinational manufacturer of generics\n\nProduces sterile and non-sterile finished products and active ingredients for vulnerable patients\n\nFDA observed multiple facilities within a single corporate umbrella with significant CGMP violations, including data integrity issues, inadequate out-of-specification result investigations, unsuitable equipment  firm required to retain independent experts to evaluate applications and CGMP activities\n\nNumerous actions  felony charges ($500m settlement), consent decree (2012, covered up to 4 facilities from 2014-2017), warning letters (at least 7 from 2002 -2022), drugs placed on import alert\n\nProblems continue\n\nIneffective CGMP remediations across network persist (e.g., facility received a letter of Consent Decree and CGMP non-compliance in 2023)\n\nMany drugs remain on Import Alert 66-40\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 182, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-19-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 19, "text": "Examples of Successful Compliance Remediation\n\nLarge multinational API manufacturer of antibiotics and sartan drugs –Produces drugs for vulnerable patient populations –Problems developed over several years culminating with WL issued in 2019; firm held regulatory meetings in 2019 and had communications over several years. Firm was re-inspected in 2022, resulting in VAI classification\n\nLarge analytical firm focused on laboratory tests across the pharmaceutical and packaging industries -Issues developed resulting in a noncompliance action in 2020. The firm worked on corrective actions -In 2022 at their follow up inspection received a VAI classification\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 127, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-20-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 20, "text": "A Call to Action: Achieving Sustainable Compliance\n\n1.\n\nIdentify and address current problems; implement long-term systemic remediation\n\n2. Ensure strong quality management oversight\n\n\"Walk the talk:” quality is top priority throughout organization • Accountability for quality\n\n3. Well-designed facilities, equipment, and processes • Upgrade to highly capable facilities and equipment • State of control vigilantly monitored\n\n4. Engineer quality system to proactively identify and remediate problems as they occur (FDA is not your quality system)\n\nPrompt attention to address emerging adverse trends and deviations\n\n Commitment to quality assurance is essential for dependable drug supply\n\n2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 135, "kind": "text"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-21-0", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 21, "text": "2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER", "n_tokens": 14, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-0-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 0, "text": "CDER New Drugs Program: 2018 Update\n\nKhushboo Sharma, MBA, RAC Chief of Staff Office of New Drugs, CDER/FDA\n\nFDA/CMS Summit December 11th, 2018", "n_tokens": 40, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-1-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 1, "text": "Housekeeping\n\n Data and analyses presented to reflect latest information,\n\nalthough usual QC for official FDA reports has not occurred. Presentation content should be considered preliminary.\n\n Pay close attention to fiscal year (FY), calendar year (CY),\n\nor academic year (AY) and cut-off dates on data presentations; denominators are important too!\n\n Talented staff at FDA provide the data and analyses for this talk each year. Special thanks and acknowledgement to: – Nader Qassim, Nancy Maizel, and Reza Kazemi-Tabriz in CDER’s\n\nOffice of Program and Strategic Analysis\n\nMike Lanthier in the Office of the Commissioner\n\n2", "n_tokens": 133, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-2-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 2, "text": "Topics to be covered\n\n New drug review process efficiency: a historical look and changes in PDUFA VI  New drug activity in 2018: approvals,\n\nworkload, international comparisons, and profiling the 2018 class of NMEs/BLAs\n\n Development phase activity: IND workload,\n\nthe breakthrough program, meeting workload and changes in PDUFA VI\n\n A look ahead to 2019\n\n3\n\n•3", "n_tokens": 77, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-3-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 3, "text": "CDER New Molecular Entity Approval Rates by PDUFA Cohort\n\nProjection estimates account for actions to date and elapsed time to date for non-approvals\n\nData as of 11/30/18\n\n4", "n_tokens": 41, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-4-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 4, "text": "New Drug Activity in 2018\n\n\n\nIn CY 2018 so far*, CDER has approved 55 NMEs, including 31 orphan drugs – 42 Priority Reviewed NME approvals, more than double the recent 5-year average\n\nof 20 priority approvals per year\n\nFor the first time ever, the majority of NMEs approved are orphan drugs to treat rare diseases\n\n2018 has a unique blend of therapeutic areas, quantity of approvals is not driven by oncology indications as in the past\n\n U.S. continues to lead the world in first approval of NMEs\n\n\n\nSeveral Notable Approvals, including: – Epidiolex (Cannabidiol) – Cannabinoid Approval\n\nErleada (Apalutamide) – Novel Endpoint\n\nLucemyra (Lofexidine Hydrochloride) - Opioid Withdrawal\n\nTPOXX (tecovirimat) – treat small pox and address the risk of bioterrorism\n\nThis information is accurate as of November 30th, 2018. In rare instances, it may be necessary for FDA to change a drug’s new molecular entity (NME) designation or the status of its application as a new biologics license application (BLA). This note applies to all references to NME/Original BLAs in this presentation.\n\n5\n\n•5", "n_tokens": 257, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-5-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 5, "text": "Notable Approvals: Not Only Quantity but Quality for 2018\n\nEpidiolex (cannabidiol): for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, for patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. It is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome.\n\nErleada (Apalutamide): for the treatment of patients with prostate cancer that has not spread (non-metastatic), but that continues to grow despite treatment with hormone therapy (castration-resistant). This is the first FDA-approved treatment for non-metastatic, castration- resistant prostate cancer using novel clinical trial endpoint.\n\nLucemyra (Lofexidine Hydrochloride) : for the non-opioid treatment for management of opioid withdrawal symptoms in adults.\n\nTPOXX (tecovirimat): the first drug with an indication for treatment of smallpox. Though the World Health Organization declared smallpox eradicated in 1980, there have been longstanding concerns that smallpox could be used as a bioweapon.\n\n6\n\n•6", "n_tokens": 261, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-6-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 6, "text": "CDER NME NDAs/BLAs† Filings and Approvals by CY as of 11/30/18\n\n† Multiple applications pertaining to a single new molecular/biologic entity are only counted once. Original BLAs that do not contain a new active ingredient are excluded. * This information is accurate as of November 30th, 2018. of its application as a new biologics license application (BLA). This note applies to all references to NME/Original BLAs in this presentation. Since applications are received and filed throughout a calendar year, the filed applications in a given calendar year do not necessarily correspond to an approval in the same calendar year. Certain applications are within their 60-day filing review period and may not be filed upon completion of the review.\n\nIn rare instances, it may be necessary for FDA to change a drug’s new molecular entity (NME) designation or the status\n\n7\n\n•7", "n_tokens": 182, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-7-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 7, "text": "NME Actions and Approvals by CY\n\nData as of 11/30/2018 Includes discrete actions on a given date for an active ingredient which, if approved, would constitute a new molecular entity. Actions for original submissions and resubmissions as well as actions for new BLAs are included. Multiple actions which occur on the same date for multiple dosage forms or indications are counted as a single regulatory action. 8", "n_tokens": 82, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-8-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 8, "text": "CDER NME NDAs/BLAs† First Action Approval Rate by FY\n\nData as of 11/30/2018 † Multiple applications pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers represented here for filings are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded.\n\n9\n\n•9", "n_tokens": 93, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-9-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 9, "text": "New Drug Activity in 2018\n\nCDER Approved Orphan Indicationsfor all NDAs and BLAs† by CY\n\nCalendar Year\n\n† Includes Efficacy Supplements * Data as of 11/30/2018\n\n10", "n_tokens": 36, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-10-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 10, "text": "USA Share of New Active Substances Launched on World Market Remains High\n\nData as of 11/30/2018\n\nSource: Scrip Magazine (1982 - 2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007 - 2017)\n\n11", "n_tokens": 54, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-11-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 11, "text": "Snapshot of CY 2018 NME NDAs/BLAs† Drug Approvals (1/2)\n\nData as of 11/30/2018 † Multiple submissions pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded. * A PDUFA Goal Date is marked as met if the NME is acted upon within its approval cycle due date.\n\n12", "n_tokens": 114, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-12-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 12, "text": "Snapshot of CY 2018 NME NDAs/BLAs† Drug Approvals (2/2)\n\nData as of 11/30/2018 † Multiple submissions pertaining to a single new molecular/biologic entity (e.g., single ingredient and combinations) are only counted once. Therefore, the numbers are not indicative of workload in the PDUFA V Program. Original BLAs that do not contain a new active ingredient are excluded. * A PDUFA Goal Date is marked as met if the NME is acted upon within its approval cycle due date.\n\n13", "n_tokens": 114, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-13-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 13, "text": "In CY 2018, CDER Continued To Ensure The Efficiency Of First Cycle Review\n\n All of the (100%) NMEs/BLAs approved to date in 2018 met their PDUFA goal dates\n\n All but three (95%) of the drugs approved to date in 2018 were approved in the first review cycle\n\n14\n\n•14", "n_tokens": 64, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-14-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 14, "text": "Utilization of Expedited Development and Review Programs Remained High in 2018\n\n Over three – quarters (76%) of the\n\ndrugs approved to date in 2018 were approved under Priority Review\n\n Almost one out of four (24%) of the drugs approved to date in 2018 received Breakthrough Therapy designation\n\n About four out of ten (44%) of the drugs approved to date in 2018 received Fast Track designation\n\n15\n\n•15", "n_tokens": 79, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-15-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 15, "text": "2018 Continues A Strong Track Record For Drug Innovation\n\n Over half (56%) of the drugs approved to date in 2018 are orphan drugs\n\n About a third (35%) of the drugs approved to date in 2018 are the first in their class\n\n Almost three\n\nquarters\n\n(71%) of the drugs approved – to date in 2018 were first approved in the U.S.\n\n16\n\n•16", "n_tokens": 75, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-16-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 16, "text": "Development Phase Work Continued to Grow in 2018\n\nData are from the PDUFA Workload Adjuster and represent a 12 month period of July 1st - June 30th\n\n17\n\n•17", "n_tokens": 34, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-17-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 17, "text": "CDER Breakthrough Therapy Requests by Division Oncology, Hematology, and Neurology account for over 50% of Breakthrough Requests.\n\nData as of 11/30/2018\n\n18\n\n18", "n_tokens": 37, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-18-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 18, "text": "CDER Breakthrough Therapy Grants by Division\n\nData as of 11/30/2018\n\n19\n\n19", "n_tokens": 17, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-19-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 19, "text": "CDER PDUFA Formal Meeting Requests by FY\n\nData as of 9/30/2018 BLAs were transferred to CDER in FY2004 *2018 Data is preliminary\n\n20\n\n•20", "n_tokens": 39, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-20-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 20, "text": "Looking ahead to 2019\n\n\n\nFDARA Section 903 Real Time Reporting:\n\nfocuses on streamlining and improving consistency in performance reporting and requires the FDA to provide Real Time reporting related to the process for the review of human drugs and biologics, medical devices, generic drugs, and biosimilar biological product.\n\nReport contains data on the number and title draft and final guidance; and the number and titles of public meetings held on topics related to the process for the review of human drug applications.\n\nhttps://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstoth eFDCAct/FDARA/ucm598050.htm\n\n\n\nContinued implementation of PDUFA VI agreements, other aspects of FDARA and 21st Century Cures\n\n\n\nContinued ongoing critical evaluation of new drug regulatory program operations to ensure that we can meet program demands and our public health obligations to the American people\n\n\n\nKeep up with CDER NME Approvals and our year end report:\n\nhttps://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm592464.htm\n\n21", "n_tokens": 236, "kind": "text"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-21-0", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 21, "text": "PAY U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-0-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 0, "text": "Future of Drug Development\n\nJanet Woodcock Director, CDER, FDA", "n_tokens": 13, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-1-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 1, "text": "THESIS", "n_tokens": 1, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-2-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 2, "text": "Multiple Forces Are Driving the Shape of the Future\n\nInternational regulatory convergence • Advanced manufacturing • Rise of biosimilars • New science and technology • Digital revolution • Drug costs THE GENERIC INDUSTRY AND ITS REGULATORS NEED TO BE AHEAD OF THESE TRENDS", "n_tokens": 46, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-3-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 3, "text": "International Regulatory Convergence\n\nThis is a good thing • Too many repetitive submissions in too many regions, too many inspection visits—leads to errors, increase costs\n\nConvergence of regulators:\n\nMutual reliance initiative between EU and US – At the end, only EU inspectors inspect in Europe and only US inspectors in USA\n\nMust go through a process, currently just for surveillance inspections, but making progress\n\nOther regulators could join – FDA interacts closely with other regulators via foreign offices", "n_tokens": 87, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-4-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 4, "text": "International Regulatory Convergence: Convergence of Standards\n\nICH\n\nRevitalized – Hope for and expect substantive industry participation – Continue to harmonize technical requirements\n\nInspection reports\n\nNeed to be able to read each other’s reports (e.g., different languages, formats)\n\nUS: piloting NIP (“new inspection protocol”), procedures and standardized, quantified assessment\n\nUltimate goal—regulators use same tool, understandable work product worldwide, industry understands standards", "n_tokens": 89, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-5-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 5, "text": "Advanced Manufacturing\n\nI believe that continuous production will be revolutionary for solid oral dosage forms over the long run\n\nFirms will be able to use various platform technologies to easily and rapidly switch among strengths and APIs.\n\nReduced costs, reduced or no off-line laboratory testing, reduced space and environmental footprint, better control of attributes, continuous 24 hr production when needed", "n_tokens": 69, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-6-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 6, "text": "Advanced Manufacturing\n\nLikely brand companies will adopt first, but ideal for manufacture of mutiple different products that are similar\n\nIt will be a number of years before the equipment, technology and know-how will be available commercially, but these will come • This advance should decrease any regulatory\n\nproblems significantly, due to ability to control attributes", "n_tokens": 63, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-7-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 7, "text": "Rise of Biosimilars\n\nBiologics are highest-priced medicines right now • Biosimilars not generics—but greatly streamlined pathway\n\nRobust program taking place at FDA and industry—but still early times\n\nAny new scientific/technical program takes years to fully develop\n\nCost pressure—rapid uptake once approved in US", "n_tokens": 63, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-8-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 8, "text": "New Science and Technology\n\nSome rapid uptake by generics—e.g., abuse deterrent opioid formulations\n\nCombination products\n\nAdvanced delivery systems\n\nInhalers • Auto-injectors • Future—into CNS, other spaces\n\nOther drug-device combos", "n_tokens": 54, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-9-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 9, "text": "New Science and Technology\n\nPrecision medicine/specialty pharma\n\nRevolution coming in the treatment of many diseases\n\nLarge number or small/orphan subgroups – May be large number of related drugs using a “platform technology” i.e., small modifications needed to address different mutations within the same gene\n\nBottom line: increased number of different drugs needed", "n_tokens": 66, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-10-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 10, "text": "Digital Revolution: How Much Can We Automate?\n\nWe are still in the pre-Henry Ford era of automation in drug development\n\nFord’s lesson: standardization needed to get efficiency in a process\n\nWe are getting electronic submissions, but the more we standardize, the fewer mistakes everyone will make and the more efficient the process will become\n\nCan’t make this too burdensome on your end, need to be congruent with business processes", "n_tokens": 86, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-11-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 11, "text": "Drug Costs\n\nWill be an ongoing theme • Generic industry (most) seen as good guys, but issues with single source products\n\nClearly will be a continued focus in US and elsewhere\n\nVarious types of pressures on regulators • We will continue to be asked ways to mitigate drug cost issues", "n_tokens": 54, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-12-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 12, "text": "GENERIC INDUSTRY AND ITS REGULATORS NEED TO BE AHEAD OF THESE TRENDS", "n_tokens": 12, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-13-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 13, "text": "GDUFA 2: Is it Forward-Looking?\n\nNot just about current efficiency/timeframes • Prepares for the future, for example\n\nFocused research to enable approval or more streamlined development of non-oral dosage forms\n\nComplex drugs program: get advice upfront on development program – Interaction and guidance", "n_tokens": 59, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-14-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 14, "text": "CDER is Planning for the Future\n\nLifecycle management\n\nAwareness of lifecycle across center – Building in awareness at time of new drug approval • Consistent, documented, automated procedures that are scalable: establishing QMS\n\nContinue to improve e-submission to streamline process and reduce cycling: hope to markedly reduce cycles so that CDER and industry can concentrate on getting work out and preparing for the future", "n_tokens": 77, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-15-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 15, "text": "Facility Assessment: An area of ongoing improvement efforts\n\nWe understand the frustration about the timelines and relative lack of transparency of current process\n\nArea of high focus and intense effort\n\nHigh priority for me personally – We will roll out new process with timelines and much more transparency\n\nORA reorganization in the spring, at that time our partners in facility assessment will be organized in a manner that will enable a much better process that reduces duplication", "n_tokens": 83, "kind": "text"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-16-0", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 16, "text": "Summary\n\nBold future for the affordable pharmaceuticals industry!\n\nPace of change will be rapid • Need to work with regulators to enable • GDUFA 2 (and BSUFA 2) are next steps • Industry undoubtedly will expand its role as major source of pharmaceutical care for the world’s population", "n_tokens": 57, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-0-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 0, "text": "Advancing Efficient and Inclusive Clinical Trials\n\nMeeting of the Directors of the NCI-designated Cancer Centers\n\nOctober 4, 2021\n\nDr. Patrizia Cavazzoni Director, Center for Drug Evaluation and Research, FDA\n\nwww.fda.gov\n\n1", "n_tokens": 47, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-1-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 1, "text": "FDA Multipronged Approach to Facilitate Innovative, Efficient, and Inclusive Clinical Trials\n\nFDA Real-World Evidence Program\n\nEfficient Safety Reporting\n\nIncreasing Diversity in Clinical Trials\n\nDecentralized Clinical Trials\n\nDigital Health Tools\n\nLessons from the Pandemic\n\nwww.fda.gov\n\n2", "n_tokens": 49, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-2-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 2, "text": "FDA Real-World Evidence Program\n\nWe want to provide the clarity needed to realize the full potential of Real-World Data\n\n2018\n\nhttps://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RealWorldEvidence/UCM627769.pdf\n\n2021\n\n3", "n_tokens": 62, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-3-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 3, "text": "Supporting Safe and Efficient Clinical Trials Efficient Safety Reporting\n\nWe are improving IND safety reporting through guidance and outreach: • Sponsor Responsibilities IND Safety Draft Guidance (June 2021): Clarifies Sponsor’s IND\n\nsafety reporting requirements. Expands recommendations for aggregate reporting and safety assessment committees. – External Webinar provided to stakeholders\n\nInvestigator Responsibilities for IND Safety Draft Guidance (September 2021): Focused investigator guidance in this space, including reporting to IRB. – External webinar will be provided to stakeholders\n\nWCG Webinar “A Fresh Perspective from the FDA on the Final IND Safety Reporting Rule” (June 2021): Dr. Temple and Dr. Corrigan-Curay presented regarding sponsor responsibilities for safety reporting.\n\nPRIM&R Annual Conference (Nov 2021): Collaborative presentation with OGCP highlighting IND safety responsibilities for sponsors, investigators and IRBs.\n\n4", "n_tokens": 169, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-4-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 4, "text": "Inclusion and Diversity in Clinical Trials\n\nWe are exploring ways to encourage the participation of racial and ethnic minorities and other underrepresented populations in clinical trials through:\n\no Issuing guidance\n\n• •\n\nEnhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs (2020) Cancer Clinical Trial Eligibility Criteria: Minimum Age Considerations for Inclusion of Pediatric Patients (2020) Inclusion of Older Adults in Cancer Clinical Trials (2020) Collection of Race and Ethnicity Data in Clinical Trials (2016)\n\no Developing tools\n\nCDER developed Drug Trials Snapshots (https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials- snapshots) as part of an overall FDA effort to make demographic data more available and transparent.\n\no Encouraging the use of innovative trial design\n\nFDA is working on guidance pertaining to the use of decentralized trials and digital health technologies.\n\n5", "n_tokens": 181, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-5-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 5, "text": "Facilitating and Encouraging Innovation e.g., Decentralized Clinical Trials (DCTs)\n\nA clinical trial where some or all the trial-related activities occur at a location separate from the investigator’s location\n\nPotential benefits:\n\nPatient convenience (avoiding travel to sites, time off work, etc.)\n\nImproved inclusivity (patients with mobility, cognitive and economic challenges)\n\nAbility to study patients in widespread locations (rare or sporadic diseases)\n\nFDA Will Issue a Guidance on DCTs\n\nwww.fda.gov\n\nhttps://ctti-clinicaltrials.org/wp-content/uploads/2021/06/CTTI_DCT_Recs.pdf\n\n6", "n_tokens": 136, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-6-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 6, "text": "Facilitating and Encouraging Innovation e.g., Digital Health Tools (DHTs)\n\nA digital health technology (DHT) is a system that uses computing platforms, connectivity, software, and/or sensors, for healthcare and related uses\n\nPotential benefits:\n\nAbility to study diseases in new ways\n\nImproved recruitment of patients (e.g., those with limited mobility)\n\nData capture outside of health care setting\n\nContinuous data rather than snapshots\n\nObjective measurements\n\nReduced missing data\n\nCapturing rare events\n\nFDA Will Issue a Guidance on Digital Health Technologies for Remote Data Acquisition in Clinical Investigations\n\nwww.fda.gov\n\n7", "n_tokens": 115, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-7-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 7, "text": "What Can We Learn From the Pandemic?\n\nInitial release date: March 18, 2020\n\nMost recent update: August 30, 2021\n\nLessons and examples from public health emergencies: • • • • •\n\nLeveraging existing healthcare infrastructure Remote assessment and monitoring Identifying & prioritizing critical processes Leveraging technology and innovations Effective communication and documentation", "n_tokens": 64, "kind": "text"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-8-0", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 8, "text": "Summary\n\nWe recognize the great potential in many evolving areas to advance drug development. •We are working to provide the needed regulatory perspective to not only facilitate, but also encourage innovations. •We are developing multiple guidances to explore the utility of RWD & RWE, and to facilitate a more efficient clinical trial design and conduct. •We are engaging with multiple partners across the Federal Government and the private sector to disseminate knowledge and to help facilitate innovative approaches.", "n_tokens": 92, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-0-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 0, "text": "National Academies of Sciences, Engineering, and Medicine\n\nThe Food and Drug Administration's Emergency Use Authorization: Lessons Learned from the Past to Guide the Future\n\nCenter for Drug Evaluation and Research Patrizia Cavazzoni, MD October 5, 2021", "n_tokens": 48, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-1-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 1, "text": "Panel 1: Use of the Emergency Use Authorization During the COVID Pandemic\n\nOpening Remarks", "n_tokens": 18, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-2-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 2, "text": "Communication is a Pillar of CDER’s Pandemic Response\n\nSince the beginning of the COVID-19 public health emergency, we have maintained constant coordination with other U.S. Government agencies, our international counterparts and the research community.\n\nExtensive coordination has been and remains essential to our ability to obtain and maintain the most up-to-date understanding of – the pathogen, including viral variants of SARS-CoV-2 – the clinical course of disease in patients – the development of potential medicines for prevention or treatment of COVID-\n\n19, and\n\nthe trajectory of the virus and the impact of interventions at the regional, national and global scales.\n\nEfficient and rapid exchange of information on a dynamic and changing pandemic allows our scientific and regulatory teams to quickly provide guidance to sponsors and other stakeholders to expedite the development of drugs.\n\n3", "n_tokens": 169, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-3-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 3, "text": "Coronavirus Treatment Acceleration Program (CTAP)\n\nEmergency program for potential coronavirus therapies created April 2020.\n\nEnabled FDA to leverage cross-agency scientific resources and expertise to facilitate COVID-19 therapeutic development and review.\n\nFacilitated fast, early, and frequent discussions between FDA and drug sponsors -- an essential element in expediting efficient development of therapies.\n\nIncludes significant emphasis on providing timely FDA feedback to industry on clinical trial development – reinforcing the gold standard for assessing whether a particular therapeutic is safe and effective for its investigational use.\n\n4", "n_tokens": 111, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-4-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 4, "text": "Surge in Workload\n\nCTAP Snapshot, as of August 31, 2021:\n\n640+ drug development programs in planning stages\n\n470+ trials reviewed by FDA\n\nPre-Pandemic (FY19) vs Pandemic (FY20) Workload Increase\n\n43%\n\n26%\n\n50%\n\nNo Corresponding Increase in Staff\n\nNew INDs received\n\nFormal meeting requests\n\nAvg time between request and meeting\n\n5", "n_tokens": 78, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-5-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 5, "text": "Applying the EUA Standard in a Dynamic Environment\n\nEUA is a mechanism to provide rapid access to potential new therapies during a public health emergency when there is no adequate, approved and available alternative and the expected potential benefit outweighs the risk\n\nEUAs are appropriate where it is reasonable to believe that the product may be effective for its proposed use, and when used for such purposes, the known and potential benefits outweigh the known and potential risks\n\nThe Agency must consider the totality of scientific evidence available, including data from adequate and well-controlled clinical trials, if available\n\nInvolves balancing early access against uncertainty\n\nThe calculus to make that determination may change over the course of the emergency as more therapeutic options emerge\n\nEUAs are a temporary measure; sponsors of products authorized under EUA are expected to continue development of an authorized product toward licensure or approval.\n\n6", "n_tokens": 171, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-6-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 6, "text": "Applying the EUA Standard in a Dynamic Environment (2)\n\nThe EUA authority is sufficiently robust and flexible to enable the Agency to:\n\no Act, when scientifically supportable, to rapidly make available potentially\n\neffective therapeutics to meet the public health need, taking into consideration adequate, approved and available alternative therapies; and\n\no Adapt to an evolving and increasingly dynamic epidemiological and clinical\n\nlandscape; or\n\no Revoke when the scientific data no longer support that the product is appropriate\n\nfor its authorized uses (e.g., new clinical trial data, circulating variants)\n\nGenerally, CDER has issued EUAs when top-line, scientifically robust and interpretable data available from at least one adequate and well-controlled clinical trial supports the Agency’s determination that the criteria for issuance of an EUA are met.\n\nCDER has required, as conditions to the EUA, not only enhanced adverse event reporting but also expedited reporting on product quality defects for authorized biologics, and, in the case of monoclonal therapies potential loss of efficacy against circulating viral variants of SARS-CoV-2\n\n7", "n_tokens": 229, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-7-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 7, "text": "Timeline of Major EUA Actions\n\nMay 8th Fresenius Kabi Propoven 2% Emulsion\n\nNov 9th Bamlanivimab\n\nMar 28th Chloroquine phosphate / Hydroxychloroquine Sulfate\n\nJune 15th Chloroquine phosphate / Hydroxychloroquine Sulfate\n\nNov 19th Baricitinib (in combo w/ Veklury)\n\nApr ‘20\n\nJuly ‘20\n\nOct ‘20\n\nJan ‘21\n\nMay 1st Remdesivir\n\nAug 28th Remdesivir\n\nOct 22nd Veklury (Remdesivir)\n\nAug 13th Baxter’s Regiocit CRRT\n\nNov 23rd REGEN-COV\n\nKey\n\nInitial Authorization\n\nRevision\n\nApproved\n\nJune 24th Actemra\n\nMay 26th Sotrovimab\n\nApr 16th Bamlanivimab\n\nJuly 28th Baricitinib (alone)\n\nApr ‘21\n\nJuly ‘21\n\nOct ‘21\n\nFeb 25th Bamlanivimab/ Etesevimab\n\nJuly 30th Bamlanivimab/ Etesevimab\n\nMar 12th Propofol-Lipuro\n\nJuly 30th REGEN-COV\n\nRevoked\n\nCRRT - Continuous Renal Replacement Therapy\n\n8", "n_tokens": 224, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-8-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 8, "text": "COVID-19 Monoclonal Antibodies: Public Health Impact\n\n2.52 million treatment courses distributed\n\n8098 sites receiving product\n\n65% 90%-\n\nReported Usage: 1.2 million treatment courses\n\nReduction in risk of COVID-19 related hospitalization or death in high-risk patients was observed in clinical trials\n\n9", "n_tokens": 63, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-9-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 9, "text": "While our work to respond to the pandemic isn’t over, we are taking stock of our experience and capturing lessons learned", "n_tokens": 26, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-10-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 10, "text": "Lessons Learned – Evidence Generation\n\nInvestigators launched clinical trials rapidly\n\nBut few were sufficiently powered to provide actionable data\n\nCollective resources were not used efficiently to generate data that could lead to authorization or approval of products\n\nThe use of different endpoints across trials made it difficult to compare therapies\n\nBugin and Woodcock, Trends in Covid 19 therapeutic clinical trials, Nature Reviews, Drug Discovery (20): 225 April 2021\n\nDespite CTAP – not all sponsors engaged with FDA on the design of their trials\n\n11", "n_tokens": 98, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-11-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 11, "text": "Lessons Learned – Evidence Generation The value of master protocols:\n\n12", "n_tokens": 12, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-12-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 12, "text": "Lessons Learned – Evidence Generation\n\nRapid implementation of master protocols and other large randomized trials requires a research ready network – Research Staff – Contracts – Central IRBs\n\nReproduced from Weber, G. Federated queries of clinical date repositories: Scaling to a national network Journal of Biomedical Informatics Vol 55 June 2015 p 231-236\n\n13", "n_tokens": 67, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-13-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 13, "text": "Public Transparency\n\nTransparency is critical to public confidence in the Agency’s scientific review process\n\nScientific reviews that underpin our decisions to issue, revise or revoke an EUA are made public on our website*\n\nHowever, there may be delays in such release as we engage with the sponsor on what must be protected from disclosure\n\nthis delays health care provider and patient access to the evidence underlying EUA\n\nWe need broader authority to disclose safety and effectiveness information that underpin our EUA decisions 14\n\nWe need broader authority to disclose safety and effectiveness information that underpin our EUA decisions 14\n\n*\n\n•", "n_tokens": 115, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-14-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 14, "text": "FDA’s Strength Is Its People\n\n43%\n\n26%\n\n50%\n\nNew INDs received\n\nFormal meeting requests\n\nAvg time between request and meeting\n\nTo be ready to respond to pandemics, FDA needs to be able to build enduring surge capacity in the core scientific disciplines and supporting operations.\n\n15", "n_tokens": 57, "kind": "text"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-15-0", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 15, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-0-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 0, "text": "Ongoing FDA Work Related to Opioid Overdose Prevention\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs Center for Drug Evaluation and Research FDA\n\nOffice of the Assistant Secretary for Health (OASH) January, 2019\n\n1", "n_tokens": 46, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-1-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 1, "text": "Recent and Ongoing Activities Related to Naloxone\n\nCo-prescribing of Naloxone with RX Opioids\n\nResults of recent public FDA Advisory Committee\n\nOver-the-Counter (OTC) Naloxone\n\nResearch to support labeling for OTC naloxone products to support product development • Role of expanded naloxone availability in USG response to opioid crisis – Systems model of opioid crisis\n\n2", "n_tokens": 90, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-2-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 2, "text": "The Opioid Crisis: FDA’s Priorities & Strategies\n\n1. Decreasing Exposure & Prevent New Addiction\n\n Appropriate Dose/Duration Labeling  Appropriate Packaging, Storage, and Disposal  Health Care Provider Education 2. Supporting the Treatment of Those With Opioid Use Disorder \n\nNaloxone Medication Assisted Treatment (MAT)\n\n3. Fostering the Development of Novel Pain Treatment Therapies  Partnerships & Meetings  Abuse Deterrent Formulations (ADFs)  Pain Treatment Alternatives 4. Improving Enforcement & Assessing Benefit-Risk Assessing Benefit-Risk\n\n3", "n_tokens": 101, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-3-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 3, "text": "I. Naloxone Co-Prescribing with Rx Opioids\n\nNaloxone prescriptions rising (336.1K dispensed in\n\n2017) but still inadequate\n\nFDA received Citizen Petition from maker of one of the naloxone products requesting FDA require co- prescribing of patients prescribed opioids\n\nFDA Advisory Committee held December 17-18 to get input from advisors and public\n\n4", "n_tokens": 86, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-4-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 4, "text": "Annual Cost of Requiring Co- Prescribing: FDA Model\n\nAll Opioid Analgesic Rx Scenario\n\nIncrease in Demand\n\n48.5 million new doses per year (4,689% increase)\n\nIncrease in Prices\n\nWith Generics: $52.63/dose  $1,287.87/dose Without Generics: $478.41/dose  $11,707.95/dose\n\nIncrease in Total Spending\n\n$579.2 billion/year (Without Generics) $63.9 billion/year (With Generics)\n\n5", "n_tokens": 113, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-5-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 5, "text": "Naloxone Advisory Committee (cont)\n\nIn general: – Harm reduction advocacy groups very strong in their view\n\nthat co-prescribing was not ‘enough’\n\nCommittee members not supportive of value of required co- prescribing\n\nConcerns expressed about cost to healthcare system and diversion of resources (both money and naloxone) away from underserved areas\n\nFocus should be on educating prescribers/patients and supportin g\n\nIn addition, Committee members called on USG to take on broader actions to ‘force’ expanded availability of naloxone. Examples: – Forced OTC switch – Revoking patents currently delaying generic/OTC product\n\nmarketing\n\nManufacturing naloxone and making it available from USG stockpile(s)\n\n– Extending expiration dating for naloxone products\n\n6", "n_tokens": 164, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-6-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 6, "text": "Next Steps\n\nFDA meeting internally on AC recommendations\n\nPlan response to Citizen Petition – Discuss ideas raised by Committee membersReview AC Docket comments (>220 comments received so far)\n\nEngage external stakeholders – Propose next steps to leadership\n\n7", "n_tokens": 44, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-7-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 7, "text": "II. Over-The-Counter Naloxone: Why OTC Naloxone?\n\nExisting expanded access programs (such as pharmacy standing order programs) are a significant tool, but more is needed – not everyone can/wants to obtain the product through a healthcare professional\n\nSurgeon General’s 2018 Advisory\n\n8", "n_tokens": 62, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-8-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 8, "text": "U.S. Surgeon General Advisory\n\n“I, Surgeon General of the United States Public Health Service, VADM Jerome Adams, am emphasizing the importance of the overdose-reversing drug naloxone. For patients currently taking high doses of opioids as prescribed for pain, individuals misusing prescription opioids, individuals using illicit opioids such as heroin or fentanyl, health care practitioners, family and friends of people who have an opioid use disorder, and community members who come into contact with people at risk for opioid overdose, knowing how to use naloxone and keeping it within reach can save a life.”\n\n9", "n_tokens": 134, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-9-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 9, "text": "Development Programs for Nonprescription Drugs\n\nOften rely on safety and efficacy established for the prescription product\n\nNew studies may be required if proposing a new indication or a new patient population for the OTC market\n\nNeed to “translate” key elements of the prescription label into consumer-friendly terms\n\nConsumer studies needed to evaluate the “OTC-ness” of product\n\n10", "n_tokens": 70, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-10-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 10, "text": "Translate the Approved RX Product Label....\n\n11", "n_tokens": 12, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-11-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 11, "text": "To a Label for OTC Products…..\n\nDrug Facts Label\n\n12", "n_tokens": 14, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-12-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 12, "text": "OTC Consumer Studies\n\nLabel Comprehension Study\n\nUnderstanding the key label messages\n\nSelf-Selection Study • Choosing the right product for “me”\n\nActual Use Study • Using according to labeled directions\n\nHuman Factors Study\n\nInteracting with the product\n\n13", "n_tokens": 42, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-13-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 13, "text": "FDA Proposed an Innovative Approach to Support OTC Naloxone Products:\n\nTo develop a model Drug Facts Label (DFL) that could be understood by all potential consumers who might use OTC naloxone\n\nTo iteratively refine the DFL and evaluate consumer comprehension through a contract with established consumer research firms with expertise in conducting label comprehension studies and interviewing substance abuse populations\n\nTo conduct an independent review of the resulting data\n\n14", "n_tokens": 86, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-14-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 14, "text": "FDA Proposed an Innovative Approach (cont’d):\n\nIf study was successful, Sponsors could adapt the model DFL to their naloxone product\n\nSponsors would only need to add information specific to their particular device and assess through human factors\n\nLabel comprehension was the key study to be conducted – self-selection and actual use are likely not needed\n\n15", "n_tokens": 69, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-15-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 15, "text": "Status of Research\n\nFDA-supported study completed December 2018 • Review by FDA scientists complete January 2019 – FDA concluded that the results of this study are acceptable to support use of the tested naloxone DFL in the OTC setting\n\nFDA in the process of making these results and findings public for use by manufacturers seeking to develop OTC naloxone products • FRN in clearance • Planned public announcement of results and article being written\n\n16", "n_tokens": 87, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-16-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 16, "text": "Drug Facts\n\nActive ingredient (in each XX) Purpose\nNaloxone hydrochioride X ma Emergency treatment of opioid overdose\n\nUses\n\n‘+ To revive” someone during an overdose from many prescription pain medications or street\ndrugs such as heroin\n\n+ _This medicine can save a life\n\nDirections\n\nStep 1: CHECK:\n\n+ CHECK for a suspected overdose. the person will not wake\nup or is very sleepy or not breathing well\n\n© yell ‘Wake up!\"\n‘© shake the person gently\n\n© if he person is not awake. go to Step 2\n\nStep 2; GIVE 1\" dose\n+ GIVE the 1% dose of this medicine\n\n+ place the injector on the LEG above the knee and press\ndown\n\nStep 3: CALL\n\n© GALL 911 immediately ater giving the 1\" dose\n\nStep 4: WATCH & GIVE\n\n© WAIT 2-3 minutes after the 1* dose to give the medicine\ntime to work\n\n‘+ ifthe person wakes up: Go to Stop 5\n‘+ ithe person does not wake up\n\n. TINUE TO GIVE doses every 2-3 minu\nthe person wakes up\n\n+ itis safe to keep giving doses\n\nStep 5: STAY\n‘+ STAY unill ambulance arrives: even if the person wakes up\n\n+ GIVE another dose if the person becomes very sleepy again\n\nYou may need to give all the doses in the pack.\n\nWamings\nWhen using this product some people may experience symptoms when they wake up. such\na8 shaking, sweating, nausea, 0: feeling angry. This is to be expected\n\nOther informations store at room temperature + [advise inser tamper evident statement here]\n\nInactive Ingredients\n\nQuestions?\n\nphone number, website)\n\nPrototype Drug Facts\nBox for OTC Naloxone", "n_tokens": 337, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-17-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 17, "text": "III. Systems Model of Opioids Crisis Including Role of Naloxone\n\nDeliverable for the BHCC • Successful model will help identify high-impact actions and anticipate consequences of policy changes\n\nExperts from across HHS providing input\n\n18", "n_tokens": 49, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-18-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 18, "text": "OVERVIEW: WHY MODELING\n\nEvents\n\nEvery day, more than 115 people in the United States die after overdosing on opioids...\n\nPatterns of behavior\n\nThe total number of overdose death has been on the rise.\n\nSystem architecture • Feedback processes • Stocks and flows • Time delays\n\nStructure of the system\n\nInformation availability • Delays, biases, error, gaps • Access & transparency\n\nMental models (of any stakeholder)\n\nActor goals and incentives • Time horizon, model boundary • Misperceptions of feedback\n\nAGENDA | PROJECT CONTEXT | SYSTEMS MODEL |PROJECT TIMELINE | DISCUSSION\n\n19\n\n19", "n_tokens": 113, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-19-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 19, "text": "Elements of Opioid Use/Misuse/Abuse Model (Simplified)\n\nOverdose\n\nGeneral population\n\nMisuse & use disorder\n\nRx policies\n\nTreatment and relapse\n\nAGENDA | PROJECT CONTEXT | SYSTEMS MODEL |PROJECT TIMELINE | DISCUSSION\n\n20", "n_tokens": 44, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-20-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 20, "text": "PROJECT TIMELINE\n\nDraft article\n\nPolicy evaluation & insight generation\n\nModel validation & analysis\n\nExpert interviews (began in Nov.)\n\nLiterature research & data analysis (began in Sep.)\n\nModel development (began in Sep.)\n\n8 1 c e D\n\n9 1 n a J\n\n9 1 b e F\n\n9 1 r a M\n\n9 1 r p A\n\n9 1 y a M\n\nESTIMATED DELIVERABLES:\n\nModel ver. 1\n\nModel ver. 2\n\nAGENDA | PROJECT CONTEXT | SYSTEMS MODEL |PROJECT TIMELINE | DISCUSSION\n\n9 1 n u J\n\nDraft article ver. 1\n\nRevise article; stakeholder review\n\n9 1\n\nl\n\nu J\n\nDraft article ver. 2\n\n9 1 g u A", "n_tokens": 131, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-21-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 21, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-22-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 22, "text": "yy U.S. FOOD & DRUG\n\nADMINISTRATION\n\nBackup Slides", "n_tokens": 12, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-23-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 23, "text": "FDA Estimates Differ from the Manufacturers Based on Several Key Assumptions\n\nKey Assumption Targeted Patient Population(s)\n\nFDA Model 0.3-58.0 million\n\nIndustry Model 34.0 million\n\nCompliance Rate\n\n100% Prescribing; 70% Fill\n\n8-10% Dispensed\n\nPrice Increase\n\nYes (up to 2,347%)\n\nNo\n\nPrescription Fill Costs\n\nYes ($3.94/dose)\n\nNo\n\nFDA Estimate for Industry Population With 70% Adoption:\n\n$24.7 Billion/Year - $224.0 Billion/Year\n\nFDA Estimate for Industry Population With 8% Adoption:\n\n$0.5 Billion/Year - $4.7 Billion/Year (Industry: $150 Million/Year)\n\n24", "n_tokens": 141, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-24-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 24, "text": "Total Annual Costs– Naloxone Co-prescribing for All Opioid Analgesic Rx Estimated At $63.9 Billion - $579.2 Billion\n\nNew Doses (With Generics): 48.5 Million x ($1,287.87 + $3.941,2) = $62.6 billion\n\nExisting Doses (With Generics): 1.0 Million x ($1,287.87 - $52.63) = $ 1.3 billion\n\nTotal (With Generics): = $63.9 billion\n\n1Coalition for Community Pharmacy Action. The Cost of Dispensing Study. September 2015. 2Takes the payroll and prescription department costs per prescription and divides this number by 2 to convert it to a per-dose basis\n\n25", "n_tokens": 166, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-25-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 25, "text": "Results: Patient Groups That Interact With the Health System\n\nPopulation\n\nAll Opioid Analgesic Rx High-Impact Chronic Pain Rx Opioid Analgesics with CNS Depressants Medication Assisted Treatment (MAT) Opioid-Related ED Visit\n\n# Patients (Millions)\n\n58.0 19.6 3.5\n\n1.4 0.8\n\nAnnual Cost w/ Generics ($ Billions) 63.9 9.5 0.6\n\n0.2 0.1\n\nAnnual Cost w/o Generics ($ Billions) 579.2 85.5 5.3\n\n1.5 0.7\n\n26", "n_tokens": 125, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-26-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 26, "text": "Results: Patient Groups That Don’t Interact With the Health System\n\nPopulation\n\n# Patients (Millions)\n\nAnnual Cost w/ Generics ($ Billions)\n\nMisusing Opioids Opioid Use Disorder Recent Criminal Justice and Rx Opioid Misuse Recent Criminal Justice and Heroin Use Recent Criminal Justice and Opioid Use Disorder\n\n11.4 2.1 0.9 0.4 0.3\n\n3.8 0.3 0.1 <0.1 <0.1\n\nAnnual Cost w/o Generics ($ Billions) 34.0 2.5 0.8 0.3 0.2\n\n27", "n_tokens": 124, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-27-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 27, "text": "OVERVIEW: WHY MODELING\n\nEvents\n\nEvery day, more than 115 people in the United States die after overdosing on opioids...\n\nPatterns of behavior\n\nThe total number of overdose death has been on the rise.\n\nSystem architecture • Feedback processes • Stocks and flows • Time delays\n\nStructure of the system\n\nInformation availability • Delays, biases, error, gaps • Access & transparency\n\nMental models (of any stakeholder)\n\nActor goals and incentives • Time horizon, model boundary • Misperceptions of feedback\n\nAGENDA | PROJECT CONTEXT | SYSTEMS MODEL |PROJECT TIMELINE | DISCUSSION\n\n28\n\n28", "n_tokens": 113, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-28-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 28, "text": "MODEL BACKBONE\n\nGeneral Population\n\nWell managed OUD\n\nOpioid Use as directed\n\nOUD (unmanaged)\n\nOverdose\n\nOpioid misuse\n\nAGENDA | PROJECT CONTEXT | SYSTEMS MODEL |PROJECT TIMELINE | DISCUSSION\n\n29\n\nOverdose Death\n\n29", "n_tokens": 43, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-29-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 29, "text": "Illustrative pathway (simplified)\n\nGeneral population\n\nMisuse & use disorder\n\nRx policies\n\nAGENDA | PROJECT CONTEXT | SYSTEMS MODEL |PROJECT TIMELINE | DISCUSSION\n\nOverdose\n\nTreatment and relapse\n\n30", "n_tokens": 36, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-30-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 30, "text": ".\n\nIllustrative pathway (detailed)\n\nMisuse & use disorder\n\nGeneral population\n\nOUD development rate without Rx\n\nPeople with OUD, without Rx\n\nOpioid Rx rate\n\nBase population\n\nTreatment of misusers without Rx\n\nMisuse by acute patient connections\n\nPatients' connections misusing opioid Rx, acute\n\nAddiction, acute patient connection\n\nRx rate acute\n\nPatient users of opioid Rx, acute\n\nRelapse to opioid Rx\n\nRx policies\n\nReceiving MAT treatment\n\nAGENDA | PROJECT CONTEXT | SYSTEMS MODEL |PROJECT TIMELINE | DISCUSSION\n\nEscalation to heroin use, without Rx\n\nOverdose death of heroin users\n\nOverdo se\n\nHeroin users\n\nTreatment and relapse\n\nRelapse to heroin\n\nTotal relapse\n\nRelapse 18\n\nRelapse 30\n\nPeople receiving treatment In treatment 30 mn\n\nIn treatment 18 mn\n\nStill-in 30\n\nStill-in 18\n\nRelapse 42\n\nIn treatment 42 mn\n\n31", "n_tokens": 180, "kind": "text"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-31-0", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 31, "text": ".\n\nTotal opioid Rx dispensed\n\nTotal opioid Rx rate\n\nOpioid Rx rate\n\nAverage opioid Rx per patient\n\nQuit misuse, chronic patient connection\n\nPatients' connections quit rate\n\nParametrization\n\nAccess rate to patients' connections\n\nPatients' connections misusing opioid Rx, chronic\n\nMisuse by chronic patient connections\n\nAddiction rate\n\nSnapshot of collected data (in progress)\n\nAddiction, chronic patient connection\n\nRx rate chronic\n\nPatient users of opioid Rx, chronic\n\nChronic patients disposing Rx\n\nMisuse rate, chronic patient\n\nPatient misuse rate\n\nOUD development rate with Rx\n\nPatients misusing opioid Rx, chronic\n\nPatient quit rate\n\nOUD development rate without Rx\n\nQuit misuse, chronic patient\n\nOverdose death of OUD without Rx\n\nPeople with OUD, without Rx\n\nOpioid Rx overdose rate\n\nOverdose death of OUD with Rx\n\nEscalation to heroin use, without Rx\n\nEsclation rate to heroin\n\nOverdose death of heroin users\n\nHeroin overdose rate\n\nActue-chronic ratio\n\nBase population\n\nInitial base population\n\nDisposal rate\n\n<Access rate to patients' connections>\n\nMisuse by acute patient connections\n\nQuit misuse, acute patient connection\n\n<Patients' connections quit rate>\n\nPatients' connections misusing opioid Rx, acute\n\nAddiction, acute patient connection\n\nTreatment of misusers without Rx\n\nPeople with OUD, with Rx\n\nTreatment of opioid Rx abusers\n\nReceiving treatment rate for opioid Rx addicts\n\nEscalation to heroin use, with Rx\n\nReceiving treatment rate for heroin users\n\nHeroin users\n\nTreatment of heroin users\n\nDirect heroin initiation\n\n<Addiction rate>\n\nRelapse to heroin\n\n<Disposal rate>\n\nRx rate acute\n\nPatient users of opioid Rx, acute\n\nMisuse rate, acute patient\n\nPatients misusing opioid Rx, acute\n\nAddiction, acute patient\n\nRelapse rate opioid Rx\n\nRelapse to opioid Rx\n\nRelapse rate heroin\n\ntime to exit table\n\nAcute patients disposing Rx\n\n<Patient misuse rate>\n\nTotal relapse\n\nQuit misuse, acute patient\n\nTime to exit 18\n\nRelapse 18\n\nTime to exit 30\n\nRelapse 30\n\nRelapse 42\n\nTime to exit 42\n\n<Patient quit rate>\n\nLong term quit\n\nReceiving MAT treatment\n\nIn treatment 18 mn\n\nStill-in 18\n\nIn treatment 30 mn\n\nStill-in 30\n\nIn treatment 42 mn\n\nAbstinence 18\n\nAbstinence 30\n\nAbstinence 42\n\nAbstinence rate\n\nAGENDA | PROJECT CONTEXT | SYSTEMS MODEL |PROJECT TIMELINE | DISCUSSION\n\n32", "n_tokens": 505, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-0-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 0, "text": "FDA Update on Drug Compounding\n\nJulie Dohm, J.D., Ph.D. Senior Science Advisor for Compounding, CDER Agency Lead on Compounding, FDA", "n_tokens": 35, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-1-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 1, "text": "Outline\n\nRegulatory Framework • Compounding Program – Compounding Policy – Inspections and Enforcement – Stakeholder Engagement", "n_tokens": 19, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-2-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 2, "text": "Compounding Provisions of Federal Law\n\nSection 503A (enacted 1997)\n\nSection 503B (enacted 2013)\n\nConditions under which drug products compounded by a licensed pharmacist in a State-licensed pharmacy or Federal facility, or by a licensed physician, can qualify for exemptions from certain requirements of the FD&C Act: (1) New drug approval requirements (section\n\nConditions under which drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility can qualify for exemptions from certain requirements of the FD&C Act: (1) New drug approval requirements (section\n\n505),\n\n505),\n\n(2) Labeling with adequate directions for use\n\n(2) Labeling with adequate directions for use\n\n(section 502(f)(1)), and\n\n(section 502(f)(1)), and\n\n(3) Drug supply chain security requirements\n\n(3) Current good manufacturing practice\n\n(section 582).\n\n(CGMP) requirements (section 501(a)(2)(B))\n\nOutsourcing facilities remain subject to CGMP requirements.", "n_tokens": 230, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-3-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 3, "text": "Compounders under Section 503A\n\nState-licensed pharmacies (e.g., hospital and community pharmacies), Federal facilities, physicians\n\nNumber in the many thousands • Generally do not register with FDA • Pharmacies primarily overseen by the states\n\nState-to-state variation in quality standards and frequency and depth of state oversight of pharmacies\n\nCompounding physicians are generally not routinely overseen by any regulatory body", "n_tokens": 84, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-4-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 4, "text": "Outsourcing Facilities under Section 503B\n\nSection 503B defines “outsourcing facility” as a facility that – Is engaged in the compounding of sterile drugs – Has elected to register as an outsourcing facility – Complies with all of the requirements in section 503B In addition, an outsourcing facility: – Is NOT required to be a licensed pharmacy, but compounding must be by or under\n\nthe direct supervision of a licensed pharmacist\n\nMay or may not obtain prescriptions for identified individual patients\n\nOutsourcing facilities are subject to CGMP requirements • ~75 outsourcing facilities registered with FDA as of 9/28/18", "n_tokens": 135, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-5-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 5, "text": "Policy, Oversight, and Stakeholder Engagement\n\nCompounding Program\n\nCompounding Policy\n\nInspections and Enforcement\n\nStakeholder Engagement", "n_tokens": 20, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-6-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 6, "text": "1.\n\n2.\n\n3.\n\n4.\n\nFDA Compounding Policy Goals and Considerations\n\nAddress significant public health concerns Provide clarification on provisions of the law and answer questions presented by stakeholders Decrease regulatory burden to the extent possible without sacrificing critical public health protections Clarify responsibilities of FDA and the States\n\nACCESS\n\nQUALITY\n\nNECESSITY\n\nPreserve access to compounded drugs when patients have a medical need for them.\n\nPromote the compounding of drugs under appropriate conditions.\n\nEncourage use of FDA-approved drugs when they meet a patient’s medical needs.", "n_tokens": 103, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-7-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 7, "text": "Final Guidances and Regulations Issued\n\nFinal Guidances\n\n– – – Mixing, diluting, and repackaging biological products – – – – – – – – – Interim policies on compounding from bulk drug substances Repackaging drugs Prescription requirement under section 503A 503B product reporting Compounding under section 503A 503B adverse event reporting 503B registration Entities considering whether to register under section 503B 503B fees\n\nCompounding and repackaging of radiopharmaceuticals Compounded drugs that are essentially copies Facility Definition\n\nFinal Rules\n\nModifications to the withdrawn or removed list under sections 503A and 503B", "n_tokens": 129, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-8-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 8, "text": "Examples of Policy Documents Under Development\n\nDraft or Revised Draft Guidances\n\nInsanitary conditions – Evaluation of bulk drug substances under section 503B – Hospital and health system compounding – CGMP Interim Guidance for Outsourcing Facilities\n\nProposed Rules\n\nBulk drug substances list under section 503A – Modifications to the withdrawn or removed list under sections 503A and 503B\n\nProposed Federal Register Notices\n\nBulk drug substances list under section 503B\n\nRevised draft memorandum of understanding", "n_tokens": 91, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-9-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 9, "text": "Examples of Policies Applicable to Compounders under Section 503A\n\nFDA-State Memorandum of Understanding • Compounding using bulk drug substances under section 503A\n\nCompounded drug products that are essentially copies of a commercially available drug product under section 503A\n\nPrescription requirement under section 503A", "n_tokens": 56, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-10-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 10, "text": "FDA-State Memorandum of Understanding\n\nStatutory Framework Under section 503A(b)(3)(B), a compounded drug may be eligible for the exemptions only if it is compounded in a State— •\n\n(i) that has entered into an MOU with FDA which addresses the distribution of inordinate amounts of compounded drug products interstate and provides for appropriate investigation by a State agency of complaints relating to compounded drug products distributed outside such State; or (ii) that has not entered into the MOU and the licensed pharmacist, licensed pharmacy, or licensed physician distributes (or causes to be distributed) compounded drug products out of the State in which they are compounded in quantities that do not exceed 5% of the total prescription orders dispensed or distributed by such pharmacy or physician.", "n_tokens": 168, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-11-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 11, "text": "Why is interstate distribution addressed?\n\nCompounders operating under section 503A are mainly overseen by their home state regulator.\n\nCongress did not intend for compounders operating under section 503A to grow into conventional manufacturing operations conducting a substantial portion of their business interstate without adequate oversight. If a substantial proportion of a compounder’s drugs are distributed outside of a State’s borders, adequate regulation of those drugs can pose logistical, regulatory, and financial challenges to State regulators; it can be difficult to investigate and address multi-state outbreaks.", "n_tokens": 107, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-12-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 12, "text": "Revised Draft FDA-State Memorandum of Understanding\n\nThe MOU – Addresses “the distribution of inordinate amounts of compounded drug\n\nproducts interstate,” and\n\nProvides “for appropriate investigation by a State agency of complaints relating to compounded drug products distributed outside such State” – Is developed in consultation with the National Association of Boards of Pharmacy (NABP)\n\nNext Steps\n\n90-day comment period (ending on December 10, 2018) – Review comments submitted and make revisions, as appropriate, to address comments\n\nDevelop and publish final MOU – Offer the MOU to states to consider signature for a period (proposal is 180 days) before beginning to enforce the 5% statutory limit on distribution out of the state for compounders located in states that have not signed the MOU", "n_tokens": 152, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-13-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 13, "text": "Bulks Provisions under Section 503A\n\nStatutory Framework\n\nA drug may be compounded using bulk drug substances that:\n\ncomply with the standards of an applicable United States Pharmacopoeia or National Formulary monograph, if a monograph exists, and the United States Pharmacopoeia chapter on pharmacy compounding;\n\nif such a monograph does not exist, are drug substances that are components of drugs approved by the Secretary; or\n\nif such a monograph does not exist and the drug substance is not a component of a drug approved by the Secretary, that appear on a list developed by the Secretary through regulations issued by the Secretary under subsection (d) . . . .", "n_tokens": 132, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-14-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 14, "text": "Section 503A Bulks List: Process\n\nSolicit nominations and open docket\n\n•\n\nSolicited nominations in 2013 and 2014 Federal Register Notices Created an open public docket in 2015 to receive new nominations or comments (FDA-2015-N-3534)\n\nIdentify those nominated with adequate support\n\n•\n\nAnnounce eligibility for interim enforcement policy (interim policy guidance, category 1) Prepare recommendations regarding inclusion on the bulks list for consideration by PCAC\n\nConsult the PCAC and USP\n\nObtain advice from the PCAC and USP regarding recommendations\n\nRulemaking\n\n• •\n\nPublish a proposed rule Evaluate comments Publish final rule", "n_tokens": 119, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-15-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 15, "text": "Development of Section 503A Bulks List\n\nPharmacy Compounding Advisory Committee (PCAC) •\n\nProvides advice on scientific, technical, and medical issues concerning certain provisions of sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act\n\nPCAC materials are available at:\n\nhttps://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Phar macyCompoundingAdvisoryCommittee/default.htm\n\nMajority of committee members have experience related to drug compounding • • 9 meetings 53 bulk drug substances considered\n\nRulemaking •\n\nProposed rule describes criteria for evaluating the bulk drug substances and addresses 10 bulk drug substances nominated for inclusion on the 503B bulks list\n\n6 recommended for inclusion – 4 recommended against inclusion\n\nFDA is working on addressing additional substances in future rulemaking", "n_tokens": 171, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-16-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 16, "text": "Essentially a Copy under Section 503A\n\nStatutory Framework •\n\nTo qualify for the exemptions under section 503A, a drug product must be compounded by a compounder that does not compound “regularly or in inordinate amounts (as defined by the Secretary) any drug products that are essentially copies of a commercially available drug product.”\n\nA compounded drug product is not essentially a copy of a commercially available drug product if “there is a change, made for an identified individual patient, which produces for that patient a significant difference, as determined by the prescribing practitioner, between the compounded drug and the comparable commercially available drug product.”", "n_tokens": 131, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-17-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 17, "text": "Importance of Copies Provision\n\nCopies provisions are important to help to:\n\nEnsure that patients do not receive a compounded drug when an approved or commercially available drug would meet their medical needs. Patients should not be unnecessarily exposed to drug products that have not been shown to be safe and effective.\n\nProtect the integrity and effectiveness of the drug approval process. Distribution of compounded copies undermines the incentive for sponsors to seek approval of innovative, life-saving new drugs, or of generic drugs.", "n_tokens": 98, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-18-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 18, "text": "Final Guidance: Compounded Drug Products that Are Essentially Copies of a Commercially Available Drug Product under Section 503A\n\nThe guidance sets forth FDA’s policies regarding – the statutory terms, including “commercially available,” “essentially a copy of a commercially available drug product,” and “regularly or in inordinate amounts” – the prescriber’s determination of significant difference\n\nDocumentation • No particular format (e.g., “No Dye X, patient allergy) • The significant difference that the prescriber identifies must be produced by the change between the compounded drug and the comparable commercially available drug", "n_tokens": 122, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-19-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 19, "text": "Prescription Requirement under Section 503A\n\nStatutory Framework\n\nSection 503A(a) of the FD&C Act requires that compounding under this section be based on the receipt of a valid prescription for an identified individual patient\n\nCompounding can occur:\n\nIn limited quantities before the receipt of such a prescription, or\n\nAfter the receipt of the prescription.\n\nImportance of Prescription Requirement\n\nEnsures that compounding under section 503A is based on individual patient need\n\nEstablishes clear lines of accountability between FDA and States\n\nDistinguishes compounders under section 503A from outsourcing facilities under section 503B. Outsourcing facilities may or may not obtain prescriptions for their compounded drugs.\n\nFDA Final Guidance issued December 2016", "n_tokens": 138, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-20-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 20, "text": "Office Stock and Access\n\nSome stakeholders have expressed concerns that: – Outsourcing facilities cannot meet healthcare providers’ needs for\n\ncompounded drugs for office use.\n\nMany compounding pharmacies that want to distribute office stock cannot register as outsourcing facilities because CGMP compliance is too onerous.\n\nFDA is engaged in numerous efforts to help outsourcing facilities meet their intended role in the continuum of care for patients. – FDA posts lists of drug products that outsourcing facilities report\n\nmaking over prior six-month periods to help health care practitioners identify and access specific compounded drugs.\n\nFDA is developing a risk-based approach to CGMP requirements for outsourcing facilities that may make it more feasible for certain smaller compounders to become outsourcing facilities.", "n_tokens": 152, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-21-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 21, "text": "Examples of Policies Applicable to Outsourcing Facilities under Section 503B\n\nCGMP interim draft guidance for outsourcing facilities\n\nCompounding using bulk drug substances under section 503B\n\nCompounded drug products that are essentially copies of approved drug products under section 503B", "n_tokens": 53, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-22-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 22, "text": "Draft CGMP Interim Guidance for Outsourcing Facilities\n\nOutsourcing facilities are subject to CGMP requirements for finished pharmaceuticals in 21 CFR Parts 201 and 211. FDA is working on CGMP regulations specific to outsourcing facilities. In the interim, FDA has issued guidance that, when final, will describe FDA's expectations regarding compliance with CGMP requirements in part 210 and 211 until the new regulations are developed. FDA is currently revising its July 2014 draft guidance in response to stakeholder feedback, and is considering how CGMP requirements should be applied in light of the size and scope of an outsourcing facility’s operations. Policy goal is to make it more feasible for more compounding pharmacies that can meet the more stringent production standards to register as 503B outsourcing facilities. This should promote more patient access to higher quality compounded medicines.", "n_tokens": 180, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-23-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 23, "text": "Bulks Provisions under Section 503B\n\nBulk drug substances used in compounding under section 503B must either:\n\nAppear on a list established by FDA identifying bulk drug substances for which there is a clinical need (“bulks list”), or\n\nThe drug compounded from such bulk drug substance must appear on the drug shortage list at the time of compounding, distribution, and dispensing.\n\nIn March 2018, FDA published the draft guidance, titled Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B\n\nThe draft guidance describes the criteria it intends to apply to evaluate whether there is a clinical need for outsourcing facilities to compound with nominated bulk drug substances.\n\nLimiting the 503B list to substances for which there is a clinical need:\n\nReduces patient exposure to drugs that have not been demonstrated to be safe and effective to those situations in which the drug is necessary for patient treatment\n\nPreserves incentives for sponsors to invest in the research and testing required to obtain FDA approval", "n_tokens": 198, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-24-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 24, "text": "Section 503B Bulks List: Process\n\nSolicit nominations and open docket\n\nSee 2013, 2014, and 2015 FRNs\n\nIdentify substances nominated with adequate support\n\n•\n\nAnnounce eligibility for enforcement policy Prepare recommendations regarding inclusion on the bulks list\n\nFederal Register Notice and PCAC consultation as needed\n\n•\n\nPublish proposed determinations on specific bulks Consult PCAC if needed Publish final determinations on specific bulks", "n_tokens": 78, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-25-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 25, "text": "Proposal in Federal Register Regarding Three Bulk Drug Substances\n\nFDA has issued a proposal not to include three bulk drug substances –bumetanide, nicardipine hydrochloride, and vasopressin—on the 503B Bulks List. – Substances are components of FDA-approved drug\n\nproducts.\n\nNominations did not indicate why the FDA-approved drug products containing these substances could not be either used or adapted instead of a bulk drug substance. • Proposal in FRN states that at this time we do not find clinical need for an outsourcing facility to use these bulk drug substances to compound finished products. • Public comment on the proposals ends on October 29, 2018.", "n_tokens": 136, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-26-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 26, "text": "Collaborative Agreements\n\nNew research collaborations to support development of the 503B bulks list with the University of Maryland and Johns Hopkins University - two of FDA’s Center of Excellence in Regulatory Science and Innovation (CERSI) partners.\n\nUniversity of Maryland will be working closely with medical specialty groups and researching information about the use of drug products including certain bulk drug substances historically and in current clinical practice. Johns Hopkins University will focus on bulk drug substances identified as used to compound drugs for patients with autism spectrum disorder by systematically studying any available information concerning the safety and effectiveness and use in clinical practice of such substances. These projects will help inform the FDA’s regulatory decision-making, including whether to place the evaluated substances on the 503B bulks list.", "n_tokens": 149, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-27-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 27, "text": "Essentially a Copy under Section 503B\n\nStatutory Framework\n\nTo qualify for the exemptions under section 503B, the drug must not be essentially a copy of one or more approved drugs.\n\nA compounded drug is essentially a copy if:\n\nIt is identical or nearly identical to a marketed unapproved OTC drug or an approved drug that is not on FDA’s drug shortage list at the time of compounding, distribution, and dispensing; or\n\nIt is not identical or nearly identical, but it contains a bulk drug substance that is a component of an approved drug or a marketed unapproved OTC drug, unless—\n\na prescriber determines that there is a change between the compounded drug and the comparable approved drug that produces a clinical difference for an individual patient.\n\nFinalGuidance\n\nSets forth policies regarding\n\nstatutory terms, including “identical or nearly identical,” and\n\nthe prescriber determination of clinical difference", "n_tokens": 184, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-28-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 28, "text": "Examples of Policies Applicable to Compounders under Sections 503A and 503B\n\nRepackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities\n\nMixing, diluting, or repackaging biological products outside the scope of an approved biologics license application Insanitary Conditions", "n_tokens": 59, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-29-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 29, "text": "Repackaging\n\nMany compounders, including pharmacies and outsourcing facilities, repackage drugs. However, repackaging is not addressed in section 503A or section 503B, and repackaged drugs are generally subject to all provisions of the FD&C Act that apply to the production of drugs. Final guidance, “Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities,” describes conditions under which FDA does not intend to enforce new drug approval, labeling with adequate directions for use, and, except with respect to outsourcing facilities, current good manufacturing practice requirements, when state- licensed pharmacies, Federal facilities, and outsourcing facilities repackage drugs. Examples of the conditions:\n\nDrug product is assigned a beyond-use-date in accordance with the guidance – State-licensed pharmacy (not an OF) or federal facility distributes the repackaged drug only after receipt of a valid prescription for an identified individual patient", "n_tokens": 201, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-30-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 30, "text": "Mixing, Diluting, or Repackaging Biological Products\n\nBiological products subject to licensure in a biologics license application under the Public Health Service Act are not covered by sections 503A or 503B, and therefore are not eligible for the exemptions in those sections.\n\nGuidance explains conditions under which FDA does not intend to take action for certain violations of the law when certain biological products are mixed, diluted, or repackaged in a manner not described in their approved labeling. These conditions are intended to reduce the public health risks of mixing, diluting, or repackaging biological products, while preserving access to those products. For example: – Limited beyond use dates, with mechanism for outsourcing facilities to assign beyond use\n\ndates to repackaged biological products based on data\n\nMixing, diluting, or repackaging does not conflict with approved product labeling (e.g., storage and handling conditions)", "n_tokens": 186, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-31-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 31, "text": "Insanitary Conditions Federal law provides that a drug is adulterated if it was prepared, packed, or held under insanitary conditions whereby it may become contaminated with filth or rendered injurious to health.\n\nUnder federal law, the prohibition on insanitary conditions applies to compounders that meet the conditions of section 503A and outsourcing facilities that meet the conditions of section 503B, and other entities that produce drugs. FDA revised draft guidance issued September 2018 provides examples of insanitary conditions related to:\n\nAseptic practices – Equipment/facilities – Sterilization – Cleaning and disinfecting\n\nThe 60-day comment period ends November 26, 2018.", "n_tokens": 138, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-32-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 32, "text": "Inspections and Enforcement\n\nCompounding Program\n\nCompounding Policy\n\nInspections and Enforcement\n\nStakeholder Engagement", "n_tokens": 15, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-33-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 33, "text": "FDA Oversight Priorities\n\nFocus oversight on entities whose practices may have the greatest impact on public health – Conduct oversight of the outsourcing facility sector to evaluate compliance with the law, encourage voluntary compliance, and pursue regulatory action when necessary.\n\nConduct risk-based oversight of entities that are not outsourcing facilities, but that engage in multi-state, large volume distribution of compounded drugs. These compounders’ interstate operations may present challenges for state regulators, and their practices may have widespread, nationwide impact.\n\nIn general, FDA does not intend to engage in routine surveillance of state-licensed\n\npharmacies that operate within their state.", "n_tokens": 124, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-34-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 34, "text": "When FDA Conducts a Compounding Inspection\n\nFor-cause (>180 inspections conducted)\n\nSerious adverse events •Product quality or facility concerns (e.g., contamination, insanitary conditions) •Complaints (e.g., compounding without patient-specific prescriptions)\n\nSurveillance (>230 inspections conducted)\n\nOutsourcing facilities •Limited risk-based surveillance of pharmacies of which FDA is aware\n\nFollow-Up (>130 inspections conducted)\n\nFollow-up on corrective actions implemented after prior FDA inspections or regulatory actions", "n_tokens": 105, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-35-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 35, "text": "Examples of Frequent Adverse Inspectional Findings\n\nInsanitary conditions\n\n• CGMP violations (only applicable to outsourcing facilities and pharmacies not in compliance with section 503A) • Non-compliance with the conditions of section 503A\n\nLack of patient-specific prescriptions – Drugs on the withdrawn or removed list\n\nNon-compliance with the conditions of section 503B\n\nLabeling deficiencies – Failure to submit a product report", "n_tokens": 85, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-36-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 36, "text": "Insanitary Condition Example\n\nVisible microbial contamination on a ceiling tile in a clean room", "n_tokens": 17, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-37-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 37, "text": "Insanitary Condition Example\n\nCeiling above the doorway to cleanroom with exposed insulation", "n_tokens": 15, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-38-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 38, "text": "Insanitary Condition Example\n\nFilth under the hood including multiple pieces of medical supply waste and dust build up in the pre-filter for the ISO 5 hood", "n_tokens": 31, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-39-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 39, "text": "Insanitary Condition Example\n\nEquipment, located in cleanroom, used to produce injectable drugs visibly dirty", "n_tokens": 21, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-40-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 40, "text": "Insanitary Condition Example\n\nGowned employee working in the cleanroom, exposing legs", "n_tokens": 16, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-41-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 41, "text": "Insanitary Condition Example\n\nPoor personnel practices – leaning into ISO-5\n\nAverage normal human sheds about 37 million CFU/hour", "n_tokens": 25, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-42-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 42, "text": "Insanitary Condition Example\n\nToaster oven used to dry heat sterilize and depyrogenate glassware; oven was not capable of reaching high enough temperature to be effective", "n_tokens": 35, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-43-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 43, "text": "Insanitary Condition Example\n\nObserved conditions: Stain due to product which had exploded due to excessive pressure applied when forcing product through a sterilizing filter. The device used to force through filter was a non-sterilized caulking gun.", "n_tokens": 49, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-44-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 44, "text": "Insanitary Condition Example\n\nCoffee filters used to filter particulates in suspensions prior to filling and autoclaving", "n_tokens": 24, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-45-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 45, "text": "Insanitary Condition Example\n\nInsects (vermin) dead or alive", "n_tokens": 13, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-46-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 46, "text": "Frequent FDA actions taken\n\nVOLUNTARY RECALLS\n\nInformal recommendations for voluntary recalls\n\nADVISORY ACTIONS\n\nWarning letters\n\nFormal FDA requests for voluntary recalls\n\nUntitled letters\n\nENFORCEMENT ACTIONS\n\nSTATE REFERRALS\n\nCivil injunctions\n\nFor 503A facilities\n\nCriminal actions\n\nInspectional findings\n\nSeizures\n\nComplaints", "n_tokens": 44, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-47-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 47, "text": "160\n\n140\n\n120\n\n100\n\n80\n\n60\n\n40\n\n20\n\n0\n\nInspections, Oversight Actions, and Recalls\n\n135\n\n141\n\n116\n\n92\n\n71\n\n65\n\n63\n\n38\n\n51\n\n45\n\n41\n\n28\n\n29\n\n25\n\n30\n\n5\n\n1\n\n9\n\n10\n\n11\n\nFY 2013\n\nFY 2014\n\nFY 2015\n\nFY 2016\n\nFY 2017\n\nInspections\n\nWarning Letters\n\nState Referral Letters\n\nRecall Events\n\n*Preliminary data\n\n129\n\n34\n\n27\n\nFY 2018\n\n50", "n_tokens": 70, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-48-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 48, "text": "50\n\n45\n\n40\n\n35\n\n30\n\n25\n\n20\n\n15\n\n10\n\n5\n\n0\n\n1\n\nFY 2013\n\nCompounding State Referral Letters\n\n45\n\nFDA refers inspectional findings for a pharmacy to a state for further action when a pharmacy • Appears to be obtaining\n\n27\n\nprescriptions for identified individual patients, • Has promised to correct\n\n9\n\n10\n\n11\n\ndeviations, and\n\nCorrective actions can be appropriately overseen by the state.\n\nFY 2014\n\nFY 2015\n\nFY 2016\n\nFY 2017\n\nFY 2018", "n_tokens": 90, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-49-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 49, "text": "90\n\n80\n\n70\n\n60\n\n50\n\n40\n\n30\n\n20\n\n10\n\n0\n\n64\n\nOutsourcing Facility Registration\n\n77\n\n68\n\n64\n\n71\n\n55\n\nFY 2015\n\nFY 2016\n\nFY 2017\n\nTotal Outsourcing Facilities Registered Outsourcing Facilities Registered at End of FY\n\n76\n\nFY 2018\n\n74", "n_tokens": 51, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-50-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 50, "text": "Compounding Policy\n\nStakeholder Engagement\n\nCompounding Program\n\nInspections and Enforcement\n\nStakeholder Engagement", "n_tokens": 15, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-51-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 51, "text": "Stakeholder Collaboration\n\nObjectives\n\nLearn stakeholders’ views regarding proposed policies, including feedback about adequacy of public health protections and implications fo current practice\n\nImprove compliance by responding to questions and providing guidance on ways to comply with statutory requirements\n\nOpportunities for collaboration\n\nAnnual listening sessions with up to 75 stakeholder groups each year – Numerous inquiry responses – Notice-and-comment guidance development process – Ad hoc listening sessions with individual organizations as resources permit – Conferences", "n_tokens": 86, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-52-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 52, "text": "State Regulator Collaboration\n\nObjectives\n\nClarify areas of primary responsibility – Discuss emerging issues of mutual concern – Share updates on FDA/State policy and enforcement matters – Identify opportunities for improved FDA/State collaboration\n\nOpportunities for collaboration\n\nAnnual Intergovernmental Working Meetings – States invited to join FDA on all inspections of compounders – Monthly meetings with the National Association of Boards of Pharmacy", "n_tokens": 69, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-53-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 53, "text": "Compounding Risk Alerts\n\nFDA began in 2017 to post “compounding risk alerts” to inform healthcare practitioners of adverse event reports associated with compounded drugs. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformatio n/PharmacyCompounding/ucm570188.htm\n\nSome FDA inspections are initiated when FDA receives adverse event reports from healthcare practitioners, patients, and others.\n\nFDA provides the information in the compounding risk alerts to health care professionals to help further the goal of promoting patient safety", "n_tokens": 116, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-54-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 54, "text": "2017-18: eye injections of a compounded drug linked to vision problems in at least 43 patients\n\nAt least 43 patients received eye injections of a drug containing triamcinolone (steroid) and moxifloxacin (anti-infective) compounded by a Texas pharmacy.\n\nPatients developed vision impairment (blurred or decreased vision), loss of color perception, glare, halos, pain, and loss of balance among other symptoms.\n\nFDA testing of Guardian’s product and in-house samples revealed:\n\n12% w/v poloxamer 407. This amount is much > the poloxamer amounts in FDA- approved ophthalmic products (e.g., 0.1-0.2%), and poloxamer 407 is not used in any FDA-approved drug product intended for intravitreal injection.\n\nPoloxamer 407 degraded upon autoclaving and sonication.\n\nFDA alert: https://www.fda.gov/Drugs/DrugSafety/ucm569114.htm", "n_tokens": 217, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-55-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 55, "text": "2018: differences in strength expression on compounded product labels may lead to dosing errors FDA received two Medwatch reports and multiple complaints concerning medication errors associated with overdoses of compounded injectable products that were labeled with the strength per mL in large font (e.g., 50 mcg/mL) and the strength per total volume (2,500 mcg/50 mL) in smaller font.\n\nThese types of dosing errors could be avoided for small volume parenteral products by expressing the drug strength per total volume as the primary and prominent expression on the principal display panel of the label, followed in close proximity by strength per milliliter enclosed by parentheses.\n\nFDA Alert: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInfo rmation/PharmacyCompounding/ucm621769.htm", "n_tokens": 178, "kind": "text"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-56-0", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 56, "text": "THANK YOU\n\nANY QUESTIONS?\n\nINTERNATIONAL\nSEMINAR", "n_tokens": 7, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-0-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 0, "text": "pda.org/2021pdafda\n\nayy PDA\n\nParenteral Orug Association\n\nCONNECTING\n\nPEOPLE\nSCIENCE*\nREGULATION\"\n\n27-29 SEPTEMBER | LIVE. INTERACTIVE. ONLINE.\n\nEXHIBITION: 27-29 SEPTEMBER\n#PDAFDA", "n_tokens": 46, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-1-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 1, "text": "Patrizia Cavazzoni, MD Director Center for Drug Evaluation and Research U.S. Food and Drug Administration\n\n2", "n_tokens": 25, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-2-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 2, "text": "Pandemic Response Highlights\n\n2021 PDA/FDA JOINT REGULATORY CONFERENCE 27-29 SEPTEMBER", "n_tokens": 17, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-3-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 3, "text": "Facilitating Development of COVID-19 Therapeutics\n\nCoronavirus Treatment Acceleration Program (CTAP)\n\n▪ 460+ trials reviewed by FDA\n\n▪ 630+ development programs for therapeutic agents in the planning\n\nstages\n\n▪ 1000+ Expanded Access requests\n\n▪ 1 approved treatment\n\n▪ 11 treatments under emergency use authorization\n\n22+ guidances on clinical development for COVID-19 therapeutics\n\n4", "n_tokens": 69, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-4-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 4, "text": "Supply Chain Surveillance\n\nExpanded CDER’s drug shortage program to include supply chain surveillance\n\n➢ Integrates data to help assess risk to critical medicines to treat COVID-19 aiming for earlier detection and response to supply disruptions\n\n➢ Provides visibility into availability, supply, and demand\n\n➢ Used to address drug shortages\n\n➢ We are enhancing this system by seeking additional data sources\n\nand deploying advanced analytics\n\n▪ Phased process to expand coverage to additional products\n\n5", "n_tokens": 85, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-5-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 5, "text": "Drug Supply Chain Signal Detection\n\nSupply chain surveillance is based on examining multiple signals for supply chain disruption\n\nDrug Identification Identify critical drugs for supply chain surveillance\n\nIntegrated Supply Chain Assessment Conduct analysis based on integrated data on key signals to determine if a drug is vulnerable to supply chain disruptions\n\nMitigation and Management Conduct additional review for drugs with signals of supply chain disruptions\n\nFacility Quality\n\nSole Source\n\nPurchasing Trends\n\nClinical Trial Impact\n\nSupply Chain Diversification\n\nRecalls\n\nHistoric Shortage\n\nCurrent Shortage\n\nProjected Demand\n\nHospital Utilization\n\n6", "n_tokens": 92, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-6-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 6, "text": "Shortage Mitigation\n\nTotal Prevented US Drug Shortages Per Year\n\nCommunications with manufacturers and others helps prevent drug shortages\n\n7", "n_tokens": 21, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-7-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 7, "text": "Understanding Shortages\n\nPercentage of Drugs Newly in Shortage by Reason, 2013-2017\n\nMost drugs in shortage were experiencing supply disruptions, with a majority caused by quality issues\n\n8", "n_tokens": 32, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-8-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 8, "text": "Enforcement Against Fraudulent COVID-19 Claims\n\nThe Challenge: Protecting patients when the market is floodedwith productsmaking unprovenclaims. Productsare unlawful and put patients at risk.\n\n(Examples: chlorine dioxide, colloidal silver, CBD, copper, honey, botanical oils)\n\nActions Taken:\n\n Warning letters for products claiming to treat COVID-19  Warning letters to Internet pharmacies claiming to treat COVID-19  Removal of contaminated hand sanitizer products\n\n9", "n_tokens": 96, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-9-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 9, "text": "Manufacturing Quality\n\n2021 PDA/FDA JOINT REGULATORY CONFERENCE 27-29 SEPTEMBER", "n_tokens": 14, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-10-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 10, "text": "Challenges of the COVID-19 Pandemic for Drug Manufacturing\n\nLong-existing quality issues are now magnified\n\n Information about current state of\n\ndrug manufacturing and distribution\n\n Supply chain vulnerabilities\n\n Shortages due to manufacturing\n\nand distribution issues\n\n11", "n_tokens": 45, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-11-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 11, "text": "Supply Constraints\n\nThe supply chain supporting the manufacture of FDA-regulated products has become constrained at multiple levels during the COVID19 public health emergency.\n\n12", "n_tokens": 29, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-12-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 12, "text": "Risk Management Focus\n\n Coronavirus Aid, Relief, and Economic Security Act (CARES Act)\n\n Includes a provision requiring manufacturers of drugs, API, or any associated medical device to develop, maintain, and implement, as appropriate, a redundancy risk management plan that identifies and evaluates risks to the supply of the drug, as applicable, for each establishment in which the drug or API is manufactured\n\n FDA draft guidance Risk Management Plans to Mitigate the Potential for Drug Shortages\n\nin development\n\n PIC/S - Recommendation “How to Evaluate/Demonstrate the Effectiveness of a Pharmaceutical Quality System in relation to Risk-based Change Management”\n\n13", "n_tokens": 121, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-13-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 13, "text": "Quality Management Maturity\n\n➢ More mature quality management systems proactively focus on\n\nperformance, especially outcomes that affect the patient, including reducing quality issues that lead to complaints, shortages, and quality-related adverse events\n\n➢ FDA has proposed a system to measure and rate a drug\n\nmanufacturing facility’s quality management maturity, and a firm’s ability to deliver high-quality drug products reliably and without disruption\n\n14", "n_tokens": 80, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-14-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 14, "text": "Quality Metrics\n\nBusiness Continuity\n\nLeadership Commitment to Quality\n\nCommunication and Collaboration\n\nQuality Culture\n\nSustainable Compliance\n\nEnhanced Pharmaceutical Quality System (PQS)\n\nManufacturing Strategy and Operations\n\nAdvanced Analytics\n\nRisk Management\n\nCustomer Experience\n\nEmployee Ownership and Engagement\n\nContinual Improvement\n\n15", "n_tokens": 42, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-15-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 15, "text": "Steps to Quality Management Maturity (QMM)\n\n➢ Current Good Manufacturing Practice (CGMP) establishes a minimum standard for systems that assure proper design, monitoring, and control of manufacturing processes and facilities\n\n➢ ICH Q10 outlines an effective pharmaceutical quality system applied throughout the product lifecycle to facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities\n\n➢ Quality management maturity – measure of the consistency, reliability, and robustness of the business processes established and maintained to achieve quality policies and objectives, including a focus on achieving continual process and system improvement.\n\n16", "n_tokens": 112, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-16-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 16, "text": "QMM and Postapproval Changes\n\n➢ Continual system and process improvement may identify the need for\n\npost-approval changes\n\n➢ Need for regulatory submissions may dissuade some manufacturers\n\nfrom making needed CMC changes\n\n➢ QMM + product and process knowledge, including relevant\n\nmanufacturing experience at the proposed commercialization site, can be leveraged to support increased regulatory flexibility for making manufacturing changes – see ICH Q12 Technical and regulatory considerations for pharmaceutical product lifecycle management\n\n17", "n_tokens": 90, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-17-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 17, "text": "Building a QMM Program\n\n➢ Learn from efforts to date\n\n▪ PDA Quality Culture Initiative ▪ ISPE Advancing Pharmaceutical Quality Program ▪ University of St. Gallen research ▪ FDA/CDRH Case for Quality Pilot Program\n\n➢ Conduct outreach to purchasing organizations, pharmacy chains, and other\n\nfederal agencies\n\n➢ Execute 2 pilot programs announced October 2020 using QMM framework\n\ndeveloped in coordination with 3rd party appraisers\n\n▪ QMM FDF Pilot Program – open to domestic manufacturers of drug products marketed\n\nin the U.S.\n\n▪ QMM API Pilot Program – open to foreign manufacturers of API used in drug products\n\nmarketed in the U.S.\n\n➢ Seek and incorporate stakeholder input\n\n18", "n_tokens": 132, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-18-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 18, "text": "Manufacturing Quality Takeaways\n\n➢ COVID-19 public health emergency has highlighted previously existing\n\nchallenges in supply chain management and drug shortages\n\n➢ Proactive risk management, which includes supply chain management, is a\n\ntheme of recent legislation and internationally harmonized guidelines\n\n➢ Quality management maturity is attained by having consistent, reliable, and\n\nrobust business processes to achieve quality objectives and promote continual improvement\n\n➢ Higher levels of QMM can support increased regulatory flexibility for post- approval changes to address supply chain and other quality challenges\n\n➢ FDA’s QMM program will build on existing programs, pilot programs, and\n\nstakeholder input\n\n19", "n_tokens": 117, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-19-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 19, "text": "Guidance for Non-sterile\nManufacturers\n\n2021 PDA/FDA JOINT REGULATORY CONFERENCE 27-29 SEPTEMBER", "n_tokens": 18, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-20-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 20, "text": "Microbiological Hazards in Non-Sterile, Water-Based Products\n\n21", "n_tokens": 14, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-21-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 21, "text": "Guidance Priority: Microbiological Considerations for Non-Sterile Drugs\n\n▪ Microbiological Quality Considerations in Non-sterile Drug Manufacturing\n\nGuidance for Industry - on the CDER agenda as a priority for issuance\n\n▪ The guidance will address the importance of a robust design and control program to prevent contamination of non-sterile products, in accordance with CGMP\n\n▪ Lifecycle attention to manufacturing quality\n\n▪ Consider intended use of each drug product and patients who may receive the drug\n\n▪ Understand the microbial risk factors associated with the product and process, and the\n\nhazard posed by objectionable microbes surviving or proliferating in the product\n\n22", "n_tokens": 122, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-22-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 22, "text": "Warning Letter Trends\n\n2021 PDA/FDA JOINT REGULATORY CONFERENCE 27-29 SEPTEMBER", "n_tokens": 15, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-23-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 23, "text": "Recent Warning Letters Themes\n\n▪ Low process capability or lapse in state of control (process validation)\n\n▪ Deficient investigations of production or laboratory problems\n\n▪ Excessive variability in component quality (supplier reliability concern)\n\n▪ Chemical or microbial contamination of drug products\n\n▪ Deficient facilities or equipment\n\n▪ Failure to meet quality unit responsibilities, including batch release requirements\n\n24", "n_tokens": 67, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-24-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 24, "text": "CGMP-Compliant Quality System (Warning Letter Excerpt)\n\n“Describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.”\n\n25", "n_tokens": 54, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-25-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 25, "text": "CGMP-Compliant Quality System (Warning Letter Excerpt)\n\n“These repeated violations demonstrate a failure of your executive management to exercise proper oversight and control over the manufacture of drugs. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and ultimately, products conform to FDA requirements.”\n\n26", "n_tokens": 67, "kind": "text"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-26-0", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 26, "text": "In Summary\n\n▪ Accelerated development and authorization of several therapeutics\n\nagainst COVID-19\n\n▪ Enhanced analytical approaches and interventions to identify and\n\nmitigate drug supply chain disruptions\n\n▪ Continued to progress the quality management maturity program\n\n▪ Highlighted the hazards posed by objectionable microbiological\n\ncontamination of non-sterile drugs\n\n▪ Continued emphasis on the critical role of CGMP-compliant quality\n\nsystems as the foundation for reliable quality and supply\n\n27", "n_tokens": 82, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-0-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 0, "text": "Bridging Justifications: Supporting the Safety of Excipients in Generic Drug Products\n\nRobert T. Dorsam, Ph.D. Office of Generic Drugs (OGD) Division of Clinical Review (DCR) Pharmacology/Toxicology Team Leader", "n_tokens": 54, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-1-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 1, "text": "Disclaimer\n\nThe opinions expressed in this presentation are those of the speaker and may not reflect the position of the U. S. Food and Drug Administration\n\n2", "n_tokens": 31, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-2-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 2, "text": "Outline\n\nExcipient safety review in generic drug applications\n\nBridging justifications for excipients in generic drugs\n\nWhat is their utility? – What are important factors to consider?\n\nCase Studies\n\nExcipient grade, dose, duration, route of administration, patient population\n\n3\n\n3", "n_tokens": 57, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-3-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 3, "text": "Excipient safety review: OGD Pharm/Tox\n\nBridging justifications are a subset of the safety assessments conducted by OGD Pharm/Tox team\n\nExcipient safety review is conducted on a consult basis:\n\nConsulted by OGD and Office of Pharmaceutical Quality (OPQ) on a fraction of OGD’s applications\n\nWhen there is a safety question (i.e. exceeds approved level, question of excipient grade, route)\n\nP/T and Clinical reviewers evaluate safety of excipients – Clinical informs context of use for product, clinical safety – Pharm/Tox evaluates available nonclinical safety information\n\n4\n\n4", "n_tokens": 137, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-4-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 4, "text": "Excipient Safety Assessments\n\nThe review is focused on safety of the proposed excipient for the patient population\n\nConsiderations\n\nRoute, dose, duration of use, existing safety info – Patient population: drug toxicity, disease\n\nUltimate Question: Will this excipient change the safety profile of the proposed drug when compared to the Reference Listed Drug (RLD)?\n\n5", "n_tokens": 73, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-5-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 5, "text": "Why this approach?\n\nNDA: Safety of drug product is qualified with data during drug development\n\nClinical\n\nPre-IND\n\nPharm/Tox\n\nCMC\n\nIND\n\nPhase 1 Phase 2 Phase 3\n\nNDA\n\nClin Pharm\n\nANDA: Bioequivalence; Reliance on prior findings of safety and efficacy • • Most ANDAs aren’t reviewed by P/T or Clinical disciplines\n\nLess qualifying data\n\nSafety? Consult\n\nControlled Correspondence Pre-ANDA Product-specific BE Guidance Prior-findings of safety and efficacy\n\nBE study\n\nBioequivalence\n\nPharm/Tox CMC\n\nANDA IND\n\nClinical\n\nBridging arguments are reviewed during a P/T consult for an ANDA\n\n6\n\n6", "n_tokens": 135, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-6-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 6, "text": "Bridging Justification\n\nAn approach for safety assessments where toxicology data for one or more compounds is applied to a different compound\n\nWhen justified, the approach uses a body of information to extrapolate safety in cases where specific data do not exist\n\nBridging justifications are used in CDER Pharm/Tox for excipient safety review in the context of an ANDA or NDA\n\n7\n\n7", "n_tokens": 81, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-7-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 7, "text": "Pharm/Tox review of excipients • OGD P/T reviews bridging justification using the approaches detailed in the guidance “Nonclinical Studies for Excipients”\n\nThe context of the drug drives the necessary nonclinical studies\n\nImportant: route, dose and duration\n\nShort-Term Use (14 days or less)\n\nIntermediate Use (14 to 90 days)\n\nLong-Term Use (90 days or recurrent)\n\nAcute Toxicology\n\nStudies from short term\n\nStudies from short and intermediate use columns\n\nADME\n\n3-month repeat dose tox in 2 species\n\n6-month general toxicology study (rodent)\n\nGenetic toxicology\n\n9-month general tox (non- rodent)\n\n1-month general tox*\n\n2-year carci study (2-species)\n\nDART (devel. and repro)\n\n8\n\n8", "n_tokens": 171, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-8-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 8, "text": "Bridging Justifications in FDA’s Excipient Guidance\n\n“Large polymers that differ from previously characterized excipients only in molecular weight (chain length) can be adequately characterized in an abbreviated manner using less safety data, provided that the new excipient and the previously studied excipient are sufficiently similar with regard to physical state, pharmacokinetics, and levels of unreacted monomers and other impurities.”\n\n“We will consider such excipients on a case-by-case basis”\n\n9\n\n9", "n_tokens": 113, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-9-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 9, "text": "Why Bridging Justifications?\n\nUse all available data to fully inform safety\n\nCan inform target organs, safety signals, tolerability\n\nApplicant’s justification is essential for review by OGD – Data and justification are a pivotal for our review – Essential for meeting review timelines – Important to understanding the excipient class\n\nReduce animal usage\n\n10", "n_tokens": 68, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-10-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 10, "text": "How does DCR approach bridging?\n\nQuestions to ask:\n\nWhat is the nature of the excipient class? • Has this been reviewed before? If yes, how? • What justifies applying safety info between grades? Similarities and differences: Manufacturing, impurities, properties that impact safety\n\nIs the referenced safety information for the correct route and duration for the current context?\n\nDo any gaps remain after applying the bridged data?\n\n11\n\n11", "n_tokens": 89, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-11-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 11, "text": "Building a Bridge\n\nExisting information\n\nProposed Generic Drug\n\nApproved: product for chronic use Approved amount Excipient characteristics General human exposure Pharm/Tox information (context)\n\n-Genetic toxicology -General toxicology -Reproductive toxicology -Carcinogenicity\n\nDuration Dose Route Properties Prior exposure P/T data\n\nProduct for chronic use Proposed amount exceeds Information on similarities and differences of excipient\n\nGeneral human exposure Pharm/Tox information (context)\n\nExisting data, relevance and\n\njustification to support bridge\n\nAddress relevance of information, any data gaps, and focus on the context of use for the proposed product 12", "n_tokens": 119, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-12-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 12, "text": "Important Factors for a Bridge\n\nData\n\nWhat safety data exists, and what is being bridged? – Clear statement of physical/chemical properties – Differences from other excipient if intending to “bridge”\n\nRoute of Administration\n\nRoute should be relevant to the proposed product\n\nDose relation\n\nHow are doses in studies relevant to your proposed product?\n\nChronicity\n\nChronicity of approved product and accompanying studies will be compared to your proposed product\n\nConsider context of use, including patient population\n\n13", "n_tokens": 90, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-13-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 13, "text": "OGD P/T Experience Bridging Justifications\n\nOGD Pharm/Tox has reviewed several dozen ANDAs that involved bridging justifications (2014-2016)\n\nOn occasion, we send an Easily Correctable Deficiency (ECD) to request further information for the bridging justification during our review\n\nP/T Team is reviewing bridging justifications within ANDAs without a disproportionate amount of deficiencies\n\n14\n\n14", "n_tokens": 91, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-14-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 14, "text": "Case Studies\n\nCases are a composite of past experience • Highlight important elements in bridging\n\njustifications\n\nCase 1: Bridging excipient grade and amount Case 2: When context differs (duration, route) Case 3: Grade and patient population Case 4: Bridging a route of administration\n\n15", "n_tokens": 61, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-15-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 15, "text": "Case 1: Higher amount of a polymer\n\nA CNS stimulant: chronic oral product for children to adults\n\nConsulted on the safety of 80 mg copolymer grade X per day – Considerations: physical/chemical properties of copolymer, available supportive data, presence in FDA-approved products\n\nPharm/Tox data\n\nThis grade is poorly absorbed and well-tolerated in general tox studies (up to 6 months in rodent alone)\n\nNegative across several genetic toxicology studies – No safety signal in developmental and reproductive tox data\n\n16\n\n16", "n_tokens": 111, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-16-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 16, "text": "Case 1: Higher amount of a polymer\n\n37.5 mg of polymer grade X is approved in another product for chronic oral use\n\nThe RLD had different grades of same polymer at higher amounts\n\nP/T data for polymer grade X lacked 2-species chronic tox but had considerable safety information\n\nBridge: The proposed amount (80 mg) was acceptable based on totality of information: Pharm/Tox info, prior use, similarity with other grades at higher levels\n\n17\n\n17", "n_tokens": 94, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-17-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 17, "text": "Case 2: Data gap for chronic toxicity\n\nProposed product: a chronically used tablet in adults – Consulted because an excipient was not in the Inactive Ingredient Database or RLD\n\n“Evaluate the submitted Pharm/Tox data to determine if this inactive ingredient is safe for use in this drug product at the level proposed”\n\nApplicant justification:\n\nNonclinical safety justification based on published literature\n\nMinimal information exists on specific compound – Applicant referred to data on other compounds in same class\n\nAvailable information: genetic toxicology and acute general toxicology on compounds with different molecular size and variable substitutions. 18", "n_tokens": 118, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-18-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 18, "text": "Case 2: Data gap for chronic toxicity\n\nEvaluated published literature and use in approved products – This compound is in an approved topical product – In an NDA review for an oral drug product, a data gap for chronic toxicology and carcinogenicity was identified, resulting in a Post- marketing Requirement (PMR)\n\nHeld meeting with NDA review team about PMR – Published info was inadequate for chronic toxicity assessment\n\nConsulted with the OND review division regarding excipient data, PMR and potential for 505(b)(2)\n\n19", "n_tokens": 109, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-19-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 19, "text": "Case 2: Data gap for chronic toxicity\n\nOGD Pharm/Tox confirmed status of PMR and potential path forward with OND division\n\nAvailable data were an insufficient bridge for chronic toxicity by the oral route of admin.\n\nSignificant gaps need to be addressed before this compound is qualified for chronic use – Applicant may remove excipient from formulation – Applicant can address chronic toxicity and\n\ncarcinogenicity under the 505(b)(2) pathway\n\n20", "n_tokens": 91, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-20-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 20, "text": "Case 3: Grade and Patient Population\n\nProposed product: Oral suspension for chronic use\n\nPatients age 2 to adult will take this on an intermittent, chronic basis\n\nDCR is consulted on the safety of the proposed maximum daily intake of 900 mg excipient\n\nApplicant Justification • Joint FAO/WHO Expert Committee on Food Additives\n\n(JECFA),\n\nNonclinical tox summary consisted of data from various excipients in class ranging in molecular weight\n\n21\n\n21", "n_tokens": 93, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-21-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 21, "text": "Case 3: Grade and Patient Population\n\nPharm/Tox: Polymer was negative for genotoxicity, low absorption of HMW polymers, NOAELs ID’d in rodent studies for various grades\n\nApproved levels – 53 mg excipient approved in another oral drug\n\nChronic use, indicated in adults\n\nGaps identified • Molecular weight of the excipient grade is markedly lower than grades\n\nwhich are evaluated in available published information – Absorption of this lower MW grade is not characterized\n\nProposed level is 18-fold higher than approved levels for this route • Safety in pediatrics is not addressed\n\nDeficiency: Clinical and P/T information on long-term safe use of this excipient grade\n\n22\n\n22", "n_tokens": 140, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-22-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 22, "text": "Case 4: Bridge for Route of Admin\n\nProposed formulation is a “film” that is delivered by the buccal route in an adult population – Requires assessment of safety for both local and potential for\n\nsystemic toxicity\n\nDCR Pharm/Tox was consulted on the safety of nine excipients in the buccal film – Polymers (n=3), flavor, preservatives\n\nApplicant submission was comprehensive – Provided controlled correspondences on excipients – Comprehensive literature review on excipients – Justification for polymers included physical description of excipient 23", "n_tokens": 116, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-23-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 23, "text": "Case 4: Bridge for Route of Admin\n\nDCR reviewed the toxicology report provided by the applicant, controlled correspondences, safety findings from bioequiv. study, FDA databases, the toxicology and medical literature\n\nEach excipient was reviewed for presence in approved products of a similar context of use – Evidence of systemic exposure and local safety in clinical and nonclinical\n\ninformation\n\nECD was sent to clarify the composition of the flavor and address the local and systemic safety of flavor components. – Qualitative and quantitative composition, synonyms for components – CFR citations, information on prior usage – Genetic toxicology and available safety information for non-CFR components – Information was updated in the DMF\n\n24", "n_tokens": 145, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-24-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 24, "text": "Case 4: Bridge for Route of Admin\n\nSeveral excipients were present in a similar approved product\n\nFlavor was reviewed using the component approach\n\nElements: presence in CFR, similar use in other flavors, local and systemic toxicity\n\nPolymer Bridge\n\nConsidered molecular characteristics, prior use in FDA-approved products, available Pharm/Tox and clinical safety experience with this compound and similar grades\n\nLow probability of absorption, so also considered relevant oral safety information\n\nAll excipients in the buccal film were acceptable based on evidence of local and systemic safety\n\n25", "n_tokens": 109, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-25-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 25, "text": "Summary\n\nOGD P/T reviews bridging justifications within ANDAs, per Excipient Guidance and similar to Office of New Drugs P/T – Pharm/Tox and Clinical disciplines evaluate excipients based on context of use\n\nImportant elements of bridging justifications:\n\nSimilarity and difference between excipients – Existing nonclinical and clinical data – Address data gaps – Address proposed context of use\n\nEach case is unique but similar principles apply. OGD P/T reviews bridging justifications with relative success as a means to ensure excipient safety in generic drugs 26\n\n26", "n_tokens": 125, "kind": "text"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-26-0", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 26, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-0-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 0, "text": "CDER 2016 Update for Rare Diseases\n\nRichard Moscicki, M.D. Deputy Center Director for Science Operations CDER, FDA", "n_tokens": 27, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-1-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 1, "text": "Challenges for Rare Disease Drug Development\n\nnatural history\n\nserious\n\nRare diseases approved therapy • Diseases tend to be progressive, Small populations lack inferential statistics Phenotypic subsets\n\nRare diseases approved therapy • Diseases tend to be progressive, Small populations lack inferential statistics Phenotypic subsets\n\nis often poorly understood/characterized\n\noften restrict study design and replication and use of usual\n\ngenetic\n\ndiversity within a disorder adds to complexity, as do\n\nendpoints\n\noutcome measures\n\nbiomarkers\n\nWell defined and validated are often lacking\n\nWell defined and validated are often lacking\n\n,\n\nEthical • Lack of\n\nfor drug development\n\n•\n\nconsiderations for children in clinical trials\n\n2", "n_tokens": 121, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-2-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 2, "text": "Predicting the Future of Rare Disease Drug Development: Orphan Designation Applications\n\nAverage # Received\n\nAverage # Designated\n\n1983-2001\n\n82\n\n59\n\n2002-2008\n\n173\n\n119\n\n2009-2016\n\n374\n\n248\n\nOffice of Orphan Products Development\n\n3", "n_tokens": 40, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-3-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 3, "text": "Orphan Drug Approvals now greater than 40% of approvals for new molecular entities in 2015 and 2016.\n\nwww.fda.gov\n\n4\n\n4", "n_tokens": 28, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-4-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 4, "text": "CDER Novel Orphan Drug Approvals CY 2014 -2016*\n\n* as of 31 December 2016\n\n5", "n_tokens": 19, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-5-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 5, "text": "Expediting Rare Diseases Drug Development\n\nPrograms have been developed to target serious diseases with unmet medical needs when a new treatment could provide meaningful clinical benefit\n\nGuidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics, May 2014\n\n6", "n_tokens": 49, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-6-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 6, "text": "7\n\nCDER Ensures That Novel Drugs Receive Expedited Review\n\n73% of new drug approvals in 2016 used an expedited pathway\n\nMore than half (68%) of the novel drugs approved to date in CY15 were approved under Priority Review\n\nAbout one-third (36%) of novel drugs approved to date in CY15 received Fast Track designation\n\n27% were Accelerated Approvals – 32% were Breakthrough designated products\n\n7", "n_tokens": 84, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-7-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 7, "text": "Evaluation of Breakthrough Therapy Designation Program\n\nPace of submissions and designations continues strong • Evaluation as of December 31, 2016\n\nReceived 412 requests for breakthrough therapy designation\n\nCDER granted 144: Hem Onc and antivirals lead but orphan diseases also common\n\n59 original/supplemental applications approved – 199 denied, 8 rescinded\n\n8", "n_tokens": 61, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-8-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 8, "text": "Impact of Breakthrough Designation\n\nFriends of Cancer Research\n\nReview time approximately 3 months faster – Development time 2.2 years less – Greater use of phase 1:2 data – Greater use of accelerated approval\n\nFDA internal analyses\n\nApproximately 3 years less development time – Review times about 1-2 months less\n\n9\n\n9", "n_tokens": 57, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-9-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 9, "text": "Expedited Clinical Development Programs CDER NME approvals 2008-2016\n\nExpedited Programs\n\nNumber Rare (n = 113)\n\nNumber Non- Rare (n = 195)\n\nPriority Review\n\n87 (77%)\n\n59 (30%)\n\nFast Track\n\n62 (55%)\n\n43 (22%)\n\nAccelerated Approval\n\n31 (27%)\n\n3 (2%)\n\nBreakthrough Therapy\n\n22 (19%)\n\n8 (4%)\n\nUsed any Expedited Program\n\n98 (87%)\n\n69 (35%)\n\n10\n\n10", "n_tokens": 100, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-10-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 10, "text": "Expedited Clinical Development Programs\n\nCDER NME approvals 2008-2016\n\nEXPEDITED PROGRAMS\n\nBreakthrough N=30\n\nFast Track N=105\n\nPriority N=146\n\nAccelerated Approval N=34\n\nRARE (N = 113)\n\n19%\n\n55%\n\n77%\n\n27%\n\nOncology\n\n28%\n\n58%\n\n84%\n\n48%\n\nNon-Oncology\n\n13%\n\n52%\n\n71%\n\n11%\n\nNON-RARE (N = 195)\n\n4%\n\n22%\n\n30%\n\n2%\n\nOncology\n\n11%\n\n42%\n\n68%\n\n11%\n\nNon-Oncology\n\n3%\n\n20%\n\n26%\n\n1%\n\n11\n\n11", "n_tokens": 112, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-11-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 11, "text": "Application of Flexible Clinical Development Programs CDER NME approvals 2008-2016\n\nFlexible Development Programs\n\nRare Approvals\n\nNon-Rare Approvals\n\nUse of > 1 flexible development approaches*\n\n88 (78%)\n\n68 (35%)\n\nTraditional development program**\n\n25 (22%)\n\n127 (65%)\n\nFlexible Development approaches are defined as approval supported by other than 2 AWC Studies and/or use of a novel end point **Traditional Development defined as >2 AWC studies using endpoints with prior precedents\n\n12", "n_tokens": 101, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-12-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 12, "text": "Flexible Clinical Development Programs\n\nCDER NME approvals 2008-2016\n\nNOVEL ENDPOINTS\n\nYes N=38\n\nNo N=270\n\nRARE, n=113\n\n22%\n\n78%\n\nOncology\n\n2%\n\n98%\n\nNon-Oncology\n\n44%\n\n56%\n\nNON-RARE, N=195\n\n7%\n\n93%\n\nOncology\n\n0%\n\n100%\n\nNon-Oncology\n\n7%\n\n93%\n\n13\n\n13", "n_tokens": 73, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-13-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 13, "text": "“Patient-focused” Drug Development\n\nWe understand that people with chronic diseases are “experts” in that disease, as far as the symptoms and the impact on QOL, and what might be acceptable tradeoffs – On risk – On uncertainty\n\nHave had >20 of 24 PFDD meetings, more to go, reports generated • How to meaningfully collect that knowledge, in rigorous manner, given that there is a spectrum of opinions and and a spectrum of disease burden in any given disease?\n\nHow to do this for the many thousands of diseases? • Working with multiple patient organizations who are pioneering patient-focused guidance development for their disease of focus\n\n14", "n_tokens": 128, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-14-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 14, "text": "Expanded Access Programs at FDA\n\nUse of an investigational drug or biologic to treat a patient with a serious or immediately life threatening disease or condition and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition. • For an investigational drug in a clinical trial, the primary intent is research\n\nThere are three types of access:\n\n• • Treatment IND (21 CFR312.320)\n\nIndividual patients (21CFR312.310) Intermediate size population (21CFR312.315)\n\nGuidance for Industry: Expanded Access to Investigational Drugs for Treatment Use – Questions and Answers, June, 2016\n\n15\n\n15", "n_tokens": 133, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-15-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 15, "text": "Expanded Access Programs at FDA\n\nSubmissions and Protocols • Of 7291 submissions and Protocols fr om FY 2010 - 2015\n\n97.3% of expanded access submissions were for single patient protocols or single patient emergency protocols\n\n99.5% were allowed to proceed\n\nSafeguards for Participants • • • Reporting requirements\n\nInformed consent IRB review\n\nhttp://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/ucm443572.htm 16\n\n16", "n_tokens": 104, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-16-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 16, "text": "Expanded Access: Improving the Regulatory Process\n\nAdverse events in EA do not derail clinical development – In 10,000 INDs only 2 temporary clinical holds due EA AE Laborious and somewhat complex process in past. This year new simplified form (3926) – Estimated time 45 minutes\n\n•\n\n3 new Guidances,\n\nQuestions and Answers; Charging for Investigational Drugs Under an IND; – Individual Patient Expanded Access Applications: Form FDA 3926 final guidance\n\nNavigating a complex landscape in expanded access\n\n17\n\n17", "n_tokens": 98, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-17-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 17, "text": "Targeted Therapies\n\nTargeted therapies have grown from 5% of new drug approvals in the 1990s to 45% in 2013. –\n\n80% of breakthrough designations and about 44% of recently approved orphan products\n\nCommon disease subsets  “orphan subsets”1\n\nE.g., BRAF V600 mutation subsets of melanoma • Rare Diseases and Rare Disease subsets\n\nSmaller subsets available for clinical trials, smaller clinical development programs – – 18\n\nE.g., Cystic Fibrosis G551D mutation subset", "n_tokens": 107, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-18-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 18, "text": "19\n\nTargeted APs Trending Up Over Time\n\nCDER Targeted Therapy NME/BLA Approvals\n\nYear 1990-1992 2000-2002 2010-2014\n\nTargeted Therapies, % of Total Rare ~30% ~45% ~45%\n\nAll ~8% ~10% ~25%\n\nCommon ~2% ~5% ~12%\n\n19", "n_tokens": 68, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-19-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 19, "text": "Rare Diseases Program in CDER\n\nEstablished in 2010\n\nLocated within the Center for Drug Evaluation and Research (CDER) in the Office of New Drugs (OND) Immediate Office\n\nAssociate Director for Rare Diseases (ADRD) was the first position created\n\nReports to Director of the Office of New Drugs – Staffing 20", "n_tokens": 61, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-20-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 20, "text": "Rare Diseases Program Projects\n\nCoordinate development of CDER Policies, Procedures and Training • Several guidances under development • Continuing involvement with Senior FDA staff re: Rare Diseases\n\nProgram\n\nReview Rare Pediatric Disease Priority Review Voucher requests and developed procedures for review and administration\n\nAssist in development of good science • Regulatory database adjudication committee for NMEs • Specific projects/peer reviewed publications\n\n21\n\n21", "n_tokens": 73, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-21-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 21, "text": "Rare Diseases: Common Issues in Drug Development August 2015 (Draft Guidance)\n\nTo assist sponsors of drug and biological products intended to treat or prevent rare diseases To help sponsors conduct more efficient and successful development programs\n\nhttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryI nformation/Guidances/UCM458485.pdf\n\n22", "n_tokens": 77, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-22-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 22, "text": "Rare Pediatric Disease (RPD) Priority Review Voucher Program\n\n2012 FDA Safety and Innovation Act (FDASIA) [Section 908]\n\nProvides an incentive to encourage the development of drugs and biologics for rare pediatric diseases\n\nUpon approval, the sponsor may be issued a voucher redeemable for a priority review for a subsequent application that may not have otherwise qualified for a priority review\n\nThe incentive offers a shorter review clock for marketing applications, 6 months compared with the 10 months standard review time\n\nRare Pediatric Disease Priority Review Vouchers, Guidance for Industry http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM423325.pdf\n\n23", "n_tokens": 137, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-23-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 23, "text": "RPD Requests and Determinations\n\nData as of September 15, 2016\n\nwww.fda.gov\n\n24", "n_tokens": 19, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-24-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 24, "text": "Rare Pediatric Disease Priority Review Voucher Program\n\nThe OOPD reviews requests for Rare Pediatric Disease designation\n\n41 Designated/6 Denied/7 Under Review\n\nVoucher requests are managed by the OND RDP\n\n11 Voucher requests were submitted with an NDA or BLA\n\n7 Vouchers awarded, 3 denied and 1 pending review\n\nTwo PRV’s have been redeemed\n\nFuture (?)\n\nSunsets - 30 September 2016 although pending legislation may be\n\nextended to 31 December 2022 (for designation)/31 December 2027 (for\n\nredemption)\n\n25", "n_tokens": 109, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-25-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 25, "text": "26\n\nRegulatory Collaborations\n\n•\n\nEnhanced international collaborations in recent years EU: – International Rare Disease research Consortium (IRDIRC)\n\nSeveral FDA members participate\n\nHarmonized orphan drug designation application form – Regular meetings on orphan drugs, cancer, and pediatrics – New Rare Disease Cluster with EMA\n\nNIH\n\nCDER-NIH CC taskforce – IND regulatory training workshop\n\n26", "n_tokens": 70, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-26-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 26, "text": "How Does FDA “view orphan diseases”\n\nIs the bar different for efficacy? – Yes and no, standards must be present to demonstrate the drug is safe and efficacious in adequate and well controlled trials but the agency has demonstrated tremendous flexibility.\n\nFunctional vs “hard” (survival) endpoints – Both acceptable if clinically meaningful and a difference is clearly demonstrable due to therapy. Intermediate clinical endpoints can be used in accelerated approvals as well as qualified surrogate markers likely to predict clinical benefit\n\nLabel “expansion” when the disease has different subpopulations – It depends but open to broad label under some circumstances Can natural history be used as a control – Yes, if collected rigorously in a truly comparable population with a well demarcated\n\nendpoint or “hard” endpoint and a major undeniable difference is identified.\n\n27\n\n27", "n_tokens": 171, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-27-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 27, "text": "Important Lessons Learned in Rare Disease Drug Development\n\nEarly natural history studies are invaluable\n\nBest if protocol driven, rigorous, consistent objective endpoints\n\nBetter translational development\n\nBiomarker assays SHOULD be qualified before clinical studies begin if they are to be seriously considered.\n\nNeed to consider randomization and placebo controls from the very beginning of clinical studies when equipoise clearly exists 28", "n_tokens": 76, "kind": "text"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-28-0", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 28, "text": "Summary\n\nMore therapies for Orphan diseases approved in 2015 than ever before, a strong trend continues (47% (n=21)) Drug Development for Orphan diseases uses expedited review to a great degree Targeted Medicines are increasing and are common among therapies for Orphan diseases with both advantages and challenges Patient centered drug development is important in orphan disease FDA is willing to be very flexible in its approach to serious rare diseases with unmet need Recent experience has taught us very valuable lessons regarding natural history, early robust assay development, and randomization from the beginning of clinical studies Rare disease voucher can be valuable incentives There is an increased level of global collaboration on rare diseases\n\n•\n\n• •\n\n•\n\n29\n\n29", "n_tokens": 140, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-0-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 0, "text": "FDA's Role in Confronting the Opioid Epidemic\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs CDER, FDA\n\nAlliance for Balanced Pain Management November 14, 2017\n\n1", "n_tokens": 39, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-1-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 1, "text": "The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA\n\n2", "n_tokens": 23, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-2-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 2, "text": "Overall Messages\n\nThe FDA work to improve the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while assuring appropriate access to effective pain treatment\n\nOngoing and planned activities reflect the commitment by FDA to use of all of our available tools to appropriately manage pain while also addressing the opioids crisis\n\n3", "n_tokens": 68, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-3-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 3, "text": "Marked Increases in Prescription Opioid and Heroin Overdose Deaths in the USA 2000 to 2015\n\nUSA 2015 Overdose Deaths: • 52,404 Any Drug • 33,091 Any Opioid\n\nAny Opioid\n\nCommonly Prescribed Opioids (natural and semi-synthetic opioids and methadone)\n\nHeroin\n\nOther Synthetic Opioids (e.g. fentanyl, tramadol)", "n_tokens": 79, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-4-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 4, "text": "Overdose Death Rates\n\n2014\n\n1999\n\nDesigned by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System\n\nScience = Solutions", "n_tokens": 35, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-5-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 5, "text": "Opioid Epidemic in Maryland\n\nIn 2015, 1259 overdose deaths state wide • In first 9 months of 2016, 1468 overdose deaths • Comparing the first 9 months of 2016 to 2015, overdose deaths increased 62%\n\n6", "n_tokens": 44, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-6-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 6, "text": "Impact of Crisis: Increasing Prenatal Exposure\n\nAdmissions for Newborn Withdrawal Syndromes (Number per 1000 Admissions)\n\nTolia VN, Patrick SW, et al. NEJM 2015;372:2118-2126", "n_tokens": 44, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-7-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 7, "text": "Impact of Crisis: Infectious Disease Transmission\n\nHIV and Hepatitis C Outbreak Linked to Oxymorphone Injection Use in Indiana, 2015\n\nPeters et al. The New England Journal of Medicine 2016;375:229-239", "n_tokens": 41, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-8-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 8, "text": "U.S. Prescribing Rates - Trends\n\nU.S. prescribing rates peaked in 2012 at 81.3 prescriptions per 100 persons11 – Total: 255 million prescriptions\n\nOpioid prescribing has been decreasing between 2012 and 2016.\n\nU.S. prescribing rate in 2016 was 66.5 prescriptions per 100 people – 214 million prescriptions • Rates continue to vary widely\n\nSome counties had rates 7 times the national average\n\n9", "n_tokens": 96, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-9-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 9, "text": "Equally Critical Social and Medical Issue: Pain in America • From the Functioning and Disability Supplement of\n\nthe 2012 National Health Interview Survey – 126.1 million adults reported some pain in the previous\n\n3 months\n\n25.3 million adults (11.2%) suffering from daily (chronic) pain\n\n23.4 million (10.3%) reporting a lot of pain. – Based on the persistence and bothersomeness of their pain, 14.4 million adults (6.4%) were classified as having the highest level of pain, category 4, with an additional 25.4 million adults (11.3%) experiencing category 3 pain.\n\nNahin RL, J.Pain, 2015 Aug;16(8):769-80\n\n10", "n_tokens": 150, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-10-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 10, "text": "Pain in America (cont) • Treatment options for pain: pharmacologic, physical medicine, behavioral medicine, neuromodulation, interventional, and surgical\n\nOptimal patient outcomes often result from a comprehensive multidisciplinary approach where pharmacologic treatment is not the sole focus\n\nPatients experience ongoing barriers to adequate pain management – “many related to non-existent or insufficient insurance\n\ncoverage and reimbursement for evidence- and consensus- based therapies”\n\n-American Academy of Pain Medicine, 2014\n\nAs a result, treatments have largely focused on prescription drugs, mainly opioids, and procedures, at least, in part, because of the reimbursement structure of our healthcare system\n\n11\n\n11", "n_tokens": 144, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-11-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 11, "text": "FDA Response to this Crisis \"Unquestionably, our greatest immediate challenge is the problem of opioid abuse. This is a public health crisis of staggering human and economic proportion … we have an important role to play in reducing the rate of new abuse and in giving healthcare providers the tools to reduce exposure to opioids to only clearly appropriate patients, so we can also help reduce the new cases of addiction.\"\n\nScott Gottlieb, FDA Commissioner Address to FDA staff, May 15, 2017\n\n12", "n_tokens": 102, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-12-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 12, "text": "Solutions Must Come from Many Sources\n\nFDA is one of many Federal agencies addressing issues involving opioids\n\nMany Federal Agencies working together on issue\n\nEach state has programs to address opioids\n\nGuidelines and educational programs are available from specialty societies and State Medical Boards\n\nHealthcare institutions • Advocacy groups • • Patients (n = millions)\n\nIndividual providers (n = 800,000+)\n\n13", "n_tokens": 72, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-13-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 13, "text": "The Opioid Crisis: An FDA Priority\n\nTake immediate steps to reduce the scope of the epidemic of opioid addiction\n\nMay 2017: Established an FDA Opioid Policy Steering Committee (OPSC)\n\nSeptember 2017: Soliciting public input on how FDA authorities can or should be used to address the crisis\n\n14", "n_tokens": 62, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-14-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 14, "text": "AANP CHRONIC PAIN SEMINAR\n\nWorking Within HHS Opioid Strategy\n\nStrengthening public health surveillance\n\nSupporting cutting- edge research\n\nAdvancing the practice of pain management\n\nTargeting availability and distribution of overdose-reversing drugs\n\nImproving access to treatment and recovery services\n\n15", "n_tokens": 47, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-15-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 15, "text": "AANP CHRONIC PAIN SEMINAR\n\nGoals of HHS Opioid Strategy\n\nEmpowering the public, patients and providers through education and awareness\n\nPreventing opioid abuse and overdose and related health consequences\n\nImproving function and quality of life for individuals living with pain\n\nEnsuring patients who need opioid addiction treatment have access to it\n\nSupporting people to achieve long-term recovery\n\n16", "n_tokens": 69, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-16-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 16, "text": "The Opioid Crisis: FDA’s Priorities\n\n1. Decreasing Exposure & Preventing New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\n17", "n_tokens": 54, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-17-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 17, "text": "FDA Priorities align to HHS Strategic Priorities and other National Activities\n\nHHS STRATEGIC PRIORITIES\n\nFDA PRIORITIES\n\nOTHER ACTIVITIES\n\nStrengthening public health surveillance\n\nTargeting availability and distribution of overdose- reversing drugs\n\nSupporting cutting-edge research\n\nImproving access to treatment and recovery services\n\nAdvancing the practice of pain management\n\n1. Decreasing Exposure & Preventing New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\nPresident’s Commission on Combatting Drug Addiction\n\nOffice of National Drug Control Policy Recommendations\n\nComprehensive Addiction and Recovery Act (CARA)\n\nNational Pain Strategy Recommendations\n\nNational Public Health Emergency\n\n18", "n_tokens": 129, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-18-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 18, "text": "1. Decreasing Exposure and Preventing New Addiction \n\nFacilitate appropriate prescribing of opioid analgesics. Evaluate indication specific doses.\n\nOngoing research and ongoing discussions within FDA\n\nAppropriate Dose/Duration Labeling\n\n\n\nHealth Care Provider Education\n\nConsider appropriateness of mandatory education and how FDA would operationalize such a requirement. Ensure training is made available to non-physician prescribers, including nurses and pharmacists.\n\nMay 9-10, 2017: FDA public\n\nworkshop on pain management training. Issued revised Blueprint. Sept 28, 2017: FDA issued REMS letters that training be made available to health care providers who prescribe IR opioid analgesics.\n\n\n\nAppropriate Packaging, Storage, and Disposal\n\nExplore how opioid analgesic drug products are packaged, stored, and discarded. Examine use of packaging strategies, such as unit-of-use packaging to improve opioid analgesic safety.\n\nJun 1, 2017: FDA/Duke Margolis workshop and white paper on packaging, storage, and disposal solutions.\n\n• Dec 11-12, 2017: FDA public workshop to gain input on packaging strategies.\n\n19", "n_tokens": 222, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-19-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 19, "text": "Example: Improving Educational Tools for Healthcare Providers • Opioid Risk Evaluation and Mitigation Strategy (REMS) program: requires drug companies making Extended- Release Long-Acting Opioids to fund continuing education programs on the use of these products – Content dictated by FDA Blueprint\n\nFDA held a public meeting regarding prescriber education on May 9 – 10, 2017\n\nFDA released a revised Blueprint with expanded topics to be included in the prescriber education program including education on pain management\n\nFDA has announced plans to expand the REMS:\n\nto include the immediate-release (IR) opioids – to include pain management in the training , and – to expand training to include more members of the healthcare 20", "n_tokens": 141, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-20-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 20, "text": "Example: Appropriate Packaging Storage & Disposal Part of Federal efforts to educate consumers about appropriate disposal of unused medicines\n\nFDA focus on disposal of selected high-potency drugs that can kill with a single dose to improve human safety\n\nExample: lethal exposure to fentanyl patches\n\n-- http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm101653.htm", "n_tokens": 80, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-21-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 21, "text": "Some Riskier Medications Should Be Flushed\n\nA few prescription medicines, primarily controlled substances, are especially harmful or even fatal if taken accidentally by someone other than the patient. For this reason, they should be flushed down the sink or toilet to eliminate them from the home.\n\n22", "n_tokens": 53, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-22-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 22, "text": "2. Supporting Treatment of Opioid Use Disorder\n\nHOW?\n\nWHAT?\n\n\n\nNaloxone\n\nExploring ways to expand access to naloxone and facilitate the switch to OTC naloxone.\n\nPrecedent setting: FDA-led labeling study to facilitate the switch from prescription to OTC naloxone.\n\nMedication Assisted Treatment (MAT)\n\nFacilitate the development of new MAT options. Take steps promote the more widespread use of existing, safe and effective, FDA approved therapies. Join efforts to break the stigma associated with medications used for treatment of addiction.\n\nIssue guidance for product developers to facilitate the development of new treatments.\n\nNIH collaboration to identify new endpoints in MAT drug development and facilitate new formulations.\n\n23", "n_tokens": 143, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-23-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 23, "text": "Example: Development of Drugs for Overdose Intervention Naloxone Distribution for opioid overdose victims. The potential for direct intervention to save lives.\n\n “Evzio” naloxone auto-injector APPROVED BY FDA, April 3, 2014\n\n “Narcan Nasal Spray” naloxone\n\nAPPROVED BY FDA, November 18, 2015\n\nScience = Solutions", "n_tokens": 72, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-24-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 24, "text": "3. Developing Novel Pain Treatment Therapies\n\nHOW?\n\nWHAT?\n\n\n\nPartnerships & Meetings\n\n\n\nAbuse Deterrent Formulations (ADFs)\n\n\n\nPain Treatment Alternatives\n\n•\n\nExpand use of partnerships with non-profit organizations, public meetings, and Advisory Committee meetings. Collaborate across HHS.\n\nSupport development of innovative ADFs, data to inform benefit-risk assessment, and transition to an ADF-prominent market. Ensure ADF label nomenclature enables providers to adequately distinguish between the risk of abuse and the risk of addiction. Explore use of Fast Track and Breakthrough Therapy Designations. Encourage novel therapies, including medical devices.\n\nFDA grant supported Drug-Free Kids campaign.\n\nPublic-private-partnership (PPP) under the Critical Path initiative. Jul 2017: Commissioned NASEM consensus report. Jul 2017: Public workshop for postmarketing ADF data and evaluation methods. Issued guidance on generic ADFs.\n\n• Sep 2017: Contracts to improve data for ADF assessment and understand nomenclature.\n\nSummer 2017: FDA/NIH meeting series on pain treatment alternatives.\n\n25", "n_tokens": 205, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-25-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 25, "text": "Example: Supporting Abuse Deterrent Formulations (ADF) of opioids\n\nFDA has a goal of incentivizing the development of opioid medications with progressively better abuse- deterrent properties and support their widespread use – Abuse-deterrent is not abuse proof\n\nFDA requiring studies to understand the impact of ADFs in real-world settings\n\nIn support of the goal, FDA has issued guidance for product development, including draft guidance on generic ADFs, reflecting importance of generic products in the US 26", "n_tokens": 100, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-26-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 26, "text": "Improving Enforcement\n\nAssessing Benefit-Risk\n\n4. Improving Enforcement & Assessing Benefit-Risk WHAT?\n\nConsider how to fully leverage FDA’s current seizure authorities. Increase oversight of Illicit trade.\n\nCollaboration with Customs and Border Protection to increase FDA staff stationed at international mail facilities (IMFs) to increase seizure of opioids being smuggled into the United States through international mail facilities (IMFs).\n\nTake action, including product market withdrawal recommendation. Improve robustness of benefit-risk assessment framework for opioid analgesic formulations.\n\nJun 2017: Requested market withdrawal of Opana ER due to abuse risks. Sep 2017: Pediatric Advisory Committee for hydrocodone or codeine containing cough treatment in pediatric patients.\n\n27", "n_tokens": 142, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-27-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 27, "text": "Example: Ongoing Work by FDA on Benefit-Risk Assessment of Opioids • Prescription opioids have impacts on both the patients when used as prescribed and on society when used inappropriately\n\nFDA considers both impacts in our regulatory decisions and is seeking to formalize that assessment – Opana decision\n\nFDA sought NASEM input on issue last year and is working to determine next steps and improve our processes – “…to ensure drug approval and removal decisions are made within a benefit-risk framework that evaluates not only the outcomes of opioids when used as prescribed, but also the public health effects of the inappropriate use of these drugs” 28", "n_tokens": 126, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-28-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 28, "text": "Summary and Conclusions\n\nFDA working to address opioid epidemic as a part of the larger HHS response – One of the FDA’s very highest priorities\n\nGoing forward, FDA is committed to taking decisive actions, grounded in the available science and appropriate public input to address this critical challenge to the US health and welfare\n\nOur focus is addressing opioid abuse while assuring appropriate access to effective pain treatment\n\n29", "n_tokens": 79, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-29-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 29, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-30-0", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 30, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-0-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 0, "text": "FDA Perspective on Abuse- Deterrent Opioid Development\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs CDER, FDA\n\nCBI Abuse Deterrent Formulations Summit\n\nMarch 7-8, 2017\n\n1", "n_tokens": 44, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-1-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 1, "text": "The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA\n\n2", "n_tokens": 23, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-2-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 2, "text": "Outline\n\nBackground on Epidemic • Federal Context for FDA Efforts to Address Prescription Opioid Abuse – Other Federal Efforts\n\nFDA Action Plan • FDA Focus on Abuse-Deterrent Formulations of Opioids\n\n3", "n_tokens": 39, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-3-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 3, "text": "Overall Message\n\nThe FDA work to improve the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while assuring appropriate access to pain treatment\n\nAbuse Deterrent Opioids are one important part of FDA work to address opioid epidemic • Ongoing and planned activities reflect the\n\ncommitment by FDA to integrate the use of all of our available tools to achieve our goals related to the safe use of prescription opioids\n\n4", "n_tokens": 91, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-4-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 4, "text": "Nationally Estimated Number of Prescriptions Dispensed for Selected* Opioid Analgesics Oral Solids and Transdermal products from U.S. Outpatient Retail Pharmacies\n\n250\n\ns n o i t p i r c s e r P d e s n e p s i D\n\n) s n o\n\ni l l i\n\nm n i (\n\n200\n\n150\n\n100\n\n148M\n\n160M\n\n171M\n\n180M\n\n188M\n\n197M\n\n206M 206M\n\n197M\n\n188M\n\n169M\n\n88%\n\n50\n\n12%\n\n0\n\n2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015\n\nGrand Total of Selected* Opioid Analgesics\n\nSelected IR Market\n\nER/LA Market\n\nSource: National Prescription Audit (NPA). Extracted May 2015 (For 2005-2014 data) and November 2016 (For 2015 data).", "n_tokens": 161, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-5-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 5, "text": "Marke\n\nd Increases in Prescription Opioid and Heroin\n\nOverdose Deaths in the USA 2000 to 2015\n\nUSA 2015 Overdose Deaths: •52,404 Any Drug •33,091 Any Opioid\n\nAny Opioid\n\nCommonly Prescribed Opioids (natural and semi-synthetic opioids and methadone)\n\nHeroin\n\nOther Synthetic Opioids (e.g. fentanyl, tramadol)", "n_tokens": 81, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-6-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 6, "text": "Overdose Death Rates\n\n2014\n\n1999\n\nDesigned by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System\n\nScience = Solutions", "n_tokens": 35, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-7-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 7, "text": "Overlap of Benzodiazepines and Opioid Opioid OD Deaths Involving Benzodiazepines & Benzodiazepine O Deaths Involving Opioids\n\ns D\n\nAAPC* = 1.5% (95% CI 0.8%-2.2%)\n\nt n e c r e P\n\nAAPC* = 8.4% (95% CI 7.1%-9.7%)\n\nAAPC = Average annual percent change\n\nScience = Solutions\n\nSource: CM Jones, JK McAninch. American Journal of Preventive Medicine 2015;49:493-501.\n\n8", "n_tokens": 127, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-8-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 8, "text": "Outbreak of HIV Linked to IDU of Oxymorphone in Indiana, 2014-2015\n\nThrough November 2015, 181 cases of HIV identified in county of ~15,000\n\n96% reported injection drug use • Of these, 92% reported injecting prescription oxymorphone in past 12 months – Frequently described preparing and injecting extended-\n\nrelease oxymorphone (Opana ER, Endo Pharmaceuticals)\n\nPublic health emergency declared—syringe exchange program established\n\nSource: Peters et al. New England Journal of Medicine 2016; 375:229-39.\n\n9", "n_tokens": 114, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-9-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 9, "text": "Increasing Neonatal Abstinence Syndrome\n\nNICU Admissions for NAS (Number per 1000 Admissions)\n\nSource: Tolia VN, Patrick SW, et al. NEJM 2015;372:2118-2126\n\nScience = Solutions", "n_tokens": 46, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-10-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 10, "text": "FDA is a Part of a Larger Governmental Response to Opioids Abuse\n\nOffice of the National Drug Control Policy (ONDCP) Plan Health and Human Services (HHS) Secretary’s Plan", "n_tokens": 39, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-11-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 11, "text": "ONDCP National Drug Abuse Prevention Plan\n\nIssued April 2011 • Four major areas of focus to reduce prescription drug abuse and other harm from drugs – Education – Monitoring – Proper medication disposal – Enforcement\n\n12", "n_tokens": 38, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-12-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 12, "text": "HHS Secretary’s Initiative to Combat Opioid Abuse\n\nImproving opioid prescribing practices to reduce opioid use disorders and overdose • Expanding use and distribution of naloxone • Expanding medication-assisted treatment (MAT) to reduce opioid use disorders and overdose\n\n--http://aspe.hhs.gov/basic-report/opioid-abuse-us-and-hhs-actions-address-opioid-drug-related-overdoses-and-deaths 13", "n_tokens": 108, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-13-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 13, "text": "Other Critical U.S. Governmental Efforts FDA is Supporting\n\nNational Pain Strategy\n\nFocuses on key areas of pain and pain care, including professional education and training, public education and communication, service delivery and reimbursement\n\nhttp://iprcc.nih.gov/docs/DraftHHSNationalPainStrategy.pdf\n\nNational Pain Research Strategy\n\nStrategic plan under development for pain research across federal agencies\n\nSurgeon General’s Call to End the Opioid Crisis – Launched a new prescriber education campaign, Turn the Tide – Issued the first-ever Surgeon General’s Report on Alcohol, Drugs and\n\nHealth: Facing Addiction in America\n\nCDC Guidelines for Prescribing Opioids for Chronic Pain\n\nProvides recommendations for the prescribing of opioid pain medication focused on the use of opioids in treating chronic pain • http://www.cdc.gov/drugoverdose/prescribing/guideline.html\n\n14", "n_tokens": 195, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-14-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 14, "text": "yy U.S. FOOD & DRUG\n\nADMINISTRATION\n\nFDA Response to Opioids Abuse", "n_tokens": 17, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-15-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 15, "text": "FDA Action Plan (February 4, 2016)\n\nIn response to the opioid abuse epidemic, FDA called for a far-reaching action plan to reassess the agency’s approach to opioid medications. The plan focused on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief.\n\n--http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm484765.htm\n\n16", "n_tokens": 101, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-16-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 16, "text": "FDA Opioids Action Plan\n\nExpand the use of advisory committees • Develop warnings and safety information for immediate- release (IR) opioid labeling\n\nStrengthen postmarket requirements to get needed data • Update Risk Evaluation and Mitigation Strategy (REMS) Program for Prescription Opioids\n\nExpand access to abuse-deterrent formulations (ADFs) to discourage abuse\n\nSupport better treatment for prescription opioid abuse and overdose\n\nReassess the risk-benefit approval framework for opioid use\n\n--www.fda.gov/NewsEvents/Newsroom/FactSheets/ucm484714.htm\n\n17", "n_tokens": 125, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-17-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 17, "text": "FDA and Abuse-Deterrent Formulations of Opioids\n\nPart of Larger FDA/HHS Efforts to Improve Tools for Pain Management", "n_tokens": 26, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-18-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 18, "text": "Development of New Pain Treatments\n\nAbuse-deterrent Opioid formulations\n\nPro-drugs\n\nNon-Opioid based analgesics Cannabinoids; Inflammatory mediators; Ion channel blockers\n\nCrush/extraction resistant formulation\n\nNon-pharmacological treatments Surgical interventions; Neural stimulation; Spinal cord stimulation\n\nDrug combinations with adverse effects if injected\n\nTranscranial Magnetic Stimulation\n\n19", "n_tokens": 73, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-19-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 19, "text": "Spurring Development of Abuse- Deterrent (AD) Opioids: FDA Goals\n\nIncentivize the development of opioid medications with progressively better AD properties and support their widespread use\n\nAssure appropriate development and availability of generics, reflecting their importance in U.S. healthcare – Generic drugs play a critical role in U.S. healthcare,\n\nincluding important role in controlling costs and expanding access\n\n20", "n_tokens": 80, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-20-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 20, "text": "FDA Tools to Support AD Formulation Development\n\nScientific Research • Regulatory Activities\n\nDecisions on applications – Sponsor discussions as a part of individual product development\n\nGuidances\n\nFinal guidance on developing AD formulations of opioids issued April 2015\n\nDraft guidance on generics development and testing issued March 2016\n\nPublic Discussion and Comment\n\nPublic meetings, including meeting held October 2014 and 2016 – Comments on draft guidance – Citizen petitions 21", "n_tokens": 75, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-21-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 21, "text": "Policy Development: Generic AD Opioids\n\nGeneric drugs play a critical role in U.S. healthcare, including important role in controlling costs and expanding access\n\nMarch, 2016: FDA released draft guidance: “General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products”\n\nOctober, 2016: FDA held a 2-day meeting to discuss draft guidance and standardization of in vitro testing for AD opioids\n\nFDA plans to publish a final guidance to the March 2016 draft in 2017 in accordance with the requirements of the Comprehensive Addiction and Recovery Act of 2016.\n\n22", "n_tokens": 114, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-22-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 22, "text": "Regulatory Activity: Supporting AD Opioid Development\n\n9 new opioids approved with abuse-deterrent formulations (latest January, 2017) (OxyContin, Targiniq ER, Embeda, Hysingla ER, MorphaBond, Xtampza ER, Troxyca ER, Arymo ER, Vantrela ER) • Work to date has often focused on use of crush/extraction-\n\nresistant and agonist/antagonist technologies, but many new approaches being explored\n\nMore than 30 active investigational new drug applications (INDs) being discussed for AD formulations\n\nNew technologies being explored by industry (e.g., pro-drugs that require activation to prevent IV abuse and snorting)\n\n23", "n_tokens": 150, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-23-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 23, "text": "Next Steps: Need for Assessment of Impact on Real-world Abuse\n\nCurrent labels based on clinical and in vitro data to predict the formulation will reduce abuse\n\nReal-world assessment needed (and ongoing) as we know AD formulations are not silver bullets and can be defeated\n\nDECIDE WHAT WORKS AND WHAT DOESN’T\n\n24", "n_tokens": 61, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-24-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 24, "text": "IR and ER/LA Opioid Prescriptions\n\nReformulated Oxycodone ER: 2% (4.7M TRx) of total opioid market in 2014\n\nNationally estimated number of prescriptions dispensed for selected IR and ER/LA opioid analgesics from U.S. outpatient retail pharmacies\n\nNo prescriptions captured for Hysingla ER or Embeda in 2014\n\nSource: IMS Health, National Prescription Audit ™ Extracted May and August 2015\n\n25\n\n25", "n_tokens": 104, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-25-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 25, "text": "Challenges in Getting to the Future for AD Opioids\n\nIncentivizing innovation: Current FDA incentives include product labeling and Hatch-Waxman exclusivity\n\nEncouraging iterative development and use of effective abuse-deterrent formulations – Challenge to assess impact of individual formulations – Challenge to encourage uptake of effective products by\n\npayers\n\nManaging expectations: abuse-deterrent opioid--\n\nAre part of larger effort on opioids – Will not ‘prevent’ abuse, and are not ‘silver bullets’ 26", "n_tokens": 104, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-26-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 26, "text": "Summary and Conclusions\n\nFDA working to address opioids epidemic as a part of the larger HHS response – One of the FDA’s highest priorities\n\nFDA Opioids Action Plan provides framework for FDA response to the challenge of opioids abuse epidemic\n\nSupporting development and use of progressively better abuse deterrent opioids one important FDA goal within the Action Plan – FDA looks forward to the day, not far in the future, when the majority of opioids on the market are known to be abuse deterrent\n\n27", "n_tokens": 102, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-27-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 27, "text": "Thank you", "n_tokens": 2, "kind": "text"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-28-0", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 28, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-0-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 0, "text": "FDA's Actions to Address the Opioid Epidemic\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs Center for Drug Evaluation and Research FDA\n\nCBI Abuse-Deterrent Formulation Summit\n\nMarch 14, 2018\n\n1", "n_tokens": 45, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-1-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 1, "text": "The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA\n\n2", "n_tokens": 23, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-2-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 2, "text": "Overall Messages\n\nThe FDA work to improve the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while assuring appropriate access to effective pain treatment\n\nOngoing and planned activities reflect the commitment by FDA to use of all of our available tools to appropriately manage pain while also addressing the opioids crisis\n\n3", "n_tokens": 68, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-3-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 3, "text": "Marked Increases in Prescription Opioid and Heroin Overdose Deaths in the USA 2000 to 2015\n\nUSA 2015 Overdose Deaths: • 52,404 Any Drug • 33,091 Any Opioid\n\nAny Opioid\n\nCommonly Prescribed Opioids (natural and semi-synthetic opioids and methadone)\n\nHeroin\n\nOther Synthetic Opioids (e.g. fentanyl, tramadol)", "n_tokens": 79, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-4-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 4, "text": "Overdose Death Rates\n\n2014\n\n1999\n\nDesigned by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System\n\nScience = Solutions", "n_tokens": 35, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-5-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 5, "text": "Impact of Crisis: Increasing Prenatal Exposure\n\nAdmissions for Newborn Withdrawal Syndromes (Number per 1000 Admissions)\n\nTolia VN, Patrick SW, et al. NEJM 2015;372:2118-2126", "n_tokens": 44, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-6-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 6, "text": "Impact of Crisis: Infectious Disease Transmission\n\nHIV and Hepatitis C Outbreak Linked to Oxymorphone Injection Use in Indiana, 2015\n\nPeters et al. The New England Journal of Medicine 2016;375:229-239", "n_tokens": 41, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-7-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 7, "text": "U.S. Prescribing Rates - Trends\n\nU.S. prescribing rates peaked in 2012 at 81.3 prescriptions per 100 persons11 – Total: 255 million prescriptions\n\nOpioid prescribing has been decreasing between 2012 and 2016.\n\nU.S. prescribing rate in 2016 was 66.5 prescriptions per 100 people – 214 million prescriptions • Rates continue to vary widely\n\nSome counties had rates 7 times the national average\n\n8", "n_tokens": 96, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-8-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 8, "text": "Nationally Estimated Number of Prescriptions Dispensed for Opioid Analgesics Products from U.S. Outpatient Retail Pharmacies\n\n300.0\n\n250.0\n\n224\n\n236\n\n245\n\n250\n\n257\n\n258\n\n260\n\n252\n\n244\n\n228\n\n216\n\ns n o\n\n200.0\n\n196\n\ni l l i\n\nm n\n\ni\n\n150.0\n\n, s n o i t p i r c s e r P\n\n100.0\n\n50.0\n\n0.0\n\n2006\n\n2007\n\n2008\n\n2009\n\n2010\n\n2011\n\n2012\n\n2013\n\n2014\n\n2015\n\n2016\n\n2017\n\nImmediate -Release Market*\n\nExtended-Release/Long-Acting Market**\n\nAbuse-Deterrent Formulations***\n\nSource: IQVIA, National Prescription Audit (NPA) and static data 2006-2011. January 2006-December 2017. Static data extracted March 2017 and 2012-2017 data extracted February 2018. *Immediate-Release formulations include oral solids, oral liquids, rectal, nasal, and transmucosal **Extended-Release/Long-Acting formulations include oral solids and transdermal patches ***Abuse-deterrent formulation opioid products include Arymo ER, Embeda ER, Hysingla ER, Morphabond ER, Xtampza ER, OxyContin ER Reformulated (Approval in April 2010) Note: Include opioid analgesics only, excluding injectable formulations as well as opioid-containing cough-cold products and opioid-containing medication-assisted treatment (MAT) products\n\nwww.fda.gov\n\n9", "n_tokens": 306, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-9-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 9, "text": "Nationally Estimated Number of Prescriptions Dispensed for Abuse-Deterrent Formulation (ADF) Opioid Analgesic Products* from U.S. Outpatient Retail Pharmacies\n\n6.0\n\n5.6M\n\ns n o\n\ni l l i\n\nm n\n\n5.0\n\n4.0\n\n5.1M\n\n4.9M\n\n4.7M\n\n4.5M\n\n4.3M\n\ni\n\n, s n o i t p i r c s e r P\n\n3.0\n\n2.0\n\n1.7M\n\n1.0\n\n0.0\n\n2009\n\n2010\n\n2011\n\n2012\n\n2013\n\n2014\n\n2015\n\n2016\n\nTotal ADF\n\n14,106\n\n1,687,156\n\n5,572,887\n\n5,112,361\n\n4,850,154\n\n4,686,484\n\n4,519,991\n\n4,264,525\n\nHysingla ER\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\n85,934\n\n166,208\n\nEmbeda ER\n\n14,106\n\n145,597\n\n35,081\n\n5\n\n1\n\n0\n\n27,775\n\n110,865\n\nXtampza ER\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\n7,880\n\nArymo ER\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\nMorphabond ER\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\n0\n\nOxyContin ER Reformulated (brand and generic)\n\n0\n\n1,541,559\n\n5,537,806\n\n5,112,356\n\n4,850,153\n\n4,686,484\n\n4,406,282\n\n3,979,572\n\nSource: IQVIA, National Prescription Audit™, Years 2009-2017. Data Extracted February 2018. *ADF Products not marketed during study period: RoxyBond (Oxycodone IR) - Approved 04/2017; Targiniq ER\n\n(oxycodone/naloxone ER) - Approved 07/2014; Troxyca ER (Oxycodone/naltrexone ER) - Approved 08/2016; Vantrela ER (Hydrocodone ER) - Approved 01/2017\n\nwww.fda.gov\n\n3.8M\n\n2017\n\n3,806,205\n\n214,954\n\n139,334\n\n88,360\n\n7,080\n\n2,540\n\n3,353,937\n\n10", "n_tokens": 461, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-10-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 10, "text": "Equally Critical Social and Medical Issue: Pain in America\n\nFrom the Functioning and Disability Supplement of the 2012 National Health Interview Survey – 126.1 million adults reported some pain in the previous\n\n3 months\n\n25.3 million adults (11.2%) suffering from daily (chronic) pain\n\n23.4 million (10.3%) reporting a lot of pain. – Based on the persistence and bothersomeness of their pain, 14.4 million adults (6.4%) were classified as having the highest level of pain, category 4, with an additional 25.4 million adults (11.3%) experiencing category 3 pain.\n\nNahin RL, J.Pain, 2015 Aug;16(8):769-80\n\n11", "n_tokens": 149, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-11-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 11, "text": "Pain in America (cont) • Treatment options for pain: pharmacologic, physical medicine, behavioral medicine, neuromodulation, interventional, and surgical\n\nOptimal patient outcomes often result from a comprehensive multidisciplinary approach where pharmacologic treatment is not the sole focus\n\nPatients experience ongoing barriers to adequate pain management – “many related to non-existent or insufficient insurance\n\ncoverage and reimbursement for evidence- and consensus- based therapies”\n\n-American Academy of Pain Medicine, 2014\n\nAs a result, treatments have largely focused on prescription drugs, mainly opioids, and procedures, at least, in part, because of the reimbursement structure of our healthcare system\n\n12\n\n12", "n_tokens": 144, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-12-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 12, "text": "FDA Response to this Crisis\n\n\"Unquestionably, our greatest immediate challenge is the problem of opioid abuse. This is a public health crisis of staggering human and economic proportion … we have an important role to play in reducing the rate of new abuse and in giving healthcare providers the tools to reduce exposure to opioids to only clearly appropriate patients, so we can also help reduce the new cases of addiction.\"\n\nScott Gottlieb, FDA Commissioner Address to FDA staff, May 15, 2017\n\n13", "n_tokens": 102, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-13-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 13, "text": "The Opioid Crisis: An FDA Priority\n\nTake immediate steps to reduce the scope of the epidemic of opioid addiction\n\nMay 2017: Established an FDA Opioid Policy Steering Committee (OPSC)\n\n2017-2018: Soliciting public input on how FDA authorities can or should be used to address the crisis – Sept 2017, January 2018: Public meetings – December 2017: Packaging solutions – February 2018: Healthcare system solutions\n\n14", "n_tokens": 85, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-14-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 14, "text": "The Opioid Crisis: FDA’s Priorities\n\n1. Decreasing Exposure & Prevent New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\n15", "n_tokens": 54, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-15-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 15, "text": "FDA Priorities align to HHS Strategic Priorities and other National Activities\n\nHHS STRATEGIC PRIORITIES\n\nFDA PRIORITIES\n\nOTHER ACTIVITIES\n\nStrengthening public health surveillance\n\nTargeting availability and distribution of overdose- reversing drugs\n\nSupporting cutting-edge research\n\nImproving access to treatment and recovery services\n\nAdvancing the practice of pain management\n\n1. Decreasing Exposure & Prevent New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\nPresident’s Commission on Combating Drug Addiction\n\nOffice of National Drug Control Policy Recommendations\n\nComprehensive Addiction and Recovery Act (CARA)\n\nNational Pain Strategy Recommendations\n\nNational Public Health Emergency\n\n16", "n_tokens": 129, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-16-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 16, "text": "1. Decreasing Exposure and Prevent New Addiction\n\nHOW?\n\nWHAT?\n\n\n\nAppropriate Dose/Duration Labeling\n\nFacilitate appropriate prescribing of opioid analgesics. Evaluate indication specific doses.\n\nJan 30, 2018: FDA public meeting to gain input on how FDA’s authorities could facilitate appropriate prescribing. Feb 15, 2018: Duke Margolis public workshop – “Strategies for Promoting the Safe Use and Appropriate Prescribing of Prescription Opioids”.\n\n\n\nAppropriate Packaging, Storage, and Disposal\n\nExplore how opioid analgesic drug products are packaged, stored, and discarded. Examine use of packaging strategies, such as unit-of-use packaging to improve opioid analgesic safety.\n\nJun 1, 2017: FDA/Duke Margolis workshop and white paper on packaging, storage, and disposal solutions.\n\nDec 11-12, 2017: FDA public workshop to gain input on packaging strategies. 17", "n_tokens": 184, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-17-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 17, "text": "1. Decreasing Exposure and Prevent New Addiction\n\nHOW?\n\nWHAT?\n\n\n\nHealth Care Provider Education\n\nConsider appropriateness of mandatory education and how FDA would operationalize such a requirement. Ensure training is made available to non-physician prescribers, including nurses and pharmacists.\n\nMay 9-10, 2017: FDA public\n\nworkshop on pain management training. Issued revised Blueprint. Sept 28, 2017: FDA issued letters notifying sponsors of IR opioids their drugs will be subject to more stringent set of requirements under REMS & should be approved Sept 2018. The training must be made available to health care providers who prescribe IR opioid analgesics.\n\n18", "n_tokens": 133, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-18-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 18, "text": "2. Supporting the Treatment of Those With Opioid Use Disorder\n\nHOW?\n\nWHAT?\n\n\n\nExploring ways to expand access to naloxone and facilitate the switch to OTC naloxone.\n\nPrecedent setting research: FDA- led labeling study to facilitate the switch from prescription to OTC naloxone.\n\nNaloxone\n\nMedication Assisted Treatment (MAT)\n\nFacilitate the development of new MAT options. Take steps promote the more widespread use of existing, safe and effective, FDA approved therapies. Join efforts to break the stigma associated with medications used for treatment of addiction.\n\nIssuing Guidances for product developers to facilitate the development of new treatments. • NIH collaboration to identify new\n\nendpoints in MAT drug development and facilitate new formulations.\n\n19", "n_tokens": 149, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-19-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 19, "text": "3. Fostering the Development of Novel Pain Treatment Therapies\n\nHOW?\n\nWHAT?\n\n\n\nPartnerships & Meetings\n\nExpand use of partnerships with non-profit organizations, public meetings, and Advisory Committee meetings. Collaborate across HHS.\n\nFDA grant supporting Drug-Free Kids campaign.\n\nPublic-private-partnership (PPP) with NIH and developers under the Critical Path initiative. Jul 2017: Commissioned NASEM consensus report. • Feb 14, 2018: Advisory\n\nCommittee meeting for Hydexor (hydrocodone/APAP/promethazine) – for short term management of acute pain while preventing and reducing opioid-induced nausea and vomiting.\n\n20", "n_tokens": 130, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-20-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 20, "text": "3. Fostering the Development of Novel Pain Treatment Therapies\n\nHOW?\n\nWHAT?\n\n\n\nAbuse Deterrent Formulations (ADFs)\n\nSupport development of innovative ADFs, data to inform benefit-risk assessment, and transition to an ADF-prominent market. Ensure ADF label nomenclature enables providers to adequately distinguish between the risk of abuse and the risk of addiction.\n\nJul 2017: Public workshop for postmarketing ADF data and evaluation methods. Issued final guidance on generic ADFs.\n\n2018: Contracts to improve data for ADF assessment and understand nomenclature.\n\n\n\nExplore use of Fast Track and Breakthrough Therapy Designations. Encourage novel therapies, including medical devices.\n\nSummer 2017: FDA/NIH meeting series on pain treatment alternatives.\n\nPain Treatment Alternatives\n\n21", "n_tokens": 148, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-21-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 21, "text": "4. Improving Enforcement & Assessing Benefit-Risk\n\nHOW?\n\nWHAT?\n\nImproving Enforcement\n\nConsider how to fully leverage FDA’s current seizure authorities. Increase oversight of Illicit trade.\n\nCollaboration with Customs and Border Protection to increase FDA staff stationed at international mail facilities (IMFs) to increase seizure of opioids being smuggled into the United States through international mail facilities (IMFs).\n\nAssessing Benefit-Risk\n\nTake action, including product market withdrawal recommendation. Improve robustness of benefit-risk assessment framework for opioid analgesic formulations.\n\nJun 2017: Requested market withdrawal of Opana ER due to abuse risks. Sep 2017: Pediatric Advisory Committee for hydrocodone or codeine containing cough treatment in pediatric patients.\n\n22", "n_tokens": 144, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-22-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 22, "text": "FDA Will Use All of its Available Tools to Accomplish These Goals\n\nImproving the safe use of opioids through careful and appropriate regulatory activities\n\nImproving the safe use of opioids through careful and appropriate policy development • Improving the treatment of pain through\n\nimproved science\n\nImproving the safe use of opioids through communication, partnership and collaboration\n\n23", "n_tokens": 64, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-23-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 23, "text": "Solutions Must Come from Many Sources • FDA is one of many Federal agencies addressing issues involving opioids\n\nMany Federal Agencies working together on issue\n\nEach state has programs to address opioids\n\nGuidelines and educational programs are available from specialty societies and State Medical Boards\n\nHealthcare institutions • Advocacy groups • • Patients (n = millions)\n\nIndividual providers (n = 800,000+)\n\n24", "n_tokens": 73, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-24-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 24, "text": "Summary and Conclusions\n\nFDA working to address opioid epidemic as a part of the larger HHS response – One of the FDA’s very highest priorities – FDA one of many groups focused on the issue\n\nGoing forward, FDA is committed to taking decisive actions, grounded in the available science and appropriate public input to address this critical challenge to the US health and welfare\n\nOur focus is addressing opioid abuse while assuring appropriate access to effective pain treatment\n\n25", "n_tokens": 89, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-25-0", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 25, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-0-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 0, "text": "FDA's Role in Confronting the Opioid Epidemic\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs CDER, FDA\n\nCEPOP September 18, 2017\n\n1", "n_tokens": 36, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-1-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 1, "text": "The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA\n\n2", "n_tokens": 23, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-2-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 2, "text": "Overall Message\n\nThe FDA response to the opioids crisis and the larger Federal efforts reflect the critical nature of the crisis and the human toll it is having\n\n3", "n_tokens": 31, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-3-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 3, "text": "Marked Increases in Prescription Opioid and Heroin Overdose Deaths in the USA 2000 to 2015\n\nUSA 2015 Overdose Deaths: • 52,404 Any Drug • 33,091 Any Opioid\n\nAny Opioid\n\nCommonly Prescribed Opioids (natural and semi-synthetic opioids and methadone)\n\nHeroin\n\nOther Synthetic Opioids (e.g. fentanyl, tramadol)", "n_tokens": 79, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-4-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 4, "text": "Overdose Death Rates\n\n2014\n\n1999\n\nDesigned by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System\n\nScience = Solutions", "n_tokens": 35, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-5-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 5, "text": "yy U.S. FOOD & DRUG\n\nADMINISTRATION\n\nHHS Response to Opioid\nEpidemic", "n_tokens": 18, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-6-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 6, "text": "AANP CHRONIC PAIN SEMINAR\n\nHHS Opioid Strategy\n\nStrengthening public health surveillance\n\nSupporting cutting- edge research\n\nAdvancing the practice of pain management\n\nTargeting availability and distribution of overdose-reversing drugs\n\nImproving access to treatment and recovery services\n\n7", "n_tokens": 45, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-7-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 7, "text": "AANP CHRONIC PAIN SEMINAR\n\nGoals of HHS Opioid Strategy\n\nEmpowering the public, patients and providers through education and awareness\n\nPreventing opioid abuse and overdose and related health consequences\n\nImproving function and quality of life for individuals living with pain\n\nEnsuring patients who need opioid addiction treatment have access to it\n\nSupporting people to achieve long-term recovery\n\n8", "n_tokens": 69, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-8-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 8, "text": "Advancing the Practice of Pain Management\n\nCDC – Prevention for States grants – CDC Opioid Prescribing Guideline implementation and associated training CMS – Reimbursement and coverage levers to increase access to full spectrum of\n\npain treatment options\n\nOASH\n\nNational Pain Strategy implementation FDA – Incentivizing development of new pain treatments – REMS and associated education, safety labeling changes\n\nNIDA\n\nWorking with researchers to better understand pain pathways and develop new treatments\n\nPartnering with industry on early-phase development of treatments – Leading the Interagency Pain Research Coordinating Committee\n\nASPE\n\n– Research on coverage and evidence base for non-opioid treatments\n\n9", "n_tokens": 126, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-9-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 9, "text": "Examples of Other Federal Efforts to Address Opioid Epidemic\n\nNational Pain Strategy\n\nFocuses on key areas of pain and pain care, including professional education and training, public education and communication, service delivery and reimbursement\n\nhttp://iprcc.nih.gov/docs/DraftHHSNationalPainStrategy.pdf\n\nNIH Pain Consortium’s Centers of Excellence in Pain Education Program. – Developed and spearheaded by NIDA\n\nhttps://painconsortium.nih.gov/nih_pain_programs/coepes.html\n\nSurgeon General’s Call to End the Opioid Crisis\n\nIncludes a new prescriber education campaign, Turn the Tide\n\nCDC Guidelines for Prescribing Opioids for Chronic Pain\n\nhttp://www.cdc.gov/drugoverdose/prescribing/guideline.html\n\nhttps://www.hhs.gov/opioids/about-the-epidemic/index.html\n\n10", "n_tokens": 201, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-10-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 10, "text": "Presidential Commission\n\nEstablished by Executive Order on March 29, 2017.\n\nMission: “to study the scope and effectiveness of the Federal response to drug addiction and the opioid crisis and to make recommendations to the President for improving that response.”\n\nInterim report release July 31, 2017*\n\nhttps://www.whitehouse.gov/sites/whitehouse.gov/files/ondcp/commissio n-interim-report.pdf\n\n11", "n_tokens": 90, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-11-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 11, "text": "yy U.S. FOOD & DRUG\n\nADMINISTRATION\n\nFDA Response to Opioid\nEpidemic", "n_tokens": 17, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-12-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 12, "text": "FDA Action Plan (February 4, 2016)\n\nIn response to the opioid abuse epidemic, FDA leadership called for a far-reaching action plan to reassess the agency’s approach to opioid medications. The plan focused on policies aimed at reversing the epidemic, while still providing patients in pain access to effective relief.\n\nhttps://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm484765.htm\n\n13", "n_tokens": 100, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-13-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 13, "text": "FDA Opioids Action Plan\n\nTo reverse the epidemic while still providing patients with access to effective relief\n\nAdvisory Committees\n\nIR Labeling\n\nPost-market\n\nREMS\n\nAbuse Deterrent\n\nSupporting Treatment\n\nRisk-Benefit\n\n14", "n_tokens": 37, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-14-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 14, "text": "FDA is using all of its Available Tools to Carry Out the Action Plan\n\nImproving the safe use of opioids through careful and appropriate regulatory activities\n\nImproving the safe use of opioids through careful and appropriate policy development • Improving the treatment of pain through\n\nimproved science\n\nImproving the safe use of opioids through communication, partnership and collaboration\n\n15", "n_tokens": 66, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-15-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 15, "text": "Updating the Risk Evaluation and Mitigation Strategy (REMS) Program\n\nREMS program: requires drug companies making Extended-Release Long-Acting Opioids to fund continuing education programs on the use of these products.\n\nFDA held a public meeting regarding prescriber education on May 9 – 10, 2017\n\nFDA has announced plans to expand the REMS:\n\nto include the immediate-release (IR) opioids – to include pain management in the training , and – to expand training to include more members of the healthcare team\n\nFDA has released a draft Blueprint with expanded topics to be included in the prescriber education program including education on pain management 16", "n_tokens": 131, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-16-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 16, "text": "Abuse Deterrent Formulations (ADF)\n\nFDA has a goal of incentivizing the development of opioid medications with progressively better abuse- deterrent properties and support their widespread use – Abuse-deterrent is not abuse proof\n\nFDA requiring studies to understand the impact of ADFs in real-world settings\n\nIn support of the goal, FDA has issued guidance for product development, including draft guidance on generic ADFs, reflecting importance of generic products in the US 17", "n_tokens": 93, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-17-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 17, "text": "Continue Work on Benefit-Risk Assessment of Opioids • Prescription opioids have impacts on both the patients when used as prescribed and on society when used inappropriately\n\nFDA considers both impacts in our regulatory decisions and is seeking to formalize that assessment – Opana decision\n\nFDA sought NASEM input on issue last year and is working to determine next steps – “…to ensure drug approval and removal decisions are made within a benefit-risk framework that evaluates not only the outcomes of opioids when used as prescribed, but also the public health effects of the inappropriate use of these drugs”*\n\nhttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/uc m566958.html\n\n18", "n_tokens": 150, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-18-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 18, "text": "Solutions will need to come from many Sources\n\nFDA is one of many Federal agencies addressing issues involving opioids (n = 1)\n\nMany Federal Agencies share\n\ninformation via the Federal Interagency Working Group on Opioids\n\nEach state has programs to address opioids\n\nGuidelines and educational programs are available from specialty societies and State Medical Boards\n\nHealthcare institutions • Advocacy groups • • Patients (n = millions)\n\nIndividual providers (n = 800,000+)\n\n19", "n_tokens": 89, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-19-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 19, "text": "What’s Next for FDA? \"Unquestionably, our greatest immediate challenge is the problem of opioid abuse. This is a public health crisis of staggering human and economic proportion … we have an important role to play in reducing the rate of new abuse and in giving healthcare providers the tools to reduce exposure to opioids to only clearly appropriate patients, so we can also help reduce the new cases of addiction.\"\n\nScott Gottlieb, FDA Commissioner Address to FDA staff, May 15, 2017\n\n20", "n_tokens": 104, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-20-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 20, "text": "Summary and Conclusions\n\nFDA working to address opioid epidemic as a part of the larger HHS response – One of the FDA’s highest priorities\n\nFDA Opioid Action Plan provides framework for FDA response to the challenge of opioids abuse epidemic\n\nSince the Action Plan was announced, FDA has continued to make significant progress on the items identified in the plan, applying of all of our available tools to achieve our goals\n\n21", "n_tokens": 83, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-21-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 21, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-22-0", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 22, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-0-0", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 0, "text": "Center Updates: CDER\n\nDouglas C. Throckmorton MD Deputy for Regulatory Programs, CDER FDA\n\nSeptember 12, 2017\n\n1", "n_tokens": 26, "kind": "text"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-1-0", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 1, "text": "Central Messages\n\nThree innovative and ongoing activities chosen • Focus on illustrating CDER support for product quality and innovation through – Process improvement – Targeted new resources\n\n2", "n_tokens": 29, "kind": "text"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-2-0", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 2, "text": "Concept of Operations for Facility Evaluations • Goals:\n\nImproved consistency, efficiency, and transparency in facility evaluations, inspections, and regulatory decision-making for marketing applications\n\nImproved FDA’s operational capacity by eliminating overlap of effort amongst various CDER and ORA offices\n\nProgress (with ORA and OC):\n\nDesigned the processes for pre-approval and surveillance inspections\n\nDefined/Clarified the roles and responsibilities of CDER and ORA\n\nNext Steps: Continue to work on implementation plan\n\n3", "n_tokens": 94, "kind": "text"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-3-0", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 3, "text": "New Inspection Protocol Project • Goal:\n\nEnhanced inspectional assessments – Enhanced production, utility, and consistency of the establishment inspection reports\n\nProgress:\n\nIn 2016, in collaboration with ORA and OC, OPQ – Completed pilot for sterile drug process facilities\n\nNext Steps: 2nd Pilot, Work on Inspection Protocols\n\n4", "n_tokens": 59, "kind": "text"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-4-0", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 4, "text": "Emerging Technology Team (ETT) • Goals:\n\nSupporting industry’s development and implementation of innovative approaches in pharmaceutical design and manufacturing\n\nShared learning about challenging areas: packaging, continuous manufacturing, delivery systems…..\n\nIdentifying/Resolving potential scientific and policy issues related to the new approach\n\nProgress:\n\nIn 2016, OPQ\n\nEnabled the approval of the first switch from batch to continuous manufacturing process for an approved drug\n\nAccepted 15 projects into the ETT on a variety of innovative technologies • Next Steps: Continued meetings. Docket open for comment to help us on our approach*. Working on Draft ETT Guidance.\n\nhttps://www.gpo.gov/fdsys/pkg/FR-2017-06-23/html/2017-13195.htm\n\n5\n\n5", "n_tokens": 157, "kind": "text"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-5-0", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 5, "text": "Conclusions\n\nSupporting innovative manufacturing and controls systems is a priority for FDA\n\n6", "n_tokens": 13, "kind": "text"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-6-0", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 6, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-0-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 0, "text": "Keynote: Generic Drug Program Update\n\nSally Choe, PhD Director, Office of Generic Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration\n\n1", "n_tokens": 32, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-1-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 1, "text": "Outline\n\n1. 2. Generic Drug Program Overview 3. Generic Drug User Fee Amendments (GDUFA) 4. Drug Competition Action Plan (DCAP) 5. Conclusion\n\nIntroduction\n\n2", "n_tokens": 36, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-2-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 2, "text": "Introduction\n\nFDA Office of Generic Drugs, CDER • FDA Office of Study Integrity and Surveillance, Office of Translational Sciences (OTS), CDER\n\nPAREXEL Consulting • FDA Office of Clinical Pharmacology, OTS, CDER • Pfizer, Ann Arbor, MI • BMS, Princeton, NJ • University of Michigan, Ann Arbor, MI 3", "n_tokens": 75, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-3-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 3, "text": "U.S. FOOD & DRUG\n\nADMINISTRATION\n\nGeneric Drug Program Overview", "n_tokens": 12, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-4-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 4, "text": "Office of Research and Standards (ORS) Director: Rob Lionberger, PhD\n\nDeputy Director: Lei Zhang, PhD\n\nDivision of Therapeutic Performance\n\nDivision of Quantitative Methods & Modeling\n\nOffice of Generic Drugs (OGD) Director: Sally Choe, PhD\n\nDeputy Director: Howard Chazin, MD (Acting)\n\nOffice of Bioequivalence (OB) Director: Dale Conner, PharmD\n\nOffice of Generic Drug Policy (OGDP) Director: Maryll Toufanian, JD\n\nActing Deputy Director: Ethan Stier, PhD\n\nDeputy Director: Kristin Davis, JD\n\nDivision of Bioequivalence I\n\nDivision of Bioequivalence II\n\nDivision of Legal and Regulatory Support\n\nDivision of Bioequivalence III\n\nDivision of Clinical Review\n\nDivision of Policy Development\n\nOffice of Regulatory Operations (ORO) Director: Edward (Ted) Sherwood\n\nDeputy Director: CDR Vincent Sansone, PharmD\n\nDivision of Labeling Review\n\nDivision of Filing Review\n\nDivision of Project Management\n\nDivision of Quality Management Systems\n\n5", "n_tokens": 193, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-5-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 5, "text": "U.S. FDA Generic Drug Program\n\nAbbreviated new drug applications (ANDAs) involve multiple offices within FDA – OGD issues regulatory actio on ANDAs\n\nn\n\nOSP\n\nOM\n\nCompliance\n\nOffice of Pharmaceutical Quality (OPQ) and OGD collaborate on technical review of ANDAs\n\nOCOMM\n\nOGD\n\nOMP\n\nMany offices across CDER and FDA contribute to program success\n\nORA OCC CDRH Others\n\nOTS\n\nORP\n\nOSE\n\nOPQ\n\nOND\n\n6", "n_tokens": 90, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-6-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 6, "text": "Generic Drug\nProgram", "n_tokens": 3, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-7-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 7, "text": "ADMINISTRATION\n\nGeneric Drug User Fee Amendments\n(GDUFA)", "n_tokens": 11, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-8-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 8, "text": "GDUFA\n\nReflects negotiated agreements with industry • Goals based on assessment of program activities\n\nGDUFA I (2012) • GDUFA II (2017)\n\nGDUFA II Commitment Letter – www.fda.gov/GDUFA\n\n9", "n_tokens": 48, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-9-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 9, "text": "GDUFA II Features\n\nI. Submission Review Performance Goals II. Original ANDA Review Program Enhancements III. Pre-ANDA Program and Subsequent Mid-\n\nReview-Cycle Meetings for Complex Products\n\nIV. DMF Review Program Enhancements V. Facilities VI. Enhanced Accountability and Reporting\n\n10", "n_tokens": 57, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-10-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 10, "text": "U.S. FOOD & DRUG\n\nADMINISTRATION\n\nGDUFA Program Performance", "n_tokens": 13, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-11-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 11, "text": "1600\n\n1400\n\n1200\n\n1000\n\n800\n\n600\n\n400\n\n200\n\n0\n\nANDA Receipts (Originals)\n\nPre-GDUFA\n\nGDUFA I\n\n813\n\n893\n\n1103\n\n968\n\n1473\n\n853\n\n1306\n\n539\n\nFY10\n\nFY11\n\nFY12\n\nFY13\n\nFY14\n\nFY15\n\nFY16\n\nFY17\n\nGDUFA II\n\n1044\n\nFY18\n\n12", "n_tokens": 74, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-12-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 12, "text": "Predictability\n\nAbbreviated New Drug Application (ANDA) Review Timeline*\nStandard Review 10-Month Goal\n\nPre-Submissio:\nActivities\nl ng Assessment*\nPrepare Final Actio\nCan be years Month Month Month Month Month Month Month Month Month Month\nor months 1 2 3} 4 5 6 7 8 9 10\n\n+ Each ANDA assessment progresses in a unique and iterative way. This is one example and is not reflective of every ANDA assessment.\n* Good ANDA Assessment MAPP\n\n13", "n_tokens": 96, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-13-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 13, "text": "Abbreviated New Drug Application (ANDA) Review Timeline*\nPre-ANDA Program 10-Month Goal\n\nProduct\nDevelopment Meeting\n\nPre-Submission | ANDA Filing DRLs | Mid-Review Regulatory\nMeeting Submission Determination Issued| Cycle Meeting Action\n\n4 4 ¢ 4 ¢\n\nPrepare Final Action\n\nCan be years Month Month Month Month Month Month Month Month Month Month\n\nor months 1 2 3 4 5 6 7 8 9 10\n\n+ Each ANDA assessment progresses in a unique and iterative way. This is one example and is not reflective of every ANDA assessment.\n% Good ANDA Assessment MAPP\n\n14", "n_tokens": 114, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-14-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 14, "text": "Regulatory Actions\n\nUnder GDUFA, FDA has committed to take regulatory actions by the goal date: 1. Approval (AP) 2. Tentative Approval (TA) 3. Complete Response Letter (CR or CRL)\n\n15", "n_tokens": 44, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-15-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 15, "text": "30 25 20 15 10 5 0\n\nFiling - Refuse to Receive (RTR) (based on cohort year of submission)\n\n19\n\n25\n\n13\n\nFY 15\n\nFY 16\n\nFY 17\n\n% RTR\n\n8.3\n\nFY 18\n\n16", "n_tokens": 47, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-16-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 16, "text": "Approval and Tentative Approval Totals\n\n1200 1000 800 600 400 200 0\n\n139\n\n426\n\n139\n\n458\n\n102\n\n517\n\n95\n\n440\n\n91\n\n409\n\nGDUFA I\n\n120\n\n492\n\n184\n\n651\n\n174\n\n763\n\nFY 10\n\nFY 11\n\nFY 12\n\nFY 13\n\nFY 14\n\nFY 15\n\nFY 16\n\nFY 17\n\nAP\n\nTA\n\nGDUFA II\n\n190\n\n781\n\nFY 18\n\n17", "n_tokens": 76, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-17-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 17, "text": "100\n\n80\n\n60\n\n40\n\n20\n\n0\n\nGUDFA Performance – Originals (new applications)\n\n93\n\n98\n\nGDUFA Goal\n\n96\n\n96\n\n15 months\n\n15 months\n\n10 months\n\n8-10 months\n\nFY 15\n\nFY 16\n\nFY 17\n\nFY 18\n\n18", "n_tokens": 47, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-18-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 18, "text": "Product-Specific Guidance (PSG)\n\nPSGs provide detailed advice on the evidence recommended to demonstrate bioequivalence for a particular RLD\n\nThey support the high first-cycle adequate rate for the bioequivalence sections of ANDAs\n\nThe PSGs web page contains almost 1700 PSGs and new guidances are added every quarter\n\n19", "n_tokens": 68, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-19-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 19, "text": "Product-Specific Guidance\n\nPosted Product Specific Guidance by Fiscal Year\n\n300 5\n\nm Revised Draft Guidance\n\n250 ~ mNew Draft Guidance\n223\n\n208\n\n194\n200 ~\n\n150 - 134 135\n\n102\n\nNumber of Guidances Posted\n\n100 -\n\n20", "n_tokens": 41, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-20-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 20, "text": "Pre-ANDA Meetings for Complex Generics\n\nPre-ANDA meetings have new GDUFA II commitments and timelines\n\nProvide opportunities to discuss new or alternative bioequivalence approaches for complex products – Focus on content not covered by PSGs\n\n21", "n_tokens": 50, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-21-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 21, "text": "d e v i e c e R s t s e u q e R f o r e b m u N\n\n90\n\n80\n\n70\n\n60\n\n50\n\n40\n\n30\n\n20\n\n10\n\n0\n\nPre-ANDA Meeting Requests\n\n30\n\n32\n\n27\n\n21\n\n14\n\nFY13\n\nFY14\n\nFY15\n\nFY16\n\nFY17\n\nFiscal Year\n\n83\n\nFY18\n\n22", "n_tokens": 67, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-22-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 22, "text": "Pre-ANDA Meeting Requests – Fiscal Year 2018\n\nTask\n\nTarget\n\nGrant or Deny Meeting within 30 Days\n\n90%\n\nHold Meeting or Written Response within 120 Days\n\n60%\n\nSend Meeting Minutes within 30 Days\n\nN/A\n\nActual\n\n99%\n\n100%\n\n100%\n\n23", "n_tokens": 48, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-23-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 23, "text": "GDUFA Science and Research\n\nProvides the scientific foundation for\n\nrecommendations on complex products – Essential for pre-ANDA meetings and product-specific\n\nguidance development\n\nIn 2018, GDUFA funded >$14M in OGD regulatory science research programs – 24 new contracts and grants – 75 ongoing research collaborations\n\nVisit www.fda.gov/gdufaregscience for more details\n\n24", "n_tokens": 75, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-24-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 24, "text": "Input into Research Priorities\n\nThe GDUFA Research program is focused on challenges to generic product development or assessment\n\nStakeholder input was considered to develop the FY19 GDUFA Regulatory Science Priorities:\n\n1. Complex active ingredients, formulations, or dosage forms 2. Complex routes of delivery 3. Complex drug-device combinations 4. Tools and methodologies for BE and substitutability evaluation\n\nYour input will determine FY20 priorities\n\n2019 Regulatory Science Initiatives Public Workshop will be held on Wednesday, May 1, 2019 on the White Oak Campus\n\n25", "n_tokens": 109, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-25-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 25, "text": "Additional Fiscal Year 2018 Program Highlights\n\nTimely and successful update of Orange Book to reflect marketing status updates as required by FDARA\n\nCompetitive generic therapy (CGT) designation and exclusivity requests\n\nDrug Competition Action Plan (DCAP)\n\n26", "n_tokens": 46, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-26-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 26, "text": "ADMINISTRATION\n\nDrug Competition Action Plan\n(DCAP)", "n_tokens": 9, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-27-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 27, "text": "DCAP Actions\n\nCommissioner announced in June 2017\n\nDCAP focuses on:\n\nImproving the efficiency of generic drug development, review, and approval processes\n\nMaximizing scientific and regulatory clarity with respect to generic drugs for complex products\n\nClosing loopholes that allow brand drug companies to “game” the system in ways that thwart generic competition\n\n28", "n_tokens": 62, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-28-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 28, "text": "Improving the Efficiency of Generic Drug Development, Review, and Approval\n\nGood ANDA Submission Practices Draft Guidance • Good ANDA Assessment Practices MAPP • ANDA Submissions--Amendments to Abbreviated New Drug Applications Under GDUFA Final Guidance\n\n29", "n_tokens": 46, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-29-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 29, "text": "Maximizing Scientific and Regulatory Clarity for Complex Generic Drug Products\n\nIssued 76 PSGs for complex generics in 2018 • Published two guidances for industry:\n\nAssessing Adhesion with Transdermal and Topical Delivery Systems for ANDAs Revised Draft Guidance\n\nAssessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs Draft Guidance\n\n30", "n_tokens": 68, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-30-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 30, "text": "Closing Loopholes that Allow Brand Drug Companies to “Game” the System\n\nIn May 2018, FDA published a list of drug products about which FDA has received inquiries related to reference listed drug access In June 2018, FDA published two draft guidances: – Development of a Shared System REMS – Waivers of the Single, Shared System REMS Requirement In October 2018, FDA published revised draft guidance: Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act\n\n31", "n_tokens": 103, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-31-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 31, "text": "Encouraging Development of Generic Drugs in Markets with Limited Competition\n\nList of Off-Patent, Off-Exclusivity Drugs without an Approved Generic (Published in June 2017; updated biannually)\n\nAddition of patent submission dates to the Orange Book where available (Nov. 2017)\n\n32", "n_tokens": 55, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-32-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 32, "text": "Resources\n\nWho to Contact for Questions Related to Generic Drugs\n\nBrief videos highlighting new features in GDUFA II on FDA.gov:\n\nGDUFA Overview • Pre-ANDA Program for Complex Products • Type II Drug Master Files (DMF) Update • Performance Goals • Goals Integration • Review Status Updates • Post Complete Response Letter (CRL) Meeting • Requests for Reconsideration • Review Classification\n\n33", "n_tokens": 81, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-33-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 33, "text": "Podcasts/Webinars\n\nSBIA Complex Generic Drug Workshop (SBIA)\n\nRegulatory Education for Industry: Complex Generic Drug Product Development Workshop\n\nMaryll Toufanian, JD\n\nUS Generic Drug Policy: Less Cost, Same Impact\n\nHoward Chazin, MD\n\nChallenges in Generic Drug Safety & Surveillance\n\nXiaohui (Jeff) Jiang, PhD\n\nAn Overview of Challenges and Opportunities in the Development of Complex Generic Drug Products\n\nKim Witzmann, MD\n\nOvercoming Barriers to Entry for Complex Generic Oral Inhalation Drug Products\n\nSam Raney, PhD\n\nFDA Champions Research to Make Complex Generic Transdermal Products Available to Patients\n\nLiang Zhao, PhD\n\nPioneering Modeling Methodologies in Generic Drug Development\n\nSeptember 2018\n\nPodcast- Recorded\n\nPodcast- Recorded\n\nMarch 6, 2018\n\nMarch 15, 2018\n\nApril 25, 2018\n\nMay 17, 2018\n\n34", "n_tokens": 153, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-34-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 34, "text": "Generic Drug\nProgram", "n_tokens": 3, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-35-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 35, "text": "Office of Generic Drugs Mission and Vision\n\nOur Mission OGD makes high quality, affordable medicines available to the public.\n\nOur Vision OGD is the world leader in the science and regulation of generic medicines.\n\n36", "n_tokens": 40, "kind": "text"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-36-0", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 36, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-0-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 0, "text": "Search for Balance: FDA’s Approach to the Opioids Crisis\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs Center for Drug Evaluation and Research FDA\n\nVirginia Pain Society March 9, 2019\n\n1", "n_tokens": 43, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-1-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 1, "text": "Topics for Today\n\nScope and sources of opioid crisis of abuse and overdose\n\nNeed for adequate pain treatment\n\nPain in America – Shortages of injectable opioids\n\nFDA response • Selected FDA activities\n\n2", "n_tokens": 39, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-2-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 2, "text": "Take Homes\n\nThe ‘Opioid Crisis’ is not one crisis, but multiple challenges to prescribers, patients and the healthcare system\n\nNo single solution is going to suffice • FDA is working in a prioritized way in multiple areas to confront opioid overdoses while working to ensure patients receive appropriate pain treatment\n\n3", "n_tokens": 66, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-3-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 3, "text": "The Opioid Challenges:\n\nOpioid Abuse and Misuse Pain in America Injectable Opioid Shortages", "n_tokens": 23, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-4-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 4, "text": "Misuse and Abuse of Prescription Opioid Analgesics Remains an Important Public Health Problem\n\nIn 2017, prescription opioids were the largest category of pharmaceutical products misused and abused in US – 11.1 million people estimated to have past-year misuse/abuse – 1.7 million people estimated with DSM IV criteria for substance\n\nuse disorder involving prescription opioid analgesics\n\nIn comparison, 886,000 estimated to have past-year heroin use\n\nSource: Substance Abuse and Mental Health Services Administration. (2018). Key substance use and mental health indicators in the United States: Results from the 2017 National Survey on Drug Use and Health (HHS Publication No. SMA 18-5068, NSDUH Series H-53). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www. samhsa.gov/data/.\n\n5", "n_tokens": 192, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-5-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 5, "text": "Consequences: Prescription Opioids and Overdose Death in the US\n\nFigure Source: National Institute on Drug Abuse Data Source: CDC Wonder Available from: https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates\n\nwww.fda.gov\n\n6", "n_tokens": 59, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-6-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 6, "text": "Sources of the Opioid Crisis\n\nPrescribed opioids pose a risk beyond the patient who receives the prescription\n\nAmong people who abuse prescription opioids, most get them – From a friend or relative for free (55%) – Prescribed by a physician (20%) – Bought from a friend or relative (11%)\n\nAmong new heroin users, about three out of four report abusing prescription opioids before using heroin.\n\nhttps://www.cdc.gov/drugoverdose/data/prescribing.html\n\nwww.fda.gov\n\n7\n\n7", "n_tokens": 116, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-7-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 7, "text": "Crisis Ongoing Despite Falling # of Prescriptions for Opioid Analgesics\n\nSource: IQVIA, National Prescription Audit (NPA) and static data 2006-2011. January 2006-December 2017. Static data extracted March 2017 and 2012-2017 data extracted February 2018. *Immediate-Release formulations include oral solids, oral liquids, rectal, nasal, and transmucosal **Extended-Release/Long-Acting formulations include oral solids and transdermal patches Note: Include opioid analgesics only, excluding injectable formulations as well as opioid-containing cough-cold products and opioid-containing medication-assisted treatment (MAT) products\n\nwww.fda.gov\n\n8", "n_tokens": 145, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-8-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 8, "text": "The FDA and Opioid Abuse/Misuse\n\n\"Unquestionably, our greatest immediate challenge is the problem of opioid abuse. This is a public health crisis of staggering human and economic proportion … we have an important role to play in reducing the rate of new abuse and in giving healthcare providers the tools to reduce exposure to opioids to only clearly appropriate patients, so we can also help reduce the new cases of addiction.“\n\n--Scott Gottlieb, FDA Commissioner Address to FDA staff, May 15, 2017\n\nwww.fda.gov\n\n9", "n_tokens": 114, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-9-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 9, "text": "www.fda.gov\n\nThe Opioid Challenges:\n\nOpioid Abuse and Misuse Pain in America Injectable Opioid Shortages", "n_tokens": 28, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-10-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 10, "text": "Equally Critical Social and Medical Issue: Pain in America\n\nFrom the Functioning and Disability Supplement of the 2012 National Health Interview Survey – 126.1 million adults reported some pain in the previous\n\n3 months\n\n25.3 million adults (11.2%) suffering from daily (chronic) pain\n\n23.4 million (10.3%) reporting a lot of pain. – Based on the persistence and bothersomeness of their pain, 14.4 million adults (6.4%) were classified as having the highest level of pain, category 4, with an additional 25.4 million adults (11.3%) experiencing category 3 pain.\n\nwww.fda.gov\n\nNahin RL, J.Pain, 2015 Aug;16(8):769-80\n\n11", "n_tokens": 154, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-11-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 11, "text": "Pain in America (cont)\n\nTreatment options for pain: pharmacologic, physical medicine, behavioral medicine, neuromodulation, interventional, and surgical\n\nOptimal patient outcomes often result from a comprehensive multidisciplinary approach where pharmacologic treatment is not the sole focus\n\nPatients experience ongoing barriers to adequate pain management – “many related to non-existent or insufficient insurance\n\ncoverage and reimbursement for evidence- and consensus- based therapies”\n\n-American Academy of Pain Medicine, 2014\n\nAs a result, treatments have largely focused on prescription drugs, mainly opioids, and procedures, at least, in part, because of the reimbursement structure of our healthcare system\n\n12\n\n12", "n_tokens": 143, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-12-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 12, "text": "The Opioid Crisis: FDA’s Priorities\n\n1. Decreasing Exposure & Prevent New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\nwww.fda.gov\n\n13", "n_tokens": 59, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-13-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 13, "text": "The Opioid Crisis: FDA’s Priorities & Strategies\n\n1. Decreasing Exposure & Prevent New Addiction\n\n Appropriate Dose/Duration Labeling  Appropriate Packaging, Storage, and Disposal  Health Care Provider Education 2. Supporting the Treatment of Those With Opioid Use Disorder \n\nNaloxone Medication Assisted Treatment (MAT)\n\n3. Fostering the Development of Novel Pain Treatment Therapies  Partnerships & Meetings  Abuse Deterrent Formulations (ADFs)  Pain Treatment Alternatives 4. Improving Enforcement & Assessing Benefit-Risk Assessing Benefit-Risk\n\n14", "n_tokens": 101, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-14-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 14, "text": "FDA Priorities Align with Recently Passed SUPPORT Act\n\nSubstance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act\n\nMany new provisions affecting FDA including tools to:\n\nmore efficiently stop illegal, illicit, unapproved, counterfeit and potentially dangerous drugs from entering the U.S. through the IMFs\n\nreduce exposure to opioids as a way to lower the rate of new addiction\n\nrequire certain packaging, such as unit dose blister packs, for opioids and other drugs that pose a risk of abuse or overdose – require that opioids be dispensed with a mail-back pouch or other\n\nsafe disposal option Implementation ongoing\n\nhttps://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624268.htm\n\nwww.fda.gov\n\n15", "n_tokens": 172, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-15-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 15, "text": "Example: Decreasing Exposure & Preventing New Addiction\n\nHOW?\n\nWHAT?\n\n\n\nAppropriate Packaging, Storage, and Disposal\n\nExplore how opioid analgesic drug products are packaged, stored, and discarded. Examine use of packaging strategies, such as unit-of-use packaging to improve opioid analgesic safety.\n\nJun 1, 2017: FDA/Duke Margolis workshop and white paper on packaging, storage, and disposal solutions.\n\nDec 11-12, 2017: Public\n\nworkshop to gain input on packaging strategies. Public docket closed March 2018 with 44 comments. Jan 2018: Requested packaging in limited amounts of over-the- counter anti-diarrheal medicine loperamide to curb intentional misuse and abuse.\n\n16", "n_tokens": 145, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-16-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 16, "text": "Opioid Analgesic Needs Vary by Condition/Procedure\n\nProcedure\n\nMean/ (range) tablets filled\n\nMean/Median tablets consumed\n\n~Days Used\n\nOutpatient Shoulder Surgery\n\n60 (n.d.)*\n\n37 (n.d.)*\n\n9-10\n\nCesarean Delivery\n\n40 (5-80)*\n\n20*\n\n4-5\n\nTooth Extraction\n\n28 (n.d.)\n\n13\n\n2-3\n\nUpper Extremity Surgery\n\n30 (n.d.)\n\n14 (Bone); 9 (Soft Tissue)\n\n2-3\n\nLaparoscopic Cholecystectomy\n\n30 (0-100)\n\n10-12\n\n2-3\n\nLaparoscopic Appendectomy\n\n30 (n.d.)*\n\n12*\n\n2-3\n\nPartial Mastectomy with Node Biopsy\n\n23 (0-60)\n\n6\n\n1-2\n\nLaparoscopic Inguinal Hernia Repair\n\n33 (15-70)\n\n9\n\n1-2\n\nOpen Inguinal Hernia Repair\n\n30 (15-120)\n\n9\n\n1-2\n\nPartial Mastectomy\n\n21 (0-50)\n\n3\n\n1\n\nDermatologic Surgery\n\n9 (3-20)\n\n4\n\n1\n\nHill, et al., Ann Surg, 2017 1. Bateman, et al., Obstet Gyn, 2017 2. 3. Maughan, et al., Drug Alc Dep, 2016\n\n4. Harris, et al., JAMA Dermatol. 2013 5. Bockman, et al. J Pain, 2017 (Abstract) 6. Kumar, et al. AJSM, 2017\n\n~Leftover tablets\n\n23\n\n20\n\n15\n\n15\n\n20\n\n18\n\n17\n\n24\n\n21\n\n18\n\n5\n\n17", "n_tokens": 327, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-17-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 17, "text": "Target: Leftover Opioid Analgesics Reported in Post-surgical Populations\n\nAcross many surgical procedures,  >50% of patients\n\nreported excess supply of opioid analgesics after treatment of acute pain\n\napercentage of patients reporting use of 15 tablets or fewer\n\n Most patients kept excess supply and stored supply in unsecured locations\n\nFigure Source: Bicket MC, Long JJ, Pronovost PJ, Alexander GC, Wu CL. Prescription Opioid Analgesics Commonly Unused After Surgery: A Systematic Review. JAMA Surg. 2017 Nov 1;152(11):1066-1071.\n\nwww.fda.gov\n\n18", "n_tokens": 133, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-18-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 18, "text": "Issue: Opioid Analgesics in the Home Can Feed Other Problems if Misused\n\nExcess Supply after Treatment of Acute Pain\n\nAvailable Supply\n\nThird Party Access\n\nMisuse and Related Outcomes\n\nNon-Secure Storage\n\nLack of Disposal\n\nwww.fda.gov\n\nAccidental Exposure\n\n19", "n_tokens": 50, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-19-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 19, "text": "FDA Response: Potential Work on Packaging\n\nExploring whether a defined, short-term supply of medication could be packaged in a manner that limits the number of pills dispensed (e.g., blister packs)\n\nExploring packaging that could make it easier to track the number of doses that have been taken or reduce the risk for third-party access, such as teens ingesting pills they found in a medicine cabinet • Work to improve storage and encourage prompt disposal to reduce the available supply of unused opioids\n\nwww.fda.gov\n\n20", "n_tokens": 110, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-20-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 20, "text": "FDA Response: Improved Data on Opioid Use\n\nContract with National Academies of Science, Engineering and Medicine (NASEM)\n\nWork:\n\nProvide best available evidence for prescribers\n\nDevelop framework for evaluating the evidence base on opioid use in specific therapeutic conditions\n\nInventory available evidence • Develop research agenda\n\nSupport development of new evidence where needed\n\nwww.fda.gov\n\n21", "n_tokens": 70, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-21-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 21, "text": "Other Packaging Work– OTC Loperamide Abuse\n\nSafe and effective for diarrhea when used as directed – Crohn’s Disease and Ulcerative Colitis\n\n~ 1.6 M people – Irritable Bowel Disease • ~ 35 M people\n\nSupra-therapeutic doses are abused and are linked to unusual and potentially fatal cardiac arrhythmia (Torsade de Pointes)\n\nFDA actions aim to prevent the abuse while preserving maximum access possible for patients\n\nwww.fda.gov\n\n22", "n_tokens": 103, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-22-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 22, "text": "FDA Actions on Loperamide to Date\n\nSafety communications highlighting risk of cardiac toxicity with loperamide abuse – https://www.fda.gov/drugs/drugsafety/ucm594232.htm\n\nStakeholder engagement\n\nConsumer Health Products Association (CHPA)\n\nSupplement request letters sent to NDA manufacturers requesting unit-dose packaging and package size limitations – F/U Discussions with individual retailers\n\nOngoing discussions about the appropriate limits for online sales\n\n23", "n_tokens": 93, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-23-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 23, "text": "SAFE OPIOID DISPOSAL AND\nSTORAGE\n\n24", "n_tokens": 8, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-24-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 24, "text": "Example: Decreasing Exposure & Preventing New Addiction\n\nHOW?\n\nWHAT?\n\n\n\nAppropriate Packaging, Storage, and Disposal\n\nExplore how opioid analgesic drug products are packaged, stored, and discarded. Examine use of packaging strategies, such as unit-of-use packaging to improve opioid analgesic safety.\n\nJun 1, 2017: FDA/Duke Margolis workshop and white paper on packaging, storage, and disposal solutions.\n\nDec 11-12, 2017: Public\n\nworkshop to gain input on packaging strategies. Public docket closed March 2018 with 44 comments. Jan 2018: Requested packaging in limited amounts of over-the- counter anti-diarrheal medicine loperamide to curb intentional misuse and abuse.\n\n25", "n_tokens": 145, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-25-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 25, "text": "Opioids and Drug Disposal\n\nPart of Federal efforts to educate consumers about appropriate disposal of unused/unneeded drugs • FDA’s drug disposal webpage is consistently among the most viewed webpages on FDA’s website • FDA updated the disposal webpage on April 23,\n\n2018 – New infographic – New scientific research on environmental impact of drugs\n\nThe website received 23,580 unique pageviews during week of April 23, 2018 leading up to DEA’s National Rx Drug Take Back Day on April 28, 2018\n\nwww.fda.gov\n\n26", "n_tokens": 111, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-26-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 26, "text": "Drug Disposal (cont)\n\nwww.fda.gov/drugdisposal\n\n27", "n_tokens": 17, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-27-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 27, "text": "Opioids and Drug Disposal: Drug Takeback Day\n\nNationwide effort to get unneeded drugs out of homes\n\nApril 2018-- 348 pounds of drugs returned at FDA main campus\n\nwww.fda.gov\n\n28", "n_tokens": 42, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-28-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 28, "text": "This opioid disposal education and outreach campaign, with digital toolkits available in English and Spanish, can be used when talking with others about safe opioid disposal.\n\n29", "n_tokens": 36, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-29-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 29, "text": "www.fda.gov\n\nTarget Audience\n\nWomen ages 35–64 who are caring for their children, grandchildren, and/or aging parents.\n\nAccording to the Department of Labor, women make 80% of health care decisions for their families • An estimated 66% of caregivers are female and are likely to be the gatekeepers to opioids in the home, knowing where they are stored and how they should be dosed for various family members\n\n30", "n_tokens": 89, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-30-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 30, "text": "www.fda.gov\n\nVideo PSAs\n\nKeep Your Family Safe From Unused Opioid Pain Medicines (0:30)\n\nMedicamentos opioides no utilizados: Mantenga a su familia segura (0:30)\n\n31", "n_tokens": 54, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-31-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 31, "text": "www.fda.gov\n\nEXPANDED NALOXONE AVAILABILITY AND USE\n\n32", "n_tokens": 14, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-32-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 32, "text": "The Opioid Crisis: FDA’s Priorities & Strategies\n\n1. Decreasing Exposure & Prevent New Addiction\n\n Appropriate Dose/Duration Labeling  Appropriate Packaging, Storage, and Disposal  Health Care Provider Education 2. Supporting the Treatment of Those With Opioid Use Disorder \n\nNaloxone Medication Assisted Treatment (MAT)\n\n3. Fostering the Development of Novel Pain Treatment Therapies  Partnerships & Meetings  Abuse Deterrent Formulations (ADFs)  Pain Treatment Alternatives 4. Improving Enforcement & Assessing Benefit-Risk Assessing Benefit-Risk\n\n33", "n_tokens": 101, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-33-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 33, "text": "Recent and Ongoing Activities Related to Naloxone\n\nCo-prescribing of Naloxone with RX Opioids\n\nResults of recent public FDA Advisory Committee\n\nOver-the-Counter (OTC) Naloxone\n\nResearch to support labeling for OTC naloxone products to support product development\n\nwww.fda.gov\n\n34", "n_tokens": 69, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-34-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 34, "text": "2. Supporting the Treatment of Those With Opioid Use Disorder (OUD)\n\nHOW?\n\nWHAT?\n\n\n\nNaloxone\n\nExploring ways to expand access to naloxone and facilitate the switch to OTC naloxone\n\nJan 2019: Precedent setting: Announced results of FDA-led labeling study to facilitate the switch from prescription to OTC naloxone.\n\n35", "n_tokens": 75, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-35-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 35, "text": "I. Naloxone Co-Prescribing with Rx Opioids\n\nNaloxone prescriptions rising (336.1K dispensed in\n\n2017) but still inadequate\n\nFDA received Citizen Petition from maker of one of the naloxone products requesting FDA require co- prescribing of patients prescribed opioids\n\nFDA Advisory Committee held December 17-18 to get input from advisors and public\n\nwww.fda.gov\n\n36", "n_tokens": 91, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-36-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 36, "text": "Naloxone Advisory Committee (cont)\n\nIn general:\n\nHarm reduction advocacy groups very strong in their view that co-prescribing was not ‘enough’ – Committee members split on value of required co- prescribing • Concerns expressed about cost to healthcare system and\n\ndiversion of resources (both money and naloxone) away from underserved areas\n\nFocus should be on educating prescribers/patients and supporting harm reduction efforts\n\nIn addition, Committee members called on USG to take on broader actions to expand availability of naloxone (e.g., OTC naloxone)\n\nFDA considering next steps\n\nwww.fda.gov\n\n37", "n_tokens": 135, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-37-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 37, "text": "II. Over-The-Counter Naloxone\n\nExisting expanded access programs (such as pharmacy standing order programs) are a significant tool, but more is needed – not everyone can/wants to obtain the product through a healthcare professional\n\nSurgeon General’s 2018 Advisory\n\nwww.fda.gov\n\n38", "n_tokens": 58, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-38-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 38, "text": "U.S. Surgeon General Advisory\n\n“I, Surgeon General of the United States Public Health Service, VADM Jerome Adams, am emphasizing the importance of the overdose-reversing drug naloxone. For patients currently taking high doses of opioids as prescribed for pain, individuals misusing prescription opioids, individuals using illicit opioids such as heroin or fentanyl, health care practitioners, family and friends of people who have an opioid use disorder, and community members who come into contact with people at risk for opioid overdose, knowing how to use naloxone and keeping it within reach can save a life.”\n\nwww.fda.gov\n\n39", "n_tokens": 139, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-39-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 39, "text": "Development Programs for Nonprescription Drugs\n\nOften rely on safety and efficacy established for the prescription product\n\nNew studies may be required if proposing a new indication or a new patient population for the OTC market\n\nNeed to “translate” key elements of the prescription label into consumer-friendly terms\n\nConsumer studies needed to evaluate the “OTC-ness” of product\n\nwww.fda.gov\n\n40", "n_tokens": 75, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-40-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 40, "text": "Translate the Approved RX Product Label....\n\n41", "n_tokens": 12, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-41-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 41, "text": "To a Label for OTC Products…..\n\nDrug Facts Label\n\n42", "n_tokens": 14, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-42-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 42, "text": "FDA Support for OTC Naloxone\n\nWith successful study results, Sponsors can adapt the model Drug Facts Labe (DFL) to their naloxone product\n\nSpeeds development\n\nSponsors would only need to add information specific to their particular device and assess through human factors\n\nLabel comprehension was the key study to be conducted – self-selection and actual use are likely not needed\n\nwww.fda.gov\n\n43", "n_tokens": 79, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-43-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 43, "text": "Status of Research\n\nFDA-supported study completed December 2018\n\nReview by FDA scientists complete January 2019 – FDA concluded that the results of this study are acceptable to support use of the tested naloxone DFL in the OTC setting\n\nFDA announced results and findings for use by manufacturers seeking to develop OTC naloxone products • Data and drug facts boxes posted\n\nhttps://www.fda.gov/NewsEvents/Newsroom/PressAnnounceme nts/ucm629571.htm\n\nwww.fda.gov\n\n44", "n_tokens": 111, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-44-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 44, "text": "Drug Facts\n\nActive ingredient (in each XX) Purpose\nNaloxone hydrochioride X ma Emergency treatment of opioid overdose\n\nUses\n\n‘+ To revive” someone during an overdose from many prescription pain medications or street\ndrugs such as heroin\n\n+ _This medicine can save a life\n\nDirections\n\nStep 1: CHECK:\n\n+ CHECK for a suspected overdose. the person will not wake\nup or is very sleepy or not breathing well\n\n© yell ‘Wake up!\"\n‘© shake the person gently\n\n© if he person is not awake. go to Step 2\n\nStep 2; GIVE 1\" dose\n+ GIVE the 1% dose of this medicine\n\n+ place the injector on the LEG above the knee and press\ndown\n\nStep 3: CALL\n\n© GALL 911 immediately ater giving the 1\" dose\n\nStep 4: WATCH & GIVE\n\n© WAIT 2-3 minutes after the 1* dose to give the medicine\ntime to work\n\n‘+ ifthe person wakes up: Go to Stop 5\n‘+ ithe person does not wake up\n\n. TINUE TO GIVE doses every 2-3 minu\nthe person wakes up\n\n+ itis safe to keep giving doses\n\nStep 5: STAY\n‘+ STAY unill ambulance arrives: even if the person wakes up\n\n+ GIVE another dose if the person becomes very sleepy again\n\nYou may need to give all the doses in the pack.\n\nWamings\nWhen using this product some people may experience symptoms when they wake up. such\na8 shaking, sweating, nausea, 0: feeling angry. This is to be expected\n\nOther informations store at room temperature + [advise inser tamper evident statement here]\n\nInactive Ingredients\n\nQuestions?\n\nphone number, website)\n\nPrototype Drug Facts\nBox for OTC Naloxone", "n_tokens": 337, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-45-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 45, "text": "The Opioid Challenges:\n\nOpioid Abuse and Misuse Pain in America Injectable Opioid Shortages", "n_tokens": 23, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-46-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 46, "text": "Shortages of Injectable Opioids\n\nOpioid shortages leave US hospitals\n\nscrambling\nIn the midst of a massive opioid crisis,\n~~ hospitals are experiencing an opioid\n\n: California te:\nla swosate SHOrtage\n\nUtah teen ge By Aaron Schachter\n\nlife for helpin\nherself\n\nHealthiest Communities The Civic Report Photos News\n\nHospitals Face Prolonged Injected Opioid Shortage\n\nThe other opioid crisis: Hospitals are frequently running out of widely used injected painkillers, and some patients are feeling the pain.\n\nHEALTHCARE OF TOMORRC\n\nThe health care industry is evolving, thanks,\n\nWe ar\nWoule 47", "n_tokens": 122, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-47-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 47, "text": "Origins of the IV Opioids Shortage\n\nCritical need for use in post-op settings • One large manufacturer reported shortages of multiple critical drugs including injectable hydromorphone and morphine due to manufacturing, distribution, third party supplier delays, as well as remediation efforts at one of their facilities, beginning in July of 2017\n\nLack of alternative sources for needed products with sufficient capacity to meet added demand\n\nwww.fda.gov\n\n48", "n_tokens": 87, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-48-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 48, "text": "FDA Work to Address IV Opioids Shortage\n\nFDA working with manufacturers to bring additional products to market\n\nExpediting review of all related applications – new approvals from two other manufacturers for morphine and hydromorphone are now being launched\n\nReleasing Carpuject syringes with potential cracked needle hubs under regulatory discretion with instructions for healthcare professionals to inspect and withdraw contents with a filter needle before administering to patients\n\nExtending expiration dating for multiple opioid products listed on the FDA website based on data from the manufacturer\n\nAllowing temporary import of unapproved hydromorphone in coordination with DEA\n\n49\n\n49", "n_tokens": 119, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-49-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 49, "text": "FDA Response to IV Opioids Shortage (cont)\n\nCoordinating with DEA on quota issues\n\nFDA shares information with DEA through a Memorandum of Understanding\n\nProviding a market assessment to DEA to assist them in their decision about whether to grant the quota\n\nwww.fda.gov\n\n50\n\n50", "n_tokens": 53, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-50-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 50, "text": "Trends in New Drug Shortages 2010-2017\n\nFrom FDA Drug Shortage Report to Congress, 2017 https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM610662. pdf\n\nwww.fda.gov\n\n51", "n_tokens": 53, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-51-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 51, "text": "What FDA Does to Address Drug Shortages\n\nDrug Shortage Staff focused on addressing drug shortages\n\nFacilitate temporary and long-term strategies to address shortages\n\nCoordinate timely and comprehensive risk/benefit decisions within FDA\n\nPersonnel across multiple FDA Offices involved in shortage response\n\nDistribute information (web posting, professional organizations): • https://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm\n\nGoal: Maintain availability while minimizing risk to patients 52", "n_tokens": 91, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-52-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 52, "text": "What FDA Cannot Do to Address Drug Shortages\n\nFDA cannot require:\n\nA company to disclose details of why a shortage occurs\n\nA company to make a drug • A company to make more of a drug • How much and to whom the drug is distributed\n\nwww.fda.gov\n\n53", "n_tokens": 53, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-53-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 53, "text": "Lessons Learned\n\nAvailability of drugs for patients is critical for healthcare – Interruptions of drug manufacturing due to any\n\nreason can lead to drug shortages with devastating impact on public health\n\nSources of drug shortages include manufacturing challenges and natural disasters – FDA response tailored to address underlying cause(s) – Communications and information sharing are critical both\n\nto preventing and to mitigating shortages\n\nRecovery from shortages takes time. Prevention is critical to reducing the numbers of drug shortages\n\nwww.fda.gov\n\n54", "n_tokens": 91, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-54-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 54, "text": "Ongoing FDA Shortage Work\n\nFDA Drug Shortage Taskforce\n\nAnnounced July 2018 • Goal of improved understanding of the forces leading to drug shortages and identify potential solutions\n\nStakeholder Listening Sessions  Pharmacies and Hospitals  Manufacturing Groups  Medical Groups  GPO’s and Distributors\n\nPublic meeting November 2018\n\nTaskforce Members\n\nFood and Drug Administration (CDER, CBER, CDRH, ORA) • Center for Medicare and Medicaid Services • The Office of the Assistant Secretary of Preparedness and Response • The Department of Veterans Affairs • The Department of Defense • The Federal Trade Commission 55\n\nFood and Drug Administration (CDER, CBER, CDRH, ORA) • Center for Medicare and Medicaid Services • The Office of the Assistant Secretary of Preparedness and Response • The Department of Veterans Affairs • The Department of Defense • The Federal Trade Commission 55", "n_tokens": 164, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-55-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 55, "text": "FDA Will Use All of its Available Tools to Accomplish These Goals\n\nImproving the safe use of opioids through careful and appropriate regulatory activities\n\nImproving the safe use of opioids through careful and appropriate policy development • Improving the treatment of pain through\n\nimproved science\n\nImproving the safe use of opioids through communication, partnership and collaboration\n\nwww.fda.gov\n\n56", "n_tokens": 69, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-56-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 56, "text": "Solutions Must Come from Many Sources • FDA is one of many Federal agencies addressing issues involving opioids\n\nMany Federal Agencies working together on issue\n\nEach state has programs to address opioids\n\nGuidelines and educational programs are available from specialty societies and State Medical Boards\n\nHealthcare institutions • Advocacy groups • • Patients (n = millions)\n\nIndividual providers (n = 800,000+)\n\nwww.fda.gov\n\n57", "n_tokens": 78, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-57-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 57, "text": "Conclusions\n\nFDA’s response to issues raised by opioids reflect unique challenges of how they are used, misused and abused\n\nOpioids are challenging on many fronts, and FDA is seeking to balance the appropriate need for them by patients with the crisis of opioid abuse and overdose\n\nOngoing and planned FDA activities will utilize all of our existing tools to forcefully address the opioid crisis while continuing to support appropriate access to effective pain management\n\nwww.fda.gov\n\n58", "n_tokens": 93, "kind": "text"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-58-0", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 58, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-0-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 0, "text": "www.fda.gov\n\nState of CDER\n\nPatrizia Cavazzoni, MD Director Center for Drug Evaluation and Research U.S. Food and Drug Administration FDLI Annual Conference May 20, 2021", "n_tokens": 42, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-1-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 1, "text": "Pandemic Response\nHighlights", "n_tokens": 5, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-2-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 2, "text": "Facilitating Development of COVID-19 Therapeutics\n\n➢ Coronavirus Treatment Acceleration Program (CTAP)\n\n▪ 440+ trials reviewed by FDA\n\n▪ 600+ development programs for therapeutic agents in the\n\nplanning stages\n\n▪ 1000+ Expanded Access requests\n\n▪ 1 approved treatment\n\n▪ 10 treatments under emergency use authorization\n\n➢ 22+ guidances on clinical development for COVID-19\n\ntherapeutics\n\n3", "n_tokens": 71, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-3-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 3, "text": "Supply Chain Surveillance\n\nExpanded CDER’s drug shortage program to include supply chain surveillance\n\n Integrates data to help assess risk to critical medicines to treat COVID-19 aiming for earlier detection and response to supply disruptions\n\n Provides visibility into availability, supply, and demand\n\n Used to address drug shortages  We are enhancing this system by investigating additional data\n\nsources and advanced analytics\n\n Phased process to expand coverage to additional\n\nproducts\n\n4", "n_tokens": 78, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-4-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 4, "text": "Drug Supply Chain Signal Detection\n\nSupply chain surveillance is based on examining multiple signals for supply chain disruption\n\nDrug Identification Identify critical drugs for supply chain surveillance\n\nIntegrated Supply Chain Assessment Conduct analysis based on integrated data on key signals to determine if a drug is vulnerable to supply chain disruptions\n\nFacility Quality\n\nSole Source\n\nSupply Chain Diversification\n\nPurchasing Trends\n\nClinical Trial Impact\n\nRecalls\n\nHistoric Shortage\n\nCurrent Shortage\n\nProjected Demand\n\nHospital Utilization\n\nMitigation and Management Conduct additional review for drugs with signals of supply chain disruptions\n\n5", "n_tokens": 92, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-5-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 5, "text": "Enforcement Against Fraudulent COVID-19 Claims\n\nThe Challenge: Protecting patients when the market is flooded with products making unproven claims. Products are unlawful and put patients at risk.\n\n(Examples: chlorine dioxide, colloidal silver, CBD, copper, honey, botanical oils)\n\nActions Taken:\n\n Issued 113 warning letters for products claiming to treat COVID-19\n\n Issued 15 warning letters to Internet pharmacies claiming to treat\n\nCOVID-19\n\n Removal of contaminated hand sanitizer products\n\n6", "n_tokens": 99, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-6-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 6, "text": "Meeting User-Fee Goals During The Pandemic\n\nCDER is on-track to meet most review performance goals despite constraints around on-site inspections\n\nWe have been conducting mission-critical and prioritized inspections and increasingly relying on alternative approaches:\n\n Reviewing facilities’ inspection history to assess feasibility of relying on\n\nrecords or trusted-partner inspections\n\n Requesting records or other information directly from facilities in lieu\n\nof drug and biological product inspections\n\n Remotely evaluating operations by livestreamed video; other remote\n\nor live interactions with facility operators\n\n7", "n_tokens": 99, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-7-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 7, "text": "Meeting User-Fee Goals During The Pandemic\n\n Published Remote Interactive Evaluations of Drug Manufacturing and Bioresearch Monitoring Facilities During the COVID-19 Public Health Emergency, Guidance for Industry (April 2021)\n\n Published guidance that answers FAQs on impact of travel restrictions on application review, CDER’s use of alternate tools for inspections, other supply chain and inspection topics (August 2020)\n\n From March 2020 - March 2021, use of alternative tools informed:\n\n➢ 150 ANDA, 84 NDA, 11 BLA\n\n➢ These actions included: 41 ANDA approvals, 59 NDA approvals, 11\n\nBLA approvals\n\n8", "n_tokens": 127, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-8-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 8, "text": "Programmatic\nUpdates", "n_tokens": 3, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-9-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 9, "text": "User-Fee Reauthorization\n\n User fees account for about 70% of CDER’s annual budget\n\n The current, 5-year authorization for PDUFA, GDUFA and BSUFA runs\n\nthrough FY22\n\n FDA and industry are engaged in reauthorization activities for PDUFA VII,\n\nGDUFA III and BSUFA III\n\n Public meetings to present the proposed reauthorization packages will\n\noccur later this year\n\n FDA will then deliver the proposed packages to Congress in January\n\n New UFA program – Implementation of OTC Monograph User Fee Act\n\n(OMUFA)\n\n10", "n_tokens": 117, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-10-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 10, "text": "Steps to Quality Management Maturity (QMM)\n\n Current Good Manufacturing Practice (CGMP)\n\nestablishes a minimum standard for systems that assure proper design, monitoring, and control of manufacturing processes and facilities\n\nCGMP\n\nICH Q10\n\nQMM\n\n ICH Q10 outlines an effective pharmaceutical quality system applied throughout the product lifecycle to facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities\n\n Quality Management Maturity (QMM) fully\n\nrealizes the 21st century pharmaceutical quality vision requiring a transparent method of evaluating and communicating the maturity of the quality management system\n\n11", "n_tokens": 108, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-11-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 11, "text": "Quality Management Maturity (QMM)\n\n Multidisciplinary, multi-center working group to facilitate the\n\ndevelopment of a QMM rating program for drug manufacturers\n\n Two pilot programs\n\n One focused on domestic manufacturers of finished dosage form\n\nproducts\n\n One focused on foreign manufacturers of active pharmaceutical\n\ningredients\n\n Site assessments to begin in May; pilots to end at the end of September\n\n CDER will use the information from the pilots and other information to formalize criteria to objectively measure a manufacturing site’s QMM\n\n12", "n_tokens": 97, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-12-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 12, "text": "CDER’s Technology Modernization Roadmap\n\nWe are leveraging integrated technology capabilities to support and modernize CDER’s internal operations\n\nThese technology capabilities for data intake, workflow management and analytics will support multiple priority initiatives across the center\n\nPortal for data intake from external stakeholders including sponsors\n\nKnowledge Aided Structured Assessment (KASA)\n\nWorkflow management for\n\nautomating CDER’s internal work processes and capture key decisions and knowledge\n\nModernization of new drug review • OMUFA work process support • Drug supply chain surveillance improvements\n\nAnalytics capabilities to support decision-making\n\nSafety signal management\n\n13", "n_tokens": 113, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-13-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 13, "text": "Post-market Safety Modernization Lifecycle Signal Tracker (LiST)\n\n Modernizes and streamlines tracking of safety signals across a drug product’s lifecycle  Enables tracking of safety signals with improved interdisciplinary collaboration and\n\neasy access to all safety signal-related documents in one location\n\n Launched in April 2020\n\nOpen a Safety Signal\n\nTriage a Safety Signal\n\nForm Safety Team and Assign Risk Classification\n\nNotify Sponsors\n\nUploads Reviews\n\nMake Final Recommen dation\n\nTake Action\n\nPre- evaluation Phase\n\nEvaluation Phase\n\nAction Phase\n\n14", "n_tokens": 96, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-14-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 14, "text": "International Convergence Work on Product Quality\n\n Harmonizing standards internationally\n\n Worked to finalize several International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines including on pharmaceutical product lifecycle management\n\n Working to secure ICH endorsement to pursue guideline work to\n\nadvance patient focused drug development\n\n CDER led the ICH group that developed a new draft ICH Guideline integrating the nonclinical (S7B) and clinical (E14) assessment of cardiac safety for new drugs\n\n Focuses on using mechanistic nonclinical assays to reduce the\n\nneed for clinical trials\n\n15", "n_tokens": 113, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-15-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 15, "text": "Complex Generic Programs\n\nPre-ANDA Program Collaborate early for long-term success\n\nCenter for Research on Complex Generics Enhance research collaborations with industry\n\n16", "n_tokens": 28, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-16-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 16, "text": "Since 2008, 100+ Complex Generic Approvals Annually\n\nNotable First Complex Generic Approvals\n\nGlucagon for injection (RLD: Glucagon)\n\nFerumoxytol injection (RLD: Feraheme)\n\nImiquimod cream (RLD: Zyclara)\n\nTreats severe hypoglycemia\n\nTreats iron deficiency anemia\n\nTreats actinic keratoses and external genital and perianal warts\n\n28 Dec. 2020\n\n15 Jan. 2021\n\n26 Jan. 2021\n\nLinaclotide capsules (RLD: Linzess)\n\nTreats IBS and chronic idiopathic constipation\n\n9 Feb. 2021\n\nLoteprednol etabonate ophthalmic gel (RLD: Lotemax)\n\nTreats post-operative inflammation and pain following ocular surgery\n\n10 Feb. 2021\n\n17", "n_tokens": 168, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-17-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 17, "text": "Opioids: Impact of COVID-19\n\nSince the start of the pandemic, opioid overdose deaths have accelerated – largely from illicit fentanyl\n\nProvisional data on overdose deaths before and during COVID-19 pandemic (past 12-month totals) Source: Data extracted 2/26/2021 from NVSS Dashboard: https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm#dashboard\n\n18", "n_tokens": 101, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-18-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 18, "text": "Bolstering Our Efforts to Fight the Opioid Epidemic\n\nDecrease exposure and Prevent New Addiction\n\nSupport the Treatment of those with Opioid Use Disorder\n\nFoster the Development of Novel Pain Treatment Therapies\n\nImprove Enforcement and Assess Benefit-Risk\n\n19", "n_tokens": 47, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-19-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 19, "text": "FDA Supports Efforts to Expand Access to Buprenorphine Treatment for OUD\n\nImproving access and availability will positively impact public health\n\nFDA recognizes that there are barriers to treatment – a complex, multi-faceted problem\n\nStigma against people with OUD and against MOUD permeates social and cultural attitudes but can also be found within institutional practices and regulations\n\nPrioritizing education and training for treating patients with OUD, in both health professional schools and treatment settings, will be critical for improving buprenorphine access\n\n20", "n_tokens": 101, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-20-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 20, "text": "Bringing Therapies to Underserved Populations with Unmet Medical Needs\n\n Areas of focus include:\n\nRare diseases and Neurodegenerative diseases\n\nInfectious/Emerging/Neglected Diseases\n\nBiosimilar insulin\n\n21", "n_tokens": 40, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-21-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 21, "text": "Rare Diseases\n\n 58% of all new drug approvals\n\nin CDER for 2020\n\n 31 Approved NMEs with\n\nOrphan Designation in 2020\n\n 29 of the 31 (94%) novel\n\norphan approved used one or more expedited program\n\n A record-breaking 284\n\npediatric rare-disease designation requests\n\n22", "n_tokens": 55, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-22-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 22, "text": "Rare Diseases\n\n In 2020, new orphan treatments for:\n\n Hutchinson-Gilford Progeria Syndrome\n\n Hereditaryangioedema\n\n CAR T cell therapy for mantle cell lymphoma\n\n Factor to control bleeding in patients with Hemophilia A or B\n\nwith inhibitors\n\n Orphan Drug Technology Modernization effort\n\n CDER’s Rare Disease Development Council\n\n Rare Disease Cure Accelerator\n\n23", "n_tokens": 68, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-23-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 23, "text": "Insulin Gains New Pathway to Increase Competition\n\n Insulin and certain other biologic drugs transitioned to a\n\ndifferent regulatory pathway (March 2020)\n\n Availability of safe and effective biosimilar and\n\ninterchangeable versions of these treatments is expected to increase patient access, adding more choices and potentially reducing costs\n\n Opens a pathway for products that are proposed as\n\nbiosimilar to, or interchangeable with, the transitioned products, including insulin\n\n24", "n_tokens": 81, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-24-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 24, "text": "Looking Forward\n\nWe have continued to acquire talent during the pandemic and attrition has been lower\n\nThe success of large platform trials and use of clinical networks will likely shape future research\n\nWe have all become much more familiar with video- interaction and other interactive technology\n\nWe have gained experience in the use of decentralized clinical trials\n\nThe importance of enrolling a diverse clinical population and understanding the barriers to achieving that goal is front and center\n\nWe have expanded our tools to evaluate manufacturing facilities and investigative sites\n\nRWE played a central role in understanding COVID-19, generating hypothesis and in the safety monitoring of therapeutics\n\n25", "n_tokens": 121, "kind": "text"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-25-0", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 25, "text": "Thank You\nTo The\nCDER Team!", "n_tokens": 8, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-0-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 0, "text": "STATE OF OGD: Pivoting to GDUFA II\n\nKathleen Uhl, MD Director, Office of Generic Drug CDER/FDA\n\nAAM Fall Technical Conference November 6, 2017\n\n1", "n_tokens": 38, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-1-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 1, "text": "Disclaimer\n\nThis presentation reflects the views of the speaker and do not reflect official FDA, HHS, or other government opinion or policy.\n\nI have nothing to disclose.\n\nFY2017 data represent preliminary data that are being further reviewed and validated for official reporting purposes. October 1, 2017 used as cut-off.\n\n2", "n_tokens": 66, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-2-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 2, "text": "Overview\n\n1. Update on GDUFA I\n\nReceipts – Actions towards Goals – Other accomplishments\n\n2. Brief comments on GDUFA II 3. Closing Comments\n\n3", "n_tokens": 31, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-3-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 3, "text": "Generic Drug Program: Current State\n\nFDA is meeting or exceeding the GDUFA goals • Numerous other significant accomplishments • Standing up/implementing GDUFA II • Evaluating FDARA - this will take time • Main outstanding challenge is multiple review cycles – Inefficient and leads to a huge amount of re-work\n\nfor FDA and applicants alike\n\n4", "n_tokens": 69, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-4-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 4, "text": "GDUFA I workload\n\nNumber of original applications exceeded estimates\n\nNumber of applications continues to rise • Number of amendments continues to rise • Number of controls continues to rise\n\nMore complex controls\n\nNumber of companies increasing • Number of facilities increasing\n\n5", "n_tokens": 45, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-5-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 5, "text": "Projected vs Actual* ANDA Receipts\n\n1600\n\n1400\n\nGDUFA implements, 10/1/12\n\n1473\n\nFDA received an average of 1,000 ANDAs per year under GDUFA I….\n\ns t p e c e R A D N A\n\ni\n\nl\n\na u t c A\n\n1200\n\n1000\n\n800\n\n600\n\n1103\n\n968\n\n539\n\n852\n\n1306\n\nAlmost 7 years of projected ANDA receipts\n\n750 Projected ANDAs per year\n\n400\n\n200\n\n0\n\nFY 12\n\nFY 13\n\nFY 14\n\nFY 15\n\nFY 16\n\nFY 17\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n6", "n_tokens": 134, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-6-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 6, "text": "s t p e c e R A D N A\n\ni\n\nANDA Receipts\n\n(Originals + CR Responses/Amendments)\n\n3,000\n\n2,500\n\n2,849\n\n2,000\n\n1,848\n\n1,500\n\n1,547\n\n1,000\n\n500\n\n0\n\nFY 15\n\nFY 16\n\nFY 17\n\n* Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n7", "n_tokens": 88, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-7-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 7, "text": "Monthly ANDA Receipts\n\n(New Originals)\n\n250\n\n225\n\n235\n\n200\n\n197\n\n175\n\n180\n\ns t p e c e R A D N A\n\ni\n\n150\n\n125\n\n100\n\n114\n\n108\n\n75\n\n50\n\n61\n\n56\n\n58\n\n78\n\n69\n\n60\n\n59\n\n81\n\n57\n\n58\n\n75\n\n25\n\n35\n\n42\n\n40\n\n0\n\n5 1 0 2 , t c O\n\n5 1 0 2 , v o N\n\n5 1 0 2 , c e D\n\n6 1 0 2 ,\n\nn a J\n\n6 1 0 2 ,\n\nb e F\n\n6 1 0 2 , r a M\n\n6 1 0 2 , r p A\n\n6 1 0 2 , y a M\n\n6 1 0 2 ,\n\nn u J\n\n6 1 0 2 , l\n\nu J\n\n6 1 0 2 , g u A\n\n6 1 0 2 ,\n\np e S\n\n6 1 0 2 , t c O\n\n6 1 0 2 , v o N\n\n6 1 0 2 , c e D\n\n7 1 0 2 ,\n\nn a J\n\n7 1 0 2 ,\n\nb e F\n\n7 1 0 2 , r a M\n\n7 1 0 2 , r p A\n\n* Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n66 67\n\n7 1 0 2 , y a M\n\n7 1 0 2 ,\n\nn u J\n\n73\n\n7 1 0 2 , l\n\nu J\n\n73\n\n7 1 0 2 , g u A\n\n202\n\n7 1 0 2 ,\n\np e S\n\n8", "n_tokens": 274, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-8-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 8, "text": "Controls Received\n\n3000\n\nGDUFA implements, 10/1/12\n\n2500\n\n2000\n\nd e v i e c e R s l o r t n o C\n\n1500\n\n1519\n\n1884\n\n1000\n\n1217\n\n953\n\n1087\n\n500\n\n0\n\nFY 12\n\nFY 13\n\nFY 14\n\nFY 15\n\nFY 16\n\n* Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. Numbers reflect controls submitted that are accepted for review, as per Controls Guidance for Industry.\n\n2666\n\nFY 17\n\n9", "n_tokens": 108, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-9-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 9, "text": "d e t t i\n\nm b u S s l o r t n o C\n\nAverage Monthly Controls Submitted\n\n250\n\nGDUFA implements, 10/1/12\n\n222\n\n200\n\n150\n\n157\n\n127\n\n100\n\n101\n\n91\n\n79\n\n50\n\n0\n\nFY 12\n\nFY 13\n\nFY 14\n\nFY 15\n\nFY 16\n\nFY 17\n\n* Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. Numbers reflect Controls submitted that are accepted for review, as per Controls Guidance for Industry.\n\n10", "n_tokens": 105, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-10-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 10, "text": "To date, FDA has met or exceeded EVERY formal negotiated GDUFA goal\n\n11", "n_tokens": 16, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-11-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 11, "text": "Original ANDAs\n\nGDUFA goal: incremental increasing % meeting shorter review goals over Years 3, 4, and 5*\n\nFDA acted on:\n\nCohort Year 3 - 97%\n\nGOAL – 60% within 15 months of submission\n\nCohort Year 4 - 100%\n\nGOAL – 75% within 15 months of submission**\n\nCohort Year 5 - 99%\n\nGOAL – 90% within 10 months of submission**\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. Cohort Year 4 (FY2016) – Some are still under review and within goal; all mature by December 31, 2017. Cohort Year 5 (FY2017) – Many are still under review and within goal; all mature by July 31, 2018. **Percent represents the current percentage of regulatory actions FDA completed within the review-time goal. Final performance will depend on the outcome of pending submissions.\n\n12", "n_tokens": 195, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-12-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 12, "text": "Total ANDA Regulatory Actions per Month (AP+TA+CR+RTR)\n\n300\n\n290\n\n250\n\n266\n\n269\n\n278\n\n223\n\n225\n\n241\n\n245\n\n239\n\n249\n\n230 229\n\n243\n\n225 227\n\n200\n\n206\n\n189\n\n178\n\n192\n\n186\n\n193\n\n173\n\n150\n\n100\n\n50\n\n0\n\n* Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n243\n\n249\n\n13", "n_tokens": 75, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-13-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 13, "text": "90%\n\n80%\n\n70%\n\n60%\n\n50%\n\n40%\n\n30%\n\n20%\n\n10%\n\n0%\n\nFirst Regulatory Action – Rates\n\nRate for all original ANDAs submitted for the respective month of submission\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. Cohort Year 4 (FY2016) – Some are still under review and within goal; all mature by December 31, 2017. Cohort Year 5 (FY2017) – Many are still under review and within goal; all mature by July 31, 2018.\n\nAP+TA\n\nCR\n\nRTR\n\n14", "n_tokens": 127, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-14-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 14, "text": "ANDA Complete Response Letters (CRLs) 200\n\n180\n\n190\n\n193\n\n190\n\n160\n\n166 169 167\n\n140\n\n147\n\n151\n\n151 150\n\n144 143\n\n136\n\ns L R C A D N A\n\n120\n\n100\n\n80\n\n105\n\n92\n\n113\n\n103\n\n129\n\n112\n\n98\n\n87\n\n60\n\n40\n\n20\n\n0\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n82\n\n155 155\n\n15", "n_tokens": 79, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-15-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 15, "text": "Overall Regulatory Actions…. Another Record Year\n\nPre-GDUFA\n\nGDUFA I\n\nFY2012\n\nFY2013\n\nFY2014\n\nFY2015\n\nFY2016\n\nANDA approvals\n\n517\n\n440\n\n409\n\n492\n\n651\n\nPAS approvals\n\n275\n\n535\n\n659\n\n624\n\n481\n\nTentative Approval (TA)\n\n102\n\n95\n\n91\n\n120\n\n184\n\nComplete Response (CR) ¥\n\n84\n\n1251\n\n1254\n\n1180\n\n1725\n\nTOTAL **\n\n978\n\n2321\n\n2413\n\n2416\n\n3056\n\nDMF Completeness Assessment (CA)\n\n0\n\n1699\n\n1706\n\n901\n\n886\n\n* Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. ** FDA will aspire to the extent possible to maintain levels of productivity at least similar to pre-GDUFA levels, while hiring and training incremental staff necessary to achieve the program performance goals, building necessary systems and implementing outlined program changes in years 1 and 2 of the program (GDUFA Commitment Letter, page 3) http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm ¥ Complete Response both with and without inspections for ANDAs.\n\nFY2017\n\n763\n\n431\n\n174\n\n1603\n\n2971\n\n820*\n\n16", "n_tokens": 293, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-16-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 16, "text": "Annual Approvals & Tentative Approvals\n\nApproval\n\nTentative Approval\n\n1000\n\nGDUFA starts, 10/1/12\n\n900\n\n800\n\n184\n\n700\n\ns A D N A\n\n600\n\n500\n\n139\n\n139\n\n102\n\n95\n\n91\n\n120\n\n400\n\n300\n\n651\n\n200\n\n426\n\n458\n\n517\n\n440\n\n409\n\n492\n\n100\n\n0\n\nFY 10\n\nFY 11\n\nFY 12\n\nFY 13\n\nFY 14\n\nFY 15\n\nFY 16\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n174\n\n763\n\nFY 17\n\n17", "n_tokens": 110, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-17-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 17, "text": "Monthly Approvals & Tentative Approvals*\n\nFull Approvals\n\nTentative Approvals\n\n120\n\n100\n\n12\n\n19\n\n80\n\n19\n\ns A D N A\n\n60\n\n16\n\n12\n\n19\n\n14\n\n11\n\n9\n\n88\n\n40\n\n77\n\n54\n\n59\n\n56\n\n51\n\n61\n\n62\n\n57\n\n20\n\n0\n\nOct-16\n\nNov-16\n\nDec-16\n\nJan-17\n\nFeb-17\n\nMar-17\n\nApr-17\n\nMay-17\n\nJun-17\n\n* Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n14\n\n68\n\nJul-17\n\n17\n\n60\n\nAug-17\n\n12\n\n70\n\nSep-17\n\n18", "n_tokens": 113, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-18-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 18, "text": "FY2017 - Notable ANDA Approvals\n\nGeneric Name\n\nReference Listed Drug\n\nOlmesartan Medoxomil Tablets, 5 mg, 20mg, and 40 mg\n\nBenicar Tablets\n\nQuetiapine Fumarate Extended-release Tablets, 50 mg, 150 mg, 200 mg, 300 mg, 400 mg\n\nSeroquel XR Tablets\n\nDexlansoprazole Delayed-release Capsules, 60 mg\n\nDexilant Capsules\n\nAtomexetine Capsules, 10 mg, 18 mg, 25 mg, 40 mg, 60 mg, 80 mg, and 100 mg\n\nStrattera Capsules\n\nMesalamine Delayed-release Tablets USP, 1.2 g, and 800 mg\n\nLialda and Asacol HD Delayed- release Tablets\n\nEmtricitabine and Tenofovir Disoproxil Fumarate Tablets, 200 mg/300 mg\n\nTruvada Tablets\n\nSevelamer Carbonate Tablets, 800 mg; Powder for Oral Suspension, 0.8 g and 2.4 g Pouches\n\nRenvela Tablets and Powder for Oral Suspension\n\nPrasugrel Tablets, 5 mg, 10 mg\n\nEffient Tablets\n\nIsoproterenol Hydrochloride Injection, USP 0.2 mg/mL and 1 mg/5 mL (0.2 mg/mL) (single-dose vials)\n\nIsuprel Injection\n\nEzetimibe and Simvastatin Tablets, 10mg/10mg, 10mg/20mg, 10mg/40mg, 10mg/80mg\n\nVytorin Tablets\n\nOseltamivir Phosphate for Oral Suspension, 6 mg (base)/mL\n\nTamiflu for Oral Suspension\n\n19", "n_tokens": 333, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-19-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 19, "text": "Prior Approval Supplements\n(PASs)\n\n20", "n_tokens": 7, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-20-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 20, "text": "GDUFA Goal: PAS\n\n100%\n\n100%\n\n100%\n\n97%\n\n94%\n\n100%\n\n100%\n\n100%\n\n100%\n\n100%\n\n98%\n\n100%\n\ne c n a m r o f r e P\n\n80%\n\n60%\n\nl\n\na u t c A A F U D G\n\n40%\n\n20%\n\n0%\n\nJan-2016.\n\nFeb-2016 Mar-2016\n\nApr-2016 May-2016\n\nJun-2016\n\nJul-2016 Month-Year\n\nAug-2016\n\nSep-2016\n\nOct-2016\n\nNov-2016\n\nGDUFA PAS Goal\n\nGoal dates provided on submissions received through December 2016, as those are the goal dates that have actually accrued. The cohort data is not mature enough to report on whole fiscal year data\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n97%\n\nDec-2016\n\n21", "n_tokens": 173, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-21-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 21, "text": "PAS Actions\n\nFY2013\n\nFY2014\n\nFY2015\n\nFY2016\n\nReceived\n\n482\n\n436\n\n480\n\n478\n\nApproved\n\n535\n\n659\n\n624\n\n481\n\nCR Letter\n\n8\n\n18\n\n185\n\n228\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\nFY2017\n\n415\n\n431\n\n223\n\n22", "n_tokens": 76, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-22-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 22, "text": "Controlled Correspondence\n“Controls”\n\n23", "n_tokens": 6, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-23-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 23, "text": "GDUFA Goal: Controlled Correspondence\n\nControlled Correspondence GDUFA Performance by FDA Receipt Date – All Disciplines\n\n100%\n\n99%\n\n96%\n\n98%\n\n97%\n\n95%\n\n99%\n\n100%\n\n98%\n\n98%\n\n97%\n\n99%\n\n80%\n\ne c n a m r o f r e P\n\n60%\n\nl\n\na u t c A A F U D G\n\n40%\n\n20%\n\n0%\n\nJul-2016 Aug-2016 Sep-2016 Oct-2016 Nov-2016 Dec-2016 Jan-2017 Feb-2017 Mar-2017 Apr-2017 May-2017 Jun-2017\n\nMonth-Year\n\nGDUFA Controlled Correspondence Goal\n\nGoal dates provided on submissions received in FY 2016 and 2017.\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm375079.htm\n\n99%\n\n24", "n_tokens": 220, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-24-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 24, "text": "CONTROLS\n\nIncreasing number of “control” submissions\n\n>8,000 controls submitted in GDUFA I\n\nIncreasing complexity • Approximately 20% controls do not follow FDA guidance\n\nPLEASE READ and FOLLOW GUIDANCE – https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM411478.pdf\n\n25", "n_tokens": 74, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-25-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 25, "text": "OGD FILING REVIEW\n\n> 1,100 original ANDAs, resubmissions, and PASs underwent filing review in FY2017\n\n26", "n_tokens": 28, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-26-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 26, "text": "REFUSE TO RECEIVE (RTR)\n\n~10-30% of ANDAs submitted get RTR • ~1% fees not paid\n\n% ANDAs RTR-ed*\n\nFY2015 (cohort Year 3)\n\n34.3\n\nFY2016 (cohort Year 4)\n\n28.3\n\nFY2017 (cohort Year 5**)\n\n10.5\n\nOverall RTR % FY15-17\n\n20.9\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. **Cohort Year 5 (FY2017) – Given the large number of ANDAs submitted in the end of FY2017, many ANDAs undergoing Filing Review. 27", "n_tokens": 151, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-27-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 27, "text": "REASONS FOR REFUSE TO RECEIVE (RTR)\n\nDEFICIENCY\n\nInadequate Stability Inadequate Dissolution Incomplete English translation No response with 7 calendar days Incomplete Response Not Q/Q Same Incomplete DMF Inadequate EA or Categorical Exclusion Incomplete/Failed BE studies Inadequate justification of excipients\n\n% 31.1% 17.8% 17.4% 6.4% 5.5% 4.6% 4.1% 3.2% 2.7% 2.7%\n\nAnalysis of FY2016 Year 4 cohort, 218 RTRs on 855 ANDAs.\n\n28", "n_tokens": 114, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-28-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 28, "text": "RTR is a CRITICAL “Vital Sign”\n\nIf ANDA received RTR…. – Less 1st cycle AP or TA – More deficiencies in CRL – Worse (“major”) deficiencies – If RTR resubmitted quickly to FDA, even lower likelihood for AP or TA\n\n29", "n_tokens": 60, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-29-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 29, "text": "RTR is a CRITICAL ANDA “Vital Sign”\n\nRegulatory Action\n\nWITH prior RTR\n\nApproved or Tentative Approval\n\n3.8%\n\nComplete Response Letter (CRL)\n\n96.2%\n\nAnalysis of FY2015 Year 3 cohort, conducted 8/9/2017; n=400 ANDAs, all underwent extensive review. Results of First Regulatory Action following first cycle review. *Does not total 100%; at time of analysis 1.6% were under active review.\n\nWITHOUT prior RTR*\n\n11.5%\n\n86.9%\n\n30", "n_tokens": 109, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-30-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 30, "text": "GDUFA I Regulatory Science Accomplishments*\n\nIssued 108 external research grants and contracts – Prepared OGD for industry interaction on complex drug products\n\nPublished 788 Product Specific Guidances (PSGs)\n\n495 new PSGs and 293 revised PSGs – Increased number for complex drug products each year\n\nReviewed 127 pre-ANDA meeting packages\n\nAlmost all for complex drug products\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n31", "n_tokens": 96, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-31-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 31, "text": "Product-Specific Guidances (PSGs)\n\n250\n\nNew Guidance\n\n223\n\nRevised Guidance\n\n194\n\n200\n\ns e c n a d u G\n\ni\n\n150\n\n134\n\n154\n\n135\n\n108\n\nf o r e b m u N\n\n100\n\n102\n\n78\n\n94\n\n61\n\n50\n\n41\n\n56\n\n69\n\n41\n\n86\n\n0\n\nFY 13\n\nFY 14\n\nFY 15\n\nFY 16\n\nFY 17*\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n32", "n_tokens": 94, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-32-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 32, "text": "Product-Specific Guidances (PSGs) Complex Drug Products\n\n250\n\nComplex?\n\n223\n\n200\n\nYes\n\nNo\n\n58\n\n194\n\ns e c n a d u G\n\ni\n\n150\n\n134\n\n135\n\n86\n\nf o r e b m u N\n\n100\n\n102\n\n32\n\n48\n\n165\n\n71\n\n50\n\n70\n\n86\n\n64\n\n108\n\n0\n\nFY13\n\nFY14\n\nFY15\n\nFY16\n\nFY17\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n33", "n_tokens": 96, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-33-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 33, "text": "GDUFA I Regulatory Research “Game Changers” ($Billion Impact)\n\nPSGs for:\n\nANDA Approvals for:\n\n17 inhalation products – Conjugated estrogens – In vitro equivalence for\n\nGeneric glatiramer acetate – Nasal spray suspension based on novel particle size methods\n\ntopical ointments, topical creams, GI binding agents, ophthalmic emulsions • Stand alone guidance for: – Generic abuse deterrent opioid formulations – BCS class III biowaivers – Synthetic peptides\n\nTopical ointments (in vitro approach)\n\nGI binding agents (in vitro\n\napproach) • Scientific Advances\n\nPolymer characterization for long-acting injectables\n\nreferencing rDNA RLDs – Adhesion for transdermals\n\nFirst open flow microdialysis BE study for a topical cream\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n34", "n_tokens": 191, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-34-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 34, "text": "FY2017 OGD Policy Accomplishments*\n\nCo-led successful re-negotiation for GDUFA II • October 2016 - Final Rule on ANDAs and 505(b)(2) Applications\n\nDeveloped policy and procedures to streamline the publication of Federal Register notices announcing the voluntary withdrawals of ANDAs under 21 CFR 314.150(c)\n\nPublished 15 guidances – 7 - GDUFA II related\n\nIssued 7 MAPPs • Orange Book Modifications\n\n~ 5,600 NDAs and ANDAs to add RS and RLD designations and\n\n~ 840 discontinued NDAs to provide RLD designations • Supporting the Commissioner’s Drug Competition Action\n\nPlan\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n35", "n_tokens": 154, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-35-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 35, "text": "FDA Commissioner Scott Gottlieb, MD\n\nHuge interest and focus on Generic Drugs\n\nNumerous internal briefings provided regarding the generic drug program, GDUFA, Hatch-Waxman, and other activities\n\nAttendance at OGD All Hands • Drug Competition Action Plan\n\n36", "n_tokens": 51, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-36-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 36, "text": "Communicating FDA’s Generic Drug Program\n\nREQUIRED: • GDUFA Performance Reports • GDUFA Financial Reports\n\nENHANCED: • GDUFA Regulatory Science Annual\n\nReport\n\nActivities Report of the Generic Drug Program\n\nQuarterly Meeting Minutes Between FDA and Industry\n\nCOMING SOON GDUFA II Dashboards: • More metrics • •\n\nDifferent reporting Not OGD reports\n\nQuarterly Generic Drug Review Dashboard\n\nANDA First Generic Drug Approvals • Office of Generic Drugs Annual Report • Generic Drugs Updates and GDUFA listserv\n\nGeneric Drug Outreach Campaign\n\n37", "n_tokens": 101, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-37-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 37, "text": "Communicating FDA’s Generic Drug Program\n\nGDUFA Outreach Videos\n\nBrief videos by FDA staff highlight new features in GDUFA II on FDA.gov. – Topics include:\n\nGDUFA Overview • Pre-ANDA Program for Complex Products • Type II Drug Master Files (DMF) Update • Performance Goals • Goals Integration • Review Status Updates • Post Complete Response Letter (CRL) Meeting • Requests for Reconsideration • Review Classification • More to come!\n\n38", "n_tokens": 95, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-38-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 38, "text": "FDA’s Generic Review Pipeline\nBy Submission Cohort as of September 30, 2017\n\n5 \" Under FDA Review\n| RSE EDA review panting A (includes many re-submissions)\n\nApproximately 2,500 Total ANDAs\n\nty", "n_tokens": 44, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-39-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 39, "text": "Getting to “Stable Footing”\n\nANDA Inventory\n\n4,000\n\n3,500\n\n3,000\n\n2,500\n\ns A D N A\n\n2,000\n\n1,500\n\n1,000\n\n500\n\n0\n\nWith FDA\n\nWith Industry\n\n*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\n\n40", "n_tokens": 68, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-40-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 40, "text": "ANDAs in CR status with industry\n\nFDA needs a better understanding of this\n\nPredictors of when amendment will be submitted to FDA\n\nWorkload predictions and forecasting, capacity analytics, etc.\n\nFDA asked industry for data/analysis during QTR GDUFA II FDA-industry meeting\n\n41", "n_tokens": 55, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-41-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 41, "text": "Application “approvability”\n\nFDA will Approve or TA an ANDA WHEN it meets the Agency’s standards for approval\n\n42", "n_tokens": 25, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-42-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 42, "text": "FIRST CYCLE APPROVALS*\n\nFY2015\n\nFY2016**\n\nFY2017**\n\n10.7%\n\n14.3%\n\n12.8%\n\nLow % • Lots of rework • Inefficient use of resources • Large number of ANDAs “pending” with industry, issued CR letters\n\nCritical to improve the ANDA Quality UP FRONT\n\nUpdated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes. Cohort Year 3 (FY2016) – Some are still under review and within goal; all mature by December 31, 2017. Cohort Year 4 (FY2017) – Many are still under review and within goal; all mature by July 31, 2018. **Percent represents the current percentage of regulatory actions FDA completed within the review-time goal. Final performance will depend on the outcome of pending submissions. DEFINITION: The percentage of AP and TA original and original-response to RTR ANDAs that were received for extensive review and were given a regulatory decision (excluding ANDAs under review). 43", "n_tokens": 223, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-43-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 43, "text": "Overview\n\n1. Update on GDUFA I\n\nReceipts – Actions towards Goals – Other accomplishments\n\n2. Brief comments on GDUFA II 3. Closing Comments\n\n44", "n_tokens": 31, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-44-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 44, "text": "GDUFA II\n\nNumerous Review Program Enhancements\n\nMid-cycle & post CR t-cons, ability to dispute a variety of CDER actions\n\nMore touch points with industry pre-, during, and post-submission\n\nPre-ANDA program for complex products\n\nMeetings, timeframes for Product-Specific Guidances, updates to Inactive Ingredients Database (IID)\n\n“PFC” – Pre-submission Facility Correspondence\n\nPriority Submission with PFC - 8 month goal\n\nAll Pre-Year 3 ANDAs get a hard GDUFA II goal date vs. TADs – DMF enhancements – Accountability and reporting enhancements – Small business relief 45", "n_tokens": 128, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-45-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 45, "text": "GDUFA II\n\n“Goals” or “Commitment” letter:\n\nhttp://www.fda.gov/downloads/forindustry/userfees/genericdruguserfees/ucm525234.pdf\n\nPLEASE READ!\n\n46", "n_tokens": 52, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-46-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 46, "text": "GDUFA II Pre-ANDA Program\n\nSession:\n\nTuesday November 7, 2017, 9:00am-10:00am\n\n47", "n_tokens": 27, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-47-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 47, "text": "GDUFA II Review Program Enhancements\n\nSessions:\n\nTuesday November 7, 2017, 10:30am-12:30pm – Tuesday November 7, 2017, 1:30pm-3:30pm\n\n48", "n_tokens": 42, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-48-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 48, "text": "Lessons learned from PDUFA I-V & GDUFA I\n\nCritical/Pivotal role of RPM • Complete Application is critical • High quality NDA & ANDA applications result in:\n\nLow Refuse To File (RTF)/Refuse to Receive (RTR) rates – First cycle approvals – Shorter time to approval\n\n49", "n_tokens": 65, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-49-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 49, "text": "PDUFA Experience: Higher first cycle approval rate achievable with high quality submissions\n\nCDER New Molecular Entity Approval Rates by PDUFA Cohort\n\n* PDUFA V estimates based on 77 NMEs submitted in FY 2013 – mid FY 2015 (it is too early to estimate performance for later submissions) Data as of 9/30/16 Projection estimates account for actions to date and elapsed time to date for non-approvals\n\n50", "n_tokens": 92, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-50-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 50, "text": "CURRENT OGD & GDUFA CHALLENGES\n\nContinue to Deliver on GDUFA I deliverables\n\nYear 4 cohort with 15 month goals all due by December 2017 – Year 5 cohort with 10 month goals all due by July 2018 • Complex scientific issues with complex active ingredients, routes of delivery, dosage forms, formulations\n\nComplex regulatory and legal issues unique to the generic/HW space\n\n51", "n_tokens": 79, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-51-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 51, "text": "CURRENT CHALLENGES\n\nHigh Rate of Refuse to Receive (RTR)\n\nRTR’ed ANDAs:\n\nRequire more cycles to approval when finally received – Contain more/worse deficiencies than non-RTR’ed ANDAs\n\nHidden facilities\n\nNot identified on 356h form – Risk getting a new/later GDUFA goal date when hidden facilities are found during review\n\nLimited awareness of benefits of Product-Specific Guidances\n\nIncreasing workload: ANDAs, amendments, controls\n\n52", "n_tokens": 91, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-52-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 52, "text": "ANDA “Approvability” Build in Quality Up Front\n\nGDUFA I Cohort Year 5 timeline:\n\nFiling Review (OGD)\n\nReview Team Assignment\n\nKick-Off Meeting\n\nAssessment #1 and Cumulative IR #1\n\nIR #1 Response Received and Reviewed\n\nComplete Inspection\n\nIR #2 Response Received and Reviewed\n\nWrap up and Final Review\n\n0 – 60d\n\nWithin 70d\n\nWithin 90d\n\nWithin 120d\n\n4mo – 6.5mo\n\nWithin 7.0mo\n\n6.5mo – 8.5mo\n\nWithin 9.0mo\n\nMajority of deficiencies issued in CR letters: 1. Dissolution 2. Stability 3. Excipients 4. Facilities\n\nAll are Quality-related (OPQ)\n\n“RIGHT THE FIRST TIME”\n\n53", "n_tokens": 143, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-53-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 53, "text": "FDA is Successfully Delivering on GDUFA\n\nFDA continues to fulfill GDUFA commitments\n\nContinue to see increasing submissions, companies, workload, etc.\n\nCreated a high functioning generic drug program – Robust, modern, state of the art tools – Sustainable and predictable – Clear and consistent communication – Fairness across applications and applicants\n\n54", "n_tokens": 62, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-54-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 54, "text": "For your feedback and endurance during the tremendous processes changes under GDUFA\n\nYour engagement and input were critical to its success • • There is still plenty of work to go around with GDUFA II It was a team effort with FDA and industry\n\n55", "n_tokens": 49, "kind": "text"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-55-0", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 55, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-0-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 0, "text": "The Public Health Role of Drug Regulation in the US\n\nDouglas C. Throckmorton, M.D. Deputy Director for Regulatory Programs, CDER, FDA March 20, 2017", "n_tokens": 36, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-1-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 1, "text": "Disclosure Statement\n\nI have no financial relationships with proprietary entities that produce health care goods and services\n\nThe opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA\n\n2", "n_tokens": 40, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-2-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 2, "text": "FDA’s Regulatory Scope: 20 cents of every GDP dollar", "n_tokens": 12, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-3-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 3, "text": "FDA Mission\n\nFDA is responsible for protecting the public health by\n\nassuring the safety, efficacy, and security of human and\n\nveterinary drugs, biological products, medical devices,\n\nour nation’s food supply, cosmetics, and products that\n\nemit radiation.\n\n4", "n_tokens": 49, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-4-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 4, "text": "FDA Mission\n\nFDA is also responsible for advancing the public health by helping to\n\nspeed innovations that make medicines more effective, safer, and\n\nmore affordable and by helping the public get the accurate, science-\n\nbased information they need to use medicines and foods to maintain\n\nand improve their health. FDA also has responsibility for regulating the\n\nmanufacturing, marketing and distribution of tobacco products to\n\nprotect the public health and to reduce tobacco use by minors.\n\n5", "n_tokens": 83, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-5-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 5, "text": "FDA Mission\n\nFinally, FDA plays a significant role in the Nation’s\n\ncounterterrorism capability. FDA fulfills this responsibility\n\nby ensuring the security of the food supply and by\n\nfostering development of medical products to respond to\n\ndeliberate and naturally emerging public health threats.\n\n6", "n_tokens": 53, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-6-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 6, "text": "A Brief History of FDA Regulation and Its Impact on Good Science\n\n1890s – Discovery of diptheria antitoxin gave rise to increased production\n\n1901 -- Problems from both public and commercial labs, especially tetanus deaths from contaminated diphtheria antitoxin and smallpox vaccine\n\n1902 – Passage of Biologics Control Act\n\nwww.fda.gov", "n_tokens": 69, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-7-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 7, "text": "A Horse Named Jim", "n_tokens": 4, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-8-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 8, "text": "1902 Biologics Control Act\n\nScientifically trained staff must supervise production of these medicines\n\nLicensing of facilities by PHS •\n\nInspections of establishments and testing of biologics for purity and potency\n\nStandards issued for products • Enhanced scientific legitimacy on firms and their products\n\nScientific infrastructure mandated under the law helped promote new product development.", "n_tokens": 62, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-9-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 9, "text": "Pre-1938\n\nFDA could only respond to problems when identified • No requirements for testing or approval • No data of any kind had to be submitted before\n\nmarketing\n\nGovernment could seek to remove dangerous or misbranded products.\n\nNot surprisingly, there were some disasters:\n\n10", "n_tokens": 51, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-10-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 10, "text": "Notable Disasters Before 1938\n\nDinitrophenol – weight loss drug, caused thousands of cataracts, enucleations in the 1930’s.\n\nElixir sulfanilamide – sulfa drug killed over 100 people in 1937, many of them children; diethylene glycol (anti- freeze) was the solvent. No animal testing. A chemist simply smelled and tasted the elixir.\n\nThese events led to \n\n11", "n_tokens": 89, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-11-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 11, "text": "The Food, Drug and Cosmetic Act of 1938 (FD&C) – Age of Safety\n\nTwo Requirements: 1. Pre-market notification 2. Demonstration of safety\n\n12", "n_tokens": 34, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-12-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 12, "text": "Next Major Turning Point:\nThalidomide\n\n1,200 U.S. DOCTORS GOT\nBANNED PILL FOR TESTS\n\nThalidomide, the sleeping pill*that has caused thou- |\nsands of infant malformations in Europe had been dis- |\n\ntributed to 1,200 physicians in the United States for\ninvestigational use since 1959, before it was banned in\n\nthe United States.\n\nThis figure has -been supplied by the William Ss. |\nMerrell Co. of Cincinnati, manufacturer of the drug, to |\nthe Food and Drug Administration here. FDA inspec-\ntors are now checking the physicians to make sure they\nhave returned or destroyed their supplies of the drug,\nas requested by the Merrell Company in March.\n\nThe investigational use of the drug in the United\nStates dates to 1959. It is not known by FDA if the\ndrug was used experimentally during early pregnancy,\nthe critical period in which the malformations are caused,\n\nSeveral malformed infants in the United States\nhave been linked to their mother's’ use of the drug; In.\nnone of these publicly-reported cases, however, was the\ndrug given by a licensed physician in the United States,\n\nhe", "n_tokens": 239, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-13-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 13, "text": "The Age of Effectiveness: The 1962 Kefauver-Harris Amendments Not obvious why thalidomide (a safety problem) led to a requirement for demonstrating effectiveness, but the 1962 Act made at least 3 important changes:\n\n1. FDA had to give positive approval before a drug could be marketed\n\n2. A meaningful requirement to study drugs under an IND and an explicit requirement for informed consent (one year before the Declaration of Helsinki).\n\n3. The effectiveness requirement\n\nDr. Francis Kelsey received the President's Award for Distinguished Federal Civilian Service\n\n14", "n_tokens": 108, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-14-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 14, "text": "Since 1962: The Era of the RCT and the Value of Empiric Testing\n\nGrowth of the medical product development enterprise – Non-clinical models of disease – Statistics of trials assessment – Placebo- and Active-controls – Clinical efficacy and safety assessment\n\nSobering experiences where predicted impact of new therapies was badly wrong: – Autologous bone marrow transplantation for treating\n\nbreast cancer\n\nSuppression of PVCs with anti-arrhythmics – Health effects of chronic non-steroidal use", "n_tokens": 100, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-15-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 15, "text": "Context: New Realities in the 21st Century • Previously we lacked effective treatments for most life-\n\nthreatening illnesses\n\nToday many more treatments are available, but patterns of manufacturing, public scrutiny of healthcare, and information available to guide use have shifted dramatically. Patients and clinicians need: – New products sooner – Accurate, up-to-date and understandable information • Result: increased public and Congressional scrutiny of CDER’s decisions", "n_tokens": 83, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-16-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 16, "text": "FDA’s Challenges for the 21st Century • Supporting Innovation and Advances in Science and Technology – Better understanding of the mechanisms of disease and human biology – Advances in biomedical engineering – Increasingly complex products; challenges for development, as well as\n\nassessment of safety, efficacy and quality\n\nNew Authorities and responsibilities given us by Congress\n\nFood Safety Modernization Act – Food and Drug Administration Safety and Innovation Act – Drug Quality and Security Act\n\nGlobalization\n\nJust as disease knows no borders, product safety and quality no longer know any borders\n\nWe live in an increasingly complex, global regulatory landscape.\n\n17", "n_tokens": 108, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-17-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 17, "text": "The FDA Today: Embracing Science- Driven Regulation and Innovation\n\nMaintaining the Balance\n\nThe task for FDA's scientist is to strike the right regulatory balance – between providing fast access to new products the one hand, and preventing harm to public health on the other\n\nWhen done right, regulation can be a pathway to achieve meaningful and lasting innovation, allowing FDA to deliver on the promise of science in the service of patients, consumers, and industry", "n_tokens": 84, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-18-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 18, "text": "Critical Part of FDA Work: Sustaining Medical Product Innovation\n\nHigh failure rates for drug development • Rising R & D costs • A limited pipeline of potential drugs • A lack of basic information about the causes of the disease and the pathways for slowing its progress", "n_tokens": 48, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-19-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 19, "text": "R & D Process\n\nDRUG DISCOVERY\n\nPRE CLINICAL\n\nCLINICAL TRIALS\n\nY R E V O C S D E R P\n\nI\n\n5,000-10,000 COMPOUNDS\n\n250\n\nA D F O T D E T T M B U S D N\n\nI\n\n5\n\nPHASE 1 PHASE 2\n\nPHASE 3 Number of Volunteers\n\n20-100\n\n100-500\n\n1000-5000\n\n3-6 YEARS\n\n6-7 YEARS\n\nI\n\n20\n\nSOURCE: PhRMA 2008, Stages of Drug Development Process and attrition rate of compounds as they travel through the drug development process over time.\n\nA D F O T D E T T M B U S A D N\n\nI\n\nFDA REVIEW\n\nLARGE SCALE MFG\n\nONE FDA- APPROVED DRUG\n\n0.5-2 YEARS\n\nE C N A L L I E V R U S G N T E K R A M T S O P\n\nI\n\n: 4 E S A H P", "n_tokens": 172, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-20-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 20, "text": "Improving Evidence Generation\nEssential\n\nClinical Expertise\n\nPatient\nValues &\nPreferences\n\nBest\nResearch\nEvidence\n\nEBP", "n_tokens": 16, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-21-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 21, "text": "Changes are Needed to Our National Clinical Research System\n\nHigh percentage of decisions not supported by evidence*\n\nHealth outcomes and disparities are not improving\n\nCurrent system is great except:\n\nToo slow, too expensive, and not reliable\n\nDoesn’t answer questions that matter most to patients\n\nUnattractive to clinicians & administrators\n\nWe are not generating the evidence we need to support the healthcare decisions that patients and their doctors have to make every day.\n\nTricoci P et al. JAMA 2009;301:831-41", "n_tokens": 101, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-22-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 22, "text": "We Need An Efficient Evidence Generation System….\n\nMore data available than ever in new forms • Much more of clinical practice could be guided by high quality evidence\n\nClinicians and their practice organizations could focus on interpreting the evidence and applying it\n\nThe role of opinion and expertise would be at least as important, but it would be put to a much higher purpose—providing precision healthcare", "n_tokens": 72, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-23-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 23, "text": "Many Stakeholders in Clinical Trials Enterprise\n\nIndustry /Payors\n\nAcademia\n\nRegulator y Agencies\n\nDrug Develop ment\n\nFederal Partners\n\nConso rtia\n\nPatient Groups, Foundati ons, and Professi onal Societies", "n_tokens": 39, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-24-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 24, "text": "Critical Part of FDA Work: the Challenges of Globalization to Product Quality and Development • When FDA was established more than a century\n\nago: – Our regulated industries were predominantly\n\nlocal\n\nThe volume of imported produce was low – The movement of good across country (and between countries) was minimal\n\nwww.fda.gov\n\n25", "n_tokens": 60, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-25-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 25, "text": "The Global Drug Manufacturing Supply Chain\n\nImported Finished Drug\n\nIngredients\n\nIngredients\n\nManufacture of Finished Drug\n\nIngredients\n\nActive (API)\n\nIllustration of drug manufacturing supply chain: A U.S. finished drug may be produced using an active pharmaceutical ingredient (API) made in China and ingredients made in Europe, Japan, or the U.S. These components may shipped to India where the finished drug is manufactured and then imported into the U.S. for distribution.", "n_tokens": 86, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-26-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 26, "text": "Old Shenzhen (1982)", "n_tokens": 5, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-27-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 27, "text": "New Shenzhen (2013)", "n_tokens": 5, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-28-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 28, "text": "Imports Continue to Increase\n\nFood\n\nApproximately 49% of fresh fruits and 25% of vegetables are imported\n\n89% of seafood eaten domestically comes from outside the United States\n\nDevices\n\nBased on dollar values, at least 35% of all medical devices used in the United States are imported\n\nDrugs/Biologics\n\n80% of Active Pharmaceutical Ingredient manufacturers are located outside the United States\n\nBased on dollar values, more than 40% of biologics are imported – 40% of finished drugs come from overseas 29", "n_tokens": 94, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-29-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 29, "text": "The Impact of Globalization on FDA’s Mission\n\n Foreign production of FDA-regulated goods and materials has exploded over the last decade\n\n FDA-regulated products originate from more than:\n\n150 countries - 130,000 importers - 300,000 foreign facilities\n\n Number of FDA-regulated shipments at 300 U.S. ports\n\nhas more than doubled during the last ten years. - From 2006, shipments of imported food and medical\n\nproducts crossing our borders went from approximately 15 million to 34 million", "n_tokens": 92, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-30-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 30, "text": "Critical Part of FDA Work: Responding to New Challenges\n\nPublic health challenges need to be addressed promptly and fully as they arise\n\nPart of FDA mission -- ‘Protect and Promote’\n\nContaminated compounded steroids and heparin • Prescription opioid abuse\n\nComplex medical, social, scientific issue • Over 15,000 overdose deaths in US last year associated with opioid use", "n_tokens": 73, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-31-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 31, "text": "Overdose Death Rates\n\n2014\n\n1999\n\nDesigned by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System\n\nScience = Solutions", "n_tokens": 35, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-32-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 32, "text": "“ Important: FDA One of Many Stakeholders\n\nFDA\n\nevaluates\nbenefits/risks\nfor the population panefits\n\nProvider\n\nevaluates\nbenefits/risks\n\nfor a patient Benefits /BEBE)\n\nPatient Benefits\n\nevaluates\nbenefits/risks\n\nin terms of\npersonal values", "n_tokens": 46, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-33-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 33, "text": "Center for Food Safety & Applied Nutrition\n\nCenter for Drug Evaluation & Research\n\nFDA Organization\n\nOffice of the Commissioner\n\nCenter for Biologics Evaluation & Research\n\nCenter for Devices & Radiological Health\n\nCenter for Veterinary Medicine\n\nOffice of Regulatory Affairs\n\nNational Center for Toxicological Research\n\nCenter for Tobacco", "n_tokens": 51, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-34-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 34, "text": "FDA’s Current Resources\n\nTotal annual budget $4.39 billion for FY 2014 • User Fees – $1.83 billion, approximately 42% of total • Appropriated Funds – $2.56 billion, about $8 per citizen\n\n15,705 FTEs, 77% with college degrees, 21% with doctorates\n\n223 U.S. offices and 13 laboratories • 11 international offices and posts in 8 countries\n\n35", "n_tokens": 84, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-35-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 35, "text": "Who Works at FDA?\n\nChemists – review the drug substance, product, and manufacturing process • Biologists – review biological products • Toxicologists – review the non-clinical studies • Pharmacologists – review drug pharmacokinetics, exposure-response, drug-drug interactions • analysis • Physicians & Pharmacists – review clinical protocols, safety and efficacy data • Manufacturing science specialists • Engineers • Project managers – the glue that holds us all together 36", "n_tokens": 94, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-36-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 36, "text": "FDA’s Reliance on Industry User Fees\n\nApproximately 42% of FDA’s funding comes from industry user fees: $1.83 billion\n\nIndustry user fees provide 64% of the funding for FDA’s human drugs program, which itself accounts for approximately 30% of FDA’s budget\n\nFDA’s medical device program accounts for 10% of FDA’s overall budget; user fees fund 25% of that program\n\nFDA’s foods program is 21% of its budget, but just 2% of that program is funded by industry user fees\n\nFDA’s tobacco regulatory program is fully funded by industry user fees\n\n37", "n_tokens": 120, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-37-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 37, "text": "What is the Role of the Regulator in Responding to Public Health Challenges and Supporting Innovation?\n\nPg#", "n_tokens": 19, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-38-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 38, "text": "FDA: First Focused on Core Business Functions\n\nPre-Market Review\n\nAssessment of safety and effectiveness of new medical technology & safety of new food ingredients\n\nProduct Safety & Compliance Inspection of manufacturing facilities and products to assure safety, quality & compliance with FDA regulations\n\nConsumer & Patient Safety\n\nPost-marketing surveillance to ensure the safety of consumers & patients who use FDA- regulated products\n\n39", "n_tokens": 70, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-39-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 39, "text": "5 “Moral Imperatives” of Government Regulation\n\nProtect the Public from Harm • Preserve Maximum Individual Freedom of Choice\n\nGuarantee Meaningful Public Participation in the Decision-Making Process\n\nPromote Consistent and Dependable Rules that are Equally Applicable to Everyone • Provide Prompt Decisions on All the Issues that Arise in a Regulatory Context\n\n---Peter Barton Hutt: Five Moral Imperatives of Government Regulation, in The Hastings Center report, February 1980\n\n40", "n_tokens": 82, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-40-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 40, "text": "Role for the FDA Beyond These Core Functions to Aid Innovation\n\nWe are uniquely situated to contribute to innovation: – Legal role in application of regulations – Focus on public health mission – Regulators in unique position to see needs across\n\ndisease areas\n\nRegulators in unique position to respond to needs – Regulators have identified obligation to support improved regulation, aided by harmonization/convergence", "n_tokens": 68, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-41-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 41, "text": "Role for the FDA Beyond These Core Functions to Aid Innovation\n\nExpanded FDA role\n\nc/w mission: …‘promote’ the availability of novel medical therapies for the US population\n\nProvide clear roadmap to speed development\n\nGuidances on innovative approaches: Adaptive Trial Designs, Use of Meta-Analysis Tools\n\nDrug Development Tools:\n\nPatient-Reported Outcomes, Biomarkers, Animal Models\n\nMeetings targeted at supporting innovation", "n_tokens": 79, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-42-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 42, "text": "Role of the Regulator: Supporting Continued Progress\n\nInvest in appropriate collaborative partnerships: interdependence is the reality – Broaden the conversations beyond usual partners and\n\ntopics for models and expertise\n\nAcknowledge differences exist (e.g., between\n\nregulators, regulations, needs, values) • Build opportunities to harmonize existing knowledge, databases and standards\n\nBe prepared to question assumptions", "n_tokens": 71, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-43-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 43, "text": "WARNING |\n\nCHALLENGES\nAHEAD", "n_tokens": 4, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-44-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 44, "text": "Summary/Conclusions\n\nThis is a transformational time in healthcare. Expectations, resources, and challenges all changing\n\nFDA has a clear and understood role to support our public health mission, including the need to support change and innovation, while remaining true to our historic mission – Transparency, focus, collaboration, and flexibility\n\nare essential for success\n\n45 45", "n_tokens": 65, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-45-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 45, "text": "The art of progress is to preserve order amid change and to preserve change amid order\n\n---Alfred North Whitehead", "n_tokens": 22, "kind": "text"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-46-0", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 46, "text": "my U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-0-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 0, "text": "The Role of Social Science in Prescription Drug Promotion at FDA and Preview of Upcoming Studies Kathryn J. Aikin, Ph.D. Senior Social Science Analyst, Research Team Lead Office of Prescription Drug Promotion | CDER | FDA\n\nDIA Advertising and Promotion Regulatory Affairs Conference Marriott Hotel and Conference Center| N. Bethesda, MD\n\nwww.fda.gov", "n_tokens": 69, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-1-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 1, "text": "Office of Prescription Drug Promotion’s (OPDP) Mission\n\nProtect the public health by helping to ensure that prescription drug information is truthful, balanced, and accurately communicated\n\nGuard against false or misleading advertising and promotion through comprehensive surveillance, enforcement, and educational programs\n\nFoster better communication of information to help patients and healthcare providers make informed decisions about treatment options 2\n\nFoster better communication of information to help patients and healthcare providers make informed decisions about treatment options 2", "n_tokens": 86, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-2-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 2, "text": "Organizational Structure\n\nwww.fda.gov 3", "n_tokens": 8, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-3-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 3, "text": "www.fda.gov 4", "n_tokens": 6, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-4-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 4, "text": "Center for Food Safety & Applied Nutrition\n\nwww.fda.gov\n\nCenter for Drug Evaluation & Research\n\nFDA Organization\n\nOffice of the Commissioner\n\nCenter for Biologics Evaluation & Research\n\nCenter for Devices & Radiological Health\n\nCenter for Veterinary Medicine\n\nNational Center for Toxicological Research\n\nCenter for Tobacco Products\n\nOffice of Regulatory Affairs\n\n5", "n_tokens": 58, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-5-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 5, "text": "OPDP Organizational Structure\n\nThomas Abrams Director\n\nMark Askine Deputy Office Director\n\nAndrew Haffer Director Division of Advertising and Promotion Review I\n\nRobert Dean Director Division of Advertising and Promotion Review II\n\nCatherine Gray Supervisor Advertising and Promotion Policy Staff\n\nwww.fda.gov\n\n6", "n_tokens": 48, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-6-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 6, "text": "OPDP/Advertising and Promotion Policy Staff\n\nCatherine Gray Supervisor\n\nKatie David (Acting) Deputy Supervisor\n\nKathryn Aikin Team Lead Research Team\n\nRobyn Tyler Team Lead Regulatory Counsel Team\n\nJason Cober Team Lead Project Management Team\n\nKevin Betts Social Science Analyst\n\nJulie Chronis Regulatory Counsel\n\nDiane Nhu Project Manager\n\nAmie O’Donoghue Social Science Analyst\n\nLauren Miller Regulatory Counsel\n\nOlga Salis Project Manager\n\nHelen Sullivan Social Science Analyst\n\nDominic Cirincione Regulatory Counsel\n\nBecki Vogt Project Manager\n\nwww.fda.gov\n\nVacant Regulatory Counsel\n\nMichael Wade Project Manager\n\nSheila Ryan Team Lead Policy Team\n\nKemi Asante Policy Analyst\n\nElizabeth Pepinsky Policy Analyst\n\nChristine Corser Policy Analyst\n\nSabrina Smith Administrative Officer 7 (serving OPDP via OMP)", "n_tokens": 142, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-7-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 7, "text": "OPDP Research Team\n\nKathryn Aikin, Ph.D. (Team Lead) • Kevin Betts, Ph.D. • Amie O’Donoghue, Ph.D. • Helen Sullivan, Ph.D., M.P.H.\n\nwww.fda.gov\n\n8", "n_tokens": 59, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-8-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 8, "text": "How Social Science Can Inform Approach to Problems\n\nHelp identify goals\n\nIdentify barriers to achieving goals ‒ Cognitive barriers (capacity, motivation, attention) ‒ Behavioral barriers (time, opportunity) ‒ Others (literacy)\n\nIdentify potential solutions\n\nTest and verify effectiveness of solutions\n\nwww.fda.gov\n\n9", "n_tokens": 54, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-9-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 9, "text": "Role of Research Team What we do\n\nProvide scientific evidence and advice to help ensure that OPDP’s policies related to prescription drug promotion have the greatest benefit to public health – Investigate issues relevant to healthcare professional and patient/consumer usage of medical product information\n\nConsider the audience’s perception and comprehension of medical product information\n\nAssess the accuracy and effectiveness of the informational messages\n\nwww.fda.gov\n\n10", "n_tokens": 77, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-10-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 10, "text": "Role of Research Team (cont.) How we do it\n\nApply social science and communication principles to OPDP’s: – Advice to industry, academia or internal FDA\n\nstakeholders\n\nGuidance and policy development – Research – Surveillance and compliance activities\n\nwww.fda.gov\n\n11", "n_tokens": 52, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-11-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 11, "text": "OPDP’s Research Agenda\n\nProvide science-based evidence and perspective • Studies are proposed and selected to fulfill a number of purposes such as: – Congressional mandate – Help inform guidance and policy development – Enhance scientific literature base\n\nwww.fda.gov\n\n12", "n_tokens": 49, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-12-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 12, "text": "Application of Social Science Principles to Research\n\nAdvertising Features ‒ Content ‒ Format\n\nTarget Population(s) • Research Quality\n\nwww.fda.gov\n\n13", "n_tokens": 27, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-13-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 13, "text": "Focus of OPDP’s Research Studies\n\nAdvertising Features\n\nHow do the features of the promotion impact the communication and understanding of prescription drug product risks and benefits?\n\nExamples include:\n\nQuantitative Information • Advertising and message elements • Disease characteristics • Product characteristics • Other elements, such as cost or comparative information\n\nwww.fda.gov\n\n14", "n_tokens": 62, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-14-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 14, "text": "Focus of OPDP’s Research Studies (cont.)\n\nTarget Population\n\nHow does understanding of prescription drug product risks and benefits vary as a function of audience?\n\nVariables include:\n\nLiteracy • Education • Age\n\nwww.fda.gov\n\n15", "n_tokens": 46, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-15-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 15, "text": "Focus of OPDP’s Research Studies (cont.)\n\nResearch Quality\n\nHow can the quality of the research data be maximized to ensure the best possible return on investment for FDA?\n\nVariables include:\n\nAnalytical methodology development • Sampling and response issues\n\nwww.fda.gov\n\n16", "n_tokens": 54, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-16-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 16, "text": "Research Design Choices\n\nSurveys\n\nSurvey of opinions of DTC promotion\n\nExperimental research\n\nStudies that employ random assignment to\n\ncondition in order to test causative hypotheses • Qualitative research for development purposes – Smaller studies designed to efficiently focus future\n\nresearch priorities and considerations\n\nwww.fda.gov\n\n17", "n_tokens": 57, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-17-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 17, "text": "Advertising Features\n\nTarget Populations\n\nResearch Quality\n\nwww.fda.gov\n\nContent\n\nFormat\n\nAccelerated Approval Disclosure Adequate Provision Adolescent DTC Ads Animation in DTC Attentional Effects Brief Summary Claim ID Comparative Composite Corrective Disclosures Disease Awareness 1 Disease Awareness 2 Display Page (Consumer) Display Page (HCP) DTC Survey 2 Format Study Focus Groups on Targeted and Natural Framing Risks Pilot Frequency of Ad Exposure HCP Survey 1 HCP Survey 2 HCP Interviews 1 HCP Interviews 2 HCP Risk Processing Hearing and Older Adults Limited Space Market Share Claims in DTC Major Statement Content Analysis Mobile Content Analysis Oncology Disclosure Oncology Online Content Analysis Online Studies Price Comparison Quant TV Study Risk Amount and Location in DTC Risk in Each Part HCP Scale Development Source Study Standardized Risk Statement DTC Supers", "n_tokens": 154, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-18-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 18, "text": "Public Comment Periods for OPDP Social Science Research\n\nTwo statutory comment periods • 60-day Federal Register Notice\n\nComments to FDA\n\n30-day Federal Register Notice\n\nComments to OMB\n\nwww.fda.gov\n\n19", "n_tokens": 39, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-19-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 19, "text": "Sneak Peek at Upcoming Research\n\nFocus groups • Surveys • Experimental studies\n\nwww.fda.gov\n\n20", "n_tokens": 18, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-20-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 20, "text": "Interpretation of Claims in Scientific Publications vs. Promotional Pieces • Subject matter: Investigate the impact of information context, information quality, and presentation of FDA approval status in healthcare professional prescription drug promotion.\n\nDescription:\n\nThree types of context (medical journal, sales aid without graphic design elements, sales aid with graphic design elements)\n\nTwo types of study quality (classified as high or low) – Presence of a sentence saying the product is approved by FDA (present, absent).\n\nWe will test promotional (sales aid) and non-promotional (journal) sources to examine the potential differences in perception that may arise by presenting the same information in different contexts.\n\nwww.fda.gov\n\n21", "n_tokens": 132, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-21-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 21, "text": "Disease Awareness and Product Promotion in DTC Television Ad Contexts\n\nSubject matter: Test the effects of similarity, positioning, and timing of disease awareness ads on consumer perception and understanding of direct-to-consumer (DTC) product ads.\n\nDescription: In two studies, we will examine the impact of – – Perceptual similarity between target ads (disease\n\nawareness and product promotion)\n\nDistance between target ads over the course of programming\n\nExposure frequency and delay.\n\nwww.fda.gov\n\n22", "n_tokens": 95, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-22-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 22, "text": "Healthcare Professional Survey of Prescription Drug Promotion\n\nSubject matter: Healthcare professional promotion of prescription drugs\n\nDescription: A nationally representative sample of HCPs will be recruited online to answer questions about their opinions, attitudes, beliefs, and intentions regarding pharmaceutical promotion directed at them.\n\nwww.fda.gov\n\n23", "n_tokens": 55, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-23-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 23, "text": "Focus Groups Examining Accelerated Approval Information\n\nSubject matter: Consumer understanding of information about the accelerated approval process.\n\nDescription:\n\nEight focus groups – Focus group moderator will explain the accelerated approval process to participants and ask for their perceptions and reactions.\n\nFocus groups will explore the types of information participants would like to have when making decisions about prescription drugs.\n\nwww.fda.gov\n\n24", "n_tokens": 70, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-24-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 24, "text": "Experimental Study of an Accelerated Approval Disclosure\n\nSubject matter: Examine utility and consumer comprehensibility of a disclosure explaining the drug's accelerated approval\n\nDescription:\n\nParticipants will view a website for a fictional oncology prescription drug and then complete a questionnaire that assesses their attention to and understanding of the product’s accelerated approval information. – Websites will vary the presence, prominence, and readability of an accelerated approval disclosure. 25\n\nParticipants will view a website for a fictional oncology prescription drug and then complete a questionnaire that assesses their attention to and understanding of the product’s accelerated approval information. – Websites will vary the presence, prominence, and readability of an accelerated approval disclosure. 25", "n_tokens": 138, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-25-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 25, "text": "Healthcare Professional Interviews: Risk Processing for Newly Promoted Drugs • Subject matter: Healthcare professional promotion\n\nof prescription drugs\n\nDescription:\n\nStudy how HCPs process risk information for newly promoted prescription drug products, including any impact of typical time constraints.\n\nThe research methodology will involve in-person, semi- structured interviews with practicing HCPs.\n\nThe study will assess attention to risk information in a mock promotional piece using eye-tracking technology.\n\nwww.fda.gov\n\n26", "n_tokens": 87, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-26-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 26, "text": "Additional Information About OPDP Research\n\nOPDP Research Website • Completed projects – Link to publication • Research in progress\n\nLink to 60day FRN, 30day FRN\n\nhttps://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDER/ucm 090276.htm 27\n\nhttps://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDER/ucm 090276.htm 27", "n_tokens": 118, "kind": "text"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-27-0", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 27, "text": "AW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-0-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 0, "text": "Addressing Opioids: The FDA Response to Challenges in Public Health\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs Center for Drug Evaluation and Research FDA\n\nFDA-CMS Summit December 12, 2018\n\n1", "n_tokens": 44, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-1-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 1, "text": "Central Message\n\nFDA is responding to the public health challenges of opioids using all of our available tools to: – Address the ongoing crisis of opioid abuse and\n\nmisuse\n\nAddress the ongoing shortages of injectable prescription opioids\n\n2", "n_tokens": 48, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-2-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 2, "text": "The Opioid Challenges:\n\nOpioid Abuse and Misuse Injectable Opioid Shortages\n\nhttps://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates", "n_tokens": 45, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-3-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 3, "text": "Misuse and Abuse of Prescription Opioid Analgesics Remains an Important Public Health Problem\n\nIn 2017, prescription opioids were the largest category of pharmaceutical products misused and abused in US – 11.1 million people estimated to have past-year misuse/abuse – 1.7 million people estimated with DSM IV criteria for substance\n\nuse disorder involving prescription opioid analgesics\n\nIn comparison, 886,000 estimated to have past-year heroin use\n\nSource: Substance Abuse and Mental Health Services Administration. (2018). Key substance use and mental health indicators in the United States: Results from the 2017 National Survey on Drug Use and Health (HHS Publication No. SMA 18-5068, NSDUH Series H-53). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www. samhsa.gov/data/.\n\n4", "n_tokens": 192, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-4-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 4, "text": "Crisis Ongoing Despite Falling # of Prescriptions for Opioid Analgesics\n\nSource: IQVIA, National Prescription Audit (NPA) and static data 2006-2011. January 2006-December 2017. Static data extracted March 2017 and 2012-2017 data extracted February 2018. *Immediate-Release formulations include oral solids, oral liquids, rectal, nasal, and transmucosal **Extended-Release/Long-Acting formulations include oral solids and transdermal patches Note: Include opioid analgesics only, excluding injectable formulations as well as opioid-containing cough-cold products and opioid-containing medication-assisted treatment (MAT) products\n\nwww.fda.gov\n\n5", "n_tokens": 145, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-5-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 5, "text": "Consequences: Prescription Opioids and Overdose Death in the US\n\nFigure Source: National Institute on Drug Abuse Data Source: CDC Wonder Available from: https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates\n\nwww.fda.gov\n\n6", "n_tokens": 59, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-6-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 6, "text": "The FDA and Opioid Abuse/Misuse\n\n\"Unquestionably, our greatest immediate challenge is the problem of opioid abuse. This is a public health crisis of staggering human and economic proportion … we have an important role to play in reducing the rate of new abuse and in giving healthcare providers the tools to reduce exposure to opioids to only clearly appropriate patients, so we can also help reduce the new cases of addiction.\" - Scott Gottlieb, FDA Commissioner Address to FDA staff, May 15, 2017\n\n7", "n_tokens": 108, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-7-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 7, "text": "The Opioid Crisis: FDA’s Priorities\n\n1. Decreasing Exposure & Prevent New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\n8", "n_tokens": 54, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-8-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 8, "text": "The Opioid Crisis: FDA’s Priorities & Strategies\n\n1. Decreasing Exposure & Prevent New Addiction\n\n Appropriate Dose/Duration Labeling  Appropriate Packaging, Storage, and Disposal  Health Care Provider Education 2. Supporting the Treatment of Those With Opioid Use Disorder \n\nNaloxone Medication Assisted Treatment (MAT)\n\n3. Fostering the Development of Novel Pain Treatment Therapies  Partnerships & Meetings  Abuse Deterrent Formulations (ADFs)  Pain Treatment Alternatives 4. Improving Enforcement & Assessing Benefit-Risk Assessing Benefit-Risk\n\n9", "n_tokens": 101, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-9-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 9, "text": "FDA Priorities align to HHS Strategic Priorities and other National Activities\n\nHHS STRATEGIC PRIORITIES\n\nFDA PRIORITIES\n\nOTHER ACTIVITIES\n\nBetter data\n\nPresident’s Opioid Initiative\n\nBetter targeting of overdose-reversing drugs\n\nBetter research\n\nBetter addiction prevention, treatment, and recovery services\n\nBetter pain management\n\n1. Decreasing Exposure & Prevent New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\nOffice of National Drug Control Policy Recommendations\n\nComprehensive Addiction and Recovery Act (CARA)\n\nNational Pain Strategy Recommendations\n\nNational Public Health Emergency\n\n10", "n_tokens": 119, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-10-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 10, "text": "FDA Priorities Align with Recently Passed SUPPORT Act\n\nSubstance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT)\n\nMany new provisions affecting FDA including tools to: – more efficiently stop illegal, illicit, unapproved, counterfeit and potentially dangerous drugs from entering the U.S. through the IMFs\n\nreduce exposure to opioids as a way to lower the rate of new addiction\n\nrequire certain packaging, such as unit dose blister packs, for opioids and other drugs that pose a risk of abuse or overdose – require that opioids be dispensed with a mail-back pouch or\n\nother safe disposal option • Implementation ongoing\n\nhttps://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624268.htm 11", "n_tokens": 164, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-11-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 11, "text": "Example: Decreasing Exposure & Preventing New Addiction\n\nHOW?\n\nWHAT?\n\n\n\nAppropriate Packaging, Storage, and Disposal\n\nExplore how opioid analgesic drug products are packaged, stored, and discarded. Examine use of packaging strategies, such as unit-of-use packaging to improve opioid analgesic safety.\n\nJun 1, 2017: FDA/Duke Margolis workshop and white paper on packaging, storage, and disposal solutions.\n\nDec 11-12, 2017: Public\n\nworkshop to gain input on packaging strategies. Public docket closed March 2018 with 44 comments. Jan 2018: Requested packaging in limited amounts of over-the- counter anti-diarrheal medicine loperamide to curb intentional misuse and abuse.\n\n12", "n_tokens": 145, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-12-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 12, "text": "Target: Leftover Opioid Analgesics Reported in Post-surgical Populations\n\nAcross many surgical procedures,  >50% of patients\n\nreported excess supply of opioid analgesics after treatment of acute pain\n\napercentage of patients reporting use of 15 tablets or fewer\n\n Most patients kept excess supply and stored supply in unsecured locations\n\nFigure Source: Bicket MC, Long JJ, Pronovost PJ, Alexander GC, Wu CL. Prescription Opioid Analgesics Commonly Unused After Surgery: A Systematic Review. JAMA Surg. 2017 Nov 1;152(11):1066-1071.\n\nwww.fda.gov\n\n13", "n_tokens": 133, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-13-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 13, "text": "Opioid Analgesic Needs Vary by Condition/Procedure\n\nProcedure\n\nMean/ (range) tablets filled\n\nMean/Median tablets consumed\n\n~Days Used\n\nOutpatient Shoulder Surgery\n\n60 (n.d.)*\n\n37 (n.d.)*\n\n9-10\n\nCesarean Delivery\n\n40 (5-80)*\n\n20*\n\n4-5\n\nTooth Extraction\n\n28 (n.d.)\n\n13\n\n2-3\n\nUpper Extremity Surgery\n\n30 (n.d.)\n\n14 (Bone); 9 (Soft Tissue)\n\n2-3\n\nLaparoscopic Cholecystectomy\n\n30 (0-100)\n\n10-12\n\n2-3\n\nLaparoscopic Appendectomy\n\n30 (n.d.)*\n\n12*\n\n2-3\n\nPartial Mastectomy with Node Biopsy\n\n23 (0-60)\n\n6\n\n1-2\n\nLaparoscopic Inguinal Hernia Repair\n\n33 (15-70)\n\n9\n\n1-2\n\nOpen Inguinal Hernia Repair\n\n30 (15-120)\n\n9\n\n1-2\n\nPartial Mastectomy\n\n21 (0-50)\n\n3\n\n1\n\nDermatologic Surgery\n\n9 (3-20)\n\n4\n\n1\n\n1. Hill, et al., Ann Surg, 2017; 2. Bateman, et al., Obstet Gyn, 2017; 3. Maughan, et al., Drug Alc Dep, 2016; 4. Harris, et al., JAMA Dermatol. 2013; 5. Bockman, et al. J Pain, 2017 (Abstract); 6. Kumar, et al. AJSM, 2017\n\n~Leftover tablets\n\n23\n\n20\n\n15\n\n15\n\n20\n\n18\n\n17\n\n24\n\n21\n\n18\n\n5\n\n14", "n_tokens": 332, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-14-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 14, "text": "Issue: Opioid Analgesic in the Home Can Feed Other Problems if Misused\n\nExcess Supply after Treatment of Acute Pain\n\nAvailable Supply\n\nThird Party Access\n\nMisuse and Related Outcomes\n\nNon-Secure Storage\n\nLack of Disposal\n\nAccidental Exposure\n\n15", "n_tokens": 45, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-15-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 15, "text": "FDA Response: Potential Work on Packaging\n\nExploring whether a defined, short-term supply of medication could be packaged in a manner that limits the number of pills dispensed (e.g., blister packs)\n\nExploring packaging that could make it easier to track the number of doses that have been taken or reduce the risk for third-party access, such as teens ingesting pills they found in a medicine cabinet • Work to improve storage and encourage prompt disposal to reduce the available supply of unused opioids\n\n16", "n_tokens": 105, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-16-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 16, "text": "The Opioid Challenges:\n\nOpioid Abuse and Misuse Injectable Opioid Shortages", "n_tokens": 20, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-17-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 17, "text": "Shortages of Injectable Opioids\n\nOpioid shortages leave US hospitals\n\nscrambling\nIn the midst of a massive opioid crisis,\n~~ hospitals are experiencing an opioid\n\n: California te:\nla swosate SHOrtage\n\nUtah teen ge By Aaron Schachter\n\nlife for helpin\nherself\n\nHealthiest Communities The Civic Report Photos News\n\nHospitals Face Prolonged Injected Opioid Shortage\n\nThe other opioid crisis: Hospitals are frequently running out of widely used injected painkillers, and some patients are feeling the pain.\n\nHEALTHCARE OF TOMORRC\n\nThe health care industry is evolving, thanks,\n\nWe ar\nWoule 18", "n_tokens": 122, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-18-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 18, "text": "Origins of the IV Opioids Shortage\n\nCritical need for use in post-op settings • One large manufacturer reported shortages of multiple critical drugs including injectable hydromorphone and morphine due to manufacturing, distribution, third party supplier delays, as well as remediation efforts at one of their facilities, beginning in July of 2017\n\nLack of alternative sources for needed products with sufficient capacity to meet added demand\n\n19", "n_tokens": 82, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-19-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 19, "text": "FDA Work to Address IV Opioids Shortage\n\nFDA working with manufacturers to bring additional products to market\n\nExpediting review of all related applications – new approvals from two other manufacturers for morphine and hydromorphone are now being launched\n\nReleasing Carpuject syringes with potential cracked needle hubs under regulatory discretion with instructions for healthcare professionals to inspect and withdraw contents with a filter needle before administering to patients\n\nExtending expiration dating for multiple opioid products listed on the FDA website based on data from the manufacturer\n\nAllowing temporary import of unapproved hydromorphone in coordination with DEA\n\n20\n\n20", "n_tokens": 119, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-20-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 20, "text": "FDA Response to IV Opioids Shortage (cont)\n\nCoordinating with DEA on quota issues\n\nFDA shares information with DEA through a Memorandum of Understanding\n\nProviding a market assessment to DEA to assist them in their decision about whether to grant the quota\n\n21\n\n21", "n_tokens": 48, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-21-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 21, "text": "Trends in New Drug Shortages 2010-2017\n\nFrom FDA Drug Shortage Report to Congress, 2017 https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM610662. pdf\n\n22", "n_tokens": 48, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-22-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 22, "text": "What FDA Does to Address Drug Shortages\n\nDrug Shortage Staff focused on addressing drug shortages\n\nFacilitate temporary and long-term strategies to address shortages\n\nCoordinate timely and comprehensive risk/benefit decisions within FDA\n\nPersonnel across multiple FDA Offices involved in shortage response\n\nDistribute information (web posting, professional organizations): • https://www.fda.gov/Drugs/DrugSafety/DrugShortages/default.htm\n\nGoal: Maintain availability while minimizing risk to patients 23", "n_tokens": 91, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-23-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 23, "text": "What FDA Cannot Do to Address Drug Shortages\n\nFDA cannot require:\n\nA company to disclose details of why a shortage occurs\n\nA company to make a drug • A company to make more of a drug • How much and to whom the drug is distributed\n\n24", "n_tokens": 48, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-24-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 24, "text": "Trends in Preventing Drug Shortages 2010-2017 (FDA)\n\nFrom FDA Drug Shortage Report to Congress, 2017 https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/U CM610662.pdf\n\n25", "n_tokens": 51, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-25-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 25, "text": "Lessons Learned\n\nAvailability of drugs for patients is critical for healthcare – Interruptions of drug manufacturing due to any\n\nreason can lead to drug shortages with devastating impact on public health\n\nSources of drug shortages include manufacturing challenges and natural disasters – FDA response tailored to address underlying cause(s) – Communications and information sharing are critical both\n\nto preventing and to mitigating shortages\n\nRecovery from shortages takes time. Prevention is critical to reducing the numbers of drug shortages\n\n26", "n_tokens": 86, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-26-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 26, "text": "Ongoing FDA Shortage Work\n\nFDA Drug Shortage Taskforce\n\nAnnounced July 2018 • Goal of improved understanding of the forces leading to drug shortages and identify potential solutions\n\nStakeholder Listening Sessions  Pharmacies and Hospitals  Manufacturing Groups  Medical Groups  GPO’s and Distributors\n\nPublic meeting November 2018\n\nTaskforce Members\n\nFood and Drug Administration (CDER, CBER, CDRH, ORA) • Center for Medicare and Medicaid Services • The Office of the Assistant Secretary of Preparedness and Response • The Department of Veterans Affairs • The Department of Defense • The Federal Trade Commission 27", "n_tokens": 109, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-27-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 27, "text": "Conclusions\n\nFDA’s response to issues raised by opioids reflect unique challenges of how they are used, misused and abused – Addressing opioid abuse crisis a top priority for FDA\n\nMultiple ongoing activities coordinated within a policy framework focused on public health impacts\n\nSeparately, injectable opioid shortages reflect the larger challenge of drug shortages today\n\nFDA response is aimed at understanding and preventing shortages where possible, and at mitigating those that cannot be avoided\n\n28", "n_tokens": 90, "kind": "text"}
{"chunk_id": "TmortonFDA_CMS1218update_50-28-0", "doc_id": "TmortonFDA_CMS1218update_50", "page": 28, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-0-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 0, "text": "Charge to the Committee\n\nNational Academies of Science, Engineering, and Medicine November 13, 2018\n\nDouglas C. Throckmorton, MD Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research, FDA", "n_tokens": 40, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-1-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 1, "text": "Drug Overdose Deaths\n\nDrugs Involved in U.S. Overdose Deaths, 2000 to 2016\n25,000\nSyntheti joids other\n20,000 than Lae nerg 20,145\nHeroin, 15,446\n15,000\nNatural and semi-\nsynthetic opioids, 14,427\n40,000 Cocaine, 10,619\nMethamphe , 7,663\n—_” Methadone, 3,314\n\n1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016\n\nDrugs Involved in U.S. Overdose Deaths* - Among the more than 64,000 drug overdose deaths estimated in 2016,\nthe sharpest increase occurred among deaths related to fentanyl and fentanyl analogs (synthetic opioids) with over\n20,000 overdose deaths. Source: CDC WONDER", "n_tokens": 164, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-2-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 2, "text": "FDA Response to this Crisis \"Unquestionably, our greatest immediate challenge is the problem of opioid abuse. This is a public health crisis of staggering human and economic proportion … we have an important role to play in reducing the rate of new abuse and in giving healthcare providers the tools to reduce exposure to opioids to only clearly appropriate patients, so we can also help reduce the new cases of addiction.\" - Scott Gottlieb, FDA Commissioner Address to FDA staff, May 15, 2017", "n_tokens": 102, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-3-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 3, "text": "The Opioid Crisis: FDA’s Priorities\n\n1. Decreasing Exposure & Prevent New Addiction\n\n2. Supporting the Treatment of Those With Opioid Use Disorder\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n4. Improving Enforcement & Assessing Benefit-Risk", "n_tokens": 53, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-4-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 4, "text": "The Opioid Crisis: FDA’s Priorities & Strategies\n\n1. Decreasing Exposure & Prevent New Addiction\n\n Appropriate Dose/Duration Labeling  Appropriate Packaging, Storage, and Disposal  Health Care Provider Education\n\n2. Supporting the Treatment of Those With Opioid Use Disorder \n\nNaloxone Medication Assisted Treatment (MAT)\n\n3. Fostering the Development of Novel Pain Treatment Therapies\n\n Partnerships & Meetings  Abuse Deterrent Formulations (ADFs)  Pain Treatment Alternatives\n\n4. Improving Enforcement & Assessing Benefit-Risk\n\nImproving Enforcement Assessing Benefit-Risk", "n_tokens": 102, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-5-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 5, "text": "Treatment Guidelines\n\nProvide best available evidence for prescribers • Support more appropriate prescribing of opioids while ensuring that patients with pain are adequately treated\n\nDevelop new evidence where needed", "n_tokens": 36, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-6-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 6, "text": "Statement of Work: Framework Development • Develop a framework for evaluating the evidence base underpinning clinical treatment guidelines for opioid prescribing for acute pain – Develop a threshold level of evidence needed to support\n\nsuch guidelines\n\nConsider standards established in the 2011 IOM Report Clinical Practice Guidelines We Can Trust and other established standards for clinical assessment", "n_tokens": 66, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-7-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 7, "text": "Statement of Work: Current State of Practice • Inventory surgical and medical conditions associated\n\nwith acute pain where opioids are used – Include available information on dose and duration of\n\nopioid use by indication\n\nIdentify existing opioid prescribing guidelines for acute pain conditions and apply framework\n\nIdentify and prioritize acute pain conditions where evidence-based practice guidelines for pain could help inform prescribing practices", "n_tokens": 80, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-8-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 8, "text": "Statement of Work: Research Agenda\n\nDevelop a prioritized research agenda for\n\nWork to develop new treatment-specific treatment guidelines\n\nWork to support additional evidence to support existing guidelines\n\nAgenda should include a minimum of 5 conditions for indications that are abuse-prone and/or commonly prescribed", "n_tokens": 52, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-9-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 9, "text": "Summary\n\nFDA goal is to improve the state of the science supporting clinical practice guidelines for acute pain – Creating a framework for evidence generation and\n\nassessment\n\nInventorying existing treatment of acute pain and available evidence on opioid use\n\nCreating a research agenda for future work\n\nThis framework can then be used to improve the prescribing of opioids while ensuring that patients with acute pain are adequately treated", "n_tokens": 76, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-10-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 10, "text": "Thank You", "n_tokens": 2, "kind": "text"}
{"chunk_id": "Tmorton_NASEM_SOW_4-11-0", "doc_id": "Tmorton_NASEM_SOW_4", "page": 11, "text": "PN U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 10, "kind": "text"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-0-0", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 0, "text": "Update: Biosimilar Program in the U.S.\n\nLeah Christl, Ph.D. Associate Director for Therapeutic Biologics and Director of Therapeutic Biologics and Biosimilars Staff CDER/FDA\n\nMedicines for Europe Biosimilar Medicines Conference April 27, 2018", "n_tokens": 58, "kind": "text"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-1-0", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 1, "text": "Biosimilars Program • As of April 1, 2018, 63 programs were enrolled in the Biosimilar Product\n\nDevelopment (BPD) Program. CDER has received meeting requests to discuss the development of biosimilars for 31 different reference products.\n\nSince program inception and as of April 1, 2018, 12 companies have publicly announced submission of 23 351(k) BLAs to FDA.\n\nAs of April 1, 2018, nine 351(k) BLAs for biosimilar products have been approved. – Zarxio (filgrastim-sndz) – Erelzi (etanercept-szzs) – Renflexis (infliximab-abda) – Mvasi (bevacizumab-awwb) − Ogivri (trastuzumab-dkst) – Ixifi (infliximab-qbtx)\n\n− Inflectra (infliximab-dyyb) − Amjetiva (adalimumab-atto) − Cyltezo (adalimumab-adbm)\n\n2", "n_tokens": 238, "kind": "text"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-2-0", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 2, "text": "FDA Biosimilars Guidance 1. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (final, 2015) 2. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (final, 2015) 3. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and\n\n4.\n\nInnovation Act of 2009 (final, 2015) Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (final, 2015)\n\n5. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (final, 2016)\n\n6. Nonproprietary Naming of Biological Products (final, 2017) 7. Best Practices for Communication Between IND Sponsors and FDA During Drug Development [to apply to communications between IND sponsors and FDA during biosimilar biological product development] (final, 2017)\n\n8. Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (draft, 2015) Labeling for Biosimilar Products (draft, 2016)\n\n9. 10. Considerations in Demonstrating Interchangeability With a Reference Product (draft, 2017) 11. Statistical Approaches to Evaluate Analytical Similarity (draft, 2017)\n\nhttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm\n\n3", "n_tokens": 289, "kind": "text"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-3-0", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 3, "text": "Development of Future Guidance  FDA has committed to publish draft, revised draft, or final guidance describing the\n\nfollowing: – Statistical Approaches to Evaluate Analytical Similarity (draft guidance published September 2017;\n\nrevised draft or final guidance by 5/21/19)\n\nConsiderations in Demonstrating Interchangeability With a Reference Product (draft guidance published January 2017; revised draft or final guidance by 5/19/19)\n\nLabeling for Biosimilar Biological Products (draft guidance published March 2016; revised draft or final guidance by 5/31/19)\n\nFormal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (final guidance published November 2015; revised draft by 9/30/18)\n\nGood Review Management Practices (revised draft by 9/30/18) – Processes and further considerations related to post-approval manufacturing changes for biosimilar biological products (draft guidance by 3/31/19)\n\n4", "n_tokens": 177, "kind": "text"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-4-0", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 4, "text": "International Activities\n\nFDA-EMA-Health Canada-PMDA biosimilars cluster\n\nSupporting an efficient global market for biosimilars entails sharing regulatory experience across national boundaries to support product development\n\nPartnerships can facilitate global economies of scale in biosimilar development programs\n\nSupporting other NRAs through FDA’s Office of International Programs\n\n5", "n_tokens": 66, "kind": "text"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-5-0", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 5, "text": "Biosimilars: FDA Strategic Priority • FDA’s 2018 Strategic Policy Roadmap announced FDA’s plan to launch a\n\ncomprehensive program to encourage biosimilar competition.\n\nGoal: to help address the high cost of medicines through the development of science-based policies that can improve competition, access, and the opportunity for patients to benefit from safe and effective, and lower cost biosimilar alternatives. – Examining biosimilar program to better integrate policy and review functions that can provide greater scientific and regulatory clarity for sponsors, and greater efficiencies in the review of biosimilar and interchangeable applications.\n\nEvaluating development of information resources and tools that can assist biosimilar sponsors in developing high quality biosimilar and interchangeable products using state of the art analytical techniques.\n\nModernizing regulatory policy to accommodate new scientific tools that can better enable comparison between biosimilars and reference products that may reduce the need for certain clinical studies. 6", "n_tokens": 194, "kind": "text"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-6-0", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 6, "text": "Education & Outreach Campaign for Biosimilars • Launched by FDA in October 2017 • Goals of this initiative are to increase:\n\nUnderstanding of biologics, reference products, biosimilars and interchangeable products.\n\nAwareness of FDA’s role in the biosimilar and interchangeable approval process.\n\nKnowledge of the data and information FDA reviews/requires to determine biosimilarity and interchangeability.\n\nKnowledge about the prescribing of biosimilar and interchangeable products.\n\nFDA offers a variety of patient and prescriber outreach materials, including graphics, drop-in content, and social media messages, to help promote understanding of biosimilars and interchangeable products.\n\n7", "n_tokens": 140, "kind": "text"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-7-0", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 7, "text": "For more information, go to www.fda.gov/biosimilars\n\n8", "n_tokens": 17, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-0-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 0, "text": "Use of Bayesian Hierarchical Models in the Presentation of Subgroup Analyses*\n\nMark Rothmann U.S. Food and Drug Administration DIA Bayesian Scientific Working Group Webinar Series November 19, 2021", "n_tokens": 38, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-1-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 1, "text": "Disclaimer\n\nThe views expressed in this talk are those of the speaker and not necessarily those of the FDA\n\n2", "n_tokens": 22, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-2-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 2, "text": "Outline\n\nDrug Trials Snapshots (DTS) • Heterogeneous Treatment Effects • Different Perspectives • Story • Shrinkage Estimation • Bayesian Hierarchical Models • Examples • Concluding Remarks\n\n3", "n_tokens": 37, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-3-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 3, "text": "Drug Trials Snapshots\n(DTS)", "n_tokens": 9, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-4-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 4, "text": "FDASIA 2012 Section 907 • SEC. 907. REPORTING OF INCLUSION OF DEMOGRAPHIC SUBGROUPS IN CLINICAL\n\nTRIALS AND DATA ANALYSIS IN APPLICATIONS FOR DRUGS, BIOLOGICS, AND DEVICES. (1) IN GENERAL.—Not later than 1 year after the date of enactment of this Act, the Secretary, acting through the Commissioner, shall publish on the Internet web site of the Food and Drug Administration a report, consistent with the regulations of the Food and Drug Administration pertaining to the protection of sponsors’ confidential commercial information as of the date of enactment of this Act, addressing the extent to which clinical trial participation and the inclusion of safety and effectiveness data by demographic subgroups including sex, age, race, and ethnicity, is included in applications submitted to the Food and Drug Administration, and shall provide such publication to Congress\n\nwww.fda.gov\n\n5", "n_tokens": 167, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-5-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 5, "text": "FDA ACTION PLAN TO ENHANCE THE COLLECTION AND AVAILABILITY OF DEMOGRAPHIC SUBGROUP DATA\n\nwww.fda.gov\n\n6", "n_tokens": 19, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-6-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 6, "text": "Message from Margaret A. Hamburg, M.D., Commissioner of Food and Drugs (continue) • … Advances in science are also playing an increasingly important role in deepening our understanding of how patients within various subgroups respond to medical products. … an action plan outlining “recommendations for improving the completeness and quality of analyses of data on demographic subgroups in summaries of product safety and effectiveness data … .”\n\n7", "n_tokens": 86, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-7-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 7, "text": "www.fda.gov\n\nPurpose of DTS • Provide consumers and healthcare professionals with information about who participated in clinical trials that supported the FDA approval of new drugs (NMEs and original biologics).\n\nProvide information on study design. • Highlight potential differences in efficacy and safety results among gender, race, and age subgroups.\n\nIncrease transparency.\n\n8", "n_tokens": 70, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-8-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 8, "text": "Snapshots are not a PI\n\nDrug Trials Snapshot • Intended for public • Consumer-friendly Language • Focus on subgroup data and\n\nPackage Insert • Intended for Physicians • Technical Language • Comprehensive Resource for drug\n\nanalyses\n\ninformation\n\nLinks to PI and reviews in Drugs@FDA\n\nNo links to reviews • Finalized with drug approval\n\nPublished on fda.gov 30 days after drug approval\n\n9\n\n9", "n_tokens": 72, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-9-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 9, "text": "Another difference between snapshots and package inserts\n\nDrug Trials Snapshots\n\nPackage Inserts\n\nSubgroup analyses, interpretations and conclusions are those of FDA\n\nNegotiated between FDA and sponsor\n\n10", "n_tokens": 34, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-10-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 10, "text": "Audience\n\nShould consider audience when constructing a DTS\n\nWhat is the effect someone like me can expect? • Increase usage of subgroup analysis in Safety\n\ntreatment-related adverse events can be more frequent as age increases\n\n11", "n_tokens": 40, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-11-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 11, "text": "Heterogeneous\nTreatment Effects (HTE)\n\nwww.fda.gov\n\n12", "n_tokens": 16, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-12-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 12, "text": "Treatment effects vary across subgroups of a factor\n\nFactor an effect modifier or • Factor associated/correlated with one or more effect modifiers\n\n13", "n_tokens": 28, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-13-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 13, "text": "Conventional subgroup analysis (1 of 3)\n\nNo. of\n\nSubgroup Patients Relative Risk\nSex ;\n\nMale 15,696 —i—\n\nFemale 4,783 a\nAge ‘\n\n<75 yr 17,947 a\n\n275 yr 2,532 +A\nInfarct location\n\nAnterior 8,933 i\n\nOther 11,400 ——\nDiabetes ‘\n\nNo 17,189 ff\n\nYes 3,060 —_*—\nPrior MI t\n\nNo 17,745 —a\n\nYes 2,659 ——\nFibrinolytic agent ‘\n\nStreptokinase 4,139 ef\n\nFibrin-specific 16,283 —a\nTime to treatment\n\n<Median 9,899 ——-\n\nMedian 10,394 ——\nOverall 20,479 <>\n\n0s 1.0\n\n14", "n_tokens": 160, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-14-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 14, "text": "Conventional subgroup analysis (2 of 3)\n\nSubject to random highs and random lows\n\nEstimated treatment effects vary more than underlying treatment effects\n\nAnalysis are typically univariate or marginal - one subgrouping variable at a time\n\nPossibly confounded by correlation between subgrouping variables – If sex and age are correlated, the difference in treatment efficacy between men and women may be confounded by age\n\nGroenwold (2009) - Aspirin’s effect on stroke was larger in women, but women were older\n\n15", "n_tokens": 100, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-15-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 15, "text": "Conventional subgroup analysis (3 of 3) • Assume treatment effect equal across subgroups (unless compelling evidence that they differ). When estimating treatment effect in interested subgroup – Equal relevancy of outcomes for patient outside interested subgroup outcome and\n\npatient in interested subgroup\n\nUnder this assumption analysis (estimation of treatment effect) is simple, easy\n\nOR use only data from patients in interested subgroup to estimate the treatment effect for interested subgroup – Patient outside interested subgroup outcome provides no information (no\n\nrelevancy)\n\nUnder this assumption analysis (estimation of treatment effect) is simple, easy\n\n16", "n_tokens": 112, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-16-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 16, "text": "Recent Symposiums and Workshops co-sponsored by FDA on Heterogeneous Treatment Effects\n\nNov 28, 2018, Symposium of Assessing and Communicating Heterogeneity of Treatment Effects for Patient Subpopulations: Challenges and Opportunities – Agenda, Slides and Recording at https://www.jhsph.edu/research/centers-and- institutes/center-of-excellence-in-regulatory-science-and-innovation/news-and- events/Critical-Issues-in-Heterogeneity-of-Treatment-Effect.html\n\nNov 30 - Dec 1, 2020, Workshop on Heterogeneity of Treatment Effects in Clinical Trials: Methods and Innovations – Agenda and Recording at https://mrctcenter.org/news-events/heterogeneity-of- treatment-effects-in-clinical-trials-methods-and-innovations/#1602863324215- 1289c9d5-a82a 17", "n_tokens": 204, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-17-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 17, "text": "Symposium of Assessing and Communicating Heterogeneity of Treatment Effects for Patient Subpopulations: Challenges and Opportunities\n\nSome messages from the session\n\nWe can do more or better at understanding heterogeneous treatment effects\n\nHave used shrinkage estimation for some drug trial snapshots • More complicated/better models could include factors known to affect the treatment effect\n\nDoable (somewhere) in some settings to have a repository of data to be used to provide individual patient advice which can account for patient preferences, patient demographics and medical history\n\nwww.fda.gov\n\n18", "n_tokens": 109, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-18-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 18, "text": "Workshop on Heterogeneity of Treatment Effects in Clinical Trials: Methods and Innovations\n\nSome Topics/Questions of interest\n\nRepresentation in clinical trials • What can a patient like me expect? • Is there consistency of treatment effect? • If there is a benefit overall, where may there not be benefit? • Difference in using subgroup analyses to make a claim vs. individual patient treatment decisions\n\nHow do overall results affect how we view subgroup results?\n\n19", "n_tokens": 87, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-19-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 19, "text": "Different\nPerspectives/\nFrameworks\n\nwww.fda.gov\n\n20", "n_tokens": 11, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-20-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 20, "text": "Different subgroup analyses perspectives/frameworks\n\nL1: Actual (signed) differences in treatment effects vs • L2: Variability in treatment effects\n\n21", "n_tokens": 28, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-21-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 21, "text": "Testing for differences in effects\n\nConsider two subgroups (e.g., one factor with two levels) • Interest in order/direction of effects and the difference in effects • Zero difference in effects is at a key (central) location\n\n| 0\n\nTreatment effect larger in Subgroup 2 than in Subgroup 1\n\nTreatment effect larger in Subgroup 1 than in Subgroup 2\n\n22", "n_tokens": 70, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-22-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 22, "text": "Estimating treatment effects across subgroups\n\nNo difference in effects is at an extreme location (i.e., 2 = 0)\n\n| 0 2 = 0\n\n100% borrowing\n\nLess Borrowing\n\n23", "n_tokens": 37, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-23-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 23, "text": "www.fda.gov\n\nStory\n\n24", "n_tokens": 7, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-24-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 24, "text": "Introductory Paragraph from the Impact Story\n\nWhen evaluating drug treatments, determining how and to what extent a drug works in different patient subgroups can be addressed by statistical approaches that make use of results from every subgroup when understanding the treatment effect for a given subgroup.\n\nusing-innovative-statistical-approaches-provide-most-reliable-treatment-outcomes\n\n25", "n_tokens": 67, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-25-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 25, "text": "Treatment Decisions\n\nPhysicians make treatment decisions on past experience with patients\n\n26", "n_tokens": 12, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-26-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 26, "text": "New Drug • Sex may or may not be an effect modifier • No other factor is considered as a possible effect modifier • Physician has experience on the use of the new drug and outcomes in\n\n2 males and 2 females\n\nThe next patient, a female, is prescribed the new drug from that physician. What can she expect? – Probably use information from all four previous patients. – Outcomes from females may be more relevant than the outcomes from\n\nmales.\n\n27", "n_tokens": 90, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-27-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 27, "text": "As Previous Experience Grows\n\nObserve the outcomes from more and more males and females • The relevancy of the results from males in what the next female can expect. Depends on – How similar the results from males are to the results from females – How much data on females\n\n28", "n_tokens": 54, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-28-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 28, "text": "Shrinkage Estimation from Bayesian Hierarchical Models Works this Way • Data from a subject in the given subgroup are more relevant than\n\ndata from a subject outside that subgroup – The relevancy goes to zero as the number of subjects in the subgroup of\n\ninterest goes to infinity\n\nThe data decide how much borrowing is done\n\nDepends on ratio of variability within subgroup to variability between subgroup • Less borrowing when within subgroup variability decreases (its sample size\n\nincreases)\n\n29", "n_tokens": 86, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-29-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 29, "text": "How much shrinkage/borrowing\n\nMore shrinkage toward the F am 4\noverall average\n\n* Overall average\n\nTTT fT htst.TCTTC\n\n0 20 40 60 80\n\nLess shrinkage toward the\noverall average\n\nret He » HH bQey\n\nOverall average\n\n100\n\nNorth America\nSouth America\nAsia\n\nEurope\n\nOther\n\na a <n ae\n\n0 20 40 60 80\n\nPercent responders\n\n100\n\n30", "n_tokens": 75, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-30-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 30, "text": "Shrinkage Estimation\n\nwww.fda.gov\n\n31", "n_tokens": 9, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-31-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 31, "text": "What is Shrinkage Estimation?\n\nA shrinkage estimate of a parameter for a subgroup\n\na weighted average of sample estimate and overall estimate (stratified by subgroup). • Could be a posterior mean in a Bayesian setting\n\nSample estimate is “shrunk” towards the overall estimate\n\n32", "n_tokens": 57, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-32-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 32, "text": "33\n\n|\n\nSample estimate\n\nNo borrowing\n\nAmount of Borrowing\n\n|\n\nShrinkage estimate\n\nSome borrowing\n\n|\n\nOverall estimate\n\n100% borrowing\n\n33", "n_tokens": 22, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-33-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 33, "text": "Two components of variability in sample estimates across subgroups\n\nThe total variability in the sample estimates is sum of\n\nthe within subgroup variability of the sample estimator and – the across subgroups variability in the underlying/true parameter values\n\n34", "n_tokens": 45, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-34-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 34, "text": "Purpose of Shrinkage Estimation\n\nTo address within study/subgroup variability in the estimation\n\nObtain estimates where unaccounted variability is across studies/subgroups variability\n\nCollection of shrinkage estimates tends to be closer to the collection of true subgroup effects than the sample estimates\n\n35", "n_tokens": 51, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-35-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 35, "text": "Importance of shrinkage in estimation\n\nGreater precision – narrower 95% CIs\n\nQuantitatively addresses random highs and random lows\n\nLipsky, A. M., Gausche-Hill, M., Vienna, M., Lewis, R. J. (2010). The importance of \"shrinkage\" in subgroup analyses. Annals of Emergency Medicine. Jun;55(6):544-552\n\nPennello G., Rothmann M., Bayesian Subgroup Analysis with Hierarchical Models, in Biopharmaceutical Applied Statistics Symposium Volume 2: Biostatistical Analysis of Clinical Trials, Eds. Karl E. Peace, Ding-Geng Chen, Sandeep Menon, Springer\n\n36", "n_tokens": 142, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-36-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 36, "text": "Model for Shrinkage Estimation\n\nDo Shrinkage Estimation through Bayesian Hierarchical Models\n\n37", "n_tokens": 15, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-37-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 37, "text": "Bayesian Hierarchical\nModels\n\nwww.fda.gov\n\n38", "n_tokens": 10, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-38-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 38, "text": "Hierarchical Models\n\nStatistical model written in multiple levels (hierarchical form).\n\n39", "n_tokens": 14, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-39-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 39, "text": "Linking\n\nTreatment effects (e.g., across studies, subgroups, products in the same class) are linked. This linking of the parameters makes their estimation linked.\n\n40", "n_tokens": 35, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-40-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 40, "text": "Exchangeability –a starting point\n\nSubgroups treatment effects are exchangeable if possible orderings of treatment effects are considered equally likely a priori (i.e., before seeing data) – This is fair, not favoring any subgroup treatment effects over any other – Joint prior distribution of subgroup treatment effects is exchangeable – Very unlikely that the joint posterior distribution will be exchangeable\n\n41", "n_tokens": 76, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-41-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 41, "text": "Common choice for a model\n\nTreatment effects drawn randomly from the same distribution implies that treatment effects are exchangeable\n\n42", "n_tokens": 21, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-42-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 42, "text": "Exchangeability\n\nExchangeability of subgroup treatment effects not always a correct assumption. – Drug expected to be more effective in subgroup of cancer patients who\n\nexhibit molecular target than subgroup of patients without target. • Shrinkage analysis incorrectly assuming exchangeability still\n\naccounts for a component of variability\n\n43", "n_tokens": 53, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-43-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 43, "text": "Smallest Expected Mean Square Error\n\nEstimation error: ෠𝜃𝑖 − 𝜃𝑖 2 • Squared error: ෠𝜃𝑖 − 𝜃𝑖 • Mean squared error at particular true effect: 𝐸( • Expected Sum of squared error (expectation over the parameter space): 𝜃1,…𝜃𝑘)\n\nRelative to joint prior distribution over parameter space, shrinkage estimation gives smallest expected sum of square error for collection of subgroup treatment effect across all joint estimators – And within each subgroup, the optimal estimator\n\n44", "n_tokens": 92, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-44-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 44, "text": "www.fda.gov\n\nExample\n\n45", "n_tokens": 7, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-45-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 45, "text": "LEADER trial\n\nCardiovascular outcome trial • Liraglutidevs. placebo • Time to first major adverse cardiac event • Rule out a hazard ratio greater than 1.3\n\nOverall Result: HR =0.87 95% CI (0.78, 0.97)\n\n46", "n_tokens": 55, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-46-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 46, "text": "Subgroup Analyses\n\nResults\n\nRegion\n\nHR (95% CI)\n\nAsia\n\n0.62 (0.37, 1.04)\n\nEurope\n\n0.82 (0.68, 0.98)\n\nNorth America\n\n1.01 (0.83, 1.22)\n\nThe Rest of The World\n\n0.83 (0.68, 1.03)\n\n47", "n_tokens": 68, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-47-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 47, "text": "Modeling Assumptions\n\n1/2 is distributed Gamma (.001, .001) •  is distributed Normal mean 0, variance 16 • i is distribution Normal mean , variance 2 i =1, 2,3 ,4 • For i = 1, 2,3, 4 Yi represents the observed subgroup log hazard ratio\n\nYi is distributed Normal mean i variance i 2 = 0.0094 and 4 2 = 0.0088, 3\n\n1\n\n2 where 2 = 0.114\n\n48", "n_tokens": 96, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-48-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 48, "text": "Defines Joint Prior Distribution\n\n1/2 is distributed Gamma (.001, .001) •  is distributed Normal mean 0, variance 16 • i is distribution Normal mean , variance 2 i =1, 2,3 ,4 • For i = 1, 2,3, 4 Yi represents the observed subgroup log hazard ratio\n\nYi is distributed Normal mean i variance i 2 = 0.0094 and 4 2 = 0.0688, 2\n\n1\n\n2 where 2 = 0.114\n\n49", "n_tokens": 98, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-49-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 49, "text": "Region\n\nAsia\n\nEurope\n\nNorth America\n\nThe Rest of the World\n\nFDA Shrinkage Analysis\n\nSample estimate\n\nBayes Shrinkage estimate\n\nHR\n\n95% CI\n\nHR\n\n95% CI\n\n0.622\n\n(0.372, 1.040)\n\n0.803\n\n(0.591, 1.089)\n\n0.815\n\n(0.678, 0.979)\n\n0.836\n\n(0.715, 0.978)\n\n1.010\n\n(0.835, 1.220)\n\n0.936\n\n(0.786, 1.115)\n\n0.833\n\n(0.676, 1.027)\n\n0.847\n\n(0.716, 1.003)\n\n50", "n_tokens": 147, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-50-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 50, "text": "Region\n\nAsia\n\nEurope\n\nNorth America\n\nThe Rest of the World\n\nFDA Shrinkage Analysis\n\nSample estimate\n\nBayes Shrinkage estimate\n\nHR\n\n95% CI\n\nHR\n\n95% CI\n\n0.622\n\n(0.372, 1.040)\n\n0.803\n\n(0.591, 1.089)\n\n0.815\n\n(0.678, 0.979)\n\n0.836\n\n(0.715, 0.978)\n\n1.010\n\n(0.835, 1.220)\n\n0.936\n\n(0.786, 1.115)\n\n0.833\n\n(0.676, 1.027)\n\n0.847\n\n(0.716, 1.003)\n\n51", "n_tokens": 147, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-51-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 51, "text": "Region\n\nAsia\n\nEurope\n\nNorth America\n\nThe Rest of the World\n\nFDA Shrinkage Analysis\n\nSample estimate\n\nBayes Shrinkage estimate\n\nHR\n\n95% CI\n\nHR\n\n95% CI\n\n0.622\n\n(0.372, 1.040)\n\n0.803\n\n(0.591, 1.089)\n\n0.815\n\n(0.678, 0.979)\n\n0.836\n\n(0.715, 0.978)\n\n1.010\n\n(0.835, 1.220)\n\n0.936\n\n(0.786, 1.115)\n\n0.833\n\n(0.676, 1.027)\n\n0.847\n\n(0.716, 1.003)\n\n52", "n_tokens": 147, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-52-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 52, "text": "Example - ACR20\nresponse\n\nwww.fda.gov\n\n53", "n_tokens": 12, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-53-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 53, "text": "Bayesian hierarchical model assumptions\n\nFor i = 1, …, k, Yi represents the estimated difference in ACR20 response in a subgroup level i, assume Yi approximately N(μi, σi2) where\n\nσi2 are the estimated CMH weighted variance of the difference in ACR20 in subgroup level I\n\nμi ~ N(μ, τ2)\n\nμ ~ N(0, ω2), 1/τ2 ~ Gamma(0.001, 0.001)\n\nω was chosen to be 4\n\nwww.fda.gov\n\n54", "n_tokens": 111, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-54-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 54, "text": "Table 1. Effects of Upadacitinib on Percent ACR20 Responders by Subgroups, Methotrexate-Controlled Trial\n\nDemographic Parameter\n\nACR20 % (n/N)\n\nTreatment Differencea\n\nMethotrexate\n\nUpadacitinib\n\n(95% CI)\n\nSex\n\nMale\n\n43% (16/37)\n\n60% (26/43)\n\n21% (2%, 40%)\n\nFemale\n\n41% (73/179)\n\n70% (121/174)\n\n28% (18%, 38%)\n\nAge in Years\n\nYounger than 40\n\n52% (12/23)\n\n82% (23/28)\n\n27% (10%, 45%)\n\n40 to 64\n\n39% (58/148)\n\n68% (100/147)\n\n28% (18%, 38%)\n\n65 or Older\n\n42% (19/45)\n\n57% (24/42)\n\n21% (4%, 38%)\n\nRace\n\nWhite\n\n43% (76/176)\n\n68% (118/173)\n\n26% (16%, 35%)\n\nBlack / African American\n\n45% (5/11)\n\n33% (5/15)\n\n6% (-32%, 43%)\n\nAsian\n\n29% (7/24)\n\n88% (21/24)\n\n51% (27%, 75%)\n\na Treatment differences and credibility intervals may not match value of (treatment - control) since estimates include relevance of outcomes from other subgroups\n\nwww.fda.gov\n\nShrinkage Estimates for Treatment Difference\n\n55", "n_tokens": 303, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-55-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 55, "text": "Concluding Remarks\n\nwww.fda.gov\n\n56", "n_tokens": 8, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-56-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 56, "text": "Other models\n\nA one-way hierarchical model that also accounts for an effect modifier – Rothmann, M., Applying Hierarchical Models When Evaluating\n\nTreatment Effects Across Regions presented at 2018 ASA Biopharmaceutical Section Regulatory-Industry Statistics Workshop\n\nA multi-way hierarchical model\n\nExample from the SOLVD trial in “Bayesian analysis of heterogeneous treatment effects for patient-centered outcomes research” by Henderson, Louis, Wang and Varadhan\n\n57", "n_tokens": 90, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-57-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 57, "text": "Let’s Do Things Better\n\nGreater precision – narrower 95% CIs\n\nAddresses random highs and random lows\n\n95% CIs have 95% coverage after the data are known\n\nWhen exchangeability assumptions do not hold, can possibly do even better\n\n58", "n_tokens": 46, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-58-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 58, "text": "Chapter from a new book\n\nPennello G., Rothmann M., Bayesian Subgroup Analysis with Hierarchical Models, in Biopharmaceutical Applied Statistics Symposium Volume 2: Biostatistical Analysis of Clinical Trials, Eds. Karl E. Peace, Ding-Geng Chen, Sandeep Menon, Springer\n\n59", "n_tokens": 65, "kind": "text"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-59-0", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 59, "text": "Thank You!\nQuestions!", "n_tokens": 5, "kind": "text"}
{"chunk_id": "ddi_figure_oct_2024-0-0", "doc_id": "ddi_figure_oct_2024", "page": 0, "text": "Key Webinar Points - FDA Drug Topics: Cannabis Products and the Potential Impact on Patients\n\nBackground:\n\n Clinical:\n\n> 500 compounds in Cannabis sativa L. plant Δ9- tetrahydrocannabinol (Δ9-THC) is intoxicating cannabidiol (CBD) alone is not intoxicating State-regulated products vary widely (medical & adult-use) Hemp products largely unregulated & widely available (e.g., gas stations, online) Products can be manufactured from plant parts or from chemicals Labeling may be misleading (e.g., hidden ingredients)\n\n Patients use cannabis or cannabis-derived products to self-medicate for pain, PTSD, sleep disorders, IBS, etc. Outside FDA approved drugs - general lack of high-quality evidence to support the above medical conditions Educate patients about risks including DDI, adverse events, abuse potential, & withdrawal syndromes (if chronic use)\n\n Approach to Patient Conversation:\n\nBrain\n\nCB1 - Euphoria, pain relief, psychosis, sedation, appetite, memory impairment\n\nHeart\n\nCB1 - Tachycardia, hypotension\n\nΔ9-THC & CBD Key Clinical Effects\n\nImmune System CB2 - Immune modulation\n\nStart: Screen high risk patients (e.g., pain, psychiatric) using open-ended questions\n\nInquire: Reasons for use of cannabis products “What benefits do you find from taking (product)?” Duration/amount - “How often have you used (product) in past month/year?”\n\nΔ9-THC Pharmacodynamics & Pharmacokinetics:\n\n Identify:\n\nOrally peaks around 1-3 hr; Duration ~7hr\n\nUser may believe desired effects did not occur & may re-dose\n\nInhalation peaks ~3-10 min; Impairment greatest in first hr; Duration ~2-4 hr\n\nMuch faster onset than oral with higher maximum plasma levels leading to more deleterious effects.\n\n Liver\n\nCBD - Elevated Transaminase Δ9-THC & CBD - numerous potential drug interactions\n\nStomach CB1 - Reduces motility/peristalis, antiemetic (central acting)\n\nSource of product “Where do you buy (product) and do you have the label?", "n_tokens": 461, "kind": "text"}
{"chunk_id": "ddi_figure_oct_2024-0-1", "doc_id": "ddi_figure_oct_2024", "page": 0, "text": "”\n\nDiscuss:\n\nPotential or active concerns (e.g., AEs, substance use disorder, side effects, DDI) Highlight available approved treatments\n\nKey Pharmacodynamic Interactions\n\nKey Pharmacokinetic Interactions\n\nPrecipitant\n\nMechanism\n\nSubstrate\n\nClinical Impacts\n\nPrecipitant\n\nMechanism\n\nSubstrate\n\nClinical Impacts\n\nCBD\n\nCombined liver inflammatory effects\n\nValproate\n\nDiscontinuation or reduction of CBD\n\nCBD/Δ9-THC\n\nCBD/Δ9-THC\n\nCYP3A4\n\nCYP2C9-inhibit/protein binding\n\nSildenafil\n\nWarfarin\n\nCase reports of MI when combined with cannabis\n\nCase reports of increased INR\n\nCBD\n\nDecreased renal clearance\n\nLithium\n\nConsider lower lithium dose, frequent monitoring while dosing\n\nCBD\n\nSmoked Cannabis\n\nCYP2C19 inhibit\n\nCYP1A2 induction\n\nDiazepam, clobazam\n\nOlanzapine, clozapine\n\nConsider lower doses of the substrate\n\nEducate, watch for change in efficacy, check drug levels\n\nΔ9-THC\n\nAdditive CNS effects\n\nAlcohol, benzos, opioids\n\nAvoid concomitant use, educate patient, monitor for CNS adverse effects\n\nFluconazole\n\nCYP2C19 inhibit\n\nCBD\n\nEducate about possible adverse effects and/or stop CBD\n\nAmiodarone\n\nCYP2C9 inhibit\n\nTHC\n\nEducate about possible adverse effects/stop THC\n\nΔ9-THC\n\nAdditive cardiac effects\n\nStimulants\n\nAvoid concomitant use, educate patients, monitor for cardiac effects (e.g., tachycardia, hypertension)\n\nKetoconazole Macrolides\n\nCYP3A4 inhibit\n\nCBD and THC\n\nEducate about possible adverse effect and/or stop CBD", "n_tokens": 341, "kind": "text"}
{"chunk_id": "ddi_figure_oct_2024-1-0", "doc_id": "ddi_figure_oct_2024", "page": 1, "text": "References:\n\n1. 2. 3.\n\n4.\n\n5. 6. 7. 8.\n\n An D, Peigneur S, Hendrickx LA, Tytgat J. 2020. Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products. Int J Mol Sci. Jul 17;21(14):5064 Antoniou T, Bodkin J, Ho JM. 2020. Drug interactions with cannabinoids. CMAJ. Mar 2;192(9):E206. Grayson L, Vines B, Nichol K, Szaflarski JP. 2017. UAB CBD Program. An interaction between warfarin and cannabidiol, a case report. Epilepsy Behav Case Rep. Oct 12;9:10- 11 Hill KP, Gold MS, Nemeroff CB, McDonald W, Grzenda A, Widge AS, Rodriguez C, Kraguljac NV, Krystal JH, Carpenter LL. Risks and Benefits of Cannabis and Cannabinoids in Psychiatry. Am J Psychiatry. 2022 Feb;179(2):98-109 Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018 Nov;84(11):2477-2482. McLeod AL, McKenna CJ, Northridge DB. 2002. Myocardial infarction following the combined recreational use of Viagra and cannabis. Clin Cardiol. Mar;25(3):133-4 Singh RK, Dillon B, Tatum DA, Van Poppel KC, Bonthius DJ. 2020. Drug-Drug Interactions Between Cannabidiol and Lithium. Child Neurol Open. Aug 13;7 Vandrey R, Herrmann ES, Mitchell JM, Bigelow GE, Flegel R, LoDico C, Cone EJ. Pharmacokinetic Profile of Oral Cannabis in Humans: Blood and Oral Fluid Disposition and Relation to Pharmacodynamic Outcomes. J Anal Toxicol. 2017 Mar 1;41(2):83-99.\n\n", "n_tokens": 461, "kind": "text"}
{"chunk_id": "ddi_figure_oct_2024-1-1", "doc_id": "ddi_figure_oct_2024", "page": 1, "text": "Examples of Position Statements from Professional Organizations:\n\n1.\n\n2.\n\n3.\n\n4.\n\n5.\n\n6.\n\n7.\n\nAAFP, 2019 All Policies: Marijuana and Cannabinoids: Health, Research and Regulatory Considerations (Position Paper), American Academy of Family Physicians (AAFP), https://www.aafp.org/about/policies/all/marijuana-position-paper.html. AAN, 2020 Advocacy: AAN Position: Use of Medical Cannabis for Neurologic Disorders, American Academy of Neurology (AAN), https://www.aan.com/advocacy/medical- cannabis-position-statement/. AES, 2022 Position Statements: AES Position Statement on Cannabis as a Treatment for Patients with Epileptic Seizures, American Epilepsy Society (AES), https://www.aesnet.org/about/about-aes/position-statements/aes-position-statement-on-cannabis-as-a-treatment-for-patients-with-epileptic-seizures. APA, 2018 Resource Documents: 2018: Opposition to Cannabis as Medicine, Approved by the Joint Reference Committee, October 2018, American Psychiatric Association (APA), https://www.psychiatry.org/Psychiatrists/Search-Directories-Databases/Resource-Documents/2018/Opposition-to-Cannabis-as-Medicine. ASAM, 2020 Public Policy Statements: 2020: Public Policy Statement on Cannabis, American Society of Addiction Medicine (ASAM), https://www.asam.org/advocacy/public- policy-statements/details/public-policy-statements/2020/10/10/cannabis. IASP, 2021 News: IASP Position Statement on the Use of Cannabinoids to Treat Pain, International Association for the Study of Pain (IASP), https://www.iasp- pain.org/publications/iasp-news/iasp-position-statement-on-the-use-of-cannabinoids-to-treat-pain/. NAADAC, 2022 Position Statements and Issue Briefs: NAADAC Position Statement on the Medical and Recreational Use of Cannabis, 2023, https://www.naadac.org/position- statement-on-the-medical-and-recreational-use-of-cannabis.", "n_tokens": 494, "kind": "text"}
{"chunk_id": "drug_resistance_book-0-0", "doc_id": "drug_resistance_book", "page": 0, "text": "Series Editor: Michael J. SelgelidPublic Health Ethics Analysis 5Euzebiusz JamrozikMichael Selgelid Editors Ethics and Drug Resistance: Collective Responsibility for Global Public Health", "n_tokens": 41, "kind": "text"}
{"chunk_id": "drug_resistance_book-1-0", "doc_id": "drug_resistance_book", "page": 1, "text": "Public Health Ethics Analysis\n\nVolume 5\n\nSeries Editor Michael J. Selgelid, Centre for Human Bioethics, Monash University, Melbourne, VIC, Australia", "n_tokens": 31, "kind": "text"}
{"chunk_id": "drug_resistance_book-2-0", "doc_id": "drug_resistance_book", "page": 2, "text": "During the 21st Century, Public Health Ethics has become one of the fastest growing subdisciplines of bioethics. This is the first Book Series dedicated to the topic of Public Health Ethics. It aims to fill a gap in the existing literature by providing thoroughgoing, book-length treatment of the most important topics in Public Health Ethics—which have otherwise, for the most part, only been partially and/or sporadically addressed in journal articles, book chapters, or sections of volumes concerned with Public Health Ethics. Books in the series will include coverage of central topics in Public Health Ethics from a plurality of disciplinary perspectives including: philosophy (e.g., both ethics and philosophy of science), political science, history, economics, sociology, anthropology, demographics, law, human rights, epidemiology, and other public health sciences. Blending analytically rigorous and empirically informed analyses, the series will address ethical issues associated with the concepts, goals, and methods of public health; individual (e.g., ordinary citizens’ and public health workers’) decision making and behaviour; and public policy. Inter alia, volumes in the series will be dedicated to topics including: health promotion; disease prevention; paternalism and coercive measures; infectious disease; chronic disease; obesity; smoking and tobacco control; genetics; the environment; public communication/trust; social determinants of health; human rights; and justice. A", "n_tokens": 290, "kind": "text"}
{"chunk_id": "drug_resistance_book-2-1", "doc_id": "drug_resistance_book", "page": 2, "text": "primary priority is to produce volumes on hitherto neglected topics such as ethical issues associated with public health research and surveillance; vaccination; tuberculosis; malaria; diarrheal disease; lower respiratory infections; drug resistance; chronic disease in developing countries; emergencies/disasters (including bioterrorism); and public health implications of climate change.", "n_tokens": 70, "kind": "text"}
{"chunk_id": "drug_resistance_book-2-2", "doc_id": "drug_resistance_book", "page": 2, "text": "More information about this series at http://www.springer.com/series/10067", "n_tokens": 21, "kind": "text"}
{"chunk_id": "drug_resistance_book-3-0", "doc_id": "drug_resistance_book", "page": 3, "text": "Euzebiusz Jamrozik • Michael Selgelid Editors\n\nEthics and Drug Resistance: Collective Responsibility for Global Public Health", "n_tokens": 25, "kind": "text"}
{"chunk_id": "drug_resistance_book-4-0", "doc_id": "drug_resistance_book", "page": 4, "text": "Editors Euzebiusz Jamrozik Monash Bioethics Centre Monash University Melbourne, VIC, Australia\n\nMichael Selgelid Monash Bioethics Centre Monash University Melbourne, VIC, Australia\n\nDepartment of Medicine, Royal Melbourne Hospital University of Melbourne Melbourne, VIC, Australia\n\nWellcome Centre for Ethics and the Humanities and The Ethox Centre, Nuffield Department of Population Health University of Oxford Oxford, UK\n\nISSN 2211-6680 Public Health Ethics Analysis ISBN 978-3-030-27873-1 https://doi.org/10.1007/978-3-030-27874-8\n\nISSN 2211-6699\n\n(electronic)\n\nISBN 978-3-030-27874-8\n\n(eBook)", "n_tokens": 159, "kind": "text"}
{"chunk_id": "drug_resistance_book-4-1", "doc_id": "drug_resistance_book", "page": 4, "text": "© The Editor(s) (if applicable) and The Author(s) 2020. This book is an open access publication. Open Access This book is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made. The images or other third party material in this book are included in the book’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the book’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained", "n_tokens": 302, "kind": "text"}
{"chunk_id": "drug_resistance_book-4-2", "doc_id": "drug_resistance_book", "page": 4, "text": "herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.", "n_tokens": 34, "kind": "text"}
{"chunk_id": "drug_resistance_book-4-3", "doc_id": "drug_resistance_book", "page": 4, "text": "This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland", "n_tokens": 33, "kind": "text"}
{"chunk_id": "drug_resistance_book-5-0", "doc_id": "drug_resistance_book", "page": 5, "text": "Introduction: Ethics and Drug Resistance\n\nBackground\n\nDrug resistance is widely acknowledged to be one of the greatest threats to global public health in the coming decades. Tedros Adhanom Ghebreyesus, Director General of the World Health Organization, describes antimicrobial resistance (AMR) as ‘a global crisis’ and ‘the perfect example of the complex, multi-sectoral, multi-stakeholder challenges we will increasingly face in the future’.1 In addition to scientific research, addressing the challenge of drug resistance requires coming to grips with numerous difficult ethical questions. This book thus provides up-to-date ethical analyses, from multiple perspectives, of many aspects of this crucial public health problem.", "n_tokens": 140, "kind": "text"}
{"chunk_id": "drug_resistance_book-5-1", "doc_id": "drug_resistance_book", "page": 5, "text": "Infectious diseases cause significant morbidity and mortality worldwide, with a disproportionately high disease burden among disadvantaged populations. Resistance to drugs for important pathogens also frequently tracks disadvantage, meaning that increasing rates of drug-resistant infections threaten to widen global health inequalities. Meanwhile, rising levels of resistance make it harder, or in some cases impossible, to effectively treat common bacterial (and other) infections. This has significant implications for healthcare and seriously jeopardises many of the gains of twentieth century clinical medicine, even in well-resourced settings. Successful surgery, transplantation, care of newborn children, and chemotherapy for cancer, for example, all depend upon effective antibiotics to treat infections that could otherwise be fatal.\n\nAMR occurs when pathogens evolve resistance mechanisms in response to anti- microbial exposure and/or when resistance is spread from one microbe to another. Resistant pathogens arise in both humans and animals, and they can spread between individuals and between species. Antimicrobial treatment, infection control prac- tices, and agricultural policies directly affect resistance patterns. This in turn raises\n\n1 https://www.who.int/antimicrobial-resistance/news/WHO-GAP-AMR-Newsletter-may-2017. pdf?ua=1\n\nv", "n_tokens": 263, "kind": "text"}
{"chunk_id": "drug_resistance_book-6-0", "doc_id": "drug_resistance_book", "page": 6, "text": "vi\n\nIntroduction: Ethics and Drug Resistance\n\ninescapable ethical questions about how to make trade-offs between different kinds of risks and benefits.\n\nIncreasing rates of increasingly drug-resistant infections might be driving humanity towards a ‘post-antibiotic era’ – i.e. a future situation analogous to the situation before effective antibiotics were discovered and/or became widely avail- able. This would involve a dramatic increase in harms to patients and the costs of treatment. It could also have significant effects on public health policy and poten- tially dramatic effects on social life.\n\nAt this critical moment in the history of medicine, public health ethics has a key role to play in the shaping of practice and policy. This book provides unprecedented, comprehensive, in-depth analysis of ethical issues associated with drug resistance.", "n_tokens": 160, "kind": "text"}
{"chunk_id": "drug_resistance_book-6-1", "doc_id": "drug_resistance_book", "page": 6, "text": "Part I: Ethics and Drug-Resistance in Context\n\nPart I provides an overview of drug resistance in multiple contexts. Chapter 1 begins with a broad survey of the causes and consequences of drug resistance as well as potential policy responses to this problem. Chapters 2, 3, and 4 focus on analyses of drug resistance in the contexts of tuberculosis (TB), HIV/AIDS, and malaria – which cause especially high disease burdens among the worst off, predominantly in low- and middle-income countries (LMICs). Drug resistance threatens to under- mine public health programmes to treat and control these diseases and could thereby stall progress in global health and socioeconomic development. Chapters 5, 6, and 7 explore the involvement of different sectors in the development of, and response to, drug resistance. These chapters focus (respectively) on private healthcare provid- ers, the hospital as a nidus of drug resistance, and drug-resistant infections in non- human animals.", "n_tokens": 192, "kind": "text"}
{"chunk_id": "drug_resistance_book-6-2", "doc_id": "drug_resistance_book", "page": 6, "text": "Chapter 2 focuses on drug-resistant (TB). In the most severe cases, patients with active multi- and extensively-drug-resistant tuberculosis (MDR- and XDRTB) have few (if any) effective treatment options and face high mortality rates. One TB con- trol strategy involves treating individuals with latent (i.e. asymptomatic) TB infec- tion (LTBI) before they develop active disease, but the treatment of resistant LTBI has until recently been a neglected topic in clinical research. Nguyen et al. focus on practical ethical challenges arising in the design and conduct of clinical research on MDR LTBI treatment in Vietnam, including community understanding of LTBI and the acceptance of such research in low-income settings. Such analyses arguably have wider implications, since asymptomatic carriage by otherwise healthy indi- viduals is a significant feature of many other (drug-resistant) pathogens, and these phenomena are often poorly understood and/or neglected by researchers, despite having significant implications for research and public health.\n\nIn Chapter 3, Bridget Haire explores ethical issues related to drug-resistant HIV/ AIDS. Highly active anti-retroviral therapy (HAART) can be highly effective in suppressing (but not curing) HIV/AIDS, thus significantly reducing rates of disease and/or transmission. Unfortunately, resistance to HAART sometimes develops,", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-7-0", "doc_id": "drug_resistance_book", "page": 7, "text": "Introduction: Ethics and Drug Resistance\n\nparticularly where HIV/AIDS patients have difficulty accessing a continuous (life- long) supply of antivirals and/or where patients are (for other reasons) not able to take medicines reliably. As Haire points out, since the development of resistance can lead to treatment failure and higher risks of disease and transmission, and since diagnostic testing for resistance and second line HAART involves significantly increased costs, policymakers face difficult trade-offs. Haire highlights the ethical aspects of priority setting and cost-effectiveness assessments in the context of HIV/ AIDS control policy, which can be particularly challenging in low-income settings where HIV/AIDS is most prevalent and public health resources are most constrained.", "n_tokens": 145, "kind": "text"}
{"chunk_id": "drug_resistance_book-7-1", "doc_id": "drug_resistance_book", "page": 7, "text": "In Chap. 4, Cheah et al. focus on malaria, a pathogen for which a mid-twentieth century global eradication effort failed, in part due to the evolution of antimalarial resistance. An especially problematic recent development is the rapid emergence of resistance to newer anti-malarials, particularly in South-East Asia (SEA). Though there are strong moral reasons to prevent the spread of resistant malaria, relevant public health interventions pose numerous ethical and practical challenges. Inter alia, several strategies would necessarily involve treating, and thereby imposing risks upon, apparently healthy individuals (including some who are asymptomati- cally infected with malaria) – just as tuberculosis interventions sometimes target those with latent infection – raising questions regarding whether, or when, such treatment would be justifiable. Furthermore, preventing the spread of resistant malaria parasites to communities with the highest malaria-related mortality (e.g. in Sub-Saharan Africa) may require intensifying intervention in other communities (e.g. in SEA), thus involving burdens for one group in order to prevent even greater burdens for others.", "n_tokens": 227, "kind": "text"}
{"chunk_id": "drug_resistance_book-7-2", "doc_id": "drug_resistance_book", "page": 7, "text": "Despite progress towards increasing access to healthcare in SEA, many individu- als in this region, as in others, rely on private decentralised health providers for access to antimicrobial drugs. Chapter 5, by Liverani and colleagues, provides a rich analysis of the links between under-regulation of the private healthcare sector and the emergence of drug resistance in SEA. Gaps in surveillance systems, high rates of overprescription, and the dispensing of low quality (and/or counterfeit) antimi- crobials are among several causes of increased risks of drug-resistant infections. Liverani et al. demonstrate the complexities of drug resistance as a public health problem across multiple pathogens highlighting tensions between access to antimi- crobials and the excesses of profligate use. These tensions, and the associated chal- lenges in the ethical governance of multiple sectors and countries, are recurring themes in the book.", "n_tokens": 194, "kind": "text"}
{"chunk_id": "drug_resistance_book-7-3", "doc_id": "drug_resistance_book", "page": 7, "text": "In Chap. 6, Gilbert and Kerridge consider how and why hospitals have often become epicentres of antibiotic resistant bacteria – and why in-hospital strategies, such as antimicrobial stewardship and infection prevention/control, have often been only partially effective. Part of the problem is that even ‘appropriate’ (i.e. not just ‘inappropriate’ and/or ‘excessive’) use of antibiotics inevitably contributes to the emergence and persistence of resistant strains of bacteria. Ethically salient consequences of antibiotic use in hospitals include direct harms related to resistant bacterial infections (in patients, staff, and – through transmission – the wider\n\nvii", "n_tokens": 132, "kind": "text"}
{"chunk_id": "drug_resistance_book-8-0", "doc_id": "drug_resistance_book", "page": 8, "text": "viii\n\nIntroduction: Ethics and Drug Resistance\n\ncommunity), stigma and other burdens endured by carriers of drug-resistant strains and those who care for them, and the significant costs of reactive (as compared to preventive) infection control interventions. They conclude by outlining moral obligations of individuals and organizations to contribute to reduction of hospital- acquired drug-resistant infections.\n\nBoden and Mellor, in Chap. 7, consider links between drug-resistance in animals and in humans. Although controversy continues to surround questions regarding the degree to which drug resistance in animals contribute to infections in humans, they characterise antibiotic resistance as a typical ‘One Health’ problem. As such, coher- ent policy responses are needed across multiple sectors (e.g. human health, animal health, food production, and environmental management). Boden and Mellor argue that international policy-making in particular should take existing socioeconomic inequities in to account, being careful to avoid unnecessarily punitive measures in LMICs which could compromise animal health as well as food production, while still attempting to reduce the incidence and spread of drug-resistant infections (across multiple species).", "n_tokens": 237, "kind": "text"}
{"chunk_id": "drug_resistance_book-8-1", "doc_id": "drug_resistance_book", "page": 8, "text": "Part II: Theoretical Approaches to Ethics and Drug Resistance\n\nIn Part II, ethical issues associated with drug resistance are analysed via diverse theoretical lenses, appealing to a variety of philosophical and economic concepts including virtue, duty, rights, capabilities, justice, and public goods.\n\nIn Chap. 8, Justin Oakley approaches ethical dilemmas in antimicrobial prescrip- tion from a virtue ethics perspective. Oakley argues that prescribers should be guided not only by patient-centred virtues, but also by community-centred virtues, including the virtue of justice, in order to strike the right balance between the ben- efits of antimicrobials for patients and the societal harms of promoting resistant infections. He argues that this is especially important where the expected benefits to the patient from antimicrobial treatment would be low and the wider societal harms are potentially significant. Oakley notes that physicians’ decisions are also influ- enced by a number of cognitive biases and situational factors. A virtuous physician would thus need to cultivate practical wisdom and meticulousness in addressing her own biases. In addition, individual prescribers need the support of healthcare poli- cymakers and institutions to situate them in systems that foster and support virtuous prescribing practices.", "n_tokens": 267, "kind": "text"}
{"chunk_id": "drug_resistance_book-8-2", "doc_id": "drug_resistance_book", "page": 8, "text": "In Chap. 9, Giubilini and Savulescu focus on cases where restricting one person’s use of antibiotics could be plausibly described as an ‘easy rescue’. These are situations in which, at little or no cost, one can consume less antibiotics and thus reduce imposition of risk on others (as well as, perhaps, reducing one’s own risk of future resistant infections). The authors argue that individuals have moral obligations to avoid imposing risks on others, including by avoiding profligate use of antibiotics. Thus, policies restricting antibiotic use would have particularly strong ethical justification in situations of ‘easy rescue’ since (other things being", "n_tokens": 135, "kind": "text"}
{"chunk_id": "drug_resistance_book-9-0", "doc_id": "drug_resistance_book", "page": 9, "text": "Introduction: Ethics and Drug Resistance\n\nequal) there would be few important countervailing moral considerations. They note that such cases are particularly likely in high-income countries, where indi- viduals have a reliable health system to support them in the event that the cost of not taking antibiotics (which is ex ante uncertain) turns out to be more significant (i.e. that the ‘rescue’ turns out to be less easy than expected). Furthermore, they argue that states have reciprocal duties to individuals whose antimicrobial use is restricted (e.g. by more stringent prescribing policies), which may plausibly include duties to provide various forms of compensation and/or healthcare. Finally, the authors situate their claims in broader notions of collective obligations to contribute to common goods and argue that antimicrobial effectiveness can be conceived of as such a common good – one that is undermined by overuse (as well as therapeuti- cally justified use) of relevant drugs.", "n_tokens": 208, "kind": "text"}
{"chunk_id": "drug_resistance_book-9-1", "doc_id": "drug_resistance_book", "page": 9, "text": "In Chap. 10, Shawa and colleagues apply a human rights approach to the prob- lem of highly resistant strains of TB, for which the development of new drugs and wider access to existing treatments are urgently needed – especially in LMICs. In addition to the right to health, the authors argue that there is a right to enjoy the benefits of scientific progress and that states and international agencies have duties to respect, protect, and fulfil both of these rights (among others). Inadequate access to effective TB drugs and the longstanding relative neglect of resistant TB by funders, researchers, and diagnostics/drug developers are therefore framed as fail- ures to fulfil (at least) these two human rights. Shawa and colleagues argue that duties to fulfil the right to enjoy the benefits of scientific progress in particular entail wide-ranging responsibilities, for example, to pursue legislation to promote TB research and expand access to newer TB drugs (even where this would involve over- riding or reducing the scope of intellectual property rights such as those implicit in patents that often make such drugs unaffordable). Noting that there has not yet been international agreement on the minimum core obligations entailed by this right, they outline potentially useful ways of specifying these in order to provide more explicit guidance for states to respond appropriately to this urgent public health problem.", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-9-2", "doc_id": "drug_resistance_book", "page": 9, "text": "Carl Coleman, in Chap. 11, looks specifically at the right to refuse treatment and the conditions under which legislation and policy should endorse isolation and/or non-consensual treatment. He argues that although laws in some jurisdictions per- mit mandatory treatment for infectious diseases such as tuberculosis, such compul- sion is ethically justifiable only in rare cases in which certain conditions are met, for example, where (i) treatment refusal poses grave risk to others, (ii) the imposed treatment is safe, effective, and not overly burdensome, and (iii) less restrictive mea- sures are infeasible. Coleman surveys international human rights documents and laws in multiple jurisdictions regarding non-consensual treatment and/or TB, noting that provisions for compelled (diagnostic testing and) treatment often exist, even if they are rarely invoked. Even in high-risk cases, such as XDR-TB, the public can usually be protected from harm by isolating the patient (whether or not the patient accepts treatment in isolation). Coleman thus argues that there would rarely be ade- quate justification for enforcing treatment on the isolated individual. In cases where, for example, isolation facilities are overwhelmed (e.g. during a large outbreak) and large numbers of people refuse effective treatment for infection, mandatory\n\nix", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-10-0", "doc_id": "drug_resistance_book", "page": 10, "text": "x\n\nIntroduction: Ethics and Drug Resistance\n\ntreatment might be more justifiable. However, Coleman points out that – in practice, particularly with adequate community engagement from public health authorities – conditions sufficient to justify such non-consensual treatment will seldom, if ever, be met.\n\nIn Chap. 12, Jamrozik and Selgelid explore the public health ethics implications of asymptomatic carriage and transmission of drug-resistant bacteria by otherwise healthy people. This chapter first summarises current evidence regarding the wide- spread carriage of key drug-resistant bacteria, noting important gaps in current data. The authors then analyse potential public health interventions for carriers in light of existing public health ethics frameworks, arguing that the relative burdens imposed by public health measures on healthy carriers (as opposed to sick individuals) war- rant careful consideration and should be proportionate to the expected public health benefits in terms of risks averted. Ultimately, more surveillance and research regard- ing community transmission will be needed in order to clarify relevant risks and design proportionate policies, although community surveillance itself also requires careful ethical consideration.", "n_tokens": 225, "kind": "text"}
{"chunk_id": "drug_resistance_book-10-1", "doc_id": "drug_resistance_book", "page": 10, "text": "In Chap. 13, Byskov et al. introduce a capability framework to enrich analysis of the burdens of public health interventions among carriers of multi-drug-resistant organisms. They note that carriers can face stigma and other harms as well as restric- tions on their particular opportunities for choices (e.g. regarding freedom to chose where to go, with whom to interact, or which occupation to pursue). Thus carriers are potentially subjected to a wide range of potential burdens and/or harms, depend- ing on the policy in question. The authors argue that examining these adverse effects in terms of reductions in the capabilities and functionings of carriers helps to illumi- nate the ways public health policies aimed at controlling the spread of resistant pathogens can constrain the lives of those affected. Because adverse effects on car- riers’ capabilities will be highly context specific, the authors ultimately aim to iden- tify a rich taxonomy of ethically relevant considerations to help policymakers (i) determine the likely burdens of being a carrier and of a given intervention and (ii) weigh these burdens against the public health benefits (and costs) of potential interventions.", "n_tokens": 242, "kind": "text"}
{"chunk_id": "drug_resistance_book-10-2", "doc_id": "drug_resistance_book", "page": 10, "text": "In Chap. 14, Michael Millar likewise draws on ‘the capabilities approach’ to illustrate the ways in which access to effective antibiotics among children is critical to secure normal childhood development and fully flourishing adult capabilities. He notes that there is significant inequality in the distribution of risk of (resistant) infec- tious disease and access to treatment. Millar argues that this is especially concern- ing where lifelong capabilities are adversely affected. Uncontrolled (or effectively untreatable) resistant infectious diseases can, furthermore, lead to a clustering of disadvantage in a particular individual or community, amplifying existing health injustices. Millar raises the compelling example of growth stunting among LMIC children. Often caused in part by early childhood infections, stunting results in poor long-term physical and cognitive outcomes. However, proposals for the mass treat- ment of children with antibiotics raise familiar tensions between assuring good health and promoting the rise of drug resistant infections. Given the global inequali- ties in the distribution of relevant risks and the potential for resistant pathogens to", "n_tokens": 219, "kind": "text"}
{"chunk_id": "drug_resistance_book-11-0", "doc_id": "drug_resistance_book", "page": 11, "text": "Introduction: Ethics and Drug Resistance\n\nspread across national borders, international co-operation is required (but can itself be threatened by persistent injustice).", "n_tokens": 28, "kind": "text"}
{"chunk_id": "drug_resistance_book-11-1", "doc_id": "drug_resistance_book", "page": 11, "text": "In Chap. 15, Francis and Francis examine the collection and use of information in the measurement of, and response to, infectious diseases with a particular focus on the value of fairness in the context of public health surveillance. Relevant types of information, broadly conceived, include data regarding infected individuals and disease transmission as well as knowledge arising from research. Francis and Francis analyse the use of such information from the interconnected perspectives regarding ‘vectors’ (those who transmit infection) and ‘victims’ (those harmed by infection), noting that people may experience both of these states (often simultane- ously). The authors emphasize that excessive focus on the vector perspective may lead to unnecessary stigmatization of individuals and punitive policies that can become counterproductive since infected individuals will have strong incentives to conceal their diagnoses. In contrast (simultaneous) concern for individuals as vic- tims may help to foster less burdensome interventions and more support for those infected, but overemphasizing such concerns may lead to, for example, overuse of antibiotics and thus more drug resistance. Francis and Francis argue that the ethical principles of fairness and reciprocity should guide infectious disease policy forma- tion to an appropriate balance of each perspective, especially where difficult trade- offs are required.", "n_tokens": 261, "kind": "text"}
{"chunk_id": "drug_resistance_book-11-2", "doc_id": "drug_resistance_book", "page": 11, "text": "In Chap. 16, Lynette Reid examines the links between drug resistance and health inequalities, illustrated by cases such as the rising resistance of many sexually trans- mitted infections (including among sex workers) and the risks of resistant intestinal parasitic infections. Reid argues that drug resistance undermines global health development narratives because worsening drug resistance may make it impossible to mitigate the persistent large infectious disease burden associated with poverty. Thus, drug resistance is predicted to increase inequality, and a focus on improve- ments in infectious disease prevention (e.g. by addressing the social and economic inequalities that predispose people to infection) would arguably do more to reduce long-term health injustice than expanding access to increasingly ineffective treat- ments. On the other hand, Reid points out that drug resistance in high-income coun- tries could lead to a ‘levelling down’ in health equality by undercutting the safety of high-cost interventions (such as complex surgery and immunosuppression). However, as effective antimicrobials become a scarce resource, their use could also be unjustly monopolized by the well-off (in both HICs and LMICs). In any case, Reid argues that policy should go well beyond assuring minimally sufficient access to water, sanitation, and antimicrobials – and address the underlying political and economic forces that result in the persistence of unjust risks of disease among", "n_tokens": 301, "kind": "text"}
{"chunk_id": "drug_resistance_book-11-3", "doc_id": "drug_resistance_book", "page": 11, "text": "underprivileged individuals.", "n_tokens": 7, "kind": "text"}
{"chunk_id": "drug_resistance_book-11-4", "doc_id": "drug_resistance_book", "page": 11, "text": "In Chap. 17, Coast and Smith focus on intersections between economic and ethi- cal analyses of antibiotic resistance. This chapter conceptualizes problems associ- ated with AMR in terms of ‘public goods’ (a concept related to the idea of common goods invoked above). In economics, public goods are said to be non-rival (i.e. one individual’s use/enjoyment of a good does not limit its use/enjoyment by others) and non-excludable (i.e. it is difficult or impossible to prevent access to the good).\n\nxi", "n_tokens": 123, "kind": "text"}
{"chunk_id": "drug_resistance_book-12-0", "doc_id": "drug_resistance_book", "page": 12, "text": "xii\n\nIntroduction: Ethics and Drug Resistance\n\nCoast and Smith note that the lack of new antibiotics is a predictable consequence of economic forces leading to market failure. They also highlight alternative sys- tems that have been proposed to stimulate useful research and development. At the level of consumers of antibiotics, they note that although many of the benefits of antibiotic use accrue locally and in the present, the harms and costs are (sometimes unfairly) distributed across space and time. Current consumption of antibiotics, for instance, may compromise interests of future people. Ultimately, they argue that economic and ethical considerations will often converge on similar policy recom- mendations. For example, they note that infection prevention (which is often more cost-effective than providing treatment once an infection becomes clinically appar- ent) and research into non-antibiotic treatments may be part of solutions aiming to achieve (economically and ethically) optimal improvements in health via a reduc- tion in the burden of infectious diseases.", "n_tokens": 203, "kind": "text"}
{"chunk_id": "drug_resistance_book-12-1", "doc_id": "drug_resistance_book", "page": 12, "text": "Part III: Ethics, Regulation, Governance, and Drug Resistance\n\nThe chapters in Part III provide unique perspectives on ethical issues associated with policy regarding drug resistance. These analyses draw on concepts related to game theory, collective action, risk limits in research, solidarity, environmental eth- ics, law, and social policy.\n\nIn Chap. 18, Jonathan Anomaly gives an account of the international co- operation urgently needed to regulate the use of antibiotics in animal agriculture. Anomaly starts by asserting that the situation of farmers deciding whether to use antibiotics as a means to sustain animals in crowded conditions is akin to the game theoretical model of a many person prisoners’ dilemma. In short, those who opt not to use antibiotics are predicted to lose out economically as factory farmers heavily using antibiotics drive down the price of meat. In the long term, resistance becomes ram- pant and all are worse off. This predictable ‘market failure’ to secure the public good of antibiotic effectiveness is one reason in favour of regulating antibiotic use. Regulation needs to reduce the negative effect of ‘free riders’ (i.e. profligate antibi- otic users) and provide assurance for individuals who use antibiotics carefully (i.e. in line with the social optimum) that others will do the same. Anomaly argues in favour of an international treaty and outlines how such a treaty might be designed and implemented.", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-12-2", "doc_id": "drug_resistance_book", "page": 12, "text": "In Chap. 19, Nichols King analyses an issue raised in many other chapters in this volume in more detail. Given what is known about the complexity of the causal and perpetuating factors involved in the problem of antimicrobial resistance, will ‘tech- nological fixes’ (e.g. new diagnostics, drugs, vaccines) alone provide an adequate response, or are broader social, behavioural, political, and economic changes more likely to achieve sustainable improvements in public health? Noting that multiple co-ordinated policy responses are likely required, King traces the history of ‘tech- nological fixes’ and examines the ways in which over-reliance on such approaches has implications for distributive justice.", "n_tokens": 149, "kind": "text"}
{"chunk_id": "drug_resistance_book-13-0", "doc_id": "drug_resistance_book", "page": 13, "text": "Introduction: Ethics and Drug Resistance\n\nIn Chap. 20, Littmann, Rid, and Buyx explore the concept of ‘rational use’ of antibiotics. They note that, in some cases, there will be ethical conflicts between patients’ interests and the need to preserve effective antibiotics for the future. Littmann et al. draw an analogy from research ethics regarding the acceptable limits to risks to which participants in research may be exposed and provide a framework for policymakers to evaluate potential antibiotic use policies ethically, particularly with respect to the degree of risk to which current patients are exposed due to poten- tial reductions in antibiotic use.", "n_tokens": 130, "kind": "text"}
{"chunk_id": "drug_resistance_book-13-1", "doc_id": "drug_resistance_book", "page": 13, "text": "In Chap. 21, Holm and Ploug also approach the problem of the ethical justifica- tion for restricting the use of antibiotics in cases where they will provide patients some benefit (but also entail risks of antibiotic resistance). They argue that the con- cept of solidarity can help to guide physicians and policymakers in such contexts, and also that it can help to promote the support of such policies among the general public. Once persons realize that each could (or anyone could) easily be affected by a drug-resistant infection, it should arguably lead them to act in solidarity with oth- ers by giving appropriate weight to the risks related to potential increases in drug resistance. Thus, such individuals would be more inclined to avoid the use of (or prescription of) antibiotics for self-limiting conditions. Furthermore, the authors give an account of how solidarity can inform public health policy, and the ways in which it might be expanded to the global level in the context of the international spread of drug-resistant infections.", "n_tokens": 209, "kind": "text"}
{"chunk_id": "drug_resistance_book-13-2", "doc_id": "drug_resistance_book", "page": 13, "text": "In Chap. 22, Nijsingh et al. examine the ethical and evidentiary justification for public health policy responses to drug-resistant infections. Evidentiary justification can be challenging where little high-quality evidence is available and where the underlying causal pathways driving drug resistance are complex and/or poorly understood. In turn, ethical analysis of current policy must often be sensitive to the (sometimes limited) degree of evidence regarding the (cost-)effectiveness of an intervention (or package of interventions). With these complexities in mind, the authors give a thorough analysis of the application and limitations of the Precautionary Principle in the context of antibiotic resistance, as well as a number of other ethical and evidentiary challenges facing policymakers.\n\nIn Chap. 23, Anne Schwenkenbecher gives an account of how prospective moral responsibility for one’s contribution to antimicrobial resistance – one’s ‘antimicro- bial footprint’ – can help to support collective action to reduce the problem. Shwenkenbecher considers arguments that failing to reduce one’s use of antimicro- bials (where it is possible to do so at acceptable costs) can contribute to unfairness and/or lead to collective harm, concluding that moral reasons to avoid contributing to collective harm (e.g. from drug resistant infection) should support individual action to reduce one’s antimicrobial footprint.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-13-3", "doc_id": "drug_resistance_book", "page": 13, "text": "The next two chapters address issues related to global health governance in the context of antimicrobial resistance. In Chap. 24, Bennett and Iredell explore the challenges of using existing governance frameworks. They begin by giving an account of the WHO/World Health Assembly 2015 Global Action Plan for Antimicrobial Resistance and the United Nations resolutions that closely followed. The complex problem(s) of antimicrobial resistance have been framed in a number\n\nxiii", "n_tokens": 93, "kind": "text"}
{"chunk_id": "drug_resistance_book-14-0", "doc_id": "drug_resistance_book", "page": 14, "text": "xiv\n\nIntroduction: Ethics and Drug Resistance\n\nof different ways in different policies, and the authors argue that policymakers will need to overcome conceptual, practical, and political challenges in order to imple- ment coherent and effective policy in this complex area. A key conceptual challenge is the need to define (and achieve international agreement on) what constitutes ‘appropriate’ antimicrobial use in order to implement effective regulation and accountability measures.\n\nIn Chap. 25, Lee and Ho also take the Global Action Plan as a starting point and complement the above analysis by offering a legal and regulatory toolkit to support effective health governance related to drug-resistant infections. The authors argue that an equitable regulatory ‘lever’ should be one key part of co-ordinated policy responses and will often be required in order to enable other policies. Lee and Ho give a detailed account of how regulation should be used to support (among other important priorities) quality assurance in antimicrobial production, optimum pre- scribing and dispensing practices, and the assurance of equitable access to antimicrobials.", "n_tokens": 223, "kind": "text"}
{"chunk_id": "drug_resistance_book-14-1", "doc_id": "drug_resistance_book", "page": 14, "text": "Finally, in Chap. 26, Littmann, Viens, and Silva describe antimicrobial resistance as a ‘super-wicked’ problem. As noted in many other chapters, drug resistance is a complex policy area: there are huge numbers of contributors, stakeholders, and causal pathways involved in creating, perpetuating, and responding to the level of drug resistance across a wide range of pathogens, sectors, and settings around the globe. Littmann et al. conclude the volume by highlighting the many distinctive ethical issues arising in relation to drug-resistant infections and the ways in which ethical analysis should inform policy and response activities.\n\nAcknowledgments\n\nDr Jamrozik worked on this volume during a residency at the Brocher Foundation. His fellowship at the University of Oxford is supported by the Wellcome Trust [216355/Z/19/Z], [203132/Z/16/Z].\n\nMonash Bioethics Centre Monash University Melbourne, Australia Department of General Medicine Royal Melbourne Hospital Melbourne, Australia Wellcome Centre for Ethics and the Humanities and The Ethox Centre, Nuffield Department of Population Health, University of Oxford Oxford, UK\n\nEuzebiusz Jamrozik\n\nMonash Bioethics Centre Monash University Melbourne, Australia\n\nMichael J. Selgelid", "n_tokens": 270, "kind": "text"}
{"chunk_id": "drug_resistance_book-15-0", "doc_id": "drug_resistance_book", "page": 15, "text": "Contents\n\nPart I\n\nEthics and Drug Resistance in Context\n\n1\n\nDrug-Resistant Infection: Causes, Consequences, and Responses . . . 3 Euzebiusz Jamrozik and Michael J. Selgelid\n\n2\n\nPreventive Therapy for Multidrug Resistant Latent Tuberculosis Infection: An Ethical Imperative with Ethical Barriers to Implementation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Binh Nguyen, Greg J. Fox, Paul H. Mason, and Justin T. Denholm\n\n3\n\nProviding Universal Access While Avoiding Antiretroviral Resistance: Ethical Tensions in HIV Treatment . . . . . . . . . . . . . . . . . . 37 Bridget Haire\n\n4\n\nEthics and Antimalarial Drug Resistance . . . . . . . . . . . . . . . . . . . . . . . 55 Phaik Yeong Cheah, Michael Parker, and Nicholas P. J. Day\n\n5\n\nAntimicrobial Resistance and the Private Sector in Southeast Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Marco Liverani, Lauren Oliveira Hashiguchi, Mishal Khan, and Richard Coker\n\n6\n\nHospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship (AMS): Dual Strategies to Reduce Antibiotic Resistance (ABR) in Hospitals . . . . . . . . . . . . . . 89 Gwendolyn L. Gilbert and Ian Kerridge\n\n7\n\nEpidemiology and Ethics of Antimicrobial Resistance in Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 Lisa Boden and Dominic Mellor\n\nxv", "n_tokens": 423, "kind": "text"}
{"chunk_id": "drug_resistance_book-16-0", "doc_id": "drug_resistance_book", "page": 16, "text": "xvi\n\nPart II\n\nTheoretical Approaches to Ethics and Drug Resistance\n\n8\n\nThe Virtuous Physician and Antimicrobial Prescribing Policy and Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Justin Oakley\n\n9\n\nMoral Responsibility and the Justification of Policies to Preserve Antimicrobial Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . 141 Alberto Giubilini and J. Savulescu\n\n10\n\nAccess to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis: Deepening the Human Rights-Based Approach . . . . . . 155 Remmy Shawa, Fons Coomans, Helen Cox, and Leslie London\n\n11\n\nThe Right to Refuse Treatment for Infectious Disease . . . . . . . . . . . . 171 Carl H. Coleman\n\n12\n\nSurveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183 Euzebiusz Jamrozik and Michael J. Selgelid\n\n13\n\nConceptualizing the Impact of MDRO Control Measures Directed at Carriers: A Capability Approach . . . . . . . . . . . . . . . . . . . 203 Morten Fibieger Byskov, Babette Olga Rump, and Marcel Verweij\n\n14\n\nA Capability Perspective on Antibiotic Resistance, Inequality, and Child Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Michael Millar\n\n15", "n_tokens": 367, "kind": "text"}
{"chunk_id": "drug_resistance_book-16-1", "doc_id": "drug_resistance_book", "page": 16, "text": "Fairness in the Use of Information About Carriers of Resistant Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243 John G. Francis and Leslie P. Francis\n\n16\n\nAntimicrobial Resistance and Social Inequalities in Health: Considerations of Justice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257 Lynette Reid\n\n17\n\nThe Economics of Resistance Through an Ethical Lens . . . . . . . . . . . 279 Richard D. Smith and Joanna Coast\n\nPart III\n\nEthics, Regulation, Governance, and Drug Resistance\n\n18\n\nAntibiotics and Animal Agriculture: The Need for Global Collective Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Jonathan Anomaly\n\n19\n\nTechnological Fixes and Antimicrobial Resistance . . . . . . . . . . . . . . . 309 Nicholas B. King\n\nContents", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-17-0", "doc_id": "drug_resistance_book", "page": 17, "text": "Contents\n\n20\n\nTackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321 Jasper Littmann, Annette Rid, and Alena Buyx\n\n21\n\nSolidarity and Antimicrobial Resistance . . . . . . . . . . . . . . . . . . . . . . . 345 Søren Holm and Thomas Ploug\n\n22\n\nJustifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 Niels Nijsingh, D. G. Joakim Larsson, Karl de Fine Licht, and Christian Munthe\n\n23\n\nAntimicrobial Footprints, Fairness, and Collective Harm . . . . . . . . . 377 Anne Schwenkenbecher\n\n24\n\nGlobal Health Governance and Antimicrobial Resistance . . . . . . . . . 389 Belinda Bennett and Jon Iredell\n\n25\n\nGlobal Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Calvin W. L. Ho and Tsung-Ling Lee\n\n26\n\nThe Super-Wicked Problem of Antimicrobial Resistance . . . . . . . . . . 421 Jasper Littmann, A. M. Viens, and Diego S. Silva\n\nIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445\n\nxvii", "n_tokens": 411, "kind": "text"}
{"chunk_id": "drug_resistance_book-18-0", "doc_id": "drug_resistance_book", "page": 18, "text": "Part I\nEthics and Drug Resistance in Context", "n_tokens": 8, "kind": "text"}
{"chunk_id": "drug_resistance_book-19-0", "doc_id": "drug_resistance_book", "page": 19, "text": "Chapter 1 Drug-Resistant Infection: Causes, Consequences, and Responses", "n_tokens": 13, "kind": "text"}
{"chunk_id": "drug_resistance_book-19-1", "doc_id": "drug_resistance_book", "page": 19, "text": "Euzebiusz Jamrozik and Michael J. Selgelid\n\nAbstract This chapter provides an overview of the causes and consequences of, and possible policy responses to, the problem of drug resistance. Throughout, we highlight the ways that ethical and conceptual analyses can help to clarify relevant issues and improve policy, especially in public health, broadly conceived. Drug resistant pathogens arise, persist, spread, and produce harm due to a complex set of causes: biological processes (e.g., related to microbial evolution, the transmission of genetic determinants of resistance between microbes, and human host immunity) as well as human behaviors (e.g., antimicrobial use and hygiene practices) and other social factors (e.g., access to clean water, sanitation, healthcare, and antimicrobials). Furthermore, the ethically salient consequences of drug resistance include not only morbidity and mortality from untreatable infections (that are often inequitably distributed), but also broader effects on human freedom, privacy, and well-being. Public health ethicists are ideally placed to identify and weigh the values that might be promoted or compromised by potential policies and/or interventions that aim to address the problem of drug resistance. This chapter concludes by discussing poten- tial policy responses, including those related to surveillance, research, animal and human antimicrobial use, the broader social determinants of health, infection con- trol practices, and vaccination.", "n_tokens": 308, "kind": "text"}
{"chunk_id": "drug_resistance_book-19-2", "doc_id": "drug_resistance_book", "page": 19, "text": "Keywords Antimicrobial resistance · Drug resistance · Drug resistant infection · Ethics · Bioethics · Public health ethics\n\nE. Jamrozik (*) Monash Bioethics Centre, Monash University, Melbourne, VIC, Australia\n\nDepartment of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia\n\nWellcome Centre for Ethics and the Humanities and The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK e-mail: zeb.jamrozik@gmail.com\n\nM. J. Selgelid Monash Bioethics Centre, Monash University, Melbourne, VIC, Australia e-mail: michael.selgelid@monash.edu\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_1\n\n3", "n_tokens": 221, "kind": "text"}
{"chunk_id": "drug_resistance_book-20-0", "doc_id": "drug_resistance_book", "page": 20, "text": "4\n\nE. Jamrozik and M. J. Selgelid\n\n1.1\n\nIntroduction", "n_tokens": 19, "kind": "text"}
{"chunk_id": "drug_resistance_book-20-1", "doc_id": "drug_resistance_book", "page": 20, "text": "It is widely acknowledged that drug resistance poses one of the greatest threats to global public health during the coming decades. Drug resistance compromises the treatment of infections (that were commonly debilitating and/or fatal before the development of antimicrobial drugs), and thereby undermines many advances in surgery, cancer treatment, and immunosuppression that depend on our ability to treat infections effectively. Microbes – bacteria, mycobacteria, parasites, fungi, and viruses – have, over billions of years and untold numbers of microbial generations, developed mechanisms (via evolutionary processes) to protect themselves from harm and transmit such portective mechanisms to other microbes (of the same or different species) (Holmes et al. 2016). The rapid increase in antimicrobial drug resistance in the twentieth and twenty-first centuries is a result of these powerful evolutionary mechanisms combined with human activities that affect the microbial world, including the widespread production and use of antimicrobial drugs. Resistance is a matter of degree (for example, low levels of resistance can be over- come with a higher dose or longer course of antimicrobials) and its impact is also relative to the availability of alternative treatments (where second line drugs are readily available, resistance to first line agents may initially be less of a concern). Thus, the recent emergence of strains of clinically important pathogens that are highly resistant to all, or", "n_tokens": 291, "kind": "text"}
{"chunk_id": "drug_resistance_book-20-2", "doc_id": "drug_resistance_book", "page": 20, "text": "nearly all, available therapies (e.g. extensively drug- resistant tuberculosis (TB) and pan-resistant gram negative bacteria) is an urgent challenge for public health (Schwaber et al. 2011; Birgand et al. 2016; World Health Organisation 2017a).", "n_tokens": 59, "kind": "text"}
{"chunk_id": "drug_resistance_book-20-3", "doc_id": "drug_resistance_book", "page": 20, "text": "Drug resistance is an important topic for ethical analysis since (i) human actions and inactions are major contributors to the problem, (ii) the consequences for human health and well-being are highly significant and inequitably distributed, and (iii) policies aiming to reduce the rates of resistant pathogens may involve balancing this reduction in risk with other morally salient risks, burdens, and benefits. Thus, this volume aims to provide a timely exploration of many of the ethical aspects of the phenomenon of drug resistance. This first chapter highlights the complex causes and significant consequences of drug resistance, and the ways in which ethical and conceptual analysis can inform and improve relevant policy responses. We link these discussions with other chapters in this volume, as well as gesturing towards future directions for ethicists, empirical scientists, and public health policymakers.\n\n1.2\n\nCauses\n\n1.2.1\n\nEvolution and Transmission of Resistance Genes\n\nThe microbial world is ancient, abundant, ubiquitous, and complex. As a result of random mutation over trillions of microbial generations, bacteria have adapted to their environments, in part by developing genes that code for mechanisms of resis- tance to various threats – including, for example, heavy metals, naturally occurring", "n_tokens": 247, "kind": "text"}
{"chunk_id": "drug_resistance_book-21-0", "doc_id": "drug_resistance_book", "page": 21, "text": "1 Drug-Resistant Infection: Causes, Consequences, and Responses\n\nantibacterial compounds (including beta-lactams such as penicillins and carbapen- ems) and synthetic antimicrobials (e.g. fluroquinolones and sulphonamides) (Holmes et al. 2016; D’Costa et al. 2011). Certain microbes are also able to horizon- tally transfer genes coding for resistance mechanisms to other microbes (Holmes et al. 2016; Chang et al. 2015). With the dramatic, unprecedented increase in human interventions in the microbial world (especially the widespread use and overuse of antimicrobial agents), strong evolutionary selection pressures have been applied to microbes leading to the emergence, increasing frequency, and persistence of resis- tant microbes in humans, animals and the environment (Holmes et al. 2016).\n\n1.2.2", "n_tokens": 187, "kind": "text"}
{"chunk_id": "drug_resistance_book-21-1", "doc_id": "drug_resistance_book", "page": 21, "text": "Antimicrobial Use in Humans\n\nIn his 1945 Nobel Prize speech, Alexander Fleming (who first discovered the anti- biotic properties of penicillin) famously noted that ‘the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant’ (Fleming 1945). If antimicrobial treatment is inadequate, that is, then resistant strains of microbes that otherwise would have been killed off may survive and become more strongly established in the absence of microbal competi- tors, in the environment of a person’s body. Resistant pathogen strains thus selected can then be transmitted to other persons. For pathogens like tuberculosis (TB) and HIV, requiring months (or, for HIV and extensively drug-resistant TB, years) of multi-drug therapy, undertreatment (e.g. due to ‘noncompliance’ of patients, or inadequate access to medicine, etc.) has played a central role in the emergence and persistence of highly resistant strains (see Chaps. 2, 3, 5, 10 and 26). In the case of malaria – where, for various reasons, parasites may be exposed (in human patients) to sporadic and/or sub-therapeutic concentrations of antimalarials, sometimes as a result of partial treatment – underuse of drugs likewise plays a role in the emergence of antimalarial resistance (White 2017) (See Chap. 4).", "n_tokens": 300, "kind": "text"}
{"chunk_id": "drug_resistance_book-21-2", "doc_id": "drug_resistance_book", "page": 21, "text": "In the case of antibiotic resistance in common bacterial pathogens, however, overuse of antibiotics is far more important than undertreatment. Despite years of rhetoric regarding the need to ‘complete the prescribed course’ for common uncom- plicated bacterial infections, this now appears, except among a subset of pathogens and specific sites of infection, to have been ill-founded1 and, on balance (when generalised to all infections), harmful advice (Llewelyn et al. 2017). Overuse and ‘appropriate’ use are much more dominant causes of resistance. This is because the human body (particularly in the digestive and respiratory tracts, and on the skin) contains billions of bacteria, many of which are indiscriminately exposed to an antibiotic used either appropriately to treat one particular pathogen (e.g. bacterial pneumonia) or inappropriately (e.g. a viral infection mistaken for a bacterial\n\n1 In part because, until recently, few trials had addressed the question of whether shorter courses for common infections may be just as effective, with less development of resistance (and less side effects) – the few trials that have now been done generally support the use of shorter courses in uncomplicated infections.\n\n5", "n_tokens": 252, "kind": "text"}
{"chunk_id": "drug_resistance_book-22-0", "doc_id": "drug_resistance_book", "page": 22, "text": "6\n\nE. Jamrozik and M. J. Selgelid", "n_tokens": 15, "kind": "text"}
{"chunk_id": "drug_resistance_book-22-1", "doc_id": "drug_resistance_book", "page": 22, "text": "infection) (Llewelyn et al. 2017; Carlet 2012). Exposure to more antibiotics in a given individual is predictive of a higher rate of asymptomatic carriage of resistant pathogens (although this rate does decrease over time) (Nasrin et al. 2002; Bryce et al. 2016). These resistant bacteria, although in usual circumstances causing no harm, can lead to invasive (resistant) disease – for example when a person’s skin is cut or incised by a surgeon, or when bowel bacteria spread to other locations in a person’s body, or when a person becomes immunosuppressed (Tischendorf et al. 2016; Safdar and Bradley 2008). Those who thus become ‘carriers’ of resistant bacteria can transmit such pathogens to others (whether the initial carrier is symp- tomatic or not) (Smith et al. 2004; Lerner et al. 2015; Jamrozik and Selgelid 2019). Overuse of antibiotics in humans is thus a collective action problem – in some respects a classic ‘tragedy of the commons’ (Hardin 2009), but complicated, inter alia, by the transmission of resistance between pathogens and also the transmission of resistant pathogens between humans.2 The (simplified) structure of the collective action problem is that each doctor or patient seeks individual benefit of the patient (minimising the risk of severe bacterial infection) by, respectively, prescribing and taking antibiotics even in cases where this may have only marginal expected bene- fits for the patient; but their decisions/actions collectively (in conjunction with other", "n_tokens": 333, "kind": "text"}
{"chunk_id": "drug_resistance_book-22-2", "doc_id": "drug_resistance_book", "page": 22, "text": "causal factors) bring about high levels of antibiotic resistance – which, in the long term, is a major threat to all.", "n_tokens": 26, "kind": "text"}
{"chunk_id": "drug_resistance_book-22-3", "doc_id": "drug_resistance_book", "page": 22, "text": "Problematic treatment decisions (that contribute to resistance) are sometimes related to diagnostic uncertainty. When a patient has symptoms associated with respiratory illness, for example, there is often no sufficiently rapid and accurate test to determine whether it is caused by a bacterial pathogen. As a result of this uncer- tainty, combined with risk-aversion among doctors and patients, and a (mis)percep- tion that a course of antibiotics ‘does no harm’ (or that the risks of side-effects and generating resistance are outweighed by potential benefits3), millions of antibiotics each year are taken when they are not required. Solutions that rely on individuals acting in accordance with the social optimum (especially if, in doing so, they take on more risk to themselves) are, at best, incomplete or, at worst, doomed.\n\nThe problems of both antimicrobial overuse and underuse are magnified in some low- and middle-income countries where many people lack access to basic diagnos- tic testing and antimicrobials—and/or where antimicrobials are commonly avail- able without prescription (Holmes et al. 2016; Laxminarayan et al. 2016; Dar et al. 2016) (see Chap. 5). There is an inherent tension between ‘access and excess’, i.e. many die because they are unable to obtain diagnosis and/or antimicrobial treatment", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-22-4", "doc_id": "drug_resistance_book", "page": 22, "text": "2 In standard commons tragedies, such as overfishing, individuals collectively deplete a common resource (e.g. by fishing), ultimately leading to its collapse. In the case of drug resistance, the resource (e.g. effective antimicrobials) can be depleted (in a way akin to standard depletion) through use of antimicrobial drugs, leading to resistance, but also, for example by the transmission of drug resistant strains from one person to another (regardless of whether either has recently used antimicrobials) – thus the relationships at play may be more complex than standard commons tragedies. 3 The actual (as opposed to perceived) risks and benefits are rarely quantified ‘at the bedside’.", "n_tokens": 156, "kind": "text"}
{"chunk_id": "drug_resistance_book-23-0", "doc_id": "drug_resistance_book", "page": 23, "text": "1 Drug-Resistant Infection: Causes, Consequences, and Responses\n\nwhen it is really needed while, at the same time, antibiotics are used when they are not required, leading to resistance. This, in turn, exacerbates problems of access – because the second line drugs required (after first line drugs have been rendered useless) are more expensive/less affordable (Laxminarayan et al. 2016; Dar et al. 2016). In parallel, the transmission of resistant pathogens is amplified by a lack of access to readily available clean water, sanitation, and well-resourced healthcare institutions. The burden of drug-resistant infections thus tracks poverty and social disadvantage both within countries and internationally (Llewelyn et al. 2017; Bryce et al. 2016; Guh et al. 2015) (See Chap. 16).\n\n1.2.3\n\nTransmission", "n_tokens": 176, "kind": "text"}
{"chunk_id": "drug_resistance_book-23-1", "doc_id": "drug_resistance_book", "page": 23, "text": "Drug-resistant microbes are transmitted between human beings just like other non- resistant pathogens – via airborne or droplet transmission, skin contact, the faecal- oral route, sexual transmission, contact with infected bodily fluids, contaminated water and food, vector transmission (e.g. mosquitoes in the case of malaria), and so on. The epidemiological significance of transmission of some pathogens in some contexts is relatively well understood, whereas the transmission of the same patho- gens in other settings may be different and/or less well-studied. In the case of drug- resistant bacteria, for example, in-hospital transmission is well-documented. Such transmission often occurs via contamination of the clinical environment and via healthcare workers – especially those who fail to adhere to basic hand hygiene prac- tices (see Chap. 6), although controversy surrounds the optimum infection control policies to prevent transmission (Morgan et al. 2017). However, the transmission of resistant bacteria (and antibiotic resistance mechanisms) in the general community (i.e. outside healthcare facilities) is poorly understood, and much more evidence is needed to guide policy (Holmes et al. 2016; Dar et al. 2016). Transmission in the community is facilitated not only by direct human contact, but also general environ- mental contamination with resistant pathogens, the mobile genetic elements that confer resistance, and even antibiotics themselves – with polluted water systems", "n_tokens": 294, "kind": "text"}
{"chunk_id": "drug_resistance_book-23-2", "doc_id": "drug_resistance_book", "page": 23, "text": "being a key link in indirect transmission between human beings, and between ani- mals and humans (Pruden et al. 2013; Martinez 2009). This problem is of greatest concern in low-income settings with poor access to clean water and sanitation, fur- ther exacerbating the inequitable distribution of harms from drug-resistant infection (Laxminarayan et al. 2016; Dar et al. 2016).", "n_tokens": 91, "kind": "text"}
{"chunk_id": "drug_resistance_book-23-3", "doc_id": "drug_resistance_book", "page": 23, "text": "The global spread of drug resistance is greatly facilitated by modern air travel. Millions of people become colonised (usually without symptoms) with resistant pathogens or other (non-pathogenic) microbes containing genetic determinants of resistance every year in locations with high rates of resistance and then fly to regions where (whether or not those colonised are sick) resistant pathogens and/or resis- tance determinants are directly or indirectly transmitted to others (Kennedy and Collignon 2010; Östholm-Balkhed et al. 2013).\n\n7", "n_tokens": 115, "kind": "text"}
{"chunk_id": "drug_resistance_book-24-0", "doc_id": "drug_resistance_book", "page": 24, "text": "8\n\nE. Jamrozik and M. J. Selgelid\n\n1.2.4\n\nAntimicrobial Use in Animals and Agriculture", "n_tokens": 29, "kind": "text"}
{"chunk_id": "drug_resistance_book-24-1", "doc_id": "drug_resistance_book", "page": 24, "text": "The widespread use of antibiotics in industrial agriculture and aquaculture, either as ‘growth promoters’ or in other mass prophylactic uses, has lead to pathogens devel- oping resistance to the agents used. This has had consequences for both animal and human health. Consequences for humans occur when clinically significant patho- gens (and/or resistance determinants) are transmitted from animals to humans (either directly via animal contact or consumption of animal products, or indirectly via environmental contamination with resistant pathogens and/or resistance deter- minants), when humans are themselves exposed to antibiotics used in the food chain (either in the products they consume, or because antibiotics and antibiotic residues are released into the environment), or when humans are exposed to pathogens (or other microbes) that become resistant (and/or carry resistance determinants) as a result of exposure to antibiotics in enviroments contaminated by agricultural use (Holmes et al. 2016; Schwaber et al. 2011; Birgand et al. 2016; Chang et al. 2015; Martinez 2009).4 The links between animal and human health via our shared micro- biome are complex, and the relative importance of different causal pathways in a particular setting is often difficult to quantify (Chang et al. 2015) (See Chap. 7). Likewise, although the agricultural industry uses more antibiotics in total tonnage than human healthcare, the relative contribution of agricultural antibiotic use to the", "n_tokens": 301, "kind": "text"}
{"chunk_id": "drug_resistance_book-24-2", "doc_id": "drug_resistance_book", "page": 24, "text": "epidemiology of resistant bacterial disease in humans is difficult to study, often unknown and likely varies widely in different settings (Holmes et al. 2016).", "n_tokens": 32, "kind": "text"}
{"chunk_id": "drug_resistance_book-24-3", "doc_id": "drug_resistance_book", "page": 24, "text": "1.3\n\nConsequences\n\n1.3.1\n\nDirect Harms to Human Beings\n\nThe true global burden of death and disease due to resistant infection is unknown, and from both ethical and scientific points of view there is an urgent need for more accurate estimates. One prominent appraisal published in 2015 suggested that at least 700,000 deaths occur each year due to drug-resistant infection worldwide, and that this annual death toll could rise to ten million by the year 2050 (Antimicrobial resistance: Tackling a crisis for the health and wealth of nations 2015). However, this analysis included only 6 pathogens and acknowledged that the true number is probably already far higher, especially given that more of the burden of disease falls on poor communities that often have incomplete disease surveillance systems and limited access to relevant diagnostic technology (Laxminarayan et al. 2016).\n\n4 In (1) microbes become resistant due to their exposure to antibiotics in animals’ bodies; in (2) microbes become resistant due to their exposure to antibiotics in people’s bodies (resulting from people’s exposure to antibiotics in contaminated environments); in (3) microbes become resistant due to their exposure to antibiotics in contaminated environments.", "n_tokens": 243, "kind": "text"}
{"chunk_id": "drug_resistance_book-25-0", "doc_id": "drug_resistance_book", "page": 25, "text": "1 Drug-Resistant Infection: Causes, Consequences, and Responses\n\nThe inequitable distribution of harms from resistant disease mirrors the inequi- table distribution of infectious disease burden more generally. In both high- and low-income countries, the heavy burden disproportionately shouldered by impover- ised people and communities is largely explained by ‘social determinants of health’ (e.g. lack of access to clean water, sanitation, wealth, education, access to a robust health system, etc). On many accounts of justice, wealthy individuals and societies have strong moral reasons to improve these basic determinants of public health for all (Selgelid 2008). Furthermore, since resistant pathogens (like other pathogens) spread across borders, the wealthy have increasingly strong self-interested reasons to provide assistance to others and to prevent others from developing resistant disease.", "n_tokens": 179, "kind": "text"}
{"chunk_id": "drug_resistance_book-25-1", "doc_id": "drug_resistance_book", "page": 25, "text": "High rates of resistant pathogens (especially common bacterial species) under- mine many of the advances of modern medicine – because the successes of surgery, transplantation, cancer treatment, immunosuppression, intensive care, and obstetric and neonatal care are very often contingent on being able to treat and cure infec- tions. Increasing drug resistance thus has widespread implications for health and healthcare. Although patients who are unwell with other comorbidities are at the highest risk (both of carrying resistant pathogens – due to recurrent treatment and hospitalisation – and of invasive disease from these pathogens), even relatively healthy people are, and will increasingly be, harmed by resistant infectious disease. Before the advent of antibiotics, a simple skin wound could lead to untreatable sepsis, amputation and/or death, and a ‘post-antibiotic era’ would entail a return to similarly grim prospects. Increasing drug resistance thus severely threatens the entire global population and, in addition, future generations.\n\n1.3.2", "n_tokens": 212, "kind": "text"}
{"chunk_id": "drug_resistance_book-25-2", "doc_id": "drug_resistance_book", "page": 25, "text": "Economic Consequences\n\nAlong with direct harms, drug resistance has severe economic consequences. Drug- resistant infections are more difficult (sometimes impossible) and more expensive to treat and cure, and they are more likely to result in incapacitation of the patient and significant economic losses for society. One estimate suggested that total global losses due to resistant infection between now and 2050 could total over $US 100 trillion (O’Neill 2015), meaning that there are powerful economic reasons to devise and implement effective measures to curb the problem (See Chap. 17).\n\nAs noted in several chapters in this book, the availability of effective antimicrobi- als has many features of a ‘public good’ in economic terms. Standard economic models predict (more or less accurately) that a free market in antimicrobials (i.e. with little or no regulation of access apart from price) leads to ‘market failure’ and the erosion of the good in question (i.e. availability of effective antimicrobials). In most societies, since access to antimicrobials occurs via healthcare practitioners, the ‘market’ is relatively controlled (as opposed to free). The incentive structures that lead to a collective action problem for doctors and patients (discussed above)\n\n9", "n_tokens": 258, "kind": "text"}
{"chunk_id": "drug_resistance_book-26-0", "doc_id": "drug_resistance_book", "page": 26, "text": "10\n\nE. Jamrozik and M. J. Selgelid\n\nnevertheless lead to a similar erosion of antimicrobial effectiveness – albeit at an attenuated rate, depending upon the degree to which regulations on prescriptions succeed. Private healthcare providers, in any case, can be difficult to regulate (see Chap. 5), especially where they are not part of a centralised and/or universal health- care system.\n\n1.3.3", "n_tokens": 93, "kind": "text"}
{"chunk_id": "drug_resistance_book-26-1", "doc_id": "drug_resistance_book", "page": 26, "text": "Burdensome Public Health Interventions\n\nThe consequences of drug resistance for human beings are more than just matters of physical health and wealth. In many cases, public health surveillance and related public health practices have ethically salient implications for other aspects of well- being, including psychological well-being (e.g. due to experiences of stigma among carriers of resistant microbes – see below), as well as privacy and other freedoms (e.g. which are compromised by mandatory physical/social distancing measures such as isolation and quarantine). Well-designed public health surveillance and research should be conducted in order to clarify the health risks and costs of resis- tant infection and the risks, benefits, and burdens of potential public health interven- tions. High quality data would help policymakers determine whether imposing certain burdens on individuals would be justified as a means to improve public health (e.g. by reducing infectious disease due to resistant organisms) (Fairchild and Bayer 2004). Unfortunately, investment in surveillance for resistance has, globally, been very low and is only just starting to be improved, particularly in wealthy settings.", "n_tokens": 229, "kind": "text"}
{"chunk_id": "drug_resistance_book-26-2", "doc_id": "drug_resistance_book", "page": 26, "text": "Those identified by surveillance as carriers of resistant pathogens while inpa- tients in healthcare settings sometimes experience stigma (Rump et al. 2017) as well as a wide range of effects on well-being, which some argue are best understood through a capabilities approach that explores the broader implications of public health policies for the flourishing of individual lives (see Chap. 13). Such an approach may also help to illustrate the broader aspects of human life that are jeop- ardised by the lack of access to effective antimicrobials, especially among children, for whom early severe infection may impair long term development (see Chap. 14). Indeed, as more people become aware of resistance, and more community sur- veillance is conducted, apparently healthy individuals in the community may be increasingly identified as asymptomatic carriers of resistant organisms (See Chap. 12). Furthermore, such individuals might be monitored, offered or required to undergo treatment, and have other liberties (freedom of movement, free choice of occupation) curtailed by public health policy (Houston and Houston 2015). Those who have had recent contact with carriers might be tested and/or quarantined. There is thus frequently a tension between the aim to protect public health (by identifying infected individuals and reducing transmission of (resistant) disease) and the aim to avoid imposing significant burdens (in terms of compromised well-being, privacy and/or liberty) on individuals", "n_tokens": 296, "kind": "text"}
{"chunk_id": "drug_resistance_book-26-3", "doc_id": "drug_resistance_book", "page": 26, "text": "in order to prevent the spread of disease to others (Viens et al. 2009).", "n_tokens": 19, "kind": "text"}
{"chunk_id": "drug_resistance_book-27-0", "doc_id": "drug_resistance_book", "page": 27, "text": "1 Drug-Resistant Infection: Causes, Consequences, and Responses\n\n1.4\n\nResponses\n\n1.4.1\n\nNew Drugs\n\nFor many decades, even where the emergence of drug resistance was recognized, much of the response (or lack thereof) by individual clinicians as well as policymakers was grounded in (apparently unfounded) confidence that new antimicrobial drugs would be discovered and developed, meaning that resistance to older drugs was of limited significance. Despite early warnings of the consequences (Holmes et al. 2016; Honigsbaum 2016) – profligate use continued and indeed accelerated in humans, animals, and agriculture. Meanwhile, the restricted use of new antimicrobials as ‘reserve’ agents – although it may help to slow the emergence of resistance – means that there are disencentives to (profit-motivated) research and development of new antimicrobials. For this and other reasons, few new antibiotic classes or agents have been developed in recent decades (Norrby et al. 2005). Boosting more relevant research and development may thus require more public effort/funding and/or realignment of pharmaceutical companies’ incentive structures (i.e. so that profit making becomes more compatible with developing products that are most important to global public health) (Banerjee et al. 2010).", "n_tokens": 268, "kind": "text"}
{"chunk_id": "drug_resistance_book-27-1", "doc_id": "drug_resistance_book", "page": 27, "text": "New drugs (or other means of treatment/prevention) are arguably most urgently needed for infections that have become nearly pan-resistant (e.g. extensively drug- resistant TB, or multi-resistant gram negative bacteria). Vis-à-vis other responses that target particular causal pathways (e.g. restrictions on prescriptions practices or agricultural use) they would provide a cross-cutting solution to the problem of drug resistance – i.e. addressing the problem regardless of the specific mechanisms by which it was brought about.\n\nIt is clear, however, that policymakers (and, indeed, patients) cannot rely on new drugs to ‘fix’ the problem(s) of drug resistance, since (i) the development of new antimicrobial drugs has, in recent decades, been slow and/or relatively unsuccess- ful, (ii) the challenges underlying difficulties with drug development have thus far proven difficult to overcome, and (iii) without other interventions to curb the increase in drug resistance, we face a never-ending problem of finding new drugs. Thus, drug resistance requires a multi-faceted and global policy response – yet one that is also tailored to the specific problems and mechanisms of resistance in a given microbe and a given context.\n\n1.4.2", "n_tokens": 261, "kind": "text"}
{"chunk_id": "drug_resistance_book-27-2", "doc_id": "drug_resistance_book", "page": 27, "text": "Research and Surveillance\n\nApart from finding new treatments, other kinds of research are urgently needed, including empirical research in diagnostics, microbiology, vaccines (and other non- drug interventions), as well as social science and public health systems research (Dar et al. 2016). As a starting point, there are large gaps in our knowledge of the\n\n11", "n_tokens": 70, "kind": "text"}
{"chunk_id": "drug_resistance_book-28-0", "doc_id": "drug_resistance_book", "page": 28, "text": "12\n\nE. Jamrozik and M. J. Selgelid\n\nepidemiology of most resistant pathogens. Improving local and international public health surveillance would help to determine the impact of various resistance mecha- nisms and evaluate the cost-effectiveness of interventions. Yet this, in turn, requires development of cost-effective and publically acceptable surveillance mechanisms that can be more widely implemented, including in LMICs, and political and scien- tific agreement on which data will be collected and shared (Tacconelli et al. 2017). It also requires careful attention to the ethical conduct of public health surveillance (World Health Organisation 2017b).\n\n1.4.2.1", "n_tokens": 142, "kind": "text"}
{"chunk_id": "drug_resistance_book-28-1", "doc_id": "drug_resistance_book", "page": 28, "text": "Reducing Use in Humans\n\nThere is an urgent need to reduce antibiotic use in human patients. The most ethi- cally straightforward cases are those in which a person is prescribed (or purchases without prescription) an antibiotic (with a risk of side-effects and resistance) for a condition for which it will provide no benefit (e.g. a viral illness) or where a shorter course of antibiotics is as effective as a longer course but the latter confers an increased risk of resistance and/or side-effects. In such cases, antibiotic use consti- tutes a net harm to the individual and, through the risk of transmission of resistant organisms, to others.\n\nOne strategy to reduce use is to develop new diagnostics, so that patients and doctors can avoid using antibiotics where they are not required. But in the absence of perfect tests, changes in professional and public culture are also required. For example, doctors should address their own cognitive biases (see Chap. 8) as well as patient concerns about avoiding the complications of infection, and public aware- ness campaigns must emphasize that antibiotics are often not required and can themselves entail significant risk (to individuals and public health) (World Health Organisation 2015). International data suggest that some countries have made sig- nificant progress in reducing antibiotic use without a significant increase in severe infections (Bronzwaer et al. 2002).", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-28-2", "doc_id": "drug_resistance_book", "page": 28, "text": "Yet, as effective antibiotics become more and more scarce, there are more diffi- cult ethical tradeoffs to be considered, involving greater uncertainty. For example, if antibiotics become reserved for severe and/or complicated infections – so that use is banned or dramatically reduced for patients with simple infections – many patients with a simple bacterial infection (e.g. mild pneumonia) may end up being more unwell for longer, or even at a small risk of severe outcomes (even though the vast majority will ultimately recover without specific curative treatment), because they do not have access to antibiotics.\n\nPolicy to reduce use in either the low risk or the higher risk cases cannot rely entirely on individuals, since the structure of the underlying collective action prob- lem leads to strong incentives to ‘free-ride’ on others’ reduction in use. Thus, some form of regulation is required – e.g. through antimicrobial stewardship (which has been a successful but resource intensive approach in healthcare institutions), and/or restrictions on physician prescribing. How best to design and enforce such regula- tion is an important matter for debate in public health ethics.", "n_tokens": 236, "kind": "text"}
{"chunk_id": "drug_resistance_book-29-0", "doc_id": "drug_resistance_book", "page": 29, "text": "1 Drug-Resistant Infection: Causes, Consequences, and Responses\n\n1.4.2.2\n\nReducing Use in Animals and Agriculture", "n_tokens": 25, "kind": "text"}
{"chunk_id": "drug_resistance_book-29-1", "doc_id": "drug_resistance_book", "page": 29, "text": "As argued in later chapters of this volume (see Chaps. 7 and 18), antibiotic use and overuse in agriculture must also be reduced. First and foremost, many have argued that the widespread use in animals of agents that are critical to human health should be dramatically reduced and/or prohibited, especially when such agents are employed for non-therapeutic purposes (e.g. as ‘growth promoters’) (Marshall and Levy 2011; World Health Organisation 2017c). But even other drugs (and non-drug agents) may lead to the co-selection of resistance determinants for critical drugs among bacteria (and fungi) shared between animals and humans. The overuse of antibiotics in agriculture in part represents a palliative for the high rates of infection in crowded ‘factory farms’, suggesting that reforming farming practices would have the dual benefits of reducing animal cruelty and reducing drug resistant infections. Reducing or eliminating meat consumption would also obviate many of the dangers to humans of resistance in animals (although not all, since companion animals can also transmit drug-resistant infection (Guardabassi et al. 2004)). The fact that some wealthy countries have dramatically reduced or eliminated profligate antibiotic use in farm animals (in part by giving animals more space and improving infection control practices) often at little or no long term economic cost suggests that it is possible to minimise this driver of drug resistance (McEwen et al. 2018). Whether such practices", "n_tokens": 296, "kind": "text"}
{"chunk_id": "drug_resistance_book-29-2", "doc_id": "drug_resistance_book", "page": 29, "text": "will be successfully implemented in lower income countries remains to be seen (Dar et al. 2016).", "n_tokens": 20, "kind": "text"}
{"chunk_id": "drug_resistance_book-29-3", "doc_id": "drug_resistance_book", "page": 29, "text": "1.4.2.3\n\nAddressing Social Determinants of Health\n\nInfectious diseases, in general, are more prevalent among poor people and commu- nities in both high and low-income countries. Many aspects of social organization and the built environment (water and sanitation systems, health systems, etc.) alter the risk of acquiring infection, and the risk of transmission of resistance mecha- nisms. Historically, improvements in living conditions arguably contributed more to the decline in infectious diseases in developed/industrialised countries than discov- eries of vaccines or antimicrobial treatments (McKeown 1976). One way of reduc- ing the prevalence of drug resistant infection would be to reduce its incidence and transmission by addressing these (and other) such social determinants of health.", "n_tokens": 160, "kind": "text"}
{"chunk_id": "drug_resistance_book-29-4", "doc_id": "drug_resistance_book", "page": 29, "text": "The rise of untreatable infections provides a new, and urgent, rationale to ensure universal access to the social conditions that enable healthy living. Even basic mea- sures, especially if provided to all, could help minimize the transmission of resis- tance (e.g. by providing access to clean water and sanitation) and reduce the use of antimicrobial drugs (e.g. by providing access to high quality, and well-regulated, health systems). Since resistant infections routinely spread via international travel, wealthy nations have reasons not only to act locally but also to act globally by assisting others with less resources (see Chap. 21) – to reduce the incidence and international transmission of resistant infection (Selgelid 2008).\n\n13", "n_tokens": 154, "kind": "text"}
{"chunk_id": "drug_resistance_book-30-0", "doc_id": "drug_resistance_book", "page": 30, "text": "14\n\nE. Jamrozik and M. J. Selgelid\n\n1.4.2.4\n\nInfection Control\n\nInfection control involves measures that aim to reduce the transmission of patho- gens in an institution or community. In healthcare institutions, this typically involves screening of patients, monitoring of those carrying (and/or suffering disease from) resistant pathogens, use of personal protective equipment, and social distancing measures such as isolation and quarantine. In some cases, it also involves decoloni- zation of patients. Methicillin-resistant Staphylococcus aureus (MRSA) decoloni- zation, for example, involves the use of antibacterial solutions on the skin, hair, and nasal membranes. More dramatically, recent studies have reported successful use of faecal transplantation to decolonize those with highly resistant bowel organisms (Freedman and Eppes 2014; Crum-Cianflone et al. 2015). In many cases, screening for resistant pathogens in hospital does not involve/require informed consent of patients, on the grounds that screening and control measures are required in order to prevent harm to others. Such policies should nonetheless be based upon careful ethical justification as well as, where possible, evidence of cost-effectiveness (see Chap. 6), especially insofar as they infringe on the lives of individual carriers (who may or may not be symptomatic) in significant ways (see Chap. 13).", "n_tokens": 308, "kind": "text"}
{"chunk_id": "drug_resistance_book-30-1", "doc_id": "drug_resistance_book", "page": 30, "text": "Infection control policies become more complex when they are applied in the general community. As more people in the community are identified as carriers of highly resistant pathogens, it remains to be seen what kinds of restrictions of indi- vidual liberty would or shoud be considered justifiable. When, if ever, for example, should travellers be screened on arrival from high-risk regions – and when should those who test positive for resistant organisms be offered (or required to have) decolonization – and/or be subject to monitoring and/or social distancing measures? Important questions such as these need to be considered (and re-evaluated) as more is learned about community and international transmission of drug-resistant organisms.\n\n1.4.2.5", "n_tokens": 153, "kind": "text"}
{"chunk_id": "drug_resistance_book-30-2", "doc_id": "drug_resistance_book", "page": 30, "text": "Vaccines\n\nVaccines are a cross-cutting intervention with the potential to obviate the need to prescribe antimicrobials for a range of pathogens. In some cases, furthermore, vaccines can prevent infections that would otherwise be untreatable/uncurable (e.g., due to high levels of drug resistance). Existing vaccines against tuberculosis and some bacterial infections (e.g. Streptococcus pneumoniae, Haemophilus influenzae) reduce the incidence of infections due to these pathogens and thereby reduce the use of relevant antimicrobials (Dar et al. 2016). Vaccines against specific resistant strains may also lead to their replacement (e.g. in a given ecological niche in the human body) by strains that are easier to treat (Dar et al. 2016), although longitudinal surveillance data regarding strain epidemiology and disease burden are needed to confirm whether such effects lead to a long-term net public health benefit.", "n_tokens": 199, "kind": "text"}
{"chunk_id": "drug_resistance_book-31-0", "doc_id": "drug_resistance_book", "page": 31, "text": "1 Drug-Resistant Infection: Causes, Consequences, and Responses\n\nEven effective vaccines against viral infections (e.g. influenza, common cold viruses) can lead to a marked reduction in antibiotic use since viral infections are often erroneously treated with antibiotics (Neuzil et al. 2000). New vaccines against malaria and typhoid may help to reduce antimicrobial use and resistance relevant to these pathogens. Because there is a great number of resistant pathogens for which we lack vaccines, however, this is an important area in need of further research and development.\n\nOf course, discovering an effective vaccine may lead to the replacement of one collective action problem (antimicrobial overuse) with another (assuring high vaccination rates) – meaning that even this ‘technical fix’ would have limitations. Like the development of new drugs, in any case, new vaccines would form only one part of the multi-pronged approach needed to control the problem of drug resistance.\n\n1.5", "n_tokens": 200, "kind": "text"}
{"chunk_id": "drug_resistance_book-31-1", "doc_id": "drug_resistance_book", "page": 31, "text": "Conclusions\n\nDrug-resistance is widely recognised to be one of the greatest threats to global pub- lic health in the coming decades. Its causes are complex, and more work is needed to determine the relative importance of different causes. The consequences for human health are already highly significant, and, if left unchecked, will be even more dramatic in the near future. These harms, taken together, represent a large, likely underestimated, and ethically salient burden of disease that disproportion- ately affects underprivileged people and communities worldwide. Yet the presence of untreatable and potentially fatal pathogens and the prospect of such infections becoming more common is a threat to all. Despite current uncertainties and urgent gaps in our knowledge regarding drug-resistant infection, there is a pressing need to develop and implement ethically informed policies to reduce rising levels of resis- tance and thereby mitigate or avert future harms and injustices. We hope that the subsequent chapters of this volume will make a significant contribution to this important area of public health ethics.", "n_tokens": 220, "kind": "text"}
{"chunk_id": "drug_resistance_book-31-2", "doc_id": "drug_resistance_book", "page": 31, "text": "References\n\nBanerjee, A., A. Hollis, and T. Pogge. 2010. The Health Impact Fund: Incentives for improving\n\naccess to medicines. The Lancet 375 (9709): 166–169.\n\nBirgand, G., L.S.P. Moore, C. Bourigault, V. Vella, D. Lepelletier, A.H. Holmes, et al. 2016. Measures to eradicate multidrug-resistant organism outbreaks: How much do they cost? Clinical Microbiology and Infection 22 (2): 162.e1–162.e9.\n\nBronzwaer, S.L.A.M., O. Cars, U. Buchholz, S. Mölstad, W. Goettsch, I.K. Veldhuijzen, et al. 2002. The relationship between antimicrobial use and antimicrobial resistance in Europe. Emerging Infectious Diseases 8 (3): 278.\n\nBryce, A., A.D. Hay, I.F. Lane, H.V. Thornton, M. Wootton, and C. Costelloe. 2016. Global preva- lence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli\n\n15", "n_tokens": 273, "kind": "text"}
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{"chunk_id": "drug_resistance_book-33-0", "doc_id": "drug_resistance_book", "page": 33, "text": "1 Drug-Resistant Infection: Causes, Consequences, and Responses\n\nMcKeown, T. 1976. The role of medicine: Dream, mirage, or nemesis? Princeton: Princeton\n\nUniversity Press.\n\nMorgan, D.J., R.P. Wenzel, and G. Bearman. 2017. Contact precautions for endemic MRSA and\n\nVRE: Time to retire legal mandates. JAMA 318 (4): 329–330.\n\nNasrin, D., P.J. Collignon, L. Roberts, E.J. Wilson, L.S. Pilotto, and R.M. Douglas. 2002. Effect of βlactam antibiotic use in children on pneumococcal resistance to penicillin: Prospective cohort study. BMJ 324 (7328): 28.\n\nNeuzil, K.M., B.G. Mellen, P.F. Wright, E.F. Mitchel Jr., and M.R. Griffin. 2000. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. New England Journal of Medicine 342 (4): 225–231.\n\nNorrby, S.R., C.E. Nord, and R. Finch. 2005. Lack of development of new antimicrobial drugs: A\n\npotential serious threat to public health. The Lancet Infectious Diseases 5 (2): 115–119.\n\nO’Neill, J. 2015. Antimicrobial resistance: Tackling a crisis for the health and wealth of nations. In\n\nThe review on antimicrobial resistance. Chaired by Jim O’Neill. December, 2014.\n\nÖstholm-Balkhed, Å., M. Tärnberg, M. Nilsson, L.E. Nilsson, H. Hanberger, A. Hällgren, et al. 2013. Travel-associated faecal colonization with ESBL-producing Enterobacteriaceae: Incidence and risk factors. Journal of Antimicrobial Chemotherapy 68 (9): 2144–2153.", "n_tokens": 425, "kind": "text"}
{"chunk_id": "drug_resistance_book-33-1", "doc_id": "drug_resistance_book", "page": 33, "text": "Pruden, A., D.G.J. Larsson, A. Amézquita, P. Collignon, K.K. Brandt, D.W. Graham, et al. 2013. Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment. Environmental Health Perspectives 121 (8): 878.\n\nRump, B., M. De Boer, R. Reis, M. Wassenberg, and J. Van Steenbergen. 2017. Signs of stigma and poor mental health among carriers of MRSA. Journal of Hospital Infection 95 (3): 268–274. Safdar, N., and E.A. Bradley. 2008. The risk of infection after nasal colonization with", "n_tokens": 156, "kind": "text"}
{"chunk_id": "drug_resistance_book-33-2", "doc_id": "drug_resistance_book", "page": 33, "text": "Staphylococcus aureus. The American Journal of Medicine 121 (4): 310–315.\n\nSchwaber, M.J., B. Lev, A. Israeli, E. Solter, G. Smollan, B. Rubinovitch, et al. 2011. Containment of a country-wide outbreak of carbapenem-resistant Klebsiella pneumoniae in Israeli hospitals via a nationally implemented intervention. Clinical Infectious Diseases 52 (7): 848–855.\n\nSelgelid, M.J. 2008. Improving global health: Counting reasons why. Developing World Bioethics\n\n8 (2): 115–125.\n\nSmith, D.L., J. Dushoff, E.N. Perencevich, A.D. Harris, and S.A. Levin. 2004. Persistent coloniza- tion and the spread of antibiotic resistance in nosocomial pathogens: Resistance is a regional problem. Proceedings of the National Academy of Sciences of the United States of America 101 (10): 3709–3714.\n\nTacconelli, E., F. Sifakis, S. Harbarth, R. Schrijver, M. van Mourik, A. Voss, et al. 2017. Surveillance\n\nfor control of antimicrobial resistance. The Lancet Infectious Diseases.\n\nTischendorf, J., R.A. de Avila, and N. Safdar. 2016. Risk of infection following colonization with carbapenem-resistant Enterobactericeae: A systematic review. American Journal of Infection Control 44 (5): 539–543.\n\nViens, A.M., C.M. Bensimon, and R.E.G. Upshur. 2009. Your liberty or your life: Reciprocity in the use of restrictive measures in contexts of contagion. Journal of Bioethical Inquiry 6 (2): 207–217.\n\nWhite, N.J. 2017. Does antimalarial mass drug administration increase or decrease the risk of", "n_tokens": 432, "kind": "text"}
{"chunk_id": "drug_resistance_book-33-3", "doc_id": "drug_resistance_book", "page": 33, "text": "resistance? The Lancet Infectious Diseases 17 (1): e15–e20.\n\nWorld Health Organisation. 2015. Antibiotic resistance: Multi-country public awareness survey.\n\nGeneva: WHO.\n\n———. 2017a. Ethics guidance for the implementation of the end TB strategy. Geneva: WHO. ———. 2017b. WHO guidelines on ethical issues in public health surveillance. Geneva: WHO. ———. 2017c. WHO guidelines on use of medically important antimicrobials in food-producing\n\nanimals. Geneva: WHO.\n\n17", "n_tokens": 113, "kind": "text"}
{"chunk_id": "drug_resistance_book-34-0", "doc_id": "drug_resistance_book", "page": 34, "text": "18\n\nE. Jamrozik and M. J. Selgelid\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 180, "kind": "text"}
{"chunk_id": "drug_resistance_book-35-0", "doc_id": "drug_resistance_book", "page": 35, "text": "Chapter 2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection: An Ethical Imperative with Ethical Barriers to Implementation?", "n_tokens": 24, "kind": "text"}
{"chunk_id": "drug_resistance_book-35-1", "doc_id": "drug_resistance_book", "page": 35, "text": "Binh Nguyen, Greg J. Fox, Paul H. Mason, and Justin T. Denholm\n\nAbstract Multidrug resistant tuberculosis (MDR-TB) has a substantial impact on individuals and communities globally, including lengthy, expensive and burden- some therapy with high rates of treatment failure and death. Strategies to prevent disease are well established for those who acquire latent tuberculosis infection (LTBI) after exposure to drug susceptible TB (DS-TB). However, there has been limited research or programmatic experience regarding the prevention of MDR-TB. Accordingly, while global recommendations strongly emphasize the need to deliver LTBI therapy after TB exposure, most programs do not do so where MDR LTBI is identified.\n\nThe paucity of prospective randomized trial evidence for the effectiveness of MDR LTBI therapy, and concerns regarding its adverse effects, have been used to justify a reluctance to scale up programmatic interventions to prevent MDR-TB, or to participate in research evaluating such strategies. However, such a response fails to adequately balance potential risks of therapy with the substantial harms associ- ated with inaction. Furthermore, the cost of inaction falls disproportionately on the\n\nB. Nguyen Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia\n\nG. J. Fox Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia", "n_tokens": 282, "kind": "text"}
{"chunk_id": "drug_resistance_book-35-2", "doc_id": "drug_resistance_book", "page": 35, "text": "Faculty of Medicine, University of Sydney, Sydney, NSW, Australia\n\nP. H. Mason Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia\n\nSchool of Social Sciences, Monash University, Melbourne, VIC, Australia\n\nJ. T. Denholm (*) Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia\n\nVictorian Tuberculosis Program at the Doherty Institute, Melbourne, VIC, Australia e-mail: justin.denholm@mh.org.au\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_2\n\n19", "n_tokens": 173, "kind": "text"}
{"chunk_id": "drug_resistance_book-36-0", "doc_id": "drug_resistance_book", "page": 36, "text": "20\n\nB. Nguyen et al.\n\nmost vulnerable members of society, including children. Delays in implementing proven preventive strategies may also mask hidden programmatic concerns, particu- larly regarding the financial cost and other burdens of treating drug resistant infec- tion. Reticence to engage with preventative therapy for MDR-TB, even in the absence of high-level evidence, may run counter to the best interests of individuals who have been exposed to MDR-TB.\n\nThis chapter will explore ethical tensions raised by expanding access to preven- tative therapies for MDR-TB, and consider how ethically optimal responses to this adverse condition may be evaluated. An ethical perspective on evidentiary burden will be addressed, emphasizing how MDR LTBI research may both offer, and be shaped by, paradigmatic insights into human research ethics more generally. Emerging research and illustrations from the authors programmatic engagement in Vietnam are offered as case examples, because social and community expectations and norms may challenge, or support, implementation of therapy for drug-resistant infection. Such circumstances prompt consideration of the broader questions of social impact, such as the potential for widespread preventive therapy to accelerate the development of antimicrobial resistance.\n\nKeywords Bioethics · Infectious diseases · Public health · Social justice · Equality and human rights · Asian culture\n\n2.1", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-36-1", "doc_id": "drug_resistance_book", "page": 36, "text": "Background\n\nMultidrug resistant tuberculosis (MDR-TB) is a global pandemic disease, charac- terised as ‘Ebola with wings’ by public health experts due to its airborne transmis- sion and significant patient mortality (Voelker 1998). With more than 450,000 cases reported in 2015, MDR-TB has become an established global health emergency (World Health Organization 2013a, 2015a, 2016; Hoang et al. 2015a). While treat- ment for drug-susceptible (DS)-TB typically involves multiple antibiotic tablets for a period of 6 months, standard MDR-TB treatment involves up to 2 years of both oral and injected antibiotics. These toxic regimens frequently cause nausea, liver damage and irreversible hearing loss, and may also require surgery or other invasive procedures (Fox et al. 2016; Torun et al. 2005). Despite the availability of these intensive regimens, MDR-TB therapy is successful in only around half of cases globally, with a high risk of treatment failure and death (Orenstein et al. 2009). In addition, the burden of MDR-TB extends far beyond its medical impact. The pro- longed illness, and its associated treatment, has major financial implications for patients and their families - incurring significant financial and housing instability (Tanimura et al. 2014). In short, MDR-TB is costly, prolonged, and complex for both individuals and health care services (Keal et al. 2013).", "n_tokens": 314, "kind": "text"}
{"chunk_id": "drug_resistance_book-36-2", "doc_id": "drug_resistance_book", "page": 36, "text": "As TB is a contagious infectious disease, those who live in close contact with affected individuals are themselves at a high risk of developing disease - around 10% of contacts with latent (asymptomatic) TB infection (LTBI) due to M. tubercu- losis will subsequently develop disease (Marks et al. 2000). Current strategies to prevent the spread of MDR-TB mainly focus upon interrupting the transmission of", "n_tokens": 90, "kind": "text"}
{"chunk_id": "drug_resistance_book-37-0", "doc_id": "drug_resistance_book", "page": 37, "text": "2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection…\n\ninfection, by identifying and treating patients with active disease (World Health Organization 2011, 2013b; Fox et al. 2013a). Such strategies are important for indi- viduals with MDR-TB, but have limited impact on preventing disease in those around them who are likely to have already been infected prior to the diagnosis of the treated patient. Transmission studies indicate that close contacts of MDR-TB patients have an elevated risk of infection. Not only are contacts exposed directly to the recognised patient, but they also share socio-economic determinants of disease (World Health Organization 2014; Grandjean et al. 2011; Fox et al. 2017a). This confers an increased risk of exposure to other affected individuals, and susceptibility to developing this dangerous and burdensome disease (Fox et al. 2013b).", "n_tokens": 184, "kind": "text"}
{"chunk_id": "drug_resistance_book-37-1", "doc_id": "drug_resistance_book", "page": 37, "text": "Given the high risk of developing active disease after infection with either DS- or MDR-TB, interventions to reduce risk among close contacts are of considerable clinical and public health importance (Trauer et al. 2016). In cases of DS-TB expo- sure, international guidelines recommend screening of exposed contacts, and a period of antibiotic therapy to prevent progression for those at highest risk of dis- ease progression – such as children under 5 years of age, or those with HIV infec- tion (World Health Organization 2015b). The effectiveness of preventative chemoprophylaxis for DS-TB is well established, including through randomized controlled trials in a variety of global settings (Lobue and Menzies 2010; Sterling et al. 2011). The importance of strategies for preventing MDR-TB has recently been summarised in national and international guidelines for the programmatic manage- ment of drug-resistant TB based on the risks of transmission, high morbidity and mortality, and the further development of drug resistance (World Health Organization 2014, 2015c; Ministry of Health 2015; European Centre for Disease Prevention and Control 2012). However, most guidelines have not recommended the routine use of targeted chemopreventive therapy for contacts of MDR-TB (Fox et al. 2017b), cit- ing insufficient evidence of effectiveness in preventing disease, instead recommend- ing programmatic surveillance of contacts. While such surveillance may lead to earlier identification of those", "n_tokens": 305, "kind": "text"}
{"chunk_id": "drug_resistance_book-37-2", "doc_id": "drug_resistance_book", "page": 37, "text": "developing disease, it fails to reduce the risk of disease among infected contacts, and hence does not prevent the consequent social and economic hardship caused by drug-resistant disease. Thus, current approaches to MDR-TB contacts recognise the high risk of disease among contacts, but do not offer routine use of preventive therapy in most settings, including Vietnam.", "n_tokens": 71, "kind": "text"}
{"chunk_id": "drug_resistance_book-37-3", "doc_id": "drug_resistance_book", "page": 37, "text": "2.2\n\nDiscussion\n\n2.2.1\n\nOngoing and Proposed Clinical Trials to Evaluate Antibiotic Therapy to Prevent Drug-Resistant Infection\n\nIn this section, we will introduce ongoing and planned clinical trials that aim to establish the effectiveness of preventive therapy for MDR-TB in order to highlight ethical issues arising from this research and reflect upon possible solutions. The first of these is the V-QUIN MDR Trial - a randomised placebo-controlled trial among infected contacts of patients with MDR-TB. Contacts are recruited from district\n\n21", "n_tokens": 107, "kind": "text"}
{"chunk_id": "drug_resistance_book-38-0", "doc_id": "drug_resistance_book", "page": 38, "text": "22\n\nB. Nguyen et al.\n\ntuberculosis clinics (DTUs) where MDR-TB treatment is delivered, throughout the Southeast Asian nation of Vietnam. The trial is underway within the Programmatic Management of Drug Resistant TB (PMDT) program at 132 clinics across 10 Provinces of the country. The primary aim of the VQUIN MDR Trial is to evaluate the effectiveness of levofloxacin (a fluoroquinolone antibiotic) in the prevention of active TB among household contacts of patients with MDR-TB with latent tubercu- losis infection. Adult contacts will receive either levofloxacin or placebo daily for 6 months. In accordance with international recommendations, contacts will then be monitored for disease progression over a further 2 years to detect incident TB disease.\n\nVietnam has the twelfth highest TB burden in the world, and is listed among the top 27 countries with the highest burden of MDR-TB (WHO 2015). The country applies regimens recommended by WHO for the treatment of MDR-TB in Vietnam, including at least 19 months of treatment. This comprises, a minimum of 6 months of intensive phase treatment (including a second line injectable antibiotic, kanamy- cin or capreomycin) and 13 months of continuation phase therapy. Antibiotic treat- ment is provided free of charge for patients meeting the eligibility criteria for the program.", "n_tokens": 282, "kind": "text"}
{"chunk_id": "drug_resistance_book-38-1", "doc_id": "drug_resistance_book", "page": 38, "text": "Despite having a nation-wide TB Program network and a structured, well- organized health service, and reporting impressive rates of treatment completion (WHO 2015), Vietnam still faces many challenges in implementing effective MDR-TB screening and treatment. Ongoing difficulties include a lack of communi- cation and consistency in implementing policy changes, a lack of integration between general district hospitals and the National TB Program network, and lim- ited resources. These health-system factors contribute to a significant gap between the estimated number of cases and the number of patients commencing treatment (Hoang et al. 2015b).", "n_tokens": 121, "kind": "text"}
{"chunk_id": "drug_resistance_book-38-2", "doc_id": "drug_resistance_book", "page": 38, "text": "In the hope of gaining more data for evidence of effective regimens in MDR-TB contacts, two other clinical trials are planned, TB-CHAMP and PHOENIx (ACTG A5300) (Clayden et al. 2015; ACTG and IMPAACT Networks 2015). Similar to V-QUIN MDR Trial using levofloxacin and placebo for intervention and control groups, TB-CHAMP study is aimed to test levofloxacin as chemoprevention in chil- dren recruited from four clinical sites in South Africa. In this trial, children under five who are household contacts of MDR-TB patients are randomized into two groups taking levofloxacin or placebo every day for 6 months and followed-up for up to 2 years (Tuberculosis child multidrug-resistant preventive therapy: TB CHAMP trial 2016). PHOENIx (ACTG A5300) run by AIDS Clinical Trials Group (ACTG) and International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) presents another different approach in which it aims to assess the efficacy of delamanid which is a new TB drug treatment for MDR-TB and XDR TB (Xavier and Lakshmanan 2014) in treating LTBI for high risk groups of house- hold contacts of MDR-TB patients by comparing its daily use in 6 months with isoniazid preventive therapy then follow up study subjects in 2 years. The trial is planned to be conducted in Africa, South America and Asia (ACTG and IMPAACT Networks 2015).", "n_tokens": 321, "kind": "text"}
{"chunk_id": "drug_resistance_book-39-0", "doc_id": "drug_resistance_book", "page": 39, "text": "2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection…\n\nObservational studies of LTBI treatment are limited. The three randomized con- trolled clinical trials on LTBI treatment in MDR-TB contacts that we outline here could well be the only research projects currently designed to address this research gap (Mitnick et al. 2016). In the following section, we will present issues and chal- lenges in more detail, informed by our work in Vietnam and discussion with other research teams and experts in the field. Programmatic and research ethics are con- textual, and specific settings may provide useful insights into the range of issues which consideration of MDR LTBI generates. In this chapter, we aim to draw on Vietnamese experience to illustrate and reflect on key ethical issues, which may be more broadly applicable in other contexts.\n\n2.2.2\n\nChallenges in the Use of Antibiotics as a Research Intervention in LTBI Treatment\n\n2.2.2.1\n\nHow to Balance Between Uncertainties and Risk of Harm: A Common Issue in Public Health Practice", "n_tokens": 213, "kind": "text"}
{"chunk_id": "drug_resistance_book-39-1", "doc_id": "drug_resistance_book", "page": 39, "text": "Medical decision-making for LTBI is replete with medical uncertainty. Diagnostic tools with the capacity to identify resistance patterns in LTBI are unavailable. Similarly, diagnostic tools capable of identifying which cases of LTBI will progress to TB disease are lacking. Developing appropriate responses with this diagnostic repertoire requires reflective engagement with medical uncertainty and the ethical challenges of emerging practices (Mason 2014a; Mason 2014b). An effective treat- ment for LTBI may well be the best method to stop progression to active disease (World Health Organization 2011; Hill et al. 2008), but puzzling questions persist about who should receive treatment for LTBI. The problem is complex enough for LTBI cases where the index patient has drug sensitive TB, but even more compli- cated for MDR LTBI, where high risk of progression is recognized but uncertainty regarding potential side effects of the drugs and the impact of preventative therapy persists. For LTBI cases who have been exposed to MDR-TB, there is little consen- sus to guide clinicians and programs towards the risk/benefit of MDR LTBI treat- ment. In contexts where existing programmatic guidelines recommend against MDR LTBI treatment on the basis of such uncertainty, additional difficulties are faced for researchers seeking to establish a study protocol, which may not align to traditional clinical views and practices in a study country site even if evidentiary equipoise is present.", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-39-2", "doc_id": "drug_resistance_book", "page": 39, "text": "In the balance between benefits and harms to receivers of MDR-TB preventive treatment, a default approach of ‘surveillance’ is frequently assumed in which “strict clinical observation and close monitoring for the development of active TB disease for at least two years is preferred over the provision of preventive treatment for contacts with MDR-TB cases” (World Health Organization 2015c). However, such a conclusion perhaps does not follow reasonably from the available evidence and resource availability in resource-limited settings. First, strict observation and\n\n23", "n_tokens": 105, "kind": "text"}
{"chunk_id": "drug_resistance_book-40-0", "doc_id": "drug_resistance_book", "page": 40, "text": "24\n\nB. Nguyen et al.\n\nclose monitoring in order to early detect active TB disease requires many resources for TB screening, diagnosis and case follow-up at a community level over a long period of time. In resource-limited settings where there is a lack of healthcare staff, diagnostic tools and competency, this approach is likely neither feasible nor sustain- able. Even if such an approach to surveillance were in place, some may argue in support of providing additional chemoprophylactic agents such as isoniazid (INH) for contacts exposed to MDR-TB patients, thus raising a question of ethical accept- ability for study protocols which use a placebo as a control arm.", "n_tokens": 140, "kind": "text"}
{"chunk_id": "drug_resistance_book-40-1", "doc_id": "drug_resistance_book", "page": 40, "text": "Based on the fact that INH or RIF has been proven to reduce the risk of develop- ing active TB by at least 60%, and widely adopted in international and national guidelines for LTBI as a standard treatment for those exposed to TB (World Health Organization 2015c; Ministry of Health 2015), the argument in favour of giving INH for MDR-TB contacts involves three rationales. The first reason is that a pro- portion of contacts with LTBI will have been infected previously, or infected by another index patient, and so will benefit from the therapy. The second is that giving INH is recommended as the standard of care in many countries, and that it would be inappropriate to deprive people of that option because even if it is less effective, it still will be somewhat effective. The third reason is INH is a relatively safe drug, particularly for those under 35 years. For small children, on the balance of risks and benefits, using INH is preferred where the risk of untreated infection leading to dis- seminated disease is high. However, considering that equipoise may be present given the lack of evidence to guide LTBI treatment for MDR-TB contacts, random- ized controlled trials using placebo with periodic follow-ups could be considered ethical for the following reasons: (a) INH is unlikely to be effective, given the most proximate exposure is with MDR-TB; (b) in settings where there is a high rate of INH resistant TB—for example, in Vietnam, at least 17% of all newly diagnosed TB is INH", "n_tokens": 329, "kind": "text"}
{"chunk_id": "drug_resistance_book-40-2", "doc_id": "drug_resistance_book", "page": 40, "text": "resistant (Nhung et al. 2015)—the effectiveness will be less even if the per- son has been infected by non-MDR-TB; (c) the current standard of care for adults is either passive case-finding or screening for prevalent TB, (d) INH has a degree of toxicity associated with its use (Denholm et al. 2014). If a drug is toxic, ineffective, and unlikely to benefit patients, then it cannot be ethically administered. Given the diagnostic and therapeutic tools available, serial follow-up by chest Xray is a prefer- able form of active intervention that exceeds the current standard of care, and will detect cases early enough to reduce serious consequences and allow referral for free treatment.", "n_tokens": 150, "kind": "text"}
{"chunk_id": "drug_resistance_book-40-3", "doc_id": "drug_resistance_book", "page": 40, "text": "Recognising that MDR-TB preventive treatment is important, more efforts should be made in finding out effective therapies when there is no standard treat- ment, or when no proven effective and safe treatment is known to exist. This brings us to our second theme about assessing the effectiveness of LTBI treatment in MDR-TB contacts. Systematic reviews highlight the lack of data and limits of stud- ies conducted in assessing the effectiveness of LTBI regimens available in relevant settings (Fraser et al. 2006; van der Werf et al. 2012). Small observational studies on LTBI regimens have reported promising results. In these studies, a combination of first and second-line TB medications, including a fluoroquinolone antibiotic, is pre- scribed to both adult and child contacts as preventive therapy from 2 to 12 months", "n_tokens": 176, "kind": "text"}
{"chunk_id": "drug_resistance_book-41-0", "doc_id": "drug_resistance_book", "page": 41, "text": "2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection…\n\nwith post treatment follow-up mean periods less than 2 years comparing with pla- cebo or no intervention. High rates of treatment completion, low rates of incident TB disease with low rates of adverse events and good tolerability are reported from the studies (Lobue and Menzies 2010; Seddon et al. 2013; Bamrah et al. 2010). Put together, this evidence suggests that LTBI treatment may be beneficial and further research on LTBI alternative therapies is necessary in producing more comprehen- sive data on both effectiveness and safety on LTBI therapies.", "n_tokens": 138, "kind": "text"}
{"chunk_id": "drug_resistance_book-41-1", "doc_id": "drug_resistance_book", "page": 41, "text": "As the risk of developing MDR-TB is acknowledged to be high in recent con- tacts, the risk of serious adverse effects from any preventative treatment would need to outweigh the potential benefits in order to justify withholding treatment. While sensible responses to identified MDR-TB exposure should prioritise those at highest risk, the institution of a surveillance strategy instead of provision of treatment with potential adverse effects would preferentially advantage those at lowest risk of developing disease. On this basis, despite imperfect objective estimation of the risks and benefits of different therapeutic options, we would argue that programs may default towards provision of potentially effective therapy for those with MDR LTBI, provided reasonable measures to minimize harms (such as pharmacovigilance pro- grams to identify adverse effects) are in place. In parallel, however, it is also contin- gent on clinicians and programs continuing to strengthen knowledge of both risks and benefits associated with MDR LTBI therapy, so that future care may be opti- mally targeted and individuals appropriately informed.\n\n2.2.2.2\n\nDevelopment of Acquired Drug Resistance during Preventive Therapy", "n_tokens": 231, "kind": "text"}
{"chunk_id": "drug_resistance_book-41-2", "doc_id": "drug_resistance_book", "page": 41, "text": "Research collaborators and infectious disease clinicians participating in the VQUIN MDR-TB Trial raised valid concerns about administering drugs with unknown effectiveness and the potential harm of selecting new strains of drug resistant TB. The use of antibiotics whose effectiveness has not been demonstrated raises potential problems for individuals and the community. An ineffective regimen may fail to protect the individual, or even result in acquired drug resistance if taken infre- quently. Consequently, acquired drug resistance, particularly fluoroquinolone resis- tance, may then lead to transmission of more advanced strains of drug resistant TB. In the case of the VQUIN MDR-TB Trial, concern hinged on two issues. First, fluoroquinolones (such as levofloxacin) are a part of the backbone of the standard regimen used to treat MDR-TB. Treatment of active TB requires effective multidrug therapy, in order to prevent resistance. If active disease is not excluded prior to com- mencing preventive therapy, single drug therapy could lead to acquired drug resis- tance. This concern underpins the reluctance of some physicians to use single-antibiotic preventive therapy in these patients. Second, in settings where LTBI is not routinely managed, clinicians and patients report reluctance to prescribe treatment in the absence of symptoms. In high-burden, low-income settings such as Vietnam, LTBI is not perceived as a disease or condition requiring treatment. Such concerns are compounded", "n_tokens": 300, "kind": "text"}
{"chunk_id": "drug_resistance_book-41-3", "doc_id": "drug_resistance_book", "page": 41, "text": "by lack of programmatic experience with the use of LTBI", "n_tokens": 12, "kind": "text"}
{"chunk_id": "drug_resistance_book-41-4", "doc_id": "drug_resistance_book", "page": 41, "text": "25", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-42-0", "doc_id": "drug_resistance_book", "page": 42, "text": "26\n\nB. Nguyen et al.\n\ntherapies more generally in resource-limited settings, as clinicians have few oppor- tunities to confidently exclude active disease and develop experience with preventa- tive therapies.\n\nResponding to perceptions of risk in relation to amplification of drug resistance is challenging, particularly when public health messaging regarding good antimi- crobial stewardship emphasizes the need to avoid unnecessary antibiotic use to pre- serve drug effectiveness (Doron and Davidson 2011). Some evidence suggests that isoniazid monotherapy to treat drug-susceptible LTBI is unlikely to contribute to drug resistance (Balcells et al. 2006). In fact, modeling data suggest that preventive therapy may actually reduce the overall prevalence of resistance in a population by its secondary effect of reduced propagation among cases that would otherwise have been generated (Fox et al. 2015). One priority is clear: assisting clinicians and com- munity members to appropriately distinguish active from latent TB is an important issue if preventive therapy is to be scaled up. This requires concerted efforts to provide education, clear guidelines and updated knowledge of TB management and research.\n\n2.2.3\n\nChallenge in Conducting Research Using Fluoroquinolone in Children", "n_tokens": 252, "kind": "text"}
{"chunk_id": "drug_resistance_book-42-1", "doc_id": "drug_resistance_book", "page": 42, "text": "A significant challenge in conducting research using levofloxacin to treat LTBI in contacts of MDR-TB patients is that fluoroquinolones are generally contraindicated in children and growing adolescents by drug manufacturers and cautiously pre- scribed by doctors, due to theoretical concerns about the toxicity of the drug class (Goldman and Kearns 2011). In Vietnam, the study proposal to use levofloxacin to treat MDR LTBI in children under 15 years old has caused some controversy among local scientists and members of national ethics committee in considering appropri- ate assessment of risks and benefits to conducting the research on children. Scientifically, the debate mainly revolves around possible adverse effects of levo- floxacin to tendon and musculoskeletal system of children. This concern originated from an association between fluoroquinolone use and irreversible joint cartilage defects in juvenile animals (Ingham et al. 1977) and reversible musculoskeletal events in children (Schaaf et al. 2006). Considering that children have an increased risk of both developing active disease and more severe disseminated forms of dis- ease, and only indirect evidence for a link between fluoroquinolones and musculo- skeletal harm exists, there is a strong argument for the inclusion of children in studies such as VQUIN. However, while strategies to deal with potential risks have been considered, including enhanced adverse effect monitoring of younger partici- pants, at present the", "n_tokens": 311, "kind": "text"}
{"chunk_id": "drug_resistance_book-42-2", "doc_id": "drug_resistance_book", "page": 42, "text": "study has only been approved for adult contacts of MDR-TB.", "n_tokens": 14, "kind": "text"}
{"chunk_id": "drug_resistance_book-43-0", "doc_id": "drug_resistance_book", "page": 43, "text": "2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection…\n\n2.2.4", "n_tokens": 19, "kind": "text"}
{"chunk_id": "drug_resistance_book-43-1", "doc_id": "drug_resistance_book", "page": 43, "text": "Poor Understanding about LTBI and the Use of Diagnostic Tests\n\nLTBI is generally poorly understood (Colson et al. 2010). Interviews with commu- nity members in a variety of contexts consistently identify confusion regarding the difference between latent and active TB, the extent of risk associated with infection, and the availability of treatment to prevent progression to disease (Wieland et al. 2012). A lack of knowledge about LTBI and its attendant risks of progression to disease presents difficulties for the introduction of preventative therapies, particu- larly where they involve prolonged treatment with some potential adverse effects.\n\nSuch uncertainty exists among healthcare workers as well as in the general com- munity. In the research of LTBI therapy given to contacts of MDR-TB patients in Provincial Hospitals and District TB Units in Vietnam, we have identified particular issues including low level of knowledge of LTBI and a general lack of knowledge of treatment options for both active MDR-TB and suspected MDR LTBI. While TB is commonly known as a transmissible airborne infection, the pathways to active disease following exposure are still poorly understood by most healthcare staff. Uncertainties have been repeatedly expressed over the use of diagnostic tests for LTBI, the type and duration of LTBI treatment, presumably reflecting a lack of familiarity with preventative therapies in this context.\n\n2.2.5", "n_tokens": 276, "kind": "text"}
{"chunk_id": "drug_resistance_book-43-2", "doc_id": "drug_resistance_book", "page": 43, "text": "Challenges in Obtaining Informed Consent and Following-up Study Participants\n\nThe requirement to obtain informed consent is central to the ethical conduct of research involving human subjects. As clinical research has become more global, bringing with it a requirement to obtain consent in different places where many disparate values are held, the obtaining of valid consent increasingly raises a range of challenges. Consent practices in resource-limited settings may be impacted by time constraints for researchers to provide detailed research information, the lack of familiarity with medical research, traditionally paternalistic doctor-patient power dynamics and communication styles, involvement of family members and commu- nity members in the decision making process, conflict of duty of healthcare provider acting as researcher (Cheah and Parker 2014; Nguyen 2016), not to mention the significant cultural dimensions involved in adapting (and asserting) this research practice in settings where it is a foreign concept (Mason et al. 2017). Suffice to say that obtaining consent in research on LTBI treatment presents complex issues posed by its research context and clinical practice in addition to the complexities of explaining LTBI to a naïve audience.\n\n27", "n_tokens": 221, "kind": "text"}
{"chunk_id": "drug_resistance_book-44-0", "doc_id": "drug_resistance_book", "page": 44, "text": "28\n\nB. Nguyen et al.\n\nBased on our experience in conducting research on LTBI therapy given to con- tacts of MDR-TB patients in Vietnam, we outline challenges generated by different understandings about research and preventive treatment. When the term “research” is translated directly into Vietnamese, it arouses commonly-held negative percep- tions within the lay Vietnamese population. Healthcare workers also often express concerns that patients will decline to participate in research studies due to these negative associations, and prefer to avoid the term. An inability to refer to a study as being “research” may obstruct appropriate consent practices, since participants may not be aware of the experimental nature of the involved procedures. This difficulty is further complicated by differing understandings about LTBI and the appropriate- ness of preventive treatment.\n\nThe practical experience of obtaining consent in Vietnam for this study has been explored in series of research staff interviews, highlighting misperceptions about preventive therapy and the low priority people give to it. A staff member who worked on the community studies of the V-QUIN TB screening commented:\n\n“Our Vietnamese common perception is that “no disease, no treatment”. Preventive treat- ment is not a priority to our people, especially people in farming regions. Their educational level is low so they don’t think about preventive treatment. They only buy drugs when they get sick” (Study staff – N01).", "n_tokens": 292, "kind": "text"}
{"chunk_id": "drug_resistance_book-44-1", "doc_id": "drug_resistance_book", "page": 44, "text": "With limited information about LTBI treatment in national guidelines, and spe- cific recommendations against MDR LTBI treatment, challenges to effective con- sent and study participation are likely. In the traditionally hierarchical Vietnamese healthcare system, the existence of guidelines recommending against MDR LTBI treatment is a strong disincentive to both clinicians and community members’ par- ticipation in research. Research into MDR LTBI treatment may be perceived as being in opposition to existing recommendations, despite the limited evidence on which they are based.\n\n2.2.6", "n_tokens": 115, "kind": "text"}
{"chunk_id": "drug_resistance_book-44-2", "doc_id": "drug_resistance_book", "page": 44, "text": "Stigmatization\n\nThe stigmatization of TB may impact upon the management of and research into LTBI. In research practice, we experienced that some MDR-TB patients are self stigmatised, or are isolated by their family members due to their disease status. Such patients may want to hide the disease from household contacts and neighbors (there- fore prefer going to a private clinic to keep their privacy) and have poor medical adherence. Those most concerned about stigma may also avoid providing accurate information about their household contacts. Study staff in collaboration with local healthcare providers have to explore the information on household contacts by grad- ually building the relationship between patients and their care-giver, if there is any. This can be achieved through talking with them and providing them more informa- tion about TB, LTBI and preventive treatment in clinical assessments performed at hospitals or district tuberculosis clinics. The same stigma may drive healthy", "n_tokens": 185, "kind": "text"}
{"chunk_id": "drug_resistance_book-45-0", "doc_id": "drug_resistance_book", "page": 45, "text": "2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection…\n\nhousehold contacts with LTBI to avoid sharing their infection status with neighbors and friends. As a result, these infected individuals do not want any home visit made by NTP staff/study staff, and do not want to be contacted and asked about the patient. This can create difficulties and challenges in approaching potential study subjects who may participate in the research. It also impedes monitoring of drug adherence and post-treatment following up. As expressed by a study staff about stigmatization in TB:\n\n“TB is a social disease. It makes participant feel ashamed of getting infection, and thus not wanting to talk about their disease status or being followed up for a long period of time in the study to have their health checked. They also avoid their neighbors knowing about the disease” (Study staff – S01).\n\n2.3", "n_tokens": 177, "kind": "text"}
{"chunk_id": "drug_resistance_book-45-1", "doc_id": "drug_resistance_book", "page": 45, "text": "Solutions for Identified Ethical Problems and Challenges\n\nSo far, we have attempted to map out a range of issues arising in the prevention of MDR-TB, current approaches to MDR LTBI therapy and in the context of doing a randomized controlled trial in LTBI with our experiences in Vietnam as an exem- plary case of high burden TB and limited resource countries. What we will propose as solutions in this chapter accordingly will be general solutions to be considered in providing LTBI treatment and in doing MDR LTBI research. They are put forward in light of the nature of the problems, challenges occurring in the research practice and practical conditions in the setting.\n\n2.3.1", "n_tokens": 136, "kind": "text"}
{"chunk_id": "drug_resistance_book-45-2", "doc_id": "drug_resistance_book", "page": 45, "text": "Developing a Comprehensive LTBI Research Agenda\n\nClinical studies are crucial in advancing medical care. They are needed to produce systematic information on pathogenesis, clinical course, potential interventions and response to treatment. Especially in LTBI, it is important to address a key ethical challenge which is balancing between uncertainties and risk of harm involved in screening and treatment provision, and from that to derive lessons and possible ways to scale up interventions at the community level. Any new scientific informa- tion or breakthroughs can bring about alterations to current accounts of scientific and ethical considerations about existing interventions. Concerns about how best to apply systematic screening of LTBI and its related accounts of risk and benefit with beneficiaries (Degeling et al. 2017) is an example which can be expected to be resolved via promising outcome of studies on new LTBI diagnostic methods and indicators of reactivation risk (Dodd and Schlesinger 2017). From our experience drawn in the setting as outlined above, we argue that systematic research, especially randomized clinical trials in evaluating the effectiveness of preventive therapy for LTBI in the contacts of patients with MDR-TB are imperative to better inform clini- cal decisions, to benefit future infected people and the public in general.\n\n29", "n_tokens": 249, "kind": "text"}
{"chunk_id": "drug_resistance_book-46-0", "doc_id": "drug_resistance_book", "page": 46, "text": "30\n\nB. Nguyen et al.\n\n2.3.2\n\nCollaboration\n\nEfforts toward the elimination of tuberculosis call for wide collaboration of various stakeholders including, but not limited to, clinicians in both public and private sec- tors, public health practitioners (Hauck and Panchal 2009; Taylor et al. 2005), researchers of all groups of expertise, funders, research communities and the public (Sablan 2009). This would serve as a ground for developing a comprehensive and balanced research agenda to inform clinical and public health practice, and to create sustainable research and public health platforms with long term facilities and com- munity support. This type of collaboration can be conducted through the format of national and international collaborative research networks, for example, The Tuberculosis Network European Trials group (TBNET) (Giehl et al. 2012), The Australasian Clinical Tuberculosis Network (ACTnet), The Union World Conference on Lung Health, and the involvement of research community, public and mass media. The primary aim of such collaborations is to engage relevant stakeholders from the beginning of a research initiative to translating research findings into prac- tice in community level on the basis of mutual understanding of a shared account of vision and mission and benefit generating for afflicted population.", "n_tokens": 254, "kind": "text"}
{"chunk_id": "drug_resistance_book-46-1", "doc_id": "drug_resistance_book", "page": 46, "text": "While collaborations are recognized as crucial to successful research schemes, effective collaborations, in our view, need to be characterized by ‘openness’ in which collaborative partners see each other having supplementary role rather com- petitors, and a shared common interest that is to contribute to the knowledge of the disease for the public good through sharing data and samples. Contributing to the framework of global health, such an open form of collaboration is aimed to protect the common interest towards the global health and stress on the duty to protect affected members of the public and the public good.\n\n2.3.3", "n_tokens": 115, "kind": "text"}
{"chunk_id": "drug_resistance_book-46-2", "doc_id": "drug_resistance_book", "page": 46, "text": "Provide Education and Raise Community Awareness of LTBI\n\nProvide necessary scientific training to healthcare workers and study staff.\n\nIn order to help ensure success in LTBI treatment program and research initia- tives, given the issues related to the lack of knowledge of current LTBI diagnostic methods and therapies which we have outlined above, training on scientific knowl- edge of LTBI and the role of research in producing systematic information to inform practice is necessary. It is importantly required for frontline health workers who directly provide healthcare to patients and communities where are most needed. These can include pharmacists, nurses, clinicians, and public health officers who serve in hospitals and community clinics. As the first and sometimes the only link to essential healthcare services in limited resource settings, this group of experts", "n_tokens": 157, "kind": "text"}
{"chunk_id": "drug_resistance_book-47-0", "doc_id": "drug_resistance_book", "page": 47, "text": "2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection…\n\nhold great potential to make a direct impact on individual and community health through supporting research activities, delivering good healthcare services and community consultation. Studies and our experience have shown that interaction and communication between health workers/study doctors and patients/study par- ticipants brings significant effect to the level of recruitment, medication adherence and treatment outcomes (Horne 1999; Dwamena et al. 2012; Sumartojo 1993). In this case of LBTI and TB control, it is knowledge of current approaches for TB control and prevention available locally and internationally, important health impli- cations of LTBI, the need to provide LTBI treatment, and associated adverse events and their management that needs to be provided and updated to health workers and study staff to equip them in delivering healthcare services at the best level and standard.", "n_tokens": 180, "kind": "text"}
{"chunk_id": "drug_resistance_book-47-1", "doc_id": "drug_resistance_book", "page": 47, "text": "Public education.\n\nWhen research participants are subject to possible sources of vulnerability, the consent process with consideration of some additional protections should aim to protect the safety and the rights of research participants and benefits of afflicted population. This duty should be taken on by ethics committees, physician- researchers, local and international research institutions and other entities involved in the research in designing, reviewing and implementing research projects. At the same time, the consent process should be developed in a way that will enhance “voluntary actions that are intended to help or benefit another individual or group of individuals” (Eisenberg and Mussen 1989a) of research participants, family mem- bers and community.", "n_tokens": 135, "kind": "text"}
{"chunk_id": "drug_resistance_book-47-2", "doc_id": "drug_resistance_book", "page": 47, "text": "In addressing the key issues in consent and the awareness of LTBI and the role of MDR LTBI treatment in the prevention of TB, we propose that educating the public about the nature of research and its necessity for the improvement and advancement of science in medicine as an overarching plan to make people understand more about the meaning of research and therefore to encourage their participation. For the purpose of raising community awareness of LTBI and the importance of doing more research on this subject, along with the general public education as mentioned above, it also requires providing education programs about clinical research and LTBI to the population and disseminating information about LTBI treatment in the forms of national guidelines with references to international guidelines, health pro- motional materials and community consultation. This form of education should be carried out on a long term and regular basis. Specific aims of these plans would be (1) to change negative attitude towards research, e.g. ‘being a Guinea Pig’; (2) to let people have a better understanding of research, scientific methods in treatment and healthcare, and the role of research in support of medicine; and (3) to maintain trust and nurture pro-social behavior that will enhance “voluntary actions that are intended to help or benefit another individual or group of individuals” in society (Eisenberg and Mussen 1989b) for research and public health agenda.\n\n31", "n_tokens": 279, "kind": "text"}
{"chunk_id": "drug_resistance_book-48-0", "doc_id": "drug_resistance_book", "page": 48, "text": "32\n\nB. Nguyen et al.\n\n2.3.4\n\nStrengthen Communication Between Research Ethics Committees (RECs) and Researchers\n\nFacilitating cooperation between RECs and scientists/researchers is necessary for mutual understanding and a rapid response in LTBI research context. One way to achieve this is to establish and maintain communication between researchers and RECs throughout research scheme. On the part of RECs, effective communication strategies with researchers will help the RECs to improve transparency in their deci- sions, understand practical challenges in doing research in the local context, develop expertise in a particular topic area, understand researchers’ perspectives and make researchers mutually understand the challenges and duties of RECs. This mutual understanding would eventually place both RECs and researchers in an engaged process whereby research participants are better protected and research can be con- ducted effectively without being subject to unnecessary delays, misunderstanding and uncertainties.\n\n2.4", "n_tokens": 177, "kind": "text"}
{"chunk_id": "drug_resistance_book-48-1", "doc_id": "drug_resistance_book", "page": 48, "text": "Conclusion\n\nIn this chapter, we have outlined key issues in preventative therapies for MDR-TB and challenges in conducting research to assess potentially effective MDR LTBI therapies. We have raised possible solutions, derived from our own work in the Vietnamese setting in juxtaposition with broader ethical considerations. We have argued that preventive therapy for MDR-TB should be a high priority. There is a need for appropriately conducted systematic research to address the spread of MDR-TB in limited-resource settings globally. Engagement with local cultural norms and priorities is critical for ensuring that such research is conducted in both ethical and effective fashion.\n\nReferences\n\nACTG and IMPAACT Networks. 2015. A5300B/IMPAACT2003B: Protecting Households On Exposure to Newly Diagnosed Index Multidrug Resistant Tuberculosis Patients (PHOENIx). Available from: http://impaactnetwork.org/studies/IMPAACT2003B.asp.\n\nBalcells, M.E., et al. 2006. Isoniazid preventive therapy and risk for resistant tuberculosis.\n\nEmerging Infectious Diseases 12 (5): 744–751.\n\nBamrah, S., et al.. 2010. An ounce of prevention: Treating MDR-TB contacts in a resource-limited setting, in International Union of Tuberculosis and Lung Disease Conference 2010: Berlin, Germany, 11–15 November, 2010. p. FA-1- 656-14:S180.\n\nCheah, P.Y., and M. Parker. 2014. Consent and assent in paediatric research in low-income set-", "n_tokens": 335, "kind": "text"}
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{"chunk_id": "drug_resistance_book-49-0", "doc_id": "drug_resistance_book", "page": 49, "text": "2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection…\n\nColson, P.W., et al. 2010. Tuberculosis knowledge, attitudes, and beliefs in foreign-born and US-born patients with latent tuberculosis infection. Journal of Immigrant and Minority Health 12 (6): 859–866.\n\nDegeling, C., et al. 2017. Eliminating latent tuberculosis in low-burden settings: Are the principal beneficiaries to be disadvantaged groups or the broader population? Journal of Medical Ethics 43: 632–636.\n\nDenholm, J.T., et al. 2014. Adverse effects of isoniazid preventative therapy for latent tuberculosis\n\ninfection: A prospective cohort study. Drug, Healthcare and Patient Safety 6: 145–149.\n\nDodd, C.E., and L.S. Schlesinger. 2017. New concepts in understanding latent tuberculosis.\n\nCurrent Opinion in Infectious Diseases 30 (3): 316–321.\n\nDoron, S., and L.E. Davidson. 2011. Antimicrobial stewardship. Mayo Clinic Proceedings 86 (11):\n\n1113–1123.\n\nDwamena, F., et al. 2012. Interventions for providers to promote a patient-centred approach in\n\nclinical consultations. Cochrane Database of Systematic Reviews 12: CD003267.\n\nEisenberg, N., and P.H. Mussen. 1989a. The roots of prosocial behavior in children. Cambridge:\n\nCambridge University Press.\n\n———. 1989b. The roots of prosocial behavior in children (Cambridge studies in social and emo-\n\ntional development), 208. Cambridge: Cambridge University Press.\n\nEuropean Centre for Disease Prevention and Control. 2012. Management of contacts of MDR TB", "n_tokens": 370, "kind": "text"}
{"chunk_id": "drug_resistance_book-49-1", "doc_id": "drug_resistance_book", "page": 49, "text": "and XDR TB patients. Stockholm: ECDC.\n\nFox, G.J., et al. 2013a. Contact investigation for tuberculosis: A systematic review and meta-\n\nanalysis. European Respiratory Journal 41: 134–150.\n\n———. 2013b. Contact investigation for tuberculosis: A systematic review and meta-analysis. The\n\nEuropean Respiratory Journal 41 (1): 140–156.\n\nFox, G.J., O. Oxlade, and D. Menzies. 2015. Fluoroquinolone Therapy for the Prevention of Multidrug-Resistant Tuberculosis in Contacts. A Cost-Effectiveness Analysis. (1535–4970 (Electronic)).\n\nFox, G.J., et al. 2016. Surgery as an adjunctive treatment for multidrug-resistant tuberculosis: An\n\nindividual patient data Metaanalysis. Clinical Infectious Diseases 62 (7): 887–895.\n\n———. 2017a. Latent tuberculous infection in household contacts of multidrug-resistant and newly diagnosed tuberculosis. The International Journal of Tuberculosis and Lung Disease 21 (3): 297–302.\n\n———. 2017b. Preventing the spread of multidrug-resistant tuberculosis and protecting contacts\n\nof infectious cases. Clinical Microbiology and Infection 23 (3): 147–153.\n\nFraser, A., et al. 2006. Drugs for preventing tuberculosis in people at risk of multiple-drug-resistant\n\npulmonary tuberculosis. Cochrane Database of Systematic Reviews 2: CD005435.\n\nGiehl, C., et al. 2012. TBNET – Collaborative research on tuberculosis in Europe. European", "n_tokens": 328, "kind": "text"}
{"chunk_id": "drug_resistance_book-49-2", "doc_id": "drug_resistance_book", "page": 49, "text": "Journal of Microbiology & Immunology 2 (4): 264–274.\n\nGoldman, J.A., and G.L. Kearns. 2011. Flouroquinolone Use in Paediatrics: Focus on Safety and Place in Therapy - A commissioned work for the Guidelines Group for the Revision of the “Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children”, World Health Organization, 30-31 March 2010, Geneva, Switzerland. 2011.\n\nGrandjean, L., et al. 2011. Tuberculosis in household contacts of multidrug-resistant tuberculosis\n\npatients. International Journal of Tuberculosis & Lung Disease 15 (9): 1164–1169.\n\nHauck, F.R., and A.S. Panchal. 2009. Latent tuberculosis infection: The physician’s role in tuber-\n\nculosis control. American Family Physician 79 (10): 845–846.\n\nHill, L., et al. 2008. Multi-level barriers to LTBI treatment: a research note. (1557–1920\n\n(Electronic)).\n\nHoang, T.T.T., et al. 2015a. Challenges in detection and treatment of multidrug resistant tubercu-\n\nlosis patients in Vietnam. BMC Public Health 15 (1): 980.\n\n———. 2015b. Challenges in detection and treatment of multidrug resistant tuberculosis patients\n\nin Vietnam. BMC Public Health 15: 980.\n\nHorne, R. 1999. Patients’ beliefs about treatment: The hidden determinant of treatment outcome?\n\nJournal of Psychosomatic Research 47 (6): 491–495.\n\n33", "n_tokens": 338, "kind": "text"}
{"chunk_id": "drug_resistance_book-50-0", "doc_id": "drug_resistance_book", "page": 50, "text": "34\n\nB. Nguyen et al.\n\nIngham, B., et al. 1977. Arthropathy induced by antibacterial fused n-alkyl-4-pyrodoine-3-carbox-\n\nylic acids. Toxicology Letters 1: 21–26.\n\nKeal, J., et al. 2013. P97 multi-drug resistant tuberculosis: The first UK guideline for treatment\n\nmonitoring. Thorax 68 (Suppl 3): A119.\n\nLobue, P., and D. Menzies. 2010. Treatment of latent tuberculosis infection: An update. Respirology\n\n15 (4): 603–622.\n\nMarks, G.B., et al. 2000. Incidence of tuberculosis among a cohort of tuberculin-positive refugees in Australia: Reappraising the estimates of risk. American Journal of Respiratory & Critical Care Medicine 162 (5): 1851–1854.\n\nMason, P.H. 2014a. The liminal body: Comment on “Privacy in the Context of ‘Re-emergent’ Infectious Diseases” by Justin T. Denholm and Ian H. Kerridge. Journal of Bioethical Inquiry 11 (4): 565–566.\n\n———. 2014b. The liminal body: Comment on “Privacy in the context of ‘re-emergent’ infectious\n\ndiseases” by Justin T. Denholm and Ian H. Kerridge. (1176–7529 (Print)).\n\nMason, P.H., I. Kerridge, and W. Lipworth. 2017. The global in Global Health is not a given. The\n\nAmerican Journal of Tropical Medicine and Hygiene 96 (4): 767–769.\n\nMinistry of Health. 2015. Guidelines for tuberculosis diagnosis, treatment and prevention. Mitnick, C.D., et al. 2016. Programmatic management of drug-resistant tuberculosis: An updated", "n_tokens": 401, "kind": "text"}
{"chunk_id": "drug_resistance_book-50-1", "doc_id": "drug_resistance_book", "page": 50, "text": "research agenda. PLoS One 11 (5).\n\nNguyen, T.C.B. 2016. The ethics of research in rapidly evolving epidemics: an international per-\n\nspective. In Kellogg. Oxford: University of Oxford.\n\nNhung, N.V., et al. 2015. The fourth national anti-tuberculosis drug resistance survey in Viet Nam.\n\nThe International Journal of Tuberculosis and Lung Disease 19 (6): 670–675.\n\nOrenstein, E.W., et al. 2009. Treatment outcomes among patients with multidrug-resistant tuber- culosis: Systematic review and meta-analysis. The Lancet Infectious Diseases 9 (3): 153–161. Sablan, B. 2009. An update on primary care management for tuberculosis in children. Current\n\nOpinion in Pediatrics 21 (6): 801–804.\n\nSchaaf, H., et al. 2006. Childhood drug-resistant tuberculosis in the Western Cape Province of\n\nSouth Africa. Acta Paediatrica 95 (5): 523–528.\n\nSeddon, J.A., et al. 2013. Preventive therapy for child contacts of multidrug-resistant tuberculosis:\n\nA prospective cohort study. Clinical Infectious Diseases 57 (12): 1676–1684.\n\nSterling, T.R., et al. 2011. Three months of rifapentine and isoniazid for latent tuberculosis infec-\n\ntion. The New England Journal of Medicine 365 (23): 2155–2166.\n\nSumartojo, E. 1993. When tuberculosis treatment fails. A social behavioral account of patient", "n_tokens": 341, "kind": "text"}
{"chunk_id": "drug_resistance_book-50-2", "doc_id": "drug_resistance_book", "page": 50, "text": "adherence. The American Review of Respiratory Disease 147 (5): 1311–1320.\n\nTanimura, T., et al. 2014. Financial burden for tuberculosis patients in low- and middle-income\n\ncountries: A systematic review. The European Respiratory Journal 43 (6): 1763–1775.\n\nTaylor, Z., C.M. Nolan, and H.M. Blumberg. 2005. Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recommendations and Reports 54 (RR-12): 1–81.\n\nTorun, T., et al. 2005. Side effects associated with the treatment of multidrug-resistant tuberculosis.\n\nThe International Journal of Tuberculosis and Lung Disease 9 (12): 1373–1377.\n\nTrauer, J.M., et al. 2016. Risk of active tuberculosis in the five years following infection … 15%?\n\nChest 149 (2): 516–525.\n\nTuberculosis child multidrug-resistant preventive therapy: TB CHAMP trial. 2016. Available\n\nfrom: http://www.isrctn.com/ISRCTN92634082.\n\nvan der Werf, M.J., et al. 2012. Lack of evidence to support policy development for manage- ment of contacts of multidrug-resistant tuberculosis patients: Two systematic reviews. The International Journal of Tuberculosis and Lung Disease 16 (3): 288–296.\n\nVoelker, R. 1998. Ebola with wings. JAMA 280 (14): 1216–1216. WHO. 2015. World Health Organization global tuberculosis report, 2015. Geneva: WHO.", "n_tokens": 353, "kind": "text"}
{"chunk_id": "drug_resistance_book-51-0", "doc_id": "drug_resistance_book", "page": 51, "text": "2 Preventive Therapy for Multidrug Resistant Latent Tuberculosis Infection…\n\nWieland, M.L., et al. 2012. Perceptions of tuberculosis among immigrants and refugees at an adult education center: A community-based participatory research approach. Journal of Immigrant and Minority Health 14 (1): 14–22.\n\nWorld Health Organization. 2011. Guidelines for the programmatic management of drug-resistant\n\ntuberculosis – 2011 update. Geneva: WHO.\n\n———. 2013a. Global tuberculosis report 2013. Geneva: World Health Organization. ———. 2013b. Systematic screening for active tuberculosis: principles and recommendations.\n\nGeneva: WHO.\n\n———. 2014. Companion handbook to the WHO guidelines for the programmatic management of\n\ndrug-resistant tuberculosis. Geneva: WHO.\n\n———. 2015a. Global tuberculosis report 2015. Geneva: World Health Organization. ———. 2015b. Guidelines on the management of latent tuberculosis infection. Geneva: WHO. ———. 2015c. Guidelines on the management of latent tuberculosis infection. Geneva:\n\nWHO. WHO/HTM/TB/2015.01. 38.\n\n———. 2016. Global tuberculosis report 2016. Geneva: WHO. Xavier, A.S., and M. Lakshmanan. 2014. Delamanid: A new armor in combating drug-resistant", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-51-1", "doc_id": "drug_resistance_book", "page": 51, "text": "tuberculosis. Journal of Pharmacology and Pharmacotherapeutics 5 (3): 222–224.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n35", "n_tokens": 191, "kind": "text"}
{"chunk_id": "drug_resistance_book-52-0", "doc_id": "drug_resistance_book", "page": 52, "text": "Chapter 3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical Tensions in HIV Treatment\n\nBridget Haire", "n_tokens": 22, "kind": "text"}
{"chunk_id": "drug_resistance_book-52-1", "doc_id": "drug_resistance_book", "page": 52, "text": "Abstract The provision of effective antiretroviral therapy is an ethical imperative, and global access to antiretroviral drugs is an important aspect of this. The other less recognised aspect of effective HIV management is in ensuring that HIV does not become resistant to the drugs used in treatment (and increasingly also in preven- tion), as multi-drug resistant HIV poses a major threat to the sustainability of cur- rent responses to HIV control. In resource-constrained environments, the rapid scale up of access to life-saving anti-HIV treatment was achieved using a public health approach that standardised antiretroviral regimens, minimised laboratory monitoring, and devolved responsibilities from clinicians where necessary. In recent years demand for antiretroviral treatment has increased due to new understandings of the clinical importance of early treatment, but global investment has declined. Exponential growth of the population using antiretrovirals without careful monitor- ing increases the risk of significant antiretroviral drug resistance. In this chapter, I consider the example of single-drug interventions to prevent parent-to-child HIV transmission, and how the implementation of that strategy increased health risks for mothers. I argue that while global antiretroviral scale up must continue, laboratory monitoring at individual and national levels needs to improve to maintain treatment effectiveness, and protocols for moving people from failing regimens need to be", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-52-2", "doc_id": "drug_resistance_book", "page": 52, "text": "strengthened.", "n_tokens": 2, "kind": "text"}
{"chunk_id": "drug_resistance_book-52-3", "doc_id": "drug_resistance_book", "page": 52, "text": "Keywords Ethics · Public health · Infectious diseases\n\nB. Haire (*) Kirby Institute, University of NSW, Sydney, Australia e-mail: b.haire@unsw.edu.au\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_3\n\n37", "n_tokens": 112, "kind": "text"}
{"chunk_id": "drug_resistance_book-53-0", "doc_id": "drug_resistance_book", "page": 53, "text": "38\n\n3.1\n\nIntroduction\n\nWith an estimated 36.9 million people living with HIV worldwide (WHO 2018), the provision of effective antiretroviral therapy (ART) is an ethical imperative. Ensuring that people with HIV can access ART is an important part of this, but another less recognised aspect is ensuring that the HIV does not become resistant to the drugs used in the treatment, as multi-drug resistant HIV poses a major threat to the sus- tainability of current responses to HIV control. There are, however, ethical tensions about striking the right balance between maximising ART access and minimising the risk of the emergence of drug resistant HIV. In resource-constrained environ- ments these tensions are concerned with relative investment in drugs as compared with laboratory monitoring, and sometimes ‘blaming’ discourses regarding non- adherent people with HIV.", "n_tokens": 174, "kind": "text"}
{"chunk_id": "drug_resistance_book-53-1", "doc_id": "drug_resistance_book", "page": 53, "text": "In 1996 it was established that antiretroviral drugs used in combination could control HIV replication (‘viral load’) in individuals and thus prevent HIV from destroying the CD4 cells that protect against infection (Arts and Hazuda 2012). Over time, the control of viral replication was shown to prevent people with HIV from becoming immune suppressed and developing the opportunistic infections associated with acquired immune deficiency syndrome (AIDS) (Moore and Chaisson 1999). ART could also reverse immune damage, to some extent (Kaufmann et al. 2005). Thus, combination ART could prevent AIDS and prolong, and perhaps save, the lives of people with HIV. Initial drug regimens however were often highly complex. The drugs were associated with serious side effects and were prohibitively expensive, as were the laboratory tests used to monitor both the impact of the drugs on viral load (viral load tests) and the degree of immune functionality (measured by CD4 cell tests). Hence there were significant barriers to access to these regimens for the majority of people living with HIV.", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-53-2", "doc_id": "drug_resistance_book", "page": 53, "text": "The stark injustice of life saving medication being inaccessible to the majority of those living with HIV, concentrated predominantly in low and middle income coun- tries (LMIC) and especially in sub-Saharan Africa, was the catalyst for a worldwide treatment access movement that put pressure on governments, drug companies and non-government organisations to find solutions to make ART access more equita- ble. In response to the treatment access movement the World Health Organization launched its first ‘public health’ program for HIV treatment, an approach that aimed for universal access, starting with the initial goal of getting 3 million people onto ART by 2005, the ‘3 by 5 Programme’ (WHO 2003a, b). This approach was sup- ported and facilitated by the creation of two major donor organisations – The Global Fund for HIV, TB and Malaria (the Global Fund), and the (US) President’s Emergency Program for AIDS Relief (PEPFAR) – that supplied drugs to LMIC (Smart 2006). Even with these donors, it was not feasible to mimic the highly indi- vidualised approach to ART prescription in affluent countries that relied heavily on expensive and resource-intensive laboratory monitoring. Accordingly, the program standardised both ART regimens (the drugs) and monitoring (including tests that measure the effect of the drugs on viral load and those that measured the impact of\n\nB. Haire", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-54-0", "doc_id": "drug_resistance_book", "page": 54, "text": "3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical…\n\nHIV on the immune system). In some LMIC, nurse-practitioners performed roles usually reserved for doctors. Thus, the ‘public health’ approach was designed to facilitate ART delivery in resource-poor settings with limited health infrastructure, simplifying, standardising and devolving responsibilities as required (WHO 2003a, b). (Note, while the ‘3 by 5 Programme’ was the initial iteration of this approach, the WHO has continued to champion universal access programmatically using a public health approach. For simplicity’s sake, in this chapter I will treat the WHO universal access/public health approach as a strategy that started with ‘3 by 5’ and has continued to this day, albeit with various adjustments and shifts in nomenclature.)", "n_tokens": 166, "kind": "text"}
{"chunk_id": "drug_resistance_book-54-1", "doc_id": "drug_resistance_book", "page": 54, "text": "This chapter will first describe the mechanism for the development of HIV drug resistance and detail elements of the ‘public health’ approach to ART. It will then discuss how and why the ‘public health’ approach to ART in lower income countries was a reasonable trade-off that enabled widespread access to HIV treatment, despite increasing the likelihood of the development of drug resistance. In the medium to long term, however, strategies to avoid, contain and diagnose drug resistance will be critical to the sustained management of the epidemic, and to reaching the global goal of virtual elimination of new HIV infections. The tensions between a public health approach that focuses on access and an increasing emphasis on effective use of resources will be explored, using the history of mother-to-child prevention pro- grams as a case study. The increasing use of ART-based prevention strategies for sexual transmission will also be considered. Finally consideration will be given to issues likely to impact on responses to drug resistant HIV in a context where guide- lines recommend universal treatment, but access to uninterrupted drug supplies and high quality monitoring standards are limited.\n\n3.2", "n_tokens": 223, "kind": "text"}
{"chunk_id": "drug_resistance_book-54-2", "doc_id": "drug_resistance_book", "page": 54, "text": "Drug Resistant HIV\n\nHIV is a highly mutable virus, meaning that as it replicates it makes errors and hence changes and evolves over time within the human host. These changes are random, though the principles of natural selection mean that over time and in the absence of treatment, changes that make the virus more replication competent will crowd out those that make it less fit.\n\nDrug resistant HIV develops when a person is taking ART that is insufficient to fully suppress viral replication. This creates the conditions of selective pressure, so that viral copies that are less sensitive to the drugs have a competitive advantage over other viral copies, and begin to push the evolution of HIV in the particular body to become increasingly resistant. If the ART regimen is sufficient to fully suppress replication, this will not occur and hence resistance will not develop. Standard ART regimens will fully suppress viral replication if adherence is good, if no biological event disrupts individual drug absorption and metabolism, and unless the person was infected with a strain of HIV that had already evolved to be resistant to some or all of the drugs in the particular ART regimen.\n\n39", "n_tokens": 219, "kind": "text"}
{"chunk_id": "drug_resistance_book-55-0", "doc_id": "drug_resistance_book", "page": 55, "text": "40\n\nIn terms of the potential development of ART resistance, all ART drugs are not equal – the strength of antiretroviral action can differ, and some drugs are more vulnerable to the development of resistance. ART drugs work by targeting and blocking selected enzymes or proteins of HIV that enable it to replicate and infect cells. Changes to particular HIV regions that the ART drugs target make the drugs less effective. Some regions of HIV are more prone to mutation than others, and some drugs lose their effectiveness in the face of HIV evolution faster than others. For example, a single mutation reduces susceptibility to the drug nevirapine (this is called having a low genetic barrier to resistance) (Luber 2005). Drug resistance is also not a black and while phenomenon, in that a particular mutation or set of muta- tions may diminish susceptibility to particular drugs, but not completely stop work- ing in terms of controlling HIV replication. For example, a person taking ART who has a detectable but low viral load may have some drug resistance, but may also be receiving clinical benefit from the drugs.", "n_tokens": 227, "kind": "text"}
{"chunk_id": "drug_resistance_book-55-1", "doc_id": "drug_resistance_book", "page": 55, "text": "ART drugs are classified into classes that are determined by where and how they target HIV replication. While ART drugs within the designated classes work in slightly different ways, developing resistance to one drug in a class can also confer either resistance (or at least reduced sensitivity) to other drugs in the class. Accordingly, if a person has to change from one ART regimen to another, the sec- ond regimen needs to comprise drugs to which there is no likely pre-existing cross resistance to maximise the likely success. Further, in high income countries like Australia, when a person is first diagnosed with HIV, genetic resistance testing determines whether the person has been infected with a resistant strain of HIV that is less likely to respond optimally to standard treatment (if resistance is found, dif- ferent regimens are used).\n\nIn summary, there are four main causes of drug resistance: acquiring a drug resis- tant strain; being prescribed a regimen that is incompletely suppressive (usually single or dual therapy combinations, or a triple combination that is too weak); non-adherence (failing to take pills as prescribed and on time); and taking drugs intermittently (where fluctuating blood levels of medication allow HIV replication under selective pressure).\n\n3.3", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-55-2", "doc_id": "drug_resistance_book", "page": 55, "text": "A Word on HIV Monitoring\n\nThere are two highly significant tests used to monitor HIV disease progression and the effectiveness of ART in an individual: Tests that count CD4 cells per cubic ml of blood, and viral load tests. CD4 cells are immune cells that are targeted by HIV. A healthy person would have a CD4 cell count in excess of 500. Once a person’s CD4 cell count drops to 200 or below s/he is at serious, imminent risk of HIV-related opportunistic infections. A person with HIV who has a CD4 cell count above 200 but below 500 is showing some HIV-related damage. There is a strong relationship between declines in CD4 cell count and disease progression, and in CD4 cell\n\nB. Haire", "n_tokens": 152, "kind": "text"}
{"chunk_id": "drug_resistance_book-56-0", "doc_id": "drug_resistance_book", "page": 56, "text": "3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical…\n\nrecovery and effective ART treatment (Mellors et al. 1997). CD4 counts are thus a useful tool in the management of HIV disease.\n\nViral load tests measure viral RNA in the peripheral blood. The higher the viral RNA number is, the greater the level of viral replication, and the greater the risk of disease progression (Mellors et al. 1996). ‘Undetectable viral load’ means that viral replication is suppressed below the level of detection on the test used (tests have become much more sensitive since they were first available). An undetectable viral load is the individual goal of ART treatment. At the strategic level, having 90% of people who know their HIV status on ART, and 90% of those with an undetectable viral load is a current global goal (UNAIDS 2017).\n\n3.4\n\nKey Elements of the ‘Public Health’ Approach to HIV\n\nTo maximise access to life-saving ART, WHO prioritised getting ART drugs into the bodies of people with HIV, and maximising the capacity to deliver ART by pro- cesses of standardisation, simplification and, where necessary, syndromic manage- ment rather than laboratory monitoring. The core underlying principles were identified as urgency, equity and sustainability (Macklin 2004).", "n_tokens": 276, "kind": "text"}
{"chunk_id": "drug_resistance_book-56-1", "doc_id": "drug_resistance_book", "page": 56, "text": "Standardised first line and second line ART regimens were a critical aspect of the approach. In determining the drugs used in these regimens, a balance had to be struck between user-friendliness (pill burden, dosing routine, side effect profile), effectiveness (probability of viral load suppression), and cost (WHO 2003a). Further, the second line regimen had to be effective against the ART resistance likely to develop (for whatever reason) to the drugs in the first line regimen. (Third line regimens are also detailed in guidelines.) These standardised regimens were presented as algorithms that were flexible enough to allow for the different avail- ability of certain drugs in particular countries due to purchasing arrangements, and to allow some substitutions for people who had different health needs, such as those who were pregnant, had other infections like TB or viral hepatitis. The standard algorithms for first and second line treatment have changed since the first iteration of the WHO universal access program, as further information about drug efficacy emerged (for example, a first line regimen recommended in 2003 was found to be insufficient of suppress very high viral loads found in people initiating treatment in advanced disease), and alternative drugs became available to replace ART associ- ated with significant toxicities (Gulick et al. 2004). Both inadequate viral suppres- sion and high levels of side effects are significant for the development of resistance –", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-56-2", "doc_id": "drug_resistance_book", "page": 56, "text": "incomplete suppression create the conditions for the emergence of resistance, and ART toxicities can reduce adherence, also potentially resulting in incomplete suppression.", "n_tokens": 26, "kind": "text"}
{"chunk_id": "drug_resistance_book-56-3", "doc_id": "drug_resistance_book", "page": 56, "text": "The issue of how to prioritise people for treatment access was another critical element of the approach. Utility, equity and concern for the worst-off (the principle of maximin) were key considerations (Macklin 2004). Initial WHO guidance for resource constrained settings recommended that ART should be commenced in\n\n41", "n_tokens": 61, "kind": "text"}
{"chunk_id": "drug_resistance_book-57-0", "doc_id": "drug_resistance_book", "page": 57, "text": "42\n\nthose at high and proximate risk of clinical disease progression and/or death (those diagnosed with Stage IV HIV disease regardless of CD4 cell count; those with CD4 cell counts below 200 regardless of disease staging; those with stage III HIV disease and CD4 counts below 35) (WHO 2003a). Targeting ART at those at experiencing or at imminent risk of serious HIV disease was acceptable in a moral sense as it prioritised treatment for those with greatest clinical need, and it also greatly reduced the pool of people eligible for treatment, as only a fraction of those living with HIV would require treatment under such guidance. The downside to this approach was that many people tested and found HIV positive would not be eligible for treatment, increasing the potential of significant loss to follow-up (Rosen and Fox 2011). It is important to note that while WHO guidelines play an important normative role in shaping standards, they are in no sense binding, and the expectation of their use is that countries draw from them and adapt them according to relevant contextual fac- tors (WHOF 2006).", "n_tokens": 222, "kind": "text"}
{"chunk_id": "drug_resistance_book-57-1", "doc_id": "drug_resistance_book", "page": 57, "text": "Laboratory monitoring was simplified in WHO guidance documents, with CD4 cell tests recommended but not mandatory both at baseline and for subsequent mon- itoring of treatment efficacy at 6–12 month intervals. Haemoglobin testing would occur depending on the drug regimen (it was required if AZT was included.) Other blood work such as white blood cell and liver function tests were to be ordered as determined by clinical symptoms, and viral load testing – the gold standard for measuring ART response – not even mentioned. Developing guidelines for the sur- veillance of drug resistance was however one of the itemised strategic actions of the initial ‘3 by 5 Programme’ (WHO 2003a, b). The low level of laboratory monitoring was contentious, given that the longer a person stays on a failing regimen, the greater the opportunity both for the development of resistance and the loss of clini- cal benefit. Accordingly, a randomised control trial (RCT) investigated whether (and to what extent) ART could be delivered safely without laboratory monitoring (the DART study). This study, first reported in 2009 and published in 2010, found that differences in outcomes occurred after the second year of treatment. Investigators argued that this justified only introducing CD4 cell tests at 24 months, and prioritis- ing spending on ART drugs rather than resource-intensive monitoring (DART Trial Team 2010). Of note, this study only looked at clinical outcomes, in people who already had advanced HIV", "n_tokens": 294, "kind": "text"}
{"chunk_id": "drug_resistance_book-57-2", "doc_id": "drug_resistance_book", "page": 57, "text": "disease, not at the drug resistance outcomes.", "n_tokens": 9, "kind": "text"}
{"chunk_id": "drug_resistance_book-57-3", "doc_id": "drug_resistance_book", "page": 57, "text": "3.5\n\nChanges in Eligibility for ART\n\nAt the inception of the global universal access program, there was no clear scientific evidence as to the best time to commence ART, except that it clearly prolonged life for those who commenced with low CD4 counts (below 200). From the mid 1990s, many argued on the basis of modelling from other infectious diseases that HIV replication should be suppressed as early and as completely as possible. ‘Hit hard, hit early’, was the catch cry (Ho 1995). Mitigating against this was the fact that seri- ous HIV disease did not usually occur until 6–10 years after infection, and the\n\nB. Haire", "n_tokens": 134, "kind": "text"}
{"chunk_id": "drug_resistance_book-58-0", "doc_id": "drug_resistance_book", "page": 58, "text": "3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical…\n\nproblem that ART regimens in the mid to late 1990s were hard to take (with high pill burdens, specific food and or fasting requirements for dosing particular drugs, and high rates of side effects). Of course the rapacious cost of ART was also signifi- cant – for example in 1997, 6 months use of the drug AZT was costed at $US 800 – it is now an estimated $US 237 (Pharmacychecker 2017).", "n_tokens": 111, "kind": "text"}
{"chunk_id": "drug_resistance_book-58-1", "doc_id": "drug_resistance_book", "page": 58, "text": "From the late 90s, a series of RCTs clarified issues pertaining to treatment com- mencement, indicating that better outcomes were achieved with earlier treatment initiation. These included CIPRA-HT001, a study in Haiti that showed that people who started ART with CD4 counts higher than 200 had a significantly reduced risk of death (Severe et al. 2010). This result was underscored by findings from the SMART Study, which was designed to test whether structured ART treatment inter- ruptions were safe (people with HIV took treatment interruptions or ‘holidays’ for a variety of reasons, including relief from side effects). The SMART Study found that not only did treatment interruptions increase the risk of disease progression at any CD4 level, but that the greater time spent with a CD4 count below 350, the greater the risk of HIV disease progression and death (Strategies for Management of Antiretroviral Therapy Study Group 2008). These findings together were the catalyst for a revision of WHO guidelines for resource-constrained environments to recommend ART commencement at the higher CD4 level of 350 (WHO 2009). Two further studies have been critical in pushing WHO ART guidelines toward recom- mending treatment at higher levels – the HPTN 052 Study, which showed that early ART treatment reduced onward HIV transmission to sexual partners by 96 % (Cohen et al. 2011), and then the START Study, reported in 2015, which showed a clear clinical benefit from early treatment initiation (at", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-58-2", "doc_id": "drug_resistance_book", "page": 58, "text": "CD4 levels of 500 and above), with people who initiated treatment immediately showing significant bene- fit compared with those who did not initiate ART until their CD4 counts had dropped to 350 or below (The Insight START Study Group 2015). This finding resulted in a revision of WHO guidelines, such that immediate ART therapy is now recom- mended for any person diagnosed with HIV, regardless of CD4 cell count.", "n_tokens": 85, "kind": "text"}
{"chunk_id": "drug_resistance_book-58-3", "doc_id": "drug_resistance_book", "page": 58, "text": "This change to WHO ART guidelines is based in robust evidence about the benefi- cial impact of immediate ART on health, and where taken up in national guidelines, may reduce the numbers of people diagnosed with HIV who get lost to follow -up due to being deemed ineligible for immediate ART. It also has some problematic implications. Firstly, it increases exponentially the estimates of people living with HIV who require ART, which may increase the likelihood of rationing taking place where supplies are inadequate. Secondly, notwithstanding the fact that some resource-poor countries may continue to align their national guidelines to earlier iterations of the WHO guidance, the expansion of eligibility for ART puts greater demand on ART stocks, and increases the risks of stock-outs, which could have an impact on the development of drug resistance. Even if drug supplies were perfect, human adherence will not be, so the logical result of millions more people taking lifelong ART over many decades must be an increase in drug resistance. Thirdly, increasing the number of people eligible for treatment may increase pressure at country level to continue to prioritise wider access to ART drugs at the expense of improving monitoring, exponentially expanding the risk that large scale poorly\n\n43", "n_tokens": 239, "kind": "text"}
{"chunk_id": "drug_resistance_book-59-0", "doc_id": "drug_resistance_book", "page": 59, "text": "44\n\nmonitored ART use poses with regard to development and transmission of drug resistant ART (at higher CD4 cell counts, the risk of death is far more remote that at lower one, so the risks of drug resistance are not so obviously balanced by the over- whelming benefit of prevention of illness and death). Fourthly, there is a major para- digm shift in terms of health communication in shifting ART treatment from something required for people with ill or declining health status to treating people who are well, and requiring this treatment to be maintained over a lifespan. Thus, well-targeted health promotion, innovative and effective adherence support, improved monitoring to detect signs of resistance early, and affordable, tolerable second, third and fourth line (or rescue) regimens all need to be integrated into this ambitious expansion of ART eligibility.\n\n3.6", "n_tokens": 170, "kind": "text"}
{"chunk_id": "drug_resistance_book-59-1", "doc_id": "drug_resistance_book", "page": 59, "text": "ART in Pregnancy in LMIC: A Case Study\n\n“Once started, antiretroviral therapy is for life….” states the introduction to the ‘3 by 5 Programme’ (WHO 2003a, b). The reason that ART treatment, once started, is to be continued for life is to maximise health by maintaining a supressed HIV viral load, and preventing the development of drug resistance that could occur if ART is started and stopped (as the various drugs in combination ART regimens have differ- ent half-lives, it is complex to stop a regimen in a way that ensures that there is no lingering, suboptimal antiviral activity that could provide the conditions for drug resistance to develop). A brief look at the history of interventions aimed at prevent- ing vertical infection (from mother-to-child), however, shows that the maxim of ART therapy being for life has frequently not been the case with regard to provi- sions of ART to pregnant women. The case study below, I suggest, is an example of how the prevention benefit of ART was initially prioritised above the healthcare of pregnant women with HIV.", "n_tokens": 236, "kind": "text"}
{"chunk_id": "drug_resistance_book-59-2", "doc_id": "drug_resistance_book", "page": 59, "text": "The prevention of HIV transmission from mother to child (PMTCT) was the first instance of effective biomedical HIV prevention, achieved in 1994 by the ACTG 076 study (Connor et al. 1994). Famously, this breakthrough spawned a series of placebo-controlled trials in LMIC using less intensive, cheaper regimens (see Wade et al. 1998). This chapter will not delve into the ethical quagmire surrounding the use of placebos despite an effective preventative intervention having been estab- lished, as this has been exhaustively covered elsewhere (see Macklin 2001). Instead, this chapter will recount and analyse what occurred programmatically in PMTCT following the results of the HIVNET 012 Trial, which established that a single dose of the ART drug nevirapine to both mother and infant reduced transmission in the first 14–16 weeks of life by nearly 50% in a breastfeeding population (Guay et al. 1999). This regimen, while not as effective as the ACTG 076 regimen, was consid- ered to be a major breakthrough for LMIC. Unlike ACTG 076, it did not require Caesarian section, it did not require treatment uptake in mid pregnancy, it did not require intravenous ART during delivery, and it appeared to work in breastfeeding populations. All of these factors made it significantly more feasible to implement at\n\nB. Haire", "n_tokens": 296, "kind": "text"}
{"chunk_id": "drug_resistance_book-60-0", "doc_id": "drug_resistance_book", "page": 60, "text": "3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical…\n\nscale in LMIC. (Of note, when the Food and Drug Administration looked at the data from this trial, it found serious anomalies in the conduct of the trial. Accordingly questions remain regarding the validity of this study’s results (Cohen 2004; Institute of Medicine Committee 2005).\n\nOne of the issues with the early WHO guidelines that recommended ART treat- ment only for people with signs of immune damage and/or HIV disease was the problem it created regarding pregnant women with HIV. Despite pregnant women in high income countries achieving excellent health and prevention outcomes with early ART, it meant that pregnant women in LMIC without clinical signs of HIV disease and with CD4 counts above levels recommended for treatment were deemed not to require ART for their own health, despite knowledge that ART would reduce transmission to infants. This created an artificial distinction between the treatment use of ART and prophylactic use in pregnant women – prophylactic use only was recommended. In other words, a pregnant woman with HIV but in otherwise good health would get access to ART to protect her infant, but this would be short-term.", "n_tokens": 236, "kind": "text"}
{"chunk_id": "drug_resistance_book-60-1", "doc_id": "drug_resistance_book", "page": 60, "text": "Despite its appeal in terms of feasibility, the nevirapine single-dose1 regimen had a very specific problem. Although a potent ART drug, nevirapine as noted earlier has a low genetic barrier to resistance, and a long half-life. Thus the drug persists in the blood stream for a long time after a dose, but at concentrations insufficient to fully suppress viraemia. This creates a good environment for the development of drug resistance, and a single dose is enough for this to occur. Exposing women and their infants to this regimen could thus potentiate the development of drug resis- tance, which might reduce the efficacy of the intervention for any subsequent preg- nancies, and limit treatment options for the mother and potentially for the infant, should the infant be HIV infected despite the use of nevirapine prophylaxis.", "n_tokens": 173, "kind": "text"}
{"chunk_id": "drug_resistance_book-60-2", "doc_id": "drug_resistance_book", "page": 60, "text": "The publication of the long-term results HIVNET 012 trial was accompanied by a controversial commentary by Karen Palmore Beckerman (2003) that argued that the implementation of single-dose nevirapine would leave ‘between 20–100% of women who received prophylaxis resistant to [the class of drugs to which nevirap- ine belongs]’. While the claim that up to 100% would develop resistance was hyper- bolic (Wilfert 2003), the issues she raised were prescient. Beckerman argued that pregnant women with HIV should be treated with effective ART regimens both for their own sake and to enable their survival – citing the devastating example that three women who participated in HIVNET 012 died of AIDS within 56 days of delivery. She suggested that adding a combination ART ‘tail’ to the nevirapine regi- men could reduce the likelihood of resistance (a suggestion later taken up in WHO guidelines in 2010), and that the primary focus be on sustained and sustainable ART treatment.\n\nBeckerman’s (2003) article built on an earlier commentary of hers (Beckerman 2002) where – again in response to the publication of short-course trial to reduce mother-to-child transmission – she argued that the risks of programs using single or\n\n1 This regimen is referred to in the literature as ‘single dose’ though it in fact involves two doses – one to mother and one to infant. For simplicity’s sake I’m adopting the common usage.\n\n45", "n_tokens": 305, "kind": "text"}
{"chunk_id": "drug_resistance_book-61-0", "doc_id": "drug_resistance_book", "page": 61, "text": "46\n\ndual ART drugs were increasing as the prospect of good treatment access in LMIC grew, given that women who had used short-course ART would be more likely to experience treatment failure due to drug resistance. With limited treatment options available, failing first line ART options would increase the risk of the mother dying, which would in turn increase risk for surviving children, Beckerman argued.\n\nThere is a considerable literature on the clinical implications of nevirapine resis- tance, with much focus on whether or not it ‘fades’ over time such that subsequent introduction of an ART regimen containing nevirapine might still have clinical util- ity as either treatment or prophylaxis (Johnson et al. 2005; Lockman et al. 2007, McConnell et al. 2007; Stringer et al. 2010). Regardless of whether or not resistance ‘fades’ to a level that would result in nevirapine-based combination being effective in women exposed to single-dose PMTCT, it is clear that, as others have noted, the prevention of transmission to infants took precedence over the health security of women with HIV, at least for a time when these single-dose nevirapine programs were widespread (Eyakuze et al. 2008). As noted in a meta-analysis, these programs ultimately resulted in a high burden of drug resistance in women and children, with significant potential to contribute to increase failure of first line ART therapy (Arrivé et al. 2007; Samuel et al. 2016).", "n_tokens": 305, "kind": "text"}
{"chunk_id": "drug_resistance_book-61-1", "doc_id": "drug_resistance_book", "page": 61, "text": "From 2003, WHO guidance recognised that pregnant women should not be pre- scribed ART regimens likely to result in drug resistance, and had specifically pro- vided a warning about the single-dose nevirapine regimen. By 2012 the policy of women cycling on and off ART with successive pregnancies was superseded by ‘Option B+’2 – a recommendation that pregnant women with HIV should be pre- scribed fully suppressive ART regimens, and kept on them for life, regardless of CD4 cell count or HIV disease stage. While Option B+ has not been fully imple- mented in all LMIC, it is the only PMTCT option that fully applies the ‘rules’ of effective ART treatment – that regimens should be fully suppressive, and taken for life. Ironically, there have been reports of significant loss to follow up with these programs, perhaps because women with HIV had being educated to accept intermit- tent therapy unless they themselves were in poor health (Tenthani et al. 2014)\n\nReflecting on the history of PMTCT, there are tensions between the prevention imperative, emerging knowledge about optimal timing of ART, the status of wom- en’s health, equity, and the constraints of the early stages of implementation of the morally praiseworthy but hugely ambitious goal of universal access. In the late 90s and early 2000s, the nevirapine single-dose regimen had appeal in terms of its simplicity, its low drug burden, and the fact that it could be implemented during", "n_tokens": 307, "kind": "text"}
{"chunk_id": "drug_resistance_book-61-2", "doc_id": "drug_resistance_book", "page": 61, "text": "2 Option B+ was added to two previous options, option A and Option B. Briefly, Under Option A, women received ARV prophylaxis prenatally and during delivery, along with an antiretroviral post- partum “tail” regimen to reduce risk of drug resistance, and their infants received postpartum antiretroviral prophylaxis throughout the duration of breastfeeding. With Option B, all pregnant and lactating women with HIV were offered ARV – beginning in the antenatal period and continu- ing throughout the duration of breastfeeding. At the end of breastfeeding those women deemed to not yet require ARV for their own health would discontinue the prophylaxis and continue to moni- tor their CD4 count, eventually re-starting ARV when their CD4 cell count fell below 350 cells.\n\nB. Haire", "n_tokens": 188, "kind": "text"}
{"chunk_id": "drug_resistance_book-62-0", "doc_id": "drug_resistance_book", "page": 62, "text": "3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical…\n\ndelivery. In short, it had been shown to be better than nothing at a time when ‘noth- ing’ was still seen in some quarters as an acceptable comparator. While the shift away from the single dose regimen happened relatively quickly (at least in terms of normative guidance, if not in practice), its impacts are likely to live on in the form of suboptimal response to first line ART regimens and transmitted drug resistance (Kébé et al. 2014).", "n_tokens": 116, "kind": "text"}
{"chunk_id": "drug_resistance_book-62-1", "doc_id": "drug_resistance_book", "page": 62, "text": "It took 6 years from the initial reporting of the SMART study – which showed that starting and stopping ART was detrimental – for PMTCT guidance to recom- mend life-long treatment for women who initiated ART due to pregnancy. On the one hand, this seems shocking. On the other hand, due to PMTCT programs even with their limitations, women in LMIC tended to access ART earlier than men, and hence have had lower risk of death from HIV disease than men (Beckham et al. 2016; Taylor-Smith et al. 2010), so further strengthening care access for women may have seemed inequitable in some contexts. It could be argued that the history of PMTCT in LMIC demonstrates a programmatic emphasis on prevention without adequate regard for the potential development of drug resistance, and subsequent drug failure in mothers and pregnant women with HIV. It is probably more reason- able, however to say that the complexity of implementing best practice PMTCT in the midst of programmatic scale up of ART access in a context where knowledge about ART changed significantly made compromise and incremental steps forward hard to avoid, if not inevitable. Nevertheless, exposure to sub-optimal therapy through PMCTC programs has left a legacy of drug resistance in some settings (Rowley et al. 2016; Cambiano et al. 2013).", "n_tokens": 272, "kind": "text"}
{"chunk_id": "drug_resistance_book-62-2", "doc_id": "drug_resistance_book", "page": 62, "text": "Now that lifelong ART from the point of diagnosis is the WHO recommendation for everyone, exponentially more people will be accessing ART prior to any clinical indications of HIV. That number will be expected to keep increasing, as ART access should enable people with HIV to live normal lifespans. In this context the risk of the development of drug resistance must necessarily increase, given the difficulties of maintaining good-enough adherence for large populations over long periods of time. While the low-level clinical monitoring approach to HIV disease had an important role in enabling the ‘public health’ roll out of ART in LMIC, this approach would not be sustainable in populations accessing treatment much earlier in HIV disease.\n\n3.7\n\nAddressing ART Resistance\n\nAddressing the risk of drug resistance requires strategic action at many levels. Action is required at the community and local levels, to develop and sustain pro- grams that support individual adherence and that work to address systemic prob- lems that can affect adherence (by improving systems of clinic appointments and transport and drug access, for example). Scaling up monitoring and investing in viral load testing will become critical so that people who are on failing regimens – for whatever reason – are identified quickly and either supported to improve adher- ence or switched to second line therapy. Development of viral load and CD4 testing\n\n47", "n_tokens": 263, "kind": "text"}
{"chunk_id": "drug_resistance_book-63-0", "doc_id": "drug_resistance_book", "page": 63, "text": "48\n\ntechnologies that are better adapted to use in remote and/or resource constrained settings, and which do not require highly trained laboratory staff, should obviously be prioritised to reduce the dependence of remote and under-resourced clinics on distant laboratory services. Research and development into new effective ART that are well tolerated and are effective against current common resistance patterns in HIV – and new modes of delivery, such as periodic injectables – are of course highly desirable.", "n_tokens": 92, "kind": "text"}
{"chunk_id": "drug_resistance_book-63-1", "doc_id": "drug_resistance_book", "page": 63, "text": "While some commentators have suggested withdrawing or withholding ART from non-adherent people rather than providing practical support and transitioning them as necessary to second line ART, this perspective positions poor adherence as an individual (and moral) issue (Chawana & Bogaert 2011). A perspective of adher- ence that is informed by public health and human rights, on the other hand, recog- nises that while adherence is an individual behaviour, it is highly determined by structural factors and social context, which can and should be modified to make adherence as simple and as socially acceptable and socially desirable as possible. There is evidence that people in certain demographics (such as young people) may have more trouble with adherence (Haire 2015). Withholding or withdrawing ART on the basis of poor adherence from young people, for example, would not only remove the benefits of early treatment from the demographic with the most to gain, it would also remove the prevention benefit from a population group highly likely to be sexually active. Accordingly, it would seriously undermine global targets for universal access. Recognising, working with, and seeking to ameliorate adherence problems in the social groups that experience them, while advocating for ART that provide different delivery options such as periodic injection, makes sense from a public health and human rights perspective. Universal access goals aim for 90% of people with HIV knowing their status, 90%", "n_tokens": 282, "kind": "text"}
{"chunk_id": "drug_resistance_book-63-2", "doc_id": "drug_resistance_book", "page": 63, "text": "of those being on ART and 90% of those having undetectable viral loads by 2020 (UNAIDS 2017). Using 2017 figures, this would require more than 14 million more people to be on ART within 2 years – considerable investment in supportive and responsive programming to achieve, sup- port and sustain adherence must be factored into such ambitious plans.", "n_tokens": 71, "kind": "text"}
{"chunk_id": "drug_resistance_book-63-3", "doc_id": "drug_resistance_book", "page": 63, "text": "3.8\n\nBiomedical Prevention and Drug Resistance\n\nBiomedical prevention is the use of antiretroviral drugs to prevent HIV transmis- sion. It includes ART use after exposure to prevent transmission (post-exposure prophylaxis or PEP), ART use prior to exposure in HIV negative people at high risk of HIV acquisition to prevent transmission (pre-exposure prophylaxis or PrEP), and ART use in HIV positive people to fully supress HIV replication, preventing onward transmission to sexual/injecting partners (‘treatment-as-prevention’). The latter two strategies are highly effective and well supported by both RCT and observa- tional data (data on PEP is less robust as it has not been tested in an RCT). PMTCT programs contain elements of two biomedical approaches: maternal viral load is reduced to reduce infectiousness, like treatment as prevention, and infants receive\n\nB. Haire", "n_tokens": 188, "kind": "text"}
{"chunk_id": "drug_resistance_book-64-0", "doc_id": "drug_resistance_book", "page": 64, "text": "3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical…\n\nART to prevent or abort HIV acquisition, similar to PrEP and PEP. The preventative aspect of early ART treatment is one aspect (in addition to the clinical benefit for the person with HIV) that makes implementation of ART programs in people immedi- ately after diagnosis attractive to governments and donors – it has the potential to reduce onward infection. Similarly, while investment in PrEP programs has been slow, there is a steady increase in availability (AVAC n.d.).", "n_tokens": 112, "kind": "text"}
{"chunk_id": "drug_resistance_book-64-1", "doc_id": "drug_resistance_book", "page": 64, "text": "In adherent participants, both PrEP and treatment -as -prevention have shown close to 100% protection in trials (Grant et al. 2014; Anderson et al. 2012; Bavinton et al. 2018; Rodgers et al. 2016, 2018; Cohen et al. 2011). There has however been at least one verified example of HIV transmission occurring in an adherent PrEP- taker, due to being exposed to HIV that was resistant to both the drugs used in the PrEP combination (Knox et al. 2016). With regard to treatment -as -prevention, having a lowered viral pool in a population would be expected to translate into fewer transmissions at population level. To have confidence in treatment -as -pre- vention at an individual level, however, the sexual partner with HIV needs to be confident that his/her viral load is sustained at an undetectable level, and that requires access to viral load tests at regular intervals. A combination of PrEP and treatment-as-prevention is being trialled in LMIC in serodiscordant couples, where the HIV positive partner is initiated on ART and the negative partner on PrEP, until such time as the positive partner has a sustained undetectable viral load. For this to succeed programmatically, viral load monitoring is required for the ongoing protection of the negative partner (should the positive partner be non-adherent, the negative partner would run the risk of acquiring HIV, and possibly drug resistant HIV), and to maintain the efficacy of the regimen for the positive partner. In this new era of", "n_tokens": 316, "kind": "text"}
{"chunk_id": "drug_resistance_book-64-2", "doc_id": "drug_resistance_book", "page": 64, "text": "biomedical prevention and all people with HIV being eligible for ART, the need to implement viral load monitoring at scale is increasingly being recog- nised (WHO 2016).", "n_tokens": 34, "kind": "text"}
{"chunk_id": "drug_resistance_book-64-3", "doc_id": "drug_resistance_book", "page": 64, "text": "3.9\n\nMonitoring Drug Resistance Beyond the Individual\n\nIn high income countries, when people are diagnosed with HIV, a blood sample is sent to a laboratory for genotypic testing – a form of analysis that provides informa- tion of whether the person has been infected with a strain of HIV that is resistant (or less susceptible) to particular ART drugs. The person is then prescribed an appropri- ate regimen that will be effective against the person’s HIV.3\n\nIn LMIC surveillance of HIV drug resistance includes country specific surveys of HIV genotypes to determine incidence of transmitted drug resistance in\n\n3 Genotyping HIV also has some risks in high income countries, such as the potential to use these data to track ‘infection trees’ – map pathways of infection. This is ethically problematic in terms of maintaining an enabling environment, as it uses information gleaned from people who test posi- tive for HIV intended to maximise their health outcomes for a purpose that could potentially lead to criminalisation.\n\n49", "n_tokens": 207, "kind": "text"}
{"chunk_id": "drug_resistance_book-65-0", "doc_id": "drug_resistance_book", "page": 65, "text": "50", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-65-1", "doc_id": "drug_resistance_book", "page": 65, "text": "populations, through a WHO network of designated laboratories (Bertagnolio et al. 2008). In LMIC this information is directed towards making country or region-wide decisions about first line treatment, and other programs such as the drugs used in post- exposure prophylaxis. In addition, early warning indicators provide informa- tion about critical aspects of whether/how people are accessing ART. These include on- time pill pickup; retention in care at 12 months following ART initiation; whether pharmacies experience stock-outs; prescribing practices (whether regimens pre- scribed meet national or international guidance regarding adequate viral suppres- sion); and, in settings where viral load testing is implemented, viral load suppression at 12 months following ART initiation. These early warning indicators are well designed to signal structural problems, like interruptions in drug supply and poor prescriber compliance with guidelines, and access issues such as whether drug col- lection systems are ‘good enough’ (reliable and convenient) for people to be able to pick up pills on time. In 2017, WHO reported ‘brisk’ implementation of these sys- tems, with 26 countries having completed or currently completing surveys, and 14 having reported data (WHO 2017). Of note, in countries or regions where drug stock outs are frequent, the benefit of putting people with high CD4 counts onto ART would need to be weighed against the individual and public health concern of the development of", "n_tokens": 299, "kind": "text"}
{"chunk_id": "drug_resistance_book-65-2", "doc_id": "drug_resistance_book", "page": 65, "text": "resistance, should ART be repeatedly started and stopped (for people with CD4 counts lowered by HIV, the clinical benefit of the ART is likely to outweigh the risk). Ideally, of course, the stock out issues should be addressed effectively.", "n_tokens": 50, "kind": "text"}
{"chunk_id": "drug_resistance_book-65-3", "doc_id": "drug_resistance_book", "page": 65, "text": "3.10\n\nConclusion\n\nAlthough hope and hype about vaccines and cures for HIV circulate, ART is cur- rently the most effective tool for the elimination of HIV as a public health threat, both in terms of treatment and prevention (in combination with or as an adjunct to condoms). Preventing the emergence of drug resistance at levels that compromises treatment efficacy and ART based prevention is crucial.", "n_tokens": 81, "kind": "text"}
{"chunk_id": "drug_resistance_book-65-4", "doc_id": "drug_resistance_book", "page": 65, "text": "With PMTCT programs, the emphasis on the simplest and cheapest regimens, maintained well after the implications for drug resistance were apparent, has already compromised optimal response to ART for too many women and children. This can- not be repeated in the expansion of ART access. Standardised first, second and third line ART has facilitated the rapid scale up of ART in LMIC, and saved many lives. To build on this, a highly strategic approach to monitoring drug resistance in popu- lations and individuals needs to be taken, with viral load monitoring supporting more rapid change to second and third line therapies as required, rather than running the risk of keeping people on failing regimens. Supporting adherence at health ser- vice, community, family and individual levels also requires investment – investment in research, to find context-appropriate solutions that work, in communities to pro- vide labour, and in systems to streamline the medical and dispensing processes and practices that can facilitate or hinder access and adherence. While refinements in drug development may make adherence simpler in years to come, the challenge is\n\nB. Haire", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-66-0", "doc_id": "drug_resistance_book", "page": 66, "text": "3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical…\n\nto ensure that programming now is responsive to problem of resistance, and that existing drugs and monitoring are carefully deployed to optimise longevity of tools currently available.\n\nReferences\n\nAnderson, P.L., D.V. Glidden, A. Liu, S. Buchbinder, J.R. Lama, J.V. Guanira, et al. 2012. Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Science Translational Medicine 4 (151): 151ra125.\n\nArrivé, E., M.-L. Newell, D.K. Ekouevi, M.-L. Chaix, R. Thiebaut, B. Masquelier, et al. 2007. Prevalence of resistance to nevirapine in mothers and children after single-dose exposure to pre- vent vertical transmission of HIV-1: a meta-analysis†. International Journal of Epidemiology 36 (5): 1009–1021.\n\nArts, E.J., and D.J. Hazuda. 2012. HIV-1 antiretroviral drug therapy. Cold Spring Harbor", "n_tokens": 262, "kind": "text"}
{"chunk_id": "drug_resistance_book-66-1", "doc_id": "drug_resistance_book", "page": 66, "text": "Perspectives in Medicine 2 (4): a007161. https://doi.org/10.1101/cshperspect.a007161.\n\nAVAC. PrEP Watch. Scaling up country updates. http://www.prepwatch.org/scaling-up/\n\ncountry-updates\n\nBavinton, B.R., A.N. Pinto, N. Phanuphak, et al. 2018. Viral suppression and HIV transmission in serodiscordant male couples: An international, prospective, observational, cohort study. Lancet. Published online July 16.\n\nBeckerman, K.P. 2002. Mothers, orphans, and prevention of paediatric AIDS. The Lancet 359\n\n(9313): 1168–1169.\n\n———. 2003. Long-term findings of HIVNET 012: The next steps. The Lancet 362 (9387):\n\n842–843.\n\nBeckham, S.W., C. Beyrer, P. Luckow, M. Doherty, E.K. Negussie, and S.D. Baral. 2016. Marked sex differences in all-cause mortality on antiretroviral therapy in low- and middle-income countries: A systematic review and meta-analysis. Journal of the International AIDS Society 19 (1): 21106.\n\nBertagnolio, S., I. Derdelinckx, M. Parker, J. Fitzgibbon, H. Fleury, M. Peeters, et al. 2008. World Health Organization/HIVResNet drug resistance laboratory strategy. Antiviral Therapy 13 (Suppl 2): 49–57.\n\nCambiano, V., S. Bertagnolio, M.R. Jordan, J.D. Lundgren, and A. Phillips. 2013. Transmission of drug resistant HIV and its potential impact on mortality and treatment outcomes in resource- limited settings. The Journal of Infectious Diseases 207 (Suppl 2): S57–S62.", "n_tokens": 435, "kind": "text"}
{"chunk_id": "drug_resistance_book-66-2", "doc_id": "drug_resistance_book", "page": 66, "text": "Chawana, R., and D.K. van Bogaert. 2011. Risk management in HIV/AIDS: Ethical and economic issues associated with restricting HAART access only to adherent patients. African Journal of AIDS Research 10 (sup1): 369–380.\n\nCohen, Jon. 2004. Allegations raise fears of backlash against AIDS prevention strategy. Science\n\n306 (5705): 2168–2169. https://doi.org/10.1126/science.306.5705.2168.\n\nCohen, M.S., Y.Q. Chen, M. McCauley, T. Gamble, M.C. Hosseinipour, N. Kumarasamy, et al. 2011. Prevention of HIV-1 infection with early antiretroviral therapy. The New England Journal of Medicine 365 (6): 493–505.\n\nConnor, E.M., R.S. Sperling, R. Gelber, P. Kiselev, G. Scott, M.J. O’Sullivan, et al. 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with Zidovudine treatment. The New England Journal of Medicine 331 (18): 1173–1180.\n\nDART Trial Team. 2010. Routine versus clinically driven laboratory monitoring of HIV antiret- roviral therapy in Africa (DART): A randomised non-inferiority trial. The Lancet 375 (9709): 123–131. https://doi.org/10.1016/S0140-6736(09)62067-5.\n\nEyakuze, C., D.A. Jones, A.M. Starrs, and N. Sorkin. 2008. From PMTCT to a more comprehen- sive aids response for women: A much-needed shift. Developing World Bioethics 8 (1): 33–42.\n\n51", "n_tokens": 413, "kind": "text"}
{"chunk_id": "drug_resistance_book-67-0", "doc_id": "drug_resistance_book", "page": 67, "text": "52\n\nGrant, R.M., P.L. Anderson, V. McMahan, A. Liu, K.R. Amico, M. Mehrotra, et al. 2014. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: A cohort study. The Lancet Infectious Diseases 14 (9): 820–829. Guay, L.A., P. Musoke, T. Fleming, D. Bagenda, M. Allen, C. Nakabiito, et al. 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to- child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. The Lancet 354 (9181): 795–802.\n\nGulick, Roy M., Heather J. Ribaudo, Cecilia M. Shikuma, Stephanie Lustgarten, Kathleen E. Squires, William A. Meyer III, Edward P. Acosta, Bruce R. Schackman, Christopher D. Pilcher, Robert L. Murphy, William E. Maher, Mallory D. Witt, Richard C. Reichman, Sally Snyder, Karin L. Klingman, and Daniel R. Kuritzkes. 2004. Triple-Nucleoside regimens ver- sus Efavirenz-containing regimens for the initial treatment of HIV-1 infection. New England Journal of Medicine 350 (18): 1850–1861. https://doi.org/10.1056/NEJMoa031772.\n\nHaire, B. 2015. Preexposure prophylaxis-related stigma: Strategies to improve uptake and adher- ence – A narrative review. HIV/AIDS – Research and Palliative Care 7: 241–249. https://doi. org/10.2147/HIV.S72419.\n\nHo, David D. 1995. Time to hit HIV, early and hard. New England Journal of Medicine 333 (7):\n\n450–451. https://doi.org/10.1056/nejm199508173330710.", "n_tokens": 486, "kind": "text"}
{"chunk_id": "drug_resistance_book-67-1", "doc_id": "drug_resistance_book", "page": 67, "text": "Institute of Medicine (US) Committee on Reviewing the HIVNET 012 Perinatal HIV Prevention Study. 2005. Review of the HIVNET 012 perinatal HIV prevention study. National Academy of Sciences. Washington, DC: National Academies Press.\n\nJohnson, J.A., Li J-f, L. Morris, N. Martinson, G. Gray, J. McIntyre, et al. 2005. Emergence of drug-resistant HIV-1 after Intrapartum administration of single-dose Nevirapine is substan- tially underestimated. The Journal of Infectious Diseases 192 (1): 16–23.\n\nKaufmann, G.R., H. Furrer, B. Ledergerber, L. Perrin, M. Opravil, P. Vernazza, M. Cavassini, E. Bernasconi, M. Rickenbach, B. Hirschel, and M. Battegay. 2005. Characteristics, determi- nants, and clinical relevance of CD4 T cell recovery <500 Cells/μL in HIV type 1 – Infected individuals receiving potent antiretroviral therapy. Clinical Infectious Diseases 41 (3): 361–372. https://doi.org/10.1086/431484.\n\nKébé, K., L. Bélec, H.D. Ndiaye, S.B. Gueye, A.A.M. Diouara, S. Ngom, et al. 2014. The case for addressing primary resistance mutations to non-nucleoside reverse transcriptase inhibitors to treat children born from mothers living with HIV in sub-Saharan Africa. Journal of the International AIDS Society 17 (1): 18526.\n\nKnox, D.C., D.H. Tan, P.R. Harrigan, and P.L. Anderson. 2016. HIV-1 infection with multiclass resistance despite Preexposure Prophylaxis (PrEP). 169aLB. In Conference on retro viruses and opportunistic infections, 22–25 February 2016, Boston, Massachusetts.", "n_tokens": 436, "kind": "text"}
{"chunk_id": "drug_resistance_book-67-2", "doc_id": "drug_resistance_book", "page": 67, "text": "Lockman, S., R.L. Shapiro, L.M. Smeaton, C. Wester, I. Thior, L. Stevens, F. Chand, J. Makhema, C. Moffat, A. Asmelash, P. Ndase, P. Arimi, E. van Widenfelt, L. Mazhani, V. Novitsky, S. Lagakos, and M. Essex. 2007. Response to antiretroviral therapy after a single, peripar- tum dose of nevirapine. New England Journal of Medicine 356 (2): 135–147. https://doi. org/10.1056/NEJMoa062876.\n\nLuber, A.D. 2005. Genetic barriers to resistance and impact on clinical response. Medscape\n\nGeneral Medicine 7 (3): 69.\n\nMacklin, R. 2001. After Helsinki: Unresolved issues in international research. Kennedy Institute of\n\nEthics Journal 11 (1): 17–36. Project MUSE. https://doi.org/10.1353/ken.2001.0005.\n\n———. 2004. Ethics and equity in access the HIV treatment 3 by 5 initiative: Background paper consultation on ethics and equitable access to treatment and care for HIV/AIDS. http://www. who.int/ethics/background-macklin2.pdf\n\nMcConnell, M.S., J.S.A. Stringer, A.P. Kourtis, P.J. Weidle, and S.H. Eshleman. 2007. Use of single- dose nevirapine for the prevention of mother-to-child transmission of HIV-1: Does development of resistance matter? American Journal of Obstetrics & Gynecology 197 (3): S56–S63.\n\nB. Haire", "n_tokens": 395, "kind": "text"}
{"chunk_id": "drug_resistance_book-68-0", "doc_id": "drug_resistance_book", "page": 68, "text": "3 Providing Universal Access While Avoiding Antiretroviral Resistance: Ethical…\n\nMellors, J.W., C.R. Rinaldo, P. Gupta, R.M. White, J.A. Todd, and L.A. Kingsley. 1996. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272 (5265): 1167–1170. Mellors, J.W., A. Munoz, J.V. Giorgi, et al. 1997. Plasma viral load and CD4+ lymphocytes as\n\nprognostic markers of HIV-1 infection. Annals of Internal Medicine 126 (12): 946–954.\n\nMoore, R.D., and R.E. Chaisson. 1999. Natural history of HIV infection in the era of combi- nation antiretroviral therapy. AIDS 13 (14): 1933–1942.. PMID 10513653. https://doi. org/10.1097/00002030-199910010-00017.\n\nPharmacychecker.\n\n2017. zidovudine/300+mg. Accessed 29 July 2017.", "n_tokens": 249, "kind": "text"}
{"chunk_id": "drug_resistance_book-68-1", "doc_id": "drug_resistance_book", "page": 68, "text": "https://www.pharmacychecker.com/generic/price-comparison/\n\nRodger AJ et al. for the PARTNER Study Group. 2016. Sexual activity without condoms and risk of HIV transmission in serodifferent couples when the HIV-positive partner is using suppres- sive antiretroviral therapy. JAMA 316 (2): 1–11. https://doi.org/10.1001/jama.2016.5148. http:// jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.5148. Accessed 12 July 2016. Rodger AJ, V. Cambiano, T. Bruun, et al. 2018. Risk of HIV transmission through condomless sex in MSM couples with suppressive ART: The PARTNER2 Study extended results in gay men. In 22nd International AIDS conference (AIDS 2018), Amsterdam, the Netherlands. Oral Abstract WEAX0104LB.\n\nRosen, S., and M.P. Fox. 2011. Retention in HIV care between testing and treatment in Sub-\n\nSaharan Africa: A systematic review. PLOS Medicine 8 (7): e1001056.\n\nRowley, C.F., I.J. MacLeod, D. Maruapula, B. Lekoko, S. Gaseitsiwe, M. Mine, et al. 2016. Sharp increase in rates of HIV transmitted drug resistance at antenatal clinics in Botswana dem- onstrates the need for routine surveillance. Journal of Antimicrobial Chemotherapy 71 (5): 1361–1366.", "n_tokens": 345, "kind": "text"}
{"chunk_id": "drug_resistance_book-68-2", "doc_id": "drug_resistance_book", "page": 68, "text": "Samuel, R., M.N. Julian, R. Paredes, R. Parboosing, P. Moodley, L. Singh, et al. 2016. HIV-1 drug resistance by ultra-deep sequencing following short course zidovudine, single-dose nevirapine, and single-dose tenofovir with emtricitabine for prevention of mother-to-child transmission. JAIDS Journal of Acquired Immune Deficiency Syndromes 73 (4): 384–389.\n\nSevere, Patrice, Marc Antoine Jean Juste, Alex Ambroise, Ludger Eliacin, Claudel Marchand, Sandra Apollon, Alison Edwards, Heejung Bang, Janet Nicotera, Catherine Godfrey, Roy M. Gulick, Warren D. Johnson Jr., Jean William Pape, and Daniel W. Fitzgerald. 2010. Early versus standard antiretroviral therapy for HIV-infected adults in Haiti. New England Journal of Medicine 363 (3): 257–265. https://doi.org/10.1056/NEJMoa0910370.\n\nSmart, T. 2006. PEPFAR and Global Fund both highly effective, but is the funding sustainable? AIDSMAP. http://www.aidsmap.com/PEPFAR-and-Global-Fund-both-highly-effective-but- is-the-funding-sustainable/page/1424121. Accessed 23 June 2006.", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-68-3", "doc_id": "drug_resistance_book", "page": 68, "text": "Strategies for Management of Antiretroviral Therapy Study Group, Sean Emery, Jacqueline A. Neuhaus, Andrew N. Phillips, Abdel Babiker, Calvin J. Cohen, Jose M. Gatell, Pierre-Marie Girard, Birgit Grund, Matthew Law, Marcelo H. Losso, Adrian Palfreeman, and Robin Wood. 2008. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. The Journal of Infectious Diseases 197 (8): 1133–1144. https://doi.org/10.1086/586713.\n\nStringer, J.S.A., M.S. McConnell, J. Kiarie, O. Bolu, T. Anekthananon, T. Jariyasethpong, et al. 2010. Effectiveness of non-nucleoside reverse-transcriptase inhibitor-based antiretroviral ther- apy in women previously exposed to a single intrapartum dose of nevirapine: A multi-country, prospective cohort study. PLOS Medicine 7 (2): e1000233.\n\nTaylor-Smith, K., H. Tweya, A. Harries, E. Schoutene, and A. Jahn. 2010. Gender differences in retention and survival on antiretroviral therapy of HIV-1 infected adults in Malawi. Malawi Medical Journal: The Journal of Medical Association of Malawi 22 (2): 49–56.", "n_tokens": 326, "kind": "text"}
{"chunk_id": "drug_resistance_book-68-4", "doc_id": "drug_resistance_book", "page": 68, "text": "Tenthani, Lyson, Andreas D. Haas, Hannock Tweya, Andreas Jahn, Joep J. van Oosterhout, Frank Chimbwandira, Zengani Chirwa, Wingston Ng’Ambi, Alan Bakali, Sam Phiri, Landon Myer, Fabio Valeri, Marcel Zwahlen, Gilles Wandeler, and Olivia Keiser. 2014. Retention in care under universal antiretroviral therapy for HIV infected pregnant and breastfeeding women (“Option B+”) in Malawi. AIDS 28 (4): 589–598. https://doi.org/10.1097/QAD.0000000000000143.\n\n53", "n_tokens": 155, "kind": "text"}
{"chunk_id": "drug_resistance_book-69-0", "doc_id": "drug_resistance_book", "page": 69, "text": "54\n\nThe INSIGHT START Study Group. 2015. Initiation of antiretroviral therapy in early asymp- tomatic HIV infection. New England Journal of Medicine 373 (9): 795–807. https://doi. org/10.1056/NEJMoa1506816.\n\nUNAIDS. 2017. 90–90–90 – An ambitious treatment target to help end the aids epidemic. http://\n\nwww.unaids.org/en/resources/documents/2017/90-90-90\n\nWade, N.A., G.S. Birkhead, B.L. Warren, T.T. Charbonneau, P.T. French, L. Wang, et al. 1998. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. New England Journal of Medicine 339 (20): 1409–1414.\n\nWilfert, C.M. 2003. HIVNET 012 and Petra. The Lancet 363 (9404): 244–245. World Health Organization. 2003a. 3 by 5 Strategy: Making it happen. http://www.who.int/3by5/\n\npublications/documents/en/3by5StrategyMakingItHappen.pdf\n\n———. 2003b. Scaling up antiretroviral therapy in resource-limited settings: Treatment guidelines for a public health approach. http://www.who.int/hiv/pub/prev_care/en/ARTrevision2003en. pdf?ua=1\n\n———. 2006. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations\n\nfor a public health approach (2006 revision). http://www.who.int/hiv/pub/ART/adult/en\n\n———. 2009. Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents.\n\nhttp://www.who.int/hiv/pub/arv/rapid_advice_art.pdf\n\n——— 2016. Global Action Plan on HIV Drug Resistance 2017–2021. https://www.who.int/hiv/", "n_tokens": 468, "kind": "text"}
{"chunk_id": "drug_resistance_book-69-1", "doc_id": "drug_resistance_book", "page": 69, "text": "drugresistance/hivdr_darft_gap.pdf\n\n———. 2017. HIV drug resistance report 2017. Geneva: World Health Organization. http://apps. who.int/iris/bitstream/handle/10665/255896/9789241512831-eng.pdf;jsessionid=9AFD8 EB2096DEF42908467A854A90A9E?sequence=1\n\n———. 2018. WHO HIV data and statistics. http://www.who.int/hiv/data/en\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\nB. Haire", "n_tokens": 298, "kind": "text"}
{"chunk_id": "drug_resistance_book-70-0", "doc_id": "drug_resistance_book", "page": 70, "text": "Chapter 4 Ethics and Antimalarial Drug Resistance", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-70-1", "doc_id": "drug_resistance_book", "page": 70, "text": "Phaik Yeong Cheah, Michael Parker, and Nicholas P. J. Day\n\nAbstract There has been impressive progress in malaria control and treatment over the past two decades. One of the most important factors in the decline of malaria- related mortality has been the development and deployment of highly effective treatment in the form of artemisinin-based combination therapies (ACTs). However, recent reports suggest that these gains stand the risk of being reversed due to the emergence of ACT resistance in the Greater Mekong Subregion and the threat of this resistance spreading to Africa, where the majority of the world’s malaria cases occur, with catastrophic consequences. This chapter provides an overview of strate- gies proposed by malaria experts to tackle artemisinin-resistant malaria, and some of the most important practical ethical issues presented by each of these interven- tions. The proposed strategies include mass antimalarial drug administrations in selected populations, and mandatory screening of possibly infected individuals prior to entering an area free of artemisinin-resistant malaria. We discuss ethical issues such as tensions between the wishes of individuals versus the broader goal of\n\nP. Y. Cheah (*) Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand\n\nCentre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-70-2", "doc_id": "drug_resistance_book", "page": 70, "text": "The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK e-mail: Phaikyeong@tropmedres.ac\n\nM. Parker The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK\n\nWellcome Centre for Ethics and Humanities, Nuffield Department of Population Health, University of Oxford, Oxford, UK e-mail: michael.parker@ethox.ox.ac.uk\n\nN. P. J. Day Mahidol Oxford Tropical Medicine Research Unit (MORU), Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand\n\nCentre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_4\n\n55", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-71-0", "doc_id": "drug_resistance_book", "page": 71, "text": "56\n\nP. Y. Cheah et al.\n\nmalaria elimination, and the risks of harm to interventional populations, and con- clude by proposing a set of recommendations.\n\n4.1", "n_tokens": 38, "kind": "text"}
{"chunk_id": "drug_resistance_book-71-1", "doc_id": "drug_resistance_book", "page": 71, "text": "The Problem, Context and Background\n\nMalaria is the most important parasitic disease of man. It remains a major cause of death in tropical countries, and an important cause of illness, particularly in child- hood. There were an estimated 435,000 deaths from malaria in 2017, of which over 90% were in Africa (Global Malaria Programme, World Health Organization 2018). Although there has been impressive progress in malaria control and treatment over the past two decades in recent years progress has stalled and there has been a resur- gence of malaria in Southeast Asia, where antimalarial drug resistance is increas- ingly prevalent (Global Malaria Programme, World Health Organization 2018). One of the most important factors in the decline of malaria related mortality since the 1990s has been the development and deployment of highly effective treatment in the form of artemisinin-based combination therapies (ACTs) (Bhatt et al. 2015). ACTs are currently the mainstay of antimalarial treatment throughout the world, recommended by the World Health Organization as the first line treatment globally for falciparum malaria (World Health Organization 2016a). Their widespread deployment, along with the expanded use of insecticide treated bed nets, accounts for a large part of the reduction in malaria deaths in Africa over the past decade (White et al. 2014).", "n_tokens": 273, "kind": "text"}
{"chunk_id": "drug_resistance_book-71-2", "doc_id": "drug_resistance_book", "page": 71, "text": "The effectiveness of current and future interventions are, however, at risk from the emergence of new forms of drug resistance. In the early 2000s malaria parasites that were partially resistant to the artemisinins emerged in Western Cambodia. The problem was identified and characterised in 2008 (Dondorp et al. 2009; Noedl et al. 2008). The hallmark of infection by these resistant parasites was slow parasite clear- ance rather than outright treatment failure (Dondorp et al. 2009). These slow clear- ing infections were associated with mutations in the PfKelch13 gene, with multiple PfKelch13 mutations described (though each parasite only carried one) (Ariey et al. 2014). By 2014 slow clearing malaria infections caused by PfKelch13 mutation- carrying artemisinin resistant parasites could be found in Myanmar, Laos, Thailand, Vietnam and Yunnan province in China, and by 2016 Pfkelch13 mutants were iden- tified in Arunachal Pradesh state in northeastern India (Ashley et al. 2014; Tun et al. 2016; Mishra et al. 2016).", "n_tokens": 226, "kind": "text"}
{"chunk_id": "drug_resistance_book-71-3", "doc_id": "drug_resistance_book", "page": 71, "text": "The initial response to the emergence of artemisinin resistance had two aspects. The major concerns were that: i. artemisinin resistance might lead to or combine with partner drug resistance resulting in resistance to ACTs. That is, to the loss of the drug combinations that are the mainstay of malaria treatment; and ii. that were this to be the case, artemisinin resistance and then ACT resistance then has the potential to spread from Southeast Asia to Africa, where the majority of the world’s malaria cases occur, with catastrophic consequences. There are precedents for this", "n_tokens": 115, "kind": "text"}
{"chunk_id": "drug_resistance_book-72-0", "doc_id": "drug_resistance_book", "page": 72, "text": "4 Ethics and Antimalarial Drug Resistance\n\nlatter concern; in the last 60 years first chloroquine resistance and then sulfadoxine- pyrimethamine resistance arose in Western Cambodia and subsequently spread to Africa, leading to millions of deaths (Verdrager 1986; Roper et al. 2004; Trape et al. 1998).\n\nRecognizing the risks and consequences of spread to Africa, the World Health Organization initially developed a plan to contain rather than eliminate the problem (World Health Organization 2011). However, this approach was criticized by some at the time who called for initiatives aimed at eliminating all malaria in the Greater Mekong Subregion, on the grounds that the resistant parasites were in fact already at that stage contained (Dondorp et al. 2017). They argued that the view that elimi- nation would be an appropriate strategy was supported by mathematical modelling that showed that as malaria was controlled and transmission fell, the proportion of infections that were resistant would increase – the ‘last man standing’ would be resistant (Maude et al. 2012). This modelling suggested that resistance could not be eliminated without eliminating all malaria in the affected regions.", "n_tokens": 237, "kind": "text"}
{"chunk_id": "drug_resistance_book-72-1", "doc_id": "drug_resistance_book", "page": 72, "text": "Bolstered by advocacy for global malaria eradication by the Bill and Melinda Gates Foundation, the WHO did eventually change its policy from containment to one of elimination (Global Malaria Programme WHO 2015), but the discovery through molecular studies that PfKelch13 mutations had arisen spontaneously and independently multiple times within the Greater Mekong Subregion (GMS) led to what some saw as a reduction in the urgency to eliminate malaria to prevent the ‘spread’ of resistant parasites (Takala-Harrison et al. 2015). Surveillance for resis- tance and an aim to eliminate malaria everywhere was now the policy of WHO (World Health Organization 2017; Global Malaria Programme WHO 2016). This necessarily spread resources more widely and reduced the focus on drug resistance. Despite this there has been considerable investment in malaria control and elimina- tion efforts in the GMS, with at least initially substantial reductions in malaria trans- mission (Dondorp et al. 2017). These successes have, however, to some extent masked the continued threat of increasingly drug resistant malaria parasites emerg- ing and spreading in the region – as the mathematical modelling had predicted (Maude et al. 2009) – with outbreaks of artemisinin-resistant malaria occurring in areas previously considered malaria free (Imwong et al. 2015).", "n_tokens": 267, "kind": "text"}
{"chunk_id": "drug_resistance_book-72-2", "doc_id": "drug_resistance_book", "page": 72, "text": "In the 10 years since the first description of artemisinin resistance the concern that ACT resistance and failure would develop has come to pass, with rising meflo- quine resistance on the Thai-Myanmar border and piperaquine resistance in Cambodia, Thailand, Southern Laos and Viet Nam (Phyo et al. 2016a; Amaratunga et al. 2016; Imwong et al. 2017). Recent evidence that most of the resistance to dihydroartemisinin-piperaquine is due to the geographical spread of a particularly fit artemisinin-resistant parasite clone which has picked up piperaquine resistance has rekindled the debate about whether urgent focus should be placed on an acceler- ated effort to eliminate artemisinin-resistant malaria in Southeast Asia, with the aim to Africa (World Health of preventing Organization 2016b).\n\nthe spread of ACT resistance\n\nAlthough the global pipeline for new malaria drugs in development is healthier than it has been for decades, all the most promising candidates (schizonticidals, that\n\n57", "n_tokens": 219, "kind": "text"}
{"chunk_id": "drug_resistance_book-73-0", "doc_id": "drug_resistance_book", "page": 73, "text": "58\n\nP. Y. Cheah et al.\n\nkill the asexual blood stage of the parasite which causes the clinical manifestations of malaria) are at least five years away from being available in the market (Phyo et al. 2016b). The RTS,S/AS01 malaria vaccine which recently received a favour- able scientific opinion from the European Medicines Agency (EMA) is only par- tially protective (Vandoolaeghe and Schuerman 2018). This means that protecting the efficacy of the currently available antimalarial drugs is of global importance. The spread of ACT resistance to Africa would threaten the loss of millions of lives, especially those of young African children. This will be a global health issue – untreatable malaria worldwide arising from resistance in Southeast Asia. A problem arising in a specific location that has the potential to threaten global health is not unique to malaria. Many ‘global health problems’ arise in low-income settings, for example outbreaks of Ebola in West Africa and Zika in South America, and are recognized as having worldwide implications. In the case of Ebola and Zika the World Health Organization formally declared a ‘Public Health Emergency of International Concern’ (PHEIC), but for the emergence of artemisinin resistant malaria in Southeast Asia WHO has as of 2018 declined to do this despite some experts calling for it to do so (World Health Organization 2016b; Talisuna et al. 2012).\n\n4.1.1", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-73-1", "doc_id": "drug_resistance_book", "page": 73, "text": "How Should the Problem of Artemisinin Resistant Malaria be Tackled?\n\nThere is now broad agreement amongst experts that to prevent the spread of artemisinin- resistant P. falciparum it is necessary to completely interrupt P. falci- parum transmission (Maude et al. 2009), and that a programme of accelerated malaria elimination is warranted in the GMS and surrounding areas. The scientific consensus is that a combination of strategies is required to achieve this (Dondorp et al. 2017; World Health Organization 2017). These include:\n\n1. Ongoing surveillance with a network of village malaria workers (VMWs) in endemic areas trained and equipped to provide early detection and treatment of malaria cases.\n\n2. Targeting of the asymptomatic malaria reservoir in so called malaria ‘hotspots’, identified through surveys of healthy individuals employing highly sensitive methods of parasite detection such as large volume quantitative PCR and highly sensitive rapid diagnostic tests (RDTs). This may take two forms: a. Mass drug administration (MDA) -WHO agrees that targeted mass antima- larial drug administration may play an important role in malaria elimination (World Health Organization, Global Malaria Programme 2015a).\n\nb. Mass screening and treatment (MSAT) using novel highly sensitive\n\ndiagnostics.", "n_tokens": 263, "kind": "text"}
{"chunk_id": "drug_resistance_book-74-0", "doc_id": "drug_resistance_book", "page": 74, "text": "4 Ethics and Antimalarial Drug Resistance\n\n3. Vector control with insecticide treated bed nets, despite these being less effective in the GMS than in Africa because of the biting habits of many of the vector spe- cies (biting in the forest rather than in houses, and in the early evening or morning).\n\n4. Targeting ‘source’ populations such as forest workers and migrants, rather than ‘sink’ populations secondarily affected. This requires an understanding of trans- mission dynamics and population movements – important in the GMS where cross border movement/migration is common.\n\n5. Mandatory screening may be necessary of possibly infected individuals entering an area free of artemisinin-resistant malaria (Houston and Houston 2015; Tatarsky et al. 2011).", "n_tokens": 154, "kind": "text"}
{"chunk_id": "drug_resistance_book-74-1", "doc_id": "drug_resistance_book", "page": 74, "text": "6. Use of effective antimalarial treatments. Most currently approved ACTs consist of only two drugs (a fast acting short half-life artemisinin and a longer half-life partner drug) and are vulnerable to the development of resistance. The testing and deployment of new triple artemisinin-based combination therapies (TACTs) has been recommended, and several of these are currently being tested in the GMS and beyond (Dondorp et al. 2017). In the face of the global threat posed by increasing ACT resistance, there is there- fore now an emerging expert consensus that the combination of strategies outlined above is the most effective way of halting or slowing its international spread provide strong ethical arguments for their rapid adoption. Each of the interventions listed above present a wide range of interconnected challenges – including, scientific, technological, governmental, economic and ethical – all of which will need to be overcome if the elimination of malaria in the region is to be achieved. In addition to these practical scientific, and political challenges, the success of each of the inter- ventions also depends upon the addressing of a number of important practical ethi- cal questions, which need to be taken into account in their design and implementation. In the next section, we outline some of the most important practical ethical issues presented by each of the interventions proposed above.\n\n4.2\n\nPractical Ethical Issues Arising in These Interventions\n\n4.2.1", "n_tokens": 287, "kind": "text"}
{"chunk_id": "drug_resistance_book-74-2", "doc_id": "drug_resistance_book", "page": 74, "text": "Ongoing Surveillance\n\nIn many countries in the Greater Mekong Subregion, networks of VMWs are the cornerstone of malaria surveillance and the delivery of malaria-related interven- tions. These networks are usually run either directly by the national malaria control programmes (NMCPs) or by NGOs working with the NMCPs, but may also be put in place by private providers such as companies running palm oil plantations. The coverage of such networks has increased impressively in many areas in SEA, par- ticularly in border areas, conflict zones and areas underserved by government health programmes. VMWs are consulted by villagers suffering from fever, and are\n\n59", "n_tokens": 133, "kind": "text"}
{"chunk_id": "drug_resistance_book-75-0", "doc_id": "drug_resistance_book", "page": 75, "text": "60\n\nP. Y. Cheah et al.", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-75-1", "doc_id": "drug_resistance_book", "page": 75, "text": "equipped with RDTs and antimalarial treatments. Where a substantial proportion of febrile illnesses are indeed caused by malaria VMWs are a valuable resource for the local population. However, the success of malaria control and elimination efforts increasingly means that a diminishing proportion of the febrile illnesses they encounter are caused by malaria. Unfortunately, VMWs are not usually equipped to deal with these alternative causes of illness. This means that as malaria rates decline there is a risk that villagers will cease consulting VMWs as more of them are told that because their fever is not clinical malaria infection, no diagnosis or treatment of the cause of their illness is available or offered. Unless these village workers are retrained for a wider role as ‘village health workers’ able to manage other febrile illnesses or simple primary health problems, they will become increasingly irrele- vant and demotivated. The consequences of this would be diminishing effectiveness of the malaria surveillance network itself, at the point in the elimination process when it is most needed and, in the absence of a wider role, for the goal of malaria elimination becoming a disincentive for the VMWs (and NMCPs), for many of whom being a VMW is a source of their livelihood. This suggests that, even if the elimination of malaria is the primary goal, there are strong arguments in favour of the provision of resources for access to health care beyond malaria in the region.\n\n4.2.2", "n_tokens": 304, "kind": "text"}
{"chunk_id": "drug_resistance_book-75-2", "doc_id": "drug_resistance_book", "page": 75, "text": "Mass Drug Administration (MDA)\n\nMDA in the context of malaria elimination consists of mass treatment with a schi- zonticide to kill the asexual blood stage of the parasite which causes the clinical manifestations of malaria combined with a transmission blocking drug to kill game- tocytes. Giving such treatment to all members of a community should eliminate the asymptomatic parasite reservoir and speed up the interruption of malaria transmis- sion. Where and when it is warranted has been the subject of much debate, but the consensus is that MDA should be targeted at communities with high transmission and a large asymptomatic reservoir (World Health Organization 2011; von Seidlein and Dondorp 2015). This requires a functioning surveillance system to identify such communities, with surveys of healthy individuals with highly sensitive tests to esti- mate accurately the scale of the asymptomatic reservoir.", "n_tokens": 184, "kind": "text"}
{"chunk_id": "drug_resistance_book-75-3", "doc_id": "drug_resistance_book", "page": 75, "text": "There are a number of important ethical considerations when determining when and where to use MDA. The first of these arises out of the fact that MDA by its nature involves administering drugs to individuals who will not benefit directly from the treatment, i.e. to healthy people in the interests of the wider community and the broader goal of elimination. In the case of transmission blocking drugs this is the entire community, and for the schizonticidal drugs this is the substantial pro- portion of the community who are not infected with malaria parasites. However, if the MDA is effective and malaria is eliminated from the area, all individuals will benefit indirectly by living in a malaria free community. In the GMS the", "n_tokens": 142, "kind": "text"}
{"chunk_id": "drug_resistance_book-76-0", "doc_id": "drug_resistance_book", "page": 76, "text": "4 Ethics and Antimalarial Drug Resistance\n\nschizonticide currently used in MDA is dihydroartemisinin-piperaquine (DP), which in the treatment of malaria is considered a safe drug. Studies of the safety of DP in this context have shown that DP is safe (Tripura et al. 2018), but widespread deployment of DP exposes much larger numbers of individuals such that its rare but serious side effects may occur (Cheah and White 2016). The transmission blocking drug currently used in MDA is primaquine, which targets the transmissible sexual gametocytes not killed by the schizonticide but has little or no impact on the asexual parasites which cause disease. Primaquine is an oxidative drug which causes hae- molysis (the rupture of red blood cells) in G6PD-deficient individuals (median 8% of the population in malaria endemic areas) when given in the large doses needed to radically cure vivax malaria (killing the hypnozoites in the liver) (Howes et al. 2012). However to kill gametocytes (rather than cure malaria) a single much lower dose is required, one considered safe to be administered to all individuals without prior G6PD testing (World Health Organization, Global Malaria Programme 2015b; Bancone et al. 2016).", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-76-1", "doc_id": "drug_resistance_book", "page": 76, "text": "A second ethically significant consideration is a worry that there is a risk that with the widespread deployment of antimalarial drugs in MDA the resulting increased drug pressure may itself lead to drug resistance, particularly in the case where elimination is not achieved. It has been argued on theoretical grounds that this is unlikely, but the risk however low highlights the importance of achieving elimination in areas where MDA is deployed (White 2017). This suggests that the initiation of MDA is only ethically justified where there is a genuine commitment to complete the elimination task. Once the process of MDA has begun, important ethi- cal issues are presented relating to the question of when such an initiative should be ended.", "n_tokens": 140, "kind": "text"}
{"chunk_id": "drug_resistance_book-76-2", "doc_id": "drug_resistance_book", "page": 76, "text": "Thirdly, the effectiveness of MDA is predicated upon high population coverage (World Health Organization 2017; Newby et al. 2015). Achieving this is a challenge for several reasons: explaining the rationale for taking antimalarials when asymp- tomatic can be difficult in the absence of an understanding of the underlying scien- tific concepts, target communities are often remote with poor access and populations can be highly mobile. For these reasons, effective community engagement efforts are essential, so that individuals are informed of the risks and benefits of malaria elimination efforts in general and MDA in particular (Adhikari et al. 2016; Peto et al. 2018). For effective community engagement those implementing MDA need to understand and adapt the information they provide and the form of the engage- ment they adopt, to the cultural and practical requirements of each community. Engagement with community leaders is essential, and coverage can be promoted by offering healthcare alongside MDA (Sahan et al. 2017; Pell et al. 2017). Effective community engagement may also minimize risks of coercion or counterproductive misunderstanding of the aims of the public health authorities (Parker and Allen 2013). The ethical issues around these concerns are similar in some respects to those encountered in the context of vaccination campaigns.\n\n61", "n_tokens": 267, "kind": "text"}
{"chunk_id": "drug_resistance_book-77-0", "doc_id": "drug_resistance_book", "page": 77, "text": "62\n\nP. Y. Cheah et al.\n\n4.2.3\n\nMass Screening and Treatment (MSAT)\n\nMass screening and treatment of village populations has been suggested as an alter- native strategy to MDA for speeding up malaria elimination. Its advantage over MDA is that only those individuals with proven asymptomatic malaria infection will be exposed to antimalarial drugs and their attendant risks, negating many of the ethical concerns described in the MDA section above. However, the likely success of this is limited by the sensitivity of the tests available for detecting low levels of parasites in the blood. Because the current tests are laboratory based there is inevi- tably considerable delay between sampling and result, which appears to limit the effectiveness of MSAT (von Seidlein 2014). Highly sensitive rapid diagnostic tests have now been developed, but these are only now being tested in the field (Slater et al. 2015). Such tests have the potential to be much quicker but they are not as sensitive as the laboratory based tests, and it possible that up to half of asymptom- atic carriers will be ‘missed’. However, the contribution to malaria transmission of individuals with very low parasitaemias at the time of testing is uncertain, and the results of studies of the field effectiveness of MSAT with highly sensitive RDTs are awaited with interest. If MSAT with highly sensitive RDTs does turn out to be effec- tive, effective community engagement will be as important as it is with MDA.\n\n4.2.4", "n_tokens": 318, "kind": "text"}
{"chunk_id": "drug_resistance_book-77-1", "doc_id": "drug_resistance_book", "page": 77, "text": "Vector Control\n\nThe distribution of insecticide treated nets (ITNs) in Africa has had a major impact on malaria there, and as a result it has become almost an article of faith in the global malaria community that ITNs should be considered the most important single inter- vention in the battle against malaria (Bhatt et al. 2015). In a WHO-sponsored meet- ing on tackling artemisinin resistant malaria in the GMS the chairman suggested that all the additional resources being made available to counter resistance in the region should be spent on ITNs (NPJD personal communication). Unfortunately, Southeast Asian malaria vectors and populations do not behave like African vectors and populations, with most transmission occurring in the forest rather than in dwell- ings (Gryseels et al. 2015; Smithuis et al. 2013a). Several studies have now con- firmed the limited efficacy of bed nets in malaria elimination effort in this region (Smithuis et al. 2013b; Satitvipawee et al. 2012). An important ethical issue here is around resource allocation, and overcoming established (but not evidence-based) pro-ITN sentiment amongst international and national policy makers. ITNs do have an important role to play and are relatively cheap to deploy, but given the evidence of differences in vector behaviours in Africa and the GMS, the relative allocation of limited resources should be driven by evidence-based health economics studies (Drake et al. 2015).", "n_tokens": 300, "kind": "text"}
{"chunk_id": "drug_resistance_book-78-0", "doc_id": "drug_resistance_book", "page": 78, "text": "4 Ethics and Antimalarial Drug Resistance\n\n4.2.5\n\nTargeting ‘Source’ Populations", "n_tokens": 19, "kind": "text"}
{"chunk_id": "drug_resistance_book-78-1", "doc_id": "drug_resistance_book", "page": 78, "text": "In the GMS, malaria transmission is concentrated in poor, hard-to-reach, highly mobile populations. Transmission is mainly occupationally related, highest among men who travel into forested areas to work. Many of the most at-risk populations are disenfranchised minority groups, often living in border regions, with little or no health infrastructure. Understanding the drivers of transmission in these populations entails acquiring better knowledge of population movement/migration, much of which is ‘illegal’. Working with these populations requires sensitivity not only to the cultural contexts but also to the uncertain legal status of many of the individuals. Several of the more endemic areas are mired in armed conflicts, and many popula- tions are vulnerable as refugees or economic migrants without papers. The area currently with the highest endemicity in the GMS, for example, is Rakhine State in Myanmar, currently undergoing considerable civil strife and large-scale movement of populations. NGOs, government workers and researchers have to work within their own externally determined constraints, limiting their ability to engage ‘source’ populations. Even if the not inconsiderable task of eliminating malaria from many of these areas were to be achieved, political difficulties, the mobile nature of these populations, and changes in the ability to access them would leave them vulnerable to the reintroduction of malaria. Furthermore, as immunity will have waned because of the", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-78-2", "doc_id": "drug_resistance_book", "page": 78, "text": "intervention the public health consequences of this reintroduction could potentially be worse than if malaria had not been eliminated in the first place.", "n_tokens": 26, "kind": "text"}
{"chunk_id": "drug_resistance_book-78-3", "doc_id": "drug_resistance_book", "page": 78, "text": "4.2.6\n\nMandatory Screening\n\nThere are a number of situations in which mandatory screening for asymptomatic malaria may be indicated to prevent individuals unwittingly spreading drug resistant malaria parasites. Following the disastrous importation of cholera into Haiti by African UN peacekeepers (leading to 8300 deaths), for example, a call has been made for Southeast Asian Peacekeepers to be screened for malaria before they travel to missions in Africa (Houston and Houston 2015). This would prevent peacekeep- ers from importing drug resistant malaria to a drug sensitive region, and could be implemented by the UN. Another situation where mandatory screening could poten- tially be introduced in the context of eliminating artemisinin-resistant malaria within the GMS, would be screening local people moving between areas where malaria has and has not been eliminated. Although practically difficult to imple- ment, this has the potential to be of real importance in geographical locations with highly mobile populations – such as along the Thai-Myanmar Border. There are a number of practical barriers to implementing such a policy, which make it unlikely to be introduced at present. However, its possibility raises important ethical ques- tions about the legitimacy of overriding personal autonomy in the global public interest and its limits.\n\n63", "n_tokens": 258, "kind": "text"}
{"chunk_id": "drug_resistance_book-79-0", "doc_id": "drug_resistance_book", "page": 79, "text": "64\n\nP. Y. Cheah et al.\n\n4.2.7\n\nTriple Artemisinin Combination Therapies (TACTs)\n\nThe rationale for TACTs is similar to that of triple or quadruple therapy in HIV, tuberculosis, leprosy and other infectious diseases – to prevent the development of resistance. Two TACTs are currently being studied in 16 sites in Asia and 1 site in Africa (web identifier: NCT02453308): dihydroartemisinin-piperaquine + meflo- quine; and artemether-lumefantrine + amodiaquine. The combination of a short act- ing artemisinin with two long acting partner drugs ensures that parasites are less likely to encounter only one long acting partner drug at any one time, minimizing the chance of resistance developing. In addition, it is hypothesized that these triple therapies could exploit potential inverse relationships between the parasite molecu- lar resistance mechanisms to the paired long-acting partner drugs. It is thought that the wide implementation of triple therapy in malaria will slow the spread of multidrug- resistant malaria in areas where artemisinin and partner drug resistance is well established, and slow down or prevent the emergence of drug resistance in areas where resistance has not yet emerged. It is in the latter case where TACTs should be most effective.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-79-1", "doc_id": "drug_resistance_book", "page": 79, "text": "There are several ethical issues to be considered here. TACTs differ from other examples of combination therapy in that the objective is to prevent antimalarial drug resistance at the population rather than at the individual level. Unlike in chronic infections such as TB and HIV development of ACT resistance within an individual patient during treatment is rare. Hence individuals are potentially exposed to the additional side effects of three rather than two drugs for little or no benefit to them- selves; it is against the interest of the individual patient (usually a child) to take three rather than two drugs. If the strategy works the benefit will be to the population, which will only indirectly benefit the individual. In addition, TACTs are expected to be most effective at countering resistance in areas where resistance has not yet developed to any of the components, so that the long acting partner drugs will pro- tect each other from the development of resistance and both will protect the short acting artemisinin component. Hence the areas where they will be most effective will be the ones where currently ACTs remain highly effective at the individual level. Preliminary evidence of triple therapy is promising but safety and efficacy data are not widely available yet. Even if evidence is available, populations where ACTs still work such as in Africa where the majority of malaria cases are in children under five, may not readily change their prescribing behaviours. Other", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-79-2", "doc_id": "drug_resistance_book", "page": 79, "text": "practical problems might be access to the triple therapy, availability of co-formulated drugs and the problem of substandard and falsified drugs especially in the private and informal sectors (Liverani et al., Chap. 5, this volume).", "n_tokens": 51, "kind": "text"}
{"chunk_id": "drug_resistance_book-80-0", "doc_id": "drug_resistance_book", "page": 80, "text": "4 Ethics and Antimalarial Drug Resistance\n\n4.3\n\nSummary of Ethical Considerations\n\nAbove we have attempted to illustrate the ethical complexity of the implementation of the strategies widely agreed by experts to be necessary for the control of resis- tance to antimalarial drugs. It is clear that there are strong ethical arguments in favour of the implementation of such strategies in the global public interest. However, the considerations outlined above suggest that such interventions raise important ethical questions both about the nature and scope of implementation itself and about the obligations of countries both outside and within the region to those who are to bear its costs. The success of an elimination strategy based on these ele- ments will depend upon these problems being addressed. In the remainder of this chapter, we summarise what we consider to be some of the most important ethical tensions and outline some preliminary thoughts about ways these might be addressed.\n\n4.3.1\n\nAutonomy and Consent Versus the Global Benefit", "n_tokens": 190, "kind": "text"}
{"chunk_id": "drug_resistance_book-80-1", "doc_id": "drug_resistance_book", "page": 80, "text": "There are a number of different ways in which the implementation of the interven- tion strategies above raises important questions about respect for autonomy. In some cases, these interventions may lead to tensions between the interests and wishes of individuals and the global benefit. During implementation of each strategy, individu- als in selected communities are subjected to interventions – ‘treatment’ or surveil- lance – not for their own good but for the common good of current and future populations both locally and internationally (see discussion on common goods in Chaps. 8 and 9) (Jamrozik and Selgelid, Chap. 1, this volume-a; Smith and Coast, Chap. 17, this volume). Under current circumstances, such interventions are volun- tary: making MDA compulsory or imposing travel restrictions on people who have come from areas with artemisinin resistant malaria is not considered achievable or justified at present. However, it is possible that as in other global health contexts this judgement might change and that individuals may lose their right to opt out of, for example, MDA. Draconian measures have been taken to contain dangerous conta- gions such as H5N1 influenza, SARS, MERS-CoV, Ebola virus, Lassa fever, and multidrug-resistant tuberculosis, which involved restriction of liberty in order to protect the public. Were compulsory approaches to be considered in the context of malaria, this would present important questions about the legitimacy of restrictions of liberty per", "n_tokens": 311, "kind": "text"}
{"chunk_id": "drug_resistance_book-80-2", "doc_id": "drug_resistance_book", "page": 80, "text": "se but also questions about how this was in fact undertaken, and about the nature of the obligations of the wider global community – particularly wealthy countries – to those who are subjected to such interventions in the global health interest.", "n_tokens": 43, "kind": "text"}
{"chunk_id": "drug_resistance_book-80-3", "doc_id": "drug_resistance_book", "page": 80, "text": "65", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-81-0", "doc_id": "drug_resistance_book", "page": 81, "text": "66\n\nP. Y. Cheah et al.\n\nQuestions about autonomy also arise in the context of voluntary approaches. Where individuals and their communities are being asked to decide about participa- tion in the strategies outlined above, it is vital that best efforts are made to ensure that any consent they give is grounded in a good understanding of the implications. However, the evidence is that valid consent is likely to be difficult to achieve in such contexts. This places particular importance on the roles of wider communication, community participation, political involvement and other forms of public engage- ment preceding and during the intervention. It has to be acknowledged that even in the context of well-resourced, evidence-based approaches to consent and commu- nity engagement, understanding is likely to be partial given the complexities of malaria transmission and how these inventions work. This need not mean that the choice to participate is invalid but it does mean that the moral basis for the interven- tion cannot rest on consent alone, even when the choice to participate is voluntary. This suggests that those who are responsible for the conduct of such strategies have obligations to ensure that they are conducted to high ethical standards, and that appropriate protections, and possibly compensation, are in place.\n\n4.3.2\n\nRisk Benefit", "n_tokens": 256, "kind": "text"}
{"chunk_id": "drug_resistance_book-81-1", "doc_id": "drug_resistance_book", "page": 81, "text": "The potential benefits of malaria elimination are substantial, including the direct burden averted and economic growth through improved educational attainment and productivity; these gains were estimated recently to far outstrip the costs required to achieve them (Purdy et al. 2013). That said it is clear from the discussion above that those who bear the consequences of malaria elimination efforts are not those who will benefit directly. The majority of the populations with the highest prevalence of resistant malaria and of submicroscopic malaria in Southeast Asia are poor and mobile forest workers (Phommasone et al. 2016; Tripura et al. 2017). This is unsur- prising as vulnerability to malaria – as is also true of many other infectious dis- eases – is largely a consequence of social determinants of health such as poverty, malnutrition and insufficient access to healthcare. Malaria burden is both a conse- quence and an illustration of global inequities. These populations are already bur- dened by their circumstances and environments. Yet they are the very individuals who will likely to be shouldering the burdens of any global intervention to curb resistant malaria. In the case of MDA, entire communities are treated whether or not they are unwell with malaria. That means that many individuals who are neither ill nor carriers of the parasite will be asked (or required) to take drugs and therefore be at some risk of potential adverse drug reactions. This uneven distribution of", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-81-2", "doc_id": "drug_resistance_book", "page": 81, "text": "indi- vidual risks and inconveniences – that is individuals in SEA shouldering the burden for the benefit of good health outcomes primarily in the interests of populations elsewhere – is a key moral challenge. Whilst at the macroeconomic level the costs of malaria elimination are outweighed by the benefits, this may well not be true at the level of the individuals involved. Important ethical questions concern the ques- tion of when, if at all, the imposition of risks of harm on (often vulnerable)", "n_tokens": 106, "kind": "text"}
{"chunk_id": "drug_resistance_book-82-0", "doc_id": "drug_resistance_book", "page": 82, "text": "4 Ethics and Antimalarial Drug Resistance\n\nindividuals is legitimate in the interests of others and the limits of this. The ethical questions here concern not only those related to whether the imposition of such burdens is justified but also, where this is the case, both the approach adopted to such implementation and the nature and scope of our obligations to those upon whom it is imposed. Is there, for example, an obligation to compensate such populations?\n\n4.3.3\n\nData and Sample Sharing", "n_tokens": 97, "kind": "text"}
{"chunk_id": "drug_resistance_book-82-1", "doc_id": "drug_resistance_book", "page": 82, "text": "Ethical issues also arise with regard to the international collaboration required to ensure high scientific and public health standards in the interventions. This is impor- tant because it is the achievement of such high standards (and hence the potential for success) that justify the imposition of risks and restrictions of liberty on vulnerable populations. In order to make the most informed decisions about planning interven- tions to eliminate malaria, there is a need to ensure that there is access to as much good quality data as possible. That is, it depends crucially upon data sharing. However, there is generally a lack of transparency and confidence in the quality of available malaria data. This can be due to poor quality data and underreporting of cases, which can in turn be due to variable availability of diagnostic tools such as rapid diagnostic tests and blood slides, unsurprising given that data are frequently collected under resource-starved conditions. This contributes to the lack of trust in the data on antimalarial resistance, and in the data used in mathematical modeling and the resulting predictions. An additional key problem is that many national malaria control programmes do not readily share their malaria data for political, economic and national security reasons. Data related to population movement and migration that could aid interventions such as MDA and engagement with “source populations” are, for example, particularly difficult to access. Although", "n_tokens": 273, "kind": "text"}
{"chunk_id": "drug_resistance_book-82-2", "doc_id": "drug_resistance_book", "page": 82, "text": "there is advantage in data sharing, it is also acknowledged that it can pose a number of ethi- cal challenges around issues of privacy, potential stigma and economic harms (Mishra et al. 2016; Bull et al. 2015; Cheah et al. 2015). This suggests that questions about the ethical tensions between the interests of individuals and the global health interest also arise at the level of institutions, health ministries, and countries.", "n_tokens": 88, "kind": "text"}
{"chunk_id": "drug_resistance_book-82-3", "doc_id": "drug_resistance_book", "page": 82, "text": "4.3.4\n\nScientific Disagreement About the Best Way Forward\n\nWe outlined a number of proposed interventions above, and given the current state of the evidence there are valid debates in the scientific community about what action or actions are appropriate where. Interventions such as TACTs and MDA are still under study. An important, as yet unresolved, scientific debate is about the way resistance spreads or emerges. There are data supporting both sides of the argu- ment – geographical spread of sporadic vs. spontaneous distributed emergence (Lu\n\n67", "n_tokens": 105, "kind": "text"}
{"chunk_id": "drug_resistance_book-83-0", "doc_id": "drug_resistance_book", "page": 83, "text": "68\n\nP. Y. Cheah et al.\n\net al. 2017). However, there is also a limited window of opportunity to act. There are strong moral reasons for acting to prevent the spread of resistance both within and beyond Southeast Asia. Inaction will almost inevitably lead to a repeat of history – the loss of safe, inexpensive and highly effective treatments and an increase in cases of severe malaria and related deaths. It may also mean that a once in a generation opportunity, capitalizing on the combination of the availability of political will and effective tools to take a big step towards the eradication of malaria, will have been missed. There remains, however, a degree of scientific uncertainty. This raises ethi- cal questions about the level of scientific consensus required for action. Understanding is likely to remain imperfect. Is it legitimate to initiate strategies such as those outlined above on the basis of good but imperfect understanding? The answer to this question cannot be ‘never’ because there is widespread agreement about the urgency of the situation and a residual degree of scientific uncertainty will always remain.\n\n4.4", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-83-1", "doc_id": "drug_resistance_book", "page": 83, "text": "Conclusions\n\nIn this chapter, we have described practical ethical issues arising in currently pro- posed interventions (and the lack of them) to reduce the risk of the movement of resistance to the current best antimalarial drugs from Southeast Asia to Africa, as well as to prevent resistance emerging in Africa. Whilst strong ethical reasons for such interventions are provided by the seriousness and scale of the threat and the existence of a degree of scientific consensus on this strategy, its implementation is ethically complex. We have outlined some of the most important practical ethical problems presented by each of possible components of the proposed strategy, and have also argued that even if the various interventions were to be ethically justified this would not be the end of the ethical debate. We have argued that important ethi- cal questions about the mode of implementation of the interventions and about the obligations of the wider community to those they affect would remain.", "n_tokens": 178, "kind": "text"}
{"chunk_id": "drug_resistance_book-83-2", "doc_id": "drug_resistance_book", "page": 83, "text": "Some of the most important of such considerations are those relating to fairness in the selection of interventional populations. All populations which meet a set of criteria for an intervention, be it MDA, TACT or travel restrictions, should where practical have the same intervention. The intervention should be evidence-based and justified, and all relevant stakeholders should be involved in the decision- making process and have meaningful input into the deliberations. The manner and context in which decisions are made should be reasonable, fair and transparent.\n\nIn addition to ethical considerations relating to the selection of such populations, we have argued that important obligations exist for those countries and governments that can afford it to assist and perhaps to compensate those individuals who are subject to such interventions and may experience harms as a result of their partici- pation (Upshur 2002). Meeting these obligations may call for the provision of com- pensation, for example where businesses suffer due to lack of mobility or where people suffer from side effects of MDA. Or perhaps, in the form of community level", "n_tokens": 210, "kind": "text"}
{"chunk_id": "drug_resistance_book-84-0", "doc_id": "drug_resistance_book", "page": 84, "text": "4 Ethics and Antimalarial Drug Resistance\n\nbenefits such as improved healthcare facilities. An important aspect of the obliga- tions of the wider world to those who live in the region is that any intervention is well-planned and adequately resourced. It is clear that curbing antimalarial resis- tance, similar to resistance of other antimicrobials, is both a global priority and a global responsibility (Jamrozik and Selgelid, Chap. 1, this volume-b). Both scien- tifically and in terms of effective public health interventions, solutions to this prob- lem are inevitably going to be collaborative. In addition to the provision of adequate resources, communities, countries, researchers and funders must be encouraged to work together. It is our view that four key requirements for a successful and appro- priate collaborative approach to addressing emerging ACT resistance, and hence ethically important requirements of those who propose such interventions, are as follows:\n\ni. Encouraging and funding more research. Research should be conducted to address the gaps needed for each of the interventions proposed by the scientific community such as determining the safety of DP for MDA, the efficacy and safety of triple therapy, and determining the way resistance spreads. More evi- dence would help channel resources to the correct people and places, and facili- tate a scientific consensus.", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-84-1", "doc_id": "drug_resistance_book", "page": 84, "text": "ii. Retraining and supporting village malaria workers so that they are able to man- age other febrile diseases and hence remain relevant and retain community sup- port. This could be provision of education and strengthening support from provincial health departments.\n\niii. Encourage collection of quality malaria data, and sharing and pooling of these data. A data sharing initiative, the WorldWide Antimalarial Resistance Network (www.WWARN.org) was established by malaria researchers in 2009 to facili- tate collaborative study groups working to answer specific research questions using pooled analyses. WWARN has had considerable success in pooling individual- participant data from multiple clinical trials from academic groups and pharmaceutical companies, but has been less successful with NMCPs. Individual research groups have also established data sharing mechanisms via a managed access route (Cheah and Day 2017).\n\niv. Engaging with affected communities in creative and sensitive ways. Some work has already been conducted to engage forest workers, minority groups and mobile populations, and much more is needed (Lim et al. 2017). This will improve understanding of the science behind malaria and malaria elimination and will facilitate interventions such as MDAs and MSATs.\n\n69", "n_tokens": 241, "kind": "text"}
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{"chunk_id": "drug_resistance_book-88-0", "doc_id": "drug_resistance_book", "page": 88, "text": "4 Ethics and Antimalarial Drug Resistance\n\nvon Seidlein, L., and A. Dondorp. 2015. Fighting fire with fire: Mass antimalarial drug adminis- trations in an era of antimalarial resistance. Expert Review of Anti-Infective Therapy 13 (6): 715–730.\n\nWhite, N.J. 2017. Does antimalarial mass drug administration increase or decrease the risk of", "n_tokens": 94, "kind": "text"}
{"chunk_id": "drug_resistance_book-88-1", "doc_id": "drug_resistance_book", "page": 88, "text": "resistance? The Lancet Infectious Diseases 17 (1): e15–e20.\n\nWhite, N.J., S. Pukrittayakamee, T.T. Hien, M.A. Faiz, O.A. Mokuolu, and A.M. Dondorp. 2014.\n\nMalaria. Lancet 383 (9918): 723–735.\n\nWorld Health Organization. 2011. A global plan for artemisinin resistance containment. Available\n\nfrom: http://apps.who.int/iris/bitstream/10665/44482/1/9789241500838_eng.pdf.\n\n———. 2016a. Guidelines for the treatment of malaria, 3rd ed. Available from: http://apps.who.\n\nint/iris/bitstream/10665/162441/1/9789241549127_eng.pdf.\n\n———. 2016b. Minutes of the Evidence Review Group meeting on the emergence and spread of multidrug-resistant Plasmodium falciparum lineages in the Greater Mekong subregion 2016. Available from: http://www.who.int/malaria/mpac/mpac-mar2017-erg-multidrug-resistance- session6.pdf?ua=1.\n\n———. 2017. A framework for malaria elimination 2017. Available from: http://apps.who.int/iris/\n\nbitstream/10665/254761/1/9789241511988-eng.pdf.\n\nWorld Health Organization, Global Malaria Programme. 2015a. The role of mass drug adminis- tration, mass screening and treatment, and focal screening and treatment for malaria 2015. http://www.who.int/malaria/publications/atoz/role-of-mda-for-malaria. Available pdf?ua=1.", "n_tokens": 409, "kind": "text"}
{"chunk_id": "drug_resistance_book-88-2", "doc_id": "drug_resistance_book", "page": 88, "text": "from:\n\n———. 2015b. Policy brief on single-dose primaquine as a gametocytocide in Plasmodium falciparum malaria 2015. Available from: http://www.who.int/malaria/publications/atoz/ who_htm_gmp_2015.1.pdf.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n73", "n_tokens": 238, "kind": "text"}
{"chunk_id": "drug_resistance_book-89-0", "doc_id": "drug_resistance_book", "page": 89, "text": "Chapter 5 Antimicrobial Resistance and the Private Sector in Southeast Asia\n\nMarco Liverani, Lauren Oliveira Hashiguchi, Mishal Khan, and Richard Coker\n\nAbstract Southeast Asia is considered a regional hotspot for the emergence and spread of antimicrobial resistance (AMR). A commonality across countries in the region, particularly those with lower incomes such as Cambodia, Myanmar, Lao PDR and Vietnam, is the high utilisation of private healthcare providers, often unregulated, which may play a role in driving AMR. In this chapter we discuss chal- lenges to the control of AMR in Southeast Asia, with a focus on the role of the pri- vate sector. After providing an overview of the problem and current policy responses, we consider ethical issues of equity and fairness that may arise from the implemen- tation of established and proposed interventions.\n\nKeywords Drug resistance · Ethics · Medicine & Pubic Health · Private sector · Southeast Asia.\n\nM. Liverani (*) Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK", "n_tokens": 226, "kind": "text"}
{"chunk_id": "drug_resistance_book-89-1", "doc_id": "drug_resistance_book", "page": 89, "text": "Faculty of Public Health, Mahidol University, Bangkok, Thailand\n\nSchool of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan e-mail: Marco.Liverani@lshtm.ac.uk\n\nL. Oliveira Hashiguchi Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK\n\nSchool of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan e-mail: Lauren.Hashiguchi@lshtm.ac.uk\n\nM. Khan · R. Coker Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK\n\nFaculty of Public Health, Mahidol University, Bangkok, Thailand e-mail: Mishal.Khan@lshtm.ac.uk; richard.coker@lshtm.ac.uk\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_5\n\n75", "n_tokens": 236, "kind": "text"}
{"chunk_id": "drug_resistance_book-90-0", "doc_id": "drug_resistance_book", "page": 90, "text": "76\n\nM. Liverani et al.\n\n5.1\n\nDiversity, Epidemiology and Surveillance Capacity", "n_tokens": 20, "kind": "text"}
{"chunk_id": "drug_resistance_book-90-1", "doc_id": "drug_resistance_book", "page": 90, "text": "Southeast Asia is a loosely defined geographic region, whose configuration is vari- able and depends on different political, institutional, and cultural perspectives. For the purpose of this chapter, we refer to Southeast Asia as the ten member countries of the Association of Southeast Asian Nations (ASEAN), that is, Brunei, Cambodia, Indonesia, Lao PDR, Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Vietnam. As such, this region includes small, wealthy countries such as Singapore (5.6 million population, US$ 52,960 per capita) and populous, lower middle-income countries such as Indonesia (261.2 million population, 3570 US per capita) (The World Bank 2017). It is also characterised by socio-cultural differences and vast diversity in ecosystems including farming, natural habitats, and urbanisa- tion. Although gaps remain in our understanding of AMR in Southeast Asia, avail- able evidence indicates that this is an important and growing challenge (Cherau et al. 2017). For example, studies have identified a high prevalence of antimicrobial resistant infections in hospitalized paediatric populations in several regional coun- tries (Al-Taiar et al. 2013; Stoesser et al. 2013; Turner et al. 2016). The Asian Network for Surveillance of Resistant Pathogens (ANSORP) reported rates of pneumococcal resistance to penicillin exceeding 50% in some contexts (Song et al. 1999) and that resistance had spread across the region. Resistance to enteric patho- gens is becoming", "n_tokens": 320, "kind": "text"}
{"chunk_id": "drug_resistance_book-90-2", "doc_id": "drug_resistance_book", "page": 90, "text": "increasingly prominent (Coker et al. 2017), with studies in Thailand and Cambodia identifying high Campylobacter coli and Campylobacter jejuni rates of resistance to ciprofloxacin among isolate samples from children hos- pitalized with acute diarrhoea (Bodhidatta et al. 2002; Meng et al. 2011). In terms of respiratory infections, the World Health Organization (WHO) 2016 Global Tuberculosis Report lists Myanmar, Indonesia, Thailand, Philippines, and Vietnam among the 27 countries bearing the highest burden of multidrug resistant tuberculo- sis in the world (WHO 2015). Drug-resistant malaria is also prevalent across the region, including resistance of the malaria parasite P. falciparum to chloroquine, sulfadoxine–pyrimethamine, and most recently, and of considerable concern, arte- misinin ( WHO 2017). It is well documented that Western Cambodia, near the bor- der with Thailand, has been an epicentre of antimalarial resistance since the 1950s (Dondorp et al. 2010; Alam et al. 2011; Vinayak et al. 2010). Despite much docu- mentation of resistance throughout the region (Ashley et al. 2014; Imwong et al. 2017), the full epidemiological profile of resistance to antimalarials in Southeast Asia, as with AMR more broadly, is not known.", "n_tokens": 307, "kind": "text"}
{"chunk_id": "drug_resistance_book-90-3", "doc_id": "drug_resistance_book", "page": 90, "text": "Fragmented surveillance systems and weak laboratory capacity remain major barriers to acquiring quality surveillance data and information for AMR in the region, especially in LMICs (Lee and Wakabayashi 2013). These barriers were echoed in the findings of the Joint External Evaluation (JEE) (WHO 2016), a WHO-led pro- cess to assess country capacity to prevent, detect, and respond to public health threats. In Southeast Asia, JEEs have been conducted in Lao PDR, Vietnam, and Cambodia. Vietnam and Cambodia, the only countries with public JEE reports at present (Joint External Evaluation of the IHR Core Capacities of the Kingdom of", "n_tokens": 130, "kind": "text"}
{"chunk_id": "drug_resistance_book-91-0", "doc_id": "drug_resistance_book", "page": 91, "text": "5 Antimicrobial Resistance and the Private Sector in Southeast Asia\n\nTable 5.1 Joint external evaluation scoring for AMR Technical Area Indicator, Cambodia and Vietnam (Joint External Evaluation Tool and Process Overview 2016; Joint External Evaluation of the IHR Core Capacities of the Kingdom of Cambodia 2017; Joint External Evaluation of IHR Core Capacities of Viet Nam 2017)\n\nCambodia 3\n\nAMR detection\n\nDeveloped capacity\n\nSurveillance of infections caused by AMR pathogens 2 Limited capacity\n\nHealthcare associated infection prevention and control programs 2 Limited capacity\n\nAntimicrobial stewardship activities 2 Limited capacity\n\nVietnam 2\n\nLimited capacity\n\n2 Limited capacity\n\n3 Developed capacity\n\n2 Limited capacity\n\nCambodia 2017; Joint External Evaluation of IHR Core Capacities of Viet Nam 2017), reported limited capacity for surveillance of infections caused by AMR pathogens and advocated improved stewardship to prevent inappropriate use of anti- microbials (Table 5.1) (see also Chap. 23 in this book).\n\n5.2", "n_tokens": 188, "kind": "text"}
{"chunk_id": "drug_resistance_book-91-1", "doc_id": "drug_resistance_book", "page": 91, "text": "Private Health Services and AMR\n\nThe private sector is the dominant health care provider in many countries in the region. For example, about 70% of Cambodian patients first seek treatment from the private sector and private drug sellers are the preferred healthcare providers for the majority of those who are ill (NIS Cambodia 2014). Across the region, out-of- pocket payment is a common method to finance health care, despite good progress toward universal health coverage in Thailand, Malaysia, Singapore, and Indonesia (Van Minh et al. 2014). Out-of-pocket health expenditure as a percentage of total health expenditure is more than 50% in Cambodia, Singapore, the Philippines, and Myanmar (Table 5.2) (The World Bank 2017). A study including data from 47 coun- tries indicated that out-of-pocket health expenditure was strongly correlated with AMR in low-income countries, with the authors concluding that high demand for the private sector may be related to higher AMR owing to heightened incentives among private providers to overprescribe and less standardized quality assurance of antimicrobials (Alsan et al. 2015).", "n_tokens": 229, "kind": "text"}
{"chunk_id": "drug_resistance_book-91-2", "doc_id": "drug_resistance_book", "page": 91, "text": "Prior to discussing the role of private providers in AMR, it is important to briefly describe the diversity of the private health sector in Southeast Asia and reasons for its popularity. Broadly, private providers include persons operating outside of the government-financed system, alone or in groups, to provide diagnosis, treatment or advice to individuals for health-related concerns. In Southeast Asia, as in other regions, the private sector includes a variety of providers, ranging from large private hospitals, small clinics and pharmacies to road-side informal drug vendors and tra- ditional healers (Khan 2016). The level of training varies greatly. Some private\n\n77", "n_tokens": 130, "kind": "text"}
{"chunk_id": "drug_resistance_book-92-0", "doc_id": "drug_resistance_book", "page": 92, "text": "78\n\nM. Liverani et al.\n\nTable 5.2 Health sector expenditure indicators in ASEAN (The World Bank 2017)\n\nPopulation (thousands), 2016\n\n423,196 Brunei 15,762,370 Cambodia 261,115,456 Indonesia 6,758,353 Lao PDR 31,187,265 Malaysia Myanmar 52,885,223 Philippines 103,320,222 5,607,283 Singapore 68,863,514 Thailand 92,701,100 Vietnam\n\nGDP (billions) 2016 11.4 20.0 932.3 15.9 296.4 67.4 304.9 297.0 406.8 202.6\n\nHealth expenditure as proportion of the GDP, 2014 2.7% 5.6% 2.9% 1.9% 4.1% 2.3% 4.7% 4.9% 4.1% 7.1%\n\nPublic health expenditure as % of total health expenditure, 2014 93.9% 22.0% 37.8% 50.5% 55.2% 45.9% 32.3% 41.7% 77.8% 54.1%\n\nOut-of-pocket health expenditure as % of total expenditure on health, 2014 6.0% 95.2% 46.9% 38.9% 35.3% 50.7% 53.7% 54.8% 11.9% 36.8%\n\npractitioners have no training or claim to have qualifications that they do not have, while others have several years of specialist training. In addition to allopathic healthcare providers, there are alternative therapeutic approaches, which include homeopathy and traditional healing. Private providers also vary in terms of the fees charged. Some are highly priced and accessible only to a fraction of the population while others are more accessible and may offer flexible payment arrangements.", "n_tokens": 376, "kind": "text"}
{"chunk_id": "drug_resistance_book-92-1", "doc_id": "drug_resistance_book", "page": 92, "text": "Why do patients use the private sector? A recent systematic review comparing the performance of private and public health-care systems in LMICs found that patients’ preferences for private providers were related to shorter waiting times, bet- ter hospitality, increased time spent with doctors, cleanliness of facilities, longer and flexible opening times, personal attitude, and better availability of staff (Basu et al. 2012). However, quality of care in terms of competence and adherence to guidelines is often low (Morgan et al. 2017).\n\nIn terms of AMR specifically, over-prescribing or over-selling of antimicrobial drugs by for-profit healthcare providers appears to be fairly common, although inappropriate prescribing practices have also been reported in public hospitals and health centres (Apisarnthanarak et al. 2008; Om et al. 2017; Yeung et al. 2011). A large study of over 400 healthcare providers including drug shops, private clinics and hospitals in Vietnam found that 79% would dispense antibiotics for common colds with fever and only 19% had knowledge of antibiotic prescribing according to national guidelines (Hoa et al. 2009). Drug sellers were more likely to dispense antibiotics inappropriately than other types of healthcare providers in this study. Other studies in the region have shown that, among drugs sold, antimicrobials are very common as they are reported to be the most profit-generating (Gollogly 2002; Chuc and Tomson 1999).", "n_tokens": 308, "kind": "text"}
{"chunk_id": "drug_resistance_book-92-2", "doc_id": "drug_resistance_book", "page": 92, "text": "Drug quality is also a problem in the region. There is evidence from Cambodia, particularly on antimalarial drugs (Novotny et al. 2016), and from neighbouring countries such as Vietnam, that unregulated drug shops often sell poor-quality", "n_tokens": 53, "kind": "text"}
{"chunk_id": "drug_resistance_book-93-0", "doc_id": "drug_resistance_book", "page": 93, "text": "5 Antimicrobial Resistance and the Private Sector in Southeast Asia\n\nmedications. According to the WHO, substandard drugs are products whose compo- sition and ingredients do not meet the correct scientific specifications (WHO 2003). This could be due to inappropriate storage at high temperature and humidity or poor quality assurance during the manufacturing process. Both of these conditions are more likely to occur in less-developed countries. Counterfeit drugs are considered a subset of substandard drugs that are deliberately and fraudulently mislabelled with respect to identity and/or source. Antibiotics and antimalarials are at particular risk of targeting by counterfeiters and drug manufacturers that use poor practices owing to large volumes of sales, their relatively low production cost, and the challenges met by regulatory mechanisms and their enforcement. In 2013, a multi- governmental investigation across Cambodia, Indonesia, Lao PDR, Myanmar, Thailand, and Vietnam found that nearly one third of both antimalarials and antibiotics were of poor quality and potentially counterfeited (Weraphong et al. 2013). Similarly, a 2004 cross-sectional survey of pharmacies and drug shops in Myanmar found an “alarming high proportion” of counterfeit artesunate (Dondorp et al. 2004), although a recent survey provides encouraging evidence that the quality of artemisinin-based combination therapies has improved (Yeung et al. 2015).", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-93-1", "doc_id": "drug_resistance_book", "page": 93, "text": "As noted earlier, this chapter focuses on the use of antimicrobials in human health. But the use in animals is also important, and is a major contributor to AMR globally (Nhung et al. 2015), as further discussed in Chaps. 7 and 18. Subtherapeutic use of antibiotics in livestock for growth promotion or prophylaxis is of particular concern, as the low doses used can lead to the emergence of drug resistance (Van Boeckel et al. 2015). While there are regulations around the use of growth promot- ers in Europe and America, the use of antibiotics by unregulated veterinarians and drug sellers in Southeast Asia is poorly understood. Multiple studies in the region do, however, indicate a high prevalence of confirmed resistance to ciprofloxacin, and gentamicin, and of particular concern, colistin among E. coli isolates in pig and chicken farms (Nhung et al. 2015, 2016; Nguyen et al. 2015, 2016). Colistin is one of the last line of drugs available for treating multidrug resistant Gram-negative pathogens in humans.\n\n5.3", "n_tokens": 243, "kind": "text"}
{"chunk_id": "drug_resistance_book-93-2", "doc_id": "drug_resistance_book", "page": 93, "text": "Policy Challenges in Tackling AMR\n\nMost governments in Southeast Asia have recognised the dangers of AMR and taken action to control the use of antimicrobials through policy making, legal provi- sions, and program implementation. Legal frameworks to regulate the pharmaceuti- cal supply chain have been improved in many countries, providing stronger legal bases to counter the problem of substandard medicines and poor management prac- tices (Lamy and Liverani 2015). Operational capacities of drug regulatory authori- ties have also increased, leading to more effective quality control, closure of unlicensed businesses and a crackdown of the trade in counterfeit medicines, with major enforcement operations being conducted throughout the Mekong region (Interpol 2015). Further, new laws have been introduced to regulate drug sellers,\n\n79", "n_tokens": 166, "kind": "text"}
{"chunk_id": "drug_resistance_book-94-0", "doc_id": "drug_resistance_book", "page": 94, "text": "80\n\nM. Liverani et al.", "n_tokens": 8, "kind": "text"}
{"chunk_id": "drug_resistance_book-94-1", "doc_id": "drug_resistance_book", "page": 94, "text": "particularly for antimalarial medications, although provisions are variable across regional countries. In Thailand, for example, the sale of antimalarial medications in the private sector is banned since 1995, but in other countries regulations are less stringent. In Myanmar, there is no prohibition, while in Lao PDR, the ban applies only to grocery stores, general retailers and itinerant vendors (Akulayi et al. 2017). Despite increasing commitment, the control of AMR remains a major policy challenge in Southeast Asia, particularly in relation to the sale and use of antibiotics. In Thailand, for example, pharmacists can dispense antibiotics without prescription, leaving more room to profit-motivated sale (Apisarnthanarak et al. 2008; Saengcharoen and Lerkiatbundit 2010). In 2007, the “Antibiotic Smart Use” pro- gramme was piloted in community health centres and hospitals to reduce unneces- sary prescription of antibiotics for respiratory infections, diarrhoea, and simple wounds. Based on promotional material and performance-based incentives, this programme was subsequently scaled up nationwide and described as a workable model to improve the rational use of antibiotics in Thailand (Akulayi et al. 2017). However, efforts to engage private pharmacies have been less effective (Chalker et al. 2005). In other countries, such as Vietnam and Indonesia, regulations on pre- scribing and dispensing of antibiotics are more restrictive, but enforcement has been difficult to achieve due", "n_tokens": 316, "kind": "text"}
{"chunk_id": "drug_resistance_book-94-2", "doc_id": "drug_resistance_book", "page": 94, "text": "to either lack of resources, weak sanctions, or challenges in monitoring compliance in highly diversified markets (Nga et al. 2014; Widayati et al. 2011; Mao et al. 2015). Antimicrobial use is particularly difficult to control in remote rural areas, where access to public health services is more limited, patients tend to self-medicate, and medicines of dubious origin are more likely to be avail- able in road stalls and other informal outlets (Lon et al. 2006; Hadi et al. 2010; Om et al. 2017).", "n_tokens": 116, "kind": "text"}
{"chunk_id": "drug_resistance_book-94-3", "doc_id": "drug_resistance_book", "page": 94, "text": "In general, AMR is a complex, multi-dimensional health issue which requires a comprehensive multi-sector policy approach, able to tackle structural drivers and determinants across human and animal health sectors. However, policy develop- ment and program implementation have often targeted particular diseases, espe- cially in LMICs where donors have prioritised vertical health programmes. In Cambodia, for example, innovative social marketing schemes have been introduced to improve access to good-quality antimalarials in the private sector and control of pharmaceutical drivers of drug resistance, such as the use of artemisinin monothera- pies (Yeung et al. 2011; Yamey et al. 2012). As in other countries, however, no comprehensive policy response to promote the responsible use of medicines has been developed to date. Professional development, supervision, and behaviour change activities are driven by vertical disease programmes as well as the systems for the collection, analysis, and dissemination of surveillance data on antimicrobial resistance. Engagement with the agricultural sector has also been relatively weak in many countries, with gaps in legal provisions and operational capacities to regulate and monitor antibiotic use for animal health prophylaxis and growth promotion (Archawakulathep et al. 2014). Further challenges result from the diversity of the livestock sector in Southeast Asia. While supervision is more feasible in large", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-95-0", "doc_id": "drug_resistance_book", "page": 95, "text": "5 Antimicrobial Resistance and the Private Sector in Southeast Asia\n\nproduction units, there is less or no control of antibiotic use in smallholders and contracted farmers (Om and McLaws 2016).", "n_tokens": 41, "kind": "text"}
{"chunk_id": "drug_resistance_book-95-1", "doc_id": "drug_resistance_book", "page": 95, "text": "In recognition of these challenges and the need for a more comprehensive policy approach, action plans on AMR have been adopted in Cambodia, Indonesia, the Philippines, Thailand, and Vietnam, while the Lao PDR, Malaysia and Singapore are currently developing their national plans (Cheng 2016). In line with WHO global guidelines (WHO 2015), these plans have been informed by One Health approaches and a commitment to strengthening cooperative arrangements across sectors and national authorities. To this end, inter-ministerial and inter-agency com- mittees have been established to guide policy implementation and monitor progress. Since these plans have been adopted only recently, it is too early to assess outcomes and their value in promoting more effective responses to AMR. However, it is expected that the achievement of the stated policy and governance goals will require a significant increase in resource allocation, which may be challenging to achieve in LMICs. Further, as in other contexts, the divisive forces of institutional mandates and professional interests are likely to counteract the imperative of multi-sectoral cooperation, requiring political will at the highest level of policymaking. Finally, as we will see below, achieving a good balance between access to antimicrobials, as well as other vital resources for human and animal health, and curbing inappropriate use and excess is arguably one the most important challenges ahead (Das and Horton 2017), posing key ethical", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-95-2", "doc_id": "drug_resistance_book", "page": 95, "text": "questions about policy choices in the short and the long term.", "n_tokens": 12, "kind": "text"}
{"chunk_id": "drug_resistance_book-95-3", "doc_id": "drug_resistance_book", "page": 95, "text": "5.4\n\nEthical Issues\n\nThe challenges to controlling the emergence of AMR in Southeast Asia are multi- sectoral and complex, requiring policies that can address the diverse range of con- tributing factors, including behaviour and practices, gaps in health service provision and regulations, and macro- and micro-economic drivers in the antimicrobial supply chain and market at the national, regional, and global level. In the process, particular attention should be given to the private health sector and food production systems, as these are arguably the largest channels for the distribution, sale, and use of a wide range of antimicrobials in many regional countries. Yet policy and planning in this area is problematic. In addition to governance challenges noted above, policy options to control AMR in the private sector raise ethical issues of equity and fair- ness, which have been recognised only recently in research and policy communities (Heyman et al. 2014; Littmann and Viens 2015). While a reduction of antibiotics use is necessary to avert the potentially disastrous impact of future drug-resistant pandemics, a single focus on this policy goal may result in undesirable conse- quences in the short term, particularly in relation to equitable access to essential goods and services, as we discuss below.\n\n81", "n_tokens": 265, "kind": "text"}
{"chunk_id": "drug_resistance_book-96-0", "doc_id": "drug_resistance_book", "page": 96, "text": "82\n\nM. Liverani et al.\n\nAccess to Health Services Informal providers account for a significant fraction of diagnosis and treatment services in parts of Southeast Asia, raising concerns about the quality of care and their role in driving AMR. Efforts are being made in some countries to ban unlicensed practitioners. However, “village doctors” and other informal providers may be the only accessible source of primary care in some areas, particularly in remote rural communities where public health facilities are hard to reach and other options are not available. In such contexts, regulatory enforcement may be necessary to control potentially harmful practices and key drivers of AMR, but may also reduce access to care where it is needed most. Engagement with the informal sector, including training and supervision programmes, might be a solu- tion to this problem. Yet informal providers have weak legitimacy in relation to the formal health system. The implicit recognition of unqualified providers as legiti- mate health workers might be challenging if conducted or sanctioned by govern- ment agencies and is likely to face strong opposition from established professional categories. On the other hand, informal providers may be reluctant to participate in projects with public health authorities for fear of being exposed (Khan et al. 2015).", "n_tokens": 245, "kind": "text"}
{"chunk_id": "drug_resistance_book-96-1", "doc_id": "drug_resistance_book", "page": 96, "text": "Access to Medicines Policy and regulations on prescription and dispensing of antimicrobials raise similar concerns (see also Chap. 24 in this book). Since 1998, the WHO has urged Member States to “prohibit the dispensing of antimicrobials without the prescription of a qualified health care professional” and to strengthen legislation “to prevent the sale of antibiotics on the informal market” (WHO 1998). In many countries, however, the government health system or other authorised sup- pliers might not be able to reach all population groups or gaps may exist in their ability to meet the demand for antimicrobials. In Cambodia and Lao PDR, for example, health volunteers have been appointed in remote communities to diagnose suspected malaria cases by using rapid diagnostic tests, administer subsidised artemisinin- based combination therapy (ACT), and refer severe patients to the near- est public health facility (Liverani et al. 2017; Alum et al. 2017). These programmes have been successful in improving adherence to malaria policy and treatment where other health services are either lacking or inadequate. However, informal drug out- lets and grocery stores remain the only accessible and affordable suppliers of medi- cines in some areas or for some hard-to-reach groups such as mobile and migrant workers. In addition, stronger quality control and higher standards are likely to increase the cost of medicines, making them less affordable to the poor. While sub- sidization of particular", "n_tokens": 306, "kind": "text"}
{"chunk_id": "drug_resistance_book-96-2", "doc_id": "drug_resistance_book", "page": 96, "text": "categories of antimicrobials, such as anti-malarial and anti- tuberculosis treatments, has been implemented with good results (Novotny et al. 2016; Hill and Mao 2007), this approach might not be feasible for mass-market drugs such as antibiotics.", "n_tokens": 56, "kind": "text"}
{"chunk_id": "drug_resistance_book-96-3", "doc_id": "drug_resistance_book", "page": 96, "text": "Access to Food As noted earlier, evidence indicates that the use of antibiotics in the livestock sector is an important driver of AMR (Witte 1998). Thus, it is sug- gested that this practice should be reduced or banned outright. However, it is also known that regulatory restrictions may have significant economic effects on farmers, as the use of antibiotics allows larger numbers of healthy animals to be", "n_tokens": 80, "kind": "text"}
{"chunk_id": "drug_resistance_book-97-0", "doc_id": "drug_resistance_book", "page": 97, "text": "5 Antimicrobial Resistance and the Private Sector in Southeast Asia\n\nmaintained with lower cost to the producer (National Research Council 1999). Further, the effects of restrictions or bans are likely to be unequally distributed across livestock production systems. While large companies and production units may replace antibiotics with other disease prevention practices and veterinary ser- vices, smallholders may not be able to do so, bearing higher cost of regulatory change. Finally, more stringent regulations raise concerns of fairness and equity in access to food. Low and sub-therapeutic use of antibiotics contributes to growth promotion and improved feed efficiency, resulting in lower costs of meat and eggs (National Research Council 1999). While the effect of reduced antibiotics use on the price of meat products is difficult to gauge with precision, organic foods are generally more expensive and therefore less affordable to lower income groups (Chander et al. 2011). As Littman (Littmann and Viens 2015) pointed out, “these considerations do not appear to weigh heavily enough to justify the continuation of current practices”; however, we should recognise, “who will be disadvantaged by proposed policy changes, and discuss what kind of subsidy or compensation may be warranted”.\n\n5.5", "n_tokens": 246, "kind": "text"}
{"chunk_id": "drug_resistance_book-97-1", "doc_id": "drug_resistance_book", "page": 97, "text": "Conclusion\n\nIn conclusion, AMR is a complex problem that extends far beyond the technical challenge of reducing or improving the use of antimicrobials, as interventions are likely to have externalities on other important issues for human well-being and live- lihood. Thus, in Southeast Asia as in other contexts, policy and planning in this area, and modelling and pilot exercises that provide evidence, will need to incorporate a wide range of issues and a calculation of costs and benefits to individuals, enter- prises, and across the whole of society. This will likely require us to find a difficult balance between the urgent need to address the rising challenge of AMR while addressing the moral obligations to broad public health benefits and limiting eco- nomic hardship. And all of this within complex social and political environments. Simple solutions are likely to induce undesirable, and perhaps unforeseen, consequences.\n\nReferences\n\nAlum, A., A. Andrada, J. Archer, E. Auko, K. Bates, P. Bouanchaud, et al. 2017. The malaria testing and treatment landscape in the southern Lao People’s Democratic Republic (PDR). Malaria Journal 16 (1): 169.\n\nAkulayi, L., A. Alum, A. Andrada, J. Archer, E. D. Arogundade, E. Auko, et al. 2017. Private sector opportunities and threats to achieving malaria elimination in the Greater Mekong Subregion: Results from malaria outlet surveys in Cambodia, the Lao PDR, Myanmar, and Thailand. Malaria Journal 16: 180.\n\n83", "n_tokens": 329, "kind": "text"}
{"chunk_id": "drug_resistance_book-98-0", "doc_id": "drug_resistance_book", "page": 98, "text": "84\n\nM. Liverani et al.\n\nAlam, M.T., S. Vinayak, K. Congpuong, C. Wongsrichanalai, W. Satimai, L. Slutsker, et al. 2011. Tracking origins and spread of sulfadoxine-resistant Plasmodium falciparum dhps alleles in Thailand. Antimicrobial Agents and Chemotherapy 55 (1): 155–164.\n\nAlsan, M., L. Schoemaker, K. Eggleston, N. Kammili, P. Kolli, and J. Bhattacharya. 2015. Out-of- pocket health expenditures and antimicrobial resistance in low- and middle-income countries. The Lancet Infectious Diseases 15 (10): 1203–1210.\n\nAl-Taiar A, M.S. Hammoud, L. Cuiqing, J.K.F. Lee, K.-M. Lui, N. Nakwan, et al. 2013. Neonatal infections in China, Malaysia, Hong Kong and Thailand. Archives of Disease in Childhood – Fetal and Neonatal Edition 98 (3): F249–F255.\n\nAnomaly, Jonathan. this volume. Antibiotics and animal agriculture: The need for global collec- tive action. In Ethics and drug resistance: Collective responsibility for Global Public Health, 299–310. Cham: Springer.\n\nApisarnthanarak, A., J. Tunpornchai, K. Tanawitt, and L.M. Mundy. 2008. Nonjudicious dispens- ing of antibiotics by drug stores in Pratumthani, Thailand. Infection Control and Hospital Epidemiology 29 (6): 572–575.\n\nArchawakulathep, A., C.T. Thi Kim, D. Meunsene, D. Handijatno, H.A. Hassim, H.R.G. Rovira, et al. 2014. Perspectives on antimicrobial resistance in livestock and livestock products in ASEAN countries. Thai Journal of Veterinary Medicine 44: 5–13.", "n_tokens": 459, "kind": "text"}
{"chunk_id": "drug_resistance_book-98-1", "doc_id": "drug_resistance_book", "page": 98, "text": "Ashley, E.A., M. Dhorda, R.M. Fairhurst, C. Amaratunga, P. Lim, S. Suon, et al. 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. The New England Journal of Medicine 371 (5): 411–423.\n\nBasu, S., J. Andrews, S. Kishore, R. Panjabi, and D. Stuckler. 2012. Comparative performance of private and public healthcare systems in low- and middle-income countries: A systematic review. PLoS Medicine 9 (6): e1001244.\n\nBoden, Lisa and Dominic Mellor. this volume. Epidemiology and ethics of antimicrobial resis- tance in animals. In Ethics and drug resistance: Collective responsibility for Global Public Health, 109–121. Cham: Springer.\n\nBodhidatta, L., N. Vithayasai, B. Eimpokalarp, C. Pitarangsi, O. Serichantalergs, and D.W. Isenbarger. 2002. Bacterial enteric pathogens in children with acute dysentery in Thailand: Increasing importance of quinolone-resistant Campylobacter. The Southeast Asian Journal of Tropical Medicine and Public Health 33 (4): 752–757.\n\nChalker, J., S. Ratanawijitrasin, N.T.K. Chuc, M. Petzold, and G. Tomson. 2005. Effectiveness of a multi-component intervention on dispensing practices at private pharmacies in Vietnam and Thailand – A randomized controlled trial. Social Science and Medicine 60: 131–141.", "n_tokens": 369, "kind": "text"}
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{"chunk_id": "drug_resistance_book-99-2", "doc_id": "drug_resistance_book", "page": 99, "text": "Organization.\n\nKhan, M. 2016. Health markets and antibiotics: Unlikely places you can buy them. Health Policy and Planning Debated Blog, London School of Hygiene and Tropical Medicine. Available from: http://blogs.lshtm.ac.uk/hppdebated/2016/11/29/health-markets-and-antibiotics/#respond [Accessed May 2020].\n\nKhan, M.S., S. Salve, and J.D.H. Porter. 2015. Engaging for-profit providers in TB control: Lessons learnt from initiatives in South Asia. Health Policy and Planning 30 (10): 1289–1295. Lamy, M., and M. Liverani. 2015. Tackling substandard and falsified medicines in the Mekong: National responses and regional prospects. Asia & the Pacific Policy Studies 2 (2): 245–254. Lee, Y., and M. Wakabayashi. 2013. Key informant interview on antimicrobial resistance (AMR)\n\nin some countries in the western pacific region. Global Health 9: 34.\n\nLittmann, J., and A.M. Viens. 2015. The ethical significance of antimicrobial resistance. Public\n\nHealth Ethics 8 (3): 209–224.\n\nLiverani, M., C. Nguon, R. Sok, D. Kim, P. Nou, S. Nguon, et al. 2017. Improving access to health care amongst vulnerable populations: A qualitative study of village malaria workers in Kampot, Cambodia. BMC Health Services Research 17 (1): 335.\n\nLon, C.T., R. Tsuyuoka, S. Phanouvong, N. Nivanna, D. Socheat, C. Sokhan, et al. 2006. Counterfeit and substandard antimalarial drugs in Cambodia. Transactions of the Royal Society of Tropical Medicine and Hygiene 100 (11): 1019–1024.", "n_tokens": 419, "kind": "text"}
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{"chunk_id": "drug_resistance_book-100-1", "doc_id": "drug_resistance_book", "page": 100, "text": "DC: The National Academies Press.\n\nNga, D.T.T., N.T.K. Chuc, N.P. Hoa, N.Q. Hoa, N.T.T. Nguyen, H.T. Loan, et al. 2014. Antibiotic sales in rural and urban pharmacies in northern Vietnam: an observational study. BMC Pharmacology and Toxicology 15 (1): 6.\n\nNguyen, V.T., J.J. Carrique-Mas, T.H. Ngo, H.M. Ho, T.T. Ha, J.I. Campbell, et al. 2015. Prevalence and risk factors for carriage of antimicrobial-resistant Escherichia coli on household and small-scale chicken farms in the Mekong Delta of Vietnam. The Journal of Antimicrobial Chemotherapy 70 (7): 2144–2152.\n\nNguyen, N.T., H.M. Nguyen, C.V. Nguyen, T.V. Nguyen, M.T. Nguyen, H.Q. Thai, et al. 2016. Use of colistin and other critical antimicrobials on pig and chicken farms in Southern Vietnam and its association with resistance in commensal Escherichia coli bacteria. Applied and Environmental Microbiology 82 (13): 3727–3735. http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4907207/\n\nNhung, N.T., N.V. Cuong, J. Campbell, N.T. Hoa, J.E. Bryant, V.N.T. Truc, et al. 2015. High levels of antimicrobial resistance among Escherichia coli isolates from livestock farms and synanthropic rats and shrews in the Mekong Delta of Vietnam. Applied and Environmental Microbiology [Internet] 81 (3): 812–820.", "n_tokens": 419, "kind": "text"}
{"chunk_id": "drug_resistance_book-100-2", "doc_id": "drug_resistance_book", "page": 100, "text": "Nhung, N.T., N.V. Cuong, G. Thwaites, J. Carrique-Mas. 2016. Antimicrobial usage and antimi- crobial resistance in animal production in Southeast Asia: A review. Antibiotics 5 (4). pii: E37. Novotny, J., A. Singh, L. Dysoley, S. Sovannaroth, and H. Rekol. 2016. Evidence of success- ful malaria case management policy implementation in Cambodia: Results from national ACTwatch outlet surveys. Malaria Journal 15 (1): 194.\n\nOm, C., and M.-L. McLaws. 2016. Antibiotics: Practice and opinions of Cambodian commer- cial farmers, animal feed retailers and veterinarians. Antimicrobial Resistance and Infection Control 5: 42.\n\nOm, C., F. Daily, E. Vlieghe, J.C. Mclaughlin, M.-L. Mclaws. 2017. Pervasive antibiotic mis- use in the Cambodian community: antibiotic-seeking behaviour with unrestricted access. Antimicrobial Resistance and Infection Control [Internet] 6: 30. Available from: https://doi. org/10.1186/s13756-017-0187-y\n\nSaengcharoen, W., and S. Lerkiatbundit. 2010. Practice and attitudes regarding the management of childhood diarrhoea among pharmacies in Thailand. The International Journal of Pharmacy Practice 18 (6): 323–331.\n\nSong, J.-H., N.Y. Lee, S. Ichiyama, R. Yoshida, Y. Hirakata, W. Fu, et al. 1999. Spread of drug- resistant Streptococcus pneumoniae in Asian Countries: Asian Network for Surveillance of Resistant Pathogens (ANSORP) study. Clinical Infectious Diseases 28 (6): 1206–1211.", "n_tokens": 421, "kind": "text"}
{"chunk_id": "drug_resistance_book-100-3", "doc_id": "drug_resistance_book", "page": 100, "text": "Stoesser, N., C.E. Moore, J.M. Pocock, K.P. An, K. Emary, M. Carter, et al. 2013. Pediatric blood- stream infections in Cambodia, 2007 to 2011. The Pediatric Infectious Disease Journal 32 (7): e272–e276.\n\nThe World Bank. 2017. World Bank Data Bank Available from: http://data.worldbank.org. Turner, P., S. Pol, S. Soeng, P. Sar, L. Neou, P. Chea, et al. 2016 Aug. High prevalence of antimicrobial- resistant gram-negative colonization in hospitalized Cambodian infants. The Pediatric Infectious Disease Journal 35 (8): 856–861.\n\nVan Boeckel, T.P., C. Brower, M. Gilbert, B.T. Grenfell, S.A. Levin, T.P. Robinson, et al. 2015. Global trends in antimicrobial use in food animals. Proceedings of the National Academy of Sciences of the United States of America 16: 1–6.", "n_tokens": 237, "kind": "text"}
{"chunk_id": "drug_resistance_book-101-0", "doc_id": "drug_resistance_book", "page": 101, "text": "5 Antimicrobial Resistance and the Private Sector in Southeast Asia\n\nVan Minh, H., N.S. Pocock, N. Chaiyakunapruk, C. Chhorvann, H.A. Duc, P. Hanvoravongchai, et al. 2014. Progress toward universal health coverage in ASEAN. Global Health Action 7. https://doi.org/10.3402/gha.v7.25856.\n\nVinayak, S., M.T. Alam, T. Mixson-Hayden, A.M. McCollum, R. Sem, N.K. Shah, et al. 2010. Origin and evolution of sulfadoxine resistant Plasmodium falciparum. PLOS Pathogens 6 (3):e 1000830.\n\nWeraphong, J., S. Pannarunothai, T. Luxananun, N. Junsri, and S. Deesawatsripetch. 2013. Catastrophic health expenditure in an urban city: Seven years after universal coverage pol- icy in Thailand. The Southeast Asian Journal of Tropical Medicine and Public Health 44 (1): 124–136.\n\nWHO. 2015. Use of high burden countries for TB by WHO in the post-2015 era. Geneva,\n\nSwitzerland: World Health Organization.\n\nWidayati, A., S. Suryawati, C. de Crespigny, and J.E. Hiller. 2011. Knowledge and beliefs about antibiotics among people in Yogyakarta City Indonesia: A cross sectional population-based survey. BMC Research Notes 4 (1): 491.\n\nWitte, W. 1998. Medical consequences of antibiotic use in agriculture. Science 279: 996–997. WHO 1998. Emerging and other communicable diseases: Antimicrobial resistance. World Health\n\nAssembly (WHA5117). Geneva, Switzerland: World Health Organization.\n\n———. 2003. Fact sheet 275: Substandard and counterfeit medicines. Geneva: World Health", "n_tokens": 430, "kind": "text"}
{"chunk_id": "drug_resistance_book-101-1", "doc_id": "drug_resistance_book", "page": 101, "text": "Organization.\n\n———. 2015. Global action plan on antimicrobial resistance. WHO Press, 1–28. Geneva, Switzerland: World Health Organization. Available from: http://www.who.int/drugresistance/ global_action_plan/en/ [Accessed May 2020].\n\n———. 2017. Global database on antimalarial drug efficacy and resistance. Geneva, Switzerland:\n\nWorld Health Organization.\n\nYamey, G., D. Montagu, and M. Schäferhoff. 2012. Piloting the affordable medicines facility- malaria: What will success look like? Bulletin of the World Health Organization 90 (6): 452–460.\n\nYeung, S., E. Patouillard, H. Allen, and D. Socheat. 2011. Socially-marketed rapid diagnostic tests and ACT in the private sector: Ten years of experience in Cambodia. Malaria Journal 10 (1): 243.\n\nYeung, S., H.L.S. Lawford, P. Tabernero, C. Nguon, A. van Wyk, N. Malik, et al. 2015. Quality of antimalarials at the epicenter of antimalarial drug resistance: Results from an overt and mystery client survey in Cambodia. The American Journal of Tropical Medicine and Hygiene 92 (Suppl 6): 39–50.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.", "n_tokens": 382, "kind": "text"}
{"chunk_id": "drug_resistance_book-101-2", "doc_id": "drug_resistance_book", "page": 101, "text": "The images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n87", "n_tokens": 74, "kind": "text"}
{"chunk_id": "drug_resistance_book-102-0", "doc_id": "drug_resistance_book", "page": 102, "text": "Chapter 6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship (AMS): Dual Strategies to Reduce Antibiotic Resistance (ABR) in Hospitals\n\nGwendolyn L. Gilbert and Ian Kerridge", "n_tokens": 46, "kind": "text"}
{"chunk_id": "drug_resistance_book-102-1", "doc_id": "drug_resistance_book", "page": 102, "text": "Abstract In this chapter we review the development of hospital infection preven- tion and control (IPC) since the nineteenth century and its increasingly important role in reducing the spread of antibiotic resistance (ABR). Excessive rates of hospital- acquired infection (HAI) fell dramatically, towards the end of the nine- teenth century, because of improved hygiene and surgical antisepsis, but treatment remained rudimentary until effective antibiotics became widely available in the mid-twentieth century. While antibiotics had profound clinical benefits, their wide- spread appropriate and inappropriate use in humans and animals inevitably led to the emergence of antibiotic resistance (ABR). Within 50 years, this could no longer be offset by a reliable supply of new drugs, which slowed to a trickle in the 1980s. In hospitals, particularly, high rates of (often unnecessary) antibiotic use and ABR are exacerbated by person-to-person transmission of multi-drug resistant organisms (MDRO), which have, so far, largely resisted the introduction of antimicrobial stew- ardship (AMS) programs and repeated campaigns to improve infection prevention and control (IPC). Despite clear evidence of efficacy in research settings, both AMS and IPC programs are often ineffective, in practice, because of, inter alia, insuffi- cient resourcing, poor implementation, lack of ongoing evaluation and failure to consult frontline staff. In this chapter we review reasons for the relatively low prior- ity", "n_tokens": 306, "kind": "text"}
{"chunk_id": "drug_resistance_book-102-2", "doc_id": "drug_resistance_book", "page": 102, "text": "given to preventive programs despite the ethical obligation of healthcare organ- isations to protect current and future patients from preventable harm. The imminent", "n_tokens": 28, "kind": "text"}
{"chunk_id": "drug_resistance_book-102-3", "doc_id": "drug_resistance_book", "page": 102, "text": "G. L. Gilbert (*) Sydney Health Ethics, University of Sydney, Sydney, NSW, Australia\n\nMarie Bashir Institute for Emerging Infections and Biosecurity, University of Sydney, Sydney, NSW, Australia e-mail: lyn.gilbert@sydney.edu.au\n\nI. Kerridge Sydney Health Ethics, University of Sydney, Sydney, NSW, Australia\n\nDepartment of Haematology, Royal North Shore Hospital, Sydney, NSW, Australia\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_6\n\n89", "n_tokens": 161, "kind": "text"}
{"chunk_id": "drug_resistance_book-103-0", "doc_id": "drug_resistance_book", "page": 103, "text": "90\n\nG. L. Gilbert and I. Kerridge\n\nthreat of untreatable infections may provide an impetus for a shared organisational and professional commitment to promoting the cultural and behavioural changes needed to successfully reduce the burdens of ABR and drug-resistant HAIs.\n\nKeywords Medicine and public health · Infectious diseases · History of medicine · Infection prevention and control · Antimicrobial resistance · Antimicrobial stewardship\n\n6.1", "n_tokens": 88, "kind": "text"}
{"chunk_id": "drug_resistance_book-103-1", "doc_id": "drug_resistance_book", "page": 103, "text": "Introduction\n\nAntibiotic resistance (ABR1) has been described as a “slowly emerging disaster” (Viens and Littmann 2015). The risk of acquired ABR was recognised before the first antibiotics were widely used and its dire consequences have been understood by experts for many years, but the magnitude of the threat and the urgent need for radical solutions to limit its impact have been widely acknowledged only recently. In this chapter, we argue that it is not too late to mitigate the disaster and check its progress, at least in hospital settings, if certain contributory factors are acknowl- edged and addressed without delay. These factors, we suggest, include naïve opti- mism, ignorance, hubris and nihilism on the part of pharmaceutical companies, healthcare professionals (mainly prescribing doctors) and health administrators, among others.\n\nBy the first half of the twentieth century, improvements in living conditions in industrialised countries contributed to rapidly falling infectious disease mortality (Armstrong et al. 1999). At the same time, surgical antisepsis, clean wards, hand washing by clinicians and skilled nursing care (Larson 1989; Gill and Gill 2005), had diminished the risk of death in hospitals from puerperal or postoperative sepsis (Gawande 2012). But the remedies for serious infections, such as bleeding, purging or toxic infusions of arsenic, mercury or opiates, probably hastened, more than they postponed, death (Funk et al. 2009).", "n_tokens": 310, "kind": "text"}
{"chunk_id": "drug_resistance_book-103-2", "doc_id": "drug_resistance_book", "page": 103, "text": "Antibiotics changed all that. From the beginning they were hailed as miracle drugs. Doctors embraced their use, not only to cure once life-threatening diseases, but also, because they seemed so free of adverse effects, to treat minor infections or even a perceived risk of infection. But, as early as 1945, Alexander Fleming, who shared a Nobel Prize for the discovery of penicillin, warned: “…the public will demand [penicillin]…then will begin an era…of abuses. The microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be\n\n1 Most of what follows applies to antimicrobial resistance (AMR), generally, but antibiotics are by far the most commonly prescribed antimicrobials, in human medicine, which is the focus of this chapter; therefore, our discussion will mainly focus on ABR.", "n_tokens": 183, "kind": "text"}
{"chunk_id": "drug_resistance_book-104-0", "doc_id": "drug_resistance_book", "page": 104, "text": "6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship…\n\npassed to other individuals ……In such a case the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally suc- cumbs to infection with the penicillin-resistant organism. ” (A. Fleming, 1945,2 quoted in (Bartlett et al. 2013)) And, indeed, within a few years most hospital iso- lates of previously susceptible Staphylococcus aureus were penicillin resistant (Barber and Rozwadowska-Dowzenko 1948).", "n_tokens": 128, "kind": "text"}
{"chunk_id": "drug_resistance_book-104-1", "doc_id": "drug_resistance_book", "page": 104, "text": "Although they recognised that overuse would promote resistance, pharmaceuti- cal companies aggressively promoted the benefits and safety of antibiotics to doc- tors and directly to the public. And, in the 1950s they recognised an even larger market when Thomas Jukes, at Lederle laboratories, demonstrated the growth- promoting effect of antibiotics in food-producing animals: “Animals receiving 10 ppm of chlortetracycline in the diet developed resistance in their intestinal bacteria in less than two days…[but] their growth rate increased. ….we concluded that if [resistant pathogens] appeared … usefulness of the antibiotic supplement would vanish and farmers would stop feeding it. …The [company] decision was strongly opposed by the veterinarians at Lederle, but their wishes were abruptly denied by Dr. Malcolm [Lederle President], who made an individual decision to go ahead. Competition was right on our heels...” (Jukes 1985). And it soon caught up: “The power of the calliope in the antibiotic bandwagon increased spectacularly during the [1950s] while poultry, pigs, and patients danced to its tune.” (T. D. Luckey, 1959,3 quoted in (Podolsky 2017)).", "n_tokens": 263, "kind": "text"}
{"chunk_id": "drug_resistance_book-104-2", "doc_id": "drug_resistance_book", "page": 104, "text": "By the mid-twentieth century, it was predicted that antibiotics (and vaccines) would put an end to infectious diseases. “[T]he belief that infectious diseases had been successfully overcome was pervasive in biomedical circles - including … a Nobel Laureate, medical Dean, and other thought leaders - from as early as 1948……..” (Spellberg and Taylor-Blake 2013). It was widely assumed that if bac- teria developed resistance to one drug, as they often did, there would soon be better ones to replace it; and, for many years, there were. Indeed there was such confi- dence that infections could be easily cured, that preventing them became a lower priority. But by the 1970s there was mounting disquiet about the emergence of ABR. Methicillin resistant S. aureus (MRSA) (Jevons et al. 1963) and transmissible resistance in Gram-negative bacteria (Datta and Pridie 1960) had emerged in the 1960s and their prevalence was increasing, especially in hospitals (Chambers 2001; Aminov 2010; Ventola 2015). The first International Conference on Nosocomial Infections, in 1970, was followed by the Study on the Efficacy of Nosocomial Infection Control (SENIC), in the USA (Forder 2007); in Australia, the handbook of “Antibiotic Guidelines” was published for the first time, in 1978 (Harvey et al. 2003). Anxiety that antibiotics would progressively lose efficacy, became more acute in the 1980s, when the seemingly unlimited flow of new antibiotics slowed to", "n_tokens": 324, "kind": "text"}
{"chunk_id": "drug_resistance_book-104-3", "doc_id": "drug_resistance_book", "page": 104, "text": "2 Alexander Fleming. Penicillin’’s finder assays its future. New York Times 26 June 1945: 21 3 Luckey TD. Antibiotics in nutrition. In: Goldberg HS, ed. Antibiotics: Their Chemistry and Non- Medical Uses. Princeton: D. Van Nostrand; 1959:174–321.\n\n91", "n_tokens": 67, "kind": "text"}
{"chunk_id": "drug_resistance_book-105-0", "doc_id": "drug_resistance_book", "page": 105, "text": "92\n\nG. L. Gilbert and I. Kerridge\n\na trickle, and pharmaceutical companies turned their attention to more profitable projects.\n\nAntibiotic use is no longer regarded as an unquestioned good. Antimicrobial resistance (AMR) is now seen as a threat to global health security and the “end of the antibiotic era” predicted; it is broadly accepted that urgent measures are needed to salvage what we can of the “antibiotic miracle”: more prudent use of existing antimicrobial agents; novel strategies to promote development of new ones; and greater attention to preventing the spread of drug resistance organisms (WHO 2012; CDC 2013).\n\n6.2\n\nHospital Infection in the “Pre-Antibiotic Era”\n\nIn nineteenth century Europe, medical science advanced rapidly; there was increas- ing demand for new hospitals, where university-trained doctors could develop and experiment with new remedies and advance their knowledge. Anaesthetics increased the scope of surgery (Gawande 2012) and pregnant women were more likely to be admitted to ‘lying-in’ hospitals, where advances in obstetrics offered relief from excessively long, difficult labour (Loudon 1986). But hospitals were overcrowded, dirty and poorly ventilated; infectious disease outbreaks were common and mater- nal mortality from childbed fever much higher in hospitals than in the community.", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-105-1", "doc_id": "drug_resistance_book", "page": 105, "text": "Alexander Gordon, an Aberdeen physician, had recognised puerperal fever as a “specific contagion or infection” that could be carried between parturient women on the hands of her attendants, in 1795 (Gordon 1795), but his work was ignored until the 1840s, when James Young Simpson, in Edinburgh (Selwyn 1965), Oliver Wendell Holmes, in Boston (Holmes 2001), and Ignaz Semmelweis (Nuland 1979; Carter 1981), in Vienna, independently came to similar conclusions. Simpson also recognised that puerperal and surgical fevers were “intercommunicable” and coined the term “hospitalism” to describe outbreaks of surgical infection, which he believed were so serious that “…every patient placed upon an operating table … is in … greater danger than a soldier entering one of the bloodiest and most fatal bat- tlefields” (J. Y. Simpson, 1859 quoted in (Selwyn 1965)).", "n_tokens": 198, "kind": "text"}
{"chunk_id": "drug_resistance_book-105-2", "doc_id": "drug_resistance_book", "page": 105, "text": "In Vienna, Semmelweis was troubled by the much higher maternal mortality, in a clinic staffed by doctors and medical students, than in an otherwise similar clinic staffed by midwives. After months of investigation, he realised that the only signifi- cant difference between the clinics was that, unlike the midwives, the students and doctors frequented the mortuary, dissecting the bodies of women who had died from childbed fever. When they returned to the clinic, they carried on their hands “cadaver particles which are not entirely removed by the ordinary method of washing the hands with soap....[Therefore] the hands of the examiner must be cleansed with chlorine, not only after handling cadavers, but likewise after examining patients” (Semmelweis 1983). After he enforced this strict hand washing regime, the mater- nal mortality in the doctors’ clinic rapidly fell to a level similar to that in the mid- wives’ clinic (Nuland 1979). Despite the evidence, Semmelweis’ findings lacked a", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-106-0", "doc_id": "drug_resistance_book", "page": 106, "text": "6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship…\n\nconceptual basis, 20 years in advance of Pasteur’s germ theory of disease, and were largely rejected by his peers. His accusation that anyone who did not follow his recommendations would be ‘murderers’, undoubtedly contributed to their antago- nism (Pittet 2004; Saint et al. 2010a).\n\nDuring the Crimean war, in 1854, the British public was scandalised by a news- paper report of deplorable conditions in the British Army hospital at Scutari. When Florence Nightingale was sent to investigate, she found vermin- and lice-infested wards, excreta on walls and floors, injured soldiers in dirty, bloodstained clothes and frequent infectious disease outbreaks. Nightingale believed that disease was caused by filth and foul air (miasmas); she overcame bitter opposition from the military surgeons and formidable logistic barriers to implement a strict regime - immediate wound care; clean dressings, clothes and bedding; nutritious food; and regular cleaning and ventilation of wards. Her meticulous records showed that soldiers were far more likely to die from preventable infection than war wounds. In the January–March quarter of 1855, the mortality at Scutari was 33%, by the July– September quarter it was 2%. While critics have belittled her achievements, her methods remain the basis of good nursing care and hospital infection control (Larson 1989; Gill and Gill 2005).", "n_tokens": 311, "kind": "text"}
{"chunk_id": "drug_resistance_book-106-1", "doc_id": "drug_resistance_book", "page": 106, "text": "In the 1860s, Joseph Lister’s knowledge of Pasteur’s germ theory informed his belief that the almost inevitable (and often fatal) suppuration that complicated com- pound fractures and amputations was due to “minute organisms suspended in [the atmosphere], which owed their energy to their vitality” (Lister 1867). By liberal use of carbolic acid to soak wound dressings and disinfect his hands, instruments and the operative site, he was able to manage most compound fractures without amputa- tion and the post-amputation mortality fell from 46% (16/35) in 1864–6 to 15% (6/40) in 1867–9 (Newsom 2003). Many of his compatriots ridiculed his methods, but they were gradually accepted, particularly in Europe. His acknowledged place as the “father of antiseptic surgery” owes much to its basis in the germ theory, which gave it an authority that Semmelweis’ earlier work lacked.\n\nAs antisepsis and later asepsis, environmental hygiene and skilled nursing care were gradually incorporated into hospital practice, hospital infection rates fell and hospitals became places of healing rather than dying.\n\n6.3", "n_tokens": 249, "kind": "text"}
{"chunk_id": "drug_resistance_book-106-2", "doc_id": "drug_resistance_book", "page": 106, "text": "The Antibiotic Era\n\nAcquired antibiotic resistance (ABR), of bacterial pathogens that affect humans, is mainly due to nearly 75 years’ of both appropriate and inappropriate antibiotic use in human medicine and dissemination of resistant organisms. Antibiotic use in agri- culture and veterinary practice and environmental contamination are also impli- cated, but their contributions are contested and vary from region to region (Landers et al. 2012; Marshall and Levy 2011; Chang et al. 2015). The dynamics are complex and incompletely understood (Turnidge and Christiansen 2005) but, in general, exposure of bacteria to antibiotics exerts powerful selection pressure; the greater the\n\n93", "n_tokens": 136, "kind": "text"}
{"chunk_id": "drug_resistance_book-107-0", "doc_id": "drug_resistance_book", "page": 107, "text": "94\n\nG. L. Gilbert and I. Kerridge\n\ntotal amount and the broader the antibacterial spectra of antibiotics used in any set- ting, such as a hospital (Willemsen et al. 2009; Xu et al. 2013) or community (Goossens et al. 2005; Bell et al. 2014), the higher the prevalence of ABR. More antibiotics (by weight) are prescribed for non-human animals than people and envi- ronmental contamination is a major contributor to ABR. Nevertheless, although inappropriate prescribing is probably the main contributor to drug resistant infec- tions humans, it is now accepted that control of AMR/ABR requires a One Health approach (Robinson et al. 2016). However, the focus of this chapter is on ABR in hospitals, where multidrug resistant organisms (MDROs)4 are most obvious and prevalent5 and preventive measures most likely to be effective.", "n_tokens": 195, "kind": "text"}
{"chunk_id": "drug_resistance_book-107-1", "doc_id": "drug_resistance_book", "page": 107, "text": "Most life-threatening infections are treated in hospitals, where the greatest vari- ety of antibiotics is used, in repeated courses or for prolonged periods. In hospitals, busy healthcare professionals often carry MDROs on their hands, exposing patients to the risk of healthcare-associated infection (HAI) or colonisation with an MDRO. Hospital laboratory reports increase prescribers’ awareness of ABR and, perhaps, promote a (mistaken) perception that it is ubiquitous; this may encourage defensive prescribing – e.g. of multiple or broad-spectrum agents - to avert treat- ment failure. Paradoxically, increased awareness of ABR is not necessarily reflected in increased adherence to measures designed to prevent it. Now that it is recognised that profligate antibiotic use promotes ABR and inadequate infection prevention and control (IPC) facilitates transmission, the challenge is to break these intersect- ing vicious cycles, particularly in hospitals, where they are most apparent.\n\n6.4", "n_tokens": 198, "kind": "text"}
{"chunk_id": "drug_resistance_book-107-2", "doc_id": "drug_resistance_book", "page": 107, "text": "Antibiotic Use and Stewardship in Hospitals\n\nAntibiotics are prescribed very frequently in hospitals; studies in USA and Australia have shown that more than 50% of hospital patients receive at least one antibiotic and up to 50% of prescriptions are unnecessary or inappropriate, according to pre- scribing guidelines (Turnidge et al. 2016; Baggs et al. 2016; Reddy et al. 2015). Making the right antibiotic prescribing decision is difficult, even for an experienced practitioner, particularly when the diagnosis is uncertain. For patients with sepsis - especially those most at risk of life-threatening infections, e.g. who are neutropenic or immune-compromised - delay can lead to serious complications or death from septic shock (Kumar et al. 2006). But antibiotics prescribed empirically are often continued, even after an alternative diagnosis is made, or not reviewed, despite labo- ratory results that indicate the empirical choice was ineffective or unnecessarily\n\n4 MDROs are resistant to more than one - usually several – classes of antibiotic; they include methi- cillin resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and extended spectrum β lactamase- and carbapenemase-producing (ESBL and CPE, respectively) Enterobacteriaceae. 5 In countries where antibiotics can be used in humans or animals without restriction, high rates of ABR occur in the community and in hospitals.", "n_tokens": 310, "kind": "text"}
{"chunk_id": "drug_resistance_book-108-0", "doc_id": "drug_resistance_book", "page": 108, "text": "6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship…\n\nbroad-spectrum (Braykov et al. 2014). Antibiotics are also often given in combina- tion, in the wrong dose, by the wrong route or for too short or too long a period (Dryden et al. 2011; Gilbert 2015). Any of these errors can contribute to ABR, without concomitant benefit to the patient herself and, potentially, with significant harm including an increased risk of Clostridium difficile infection, MDRO acquisi- tion or prolonged disruption of the gut microbiome, with potentially serious adverse effects (Dingle et al. 2017; Becattini et al. 2016).", "n_tokens": 155, "kind": "text"}
{"chunk_id": "drug_resistance_book-108-1", "doc_id": "drug_resistance_book", "page": 108, "text": "Diagnostic uncertainty is not the only, or even the most common, reason for inappropriate prescribing. The prescriber’s rational concern can transform into excessive risk aversion, without regard for antibiotic conservation or potential adverse effects on the patient. A junior hospital doctor may consider ABR “morally and professionally important...” but “of limited concern at the bedside” (Broom et al. 2014). Fear of missing something or being criticised, by peers or superiors, outweighs consideration of long-term risks to future patients or the environment. She may prescribe an antibiotic, even if she thinks it unnecessary or futile, because of inexperience, her consultant’s routine practice or a duty of benevolence towards her patient that makes her want to do something. Junior doctors are required to make complicated prescribing decisions, often in the face of conflicting, inconsis- tent (or no) advice or feedback (Mattick et al. 2014). Broom et al. (Broom et al. 2014) concluded that “..social risks, including the peer-based and hierarchical repu- tational consequences associated with ‘not doing enough’” are far more potent than the risk of ABR (Broom et al. 2014).", "n_tokens": 264, "kind": "text"}
{"chunk_id": "drug_resistance_book-108-2", "doc_id": "drug_resistance_book", "page": 108, "text": "Over the past 10 years, programs have been introduced into hospital practice in many countries with the aim of minimising inappropriate antibiotic therapy. Antimicrobial stewardship (AMS) programs aim to ensure that patients are given antibiotics when they need them – “the right drug, at the right time, in the right dose and for the right duration” (Dryden et al. 2011; Doernberg and Chambers 2017) – with the least possible selection pressure. They consist of ‘bundles’ of interventions, including: restrictions on the use of certain key antibiotics, except with specific authorisation; prescriber education and academic detailing; audit of prescribing pat- terns, with feedback to prescribers; optimisation of laboratory testing, including rapid diagnostics; and technological support such as electronic access to microbiol- ogy results and computerised decision support systems (Davey et al. 2017).", "n_tokens": 188, "kind": "text"}
{"chunk_id": "drug_resistance_book-108-3", "doc_id": "drug_resistance_book", "page": 108, "text": "AMS programs depend on multidisciplinary teams - including infectious disease physicians, clinical microbiologists, specialist antimicrobial pharmacists and/or IPC professionals - whose complementary expertise and spheres of influence pro- vide mutual support and greater authority than each has, individually. The specialist pharmacist’s expertise in drug dosing, interactions and administration and her role in implementing regulations, such as automatic stop orders or restricted drug authorisation, and auditing prescribing records, are critical to an AMS program. Nevertheless, even the most experienced pharmacist or AMS team can encounter resistance from a senior specialist who may regard their advice as a threat to her autonomy and clinical experience (Broom et al. 2016).\n\nHow effective an AMS program will be depends on what it includes and how it is implemented. A recent systematic review (Davey et al. 2017) showed that\n\n95", "n_tokens": 188, "kind": "text"}
{"chunk_id": "drug_resistance_book-109-0", "doc_id": "drug_resistance_book", "page": 109, "text": "96\n\nG. L. Gilbert and I. Kerridge\n\nproviding advice and feedback to clinicians improved prescribing and reduced over- all antibiotic use more than simply imposing rules and restrictions, suggesting that AMS programs that support prescribers help to mitigate the fear of censure or litiga- tion that often drives inappropriate prescribing. Overall, studies of AMS show that it can reduce inappropriate prescribing, pharmacy costs and avoidable drug reac- tions; improve therapeutic drug monitoring; shorten hospital length of stay by an average of 2 days; and may reduce rates of C. difficile, fungal and MDRO infections (Davey et al. 2013; Baur et al. 2017). Although some studies have confirmed the cost-effectiveness of AMS, more high-quality research is needed (Coulter et al. 2015).\n\nClearly, eliminating inappropriate antibiotic use is necessary, but not sufficient,\n\nto reduce the impact of ABR, which is exacerbated by hospital spread of MDROs.\n\n6.5\n\nHospital Infection Prevention and Control (IPC) and ABR\n\n6.5.1\n\nHealthcare-Associated Infections and Their Consequences", "n_tokens": 243, "kind": "text"}
{"chunk_id": "drug_resistance_book-109-1", "doc_id": "drug_resistance_book", "page": 109, "text": "According to WHO “…..HAI is the most frequent adverse event in health care [but] its true global burden remains unknown because of the difficulty in gathering reli- able data” (WHO 2011). A systematic review of HAIs in high and middle/low- income countries showed that 3.5%–12% of hospitalised patients develop at least one HAI (WHO 2011), of which 50%, or more, are potentially preventable (Harbarth et al. 2003; Umscheid et al. 2011). The estimated number of people, globally, who die from drug-resistant infections each year – currently at least 700,000 - is pre- dicted to increase to ten million by 2050 (O’Neill 2016). HAIs caused by MDROs are more difficult to treat, more likely to be fatal and more costly than comparable HAIs due to antibiotic-susceptible pathogens (Cosgrove 2006; de Kraker et al. 2011). HAI risks are associated with patient factors: severity of illness and co- morbidities such as chronic organ failure, malnutrition, immune-suppression, seri- ous trauma or contaminated surgery; and organisational factors: bed occupancy rate; staff workload; hospital environment and infrastructure; prevalence of endemic or introduced MRDO pathogens; adherence of healthcare workers to basic hygiene principles (Clements et al. 2008; Daud-Gallotti et al. 2012; Scheithauer et al. 2017). Hospital IPC policies are designed to minimise these risks and the burden of HAIs and ABR. Unlike other adverse hospital events, MDRO colonisation and HAIs are not confined to individuals; they are", "n_tokens": 354, "kind": "text"}
{"chunk_id": "drug_resistance_book-109-2", "doc_id": "drug_resistance_book", "page": 109, "text": "communal threats that affect other patients, hospital staff and the wider community and add to the burden of AMR.", "n_tokens": 22, "kind": "text"}
{"chunk_id": "drug_resistance_book-110-0", "doc_id": "drug_resistance_book", "page": 110, "text": "6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship…\n\nEven without clinically significant infection, MDRO colonisation has significant impacts. Patients colonised with certain high-impact MDROs6 are identified by active admission screening and isolated in single rooms, with contact precautions.7 These are expensive measures and they can adversely affect patient care and wellbe- ing. Patients in contact isolation are, on average, visited by healthcare workers less often and for shorter periods; less likely to be examined by a doctor; more likely to suffer non-infectious adverse effects, such as falls, pressure sores and fluid and elec- trolyte imbalance; and more likely to express dissatisfaction with their hospital care, than other patients (Saint et al. 2003; Stelfox et al. 2003; Morgan et al. 2014). They may feel stigmatised and anxious about risks to family members; they and their visi- tors are often inadequately informed or given conflicting information about the implications of MDRO colonisation and how to protect themselves and others (Wyer et al. 2015; Seibert et al. 2017). Contact isolation is also burdensome to healthcare workers. Compliance with hand hygiene and use of personal protective equipment (and, thus, the effectiveness of contact isolation) is often relatively poor and likely to deteriorate as the number of isolated patients increases (Clock et al. 2010; Dhar et al. 2014).", "n_tokens": 299, "kind": "text"}
{"chunk_id": "drug_resistance_book-110-1", "doc_id": "drug_resistance_book", "page": 110, "text": "Moreover, there is conflicting evidence (Cohen et al. 2015; Morgan et al. 2017), as to whether active screening and contact isolation prevent MDRO transmission more effectively than less expensive and burdensome measures such as strict adher- ence to standard precautions8 (Huskins et al. 2011) and/or targeted contact isolation of patients with other risk factors (e.g. diarrhoea, open wounds) (Djibre et al. 2017). This raises the question as to whether these practices are ethically justified, based on the precautionary principle - i.e. that they might prevent harm to others - or cost- effective. Patients are rarely asked for their consent to be screened or informed of the consequences of a positive result, although contact isolation will restrict their liberty for others’, but not their own, benefit. It is arguable that these measures are ethically justifiable if: the specific MRDO for which they are implemented is par- ticularly dangerous; patients are fully informed, before they are screened, of the reasons, implications and benefits of MDRO colonisation; and there is adequate staffing to ensure they are implemented with optimal effectiveness and minimal risk. An alternative approach would be to promote strict adherence to standard pre- cautions, by all staff, behind a “veil of ignorance” by assuming that any patient might be MDRO-colonised and engaging patients - when their condition permits - and their visitors as active participants in IPC (Ahmad et al. 2016). If given an", "n_tokens": 317, "kind": "text"}
{"chunk_id": "drug_resistance_book-110-2", "doc_id": "drug_resistance_book", "page": 110, "text": "opportunity and adequate information, patients can make positive contributions to IPC, including how to minimise MDRO transmission and the adverse effects of contact isolation (Wyer et al. 2015).", "n_tokens": 38, "kind": "text"}
{"chunk_id": "drug_resistance_book-110-3", "doc_id": "drug_resistance_book", "page": 110, "text": "6 MDROs for which special control measures are used are chosen according to criteria such as: extent of resistance, transmissibility, virulence and local prevalence: e.g. they often include MRSA, VRE and CPE. 7 Contact precautions include routine use of gown and gloves when caring for patients in isolation, in addition to standard precautions, which include hand hygiene as the main component, and use of personal protective equipment when exposure to patient’s blood or body fluid is anticipated 8 Mainly strict compliance with hand hygiene.\n\n97", "n_tokens": 108, "kind": "text"}
{"chunk_id": "drug_resistance_book-111-0", "doc_id": "drug_resistance_book", "page": 111, "text": "98\n\nG. L. Gilbert and I. Kerridge\n\n6.5.2\n\nHospital IPC Programs\n\nGiven the adverse individual and communal effects and excess costs of HAIs and MDRO colonisation, healthcare organisations and professionals have an unequivo- cal duty-of-care and ethical responsibility to take appropriate measures to prevent them. Hospital IPC programs include, inter alia: hand hygiene; appropriate use of personal protective equipment; aseptic technique for invasive procedures; environ- mental hygiene; air flow; bundles of measures to prevent certain HAI syndromes, such as device-related blood stream infections; surveillance of selected HAIs and feed-back of data to clinicians; and isolation of infected and MDRO-colonised patients, with the caveats outlined above (Sydnor and Perl 2011).\n\nIt is usually impossible to trace an HAI or MRDO transmission event to a spe- cific action, omission or individual healthcare worker, because there are inevitable time gaps and multiple factors and people involved (McLaws 2015). HAIs “do not carry fingerprints … to identify the offending healers who failed the patient.” (Palmore and Henderson 2012).", "n_tokens": 245, "kind": "text"}
{"chunk_id": "drug_resistance_book-111-1", "doc_id": "drug_resistance_book", "page": 111, "text": "The effectiveness of an IPC program depends on organisational commitment, adequate resources and participation of everyone in the hospital community. Despite the compelling ethical imperative to “do no harm”, the economic burden of HAIs (Stone 2009) and proven cost-effectiveness (Dick et al. 2015) of IPC programs, they often struggle to attract the necessary support and resources. Their beneficiaries, like those of any preventive program, are unknown “statistical lives” whose demands are far less compelling than those of known “identified lives” who need immediate, often expensive, interventions (Cookson et al. 2008; Beauchamp and Childress 2009). The typically low priority of IPC is reflected in a vicious cycle of inadequate resources, poor compliance - and, hence, limited effectiveness - which can then seem to justify further cost cutting.", "n_tokens": 169, "kind": "text"}
{"chunk_id": "drug_resistance_book-111-2", "doc_id": "drug_resistance_book", "page": 111, "text": "The basic principles of hospital IPC were recognised in the nineteenth century and incorporated into routine hospital policy in the latter part of the twentieth, when it became clear that antibiotics, alone, could not prevent morbidity and mortality from HAIs. Nevertheless, implementation and maintenance of IPC programs remain a major challenge. Variation in HAI rates, between otherwise comparable hospitals, presumably reflects differences in organizational cultures, policies, working condi- tions (Daud-Gallotti et al. 2012; Krein et al. 2010) and professional attitudes, behav- iours and leadership (Saint et al. 2010a), suggesting that improvement is possible.\n\n6.5.3\n\nThe Central Role of Hand Hygiene in IPC\n\n“In the absence of the possibility to directly link individual infectious outcomes to individual hand hygiene failures… hand hygiene performance remains the only measure to judge the degree of system safety….” (Stewardson et al. 2011). Despite the proven effectiveness of hand hygiene in preventing MDRO transmission (Pittet et al. 2000; Johnson et al. 2005), compliance is often poor. The discovery, about", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-112-0", "doc_id": "drug_resistance_book", "page": 112, "text": "6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship…\n\n20 years ago, that it could be improved by use of alcohol-based hand rub (ABHR), was a major breakthrough. ABHR has significant advantages over traditional hand washing with soap and water: it takes less time, is less irritant to hands, accessible at the point-of-care and in settings without access to clean water and has more rapid and potent antibacterial action (Pittet et al. 2000; Widmer 2000). In 2007, “My Five Moments of Hand Hygiene” was introduced to improve healthcare worker training and standardise monitoring and reporting of hand hygiene compliance (Sax et al. 2007); in 2009, the “Five Moments” were incorporated into WHO hand hygiene guidelines. Since then, there have been numerous studies and reviews of factors affecting compliance and interventions to improve it (Erasmus et al. 2009; Huis et al. 2012; Neo et al. 2016; Kingston et al. 2016).", "n_tokens": 211, "kind": "text"}
{"chunk_id": "drug_resistance_book-112-1", "doc_id": "drug_resistance_book", "page": 112, "text": "One review reported an overall average compliance of 40%; it was lower in ICUs (30–40%) than other settings (50–60%); among doctors (32%) than nurses (48%) and for moment one (before patient contact; 21%) than moment four (after patient contact; 47%). Performing dirty tasks, availability of ABHR, and performance feed- back were associated with better compliance (Erasmus et al. 2009). A review of interventions reported an average pre-intervention compliance of 34% with vari- able, but modest improvements (8–31%) and mean post-intervention compliance of 57%. Multimodal interventions included various combinations of staff education, facility design and planning, HAI surveillance and/or compliance monitoring with feedback, financial incentives and active support by clinical champions and hospital administrations (Kingston et al. 2016).", "n_tokens": 180, "kind": "text"}
{"chunk_id": "drug_resistance_book-112-2", "doc_id": "drug_resistance_book", "page": 112, "text": "These studies illustrate the enormous effort entailed in achieving even modest, often short-term, improvements. They contrast with the, apparently, much better compliance achieved by the Australian National Hand Hygiene Initiative, which was established in 2009 as a “standardised hand hygiene culture-change program throughout all Australian hospitals to improve … compliance among Australian health care workers; establish a validated system of …auditing to allow local, national and international benchmarking…” (Grayson et al. 2011). Between 2009 and June 2017, overall compliance increased, steadily, from 63% to 85%, which clearly represents major improvement, to above the national benchmark (70%) (http://www.hha.org.au/). But it obscures significant variation (e.g. between hospi- tals, professional groups and moments) and sampling biases, suggesting aggregated national data can be misleading. Moreover, the estimated auditing cost is AU$2.2 million per annum for an annual improvement (adjusted for sampling) of 1% com- pliance (Azim and McLaws 2014).", "n_tokens": 230, "kind": "text"}
{"chunk_id": "drug_resistance_book-112-3", "doc_id": "drug_resistance_book", "page": 112, "text": "How should these data be interpreted? Routine audits, by direct observation, necessarily involve short periods of observation (20–30 minutes) at times of conve- nience and so are not representative of 24 hour/whole-of-hospital activity; it was estimated that <2% of total daily hand hygiene opportunities are sampled during a 60-minute audit (Fries et al. 2012). Auditing by direct observation is subject to the Hawthorne effect9 (Srigley et al. 2014) and observer bias; it does not assess whether hand hygiene is performed correctly and, when compared with continuous\n\n9 Hawthorne effect: individuals modify their behaviour in response to awareness of being observed.\n\n99", "n_tokens": 137, "kind": "text"}
{"chunk_id": "drug_resistance_book-113-0", "doc_id": "drug_resistance_book", "page": 113, "text": "100\n\nG. L. Gilbert and I. Kerridge\n\nautomated monitoring, overestimates compliance (Kwok et al. 2016). Furthermore, there is no consensus as to what target compliance rate is necessary or realistic (Mahida 2016). Video or electronic monitoring systems would reduce workload, measure compliance more consistently and could improve it, by providing rapid feedback and prompts (Srigley et al. 2015), but experience with their use is limited and there are many logistic, industrial, and ethical challenges (Palmore and Henderson 2012; Conway 2016). There is clearly a need to establish realistic com- pliance targets, more accurate, less labour intensive auditing methods and a more holistic approach to IPC monitoring.\n\n6.5.4\n\nDoctors and IPC", "n_tokens": 159, "kind": "text"}
{"chunk_id": "drug_resistance_book-113-1", "doc_id": "drug_resistance_book", "page": 113, "text": "There is extensive evidence than doctors’ hand hygiene compliance is consistently less than that of nurses, overall, albeit highly variable (Pittet et al. 2004; Cantrell et al. 2009). In one hospital it was more than 80% among physicians and paediatri- cians but only 30% among surgeons and anaesthetists (Pittet et al. 2004). Compliance has been associated with an emotional, outcome-oriented, rather than a ‘rational’, thinking style – typically associated with nurses and doctors, respectively (Sladek et al. 2008) - and inversely correlated with professional education level i.e. senior doctors were less compliant than junior doctors or nurses (Duggan et al. 2008). These differences matter: senior doctors have status and power within hospital com- munities and their attitudes and behaviours disproportionately influence those of other staff (Lankford et al. 2003). Poorly compliant, peripatetic junior doctors can act as “super-spreaders”, with many opportunities to transmit pathogens between the numerous individual patients they encounter each day (Temime et al. 2009; Hornbeck et al. 2012). Doctors are more likely to perform hand hygiene after patient contact, to avoid a perceived personal risk, than before contact, to protect patients (Scheithauer et al. 2011). Many believe these are equivalent, but overlook the many opportunities for contamination of their hands, from bed curtains, patient notes, door handles, computer keyboards etc., between patients. In a focus-group study of", "n_tokens": 324, "kind": "text"}
{"chunk_id": "drug_resistance_book-113-2", "doc_id": "drug_resistance_book", "page": 113, "text": "hospital staff, most non-physician participants said they noticed the hand hygiene practices of other staff and rated doctors least compliant. Doctors were confident of their hand hygiene knowledge but discounted its importance before patient contact. They rarely noticed the practices of others, apart from their senior colleagues; medi- cal students said that senior doctors’ hand hygiene practices influenced their own (Jang et al. 2010a, 2010b).", "n_tokens": 83, "kind": "text"}
{"chunk_id": "drug_resistance_book-113-3", "doc_id": "drug_resistance_book", "page": 113, "text": "The reasons for some doctors’ apparent lack of commitment to IPC may lie in the medical practice model, which focuses on individual patient’s clinical problems, which require investigation, decision-making, intervention, often with tangible results. IPC policies fit poorly with this model; they lack obvious utility, since they do not, meaningfully, influence clinical practice. The common perception that HAIs", "n_tokens": 78, "kind": "text"}
{"chunk_id": "drug_resistance_book-114-0", "doc_id": "drug_resistance_book", "page": 114, "text": "6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship…\n\nand MDRO acquisition are rare, but unavoidable, can promote a sense of nihilism – that they are inevitable features of contemporary healthcare. Often this is attribut- able to ignorance of the impacts of HAIs and benefits of IPC, which is partly because of inadequate surveillance and feedback to clinicians.", "n_tokens": 85, "kind": "text"}
{"chunk_id": "drug_resistance_book-114-1", "doc_id": "drug_resistance_book", "page": 114, "text": "Some doctors’ apparent indifference or even hostility towards IPC may also reflect aspects of professional and organisational cultures. Traditionally, IPC has been a nursing responsibility; the role of infection control practitioners’ (usually nurses) is to implement IPC policies on behalf of hospital management, who have to report, against mandatory IPC performance indicators, to a central authority (e.g. Ministry of Health). Responsibility for monitoring these indicators, such as hand hygiene compliance, is often devolved to nurse managers, who are held to account if targets are not met. But they have little influence over doctors, who choose to ignore rules they see as unnecessary or excessive or who object, on principle, to any regulation, imposed by nurses or managers. “Senior doctors consider themselves exempt from following policy and practice within a culture of perceived autono- mous decision-making that relies more on personal knowledge and experience than formal policy” (Charani et al. 2013). This professional antipathy to IPC, may also reflect the historical - but gradually changing - gender distribution between nursing, which has been a largely female profession, and medicine, traditionally dominated by men, particularly in senior positions. Doctors’ attitudes to IPC are consistent with a more general failure - there are many exceptions - to engage in quality improvement activities or comply with organisational policies, which have been linked to an entrenched", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-114-2", "doc_id": "drug_resistance_book", "page": 114, "text": "medical culture (Jorm and Kam 2004) and/or to the per- ceived loss of professional autonomy and dominance associated with managerial- ism (Davies and Harrison 2003).", "n_tokens": 38, "kind": "text"}
{"chunk_id": "drug_resistance_book-114-3", "doc_id": "drug_resistance_book", "page": 114, "text": "How widespread these attitudes are and how the hospital management handles them will determine the success or failure of hospital-wide quality improvement programs such as IPC or AMS. If they are tolerated or seen as “too hard” to address, the morale of other staff and the success of the program will be compromised and recalcitrant doctors’ skepticism about its relevance, reinforced. On the other hand, some IPC rules are unnecessarily rigid and officiously enforced. They may seem straightforward to their authors, but poor compliance is sometimes due to clini- cians’ finding them confusing, incompatible with the realities of frontline practice or inappropriate in some settings (Hor et al. 2017). There are faults on both sides when, ideally, all “sides” should be working collaboratively to promote patient safety. The issues need to be addressed if healthcare management and staff are to fulfil their moral responsibility to support and participate in programs that promote patient safety. Individuals “are not somehow ‘outside’ and separate from ‘systems’: they create, modify and are subject to the social forces that are an inescapable fea- ture of any organizational system; each element acts on the other” (Aveling et al. 2016). The success of any program is likely to hang on the extent to which the val- ues and goals of all of its members – particularly the most influential - align with, and contribute to, those of the organisation.\n\n101", "n_tokens": 302, "kind": "text"}
{"chunk_id": "drug_resistance_book-115-0", "doc_id": "drug_resistance_book", "page": 115, "text": "102\n\nG. L. Gilbert and I. Kerridge\n\n6.5.5", "n_tokens": 16, "kind": "text"}
{"chunk_id": "drug_resistance_book-115-1", "doc_id": "drug_resistance_book", "page": 115, "text": "The Organization’s Role in IPC/AMS Programs\n\nGovernment and private healthcare funding bodies generally mandate that each hos- pital has established IPC and AMS programs and reports regularly, sometimes pub- licly, against mandatory performance targets. This does not necessarily guarantee the programs’ success; there are wide variations in practices and outcomes between apparently similar hospitals. Most studies of successful IPC/AMS interventions have focused on “what” works, rather than “why” it works. The components of organisational culture likely to determine the success or failure of program imple- mentation are leadership, shared vision and values, inter-professional relationships, resources and service priorities (Krein et al. 2010). Successful implementation of IPC/AMS, requires commitment by hospital management, strong clinical leader- ship (Saint et al. 2010b), highly motivated champions (Damschroder et al. 2009) and interdisciplinary departmental teams. The goals, benefits and measures of suc- cess of the programs need to be clearly defined, but flexible enough to allow local modification, based on the knowledge and experience of frontline staff. Imposing cultural change from without is less likely to be sustainable than allowing frontline staff to discover how to change it from within (Iedema et al. 2015; Zimmerman et al. 2013). Measures of success should be defined, monitored and rewarded, at least by timely feedback, if not more tangible recognition.\n\n6.6", "n_tokens": 300, "kind": "text"}
{"chunk_id": "drug_resistance_book-115-2", "doc_id": "drug_resistance_book", "page": 115, "text": "Conclusions\n\nAMR is an acknowledged threat to global health security and will not be adequately addressed by development of new antibiotics. The most urgent priority is to curtail the inappropriate use of antibiotics and spread of MDROs, which are most prevalent in hospitals where they are also most amenable to control. Despite evidence that properly implemented hospital AMS/IPC programs can reduce the burden of ABR, the increasing prevalence of preventable HAIs, show that many healthcare organisa- tions have either not recognised, or failed to meet, the challenge. In this chapter, we have identified some of the barriers to successful implementation of AMS/IPC pro- grams; although they are usually mandatory, in hospitals, their quality and outcomes vary. The organisational characteristics most likely to assure successful implemen- tation include: commitment to a shared vision and values; strong leadership, gover- nance and systems; respectful, collaborative inter-professional relationships and fair, cost-effective resource allocation.", "n_tokens": 201, "kind": "text"}
{"chunk_id": "drug_resistance_book-115-3", "doc_id": "drug_resistance_book", "page": 115, "text": "Healthcare organisations and hospital managers have ethical and legal responsi- bilities to protect existing patients, employees and the public – and future patients whose treatment will be compromised by a lack of effective antimicrobial therapy - from preventable harm originating in hospital facilities or activities. Unfortunately, preventive programs are often a low priority because their beneficiaries are unknown future persons whose claims are eclipsed by known, present persons and powerful professional or commercial interests. Preventive programs also generally lack the", "n_tokens": 100, "kind": "text"}
{"chunk_id": "drug_resistance_book-116-0", "doc_id": "drug_resistance_book", "page": 116, "text": "6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship…\n\nsolid, cost-effectiveness data that administrators demand before committing resources, especially if it is at the expense of therapies. A case for adequate resources to sustain AMS/IPC programs would, ideally, include local, as well as published, statistics on current rates, costs and adverse consequences of HAIs and ABR and personal histories of known patients who have suffered adverse effects from an HAI, contact isolation or inappropriate antibiotic administration.\n\nSuccessful AMS/IPC policies will be adaptable to unit/department-specific requirements rather than rigidly imposed rules and restrictions, which fail to account for variable, unpredictable clinical exigencies and so are liable to be ignored or circumvented. Effective policy implementation needs frontline ownership of “practice- based guidelines”, based on local knowledge, including potential patient participation.", "n_tokens": 184, "kind": "text"}
{"chunk_id": "drug_resistance_book-116-1", "doc_id": "drug_resistance_book", "page": 116, "text": "Policies and implementation plans often fail to clearly define their goals or how success will be measured. Evidence of success that can be rapidly fed back to staff is a strong motivator of adherence, but many hospital managers fail to invest in HAI surveillance and feedback to clinicians that is relevant, accessible and timely enough to motivate improvement. Despite the importance of hand hygiene compliance, its prominence as a single (often inaccurate) measure of IPC practice risks neglecting other important cultural and behavioural factors – teamwork, interdisciplinary co- operation and motivation – that determine the effectiveness of a hospital’s AMS/IPC programs.\n\nSecuring the commitment, of an often small, but powerful, minority of senior medical staff, who regard AMS/IPC programs as a threat to professional autonomy and status, remains a challenge for many hospitals. It requires, as a minimum, respectful consultation during program planning, recruitment of clinical leaders and champions and, once a decision is made to adopt it, clarity that all staff are expected to support and participate in programs to which the organisation is committed.\n\nReferences\n\nAhmad, R., et al. 2016. Defining the user role in infection control. The Journal of Hospital\n\nInfection 92 (4): 321–327.\n\nAminov, R.I. 2010. A brief history of the antibiotic era: Lessons learned and challenges for the", "n_tokens": 274, "kind": "text"}
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{"chunk_id": "drug_resistance_book-119-1", "doc_id": "drug_resistance_book", "page": 119, "text": "Hospital Infection 76 (1): 87–89.\n\nJevons, M.P., A.W. Coe, and M.T. Parker. 1963. Methicillin resistance in staphylococci. Lancet 1\n\n(7287): 904–907.\n\nJohnson, P.D., et al. 2005. Efficacy of an alcohol/chlorhexidine hand hygiene program in a hospital with high rates of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection. The Medical Journal of Australia 183 (10): 509–514.\n\nJorm, C., and P. Kam. 2004. Does medical culture limit doctors’ adoption of quality improvement?\n\nLessons from Camelot. Journal of Health Services Research & Policy 9 (4): 248–251.\n\nJukes, T.H. 1985. Some historical notes on chlortetracycline. Reviews of Infectious Diseases 7 (5):\n\n702–707.\n\nKingston, L., N.H. O’Connell, and C.P. Dunne. 2016. Hand hygiene-related clinical trials reported\n\nsince 2010: A systematic review. The Journal of Hospital Infection 92 (4): 309–320.\n\nKrein, S.L., et al. 2010. The influence of organizational context on quality improvement and patient safety efforts in infection prevention: A multi-center qualitative study. Social Science & Medicine 71 (9): 1692–1701.\n\nKumar, A., et al. 2006. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical Care Medicine 34 (6): 1589–1596.\n\nKwok, Y.L., C.P. Juergens, and M.L. McLaws. 2016. Automated hand hygiene auditing with and\n\nwithout an intervention. American Journal of Infection Control 44 (12): 1475–1480.", "n_tokens": 424, "kind": "text"}
{"chunk_id": "drug_resistance_book-119-2", "doc_id": "drug_resistance_book", "page": 119, "text": "Landers, T.F., et al. 2012. A review of antibiotic use in food animals: Perspective, policy, and\n\npotential. Public Health Reports 127 (1): 4–22.\n\nLankford, M.G., et al. 2003. Influence of role models and hospital design on hand hygiene of\n\nhealthcare workers. Emerging Infectious Diseases 9 (2): 217–223.\n\nLarson, E. 1989. Innovations in health care: Antisepsis as a case study. American Journal of Public\n\nHealth 79 (1): 92–99.\n\nLister, J. 1867. Antiseptic principles in the practice of surgery. British Medical Journal (Sept, 21):\n\n246–248.\n\nLoudon, I. 1986. Deaths in childbed from the eighteenth century to 1935. Medical History 30\n\n(1): 1–41.\n\nMahida, N. 2016. Hand hygiene compliance: Are we kidding ourselves? The Journal of Hospital\n\nInfection 92 (4): 307–308.\n\nMarshall, B.M., and S.B. Levy. 2011. Food animals and antimicrobials: Impacts on human health.\n\nClinical Microbiology Reviews 24 (4): 718–733.\n\nMattick, K., N. Kelly, and C. Rees. 2014. A window into the lives of junior doctors: Narrative interviews exploring antimicrobial prescribing experiences. The Journal of Antimicrobial Chemotherapy 69 (8): 2274–2283.", "n_tokens": 307, "kind": "text"}
{"chunk_id": "drug_resistance_book-120-0", "doc_id": "drug_resistance_book", "page": 120, "text": "6 Hospital Infection Prevention and Control (IPC) and Antimicrobial Stewardship…\n\nMcLaws, M.L. 2015. The relationship between hand hygiene and health care-associated infection:\n\nit’s complicated. Infection and Drug Resistance 8: 7–18.\n\nMorgan, D.J., K.S. Kaye, and D.J. Diekema. 2014. Reconsidering isolation precautions for endemic methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus. JAMA 312 (14): 1395–1396.\n\nMorgan, D.J., R.P. Wenzel, and G. Bearman. 2017. Contact precautions for endemic MRSA and\n\nVRE: Time to retire legal mandates. JAMA 318 (4): 329–330.\n\nNeo, J.R., et al. 2016. Evidence-based practices to increase hand hygiene compliance in health care facilities: An integrated review. American Journal of Infection Control 44 (6): 691–704. Newsom, S.W. 2003. Pioneers in infection control-Joseph Lister. The Journal of Hospital Infection\n\n55 (4): 246–253.\n\nNuland, S.B. 1979. The enigma of Semmelweis--an interpretation. Journal of the History of\n\nMedicine and Allied Sciences 34 (3): 255–272.\n\nO’Neill, J. 2016. Tackling drug-resistant infections globally: final report and recommendations. In", "n_tokens": 311, "kind": "text"}
{"chunk_id": "drug_resistance_book-120-1", "doc_id": "drug_resistance_book", "page": 120, "text": "The review on antimicrobial resistance, ed. J. O’Neill. London, UK.\n\nPalmore, T.N., and D.K. Henderson. 2012. Big brother is washing...Video surveillance for hand hygiene adherence, through the lenses of efficacy and privacy. Clinical Infectious Diseases 54 (1): 8–9.\n\nPittet, D. 2004. The Lowbury lecture: Behaviour in infection control. The Journal of Hospital\n\nInfection 58 (1): 1–13.\n\nPittet, D., et al. 2000. Effectiveness of a hospital-wide programme to improve compliance with\n\nhand hygiene. Infection Control Programme. Lancet 356 (9238): 1307–1312.\n\n———. 2004. Hand hygiene among physicians: Performance, beliefs, and perceptions. Annals of\n\nInternal Medicine 141 (1): 1–8.\n\nPodolsky, S.H. 2017. Historical perspective on the rise and fall and rise of antibiotics and human\n\nweight gain. Annals of Internal Medicine 166 (2): 133–138.\n\nReddy, S.C., et al. 2015. Antibiotic use in US hospitals: Quantification, quality measures and stew-\n\nardship. Expert Review of Anti-Infective Therapy 13 (7): 843–854.\n\nRobinson, T.P., et al. 2016. Antibiotic resistance is the quintessential one health issue. Transactions\n\nof the Royal Society of Tropical Medicine and Hygiene 110 (7): 377–380.\n\nSaint, S., et al. 2003. Do physicians examine patients in contact isolation less frequently? A brief\n\nreport. American Journal of Infection Control 31 (6): 354–356.\n\nSaint, S., J.D. Howell, and S.L. Krein. 2010a. Implementation science: How to jump-start infection", "n_tokens": 383, "kind": "text"}
{"chunk_id": "drug_resistance_book-120-2", "doc_id": "drug_resistance_book", "page": 120, "text": "prevention. Infection Control and Hospital Epidemiology 31 (Suppl 1): S14–S17.\n\nSaint, S., et al. 2010b. The importance of leadership in preventing healthcare-associated infection: Results of a multisite qualitative study. Infection Control and Hospital Epidemiology 31 (9): 901–907.\n\nSax, H., et al. 2007. ‘My five moments for hand hygiene’: A user-centred design approach to under- stand, train, monitor and report hand hygiene. The Journal of Hospital Infection 67 (1): 9–21. Scheithauer, S., et al. 2011. Suspicion of viral gastroenteritis does improve compliance with hand\n\nhygiene. Infection 39 (4): 359–362.\n\n———. 2017. Workload even affects hand hygiene in a highly trained and well-staffed setting: A prospective 365/7/24 observational study. The Journal of Hospital Infection 97 (1): 11–16. Seibert, G., et al. 2017. What do visitors know and how do they feel about contact precautions?", "n_tokens": 239, "kind": "text"}
{"chunk_id": "drug_resistance_book-120-3", "doc_id": "drug_resistance_book", "page": 120, "text": "American Journal of Infection Control.\n\nSelwyn, S. 1965. Sir James Simpson and Hospital cross infection. Medical History 9: 241–248. Semmelweis, I. 1983. The etiology, concept and prophylaxis of childbed fever, Wisconsin Publications in the History of Science and Medicine. London: University of Wisconsin Press. Sladek, R.M., M.J. Bond, and P.A. Phillips. 2008. Why don’t doctors wash their hands? A cor- relational study of thinking styles and hand hygiene. American Journal of Infection Control 36 (6): 399–406.\n\nSpellberg, B., and B. Taylor-Blake. 2013. On the exoneration of Dr. William H. Stewart: debunk-\n\ning an urban legend. Infectious Diseases of Poverty 2 (1): 3.\n\n107", "n_tokens": 179, "kind": "text"}
{"chunk_id": "drug_resistance_book-121-0", "doc_id": "drug_resistance_book", "page": 121, "text": "108\n\nG. L. Gilbert and I. Kerridge\n\nSrigley, J.A., et al. 2014. Quantification of the Hawthorne effect in hand hygiene compliance moni- toring using an electronic monitoring system: A retrospective cohort study. BMJ Quality and Safety 23 (12): 974–980.\n\n———. 2015. Hand hygiene monitoring technology: A systematic review of efficacy. The Journal\n\nof Hospital Infection 89 (1): 51–60.\n\nStelfox, H.T., D.W. Bates, and D.A. Redelmeier. 2003. Safety of patients isolated for infection\n\ncontrol. JAMA 290 (14): 1899–1905.\n\nStewardson, A., et al. 2011. Back to the future: Rising to the Semmelweis challenge in hand\n\nhygiene. Future Microbiology 6 (8): 855–876.\n\nStone, P.W. 2009. Economic burden of healthcare-associated infections: An American perspective.\n\nExpert Review of Pharmacoeconomics & Outcomes Research 9 (5): 417–422.\n\nSydnor, E.R., and T.M. Perl. 2011. Hospital epidemiology and infection control in acute-care set-\n\ntings. Clinical Microbiology Reviews 24 (1): 141–173.\n\nTemime, L., et al. 2009. Peripatetic health-care workers as potential superspreaders. Proceedings of the National Academy of Sciences of the United States of America 106 (43): 18420–18425. Turnidge, J., and K. Christiansen. 2005. Antibiotic use and resistance--proving the obvious. Lancet\n\n365 (9459): 548–549.\n\nTurnidge, J.D., et al. 2016. Antimicrobial use in Australian hospitals: How much and how appro-", "n_tokens": 395, "kind": "text"}
{"chunk_id": "drug_resistance_book-121-1", "doc_id": "drug_resistance_book", "page": 121, "text": "priate? The Medical Journal of Australia 205 (10): S16–S20.\n\nUmscheid, C.A., et al. 2011. Estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality and costs. Infection Control and Hospital Epidemiology 32 (2): 101–114.\n\nVentola, C.L. 2015. The antibiotic resistance crisis: Part 1: Causes and threats. P T 40 (4): 277–283. Viens, A.M., and J. Littmann. 2015. Is antimicrobial resistance a slowly emerging disaster? Public\n\nHealth Ethics 8 (3): 255–265.\n\nWHO. 2011. Report on the burden of endemic health care-Associated infection worldwide.\n\nGeneva: WHO.\n\n———, The evolving threat of antimicrobial resistance. Options for action. 2012 WHO: Geneva. Widmer, A.F. 2000. Replace hand washing with use of a waterless alcohol hand rub? Clinical\n\nInfectious Diseases 31 (1): 136–143.\n\nWillemsen, I., et al. 2009. Correlation between antibiotic use and resistance in a hospital:\n\nTemporary and ward-specific observations. Infection 37 (5): 432–437.\n\nWyer, M., et al. 2015. Involving patients in understanding hospital infection control using visual\n\nmethods. Journal of Clinical Nursing 24 (11–12): 1718–1729.\n\nXu, J., et al. 2013. Surveillance and correlation of antimicrobial usage and resistance of\n\nPseudomonas aeruginosa: A hospital population-based study. PLoS One 8 (11): e78604.\n\nZimmerman, B., et al. 2013. Front-line ownership: Generating a cure mindset for patient safety.", "n_tokens": 376, "kind": "text"}
{"chunk_id": "drug_resistance_book-121-2", "doc_id": "drug_resistance_book", "page": 121, "text": "Healthcare Papers 13 (1): 6–22.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 176, "kind": "text"}
{"chunk_id": "drug_resistance_book-122-0", "doc_id": "drug_resistance_book", "page": 122, "text": "Chapter 7 Epidemiology and Ethics of Antimicrobial Resistance in Animals\n\nLisa Boden and Dominic Mellor", "n_tokens": 23, "kind": "text"}
{"chunk_id": "drug_resistance_book-122-1", "doc_id": "drug_resistance_book", "page": 122, "text": "Abstract Despite a large and rapidly growing volume of research activity and out- put, primarily on the biological bases of antimicrobial resistance (AMR), epidemio- logical understanding of the causal mechanisms at play behind the apparent recent global rise in prevalence of AMR has, arguably, progressed very little. Despite this inconvenient fact, political imperative and expedience, among other drivers, have given substantial impetus to an interventionist approach against what are considered to be the culprits for the apparent growing prevalence of AMR and its impacts. Concern about the rise in prevalence of microbial infections that are resistant to therapeutic agents designed to kill them has arisen almost exclusively in relation to human health. (Public awareness and concern about antihelmintic resistance, for which the impacts are much more substantial for animal health, at least in developed temperate countries, are trivial by comparison). Nevertheless, antimicrobial drugs have been, and are, widely used in animal health and production throughout the world, and the contribution of this diverse usage to the ‘global AMR problem’ has historically been controversial. There is growing acceptance, notwithstanding the limitations in causal understanding noted previously, of AMR as an ecological prob- lem of competing populations of microorganisms experiencing both natural and anthropogenic selection pressures in compartments that transcend species and other boundaries.", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-122-2", "doc_id": "drug_resistance_book", "page": 122, "text": "Typifying what is described as a ‘One Health’ problem, AMR is there- fore considered to be most amenable to conjoint mitigation efforts in all compart- ments: i.e. interventions in human health, animal health, food and the environment in a coherent manner.", "n_tokens": 65, "kind": "text"}
{"chunk_id": "drug_resistance_book-122-3", "doc_id": "drug_resistance_book", "page": 122, "text": "In animals, this calls into question the motivations and practices for antimicro- bial drug usage, the majority of which are justified on the basis of promoting animal\n\nL. Boden Global Academy of Agriculture and Food Security, The Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of Edinburgh, Edinburgh, UK e-mail: lisa.boden@ed.ac.uk\n\nD. Mellor (*) School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK e-mail: dominic.mellor@glasgow.ac.uk\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_7\n\n109", "n_tokens": 194, "kind": "text"}
{"chunk_id": "drug_resistance_book-123-0", "doc_id": "drug_resistance_book", "page": 123, "text": "110\n\nL. Boden and D. Mellor\n\nhealth and welfare and securing a food supply for a growing human population. Not surprisingly, there are great differences in animal husbandry and food demand, and in availability, access and regulation of antimicrobial usage in animals, and in surveillance of AMR, which are likely to be starkest between developed and devel- oping countries. Thus, it is unlikely that the impacts of AMR, and the impacts of efforts to mitigate AMR that are directed to the ‘animal compartment’ of the ecosys- tem, will be felt equally across the world.\n\nKeywords AMR · Ethics · One Health · Veterinary · Animal · Causality\n\n7.1", "n_tokens": 146, "kind": "text"}
{"chunk_id": "drug_resistance_book-123-1", "doc_id": "drug_resistance_book", "page": 123, "text": "Introduction: Evolutionary History of Antimicrobial Resistance as a Natural Phenomenon\n\nAntimicrobial resistance has occurred as a natural phenomenon for millennia, as a response to inhibitory substances produced by microbial populations competing for resources in different ecosystems (Hall and Barlow 2004). Human discovery of the existence of these substances was exploited in the early twentieth century leading to the development of the first antibacterial drugs for therapeutic use. The rapid dis- covery and development of both natural and synthetic antimicrobial drugs (active against bacteria, fungi, viruses, and protozoa), and their widespread use to treat and prevent human and animal infectious diseases, took place throughout the latter half of the twentieth century. As predicted by Alexander Fleming himself, as therapeutic use of antibiotics grew there closely followed the emergence of untreatable strains of organisms that had hitherto responded to treatment.", "n_tokens": 177, "kind": "text"}
{"chunk_id": "drug_resistance_book-123-2", "doc_id": "drug_resistance_book", "page": 123, "text": "Any microorganism that isn’t inhibited or killed by appropriate, effective antimi- crobials is classified as resistant (Ridge et al. 2011). This phenomenon is now widely explained in terms of a ‘selection pressure’ being exerted on the populations of microorganisms which are exposed to antimicrobial agents. Such microbial pop- ulations are usually comprised of an almost unimaginable number and diversity of individual organisms, amongst which the target ‘pathogen’ population for antimi- crobial therapy may constitute only a fraction of those exposed to the agent. Under these circumstances, those organisms susceptible to the agent are inactivated, and cease to compete for resources, and those that are equipped with mechanism(s) to resist the effects of the agent thrive through access to the resources no longer con- sumed by the inactivated organisms (Levin et al. 2000). In the case of therapeutic use of antimicrobial agents, if the organisms equipped with mechanism(s) to resist the effects of the agent are members of the ‘pathogen’ population, the result is likely to be treatment failure and prolonged clinical disease for the patient. If the organ- isms equipped with mechanism(s) to resist the effects of the agent are members of the non-pathogen population (usually referred to as commensals), the effect is to select for populations that carry resistance mechanisms, but is unlikely to result in treatment failure at that time. Nevertheless, and especially for bacteria, many of", "n_tokens": 308, "kind": "text"}
{"chunk_id": "drug_resistance_book-123-3", "doc_id": "drug_resistance_book", "page": 123, "text": "the mechanisms to resist the effects of antimicrobial agents are coded for by genes", "n_tokens": 17, "kind": "text"}
{"chunk_id": "drug_resistance_book-124-0", "doc_id": "drug_resistance_book", "page": 124, "text": "7 Epidemiology and Ethics of Antimicrobial Resistance in Animals\n\ncarried on transmissible genetic elements which can be passed between organisms of the same or different species or genera. Thus, selection for resistance in members of the non-pathogen population could subsequently lead to transfer to ‘pathogen’ populations and increased likelihood of subsequent treatment failure.\n\n7.2", "n_tokens": 70, "kind": "text"}
{"chunk_id": "drug_resistance_book-124-1", "doc_id": "drug_resistance_book", "page": 124, "text": "Drug Resistance as an Animal or Public Health Concern\n\nTreatment failure and prolonged and/or more serious clinical disease for the patient are probably much more widely recognized consequences of drug resistance in human than in veterinary medicine. In efforts to mitigate these principally public health effects of antimicrobial resistance in the developed world, much attention has been focussed on human healthcare settings, particularly hospitals and care homes (Edwards et al. 2012). Efforts to improve infection prevention and control (IPC) in these settings are paramount, because they are needed not only to reduce the trans- mission between people of infectious agents likely to require drug therapy, but also the transmission of antimicrobial resistance genes. Principles of IPC form the main- stays of current strategies to combat antimicrobial resistance and are coupled with measures to promote ‘better’ prescribing of antimicrobial agents through guidelines and audit, and initiatives to educate the healthcare profession and the public. Judicial antimicrobial use (i.e. “better prescribing”) is based on evidence which supports using a particular agent against a particular organism in a particular patient for a particular reason and period of time (e.g. British Veterinary Association 2015).", "n_tokens": 248, "kind": "text"}
{"chunk_id": "drug_resistance_book-124-2", "doc_id": "drug_resistance_book", "page": 124, "text": "The contribution and nature of veterinary use of antimicrobial agents to the prob- lem of antimicrobial resistance on a global scale has been a controversial issue for many years, with conflicting, polarized views espoused by different respected research groups (Aarestrup et al. 2000; Collignon 2013; Mather et al. 2013; van Bunnik and Woolhouse 2017). Much has been made of the widespread and varied use of antimicrobial agents in veterinary medicine and the potential for this to con- tribute to the (largely) public health problem posed by antimicrobial resistance. In this, it is noteworthy that, with few exceptions, relatively little is made of treatment failure and prolonged and/or more serious clinical disease for animal patients. The use of the broad term ‘antimicrobial’ has been unhelpful in this regard as it is inclu- sive of agents such as anti-coccidials, which are important for animal health and food security, but have no effect on other organisms (such as bacteria or fungi) which drive resistance in humans (Mendelson et al. 2017). Mendelson et al. (2017) argue for more precision in the language around drug-resistant infections, and for more specific terms such as “antibiotic” or “antifungal” to be used in preference to ‘“antimicrobials” when referring to medicines against a specific type of organism.", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-124-3", "doc_id": "drug_resistance_book", "page": 124, "text": "There is a growing acceptance that drug-resistant infections are a ‘One Health’ problem that transcends species (and other) barriers (Karesh et al. 2012). Expanding on this, it is obvious that agents that carry resistance determinants exist very well and evolve outside animal or human hosts. There is increasing recognition of the need to consider environmental reservoirs, and inanimate vehicles of transmission,\n\n111", "n_tokens": 83, "kind": "text"}
{"chunk_id": "drug_resistance_book-125-0", "doc_id": "drug_resistance_book", "page": 125, "text": "112\n\nL. Boden and D. Mellor", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-125-1", "doc_id": "drug_resistance_book", "page": 125, "text": "not least among which are foods of animal origin – home produced and imported – and integrate these into thinking about the ecology and epidemiology of resistance (Wellington et al. 2013). Resistance genes may spread directly from people to ani- mals and from animals to people through food-borne and environmental contamina- tion (via wastewater, soil and the spread of contaminated manure from livestock and wild animals) (Casey et al. 2013; Kim et al. 2013; Davis and Rutkow 2012; Johnson and Becker 2010; Cantas et al. 2013; Roe and Pillai 2003; Soonthornchaikul and Garelick 2009; Levy et al. 1976; Thanner et al. 2016; Literak et al. 2011). However, the relative importance of these routes of transmission is uncertain; exposure is complex and not unequivocally in one direction (Carlet et al. 2011; Mather et al. 2013; Zhu et al. 2013). Additionally, there are other epidemiological pathways (such as transmission of resistance via irrigation and waste-water, plant production and the disposal or presence of disinfectants and heavy metals in the environment) that have been shown to be associated with the emergence of drug resistance. These are not well researched due to the lack of analytical methods to monitor contami- nants in waste, surface and drinking water and soil (Thanner et al. 2016). Thus, the epidemiological drivers associated with the selection for and against resistant organ- isms in animals are unlikely to be different to the causal mechanisms believed to exist in", "n_tokens": 334, "kind": "text"}
{"chunk_id": "drug_resistance_book-125-2", "doc_id": "drug_resistance_book", "page": 125, "text": "humans or the environment. There are important caveats to this assertion: (1) many parts of the relevant ecosystem are ignored by surveillance approaches adopted to date, notably the environment and food (home produced and imported), (2) it is difficult to partition antibiotic resistance into that which arises naturally from bacterial competition in various ecological niches and that which is selected for anthropogenically through therapeutic or other use of drugs and/or biocides. Of course, the relative intensity of the various selection pressures for the emergence of drug-resistant infections is itself driven in part by broader socio-economic issues (e.g. poverty, sanitation, hygiene and public health resources) which are harder to quantify and even more difficult for governments to address. These caveats arise due to the limitations of the evidence provided by surveillance for drug-resistant infections, which has largely focused on trying to compare observations of antibi- otic resistance in bacterial isolates from human patients to those of antibiotic resis- tance in animal populations (often using different methods of antimicrobial resistance determination) in developed countries.", "n_tokens": 226, "kind": "text"}
{"chunk_id": "drug_resistance_book-125-3", "doc_id": "drug_resistance_book", "page": 125, "text": "High rates of drug-resistant infections are found in densely populated, develop- ing countries where there is corruption and unreliable enforcement of laws and regulations pertaining to the practice of human and veterinary medicine (Collignon et al. 2015). Individuals who are exposed to resistant bacteria or fungi in these hotspots through international travel and medical tourism can subsequently import resistance into other countries, resulting in rapid global spread (World Health Assembly Resolution 51.9 1998).\n\nThere is still a need to convince some sectors that this is a shared problem with shared accountability and shared responsibility, but that principle is pretty much implicit in nationally and internationally agreed accords (e.g. Department of Health 2013; O’Neill 2016). Based on experience from the UK, plans to implement the recommendations of such accords, whilst all claiming to be taking a ‘One Health’", "n_tokens": 171, "kind": "text"}
{"chunk_id": "drug_resistance_book-126-0", "doc_id": "drug_resistance_book", "page": 126, "text": "7 Epidemiology and Ethics of Antimicrobial Resistance in Animals\n\napproach, can vary even among devolved administrations. In this sense, creation of a bespoke ‘One Health’ agency, with appropriately balanced multidisciplinary rep- resentation (and buy-in and trust), acting in a collegiate manner to coordinate a collective and coherent response seems intuitively more likely to succeed than sim- ply hoping that separate agencies will be able to work in parallel towards a common aim without ‘funding the arrows’ (Campbell 2006).\n\nIn conclusion, considering the epidemiology of drug-resistance in animals in\n\nisolation is missing the point.\n\n7.3", "n_tokens": 137, "kind": "text"}
{"chunk_id": "drug_resistance_book-126-1", "doc_id": "drug_resistance_book", "page": 126, "text": "Antimicrobial Use in Animals\n\nSimilar to antimicrobial use in humans, there is substantial variation throughout the world in the availability, regulation, control and administration of antimicrobials to animals. Whilst these factors themselves are not expected to alter the postulated causal mechanisms by which drug use affects drug resistance in microorganisms, they are likely to modify the extent to which these mechanisms have the opportunity to act. Simply put, it appears that greater usage of particular antimicrobial drugs, in a relevant time and place, is positively correlated with greater proportions of isolates tested for susceptibility in that time and place being designated as resistant. Thus, greater control over the quality and supply of antimicrobial drugs and greater regu- lation and professionalism over their administration should correlate with reduced proportions of resistant isolates.", "n_tokens": 174, "kind": "text"}
{"chunk_id": "drug_resistance_book-126-2", "doc_id": "drug_resistance_book", "page": 126, "text": "It is worthy of note that this general observation appears also to be true of anthel- mintic drugs, although the ecology of macroparasites is of course different to microbes. However, in the developed world, the problem of anthelmintic resistance is more of an immediate issue for animals than humans, which means that it has received much less attention from a public health point of view. Nevertheless, sophisticated guidance on control of parasitic infestations, based on understanding their ecology, and seeking to preserve the efficacy of anthelmintic drugs, are seen as critical to future food security (e.g. see Sustainable Control of Parasites in Sheep (http://www.scops.org.uk/)).", "n_tokens": 149, "kind": "text"}
{"chunk_id": "drug_resistance_book-126-3", "doc_id": "drug_resistance_book", "page": 126, "text": "A range of antimicrobial drugs is used widely to treat disease in domestic ani- mals through a large and internationally varying number of preparations and through a number of different routes of administration. In most developed countries of the world, the classes of antimicrobial drug available for animal administration, and the preparations and routes by which they can be administered, have to be specifically licensed for animal use and are highly regulated, especially for animal species likely to enter the human food chain. In these countries, there are also strictly enforced ‘withdrawal periods’ which define for how long an animal must be ‘off’ treatment before products form that animal can be used for human consumption. In some parts of the world, so-called ‘off-label’ use (i.e. an unlicensed product and/or an unli- censed route of administration) is sometimes permitted under derogation for the treatment of companion animals. Lists of critically important antimicrobials (CIAs)\n\n113", "n_tokens": 203, "kind": "text"}
{"chunk_id": "drug_resistance_book-127-0", "doc_id": "drug_resistance_book", "page": 127, "text": "114\n\nL. Boden and D. Mellor\n\nin humans and animals have been agreed, and are periodically updated, by the OIE and WHO and others, and the use of these drugs should be restricted to treating infections that have been demonstrated to be susceptible (and resistant to less important, so-called first-line, drugs) (OIE list of antimicrobials of veterinary importance 2007; WHO list of Critically Important Antimicrobials (CIA) 2017). In developing countries, due to limitations in infrastructure, such regulations, where they exist, are much more difficult to make effective. Coupled with a very high demand due to a high disease burden and often high population densities, and issues such as uncontrolled, unauthorized markets and counterfeit drugs, the conditions appear likely to favour intense selection for antimicrobial resistance and subsequent dissemination, though there are few reliable data to provide firm evidence of this.", "n_tokens": 189, "kind": "text"}
{"chunk_id": "drug_resistance_book-127-1", "doc_id": "drug_resistance_book", "page": 127, "text": "Much of the controversy around use of antimicrobials in animals has concen- trated on their use as growth promoters. It has been considered that routine addition of some antimicrobial compounds (usually antibacterial drugs and often at sub- therapeutic concentrations) to livestock feed increases food conversion efficiency by more than enough to outweigh the cost of adding the drugs, though this is dis- puted (Graham et al. 2007). However, other agents, such as anti-coccidials used by the poultry sector, are also included in this broad classification (Mendelson et al. 2017). Use of antibiotic growth promoters is considered by many to be particularly undesirable due to the selection pressure being applied in an almost unrelenting way to the populations of microorganisms colonizing these animals, especially in instances in which drugs are used at sub-therapeutic concentrations, as this is thought to select more strongly for antimicrobial resistance. Much research has sought to investigate the impact of the use of antimicrobials for growth promotion and has been interpreted by most as demonstrating a positive association with increased prevalence of resistant organisms in exposed microbial populations (O’Neill (2015)). On the basis of this evidence, their use as growth promoters has been banned in many parts of the world, notably Europe, yet still persists in others. In the EU, “the use of agents from classes which are or may be used in human or veterinary medicine (i.e. where", "n_tokens": 314, "kind": "text"}
{"chunk_id": "drug_resistance_book-127-2", "doc_id": "drug_resistance_book", "page": 127, "text": "there is a risk of selecting for cross-resistance to drugs used to treat bacterial infections)” as growth promoters has not been permit- ted since 2006 (Regulation (EC) No 1831/2003/EC) and withdrawal periods for antimicrobial use prior to animal slaughter are designed to ensure that there are no antimicrobial residues in food. In the USA, non-therapeutic use is still widespread in industrial farming. The USA FDA has historically been slow to respond to calls to reduce antimicrobial use and unwilling to exert its authority over the antimicro- bial approval process (see Natural Resources Defense Council, et al. v. United States Food and Drug Administration, et al.). Until recently, the FDA implemented a voluntary approach to antimicrobial conservation that encouraged drug companies to withdraw approvals for antimicrobials for non-therapeutic use and replace them with approvals for other uses such as chemoprophylaxis (USDA 2012a, b). However, this policy has had little real effect on antimicrobial usage because, in many cases, the doses and durations of drug use for chemoprophylaxis and growth promotion are the same (Outterson 2014).", "n_tokens": 256, "kind": "text"}
{"chunk_id": "drug_resistance_book-128-0", "doc_id": "drug_resistance_book", "page": 128, "text": "7 Epidemiology and Ethics of Antimicrobial Resistance in Animals", "n_tokens": 15, "kind": "text"}
{"chunk_id": "drug_resistance_book-128-1", "doc_id": "drug_resistance_book", "page": 128, "text": "In emerging economies, such as the BRICS and MINT countries, it is anticipated that non-therapeutic use of antibiotics in animals may exponentially increase because of increasing intensification of agriculture/aquaculture, high prevalences of production and endemic diseases (which are likely to be better controlled in other countries) and lack of resources to ensure appropriate governance over antimicro- bial use (Carlet et al. 2011; Van Boeckel 2015). In some of these countries, AMR and antimicrobial conservation aren’t on the “political agenda” at all (Grace 2015 at p 11–12) because addressing other issues such as poverty, starvation, malnutrition through (un)sustainable livestock and farmed fish production are more urgent for the current population. The impact of antimicrobial use on accessibility of animal food sources hasn’t been quantified for most countries, partly due to the variability and uncertainty regarding the quantities of antimicrobials used even in similarly intensive systems elsewhere (Rushton et al. 2014), and there is no agreement on the desired levels of antimicrobial consumption. Even if an enforced ban on the non- therapeutic use of antimicrobials were to be introduced, in some places, the absence of national R&D investment means that there are few alternative mechanisms (such as vaccines) to concurrently improve animal husbandry and avoid production losses which could paradoxically increase AMR prevalence through off-label or unpre- scribed use of poor", "n_tokens": 309, "kind": "text"}
{"chunk_id": "drug_resistance_book-128-2", "doc_id": "drug_resistance_book", "page": 128, "text": "quality or counterfeit antimicrobials. The relative costs of not using antimicrobials on the security of the global food supply and the success of the Sustainable Development Goals (in eradicating poverty and hunger in the current generation) have not been compared to AMR treatment failure in people (in future generations). Although developed countries arguably have sufficient means to assist developing countries address some of these issues, they have so far focussed on their own national priorities in order to achieve wider international societal benefits (Clift 2013).", "n_tokens": 110, "kind": "text"}
{"chunk_id": "drug_resistance_book-128-3", "doc_id": "drug_resistance_book", "page": 128, "text": "Distinction is made in veterinary medicine (at least in the developed world) between prophylactic (administering antimicrobial drugs to prevent anticipated infection) and metaphylactic use of antimicrobials (administering antimicrobial drugs to clinically well members of a population in contact with an index case of infectious disease to prevent anticipated infection), which is not recognized in human medicine. Prophylaxis in veterinary medicine is criticized by many as an excuse for poor infection prevention and control (often referred to as ‘biosecurity’ in animal production) in a particular animal husbandry system, but presents ethical dilemmas to veterinarians who struggle with the notion of withholding treatment in the face of what is considered to be almost inevitable disease and associated welfare compromise. In many instances, the clinical use of antimicrobials in animals is empirical and sensitivity testing of an isolate of the putative causative agent of infection is not carried out. The reasons for this are largely to do with cost and expe- diency in starting treatment to improve the clinical condition of the patient. Thus, data that characterize the resistance profiles of clinical isolates from animals repre- sent a very small proportion of the putative infections treated by veterinarians, and their use for epidemiological purposes often appears to overlook this fact. However, this is also true of human medicine.\n\n115", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-129-0", "doc_id": "drug_resistance_book", "page": 129, "text": "116\n\nL. Boden and D. Mellor\n\nThe notion that antimicrobial resistant organisms somehow ‘arise’ in animals, driven by selection pressures applied by veterinary use of antimicrobials, and pass to humans, principally through the food chain, has been a popular model of antimi- crobial resistance ‘acquisition’ for some time. However, some recent research shows that transmission is likely to occur in both directions between animals and people directly and indirectly through the environment and various fomites (Mather et al. 2013). As discussed in the introduction, it is probably more reasonable to think of animals and people as inextricably linked ‘samplers’ of a shared environmental pool of organisms subject to different selection pressures in different compartments.\n\n7.4", "n_tokens": 157, "kind": "text"}
{"chunk_id": "drug_resistance_book-129-1", "doc_id": "drug_resistance_book", "page": 129, "text": "Surveillance for Antimicrobial Resistance in Animals\n\n‘Better’ surveillance for antimicrobial resistance in animals is a more or less univer- sal feature of international concordats, calls to action and other declarations on anti- microbial resistance (Department of Health 2013; O’Neill 2016). As the bedrock of epidemiology, surveillance activity, and the intelligence generated by it, offers the greatest potential to understand fully the causal relationships at play within the complex landscape ecology underlying the antimicrobial resistance ‘phenomenon’ (Singer et al. 2006). Nevertheless, there are a great many limitations, often over- looked, that can apply to data derived from surveillance of infections in animals (and people) for the purposes of exploring causal relationships of relevance to the emergence and spread of antimicrobial resistance. Chief among these is the ques- tion of how well the isolate(s) derived from the sample(s) collected from the individual(s) and/or their environment(s) under study represent the actual nature and dynamics of the interactions between host and microbial populations and the selection pressures experienced by them. Confounding this, in many instances, is a lack of standardization of the microbiological methods applied and inconsistent definitions of how antimicrobial sensitivity or lack of it is defined for individual drug/bug combinations derived from different species (animals and humans).", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-129-2", "doc_id": "drug_resistance_book", "page": 129, "text": "The World Health Organization (WHO) has led international efforts to develop action plans to monitor and reduce drug-resistant infections (WHO Strategy 2001). However, without a legally-binding mandate, it has been difficult implement this strategy within Member States. Indeed, between 1998 and 2015 (when the WHO first published its global action plan), there have been at least seven World Health Assembly (WHA) Resolutions promoting surveillance of drug-resistant infections, but still no internationally coordinated or standardized AMR surveillance strategy within either the human or veterinary sectors. Although collaboration between the WHO, Food and Agricultural Organization of the United Nations (FAO) and World Organization of Animal Health (OIE) is improving coordination between human and animal surveillance, within individual Member States the two sectors remain distinct and regulated independently of one another. Surveillance, if undertaken at all, has hitherto been implemented separately by each sector, without harmonization or standardization of approach.", "n_tokens": 187, "kind": "text"}
{"chunk_id": "drug_resistance_book-130-0", "doc_id": "drug_resistance_book", "page": 130, "text": "7 Epidemiology and Ethics of Antimicrobial Resistance in Animals", "n_tokens": 15, "kind": "text"}
{"chunk_id": "drug_resistance_book-130-1", "doc_id": "drug_resistance_book", "page": 130, "text": "Existing national action plans within Member States describe broad strategic aims to mitigate, and reduce current rates of drug-resistant infections and resultant treatment failures. These include: improvements in infection prevention and con- trol, education and training initiatives, optimization of prescribing practices (par- ticularly in animals with respect to critically important antimicrobials) and incentives to innovate new, effective therapies. For the most part, these aims have not been translated yet into specific actions with explicit timescales for delivery or agreed outcome metrics. In some countries, technical and financial constraints, such as lack of existing public health infrastructure, access to diagnostic technologies and chang- ing public attitudes towards public health mean that surveillance is poor (STAG- AMR 2013; WHO 2011). Accurate inferences (and/or between-country comparisons) about antibiotic or antifungal consumption rates aren’t always possible because of the scarcity and variability of available information on consumption, species treated, routes of administration, dose rate, and pharmaceutical costs (Rushton et al. 2014 at p 11). Other important differences, such as husbandry practices, diversity of avail- able drugs and prescribing habits of veterinarians, mean that comparisons of antimi- crobial use based on animal demographics are potentially misleading. For example, Chile is the second largest producer of farmed salmon and the only", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-130-2", "doc_id": "drug_resistance_book", "page": 130, "text": "important devel- oping country producer. However, it uses around 300 times more antibiotics than the largest salmon producer, Norway because Norway has the resources to access and implement vaccination and alternative husbandry measures instead of antimi- crobials to control diseases (Grace 2015 at page 11). Thus, it is currently not pos- sible to accurately chart progress towards AMR reduction or identify early-warning performance indicators for actions that aren’t effective in achieving these aims.", "n_tokens": 99, "kind": "text"}
{"chunk_id": "drug_resistance_book-130-3", "doc_id": "drug_resistance_book", "page": 130, "text": "Despite these limitations, surveillance and research data generated, principally in the developed world, are subject to ever more sophisticated epidemiological analy- ses to infer risk factors and causal relationships for resistance emergence, persis- tence and spread. Entrenched in this aim is the notion that population patterns of drug-resistant infections can be explained by a complex web of multiple intercon- nected factors, which if identified, can be used to inform and target interventions to improve public health (Krieger 1994). Increasingly, these analyses seek to be com- parative and inferential about the impacts of antimicrobial use in one species (ani- mals or man) on antimicrobial resistance in the other, as the ‘One Health’ construct of drug resistance becomes more widely accepted. However, caution is required in the interpretation of these findings. ‘Causal webs’ are not unbiased; they are neces- sarily hierarchical, focusing “attention on risk factors closest to the outcome under inspection”, inevitably prioritizing biological factors (amenable to medical or vet- erinary intervention) over other broader social or environmental determinants which could be addressed through social action (Krieger 1994; Thanner et al. 2016). For example, addressing a lack of access to education, sanitation and adequate health- care (including infection prevention and control, scarcity of new antibiotics, poor prescribing practices and absence of concurrent diagnostic tools to", "n_tokens": 306, "kind": "text"}
{"chunk_id": "drug_resistance_book-130-4", "doc_id": "drug_resistance_book", "page": 130, "text": "ensure appropri- ate treatment) will affect rates of disease, which will influence subsequent amounts of antimicrobial used (Buckland Merrett 2013). Reduction of antimicrobial use may reduce selection pressure for resistance, but at the same reduces the numbers of", "n_tokens": 56, "kind": "text"}
{"chunk_id": "drug_resistance_book-130-5", "doc_id": "drug_resistance_book", "page": 130, "text": "117", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-131-0", "doc_id": "drug_resistance_book", "page": 131, "text": "118\n\nL. Boden and D. Mellor\n\nantimicrobial ‘customers’ and thus incentives to innovate new drugs. Equally, eco- nomic strategies that are driven by sales rewards will inevitably conflict with prin- ciples of conservation and IPC. Understanding of the epidemiology of AMR (and this broader socio-economic and ecological ‘web of causation’) and an appreciation for the gaps in communication and coordination between stakeholders and regula- tors involved across multiple sectors and disciplines at each of these foci is therefore necessary to ensure policy decisions are robust and ethical.\n\n7.5", "n_tokens": 128, "kind": "text"}
{"chunk_id": "drug_resistance_book-131-1", "doc_id": "drug_resistance_book", "page": 131, "text": "Summary and Conclusion\n\nThe epidemiology of antimicrobial resistance in animals seems very unlikely to be extricable or distinct from that in people. A powerful epidemiological model of the causation and dissemination of antimicrobial resistance as a feature of microbio- logical ecology among a very complex web of interconnected host and environmen- tal compartments has emerged and gained widespread acceptance under the construct of ‘One Health’. However, the limitations in the quality of the data that have been used to build this model leave room for uncertainty about its validity. In addition, there needs to be ‘thinking time and space’ to consider and account for cognitive biases in such models and to incorporate socio-economic modifiers of such biological models in order to inform efficient and effective measured interven- tions. As rapidly developing scientific advances offer the potential to improve the quality (e.g. WGS) and representativeness (e.g. through properly and purposively designed comparative surveillance programmes) of data, it is to be hoped that epi- demiological inference will be able to keep pace and offer better, and what yet may be surprising, insights into the problem of antimicrobial resistance and ways in which it might be tackled.", "n_tokens": 260, "kind": "text"}
{"chunk_id": "drug_resistance_book-131-2", "doc_id": "drug_resistance_book", "page": 131, "text": "References\n\nAarestrup, F.M., Y. Agerso, P. Gerner-Schmidt, M. Madsen, and L.B. Jense. 2000. Comparison of antimicrobial resistance phenotypes and resistance genes in Enterococcus faecalis and Enterococcus faecium from humans in the community, broilers and pigs in Denmark. Diagnostic Microbiology and Infectious Disease 27: 127–137.\n\nBritish Veterinary Association. 2015. Responsible use of antimicrobials in veterinary practice. Available from: https://www.bva.co.uk/uploadedFiles/Content/News,_campaigns_and_poli- cies/Policies/Medicines/responsible-use-of-antimicrobials-in-veterinary-practice.pdf.\n\nBuckland Merrett, G.L. 2013. Tackling antibiotic resistance for greater global health security. Centre on Global Health Security. Available from: http://www.chathamhouse.org/sites/files/ chathamhouse/public/Research/Global%20Health/1013bp_antibioticresistance.pdf.\n\nCampbell, A. 2006. The Australian natural resource management knowledge system. Available\n\nfrom: http://lwa.gov.au/products/pr061081.\n\nCantas, L., S.Q.A. Shah, L.M. Cavaco, C.M. Manaia, F. Walsh, M. Popowska, H. Garelick, H. Bürgmann, and H. Sørum. 2013. A brief multi-disciplinary review on antimicrobial", "n_tokens": 349, "kind": "text"}
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{"chunk_id": "drug_resistance_book-133-1", "doc_id": "drug_resistance_book", "page": 133, "text": "———. 2016. Tackling drug-resistant infections globally: Final report and recommendations. Available from: https://amr-review.org/sites/default/files/160525_Final%20paper_with%20 cover.pdf.\n\nOIE list of antimicrobials of veterinary importance. 2007. Available from: https://www.oie.int/ fileadmin/Home/eng/Our_scientific_expertise/docs/pdf/AMR/A_OIE_List_antimicrobials_ July2019.pdf\n\nOutterson, K. 2014. New business models for sustainable antibiotics. Centre on global health secu- rity working group papers 1–31. Available from: http://www.chathamhouse.org/sites/files/cha- thamhouse/public/Research/Global%20Health/0214SustainableAntibiotics.pdf.\n\nRegulation (EC) No 1831/2003/EC Of The European Parliament and of the Council of 22 September 2003 On additives for use in animal nutrition, replacing directive 70/524/EEC on additives in feeding-stuffs. 2003. Official Journal of the European Union L 268: 0029–0043. Ridge, K.W., K. Hand, M. Sharland, I. Abubakar, and D.M. Livermore. 2011. Antimicrobial resis- tance. In The annual report of the chief medical officer volume 2, Infections and the rise of anti- microbial resistance. Available at https://www.gov.uk/government/uploads/system/uploads/ attachment_data/file/138331/CMO_Annual_Report_Volume_2_2011.pdf\n\nRoe, M.T., and S.D. Pillai. 2003. Monitoring and identifying antibiotic resistance mechanisms in", "n_tokens": 404, "kind": "text"}
{"chunk_id": "drug_resistance_book-133-2", "doc_id": "drug_resistance_book", "page": 133, "text": "bacteria. Poultry Science 82: 622–626.\n\nRushton, J., J. Pinto Ferreira, and K.D. Stärk. 2014. Antimicrobial resistance: The use of antimi- crobials in the livestock sector, OECD Food, Agriculture and Fisheries Papers No. 68. Paris: OECD Publishing. https://doi.org/10.1787/5jxvl3dwk3f0-en.\n\nSinger, R.S., M.P. Ward, and G. Maldonado. 2006. Can landscape ecology untangle the complexity\n\nof antimicrobial resistance? Nature Reviews Microbiology 4: 943–952.\n\nSoonthornchaikul, N., and H. Garelick. 2009. Antimicrobial resistance of campylobacter species isolated from edible bivalve molluscs purchased from Bangkok markets, Thailand. Foodborne Pathogens and Disease 6: 947–951. https://doi.org/10.1089/fpd.2008.0236.\n\nStrategic and Technical Advisory Group on Antimicrobial Resistance (STAG-AMR). Report of the first meeting Geneva, 19–20 September 2013. Available from: http://www.who.int/drugresis- tance/stag/amr_stag_meetingreport0913.pdf.\n\nSustainable Control of Parasites in Sheep. Available from: http://www.scops.org.uk/. Thanner, S., D. Drissner, and F. Walsh. 2016. Antimicrobial resistance in agriculture. MBio 7 (2):\n\ne02227–e02215. https://doi.org/10.1128/mBio.02227-15.\n\nVan Boeckel, T.P. 2015. Global Trends In Antimicrobial Use In Food Animals. Proceedings of the National Academy of Science 112 (18): 649–5654. https://doi.org/10.1073/pnas.1503141112.", "n_tokens": 450, "kind": "text"}
{"chunk_id": "drug_resistance_book-134-0", "doc_id": "drug_resistance_book", "page": 134, "text": "7 Epidemiology and Ethics of Antimicrobial Resistance in Animals\n\nvan Bunnik, B.A.D., and M.E.J. Woolhouse. 2017. Modelling the impact of curtailing antibi- otic usage in food animals on antibiotic resistance in humans. Royal Society Open Science 4: 161067. https://doi.org/10.1098/rsos.161067.\n\nWellington, E.M.H., A.B.A. Boxall, P. Cross, E.J. Feil, W.H. Gaze, P.M. Hawkey, A.S. Johnson- Rollings, D.L. Jones, N.M. Lee, W. Otten, C.M. Thomas, and A.P. Williams. 2013. The role of the natural environment in the emergence of antibiotic resistance in Gram-negative bacteria. Lancet Infectious Diseases 13: 155–165.\n\nWorld Health Assembly Resolution 51.9. 1998. Emerging and other communicable diseases: Antimicrobial resistance. In 51st world health assembly. Available from: http://apps.who.int/ medicinedocs/index/assoc/s16335e/s16335e.pdf?ua=1.\n\nWorld Health Organisation. 2001. WHO global strategy for containment of antimicrobial resistance.\n\nAvailable from: http://www.who.int/drugresistance/WHO_Global_Strategy_English.pdf.\n\n———. 2011. Tackling antibiotic resistance from a food safety perspective in Europe. Available from: http://www.euro.who.int/__data/assets/pdf_file/0005/136454/e94889.pdf at page 9. World Health Organisation List of Critically Important Antimicrobials (CIA). 2017. Available", "n_tokens": 400, "kind": "text"}
{"chunk_id": "drug_resistance_book-134-1", "doc_id": "drug_resistance_book", "page": 134, "text": "from: https://www.who.int/foodsafety/publications/antimicrobials-sixth/en/\n\nZhu, Y.-G., T.A. Johnson, J.-Q. Su, M. Qiao, G.-X. Guo, R.D. Stedtfield, S.A. Hashsham, and J.M. Tiedje. 2013. Diverse and abundant antibiotic resistance genes in Chinese swine farms. Proceedings of the National Academy of Science 110 (9): 3435–3440.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n121", "n_tokens": 283, "kind": "text"}
{"chunk_id": "drug_resistance_book-135-0", "doc_id": "drug_resistance_book", "page": 135, "text": "Part II Theoretical Approaches to Ethics and Drug Resistance", "n_tokens": 9, "kind": "text"}
{"chunk_id": "drug_resistance_book-136-0", "doc_id": "drug_resistance_book", "page": 136, "text": "Chapter 8 The Virtuous Physician and Antimicrobial Prescribing Policy and Practice\n\nJustin Oakley\n\nAbstract In this chapter, I outline some key patient-centred medical virtues and several community-centred medical virtues, and I consider what sorts of antimicro- bial prescribing decisions such virtues would lead physicians to make. I argue that practically-intelligent virtuous physicians should also have an awareness of the sorts of cognitive biases that are especially likely to distort their antimicrobial pre- scribing decisions, and I urge physicians to develop ways of avoiding or counteract- ing such biases. Further, I argue that effectively addressing the impact of these biases and other countervailing factors that inhibit virtuous prescribing practices is the responsibility not only of individual physicians, but also of institutions and regu- lators. I outline some strategies that individual physicians, institutions, and health- care policymakers could develop to help physicians hit the targets of those patient-centred and community-centred medical virtues, and to thereby play their part in redressing the problems of antimicrobial resistance.\n\nKeywords Medical virtue · Practical intelligence · Justice · Antibiotic overprescribing · Cognitive bias", "n_tokens": 252, "kind": "text"}
{"chunk_id": "drug_resistance_book-136-1", "doc_id": "drug_resistance_book", "page": 136, "text": "The detrimental health impact of antimicrobial resistance raises significant ques- tions about physicians’ antimicrobial prescribing decisions, so it is important to investigate what sorts of prescribing decisions about antimicrobials would be made by a virtuous physician in various contexts. Antimicrobial resistance has become a\n\nAn earlier version of this chapter was presented at the 2018 Effective Altruism Global Conference, Melbourne, where I received some helpful comments on this chapter. I also received some useful feedback on these ideas in medical ethics seminars at Monash University, and I thank students at these seminars for this. I am very grateful to Zeb Jamrozik for his resourcefulness and his excellent suggestions about relevant sources, and I wish to thank Michael Selgelid and Zeb for their invalu- able advice with this chapter.\n\nJ. Oakley (*) Monash Bioethics Centre, Monash University, Melbourne, VIC, Australia e-mail: justin.oakley@monash.edu\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_8\n\n125", "n_tokens": 281, "kind": "text"}
{"chunk_id": "drug_resistance_book-137-0", "doc_id": "drug_resistance_book", "page": 137, "text": "126\n\nJ. Oakley\n\nmajor global health concern, as the resistance of disease-causing microorganisms to antimicrobials can completely undermine the effectiveness of many antibiotics and other antimicrobials that are commonly used to treat a variety of diseases, and to lower the risks of post-surgical infections. The dwindling effectiveness of many antimicrobials has been implicated in a growing number of patient deaths world- wide, often from conditions such as respiratory and wound infections which had previously been responsive to antimicrobial treatments. Addressing what sorts of antimicrobial prescribing decisions a virtuous physician would make seems espe- cially challenging for virtue ethics approaches to medical practice. For such approaches typically evaluate physician decision-making by reference to patient- centred role virtues like medical beneficence, medical courage, and trustworthiness, but tend to say little about broader medical virtues that help physicians act in the best health interests of the community, which is a crucial consideration in ethically justifiable clinician decision-making regarding antimicrobials.", "n_tokens": 222, "kind": "text"}
{"chunk_id": "drug_resistance_book-137-1", "doc_id": "drug_resistance_book", "page": 137, "text": "In this chapter, I discuss some key patient-centred medical virtues and several candidate community-centred medical virtues, and I consider what sorts of antimi- crobial prescribing decisions such virtues would lead physicians to make. I draw out the moral significance of these community-centred medical virtues by examining certain cases where prescribing an antimicrobial seems likely to be in the best inter- ests of the patient in question, but seems unlikely to be in the best health interests of the community overall. In doing so, I consider some analogies with other sorts of cases involving seemingly divergent virtue directives, such as those involving psy- chiatrists breaching patient confidentiality to protect third parties from harm. Also, I argue that practically-intelligent virtuous physicians should have an awareness of the sorts of cognitive biases that are especially likely to distort their antimicrobial prescribing decisions, and I urge physicians to develop ways of avoiding or counter- acting such biases. Further, effectively addressing the impact of these biases and other countervailing factors that inhibit virtuous prescribing practices is, I argue, the responsibility not only of individual physicians, but also of institutions and regula- tors. Therefore, I also consider the prospects of certain institutional and regulatory initiatives which aim to reduce antimicrobial over-prescribing by highlighting and undermining such biases in clinical practice.\n\n8.1", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-137-2", "doc_id": "drug_resistance_book", "page": 137, "text": "Antimicrobial Resistance and Virtue Ethics\n\nRising global concerns about antimicrobial resistance has prompted many national and international agencies, professional medical associations, and policymakers to investigate what sorts of factors are contributing to this problem, and to the resulting significant increases in morbidity and mortality rates of certain diseases in many countries around the world. The accelerating resistance of microorganisms to anti- biotics and other antimicrobial agents commonly used in medical treatment has substantially reduced – and at times entirely removed – effective microbial treat- ment options for some patients with serious conditions such as pneumonia,", "n_tokens": 120, "kind": "text"}
{"chunk_id": "drug_resistance_book-138-0", "doc_id": "drug_resistance_book", "page": 138, "text": "8 The Virtuous Physician and Antimicrobial Prescribing Policy and Practice", "n_tokens": 18, "kind": "text"}
{"chunk_id": "drug_resistance_book-138-1", "doc_id": "drug_resistance_book", "page": 138, "text": "tuberculosis, or septicaemia, and a number of those patients have subsequently died. Further, antibiotic-resistant ‘superbugs’ like methicillin-resistant staphylococcus aureus (MRSA) have been found in significant quantities in some of the world’s major hospitals, and many patients worldwide have died from hospital-acquired MRSA infections.1 Antimicrobial resistance is a major problem in high-income countries and also in low- and middle-income countries. For example, China has the world’s highest prevalence of MRSA, and this bacterium is associated with higher mortality rates for hospitalised patients there.2 Also, the prevalence of multi-drug resistant tuberculosis is relatively high in countries such as India and Russia – it has recently been predicted that 12.4% of all cases of TB will soon be multi-drug resis- tant in India, and that 32.5% of all cases of TB will soon be multi-drug resistant in Russia.3 It has also been reported that over 50% of microorganisms involved in hospital-acquired infections in Greece seem to be resistant to all available antibiot- ics.4 Effective antimicrobial treatments have therefore become a somewhat scarce resource in clinical practice in a number of contexts, and many countries have now introduced new government regulations and clinical guidelines aimed at encourag- ing more responsible use and stewardship of antimicrobials. While antibiotics are one among several antimicrobial agents, I will focus here on the prescription of antibiotics,", "n_tokens": 319, "kind": "text"}
{"chunk_id": "drug_resistance_book-138-2", "doc_id": "drug_resistance_book", "page": 138, "text": "as inappropriate antibiotic prescribing appears to be a major contributor to antimicrobial resistance, which is why many of the efforts to improve antimicro- bial prescribing practices are directed at antibiotic prescribing in particular.", "n_tokens": 53, "kind": "text"}
{"chunk_id": "drug_resistance_book-138-3", "doc_id": "drug_resistance_book", "page": 138, "text": "This accelerating growth in antimicrobial resistance is due to a range of factors, including widespread farming practices, patient misuse of antimicrobials, and inap- propriate antimicrobial prescribing practices by physicians. These contributing fac- tors are now being targeted by a range of initiatives from government agencies, national and international medical and health care organisations, and at the level of hospital management. Thus, the WHO recently modified its longstanding Essential Medicines List by introducing recommendations that prioritise the use of some anti- biotics over others in certain contexts – for example, the list recommends that amoxicillin be made widely available to treat common infections, such as pneumo- nia, but that other antibiotics should be reserved for use as a last resort when a life- threatening infection has failed to respond to other antibiotics.5 And the clinical practice guidelines about antibiotic prescribing in Australia’s Therapeutic Guidelines: Antibiotic also encourage the responsible use by clinicians of antibiot- ics in treating a wide variety of conditions, and thus discourage the over-prescribing of antibiotics.6 However, questions have arisen about the effectiveness of clinical", "n_tokens": 248, "kind": "text"}
{"chunk_id": "drug_resistance_book-138-4", "doc_id": "drug_resistance_book", "page": 138, "text": "1 Staphylococcus aureus already exist in (e.g.) our respiratory tract, and some of those bacteria will already be antimicrobial-resistant, but antibiotic treatment allows those antimicrobial resistant S. aureus to potentially multiply. 2 See Dan Cui et al. (2017), and Zhenjiang Yao et al. (2015). 3 Aditya Sharma et al. (2017). 4 Stavros Saripanidas (2016). 5 See http://www.who.int/mediacentre/news/releases/2017/essential-medicines-list/en/. 6 Antibiotic Expert Groups (2019).\n\n127", "n_tokens": 144, "kind": "text"}
{"chunk_id": "drug_resistance_book-139-0", "doc_id": "drug_resistance_book", "page": 139, "text": "128\n\nJ. Oakley\n\nguidelines aimed at improving antibiotic prescribing. For example, a recent Australian study concluded that “Antibiotics are prescribed for ARIs [acute respira- tory infections] at rates 4–9 times as high as those recommended by clinical guide- lines. The potential for reducing rates of antibiotic prescription and to thereby reduce rates of antibiotic-related harms, particularly bacterial resistance, is there- fore substantial.”7 Physician decision-making in relation to antibiotics has thus been identified as a major contributor to the problem of antimicrobial resistance,8 and so this remains a promising context on which to focus in developing effective ways of redressing this problem. In this chapter, therefore, I concentrate on the antimicrobial prescribing behaviour of physicians, and on what would plausibly be required of a virtuous physician in regard to antimicrobial prescribing.", "n_tokens": 189, "kind": "text"}
{"chunk_id": "drug_resistance_book-139-1", "doc_id": "drug_resistance_book", "page": 139, "text": "The emphasis in virtue ethics on the character and moral psychology of virtuous agents have led some to regard this approach as excessively individualistic, and so it might be wondered whether virtue ethics is capable of providing useful guidance on addressing antimicrobial resistance, which is a complex multi-dimensional prob- lem on an international scale. However, as noted above, physician prescribing behaviour is a major contributing factor to antimicrobial resistance, and so to this extent, focusing on what decisions a virtuous physician would make in relation to the prescription of antimicrobials would seem to offer a promising line of response to this problem. Further, recent empirically-informed accounts of the Aristotelian idea of practical intelligence (phronesis) emphasise the importance of agents being aware of, and having strategies to counteract, common decision-making biases that can divert their virtuous dispositions from hitting the target of the relevant virtue.9 Physicians are evidently not immune from such biases,10 and these biases may well contribute to physicians’ inappropriate antimicrobial prescribing in certain sorts of cases.11 So applying recent empirically-informed accounts of virtues and practical intelligence to physicians’ roles and to their antimicrobial prescribing behaviour would seem to be a useful way of approaching the problems of antimicrobial resistance.", "n_tokens": 283, "kind": "text"}
{"chunk_id": "drug_resistance_book-139-2", "doc_id": "drug_resistance_book", "page": 139, "text": "Generally speaking, virtue ethics evaluates actions by asking, ‘what sort of per- son would do a thing like that?’ For example, we can ask whether an action was generous or mean-spirited, courageous or cowardly, and we can examine whether this is the sort of thing which a kind person or a just person would do in the circum- stances. Virtue ethics can therefore draw upon such considerations to provide the elements of a criterion of right action. A virtue ethics criterion of right action can be\n\n7 Amanda R. McCullough et al. (2017). 8 See e.g. the US Centers for Disease Control and Prevention statement, ‘About Antimicrobial Resistance’: “The use of antibiotics is the single most important factor leading to antibiotic resis- tance around the world. Simply using antibiotics creates resistance. These drugs should only be used infections.” https://www.cdc.gov/drugresistance/about.html. [accessed 1 November 2018]. 9 See Justin Oakley (2018a, b). 10 See Blumenthal-Barby and Krieger (2015) and Saposnik et al. (2016). 11 See e.g. Jeffrey et al. (2014).\n\nto manage", "n_tokens": 262, "kind": "text"}
{"chunk_id": "drug_resistance_book-140-0", "doc_id": "drug_resistance_book", "page": 140, "text": "8 The Virtuous Physician and Antimicrobial Prescribing Policy and Practice\n\nstated initially in broad terms as holding that: An action is right if, and only if, it is what an agent with a virtuous character would do in the circumstances.12 Virtue ethi- cists have also applied such an appeal to exemplars in developing accounts of right action in the context of various professional roles, such as medical and legal prac- tice. An influential version of these accounts highlights links between the proper goal/s of the profession in question – such as health and justice for medicine and law, respectively – and an Aristotelian conception of human flourishing, or eudai- monia. The proper goal/s of a profession can, in turn, provide the basis for an account of the role virtues for that profession. Thus in the case of medical practice, the role virtues for doctors can be understood as those character traits that enable doctors to serve the goal of health. These traits have been thought to include patient- centred dispositions such as medical beneficence, medical courage, and trustworthi- ness, along with community-centred dispositions such as justice.13\n\n8.2\n\nMedical Virtues and Antimicrobial Prescribing", "n_tokens": 260, "kind": "text"}
{"chunk_id": "drug_resistance_book-140-1", "doc_id": "drug_resistance_book", "page": 140, "text": "We saw in the previous section that inappropriate prescribing decisions by physi- cians in relation to antibiotics is highlighted as one of the most important contribut- ing factors to antimicrobial resistance and its resulting problems. Physicians in many countries are evidently over-prescribing antibiotics, and for a variety of condi- tions. For example, a recent study by Katherine Fleming-Dutra and colleagues found that during 2010–2011 physicians in US clinics prescribed antibiotics for acute respiratory infections at double the rates that were clinically appropriate for such infections – in other words, around half of those antibiotic prescriptions were clinically inappropriate.14 Also, the 2018 national survey of antimicrobial prescrib- ing practices in Australian hospitals found that 21.4% of antimicrobials prescribed during that year were classified as inappropriate prescriptions.15 And a recent study using survey data from 2010–2015 on antibiotic prescribing rates in general practice found that Australian GPs are prescribing antibiotics for acute respiratory infections at rates up to nine times higher than those recommended by the national Therapeutic Guidelines: Antibiotic. These researchers found, for example, that “Despite the rec- ommendation in these guidelines against prescribing antibiotics for bronchitis, gen- eral practitioners were estimated to have prescribed antibiotics for patients with bronchitis in 85% of cases during 2010–2015”.16 A subsequent", "n_tokens": 297, "kind": "text"}
{"chunk_id": "drug_resistance_book-140-2", "doc_id": "drug_resistance_book", "page": 140, "text": "interview with study co-author Chris Del Mar reported that he felt “doctors were acting out of a mis- placed sense of caution, as many conditions requiring treatment with antibiotics", "n_tokens": 34, "kind": "text"}
{"chunk_id": "drug_resistance_book-140-3", "doc_id": "drug_resistance_book", "page": 140, "text": "12 Rosalind Hursthouse (1999). 13 See e.g. Justin Oakley and Dean Cocking (2001). 14 Katherine E. Fleming-Dutra et al. (2016). 15 Australian Commission on Safety and Quality in Health Care (2020). 16 McCullough et al. (2017), op. cit., p. 68.\n\n129", "n_tokens": 76, "kind": "text"}
{"chunk_id": "drug_resistance_book-141-0", "doc_id": "drug_resistance_book", "page": 141, "text": "130\n\nJ. Oakley\n\nshare similar symptoms to those that do not…. doctors needed to stop considering a prescription for antibiotics as their first port of call. ‘The idea that we have as GPs, that writing a prescription for antibiotics just in case, is probably not so effective…, That in fact not using antibiotics at all is actually safe, you don’t end up with missed cases of meningitis and Lemierre’s disease – all sorts of really nasty things.’”17", "n_tokens": 99, "kind": "text"}
{"chunk_id": "drug_resistance_book-141-1", "doc_id": "drug_resistance_book", "page": 141, "text": "Given that patients frequently request antibiotics for acute respiratory infections, and are usually keen to get better sooner, it is perhaps not surprising that there is a tendency among physicians in many countries to over-prescribe antibiotics for such infections in responding to such requests. But while yielding to patient pressure results in physicians over-prescribing antibiotics, there is also evidence that antibi- otics are prescribed inappropriately because physicians overestimate patients’ expectations of receiving these drugs. Thus, in a 1997 study of antibiotic prescrib- ing decisions by UK General Practitioners, Macfarlane and colleagues found that “Non-clinical factors influence the decision to prescribe antibiotics for nearly a half of those receiving one. Patient pressure was cited most frequently…and identified by the Audit Commission as an important reason for the excess use of antibiotics in the community. Pressure from patients to prescribe antibiotics, particularly for respiratory symptoms, has been identified as the commonest reason for doctors’ discomfort with prescribing decisions. General practitioners can, however, overesti- mate patients’ expectations. A quarter of our patients received antibiotics when they stated that before the consultation they had not wanted antibiotics”.18 A survey of 544 patients of inner London general practitioners found further evidence that phy- sicians are overly influenced by their perceptions of patients’ hopes and", "n_tokens": 269, "kind": "text"}
{"chunk_id": "drug_resistance_book-141-2", "doc_id": "drug_resistance_book", "page": 141, "text": "expecta- tions of receiving a medication prescription, and those perceptions frequently seemed to be inaccurate: “A third [31%] of the prescriptions [which were some- times for antibiotics] written in this study were either not indicated or not hoped for, with 3% being neither indicated nor hoped for…. The writing of nonindicated pre- scriptions was primarily associated with the doctor’s sense of feeling pressurised [by the patient to write a prescription]”.19 This survey also found that “In a fifth [22%] of consultations in which a prescription was written, the prescription was not strictly indicated on purely medical grounds”.20 Overall, the strongest influence on a physician’s decision to prescribe a medication was found in this study to be the physician’s perceptions of their patients’ hopes and expectations about receiving that medication.", "n_tokens": 176, "kind": "text"}
{"chunk_id": "drug_resistance_book-141-3", "doc_id": "drug_resistance_book", "page": 141, "text": "17 Angus Randall (2017). 18 John Macfarlane et al. (1997), p. 1213. There is also evidence that UK General Practitioners have overestimated patients’ expectations of receiving a prescription, not only in cases involving antibi- otics, but also with other sorts of medication: see Nicky Britten (1995), p. 1084: “When general practitioners are surveyed they describe high levels of demand, but objective evidence consistently suggests that doctors overestimate patients’ expectations. Reanalysis of published data shows that about a fifth of patients leave general practice consultations with prescriptions they did not expect.” 19 Nicky Britten and Obioha Ukoumunne (1997), p. 1509. 20 Ibid, p. 1510.", "n_tokens": 156, "kind": "text"}
{"chunk_id": "drug_resistance_book-142-0", "doc_id": "drug_resistance_book", "page": 142, "text": "8 The Virtuous Physician and Antimicrobial Prescribing Policy and Practice", "n_tokens": 18, "kind": "text"}
{"chunk_id": "drug_resistance_book-142-1", "doc_id": "drug_resistance_book", "page": 142, "text": "In some of the above types of cases where physicians prescribe antibiotics inap- propriately, they may well be acting from a beneficent motivation to serve the best interests of their patient in some way – particularly where, as mentioned above, physicians prescribe an antibiotic “just in case” the patient has a serious, albeit rare, type of infection where antibiotic treatment at that stage would likely benefit the patient in the longer-term. However, physicians are frequently in a position to accu- rately diagnose that a patient has the less serious condition of acute bronchitis, and to recognise that it is in the long-term best interests of such a patient not to be pre- scribed an antibiotic now.21 Where physicians prescribing antibiotics are acting in misguided ways from motives of beneficence towards their patients, these cases can be usefully characterised as involving a failure of such motives to hit the target of the patient-centred virtue of medical beneficence.22 Cognitive biases seem to be an important factor in explaining why physicians’ beneficent motives can fail to hit the target of the virtue of medical beneficence in their prescribing decisions. An illumi- nating recent study of Australian GP trainees (registrars) describes their decision- making processes in deciding whether or not to prescribe an antibiotic for the patient. A number of these registrars explained that, while they realised prescribing an antibiotic was often not in the patient’s best", "n_tokens": 319, "kind": "text"}
{"chunk_id": "drug_resistance_book-142-2", "doc_id": "drug_resistance_book", "page": 142, "text": "interests, and that it was important to avoid antibiotic over-prescribing, the registrars indicated how they rationalised pre- scribing an antibiotic in certain cases – for instance, telling themselves that it was in the patient’s best interests to receive an antibiotic. The study found that: “Many registrars were concerned about patient safety and avoiding subsequent hospital presentations [for example, one registrar said]: ‘I tend to probably cover things a bit more because…if something goes wrong I want to make sure that the patient is going to be safe.’ (Registrar 9)”.23 In certain cases this seems to be an overly cau- tious approach, which may indicate that a registrar is unduly influenced by the well- known ‘framing effect’, whereby possible losses loom larger to the agent than do possible gains.24 The researchers also mentioned that: “Barriers to evidence-based prescribing included role-modelling outdated practices, or setting a precedent of", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-142-3", "doc_id": "drug_resistance_book", "page": 142, "text": "21 See McCullough et al., op. cit. For a useful systematic review of studies on how individuals treated with an antibiotic for respiratory and urinary infections can subsequently develop a higher level of bacterial resistance to that antibiotic for several months, see Céire Costelloe et al. (2010). 22 Christine Swanton emphasizes the importance of virtues ‘hitting the target’ of the contextually- relevant virtue, and she discusses various examples of candidate virtues that fail to hit their target (see Christine Swanton 2003). Similarly, Dean Cocking and I have argued that each virtue involves being guided by a ‘regulative ideal’: “To say that an agent has a regulative ideal is to say that they have internalised a certain conception of correctness or excellence, in such a way that they are able to adjust their motivation and conduct so that it conforms – or at least does not conflict – with that standard” (Oakley and Cocking 2001, op. cit., p. 25). 23 Anthea Dallas et al. (2014), p. e564. While antibiotic over-prescribing seemed due in part to certain cognitive biases in the registrars, “many registrars described a dissonance between their attitudes to guidelines and their prescribing behaviours, producing dissatisfaction with their own prescribing…: ‘There’s probably been times where I’ve given them the script and kind of felt a bit disappointed in myself afterwards.’(Registrar 14)” p. e563. 24 See Amos Tversky and Daniel Kahneman (1981).\n\n131", "n_tokens": 338, "kind": "text"}
{"chunk_id": "drug_resistance_book-143-0", "doc_id": "drug_resistance_book", "page": 143, "text": "132\n\nJ. Oakley\n\nprescribing that created patient expectations and pressure on the registrar: ‘I do know one supervisor in particular will give his patients antibiotics even for some- thing that sounds very viral, and therefore when I see his patients, I feel I’m expected to do that as well, because his patients have been seeing him for many years. So they expect it too, so I’m definitely more likely to give his patients antibiotics even when I don’t think it’s justified.’”(Registrar 10)25 This sort of approach may manifest a form of ‘authority bias’, whereby the registrar shows undue deference towards the antibiotic prescribing practices of his or her clinical supervisor.26", "n_tokens": 148, "kind": "text"}
{"chunk_id": "drug_resistance_book-143-1", "doc_id": "drug_resistance_book", "page": 143, "text": "According to some influential recent empirically-informed accounts of virtue and virtue ethics, acting virtuously requires (among other things) agents to employ certain deliberative strategies to counteract common decision-making biases and other countervailing factors which can impede virtuous actions. These accounts develop a comprehensive conception of virtuous character-traits, which include an awareness of situational factors that conduce to or inhibit virtuous behaviour.27 The misguided beneficent efforts of those registrars who were (or could reasonably have been) aware that prescribing an antibiotic was not in their patient’s best interests can be helpfully understood as failures to exercise the central Aristotelian virtue of phronesis, or practical intelligence, in this context.28 Broadly speaking, phronesis is an overarching normative disposition that regulates the more specific dispositions involved in particular virtues, to enable their more context-sensitive expression. Developing such practical intelligence can help well-motivated agents to avoid two potential deficiencies that can undermine their attempts to hit the target of the rele- vant virtue – i.e. moral ineptitude, and failures of meticulousness. Moral ineptitude is shown by agents who are well-intentioned but lack sufficient practical know-how or emotional intelligence to succeed in bringing about the good which they intend to bring about. Unmeticulous agents have the relevant practical know-how and", "n_tokens": 300, "kind": "text"}
{"chunk_id": "drug_resistance_book-143-2", "doc_id": "drug_resistance_book", "page": 143, "text": "emo- tional intelligence, but their efforts fall short as they do not apply strategies to cir- cumvent decision-making biases (and similar countervailing factors) that are prevalent in the context.29 Thus, the registrars who prescribed antibiotics against their patients’ longer-term best interests failed to exercise the virtue of practical intelligence here, because the registrars were not sufficiently meticulous in prevent- ing cognitive biases and other countervailing factors from undermining their efforts to make prescribing decisions in their patients’ best interests.30", "n_tokens": 116, "kind": "text"}
{"chunk_id": "drug_resistance_book-143-3", "doc_id": "drug_resistance_book", "page": 143, "text": "25 Dallas et al., p. e565. 26 The phenomenon of ‘authority bias’ was famously observed in Stanley Milgram’s experiments on obedience to authority. See Stanley Milgram (2010). 27 See e.g. Daniel C. Russell (2009), e.g. p. 140; Nancy E. Snow (2009), p. 563; and Nancy E. Snow (2010), especially her pp. 34–7 discussion of how people can effectively confront and combat any prejudices they might hold. These conceptions of virtue and virtue ethics have been developed in response to ‘situationist’ critiques of earlier accounts of virtue ethics. 28 Aristotle (1980); and Russell (2009), op. cit. 29 For further details about these executive failings, and their relevance to practical intelligence and medical virtues, see Oakley (2018b), op. cit. See also Oakley (2018a), op. cit. 30 See also Daniel Russell’s helpful discussion of how agents may ascertain the specific ends of virtuous actions, in: Daniel C. Russell (2015).", "n_tokens": 234, "kind": "text"}
{"chunk_id": "drug_resistance_book-144-0", "doc_id": "drug_resistance_book", "page": 144, "text": "8 The Virtuous Physician and Antimicrobial Prescribing Policy and Practice\n\nIndeed, there is evidence of other cognitive biases diverting physicians’ prescrib- ing decisions from patients’ best interests. For example, a recent US study found that as the number of prescribing decisions made by each primary care physician increased through the morning and into the afternoon, each physician became more likely to issue an antibiotic prescription that was not in the patient’s best interests. This study suggests that good prescribing behaviour can be undermined by a form of ‘decision fatigue’ (a phenomenon seen in many other contexts), which seemed to lead the physicians to become less able to resist providing inappropriate antibiotic prescriptions.31 So, developing ways of effectively addressing these (and potentially other) cognitive biases that appear to be contributing to physicians prescribing anti- biotics in cases where this is likely to be contrary to the patient’s long-term best interests, would seem a promising strategy supported by an empirically-informed virtue ethics approach (and perhaps also by certain other ethical approaches) to the problems of antimicrobial resistance.\n\n8.3\n\nCommunity-Centred Medical Virtues and Antimicrobial Prescribing Practice and Policy", "n_tokens": 258, "kind": "text"}
{"chunk_id": "drug_resistance_book-144-1", "doc_id": "drug_resistance_book", "page": 144, "text": "Virtue ethics approaches to medical practice have tended to focus predominantly on patient-centred virtues, such as medical beneficence and medical courage, which help an individual doctor serve well the best interests of their patients. But while it is important that these virtues correct any physician tendencies to make unreflective assumptions about what prescribing decisions are best for their patients, patient- centred virtues are not the only role virtues which are relevant to ethically justifiable prescribing behaviour and the problem of antimicrobial resistance. For the antimi- crobial prescribing decisions by physicians have also contributed to broader com- munity harms, such as the diminishing effectiveness of antibiotic treatments for other patients, and the scarcity of more expensive, last resort, antibiotics due to their increasing use as first-line treatments (and which have become unaffordable to patients in some countries). So, ethically responsible antibiotic prescribing prac- tices by physicians must also take into account the broader effects that their pre- scribing decisions are likely to have on the community. The virtuous antimicrobial prescriber thus needs to take account of a wider moral universe, beyond that of the best interests of their own patients. They would therefore be guided in their antimi- crobial prescribing decisions by community-centred medical virtues, such as justice and a readiness to serve the broader community, along with", "n_tokens": 302, "kind": "text"}
{"chunk_id": "drug_resistance_book-144-2", "doc_id": "drug_resistance_book", "page": 144, "text": "patient-centred virtues such as medical beneficence. The virtue of justice requires physicians to allocate fairly the medical resources under their control.32 In Aristotelian terms, allocating", "n_tokens": 40, "kind": "text"}
{"chunk_id": "drug_resistance_book-144-3", "doc_id": "drug_resistance_book", "page": 144, "text": "31 Linder et al. (2014), op. cit. 32 For a useful discussion of how medical benevolence should be constrained by the virtue of jus- tice, see Roger Crisp (2015).\n\n133", "n_tokens": 48, "kind": "text"}
{"chunk_id": "drug_resistance_book-145-0", "doc_id": "drug_resistance_book", "page": 145, "text": "134\n\nJ. Oakley\n\nmedical resources fairly (particularly when medical resources are scarce) can be understood as making allocation decisions in such a way as to provide each person who is affected by the decision an equal chance of developing and exercising their capabilities to live a flourishing human life. These capabilities include those elaborated in the Nicomachean Ethics, such as being able to understand the world, to engage in practical reasoning about our lives, and to form personal relationships with others.33 The readiness to serve others is another community-centred medical virtue, which requires physicians to make their services broadly available to the community, and so (for example) to avoid picking and choosing their patients according to the physician’s personal preferences. This virtue is plausibly under- stood as applying to physicians qua professionals, who ought to provide this readi- ness to serve the community in return for being granted a monopoly of expertise over the provision of key goods – i.e. those that serve patients’ health.34", "n_tokens": 199, "kind": "text"}
{"chunk_id": "drug_resistance_book-145-1", "doc_id": "drug_resistance_book", "page": 145, "text": "In the context of antimicrobial prescribing, the virtue of justice requires physi- cians to consider whether prescribing antibiotics for patients in certain circum- stances is likely to detrimentally affect the availability of effective antibiotics for other patients, even if there are grounds for believing that an antibiotic prescription is likely to be of some benefit to the former patients. While it is plausible to believe that physicians often serve the health of the community best by making antibiotic prescribing decisions that are in the best interests of their own patients, there will be cases where these two goals come into conflict – because the community’s interest in constraining antimicrobial resistance can sometimes be served best by the physi- cian refraining from providing an antibiotic which may be of some benefit to their patient. Where the likely benefit to the patient in such conflict cases is only mar- ginal, the virtue of justice will require a physician not to prescribe antibiotic treat- ment to their own patient. Of course, it is possible that justice could also sometimes require withholding from a patient an antibiotic that is likely to be of greater than marginal benefit – for instance, where there is only a single last-resort antibiotic available, and one patient is likely to derive much greater benefit from receiving this antibiotic than is another patient, then justice could arguably require that the first patient be provided with this antibiotic.", "n_tokens": 298, "kind": "text"}
{"chunk_id": "drug_resistance_book-145-2", "doc_id": "drug_resistance_book", "page": 145, "text": "(This is analogous to situations where jus- tice can plausibly require the allocation of the only available ICU bed to a patient who is likely to benefit more from this resource than will another patient, even if this second patient may suffer considerable harm as a consequence.) In what follows, I will concentrate on the first kind of conflict cases.", "n_tokens": 72, "kind": "text"}
{"chunk_id": "drug_resistance_book-145-3", "doc_id": "drug_resistance_book", "page": 145, "text": "Suppose a child presents to their physician with acute otitis media. Prescribing an antibiotic in such cases would appear likely to confer marginal benefits for the child – but as Collignon explains, “with an absolute reduction in pain in only 5%. Most cases resolve spontaneously. Seventeen children must be treated to prevent\n\n33 See the capabilities approach developed by Martha C. Nussbaum (2006). Nussbaum draws on Aristotle’s view that “the form of government is best in which every man, whoever he is, can act best and live happily” (Politics 1324a23–5). See also Justin Oakley (1994); and Millar, M. (2020). 34 This community-centred virtue becomes especially relevant in discussions of ethically justifiable limits on conscientious objection by physicians.", "n_tokens": 171, "kind": "text"}
{"chunk_id": "drug_resistance_book-146-0", "doc_id": "drug_resistance_book", "page": 146, "text": "8 The Virtuous Physician and Antimicrobial Prescribing Policy and Practice", "n_tokens": 18, "kind": "text"}
{"chunk_id": "drug_resistance_book-146-1", "doc_id": "drug_resistance_book", "page": 146, "text": "one child having some pain after two days. Antibiotics have no effect on hearing problems or other complications”.35 In these sorts of cases, despite the possible minor benefits of the child receiving an antibiotic, the detrimental impact which such patterns of antibiotic prescribing have on antimicrobial resistance in the broader community suggests that the virtue of justice would require physicians not to prescribe antibiotics in such cases, and to provide the child with other medica- tion, to relieve their symptoms. The dictates of justice in these sorts of cases can be compared with what justice would plausibly require of psychiatrists deliberating about whether to breach patient confidentiality to protect third parties from harm. Where a patient confides to his or her psychiatrist a credible threat to significantly harm a third party, and the psychiatrist is able to take steps to see that the third party is warned about this threat, the virtue of justice plausibly requires the psychiatrist to take such steps in the interests of this third party.36 While maintaining absolute patient confidentiality might sometimes be in the best interests of the patient involved, and so might be thought consistent with the virtue of medical beneficence, the overarching virtue of justice requires that confidentiality be breached here. (Indeed, in many such cases this course of action will not be contrary to the virtue of medical beneficence – for instance, where confiding such a threat is", "n_tokens": 292, "kind": "text"}
{"chunk_id": "drug_resistance_book-146-2", "doc_id": "drug_resistance_book", "page": 146, "text": "actually a ‘cry for help’ from the patient – even if beneficence provides some grounds for maintaining confidentiality here).", "n_tokens": 27, "kind": "text"}
{"chunk_id": "drug_resistance_book-146-3", "doc_id": "drug_resistance_book", "page": 146, "text": "But while the virtue of justice and its concerns for the broader interests of the community can in certain circumstances require physicians to refrain from provid- ing a patient with an antibiotic that is likely to benefit that patient, there is evidence that physicians relegate these broader interests to the periphery of their antibiotic prescribing decision-making. A 2002 US survey of 400 generalist physicians and 429 infectious diseases specialists found that: “The risk of contributing to the prob- lem of antibiotic resistance was ranked lowest, overall and by generalists, and sec- ond lowest by ID specialists”37 The researchers concluded that “…neither generalists nor infectious disease specialists emphasize the relative societal risks of antimicro- bial drug selection in their treatment decisions for patients with community-acquired pneumonia. Instead, they emphasize providing the newest and best treatments for each individual patient even though this approach may not be supported by current guidelines or public health policy”.38 One explanation of the insufficient weight given by these doctors to the risk of generating antimicrobial resistance was an overconfidence that their own antibiotic prescribing decisions were unlikely to negatively impact on antimicrobial resistance. This can be seen as an example of the cognitive bias known as ‘the overconfidence effect’, whereby agents have greater confidence in their judgements than is warranted by the evidence. There is much", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-146-4", "doc_id": "drug_resistance_book", "page": 146, "text": "35 Peter J. Collignon (2002), p. 328. 36 See, for example, the much-discussed 1969 case of Tatiana Tarasoff, as described in Marilyn McMahon (1992), pp. 12–16. 37 Joshua P. Metlay et al. (2002), p. 90. 38 Ibid., p. 93.\n\n135", "n_tokens": 75, "kind": "text"}
{"chunk_id": "drug_resistance_book-147-0", "doc_id": "drug_resistance_book", "page": 147, "text": "136\n\nJ. Oakley\n\nevidence that physician decision-making can be distorted by an overconfidence bias, which is one of the most frequently studied biases in medical decision- making.39 Further evidence that cognitive biases can lead physicians to give insuf- ficient weight to their own contributions to antimicrobial resistance is provided in an illuminating recent survey of 889 US physicians, which indicated that they often lacked insight into the broader harms of their own antibiotic prescribing decisions. Most of the respondents expressed concern about the problem of antimicrobial resistance. However, the researchers found that: “While 62% of respondents agreed that other doctors overprescribe antibiotics, only 13% agreed that they themselves overprescribe antibiotics”.40 The researchers concluded that “While most respon- dents agreed that other doctors overprescribe antibiotics, a much smaller proportion (especially of faculty) felt that they themselves overprescribe”.41 This significant underestimation by physicians of the contribution that their own antibiotic prescrib- ing decisions are likely having on the broader problems of antimicrobial resistance can be characterised as an example of confirmation bias, where an agent interprets information in a way that confirms a view that they already hold, regardless of whether this information actually supports or undermines that view.", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-147-1", "doc_id": "drug_resistance_book", "page": 147, "text": "Thus, cognitive biases also seem to be diverting physicians’ community-centred dispositions to act in accordance with the virtue of justice from hitting its target, in the context of their antibiotic prescribing decisions. A promising way of addressing this problem is for physicians to develop various ‘debiasing’ strategies, which can help them carry out what justice requires of them here in more practically intelligent ways. For example, Ian Scott and colleagues suggest that physicians’ awareness of their cognitive biases, and their ability to counteract the detrimental effects such biases can have on medical decision-making, can be enhanced by providing them with powerful narratives of patients who have been harmed (e.g. by antimicrobial resistance), and by reflective practice and role modelling.42 But while the prescrib- ing decisions of individual physicians are clearly a significant contributor to the problem of antimicrobial resistance, effectively addressing this problem goes well beyond the responsibility of each individual physician to ‘smarten up’ their own decision-making about antibiotic prescribing by strengthening their medical virtues on their own initiative. For these individual efforts must be complemented by the responsibilities of governments, international organisations, policymakers, and healthcare institutions to create institutional and regulatory environments which are conducive to physicians hitting the targets of the role virtues of medical", "n_tokens": 273, "kind": "text"}
{"chunk_id": "drug_resistance_book-147-2", "doc_id": "drug_resistance_book", "page": 147, "text": "beneficence and justice. For it can sometimes be difficult for physicians in their antibiotic pre- scribing behaviour to succeed in hitting the targets of the virtues of medical benefi- cence and justice, when they are working in contexts where they are frequently", "n_tokens": 55, "kind": "text"}
{"chunk_id": "drug_resistance_book-147-3", "doc_id": "drug_resistance_book", "page": 147, "text": "39 See Saposnik et al. (2016), op. cit. Overconfidence and availability bias are the two most fre- quently researched biases in medical decision making, and they appear to be highly prevalent in this context (though their precise prevalence levels here have not been determined). 40 Lilian Abbo et al. (2011), p. 715. 41 Ibid., p. 716. 42 Ian A Scott et al. (2017). See also Ateev Mehrotra and Jeffrey A. Linder (2017).", "n_tokens": 120, "kind": "text"}
{"chunk_id": "drug_resistance_book-148-0", "doc_id": "drug_resistance_book", "page": 148, "text": "8 The Virtuous Physician and Antimicrobial Prescribing Policy and Practice\n\nconfronted with patients’ requests for antibiotics, in circumstances where prescrib- ing an antibiotic would be clinically inappropriate.\n\nA good example of such government efforts is the Australian ‘Choosing Wisely’ initiative, which aims to reduce antibiotic overprescribing (and other forms of poor clinical practice) by providing patients and physicians with guidelines and specific examples of when medications such as antibiotics would be inappropriate. For instance, one such guideline advises against prescribing antibiotics for patients with uncomplicated acute bronchitis.43 These guidelines and examples on the Choosing Wisely website encourage discussions between physicians and patients about the appropriateness or otherwise of such medications in the circumstances, and make the boundaries of good medical practice more transparent to patients and doctors. Similarly, the UK Behavioural Insights Team successfully reduced the overpre- scription of antibiotics by sending letters to GPs in practices with relatively high rates of antibiotic prescription, stating that “80% of practices in your local area prescribe fewer antibiotics per head than yours”.44 Providing these doctors with such benchmarking information helped nudge them to recognise and counteract their biases towards prescribing antibiotics, and thereby helped enable these doctors’ medical dispositions to hit their proper targets.45", "n_tokens": 273, "kind": "text"}
{"chunk_id": "drug_resistance_book-148-1", "doc_id": "drug_resistance_book", "page": 148, "text": "Also, a worthwhile institutional initiative here could be to address authority bias through the creation of ‘safe spaces’ for junior doctors to be able to anonymously report established practices of poor antibiotic prescribing, without necessarily jeopardising their professional relationships with consultants and senior physicians.\n\n8.4\n\nConclusion\n\nThe antibiotic prescribing decisions made by physicians have clearly played a sig- nificant role in increasing antimicrobial resistance. Due to their monopoly of exper- tise in their professional roles, physicians are especially well-placed to be aware of, and to combat, the broader problems which certain sorts of antimicrobial prescrib- ing decisions can result in. Virtuous physicians owe the community a readiness to serve it by taking steps to reduce – and hopefully eliminate altogether – antibiotic prescribing decisions that are contrary to the virtues of medical beneficence and justice. In this chapter, I have outlined some strategies that individual physicians, institutions, and healthcare policymakers can develop to help physicians to hit the targets of those virtues, and to thereby play their part in redressing the problems of antimicrobial resistance.\n\n43 See Choosing Wisely Australia, https://www.choosingwisely.org.au/. 44 Michael Hallsworth et al. (2016). See also David Halpern (2015). 45 See also Kiran Iyer (2017), and Fay Niker (2018).\n\n137", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-149-0", "doc_id": "drug_resistance_book", "page": 149, "text": "138\n\nJ. Oakley\n\nReferences\n\nAbbo, Lilian, et al. 2011. Faculty and resident physicians’ attitudes, perceptions, and knowledge about antimicrobial use and resistance. Infection Control and Hospital Epidemiology 32 (7): 714–718.\n\nAntibiotic Expert Groups. 2019. Therapeutic guidelines: Antibiotic, version 16. Melbourne, Therapeutic Guidelines. https://tgldcdp.tg.org.au/guideLine?guidelinePage=Antibiotic&from page=etgcomplete\n\nAristotle. 1980. The Nicomachean Ethics. Trans. W.D. Ross. Oxford: Oxford University Press. Australian Commission on Safety and Quality in Health Care. 2020. Antimicrobial prescrib- ing practice in Australian hospitals: Results of the 2018 Hospital National Antimicrobial Prescribing Survey, January 2020. https://www.ncas-australia.org/ncas-publications.\n\nBlumenthal-Barby, J.S., and H. Krieger. 2015. Cognitive biases and heuristics in medical decision-\n\nmaking: A critical review. Medical Decision Making 35 (4): 539–557.\n\nBritten, Nicky. 1995. Patients’ demands for prescriptions in primary care. British Medical Journal\n\n310 (29): 1084–1085.\n\nBritten, Nicky, and Obioha Ukoumunne. 1997. The influence of patients’ hopes of receiving a pre- scription on doctors’ perceptions and the decision to prescribe: A questionnaire survey. British Medical Journal 315 (7121): 1506–1510.", "n_tokens": 340, "kind": "text"}
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{"chunk_id": "drug_resistance_book-150-2", "doc_id": "drug_resistance_book", "page": 150, "text": "Theory and Moral Practice 12 (5): 555–568.\n\n———. 2010. Virtue as social intelligence: An empirically grounded theory. New York: Routledge. Swanton, Christine. 2003. Virtue ethics: A pluralistic view. Oxford: Oxford University Press. Tversky, Amos, and Daniel Kahneman. 1981. The framing of decisions and the psychology of\n\nchoice. Science 211 (4481): 453–458.\n\nYao, Zhenjiang, et al. 2015. Healthcare associated infections of Methicillin-resistant Staphylococcus\n\naureus: A case-control-control study. PLoS One 10 (10): e0140604.\n\n139", "n_tokens": 146, "kind": "text"}
{"chunk_id": "drug_resistance_book-151-0", "doc_id": "drug_resistance_book", "page": 151, "text": "140\n\nJ. Oakley\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 169, "kind": "text"}
{"chunk_id": "drug_resistance_book-152-0", "doc_id": "drug_resistance_book", "page": 152, "text": "Chapter 9 Moral Responsibility and the Justification of Policies to Preserve Antimicrobial Effectiveness\n\nAlberto Giubilini and J. Savulescu\n\nAbstract Restrictive policies that limit antimicrobial consumption, including ther- apeutically justified use, might be necessary to tackle the problem of antimicrobial resistance. We argue that such policies would be ethically justified when forgoing antimicrobials constitutes a form of easy rescue for an individual. These are cases of mild and self-limiting infections in otherwise healthy patients whose overall health is not significantly compromised by the infection. In such cases, restrictive policies would be ethically justified because they would coerce individuals into ful- filling a moral obligation they independently have. However, to ensure that such justification is the strongest possible, states also have the responsibility to ensure that forgoing antimicrobials is as easy as possible for patients by implementing adequate compensation measures.\n\nKeywords Bioethics · Public health ethics · Antimicrobial resistance · Collective responsibility · Easy rescue\n\nA. Giubilini (*) Wellcome Centre for Ethics and Humanities, University of Oxford, Oxford, UK\n\nOxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, UK e-mail: alberto.giubilini@philosophy.ox.ac.uk\n\nJ. Savulescu Oxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, UK", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-152-1", "doc_id": "drug_resistance_book", "page": 152, "text": "Visiting Professorial Fellow in Biomedical Ethics, Murdoch Children’s Research Institute, Melbourne, Australia\n\nDistinguished Visiting Professor on Law, Melbourne Law School, University of Melbourne, Melbourne, Australia\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_9\n\n141", "n_tokens": 105, "kind": "text"}
{"chunk_id": "drug_resistance_book-153-0", "doc_id": "drug_resistance_book", "page": 153, "text": "142\n\nA. Giubilini and J. Savulescu\n\n9.1\n\nThe Problem of Antimicrobial Resistance\n\nWhen Alexander Fleming was awarded the Nobel Prize for Medicine in 1945, he warned in his acceptance speech of the risk that some bacteria could develop resis- tance to penicillin, which he had discovered 17 years earlier. It cannot be overstated how longsighted Fleming was. Today, “bacteria are resistant to nearly all antibiotics that were earlier active against them” (Herrmann and Laxminarayan 2010, p. 4.2), and “700,000 people die of resistant infections every year” (O’Neill 2016, p. 4). As estimated by the Review on Antimicrobial Resistance commissioned by the UK government, “by 2050 10 million lives a year are at risk due to drug resistant infec- tions, as are 100 trillion USD of economic output” (O’Neill 2016). Examples of diseases associated with antimicrobial resistance (AMR) include tuberculosis, gon- orrhoea, typhoid fever, and group A streptococcus (Van der Velden et al. 2013). The problem of AMR has been framed by some in terms of a “slowly emerging disaster” (Littmann and Viens 2015) and of a “global health security issue” (Balasegaram et al. 2015).", "n_tokens": 292, "kind": "text"}
{"chunk_id": "drug_resistance_book-153-1", "doc_id": "drug_resistance_book", "page": 153, "text": "AMR is a naturally occurring phenomenon: microbes naturally tend to adapt to antimicrobials and develop resistance. However, AMR is accelerated by human behaviour (Jamrozik and Selgelid 2019), and particularly the use and abuse of anti- microbials, both in livestock (Anomaly 2019; Giubilini et al. 2017; O’Neill 2015; Anomaly 2009) and in humans (O’Neill 2016). This paper is focussed on AMR caused by human consumption of antimicrobials, and therefore on the human factor in the development of AMR. There is a positive correlation between antimicrobial resistance rates and antimicrobial consumption in humans (Van der Velden et al. 2013, pp. 318–19). In fact, in the case of antibiotics, it is now widely accepted that “the use of antibiotics is the single most important factor leading to antibiotic resis- tance around the world: simply using antibiotics creates resistance” (CDC, About antimicrobial resistance), even when antibiotic use is medically indicated to treat infections (which is what makes AMR a particularly difficult ethical issue). Thus, the paradox of antibiotic and certain other kind of antimicrobial consumption is that while certain antimicrobials can be beneficial to individuals, their use also poses a threat to public health, to the lives of millions of people, and to the world economy. If they are not used more wisely than they currently are, i.e. if their consumption is not reduced, we might face a “post antibiotic” era (Alanis 2005; WHO 2014) char- acterized by", "n_tokens": 347, "kind": "text"}
{"chunk_id": "drug_resistance_book-153-2", "doc_id": "drug_resistance_book", "page": 153, "text": "two undesirable outcomes. First, we might no longer have effective means of treating severe infections. Second, medicine’s achievements that require effective antibiotics, such as organ transplantation, cancer chemotherapy, and major surgery, might no longer be available (WHO, Antimicrobial resistance).", "n_tokens": 60, "kind": "text"}
{"chunk_id": "drug_resistance_book-153-3", "doc_id": "drug_resistance_book", "page": 153, "text": "To be sure, the problem of reducing antibiotic and certain type of antimicrobial consumption mainly concerns those countries with easy access to and massive con- sumption of antimicrobials. These are mainly high-income countries (HICs). The consumption rate of antimicrobials in most low- and middle-income countries (LMICs), although it increased dramatically in recent years, remains much lower than that in HICs, and in many LMICs the burden of infectious disease still out- weighs the burden of resistance; the increase in consumption in such countries", "n_tokens": 118, "kind": "text"}
{"chunk_id": "drug_resistance_book-154-0", "doc_id": "drug_resistance_book", "page": 154, "text": "9 Moral Responsibility and the Justification of Policies to Preserve Antimicrobial…\n\nought to be closely monitored, but drastic measures to reduce antibiotic consump- tion need to be implemented primarily in HICs (Klein et al. 2018). Reduction of therapeutically justified antimicrobial consumption in LMICs for conservation pur- poses might have undesirable outcomes, especially in those countries where the level of public health is already poor. There might be exceptions, of course; for instance, India is a lower-income country and one of the major contributors to resis- tance through very high consumption rates (Kumar et al. 2013; WHO India 2018), so perhaps significant restrictions on antibiotic access – that is, restrictions that apply also to therapeutically justified use – should be implemented in such context as well. However, to make our arguments the least controversial possible, we take them to apply only to HICs where a good level of public health might allow leaving certain mild and self-limiting infections untreated without posing significant costs on patients.", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-154-1", "doc_id": "drug_resistance_book", "page": 154, "text": "This paper is focussed on two often neglected aspects of the problem of AMR, namely on the individual moral obligations with regard to antimicrobial consump- tion and on the type of justification that health authorities could and should offer for restricting access to antimicrobials in order to preserve antimicrobial effectiveness. As we will argue in Sect. 9.3, these two aspects are closely related: the state has an obligation to provide the strongest justification possible for restrictive interventions aimed at limiting antimicrobial consumption, and the strongest justification is one based on the existence of an individual moral obligation to forgo antimicrobials, perhaps (as we will suggest in Sect. 9.4) even in case of mild self-limiting infections that do not significantly risk worsening the individual’s general health. The fact that even justified use of antimicrobials, i.e. the use that is medically necessary to treat infections (as opposed to unjustified use, e.g. when antibiotics are prescribed for viral infections, a practice that is not uncommon unfortunately), contributes to anti- microbial resistance determines a moral conflict between individual interest and collective interest that might require individuals to make sacrifices for the sake of the common good.", "n_tokens": 258, "kind": "text"}
{"chunk_id": "drug_resistance_book-154-2", "doc_id": "drug_resistance_book", "page": 154, "text": "Such moral conflict gives rise to a “tragedy of the commons” scenario (Hollis and Maybarduk 2015), which will be presented in Sect. 9.2: we will argue, follow- ing Garrett Hardin, that the tragedy of the commons has an ethical solution, which will be presented in Sect. 9.4, where we will argue that there is a moral obligation to contribute to the preservation of the common good of antimicrobial effectiveness which might entail a moral obligation not to use antimicrobials in some cases of mild, self-limiting infections, provided that certain conditions obtain and that the state takes all the measures that are necessary to ensure that forgoing antimicrobials in those cases approximates a form of “easy rescue”.\n\nThus, in Sect. 9.4 we will draw the policy implications of this ethical solution to the tragedy of the commons: the moral obligation to sometimes forgo antimicrobi- als, grounded in a duty of easy rescue, strengthens the justification for state inter- ventions that prohibit or discourage the use of antimicrobials in certain cases. Since states should be able to provide the strongest justification possible for implementing restrictive policies that discourage or prohibit antimicrobial consumption, appeal to individual moral obligations to sometimes forgo antimicrobials has a political weight in terms of justification of state-imposed restrictions on antimicrobial use.\n\n143", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-155-0", "doc_id": "drug_resistance_book", "page": 155, "text": "144\n\nA. Giubilini and J. Savulescu\n\nHowever, as we will suggest in conclusion of Sect. 9.4, the moral obligation of the state to provide the strongest justification possible for restricting access to anti- microbials implies an obligation on the state to ensure that forgoing antimicrobials does represent a form of easy rescue, i.e. that individuals bear as small a cost as possible for leaving certain infections untreated with antimicrobials (assuming this measure is necessary). This means, in practice, that the state has moral obligations towards individuals who are requested to forgo antimicrobial for the sake of the col- lective good, such as the obligation to provide enhanced medical follow up and to adequately compensate, financially or in other ways (e.g. higher priorities on wait- ing lists for other medical treatments), these individuals.\n\n9.2", "n_tokens": 187, "kind": "text"}
{"chunk_id": "drug_resistance_book-155-1", "doc_id": "drug_resistance_book", "page": 155, "text": "Public Goods, Tragedy of the Commons, and Policies to Address Antimicrobial Resistance\n\nIt has been claimed that “if effective antibiotics are seen as a public good, their overuse may be likened to the tragedy of the commons scenario” (Littmann and Viens 2015, p. 214). This statement is not entirely correct in the way the notion of ‘public good’ is applied. As we are going to see in this section, antibiotic and more generally antimicrobial effectiveness shares an essential feature with common goods or common pool resources, rather than with public goods. Let’s see more in detail what this terminology means when the concepts of “public goods” and of “common goods” are applied to the case of antimicrobial effectiveness.", "n_tokens": 155, "kind": "text"}
{"chunk_id": "drug_resistance_book-155-2", "doc_id": "drug_resistance_book", "page": 155, "text": "Some benefits associated with antimicrobial effectiveness can certainly be con- sidered public goods. These include freedom from infectious diseases (Selgelid 2007, p. 226), the containment of infectious diseases (Woodward and Smith 2003, p. 10), or the reduced risk of infection by a resistant disease (Smith and Coast 2003, p. 78). These benefits are public goods in the technical sense of the term: they are non-excludable, in the sense that people cannot be excluded from benefitting from them; and they are non-rivalrous, in the sense that the fact that a person benefits from them does not affect the way and the extent to which others benefit as well (Cowen 2008). More precisely, freedom from infectious diseases, infectious disease containment, and the reduced risk of infection can be conceived as global public goods, i.e. goods “exhibiting a significant degree of publicness (i.e. non- excludability and non-rivalry) across national boundaries” (Woodward and Smith 2003, p, 8).", "n_tokens": 219, "kind": "text"}
{"chunk_id": "drug_resistance_book-155-3", "doc_id": "drug_resistance_book", "page": 155, "text": "Effective antimicrobials are the means through which such public goods are pre- served. But antimicrobial effectiveness is a common good rather than a public good because antimicrobial effectiveness is rivalrous in consumption, in virtue of what Anne Schwenkenbecher in a chapter of this volume calls “the antimicrobial foot- print” of antimicrobial consumptions: “simply using antibiotics [or other antimicro- bials] creates resistance” (CDC, About Antimicrobial resistance) and “more consumption of antibiotics directly leads to more resistance” (O’Neill 2016, p. 17), regardless of whether antimicrobial use is therapeutically justified or not. The use of the resource of antimicrobial effectiveness through antimicrobial consumption erodes", "n_tokens": 166, "kind": "text"}
{"chunk_id": "drug_resistance_book-156-0", "doc_id": "drug_resistance_book", "page": 156, "text": "9 Moral Responsibility and the Justification of Policies to Preserve Antimicrobial…\n\nthe resource and therefore diminishes its availability. As put by Jonny Anomaly, “individually rational choices produce substantial social costs by creating reservoirs of antibiotic-resistant bacteria in human hosts and more generally in our shared microbial environment” (Anomaly 2013, p. 753). It is important to point out that, while antimicrobial use might benefit individuals in the short term, this is not neces- sarily the case in the long term: individuals can incur a portion of the costs associated with antimicrobial resistance (Anomaly 2013, p. 752). For example, the individual who takes antibiotics can become a carrier of resistant bacteria, which means that the individual is at greater risk in case of subsequent infections (Cars et al. 2008).\n\nIt has been observed that the effectiveness of antimicrobials can “be modelled as a natural resource in much the same way as are fish, tree, oil, and other resources” (Herrmann and Laxminarayan 2010, p. 4.3). According to John Conly, for example,\n\nantimicrobial resistance may be likened to [the] overfishing scenario, to cattle overgrazing the grass in the commons or to deforestation on Easter Island, which led to population dying out. Antimicrobial resistance is a consequence of continued overuse of antibiotics com- bined with the constant growth of resistance overtime. (WHO 2010)", "n_tokens": 309, "kind": "text"}
{"chunk_id": "drug_resistance_book-156-1", "doc_id": "drug_resistance_book", "page": 156, "text": "Typically, consumption of natural resources determines a ‘tragedy of the com- mons’ scenario (Ostrom et al. 1999,). Garrett Hardin first described the “tragedy of the commons” in an article he published in Science (Hardin 1968). Hardin illustrated the problem through the example of a commons to which some herdsmen have access. The tragedy occurs when many herdsmen, acting merely out of self-interest, have their cattle overgraze the commons, thus eroding the resource (Hardin 1968, p. 1244). Particularly in a context of growing population, all herdsmen acting in the same way deplete the common good. In the context of antimicrobial effectiveness, the same problem arises (Hollis and Maybarduk 2015). As Jonny Anomaly put it, “the benefits of [antibiotic] use are borne by the individual, the costs are socialised, and the conse- quent harm is the product of many independent actions” (Anomaly 2013, p. 752).\n\nAccording to Hardin, one characteristic of a tragedy of the commons is the fact that there is no “technical” solution to the problem, meaning that there is no solution “that requires a change only in the techniques of the natural sciences, demanding little or nothing in the way of change in human values or ideas of morality” (Hardin 1968, p. 1243). On the contrary, Hardin argued, the solution requires a “fundamen- tal extension” of our morality (Hardin 1968, p. 1243), i.e. acting in view of protect- ing the public interest rather than in a merely self-interested way.", "n_tokens": 337, "kind": "text"}
{"chunk_id": "drug_resistance_book-156-2", "doc_id": "drug_resistance_book", "page": 156, "text": "However, Hardin seemed to be sceptical about the possibility that such an exten- sion of morality could occur, at least without some external coercive intervention (which on most accounts of morality would arguably undermine the authentically “moral” nature of the change invoked). He believed that the best way to solve a tragedy of the commons is through some degree of “mutually agreed upon” coer- cion (Hardin 1968, p. 1247), for example in the form of taxation that would allow to internalize the negative externalities of individual consumption.1\n\n1 Another solution Hardin proposed is the privatization of the commons (Hardin 1968, p. 1245), which in the case of antimicrobials might consist in “extending the period of exclusivity, possibly\n\n145", "n_tokens": 163, "kind": "text"}
{"chunk_id": "drug_resistance_book-157-0", "doc_id": "drug_resistance_book", "page": 157, "text": "146\n\nA. Giubilini and J. Savulescu\n\nAnd indeed, some have suggested that the negative externalities of antimicrobial use could be internalised through the introduction of user fees or consumption taxes (Littmann and Viens 2015; Anomaly 2013; Herrmann and Laxminarayan 2010). Internalization is typically achieved by “taxing negative externalities (…) at a rate that would offset the social cost of the activities that generate the externalities, and then (ideally) using the revenues from the tax to fund socially useful projects” (Anomaly 2009, p. 433). The idea behind the concept of internalization is that it is those who are responsible for a negative externality that should bear the cost for it. However, it might not be possible to fully internalise the collective cost of anti- microbial consumption and to disincentivize consumers through a tax: selection for AMR will probably continue to occur in spite of the tax and in spite of the invest- ment of the revenue in strategies to contain AMR such as research on new antimi- crobials. For this reason, it has been suggested that we might need at some point to introduce policies to restrict antimicrobial use only to the most serious infections, i.e. that it might be necessary to prevent, if necessary through legal prohibition, their use in the case of milder self-limiting infections (Foster and Grundmann 2006, p. 179). We will return to this point in Sect. 9.4.", "n_tokens": 319, "kind": "text"}
{"chunk_id": "drug_resistance_book-157-1", "doc_id": "drug_resistance_book", "page": 157, "text": "Policies might therefore aim to disincentivize individuals from using antimicro- bials, in the case of taxation; or they might coercively impose restrictions on antimi- crobial use, in the case of outright prohibition of antimicrobial use in certain circumstances. As said before, we are interested here not so much in determining which policies would be more effective and ethically acceptable. Thus, we do not intend to provide arguments for or against taxation of antibiotics or restrictions on their use. Rather, we are interested in what justification an authority might offer for implementing restrictive policies, whatever form they take. While such policies might be justified by considerations of public interest, it is important that the type of justification that a state can provide for interventions that limit or discourage anti- microbial use be the strongest justification possible, given that such interventions might require individuals to sacrifice some significant personal interest, such as the interest in accessing effective health care, for the sake of the common good. As we are going to argue in the next section, considerations about the morality of individ- ual choices regarding antimicrobial consumption can strengthen the justification for such policies.\n\n9.3", "n_tokens": 241, "kind": "text"}
{"chunk_id": "drug_resistance_book-157-2", "doc_id": "drug_resistance_book", "page": 157, "text": "Morality and Antimicrobial Consumption\n\nRestrictive and coercive interventions might be efficacious at protecting the com- mon goods associated with AMR containment and in preserving the common good of antimicrobial effectiveness. However, the “tragedy of the commons” scenario\n\nindefinitely” of the patents, thus giving “the patentee the ability to charge high prices and thus indirectly restrain overuse by some users” (Hollis and Maybarduk 2015, p. 33).", "n_tokens": 95, "kind": "text"}
{"chunk_id": "drug_resistance_book-158-0", "doc_id": "drug_resistance_book", "page": 158, "text": "9 Moral Responsibility and the Justification of Policies to Preserve Antimicrobial…\n\nwhich preservation of antimicrobial effectiveness gives rise to suggests that there is an independent ethical dimension to the problem of AMR. In this section we will explain why discussing such an independent ethical dimension is important from a political point of view, i.e. in view of justifying coercive policies aimed at restricting antimicrobial use.\n\nEstablishing an independent moral responsibility to make a more appropriate use of antimicrobials would make the justification that a state could provide for policies that restrict or discourage antimicrobial use the strongest possible. And, arguably, the state does have a duty to provide individuals with the strongest justification pos- sible for implementing policies that restrict or discourage a treatment that is in the individuals’ best interest, as is often the case with antimicrobials.", "n_tokens": 178, "kind": "text"}
{"chunk_id": "drug_resistance_book-158-1", "doc_id": "drug_resistance_book", "page": 158, "text": "Restrictive policies might be justified in light of a state’s duty to protect certain common goods and public goods, such as the public goods associated with AMR containment. These possible interventions range from those that are minimally intrusive to those that more substantially infringe rights or important interests of individuals. Thus, at one end of the spectrum we find policies such as information campaigns, nudging, or incentivisation of certain pro-social behaviours; and at the other end we find more restrictive policies such as taxation and compulsion. In all such cases, the authority enforcing such policies should be able to provide the stron- gest justification possible for its interventions, but the more restrictive the policies become, the more difficult it is for the authority to meet such requirement. A state’s duty to protect public goods and common goods by itself does not provide the stron- gest justification possible for interventions that sacrifice important individual inter- ests. The justification would be stronger if, in addition to considerations of public interest, there were independent individual moral obligations to make those indi- vidual sacrifices that are required by the restrictive policy (Giubilini et al. 2018) Thus, one way to strengthen the justification for state interventions such as taxation of antimicrobials or prohibition of certain antimicrobial uses is to identify a pre- existing individual moral obligation not to use antimicrobials", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-158-2", "doc_id": "drug_resistance_book", "page": 158, "text": "in certain cases. Such independent moral obligation to prioritize other-regarding choices over self- interested choices would make the case for introducing restrictive policies that limit or discourage antimicrobial use as compelling as possible: such policies would sim- ply impose or encourage choices that individuals have an independent moral obliga- tion to make anyway.", "n_tokens": 69, "kind": "text"}
{"chunk_id": "drug_resistance_book-158-3", "doc_id": "drug_resistance_book", "page": 158, "text": "9.4\n\nIndividual Responsibility and Duty of Easy Rescue: The Ethical Solution to the Tragedy of the Commons and the Responsibilities of the State\n\nWe have noted above that, as Hardin himself acknowledged, the tragedy of the com- mons is first and foremost an ethical problem. Therefore, it has an ethical solution that is independent from the justification for legislative coercive solutions. Now,\n\n147", "n_tokens": 75, "kind": "text"}
{"chunk_id": "drug_resistance_book-159-0", "doc_id": "drug_resistance_book", "page": 159, "text": "148\n\nA. Giubilini and J. Savulescu\n\n“ethical solution” means, according to Hardin’s phrasing, a change in “human val- ues” informing human behaviour. Thus, in the case of antimicrobial consumption, the ethical solution to the tragedy of the commons consists in justifying the exis- tence of an individual moral obligation to act contrary to one’s (short term) self interest in order to contribute to the preservation of the common good of antimicro- bial effectiveness. In other words, the ethical solution consists in finding a justifica- tion for a moral duty not to use antimicrobials, if necessary even at the cost of leaving some infections untreated, in order to protect the common good of antimi- crobial effectiveness. In this section we are going to provide this justification.", "n_tokens": 183, "kind": "text"}
{"chunk_id": "drug_resistance_book-159-1", "doc_id": "drug_resistance_book", "page": 159, "text": "It is plausible to assume that individuals have what might be called a “duty of easy rescue” (Savulescu 2007). That is, if doing X (or refraining from doing Y) entails a small cost to an individual and a large benefit (or prevention of a large harm) to others, the individual has a clear prima facie moral obligation to do X (or to refrain from doing Y). Morality is essentially different from prudence, and requires the sacrifice of one’s own interests for others. It is debatable what kind of individual sacrifices morality requires, but if morality requires anything, almost everyone would agree that it certainly requires at least small sacrifices for the sake of preventing great harm. This does not mean that an individual does not have a moral obligation when the cost to her is not small. However, in easy rescue case, such moral obligation seems uncontroversial. A formulation of the duty of easy rescue was famously provided by Peter Singer, according to whom “if it is in our power to prevent something bad from happening, without thereby sacrificing any- thing of comparable moral importance, we ought, morally, to do it” (Singer 1972, p. 230, emphasis added). A roughly equivalent, though way less demanding, formu- lation has been provided by Tim Scanlon, according to whom “[i]f we can prevent something very bad from happening to someone by making a slight or even moder- ate sacrifice, it would be wrong not to do so” (Scanlon 1998, p. 224). The fact that some version of a duty of", "n_tokens": 332, "kind": "text"}
{"chunk_id": "drug_resistance_book-159-2", "doc_id": "drug_resistance_book", "page": 159, "text": "easy rescue can be defended both from a utilitarian per- spective- in the case of Singer – and a contractualist perspective- in the case of Scanlon – supports the idea that it is a fundamental requirement of morality on which reasonable people could agree.", "n_tokens": 53, "kind": "text"}
{"chunk_id": "drug_resistance_book-159-3", "doc_id": "drug_resistance_book", "page": 159, "text": "The existence of a duty of easy rescue implies an individual moral obligation to forgo antimicrobials for the sake of the common good of antimicrobial effective- ness, when forgoing antimicrobials comes at a sufficiently small cost to individuals. This would be the case, for example, when antimicrobials are not necessary to treat an infection (for example in the case of viral infections), in which case there would be no cost at all in forgoing antimicrobials. But forgoing antimicrobials would also come at a relatively small cost to individuals when individuals have minor self- limiting infections or low risk mild infections (for example, skin infections which could be treated topically with antiseptics) that do not significantly worsen the gen- eral state of health of the individual, where the risks of complications is adequately monitored, and when the individual is adequately compensated for any financial and non-financial cost she might incur as a consequence of leaving that infection untreated. As some have suggested (Foster and Grundmann 2006) it might at some", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-160-0", "doc_id": "drug_resistance_book", "page": 160, "text": "9 Moral Responsibility and the Justification of Policies to Preserve Antimicrobial…\n\npoint be necessary to leave such self-limiting infections untreated in order to pre- serve antimicrobial effectiveness.\n\nThe moral duty of easy rescue represents the ethical solution to the tragedy of the commons in the context of antimicrobial consumption that Hardin advocated: indi- viduals have a moral obligation to prioritize the public interest in the preservation of the commons of antimicrobial effectiveness over their own interest in treating with antimicrobials any type of infection (including mild and self-limiting ones), because doing so comes at a small cost to individuals, at least when all that is required of individuals is to leave self-limiting mild or minor infections untreated in circum- stances in which this would not significantly worsen individual health and where adequate compensatory measures are in place.", "n_tokens": 186, "kind": "text"}
{"chunk_id": "drug_resistance_book-160-1", "doc_id": "drug_resistance_book", "page": 160, "text": "Now, since it is necessary that a large number of individuals fulfil a duty of easy rescue in order for a public benefit to obtain, we can say that there is not only an individual, but also a collective responsibility to forgo antimicrobials when doing so is a way of fulfilling a duty of easy rescue. Now, in some cases of collective action, any individual contribution to a collective good, or to the prevention of a collective harm, is insignificant; for example, the contribution each individual could make to the realisation of herd immunity through individual vaccination, or the contribution each individual could make to the prevention of global warming by avoiding driving just for fun, are both negligible. However, in the case of containment of antimicro- bial resistance every single individual forgoing antimicrobials could make a differ- ence, because every single individual could become the carrier of resistant microbes that are then passed onto other people. For example, it has been shown that individu- als who take antibiotics for respiratory and urinary infections might develop bacte- rial resistance that could last up to 12 months (Costelloe et al. 2010). Thus, the need to preserve the common good of antimicrobial effectiveness implies not only a col- lective responsibility, but also an individual responsibility not to use antimicrobials so as to benefit others by contributing to the preservation of antimicrobial effective- ness, at least as long as forgoing", "n_tokens": 310, "kind": "text"}
{"chunk_id": "drug_resistance_book-160-2", "doc_id": "drug_resistance_book", "page": 160, "text": "antimicrobials comes at a small enough cost to individuals.", "n_tokens": 14, "kind": "text"}
{"chunk_id": "drug_resistance_book-160-3", "doc_id": "drug_resistance_book", "page": 160, "text": "When forgoing antimicrobials is a moral duty of easy rescue, we can claim that the state is in the position to fulfil its obligation to provide the strongest justification possible for prohibiting or at least discouraging the use of antimicrobials: as we said in Sect. 9.3, the state would be discouraging or preventing individuals from doing only what they have a moral obligation not to do anyway. Therefore, being the state in the position to fulfil its moral obligations in implementing restrictive measures, such restrictive measures regarding antimicrobial use are ethically justified. As one of us put it, “when the cost to us of forgoing some activity is small (…) and the harm to others which thereby does not occur is great (prevention of serious disease), then liberals might require that the state prevent this harm” (Savulescu 2007, p. 10).\n\n“Duty to rescue” laws exist in many European countries; for instance, in Germany and France it is illegal not to assist a person in danger when providing assistance entails a small or no risk to the potential rescuer. From what we have said so far, laws restricting antimicrobial use could be ethically justified as special cases of “duty to rescue” laws of this kind.\n\n149", "n_tokens": 268, "kind": "text"}
{"chunk_id": "drug_resistance_book-161-0", "doc_id": "drug_resistance_book", "page": 161, "text": "150\n\nA. Giubilini and J. Savulescu\n\nThe individual moral responsibility to forgo antimicrobials in certain circum- stances implies that there are two other actors with specific moral responsibilities, besides patients with minor or mild self-limiting infections.\n\nFirst, doctors have the responsibility to assess whether a certain infection is self- limiting and, more in general, whether leaving a certain infection untreated is com- patible with a good enough level of individual health. In one important sense, the fact that the state has the strongest justification possible for imposing bans on anti- microbial use or for discouraging through taxation antimicrobial consumption takes the responsibility for decisions about antimicrobial prescription out of the hands of doctors: if a certain infection is mild and self limiting and leaving it untreated does not significantly worsen the general state of health of the patient, then the state, rather than the doctor, is justified in preventing the use of antimicrobials for the sake of the common good. However, the doctors would still have the important responsi- bility of determining whether the conditions specified in such laws would apply, and thus they would still be the ultimate gate-keepers of antimicrobials.", "n_tokens": 259, "kind": "text"}
{"chunk_id": "drug_resistance_book-161-1", "doc_id": "drug_resistance_book", "page": 161, "text": "Second, but equally important, healthcare systems and states have important moral responsibilities too. We have said that having an uncontroversial individual moral obligation based on a duty of easy rescue to sometimes forgo antimicrobials strengthens the justification for state interventions that forbid or discourage antimi- crobial use. Therefore, the state or the healthcare system have the responsibility to ensure that forgoing antimicrobials does represent a form of easy rescue, i.e. that it is not too burdensome for patients, so that the justification for state intervention is the strongest possible. This means, at the very least, that patients who are denied antimicrobials should be carefully monitored and provided with adequate and enhanced medical follow up to make sure that forgoing antimicrobial treatment does not significantly worsen the general state of health of the individual. It is the responsibility of states and of healthcare systems to ensure that adequate measures are in place in order to guarantee monitoring and medical supervisions of those patients who sacrifice their self-interest for the sake of the collective good, so that their sacrifice would represent a form of easy rescue.", "n_tokens": 232, "kind": "text"}
{"chunk_id": "drug_resistance_book-161-2", "doc_id": "drug_resistance_book", "page": 161, "text": "However, we claim that the responsibility of states extends beyond the provision of medical supervision and follow up. We propose that a further measure that might be implemented in order to ensure that the rescue is an easy rescue is that of com- pensating individuals who make a sacrifice for the sake of the collective good. Compensation – financial or of other kind – would be an appropriate measure because it would provide individuals with an additional reason for forgoing antimi- crobials in certain circumstances, it would be fair in consideration of the sacrifice individuals are making for the sake of the collective good, and, more importantly, if the right type of compensation is offered, it could make their condition easier to bear, thus approximating a form of easy rescue and providing a further reason for the existence of an individual ethical obligation. For example, those who forgo anti- microbials and leave infections untreated could be offered first call on future medi- cal treatments, even for conditions that are not related to the current infection; or", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-162-0", "doc_id": "drug_resistance_book", "page": 162, "text": "9 Moral Responsibility and the Justification of Policies to Preserve Antimicrobial…\n\nthey might be offered discounts when they buy other medicines, such as painkillers, or discounts on future medical treatments; alternatively, they might be offered out- right financial compensation, for example in the form of tax relief or by directly paying them, which would account for any financial loss that might result from enduring a prolonged infections. In this way, they would derive at least some benefit from the sacrifice they are making, which would render the sacrifice easier to bear, and at the same time society would be “making up” for the sacrifice it is imposing on these individuals.\n\nGranted, preserving antimicrobial effectiveness by financially compensating those who forgo antimicrobials might involve a significant cost for the state. However, we saw in the introduction that there will be significant costs associated with AMR if we don’t intervene now; therefore, investing money now to compen- sate and to guarantee adequate medical follow up to those who make sacrifices in order to contain AMR might be a good strategy also from the point of view of cost-effectiveness.\n\n9.5\n\nConclusions", "n_tokens": 238, "kind": "text"}
{"chunk_id": "drug_resistance_book-162-1", "doc_id": "drug_resistance_book", "page": 162, "text": "When is it necessary to leave infections untreated in order to preserve the common good of antimicrobial effectiveness? This is an empirical issue and the answer depends on whether and to what extent the societal optimum of antimicrobial con- sumption differs from the individual optimum. In other words, it concerns the issue whether and to what extent the level of individual consumption that is consistent with satisfactory AMR containment (the societal optimum) differs from the level of consumption that would effectively treat infections in any individual (the individual optimum). As Kevin Foster and Hajo Grundmann (2006, pp. 178–9) have explained, if individual and societal optima were similar, it would be sufficient to avoid inap- propriate antimicrobial use, such as using antibiotics in the case of viral infections, an abuse which often occurs (Van der Velden et al. 2013). Only inappropriate use of antimicrobials would then be morally impermissible. However, if individuals and societal optimum differed significantly, in order to protect the societal interest in AMR containment individuals might be required to leave minor and mild self- limiting infections untreated in order to reserve antimicrobials for serious major infections. In such cases, coercive policies that restrict access to some therapeuti- cally justified use of antimicrobials are ethically permissible, or so we have argued. However, when implementing such restrictive policies, state and health authorities have", "n_tokens": 309, "kind": "text"}
{"chunk_id": "drug_resistance_book-162-2", "doc_id": "drug_resistance_book", "page": 162, "text": "responsibilities not only towards the collective, but also towards individuals who make (small) sacrifices for the sake of the collective interested, and who should be guaranteed adequate compensation in exchange for leaving certain infections untreated.", "n_tokens": 42, "kind": "text"}
{"chunk_id": "drug_resistance_book-162-3", "doc_id": "drug_resistance_book", "page": 162, "text": "151", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-163-0", "doc_id": "drug_resistance_book", "page": 163, "text": "152\n\nA. Giubilini and J. Savulescu\n\nAcknowledgment AG and JS were funded by the Wellcome Centre for Ethics and Humanities, University of Oxford, which is supported by a Wellcome Centre Grant (203132/Z/16/Z), and by the Wellcome Trust grant 104848/Z/14/Z. Through his involvement with the Murdoch Children’s Research Institute, JS was supported by the Victorian Government’s Operational Infrastructure Support Program. AG was also supported by the Oxford Martin School through the Oxford Martin Program on ‘Collective responsibility for infectious disease’.\n\nReferences\n\nAlanis, Alfonso J. 2005. Resistance to antibiotics: Are we in the post-antibiotics era? Archives of\n\nMedical Research 36 (6): 597–705.\n\nAnomaly, Jonny. 2009. Harm to others: The social cost of antibiotics in agriculture. Journal of\n\nAgricultural and Environmental Ethics 22: 423–435.\n\n———. 2013. Collective action and individual choice: Rethinking how we regulate narcotics and\n\nantibiotics. Journal of Medical Ethics 39: 752–756.\n\n———. 2019. Antibiotics and animal agriculture the need for global collective action. In Ethics\n\nand drug resistance: Collective responsibility for global public health. Cham: Springer.\n\nBalasegaram, Manica, et al. 2015. The global innovation model for antibiotics needs reinvention.", "n_tokens": 293, "kind": "text"}
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{"chunk_id": "drug_resistance_book-163-3", "doc_id": "drug_resistance_book", "page": 163, "text": "otic resistance. The Journal of Law, Medicine, and Ethics 43 (S3): 17–21.\n\nFoster, Kevin, and Hajo Grundmann. 2006. Do we need to put society first? The potential for trag-\n\nedy in antimicrobial resistance. PLoS Medicine 3 (2): 177–180.\n\nGiubilini, A., et al. 2017. Taxing meat: Taking responsibility for one’s contribution to antibiotic\n\nresistance. Journal of Agricultural and Environmental Ethics 30 (2): 179–198.\n\nGiubilini, A., T. Douglas, J. Savulescu, and Hannah Maslen. 2018. Quarantine, isolation, and the\n\nduty of easy rescue in public health. Developing World Bioethics 18 (2): 182–189.\n\nHardin, Garrett. 1968. The tragedy of the commons. Science 162: 1243–1248.", "n_tokens": 192, "kind": "text"}
{"chunk_id": "drug_resistance_book-164-0", "doc_id": "drug_resistance_book", "page": 164, "text": "9 Moral Responsibility and the Justification of Policies to Preserve Antimicrobial…\n\nHeld, Virginia. 1970. Can a random collection of individuals be morally responsible? The Journal\n\nof Philosophy 57 (14): 471–481.\n\nHerrmann, Markus, and Ramanan Laxminarayan. 2010. Antibiotic effectiveness: New challenges in natural resource management. The Annual Review of Resource Economics 2 (4): 1–14. Hoffman, Steven, and Trygve Ottersen. 2015. Addressing antibiotic resistance requires robust inter- national accountability mechanisms. The Journal of Law, Medicine, and Ethics 43 (S3): 53–64. Hoffman, Steven, et al. 2015. International law has a role to play in addressing antibiotic resis-", "n_tokens": 154, "kind": "text"}
{"chunk_id": "drug_resistance_book-164-1", "doc_id": "drug_resistance_book", "page": 164, "text": "tance. The Journal of Law, Medicine, and Ethics 43 (S3): 65–67.\n\nHollis, Aidan, and Peter Maybarduk. 2015. Antibiotic resistance is a tragedy of the commons that necessitates global cooperation. The Journal of Law, Medicine, and Ethics 43 (S3): 33–37. Jamrozik, E., and M.J. Selgelid. Drug-resistant infection: Causes, consequences, and responses. In Ethics and drug resistance: Collective responsibility for global public health. Cham: Springer. Klein, Eili, et al. 2018. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. In Proceedings of the National Academy of Sciences of the United States of America.\n\nKumar, S.G., C. Adithan, B.N. Harish, S. Sujatha, G. Roy, and A. Malini. 2013. Antimicrobial resistance in India: A review. Journal of Natural Science, Biology, and Medicine 4 (2): 286–291.\n\nLewis, H.D. 1948. Collective responsibility. Philosophy 23 (84): 3–18. Littmann, J., and A.M. Viens. 2015. The ethical significance of antimicrobial resistance. Public\n\nHealth Ethics 8 (3): 209–224.\n\nLittmann, J., A. Buyx, and O. Cars. 2015. Antibiotic resistance: An ethical challenge. International", "n_tokens": 310, "kind": "text"}
{"chunk_id": "drug_resistance_book-164-2", "doc_id": "drug_resistance_book", "page": 164, "text": "Journal of Antimicrobial Agents 46: 359–361.\n\nMiller, Seamus. 2006. Collective responsibility: An individualist account. Midwest Studies in\n\nPhilosophy 30: 176–193.\n\nNarveson, J. 2002. Collective responsibility. The Journal of Ethics 6: 179–198. O’Neill, Jim. 2015. Antimicrobials in agriculture and the environment: Reducing unnecessary use and waste. The Review on Antimicrobials Resistance. Available at: https://amr-review.org/sites/ default/files/Antimicrobials%20in%20agriculture%20and%20the%20environment%20-%20 Reducing%20unnecessary%20use%20and%20waste.pdf. Last access 8 Oct 2016.\n\nO’Neill. 2016. Tackling drug resistant infections globally: Final report and recommendations. The Review on Antimicrobial Resistance. Available at: http://amr-review.org/sites/default/ files/160518_Final%20paper_with%20cover.pdf. Last access 16 Aug 2016.\n\nOczkowski, Simon. 2017. Antimicrobial stewardship programmes: Bedside rationing by another", "n_tokens": 264, "kind": "text"}
{"chunk_id": "drug_resistance_book-164-3", "doc_id": "drug_resistance_book", "page": 164, "text": "name? Journal of Medical Ethics 43 (10): 684–687.\n\nOstrom, E., J. Burger, C.B. Field, R.B. Norgaard, and D. Policansky. 1999. Sustainability –\n\nRevisiting the commons: Local lessons, global challenges. Science 284: 278–282.\n\nPodolski, Scott, et al. 2015. History teaches us that confronting antibiotic resistance requires stron-\n\nger global collective action. The Journal of Law, Medicine, and Ethics 43 (S3): 27–32.\n\nSavulescu, Julian. 2007. Future people, involuntary medical treatment in pregnancy, and the duty\n\nof easy rescue. Utilitas 19 (1): 1–20.\n\nScanlon, T. 1998. What We Owe to Each Other. Cambridge, MA: Harvard University Press. Schwenkenbecher, Anne. forthcoming. Antimicrobial footprints, fairness, and collective harm. In Ethics and drug resistance: Collective responsibility for global public health. Cham: Springer.\n\nSelgelid, M. 2007. Ethics and drug resistance. Bioethics 21 (4): 218–229. Singer, P. 1972. Famine, affluence, and morality. Philosophy and Public Affairs 1 (3): 229–243. Smith, Richard, and Joanna Coast. 2002. Antimicrobial resistance: A global response. Bulletin of\n\nthe World Health Organization 80 (2): 126–133.\n\n———. 2003. Antimicrobial drug resistance. In Global public goods for health, ed. Smith et al.,\n\n73–93. New York: Oxford University Press.\n\nVan der Velden, A., et al. 2013. Prescriber and patient responsibilities in treatment of acute respira-\n\ntory tract infection – Essential for conservation of antibiotics. Antibiotics 2: 316–327.\n\n153", "n_tokens": 390, "kind": "text"}
{"chunk_id": "drug_resistance_book-165-0", "doc_id": "drug_resistance_book", "page": 165, "text": "154\n\nA. Giubilini and J. Savulescu\n\nWHO. 2010. Antimicrobial resistance: Revisiting the “tragedy of the commons”. Bulletin of the World Health Organization 88: 11. Available at http://www.who.int/bulletin/ volumes/88/11/10-031110/en/.\n\n———. 2014. Antimicrobial resistance: Global report on surveillance 2014. Geneva: World\n\nHealth Organization.\n\n———. Antimicrobial resistance, Fact sheet n 194, updated 2015. Available at: http://www.who.", "n_tokens": 127, "kind": "text"}
{"chunk_id": "drug_resistance_book-165-1", "doc_id": "drug_resistance_book", "page": 165, "text": "int/mediacentre/factsheets/fs194/en/. Last access 17 Aug 2016.\n\nWHO India. 2018. Combating antimicrobial resistance in India. Available at: http://www.searo. who.int/india/topics/antimicrobial_resistance/Combating_Antimicrobial_Resistance_in_ India/en/. Last access 19 Nov 18.\n\nWoodward, David, and Richard D. Smith. 2003. Global public goods and health: Concepts and issues. In Global public goods for health, ed. Smith et al., 3–29. New York: Oxford University Press.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 301, "kind": "text"}
{"chunk_id": "drug_resistance_book-166-0", "doc_id": "drug_resistance_book", "page": 166, "text": "Chapter 10 Access to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis: Deepening the Human Rights-Based Approach\n\nRemmy Shawa, Fons Coomans, Helen Cox, and Leslie London", "n_tokens": 39, "kind": "text"}
{"chunk_id": "drug_resistance_book-166-1", "doc_id": "drug_resistance_book", "page": 166, "text": "Abstract The lack of access to effective diagnosis and treatment for drug-resistant tuberculosis (DR-TB) remains a persistent ethical, human rights and public health challenge globally. In addressing this challenge, arguments based on a Human Rights-Based Approach (HRBA) to health have most often been focused on the Right to Health. However, a key challenge in multidrug-resistant (MDR-) and extensively drug-resistant (XDR-) TB is the glaring absence of scientific research; ranging from basic science and drug discovery through to implementation science once new tools have been developed. Although the Right to Enjoy the Benefits of Scientific Progress and its Applications (REBSP) is a little theorised human right, it has the potential to enrich our understanding and use of the Rights-Based Approach to health. In this chapter, we argue that States’ duties to respect, protect and fulfil the REBSP within and outside their borders is an important vehicle that can be drawn on to redress the lack of research into new drug development and appropriate use of existing drugs for DR-TB in high burden settings. We call for urgent attention to minimum core obligations for the REBSP and the need for a General Comment by a UN human rights monitoring body to provide for its interpretation. We also note that conceptualization of the REBSP has the potential to complement Right to Health claims intended to enhance access to treatment for DR-TB on a global scale.", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-166-2", "doc_id": "drug_resistance_book", "page": 166, "text": "R. Shawa (*) School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa\n\nF. Coomans Department of International and European Law, Maastricht University, Maastricht, The Netherlands\n\nH. Cox Division of Medical Microbiology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa\n\nL. London Division of Public Health Medicine, University of Cape Town, Cape Town, South Africa\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_10\n\n155", "n_tokens": 166, "kind": "text"}
{"chunk_id": "drug_resistance_book-167-0", "doc_id": "drug_resistance_book", "page": 167, "text": "156\n\nR. Shawa et al.\n\nKeywords Drug resistance · Human rights · Tuberculosis · Scientific progress · Rights-based approach\n\n10.1\n\nIntroduction\n\nIn this chapter we explore how the Right to Enjoy the Benefits of Scientific Progress and its Applications (REBSP), a little theorized human right found in both the Universal Declaration of Human Rights (UDHR) and the International Covenant on Economic, Social and Cultural Rights (ICESCR), can deepen our understanding of a Human Rights Based Approach (HRBA) to health, taking access to effective treat- ment for drug-resistant tuberculosis (DR-TB) as an example. We bring attention to the slow progress in research, development and implementation of new and repur- posing of existing drugs for treating DR-TB. Further, we attempt to frame poor access to effective diagnosis and treatment as a human rights problem, not only with respect to the right to health, but also with respect to the REBSP. In locating DR-TB within this right, we articulate what we mean by scientific progress, or lack of, in DR-TB, and discuss the broad context in which scientific progress must occur. Finally, we highlight some of the challenges in the conceptualization and realization of the REBSP, and make recommendations calling for urgent attention to minimum core obligations for the right and the need for a General Comment by a UN human rights monitoring body to provide for its interpretation.", "n_tokens": 291, "kind": "text"}
{"chunk_id": "drug_resistance_book-167-1", "doc_id": "drug_resistance_book", "page": 167, "text": "Tuberculosis remains the world’s deadliest communicable disease, responsible for more than 1.6 million deaths in 2017 alone (WHO 2018). More than a century after the bacterium causing TB was first identified, it continues to kill millions of people because diagnostic tools remain poor and current life-saving, essential medi- cines require a minimum of 6 months to effect cure. TB is particularly difficult to both diagnose and treat when TB bacteria have become resistant to available drugs. While standard care for drug-sensitive TB requires 6 months of treatment, DR-TB treatment may take up to 2 years. Access to diagnostic tools for DR-TB remains limited with currently available technology, despite some progress such as the GeneXpert MTB/RIF (a relatively rapid test that can, in some cases, quickly diag- nose TB and some types of resistance) (Evans 2011), for which accessibility is limited due to the slow pace of implementation and high costs. In 2016, only 25% of the estimated number of multidrug-resistant (MDR-) or rifampicin-resistant (RR-) TB patients emerging that year were diagnosed, and even fewer started on treatment(WHO 2017). Of those who received treatment, only 54% of MDR/RR-TB patients are successfully treated and only 26% of those treated for extensively drug- resistant (XDR-) TB were successfully treated(WHO 2017). Current treatments for RR-TB (which includes MDR- and XDR-TB) are long, and have debilitating and often severe side effects, including irreversible", "n_tokens": 334, "kind": "text"}
{"chunk_id": "drug_resistance_book-167-2", "doc_id": "drug_resistance_book", "page": 167, "text": "hearing loss in more than a third of patients (Seddon et al. 2012). Other drugs included in the currently recommended", "n_tokens": 26, "kind": "text"}
{"chunk_id": "drug_resistance_book-168-0", "doc_id": "drug_resistance_book", "page": 168, "text": "10 Access to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis…\n\nMDR/RR-TB regimen have been known to cause renal failure, cardiac arrhythmias, and psychiatric disturbances (Skrahina et al. 2016).\n\nAs much as DR-TB is a public health problem, it is also a human rights problem because it compromises the rights and dignity of the individuals who get infected. DR-TB highlights the glaring divide that exists between high-income countries (HICs) and low-middle income countries (LMICs), as well as the divide between the rich and the poor within countries. The majority of those who get TB and DR-TB reside in LMICs (WHO 2016). In HICs, TB and DR-TB are predominantly among the vulnerable and marginalized such as migrants and refugees (Figueroa-Munoz and Ramon-Pardo 2008). This skewed burden of TB disease effectively makes it a disease of the poor, who have little capacity to pay for medical care. Eliminating TB will require special attention to these marginalized populations as part of the moral duty of HICs and LMICs alike. Therefore, framing poor access to effective treat- ment for DR-TB as both a public health and human rights issue calls for solutions beyond public health, into the sphere of human rights. Moreover, human rights and public health are irrevocably inter-related; the promotion of one significantly con- tributes to the realization of the other, while, conversely, the infringement of human rights has negative effects on public health (Mann et al. 1994).", "n_tokens": 328, "kind": "text"}
{"chunk_id": "drug_resistance_book-168-1", "doc_id": "drug_resistance_book", "page": 168, "text": "10.2\n\nAccess to Effective DR-TB Diagnosis and Treatment\n\nAccess to effective diagnosis and treatment for DR-TB is constrained by multiple problems; three of which are discussed in this chapter. The first problem is slow, or lack of progress and innovation in TB with regard to the development of new drugs or diagnostic technology. For example, since the introduction of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, in the 1970s (Zumla et al. 2013), there were no novel drugs developed until the appearance of bedaquiline in 2012 (Cox et al. 2015); this is in spite of TB being one of the oldest diseases, spanning centuries (Daniel 2006). The current vac- cine for TB, BCG, is almost 100 years old, and is considered effective in reducing severe and disseminated TB in young children but is not effective in adults (Kernodle 2010).", "n_tokens": 208, "kind": "text"}
{"chunk_id": "drug_resistance_book-168-2", "doc_id": "drug_resistance_book", "page": 168, "text": "In most high TB burden settings the mainstay of TB diagnosis remains sputum smear microscopy, a test essentially unchanged in a century (Steingart et al. 2006). The slow or absent innovation in TB diagnosis and treatment arises from major challenges at different stages of the research continuum from basic science through to product availability. TB drug research is hugely underfunded, and key players in the pharmaceutical industry have been withdrawing from or cutting down on their investment in TB research and drug development, predominantly due to the real or perceived lack of a profitable market (Frick 2016). While treatment of drug sensitive TB still relies on the four drug combination developed more than 40 years ago, treatment of DR-TB has utilized both older drugs previously replaced in TB treat- ment due to lower efficacy and/or high side effects, along with drugs that were\n\n157", "n_tokens": 172, "kind": "text"}
{"chunk_id": "drug_resistance_book-169-0", "doc_id": "drug_resistance_book", "page": 169, "text": "158\n\nR. Shawa et al.\n\noriginally meant to treat other illnesses, repurposed for TB (Zumla et al. 2013). Currently, these repurposed drugs, together with some of the new drugs on the mar- ket are being used to improve treatment success rates for MDR-TB (Ndjeka et al. 2015).\n\nThe second problem is inadequate evidence-based guidance on effective use of new or repurposed drugs. New drugs need to be registered through clinical trials, which are often lengthy and costly; and guidance on use of new drugs is restricted until further clinical trials are conducted. For example, bedaquiline is not registered for use by the FDA and other agencies in pregnant women, children or people living with HIV who are co-infected with MDR-TB (Mase et al. 2013) because there were no clinical trials on its use in these populations. Yet, in many high burden countries, co-infection with HIV and TB is very common, and in reality bedaquiline is being used in these populations (Ndjeka et al. 2015). Similarly, for repurposed medicines, the evidence base to inform guidelines for their use is inadequate (London et al. 2016; Mafukidze et al. 2016). The third problem, which is often a result of the first two, is the high cost and complexity of diagnostics and treatment, and the lack of feasible models of care for scale-up in high burden settings.\n\n10.3", "n_tokens": 313, "kind": "text"}
{"chunk_id": "drug_resistance_book-169-1", "doc_id": "drug_resistance_book", "page": 169, "text": "Rights Based Approach to DR-TB\n\nTo appreciate a rights-based approach to DR-TB, one needs to have an appreciation for human rights in general. Human rights are entitlements and freedoms that peo- ple have simply because they are human. They refer to moral principles or norms, which describe certain standards and moral beliefs that people have. For example, the right to food was a result of the moral belief that people should not die of starva- tion. Similarly, moral beliefs have been significant in defining human rights, “from resisting torture and arbitrary incarceration to demanding the end of hunger and of medical neglect” (Sen 2005). This view of human rights as morally justifiable claims entails that, if a moral claim is that no person should be enslaved to another, then the claim not to be enslaved is, by a matter of law, a human right (McFarland 2015). Likewise, the moral belief that everyone deserves equal opportunities to be in a state of mental, physical and emotional wellbeing, gives credence to the right to health. But the right to health alone is not adequate to fulfill this moral belief. Without scientific progress in prevention, treatment, or in addressing determinants of ill-health, the aspiration of good health cannot be realized. Similarly, without good trade policies, proper housing adequate food or adequate infrastructure, secur- ing good health becomes an unrealistic aspiration.", "n_tokens": 297, "kind": "text"}
{"chunk_id": "drug_resistance_book-169-2", "doc_id": "drug_resistance_book", "page": 169, "text": "A human rights-based approach (HRBA) to health is a way of analysing health through the framework of human rights. It entails examining the impact of health policies and programmes on human rights, and likewise, how promotion or viola- tion of human rights impact public health. A rights-based approach to health focuses on equity of health outcomes by analyzing and addressing the inequalities, discrimi- natory practices (de jure and de facto) and unjust power relations which are often at the center of health problems. Under a rights-based approach, health is anchored in", "n_tokens": 123, "kind": "text"}
{"chunk_id": "drug_resistance_book-170-0", "doc_id": "drug_resistance_book", "page": 170, "text": "10 Access to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis…\n\na system of the recognition of individuals as right-holders and states as duty- bearers. A State has obligations to realize the human rights of its people, governed by inter- national law. Perhaps, even more importantly, a rights-based approach to health means that citizens have the power and means to hold their governments account- able to their duties and responsibilities, and in turn, governments account to their citizens in a just and transparent manner.\n\nThe right to health is included in the ICESCR, which is a legally binding treaty. Article 12(2d) provides for an obligation for States to take steps for the creation of conditions which would assure medical services and medical attention to all in the event of sickness. The United Nations Committee on Economic, Social and Cultural Rights summed up the obligations of the State as the obligation to respect, protect and fulfill. Each treaty body adopts its interpretation of the provisions of its respec- tive treaty in the form of “general comments” or “general recommendations”. The Committee’s guidance on the right to health in General Comment no. 14 provides an authoritative interpretation of the right to health), and unpacks state obligations and what this right looks like in real terms.", "n_tokens": 261, "kind": "text"}
{"chunk_id": "drug_resistance_book-170-1", "doc_id": "drug_resistance_book", "page": 170, "text": "The emergence of the rights-based approach to health in recent years brought with it a paradigm shift in the fields of public health and human rights, owing, in part, to the HIV epidemic, but also to stronger civil society movements working on both health and human rights. But what does a rights-based approach to health mean for access to effective treatment of drug-resistant tuberculosis? And what human rights, other than the right to health can this approach be anchored in? Previously, public health concerns focused on the epidemiology of diseases, analysis of risk factors and interventions to control morbidity and prevent mortality. Particularly for TB, a communicable disease, the concern was around infection control and protect- ing the health of the public rather than those affected (London 2008). In this “public health view” of the TB disease, the State embarks on efforts to respond to TB because it is a public health threat, and not because the State is obligated to provide for the right to health of its citizens.\n\n10.4", "n_tokens": 212, "kind": "text"}
{"chunk_id": "drug_resistance_book-170-2", "doc_id": "drug_resistance_book", "page": 170, "text": "The Right to Enjoy the Benefits of Scientific Progress\n\nThe REBSP is proclaimed in article 15 paragraph 1(b) of the ICESCR; that [every- one has the right] to enjoy the benefits of scientific progress and its applications. This right is closely related to other rights contained in article 15; namely, the right to take part in cultural life (article 15, paragraph 1(a); the right of everyone to ben- efit from the protection of moral and material interests resulting from any scientific, literary or artistic production of which they are the author (article 15, paragraph 1(c)); and the right to freedom indispensable for scientific research and creative activity (article 15, paragraph 3).\n\nAlthough it is proclaimed in these two important human rights documents, the REBSP is one of the least theorised human rights, and consequently, one of the least realized. Despite its textual existence dating back to the 1940s, in the UDHR, this right is relatively new in terms of its conceptualisation (Shaver 2015). Even human\n\n159", "n_tokens": 220, "kind": "text"}
{"chunk_id": "drug_resistance_book-171-0", "doc_id": "drug_resistance_book", "page": 171, "text": "160\n\nR. Shawa et al.\n\nrights activists and lawyers are all too often unaware of the existence of the REBSP, much less of its meaning (Chapman 2009). As such, the REBSP is one right whose conceptual content needs to be interrogated and further developed (Shaver 2015). Despite its lack of clarity, the REBSP cannot be isolated from other human rights; because of the interdependent nature of human rights (United Nations 2005), but also because science is a vehicle that is used in almost every sphere of human devel- opment (UNDP 2012). This interrelation is best exemplified in debates about unequal access to the benefits of scientific progress – not only in relation to access to essential medicines (the right to health) (FM’t Hoen 2002) but also in access to seed technology (the right to food) (Dommen 2002) to scientific discoveries that can improve environmental protection (the right to a safe environment) (Maskus 2002) and to information and communication technologies (right to privacy and access to information).\n\nThree types of obligations result from the right to enjoy the benefits of scientific\n\nprogress.\n\n10.4.1", "n_tokens": 244, "kind": "text"}
{"chunk_id": "drug_resistance_book-171-1", "doc_id": "drug_resistance_book", "page": 171, "text": "The Obligation to Respect\n\nFor the REBSP, the State’s obligation to respect this right means that the State must desist from curtailing, or interfering with people’s ability to access the benefits of scientific progress. In relation to access to treatmemt for DR-TB, the state must therefore not interfere with the production of medicines and technology necessary for treatment and prevention of DR-TB. Such interference can take many forms, from having overly bureaucratic procedures for acquiring ethical clearance for research in drug development to unnecessary delay in approval of new drugs that have already been approved in other countries. Another interference might be in the form of patent protection laws and policies that prioritise protection of patents resulting from research and development ahead of access to treatment. The World Trade Organization adopted rules on intellectual property rights, which impose obligations on states to protect patents on new and existing medicines. Such rules often act as obstacles to making medicines available and accessible to all.\n\n10.4.2", "n_tokens": 196, "kind": "text"}
{"chunk_id": "drug_resistance_book-171-2", "doc_id": "drug_resistance_book", "page": 171, "text": "The Obligation to Protect\n\nWhile a State may not engage in deliberate efforts to violate the REBSP, a failure to protect people from third parties constitutes a potential infringement on the right, and a violation of its obligation to protect. High pricing of life-saving medicines by private corporations through, for example, anti-competitive protectionism, requires the State to act in defence of people’s REBSP. For example, where a pharmaceutical company holds a patent of essential TB drugs, the State can incorporate into its", "n_tokens": 102, "kind": "text"}
{"chunk_id": "drug_resistance_book-172-0", "doc_id": "drug_resistance_book", "page": 172, "text": "10 Access to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis…\n\nlaws, some of the TRIPS1 flexibilities, such as compulsory licensing. In both South Africa and Kenya, the States compelled pharmaceutical companies holding patents to Antiretroviral drugs (ARVs), to enter into “voluntary” licencing agreements with local producers (Musungu et al. 2006).\n\n10.4.3\n\nObligation to Fulfill\n\nThe obligation to fulfill is the third obligation. It speaks to the State’s duty to adopt positive measures, and create an enabling environment for human rights to be realised. These measures may include “legislative, administrative, judicial, promo- tional and other measures” (CESCR 2006). Some of the challenges in drug develop- ment, or in research and development in general, are lack of infrastructure and unfriendly regulatory policies. For the state to fulfill the REBSP for TB patients, therefore, it has to take deliberate steps, within its means, to create an environment for science to thrive. These steps do not necessarily require financial expenditure, but would entail mobilising political will for agenda setting and intentional policies to encourage the sharing of scientific knowledge.", "n_tokens": 245, "kind": "text"}
{"chunk_id": "drug_resistance_book-172-1", "doc_id": "drug_resistance_book", "page": 172, "text": "For DR-TB, the State’s duty to respect, protect and fulfil, does not solely apply to the state with the burden of the disease; countries with a low DR-TB burden, but whose multinational corporations manufacture drugs for use in high burden coun- tries, have an ethical obligation to protect citizens of in other countries from exploi- tation by their multinational corporations. This speaks to what others have termed ‘extraterritorial obligations’- human rights obligations that a state has beyond its borders (Coomans and Kamminga 2004). And in the context of extraterritorial obli- gations, states that have the skills and resources to develop better and effective med- icines, need to also put in place deliberate measures that would make access to such drugs possible outside their jurisdiction.\n\n10.4.4", "n_tokens": 174, "kind": "text"}
{"chunk_id": "drug_resistance_book-172-2", "doc_id": "drug_resistance_book", "page": 172, "text": "Realising the REBSP\n\nCrucial to the realisation of the REBSP is the understanding of who the right hold- ers and duty bearers of the right are. Primary duty bearers of any given right are the States, but also the International community (other States and international agen- cies); they have the duty to respect, protect and fulfil rights. The people, as individu- als and as a collective, are therefore rights holders, in that they have individual and collective rights, and hold claims to entitlements provided for in a particular right. One of the most important issues in human rights is to understand different actors and the relationship between rights holders and duty bearers. A distinction should\n\n1 Trade-Related Aspects of Intellectual Property Rights.\n\n161", "n_tokens": 161, "kind": "text"}
{"chunk_id": "drug_resistance_book-173-0", "doc_id": "drug_resistance_book", "page": 173, "text": "162\n\nR. Shawa et al.\n\nbe made between duties and responsibilities. For example, under the right to health, the state has the duty to provide health care to the people, and may do so through private and public health providers; in that case, health providers assume the respon- sibility to provide health care, but the State still holds the duty under international law. Similarly, under the REBSP, the state has a series of obligations such as creat- ing an enabling environment for scientific progress to thrive, ensuring that people benefit from such scientific progress; non-state actors, such us the private sector (corporations), and academic institutions, have the responsibility to meaningfully contribute to scientific progress through their work. Under international law non- state actors, such as companies or private health providers, do not have legal obliga- tions, only responsibilities. The legal nature of the latter is much weaker.\n\n10.4.5", "n_tokens": 193, "kind": "text"}
{"chunk_id": "drug_resistance_book-173-1", "doc_id": "drug_resistance_book", "page": 173, "text": "Minimum Core Obligations\n\nCore obligations are important in realising human rights as they provide a frame of reference in determining what the State needs to do, at the bare minimum (and not subject to progressive realisation2). Minimum core obligations require the State to demonstrate that it has made every effort to use all available resources to satisfy, as a matter of priority, those core obligations. In the General Comment on the interpre- tation of the nature of ICECR obligations, General Comment No. 3 (1990), the Committee on Economic, Social and Cultural Rights stated that “States parties have a core obligation to ensure the satisfaction of minimum essential levels of each of the rights enunciated in the Covenant.” Core obligations should be framed as both positive steps to be taken by the State, and actions that the state will need to refrain from.\n\nUnfortunately, for the REBSP, there are, as yet, no defined core obligations, mak- ing the application of the right difficult. As a result, there is no standard or bench- mark against which people and Civil Society can compel the State’s immediate efforts to realize the right. Secondly, the State lacks guidance on what it has to pri- oritise within its minimal resources. There is therefore an urgent need for agreed minimum core obligations under the REBSP, which would also apply to scientific progress in DR-TB.", "n_tokens": 281, "kind": "text"}
{"chunk_id": "drug_resistance_book-173-2", "doc_id": "drug_resistance_book", "page": 173, "text": "For example, minimum core obligations in REBSP could be used to prevent harmful effects of science, to promote access to benefits and to encourage interna- tional cooperation:\n\n(a) To monitor the potential harmful effects of science and technology, to effec- tively react to the findings and inform the public in a transparent way; for\n\n2 Given the resource and knowledge restraints faced by many countries, the CESCR recognizes that the fulfillment of economic and social rights can only be achieved over time, and calls for the progressive realization of ESCR.", "n_tokens": 113, "kind": "text"}
{"chunk_id": "drug_resistance_book-174-0", "doc_id": "drug_resistance_book", "page": 174, "text": "10 Access to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis…\n\ninstance, where drug development for TB poses threats to the people, the state does not need to wait before it intervenes and prevents such harm.\n\n(b) To promote access to the benefits of science and its applications on a non- discriminatory basis including measures necessary to address the needs of dis- advantaged and marginalized groups. This includes ensuring that TB patients, especially the poor and marginalized, benefit from scientific progress that informs the development of new drugs, the use of repurposed drugs as well as the application of such drugs in high burden settings;\n\n(c) To take measures to encourage and strengthen international cooperation and assistance in science and technology to the benefit of all people and to comply in this regard with the States’ obligations under international law. This includes, inter-alia, the state entering into international agreements that fosters exchange of knowledge and products of such knowledge. It also implies that states push for better patent laws, which promote access to scientific knowledge even for those in LMICs.\n\n10.5", "n_tokens": 220, "kind": "text"}
{"chunk_id": "drug_resistance_book-174-1", "doc_id": "drug_resistance_book", "page": 174, "text": "Lack of Scientific Progress in DR-TB\n\nA critical element of scientific progress is research and development (R&D), which is key to ensuring access to effective medicines, especially when coupled with deliberate policies to address access-related challenges for the poor and the margin- alized. In the current environment, research can either be for-profit or not, regard- less of whether it is meant to add value to people’s health. Unfortunately, investments in not-for-profit research tend to be significantly lower than investments in for-profit research. Modern research is largely driven by funding external to the researchers/ scientists and that how research is financed will determine how the knowledge aris- ing from it will be used (Yamey 2008).", "n_tokens": 151, "kind": "text"}
{"chunk_id": "drug_resistance_book-174-2", "doc_id": "drug_resistance_book", "page": 174, "text": "While not being the only element of the right, access to the benefits of scientific progress is one that is most controversial as it involves navigating the political land- scapes in the production of science itself (Besson 2015a, b) and foregrounds the need for universal agreement on what defines scientific progress (Donders 2015). Moreover, the context in which the production of science takes place, often stretches beyond national jurisdictions (Besson 2015a, b). For example, for pharmaceutical companies based in HICs to test the effectiveness of new and repurposed drugs for TB, they need to conduct clinical trials in high burden settings like South Africa. Therefore, defining scientific progress is not the responsibility of one state, but requires a shared understanding by both those on the giving and receiving end of scientific development. Progress in TB is not just about the development of new drugs. It is also about the discovery and sharing of knowledge; and ensuring that such knowledge is accessible to those who need it the most.\n\nNevertheless, one of the main barriers is that countries from the North and the pharmaceutical companies domiciled there are reluctant to share and transfer knowledge with and to the South because of economic competition and return upon\n\n163", "n_tokens": 244, "kind": "text"}
{"chunk_id": "drug_resistance_book-175-0", "doc_id": "drug_resistance_book", "page": 175, "text": "164\n\nR. Shawa et al.\n\ninvestment reasons. To counter the current static positions, the WHO, in partnership with United Nations Conference on Trade and Development (UNCTAD) and the International Centre for Trade and Sustainable Development, initiated a project on Improving Access to Medicines in Developing Countries through Technology Transfer and Local Production. One of the findings of the project has been that local production has the potential to enhance access to affordable medicines if supported by appropriate and accessible technology (WHO 2011).", "n_tokens": 97, "kind": "text"}
{"chunk_id": "drug_resistance_book-175-1", "doc_id": "drug_resistance_book", "page": 175, "text": "Furthermore, the benefits of scientific progress, as opposed to the protection of scientific discoveries and production have not been well explored. The latter has been a topic of thorough discussion and debate under intellectual property rights and law (Besson 2015a, b). This has arguably led to a situation where attention (and legal protection) is typically given to creation of scientific knowledge most likely to benefit the innovators (Yamey and Torreele 2002), while knowledge to address key public health problems of significant magnitude, particularly for poor populations unable to purchase the applications of scientific progress, have been neglected. Or if pursued, the scientific discoveries have been too costly to benefit the majority in need (Yamey 2008). International treaties and agreements on the development, sharing and use of science need to account for the fact that, although the capacity of most LMICs to contribute to scientific progress is more limited than for high income countries, their need to benefit is far greater than that of high-income countries. This imbalance in need versus capacity should be factored into the discourse on intel- lectual property rights, particularly in terms of impact on access to essential life- saving medicines.\n\n10.6", "n_tokens": 240, "kind": "text"}
{"chunk_id": "drug_resistance_book-175-2", "doc_id": "drug_resistance_book", "page": 175, "text": "Intellectual Property Rights and Access to Essential Medicines\n\nThe dominant paradigm in scientific development favours the strengthening and protection of Intellectual Property Rights (IPRs) in efforts to encourage and reward innovation. This paradigm was institutionalised after the introduction of patents, which in turn made scientific research more lucrative (Timmermann 2014). A patent is a “government-granted limited property right to exclude others from making, using or selling the patented invention” (Clark et al. 2000).\n\nPatents can have a dramatic impact on access to medicines when they are used to prevent competition. A drug company that holds patents on a medicine has the right to prevent others from manufacturing it and therefore can charge an artificially high price. When a company is selling commodities such as computer components, for example, this might be of no great significance. But when life-saving treatments for diseases such as HIV or cancer become unaffordable to those that need them, the consequences can be – and are – devastating. In many LMICs, where people pay for drugs out of their own pockets and very seldom have health insurance, the high price of medicines becomes a question of life and death.", "n_tokens": 231, "kind": "text"}
{"chunk_id": "drug_resistance_book-176-0", "doc_id": "drug_resistance_book", "page": 176, "text": "10 Access to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis…\n\nTo advance the protection of intellectual property rights, the Member States of the World Trade Organization (WTO) agreed on the Trade-Related Aspects of Intellectual Property Rights (TRIPS) legal regime that progressively became effec- tive from 1994 onwards (Correa 2007). TRIPS elicited a challenge from developing countries and from Civil Society across the globe, who saw them as an impediment to access to essential medicines. Prior to TRIPS, patent protection on pharmaceuti- cals was almost non-existent in developing countries and the absence of patents led to the flourishing of generic medicine production in these countries, which signifi- cantly lowered the cost of essential medicines. While rewarding innovation is important, it should not occur at the expense of access to the benefits. What is needed is a system for balancing promotion of innovation and access to benefits, which is what the REBSP potentially provides.", "n_tokens": 200, "kind": "text"}
{"chunk_id": "drug_resistance_book-176-1", "doc_id": "drug_resistance_book", "page": 176, "text": "For example, in 2001, developing countries initiated negotiations on the interpre- tations of TRIPS Agreement because they restricted access to drugs for patients with HIV infection, the majority of whom live in developing countries (Correa and WHO 2002). Although the TRIPS agreement itself did not change, a compromise was reached in Doha3 in the form of a Declaration that clarified that TRIPS should not prevent developing states from dealing with public health crises, that they should not restrict universal access to essential medicines and provided for mechanisms to bypass potential IP obstacles when public health was at stake. This is a case where the right to health was used as a basis to facilitate international trade agreements that would favour access to life-saving medicines, thereby also opening opportunities for realising the benefits of scientific progress.\n\n10.7", "n_tokens": 157, "kind": "text"}
{"chunk_id": "drug_resistance_book-176-2", "doc_id": "drug_resistance_book", "page": 176, "text": "Creating an Enabling Environment\n\nIn order for scientific progress in TB to thrive, states need to create an enabling environment for research. State duties to meet this right might include those pro- posed by London, Cox and Coomans (2016): – (i) measures to ensure that research- ers have access to infrastructure and equipment to conduct research such as drug development; (ii) adoption of research policies and strategies that foreground research to develop applications for neglected diseases of the poor; (iii) shaping of research funding opportunities to make more attractive research that has lower com- mercial opportunity; (iv) capacity building of researchers; but also, (v) Public- Private Partnerships to encourage the public sector to contribute to access to treatment; (vi) strengthening collaboration with other countries, especially those contributing to R&D; (vii) reprioritising resources from other sectors such as mili- tary to health; and (vi) putting in place more efficient regulatory laws and policies, for providing approval for both research and new drugs.\n\n3 Declaration on the TRIPS Agreement and Public Health, adopted 14 November 2001 by the Ministerial Conference of the World Trade Organisation.\n\n165", "n_tokens": 236, "kind": "text"}
{"chunk_id": "drug_resistance_book-177-0", "doc_id": "drug_resistance_book", "page": 177, "text": "166\n\nR. Shawa et al.\n\nHowever, for the realisation of the REBSP, there has to be a vehicle or pathways for benefits to be derived from this progress and its applications. Put simply, such a system needs to ensure access to effective treatments for people needing treatment. Where appropriate, the State should make use of the TRIPS flexibilities to develop domestic policies that foster scientific progress in TB as a neglected disease. The case of South Africa and Kenya, which made use of TRIPS flexibilities to enforce compulsory licencing of patents to local producers (Musungu et al. 2006) is an example of the State ensuring access to ARVs. Others efforts can take the form of subsidies for researchers, and tax benefits to encourage research in DR-TB.\n\n10.8\n\nInternational Cooperation to Improve Access to DR-TB Drugs", "n_tokens": 172, "kind": "text"}
{"chunk_id": "drug_resistance_book-177-1", "doc_id": "drug_resistance_book", "page": 177, "text": "International cooperation is integral to the international human rights framework, requiring states to recognise the role of international cooperation in realising human rights globally.. Article 2 of the ICESCR sets out that governments are obligated to “[…] take steps, individually and through international assistance and co-operation, […] to the maximum of its available resources, with a view to achieving progres- sively the full realization of the rights recognized in the present Covenant […]. The REBSP is not exempted from the international cooperation. Science is too broad to be pursued within the confines of one country, and its benefits, particularly in TB, are far reaching. The new drugs bedaquiline and delamanid have a larger market in LMICs than in high-income countries in which they were developed. Similarly, with ARVs, the market is larger in less-developed countries hit by the HIV epi- demic, than it is in the high-income countries, where most R&D takes place. The REBSP, like other social and economic rights, has collective dimensions, in that its realization requires functioning social systems involving population-wide applica- tion rather than being a right exercised for any particular individual. This is further underscored by the international dimensions of cooperation across communities and territories. Furthermore, while the REBSP can benefit from international coop- eration, it can also be a vehicle to promote such cooperation through the sharing of", "n_tokens": 301, "kind": "text"}
{"chunk_id": "drug_resistance_book-177-2", "doc_id": "drug_resistance_book", "page": 177, "text": "knowledge and its application.", "n_tokens": 5, "kind": "text"}
{"chunk_id": "drug_resistance_book-177-3", "doc_id": "drug_resistance_book", "page": 177, "text": "Some initiatives have been established, proposing how this global ethical respon- sibility might actually be operationalised in the DR-TB response. One of such ini- tiatives is the 3P project,4 which seeks to encourage the development of affordable, effective new drugs to treat TB. It makes use of an open collaborative approach to conduct drug research and development (R&D), and recommends some new ways of funding and coordinating the drug research and development process. The\n\n4 https://www.msfaccess.org/sites/default/files/MSF_assets/TB/Docs/TB_briefing_3P-2016 _EN.pdf.", "n_tokens": 140, "kind": "text"}
{"chunk_id": "drug_resistance_book-178-0", "doc_id": "drug_resistance_book", "page": 178, "text": "10 Access to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis…\n\nprocess has identified significant weaknesses in the process that hamper develop- ment of new regimens and proposes three interventions to address the weakness, these are\n\nPush funding to finance R&D activities upfront (i.e. through grants); • Pull funding to incentivise R&D activities through the promise of financial rewards on the achievement of certain R&D objectives (i.e. through mile- stone prizes)\n\nPooling of data and intellectual property to ensure open collaborative research and to ensure fair licensing for competitive production of the final products.\n\n10.9", "n_tokens": 128, "kind": "text"}
{"chunk_id": "drug_resistance_book-178-1", "doc_id": "drug_resistance_book", "page": 178, "text": "Conclusion\n\nIn conclusion, the REBSP offers great potential for deepening the rights-based approach to health, as well as for enhancing access to effective diagnosis and treat- ment of DR-TB, and by extension other neglected diseases of the poor, by promot- ing the development of new drugs, and research in the use of existing regimens in high burden settings. However, the right needs clarity and a universal understanding of the entitlements it confers on right-holders and corresponding obligations of duty bearers. There is also need for clarity on the application of the right beyond national borders, to account for the broad scope of science or global trade-related policies. A thorough conceptualisation of the REBSP will require more than the attention of human rights experts, but also trade experts as well as research and development practitioners.", "n_tokens": 170, "kind": "text"}
{"chunk_id": "drug_resistance_book-178-2", "doc_id": "drug_resistance_book", "page": 178, "text": "Despite progress made to advance the right to health, health inequality continues to undermine human rights. For DR-TB, health inequality is apparent at multiple levels; the burden of disease is higher in poorer countries, while access to effective treatment is lower. The moral belief that every human being has the right to health entails a collective global responsibility to those people or countries with poor health outcomes. Therefore, “Everyone with TB should have access to the innova- tive tools and services they need for rapid diagnosis, treatment and care” (WHO 2015) particularly with DR-TB, ensuring access to products and services will not only benefit patients of TB, but will also benefit global health security. This requires a closer look at how other human rights can, together with the right to health, advance health for all. The REBSP is such a right.", "n_tokens": 171, "kind": "text"}
{"chunk_id": "drug_resistance_book-178-3", "doc_id": "drug_resistance_book", "page": 178, "text": "The responsibility to ensure scientific progress in DR-TB and access to such progress cannot lie on most affected countries alone. DR-TB will require a global response and a collective responsibility in an effort to advance the right to health. States’ duties to respect, protect and fulfill the REBSP within and beyond their bor- ders is an important vehicle to redress the lack of research into new drug develop- ment and repurposing existing drugs for DR-TB and their use in high burden settings. REBSP provides some practical ways in which countries can strengthen their rights based approaches to DR-TB. This includes creating an enabling\n\n167", "n_tokens": 131, "kind": "text"}
{"chunk_id": "drug_resistance_book-179-0", "doc_id": "drug_resistance_book", "page": 179, "text": "168\n\nR. Shawa et al.\n\nenvironment for R&D, promoting public-private partnerships, strengthening inter- national cooperation, prioritizing resources to DR-TB, and implementing more effi- cient regulatory process for new drugs.\n\nReferences\n\nBesson, S. 2015a. Mapping the issues. European Journal of Human Rights 2015: 403–411. ———. 2015b. Science without borders and the boundaries of human rights: Who owes the human\n\nright to science ? European Journal of Human Rights 2015: 462–486.\n\nCESCR. 2006. General comment 17: The right of everyone to benefit from the protection of the moral and material interests resulting from any scientific, literary or artistic production of which he or she is the author. New York: United Nations Economic and Social Council.\n\nChapman, A.R. 2009. Towards an understanding of the right to enjoy the benefits of scientific\n\nprogress and its applications. Journal of Human Rights 8: 1–36.\n\nClark, J., et al. 2000. Patent pools: A solution to the problem of access in biotechnology patents?\n\nWashington, DC: United States Patent and Trademark Office.\n\nCoomans, F., and M.T. Kamminga. 2004. Extraterritorial application of human rights treaties.\n\nAntwerp: Intersentia.\n\nCorrea, C. 2007. Trade related aspects of intellectual property rights: A commentary on the TRIPS", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-179-1", "doc_id": "drug_resistance_book", "page": 179, "text": "Agreement. Oxford: Oxford University Press.\n\nCorrea, C.M., and WHO. 2002. Implications of the Doha Declaration on the TRIPS Agreement\n\nand public health. Geneva: World Health Organisation.\n\nCox, H.S., et al. 2015. The need to accelerate access to new drugs for multidrug-resistant tubercu-\n\nlosis. Bulletin of the World Health Organization 93: 491–497.\n\nDaniel, T.M. 2006. The history of tuberculosis. Respiratory Medicine 100 (11): 1862–1870. Dommen, C. 2002. Raising human rights concerns in the World Trade Organization actors, pro-\n\ncesses and possible strategies. Human Rights Quarterly 24 (1): 1–50.\n\nDonders, Y. 2015. Balancing interests: Limitations to the right to enjoy the benefits of scientific\n\nprogress and its applications. European Journal of Human Rights 2015: 486–504.\n\nEvans, C.A. 2011. GeneXpert – A game-changer for tuberculosis control? PLoS Medicine 8 (7):\n\ne1001064.\n\nFigueroa-Munoz, J.I., and P. Ramon-Pardo. 2008. Tuberculosis control in vulnerable groups.\n\nBulletin of the World Health Organization 86 (9): 733–735.\n\nFM’t Hoen, E. 2002. TRIPS, pharmaceutical patents and access to essential medicines: Seattle,\n\nDoha and beyond. Journal of International Law 3: 39–68.\n\nFrick, M. 2016. 2016 report on tuberculosis research funding trends, 2005–2015: No time to lose.", "n_tokens": 328, "kind": "text"}
{"chunk_id": "drug_resistance_book-179-2", "doc_id": "drug_resistance_book", "page": 179, "text": "New York: Treatment Action Group.\n\nKernodle, D.S. 2010. Decrease in the effectiveness of Bacille Calmette-Guérin vaccine against pulmonary tuberculosis: A consequence of increased immune suppression by microbial anti- oxidants, not over attenuation. Clinical Infectious Diseases 51 (2): 177–184.\n\nLondon, L. 2008. What is a human-rights based approach to health and does it matter? Health and\n\nHuman Rights 10: 65–80.\n\nLondon, L., et al. 2016. Multidrug-resistant TB: Implementing the right to health through the right to enjoy the benefits of scientific progress. Health & Human Rights: An International Journal 18 (1).\n\nMafukidze, A., et al. 2016. An update on repurposed medications for the treatment of drug- resistant\n\ntuberculosis. Expert Review of Clinical Pharmacology 9 (10): 1331–1340.\n\nMann, J., L. Gostin, S. Gruskin, T. Brennan, Z. Lazzarini, and H.V. Fineberg. 1994. Health and\n\nhuman rights. Health and Human Rights 1 (1): 6–24.\n\nMase, S., et al. 2013. Provisional CDC guidelines for the use and safety monitoring of bedaqui- line fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. Morbidity and Mortality Weekly Report: Recommendations and Reports 62 (9): 1–12.", "n_tokens": 313, "kind": "text"}
{"chunk_id": "drug_resistance_book-180-0", "doc_id": "drug_resistance_book", "page": 180, "text": "10 Access to Effective Diagnosis and Treatment for Drug-Resistant Tuberculosis…\n\nMaskus, K.E. 2002. Regulatory standards in the WTO: Comparing intellectual property rights with competition policy, environmental protection, and core labor standards. World Trade Review 1 (2): 135–152.\n\nMcFarland, S. 2015. Culture, individual differences, and support for human rights: A general\n\nreview. Peace and Conflict: Journal of Peace Psychology 21 (1): 10.\n\nMusungu, S.F., et al. 2006. The use of flexibilities in TRIPS by developing countries: Can they\n\npromote access to medicines? Geneva: World Health Organisation.\n\nNdjeka, N., et al. 2015. Treatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence setting: An interim cohort analysis. The International Journal of Tuberculosis and Lung Disease 19 (8): 979–985.\n\nSeddon, J.A., et al. 2012. Hearing loss in patients on treatment for drug-resistant tuberculosis.\n\nEuropean Respiratory Journal 40 (5): 1277.\n\nSen, A. 2005. Human rights and capabilities. Journal of Human Development 6 (2): 151–166. Shaver, L. 2015. The right to science: Ensuring that everyone benefits from scientific and techno-\n\nlogical progress. European Journal of Human Rights 2015: 411–431.\n\nSkrahina, A., et al. 2016. Bedaquiline in the multidrug-resistant tuberculosis treatment: Belarus", "n_tokens": 315, "kind": "text"}
{"chunk_id": "drug_resistance_book-180-1", "doc_id": "drug_resistance_book", "page": 180, "text": "experience. International Journal of Mycobacteriology 5: S62–S63.\n\nSteingart, K.R., et al. 2006. Sputum processing methods to improve the sensitivity of smear micros- copy for tuberculosis: A systematic review. The Lancet Infectious Diseases 6 (10): 664–674. Timmermann, C. 2014. Sharing in or benefiting from scientific advancement? Science and\n\nEngineering Ethics 20: 111–133.\n\nUNDP. 2012. MDG report 2012: Assessing progress in Africa toward the Millennium Development\n\nGoals. Addis Ababa: Economic Commission for Africa.\n\nUnited Nations. 2005. Economic, social and cultural rights: Handbook for national human rights\n\ninstitutions. New York: United Nations.\n\nWHO. 2011. Local production for access to medical products: Developing a framework to improve\n\npublic health, 32–36. Geneva: World Health Organisation.\n\n———. 2015. The end TB strategy. Geneva: World Health Organisation. ———. 2016. Global tuberculosis report. Geneva: World Health Organisation. ———. 2017. Multidrug- resistant tuberculosis (MDR) TB 2017 update. Geneva: World Health", "n_tokens": 241, "kind": "text"}
{"chunk_id": "drug_resistance_book-180-2", "doc_id": "drug_resistance_book", "page": 180, "text": "Organisation.\n\n———. 2018. Global tuberculosis report. Geneva: World Health Organisation. Yamey, G. 2008. Excluding the poor from accessing biomedical literature: A rights violation that\n\nimpedes global health. Health and Human Rights 10: 21–42.\n\nYamey, G., and E. Torreele. 2002. The world’s most neglected diseases. The British Medical\n\nJournal 325: 176–177.\n\nZumla, A., et al. 2013. Advances in the development of new tuberculosis drugs and treatment regi-\n\nmens. Nature Reviews Drug Discovery 12 (5): 388–404.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n169", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-181-0", "doc_id": "drug_resistance_book", "page": 181, "text": "Chapter 11 The Right to Refuse Treatment for Infectious Disease", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-181-1", "doc_id": "drug_resistance_book", "page": 181, "text": "Carl H. Coleman\n\nAbstract One of the central tenets of contemporary bioethics is that mentally com- petent persons have a right to refuse medical treatment, even if the refusal might lead to the individual’s death. Despite this principle, laws in some jurisdictions authorize the nonconsensual treatment of persons with tuberculosis (TB) or other serious infectious diseases, on the grounds that doing so is necessary to protect the safety of others. This chapter argues that, in the vast majority of situations, overrid- ing a refusal of treatment for infectious disease is not justifiable, as the risk to third parties can be avoided by the less restrictive alternative of isolating the patient. At the same time, it rejects the extreme position that the nonconsensual treatment of infectious disease is never appropriate. Instead, it concludes that compelling an individual to undergo treatment for infectious diseases may be ethically justifiable in exceptional situations if a refusal of treatment poses a grave risk to third parties, the treatment is not overly burdensome and has been established to be safe and effective, and less restrictive alternatives, including humanely isolating the patient, are not feasible under the circumstances. The burden should be on those seeking to compel unwanted treatment to demonstrate that these requirements have been met.\n\nKeywords Bioethics · Public Health · Infectious Diseases · Medical Law · Human Rights\n\n11.1", "n_tokens": 279, "kind": "text"}
{"chunk_id": "drug_resistance_book-181-2", "doc_id": "drug_resistance_book", "page": 181, "text": "The Right to Refuse Medical Treatment\n\nIf there is one unifying concept that runs through the field of bioethics, it is the doctrine of informed consent — i.e., the principle that individuals have the right to make their own decisions about medical treatment after having been informed of the risks, potential benefits, and reasonably available alternatives (Beauchamp and Childress 2013). The principle of informed consent is grounded in two interrelated\n\nC. H. Coleman (*) School of Law, Seton Hall University, Newark, NJ, USA e-mail: carl.coleman@shu.edu\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_11\n\n171", "n_tokens": 190, "kind": "text"}
{"chunk_id": "drug_resistance_book-182-0", "doc_id": "drug_resistance_book", "page": 182, "text": "172\n\nC. H. Coleman\n\njustifications. First, by conditioning the imposition of medical treatment on the indi- vidual’s authorization, informed consent protects persons’ right to bodily integrity. Second, by requiring the provision of information needed to evaluate the desirabil- ity of proposed treatments, informed consent shows respect for individuals as autonomous decision-makers. The right to refuse medical treatment is “the logical corollary” of the informed consent doctrine: if there were no right to refuse pro- posed treatments, the process of soliciting consent would be a hollow charade (Cruzan v. Director 1990).", "n_tokens": 129, "kind": "text"}
{"chunk_id": "drug_resistance_book-182-1", "doc_id": "drug_resistance_book", "page": 182, "text": "In addition to its ethical foundations, the right to refuse medical treatment is sup- ported by internationally-recognized human rights principles. These principles include the right to security of the person (International Covenant on Civil and Political Rights 1976), the right not to be subjected to torture or to inhuman or degrading treatment (International Covenant on Civil and Political Rights 1976; European Convention on Human Rights 2010), and the right to health (International Covenant on Economic, Social and Cultural Rights 1976). The United Nations Committee on Economic, Social, and Cultural Rights has specifically recognized that the right to health includes the “right to be free from … non-consensual treat- ment” (United Nations Committee on Economic, Social and Cultural Rights 2000). Courts have upheld mentally competent individuals’ right to refuse medical treatment in a variety of situations, including those in which the refusal of treatment might strike some observers as irrational or unwise. For example, in the case of Fosmire v. Nicoleau, the New York Court of Appeals found that an adult Jehovah’s Witness had the right to refuse blood transfusions prior to and immediately after the delivery of her baby, despite her physicians’ belief that without the transfusions she was likely to die (Matter of Fosmire v. Nicoleau 1990). While some older judicial decisions in the United States suggested that the right to refuse treatment must be balanced against the state’s", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-182-2", "doc_id": "drug_resistance_book", "page": 182, "text": "interests in the preservation of life, the prevention of suicide, and “the maintenance of the ethical integrity of the medical profession” (Annas 1992), there are no recent cases in which any of these state interests has been deemed sufficient to override the refusal of treatment by a mentally compe- tent adult.", "n_tokens": 63, "kind": "text"}
{"chunk_id": "drug_resistance_book-182-3", "doc_id": "drug_resistance_book", "page": 182, "text": "However, like most individual rights, the right to refuse treatment is not absolute. First, refusals of treatment may be overridden when the patient lacks the mental capacity to provide informed consent and the imposition of treatment would be in his or her medical best interests (Steele v. Hamilton Cty. Community Mental Health Bd. 2000). This justification for compelled treatment typically arises in the psychi- atric context, where a refusal of treatment may be the result of an underlying mental illness rather than the manifestation of a genuinely voluntary choice. The main issues in these situations involve the standards and procedures for determining the patient’s mental incapacity (Klein 2012), as well as the appropriate role of family members and other surrogates in making decisions on the patient’s behalf (Vars 2008).\n\nSecond, the nonconsensual treatment of mentally competent persons may be authorized when doing so is necessary to protect the safety of others. For example, courts have upheld the forcible medication of violent patients in emergency", "n_tokens": 210, "kind": "text"}
{"chunk_id": "drug_resistance_book-183-0", "doc_id": "drug_resistance_book", "page": 183, "text": "11 The Right to Refuse Treatment for Infectious Disease\n\nsituations “when there is an imminent danger to a patient or others in the immediate vicinity” (Rivers v. Katz 1986). Courts have interpreted the danger-to-others ratio- nale particularly broadly in the context of prisoners. For example, some courts have authorized the forcible feeding of prison inmates on hunger strikes on the theory that a hunger strike can threaten “institutional order and security” (Matter of Bezio v. Dorsey 2013).", "n_tokens": 100, "kind": "text"}
{"chunk_id": "drug_resistance_book-183-1", "doc_id": "drug_resistance_book", "page": 183, "text": "Finally, competent individuals may sometimes be compelled to submit to medi- cal interventions as part of the process of investigating or adjudicating criminal responsibility. For example, criminal suspects may be required to undergo physical examinations, which may include the collection of bodily fluids such as saliva or blood (Maryland v. King 2013; Missouri v. McNeely 2013). In addition, courts in the United States have authorized the government to administer medications to ren- der mentally ill criminal defendants competent to stand trial, citing the governmen- tal interest “in bringing to trial an individual accused of a serious crime.” However, the forcible medication of criminal defendants is permissible only “if the treatment is medically appropriate, is substantially unlikely to have side effects that may undermine the trial’s fairness, and, taking account of less intrusive alternatives, is necessary significantly to further important governmental trial-related interests” (Sell v. United States 2003).\n\n11.2", "n_tokens": 196, "kind": "text"}
{"chunk_id": "drug_resistance_book-183-2", "doc_id": "drug_resistance_book", "page": 183, "text": "Existing Approaches to Compelled Treatment for Infectious Diseases\n\nSeveral jurisdictions have laws that authorize the nonconsensual treatment of per- sons with serious communicable diseases. For example, in the early 1990s, in response to a dramatic increase in TB cases, New York City amended its health code to authorize the Commissioner of Health to compel TB patients to complete treat- ment and, if necessary, to detain them during the process (Gasner et al. 1999). Under the law, detention can be authorized for persons with active TB “where there is a substantial likelihood, based on such person’s past or present behavior, that he or she can not be relied upon to participate in and/or to complete an appropriate pre- scribed course of medication for tuberculosis” (N.Y.C. Health Code §11.21(d)(5)). In most cases, treatment under detention is sought only after other less restrictive alternatives, including directly-observed therapy, have already been attempted (Gasner et al. 1999). However, the Department of Health has the discretion to order treatment under detention as a first resort if it concludes attempting outpatient treat- ment would be futile in light of the patient’s history of nonadherence.", "n_tokens": 260, "kind": "text"}
{"chunk_id": "drug_resistance_book-183-3", "doc_id": "drug_resistance_book", "page": 183, "text": "Similar laws exist in other jurisdictions. For example, South Africa’s National Health Act provides for an exception to the requirement to obtain informed consent to medical treatment in cases where “failure to treat the user … will result in a seri- ous risk to the public health” (Republic of South Africa National Health Act § 7(1) (d)). Relying in part on this provision, the High Court of South Africa has upheld the\n\n173", "n_tokens": 91, "kind": "text"}
{"chunk_id": "drug_resistance_book-184-0", "doc_id": "drug_resistance_book", "page": 184, "text": "174\n\nC. H. Coleman\n\ninvoluntary isolation and treatment of patients with multi-drug resistant (MDR) TB (Minister of Health v. Goliath 2008). Similarly, Canadian courts have upheld orders requiring patients with TB to submit to mandatory detention and treatment (Ries 2007), relying on provincial legislation authorizing the board of health to issue orders requiring the “care and treatment” of persons with “virulent” communicable diseases (Ontario Health Protection and Promotion Act § 22(4)(g); Silva 2011). The state of Alabama also has a law authorizing the “compulsory treatment and quaran- tine” of TB patients, but with an unusual exception: Confined patients are permitted to refuse treatment if they “desire treatment by prayer or spiritual means” (Ala. Code § 22-11A-10). The Alabama law does not permit patients to refuse treatment for reasons unrelated to religion.", "n_tokens": 189, "kind": "text"}
{"chunk_id": "drug_resistance_book-184-1", "doc_id": "drug_resistance_book", "page": 184, "text": "In contrast, laws in some jurisdictions provide that patients with infectious dis- eases can be subject to mandatory detention but not forcible treatment. For example, the state of Minnesota authorizes the involuntary isolation of persons with diseases “that can be transmitted person to person and for which isolation or quarantine is an effective control strategy,” but it specifically provides that isolated patients have “a fundamental right to refuse medical treatment” (Minn. Statutes 144.419). Similarly, Israeli law permits the involuntary isolation of persons with TB or other serious infectious diseases, but isolated patients may not be forced to undergo unwanted medical treatment (Weiler-Ravell et al. 2004). The law in Iceland appears to follow a similar approach (Eggertsson 2004).\n\nThe Model State Emergency Health Powers Act, a proposed law developed by the Center for Law and the Public’s Health, initially included provisions authorizing forcible treatment of patients during an infectious disease outbreak, but after exten- sive criticism, those provisions were eliminated from the proposal (Annas et al. 2008). The proposed law now provides that “persons who are unable or unwilling for reasons of health, religion, or conscience to undergo treatment” may be subject to isolation (Center for Law and the Public’s Health 2001). The implication is that, once isolated, infectious persons may not be subjected to treatment involuntarily.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-184-2", "doc_id": "drug_resistance_book", "page": 184, "text": "It is unclear whether compelled treatment for infectious disease would be permit- ted under international human rights law. On the one hand, some human rights doc- uments cite “the prevention and control of communicable diseases” as a situation in which “coercive medical treatments” could be justified on an “exceptional basis” (United Nations Committee on Economic, Social and Cultural Rights 2000). In addition, the European Court of Human Rights (ECHR) has found that requiring individuals to undergo TB screening by means of a tuberculin skin-reaction test or chest X-ray “can be considered necessary in a democratic society for the protection of health” (Acmanne and others v. Belgium 1984). On the other hand, no human rights tribunal has directly addressed the permissibility of compelling individuals to undergo treatment (as opposed to testing) for infectious diseases. Moreover, citing ECHR decisions condemning the force-feeding of prisoners, a World Health Organization (WHO) mission to the Ukraine concluded that “administering a TB treatment without the consent of the patient is an intrusive major intervention that constitutes a prohibited interference with a person’s rights under the ECHR” (Dagron 2016).", "n_tokens": 245, "kind": "text"}
{"chunk_id": "drug_resistance_book-185-0", "doc_id": "drug_resistance_book", "page": 185, "text": "11 The Right to Refuse Treatment for Infectious Disease\n\nFinally, it is worth noting that, although “compulsory vaccination” laws are sometimes cited as support for overriding the right to refuse treatment for patients with infectious diseases (Valenti 2012), those laws do not actually support the forc- ible imposition of medical interventions over a patient’s objection. For example, in the United States, unvaccinated children who have not received an exemption from a state’s vaccination requirements may be denied enrollment in the public schools (Barraza et al. 2017), but they will not be forcibly given vaccines to which their parents have objected. In a few other countries, parents can be fined for refusing to vaccinate their children (Reuters 2017), but, again, forcible vaccination does not appear to be authorized. Similarly, in the frequently-cited U.S. Supreme Court case of Jacobson v. Massachusetts, which upheld a Massachusetts law requiring indi- viduals to be vaccinated for smallpox, the plaintiff was never actually required to undergo vaccination. Instead, the consequence of his refusal of the vaccine was a fine of five dollars (Jacobson v. Massachusetts 1905).\n\n11.3", "n_tokens": 255, "kind": "text"}
{"chunk_id": "drug_resistance_book-185-1", "doc_id": "drug_resistance_book", "page": 185, "text": "Ethical Analysis\n\nAs discussed in the preceding section, there are two dominant legal approaches to protecting third parties from the risk of serious infectious diseases: compelling such persons to undergo medical treatment, or isolating them without forcing them to accept treatments to which they object. While the latter approach does not techni- cally override the individual’s right to refuse treatment, an offer of treatment that can be refused only by submitting to isolation is inherently coercive. Because “[v]oluntary consent is usually thought incompatible with coercion” (Eyal 2012), both approaches can be seen as exceptions to the general principle that medical treatment requires the patient’s voluntary informed consent.\n\nRecognizing an exception to informed consent for patients with infectious dis- eases can be compared to cases authorizing nonconsensual medical treatment when necessary to protect third parties from violence. As an ethical matter, both situations implicate John Stuart Mill’s “harm principle,” which provides that individual liberty does not include the right to cause harm to third parties (Brink 2014). As Marcel Verweij explains, “[i]f patients with infectious diseases neglect the treatment they need, this could have harmful implications for others, and that may be reason to overrule the requirements of informed consent” (Verweij 2011).", "n_tokens": 272, "kind": "text"}
{"chunk_id": "drug_resistance_book-185-2", "doc_id": "drug_resistance_book", "page": 185, "text": "However, even if the harm principle can justify an exception to informed consent in some situations, the mere possibility of harm, standing alone, is an insufficient basis to justify compulsion. Instead, a full analysis must consider factors such as the likelihood and magnitude of the potential harm, the burdens of compulsion on the individuals affected, the likely effectiveness of the proposed interventions, and the alternatives that are realistically available under the circumstances. This kind of fact-sensitive inquiry is an implicit requirement of consequentialist ethical theories, which require assessing the aggregate balance of potential benefits and harms of any proposed course of action (Sinnott-Armstrong 2015). It is also supported by the\n\n175", "n_tokens": 137, "kind": "text"}
{"chunk_id": "drug_resistance_book-186-0", "doc_id": "drug_resistance_book", "page": 186, "text": "176\n\nC. H. Coleman\n\nhuman rights principle of proportionality, which requires a “fair balance between the demands of the general interest of the community and the requirements of the protection of the individual’s fundamental rights” (Soering v. UK 1989).\n\nCoercive action is most justifiable in cases of highly contagious, life-threatening illnesses, such as MDR-TB. As the likelihood of transmission and/or the conse- quences of infection lessen, the justification for coercion diminishes as well. The precise point at which a refusal of treatment becomes sufficiently dangerous to jus- tify coercion can be difficult to determine. For example, as Richard Coker asks, “given that the risk of relapse is higher if compliance with [TB] treatment ceases after two months of treatment compared with, say, five months (where, in most cases it is probably very small indeed), should those who fail to comply after two months face the prospect of detention if they fail to comply, whereas those who do so only after five months remain at liberty?” In answering these questions, “one is forced to question issues relating to utility, about how one measures the burden of risk, and utility gains and losses. Objective evidence to support decisions is largely lacking” (Coker 2000).", "n_tokens": 276, "kind": "text"}
{"chunk_id": "drug_resistance_book-186-1", "doc_id": "drug_resistance_book", "page": 186, "text": "For many diseases, both the likelihood and magnitude of potential harm exist on a lengthy continuum. With respect to the likelihood of transmission, consider the case of sexually-transmitted infections (STIs). Many persons with STIs pose little or no risk to others because they are either sexually inactive or consistently use bar- rier protection. However, the level of risk increases if they engage in unprotected sexual encounters with multiple partners. The likelihood of transmission is particu- larly high for persons whose sexual partners do not recognize the need to take pre- cautions against transmission, such as spouses who may mistakenly assume that their relationships are exclusive. In light of these uncertainties, is the likelihood of harm to unknowing third parties sufficient to justify the use of compulsion? While public health authorities generally favor a voluntary approach to STI testing and treatment (WHO Statement 2012), efforts to use compulsion sometimes occur. For example, under 2017 guidelines from the British Columbia Centre for Disease Control, public health authorities may issue orders compelling HIV-positive indi- viduals to initiate and continue HIV treatment if they engage in high-risk sexual behavior or share needles and/or other drug paraphernalia with other persons and do not disclose their HIV status (British Columbia Centre for Disease Control 2017). Violation of such orders can result in court-ordered detention under the British Columbia Public", "n_tokens": 281, "kind": "text"}
{"chunk_id": "drug_resistance_book-186-2", "doc_id": "drug_resistance_book", "page": 186, "text": "Health Act, which allows medical health officers “to do anything that the … officer reasonably believes is necessary … to prevent the transmission of an infectious agent” (British Columbia Public Health Act). In 2018, a man from Vancouver was charged under these provisions for allegedly refusing to comply with a medical officer’s order to submit to HIV treatment (Proctor). Similarly, a man in Fayetteville, Arkansas was charged in 2016 for a misdemeanor public health vio- lation for refusing to undergo treatment for syphilis (Vendituoli 2016).", "n_tokens": 115, "kind": "text"}
{"chunk_id": "drug_resistance_book-186-3", "doc_id": "drug_resistance_book", "page": 186, "text": "Similar uncertainties relate to the magnitude of harm resulting from an individu- al’s refusal of treatment. For example, seasonal influenza typically resolves itself without any long-term consequences, but it can be life threatening for elderly patients or those with compromised immune systems. If a treatment were developed", "n_tokens": 61, "kind": "text"}
{"chunk_id": "drug_resistance_book-187-0", "doc_id": "drug_resistance_book", "page": 187, "text": "11 The Right to Refuse Treatment for Infectious Disease\n\nthat quickly made patients with seasonal influenza incapable of transmitting the ill- ness, would the magnitude of avoidable harm justify imposing this treatment over a patient’s objection? Even seemingly innocuous infections diseases, such as athlete’s foot, can cause severe consequences in some subgroups of patients (e.g., persons with diabetes). So far, no one has seriously proposed compelling individuals with athlete’s foot to use anti-fungal medications, or to threaten infected persons with detention if they visit a public swimming pool with bare feet during an outbreak. Yet, the idea of invoking the harm principle in this situation might seem perfectly reasonable to a diabetic patient who is forced to undergo a foot amputation after being exposed to an untreated fungal infection.", "n_tokens": 164, "kind": "text"}
{"chunk_id": "drug_resistance_book-187-1", "doc_id": "drug_resistance_book", "page": 187, "text": "In determining whether the likelihood and magnitude of harm are sufficient to justify compulsion, some commentators have suggested that the risks posed by an individual’s refusal of treatment should be compared to the other risks that individu- als typically confront on a day-to-day basis. For example, Mark Cherry argues that compelled treatment for infectious disease can be justified when necessary to pre- vent “significant and unusual risk” to “non-consenting others.” He gives the exam- ple of legally-mandated treatment for patients with extensively drug-resistant TB, explaining that “[t]he risks associated with such diseases are significantly greater than the background risks that one generally assumes in daily life” (Cherry 2010).\n\nYet, while a comparison to the risks of daily life provides a useful framework for analysis, it does not follow that, as long as the risks of refusal are greater than the risks of daily life, the use of compulsion is necessarily warranted. Instead, the exis- tence of a “significant and unusual risk” should be considered a necessary but insuf- ficient criterion for justifying compulsion. In other words, if the risks of treatment refusal are less than the risks of daily life, the use of compulsion should not even be considered; if the risk are greater, compulsion might be justifiable, but additional considerations must also be factored into the analysis.", "n_tokens": 282, "kind": "text"}
{"chunk_id": "drug_resistance_book-187-2", "doc_id": "drug_resistance_book", "page": 187, "text": "One of these additional considerations is the burden of compulsion on the indi- viduals affected. For example, in upholding Belgium’s policy of mandatory skin- tests and chest X-rays for TB, the ECHR pointed to the absence of evidence suggesting that those interventions involved “disadvantages comparable to the for- mer ravages of tuberculosis” (Acmanne and others v. Belgium 1984). The implica- tion was that more burdensome interventions would require a more compelling justification.\n\nSome interventions might be too burdensome to be justifiable under any circum- stances. By way of analogy, in refusing to authorize a Caesarean section on a dying woman who had refused the procedure, the District of Columbia Court of Appeals noted that, to perform the procedure, the patient “would have to be fastened with restraints to the operating table, or perhaps involuntarily rendered unconscious by forcibly injecting her with an anesthetic, and then subjected to unwanted major surgery.” It concluded that “[s]uch actions would surely give one pause in a civilized society, especially when [the patient] had done no wrong” (In re A.C. 1990). For similar reasons, it is difficult to imagine a scenario in which it would be acceptable to force a patient with an infectious disease to submit to a major surgical procedure, even if doing so were the only way to render the patient non-infectious.\n\n177", "n_tokens": 299, "kind": "text"}
{"chunk_id": "drug_resistance_book-188-0", "doc_id": "drug_resistance_book", "page": 188, "text": "178\n\nC. H. Coleman\n\nAnother consideration is the likelihood that the proposed intervention will be effective in reducing the risk that the disease will be transmitted to third parties. At a minimum, as the World Health Organization emphasizes, overriding an individu- al’s refusal of a medical intervention for the treatment of an infectious disease should not be considered unless the proposed intervention “has proven to be safe and effective and is part of the accepted medical standard of care” (World Health Organization 2016). Likewise, requiring individuals who refuse treatment to undergo isolation would not be justifiable if the disease is already so prevalent in a population that isolating untreated patients is unlikely to make a significant differ- ence in reducing transmission.", "n_tokens": 147, "kind": "text"}
{"chunk_id": "drug_resistance_book-188-1", "doc_id": "drug_resistance_book", "page": 188, "text": "Finally, even if an individual’s refusal of treatment creates a sufficient risk of harm to others to justify the use of compulsion, the type of compulsion used should be the least restrictive option reasonably available under the circumstances. The “least restrictive alternative” requirement is a well-established principle of human rights jurisprudence. For example, the Siracusa Principles on the Limitation and Derogation Provisions in the International Covenant on Civil and Political Rights provides that any restrictions on human rights must be “strictly necessary” and that “there must be no other, less intrusive means available to reach the same objective” (American Association for the International Commission of Jurists 1985). The United States Supreme Court applies a similar standard in analyzing restrictions on fundamental constitutional rights (Chemerinsky 2015), as does the European Court of Human Rights (Brems and Lavrysen 2015).\n\nIn light of this principle, if it is possible to protect the public from harm by isolat- ing the patient, there would be no justification for insisting that the patient, once isolated, submit to medical treatments to which he continues to object. The WHO Ethics Guidance for the Implementation of the End TB Strategy makes this point forcefully:", "n_tokens": 242, "kind": "text"}
{"chunk_id": "drug_resistance_book-188-2", "doc_id": "drug_resistance_book", "page": 188, "text": "While contagious persons with TB who do not adhere to treatment or who are unable or unwilling to comply with infection prevention and control measures pose significant risks to the public, those risks can be addressed by isolating the patient. Patients who are isolated should still be offered the opportunity to receive treatment, but if they do not accept it, their informed refusal should be respected. Forcing these patients to undergo treatment over their objection would require an unacceptable invasion of bodily integrity, and also could put health care providers at risk. Moreover, as a practical matter, it would likely be impossible to provide effective treatment without the patient’s cooperation. Nevertheless efforts to con- vince the patient and re-examine his or her refusal should not be abandoned (World Health Organization 2017).\n\nThe Belgian Advisory Committee on Bioethics takes a similar position, finding that “if an MDR patient who does not have any psychiatric problems rendering him incapable of giving his consent refuses a treatment, the health authorities can hold him in isolation to avoid the spread of the disease but cannot force him to receive treatment” (Belgian Advisory Committee on Bioethics 2013).\n\nThis position is consistent with the logic of the danger-to-others exception to the informed consent requirement. In particular, cases involving the forcible medication of violent patients emphasize that the use of force is justified only as a temporary", "n_tokens": 271, "kind": "text"}
{"chunk_id": "drug_resistance_book-189-0", "doc_id": "drug_resistance_book", "page": 189, "text": "11 The Right to Refuse Treatment for Infectious Disease\n\nmeasure, “continuing only as long as the emergency persists” (Rivers v. Katz 1986). Once a violent patient has been medicated to a point that he can safely be isolated, there would be no justification for further medication unless another basis for over- riding consent, such as mental incapacity, also exists.\n\nTaken together, the considerations discussed above suggest that nonconsensual treatment for infectious disease will rarely be justifiable. Even if the magnitude and severity of harm resulting from a treatment refusal are significant, and even if the proposed treatment is not especially burdensome and is likely to work, the less restrictive alternative of isolating the patient will usually be sufficient to protect the public from harm. While involuntary isolation still involves an element of coercion, in most cases it should be up to the patient to decide whether this option is prefera- ble to submitting to an unwanted medical intervention.", "n_tokens": 195, "kind": "text"}
{"chunk_id": "drug_resistance_book-189-1", "doc_id": "drug_resistance_book", "page": 189, "text": "Yet, it would be a mistake to think that the option of isolation will always elimi- nate the need to consider the appropriateness of nonconsensual treatment. One situ- ation in which isolation may be impractical is when individuals are already living in confined settings, such as in prisons or the military. While isolating a small number of individuals in these settings may be possible, the available space for isolation is likely to be limited. In addition, there may be other persons with a stronger case for access to these limited facilities — for example, prisoners who need to be separated from the general population because they are at heightened risk of violent attack.", "n_tokens": 134, "kind": "text"}
{"chunk_id": "drug_resistance_book-189-2", "doc_id": "drug_resistance_book", "page": 189, "text": "Another situation in which isolation may not be a practical alternative is during an epidemic outbreak involving substantial numbers of persons with contagious infections, particularly in low-resource settings with a limited capacity to provide humane isolation facilities. In some cases, voluntary isolation at home may be a reasonable alternative, but this will work only if the patient is willing and able to follow infection control precautions (World Health Organization 2017). Otherwise, if isolation facilities are limited, protecting the public may sometimes require con- sideration of nonconsensual treatment. Yet, even in these scenarios, compelled treat- ment would be justified only if a safe and effective treatment exists that would not be unduly burdensome to the patient. If there is such a treatment, it seems unlikely that the number of people refusing it would be high enough to overwhelm available isolation facilities, particularly if public health authorities have engaged in an ade- quate process of community engagement (World Health Organization 2016). Thus, as a practical matter, the need to invoke this exception may be more theoretical than real.", "n_tokens": 219, "kind": "text"}
{"chunk_id": "drug_resistance_book-189-3", "doc_id": "drug_resistance_book", "page": 189, "text": "In all cases, the burden should be on those seeking to compel unwanted treatment to demonstrate that no less restrictive alternatives, including isolation, are realisti- cally available under the circumstances. As the World Health Organization recom- mends, “objections to diagnostic, therapeutic, or preventive measures should not be overridden without giving the individual notice and an opportunity to raise his or her objections before an impartial decision-maker, such as a court, interdisciplinary review panel, or other entity not involved in the initial decision” (World Health Organization 2016). Such a process provides an important check against abuse and can avoid undermining public trust in the integrity of the public health system.\n\n179", "n_tokens": 143, "kind": "text"}
{"chunk_id": "drug_resistance_book-190-0", "doc_id": "drug_resistance_book", "page": 190, "text": "180\n\nC. H. Coleman\n\nReferences\n\nAcmanne and others v. Belgium, No. 10435/83 (European Court of Human Rights 1984). Ala. Code § 22-11A-10. American Association for the International Commission of Jurists. 1985. Siracusa principles on the limitation and derogation provisions in the International Covenant on Civil and Political Rights. http://icj.wpengine.netdna-cdn.com/wp-content/uploads/1984/07/Siracusa-principles- ICCPR-legal-submission-1985-eng.pdf.\n\nAnnas, George J. 1992. The rights of patients: The basic ACLU guide to patient rights. Springer. Annas, George J., Wendy K. Mariner, and Wendy E. Parmet. 2008. Pandemic prepared- ness: The need for a public health--not a law enforcement/National Security--Approach. ACLU. https://www.aclu.org/files/images/asset_upload_file399_33642.pdf.\n\nBarraza, Leila, Cason Schmit, and Aila Hoss. 2017. The latest in vaccine policies: Selected issues in school vaccinations, healthcare worker vaccinations, and pharmacist vaccination authority Laws. Journal of Law, Medicine and Ethics 45 (S1): 16–19.\n\nBeauchamp, Tom L., and James F. Childress. 2013. Principles of biomedical ethics. 7th ed.\n\nNew York: Oxford University Press.\n\nBelgian Advisory Committee on Bioethics. 2013. Opinion No. 55 of 13 May 2013 on the Treatment", "n_tokens": 355, "kind": "text"}
{"chunk_id": "drug_resistance_book-190-1", "doc_id": "drug_resistance_book", "page": 190, "text": "of Patients with Multidrug- Resistant Tuberculosis from a Public Health Perspective.\n\nBrems, Eva, and Laurens Lavrysen. 2015. ‘Don’t use a sledgehammer to crack a nut’: Less restric- tive means in the case law of the European Court of Human Rights. Human Rights Law Review 15 (1): 139–168. https://doi.org/10.1093/hrlr/ngu040.\n\nBrink, David. 2014. Mill’s moral and political philosophy. In The Stanford Encyclopedia of phi- losophy, ed. Edward N. Zalta. Metaphysics Research Lab, Stanford University. https://plato. stanford.edu/archives/win2016/entries/mill-moral-political/.\n\nBritish Columbia Centre for Disease Control. 2017. Guidelines for medical health officers: Approach to people with HIV/AIDS who may pose a risk of harm to others. http://www.bccdc. ca/resource-gallery/Documents/Communicable-Disease-Manual/Chapter%205%20-%20STI/ MHO-guidelines-PLWH-risk-of-transmission.pdf\n\nBritish Columbia Public Health Act § 27. Center for Law and the Public’s Health. 2001. Model State Emergency Health Powers Act. http://\n\nwww.publichealthlaw.net/MSEHPA/MSEHPA.pdf.\n\nChemerinsky, Erwin. 2015. Constitutional\n\nlaw: Principles and policies. 5th ed. http://www.wklegaledu.com/aspen-student-treatise-series/id-9781454849476/ Constitutional_Law_Principles_and_Policies_Fifth_Edition.\n\nCherry, Mark J. 2010. Non-consensual treatment is (nearly always) morally impermissible. Los", "n_tokens": 390, "kind": "text"}
{"chunk_id": "drug_resistance_book-190-2", "doc_id": "drug_resistance_book", "page": 190, "text": "Angeles, CA: SAGE Publications Sage CA.\n\nCoker, Richard. 2000. Tuberculosis, non-compliance and detention for the public health. Journal\n\nof Medical Ethics 26 (3): 157–159.\n\nCruzan v. Director, Mo. Dept. of Health, 497 US 261 (U.S. Supreme Court 1990). Dagron, Stéphanie. 2016. Tuberculosis control and human rights in the National Legislation of\n\nUkraine, report of a Mission 20–24 April 2015.\n\nEggertsson, Dagur B. 2004. Tuberculosis and human rights in Iceland. http://lup.lub.lu.se/student-\n\npapers/record/1554865/file/1563469.pdf.\n\nEyal, Nir. 2012. Informed consent. In The Stanford encyclopedia of philosophy, ed. Edward N. Zalta. Metaphysics Research Lab, Stanford University. https://plato.stanford.edu/archives/ fall2012/entries/informed-consent/.\n\nGasner, M. Rose, Khin Lay Maw, Gabriel E. Feldman, Paula I. Fujiwara, and Thomas R. Frieden. 1999. The Use of Legal Action in New York City to Ensure Treatment of Tuberculosis. New England Journal of Medicine 340 (5): 359–366.", "n_tokens": 270, "kind": "text"}
{"chunk_id": "drug_resistance_book-191-0", "doc_id": "drug_resistance_book", "page": 191, "text": "11 The Right to Refuse Treatment for Infectious Disease\n\n“International Covenant on Civil and Political Rights,” 1976. http://www.ohchr.org/Documents/\n\nProfessionalInterest/ccpr.pdf.\n\n“International Covenant on EconomicEconomics, Social and Cultural Rights,” 1976. http://www.\n\nohchr.org/EN/ProfessionalInterest/Pages/CESCR.aspx.\n\nIn re AC, 573 A. 2d 1235 (D.C. Court of Appeals 1990). Jacobson v. Massachusetts, 197 US 11 (U.S. Supreme Court 1905). Klein, Dora W. 2012. When coercion lacks care: Competency to make medical treatment decisions and parens patriae civil commitments. University of Michigan Journal of Law Reform 45 (3): 561–593.\n\nMaryland v. King, 133 S. Ct. 1958 (U.S. Supreme Court 2013). Matter of Bezio v. Dorsey, 21 NY.3d 93 (N.Y. Court of Appeals 2013). Matter of Fosmire v. Nicoleau, 75 NY 2d 218 (N.Y. Court of Appeals 1990). Minister of Health v. Goliath, No. 13741/07 (High Court of South Africa 2008). Minn. Statutes § 144.419. Missouri v. McNeely, 133 S. Ct. 1552 (U.S. Supreme Court 2013). N.Y.C. Health Code § 11.21(d)(5). Ontario Health Protection and Promotion Act § 22(4)(g). Proctor J. Vancouver man charged with ignoring medical health officer’s orders. CBC News,\n\nAugust 24, 2018.\n\nReuters. “Italy Passes Law Obliging Parents to Vaccinate Children.” May 19, 2017. http://www.", "n_tokens": 393, "kind": "text"}
{"chunk_id": "drug_resistance_book-191-1", "doc_id": "drug_resistance_book", "page": 191, "text": "reuters.com/article/us-italy-politics-vaccines-idUSKCN18F1J7.\n\nRepublic of South Africa National Health Act § 7(1)(d). Ries, Nola M. 2007. Legal issues in disease outbreaks: Judicial review of public health powers.", "n_tokens": 64, "kind": "text"}
{"chunk_id": "drug_resistance_book-191-2", "doc_id": "drug_resistance_book", "page": 191, "text": "Health Law Review 16 (1): 11–16.\n\nRivers v. Katz, 67 NY 2d 485 (N.Y. Court of Appeals 1986). Sell v. United States, 539 US 166 (U.S. Supreme Court 2003). Silva, Diego S. 2011. Tuberculosis and persons with severe and persistent mental illnesses: When (treatment) worlds collide? Munk School Briefings, 2010. Munk School of Global Affairs, University of Toronto.\n\nSinnott-Armstrong, Walter. 2015. Consequentialism. In The Stanford encyclopedia of philosophy, ed. Edward N. Zalta. Metaphysics Research Lab, Stanford University. https://plato.stanford. edu/archives/win2015/entries/consequentialism/.\n\nSoering v. UK, 11 EHHR 439 (European Court of Human Rights 1989). Steele v. Hamilton Cty. Community Mental Health Bd., 90 Ohio St. 3d 176 (Supreme Court of\n\nOhio 2000).\n\nUnited Nations Committee on EconomicEconomics, Social & Cultural Rights 2000. General comment No. 14: The right to the highest attainable standard of health (Article 12 of the International Covenant on Economic, Social and Cultural Rights). http://www.nesri.org/sites/ default/files/Right_to_health_Comment_14.pdf.\n\nValenti, Joseph Anthony. 2012. Circumstances when medical treatment may be forcibly imposed despite a patient’s explicit refusal: A comprehensive analysis of Pennsylvania law. Widener Law Review 18: 27.\n\nVars, Frederick E. 2008. Illusory consent: When an incapacitated patient agrees to treatment.", "n_tokens": 346, "kind": "text"}
{"chunk_id": "drug_resistance_book-191-3", "doc_id": "drug_resistance_book", "page": 191, "text": "Oregon Law Review 87 (2): 353–398.\n\nVendituoli, Monica. 2016. Fayetteville man accused of refusing treatment for syphilis. Fayeteville\n\nObserver 6.\n\nVerweij, Marcel. 2011. Infectious disease control. In Public health ethics: Key concepts and issues in policy and practice, ed. Angus Dawson, 100–142. Cambridge/New York: Cambridge University Press.\n\n181", "n_tokens": 88, "kind": "text"}
{"chunk_id": "drug_resistance_book-192-0", "doc_id": "drug_resistance_book", "page": 192, "text": "182\n\nC. H. Coleman\n\nWeiler-Ravell, D., A. Leventhal, R.J. Coker, and D. Chemtob. 2004. Compulsory detention of recalcitrant tuberculosis patients in the context of a new tuberculosis control programme in Israel. Public Health 118 (5): 323–328. https://doi.org/10.1016/j.puhe.2003.10.005.\n\nWorld Health Organization. 2012. Statement on HIV testing and Counseling: WHO, UNAIDS testing. http://www.who.int/hiv/events/2012/\n\nre-affirm opposition world_aids_day/hiv_testing_counselling/en/.", "n_tokens": 149, "kind": "text"}
{"chunk_id": "drug_resistance_book-192-1", "doc_id": "drug_resistance_book", "page": 192, "text": "to mandatory HIV\n\n———. 2017. Ethics guidance for the implementation of the end TB strategy. http://apps.who.int/\n\niris/bitstream/10665/254820/1/9789241512114-eng.pdf?ua=1.\n\n———. 2016. Guidance for managing ethical issues in infectious dsease outbreaks. http://apps.\n\nwho.int/iris/bitstream/10665/250580/1/9789241549837-eng.pdf.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 279, "kind": "text"}
{"chunk_id": "drug_resistance_book-193-0", "doc_id": "drug_resistance_book", "page": 193, "text": "Chapter 12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\nEuzebiusz Jamrozik and Michael J. Selgelid", "n_tokens": 32, "kind": "text"}
{"chunk_id": "drug_resistance_book-193-1", "doc_id": "drug_resistance_book", "page": 193, "text": "Abstract Drug-resistant bacterial infections constitute a major threat to global public health. Several key bacteria that are becoming increasingly resistant are among those that are ubiquitously carried by human beings and usually cause no symptoms (i.e. individuals are asymptomatic carriers) until a precipitating event leads to symptomatic infection (and thus disease). Carriers of drug-resistant bacteria can also transmit resistant pathogens to others, thus putting the latter at risk of infec- tions that may be difficult or impossible to treat with currently available antibiotics. Accumulating evidence suggests that such transmission occurs not only in hospital settings but also in the general community, although much more data are needed to assess the extent of this problem. Asymptomatic carriage of drug-resistant bacteria raises important ethical questions regarding the appropriate public health response, including the degree to which it would be justified to impose burdens and costs on asymptomatic carriers (and others) in order to prevent transmission. In this paper, we (i) summarize current evidence regarding the carriage of key drug- resistant bacteria, noting important knowledge gaps and (ii) explore the implications of existing public health ethics frameworks for decision- and policy-making regarding asymptomatic carriers. Inter alia, we argue that the relative burdens imposed by public health mea- sures on healthy carriers (as opposed to sick individuals) warrant", "n_tokens": 290, "kind": "text"}
{"chunk_id": "drug_resistance_book-193-2", "doc_id": "drug_resistance_book", "page": 193, "text": "careful consider- ation and should be proportionate to the expected public health benefits in terms of risks averted. We conclude that more surveillance and research regarding com- munity transmission (and the effectiveness of available interventions) will be needed in order to clarify relevant risks and design proportionate policies, although extensive community surveillance itself would also require careful ethical consideration.", "n_tokens": 71, "kind": "text"}
{"chunk_id": "drug_resistance_book-193-3", "doc_id": "drug_resistance_book", "page": 193, "text": "E. Jamrozik (*) Monash Bioethics Centre, Monash University, Clayton, VIC, Australia\n\nRoyal Melbourne Hospital Department of Medicine, University of Melbourne, Parkville, VIC, Australia\n\nWellcome Centre for Ethics and the Humanities and The Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK e-mail: zeb.jamrozik@gmail.com\n\nM. J. Selgelid Monash Bioethics Centre, Monash University, Melbourne, VIC, Australia\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_12\n\n183", "n_tokens": 182, "kind": "text"}
{"chunk_id": "drug_resistance_book-194-0", "doc_id": "drug_resistance_book", "page": 194, "text": "184\n\nE. Jamrozik and M. J. Selgelid\n\nKeywords Antimicrobial resistance · Drug resistance · Asymptomatic infection · Drug-resistant infection · Ethics · Public health ethics\n\n12.1\n\nIntroduction\n\nThe human body contains more bacterial cells than human cells. We all, thus, “carry” bacteria--especially in our digestive, respiratory, and urogenital tracts – and on our skin (Sender et al. 2016). Bacteria travel with and between human beings, following the daily flux of commuters in cities and crossing the world with interna- tional travellers. These ‘fellow travellers’ are often unsuspected since most of these bacteria cause no overt symptoms (i.e. the human carriers are mostly ‘asymptom- atic’), and some even have symbiotic benefits for humans.1 Yet, under certain cir- cumstances (e.g., skin breakdown, bowel surgery, or the use of immunosuppression), some ubiquitous species of bacteria cause ‘invasive’ disease that may require anti- biotic treatment and be life threatening if such treatments are ineffective or unavail- able. With increasing use (and overuse) of antibiotics in recent decades, such ubiquitously carried bacteria have in many cases become increasingly resistant to first line (and, in some cases, second line and/or ‘reserve’) treatments (See Table 12.1). Some have become effectively untreatable with standard antibiotics, and those who develop invasive disease are at high risk of death and/or permanent morbidity (Klein et al. 2007; Tischendorf et al. 2016).", "n_tokens": 349, "kind": "text"}
{"chunk_id": "drug_resistance_book-194-1", "doc_id": "drug_resistance_book", "page": 194, "text": "Asymptomatic carriers of resistant ubiquitous bacteria vastly outnumber symp- tomatic cases (Tischendorf et al. 2016; Smith et al. 2004; Safdar and Bradley 2008) and may carry them unknowingly for months or years (Smith et al. 2004; Carlet 2012; Zimmerman et al. 2013; Marchaim et al. 2007; Kennedy and Collignon 2010), creating risks of disease for carriers as well as risks of transmission to others\n\nTable 12.1 Pathogens frequently carried by healthy individuals\n\nPathogen Enterobacteriaceaea Enterococcus faecium Clostridium difficile Staphylococcus aureus Streptococcus pneumonia\n\nHaemophilus influenzae\n\nExamples of resistant form(s) of public health importanceb CRE (carbapenem resistant enterobacteriaciae) VRE (vancomycin-resistant enterococci Vancomycin resistant strains MRSA (methicillin-resistant S. aureus) Penicillin resistant strains\n\nPenicillin / macrolide resistant strains\n\nSite of carriage Digestive tract Digestive tract Digestive tract Skin, nose Respiratory tract Respiratory tract\n\naEnterobacteriaciae include: Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., and Providencia spp, Morganella spp. bAdapted from WHO List of Priority Resistant Pathogens\n\n1 Others can lead to indirect benefits because their presence in the ecological niche of asymptom- atic carriage excludes and/or inhibits other more harmful organisms.", "n_tokens": 340, "kind": "text"}
{"chunk_id": "drug_resistance_book-195-0", "doc_id": "drug_resistance_book", "page": 195, "text": "12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\n(Klein et al. 2007; Tischendorf et al. 2016; Safdar and Bradley 2008; Carlet 2012; Giske et al. 2008). In light of the potential transmission of resistant bacteria from asymptomatic carriers to others, asymptomatic carriage (otherwise referred to as asymptomatic infection, colonization, commensalism, persistence, the carrier state, etc. (Casadevall 2000)) has underexplored ethical implications for public health programs aimed at controlling the spread of drug resistant bacteria.", "n_tokens": 130, "kind": "text"}
{"chunk_id": "drug_resistance_book-195-1", "doc_id": "drug_resistance_book", "page": 195, "text": "Though infection control policies often focus on symptomatic cases, in some cases they also apply to apparently healthy individuals (for example, quarantine involves those suspected, but not known, to be infected (Morgan et al. 2017; Kass 2001; Selgelid 2009; Millar 2009)). As more knowledge is gained regarding com- munity (as opposed to in-hospital) transmission of drug-resistant bacteria, policy- makers will need to determine appropriate responses to this relatively new set of public health problems in the general community. Policy options could include screening and other kinds of interference with the lives of apparently healthy indi- viduals. When potentially transmissible (resistant) asymptomatic carriage is diag- nosed, there may sometimes be an ethical rationale for public health interventions to prevent transmission, and these measures (as well as screening itself) may entail significant burdens2 for carriers (and others) as well as public health benefits. Beyond screening, interventions could include reporting the diagnosis of asymptomatic car- riage to authorities, notification of third parties, monitoring of carriers, restrictions on freedom of movement (e.g. quarantine, isolation, travel bans), exclusion of carri- ers from working in certain occupations, and/or possibly even requirements for treat- ment of carriers in certain circumstances (See Table 12.1). Where the rate of carriage of highly resistant (i.e. effectively untreatable) bacteria is increasing and/or", "n_tokens": 312, "kind": "text"}
{"chunk_id": "drug_resistance_book-195-2", "doc_id": "drug_resistance_book", "page": 195, "text": "where community transmission poses significant risks, such public health interventions could have wide-ranging effects on social norms and the everyday lives of healthy individuals (as was the case for tuberculosis and HIV prior to the availability of effec- tive treatments (Fitzgerald 2007)) resulting in stigma and/or social exclusion, in addi- tion to the direct burdens of complying with public health interventions.", "n_tokens": 81, "kind": "text"}
{"chunk_id": "drug_resistance_book-195-3", "doc_id": "drug_resistance_book", "page": 195, "text": "A key ethical question concerns whether or not, or the extent to which, public health decision makers should be especially reluctant to impose public health mea- sures that infringe upon the lives of those who are healthy (as opposed to those who are sick). In this chapter, we summarize current knowledge regarding asymptomatic carriage and community transmission, and argue that (i) beliefs that only those with symptoms pose risks to others (and related views, such as ‘microbial determinism’ – i.e. the idea that all those who acquire a pathogen will develop symptoms) should be discarded, (ii) policymakers should consider the risks posed by asymptomatic carriers of resistant organisms, and (iii) policy formation should be guided public health ethics frameworks such that the burdens imposed on carriers (and others) are minimized (and/or offset) and proportionate to the public health benefits in terms of risks averted; and (iv) designing proportionate interventions will require, inter alia, careful assessments of the risks related to asymptomatic carriage, including through expanded, ethically designed, public health surveillance programs.\n\n2 In this chapter we use the term ‘burden’ to refer to compromises of people’s (especially carriers’) liberties and/or wellbeing.\n\n185", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-196-0", "doc_id": "drug_resistance_book", "page": 196, "text": "186\n\nE. Jamrozik and M. J. Selgelid\n\n12.1.1\n\nHistory\n\nIn the late nineteenth and early twentieth centuries, pioneering microbiologists such as Robert Koch significantly improved scientific understanding of the microbial agents of infectious disease. In 1890, Koch laid out criteria for inferring causal links between pathogens and disease states, including a requirement that every person with the microbe must show signs of the relevant disease. Only 3 years later Koch realized that this was an error since many people carry pathogenic microbes and can transmit them to others, without themselves showing signs of disease. This insight went against common wisdom at the time and was illustrated in famous cases such as that of ‘Typhoid Mary’ in New York in 1907: despite being asymptomatic, Mary Mallon transmitted typhoid to many other people through her work as a cook, result- ing in several deaths (Soper 1939).\n\n12.1.2", "n_tokens": 196, "kind": "text"}
{"chunk_id": "drug_resistance_book-196-1", "doc_id": "drug_resistance_book", "page": 196, "text": "Against Microbial Determinism\n\nDespite this, people might be tempted to think that such cases (of asymptomatic carriage) are exceptions and that the acquisition of potentially pathogenic microbes by a human being (or other animal) will always (or almost always) lead to symp- tomatic infection (i.e. disease). In some ways, the false view that one’s infectious disease status is determined by the pathogens in one’s body (which we call ‘micro- bial determinism’) is akin to an erroneous view in genetics (‘genetic determinism’), according to which phenotype is determined by genotype (de Melo-Martín 2005). Just as particular genetic polymorphisms do not always give rise to particular phe- notypes (because many environmental factors as well as cellular and other causal processes are required), acquiring particular pathogens does not always lead to the relevant infectious diseases. Upon acquisition of a pathogen, a complex set of host- pathogen interactions (involving immunological and other causal processes) can lead to a variety of outcomes – e.g. the microbe being eliminated without symp- toms, short- or long-term asymptomatic carriage, or symptomatic infection/disease (with rapid or delayed onset)(Casadevall 2000).\n\n12.1.3", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-196-2", "doc_id": "drug_resistance_book", "page": 196, "text": "Key Drug-Resistant Pathogens\n\nThis chapter focuses on the ethical implications associated with a subset of WHO Priority Resistant Pathogens (World Health Organisation 2017a): among those with resistance profiles of public health concern, we concentrate on pathogens that are ubiquitous organisms in the bacterial flora of the human body in healthy individuals (Table 12.1) where – in the majority of carriers, whether the bacteria are resistant or", "n_tokens": 81, "kind": "text"}
{"chunk_id": "drug_resistance_book-197-0", "doc_id": "drug_resistance_book", "page": 197, "text": "12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\nnot – they usually cause no symptoms3 until a precipitating event leads to invasive disease (Tischendorf et al. 2016; Safdar and Bradley 2008; Carlet 2012). Such inva- sive disease can occur in otherwise completely healthy carriers, although it is more common in those with comorbidities, especially those associated with reduced immune function (e.g. diabetes, HIV etc.). We are also particularly concerned with community as opposed to in-hospital transmission, as the latter has received more analysis elsewhere (Millar 2012), including in this volume.\n\nMany of our arguments may be relevant to other increasingly resistant bacteria, including (i) gastro-intestinal and sexually transmitted pathogens that are associated with a high rate of symptomatic infection when a person is first exposed (e.g. Campylobacter, Salmonella (including typhoid), Shigella, and Gonorrhea) follow- ing which only some people will become chronic asymptomatic carriers, and (ii) Helicobacter pylori, a less ubiquitous pathogen for which carrier status is associ- ated with a range of clinical severity from no symptoms to mild indigestion to overt peptic ulcer disease and/or stomach cancer.\n\n12.2", "n_tokens": 290, "kind": "text"}
{"chunk_id": "drug_resistance_book-197-1", "doc_id": "drug_resistance_book", "page": 197, "text": "The Public Health Problem\n\nWith widespread use (and overuse) of antibiotics, the number of asymptomatic car- riers of resistant bacteria (henceforth ‘asymptomatic carriers’) is increasing. It is difficult to characterize the overall carriage rates of the many different types of clinically significant resistant organisms, since the rate of carriage (and the rate of invasive infection) of each varies considerably between populations, and quoted rates will depend on the quality and extent of public health surveillance in different settings (Laxminarayan et al. 2016; Bryce et al. 2016; Bernabé et al. 2017; Nordmann et al. 2011; Schwaber and Carmeli 2013). In any case, symptomatic resistant bacte- rial infections already cause hundreds of thousands of deaths globally per year (although few estimates of the total burden are available) (Laxminarayan et al. 2016; O’Neill 2015) and increase healthcare costs by billions of dollars (Klein et al. 2007; Giske et al. 2008; O’Neill 2015). The true population prevalence of asymp- tomatic carriage of resistant bacteria is often unknown, because not enough com- munity surveillance data are available. Most data come from hospital settings and are biased by the inclusion of a disproportionate number of symptomatic cases and a focus on patients who have contact with healthcare institution(s) as opposed to the wider community (World Health Organization 2014).", "n_tokens": 308, "kind": "text"}
{"chunk_id": "drug_resistance_book-197-2", "doc_id": "drug_resistance_book", "page": 197, "text": "Globally, the rate of carriage and/or disease from resistant organisms tracks dis- advantage, with higher rates in many low- and middle-income countries (LMICs) (Bernabé et al. 2017). For example, a recent study in a Malaysian hospital found that around 50% of patients screened on arrival to hospital were carrying\n\n3 Emerging microbiome research programs are, however, seeking links between strains of coloni- zation and a wide range of ‘subclinical’ physical and mental health outcomes.\n\n187", "n_tokens": 107, "kind": "text"}
{"chunk_id": "drug_resistance_book-198-0", "doc_id": "drug_resistance_book", "page": 198, "text": "188\n\nE. Jamrozik and M. J. Selgelid\n\ncarbapenem resistant Enterobacteriaciae (CRE)4 in their digestive tract (Zaidah et al. 2017) – of whom perhaps up to 1 in 6 can be expected to develop invasive disease, with overall mortality among carriers reportedly around 10% (Tischendorf et al. 2016). In general, there is a much higher rate of mortality from resistant infec- tions in poor communities, including among infants – some of whom acquire resis- tant infections from mothers and/or family members (and/or, for infants admitted to hospital, from staff or other patients) who are asymptomatic carriers (Chan et al. 2013). One 2016 estimate suggested that of the 680,000 annual neonatal deaths due to bacterial infection, the vast majority of which occur in LMICs, around 31% (214,500) were due to resistant infections (Laxminarayan et al. 2016).\n\nYet the problem is by no means confined to developing regions. A 2016 system- atic review of E. coli5 urinary infections among children (with the usual source of such infections being asymptomatic carriage of E. coli in the child’s digestive tract) found that the highest rates of resistance to first-line penicillin antibiotics occurred in (lower income) non-OECD countries (79.8%), but rates in (higher income) OECD countries were still relatively high (53.4%) (Bryce et al. 2016).", "n_tokens": 332, "kind": "text"}
{"chunk_id": "drug_resistance_book-198-1", "doc_id": "drug_resistance_book", "page": 198, "text": "More epidemiological research is urgently needed to quantify the rates of car- riage of key pathogens in different populations, as well as the rates of disease among carriers and the rates of transmission from (symptomatic and asymptomatic) carri- ers to others in different contexts. Novel, less expensive, genomic screening tech- niques are expected to facilitate such investigations (Kwong et al. 2017).\n\n12.2.1\n\nAntibiotic Use and Drug Resistance\n\nThe use of antibiotics that kill sensitive bacteria in the human microbiome inevita- bly leads to the evolutionary selection of drug resistant bacteria. Despite concerns regarding underuse, the vast majority of drug resistant bacteria in humans arise due to antibiotic overuse and ‘appropriate’ use (Llewelyn et al. 2017).6 Importantly, when antibiotics are prescribed/taken to treat one type of (suspected or confirmed) infection, many other bacteria carried in the body are exposed to the same antibiot- ics, which select for resistant strains by killing sensitive ones. It is mainly these ‘off-target’ effects that lead to asymptomatic carriage of resistant forms of ubiqui- tous bacteria (Llewelyn et al. 2017). This means that whether a given prescription for antibiotics is ‘appropriate’ (e.g. because the patient actually has a symptomatic infection with the pathogen for which she is being treated) or not, each additional dose of antibiotics potentially adds to the burden of resistant bacteria carried in the", "n_tokens": 320, "kind": "text"}
{"chunk_id": "drug_resistance_book-198-2", "doc_id": "drug_resistance_book", "page": 198, "text": "4 i.e. highly resistant bacteria predominantly found in the digestive tract, a group considered “criti- cal” (i.e. of highest importance) on the WHO Priority list. 5 E. coli is an important species in the family of Enterobacteriaciae, carried primarily in the diges- tive tract (see Table 12.1 and footnote above). 6 In this paper we focus on human use, although animal and agricultural use is an important con- tributor to drug-resistant human infection.", "n_tokens": 111, "kind": "text"}
{"chunk_id": "drug_resistance_book-199-0", "doc_id": "drug_resistance_book", "page": 199, "text": "12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\nbody (Carlet 2012). Furthermore, at the population level, it is otherwise relatively healthy occasional users of antibiotics (taken together) who contribute the most to the prevalence of (asymptomatic carriage of) drug-resistant bacteria, rather than the relatively few, relatively sick individuals whose antibiotic use is more frequent and/ or intensive (Olesen et al. 2018). In any case, although reducing the use of antibiot- ics is one important policy to reduce carriage of drug-resistant bacteria, this chapter focuses on other potential community interventions that have received less ethical analysis in this context (Bryce et al. 2016; Barbosa and Levy 2000; Bronzwaer et al. 2002).\n\n12.2.2", "n_tokens": 168, "kind": "text"}
{"chunk_id": "drug_resistance_book-199-1", "doc_id": "drug_resistance_book", "page": 199, "text": "Transmission\n\nEven those who never use antibiotics can acquire resistant pathogens through (direct or indirect) contact with carriers (Zimmerman et al. 2013; Schwaber and Carmeli 2013; Waters et al. 2004; Paterson 2006). Living in close contact with carri- ers (Eveillard et al. 2004; Granoff and Daum 1980), hospitalization(Eveillard et al. 2004; Cronin et al. 2017), working in healthcare (Eveillard et al. 2004; Albrich and Harbarth 2008), and travel to countries with high rates of resistant organ- isms (Kennedy and Collignon 2010) are all risk factors for the acquisition of resis- tant pathogens via transmission. Increasingly, outbreak investigations have demonstrated transmission networks that connect symptomatic and asymptomatic individuals both within hospitals and in the wider community (Smith et al. 2004; Kwong et al. 2017). Community transmission of some pathogens is relatively well understood; for example, colonization with methicillin resistant S. aureus (MRSA) is associated with transmission within families (Eveillard et al. 2004; Fritz et al. 2014; Manian 2003), while the transmission of many other resistant pathogens has been primarily studied in the hospital setting (if at all).\n\n12.2.3", "n_tokens": 281, "kind": "text"}
{"chunk_id": "drug_resistance_book-199-2", "doc_id": "drug_resistance_book", "page": 199, "text": "Duration of Carriage\n\nOnce an individual becomes a carrier of resistant bacteria, the duration of carriage depends on complex local factors at the site of carriage including competition from other strains or other species of bacteria, as well as the carrier’s immune response, and whether (more) antibiotics are used (Andersson and Hughes 2010). Few studies have estimated the average duration of carriage of key resistant bacteria in the gen- eral population; studies in returned travellers have suggested a decrease in carriage over months, with most individuals carrying detectable levels of resistant strains for a few months and a minority (around 10%) developing long-term carriage of 6 months or more (Kennedy and Collignon 2010).\n\n189", "n_tokens": 139, "kind": "text"}
{"chunk_id": "drug_resistance_book-200-0", "doc_id": "drug_resistance_book", "page": 200, "text": "190\n\nE. Jamrozik and M. J. Selgelid\n\n12.3\n\nPotential Public Health Responses\n\nStrategies for preventing the transmission of drug-resistant bacteria from asymp- tomatic carriers include a wide range of potential interventions (Table 12.2). Each of these interventions could involve burdens for carriers (and others, for example family members) – to a greater or lesser degree, depending on the chosen policy and its implementation. Such burdens may include reduced well-being, infringements on privacy,7 restrictions of other freedoms (including freedom of movement and freedom to decide on the medical interventions to which one will be subjected (Table 12.2)8) (Inness 1996), and significant financial costs.9 Interventions can be more or less coercive ranging from being offered, recommended, or self-enforced to strictly coerced and/or backed by legal sanctions including fines and/or prison terms. Thus, the design and implementation of infection control policy will inevitably involve ethical tradeoffs (Millar 2009; Millar 2012). The focus of most drug- resistant infection policy regarding asymptomatic carriers has been on healthcare contexts (primarily hospitals), yet – with few exceptions (Millar 2009; Millar 2012) – there has been little explicitly ethical analysis of such policies. There has", "n_tokens": 269, "kind": "text"}
{"chunk_id": "drug_resistance_book-200-1", "doc_id": "drug_resistance_book", "page": 200, "text": "Table 12.2 Infection control interventions and potential burdens\n\nPublic health interventions that could lead to reduced well-being, privacy infringements, and reductions in other freedoms (e.g. freedom of movement, freedom to decide on medical interventions) Intervention Types Screening\n\nDescription/examples Testing apparently healthy individuals for carriage Communicating and explaining the diagnosis of a carrier state Requirements for health workers to report the diagnosis of carrier status Serial (re)testing to assess carrier status Skin/nasal decolonization of MRSA; faecal transplant for CRE Isolation, quarantine, travel bans Change of occupation, altered norms of social interaction\n\nInforming carriers of their status\n\nNotifying public health authorities\n\nMonitoring\n\nTreatment or decolonization\n\nLimitations on freedom of movement Limitations on social practices\n\n7 We consider privacy to be a freedom; see, for example, Inness (1996). 8 This paper focuses on burdensome interventions for carriers; there are of course a range of other interventions including nudging or minimally-burdensome behavioral interventions (we thank an anonymous reviewer for pointing this out) and interventions to change healthcare worker behav- iors such as antibiotic prescribing (which have received some discussion elsewhere). 9 Costs arise both for the individuals directly affected and, where public health measures are financed through taxation, for the whole community.", "n_tokens": 265, "kind": "text"}
{"chunk_id": "drug_resistance_book-201-0", "doc_id": "drug_resistance_book", "page": 201, "text": "12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\nbeen even less ethical analysis of public health infection control interventions to prevent the transmission of drug resistant bacteria in the general community (i.e. outside healthcare settings).\n\n12.3.1", "n_tokens": 54, "kind": "text"}
{"chunk_id": "drug_resistance_book-201-1", "doc_id": "drug_resistance_book", "page": 201, "text": "Surveillance, Notification, and Monitoring\n\nScreening is routinely used to detect asymptomatic carriage of resistant bacteria among hospital patients (Morgan et al. 2017; Perencevich et al. 2004; Cooper et al. 2004). In many jurisdictions, hospitals are required to notify or report the diagnosis of asymptomatic carriage to local infectious diseases departments and/or central agencies, resulting in exceptions to the usual right to privacy over one’s own health information (Morgan et al. 2017; Inness 1996; World Health Organisation 2017b). In order to form a more accurate estimate of the reservoir of asymptomatic infection in the community, and accurately assess the transmissibility and invasiveness (i.e. propensity to cause symptomatic disease) of a given pathogen, surveillance would ideally go beyond (hospital) patients and include members of the general commu- nity such as (but not necessarily limited to) the close contacts of those known to be carriers. Yet this raises questions regarding how policy should address potential sce- narios in which large numbers of asymptomatic carriers of highly resistant patho- gens are identified. Furthermore, the accuracy of tests used in surveillance has ethical implications especially where, for example, a false positive test result leads to significant burdens for someone who is not actually a carrier of resistant microbes (or where a false negative result provides false reassurance).\n\n12.3.2", "n_tokens": 301, "kind": "text"}
{"chunk_id": "drug_resistance_book-201-2", "doc_id": "drug_resistance_book", "page": 201, "text": "Restrictions of Freedom of Movement (Isolation, Quarantine, Travel Bans)\n\nAlthough isolation and quarantine of asymptomatic carriers and/or their contacts have sometimes been successful in hospitals, whether such measures would be fea- sible and/or successful in the general community (e.g. where community members are identified as carriers by public health surveillance) remains uncertain. Restricting the freedom of movement of healthy carriers (or those suspected to be carriers) in the general community would plausibly involve significant infringements on indi- vidual liberty, and such restrictions might often lead to greater burdens for healthy carriers than for those suffering with the symptoms of the relevant disease (or, for example, confined to hospital for other reasons), as discussed below (See Sect. 12.4.2).\n\n191", "n_tokens": 169, "kind": "text"}
{"chunk_id": "drug_resistance_book-202-0", "doc_id": "drug_resistance_book", "page": 202, "text": "192\n\nE. Jamrozik and M. J. Selgelid\n\n12.3.3\n\nTreatment and Decolonization\n\nMany asymptomatic bacterial infections in certain populations – for example, asymptomatic bacteriuria in most females – do not require treatment because they lead to a low rate of disease in the carrier (Nicolle et al. 2005). In other cases, either because of risks to the carrier or to others, treatment may lead to a net benefit (although not necessarily to the carrier herself). Treatment of asymptomatic resis- tant bacteria is often more difficult and sometimes referred to as decolonization. Decolonization strategies have been used for MRSA, primarily carried on the skin and in the nose – which allows for topical (i.e. non-invasive) bactericidal treatment10 (Coates et al. 2009). Although decolonization has primarily been used in carriers with recurrent symptomatic infection in order to benefit the carrier herself, they have also been used in family members (and pets) of at-risk patients and healthcare workers in order to prevent harm to others (Albrich and Harbarth 2008; Guardabassi et al. 2004).", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-202-1", "doc_id": "drug_resistance_book", "page": 202, "text": "Decolonization for organisms carried in the digestive tract is sometimes more invasive than decolonization of the skin. For example, an effective, last-line treat- ment for resistant C difficile11 is faecal transplantation (i.e. decolonization (Morgan et al. 2015)), whereby the bowel microbiome of the patient is replaced by feces from a healthy donor (Van Nood et al. 2013). There have been recent reports of the suc- cessful use of fecal transplantation to clear (symptomatic or asymptomatic) carriage of ubiquitous bowel organisms that have become highly resistant (e.g. CRE), Freedman and Eppes 2014; Manges et al. 2016; Crum-Cianflone et al. 2015). At present, the use of such procedures has been largely confined to unwell patients, including in intensive care units (Carlet 2012). Yet if such strategies prove to be safe, effective and reliable, they could be more widely implemented to address the carriage and transmission of resistant bowel organisms.\n\n12.4", "n_tokens": 237, "kind": "text"}
{"chunk_id": "drug_resistance_book-202-2", "doc_id": "drug_resistance_book", "page": 202, "text": "Ethical Issues\n\nAsymptomatic infection raises a number of important ethical issues. In this chap- ter we focus on ethical considerations related to policy responses to the problem of asymptomatic carriage of resistant strains of ubiquitous bacteria because, as described earlier (i) asymptomatic carriers of such pathogens vastly outnumber symptomatic cases, (ii) carriers are at risk of severe and difficult to treat invasive disease, (iii) carriage of resistant pathogens places others in the community at risk,\n\n10 One limitation of S. aureus decolonization is that it uses bactericidal products (albeit with differ- ent formulations to other relevant antibiotics) to which the organism can also become resistant. 11 C. difficile: a species of bacteria that is commonly (but not ubiquitously) carried asymptomati- cally in the bowel and most frequently causes disease in individuals already treated with antibiotics for other conditions.", "n_tokens": 199, "kind": "text"}
{"chunk_id": "drug_resistance_book-203-0", "doc_id": "drug_resistance_book", "page": 203, "text": "12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\nand (iv) public health interventions to prevent the transmission of resistant bacteria are potentially associated with significant burdens for carriers (and others). Determining the appropriate responses will thus require scientific data regarding the risks involved (e.g. for a given pathogen or resistance mechanism in a given popula- tion) as well as moral judgments about the degree to which burdensome interven- tions to prevent these risks would be justified. An initial question relates to the extent to which the ethical permissibility of a burdensome infection control measure depends on whether contagious carriers are symptomatic as opposed to asymptom- atic (i.e. ‘healthy’). We begin by arguing for a useful way of applying existing pub- lic health ethics frameworks to policy questions, and then give an account of how the principles in such frameworks should be used to inform policy related to asymp- tomatic carriers.\n\n12.4.1", "n_tokens": 213, "kind": "text"}
{"chunk_id": "drug_resistance_book-203-1", "doc_id": "drug_resistance_book", "page": 203, "text": "Applying Public Health Ethics Frameworks\n\nExisting public health ethics frameworks are applicable to the problem of the car- riage and community transmission of resistant bacteria by asymptomatic carriers. The principles in different frameworks overlap considerably; Table 12.3 provides a list of relevant principles and examples of how they might be interpreted (based on previous work (Selgelid 2009)). These principles are usually framed as necessary conditions for determining when a given intervention would be justifiable. However, were this to be so, it might seem that certain principles would be difficult to satisfy\n\nTable 12.3 Principles from public health ethics Frameworks\n\nPublic Health Ethics Principle Need for evidence\n\nLeast restrictive alternative\n\nProportionality\n\nEquity\n\nLeast harmful alternative Reciprocity", "n_tokens": 146, "kind": "text"}
{"chunk_id": "drug_resistance_book-203-2", "doc_id": "drug_resistance_book", "page": 203, "text": "Due legal process\n\nInterpretation/Example Evidence of efficacy is needed to justify imposition of potentially burdensome public health interventions. Where two interventions are expected to be equally effective, the intervention that involves the least restrictions of liberty should be selected. The burdens involved in an intervention should be outweighed by public health benefits achieved. The intervention should be implemented (and burdens imposed) in an equitable, non-discrimintory manner. Where two interventions are expected to be equally effective, the intervention that involves the least harms should be selected. Those who benefit from public health policies/interventions have a reciprocal duty to assist and/or compensate those on whom burdens are imposed. Appropriate legal procedures should be followed and individuals should have the right of appeal. Policymaking should be transparent and democratic.\n\nTransparency\n\n193", "n_tokens": 162, "kind": "text"}
{"chunk_id": "drug_resistance_book-204-0", "doc_id": "drug_resistance_book", "page": 204, "text": "194\n\nE. Jamrozik and M. J. Selgelid", "n_tokens": 15, "kind": "text"}
{"chunk_id": "drug_resistance_book-204-1", "doc_id": "drug_resistance_book", "page": 204, "text": "(as necessary conditions) in the context of asymptomatic carriage of drug-resistant bacteria (and/or in many other public health contexts). If the existence of evidence of an intervention’s effectiveness is conceived as a necessary condition, for exam- ple, then some might think that the current lack of evidence (e.g. of the risks of community transmission of resistant bacteria) precludes the implementation of rel- evant public health interventions. Such an approach would likely reduce the scope of legitimate public health interventions to a very narrow set (for example, those for which we have very substantial evidence regarding the effectiveness of relevant interventions, and where the attendant burdens are well characterized, etc.). For this and other reasons it is arguably more useful to conceive of such principles as point- ing to ethically relevant desiderata the are achieved to a greater or lesser degree (i.e. on a scale) rather than as necessary conditions that are either satisfied or unsatisfied depending on whether some threshold has been crossed (Selgelid 2016).12 For example, there can be more or less (reliable) evidence regarding the expected public health benefits associated with a given intervention—and a relative lack of evidence (such as the current gaps regarding our knowledge of community transmission of drug-resistant pathogens) might suggest that an intervention should first be insti- tuted as (public health) research (rather than suggesting that it would", "n_tokens": 299, "kind": "text"}
{"chunk_id": "drug_resistance_book-204-2", "doc_id": "drug_resistance_book", "page": 204, "text": "be ethically unacceptable to implement it at all), and re-evaluated as more evidence comes to light. Furthermore, since there is not likely to be widespread agreement among pub- lic health practitioners on any threshold that could be used to characterize a suffi- cient amount of evidence to justify the implementation of a given intervention (in public health practice, rather than in research), policymakers should consider both evidence and ethical acceptability as matters of degree existing on a scale—the idea being that the more (reliable) evidence one has that an intervention is likely to create a net public health benefit, the more ethically acceptable it would be to implement it in policy, other things being equal.", "n_tokens": 142, "kind": "text"}
{"chunk_id": "drug_resistance_book-204-3", "doc_id": "drug_resistance_book", "page": 204, "text": "Likewise the harms of potential interventions should be considered to exist on a spectrum from least to most harmful, liberty infringements on a spectrum from least (e.g., minor and/or short-term) to most restrictive (e.g. major and/or longer duration),13 and transparency of policy making on a spectrum from least to most", "n_tokens": 72, "kind": "text"}
{"chunk_id": "drug_resistance_book-204-4", "doc_id": "drug_resistance_book", "page": 204, "text": "12 For illustration of how such an approach might work in the context of public health policy regarding gain-of-function research see Selgelid (2016). 13 Although the Least Restrictive Alternative and Least Harmful Alternative principles are usually framed as necessary conditions, there are often cases where policymakers will be uncertain whether one intervention is more effective and/or less restrictive or harmful than another. In such cases of uncertainty, a scalar framing of the principles might run as follows: “The more confidence policymakers have that two interventions are associated with similar expected public health bene- fits and significantly different restrictions, the more moral considerations would support selecting the less restrictive alternative, other things being equal. The more confidence policymakers have that two interventions are associated with similar expected public health benefits and significantly different burdens, the more moral considerations would support selecting the less harmful/burden- some alternative, other things being equal.” However, in a restricted set of cases where policymak- ers are very certain that one intervention is equally (or more) effective and less restrictive or harmful, interpreting the principles as necessary conditions will yield similar guidance, other", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-205-0", "doc_id": "drug_resistance_book", "page": 205, "text": "12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\ntransparent, and so on—the idea being that the ethical acceptability of interventions will be a matter of degree, and a function of the extent to which they are harmful, restrictive, transparent, etc., other things being equal (Allen and Selgelid 2017). There might often be reasonable disagreement about exactly how the estimated degrees of evidence, harmfulness, restrictiveness, transparency, etc. can/should determine what ultimately ought to be done; but, as a starting point, policymakers should consider how well, or poorly, each available intervention fares with respect to the values/concerns highlighted by each principle before making judgements regarding what policies/interventions should be implemented. We consider this to be a practical approach to ethically sensitive public health policymaking; in the next section we illustrate such an approach in the context of asymptomatic carriage of drug resistance.\n\n12.4.2", "n_tokens": 197, "kind": "text"}
{"chunk_id": "drug_resistance_book-205-1", "doc_id": "drug_resistance_book", "page": 205, "text": "Public Health Intervention for Healthy Carriers\n\nOne might think that public health agencies should be more reluctant to interfere with the lives of healthy asymptomatic carriers as opposed to sick individuals who carry, and/or are suffering from clinical infection due to, the same (resistant) patho- gens. The proportionality principle may help to explain such intuitions. Firstly, one way in which it may make a difference, ethically speaking, whether a carrier is symptomatic or not when imposing potentially burdensome public health interven- tions is that asymptomatic carriers are more likely to be living active lives in general society; whereas the more symptomatic one is, the more likely it is that they will be bedbound and/or admitted to a healthcare facility. In the latter kind of case, one’s liberty and well-being are in a sense already impaired by illness, and so some restrictions (to prevent transmission of drug-resistant bacteria) may impose few, if any, additional burdens.14 For example, public health measures limiting the freedom of movement of carriers (See Table 12.2) would be a more significant burden for healthy carriers whereas the isolation of sick individuals is a relatively minor addi- tional burden, since such individuals are more likely to be restricted in their move- ment (e.g. confined to a healthcare facility) due to illness.15 Thus, if the risk of transmission from a healthy individual is similar to, or less than, the risk from a sick", "n_tokens": 311, "kind": "text"}
{"chunk_id": "drug_resistance_book-205-2", "doc_id": "drug_resistance_book", "page": 205, "text": "things being equal. We thank an anonymous reviewer for pressing us on this point. For more on this kind of approach to public health ethics frameworks, see Allen and Selgelid (2017). 14 Those who are ill may also be more likely to understand and comply with burdensome restric- tions because they can more easily perceive that they are infected and a risk to others; in some such cases restrictive measures may even be unnecessary since voluntary measures suffice. We thank an anonymous reviewer for suggesting this point. 15 Some might worry that the systematic imposition of additional burdens on those who are already (in one sense) badly off due to illness would be inequitable; arguably, this would be particularly worrisome if these burdens were disproportionate (see following discussion of proportionality) to the risks averted which is less likely in cases where (i) the additional burden is small and/or (b) the risk of transmission from sick individual carriers is at least as high as, or higher than, the risk from healthy carriers (i.e. most cases).\n\n195", "n_tokens": 227, "kind": "text"}
{"chunk_id": "drug_resistance_book-206-0", "doc_id": "drug_resistance_book", "page": 206, "text": "196\n\nE. Jamrozik and M. J. Selgelid", "n_tokens": 15, "kind": "text"}
{"chunk_id": "drug_resistance_book-206-1", "doc_id": "drug_resistance_book", "page": 206, "text": "individual, the burdens would be higher when imposing a given intervention on healthy carriers. Secondly, there may be cases in which healthy carriers and sick carriers impose different risks of transmission to others. Sick carriers may impose higher risks of transmission because (i) in at least some cases, the degree of symp- toms (e.g. related to the resistant bacterial infection in question) is correlated with the risk of transmission16 (Lerner et al. 2015) or because (ii) hospitalisation for ill- ness places one in (direct or indirect) contact with other patients who are at particu- larly high risk of acquiring and suffering from (resistant) infection due to medical comorbidities and/or contamination of the shared hospital environment. In cases where such conditions hold, not only would the burdens of certain interventions be lower among sick carriers (as discussed above), but the risks (to others) averted would be greater, meaning that imposing similarly restrictive interventions on healthy carriers would be comparatively less proportionate (because more signifi- cant burdens would be imposed to avert lower risks). On the other hand, there might be cases in which healthy carriers impose higher risks on others. For example, healthcare workers or food handlers who carry resistant pathogens might impose increased risks on others because of the nature of their work. In such cases, it may be more justifiable to impose burdensome restrictions on such individuals, because these", "n_tokens": 299, "kind": "text"}
{"chunk_id": "drug_resistance_book-206-2", "doc_id": "drug_resistance_book", "page": 206, "text": "would be more proportionate to the risks involved (c.f. vaccination of health- care workers (van Delden et al. 2008)).", "n_tokens": 33, "kind": "text"}
{"chunk_id": "drug_resistance_book-206-3", "doc_id": "drug_resistance_book", "page": 206, "text": "12.4.3\n\nBurdens of Interventions and Support for Carriers\n\nAs noted previously, public health interventions to control the spread of resistant bacteria in the general community could potentially burden carriers to a greater or lesser degree. They may also involve burdens for family members and contacts of known carriers, as well as direct financial costs for those involved and funding costs of relevant public health policy options (which are borne by the wider community and/or lead to forgoing other opportunities to improve public health)17. While the threat of drug-resistant infections as an urgent public health problem might prompt some to consider or propose particularly far-reaching and/or coercive interventions, several other public health ethics principles (in addition to the proportionality prin- ciple) can provide useful guidance regarding the ethical reasons to ensure that the burdens (and costs) of an intervention are not only proportionate to the public health benefits but also as low as possible (i.e. without unduly compromising the goals of a policy to reduce risks and thereby lead to public health benefits).", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-206-4", "doc_id": "drug_resistance_book", "page": 206, "text": "16 for example, urinary frequency and incontinence related to urinary tract infection (e.g. with E. coli), diarrhea (e.g. from resistant Clostridium difficile), etc. potentially increase the risk of transmission to others. 17 We thank anonymous reviewers for emphasizing the implications for family members and for pointing out the opportunity cost of public health policies.", "n_tokens": 86, "kind": "text"}
{"chunk_id": "drug_resistance_book-207-0", "doc_id": "drug_resistance_book", "page": 207, "text": "12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\nFirst, the least harmful alternative principle holds that interventions must be no more harmful to carriers than necessary (i.e. minimally harmful) – because compro- mising individuals’ well-being requires justification. If two alternative policies/ interventions are expected to be equally beneficial interms of public health protec- tion, then the alternative that is less harmful to carriers should be preferred, other things being equal – See Table 12.3. Second, the reciprocity principle entails that policymakers should consider obligations to assist and support carriers as part of policy implementation so as to reduce or offset the ‘net burdens’ for those affected. This could include preferential/non-discriminatory access to healthcare, psycho- logical support, assistance with finances or finding other employment, etc.", "n_tokens": 177, "kind": "text"}
{"chunk_id": "drug_resistance_book-207-1", "doc_id": "drug_resistance_book", "page": 207, "text": "More broadly, public health agencies should aim to reduce burdens related to stigma through public education campaigns and through informing carriers about important aspects of carriage (for example, that carriage of resistant organisms is frequently not permanent) at the time of diagnosis. Overly burdensome interven- tions may also lead to perverse incentives for (potential) carriers to avoid diagnosis and/or contact with health authorities, which could lead to greater risks for the car- rier and others, undermining the purported public health benefits of a given policy (meaning that the need for evidence includes evidence regarding how well a policy actually works in practice).18\n\n12.5", "n_tokens": 130, "kind": "text"}
{"chunk_id": "drug_resistance_book-207-2", "doc_id": "drug_resistance_book", "page": 207, "text": "The Need for More Surveillance and Research\n\nPractical ethical deliberations guided by the above principles should always be informed by the best available empirical data on the relevant risks related to carriage of a given pathogen and the expected benefits of an intervention. An initial chal- lenge is that, for many infections transmitted by asymptomatic carriers, the risks are not yet well understood because few data are available. There is thus an ethical imperative for increased public health surveillance and research on such infections, including programs aimed at collecting and analyzing long-term data (i.e. involving monitoring) related to asymptomatic carriage in the general community. This again requires careful ethical consideration, since ethically appropriate surveillance also requires striking a balance between public health goals and individual interests; here, too, public health ethics principles and analysis should help to guide policy formation (World Health Organisation 2017b). Likewise, there is an urgent need for more research regarding the relative effectiveness of different potential public health interventions, as well as qualitative research aimed at better characterizing the bur- dens experienced by carriers. Being able to draw on such empirical data will only serve to improve public health ethics analysis and, ultimately, public health policy.", "n_tokens": 247, "kind": "text"}
{"chunk_id": "drug_resistance_book-207-3", "doc_id": "drug_resistance_book", "page": 207, "text": "18 We thank the participants at the 2018 Brocher workshop “Invisible epidemics: ethics and inter- ventions for asymptomatic carriers of infectious diseases.”, in particular Niels Nijsingh and Christian Munthe for helpful discussions of this point.\n\n197", "n_tokens": 56, "kind": "text"}
{"chunk_id": "drug_resistance_book-208-0", "doc_id": "drug_resistance_book", "page": 208, "text": "198\n\nE. Jamrozik and M. J. Selgelid\n\n12.6\n\nConclusions\n\nAll human beings are asymptomatic carriers of bacteria, meaning that ‘microbial determinism’ is false. The increasing prevalence of carriage of resistant strains of ubiquitous bacteria is an urgent public health issue, and many apparently healthy individuals are at risk of resistant infections and risk transmitting such pathogens to others. Deliberations regarding the design and implementation of public health pol- icy should be guided not only by empirical data regarding the health risks of a given resistant strain and the public health benefits of a given intervention (and much more data are needed to clarify these risks and benefits), but also by ethical analysis regarding the justification of burdens imposed on carriers. Principles of existing public health ethics frameworks should help policymakers identify important con- siderations that have particular implications for the design and implementation of infection control policies regarding asymptomatic carriers. The proportionality principle in particular provides reasons for being wary about imposing potentially burdensome interventions on otherwise healthy carriers of drug resistant patho- gens—which is not to say that such interventions would never be ethically appropriate.", "n_tokens": 236, "kind": "text"}
{"chunk_id": "drug_resistance_book-208-1", "doc_id": "drug_resistance_book", "page": 208, "text": "Acknowledgement Reprinted with permission of John Wiley and Sons (Licence 4890151079850); original citation: Jamrozik, E., & Selgelid, M. J. (2019). Surveillance and control of asymptomatic carriers of drug‐resistant bacteria. Bioethics, 33(7), 766–775.\n\nReferences\n\nAlbrich, W.C., and S. Harbarth. 2008. Health-care workers: Source, vector, or victim of MRSA?\n\nThe Lancet Infectious Diseases 8 (5): 289–301.\n\nAllen, T., and M.J. Selgelid. 2017. Necessity and least infringement conditions in public health\n\nethics. Medicine, Health Care and Philosophy 20 (4): 525–535.\n\nAndersson, D.I., and D. Hughes. 2010. Antibiotic resistance and its cost: Is it possible to reverse\n\nresistance? Nature Reviews Microbiology 8 (4): 260–271.\n\nBarbosa, T.M., and S.B. Levy. 2000. The impact of antibiotic use on resistance development and", "n_tokens": 236, "kind": "text"}
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{"chunk_id": "drug_resistance_book-211-0", "doc_id": "drug_resistance_book", "page": 211, "text": "12 Surveillance and Control of Asymptomatic Carriers of Drug-Resistant Bacteria\n\nVan Nood, E., A. Vrieze, M. Nieuwdorp, et al. 2013. Duodenal infusion of donor feces for recur-\n\nrent Clostridium difficile. New England Journal of Medicine 368 (5): 407–415.\n\nWaters, V., E. Larson, F. Wu, et al. 2004. Molecular epidemiology of gram-negative bacilli from infected neonates and health care workers’ hands in neonatal intensive care units. Clinical Infectious Diseases 38 (12): 1682–1687.\n\nWorld Health Organisation. 2017a. WHO guidelines on use of medically important antimicrobials\n\nin food-producing animals. Geneva: WHO.\n\n———. 2017b. WHO guidelines on ethical issues in public health surveillance. Geneva. World Health Organization. 2014. Antimicrobial resistance: global report on surveillance: World", "n_tokens": 207, "kind": "text"}
{"chunk_id": "drug_resistance_book-211-1", "doc_id": "drug_resistance_book", "page": 211, "text": "Health Organization.\n\nZaidah, A.R., N.I. Mohammad, S. Suraiya, and A. Harun. 2017. High burden of Carbapenem- resistant Enterobacteriaceae (CRE) fecal carriage at a teaching hospital: Cost-effectiveness of screening in low-resource setting. Antimicrobial Resistance & Infection Control 6 (1): 42. Zimmerman, F.S., M.V. Assous, T. Bdolah-Abram, T. Lachish, A.M. Yinnon, and Y. Wiener-Well. 2013. Duration of carriage of carbapenem-resistant Enterobacteriaceae following hospital dis- charge. American Journal of Infection Control 41 (3): 190–194.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n201", "n_tokens": 331, "kind": "text"}
{"chunk_id": "drug_resistance_book-212-0", "doc_id": "drug_resistance_book", "page": 212, "text": "Chapter 13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers: A Capability Approach\n\nMorten Fibieger Byskov, Babette Olga Rump, and Marcel Verweij\n\nAbstract Many countries have implemented specific control measures directed at carriers of multidrug-resistant organisms (MDRO) in order to prevent further intro- duction and transmission of resistant organisms into hospitals and other healthcare related settings. These control measures may in many ways affect the lives and well- being of carriers of MDRO, resulting in complex ethical dilemmas that often remain largely implicit in practice. In this chapter, we propose to conceptualize the impact of MDRO control measures on the well-being of individual carriers in terms of capabilities and functionings. A capabilitarian framework for the ethical treatment of MDRO carriers commits us to conceptualize the harm done to carriers in terms of the impact that MDRO control measures have on what they are able to do or be. Adopting and adapting Nussbaum’s list of ten central human capabilities, we pres- ent a taxonomy of capabilities and functionings that are normatively relevant for the design and evaluation of MDRO control measures.\n\nKeywords Bioethics · Moral philosophy · Public health · Drug resistance\n\n13.1", "n_tokens": 255, "kind": "text"}
{"chunk_id": "drug_resistance_book-212-1", "doc_id": "drug_resistance_book", "page": 212, "text": "Introduction\n\nAntimicrobial resistance (AMR) has been described as one of the major threats to individual and public health (WHO 2014). This threat has justified extensive restric- tions on the freedom of individuals (Krom 2011; Littmann 2014; Littmann and\n\nM. F. Byskov (*) · M. Verweij Communication, Philosophy, and Technology, Wageningen University & Research, Wageningen, Netherlands e-mail: morten.byskov@wur.nl; Marcel.verweij@wur.nl\n\nB. O. Rump The Netherlands National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_13\n\n203", "n_tokens": 218, "kind": "text"}
{"chunk_id": "drug_resistance_book-213-0", "doc_id": "drug_resistance_book", "page": 213, "text": "204\n\nM. F. Byskov et al.\n\nViens 2015). Many countries have implemented control measures in order to pre- vent further introduction and spread of MDRO. Some more general, as addressed in Chap. 6 by Gilbert et al., and some more specific, like those targeting the individual who is found to carry an MDRO. Measures directed at MDRO carriers aim to limit the introduction and further transmission of multidrug-resistant organism (MDRO) in hospitals and other healthcare-related settings. The measures vary per micro- organism and include for instance isolation and quarantine; contact precaution; eradication treatment; restrictions in the workplace; refusal of access to important activities; or contact restrictions at the one’s family farm. They may in many ways affect the lives and well-being of carriers, resulting in complex ethical dilemmas that often remain largely implicit in practice.", "n_tokens": 184, "kind": "text"}
{"chunk_id": "drug_resistance_book-213-1", "doc_id": "drug_resistance_book", "page": 213, "text": "Within the literature, little attention has been paid to how we treat carriers of MDRO, however, and Littmann et al. (2015) includes it as one of four ethical issues that needs further examination when addressing MDRO. In this chapter we aim to start filling this lacuna by proposing to conceptualize the impact of MDRO control measures on the well-being of individual carriers in terms of capabilities and func- tionings. A capabilitarian framework for the ethical treatment of MDRO carriers commits us to conceptualize the harm done to carriers in terms of the impact that MDRO control measures have on what they are able to do or be. Adopting and adapting Nussbaum’s list of ten central human capabilities, we present a taxonomy of capabilities and functionings that are normatively relevant for the design and evaluation of MDRO control measures. Chapter 16 addresses the implications of AMR for child development and adult capabilities.", "n_tokens": 190, "kind": "text"}
{"chunk_id": "drug_resistance_book-213-2", "doc_id": "drug_resistance_book", "page": 213, "text": "The chapter is structured as follows: In Sect. 13.2, we shortly present the issue of treating MDRO carriers as an ethical problem before we turn, in Sect. 13.3, to pro- pose a capabilitarian framework for the conceptualization of the impact that MDRO control measures have on the well-being of carriers. In Sects. 13.4 and 13.5, we adapt Nussbaum’s list of ten central human capabilities in order to develop a tax- onomy of normatively relevant capabilities and functionings in the context of MDRO. In Sect. 13.4, we first present Nussbaum’s list of capabilities before we argue that this list needs further specification when applied to the case of MDRO. In Sect. 13.5, we proceed to propose a taxonomy of ethical domains and normatively relevant capabilities and functionings in the context of responsible care for MDRO carriers. In Sect. 13.6, we finally argue that and show how this capabilitarian tax- onomy can provide a crucial input to procedures for ethical decision-making on appropriate MDRO control measures.", "n_tokens": 232, "kind": "text"}
{"chunk_id": "drug_resistance_book-214-0", "doc_id": "drug_resistance_book", "page": 214, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\n13.2\n\nThe Ethical Treatment of MDRO Carriers: A Neglected Issue\n\nTreating MDRO as an ethical issue is a double-sided coin. On the one side, it involves a concern for public health and how we can ensure that everyone, now and in the future, have access to antimicrobial treatment while minimizing the risk of further spread of MDRO. From this side of the coin, addressing MDRO is primarily an issue of global distributive justice (Littmann 2014; Littmann et al. 2015, 360): how can we distribute antimicrobials in a way that, on the one hand, adequately protects public health by ensuring that everyone has access to antibiotics while, on the other hand, ensuring that antibiotics do not become useless? In the following, however, we shall not primarily be concerned with this distributive question.1", "n_tokens": 196, "kind": "text"}
{"chunk_id": "drug_resistance_book-214-1", "doc_id": "drug_resistance_book", "page": 214, "text": "The distributive focus has often been accompanied by a discussion of what kinds of control measures we can take to prevent the further spread of MDRO (Selgelid et al. 2009; Coleman et al. 2010): how can we treat carriers in a way that minimizes the risk that they contaminate other individuals? An important element in the fight against MDRO is to adequately treat infections with multi-resistant microbes in patients and to prevent that these persons are re-infected or will infect others with a resistant organism. Due to the threat that MDRO poses to individual and public health (WHO 2014), many countries have implemented specific MDRO control measures in order to prevent further introduction and spread of MDRO. Measures to prevent and control the spread of MDRO may include isolation and quarantine; eradication therapy; restrictions in the workplace; refusal of access to important activities; or contact restrictions with one’s family (Verweij and Dawson 2010).", "n_tokens": 201, "kind": "text"}
{"chunk_id": "drug_resistance_book-214-2", "doc_id": "drug_resistance_book", "page": 214, "text": "Many of these control measures threaten to seriously affect the lives of individual carriers, however, and as important as such prevention and control is, it may have burdensome implications for infected patients and healthy persons in whom a resis- tant organism has been colonized: they may feel stigmatized, face restrictions in their work or private life, or might be refused access to certain institutions. For example, in a healthcare context, control measures may mean that surgeons should refrain from operating due to carriership, that infected nurses should not perform patient-related activities, or that we ask infected residents of a nursing home to keep away from social activities.\n\nIn some extreme cases it is almost impossible to eradicate the resistant organism and then it may be impossible for the person to return to what used to be his/her normal life. Consider, for example, the case of a medical student who was repeat- edly diagnosed as carrier of Methicillin-Resistant Staphylococcus Aureus (MRSA) (Rump 2011; Rump et al. 2016). In line with the MDRO control guidelines, the student was not allowed to be involved in patient-care, which is an implicit part of completing the internships necessary to graduate. Because of this, the student had to", "n_tokens": 259, "kind": "text"}
{"chunk_id": "drug_resistance_book-214-3", "doc_id": "drug_resistance_book", "page": 214, "text": "1 For a discussion of different approaches to the distribution of antimicrobials, see especially Anomaly (2010, 2013), Daulaire et al. (2015), Littmann (2014), and Selgelid (2007). For an intro- duction to and overview of distributive justice in general, see Lamont and Favor (2016).\n\n205", "n_tokens": 80, "kind": "text"}
{"chunk_id": "drug_resistance_book-215-0", "doc_id": "drug_resistance_book", "page": 215, "text": "206\n\nM. F. Byskov et al.\n\neventually discontinue his studies. Whether this outcome was indeed necessary or not remains unclear, though, since the risk of further contamination could have been minimized through proper hygiene and guidance.\n\nThe consequences of MDRO carriership certainly have the potential to affect the lives and well-being of not only carriers themselves, but also their social connec- tions, such as family members, friends, and colleagues. Yet, it is unclear in what ways MDRO and MDRO carriership affect these individuals. In the remainder of this chapter, we will offer a novel conceptualization of how MDRO control mea- sures can harm carriers and other affected individuals and further reflect on how this conceptualization, and the normatively relevant issues that are thereby revealed, influences the design and evaluation of MDRO control measures. We argue that adopting a capabilitarian framework for the conceptualization of ‘harm’ done to (potential) carriers can help us make better and more informed decision about what control measures to implement. According to a capabilitarian framework, MDRO control measures may harm individual carriers by negatively affecting their capa- bilities and functionings.\n\n13.3", "n_tokens": 250, "kind": "text"}
{"chunk_id": "drug_resistance_book-215-1", "doc_id": "drug_resistance_book", "page": 215, "text": "A Capabilitarian Framework for Conceptualizing the Impact of MDRO Control Measures\n\nWhat is the capability approach and how can it be used to conceptualize the (nega- tive) impact that MDRO control measures have on the lives and well-being of indi- vidual carriers?2 Originally conceived by the Indian philosopher-economist Amartya Sen (1979) and further developed by a number of theorists, such as Martha Nussbaum, David A. Crocker, and Ingrid Robeyns, the capability approach is a normative framework for the conceptualization of human well-being (Robeyns 2016a). According to this framework, human well-being should be conceptualized in terms of capabilities and functionings. Capabilities are the real freedom that peo- ple have to do or be certain things, such as falling in love, getting an education, being politically active, riding a bike, reading a book, and so on. Functionings are", "n_tokens": 199, "kind": "text"}
{"chunk_id": "drug_resistance_book-215-2", "doc_id": "drug_resistance_book", "page": 215, "text": "2 It is possible that the capability approach can also be used to conceptualize ‘harm’ within three other related domains of application, which we will not discuss in this chapter. First, we can con- ceptualize the risk that the spread MDRO poses to the well-being of members of the public in terms of their capabilities and functionings. For a discussion of how to conceptualize public health in terms of the capability approach, see Prah Ruger (2010), Venkatapuram (2011), and Nielsen (2014). Secondly, the capability approach can be used to conceptualize the ‘harm’ of control mea- sures within infectious disease control in general. While the taxonomy that we provide in Sect. 13.5 may also apply within infectious disease control in general, more research needs to be done in this regard as different capabilities may be relevant in relation to different diseases. Thirdly, the capability approach has been used to conceptualize the idea of ‘person-centered healthcare,’ what it means to treat patients as persons (Entwistle and Watt 2013).", "n_tokens": 224, "kind": "text"}
{"chunk_id": "drug_resistance_book-216-0", "doc_id": "drug_resistance_book", "page": 216, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\ncapabilities that have been realized either by choice or by chance. A person’s capability- set refers to all the capabilities and functionings that that individual has.3 Real freedom in this sense means that there are no restrictions on achieving a particular functioning. Whether or not one has such real freedom crucially depends on certain conversion factors. Conversion factors are personal, social, and environ- mental circumstances that affect the extent to which one can achieve certain doings and beings. For example, whether or not one has the real freedom to be healthy – that is, whether or not one has the capability of achieving the functioning of being healthy – depends on one’s physical health, for example the strength of one’s immune defense system (personal conversion factors), the extent to which one can rely on family and social relations for care (social conversion factors), and where one lives and whether there are adequate infrastructures, such as accessible health care facilities (environmental conversion factors).4", "n_tokens": 212, "kind": "text"}
{"chunk_id": "drug_resistance_book-216-1", "doc_id": "drug_resistance_book", "page": 216, "text": "Through the notion of conversion factors, the capability approach captures the fact that human beings are diverse: different people living in different societies would have different needs and capabilities. As we shall see in Sect. 13.5, the differ- ent conversion factors are relevant when we consider how MDRO control measures affect the lives and well-being of individual carriers.", "n_tokens": 71, "kind": "text"}
{"chunk_id": "drug_resistance_book-216-2", "doc_id": "drug_resistance_book", "page": 216, "text": "The capability approach moves the focus from the means that people have to their ends – what they are able to do or be with these means, such as goods, resources, and formal freedoms. As Sen (1979) argues, this shift in focus is justified because resources and goods alone do not ensure that people are equally able to convert them into doings and beings. Consider, for example, two persons – one disabled, the other able-bodied – with the same amount of resources. According to Sen, the dis- abled person is disadvantaged relative to the able-bodied person in two regards. First, she is disadvantaged in terms of what she can do or be with her means and resources. She may, for example, be less able to move around because she is con- fined to a wheelchair. Secondly, she may even be doubly worse off because she only receive the same amount of resources as the able-bodied person, even though she has more expenses in order to correct for her disability, whereas the able-bodied person, ex hypothesi, can spend all of her resources to pursue her valued ends. Hence, when evaluating the well-being of individuals, we cannot merely compare the amount of resources that they have without also looking at what they are able to do or be with these resources.", "n_tokens": 268, "kind": "text"}
{"chunk_id": "drug_resistance_book-216-3", "doc_id": "drug_resistance_book", "page": 216, "text": "3 Capabilities and functionings can be both positive and negative, as well as neutral (Robeyns 2016b). Positive capabilities are what we consider valuable for someone to do or be. Examples of positive capabilities are good health, adequate nutrition, falling in love, and getting an education. While most applications of the capability approach are primarily concerned with positive capabili- ties, there are also cases where we want to consider their negative capabilities. When evaluating a person’s well-being, for example, it is relevant whether her capability-set include the capabilities to be murdered or raped. Insofar as we, usually, do not consider these capabilities to be valuable, a capability-set that allows for the risks of being murdered or raped would be less valuable than a capability-set that protects the individual from these risks. 4 This example is adapted from Crocker and Robeyns (2010).\n\n207", "n_tokens": 185, "kind": "text"}
{"chunk_id": "drug_resistance_book-217-0", "doc_id": "drug_resistance_book", "page": 217, "text": "208\n\nM. F. Byskov et al.\n\nThe concepts of capabilities and functionings can help us to better understand how MDRO control measures can ‘harm’ (potential) carriers of MDRO in terms of how MDRO control measures influence the real freedom that MDRO carriers have to do or be certain normatively relevant things. MDRO control measures can affect the capability-sets of (potential) carriers in at least two ways. First, they may impose certain requirements on (potential) carriers. This is, for example, the case when we subject nurses to strict hygiene regimes or demand that carriers undergo mandatory screenings and eradication therapies. In terms of the capability approach, MDRO control measures thus impose certain doings and beings – that is, functionings – on carriers. Secondly, MDRO control measures can reduce the choices that carriers have to choose from (i.e., the capabilities that they can choose to turn into realized functionings). This is, for example, the case when we place carriers in isolation or ban them from social activities.5", "n_tokens": 217, "kind": "text"}
{"chunk_id": "drug_resistance_book-217-1", "doc_id": "drug_resistance_book", "page": 217, "text": "Rather than merely focusing on whether or not the autonomy of carriers is being respected (Beauchamp and Childress 2001), by conceptualizing the potential impact of MDRO control measures in terms of capabilities and functionings, we get a broader picture of the many ways in which carriers are affected. In other words, it allows us to move from a singular basis for evaluation, namely in terms of their autonomy, to a multi-dimensional one. The same carrier may be impacted in many different ways by a particular control measure. For example, restricting a resident of a nursing home from participating in the weekly bingo nights not only restricts her capability for participating in social activities, but may also take away an important source of pleasure and happiness or may even lead to stigmatization. Likewise, a particular control measure may impact different carriers in different ways. For example, a child who is at a crucial stage in her social and cognitive development would arguably be negatively affected to a greater extent from being taken out of daycare (even for a short period of time) than a child who is not in this crucial stage of development (Piaget 1971).", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-217-2", "doc_id": "drug_resistance_book", "page": 217, "text": "Moreover, the capability perspective gives substance to carriers’ autonomy: it allows us to identify in which ways MDRO control measures have the potential to (negatively) impact the capabilities of (potential) carriers. We are not merely con- cerned with the limitation of options that carriers can choose from. Rather, the capa- bility perspective tells us that carriers are concerned with particular opportunities for choice (Sen 1991), such as access to day care centers, nursing homes, and phys- iotherapy; participation in social and leisure activities; opportunities for education and employment; freedom from stigmatization and discrimination; and possibilities\n\n5 That is, there might still be good normative reasons to override this concern for carriers’ capabili- ties, for example out of a concern for the public health. While we do not engage with the discussion on how to weigh the violation of carriers’ capabilities against concerns for public health in this paper, do see Sect. 13.6 for an example of how such weighing can take place within an open-ended decision-making framework. The point here is, rather, that there are certain capabilities that are so normatively relevant that we should take them into consideration when deciding on appropriate MDRO control measures – again, even if we do not consider them to have overriding norma- tive status.", "n_tokens": 269, "kind": "text"}
{"chunk_id": "drug_resistance_book-218-0", "doc_id": "drug_resistance_book", "page": 218, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\nfor forming and sustaining relationships to friends, family, and pets. Indeed, by employing the capability approach to conceptualize the ‘harm’ done by MDRO control measures to individual carriers we gain a greater, more in-depth, and more specific understanding of this impact.\n\nAs noted, this focus on particular opportunities for choice – rather than freedom or autonomy, in general – moves the discussion away from the singular dichotomy between public health versus the freedom of the individual carrier. The restriction of freedom is not necessarily a bad thing on the capabilitarian view.6 The restriction of an individual carrier’s freedom out of concern for public health is perfectly compat- ible with the protection of her valued capabilities. What the capability perspective does highlight, though, is that the restriction of some freedoms and opportunities, however prima facie insignificant, may affect capabilities that we do find norma- tively valuable. For example, restricting an MRSA positive child from attending kindergarten for just a few months may not seem like a big deal. However, that restriction may negatively affect a normatively crucial aspect of a person’s life, namely the opportunity for a normal social, cognitive, and physical development if the MRSA positive child were, at the moment of isolation, at a crucial stage of her development.", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-218-1", "doc_id": "drug_resistance_book", "page": 218, "text": "To see how MDRO control measures can (negatively) affect the lives of MDRO carriers, it is crucial to identify what capabilities and functionings that are norma- tively relevant for carriers in the context of MDRO. In the following two sections, we present a taxonomy of capabilities and functionings that may be normatively relevant when deciding on appropriate control measures. This taxonomy builds on one prominent instantiation of the capability approach, namely Nussbaum’s list of ten central capabilities. We first discuss Nussbaum’s list in Sect. 13.4 and argue that it needs further adaptation and specification when applied to the context of deciding on appropriate MDRO control measures before we explain the taxonomy in greater detail in Sect. 13.5. In Sect. 13.6, we finally show how this capabilitarian taxonomy can help us make better and more informed decisions when deciding on appropriate MDRO control measures.\n\n13.4", "n_tokens": 189, "kind": "text"}
{"chunk_id": "drug_resistance_book-218-2", "doc_id": "drug_resistance_book", "page": 218, "text": "Nussbaum’s Ten Central Capabilities: A Starting Point\n\nWhat capabilities should we be concerned about protecting when implementing certain measures to prevent the spread of MDRO?7 A good starting point is Nussbaum’s influential list of ten central capabilities that, she argues, every\n\n6 See, though, Carter (2014) for a dissenting view. 7 We have employed what Byskov (forthcoming) refers to as a synthesizing method to identify the relevant capabilities. Synthesizing methods compare and reconcile two or more lists of capabilities derived from different theoretical and empirical sources. We have here reconciled Nussbaum’s (2000) list of central human capabilities with (i) other lists of relevant normatively domains in healthcare literature, such as Entwistle and Watt (2013) and Huber et al. (2016), (ii) empirical\n\n209", "n_tokens": 174, "kind": "text"}
{"chunk_id": "drug_resistance_book-219-0", "doc_id": "drug_resistance_book", "page": 219, "text": "210\n\nM. F. Byskov et al.\n\ngovernment should provide for their citizens. While Nussbaum’s list is thus derived from a discussion on global justice, it can nevertheless be useful for conceptualizing what kinds of capabilities that are important because it helps us to identify how well-off individuals truly are.8 The most influential version of Nussbaum’s list of capabilities can be found in her book Women and Human Development (Nussbaum 2000)9:\n\n1. Life: Ability to live to the end of a normal length human life, and not to have one’s life reduced to not worth living.\n\n2. Bodily health: Ability to have a good life, which includes – but is not limited to – reproductive health, nourishment, and shelter.\n\n3. Bodily integrity: Ability to change locations freely, in addition to having sover- eignty over one’s body, which includes being secure against assault (e.g., sexual assault, child abuse, and domestic violence) and the opportunity for sexual satisfaction.\n\n4. Senses, imagination, and thought: Ability to use one’s senses to imagine, think, and reason in a ‘truly human way’ informed by an adequate education. The ability to produce self-expressive works and engage in religious rituals without fear of political ramifications. The ability to have pleasurable experiences and avoid unnecessary pain. Finally, the ability to seek the meaning of life.", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-219-1", "doc_id": "drug_resistance_book", "page": 219, "text": "5. Emotions: Ability to have attachments of things outside of ourselves, including being able to love others, grieve at the loss of loved ones, and be angry when it is justified.\n\n6. Practical reason: Ability to form a conception of the good and critically reflect on it. 7. Affiliation:\n\n(a) Ability to live with and show concern for others, empathize with and show compassion for others, and the capability of justice and friendship. Institutions help develop and protect forms of affiliation.\n\n(b) Ability to have self-respect and not be humiliated by others (i.e., being treated with dignity and equal worth). This entails at least protections from being discriminated on the basis of race, sex, sexuality, religion, caste, eth- nicity, and nationality. In work, this means entering relationships of mutual recognition.", "n_tokens": 178, "kind": "text"}
{"chunk_id": "drug_resistance_book-219-2", "doc_id": "drug_resistance_book", "page": 219, "text": "analysis of a database of ethical and practical questions concerning MDRO raised within the Dutch healthcare system as well as (iii) participatory case discussions with practitioners working with infectious disease control. For overviews of the various methods for the selection of capabilities, see Ballon (2013) and Byskov (forthcoming). 8 Several scholars have taken build on Nussbaum’s list and made changes to it, as necessary, when applied in practice (e.g., Alkire 2002). Thus, to be clear, we do not take Nussbaum’s list at face value but rather hold that we can compare and specify this list to the particular case of MDRO. 9 See also Nussbaum (1992, 2011) for similar iterations of her list, albeit based on different norma- tive justifications.", "n_tokens": 171, "kind": "text"}
{"chunk_id": "drug_resistance_book-220-0", "doc_id": "drug_resistance_book", "page": 220, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\n8. Other species: Ability to have concern for and live with other animals, plants, and the environment at large.\n\n9. Play: Ability to laugh, play, and enjoy recreational activities. 10. Control over one’s environment:\n\n(a) Political: Ability to effectively participate in the political life, including\n\nhaving the right to free speech and association.\n\n(b) Material: Ability to own property, not just formally but materially. Furthermore, having the ability to seek employment on an equal basis and the freedom from unwarranted search and seizure.\n\nNussbaum’s list of central human capabilities provides a good starting point for our attempt to identify what capabilities and functionings that are relevant for evaluat- ing the extent to which MDRO control measures excessively interfere with the lives of MDRO carriers. However, when Nussbaum specifies a list of capabilities she is not concerned with the case of MDRO control measures and the well-being of indi- vidual carriers of MDRO but rather with setting out a partial theory of justice. For this reason, when adapting Nussbaum’s list to the context of MDRO carriership, we still need to ask (a) whether all items on her list are relevant and (b) to what extent they need to be further specified and/or supplemented by additional capabilities.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-220-1", "doc_id": "drug_resistance_book", "page": 220, "text": "First of all, while some of the items on Nussbaum’s list may also be relevant for the evaluation MDRO control measures other capabilities are clearly not applicable. For example, while the capability for bodily integrity, seems to be of utmost impor- tance for this discussion, the capability for senses, imagination and thought do not seem to be at stake here. The reason for this is not that being able to use one’s senses, imagination, or thoughts are not important human characteristics. Rather, the reason that these capabilities are of little importance in the context of MDRO is that it can be argued that there are no control measures that have the potential to restrict one’s use of the senses, imagination, and thoughts. Likewise, it is question- able whether the capability for practical reason – one’s ability to form a conception of the good and critically reflect on it – would be thwarted or under threat by any conceivable measure we can take to control MDRO. (However, do note that we sug- gest to subsume (and expand) the capability for education, which is part of the capability for practical reason, under the capability for life as the capability for proper social, physical, and cognitive development.)", "n_tokens": 254, "kind": "text"}
{"chunk_id": "drug_resistance_book-220-2", "doc_id": "drug_resistance_book", "page": 220, "text": "This leaves us the following list of capabilities that we can tentatively assume are relevant for the context of MDRO: Life, bodily health, bodily integrity, affiliation (in both senses), other species, play, and control over one’s environment (in both senses). Now, we still need to ask whether these seven items are sufficient for our present purpose. This is so in two ways. We need to ask, first, whether these seven capabilities are comprehensive in the sense that we do not need to add additional capabilities and, second, whether they are sufficiently specified to capture what is at stake in the context of MDRO.\n\nIn the first case, are the seven capabilities that we retain from Nussbaum’s list sufficient to capture all relevant ethical aspects of the context of MDRO? Do we need to add any further capabilities? In order to answer this, let us first distinguish\n\n211", "n_tokens": 180, "kind": "text"}
{"chunk_id": "drug_resistance_book-221-0", "doc_id": "drug_resistance_book", "page": 221, "text": "212\n\nM. F. Byskov et al.\n\nbetween Nussbaum’s categories of capabilities and the more specific capabilities that are included within the categories. Thus, for example, the category of ‘bodily health’ includes the more specific capabilities of adequate health, nourishment, shelter, and reproductive health. Though all of these specific capabilities support the more general categorical capability of bodily health, they can neither be reduced to each other nor to the general category. In other words, the more specific capabilities are distinct capabilities in themselves.", "n_tokens": 109, "kind": "text"}
{"chunk_id": "drug_resistance_book-221-1", "doc_id": "drug_resistance_book", "page": 221, "text": "Are the seven categories of capabilities sufficient to capture all ethical aspects of MDRO? In general, the categories on Nussbaum’s list seem comprehensive. However, it may be helpful to distinguish carriers’ mental well-being from Nussbaum’s category of bodily health. Many of the MDRO control measures have little impact on one’s physical or bodily health. Even decreases in bodily health – for example, the displeasure caused by eradication therapies – are only temporary. The mental impact, however, may be just as profound and long lasting. Being sub- ject to isolation measures, for instance, is known to increase the levels of perceived stress and anxiety and the stigma of having been a carrier can continue long after carriage has ceased. Thus, the mental impact of MDRO control measures can and should be seen independently from their physical impact. Let us therefore add an additional category, namely mental health.", "n_tokens": 185, "kind": "text"}
{"chunk_id": "drug_resistance_book-221-2", "doc_id": "drug_resistance_book", "page": 221, "text": "How about the more specific capabilities on Nussbaum’s list? Does Nussbaum identify all relevant capabilities to adequately capture what is at stake within the seven general categories in relation to the context of MDRO? Given the particular focus of her own list, Nussbaum naturally leaves off many capabilities that are rel- evant in the context of MDRO. For example, when deciding on how to treat children and adolescents, a major concern is how the control measure affects their physical and mental development. Prolonged isolation of children in certain age groups may cause setbacks in speech or reading that will disadvantage them later in life. Moreover, Nussbaum does not explicitly address concerns related to healthcare, such as access to timely and effective treatment and protection against intrusive and excessive examinations and therapy.", "n_tokens": 160, "kind": "text"}
{"chunk_id": "drug_resistance_book-221-3", "doc_id": "drug_resistance_book", "page": 221, "text": "Nor are Nussbaum’s capabilities sufficiently specified to the context of MDRO carriership and MDRO control measures. For example, the way Nussbaum defines sovereignty over one’s body (a part of bodily integrity) seems overly abstract. In the context of MDRO, what we mean by bodily integrity and sovereignty concerns not being subjected to unnecessary, intrusive, or excessive examinations and eradica- tion therapies. Likewise, since a large issue in relation to MDRO is how it might contribute to the stigmatization of carriers (Rump et al. 2015), we need to include protection from stigmatization along with the protection from discrimination (a part of the capability for affiliation).\n\nThus, we can also answer the second question that we asked above, namely whether Nussbaum’s capabilities are sufficiently and adequately specified to cap- ture the context of MDRO. There are good reasons to argue that Nussbaum’s list needs to be further specified and supplemented with additional capabilities when setting out a taxonomy of normatively relevant capabilities and functionings in the", "n_tokens": 223, "kind": "text"}
{"chunk_id": "drug_resistance_book-222-0", "doc_id": "drug_resistance_book", "page": 222, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\ncontext of how MDRO control measures and carriership may affect the lives and well-being of carriers.\n\nIn sum, although Nussbaum’s list of ten central capabilities provides a useful starting point for identifying the normatively relevant aspects of how MDRO con- trol measures have the potential to impact the lives of individuals, it still needs to be adapted and specified to this particular context. This is so in several ways: first, some capabilities on Nussbaum’s list are irrelevant for the case of MDRO; secondly, Nussbaum’s list does not distinguish all relevant capabilities, such as mental health; and, thirdly, Nussbaum’s capabilities must be specified to the context of MDRO. In the following section, we proceed to present a taxonomy of normatively relevant capabilities and functionings that we need to take into consideration when deciding on and evaluating MDRO control measures.\n\n13.5\n\nA Taxonomy of Normatively Relevant Capabilities in the Context of Addressing MDRO Carriership", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-222-1", "doc_id": "drug_resistance_book", "page": 222, "text": "What does a taxonomy of normatively relevant capabilities and functionings look like in the context of MDRO? How can it help us understand what is at stake when deciding on measures to contain the spread of MDRO? Building on Nussbaum’s list of central human capabilities, in this section we present a taxonomy that adapts and specifies Nussbaum’s list to the particular context of assessing and evaluating MDRO control measures. The taxonomy supplements Nussbaum’s list through an analysis of empirical literature and studies on what practitioners and MDRO carri- ers express as normatively relevant and divides the relevant capabilities into four ethical domains.\n\nTable 13.1 presents a systematic overview of how MDRO control measures can potentially affect the lives and opportunities of individual carriers. The table is divided into three columns, which, from left to right, moves from four general domains of human life (the personal, the social, the institutional, and the environ- mental) to the more specific capabilities and functionings that are relevant in the context of MDRO.\n\nOn the right-hand side of the table, we find a list of the various capabilities and functionings that are (a) normatively relevant for living a decent or flourishing human life, as revealed by Nussbaum’s list of capabilities, and (b) specifically rel- evant within the context of MDRO, as revealed by our empirical analyses.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-222-2", "doc_id": "drug_resistance_book", "page": 222, "text": "In the first case, capabilities such as nourishment, shelter, the right to association, and being treated with dignity and equal worth are relevant for human life regard- less of whether it involves MDRO or not. In the second case, there are capabilities that only or primarily come become relevant when combined with MDRO, such as protection against stigmatization and pathologization, protection against unneces- sary or intrusive examinations and therapy, and the ability to engage in recreational activities.\n\n213", "n_tokens": 105, "kind": "text"}
{"chunk_id": "drug_resistance_book-223-0", "doc_id": "drug_resistance_book", "page": 223, "text": "214\n\nM. F. Byskov et al.\n\nTable 13.1 Ethical domains and normatively relevant capabilities and functionings for the evaluation of the impact of MDRO control measures on (potential) carriers, partly adapted from Nussbaum (2000). Additional items and specifications in bold\n\nDomain Personal\n\nCategory Life\n\nBodily health\n\nMental health\n\nBodily integrity\n\nSpecific capability Not having one’s life reduced to not worth living (especially for elderly) Proper social, physical, and cognitive development (especially for children and adolescents) Adequate health (e.g., to fight off infections) Nourishment Shelter Reproductive health Happiness and peace of mind Self-respect and self-esteem (e.g., being able not to see oneself as sick or as merely a patient) Protection against internalized pathologization Future prospects (e.g., of a speedy recovery) Sovereignty over one’s body (e.g., not being subjected to unnecessary, intrusive, or excessively costly examinations and intensive eradication therapy) Appearance (i.e., being able to appear in public without shame) Freedom of choice and opportunity, both in life and in relation to one’s body Choice in matters of reproduction Protection against internalized pathologization Ability to enjoy social and recreational activities\n\nPlay\n\n(continued)", "n_tokens": 264, "kind": "text"}
{"chunk_id": "drug_resistance_book-224-0", "doc_id": "drug_resistance_book", "page": 224, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\n215\n\nTable 13.1 (continued)\n\nDomain Social and community\n\nCategory Bodily integrity\n\nAffiliation\n\nSpecific capability Protection against assault (e.g., not being seen as merely a threat), also in the case of relatives of carriers A Ability to live with others\n\nFriendship Family (incl. reproductive rights)\n\nB Being treated with equal dignity and respect\n\nInstitutional\n\n(Health) care related\n\nPlay\n\nControl over one’s environment A\n\nBodily health\n\nBodily integrity\n\nSocial status and prestige Ability to engage and participate in social and recreational activities Right to association Ability to form and engage in social relations Access to adequate (i.e., timely and effective) health care Security against assault in the form of intrusive and excessive examinations and eradication therapy\n\nControl over one’s environment\n\nAffiliation\n\nA Access to just and fair healthcare\n\ntreatment\n\nB Freedom from unwarranted search and seizure (e.g., having to pay oneself for excessively expensive examinations) A Institutions help develop and protect forms of affiliation, self-respect, and dignity B Being treated with dignity and equal worth\n\nProtection from discrimination and stigmatization\n\nPublic life", "n_tokens": 230, "kind": "text"}
{"chunk_id": "drug_resistance_book-224-1", "doc_id": "drug_resistance_book", "page": 224, "text": "Control over one’s environment\n\nA Ability to effectively participate in political\n\nand public life (incl. free speech and association) Access to just and fair institutions B Ability to seek employment on an equal\n\nbasis Decent working environment (incl. protection against discrimination and abuse) Freedom from unwarranted search and seizure (e.g., having to pay oneself for excessively expensive examinations) Economic security\n\n(continued)", "n_tokens": 83, "kind": "text"}
{"chunk_id": "drug_resistance_book-225-0", "doc_id": "drug_resistance_book", "page": 225, "text": "216\n\nM. F. Byskov et al.\n\nTable 13.1 (continued)\n\nDomain Environmental\n\nCategory Bodily integrity\n\nOther species\n\nControl over one’s environment B\n\nSpecific capability Ability to change locations freely/freedom of movement (incl. the ability to live where one chooses to) Ability to live with other animals (i.e., pets and livestock), plants (incl. crops), and the environment at large Ability to own property (e.g., livestock)", "n_tokens": 98, "kind": "text"}
{"chunk_id": "drug_resistance_book-225-1", "doc_id": "drug_resistance_book", "page": 225, "text": "The eight categories of capabilities can, in turn, be relevant within one or more of four domains of human life, identified on the left-hand side of the table: the per- sonal, the social, the institutional, and the environmental. Within the personal domain, MDRO control measures influence the relationship that a carrier has to herself, her own body, and her mental satisfaction. In particular, this includes her bodily health, in the sense of being healthy, well-nourished, and having access to adequate accommodation, her mental health, including being happy, feeling digni- fied, and being free from stigmatization, and her bodily integrity, most importantly not being subject to excessive and intrusive examinations and eradication therapies. The social domain concerns individual carriers’ relationships to friends and fam- ily and the ability to participate in social activities. Human well-being to a large degree depends on well-functioning social relationships, both instrumentally and intrinsically. Not only do we count on friends and family to help us realize certain ends and goals in life; we also attribute intrinsic value to social relationship: we engage in and enjoy social relationships for their own sake and not because they help us fulfill personal goals.", "n_tokens": 252, "kind": "text"}
{"chunk_id": "drug_resistance_book-225-2", "doc_id": "drug_resistance_book", "page": 225, "text": "Hence, whenever our social relationships break down it is likely to harm our well-being. Social relationships are especially vulnerable to MDRO and MDRO control measures. Stigmatization and pathologization are social mechanisms by which we respond to perceived threats. In this way, the case of MDRO has a lot in common with the plight of AIDS carriers in the 1980s. However, stigmatization and pathologization are only two ways in which MDRO measures can harm our well- being in a social context. More generally, since we derive pleasure from engaging in social relationships, MDRO measures that restrict the extent to which we can engage in social relations have the potential to lead to a decrease in our well-being.", "n_tokens": 147, "kind": "text"}
{"chunk_id": "drug_resistance_book-225-3", "doc_id": "drug_resistance_book", "page": 225, "text": "On the institutional level, we are interested in the carriers’ relationship to and standing within institutions, primarily (but not limited to) health care facilities. MDRO is primarily an issue when it comes into contact with a healthcare setting. That is, MDRO is primarily a risk when it comes into contact with already vulner- able individuals who depend on effective antimicrobial treatments for their health and survival. Such individuals are more often found within care facilities, such as hospitals, nursing homes, and rehabilitation centers. Moreover, healthcare settings also provide more fertile breeding grounds for the emergence of multidrug-resistant organism because of the increased exposure to antimicrobials and, hence, the risk that organisms will evolve resistance to these antimicrobials.", "n_tokens": 154, "kind": "text"}
{"chunk_id": "drug_resistance_book-226-0", "doc_id": "drug_resistance_book", "page": 226, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…", "n_tokens": 14, "kind": "text"}
{"chunk_id": "drug_resistance_book-226-1", "doc_id": "drug_resistance_book", "page": 226, "text": "Within the environmental domain, we are primarily concerned with carriers’ relations with their environments. To what extent, we ask, are carriers able to con- nect with their environment? Are they able to exercise any control over their envi- ronment? We can talk about a person’s relationship to their environment in both literal and figurative terms. Literally, we talk about the environment as something that is there: a physical presence that we can interact with and influence. In this sense, our relationship with the environment concerns our ability to interact with physical entities such as plants, including flowers, trees, fungi, and so on, as well as animals, including both pets and livestock. In a figurative sense, the environment is a more abstract and indefinite entity. This is so in two ways. First, we can talk about the environment at large, including in the senses of nature and the climate without referring to specific plants or animals. This way of understanding the environment is of little relevance to the context of MDRO. However, secondly, the environment can also be understood as the indefinite but physical space that surrounds us and which we can move around within. In other words, in this sense we understand one’s environment as something within which she (can) has control over herself and her choices. Given that two of the primary MDRO control measures – quarantine and isolation – aim to restrict (potential) carriers’ ability to move around, this sec- ond", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-226-2", "doc_id": "drug_resistance_book", "page": 226, "text": "figurative understanding of the environment is highly relevant to the context of MDRO.", "n_tokens": 15, "kind": "text"}
{"chunk_id": "drug_resistance_book-226-3", "doc_id": "drug_resistance_book", "page": 226, "text": "Crucially, a category of capabilities can be specified differently within different domains. For example, the capability for control over one’s environment in the con- text of the social domain concerns one’s right and freedom to form social relation- ships, while in the institutional domain it rather concerns one’s institutional status, such as the freedom to participate in political and public life and access to just and fair institutions. Thus, although the different categories of capabilities can be rele- vant within different domains, the more specific capabilities that they contain depend on the domain.\n\nIt is important to stress that the taxonomy here does not make any claims about which capabilities and functionings that cannot be violated by MDRO control mea- sures. Rather, it provides a structural overview of how MDRO control measures may affect the lives and opportunities of individual carriers. We still need to engage in a weighing of the relevant capabilities and functionings in individual cases in order to determine whether they provide overriding normative reasons not to imple- ment a particular control measure. Such weighing would take place on a case-by- case basis because each case includes contextual circumstances that influence what the best course of action would be. Hence, it is not possible to a priori determine what control measure (if any) to implement.", "n_tokens": 265, "kind": "text"}
{"chunk_id": "drug_resistance_book-226-4", "doc_id": "drug_resistance_book", "page": 226, "text": "However, by offering a taxonomy of relevant domains and capabilities we do make a claim about what is normatively important and relevant when addressing MDRO. First, as argued in Sect. 13.3, MDRO control measures affect carriers in terms of their capability-sets – what they have the real freedom to do or be. Hence, it is claimed that we ought to conceptualize and describe the impact that MDRO control measures have on individual carriers in terms of capabilities and functionings.\n\n217", "n_tokens": 98, "kind": "text"}
{"chunk_id": "drug_resistance_book-227-0", "doc_id": "drug_resistance_book", "page": 227, "text": "218\n\nM. F. Byskov et al.\n\nSecondly, however incomplete and underspecified, we make a claim about the kinds of capabilities and functionings that are normatively important for (potential) carriers of MDRO and which should be taken into account when deciding on the best course of action. That is, there are good reasons to claim that these particular capabilities have the potential to be normatively relevant when dealing with cases of MDRO. There are both normative and empirical reasons for this claim. Normatively speaking, Nussbaum’s list of capabilities provides a normative philosophical grounding of the capabilities: these are capabilities that can be subject to an overlap- ping consensus. Moreover, there is empirical evidence that (some or most of) these capabilities are of relevance to practitioners and carriers when dealing with cases of MDRO in a healthcare setting. The comparison with real-life queries about how to ethically address MDRO – as represented by our database and deliberations with carriers and practitioners10 – provide empirical basis for the claim that these are the kinds of capabilities that are of concern when deciding on control measures.\n\nHow can this taxonomy be implemented in practice to analyze particular cases of MDRO and decide on appropriate control measures? In the final section, we show how our taxonomy can provide an input into ethical decision-making procedures on the appropriate measure to address MDRO carriership.\n\n13.6", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-227-1", "doc_id": "drug_resistance_book", "page": 227, "text": "Applying the Capabilitarian Taxonomy in Practice\n\nWe have in the previous section repeatedly argued that the more general categories of capabilities that Nussbaum identifies – life, bodily health, mental health, bodily integrity, play, affiliation, control over one’s environment, and other species – can and should be specified to the particular context of how MDRO control measures impact the lives and freedoms of individual carriers. We further argued that we can and should specify these categories of capabilities differently according to whether they relate to either of four domains of human life, namely the personal, the social, the institutional, and the environmental. While the taxonomy that we have presented in Table 13.1 provides an overview of how the different categories of capabilities can be specified in relation to the different domains, how it contributes to the prac- tice of implementing appropriate MDRO control measures is still unclear.", "n_tokens": 175, "kind": "text"}
{"chunk_id": "drug_resistance_book-227-2", "doc_id": "drug_resistance_book", "page": 227, "text": "The above taxonomy can provide a useful input to ethical decision-making pro- cedures on the implementation of MDRO control measures, such as the frameworks developed by Verweij et al. (2012; Krom 2014) or Grill and Dawson (2015). How does the capabilitarian framework help us make decisions about how to address MDRO? How can our taxonomy help us make better and more informed decisions about what kinds of MDRO control measures that are preferable, acceptable, or justifiable? In this section, we briefly consider how the capabilitarian taxonomy can be applied in practice to ethical deliberations on MDRO and what issues that are left unaddressed.\n\n10 See footnote 7.", "n_tokens": 150, "kind": "text"}
{"chunk_id": "drug_resistance_book-228-0", "doc_id": "drug_resistance_book", "page": 228, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\nThe capabilitarian taxonomy presented in this chapter is especially useful in two regards. First, it can help professionals better describe cases of MDRO by making explicit what is at stake for the individual carriers and relevant stakeholders. Secondly, it can help us to identify and evaluate possible courses of action by show- ing how various MDRO control measures may impact the capabilities and function- ings of affected carriers and stakeholders. Let us, by way of a case study, briefly show how the taxonomy of normatively relevant capabilities can be put into practice in these two ways.", "n_tokens": 127, "kind": "text"}
{"chunk_id": "drug_resistance_book-228-1", "doc_id": "drug_resistance_book", "page": 228, "text": "To illustrate how the capabilitarian taxonomy can be applied in practice, con- sider, for example, the case of a young, 19-year-old mother with no income or higher education who shares a household with her own mother. The father of her newborn child is unknown or absent and the woman therefore relies on her own mother for economic assistance and care help. However, the grandmother of the child turns out to be MDRO positive and there are concerns that she is a threat to the health of the newborn child. If there is close contact, it is very likely that the grand- mother would transmit the resistant organism to the newborn. To make matters worse, the child in case has a heart valve condition and needs to go to the hospital for regular check-ups. Because of the likelihood that the child will become an MDRO carrier if the grandmother is involved in the post-partum care of the child, the hospital insists that the grandmother cannot provide this care or that she should take far-reaching protection measures, such as wearing gowns and masks, that would interfere with the bond between child and grandmother.", "n_tokens": 227, "kind": "text"}
{"chunk_id": "drug_resistance_book-228-2", "doc_id": "drug_resistance_book", "page": 228, "text": "How can our taxonomy contribute to the understanding and resolution of this case? What capabilities are at stake in this case? While this case involves a lot of different capabilities within several domains, the primary concern here is the ability to live with others, including family (part ‘affiliation A’ within the social domain). This capability is restricted not only for the young mother but also for the newborn child as well as the grandmother. However, although we can assume that they value this relationship intrinsically – and hence contributes to the capability of happiness and peace of mind (a part of the capability for ‘mental health’ within the personal domain) – in this case there are at least two instrumental reasons why this capability is important.", "n_tokens": 143, "kind": "text"}
{"chunk_id": "drug_resistance_book-228-3", "doc_id": "drug_resistance_book", "page": 228, "text": "First of all, bonding with relatives may be considered an important part of a child’s development (a part of the capability for ‘life’) and restricting the newborn child’s relationship to the grandmother risks harming this development. Secondly, in this case, the social relationship between the young mother and her own mother can also be seen as a proxy for more formal institutional care-relationships. That is, not allowing the grandmother to care for the newborn child is mainly problematic insofar as the mother does not have alternative opportunities for care assistance. Within the taxonomy this is represented by the institutional capabilities for ‘bodily health’ (access to timely and effective healthcare) and ‘affiliation A’ (institutions help develop and protect forms of affiliation).\n\nIn the described case we have multiple courses of action, which can be employed either independently or in conjunction. How can the capabilitarian taxonomy help us identify and evaluate possible measures? Some of the measures would be directed\n\n219", "n_tokens": 194, "kind": "text"}
{"chunk_id": "drug_resistance_book-229-0", "doc_id": "drug_resistance_book", "page": 229, "text": "220\n\nM. F. Byskov et al.\n\nsolely or primarily at the grandmother. First of all, in order to minimize contamina- tion, we could demand that the grandmother undergoes eradication therapy and sub- sequently attends regular screenings. Secondly, we could demand that the grandmother adhere to a strict hygiene regiment, including the donning of a gown, mask, and gloves when tending to the child. Other measures would be directed at the other stakeholders, in particular the newborn child. For example, thirdly, we could subject the newborn to regular screenings to test for MDRO and, when posi- tive, to eradication therapy.\n\nHowever, as the case describes, these measures have potentially negative conse- quences for not only the mother’s abilities to engage in social relations and to care for her child, but also the child’s well-being, especially in relation to her early child- hood development as well as her capability to form an affiliation with her grand- mother. From a capability perspective, then, we would do well to look for alternative courses of action that provide better protection of these normatively valuable capabilities.", "n_tokens": 237, "kind": "text"}
{"chunk_id": "drug_resistance_book-229-1", "doc_id": "drug_resistance_book", "page": 229, "text": "The analysis of the case from the capability perspective shows that a major issue is that the mother is reliant on informal care for her child. Informal care is – usually unpaid – care that is provided by family members or social relations. In contrast, formal care is institutionalized and usually performed by trained professionals. By applying the taxonomy, our analysis shows that the case extends beyond the per- sonal and social domains to reveal a lack of normatively relevant capabilities and functionings at within institutional domain. In the present case, then, a possible solution to the issue could be to increase the access to formal institutional health- care for the young mother and her infant, so that she does not have to rely so much on informal care, thereby avoiding many of the negative consequences that follow from limiting the analysis to focus solely on the informal care-relation between the child, the mother, and the grandmother.11", "n_tokens": 181, "kind": "text"}
{"chunk_id": "drug_resistance_book-229-2", "doc_id": "drug_resistance_book", "page": 229, "text": "While the proposed course of action in this case might be intuitively clear, in general, a major issue of applying the capabilitarian taxonomy in practice, espe- cially when evaluating the various MDRO control measures, concerns the question of how to weigh different capabilities against each other. That is, we need to ask, when does the reduction of a carrier’s capability-set provide an overriding reason to dismiss or provide compensation for a particular control measure? When applying the capabilitarian taxonomy in practice to evaluate different control measures, we should weigh capabilities on at least three levels, namely the intrapersonal, the interpersonal, and the public health level.\n\nThe first level at which we need to weight the importance or value of different capabilities against each other when evaluating potential MDRO control measures is at the intrapersonal level. At the intrapersonal level, we ask whether a person is better off within one scenario as compared to other scenarios. That is, we can ask, is the person’s capability-set more valuable as a result of a particular control\n\n11 A possible objection, also based on the capabilitarian taxonomy, to the proposed solution is that it would negatively affect the grandmother’s capability for affiliation with her grandchild.", "n_tokens": 253, "kind": "text"}
{"chunk_id": "drug_resistance_book-230-0", "doc_id": "drug_resistance_book", "page": 230, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\nmeasure (or combination of control measures) than it would be if we implement another (combination of) control measure(s)?\n\nAt the interpersonal level, second, we are concerned with comparing the capability- sets of different stakeholders within one particular scenario. Here we should ask: does a particular control measure diminish the value of the capability sets of one or more of the relevant stakeholders to the extent that it outweighs the positive impact on the value of the capability sets of other relevant stakeholders?12 Finally, thirdly, we should weigh the positive or negative impact to the value of the capability-sets of individual stakeholders against the estimated benefit to public health that the implementation of a particular MDRO control measure has.", "n_tokens": 159, "kind": "text"}
{"chunk_id": "drug_resistance_book-230-1", "doc_id": "drug_resistance_book", "page": 230, "text": "It is beyond the scope of this chapter to consider how such a weighing may be done. Since this decision must eventually be made on a case-by-case basis, it must be a subject for further research to set out normative (or pragmatic) principles for the weighing of capabilities. Such principles might include a threshold level of capabilities and functionings: do we really need to compensate someone for a lost job-opportunity if she already has ample opportunity to find alternative employ- ment? Other principles are principles of proportionality and acceptable risk, that can help us determine when a particular MDRO control measure is (dis)proportionate to the harm, conceptualized in terms of capabilities and functionings, that it does to the individual carrier. In this regard, possible connections could, for example, be made between our capabilitarian taxonomy and the approaches of Viens et al. (2009), who set out a principle of reciprocity, Krom (2011), who discusses the shortcomings of the harm principle in infectious disease control, and Grill and Dawson (2015) who propose a value-based approach.", "n_tokens": 231, "kind": "text"}
{"chunk_id": "drug_resistance_book-230-2", "doc_id": "drug_resistance_book", "page": 230, "text": "Moreover, the weighing of capabilities and capability-sets should be done in consultation with the relevant stakeholders in order to identify relevant capabilities and their normative weight. This leaves quite a bit of space for professional auton- omy in ethical decision-making. It is simply quite impossible a priori to determine the normatively relevant capabilities and their relative, normative weight. In this regard, the taxonomy of normatively relevant capabilities and functionings pre- sented in this chapter should be taken as an open-ended and underspecified basis for further deliberation between the various stakeholders (carriers, relatives, profes- sionals, and possibly policy-makers) on a case-by-case basis. Again, how much room to leave for professional autonomy and how exactly to conduct such delibera- tive exercises must be subject to further research. We have here proposed two prom- ising frameworks for ethical decision-making, namely Verweij et al. (2012; Krom 2014) or Grill and Dawson (2015).\n\nFinally, it might be objected that, while intuitively attractive, the capabilitarian taxonomy presented in this chapter does not add to professional practice on MDRO. That is, it is not clear that the capability perspective would change what professionals already do when addressing cases of MDRO. This objection holds", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-230-3", "doc_id": "drug_resistance_book", "page": 230, "text": "12 Conversely, this could also be framed as: does a particular control measure increase the value of the capability sets of one or more of the relevant stakeholders to the extent that it outweighs the negative impact on the value of the capability sets of other relevant stakeholders?\n\n221", "n_tokens": 54, "kind": "text"}
{"chunk_id": "drug_resistance_book-231-0", "doc_id": "drug_resistance_book", "page": 231, "text": "222\n\nM. F. Byskov et al.\n\nthat one of the supposed advantages of adopting the taxonomy of capabilities, namely its intuitive appeal, at the same time makes the contribution of this chapter trivial. However, even if the taxonomy largely corresponds to existing practice, there are at least four benefits to making the tacit or implicit assumptions of profes- sional practice explicit through the language of the capability approach and the taxonomy that has been presented in this chapter.", "n_tokens": 93, "kind": "text"}
{"chunk_id": "drug_resistance_book-231-1", "doc_id": "drug_resistance_book", "page": 231, "text": "First of all, the taxonomy provides a substantive – yet underspecified and open- ended – view of carriers’ well-being. Rather than a person’s autonomy, generally speaking, we are, on this view, concerned with protecting carriers’ normatively rel- evant or valuable capabilities and functionings. This allows us, secondly, to provide a structured way of discussing how MDRO control measures impact the lives and well-being of carriers, namely by influencing their normatively relevant or valuable doings and beings. In this sense, the proposed taxonomy could serve as a basis for consultation among professionals and with relevant stakeholders. Third, the capa- bility view presents a multi-dimensional view of the impact that MDRO control measures can have. Different individuals might be impacted in different ways by similar control measures and one individual might be affected in many different ways by a particular control measure. Fourth, by conceptualizing the impact of MDRO control measures in terms of people’s capabilities and functionings, it pos- sible to see how affecting one aspect of an individual’s life may affect other, less immediately obvious, capabilities and functionings.\n\nIn sum, the capability framework to MDRO and the accompanying taxonomy of normatively relevant capabilities does contribute to both the literature on the ethical aspects of MDRO as well as, potentially, to real practice of addressing cases of MDRO.\n\n13.7", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-231-2", "doc_id": "drug_resistance_book", "page": 231, "text": "Concluding Remarks\n\nIn this chapter, we have presented and discussed a capabilitarian conceptualization of how MDRO control measures can (negatively) impact the lives and well-being of individual MDRO carriers. According to the capability approach, we should mea- sure and evaluate this impact in terms of how MDRO control measures (negatively) influence what they are able to do or be. Building on Nussbaum list of central human capabilities, we introduced a taxonomy of normatively relevant capabilities and functionings in the context of MDRO. This taxonomy proposes that measures to contain the spread of MDRO may potentially affect carriers in one or more of four domains human life, namely the personal, social, institutional, and environmental domains. We identified eight categories of capabilities – life, bodily health, mental health, bodily integrity, affiliation, other species, play, and control over one’s envi- ronment – that can and should be specified differently within the four domains of human life when applied to the context of analyzing how MDRO control measures impact the lives of individual carriers. An overview of this taxonomy can be found in Table 13.1.", "n_tokens": 230, "kind": "text"}
{"chunk_id": "drug_resistance_book-232-0", "doc_id": "drug_resistance_book", "page": 232, "text": "13 Conceptualizing the Impact of MDRO Control Measures Directed at Carriers…\n\nThe taxonomy, we finally argued, should be used as an ethical input to a decision- making framework when deciding on the best measures to take when dealing with cases of MDRO. As such, the taxonomy is both underspecified and open-ended: it still needs to be expanded and adapted when applied to particular, individual cases of MDRO. It does not, by itself, determine when the infringement of a particular capability or range of capabilities is unjust and should be supplemented with a notion of when the reduction of a carrier’s capability-set provides an overriding reason to dismiss a particular control measure.\n\nReferences\n\nAlkire, S. 2002. Valuing Freedoms. Oxford: Oxford University Press. Anomaly, J. 2010. Combating resistance: The case for a global antibiotics treaty. Public Health\n\nEthics 3: 13–22.\n\n———. 2013. Collective action and individual choice: Rethinking how we regulate narcotics and\n\nantibiotics. Journal of Medical Ethics 39: 752–756.\n\nBallon, P. 2013. The selection of functionings and capabilities: A survey of empirical studies.\n\nPartnership for Economic Policy (PEP).\n\nBeauchamp, T.L., and J.F. Childress. 2001. Principles of biomedical ethics. Oxford: Oxford", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-232-1", "doc_id": "drug_resistance_book", "page": 232, "text": "University Press.\n\nByskov, M.F. forthcoming. Methods for the selection of capabilities and functionings. In New frontiers of the capability approach, ed. F. Comim, S. Fennell, and P.B. Anand. Cambridge: Cambridge University Press.\n\nCarter, I. 2014. Is the capability approach paternalist? Economics and Philosophy 30: 75–98. Coleman, C.H., Organization WH, E. Jaramillo, et al. 2010. Guidance on ethics of tuberculosis\n\nprevention, care and control. Geneva: World Health Organization.\n\nCrocker, D.A., and I. Robeyns. 2010. Capability and agency. In Amartya Sen, ed. C. Morris, 60–90.", "n_tokens": 154, "kind": "text"}
{"chunk_id": "drug_resistance_book-232-2", "doc_id": "drug_resistance_book", "page": 232, "text": "Cambridge: Cambridge University Press.\n\nDaulaire, N., A. Bang, G. Tomson, et al. 2015. Universal access to effective antibiotics is essential\n\nfor tackling antibiotic resistance. The Journal of Law, Medicine & Ethics 43: 17–21.\n\nEntwistle, V.A., and I.S. Watt. 2013. Treating patients as persons: A capabilities approach to sup-\n\nport delivery of person-centered care. The American Journal of Bioethics 13: 29–39.\n\nGrill, K., and A. Dawson. 2015. Ethical frameworks in public health decision-making: Defending\n\na value-based and pluralist approach. Health Care Analysis: 1–17.\n\nHuber, M., M. van Vliet, M. Giezenberg, et al. 2016. Towards a “patient-centred” operationalisa-\n\ntion of the new dynamic concept of health: A mixed methods study. BMJ Open 6: 1–11.\n\nKrom, A. 2011. The harm principle as a mid-level principle? Three problems from the context of\n\ninfectious disease control. Bioethics 25: 437–444.\n\n———. 2014. Not to be sneezed at. On the possibility of justifying infectious disease control by\n\nappealing to a mid-level harm principle. Utrecht University.\n\nLamont, J., and C. Favor. 2016, Winter. Distributive justice. In The stanford encyclopedia of phi-\n\nlosophy, ed. E.N. Zalta.\n\nLittmann, J. 2014. Antimicrobial resistance and distributive justice. Doctoral, UCL (University\n\nCollege London).\n\nLittmann, J., and A.M. Viens. 2015. The ethical significance of antimicrobial resistance. Public", "n_tokens": 381, "kind": "text"}
{"chunk_id": "drug_resistance_book-232-3", "doc_id": "drug_resistance_book", "page": 232, "text": "Health Ethics: phv025.\n\nLittmann, J., A. Buyx, and O. Cars. 2015. Antibiotic resistance: An ethical challenge. International\n\nJournal of Antimicrobial Agents 46: 359–361.\n\nNielsen, L. 2014. Why health matters to justice: A capability theory perspective. Ethical Theory\n\nand Moral Practice: 1–13.\n\n223", "n_tokens": 79, "kind": "text"}
{"chunk_id": "drug_resistance_book-233-0", "doc_id": "drug_resistance_book", "page": 233, "text": "224\n\nM. F. Byskov et al.\n\nNussbaum, M. 1992. Human functioning and social justice: In defence of Aristotelian essential-\n\nism. Polit Theory 20: 202–246.\n\n———. 2000. Women and human development. The capabilities approach. Cambridge: Cambridge\n\nUniversity Press.\n\n———. 2011. Creating capabilities. The human development approach. Cambridge, MA: Belknap\n\nPress of Harvard University Press.\n\nPiaget, J. 1971. The theory of stages in cognitive development. In Measurement and Piaget, ix,\n\n283. New York: McGraw-Hill.\n\nPrah Ruger, J. 2010. Health capability: Conceptualization and operationalization. American\n\nJournal of Public Health 100: 41–49.\n\nRobeyns, I. 2016a, Winter. The capability approach. In The Stanford Encyclopedia of philosophy,\n\ned. E.N. Zalta. Metaphysics Research Lab, Stanford University.\n\n———. 2016b. Capabilitarianism. Journal of Human Development and Capabilities 17: 397–414. Rump, B. 2011. Stoppen met de studie geneeskunde omwille van MRSA-dragerschap? Ethiek\n\nInfect 19.\n\nRump B., M. De Boer, R. Reis, et al. 2015. Signs of stigma and poor mental health among carri-", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-233-1", "doc_id": "drug_resistance_book", "page": 233, "text": "ers of MRSA.\n\nRump, B., C. Kessler, E. Fanoy, et al. 2016. Case 2: Exceptions to national MRSA prevention policy for a medical resident with untreatable MRSA colonization. In Public health ethics: Cases spanning the globe, ed. D.H. Barrett, L.W. Ortmann, A. Dawson, et al., 191–194. Berlin: Springer.\n\nSelgelid, M.J. 2007. Ethics and drug resistance. Bioethics 21: 218–229. Selgelid, M.J., A.R. McLean, N. Arinaminpathy, and J. Savulescu. 2009. Infectious disease ethics:\n\nLimiting liberty in contexts of contagion. Journal of Bioethical Inquiry 6: 149–152.\n\nSen, A. 1979. Equality of what? Tann Lect Hum Values: 197–220. ———. 1991. Welfare, preference and freedom. Journal of Econometrics 50: 15–29. Venkatapuram, S. 2011. Health justice. An argument from the capability approach. Cambridge:\n\nPolity Press.\n\nVerweij, M., and A. Dawson. 2010. Shutting up infected houses: Infectious disease control, past\n\nand present. Public Health Ethics: 1–3.\n\nVerweij, M., A. Krom, and J. Van Steenbergen. 2012. Ethische kwesties in de infectieziektebestri-\n\njding. Rijksinstituut voor Volksgezondheid and Milieu.\n\nViens, A.M., C.M. Bensimon, and R.E.G. Upshur. 2009. Your liberty or your life: Reciprocity in the use of restrictive measures in contexts of contagion. Journal of Bioethical Inquiry 6: 207–217.\n\nWHO. 2014. Antimicrobial resistance global report on surveillance: 2014 summary. Geneva:", "n_tokens": 421, "kind": "text"}
{"chunk_id": "drug_resistance_book-233-2", "doc_id": "drug_resistance_book", "page": 233, "text": "World Health Organization.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 169, "kind": "text"}
{"chunk_id": "drug_resistance_book-234-0", "doc_id": "drug_resistance_book", "page": 234, "text": "Chapter 14 A Capability Perspective on Antibiotic Resistance, Inequality, and Child Development", "n_tokens": 15, "kind": "text"}
{"chunk_id": "drug_resistance_book-234-1", "doc_id": "drug_resistance_book", "page": 234, "text": "Michael Millar\n\nAbstract Nussbaum’s capability theory by drawing attention to multiple determi- nants of wellbeing provides a rich and relevant evaluative space for framing antibi- otic resistance. I consider the implications of antibiotic resistance for child development and adult capabilities. There are common risk factors for childhood growth stunting and the spread of infectious diseases in both antibiotic sensitive and resistant forms. The interaction between infectious diseases, antibiotic resistance and growth stunting illustrates a clustering of disadvantage. The control of antibi- otic resistance requires wide-ranging cooperative action. Cooperation is predicated on an expectation of equitable access to effective antibiotics. This expectation is confounded by inequality both in access to antibiotics, and in the risk that available antibiotics will be ineffective. Securing child development (and adult capabilities) requires that inequalities both in access to antibiotics and in risk factors for the dis- semination and transmission of antibiotic resistance are addressed. Inequality undermines the cooperative activity that is control of infectious diseases and com- pounds the threat to the securing of capabilities that arises from antibiotic resistance.\n\nKeywords Antibiotics · Capabilities and growth stunting · Social justice · Mother and child health · Infectious Disease\n\n14.1", "n_tokens": 250, "kind": "text"}
{"chunk_id": "drug_resistance_book-234-2", "doc_id": "drug_resistance_book", "page": 234, "text": "Introduction\n\nAntibiotic resistance has been framed as a problem consequent on the lack of devel- opment of new antibiotics and overuse of existing antibiotics. How we frame a problem is important in determining our responses to the problem (Tversky and Kahneman 1981). Unsurprisingly solutions to antibiotic resistance have been\n\nM. Millar (*) Barts Health NHS Trust, London, UK e-mail: M.R.Millar@qmul.ac.uk\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_14\n\n225", "n_tokens": 172, "kind": "text"}
{"chunk_id": "drug_resistance_book-235-0", "doc_id": "drug_resistance_book", "page": 235, "text": "226\n\nM. Millar\n\nfocused on developing new antibiotics, and constraining the use of existing antibiot- ics (see for example http://drive-ab.eu, and https://www.bu.edu/law/faculty-scholar- ship/carb-x). Yet, new antibiotics and constraints on use of existing antibiotics can never be a solution to the potentiation of infectious disease transmission (in antibi- otic sensitive or resistant forms) consequent on poverty, over-crowding, malnutri- tion, limited educational opportunity, environmental degradation, poor water quality, inadequate sanitation or conflict.\n\n14.2", "n_tokens": 138, "kind": "text"}
{"chunk_id": "drug_resistance_book-235-1", "doc_id": "drug_resistance_book", "page": 235, "text": "Capability Theory\n\nCapability theory has been influential in defining measures of human development, and quality of life, and in the evaluation of the justice of social arrangements. Sen (1999) defined a capability as a ‘substantial freedom he or she enjoys to lead the kind of life he or she has reason to value’. Nussbaum emphasises the importance of capabilities for human dignity, and derives entitlements from reflecting on the requirements for equal dignity and respect. She describes necessary conditions for a decently just society, in the form of a set of ten fundamental entitlements for all citizens (Nussbaum 2006). More recently capability theory has been applied to chil- dren (Biggeri et al. 2011) and child development (Peleg 2013). Nussbaum and Dixon (2012) have proposed that capability theory can be used to provide theoreti- cal justification, and to justify a degree of special state priority for children’s rights – based on the ‘unique vulnerability of children to the decisions of others’ (Nussbaum and Dixon 2012, p. 575).", "n_tokens": 223, "kind": "text"}
{"chunk_id": "drug_resistance_book-235-2", "doc_id": "drug_resistance_book", "page": 235, "text": "Antibiotic resistance has implications for child development, basic capabilities, and the securing of adult capabilities. There is on-going debate about the elements that should be included in a capabilities list that is appropriate for adults (Wolff and De-Shalit 2007) or children (Biggeri and Mehrotra 2011). Children develop in to adults, moving through different developmental stages and capabilities at different ages. Child development both depends on the capabilities of adult carers, and deter- mines the potential for adult capabilities. For the purposes of this chapter I have accepted the list that Nussbaum proposes as appropriate for adults, and that achieve- ment of thresholds of adult capabilities is substantially dependent on child develop- ment. The capabilities listed by Nussbaum (2006, p. 154) encompass life expectancy, bodily health & integrity, sense, imagination and thought, emotions, practical rea- son, affiliation, relations with other species, play and control over one’s environment.\n\n14.3\n\nInfectious Disease and Capabilities\n\nThe use of antibiotics can be conceptualised as an attempt to try to prevent damage caused by infection to established capabilities (adults) or the potential for capabili- ties (children). One consequence of the use of antibiotics is antibiotic resistance.", "n_tokens": 256, "kind": "text"}
{"chunk_id": "drug_resistance_book-236-0", "doc_id": "drug_resistance_book", "page": 236, "text": "14 A Capability Perspective on Antibiotic Resistance, Inequality, and Child…\n\nThe rate at which antibiotic resistance develops is a function of usage, time, control measures, and the context of use. The availability of effective treatments for infec- tious disease is a substantial determinant of health. The interactions between health and the determinants of health are complex and not unidirectional, so for example health both determines and is determined by nutrition, education, and social status. The extent of capability fulfilment can be used to define health, while health is required for the fulfilment of capabilities (Venkatapuran 2011, 2013). Uncontrolled infectious disease subverts the achievement of adult capabilities through multiple pathways including through damage to child development. Damage to the capabili- ties of adult carers also has consequences for child development.", "n_tokens": 181, "kind": "text"}
{"chunk_id": "drug_resistance_book-236-1", "doc_id": "drug_resistance_book", "page": 236, "text": "The control of infectious diseases (antibiotic sensitive and resistant) requires ful- filment of multiple entitlements. An entitlement to bodily health requires that an individual is able to have good health, including reproductive health; to be ade- quately nourished; and to have adequate shelter. The adequacy of shelter is impor- tant as a risk factor for the spread of infectious disease, and for damage to child development (see for example Shelter 2006). Nutrition influences both child devel- opment and infectious disease susceptibility (Gough et al. 2014). Maternal repro- ductive health is an important determinant of child development and vulnerability to infectious disease. A capability for senses, imagination, and thought requires educa- tion. To secure child development we must secure the capabilities of those who care for them. Nussbaum and Dixon (2012) emphasise that ‘the goal remains the full empowerment of all individuals’ (p. 578). Maternal education is a key element in assuring healthy child development (see discussion of growth stunting below). Maternal education and parental control of their local environment are necessary elements in protecting children from infectious disease. The entitlements to be able to play and to have relationships with the world of nature can be qualified by adding ‘safely’. Children in developing countries may not be able to live and play without exposure to the risk of infectious diseases (antibiotic sensitive and resistant) trans-", "n_tokens": 307, "kind": "text"}
{"chunk_id": "drug_resistance_book-236-2", "doc_id": "drug_resistance_book", "page": 236, "text": "mitted as a result of poor sanitation, close proximity to animals with zoonotic infec- tion, and vectors for disease (such as malaria mosquitoes). Infectious disease contributes to impairment of child development through multiple pathways includ- ing growth stunting (discussed further below).", "n_tokens": 61, "kind": "text"}
{"chunk_id": "drug_resistance_book-236-3", "doc_id": "drug_resistance_book", "page": 236, "text": "The capabilities listed by Nussbaum remind us of important dimensions of the individual experience of infectious disease (such as freedom of movement and engagement in social interactions). The entitlement to affiliation requires that an individual is able to live for and in relation to others, to recognize and show concern for other human beings, and to engage in various forms of social interaction. Bodily integrity requires that an individual can move freely from place to place. These last two entitlements can be breached by restrictions taken to control the spread of infec- tious disease (antibiotic sensitive or resistant), and by the social consequences of infectious disease, particularly when associated with treatment (antibiotic) resis- tance (see for example Upshur et al. 2009).\n\nConstraints on freedoms to prescribe, to purchase, to manufacture and formulate, to dispose, to pollute, and to use antibiotics for economic gain can all contribute to the control of antibiotic resistance. Nussbaum’s approach does not preclude\n\n227", "n_tokens": 208, "kind": "text"}
{"chunk_id": "drug_resistance_book-237-0", "doc_id": "drug_resistance_book", "page": 237, "text": "228\n\nM. Millar", "n_tokens": 5, "kind": "text"}
{"chunk_id": "drug_resistance_book-237-1", "doc_id": "drug_resistance_book", "page": 237, "text": "limitations on freedoms with respect to the use of antibiotics. Nussbaum gives emphasis to the need to limit freedoms when those freedoms adversely impact on the central capabilities. She states that ‘no society that pursues equality or even an ample social minimum can avoid curtailing freedom in very many ways, and what it ought to say is those freedoms are not good, they are not part of a core group of entitlements required by the notion of social justice, and in many ways, indeed, they may subvert those core entitlements’ (Nussbaum 2011, p. 73). ‘In other words, all societies that pursue a reasonably just political conception have to evaluate human freedoms, saying that some are central and some trivial, some good and some actively bad, some deserving of special protection and others not’ (Nussbaum 2011, pp. 74–75). Framing the actions, constraints and precautions from a capability per- spective also identifies limits to the precautions that we can take and gives priority to actions, which do not undermine capability entitlements. A policy that results in a substantial loss of a capability for some can be challenged from a capability per- spective, even if there was an overall benefit. Stigmatisation, isolation, and segrega- tion of individuals to prevent the spread of treatment resistant infection (such as leprosy historically) would not be consistent with a capability perspective while there remain feasible alternative courses of action. The non-availability of effective", "n_tokens": 307, "kind": "text"}
{"chunk_id": "drug_resistance_book-237-2", "doc_id": "drug_resistance_book", "page": 237, "text": "treatments resulting from antibiotic resistance restricts alternative courses of action. For much of the twentieth century women with leprosy were actively discouraged or prevented from having children. New-born babies of mothers with leprosy were taken from their parents at birth, because otherwise the child would also develop leprosy (see for example International Leprosy Association, History of Leprosy). Capabilities related to childbirth including the opportunities to have and to look after a child were removed. Leprosy has now been controlled to a large extent by the advent and availability of effective antibiotic treatments.", "n_tokens": 118, "kind": "text"}
{"chunk_id": "drug_resistance_book-237-3", "doc_id": "drug_resistance_book", "page": 237, "text": "14.4\n\nHuman Dignity and Infectious Disease\n\nAn emphasis on the importance of human dignity is a substantial element within Nussbaum’s capability theory. There is a lack of consensus on how best to define and measure human dignity (Ashcroft 2005). Dignity can be defined positively but also negatively as freedom from sources of humiliation (see Shultziner and Rabinovici 2011). Nussbaum, while acknowledging that dignity is a poorly defined concept, uses human dignity as a touchstone for the selection of capabilities. Nussbaum’s list of capabilities is a list of positive entitlements (capabilities) that are necessary for the living of a life with human dignity. Respect for the dignity of oth- ers is an important social and political value. Conditions must pertain that reflect that value and these include conditions that foster a sense of personal worth in each person.\n\nThere are strong associations between social status, self-esteem and health (Mann 1998; Marmot 2003; Chilton 2006). There are many ways in which dignity interacts with infectious diseases. There are common risk factors for violations of", "n_tokens": 226, "kind": "text"}
{"chunk_id": "drug_resistance_book-238-0", "doc_id": "drug_resistance_book", "page": 238, "text": "14 A Capability Perspective on Antibiotic Resistance, Inequality, and Child…", "n_tokens": 14, "kind": "text"}
{"chunk_id": "drug_resistance_book-238-1", "doc_id": "drug_resistance_book", "page": 238, "text": "dignity and infectious diseases, for example lack of access to safe toilets contributes to loss of dignity, gender-based violence, and the transmission of infectious disease (see WHO factsheet 392). Inadequate shelter threatens dignity and increases infec- tious disease risks (Shelter 2006). Some infectious diseases, particularly those that are difficult to treat, such as antibiotic resistant tuberculosis, increase the risk that the dignity of adults will be violated (Upshur et al. 2009). Children with HIV or with a parent with HIV can suffer a substantial loss of self-esteem (Chi and Li 2014). An individual or group with an infectious disease may suffer from stigmati- sation, social isolation, and a resultant loss of a sense of self-worth. Social conse- quences of infection for individuals, groups and institutions also include blame and shame (Sontag 1989). Acquisition and carriage of antibiotic resistant bacteria by individuals while undergoing healthcare can be associated with stigmatisation (Rump et al. 2017). Public health policies designed to support the control of antibi- otic resistant bacteria can also lead to stigmatisation of individuals (Ploug et al. 2015). Violations of dignity and damage to self-esteem can increase infectious dis- ease risk through changes in human behaviour. Low self-esteem is associated with sexual risk taking behaviour and sexually transmitted disease (see Byrnes et al. 1999; Ethier et al. 2006).", "n_tokens": 301, "kind": "text"}
{"chunk_id": "drug_resistance_book-238-2", "doc_id": "drug_resistance_book", "page": 238, "text": "There are common risk factors for violations of dignity and infectious diseases, violations of dignity increase infectious disease risk, and infectious disease increases the risk that dignity will be violated.\n\n14.5", "n_tokens": 36, "kind": "text"}
{"chunk_id": "drug_resistance_book-238-3", "doc_id": "drug_resistance_book", "page": 238, "text": "Clustering of Disadvantage: The Example of Growth Stunting\n\nIn discussing actions which lead to the destruction of capabilities Nussbaum states that ‘We can certainly agree that capability-destruction in children is a particularly grave matter and as such should be off-limits’. ‘Usually situations are not so grave, and thus in many such cases the approach has little to say, allowing matters to be settled through the political process’ (Nussbaum 2011, p. 27). Unfortunately capability- destruction is not unusual in many countries. It is estimated that more than 40% of children in lower and middle income countries are at risk of impaired development (Black et al. 2016). A period of particular risk to development is that between conception and 3 years of age. More than 25% of children <5 years of age globally have stunted growth (low height-for-age). Stunting is associated with long- term cognitive and physical impairment (Hair et al. 2015; Noble et al. 2015) and substantial economic consequences for individuals, communities and countries (Horton and Steckel 2013). The WHO Conceptual Framework for stunted growth (Stewart et al. 2013) identifies a range of community and societal contextual factors underlying the causes of stunting of growth of children. These factors include politi- cal arrangements, poverty, regulatory frameworks, healthcare systems, beliefs and norms, the status of women, access to safe foods, sanitation, population density, and\n\n229", "n_tokens": 296, "kind": "text"}
{"chunk_id": "drug_resistance_book-239-0", "doc_id": "drug_resistance_book", "page": 239, "text": "230\n\nM. Millar\n\nnatural and manmade disasters. Solutions require intervention in multiple sectors with specific emphasis given to the way in which resources are controlled and dis- tributed through the political and economic system, food security, education (par- ticularly of females), water quality, sanitation (and hygiene), ameliorating poverty and vulnerability, and access to healthcare (Casanovas et al. 2013). Nussbaum’s capability approach specifies a broad range of entitlements and in so doing is well placed to explicitly accommodate these multiple and complex requirements.", "n_tokens": 119, "kind": "text"}
{"chunk_id": "drug_resistance_book-239-1", "doc_id": "drug_resistance_book", "page": 239, "text": "Infections are thought to contribute to the pathogenesis of growth stunting and infections are both more common and more serious in children with stunting. Recently it has been suggested that administration of antibiotics to populations of children could be used to prevent stunted growth (Gough et al. 2014). The proposal to use antibiotics as a population level intervention to mitigate the risk of stunting illustrates the tension between sustaining effective antibiotics while assuring access for those in pressing need. Population level antibiotic interventions have profound implications for present and future generations particularly when the target popula- tions live under conditions of relative deprivation that facilitate the spread of agents of infection in sensitive and resistant forms. Common risk factors for stunting and for the spread of infectious diseases include overcrowding, poor education (particu- larly maternal), poor nutrition, inadequate sanitation, and poor water quality. Capability insufficiencies (such as poor shelter, threats to bodily health, lack of access to maternal education) contribute both to the transmission of infectious dis- ease and to host susceptibility to disease, and potentially to the burden of antibiotic resistance. There is a clustering of disadvantage in that infectious disease amplifies other disadvantages consequent on capability insufficiencies.", "n_tokens": 258, "kind": "text"}
{"chunk_id": "drug_resistance_book-239-2", "doc_id": "drug_resistance_book", "page": 239, "text": "The use of antibiotics in many developed economies has extended beyond the treatment and prevention of life-threatening human infections to include the mitiga- tion of symptoms of self-limiting disease(s), animal husbandry, fish farming, and to allow us to extend the range of medical and surgical interventions including those with limited health benefits such as some forms of cosmetic surgery. In developed countries antibiotics have become a means to a variety of ends, with varying degrees of relationship with mitigation of harm to human capabilities. Despite this there is evidence that the use of antibiotics in developed countries has stabilised or fallen this century (van Boeckel et al. 2014). Most of the recent increase in use of antibiot- ics has been in rapidly developing countries including Brazil, Russia, India, China and South Africa (BRICS countries). Holland particularly has shown how it is pos- sible for developed countries to have low levels of human antibiotic usage and low levels of antibiotic resistance associated with patients (http://www.ecdc.europa.eu/ en/activities/surveillance/EARS-Net/Pages/Index.aspx). By contrast antibiotic resistance is more prevalent now in developing countries with high levels of depri- vation than in developed countries (WHO Report 2014). This situation probably reflects the capacity of countries to expend resources on trying to assure socio- economic conditions (and capability entitlements) such as education, health, nutri- tion,", "n_tokens": 311, "kind": "text"}
{"chunk_id": "drug_resistance_book-239-3", "doc_id": "drug_resistance_book", "page": 239, "text": "sanitation, and housing which are significant determinants of the epidemiology of infectious disease. An oft-quoted example of this relationship is that of tubercu- losis. The incidence of tuberculosis (TB) and the requirement to treat TB has", "n_tokens": 53, "kind": "text"}
{"chunk_id": "drug_resistance_book-240-0", "doc_id": "drug_resistance_book", "page": 240, "text": "14 A Capability Perspective on Antibiotic Resistance, Inequality, and Child…\n\ndeclined dramatically over recent decades in developed countries and this decline has been attributed to improvements in socio-economic conditions (Comstock 2000). By contrast with developed countries such as Holland the context of use of antibiotics in low to middle income countries frequently involves heightened condi- tions for the spread of infectious diseases both in antibiotic sensitive and resis- tant forms.\n\nAntibiotic resistance considered from within a capability perspective draws attention to the importance of the social, political and economic context in deter- mining infectious disease risks. Antibiotic resistance threatens to place an addi- tional burden on communities where growth stunting and infection are already prevalent, because many of the risk factors for growth stunting also determine the risk that antibiotic resistance will spread. Capabilities may be incommensurable but capabilities still interact with each other in contributing to a state of wellbeing. In the real world these interactions may lead to clustering of disadvantage (Wolff and De-Shalit 2007). The interaction of infection with growth stunting in children illus- trates the clustering of disadvantage and the importance of addressing the broad range of capability deficiencies. Otherwise preventable childhood stunting has the potential to persist alongside burgeoning levels of antibiotic resistance.\n\n14.6", "n_tokens": 269, "kind": "text"}
{"chunk_id": "drug_resistance_book-240-1", "doc_id": "drug_resistance_book", "page": 240, "text": "Capability Thresholds and Inequality?\n\n‘The basic claim of my account of social justice is this: respect for human dignity requires that citizens be placed above an ample threshold of capability in all ten of those areas’ (Nussbaum 2011, p. 36). In this section I ask if capability thresholds can be achieved while there remains avoidable and substantial inequality in access to effective antibiotics and in the determinants of infectious disease. Inequality can be and often is harmful to human wellbeing (Picket and Wilkinson 2010). Our sense of self-worth, our social status, our wellbeing and inequalities are intertwined (Marmot 2003, 2005). Thresholds of capability may not achievable while substan- tial inequalities remain. Wolff and De-Shalit (2007, p. 10) define a society of equals as one in which ‘disadvantages do not cluster, where there is no clear answer to the question of who is the worst off’. Certainly countries are not equal partners and neither are individuals within countries, when account is taken of the burdens of infectious disease – as exemplified by the contrasting patterns of child development and the clustering of disadvantage.", "n_tokens": 246, "kind": "text"}
{"chunk_id": "drug_resistance_book-240-2", "doc_id": "drug_resistance_book", "page": 240, "text": "There is inequality in access to effective antibiotics (Laxminarayan et al. 2016). Pneumonia is still responsible for 1 in 5 deaths of children less than five years old in the world today. Ensuring access of children with pneumonia to antibiotics has been a major objective of the WHO and UNICEF over the last decade (WHO 2013). There is also inequality in the risk of acquisition of antibiotic resistant bacteria. There is increasing evidence of extensive environmental contamination with antibi- otics and antibiotic resistant bacteria (Lubbert et al. 2017), particularly from antibi- otic manufacturing plants, from use of antibiotics in meat production, from hospitals\n\n231", "n_tokens": 132, "kind": "text"}
{"chunk_id": "drug_resistance_book-241-0", "doc_id": "drug_resistance_book", "page": 241, "text": "232\n\nM. Millar", "n_tokens": 5, "kind": "text"}
{"chunk_id": "drug_resistance_book-241-1", "doc_id": "drug_resistance_book", "page": 241, "text": "and urban conurbations (Berendonk et al. 2015). There is increasing use of antibiot- ics to support animal meat production even in countries with high levels of child- hood growth stunting (see Centre for Science and Environment Report 2014). It is estimated that by 2030 the use of antibiotics in livestock production in the US and China will account for 40% of global antibiotic use (Van Boeckel et al. 2015). Antibiotic resistant bacteria, selected in humans and animals, are shared through environmental pollution with both those who can and those who cannot afford to eat meat. Often those with less or no access to antibiotics live in conditions, which promote the spread of antibiotic resistance. These differences are particularly strong in countries where some live in relative affluence in close proximity to slums. Those who are better off have access to the best medical advice, diagnostics for antibiotic resistance, and the latest treatments including antibiotics. When antibiotic resistant bacteria contaminate the environment of people with inadequate sanitation, poor education and with a heightened susceptibility to disease then spread is facilitated. Contamination of the Ganges provides a specific example. While the rich can afford cremation on the Ganges, and pilgrimage to the upper Ganges, the poor cannot. The water of the Ganges has become highly polluted with antibiotic resistant bacteria including a particularly worrying form of antibiotic resistance called New Delhi", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-241-2", "doc_id": "drug_resistance_book", "page": 241, "text": "Metallo-β-lactamase (NDM-1) (Ahammad et al. 2014). Poor people use the water of the Ganges for recreation, washing, and drinking. Poor people with limited access to medical care or antibiotics are exposed to extreme forms of antibiotic resistance through day-to-day activities, with implications for the efficacy of antibiotics, their health and for the health of those around them. There is inequality in the risk of acquisition of antibiotic resistance as well as inequality in access to effective antibi- otics (see Note 1).", "n_tokens": 118, "kind": "text"}
{"chunk_id": "drug_resistance_book-241-3", "doc_id": "drug_resistance_book", "page": 241, "text": "14.7\n\nInternational Cooperation, Unequal Partners\n\nCurrently the majority of countries collaborate on the control of infectious diseases. One hundred and ninety-six countries have signed up to the International Health Regulations (2005) (developed after the SARS outbreak in 2003), which are designed to control the international spread of infectious disease. The control of epidemic diseases is included in the United Nations Rights Document A/6316 (1996). Over recent years antibiotic resistance has become a focus of international concern. The World Health Organisation (2015) has developed an action plan for antimicrobial resistance, which recognises the need for international collaboration (for example see Section 21 (4), Global Action Plan). There is also broad accep- tance in the scientific literature (see for example Institute of Medicine 2010) that control of antibiotic resistance requires international cooperative action.\n\nUnequal relationships between countries can subvert cooperation. For example Indonesia has had outbreaks of avian influenza, which have been associated with high mortality, yet withdrew from cooperation with the WHO Global Influenza Surveillance Network (GISN) in 2007. The position from the Indonesian", "n_tokens": 227, "kind": "text"}
{"chunk_id": "drug_resistance_book-242-0", "doc_id": "drug_resistance_book", "page": 242, "text": "14 A Capability Perspective on Antibiotic Resistance, Inequality, and Child…\n\nperspective is described in a journal article as follows – ‘Indonesia believes that the world must work in unity against the H5N1 virus infection…. The work must be conducted side by side with mutual trust, transparency and equity as global citizens professionals, taking into consideration the elements of human dignity and solidar- ity.’ ‘The avian influenza case in Indonesia has demonstrated once again the unre- solved ‘high-tech’ countries and poor agriculture- based countries. Countries that are the hardest hit by a disease must also bear the burden of the cost of the vaccine, therapeutics and other products, while the monetary and non-monetary benefits of these products go to the manufacturers that are mostly in the industrialised countries’ (Sedyaningsih et al. 2008, p. 487). Indonesia and other resource poor countries were expected to participate in cooper- ating in the control of infectious disease, yet there was a belief that the benefits of cooperation were unequally distributed. Subsequently an agreement was reached which stipulated arrangements for more equitable cooperative arrangements (World Health Assembly 2011).\n\nimbalance between", "n_tokens": 240, "kind": "text"}
{"chunk_id": "drug_resistance_book-242-1", "doc_id": "drug_resistance_book", "page": 242, "text": "the affluent\n\nAnother example of an unequal international relationship that relates more directly to the control of antibiotic resistance arises from the Kumarasamy et al. report in 2010 that New Delhi Metallo-β-lactamase-1 was widespread in India. The Indian government considered this name to be ‘unfair’ and stigmatising, and poten- tially undermined the burgeoning health tourist market in India (see Pandey 2010). The Editor of the Lancet subsequently described the use of this name as an error and apologized stating that the name had ‘unnecessarily stigmatised a single country and city’ (Sinhal 2011). This interaction has compromised research on the epidemi- ology of NDM-1 in India according to the lead author of the Lancet report (Tim Walsh), who named this form of resistance NDM-1. He stated that ‘We were banned from India and India had a massive clampdown on sending (biological) strains out’ (Sugden 2013). Health tourism is developing fast in India and the stigma associated with the potential acquisition of antibiotic resistant bacteria was characterised by Indian politicians as an international plot to undermine that development. Unfortunately NDM1 is now globally distributed (Berrazeg et al. 2014). Conflict between the Lancet and the Indian government over health policy has continued (Sinhal 2015).", "n_tokens": 287, "kind": "text"}
{"chunk_id": "drug_resistance_book-242-2", "doc_id": "drug_resistance_book", "page": 242, "text": "This second story illustrates aspects of the epidemiology of antibiotic resistance. When social conditions are poor then antibiotics quickly become ineffective, antibi- otic resistant bacteria can be rapidly spread around the world, and there is a relation- ship between the sustaining of the functions of antibiotics and other socio-economic ‘goods’ such as adequate shelter, and clean water. This example also illustrates a relationship between antibiotic resistance, and stigma, which can undermine coop- eration in the control of antibiotic resistance. There is considerable inequality in the international influence of the biomedical press with a bias towards developed coun- tries with a strong research base. Combinations of economic inequality, antibiotic prescribing practice norms, and publication practice have marked out India in a way that adds additional disadvantage in a competitive global market for medical tourism.\n\n233", "n_tokens": 168, "kind": "text"}
{"chunk_id": "drug_resistance_book-243-0", "doc_id": "drug_resistance_book", "page": 243, "text": "234\n\nM. Millar\n\n14.8\n\nA Relational Approach to Capability Inequality\n\nNussbaum argues that a contractualist account (such as that proposed by Scanlon 1998) based on individuals as moral equals ‘is a powerful intuitive way of capturing the idea that human beings are moral equals despite their widely differing circum- stances in an unequal world’ (Nussbaum 2006, p. 272). Nussbaum states that ‘I employ the notion of reasonable rejection, or something very close to it, in articulat- ing my account of political justification’ (Nussbaum 2011, p. 89). Her approach ‘is a partial account of specifically political entitlements’ (Nussbaum 2011, p. 96).", "n_tokens": 153, "kind": "text"}
{"chunk_id": "drug_resistance_book-243-1", "doc_id": "drug_resistance_book", "page": 243, "text": "Scanlon provides an account of why and when we can reject both distributive and non-distributive inequalities (see Scanlon 2003, 2013) which can be applied to Nussbaum’s evaluative capability framework. Reasonable rejection and justification to others provide the substantial focus of Scanlon’s contractualist approach (Scanlon 1998) (for more discussion of Scanlon’s approach see Note 2). Interactions between individuals and groups determine the epidemiology of infectious diseases. Human relations directly or indirectly have a substantial role in the spread of infectious diseases. In addition many of the transactions that determine the use of antibiotics and the consequences of use involve individuals, institutions and nations in dia- logue. Examples include healthcare workers (such as doctors) agreeing treatment plans with patients, or healthcare authorities and institutions agreeing antibiotic policies within nations, or nations agreeing approaches to international collabora- tion on the control of antibiotic resistance. Justification is a key element to these relational interactions and it seems intuitively attractive to start from an acknowl- edgement of the importance of justification in assuring the validity of principles and agreements. Another attractive feature of Scanlon’s approach is a concern with assuring the conditions for self-worth. This is significant both in relation to the epi- demiology of infectious disease (as previously discussed) and in relation to a", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-243-2", "doc_id": "drug_resistance_book", "page": 243, "text": "con- cern with assuring the conditions for a life with human dignity (a substantial concern for Nussbaum’s capability theory) (Fitzpatrick 2008).", "n_tokens": 33, "kind": "text"}
{"chunk_id": "drug_resistance_book-243-3", "doc_id": "drug_resistance_book", "page": 243, "text": "For Scanlon everyone counts morally, regardless of race, gender, or where they live. The different reasons for rejecting inequalities are dependent ‘on the way that an inequality affects or arises from the relations between individuals’ (see Scanlon lecture – Why does inequality matter?). Reasons for rejecting inequalities ‘presup- pose some form of relationship or interaction between unequal parties’ and are based on comparing the differences in the situations of individuals (Scanlon (2004) lecture – When does equality matter?). For Scanlon (2006) reasonable rejec- tion does not depend on rejection of the distribution of goods, but rather it depends on assuring equal respect and fairness. Nussbaum’s capability theory provides an evaluative framework for the extent to which equal respect and fairness are achieved, without being itself a complete theory of distributive justice.\n\nScanlon argues that ‘relief of suffering, avoidance of stigmatising differences in status, prevention of domination by others, and the preservation of conditions of procedural fairness are basic and important moral values’ (Scanlon 2003, p. 218) that can give reason to reject inequalities. Inequalities can also be rejected when", "n_tokens": 252, "kind": "text"}
{"chunk_id": "drug_resistance_book-244-0", "doc_id": "drug_resistance_book", "page": 244, "text": "14 A Capability Perspective on Antibiotic Resistance, Inequality, and Child…\n\nthere are institutional obligations to provide certain benefits in an even-handed way, or ‘cases in which individuals, as participants in a cooperative endeavour, have at least a prima facie claim to an equal share of the goods which that endeavour pro- duces’ (Scanlon 2013, p. 463). The control of antibiotic resistance is a cooperative exercise. Cooperation is predicated on an expectation of a share in access to effec- tive antibiotics. Importantly the scope of these reasons for rejection of inequalities extends beyond national boundaries (for a fuller discussion see O’Neill 2013).\n\n14.9\n\nInequalities Subvert Capabilities\n\nInequalities can lead to substantial disadvantage, furthering inequalities in a com- petitive world, and cluster to give multiple disadvantages. Inequalities can result in stigmatising differences in status, both at the level of the individual and the state as shown by the example of NDM-1 antibiotic resistance described above. Inequalities in access to antibiotics coexist with inequalities in risk factors for infection, and risk factors for antibiotic resistance. These inequalities can and do contribute to social, political and economic disadvantage, as exemplified by the interactions between childhood growth stunting, infectious diseases and antibiotic access.", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-244-1", "doc_id": "drug_resistance_book", "page": 244, "text": "Wealth determines access to healthcare, medicines (including antibiotics) and healthy living conditions. The less wealthy in many countries have less access to high quality medicines, little access to medical advice, or diagnostic facilities, often live under conditions that may facilitate the spread of antibiotic resistant bacteria, may be exposed to resistant bacteria even before exposure to antibiotics, and are more at risk of infection, and of the serious consequences from infection. Securing child development requires control of infectious diseases in treatment sensitive and resistant forms. There is an unequal distribution of childhood burdens and benefits associated with antibiotics and antibiotic resistance both within and between coun- tries. These inequalities contribute to avoidable suffering (preventable infectious disease), differences in status (growth stunting), and potentially domination of vul- nerable children by others. Inequalities subvert the achievement of capability thresholds.\n\n14.10", "n_tokens": 181, "kind": "text"}
{"chunk_id": "drug_resistance_book-244-2", "doc_id": "drug_resistance_book", "page": 244, "text": "Addressing Inequalities, Achieving Capability Thresholds\n\nControl of antibiotic resistance is a cooperative enterprise with shared objectives and shared responsibilities. Countries cooperate in the control of infectious disease including antibiotic-resistant agents of infection. If we accept that all of the parties engaged in the control of antibiotic resistance should have an equal prima facie claim to access to effective antibiotics then when inequalities exist we can ask if\n\n235", "n_tokens": 84, "kind": "text"}
{"chunk_id": "drug_resistance_book-245-0", "doc_id": "drug_resistance_book", "page": 245, "text": "236\n\nM. Millar\n\nthose inequalities can be justified – ‘basic structures need to be justified to all who are asked to accept them’ (Scanlon lecture – Why Does Inequality Matter?) (see Note 3).", "n_tokens": 47, "kind": "text"}
{"chunk_id": "drug_resistance_book-245-1", "doc_id": "drug_resistance_book", "page": 245, "text": "Developed countries have used antibiotics for much longer and in much larger quantities and for a wider range of reasons than most developing nations. India is subject to criticism for insufficient regulation of antibiotic prescribing. Yet, even by 2010, India used half the number of antibiotic units per person compared with the USA (Laxminarayan and Chaudhury 2016). Historically while new antibiotics were regularly coming to the market there was no commercial motivation to constrain antibiotic use because antibiotic resistance was a major justification for using the new antibiotic(s). The profits from antibiotic sales were largely accrued by compa- nies based in the developed world. Marketing decisions were dominated by consid- eration of profit maximisation with a relatively low priority given to public health. The United Nations has accepted that developed nations should take up a greater part of the responsibility for the control of greenhouse gases than developing coun- tries. ‘Common but Differentiated Responsibilities’ (UNFCCC 2015) are justified because there are differences in capacity to respond, different priorities, and differ- ences in the historical contribution to the problem of greenhouse gas emissions between developed and developing countries. These differences also apply to anti- biotic resistance.", "n_tokens": 251, "kind": "text"}
{"chunk_id": "drug_resistance_book-245-2", "doc_id": "drug_resistance_book", "page": 245, "text": "In the World Health Assembly Global Action Plan for Antimicrobial Resistance (2015) Section 21. (3) Access states that ‘The aim to preserve the ability to treat serious infections requires both equitable access to, and appropriate use of, existing and new antimicrobial medicines’. Currently despite the high level of international concern there is no international agreement as to what constitutes ‘appropriate’ use of antibiotics. Equitable access is a long way away when account is taken of the lack of access to antibiotics for the treatment of life-threatening infection in many parts of the world while antibiotics are used extensively without human health benefit in many other parts of the world. I have previously argued that appropriate use is that which prevents some substantial risk of irretrievable harm in patients or their con- tacts, where a substantial risk is a level of risk which exceeds the range of risks of irretrievable harm that we tolerate in our day to day lives (Millar 2012). Use of antibiotics to support (non-human) animal growth promotion is inappropriate use. Use of antibiotics for animal growth promotion has been reported to be increasing in both developed and developing countries (Van Boeckel et al. 2015), including in areas where human growth stunting is particularly prevalent such as Sub-Saharan Africa. In developing countries people are more likely to live in close proximity to animals, so that the risks that antibiotic resistant bacteria will spread", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-245-3", "doc_id": "drug_resistance_book", "page": 245, "text": "from animals, and that people will be exposed to antibiotics present in their environment, is increased compared with developed countries where the close proximity of farm animals with people is less common. It is strikingly inappropriate for many children to have limited access to antibiotics while antibiotics are being used as animal growth promoters. Developed countries should take a lead in limiting use of antibi- otics as animal growth promoters.", "n_tokens": 79, "kind": "text"}
{"chunk_id": "drug_resistance_book-246-0", "doc_id": "drug_resistance_book", "page": 246, "text": "14 A Capability Perspective on Antibiotic Resistance, Inequality, and Child…\n\nThe UN has given a substantial place to human dignity in the Sustainable Development Goals (UN 2014). These goals include improvements in education, housing, nutrition, water quality, and sanitation. The scope for international action on antibiotic resistance includes the amelioration of the conditions that potentiate the need for antibiotics and the spread of resistant forms of agents of infection. Improving living conditions (including housing), nutrition, education (for example with respect to risk factors for disease), and other determinants of human dignity such as female empowerment have been shown to reduce the risk of stunting, but these are also important factors in the control of infectious disease transmission and potentially antibiotic resistance. Achieving UN Development Goals (assuming that fairly and honestly set – see Hickel 2017) for 2030 would do much to mitigate the risk factors for both stunting and the transmission of agents of infection in both antibiotic sensitive and resistant forms.\n\n14.11", "n_tokens": 204, "kind": "text"}
{"chunk_id": "drug_resistance_book-246-1", "doc_id": "drug_resistance_book", "page": 246, "text": "Conclusions\n\nNussbaum’s capability theory (Nussbaum 2006) provides a rich and relevant evalu- ative space for framing antibiotic resistance. Securing child development and adult capabilities requires that we address inequalities in access, regulate ‘appropriate prescribing’, and clarify responsibilities for addressing inequalities in risk factors for the dissemination and transmission of antibiotic resistance. Historical and cur- rent patterns of antibiotic use impose a burden of responsibility on developed coun- tries to ensure that their own use is appropriate, and raise questions with respect to the responsibilities of developed countries to address risk factors for antibiotic resis- tant infection in developing countries. Antibiotics and antibiotic resistant bacteria pollute the environment (particularly when sanitation standards are poor) – com- pounding the inequality and disadvantage of those without equivalent access to effective antibiotics. Inequality undermines the cooperative activity that is control of infectious diseases and compounds the threat to the securing of child develop- ment and adult capabilities that comes from antibiotic resistance.\n\nNote 1 There is some empirical evidence that European countries with more income inequality have higher levels of antibiotic resistance than those with less inequality (Kirby and Herbert 2013). Lack of access to high quality data makes this relation- ship difficult to study more generally.", "n_tokens": 259, "kind": "text"}
{"chunk_id": "drug_resistance_book-246-2", "doc_id": "drug_resistance_book", "page": 246, "text": "Note 2 For Scanlon, reasons are facts (Scanlon 2014, p. 30, note 20), natural (e.g., that you will enjoy some activity) or normative (e.g., a law’s being unjust or your having reason to go on living; Scanlon 2014, p. 32). These facts are an essential part of a relation to an agent: consideration (or fact) p is a reason for x to do a in circum- stances c. ‘Is a reason for’ is a four-place relation, R(p, x, c, a) (pp. 31, 37). For Scanlon there are cases where the relative strength of reasons is derived from the\n\n237", "n_tokens": 154, "kind": "text"}
{"chunk_id": "drug_resistance_book-247-0", "doc_id": "drug_resistance_book", "page": 247, "text": "238\n\nM. Millar\n\nrelative amounts of something (such as capabilities), even so he considers it to be a mistake to consider that there must inevitably be a quantitative property which determines the relative strength of reasons (p. 110). ‘The strength of a reason is an essentially comparative notion, understood only in relation to other particular rea- sons’ (p. 111). When we judge that certain considerations provide conclusive rea- sons for (or against) certain actions in certain circumstances, justification comes our understanding of a relationship with other rational beings that we have reason to want, specifically, the relationship of seeing them as beings to whom justification is owed (p. 115). Scanlon acknowledges that ‘when we are assessing the justifiability of moral principles we must have reason to appeal to things that individuals have reason to want, and that many of these are things that contribute to well-being intui- tively understood.’ However, ‘we cannot delimit the range of considerations that figure in justification by defining the boundaries of well-being’ (Scanlon 1998, p. 140; see Putnam 2008).", "n_tokens": 232, "kind": "text"}
{"chunk_id": "drug_resistance_book-247-1", "doc_id": "drug_resistance_book", "page": 247, "text": "Note 3 Scanlon emphasises the importance of probabilities in determining the degree of effort that we make to control risks. ‘The probability that a form of conduct will cause harm can be relevant not as a factor diminishing the ‘complaint’ of the affected parties (discounting the harm by the likelihood of their suffering it) but rather as an indicator of the care that the agent has to take to avoid causing harm’. Scanlon states that ‘..the cost of avoiding all behaviour that involves risk of harm would be unac- ceptable. Our idea of ‘reasonable precautions’ defines the level of care that we think can be demanded: a principle that demanded more than this would be too confining, and could reasonably be rejected on that ground’ (Scanlon 1998, p. 209 & pp. 235–6; see Kumar 2016). Scanlon’s emphasis on reasons allows the inclusion of morally salient considerations such as responsibility and fairness (Scanlon 1998, p. 243). ‘Responsibility of an agent for wrongful conduct, responsibility for creating a situ- ation that gives reason to break a promise, responsibility for engaging in risky con- duct that leads to harm and responsibility for misfortune that puts one in need of aid’ (Scanlon 1998, p. 244) are all morally salient considerations. The question that arises is ‘who has responsibility for ‘reasonable precautions’ when it comes to anti- biotic resistance in developing countries’, and what is reasonable?", "n_tokens": 307, "kind": "text"}
{"chunk_id": "drug_resistance_book-247-2", "doc_id": "drug_resistance_book", "page": 247, "text": "Acknowledgement I’d like to thank Dr. Andrew Prendergast for raising the issue of growth stunt- ing and the interaction with infectious disease.\n\nReferences\n\nAhammad, Z.S., T.R. Sreekrishnan, C.L. Hands, C.W. Knapp, and D.W. Graham. 2014. Increased waterborne blaNDM-1 resistance gene abundances associated with seasonal human pilgrim- ages to the upper Ganges river. Environmental Science & Technology 48 (5): 3014–3020. https://doi.org/10.1021/es405348h.\n\nAshcroft, R.E. 2005. Making sense of dignity. Journal of Medical Ethics 31: 679–682.", "n_tokens": 157, "kind": "text"}
{"chunk_id": "drug_resistance_book-248-0", "doc_id": "drug_resistance_book", "page": 248, "text": "14 A Capability Perspective on Antibiotic Resistance, Inequality, and Child…\n\nBerendonk, T.U., C.M. Manaia, C. Merlin, D. Fatta-Kassinos, E. Cytryn, F. Walsh, H. Bürgmann, H. Sørum, M. Norström, M.N. Pons, N. Kreuzinger, P. Huovinen, S. Stefani, T. Schwartz, V. Kisand, F. Baquero, and J.L. Martinez. 2015. Tackling antibiotic resistance: The environ- mental framework. Nature Reviews. Microbiology 13 (5): 310–317. https://doi.org/10.1038/ nrmicro3439.\n\nBerrazeg, M., S.M. Diene, L. Medjahed, P. Parola, M. Drissi, D. Raoult, and J.M. Rolain. 2014. New Delhi metallo-beta-lactamase around the world: An eReview using Google Maps. Eurosurveillance 19 (20): pii=20809.\n\nBiggeri, M., and S. Mehrotra. 2011. Child poverty as capability deprivation: How to choose domains of child well-being and poverty. In Children and the capability approach, ed. M. Biggeri, J. Ballet, and F. Comim. Basingstoke: Palgrave Macmillan.\n\nBiggeri, M., J. Ballet, and F. Comim, eds. 2011. Children and the capability approach. Basingstoke:\n\nPalgrave Macmillan.\n\nBlack, R.E., C. Levin, N. Walker, D. Chou, M. Temmerman, and for the DCP3 RMNCH Authors Group. 2016. Reproductive, maternal, newborn, and child health: Key messages from disease control priorities 3rd edition. Lancet 388: 2811–2824.\n\nByrnes, J.P., D.C. Miller, and W.D. Schafer. 1999. Gender differences in risk taking: A meta-", "n_tokens": 460, "kind": "text"}
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{"chunk_id": "drug_resistance_book-251-0", "doc_id": "drug_resistance_book", "page": 251, "text": "242\n\nM. Millar\n\n———. 2013. Pneumonia still responsible for one fifth of child deaths. http://www.who.int/media-\n\ncentre/news/releases/2013/world-pneumonia-day-20131112/en/. Accessed May 2017.\n\n———. 2014. Antimicrobial resistance: global report on surveillance. Geneva: World Health\n\nOrganisation.\n\n———. 2015. Global action plan on antimicrobial resistance. Geneva: World Health Organisation. World health Organisation. Factsheet 392. Available at http://www.who.int/mediacentre/fact-\n\nsheets/fs392/en/. Accessed May 2017.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 310, "kind": "text"}
{"chunk_id": "drug_resistance_book-252-0", "doc_id": "drug_resistance_book", "page": 252, "text": "Chapter 15 Fairness in the Use of Information About Carriers of Resistant Infections\n\nJohn G. Francis and Leslie P. Francis\n\nAbstract One standard menu of approaches to the prevalence of anti-microbial resistance diseases is to enhance surveillance, fund research to develop new antimi- crobials, and educate providers and patients to reduce unnecessary antimicrobial use. The primarily utilitarian reasoning behind this menu is unstable, however, if it fails to take fairness into account. This chapter develops an account of the fair uses of information gained in public health surveillance. We begin by sketching informa- tion needs and gaps in surveillance. We then demonstrate how analysis of informa- tion uses is incomplete if viewed from the perspectives of likely vectors of disease who may be subjects of fear and stigma and likely victims who may be coerced into isolation or quarantine. Next, we consider aspects of fairness in the use of informa- tion in non-ideal circumstances: inclusive participation in decisions about informa- tion use, resource plans for those needing services, and assurances of reciprocal support. Fairness in information use recognizes the ineluctable twinning of victims and vectors in the face of serious pandemic disease.", "n_tokens": 247, "kind": "text"}
{"chunk_id": "drug_resistance_book-252-1", "doc_id": "drug_resistance_book", "page": 252, "text": "Keywords Fairness · Data use · Privacy · Surveillance\n\nAs many chapters in this volume emphasize, the prevalence of anti-microbial resis- tant diseases and the comparative paucity of available treatments presents a public health crisis. One standard menu of approaches to this crisis is to enhance surveil- lance to gain information needed to identify potential disease vectors and to ascer- tain likely modes of transmission; to fund research to develop new treatments and\n\nJ. G. Francis Department of Political Science, University of Utah, Salt Lake City, USA e-mail: john.francis@utah.edu\n\nL. P. Francis (*) College of Law & Department of Philosophy, University of Utah, Salt Lake City, USA e-mail: francisl@law.utah.edu\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_15\n\n243", "n_tokens": 229, "kind": "text"}
{"chunk_id": "drug_resistance_book-253-0", "doc_id": "drug_resistance_book", "page": 253, "text": "244\n\nJ. G. Francis and L. P. Francis\n\nantimicrobials; and to intervene through education, treatment, and careful steward- ship of the existing antimicrobials that retain some efficacy. This combination of approaches is founded primarily in utilitarian reasoning, attempting to achieve the best possible mitigation of the current crisis in the hopes that effective new treat- ment methods may soon become available.", "n_tokens": 86, "kind": "text"}
{"chunk_id": "drug_resistance_book-253-1", "doc_id": "drug_resistance_book", "page": 253, "text": "Such utilitarian reasoning is not entirely stable in practice, however. On the one hand, when the prospects of exposure to untreatable and potentially fatal disease appear imminent, fear may become the overriding reaction to those who are identi- fied as ill. The result may be forms of coercion against people suspected of being vectors of disease that appear prudential in the short term but that are insufficiently grounded in science and potentially counter-productive in the longer term. People may hide to avoid disclosure and deleterious consequences of over-regulation may lead to under-regulation. Recent examples include demands to compel isolation of people believed to have been exposed to Ebola or for banning travel from regions where outbreaks of conditions such as Ebola or Zika have been identified. On the other hand, concerns for victims may generate outpourings of resources for treat- ment, calls for investment in public health resources in underserved areas, and renewed emphasis on privacy protections. These too may be counterproductive if they result in confusion and waste of resources or multiple conflicting strategies. The upshot may be policies that oscillate between treating people as vectors and treating them as victims but without significant or coordinated progress against the problem of resistance.", "n_tokens": 256, "kind": "text"}
{"chunk_id": "drug_resistance_book-253-2", "doc_id": "drug_resistance_book", "page": 253, "text": "Each of these perspectives—victim-hood and vector-hood—is morally impor- tant. But in our judgment analysis that is limited to these perspectives is incomplete in its failure to take certain considerations of fairness into account. Our specific focus here is the use of information, but similar points could be made about other types of resources as well. Collection, uses, and access to information, we contend in what follows, must be rooted in the effort to make progress against serious public health problems in a manner that is reasonably fair under the circumstances. This requires not only concern for people as victims and vectors but concerns about how the impact of policies are distributed and foster cooperative connections in both the shorter and the longer term.\n\n15.1\n\nThe Important Roles of Information\n\nTraditional public health surveillance methods are both individual and population based. Where particular individuals are concerned, the role of information is pri- marily to enable strategies to interrupt disease transmission. Case identification, case reporting, contact tracing, treatment if possible, and education and intervention if needed to prevent transmission come to the fore. At every stage, information is critical. If individuals with transmissible disease are unknown or cannot be located, efforts to interrupt transmission will fail. Efforts will also fail if information is not transmitted to those who are capable of acting, whether they be authorities", "n_tokens": 263, "kind": "text"}
{"chunk_id": "drug_resistance_book-254-0", "doc_id": "drug_resistance_book", "page": 254, "text": "15 Fairness in the Use of Information About Carriers of Resistant Infections\n\ndesignated to enforce quarantine or isolation or health care personnel equipped to offer treatment or prophylaxis. Education requires information, too, about where to direct educational efforts and what these efforts might contain. Importantly, if peo- ple who might suffer exposures are insufficiently informed about the likelihood and seriousness of contagion and the need for precautions, they may unwittingly become infected vectors as well as victims themselves. Such was the case for health care workers during the SARS epidemic of 2003 and for many during the Ebola epi- demic of 2014.\n\nInformation gleaned in population-level surveillance plays many additional important roles in addressing the problem of anti-microbial resistance. A longstand- ing recommendation of the WHO, codified in the World Health Regulations that entered into force in 2007 in article 44, is international cooperation in the develop- ment of surveillance capacities for the identification of potential global health emer- gencies of international concern (WHO 2005). Surveillance can help to identify rates of incidence and prevalence of resistant disease. Testing samples can yield information about histories and patterns of disease spread. Samples also can be used to identify biological characteristics of resistant infectious agents that may be help- ful in developing methods of treatment or identifying new anti-microbial agents.", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-254-1", "doc_id": "drug_resistance_book", "page": 254, "text": "Population level surveillance can be targeted to identifying the incidence and prevalence of resistant disease in particular geographical areas. Gonorrhea is an example. There were 78.3 million estimated new cases of gonorrhea worldwide in 2012; the highest number occurred in low-income areas of the western Pacific. Resistant disease has become increasingly prevalent, especially in these areas and among groups such as sex workers and truck drivers (Unemo et al. 2017). Extensively drug-resistant (XDR) gonorrhea cases also have appeared in Spain and in France, although these strains do not appear to have spread, possibly because they are less hardy and so less likely to be passed on. However, significant resistance may not be detected because of “suboptimal antimicrobial resistance surveillance in many set- tings” (Unemo et al. 2017). A recent international panel reviewing resistant gonor- rhea recommends strategies of case management, partner notification, screening (especially of sex workers and men having sex with men), and evidence-based treat- ment (Unemo et al. 2017); these recommendations are based on surveillance data.", "n_tokens": 232, "kind": "text"}
{"chunk_id": "drug_resistance_book-254-2", "doc_id": "drug_resistance_book", "page": 254, "text": "Population-level surveillance information may also be useful in identifying risks associated with providing humanitarian treatment. Over 30,000 young people wounded in the Libyan civil war that began in 2011 were evacuated elsewhere for treatment. Concerns arose that many of these patients were recognized to carry with them resistant organisms—thus bringing along with their needs for treatment risks to other patients being treated in the host facilities (Zorgani and Ziglam 2013). Institutions accepting these patients were informed of this risk so that they could take appropriate precautions. Libya itself was identified as a region with high preva- lence of resistant organisms, despite the limited surveillance capacities in that conflict- torn nation. Recommendations included improving surveillance in Libya— which lacks a national surveillance system—and implementation of infection pre- vention measures in Libyan hospitals.\n\n245", "n_tokens": 160, "kind": "text"}
{"chunk_id": "drug_resistance_book-255-0", "doc_id": "drug_resistance_book", "page": 255, "text": "246\n\nJ. G. Francis and L. P. Francis\n\nSurveillance is also used to identify practices that might contribute to the devel- opment of resistance. Use of antimicrobials in agriculture is one area of inquiry, although its precise contribution to the problem is not easy to quantify (e.g. Hoelzer et al. 2017). There have been many studies of problematic prescribing practices among physicians in the US (Wigton et al. 2008), Europe (e.g. Jørgensen et al. 2013), Asia (Lam and Lam 2003), and elsewhere (Trap and Hansen 2002), along with efforts to educate physicians about appropriate antimicrobial use.", "n_tokens": 147, "kind": "text"}
{"chunk_id": "drug_resistance_book-255-1", "doc_id": "drug_resistance_book", "page": 255, "text": "Ever since the recognition grew that crowds celebrating the return of soldiers from World War I had created a ready opportunity for transmission of the Spanish influenza, epidemiologists have observed the potential health risks of large gather- ings that concentrate people together, even for brief periods of time. Examples include music festivals, major sporting competitions, other large festivals, and reli- gious gatherings such as the Hajj or other pilgrimages. The largest estimated gather- ing is the periodic Kumbh Mela pilgrimage in which Hindus come together to bathe in a sacred river such as the Ganges; over 40 million people, drawn largely from the Indian subcontinent but increasingly international, attend the event (Gautret and Steffen 2016). The largest annual gathering of pilgrims is the Hajj at Mecca which draws over two million people; the Fifth Pillar of Islam is the obligation to under- take the once in a lifetime journey for those who can physically or financially afford to do so. With such great numbers of people together for sustained periods of time, there is a risk of disease outbreaks and the spread of resistant infections. Such events may strain existing sanitation systems or health care facilities if people become ill. Crowding and inadequate facilities contribute to the potential for disease outbreaks (Gautret and Steffen 2016). These events draw people from around the globe and thus may result in the international spread of disease (Gautret and Steffen", "n_tokens": 290, "kind": "text"}
{"chunk_id": "drug_resistance_book-255-2", "doc_id": "drug_resistance_book", "page": 255, "text": "2016).", "n_tokens": 3, "kind": "text"}
{"chunk_id": "drug_resistance_book-255-3", "doc_id": "drug_resistance_book", "page": 255, "text": "At the same time, many of these events are of great cultural importance and sup- pression of them is neither a realistic nor a desirable option. There have been exten- sive discussions of how to address the public health needs of the great numbers of people who undertake pilgrimages or who attend other events that draw great num- bers of people together. Vaccination may create herd immunities that reduce risks of disease transmission; for example, for this year’s Hajj the Saudi Arabian govern- ment is requiring proof of a quadrivalent Meningococcal vaccination in order to receive a visa (Ministry of Hajj 2017). Nonetheless, risks may remain significant for conditions that cannot currently be addressed by vaccination or that are difficult to treat, such as Middle East respiratory syndrome coronavirus (MERS-CoV) or resis- tant infections. Information too is critical: such well-attended events require imagi- native and thoughtful surveillance that informs short-term medical care. Because Saudi Arabia has had the largest number of human cases of MERS-CoV—an esti- mated 80% (WHO 2017b)—travelers for this year’s Hajj are being warned to take extra precautions with respect to sanitation and personal hygiene measures such as handwashing or avoiding direct contact with non-human animals (New Zealand Ministry of Foreign Affairs 2017).", "n_tokens": 292, "kind": "text"}
{"chunk_id": "drug_resistance_book-255-4", "doc_id": "drug_resistance_book", "page": 255, "text": "Still other social factors may contribute to the development of resistant disease that can be identified through surveillance. Given the difficulties for women in Saudi Arabia to see physicians without being escorted, it is understandable that in", "n_tokens": 40, "kind": "text"}
{"chunk_id": "drug_resistance_book-256-0", "doc_id": "drug_resistance_book", "page": 256, "text": "15 Fairness in the Use of Information About Carriers of Resistant Infections\n\nSaudi Arabia many community pharmacies will dispense antibiotics without a pre- scription. Zowasi (2016) recommends addressing these issues by increased educa- tion especially through social media as to the best approach to respond to the risk of anti-microbial resistant organism.", "n_tokens": 70, "kind": "text"}
{"chunk_id": "drug_resistance_book-256-1", "doc_id": "drug_resistance_book", "page": 256, "text": "Still other recommendations about information use involve research on the development of new forms of antimicrobials. According to the most recent review article (Butler et al. 2017), antibiotics “are dramatically undervalued by society, receiving a fraction of the yearly revenue per patient generated by next-generation anticancer drugs.” They are in the judgment of these authors an “endangered spe- cies,”—but there is some faint encouraging news. WHO and a number of national governments have recently begun to direct attention to the potential threat of resis- tance and lack of new drugs. Since 2000, five new-in-class antibiotics have been marketed, but these unfortunately only target gram-positive organisms not the gram-negative organisms that are likely to be resistant. Other compounds are also in various stages of the process of clinical trials, but these too are more likely to be active against gram-positive bacteria. In the judgment of the authors of this review article, “the acute positive trend of new approvals masks a chronic underlying mal- aise in antibiotic discovery and development.” Interest in antibiotic development is more likely to be present in smaller biotech companies and in biotech companies located in Europe. The authors conclude: “The only light on the horizon is the con- tinued increase in public and political awareness of the issue.” They also observe that with the retrenchment in investment, “we potentially face a generational knowl- edge gap” and", "n_tokens": 305, "kind": "text"}
{"chunk_id": "drug_resistance_book-256-2", "doc_id": "drug_resistance_book", "page": 256, "text": "drug development “is now more important than ever.”", "n_tokens": 11, "kind": "text"}
{"chunk_id": "drug_resistance_book-256-3", "doc_id": "drug_resistance_book", "page": 256, "text": "To address this perilous juncture in antimicrobial research, the Pew Charitable Trust convened a scientific expert group in 2016. The premise of the group was that regulatory challenges, scientific barriers, and diminishing economic returns have led drug companies largely to abandon antibiotic research—yet antimicrobial resis- tance is accelerating. No entirely new classes of antibiotics useful against resistant organisms have been brought to market that are not derivatives of classes developed before 1984—over 30 years ago. The Pew report advances many explanations for this dismal situation, including importantly the lack of coordinated investment in the relevant basic and translational research. One aspect of the report detailed the major role played by information gaps. Published research is out of date and out of print. Moreover, in today’s world of investment in drug discovery, “creating an envi- ronment in which data exchange and knowledge sharing are the status quo will be difficult given proprietary concerns and the variety of information types and for- mats, which may range from historical data to new findings produced as part of this research effort.” The Pew consensus is that the following forms of information shar- ing are needed: a review of what is known about compounds that effectively pene- trate gram-negative bacteria, a searchable catalogue of chemical matter including an ongoing list of promising antibacterial compounds, information on screening assays and", "n_tokens": 283, "kind": "text"}
{"chunk_id": "drug_resistance_book-256-4", "doc_id": "drug_resistance_book", "page": 256, "text": "conditions tested, and an informational database of available biological and physicochemical data. Mechanisms must also be developed for sharing drug discov- ery knowledge in the area (Pew, pp. 19–20).", "n_tokens": 45, "kind": "text"}
{"chunk_id": "drug_resistance_book-256-5", "doc_id": "drug_resistance_book", "page": 256, "text": "247", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-257-0", "doc_id": "drug_resistance_book", "page": 257, "text": "248\n\nJ. G. Francis and L. P. Francis\n\nIn line with Pew, a European antimicrobial resistance project suggests that research is seriously underfunded (Kelly et al. 2015). This group argues that the bulk of the publicly funded research is in therapeutics (63%); among the remainder, 14% of the research was on transmission and only 3% specifically on surveillance. This group also concluded that research is not coordinated and there is little atten- tion to data sharing or sharing of research results. Funding is fragmented, too, with many smaller grants addressing smaller projects independently rather than in a way that builds. This group summarizes: “to conclude, investment at present might not correspond with the burden of antibacterial resistance and the looming health, social, and economic threat it poses on the treatment of infections and on medicine in general. Antibacterial resistance clearly warrants increased and new investment from a range of sources, but improved coordination and collaboration with more informed resource allocation are needed to make a true impact. Hopefully, this anal- ysis will prompt nations to pay due consideration to the existing research landscape when considering future investments.”", "n_tokens": 239, "kind": "text"}
{"chunk_id": "drug_resistance_book-257-1", "doc_id": "drug_resistance_book", "page": 257, "text": "Additional recommendations from other groups include novel methods for man- agement of resistant disease, such as addressing the intestinal microbiome (e.g. Bassetti et al. 2017); these methods, too, may be furthered by surveillance informa- tion as well as information about individual patients.\n\nAnalysis of these uses of information from the perspective of vector or victim\n\nare, we now argue, incomplete.\n\n15.2", "n_tokens": 87, "kind": "text"}
{"chunk_id": "drug_resistance_book-257-2", "doc_id": "drug_resistance_book", "page": 257, "text": "The Vector Perspective\n\nWhen contagious diseases are serious or highly likely to be fatal and treatments for them are limited at best, fear is understandable. Fear may be magnified if the disease is poorly understood, especially until modes of transmission have been identified. Fear may also be magnified if there are no known effective treatments for the dis- ease, as may be the case for extremely drug resistant infections. It is therefore understandable that proposals may come to the fore that emphasize isolation of those who are known to be infected, quarantine of those who have been exposed, or travel bans from areas of known disease outbreaks. Proposals may even include criminalization of those who knowingly or even negligently take risks of infect- ing others.\n\nAll of these possibilities and more were features of the HIV epidemic. Even as understanding of the disease grew and effective treatment became increasingly available, some of these remain. Criminalization of HIV transmission has not waned, despite the many objections raised to it (e.g. Francis and Francis 2013a, b). Although the US ended its immigration ban on HIV+ individuals in 2010, concerns remain about the risks of undiagnosed infections among immigrant populations in the U.S. (Winston and Beckwith 2011) and some countries (for example, Singapore) continue to ban entry for HIV+ travelers planning stays over thirty days (The Global Database 2017).", "n_tokens": 287, "kind": "text"}
{"chunk_id": "drug_resistance_book-258-0", "doc_id": "drug_resistance_book", "page": 258, "text": "15 Fairness in the Use of Information About Carriers of Resistant Infections\n\nAs epidemic fears have waxed and waned over recent decades, so have impera- tives for identifying vectors and constraining their activities. These patterns have been apparent for avian influenza, SARS, Ebola, and Zika, among others. The US still bars entry by non-citizens with a list of conditions including active TB, infec- tious syphilis, gonorrhea, infectious leprosy, and other conditions designated by Presidential Executive order such as plague or hemorrhagic fevers (CDC 2017).", "n_tokens": 127, "kind": "text"}
{"chunk_id": "drug_resistance_book-258-1", "doc_id": "drug_resistance_book", "page": 258, "text": "Indeed, resistant TB has been a frequent illustration of the vector perspective in operation. Multi-drug resistant tuberculosis is transmissible, difficult to treat, and poses a significant public health problem. Its presence can be identified by methods such as testing of sputum samples. When patients are identified with resistant dis- ease, public health authorities may seek to compel treatment or isolation, especially for patients judged unreliable about compliance with treatment. To avoid transmis- sion, public health authorities have proposed isolating patients who have been iden- tified as infected. Because a course of treatment for TB may take many months—and failure to complete the full course may increase the likelihood of resistant disease— isolation may continue for long periods of time. Controversially, during the early 1990s public health officials in New York isolated over 200 patients identified with MDR TB on Roosevelt Island for treatment out of concern that they would be non- compliant with treatment even when they were unlikely to infect others (Coker 2001). Perhaps one of the most highly publicized events involving a single patient was the odyssey of Andrew Speaker, a lawyer believed to have extremely resistant TB who eluded authorities as he took airplane flights around the globe in the effort to return home. Speaker’s journey created an international scare and calls for travel restrictions. Speaker’s lawsuit against the Centers for Disease Control and", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-258-2", "doc_id": "drug_resistance_book", "page": 258, "text": "Prevention alleging violations of the federal Privacy Act, he claimed by revealing more infor- mation than was necessary for public health purposes, was ultimately resolved on summary judgment for the government, largely because the challenged disclosures had been made by Speaker himself. (Speaker v. U.S. Department of Health and Human Services Centers for Disease Control and Prevention, 489 Fed. Appx. 425 (2012); Associated Press 2010) But the saga reveals how individuals perceived as threats may be vilified for what were understandable, if unwise, efforts at self-protection.", "n_tokens": 117, "kind": "text"}
{"chunk_id": "drug_resistance_book-258-3", "doc_id": "drug_resistance_book", "page": 258, "text": "WHO travel guidelines provide that individuals known to be infected with resis- tant TB should not travel until sputum analysis confirms that they are not at risk of disease transmission (WHO 2017). Evidence is limited, however, about the need for this policy. The most recent literature review suggests that risks of transmission dur- ing air travel are very low and that there is need for ongoing international collabora- tion in contact tracing and risk assessment (Kotila et al. 2016). Blanket travel bans encouraging actions that elude detection may reduce, rather than enhance, this needed collaboration. More subtle policies tailored to need would be preferable, but the fears generated by a focus on fear of vectors may make them unlikely to be developed or implemented.\n\nAt best, therefore, the vector perspective is incomplete. Focus on it may be counter- productive, if people hide or try to avoid education. It may encourage expenditures on efforts to identify suspected vectors rather than on evidence based\n\n249", "n_tokens": 199, "kind": "text"}
{"chunk_id": "drug_resistance_book-259-0", "doc_id": "drug_resistance_book", "page": 259, "text": "250\n\nJ. G. Francis and L. P. Francis\n\nefforts to identify risks of transmission and effective modes of prevention. And, of course, it ignores the plight of victims, to which we now turn.\n\n15.3\n\nThe Victim Perspective\n\nPeople with resistant infections are not only vectors, they are also victims of disease and have ethical claims to be treated as such (Battin et al. 2007). Indeed, it is likely that vectors will themselves be victims, unless they are carriers of the disease in a manner that does not affect them symptomatically.\n\nConcern for victims may take the form of seeking to ease the burdens of con- straints such as isolation. A good illustration of the victim perspective in operation is the WHO publication of a pamphlet on “psychological first aid” to those affected by Ebola. The pamphlet is designed to provide comfort to and meet the basic needs of people infected by Ebola and those who are close to them, while maintained the safety of aids workers (WHO 2014). The recommendations rest on the importance of respect for the dignity of those who are suffering amidst disease outbreaks. It also emphasizes the importance of respect for rights such as confidentiality and non- discrimination. The pamphlet is provisional and designed to be updated as knowl- edge of safety measures improves; this provisional nature is a recognition of the importance of ongoing development of information about how victims’ needs can be safely met.", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-259-1", "doc_id": "drug_resistance_book", "page": 259, "text": "Despite the concern for victims, foremost in the pamphlet’s recommendations is safety, both of aid workers and of disease victims, so that no one is further harmed including victims themselves and others close to them. Overall, the pamphlet attempts to counter impulses to come to the aid of victims that may increase trans- mission risks, such as unprotected contact with those who are ill. But unexplored tensions remain in the document’s recommendations. For example: “Respect pri- vacy and keep personal details of the person’s story confidential, if this is appropri- ate” (p. 22). Nowhere does the document discuss when confidentiality is appropriate or what personal details may be revealed and in what ways. Its manifest and impor- tant concern for victims is countered by safety but without discussion of how these goals might be implemented together or reasonably reconciled in practice.", "n_tokens": 182, "kind": "text"}
{"chunk_id": "drug_resistance_book-259-2", "doc_id": "drug_resistance_book", "page": 259, "text": "The WHO’s most recently-adopted strategy for dealing with health emergencies, the Health Emergencies Programme, provides another illustration of concern for victims that may lie in unexplored tension with other values. The Programme urges cooperative methods to meet the immediate health needs of threatened populations through humanitarian assistance while also addressing causes of vulnerability and recovery (WHO 2016). It is a coordinated strategy for emergency response that will move far beyond merely technical help; WHO describes it as a “profound change for WHO, adding operational capabilities to our traditional technical and normative roles” (WHO 2016). It is aimed to provide crisis help, such as to Hurricane Matthew in Haiti or to areas affected by the Zika virus. It requires a major increase in funding devoted to core emergency efforts. Core funding will come from assessed contribu- tions, flexible contributions that the Director-General has discretion to allocate, and", "n_tokens": 181, "kind": "text"}
{"chunk_id": "drug_resistance_book-260-0", "doc_id": "drug_resistance_book", "page": 260, "text": "15 Fairness in the Use of Information About Carriers of Resistant Infections\n\nearmarked voluntary contributions. But it is clearly under-funded; WHO reported a 44% funding gap as of October 2016, just to meet the program’s core capabilities. Moreover, WHO also reported that it has raised less than a third of the funding needed for the WHO Contingency Fund for Emergencies, a fund deployed for the initial 3 months of an emergency before donor funding becomes available (WHO 2016).", "n_tokens": 96, "kind": "text"}
{"chunk_id": "drug_resistance_book-260-1", "doc_id": "drug_resistance_book", "page": 260, "text": "The Health Emergencies Programme reflects reactions to the humanitarian disas- ter of the Ebola epidemic and criticisms of the WHO level of response. The WHO 2016–2017 budget reflects this response as well (WHO 2015). That budget “demon- strates three strategic shifts” (WHO 2015, p. 2). The first is application of the les- sons from Ebola especially the need to strengthen core capacities in preparedness, surveillance and response. The second strategic shift is a focus on universal health coverage, which includes enhancing contributions to maternal and child health, speeding progress towards elimination of malaria, and enhancing work on non- communicable diseases, among other worthy goals. The final strategic shift is towards “emerging threats and priorities”; illustrations of these are “antimicrobial resistance, hepatitis, ageing, and dementia.” These are not an obvious group to char- acterize as “emerging,” to the extent that this suggests a developing threat that has not yet become urgent but that may be expected to become so in the near future. Nor are they an obvious group to link together in the same category. This mixture of budgetary priorities suggests is responsiveness to issues raised through consultation with WHO member states, rather than proactive planning.", "n_tokens": 254, "kind": "text"}
{"chunk_id": "drug_resistance_book-260-2", "doc_id": "drug_resistance_book", "page": 260, "text": "WHO specific efforts directed to resistance can be characterized as primarily coordination. The WHO website devoted to resistance promotes information shar- ing and lists research questions and potential funding agencies (WHO 2017a). WHO expresses no judgment about either funding agencies or which of the nearly 100 listed research questions—ranging from research on resistance in day care cen- ters to the biological price that microorganisms pay for resistance—might be fruit- fully addressed first or how they might be interconnected.\n\nConcern for victims is surely part of a response to a humanitarian emergency. Responsiveness to urgent health needs is an important goal. Including antimicrobial resistance in a list of “emerging” issues is at least recognition of the problem. But the WHO response to Ebola and the WHO budget overall can be characterized as less than fully set into context in a reasoned way.\n\nThus, we contend, neither vector nor victim perspectives are adequate. One risks falling prey to fear while the other risks responses that are well-intentioned but that may be difficult to meet or compete with other values in ways that remain underex- plored. These perspectives are inevitable and important, but they are each incomplete.\n\n15.4", "n_tokens": 240, "kind": "text"}
{"chunk_id": "drug_resistance_book-260-3", "doc_id": "drug_resistance_book", "page": 260, "text": "Fairness in Information Use\n\nIn our judgment, a primary difficulty with both vector and victim perspectives is that neither are set into context or seen as interconnected. This section suggests how fairness considerations may help in focusing attention to the most pressing\n\n251", "n_tokens": 46, "kind": "text"}
{"chunk_id": "drug_resistance_book-261-0", "doc_id": "drug_resistance_book", "page": 261, "text": "252\n\nJ. G. Francis and L. P. Francis\n\nquestions to ask about antimicrobial resistance and the directions for surveillance and information use to take.", "n_tokens": 32, "kind": "text"}
{"chunk_id": "drug_resistance_book-261-1", "doc_id": "drug_resistance_book", "page": 261, "text": "Fairness entered the philosophical lexicon in discussions about justice as proce- dural, most famously in John Rawls’s “Justice as Fairness” (Rawls 1958). As Rawls initially conceptualized his view, it involved a decision procedure for selecting basic principles of justice in which people were unable to gain unfair advantage. As the debates about Rawlsian justice unfolded, a fundamental issue was whether people with radically different capacities and views of the good life could be expected to accept the results of the decision procedure as formulated. Thus critics raised the concern that people with disabilities might be left out of the decision procedure as “non-contributors” to the practice of justice (Nussbaum 2007; Stark 2007). Critics also pressed the argument that people with radically illiberal conceptions of the good would ultimately destabilize the practice of justice in a Rawlsian ideal society (e.g. Williams 2007a, b). Rawls ultimately accepted the point that proceduralism could not yield a universal theory of justice, pulling back his view to the claim that it only represented a vision of justice for a certain kind of liberal society (Rawls 1993). But fairness also entered the debates about justice in a more substantive way, especially in bioethics. Norman Daniels (1985), for example, expanded a Rawlsian approach to consider justice in health care. The British idea of a “fair innings,” in which the opportunities of each to reasonable health over a normal life", "n_tokens": 301, "kind": "text"}
{"chunk_id": "drug_resistance_book-261-2", "doc_id": "drug_resistance_book", "page": 261, "text": "span are prioritized, was raised particularly with respect to the distribution of health care resources to the elderly (Bognar 2015; Farrant 2009; Harris 1985; Williams 2007b). Like the metaphor of a level playing field, the fair innings argument comes from sports (Francis 2017). It reflects the idea of everyone having a chance to participate in a game that at least gives them a reasonable opportunity for success. There are four aspects of such opportunity: who plays and whether the rules are constructed to give each an opportunity to win that is reasonable are two. Also important is the balance among opportunities to succeed, so that there aren’t consistent tilts in one direction or another, as might be characterized by the further metaphor of leveling the playing field. Finally, attention to the interaction between advantages and disad- vantages matters, so that participants are encouraged to continue playing the game rather than dropping out.", "n_tokens": 185, "kind": "text"}
{"chunk_id": "drug_resistance_book-261-3", "doc_id": "drug_resistance_book", "page": 261, "text": "Our invocation of fairness as a concept is rooted in the judgment that antimicro- bial resistance—or other pressing global public health problems, for that matter— exemplify multiple aspects of non-ideal and partial compliance circumstances. Natural circumstances are less than forgiving; new health threats emerge on a regu- lar basis. Antimicrobial resistance is an ongoing natural challenge to effective ther- apy for deadly diseases. Social circumstances are imperfect, too: overcrowding, poor sanitation, straitened resources for public health and health care, and cultural practices that increase potential for disease transmission all play roles in the devel- opment of resistance. Alexander Fleming, the discoverer of penicillin, warned that the development of resistance was likely, but his warning appears not to have been well heard. Finally, efforts to address antimicrobial resistance are riven with non- compliance: over-prescribing by physicians, over-use of antimicrobials in agricul- ture, individual failures to take medications as prescribed, and concealment of disease out of fear of discovery and persecution. Because the conditions that give", "n_tokens": 237, "kind": "text"}
{"chunk_id": "drug_resistance_book-262-0", "doc_id": "drug_resistance_book", "page": 262, "text": "15 Fairness in the Use of Information About Carriers of Resistant Infections\n\nrise to these problems of non-compliance may seem urgent—people seeking anti- microbials are in pain or ill, perhaps gravely; people in hiding from health authori- ties may fear stigmatization or death—they raise in particularly poignant form questions of the extent of obligations under circumstances in which others are not doing what arguably is their fair share (e.g. Stemplowska 2016; Murphy 2000).", "n_tokens": 99, "kind": "text"}
{"chunk_id": "drug_resistance_book-262-1", "doc_id": "drug_resistance_book", "page": 262, "text": "Fairness as an ethical concept is especially suited to such imperfect circum- stances. It directs attention to how improvements are distributed. Distributions can be more or less fair, if they distribute benefits and burdens in an increasingly inclu- sive manner (e.g. Francis and Francis 2013a, b). Fairness thus construed is at the heart of perhaps the most influential set of recommendations for ethical pandemic planning, the Canadian Stand on Guard for Thee (Toronto Joint Centre 2005). Although much of the discussion of fairness in this document emphasizes inclusive procedures, so that engagement may lead to acceptance of choices as fairly made (e.g., p. 1), the recommendations also contain substantive dimensions. These include fair resource plans for those who fall ill providing necessary services during a pan- demic (p. 11) and assurance that people who are affected by choices are reciprocally supported in a way that they do not suffer “unfair economic penalties” (p. 13). Here, the links between fairness and reciprocity are explicit.", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-262-2", "doc_id": "drug_resistance_book", "page": 262, "text": "These four aspects of fairness—who is included in the play, what opportunities they have, how these opportunities are balanced, and whether there are elements of reciprocity—can be used to set vector and victim perspectives into context in addressing the gathering and use of information about antimicrobial resistance. Over-emphasizing vectors threatens their opportunities and even possible participa- tion. Overemphasizing victims tilts the field unidirectionally, understandably direct- ing resources to immediate need but without consideration of longer-term consequences. Reciprocity may be the most important of all, creating commitment to workable strategies for addressing resistance when there are difficult choices to be made.", "n_tokens": 140, "kind": "text"}
{"chunk_id": "drug_resistance_book-262-3", "doc_id": "drug_resistance_book", "page": 262, "text": "Fear, understood as a threat personal health, is often an ally in persuading people to seek preventive care and to change life styles, or to persuade policy makers to create incentives or penalties for decisions that contribute to poor health. But great fear can also lead to immobility. The real threat posed by the rise of antimicrobial resistance does not seem to be easily addressed by a successful alternative in the view of victims or policy makers. Medical personnel are fearful of not responding to the demands of patients for immediate reductions in pain or suffering at relatively low costs. The scale of the threat posed by rapid rise of antimicrobial resistance may be daunting to policy makers especially as funders of research. The cost of develop- ing ever-new generations of antibiotics seems to suggest a great series of short-term solutions especially as pharmaceutical companies respond to incentives to generate near-term profits. In this context, it is worth recalling how the development of the first antimicrobials contributed to more generally shared benefits: when penicillin became known to people as a wonderful drug it actually helped to speed the adop- tion of the National Health Service in Britain. The popular expectation was health care for all facilitated with the rise of a new generation of low cost wonder drugs and reinforced by low cost vaccinations (Webster 2002). But some of the advan- tages were short-lived, as the costs of pharmaceuticals grew", "n_tokens": 294, "kind": "text"}
{"chunk_id": "drug_resistance_book-262-4", "doc_id": "drug_resistance_book", "page": 262, "text": "exponentially and", "n_tokens": 3, "kind": "text"}
{"chunk_id": "drug_resistance_book-262-5", "doc_id": "drug_resistance_book", "page": 262, "text": "253", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-263-0", "doc_id": "drug_resistance_book", "page": 263, "text": "254\n\nJ. G. Francis and L. P. Francis\n\ninadequate attention was paid to the risks of overprescribing—once again a caution- ary reminder of the importance of emphasizing balance rather than one particular perspective such as victimhood. If a promise of sustaining production at lower costs of ever-new generations of antimicrobials from how information is used can offer benefits more widely, then it becomes easier to impose tougher regulations on anti- microbial use that may to some extent stave off the development of resistance.", "n_tokens": 109, "kind": "text"}
{"chunk_id": "drug_resistance_book-263-1", "doc_id": "drug_resistance_book", "page": 263, "text": "This approach in terms of fairness directs attention not only to vectors and to victims seen as separate entities. It also directs attention to how they are often, and unpredictably, twinned—given the epidemiology of resistance spread, it is likely to begin within interlaced communities where vectors are also victims. But it also directs our attention to these issues set in distributive context, raising questions such as these: Who is most likely to be affected by resistance? Who will suffer the most severe consequences from resistance? Who is most likely to be disadvantaged by information gained to counter resistance? Who will suffer the most severe disadvan- tage? Who will benefit from efforts to counter resistance? How can these benefits be spread more inclusively? And, how are the benefits and burdens of addressing resis- tance intertwined? Are some primarily beneficiaries, while others are primarily bur- dened? Are there ways to increase reciprocal linkages in these benefits and burdens, so that efforts to counter resistance are accepted and supported more widely? These are the kinds of questions that need to guide how surveillance is deployed in the effort to counter resistance, not vague generalities about the importance of address- ing health infrastructure or bromides about the need to increase resources.", "n_tokens": 265, "kind": "text"}
{"chunk_id": "drug_resistance_book-263-2", "doc_id": "drug_resistance_book", "page": 263, "text": "References\n\nAssociated Press. 2010. Georgia: Suit against disease centers is revived. The New York Times (Oct. 22) [online]. http://www.nytimes.com/2010/10/23/us/23brfs-SUITAGAINSTD_BRF.html. Bassetti, Matteo, Garyphallia Poulakou, Etienne Ruppe, Emilio Bouza, Sebastian J. Van Hal, and Adrian Brink. 2017. Antimicrobial resistance in the next 30 years, humankind, bugs and drugs: A visionary approach. Intensive Care Medicine, epub https://link.springer.com/article/10.100 7%2Fs00134-017-4878-x.\n\nBattin, Margaret P., Leslie P. Francis, Jay A. Jacobson, and Charles B. Smith. 2007. The patient as\n\nvictim and vector: Ethics and infectious disease. New York: Oxford University Press.\n\nBognar, Greg. 2015. Fair innings. Bioethics 29 (4): 251–261. Butler, Mark S., Mark A.T. Blaskovich, and Matthew A. Cooper. 2017. Antibiotics in the clinical\n\npipeline at the end of 2015. The Journal of Antibiotics 70: 3024.\n\nCenters for Disease Control and Prevention. 2017. Immigrant and refugee health. https://www.cdc.\n\ngov/immigrantrefugeehealth/laws-regs/hiv-ban-removal/final-rule-general-qa.html.\n\nCoker, Richard. 2001. Just coercion? Detention of nonadherent tuberculosis patients. Annals of the", "n_tokens": 344, "kind": "text"}
{"chunk_id": "drug_resistance_book-263-3", "doc_id": "drug_resistance_book", "page": 263, "text": "New York Academy of Sciences 953b: 216–223.\n\nDaniels, Norman. 1985. Just health care. 1st ed. New York: Cambridge University Press. Farrant, Anthony. 2009. The fair innings argument and increasing life spans. British Medical\n\nJournal 35: 53–56.\n\nFrancis, Leslie P. 2017. Promoting equality in and through the paralympics. In Philosophy: Sport. Macmillan interdisciplinary handbooks, ed. R. Scott Kretchmar, 245–262. Farmington Hills: Macmillan Reference USA.", "n_tokens": 105, "kind": "text"}
{"chunk_id": "drug_resistance_book-264-0", "doc_id": "drug_resistance_book", "page": 264, "text": "15 Fairness in the Use of Information About Carriers of Resistant Infections\n\nFrancis, Leslie P., and John G. Francis. 2013a. HIV treatment as prevention: Not an argument for continuing criminalization of HIV transmission. International Journal of Law in Context 9 (4): 520–534.\n\n———. 2013b. Informatics and public health surveillance. In Bioinformatics law: Legal issues for computational biology in the post-genome era, ed. Jorge Contreras and James Cuticcia. Cleveland: American Bar Association.\n\nGautret, Philippe, and Robert Steffen. 2016. Communicable diseases as health risks at mass gath- erings other than Hajj: What is the evidence? International Journal of Infectious Diseases 47: 46–52.\n\nHarris, John. 1985. The value of life. London: Routledge & Kegal Paul. Hoelzer, Karin, Nora Wong, Joe Thomas, Kathy Talkington, Elizabeth Jungman, and Allan Coukell. 2017. Antimicrobial drug use in food-producing animals and associated human health risks: What, and how strong, is the evidence? BMC Veterinary Research 13: 211. https://doi. org/10.1186/s12917-017-1131-3.\n\nJørgensen, Lars Christian, Sarah Friis Christensen, Gloria Cordoba Currea, Carl Llor, and Lars Bjerrum. 2013. Antibiotic prescribing in patients with acute rhinosinusitis is not in agree- ment with European recommendations. Scandinavian Journal of Primary Health Care 31 (2): 101–105.", "n_tokens": 340, "kind": "text"}
{"chunk_id": "drug_resistance_book-264-1", "doc_id": "drug_resistance_book", "page": 264, "text": "Kelly, Ruth, Ghada Zoubiane, Desmond Walsh, Rebecca Ward, and Herman Goossens. 2015. Public funding for research on antibacterial resistance in the JPIAMR countries, the European Commission, and related European Union agencies: A systematic observational analysis. The Lancet Infectious Diseases 16 (4): 431–440.\n\nKotila, S.M., L. Payne Hallström, N. Jansen, P. Helbling, and I. Abubakar. 2016. Review: Systematic review on tuberculosis transmission on aircraft and update of the European Centre for Disease Prevention and Control risk assessment guidelines for tuberculosis transmitted on aircraft (RAGIDA-TB). Eurosurveillance 21 (4): 30114. http://www.eurosurveillance.org/ ViewArticle.aspx?ArticleId=21357#aff1.\n\nLam, T.P., and K.F. Lam. 2003. What are the non-biomedical reasons which make family doctors over-prescribe antibiotics for upper respiratory tract infection in a mixed private/public Asian setting? Journal of Clinical Pharmacy and Therapeutics 28 (3): 197–201.\n\nMinistry of Hajj, Kingdom of Saudi Arabia. 2017. Saudi Ministry of Health Requirements and\n\nHealth Matters. http://www.hajinformation.com/main/t20.htm.\n\nMurphy, Liam B. 2000. Moral demands in nonideal theory. Oxford: Oxford University Press. New Zealand Ministry of Foreign Affairs. 2017. Hajj pilgrimage. Live News (Aug. 14) [online].\n\nhttps://livenews.co.nz/2017/08/14/hajj-pilgrimage/.\n\nNussbaum, Martha C. 2007. Frontiers of justice: Disability, nationality, species membership.", "n_tokens": 384, "kind": "text"}
{"chunk_id": "drug_resistance_book-264-2", "doc_id": "drug_resistance_book", "page": 264, "text": "Cambridge, MA: Harvard University Press.\n\nRawls, John. 1958. Justice as fairness. The Philosophical Review 67 (2): 164–194. ———. 1993. Political liberalism. New York: Columbia University Press. Stark, Cynthia A. 2007. How to include the severely disabled in the contractarian theory of justice.\n\nJournal of Political Philosophy 15 (2): 127–145.\n\nStemplowska, Zofia. 2016. Doing more than one’s fair share. Critical Review of International\n\nSocial and Political Philosophy 19 (5): 591–608.\n\nThe Global Database on HIV-Specific Travel & Residence Restrictions. 2017. Regulations on entry, stay and residence for PLHIV. http://www.hivtravel.org/Default.aspx?PageId=143&M ode=list&StateId=2.\n\nThe PEW Charitable Trusts (Pew). 2016. A scientific roadmap for antibiotic discovery. (May 11). http://www.pewtrusts.org/en/research-and-analysis/reports/2016/05/a-scientific-roadmap- for-antibiotic-discovery.\n\nTrap, Birna, and E.H. Hansen. 2002. Treatment of upper respiratory tract infections—A com- parative study of dispensing and non-dispensing doctors. Journal of Clinical Pharmacy and Therapeutics 27 (4): 289–298.\n\n255", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-265-0", "doc_id": "drug_resistance_book", "page": 265, "text": "256\n\nJ. G. Francis and L. P. Francis\n\nUnemo, Magnus, Catriona S. Bradshaw, Jane S. Hocking, Henry J. C. de Vries, Suzanna C. Francis, David Mabey, Jeanne M. Marrazzo, Gerard J.B. Sonder, Jane R. Schwebke, Elske Hoornenborg, Rosanna W. Peeling, Susan S. Philip, Nicola Low, & Christopher K. Fairley. 2017. Sexually transmitted infections: challenges ahead. Lancet Infectious Diseases. 17(8):e235-e279. 10.1016/S1473-3099(17)30310-9. Epub 9 July 2017.\n\nUniversity of Toronto Joint Centre for Bioethics Pandemic Influenza Working Group (Toronto Joint Centre). 2005. Stand on Guard for Thee: Ethical considerations in preparedness planning for pandemic influenza. http://www.jcb.utoronto.ca/people/documents/upshur_stand_guard.pdf. Webster, Charles. 2002. The National Health Service: A political history. Oxford: Oxford\n\nUniversity Press.\n\nWHO. 2005. International Health Regulations, 3rd ed. http://apps.who.int/iris/bitstream/10665\n\n/246107/1/9789241580496-eng.pdf?ua=1.\n\n———. 2014. Psychological first aid during Ebola virus disease outbreaks: Provisional version.\n\nhttp://apps.who.int/iris/bitstream/10665/131682/1/9789241548847_eng.pdf?ua=1.\n\n———. 2015. Programme Budget 2016–2017. http://who.int/about/finances-accountability/\n\nbudget/PB201617_en.pdf.\n\n———. 2016. WHO’s new Health Emergencies Programme. http://www.who.int/features/qa/", "n_tokens": 423, "kind": "text"}
{"chunk_id": "drug_resistance_book-265-1", "doc_id": "drug_resistance_book", "page": 265, "text": "health-emergencies-programme/en/.\n\n———. 2017a. Drug resistance. http://www.who.int/drugresistance/infosharing/en/. ———. 2017b. Middle East respiratory syndrome coronavirus (MERS-CoV) (May). http://www.\n\nwho.int/mediacentre/factsheets/mers-cov/en/.\n\nWigton, Robert S., Carol A. Darr, Kitty K. Corbett, Devin R. Nickol, and Ralph Gonzales. 2008. How do community practitioners decide whether to prescribe antibiotics for acute respiratory infections? Journal of General Internal Medicine 23: 1615–1620.\n\nWilliams, Alan. 2007a. Intergenerational equity: An exploration of the ‘fair innings’ argument.\n\nHealth Economics 6 (2): 117–132.\n\nWilliams, Bernard. 2007b. In In the beginning was the deed: Realism and moralism in political\n\nargument, ed. Geoffrey Hawthorn. Princeton: Princeton University Press.\n\nWinston, Susanna E., and Curt G. Beckwith. 2011. The impact of removing the immigration ban\n\non HIV-infected persons. AIDS Patient Care and STDs 25 (12): 709–711.\n\nWorld Health Organization (WHO). 2017. International travel and health: Tuberculosis (TB).\n\nhttp://www.who.int/ith/diseases/tb/en/.\n\nZorgani, Abdulaziz, and Hisham Ziglam. 2013. Letter: Injured Libyan combatant patients: Both vectors and victims of multiresistance bacteria? Libyan Journal of Medicine 58: 20325. https://doi.org/10.3402/ljm.v8i0.20325.\n\nZowasi, Hosam M. 2016. Antimicrobial resistance in Saudi Arabia: An urgent call for an immedi-", "n_tokens": 397, "kind": "text"}
{"chunk_id": "drug_resistance_book-265-2", "doc_id": "drug_resistance_book", "page": 265, "text": "ate action. Saudi Medical Journal 37 (9): 935–940.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 182, "kind": "text"}
{"chunk_id": "drug_resistance_book-266-0", "doc_id": "drug_resistance_book", "page": 266, "text": "Chapter 16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\nLynette Reid", "n_tokens": 23, "kind": "text"}
{"chunk_id": "drug_resistance_book-266-1", "doc_id": "drug_resistance_book", "page": 266, "text": "Abstract Within-country social inequalities in health have widened while global health inequalities have (with some exceptions) narrowed since the Second World War. On commonly accepted prioritarian and sufficientist views of justice and health, these two trends together would be acceptable: the wealthiest of the wealthy are pulling ahead, but the worst off are catching up and more are achieving suffi- ciency. Such commitments to priority or sufficiency are compatible with a common “development” narrative about economic and social changes that accompany changes (“transitions”) in population health. I set out a very simple version of health egalitarianism (without commitment to any particular current theory of justice) and focus on two common objections to egalitarianism. Priority and sufficiency both address the levelling down and formalism objections, but these objections are dis- tinct: giving content to equality (I argue here) places in question the claimed norma- tive superiority of priority and sufficiency. Using examples of the role of antimicrobials in both these trends – and the future role of AMR – I clarify (first) the multiple forms and dimensions of justice at play in health, and (second) the different mechanisms at work in generating the two current patterns (seen in life course nar- ratives and narratives of political economy). The “accelerated transition” that nar- rowed global health inequalities is fed by anti-microbials (among other technology transfers). It", "n_tokens": 309, "kind": "text"}
{"chunk_id": "drug_resistance_book-266-2", "doc_id": "drug_resistance_book", "page": 266, "text": "did not accelerate but replaced the causal processes by which current HICs achieved the transition (growing and shared economic prosperity and widen- ing political franchise). The impact of AMR on widening social inequalities in health in HICs will be complex: inequality has been fed in part by tertiary care enabled by antimicrobials; AMR might erode the solidarity underlying universal health systems as the well-off seek to maintain current expectations of curative and rehabilitative surgery and chemotherapy while AMR mounts. In light of both specu- lations about the impact of AMR on social and global health inequalities, I close with practical and with theoretical reflection. I briefly indicate the practical impor-", "n_tokens": 146, "kind": "text"}
{"chunk_id": "drug_resistance_book-266-3", "doc_id": "drug_resistance_book", "page": 266, "text": "L. Reid (*) Department of Bioethics, Dalhousie University, Halifax, Canada e-mail: Lynette.Reid@dal.ca\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_16\n\n257", "n_tokens": 104, "kind": "text"}
{"chunk_id": "drug_resistance_book-267-0", "doc_id": "drug_resistance_book", "page": 267, "text": "258\n\ntance of understanding AMR from the perspective of health justice for policy response. Then, from a broader perspective, I argue that the content by which I meet the formalism objection demonstrates that the two trends (broadening within- country inequality and narrowing global inequality) are selective and biased samples of a centuries-long pattern of widening social inequalities in health. We are not in the midst of a process of “catching up”. In light of the long-term pattern described here, is the pursuit of sufficiency or priority morally superior to the pursuit of equality as a response to concrete suffering – or do they rationalize a process more objectively described as the best-off continuing to take the largest share of one of the most important benefits of economic development?\n\nKeywords Bioethics · Public health ethics · Antimicrobial resistance · Health inequality · Health justice\n\n16.1", "n_tokens": 181, "kind": "text"}
{"chunk_id": "drug_resistance_book-267-1", "doc_id": "drug_resistance_book", "page": 267, "text": "Introduction\n\nWhat is the significance of antimicrobial resistance (AMR) for health inequalities? This question refers not just to the extent to which AMR might exacerbate or miti- gate health inequalities, but to the ways that we should think about health inequali- ties in order to be adequately sensitive to the justice dimensions of AMR and to the lessons that AMR might offer about the nature of health inequalities as such and their normative status (or the normative plausibility of responses to health inequalities).\n\nThe development of AMR in bacteria, viruses, fungi, and parasites detrimental to human health is already a substantial public health concern; it is estimated to cause 700,000 deaths a year globally. The UK government’s O’Neill report paints what it calls a worst-case scenario—a post-antimicrobial world in which antimicrobial- resistant infections are collectively the second leading cause of death by 2050, caus- ing 10 million deaths a year and lowering world population by 700 million (O’Neill 2014, 2016). This “worst case scenario” is based on projecting the consequences of AMR for a small selection of conditions and as such may underestimate the poten- tial consequences of AMR (Jamrozik and Selgelid, Chap. 1, this volume).", "n_tokens": 291, "kind": "text"}
{"chunk_id": "drug_resistance_book-267-2", "doc_id": "drug_resistance_book", "page": 267, "text": "It is widely acknowledged that the development of AMR will have different effects on high-income, middle-income, and low-income countries. Other chapters in this volume propose or evaluate policies to address and mitigate AMR as these matter for health equity and for global health.\n\nIn this chapter, I situate the use of antimicrobials and the growth of AMR in a narrative of population health (Valles 2018), specifically the story of narrowing global (between country) and widening local (within country) health inequalities, and argue that the development of AMR puts pressure on normative commitments to sufficientism and prioritarianism as purportedly more feasible and more norma- tively satisfying goals for health justice.\n\nL. Reid", "n_tokens": 154, "kind": "text"}
{"chunk_id": "drug_resistance_book-268-0", "doc_id": "drug_resistance_book", "page": 268, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\nFaced with data showing that people who live in one neighbourhood may have a life expectancy 10–20 years lower than people in a nearby neighbourhood, or that the difference in life expectancy between countries is in some cases as high as 35 years, many express a normative worry that social inequality in health and global health inequalities are unjust (Marmot 2015). However, among academics who dis- cuss health justice, few are egalitarians about health. Sufficiency – the attainment of a decent minimum – is often argued to be an appropriate goal; priority for the worst- off is argued to be adequately action-guiding. The question of sufficiency, priority, or equality can be deferred to ideal theory; we need not agree on an ultimate goal in order to act. For example, if we can agree that AMR is likely to hit the worst-off the hardest, as the O’Neill report projects, then sufficientists, prioritarians, and egalitar- ians alike can focus their attention on alleviating its effects for the worst-off while still remaining faithful to their diverging commitments if they wish.\n\n16.2", "n_tokens": 262, "kind": "text"}
{"chunk_id": "drug_resistance_book-268-1", "doc_id": "drug_resistance_book", "page": 268, "text": "Health Inequalities and Health Egalitarianism: Definitions\n\nIn this chapter, I use the term “social inequality in health” to refer to inequalities in some health indicator across socioeconomic status (SES) or other category of inter- est to justice within countries. I will refer to life expectancy or mortality, but metrics of inequality include other key indicators, for example, infant mortality or work- place mortality. I will use “global health inequality” to refer to inequality in such indicators across low-, middle-, and high-income countries (typically referring to LMICs on the one hand and HICs on the other).1 Granted that there is normatively significant variation in what counts as socioeconomic status and how it is measured, I speak broadly of socioeconomic inequalities in health, while not intending any specific version of the concept as fundamental. (I motivate/explain this below.)\n\nThe core commitment of a health egalitarian is that, all things being equal, a society in which persons of different socioeconomic status can lead full lives with minimization and mitigation of health-related disruptions to those lives is more just than a society in which the possibility of a healthy life is patterned by", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-268-2", "doc_id": "drug_resistance_book", "page": 268, "text": "1 The less cumbersome phrase “health equality” refers simply to the distribution of life years across a population, not correlated with any other variable of interest to justice. For example, Strømme and Norheim recently claim that both global and national health inequalities are shrinking (Strømme and Norheim 2017). They base this claim on a univariate measure of the distribution of a health indicator alone (age at death) within a population: their empirical claim is that the distribu- tion of age at death is becoming more closely clustered around a value rather than spread widely or polarized while their implicit normative claim is that form of health inequality is what matters to justice. Such univariate measures of health inequality, however, capture nothing about who is dying early or late within that narrower distribution – for example, the rich or the poor, the racial- ized or the non-racialized, those of higher or lower educational attainment, or all social classes equally (Regidor 2004). Life expectancy could cluster around a given value without any change in the gap between the rich and the poor.\n\n259", "n_tokens": 236, "kind": "text"}
{"chunk_id": "drug_resistance_book-269-0", "doc_id": "drug_resistance_book", "page": 269, "text": "260\n\nsocioeconomic status. That is, a society in which service workers, manual labourers, or those excluded from labour market participation live lives as long and healthy as executives or professors is more just than a world in which this is not the case. On a global scale, a world in which such possibilities of health are not patterned by acci- dent of global birth is more just than a world in which that is not the case.\n\nFollowing Temkin (2000, 2003), I explore the health egalitarian commitment without assuming a specific view on whether this commitment should dominate feasibility considerations or other values that may conflict with the achievement of social equality in health or global health equality. For example, a commitment to cultural self-determination may outweigh a commitment to health egalitarianism in specific cases, granting the moral and political right of a community to pursue eco- nomic activity and social organization that exposes it to different supports for and risks to health, such that life expectancy differs from that obtained in urban settings in HICs.", "n_tokens": 211, "kind": "text"}
{"chunk_id": "drug_resistance_book-269-1", "doc_id": "drug_resistance_book", "page": 269, "text": "The leveling down objection seems particularly acute for health egalitarians: while it may be acceptable to take financial resources from people for redistribution, can it ever be acceptable to worsen the health of some people in order to achieve some increment of improvement in the health of the less well off? Temkin’s approach avoids the common use of this “leveling down” objection (Parfit 1997, 2012) to take egalitarianism off the table. We can explore the normative importance of social equality in health without ipso facto committing ourselves to the view that it has such normative weight that it trumps other considerations and values.\n\n16.2.1\n\nToward a Multi-dimensional Account of Justice, Health, and Equality as a Normative Goal", "n_tokens": 157, "kind": "text"}
{"chunk_id": "drug_resistance_book-269-2", "doc_id": "drug_resistance_book", "page": 269, "text": "A health egalitarian faces (at least) three substantial challenges: the leveling down objection (discussed in the previous section), the challenge that health inequalities qua natural can only be matters of justice insofar as they cause or are caused by unjust social inequalities, and the challenge of motivating normatively a concern with the abstract and interpersonal measure of inequality. These three challenges – the leveling down objection, the natural difference objection, and the formalism objection – are closely related. For example, one might focus on concrete normative concerns – suffering (and its alleviation) or sufficient health (and its achievement) – and, by adopting prioritarianism or sufficientism, avoid both the formalism and the leveling down objections (as in Anderson (1999, 2010) and other proponents of capabilities (Nussbaum 2006; Venkatapuram and Marmot 2013)). However, these objections are conceptually distinct. Filling out the concrete realities that are reflected in formal measures of inequalities might bolster rather than undermine the case for equality over sufficiency or priority as a normative goal.\n\nIn this paper I use examples drawn from antimicrobials and antimicrobial resis- tance to give content to concerns about social equality in health, showing that the\n\nL. Reid", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-270-0", "doc_id": "drug_resistance_book", "page": 270, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\nformalist challenge can be met without adopting a sufficientist or prioritarian alter- native to egalitarianism. I do not offer or adopt a specific comprehensive theory of justice or even of justice and health; rather, using examples from antimicrobials and antimicrobial resistance, I explore different forms of justice and different relation- ships between justice and health. These are phenomena that an adequate account of health justice should capture, but what account of health justice in what form will do that adequately is not a question I attempt to resolve here.2\n\nCertainly, injustices in domains other than health affect health outcomes; health states lead to injustices in other domains (e.g. fair opportunity, strict equality, reward for merit, reciprocity, respect for privacy or property, etc.). For these reasons, judge- ments of justice and injustice in other domains inform the normative evaluation of the justice or injustice of social inequalities in health and global health inequalities. But health needs also constitute specific claims for recognition, in response to which we should, as a matter of justice, express respect for equal human worth. That is, health inequalities, in addition to causing and being caused by other unjust inequali- ties, also constitute and express specific relations of equality and inequality that are of concern to justice.3", "n_tokens": 297, "kind": "text"}
{"chunk_id": "drug_resistance_book-270-1", "doc_id": "drug_resistance_book", "page": 270, "text": "Furthermore, unequal responsiveness to health needs creates social inequalities that are sui generis and that are politically significant in sui generis ways. Consider that the inability to access medical treatment that could address a serious health condition creates desperation which may motivate people to enter into social rela- tions they would not otherwise contemplate. For example, in moral reasoning tests, psychological researchers ask participants to evaluate a scenario in which a person needs a medication they cannot afford for their fatally ill spouse. This is the paradig- matic case in which otherwise socially unacceptable actions become reasonable and moral responses to inequality.\n\nMy pluralism about forms of justice is not in the first instance motivated by the idea that liberal public policy must avoid commitment where individual moral views diverge. Any claim to neutrality is dubious. Rather, it is an acknowledgement that conceptions of justice and fairness can take different contextually-relevant forms (e.g. fair reward for effort; fair opportunity; recognition of achievement; acknowl- edgement of and response to need), as can oppression (e.g. economic exploitation; exclusion from wealth or resource base; denial of voice). Inequality or oppression in any of these forms may be produced by other inequalities that themselves raise question of justice, and may produce further such inequalities. As Wolff and", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-270-2", "doc_id": "drug_resistance_book", "page": 270, "text": "2 This complexity may not be captured by a “spheres of justice” view, where a given domain of human endeavour is governed by a single form of justice (Walzer 2008). Consider that educational policy must be responsive both to the importance of reward for merit and to the importance of equal opportunity for achievement of a reasonable standard of literacy for citizenship and fulfill- ment. No education system only rewards achievement or only brings the population to whatever minimal or reasonable standard can be achieved by all. 3 Sen (2002) makes something like this point about the concept of health equity as a multi-dimen- sional concept: there are several forms that equity takes in relation to health and in relation to matters that have bearing on health and all of these must be taken into account in a treatment of health equity.\n\n261", "n_tokens": 163, "kind": "text"}
{"chunk_id": "drug_resistance_book-271-0", "doc_id": "drug_resistance_book", "page": 271, "text": "262\n\nda- Shalit have argued, injustices that compound in these ways may be of particular concern (Wolff and da Shalit 2007).\n\nAnswering the formalist challenge involves contextualization and narrative exploration to evaluate the significance of what is portrayed in health statistics. The relevant narratives include individual lives (life-course narratives) within the con- text of social structures and broad changes in those structures – i.e. narratives of political economy. Both population level narratives of political economy and indi- vidual narratives of life courses contribute to understanding the human and norma- tive significance of broad epidemiological changes in longevity and the social and global equality and inequality in these measures.\n\n16.3\n\nExamples\n\nIn this section, I show these multiple relations of health and justice by taking two examples from microbial disease, antimicrobials, and AMR.\n\n16.3.1", "n_tokens": 180, "kind": "text"}
{"chunk_id": "drug_resistance_book-271-1", "doc_id": "drug_resistance_book", "page": 271, "text": "Example: AMR, Sex, and Gender\n\nWomen’s health as measured at the population level is strongly influenced by sexual and reproductive health, and these are in turn conditioned by reproductive auton- omy or its absence, as a matter of technology and crucially as a matter of gender politics. (The influence of perinatal experiences on population health measures is substantial; to be discussed below.) At the level of individual life narratives, child- bearing is a normative, but of course not a universal, experience for women.\n\nAntibiotics are used prophylactically in childbirth to address the risk of maternal and infant morbidity and mortality from infections. I have been unable to locate in the medical literature discussion of the implications of AMR for obstetric practice, such as discussion of whether prophylactic use constitutes a sustainable form of anti-microbial stewardship, under what conditions it might be abandoned by choice or triaged by need, or what the implications of its waning efficacy would be for women’s health. Neither have I been able to locate discussions of the implications of AMR for handling the infections that will be more common if the efficacy of prophylactic antibiotics is lost. Presumably this would have a significant impact on women’s reproductive health.", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-271-2", "doc_id": "drug_resistance_book", "page": 271, "text": "Childbirth is normative for women but not universal – many women give birth and there are cultural expectations whose negotiation characterizes women’s lives whether they themselves give birth or not. There are different pathways by which women come through sexual intercourse to childbirth, with greater or lesser degrees of autonomy and under different conditions of gender-related and economic justice and injustice. Sexual assault is both a concern of justice as a criminal matter and a concern of political justice, insofar as it is an expression and a tool of gender-based\n\nL. Reid", "n_tokens": 107, "kind": "text"}
{"chunk_id": "drug_resistance_book-272-0", "doc_id": "drug_resistance_book", "page": 272, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\ndomination. The sequelae of sexual assault sometimes include health and social effects (e.g. sexual transmitted infections, pregnancy, trauma, altered social stand- ing, and deep effects on current or future intimate relations, exposure to a criminal justice system that may be partly or entirely inadequate to victims’ needs, etc.); these have further health and social effects (infection in childbirth, to return to the original example).\n\nSome of the health-related harms of sexual intercourse are harms that we have been able to mitigate with antimicrobials (e.g. gonorrhoea, HIV/AIDS, infections arising from termination, infections arising in childbirth) for the last decades. These will be affected by AMR. Noting substantial disagreement about the moral and political status of sex work, sex workers and/or persons subject to sexual exploita- tion will be particularly affected by AMR. Some will take this as compounding the injustice of sexual exploitation and others will take it as compounding the injustice of the stigmatization of sex work. As such, AMR will alter the experience of sexual activity and affect concerns of justice in relation to sexual activity.\n\n16.3.2", "n_tokens": 263, "kind": "text"}
{"chunk_id": "drug_resistance_book-272-1", "doc_id": "drug_resistance_book", "page": 272, "text": "Example: AMR and Parasitic Infection\n\nHookworm is a parasitic infection caused by inadequate public health infrastructure (Pilkington 2017). It is virtually unknown in HICs; the United States is an exception to this, which may not be surprising given that it boasts the highest GINI co- efficient (greatest economic inequality) of HICs and captures a low proportion of its national income (30%) for state expenditure (Piketty 2014, pp. 475–6). Anthelmintic resis- tance (resistance to the anti-parasitic agents used in treatment) is a growing concern for hookworm (Harhay et al. 2010).\n\nThe conditions for hookworm arise directly from the legacy of indentured labour on large estates where land was held by a small elite, and so it is strongly condi- tioned by historical injustices in colonial and slave-holding societies. As a hygienic disease it is tied closely to place, and place is tied closely to identity for many groups subject to colonialism – whether they were brought as slaves to work in a place that is now home or they experienced colonial occupation and seizure of their lands, transforming their status as labourers on those lands.", "n_tokens": 246, "kind": "text"}
{"chunk_id": "drug_resistance_book-272-2", "doc_id": "drug_resistance_book", "page": 272, "text": "In turn, hookworm has health sequelae detrimental to participation in the labour market and fulfillment of care responsibilities in the home (McKenna et al. 2017) and so it also has forward-looking intergenerational effects that are of concern for justice and the perpetuation of relations of economic inequality in post-colonial societies. This compounds the historical colonial relations that gave rise to the risk exposure.\n\nThese injustices are compounded by the fact that there is little or no investment in research to tackle this problem. Instead, anthelmintic drug development serves the agricultural industry, with the goal of increasing efficiencies in food production for the better-off, rather than serving the medical needs of the worse-off – human\n\n263", "n_tokens": 148, "kind": "text"}
{"chunk_id": "drug_resistance_book-273-0", "doc_id": "drug_resistance_book", "page": 273, "text": "264\n\nbeings who live in conditions that make them vulnerable to the parasite (Hu et al. 2013).\n\n16.3.3\n\nSummary of Examples\n\nIn these examples, justice concerns and health inequalities are intimately and com- plexly linked. A given health advantage or detriment can reflect justice or injustice in gender relations, in criminal justice matters, in labour relations, in global eco- nomic and colonial relations involving claims to land, resources, and sovereignty – in addition to the common justice-related concerns about the fair distribution of scarce resources within health care.\n\nThe forms of stigmatization to which infectious and hygienic disease are subject are paradigmatic and concrete forms of stigmatization. Shame involves the source of the infection (in sexual relations, or in place for historically constituted commu- nities consigned to exposure to hygienic disease) and this extends to shame about the resulting health state, in ways closely tied to disease-related identities, to sym- bolic and quasi-symbolic stigma (denigration, shunning, isolation, social distanc- ing) and to concrete stigmatization (violation of civil liberties, detention; situating waste disposal on “unproductive” land where this is land occupied by indigenous and poor communities).", "n_tokens": 266, "kind": "text"}
{"chunk_id": "drug_resistance_book-273-1", "doc_id": "drug_resistance_book", "page": 273, "text": "AMR has its effects in these fields. As it renders infectious and hygienic diseases less susceptible to treatment, it will exacerbate the ongoing legacies of these histori- cal harms and their forward-reaching effects, in part by compounding the relevant health effects, and in part by the effects of policy responses on marginalized popula- tions. For example, persons exposed to STIs through sex work or sexual exploita- tion and persons exposed to hookworm through colonialism and its legacy of land marginalization may in turn be subject to increased state surveillance and control, even risk of criminalization, insofar as their health state is seen to pose a threat to others, or insofar as their health state gives them a claim resources that increasingly come to be seen and managed as scarce public or common goods (Smith and Coast, Chap. 17, this volume; Giubilini and Savulescu, Chap. 9, this volume).", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-273-2", "doc_id": "drug_resistance_book", "page": 273, "text": "In describing the examples, I draw on (not very detailed) meso-level narratives in which justice considerations abound – narratives that involve local manifestations of broader structural relations for specific communities. In these narratives, it is relatively clear how justice considerations relate to health and how health differen- tials can intrinsically constitute the justice or injustice of relevant relationships. But what connection can we draw from here to the broadest population metrics of health inequalities? What roles have antimicrobials played in these population narratives and what role might AMR play?\n\nL. Reid", "n_tokens": 119, "kind": "text"}
{"chunk_id": "drug_resistance_book-274-0", "doc_id": "drug_resistance_book", "page": 274, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\n16.4\n\nHealth Inequalities: The Development Narrative\n\nRecall the 10–20 year within-country differences in life expectancy between high- and low-income neighbourhoods and the 30–40 year differences in life expectancy between HICs and LMICs. Do the differences among groups captured in the popu- lation health metrics matter normatively, and are they a concern of justice? What role did antimicrobials play in generating these differences and how might AMR affect these differences?", "n_tokens": 120, "kind": "text"}
{"chunk_id": "drug_resistance_book-274-1", "doc_id": "drug_resistance_book", "page": 274, "text": "Now, these formal measures might matter because those at the low end of the distribution are experiencing health deficits which we want to address as a matter of beneficence, or as a reciprocal obligation to supply a decent minimum arising from our economic inter-dependence – or they might matter because the inequalities of which they form one extreme matter. It is easy to elicit some kind of normative concern about these inequalities but much more difficult to specify exactly what matters about them as inequalities. Two persons might have different life expectan- cies because of accident or genetic endowment; it’s not obvious why group differ- ences matter. One possible starting place is the thought that if all else were equal the poor would be as healthy as the rich. That is, the poor do not constitute a separate natural kind with different potential to be healthy. If they are differentially unhealthy, it is because we fail to ensure that everyone has access to their potential to be healthy, because incomes are inadequate, housing poor, food of low quality, work hazardous, childbirth ill-supported, and access to care and social support for recov- ery from ill health limited. This line of thought is similar to the view of that health inequalities matter to justice when they are caused by or cause other injustices, but it maintains at its core the idea that health inequalities matter as such and can con- stitute injustice.", "n_tokens": 302, "kind": "text"}
{"chunk_id": "drug_resistance_book-274-2", "doc_id": "drug_resistance_book", "page": 274, "text": "By analyzing the role of antimicrobials in broad trends for social inequality in health and global health inequality, I argue that understanding the causes and the narrative constitution of these trends renders sufficientism and prioritarianism less attractive as normative stands.\n\nA common account of the broad trends in both global health and economic development in recent decades is that within-country inequalities are widening, but between-country inequalities are narrowing – a narrowing that is particularly dra- matic since the 1950s for health and 1980s for economic status. The normative claim attached to this account (implicitly or explicitly) is a prioritarian or sufficien- tist claim that while things may look grim from the perspective of the middle classes of HICs, from the perspective of those who are truly the worst off, things have never looked better: more and more people in the world are relieved of the worst form of poverty (“absolute poverty”) and are achieving a sufficiency of health. In health, the worst off are doing even better: life expectancy is advancing faster than it did when the current HICs built their prosperous economies over the course of the nineteenth and twentieth centuries.\n\nIn the examples of the previous section (16.3), I outlined different ways that justice questions might reflect, be reflected by, or otherwise enter into health\n\n265", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-275-0", "doc_id": "drug_resistance_book", "page": 275, "text": "266\n\ninequalities, by tying life course narratives to narratives that matter to justice – polit- ical and cultural economy, including gender relations. In the same manner, I will approach the significance of population health metrics in relation to justice by exploring the meaning of these metrics in terms of the typical and divergent life courses of the members of a population and in terms of the political and cultural economy of the communities in question (within-country communities and global communities).\n\nThe common narrative reflecting the sufficientist or prioritarian reading of nar- rowing health inequalities is the development narrative (political economy) linked to life course narratives via “transition” theory (demography and epidemiology).", "n_tokens": 147, "kind": "text"}
{"chunk_id": "drug_resistance_book-275-1", "doc_id": "drug_resistance_book", "page": 275, "text": "Demographers long ago observed the tendency of populations to pass succes- sively through certain stages, tied to their economic development: populations move from having a high birth rate along with a high death rate (in foraging or pastoral economies), to a more stable and dropping death rate, while the birth rate remains high, resulting in a population explosion (from agricultural to early industrial econ- omies), to a low birth rate-low death rate stage, which we see in the stable or shrink- ing populations of modern HICs (which depend at this stage on immigration for economic growth). Epidemiologists in the mid-twentieth century linked these demographic changes to patterns of health and disease: the first stage of “pestilence and famine” with its characteristic population swings is followed by a second stage of greater stability but low life expectancy conditioned by infectious and hygienic diseases, initially from the close co-habitation of animals and humans and then the increasingly crowded, eventually urban, living conditions of humans with one another. With improvements in living standards and public health infrastructure, we enter a third stage where chronic (“man-made and degenerative”) diseases of later middle age emerge as common causes of death (Omran 1971). A combination of so-called lifestyle changes (e.g. smoking cessation, moderation of red meat con- sumption) and advanced medical technologies (e.g. cancer treatment) have pushed back these diseases of", "n_tokens": 305, "kind": "text"}
{"chunk_id": "drug_resistance_book-275-2", "doc_id": "drug_resistance_book", "page": 275, "text": "midlife and created the ongoing extension in lifespan that HICs are now experiencing, which some describe as a “fourth stage” of epidemio- logical transition (Olshansky and Ault 1986).", "n_tokens": 43, "kind": "text"}
{"chunk_id": "drug_resistance_book-275-3", "doc_id": "drug_resistance_book", "page": 275, "text": "These are the economic and epidemiological narratives behind how a non- transparent metric like life expectancy is read in health policy and understood to be a normative concern or a concern of justice. A life expectancy in the 40s reflects substantial maternal, infant, and child mortality caused by infectious and hygienic disease and the lack of empowerment of women to control their sexual and repro- ductive lives. A life expectancy in the 60s reflects a society in which heart disease and cancer are leading causes of death in later middle life, a phenomenon that emerged over the course of the twentieth century in HICs. A life expectancy in the 80s reflects improved prevention and treatment of these major killers and the emer- gence of new common forms of dying in advanced old age, e.g. frailty and dementia. The dramatic narrowing of global health inequalities since the 1950s is called, within this narrative, the “accelerated transition,” reflecting the success of the inter- national development agenda in achieving improvements in health status that out- strip the economic and political development of the countries in question – that is, that outstrip both growth in GDP and changes in the franchise and effective political\n\nL. Reid", "n_tokens": 247, "kind": "text"}
{"chunk_id": "drug_resistance_book-276-0", "doc_id": "drug_resistance_book", "page": 276, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\norganization of workers to demand the health, education, and safety benefits of modern welfare states. By these means, industrialization and urbanization raised GDP while political change led to a larger proportion of the GDP being invested in the well-being of the population, in a process that involved the empowerment of workers and women, improving population health – although (given the dynamics of democratic pressure) achieving less success in addressing the needs of so-called minorities.4\n\nOn this narrative, it seems natural to see the changes in global economic and health equalities and inequalities in terms of the idea that some countries got a head start and some lag behind. A common economic belief is that open markets and the transfer of skills and technology will ensure that LMICs continue to advance towards (eventually) “catching up.” The common narrative in health is that some (both low and high tech) public health technologies could be transferred in advance of economic development, offering LMICs a leg up in the development process.\n\n16.4.1", "n_tokens": 224, "kind": "text"}
{"chunk_id": "drug_resistance_book-276-1", "doc_id": "drug_resistance_book", "page": 276, "text": "Is the Development Narrative True?\n\nIs this development narrative true? Does it do the normative work it claims to do?\n\nOne important critique of formal measures of equality and inequality is that they are not transparently related to the underlying realities they measure (King et al. 2012; Harper et al. 2010; Mackenbach 2015, Mackenbach et al. 2016). King et al. point out that the same underlying reality can be represented as a narrowing of abso- lute inequalities or a widening of relative inequalities, for example. Similarly, the same numeric change may represent different causal pathways or encapsulate dif- ferent social relations with different significance in terms of justice and injustice and different distributions of well being and suffering. This has implications for the normative concern that these measurements might inspire (which inequalities should we tackle?) and may even raise questions about the reality of abstract inter- personal measures (are inequalities simply imposed on the individual phenomena that, sufficientists and prioritarians argue, should be the object of our moral concern?).\n\n16.4.2", "n_tokens": 231, "kind": "text"}
{"chunk_id": "drug_resistance_book-276-2", "doc_id": "drug_resistance_book", "page": 276, "text": "Underlying Realities\n\nThe narrative that LMICs are “catching up” suggests that they are achieving what HICs have achieved, but doing so later. However, this suggestion is false. The accel- erated narrowing of global health inequalities represents fundamentally different epidemiological patterns, causal pathways, and relations of concern to justice.\n\n4 In the current HICs this process led to the state capturing 40–55% of national income for its spending (Piketty 2014, pp. 475–6).\n\n267", "n_tokens": 104, "kind": "text"}
{"chunk_id": "drug_resistance_book-277-0", "doc_id": "drug_resistance_book", "page": 277, "text": "268\n\nI described above how a population’s life expectancy in a given decade is “read” epidemiologically, and I noted that many different underlying patterns of health and disease can generate the same measure. Substantial infant and early childhood mor- tality in a subpopulation might depress life expectancy as much as widespread exposure of young adults to interpersonal violence, workplace hazards, tuberculo- sis, or HIV. Different narratives of political economy can in turn generate these patterns – the sub-population with elevated early childhood mortality may be indig- enous or migrant; interpersonal violence may be a matter of warfare or the combina- tion of lack of opportunity, crime, availability of guns, policing, and racialization.", "n_tokens": 153, "kind": "text"}
{"chunk_id": "drug_resistance_book-277-1", "doc_id": "drug_resistance_book", "page": 277, "text": "The picture offered by transition theory is simplified (Frenk et al. 1991; Defo 2014). Researchers now emphasize that the same life expectancy in different popu- lations may reflect different realities. They describe the transitions of LMICs as “incomplete” transitions, highlighting counter-transitions within LMICs and even within HICs. For example, LMICs did not leave infectious and hygienic disease behind. Rather, they are taking on the so-called diseases of affluence – diseases that arise from changes in work, nutrition, energy, and transportation – in addition to carrying an on-going burden of infectious and hygienic disease (Santosa et al. 2014; Defo 2014). Specific population groups within HICs experience the re-emergence of infectious and hygienic disease, while the emergence of so-called “diseases of despair” (suicide and substance abuse) may reverse health gains in HICs for some groups (Case and Deaton 2015) or for entire countries (some of the former eastern bloc). Global migration resulting from instability and lack of opportunity in LMICs and the need for low-wage workers particularly in the agricultural sector in HICs brings together the AMR diseases of LMIC and the population health profile of HICs (Suk et al. 2009).", "n_tokens": 270, "kind": "text"}
{"chunk_id": "drug_resistance_book-277-2", "doc_id": "drug_resistance_book", "page": 277, "text": "Furthermore, insofar as LMICs have substantially reduced childhood and young adult mortality from infectious and hygienic diseases, these reductions did not come from the developments in political economy that led to such improvements in HICs. In HICs, rising GDP went along with political changes (universal suffrage extend- ing beyond male property owners to labourers and women, and various political movements organized around these identities) and these brought about improve- ments in determinants of infectious and hygienic disease. In HICs, antibiotics joined and accelerated an existing process of decline in infectious and hygienic disease after the Second World War (Mackenbach 1996). In LMICs, on the other hand, growth in GDP resulting from urbanization has not been distributed or re- distributed and invested to improve living standards and public health infrastructure to the same extent. Political empowerment is limited, in part by the actions of the very same global corporations that bring (some) growth in income to LMICs. In its place, a global network of health philanthropy has delivered effective prevention with vac- cines and mosquito nets and treatment with antimicrobials for infectious and hygienic diseases that remain endemic. Antimicrobials played an important role in this so-called “accelerated” transition. The infectious and hygienic diseases that result from crowding and exposure to waste are managed medically e.g. by vaccina- tion for prevention or by", "n_tokens": 298, "kind": "text"}
{"chunk_id": "drug_resistance_book-277-3", "doc_id": "drug_resistance_book", "page": 277, "text": "antimicrobials for treatment, and not by improved housing for primordial prevention. This is not a lag in economic development or in the", "n_tokens": 31, "kind": "text"}
{"chunk_id": "drug_resistance_book-277-4", "doc_id": "drug_resistance_book", "page": 277, "text": "L. Reid", "n_tokens": 3, "kind": "text"}
{"chunk_id": "drug_resistance_book-278-0", "doc_id": "drug_resistance_book", "page": 278, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\nuptake of health-related technologies; it is a different path of economic and social change. Even to describe it as “incomplete” is misleading, insofar as the term “incomplete” suggests that LMICs have reached a different point on the same path- way instead of achieving the partial benefits they have achieved from a different trajectory.", "n_tokens": 86, "kind": "text"}
{"chunk_id": "drug_resistance_book-278-1", "doc_id": "drug_resistance_book", "page": 278, "text": "This is evident at the level of life course narratives. What a life expectancy of 60 looks like in a current MIC is not what a life expectancy of 60 looked like when HICs reached that stage. Parents in HICs may feel that childhood and adolescence are times of risk and danger, but very few children in HICs experience life- threatening diarrhea or pneumonia and virtually no adolescents and young adults experience TB. (The exceptions to this general picture are in communities within HICs that bear a heavy burden of colonialism such as indigenous communities (Orr 2013 and Møller 2010) and in the globally mobile working class (MacPherson et al. 2009), where migration is also conditioned by colonial histories in addition to cur- rent global supply chains.) Parents in LICs with superficially similar mortality fig- ures continue to experience episodes in which their children’s lives threatened with diarrhea in infancy – but they now know how to treat it, as few people would have known in the HICs’ pre-transition period, and they have antibiotics available for managing severe cases where this is appropriate. Children in MICs do not enjoy a trouble-free childhood, but go through the distress of under-5 pneumonia or adoles- cent TB, while their parents experience the anxiety of trying to secure the antimicro- bials needed to treat these conditions: for 5 million children with pneumonia in LMICs annually, their parents are unable to do this (Laxminarayan et al. 2016). The use of", "n_tokens": 312, "kind": "text"}
{"chunk_id": "drug_resistance_book-278-2", "doc_id": "drug_resistance_book", "page": 278, "text": "antimicrobials along with other readily transferable technologies sustain different underlying life course narratives in LMICs compared to those that typify HICs.", "n_tokens": 31, "kind": "text"}
{"chunk_id": "drug_resistance_book-278-3", "doc_id": "drug_resistance_book", "page": 278, "text": "16.4.3\n\nUnderlying Causes\n\nWithout a basic understanding of the causal processes that characterize changes in population health and health inequalities, it is not possible to evaluate normative claims about the co-existence of narrowing global health inequalities and the within country widening health inequalities. Sampling changes in a given time period and presenting them as trends (or as trends that are causally linked – with the suggestion that health benefits are, as it were, transferred from the middle classes of HICs to the workers of LMICs) can misrepresent the broad causal picture as it unfolds.\n\nThe last 100 years, both globally and within country, constitute one period in a long-term process of widening social inequality in health. Broadly speaking, social inequality in health has risen ever since the Middle Ages (perhaps surprisingly), when nobles and peasants seem to have had similar life expectancies (Antonovsky 1967; Bengtsson and van Poppel 2011). The late 19th and early 20th century period – in which social inequalities in health narrowed within those countries that emerged as HICs – was an anomaly.\n\n269", "n_tokens": 233, "kind": "text"}
{"chunk_id": "drug_resistance_book-279-0", "doc_id": "drug_resistance_book", "page": 279, "text": "270\n\nTo relate the trends to transition theory, roughly speaking, we can say that pesti- lence and famine affect all social classes; as societies transition to agriculture, the wealthy still have surprisingly little protection from the infectious and hygienic diseases that characterize this stage of close co-habitation with animals and increased human crowding. This “agricultural transition” lowers life expectancy for individuals while increasing population size – a qualified form of “improvement” in population health. Urbanization and the initially slow but eventually rapid growth in economic productivity associated with it, by contrast, both raise the life expectancy of the population and increase its size. However, this improvement both for indi- viduals and for populations benefits those of higher SES more than those of lower SES, opening up differences in life expectancy that persist and for the most part continue to grow.\n\nThe only period in which social inequalities in health narrowed for a time was the classic period of hygienic and sanitary reform at the end of the 19th and begin- ning of the 20th centuries – when initial steps to establish safety of the food supply, clean water, and sewage were taken in HICs (Soares 2007). At this point, the happy confluence of political change (increasingly wide suffrage), scientific development (the germ theory of disease), and growth in GDP contributed strongly to this narrowing.", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-279-1", "doc_id": "drug_resistance_book", "page": 279, "text": "The post-war growth of the welfare state, including systems of universal health coverage, by contrast, has at best slowed the growth of social inequality in health: it has not moved us in the direction of social equality in health (Sreenivasan 2007; Mackenbach 2012; Reid 2016). The better off get more out of the “fourth stage” of epidemiological transition by the differential benefit they derive from programs like universal health coverage. This is not to say that such programs do not promote social equality in health: it is plausible that the poor would have been left yet further behind without them (Reid 2016).", "n_tokens": 127, "kind": "text"}
{"chunk_id": "drug_resistance_book-279-2", "doc_id": "drug_resistance_book", "page": 279, "text": "This sampling question is significant for the normative work that the develop- ment narrative is supposed to do. The narrative of local divergence (the almost-best- off falling a bit behind) and global convergence (the worst off catching up) relies on sampling HICs just after the one period in which inequalities narrowed (thereby excluding that narrowing) and sampling LMICs at a moment in history that includes the LMIC version of that era in which (in HICs) inequalities narrowed. The underly- ing dynamic is that as health improves, it improves more for the better off than the worse off, absent a period where we acted on the gains that could be made by pro- viding the basic infrastructure of public health. The broad trend is the same globally and within country: it does not reflect a tradeoff in which we forgo goods for the already pretty-well-off and give them to the worse-off. On the contrary, as we saw in the previous section, we have taken a path to improving life expectancy in LMICs that seems likely not to lead to the same gains. The inference from a given period of narrowing to a broader pattern of a gap being closed is illicit.\n\nL. Reid", "n_tokens": 253, "kind": "text"}
{"chunk_id": "drug_resistance_book-280-0", "doc_id": "drug_resistance_book", "page": 280, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\n16.4.4", "n_tokens": 23, "kind": "text"}
{"chunk_id": "drug_resistance_book-280-1", "doc_id": "drug_resistance_book", "page": 280, "text": "Implications for Global AMR Policy\n\nThe narrative of catching up ignores longer-term trends and obscures differences in typical and various life courses that cause the life expectancy gains in LMICs. Waning antimicrobial effectiveness will reveal the different underlying causes of these gains.\n\nCurrent approaches to addressing the role of social determinants of health (SDOH) in the impact of AMR, consistent with the model of global health that gave us the accelerated transition, is medicalized: medical technology transfer again takes the place of political development; inappropriate standards of evidence (the movement towards implementing evidence-based standards in development) direct efforts towards primary prevention and treatment and away from inter-sectoral cooperation on health-related primordial prevention. (See King, Chap. 19, this vol- ume; Silva et al. 2020.) The WHO Global Action Plan (2015a) speaks, for example, of “effective prevention of infections transmitted through sex or drug injection as well as better sanitation, hand washing, and food and water safety” as “core compo- nents of infectious disease prevention,” (§36) and “more widespread recognition of antimicrobial medicines as a public good … [being] needed in order to strengthen regulation of their distribution, quality, and use” (§41) to address inappropriate anti- microbial use, and the development of awareness and improved veterinary educa- tion to address the overuse of antimicrobials in agriculture.", "n_tokens": 302, "kind": "text"}
{"chunk_id": "drug_resistance_book-280-2", "doc_id": "drug_resistance_book", "page": 280, "text": "Awareness and education are inadequate to address the struggles of LMICs to promote appropriate antimicrobial use. These countries often make do with half the tax revenues proportionate to GDP or national income that HICs expect: enforce- ment to tame diversion and over-the-counter sales of antibiotics or the for-profit healthcare sector (a substantial source of poor prescribing – Kuo et al. 2017; Haire, Chap. 3, this volume; Liverani et al., Chap. 5, this volume; Ho and Lee, Chap. 25, this volume) are not free. Neither can LMICs confront the globalized agricultural sector that moves agricultural practices that involve the overuse of antibiotics from the increasingly intolerant regulatory environments of HICs to their permissive regu- latory environments. To confront this would in turn require an end to pressure from global supply chains serving HIC- consumers against environmental and labour regu- lation in LMICs (the justice dimensions of such dependencies are explored in the social connectionist model of Young 2006). Focusing innovation in anthelmintics, for example, on the needs of human beings vulnerable to parasites would change treatment possibilities (in accordance with the call of Shawa et al., Chap. 10, this volume), while reducing or eliminating agricultural use and improving health-related infrastructure – both of which involve political and economic change – would change the distribution of health benefits.", "n_tokens": 297, "kind": "text"}
{"chunk_id": "drug_resistance_book-280-3", "doc_id": "drug_resistance_book", "page": 280, "text": "In addition, there is another global structural relationship in inequalities related to antimicrobial use, insofar as antimicrobials are a common or public good, as discussed elsewhere in this volume (Smith and Coast, Chap. 17, this volume; Giubilini and Savulescu, Chap. 9, this volume). LMICs cannot “catch up” in antimicrobial use because HICs are on track to use them up, for their own needs or in service of HIC-led policies that encourage antimicrobial use in LMICs instead of balanced development,\n\n271", "n_tokens": 129, "kind": "text"}
{"chunk_id": "drug_resistance_book-281-0", "doc_id": "drug_resistance_book", "page": 281, "text": "272\n\nhigh taxation and regulation, and democratic empowerment, the context in which conservative antimicrobial use can be implemented as policy.\n\nThe problem of effective regulation and orientation of the pharmaceutical indus- try towards population needs is not isolated to LMICs. Generic drug shortages in HICs contribute to AMR by driving inappropriate prescribing (Shoham et al. 2016), and every action plan on AMR highlights the failure of industry to invest in new antimicrobials, and not the problem that new antimicrobials, when found, continue to be marketed and deployed in ways that encourage non-beneficial and marginally beneficial use.\n\n16.4.5", "n_tokens": 136, "kind": "text"}
{"chunk_id": "drug_resistance_book-281-1", "doc_id": "drug_resistance_book", "page": 281, "text": "AMR and Widening Within-Country Social Inequality in Health\n\nAntimicrobials played a role in the so-called “fourth stage” of epidemiological tran- sition, in which life expectancy has been extended by effective prevention and treat- ment for cancer and heart disease, among other medical conditions. Insofar as progress in addressing these large sources of disease burden for HICs involves advanced surgical and other tertiary care techniques (in addition to dietary change and tobacco control), this fourth transition relies on antibiotics that make surgical and immune-system suppressing chemotherapeutics possible. Even in countries with universal, comprehensive health care without financial barriers to access (like Canada), innovations in tertiary care provide more benefit to the better-off than the worse-off (Starfield 2011; Asada and Kephart 2007)5 – contributing to the return to growing social inequality in health despite universal health coverage in contempo- rary medical care.", "n_tokens": 198, "kind": "text"}
{"chunk_id": "drug_resistance_book-281-2", "doc_id": "drug_resistance_book", "page": 281, "text": "At a superficial level, we could speculate that the development of AMR in HICs could undo a line of medical progress that has widened social inequalities in health. But there would be many opportunities for reassertion of the general pattern of the last several centuries, the pattern of the well-off capturing a greater share of benefits and experiencing a lower share of burdens. Moderating the use of antimicrobials to preserve their effectiveness calls on solidarity as a value (Holm and Ploug, Chap. 21, this volume); the implications of waning antimicrobial efficacy will put stress on this same value. For example, the tertiary care interventions of the fourth epidemio- logical stage are becoming increasingly expensive due to AMR (Smith and Coast 2013; Cosgrove 2006; Teillant et al. 2015). This will continue for some time as those interventions gradually take on an unfavourable intrinsic harm-benefit trad- eoff for the individual patient directly involved. It is only at this last stage (where the\n\n5 This is thought to be because the worse-off face barriers to access that are both practical and social (e.g. geographical proximity and social capital that generates attention to the expression of need and referrals); when they do access care, they have fewer resources that would enable them to benefit from it, e.g. the social and income support to enable recovery; furthermore, the care is less suited to their needs, given that complex chronic conditions have a social gradient.", "n_tokens": 319, "kind": "text"}
{"chunk_id": "drug_resistance_book-281-3", "doc_id": "drug_resistance_book", "page": 281, "text": "L. Reid", "n_tokens": 3, "kind": "text"}
{"chunk_id": "drug_resistance_book-282-0", "doc_id": "drug_resistance_book", "page": 282, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\nharm-benefit tradeoff shifts) that the loss of this technology would potentially nar- row health inequalities by de-implementation of “fourth stage” interventions that have widened social inequalities in health. The effects of specialty and disease inter- est group advocacy in the intervening period may well result in even greater capture of the resources of the system for the better-off. The increasing cost of supportive care to maintain current surgical interventions while responding to AMR may also feed a political discourse around system sustainability that contributes to eroding the comprehensiveness and depth of universal healthcare coverage. Social inequali- ties in health could continue to widen as services for those with less voice are eroded to enable the higher cost of coping with AMR in the tertiary care sector that has served higher income persons well.", "n_tokens": 183, "kind": "text"}
{"chunk_id": "drug_resistance_book-282-1", "doc_id": "drug_resistance_book", "page": 282, "text": "This is not just a HIC story. The Millennial Development Goals focused on child mortality and mortality of late adolescence/early adulthood (TB; the infectious and hygienic diseases), while the Sustainable Development Goals (SDG) on which the WHO embarked in 2015 focus on developing universal health coverage (UHC) and access to tertiary care – important for delivering the care necessary for chronic dis- eases and causes of midlife mortality that middle income countries are beginning to experience (WHO 2015b). The expected health transition from a higher burden of infectious and hygienic diseases to a higher burden of chronic, noncommunicable disease has informed this policy move. However, as we saw, MICs in particular are subject to the double burden of emerging chronic noncommunicable diseases along- side persistent infectious and hygienic diseases; they also experience a heavy bur- den from counter-transitions as new infectious and hygienic burdens arise (Cook and Dummer 2004; Santosa et al. 2014; Defo 2014). There is evidence that the prevalence of hospital-based resistant microbes is inversely associated with national income (Alvarez-Uria et al. 2016), suggesting that LMICs will also bear a heavier burden of hospital-based AMR than HICs, at the same time that they face a heavier burden of community-based resistant diseases. These new health systems will face the same kinds of political struggles about universality, depth, and sustainability that are in play in HICs", "n_tokens": 314, "kind": "text"}
{"chunk_id": "drug_resistance_book-282-2", "doc_id": "drug_resistance_book", "page": 282, "text": "(Norheim et al. 2014). Given the extent of economic inequalities within these countries, they will face these political struggles without the social solidarity that is somewhat protective of the breadth and depth of UHC in HICs. Indeed, some have speculated that AMR could entirely derail the SDG of UHC (Jasovský et al. 2016).", "n_tokens": 76, "kind": "text"}
{"chunk_id": "drug_resistance_book-282-3", "doc_id": "drug_resistance_book", "page": 282, "text": "16.5\n\nConclusion\n\nThe debate between sufficientists and prioritarians on the one hand and egalitarians on the other turns on deep relationships between concerns about the formalism of interpersonal measures and (by contrast) the evident strength of the moral claim of the needs of the worse off. It is true that formal interpersonal measures can mask different underlying realities that would engage different concerns about justice (and other important values). Nonetheless, a fully developed picture of those\n\n273", "n_tokens": 95, "kind": "text"}
{"chunk_id": "drug_resistance_book-283-0", "doc_id": "drug_resistance_book", "page": 283, "text": "274\n\nunderlying realities does not necessarily support the case for priority or sufficiency as goals – whether on normative grounds or on grounds of practicality. Perhaps put- ting the breaks on an underlying reality (the long term trend of growing social inequality in health) is not ultimately feasible: the role that antimicrobials have played in narrowing global health inequalities suggests as much.\n\nThe current narrowing of the global gap in life expectancy will not lead to the gap closing if there are fundamental barriers to narrowing the gap built into the path to the current achievement. What looks like a normatively satisfying narrowing of the gap is in reality a period in which a limited version of a familiar (and known to be temporary) reversal of a long term trend is playing out.\n\nIn the mid to late 20th century, it was thought that there was a limit to the long- term trend of growing health inequalities – perhaps a natural limit around 75, at which point the better-off would stop gaining life expectancy and then further gains would involve the worse-off (within and between countries) catching up. This has not come about: life expectancy at the top of the scale continues to advance and cautious observers no longer try to predict the upper limit. There is no known end to improvements in the upper limit figure, and so no natural limit to the growth of social inequality in health.", "n_tokens": 282, "kind": "text"}
{"chunk_id": "drug_resistance_book-283-1", "doc_id": "drug_resistance_book", "page": 283, "text": "This growing gap is morally complex: Who can object to saving a life of a fellow citizen on the grounds that someone far away does not have access to the same treat- ment? But our failure to imagine the downside of some having access to lifesaving interventions in their 10th and 11th decades and beyond while others have their prospects for a long and healthy life compromised by social determinants is just that – a failure of imagination.", "n_tokens": 88, "kind": "text"}
{"chunk_id": "drug_resistance_book-283-2", "doc_id": "drug_resistance_book", "page": 283, "text": "A century ago, social inequality in health meant that some buried half or more of their children before the age of 5 while others experienced this heartache less fre- quently. The moral concern we feel when learning of a gap in life expectancy between 40 and 70 is palpable; we are familiar with these narratives and the death of children is a tragedy for which children are not blamed. Social inequality in health now looks quite different. It may mean that some will enjoy long and active retirements approaching the length of their working lives, helping with grandchil- dren and greeting great-grandchildren, while others manage multiple morbidities related to chronic disease while in their later working lives, juggling this simultane- ously with responsibilities to others – perhaps the mental health challenges faced by their children, the substance use entanglements of their partner, and the caregiving needs of their parents who are in turn suffering in their 70s from the cumulative effects of their own chronic conditions as the life narrative legacy of their exposure to the social determinants of ill health. These caregiving responsibilities lead to loss of mobility and skill upgrading, leading to missed work opportunities and, in a technology-driven economy, even loss of work – and so (in turn) to late-life poverty and death shortly after retirement (if retirement is an option at all).", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-283-3", "doc_id": "drug_resistance_book", "page": 283, "text": "Through the lens of literature, we can look back sympathetically at the concrete social shape that health inequalities took in earlier eras (with Dickens, for example); the form they are taking today are often presented in statistical terms and we have yet to develop a cultural narrative that explores the relations of domination and\n\nL. Reid", "n_tokens": 66, "kind": "text"}
{"chunk_id": "drug_resistance_book-284-0", "doc_id": "drug_resistance_book", "page": 284, "text": "16 Antimicrobial Resistance and Social Inequalities in Health: Considerations of Justice\n\nsubordination and shapes the sense of intrinsic moral concern that might be raised by these differences. We are likely to think that individuals bear responsibility for these conditions (utilitarian reformers of the nineteenth century likewise thought those who were worse off responsible for their poor health). Who fundraises by run- ning a race for the cure in their 60s and who is crowd-sourcing to raise money for their own cancer treatment (for travel and loss of work income if that treatment is covered under a universal health system, or for expensive therapeutics not covered in that universal system) – and what micro, meso, and macro relations of power are embodied here?", "n_tokens": 153, "kind": "text"}
{"chunk_id": "drug_resistance_book-284-1", "doc_id": "drug_resistance_book", "page": 284, "text": "The prima facie moral plausibility of a prioritarian or sufficientist commitment is placed in question by a long-term trend towards a world in which the well-off enjoy a life expectancy – perhaps – double that of the worse-off. Suppose that the situation continued such that the person running for the cure in their 60s would become the centenarian running for the cure, and so on. How long would one remain a sufficientist? At what point would the gap become large enough that an appeal to sufficiency would ring hollow, and closing the gap would become a worthy moral commitment? If AMR makes the tertiary care that has continued the widening of the gap in the fourth stage of epidemiological transition even more expensive, at what cost and opportunity cost will we pursue the continuation of that trend or resist its reversal?", "n_tokens": 170, "kind": "text"}
{"chunk_id": "drug_resistance_book-284-2", "doc_id": "drug_resistance_book", "page": 284, "text": "Globally, the response to AMR must move beyond lip service to the most mini- mal social determinants of health (sanitation and water) and engage with the politi- cal and economic process of redistributing resources and power so that governments and professional bodies can effectively regulate pharmaceutical production, distri- bution, and prescribing across the public and private sectors, and so that the global working class and those living with the legacy of colonization and resource theft (Wenar 2008) – whose housing conditions and social security currently preclude them from benefiting from the primordial prevention of infectious and hygienic disease that most residents of HICs have at this point enjoyed for most of the past century – can survive and even flourish despite the loss of the contribution of anti- microbials to the so-called accelerated epidemiological transition.\n\nReferences\n\nAlvarez-Uria, G., S. Gandra, and R. Laxminarayan. 2016. Poverty and prevalence of antimicrobial\n\nresistance in invasive isolates. International Journal of Infectious Diseases 52: 59–61.\n\nAnderson, E. 1999. What is the point of equality? Ethics 109 (2): 287–337. ———. 2010. Justifying the capabilities approach to justice. In Measuring justice: Primary goods and capabilities, ed. H. Brighouse and I. Robeyns, 81–100. Cambridge: Cambridge University Press.\n\nAntonovsky, A. 1967. Social class, life expectancy and overall mortality. The Milbank Memorial", "n_tokens": 318, "kind": "text"}
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{"chunk_id": "drug_resistance_book-287-2", "doc_id": "drug_resistance_book", "page": 287, "text": "approach. New York: Wiley.\n\nWalzer, M. 2008. Spheres of justice: A defense of pluralism and equality. New York: Basic Books. Wenar, L. 2008. Property rights and the resource curse. Philosophy & Public Affairs 36: 2–32. Wolff, J., and A. da Shalit. 2007. Disadvantage. Oxford: Oxford University Press. World Health Organization (WHO). 2015a. Global action plan on antimicrobial resistance. http://www.who.int/antimicrobial-resistance/publications/global-action-plan/en/. Accessed 13 Dec 2018.\n\n———. 2015b. Health in 2015: from Millennium Development Goals (MDG) to Sustainable Development Goals (SDG). https://www.who.int/gho/publications/mdgs-sdgs/en/. Accessed 13 Dec 2018.\n\nYoung, I.M. 2006. Responsibility and global justice: A social connection model. Social Philosophy\n\nand Policy 23: 102–130.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.", "n_tokens": 308, "kind": "text"}
{"chunk_id": "drug_resistance_book-287-3", "doc_id": "drug_resistance_book", "page": 287, "text": "The images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\nL. Reid", "n_tokens": 76, "kind": "text"}
{"chunk_id": "drug_resistance_book-288-0", "doc_id": "drug_resistance_book", "page": 288, "text": "Chapter 17 The Economics of Resistance Through an Ethical Lens\n\nRichard D. Smith and Joanna Coast\n\nAbstract Economics is concerned with the analysis of choice and the efficient use of resources. Markets for antibiotics are heavily affected by their ‘public good’ nature and the externality that results from their consumption in terms of resistance. The non-excludability and non-rivalry associated with knowledge production in antibiotic development also has implications for the supply of antibiotics. On the demand side there are ethical issues associated with free-riding by consumers, free- riding across nations and free-riding across time. On the supply side, the lack of a pipeline for new antibiotics for the future causes both ethical and economic issues – and from both perspectives, efforts should perhaps focus more on alternatives to antibiotics and adjustments to heath care systems to reduce reliance on antibiotics. Indeed, unlike many areas of health care, where economics and ethical perspectives may differ, antimicrobial resistance is a case where the two perspectives align in terms of ensuring efficient and sustainable development and use of this precious resources. All strategies for dealing with resistance should share the same goals of achieving an optimal balance in the use of antimicrobial agents and explicit consid- eration of the distributional implications.\n\nKeywords Economics · Externalities · Public-goods · Free-riding · Discounting\n\n17.1", "n_tokens": 269, "kind": "text"}
{"chunk_id": "drug_resistance_book-288-1", "doc_id": "drug_resistance_book", "page": 288, "text": "Introduction\n\nAntimicrobial resistance has finally come to the fore on national and international agendas, and is now recognised as a critical threat to public health, modern health systems, and economies (Smith 2015) [Ref: Chap. 1]. Although the broad potential\n\nR. D. Smith (*) College of Medicine and Health, University of Exeter, Exeter, UK e-mail: rich.smith@exeter.ac.uk\n\nJ. Coast Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_17\n\n279", "n_tokens": 176, "kind": "text"}
{"chunk_id": "drug_resistance_book-289-0", "doc_id": "drug_resistance_book", "page": 289, "text": "280\n\nR. D. Smith and J. Coast\n\nimpacts of resistance are clear – that less effective treatments means greater morbid- ity and mortality, more expensive treatments or hospital care, and more time off work – robust evidence on the extent of likely impacts of resistance on population health, health care and economies remains relatively limited and often contentious (Coast et al. 1996, 2002; O’Neill 2014; Smith and Coast 2013; Wilton et al. 2002). Like climate change, this lack of clarity stems from inherent uncertainty; in the case of resistance, relating to uncertainties around the growth path of resistance over time, the functional form of the relationship between resistance and antibiotic use, and estimates of the direct morbidity and mortality impacts attributable to resistance rather than underlying infection or other causes (Cormican and Vellinga 2012; Courvalin 2008).", "n_tokens": 179, "kind": "text"}
{"chunk_id": "drug_resistance_book-289-1", "doc_id": "drug_resistance_book", "page": 289, "text": "However, apart from such uncertainties, a significant issue is the nature of the decision- making around the production and consumption of antibiotics. Although an intrinsically biological phenomenon, the conditions promoting, or mitigating against, the development and spread of antimicrobial resistance are shaped by choices that are made by farmers and vets, doctors and patients, industry and gov- ernments, amongst others, concerning what antibiotics to produce, purchase and use (Smith 2015). Economics, at its foundation, is concerned with analysing and evalu- ating such choices: what and why certain choices are made over others; the condi- tions under which such choices are made, and how different conditions affect those choices; and, crucially, whether these choices are the ‘best’ ones (that is, whether they are ‘efficient’ in the sense that no greater benefit could be gained from another choice that was available).", "n_tokens": 190, "kind": "text"}
{"chunk_id": "drug_resistance_book-289-2", "doc_id": "drug_resistance_book", "page": 289, "text": "These choices are determined through some sort of ‘market’, broadly defined as a place (physical or virtual) where goods are traded. In this case, for example, a market is where patients and doctors will determine whether an antibiotic will be prescribed, or where a vet and a farmer agree on a course of action for sick animals. Regardless of whether money changes hands, this is the point where an antibiotic supplier will engage with the consumer. Markets also underpin whether, what and how much a producer may invest in production of antibiotics, and the price that the payer (the consumer or their agent, often governments or insurers in the case of healthcare) will pay.\n\nHowever, markets for antibiotics are heavily affected by two forces which are important when considering the development of antimicrobial resistance and strate- gies to reduce resistance. First, there are significant ‘public good’ attributes to anti- biotics that affect use and distribution. This means that markets, left alone, will ‘fail’; that is, they will not result in a socially optimal level of either production or consumption of antibiotics (Smith and Coast 2003). Second, there are ‘externality’ effects – effects not included in the decision to consume – that are important, and again means that, left alone, the market will ‘fail’ and not result in a social optimum of antibiotic consumption (Coast et al. 1998).", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-289-3", "doc_id": "drug_resistance_book", "page": 289, "text": "Together, these two forces drive the under- and/or over-use of antibiotics com- pared to what is optimal from a societal perspective. This creates major issues for economic efficiency, as different choices would improve overall societal welfare, but also for ethics, in the sense that there will be equity impacts that create problems", "n_tokens": 64, "kind": "text"}
{"chunk_id": "drug_resistance_book-290-0", "doc_id": "drug_resistance_book", "page": 290, "text": "17 The Economics of Resistance Through an Ethical Lens\n\nof distributive (in)justice in access to antibiotics and in the impact of antimicrobial resistance (Coast and Smith 2015).\n\nThis chapter describes the core economic features of antimicrobial resistance – the public good and externality forces – through an ethics ‘lens’, focussing espe- cially on the resultant economic and ethical problems of free-riding in both production and consumption. The chapter begins with outlining the core economic perspective on antimicrobial resistance – the market, public goods and externali- ties – in more detail. From this basis, the chapter then turns to consider the specific issues related to the demand side and then the supply side, focussing on the ethics of the economics, and reflecting on possible strategies to address resistance. In par- ticular, these sections consider the development of appropriate incentives by gov- ernments to address free-riding within countries and the development of appropriate incentives by international agencies to address free-riding across countries. Such incentive mechanisms are evaluated both in terms of their value in addressing the economic market- failure and their ethical implications. The chapter concludes with a brief reflection on antimicrobial resistance as a specific case where economic and ethical concerns converge.\n\n17.2\n\nAntimicrobial Resistance and ‘The Market’", "n_tokens": 271, "kind": "text"}
{"chunk_id": "drug_resistance_book-290-1", "doc_id": "drug_resistance_book", "page": 290, "text": "At its most fundamental, the market for antibiotics seeks to equate demand for them by patients (and farmers or those with pets, although in this chapter we will focus on use in humans only) with supply by providers (doctors, pharmacists or over-the- counter stores for example). Patients demand antibiotics because of the impact they (are believed to have) on a health issue, such as a sore throat or urinary-tract infec- tion. There are well-known problems in the market for healthcare goods and ser- vices, including the lack of information held by the patient upon which to decide on whether, or how much, healthcare to demand, the resultant need of the patient to rely on an (in economic terminology) ‘agent’ (usually a medical professional) to help the patient decide on what to consume, and, often, the separation of the patient from payment through the role of a third-party funder – typically government or insurer (Guiness and Wiseman 2011). Markets in healthcare are, therefore, far from perfect, and thus often subject to government intervention in their provision and/or financing. These problems are also, at least partly, responsible for ethical concerns for distributive justice, as they can leave many individuals with no, or inadequate, access to healthcare. Over time, this has led to increased calls for initiatives to ensure ‘universal health coverage’; it is now a major thrust of the World Health Organization and World Bank to deal with general market failures in healthcare", "n_tokens": 315, "kind": "text"}
{"chunk_id": "drug_resistance_book-290-2", "doc_id": "drug_resistance_book", "page": 290, "text": "and to increase access (World Health Organization 2015), whilst the specific market failures around antimicrobial resistance are dealt with through other agendas, such as the Sustainable Development Goals (Hanefeld et al. 2017).", "n_tokens": 46, "kind": "text"}
{"chunk_id": "drug_resistance_book-290-3", "doc_id": "drug_resistance_book", "page": 290, "text": "281", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-291-0", "doc_id": "drug_resistance_book", "page": 291, "text": "282\n\nR. D. Smith and J. Coast\n\n17.2.1\n\nExternalities", "n_tokens": 17, "kind": "text"}
{"chunk_id": "drug_resistance_book-291-1", "doc_id": "drug_resistance_book", "page": 291, "text": "Beyond general issues of failure in healthcare markets, there are two specific fea- tures of the market for antibiotics that are significant in considering the generation of antimicrobial resistance, and in establishing policies to contain it (Coast et al. 1998). First, there are externality effects from the consumption of antibiotics. An externality is an effect that is outside of the immediate producer or consumer, and thus does not influence decision-making in the choice about whether to produce or consume that antibiotic. So, for the patient, the direct (expected) benefit of the anti- biotic in treating an infection informs his or her decision, as do possible side-effects from taking it, along with any monetary cost associated with its purchase. However, a ‘positive externality’ that is not generally expected to be taken into account by this patient is the benefit to those individuals who would, in the absence of antibiotics, have been infected by them – that is, there is an external benefit associated with reduced transmission of pathogens. The existence of this positive externality means that, the market will under-provide antibiotics; it might be a good reason for a sub- sidy or other policy to reduce the private cost to individuals. There is also an ethical issue involved here. There is a responsibility for each individual to consider the impact of their choice about receiving treatment on the wider community – that part of their decision to take treatment should,", "n_tokens": 290, "kind": "text"}
{"chunk_id": "drug_resistance_book-291-2", "doc_id": "drug_resistance_book", "page": 291, "text": "morally, include consideration of the impact of (reduced) infection on the wider population.", "n_tokens": 17, "kind": "text"}
{"chunk_id": "drug_resistance_book-291-3", "doc_id": "drug_resistance_book", "page": 291, "text": "More critically for the discussion here is that there is also a major ‘negative’ externality from consumption of antibiotics – antimicrobial resistance. It is impor- tant to note that this externality is not associated with the production of antibiotics but with their consumption. The effects of antibiotic use, in terms of the sustained effectiveness of that antibiotic for others, or for the same individual in the future, do not influence the costs that must be paid by the patient, nor the benefits to them of taking the antibiotic now. They are therefore unlikely to be considered in the deci- sion to purchase and consume that antibiotic (by either the patient or the health professional acting as their agent). From a societal perspective there is thus an over- consumption of antibiotics. Again, there are distributive issues here around the use of a limited resource knowing that it will generate possible greater ill-health in the future and/or for others.", "n_tokens": 196, "kind": "text"}
{"chunk_id": "drug_resistance_book-291-4", "doc_id": "drug_resistance_book", "page": 291, "text": "On balance, the optimal consumption of antibiotics from a societal perspective is a balance of the costs and benefits that accrue directly to the individual concerned, plus these external benefits and costs to society (Coast et al. 1998). In recent years, consensus has been that on balance there is over-consumption – that the private costs and benefits and the positive externality are being severely compromised by not accounting for the negative externality of resistance. Focus has therefore been to see how these external costs of resistance can be internalised in to the decision to consume (in addition to how to increase the supply of effective antibiotics). We look at these strategies – affecting the demand and supply sides respectively – later in this chapter.", "n_tokens": 143, "kind": "text"}
{"chunk_id": "drug_resistance_book-292-0", "doc_id": "drug_resistance_book", "page": 292, "text": "17 The Economics of Resistance Through an Ethical Lens\n\n17.2.2", "n_tokens": 14, "kind": "text"}
{"chunk_id": "drug_resistance_book-292-1", "doc_id": "drug_resistance_book", "page": 292, "text": "Public Goods\n\nSecond, there are ‘public good’ aspects associated with antibiotics [Ref: Chap. 8]. Most goods are what we term as ‘private’ in nature: their consumption can be with- held until a payment is made in exchange, and once consumed they cannot be con- sumed again (Woodward and Smith 2003). For example, the consumption of a cake can be withheld from the consumer until the consumer pays the baker a price, and once the consumer has eaten that cake it cannot be eaten again. A private good is therefore considered ‘excludable’ and ‘rival in consumption’. At the other end of the spectrum lie public goods, which are defined as having the opposite characteristics. That is, the benefits, once the good is provided, cannot be restricted and are there- fore available to all (i.e. non-excludable), and consumption by one individual does not limit consumption of that same good by others (i.e. non-rival in consumption). A classic example is the service provided by a lighthouse: the warning it provides is available to all who would benefit from it, and one ship’s use of it does not limit the ability of other ships to use it. Virtually all public goods are such services or other intangibles, with few, if any, ‘commodities’ (in the narrow sense of physical objects) meeting these criteria (the exception to this being physical infrastructure, such as sewage systems, which once completed are largely non-rival in consumption, and difficult to exclude people from using).", "n_tokens": 323, "kind": "text"}
{"chunk_id": "drug_resistance_book-292-2", "doc_id": "drug_resistance_book", "page": 292, "text": "However, both excludability and rivalry are relative, not absolute, concepts, and there is a scale of both rivalry and excludability. For example, access to public goods in particular may be specific to geography (e.g. conventional television broadcasts, while they broadly satisfy the criteria for a public good, reach only an area defined by the location of transmitters, the strength of signals and topographi- cal constraints) or can be artificially made excludable (such as by using encryption services for satellite broadcasts). These create ‘club goods’, which are non-rival and are non-excludable to those who can access the ‘club’, but excludable to those out- side of the club. Thus, some people could be (and often are) excluded from the benefits of most theoretically defined public goods through geographic, monetary or administrative prohibition. Similarly, rivalry in consumption may be relative to capacity, particularly in the case of physical infrastructure. For example, if a sewage system has spare capacity its use is non-rival, but as the capacity constraint is approached, its use becomes rivalrous; that person whose use of it causes capacity to be reached has effectively prevented the next person wishing to use it from doing so. Perhaps more usual is that the consumption of a particular good may not prevent others from using it, but simply reduces the benefits available. For example, one person’s use of a road does not usually prevent use by others, but the use of the", "n_tokens": 309, "kind": "text"}
{"chunk_id": "drug_resistance_book-292-3", "doc_id": "drug_resistance_book", "page": 292, "text": "road becomes less beneficial as more and more people use it and the road consequently becomes more congested. This is sometimes termed the ‘tragedy of the commons’ (Hardin 1968), Chap. 8.", "n_tokens": 41, "kind": "text"}
{"chunk_id": "drug_resistance_book-292-4", "doc_id": "drug_resistance_book", "page": 292, "text": "Of key importance, is that ‘markets’ under-supply public goods. First, non- excludability means that a price cannot be enforced, leading to ‘free-riding’ (one person can benefit from the actions of another person without reciprocation) and\n\n283", "n_tokens": 57, "kind": "text"}
{"chunk_id": "drug_resistance_book-293-0", "doc_id": "drug_resistance_book", "page": 293, "text": "284\n\nR. D. Smith and J. Coast\n\nthus there is no incentive for anyone to produce or purchase the good. Second, non- rivalry means that the socially optimal level of consumption is far greater than the level that occurs at the ‘market price’ (Smith and Coast 2003).\n\nTo be clear, antibiotics are not themselves public goods – they can be made excludable, and they are rival in the sense that if I use one dose no one else can use that exact same dose.", "n_tokens": 101, "kind": "text"}
{"chunk_id": "drug_resistance_book-293-1", "doc_id": "drug_resistance_book", "page": 293, "text": "However, the knowledge they embody in their development, and the resultant property of reduced infection (bearing in mind the externality properties above) means that they have significant public good attributes associated with them. Once developed, the knowledge required to produce the antibiotic can be made (virtually) freely available as dissemination of it is quick and cheap, and any one firm using it to produce the antibiotic does not prevent another from doing so. We will return to this aspect in the section concerning the supply of antibiotics in light of resistance. It also means that the benefits resulting from the consumption of the antibiotic, of reduced infection, cannot be made excludable – we all benefit from reduced trans- mission of pathogens – and is non-rival – my benefiting from this reduced risk of infection does not diminish you equally benefitting from it. And vice-versa – the reduced effectiveness of antibiotics due to resistance is also non-rival and non- excludable. It is this consumption side to which we now turn.\n\n17.3\n\nThe Ethics and Economics of Demand\n\nThe characteristics of non-excludability and non-rivalry have important implica- tions for the economics and ethics of the demand/consumption side of the market for antibiotics from a number of perspectives.\n\n17.3.1", "n_tokens": 265, "kind": "text"}
{"chunk_id": "drug_resistance_book-293-2", "doc_id": "drug_resistance_book", "page": 293, "text": "Free-Riding by Consumers\n\nConsumers have an incentive to engage in free-riding, meaning that they have no incentive to reduce their own use of antibiotics, but rather to wait for others to do so, Chap. 21. This is perhaps also seen as morally acceptable as each individual consumption of each individual course of antibiotics will only add infinitesimally to the problem of resistance; an individual’s personal consumption of antibiotics really is a ‘drop in the ocean’ relative to the total consumption of antimicrobials (Smith and Coast 2013). There are strong parallels here with climate change of course. Overall, the antimicrobial resistance problem is the accumulation of many millions of decisions by different decision makers for different patients in different health systems and facing different personal, financial and organizational incentives. Economic policies in general aim to induce consumers to internalize the costs of any negative externality, but because of the huge diffusion of the problem in relation to resistance, such policies may be very challenging if even possible at all.", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-294-0", "doc_id": "drug_resistance_book", "page": 294, "text": "17 The Economics of Resistance Through an Ethical Lens\n\nFor example, system interventions to address free-riding include taxation (akin to Pigovian taxes or pollution charges in the case of climate change), subsidy, per- mits or regulation (Coast et al. 1998; Laxminarayan et al. 2010; Smith and Coast 1998) although each of these would have their own distributional implications (Coast and Smith 2015), Chap. 8. Examples of clinical interventions that may address this issue may include better diagnostics (Kolmos and Little 1999; Oppong et al. 2013; Rice 2011) or educational campaigns providing better information (Goossens et al. 2006; Huttner et al. 2010), combined with a gatekeeping role from healthcare providers. Other possibilities include focussing more on assessing option or existence value (the idea that individuals have some personal utility from know- ing that the option for them to consume antimicrobials in the future will be retained) (Coast et al. 2006). However, it is more likely that benefits may come from encour- aging a greater moral responsibility to avoid resistance within society, such as has been undertaken with climate change and pollution, or as a parallel to stronger regu- lations, such as with banning smoking in public places, compulsory wearing of seatbelts in cars or drink-driving campaigns.\n\n17.3.2", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-294-1", "doc_id": "drug_resistance_book", "page": 294, "text": "Free-Riding Across Nations\n\nThese issues of individual free-riding are also paralleled by free-riding across macro-settings. Actions taken by current patients have the potential to transmit resistance, through the pathogen this resistance is associated with, across interna- tional, cultural and ethnic boundaries. Antimicrobial resistance does not respect regional or national boundaries, with resistant organisms being able to travel from one setting to another just as easily as sensitive ones (Smith and Coast 2002). Globalization has increased the rate at which infectious diseases can travel, and resistances identified in one area are rapidly found in other countries and on other continents. Such spread will be dependent on many epidemiological factors, includ- ing for example, socio-demographic factors, density of the population, natural disasters, hygiene levels and so on. Areas with greater poverty may be particularly susceptible to the rapid spread of infection and thus the deleterious effects of resistance.\n\nTransmission of resistance may have particularly severe consequences for econ- omies which already suffer greatly from infectious disease – countries where living conditions are poor and where there are high proportions of individuals with immune-compromise – but it will also have significant economic and health conse- quences at a global level (Smith and Coast 2002).", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-294-2", "doc_id": "drug_resistance_book", "page": 294, "text": "Indeed, transmission of resistance across national boundaries compromises mea- sures that individual countries may put in place to try to combat resistance; import- ing resistance from elsewhere may negate national initiatives, rendering them effectively pointless. Conversely, countries may do little to address resistance within their own borders, relying on the activities of other countries to reduce levels of resistance that come in and out of the country; effectively, individual countries may\n\n285", "n_tokens": 86, "kind": "text"}
{"chunk_id": "drug_resistance_book-295-0", "doc_id": "drug_resistance_book", "page": 295, "text": "286\n\nR. D. Smith and J. Coast\n\n‘free-ride’ on the actions of the wider global community and the containment poli- cies operated in other settings. The potential for resistance to spread across bound- aries reduces the incentive for any single country to act against resistance – either because it will appear futile in the face of a global rise in resistance, or because the optimal approach is to await every other country to act first – which means that none will.\n\nThe total effort devoted to containing antimicrobial resistance is thus likely to be suboptimal because some nations will rely on the efforts of other nations. This dilemma facing the creation of collective action against antimicrobial resistance at the global level has been highlighted elsewhere (Årdal et al. 2016; Smith and Coast 2002), although it has recently been suggested that international law may provide a means of dealing with the problem of collective action in this context (Hoffman et al. 2015a; Walls and Ooms 2017), Chaps. 24 and 25.", "n_tokens": 210, "kind": "text"}
{"chunk_id": "drug_resistance_book-295-1", "doc_id": "drug_resistance_book", "page": 295, "text": "Despite the importance of the global issue in this context, economic (and other) assessments tend to be conducted on a national basis as if systems are closed to the outside world. Opening this up would promote awareness that it is in national self- interest to look to address resistance in other countries, and thus contribute to global initiatives, as well as be open to moral arguments, such as those that drive consider- able development funds each year from developed to less developed nations (Molzon et al. 2011).\n\n17.3.3\n\nTime Preference and Discounting: Free-Riding Across Time\n\nThe externality effect is also inter-generational, generating significant issues of inter- generational as well as regional equity. Actions taken by current patients will impact on the transmission and emergence of resistance for future generations, but with similar lack of incentive for either individual consumers or nation states to fully account for the impact of their decisions on others.", "n_tokens": 186, "kind": "text"}
{"chunk_id": "drug_resistance_book-295-2", "doc_id": "drug_resistance_book", "page": 295, "text": "The relevant economic concept here is that of time-preference and discounting – that people place higher weight on benefits that occur now and costs that occur in the future, thus biasing decisions and choices against future generations (even including themselves in that future generation). The discount rate is the amount at which future years are ‘discounted’, where a rate of 0 would give equal weight to the current and any future year, and 100% would give total weight to the current year and count future years as worthless. Thus, a higher rate places more weight on the present. Empirical literature finds huge variance in expressed discount rates, but this is overwhelmingly based on personal perspectives (Asenso-Boadi et al. 2008). These, typically high, rates are not consistent with the normative arguments that are considered when intergenerational equity is discussed, and less weighting explicitly given to current generations (Olsen and Richardson 2013; Richardson and McKie 2007). The authors have also previously noted that discount rates with respect to", "n_tokens": 206, "kind": "text"}
{"chunk_id": "drug_resistance_book-296-0", "doc_id": "drug_resistance_book", "page": 296, "text": "17 The Economics of Resistance Through an Ethical Lens\n\nantimicrobial resistance “should reflect collective value judgements and moral issues, rather than just the preference that individuals have for their own consump- tion over time” (Coast et al. 1996). This is important as high discount rates would result in an almost exclusive focus on the current population, and would probably also mean that the focus would be on interventions intended to reduce transmission of antimicrobial resistance, which has relatively short-term gains, rather than inter- ventions intended to reduce emergence of new resistances, which may be further down the line (but where the total benefits in the absence of discounting may be much greater). This issue is examined in greater detail elsewhere (Coast et al. 2002).\n\n17.3.4", "n_tokens": 164, "kind": "text"}
{"chunk_id": "drug_resistance_book-296-1", "doc_id": "drug_resistance_book", "page": 296, "text": "The Importance of Context\n\nOn the consumption side, therefore, the focus of policy is on incentives and systems to influence demand through education of patients, restriction of availability through regulation, or greater guidance to providers (Dar et al. 2016). There are huge chal- lenges in this respect, not only of construction, enforcement and evaluation of any single policy, but also across contexts. Policy in most developed countries is con- cerned with reducing the over-use of antibiotics – their use where there is little or no clinical indication, such as for the common cold, their use where there is marginal clinical benefit (e.g. many minor infections in otherwise healthy people, which may hasten their cure by a few days only) and even use where there may be greater mor- bidity but the disease is not fatal. In contrast in many low- and middle-income coun- tries the challenges are to increase use, where appropriate, to reduce pools of infection, and to reduce practices of dose splitting, use of sub-standard, out-of-date or counterfeit medicines, and cross use of antibiotics for humans and animals (Review on antimicrobial resistance 2015a).\n\n17.4", "n_tokens": 244, "kind": "text"}
{"chunk_id": "drug_resistance_book-296-2", "doc_id": "drug_resistance_book", "page": 296, "text": "The Ethics and Economics of Supply\n\nExternality and public good aspects are not only relevant to consumers, but also to the producers of antibiotics. The supply-chain of antibiotics is long – from original discovery, research and development, which may be in universities, through testing and eventual production by a pharmaceutical company, through wholesalers, health systems or private pharmacy and retailers (with prospects for counterfeit or sub- standard antibiotics being introduced along the way), Chap. 5 However, critical to this discussion is the core discovery, development and production of the antibiotics; especially that undertaken in the private sector.\n\nIt has been noted many times that there has been a distinctly dry pipeline for new antibiotics over recent decades, with no new class of antibiotic being discovered for many years and declining investment by the pharmaceutical industry in the area of anti-infectives (Cormican and Vellinga 2012). What underlies this is the current\n\n287", "n_tokens": 187, "kind": "text"}
{"chunk_id": "drug_resistance_book-297-0", "doc_id": "drug_resistance_book", "page": 297, "text": "288\n\nR. D. Smith and J. Coast\n\nbusiness model for the development of pharmaceuticals, which is based on a market response to ‘free-riding’ (Smith et al. 2009).\n\n17.4.1\n\nFree-Riding and Intellectual Property\n\nBasic research and development of new drugs is hugely expensive, but the informa- tion that is produced from this research and development activity – such as the chemical formulation of a new antibiotic – is almost costless to disseminate, is very hard (especially in the internet age) to exclude other companies having access to, and is non-rival in the sense that me using this information to produce the drug does not prevent you also using the information to produce the drug. Thus, given the non- excludability of this information, it is socially optimal to encourage wide dissemi- nation and use of it, which can be achieved at almost zero cost once produced. But, the inability to exclude means that a high-price cannot be charged for it to recoup the original investment in its production, and so other producers can ‘free-ride’ on the back of the one who first produced the information. Since the original producers cannot recoup their costs, let alone gain a profit, then there is no incentive for that information to be produced. Hence, left to this pure market system, there would be no medicines developed (Smith and Coast 2003).", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-297-1", "doc_id": "drug_resistance_book", "page": 297, "text": "The ‘solution’ to this situation has been to develop an artificial exclusion system to enable the original producer who discovers and develops the information to charge a higher price to compensate for the research and development costs incurred. This is the ‘Intellectual Property Right’ system, which in the case of pharmaceuti- cals is operationalised through a patent (Smith et al. 2009). This system confers a legal exclusion to be placed on others using material that is patented for a specified number of years – usually 20–30. During this time whoever filed the patent, such as the pharmaceutical company, has exclusive rights to use it and can therefore charge a sufficiently high price for the medicine it develops from it to allow it to recoup the costs invested, and to make a profit (Yamabhai and Smith 2015).", "n_tokens": 167, "kind": "text"}
{"chunk_id": "drug_resistance_book-297-2", "doc_id": "drug_resistance_book", "page": 297, "text": "This ‘solution’, however, creates a critical problem for both efficiency and ethics. Due to the non-rival nature of the information – and the non-rival nature of the resultant reduction in infectious disease risk from taking the antibiotic that is based on the information – it is most socially efficient if it is widely disseminated and used. The patent system creates a restriction on that use, since only those who can afford to pay the price now charged can access it, which will be at a level lower than is socially optimal. Ethically, it also means that the information – and resultant anti- biotics – are only available at a much higher price than the production cost, with the known consequence that there will be people who can benefit who are being denied that treatment (Mendelson et al. 2016). The ‘patent wedge’ between cost price and the price charged by the patent holder can typically by seen when the patent period expires and ‘generic’ versions of branded pharmaceuticals are made available, which are often hundreds of times cheaper (Smith et al. 2009). During the patent period there are clearly therefore poorer people, and countries, that are not able to", "n_tokens": 238, "kind": "text"}
{"chunk_id": "drug_resistance_book-298-0", "doc_id": "drug_resistance_book", "page": 298, "text": "17 The Economics of Resistance Through an Ethical Lens\n\nafford to access these drugs and where ill-health is suffered as a result. For example, the most infamous case is that relating to anti-retroviral therapies for HIV/AIDS which were priced at over US$10,000 per person per year by those producing branded products, but could be produced by generic manufacturers for US$365 per patient per year (Keppler 2013). This is both inefficient and unethical (Laxminarayan et al. 2016). Inequality in access due to price – especially for those in low-income settings – has been the cause of considerable debate more widely with respect to medicines (Trouiller et al. 2002).\n\nThere is added complexity in the case of antibiotics, compared to other medi- cines, in part due to the nature of antibiotics, which are relatively inexpensive com- pared to other drugs that could be developed and are used for short periods of time (thus reducing the potential profit), and in part due to the development of resistance, as polices elsewhere seek to reduce and restrict use. This is especially the case in high-income countries, which is where the major markets for new antibiotics are based and where companies expect to be able to charge the higher-prices required to support research and development. The combination then of the high develop- ment cost, with reduced market volume, has discouraged investment in this area.\n\n17.4.2", "n_tokens": 304, "kind": "text"}
{"chunk_id": "drug_resistance_book-298-1", "doc_id": "drug_resistance_book", "page": 298, "text": "Alternative Systems\n\nOver the years there have been growing calls for changes to the patent system as underpinning research and development in pharmaceutical in general, largely from those concerned about the bias towards health needs of high-income countries who are the major markets, resulting in concerns around ‘neglected diseases’ (Trouiller et al. 2002), Chap. 10. More recently, especially following the report from the Independent Review on Antimicrobial Resistance, chaired by Lord Jim O’Neill, there has been a renewed push for the development of new systems for incentivising investment in new antibiotics, where high-income countries too have considerable need that is not being met (Review on antimicrobial resistance 2015a).", "n_tokens": 147, "kind": "text"}
{"chunk_id": "drug_resistance_book-298-2", "doc_id": "drug_resistance_book", "page": 298, "text": "One popular alternative is the de-linking of profitability from sales volumes (Brogan and Mossialos 2016; Review on antimicrobial resistance 2015b; Wise 2015). For example, pre- purchase agreements could be made by governments to guarantee the pharmaceutical company a minimum ‘market’ in terms of sales, but then the government can choose whether and how those drugs would be dissemi- nated. This builds on other recent work, such as by Chatham House, a think-tank on international affairs, which has outlined alternative business models to similarly change the current financial models for encouraging and supporting research and development in new antibiotics (Kesselheim and Outterson 2010; Outterson 2014; Outterson et al. 2015). There is a lot of work and funding also now going in to research and development by governments themselves to directly develop new anti- biotics. For example, The U.S. granted GlaxoSmithKline US$200 million for investment in new antibiotic research and development (GlaxoSmithKline 2013). There are also other initiatives. In the United States for instance there has been an\n\n289", "n_tokens": 237, "kind": "text"}
{"chunk_id": "drug_resistance_book-299-0", "doc_id": "drug_resistance_book", "page": 299, "text": "290\n\nR. D. Smith and J. Coast\n\nextension to marketing exclusivity, accelerated review, and a relaxation of require- ments for approval by the Food and Drug Administration (Hatch 2015). Although this leniency may have increased the development and launch of new antibiotics, there is worrying evidence that such ‘fast tracking’ may generate considerable adverse effects (Doshi 2015).", "n_tokens": 79, "kind": "text"}
{"chunk_id": "drug_resistance_book-299-1", "doc_id": "drug_resistance_book", "page": 299, "text": "Critical, of course, is the basic fact that because resistance to an antibiotic begins as soon as it is developed, new agents can never be the sole solution—and are unlikely to be the most cost-effective or sustainable, Chap. 19. Thus, in addition to looking at encouragement of new drug discovery, another focus has been on initia- tives to support the sustainable use of current antibiotics through the development of rapid diagnostic tests to support the more ‘appropriate’ use of antibiotics (Review on antimicrobial resistance 2015a). In the UK there have been specific funds made available to support diagnostics research and development through the UK Research Councils (Medical Research Council 2014), and the Longitude Prize, where £1 m is to be awarded to whoever first develops a specific rapid – and affordable – diagnos- tic tool (Nesta 2014). The critical issue here is the last one – affordability. Diagnostic tests face a challenge of affordability in relation to the option to simply take the – currently cheaper – antibiotic. The cost of the test relative to the cost of the antibi- otic is critical – if the test costs more than, or even approximates, the antibiotic cost then it is likely to be rational for individuals to simply take the antibiotic and risk it not working – if it does work they save the cost of the test, if it does not work then they may need another drug but have still saved the cost of the test, whereas if they have the test and don’t need an antibiotic", "n_tokens": 315, "kind": "text"}
{"chunk_id": "drug_resistance_book-299-2", "doc_id": "drug_resistance_book", "page": 299, "text": "they may have incurred a cost greater than that of simply taking the antibiotic, and if the test suggests they do need that antibi- otic all they have done is add a cost of the test on to what they would have paid in any case. There are challenges especially for this in community settings, rather than hospitals, and in low- and middle-income countries.", "n_tokens": 76, "kind": "text"}
{"chunk_id": "drug_resistance_book-299-3", "doc_id": "drug_resistance_book", "page": 299, "text": "Given that a critical feature of antimicrobial resistance is that it occurs naturally for all antibiotics, developing new drugs may win successive battles but not the war. It is possible that genomic developments may produce antibiotics where resistance is not seen, or new ways to tackle pathogens. However, in the absence of those, the most serious issue is not, perhaps, systems for encouraging development in new technologies, but rather how to design health systems that are less reliant on antibi- otics. Modern healthcare especially, has been built on the basis that infections can be prevented or treated easily and cheaply. Healthcare has become increasingly technological and invasive, and antibiotics have become integrated in many aspects of care, from prevention of iatrogenic infection in surgery, to women delivering by caesarean section to those having cancer treatment (Smith 2015). From both eco- nomic and ethical perspectives efforts should perhaps focus more on alternatives to antibiotics and on adjustments to health systems and care pathways to reduce reli- ance upon antibiotics.", "n_tokens": 206, "kind": "text"}
{"chunk_id": "drug_resistance_book-300-0", "doc_id": "drug_resistance_book", "page": 300, "text": "17 The Economics of Resistance Through an Ethical Lens\n\n17.5", "n_tokens": 12, "kind": "text"}
{"chunk_id": "drug_resistance_book-300-1", "doc_id": "drug_resistance_book", "page": 300, "text": "Discussion: The Convergence of Ethics and Economics\n\nFar from the ‘dismal science’, or the often perceived amoral (if not immoral) nature of economics being in conflict with ethics, antimicrobial resistance is a case where the two perspectives are frequently aligned. Many of the economic imperatives for ensuring the efficient and sustainable development and use of antibiotics are in-line with major ethical principles to secure benefits that are equitably available and dis- tributed. In this sense, from an economic and ethical perspective, we are seeking to:\n\nDevelop alternative systems to support the discovery, development and produc- tion of new antibiotics that are effective for all major infectious diseases globally • Ensure that these antibiotics are available to those populations that would benefit from them, wherever they are in the world\n\nLook for alternatives to reduce reliance on antibiotics – alternatives for the same treatment or prevention of infection, and alternatives to avoid infection and risk of infection and hence requirement for antibiotics or their substitutes It is also important to note that, at least from an economics perspective, the ‘erad- ication’ of resistance is not necessarily a desirable goal. To eradicate resistance entirely – or even to maintain resistance at current levels – would require significant, if not total, reduction in the use of antibiotics, as the use of any antibiotic will lead to the development of some resistance.", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-300-2", "doc_id": "drug_resistance_book", "page": 300, "text": "Such a goal would imply allowing significant mortality and morbidity to be incurred – far in excess of that caused by the resistance itself. The aim must there- fore be to use the available strategies to optimise the balance between the current use of effective antibiotics to treat infection, and thus reduce morbidity and mortal- ity today, and minimising the emergence and spread of resistance to these antibiot- ics and the consequent increased future morbidity and mortality. This balance depends upon the relative costs and benefits of the positive and negative effects involved. It is determining this balance that is critical, and requires consideration from both an economics and an ethical perspective, as it encompasses significant inter-generational and inter-regional distributional aspects.\n\nGiven the diverse contexts of the developed and developing nations, it is likely that optimal strategies will vary considerably across these them, but all strategies should share the same goals of achieving an optimal balance in the use of antimicro- bial agents (Hoffman et al. 2015b; Woolhouse and Farrar 2014) and explicit consid- eration of the distributional implications.\n\n291", "n_tokens": 232, "kind": "text"}
{"chunk_id": "drug_resistance_book-301-0", "doc_id": "drug_resistance_book", "page": 301, "text": "292\n\nR. D. Smith and J. Coast\n\nReferences\n\nÅrdal, C., K. Outterson, S.J. Hoffman, A. Ghafur, M. Sharland, N. Ranganathan, et al. 2016. International cooperation to improve access to and sustain effectiveness of antimicrobials. The Lancet 387 (10015): 296–307.\n\nAsenso-Boadi, F., T.J. Peters, and J. Coast. 2008. Exploring differences in empirical time prefer- ence rates for health: An application of meta-regression. Health Economics 17: 235–248. Brogan, D.M., and E. Mossialos. 2016. Systems, not pills: The options market for antibiotics seeks\n\nto rejuvenate the antibiotic pipeline. Social Science & Medicine 151: 167–172.\n\nCoast, J., and R.D. Smith. 2015. Distributional considerations in economic responses to antimicro-\n\nbial resistance. Public Health Ethics 8 (3): 225–237.\n\nCoast, J., R.D. Smith, and M.R. Millar. 1996. Superbugs: Should antimicrobial resistance be\n\nincluded as a cost in economic evaluation? Health Economics 5: 217–226.\n\n———. 1998. An economic perspective on policy to reduce antimicrobial resistance. Social", "n_tokens": 289, "kind": "text"}
{"chunk_id": "drug_resistance_book-301-1", "doc_id": "drug_resistance_book", "page": 301, "text": "Science and Medicine 46 (1): 29–38.\n\nCoast, J., R.D. Smith, P. Wilton, A.M. Karcher, and M.R. Millar. 2002. Superbugs II: How should economic evaluation be conducted for interventions which aim to reduce antimicrobial resis- tance? Health Economics 11 (7).\n\nCoast, J., R.D. Smith, and M.R. Millar. 2006. Disentangling value: Assessing the benefits of containing antimicrobial resistance. In The economics of infectious disease, ed. J.A. Roberts, 201–214. Oxford: Oxford University Press. (Reprinted from: In File).\n\nCormican, M., and A. Vellinga. 2012. Existing classes of antibiotics are probably the best we will\n\never have. British Medical Journal 344: e3369.\n\nCourvalin, P. 2008. Predictable and unpredictable evolution of antibiotic resistance. Journal of", "n_tokens": 209, "kind": "text"}
{"chunk_id": "drug_resistance_book-301-2", "doc_id": "drug_resistance_book", "page": 301, "text": "Internal Medicine 264 (1): 4–16.\n\nDar, O.A., R. Hasan, J. Schlundt, S. Harbarth, G. Caleo, F.K. Dar, et al. 2016. Exploring the evi- dence base for national and regional policy interventions to combat resistance. The Lancet 387 (10015): 285–295.\n\nDoshi, P. 2015. Speeding new antibiotics to market: A fake fix? BMJ: British Medical Journal\n\n350: h1453.\n\nGlaxoSmithKline. 2013. GlaxoSmithKline awarded up to $200 million by U.S. Government to\n\ndevelop new antibiotics. Middlesex: GlaxoSmithKline.\n\nGoossens, H., D. Guillemot, M. Ferech, B. Schlemmer, M. Costers, M. Van Breda, L.J. Baker, et al. 2006. National campaigns to improve antibiotic use. European Journal of Clincal Pharmacology 62: 373–379.\n\nGuiness, L., and V. Wiseman. 2011. Introduction to health economics. 2nd ed. Maidenhead:", "n_tokens": 256, "kind": "text"}
{"chunk_id": "drug_resistance_book-301-3", "doc_id": "drug_resistance_book", "page": 301, "text": "McGraw-Hill Education.\n\nHanefeld, J., M. Khan, G. Tomson, and R. Smith. 2017. Trade is central to achieving the sustain-\n\nable development goals: A case study of antimicrobial resistance. BMJ 358: j3505.\n\nHardin, G. 1968. The tragedy of the commons. Science 162 (3859): 1243–1248. Hatch, O. 2015. Promise for antibiotics and therapeutics for health act or the PATH act. In. www. congress.gov/bill/114th-congress/senate-bill/185?q=%7B%22search%22%3A%5B%22s.1 85%22%5D%7D.\n\nHoffman, S.J., K. Outterson, J.-A. Røttingen, O. Cars, C. Clift, Z. Rizvi, et al. 2015a. An inter- national legal framework to address antimicrobial resistance. Bulletin of the World Health Organization 93 (2): 66–66.\n\nHoffman, S.J., J.-A. Røttingen, and J. Frenk. 2015b. Assessing proposals for new global health treaties: An analytic framework. American Journal of Public Health 105 (8): 1523–1530. Huttner, B., H. Goossens, T. Verheij, and S. Harbarth. 2010. Characteristics and outcomes of pub- lic campaigns aimed at improving the use of antibiotics in outpatients in high- income coun- tries. Lancet Infectious Diseases 10: 17–31.\n\nKeppler, H. 2013. The untold AIDS story: How access to antiretroviral drugs was obstruced\n\nin Africa.", "n_tokens": 385, "kind": "text"}
{"chunk_id": "drug_resistance_book-302-0", "doc_id": "drug_resistance_book", "page": 302, "text": "17 The Economics of Resistance Through an Ethical Lens\n\nKesselheim, A.S., and K. Outterson. 2010. Fighting antibiotic resistance: Marrying new financial\n\nincentives to meeting public health goals. Health Affairs 29 (9): 1689–1696.\n\nKolmos, H.J., and P. Little. 1999. Should general practitioners perform diagnostic tests on patients\n\nbefore prescribing antibiotics? British Medical Journal 318: 799–802.\n\nLaxminarayan, R., I.W.H. Parry, D.L. Smith, and E.Y. Klein. 2010. Should new antimalarial drugs\n\nbe subsidized? Journal of Health Economics 29: 445–456.\n\nLaxminarayan, R., P. Matsoso, S. Pant, C. Brower, J.-A. Røttingen, K. Klugman, and S. Davies. 2016. Access to effective antimicrobials: A worldwide challenge. The Lancet 387 (10014): 168–175.\n\nMedical Research Council. 2014. Tackling AMR\n\ntherapeu- In. www.mrc.ac.uk/funding/browse/\n\ntheme 2: Accelerating\n\ntic tackling-amr-theme-2-accelerating-therapeutic-and-diagnostics-development-eoi.\n\nand\n\ndiagnostics", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-302-1", "doc_id": "drug_resistance_book", "page": 302, "text": "development\n\nEOI.\n\nMendelson, M., J.-A. Røttingen, U. Gopinathan, D.H. Hamer, H. Wertheim, B. Basnyat, et al. 2016. Maximising access to achieve appropriate human antimicrobial use in low-income and middle-income countries. The Lancet 387 (10014): 188–198.\n\nMolzon, J.A., A. Giaquinto, L. Lindstrom, T. Tominaga, M. Ward, P. Doerr, et al. 2011. The value and benefits of the international conference on harmonisation to drug regulatory authorities: Advancing harmonization for better public health. Clinical Pharmacology & Therapeutics 89 (4): 503–512.\n\nNesta. 2014. The challenge: Reduce the use of antibiotics. In. https://longitudeprize.org/challenge. O’Neill, J. 2014. Review on antimicrobial resistance. Antimicrobial resistance: Tackling a crisis\n\nfor the health and wealth of nations. London: HM Government; Wellcome Trust.\n\nOlsen, J.A., and J. Richardson. 2013. Preferences for the normative basis of health care priority\n\nsetting: Some evidence from two countries. Health Economics 22 (4): 480–485.\n\nOppong, R., M. Jit, R.D. Smith, C.C. Butler, H. Melbye, S. Molstad, and J. Coast. 2013. Cost- effectiveness of point-of-care C-reactive protein testing to inform antibiotic prescribing deci- sions. British Journal of General Practice 63 (612): e465–e471.\n\nOutterson, K. 2014. New business models for sustainable antibiotics. London: Chatham House. Outterson, K., J.H. Powers, G.W. Daniel, and M.B. McClellan. 2015. Repairing the broken market", "n_tokens": 429, "kind": "text"}
{"chunk_id": "drug_resistance_book-302-2", "doc_id": "drug_resistance_book", "page": 302, "text": "for antibiotic innovation. Health Affairs 34 (2): 277–285.\n\nReview on antimicrobial resistance. 2015a. Tackling a global health crisis: Initial steps. ———. 2015b. Securing new drugs for future generations: The pipeline of antibiotics. Rice, L.B. 2011. Rapid diagnostics and appropriate antibiotic use. Clinical Infectious Diseases 52\n\n(Suppl 4): S357–S360.\n\nRichardson, J., and J. McKie. 2007. Economics, political philosophy and ethics: The role of pub- lic preferences in health care decision–making. In Principles of health care ethics, 2nd ed., 569–576.\n\nSmith, R. 2015. Antimicrobial resistance is a social problem requiring a social solution. BMJ:\n\nBritish Medical Journal 350: h1453.\n\nSmith, R.D., and J. Coast. 1998. Controlling antimicrobial resistance: A proposed transferable\n\npermit market. Health Policy 43: 219–232.\n\n———. 2002. Antimicrobial resistance: a global response. Bulletin of the World Health", "n_tokens": 234, "kind": "text"}
{"chunk_id": "drug_resistance_book-302-3", "doc_id": "drug_resistance_book", "page": 302, "text": "Organization 80: 126–133.\n\n———. 2003. Antimicrobial drug resistance. In Global public goods for health: A health economic and public health perspective, ed. R.D. Smith, R. Beaglehole, D. Woodward, and N. Drager. Oxford: Oxford University Press.\n\nSmith, R., and J. Coast. 2013. The true cost of antimicrobial resistance. BMJ 346 (f1493): 1–5. Smith, R.D., C. Carlos, and O. Cecilia. 2009. Trade, TRIPS, and pharmaceuticals. Lancet 373\n\n(9664): 684–691.\n\nTrouiller, P., P. Olliaro, E. Torreele, J. Orbinski, R. Laing, and N. Ford. 2002. Drug development for neglected diseases: A deficient market and a public-health policy failure. The Lancet 359 (9324): 2188–2194.\n\n293", "n_tokens": 213, "kind": "text"}
{"chunk_id": "drug_resistance_book-303-0", "doc_id": "drug_resistance_book", "page": 303, "text": "294\n\nR. D. Smith and J. Coast\n\nWalls, H.L., and G. Ooms. 2017. Innovative use of the law to address complex global health problems: Comment on the legal strength of international health instruments-what it brings to global health governance? International Journal of Health Policy Management 6.\n\nWilton, P., R.D. Smith, J. Coast, and M.R. Millar. 2002. Strategies to contain the emergence of antimicrobial resistance: A systematic review of effectiveness and cost- effectiveness. Journal of Health Services Research and Policy 7: 111–117.\n\nWise, J. 2015. Report calls for $2 bn global fund to kickstart antibiotic development. BMJ: British\n\nMedical Journal 350: h2635.\n\nWoodward, D., and R.D. Smith. 2003. Global public goods for health: Concepts and issues. In Global public goods for health: A health economic and public health perspective, ed. R.D. Smith, R. Beaglehole, D. Woodward, and N. Drager. Oxford: Oxford University Press. Woolhouse, M., and J. Farrar. 2014. Policy: An intergovernmental panel on antimicrobial resis-\n\ntance. Nature 509 (7502): 555–557.\n\nWorld Health Organization. 2015. Tracking universal health coverage: First global monitoring", "n_tokens": 287, "kind": "text"}
{"chunk_id": "drug_resistance_book-303-1", "doc_id": "drug_resistance_book", "page": 303, "text": "report. Geneva: World Health Organization.\n\nYamabhai, I., and R.D. Smith. 2015. To what extent are pharmaceutical prices determined by pat- ents? A case study of oncology medicines in Thailand. Journal of Intellectual Property Rights 20: 89–95.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 224, "kind": "text"}
{"chunk_id": "drug_resistance_book-304-0", "doc_id": "drug_resistance_book", "page": 304, "text": "Part III Ethics, Regulation, Governance, and Drug Resistance", "n_tokens": 11, "kind": "text"}
{"chunk_id": "drug_resistance_book-305-0", "doc_id": "drug_resistance_book", "page": 305, "text": "Chapter 18 Antibiotics and Animal Agriculture: The Need for Global Collective Action\n\nJonathan Anomaly\n\nKeywords Drug Resistance · Political philosophy · Moral philosophy · Economics\n\nThe use of antibiotics in animal agriculture is steadily increasing, especially in developing countries. The European Union and a handful of developed countries have implemented policies to scale back the use of antibiotics, recognizing its role in the global rise of antibiotic resistance. But many farmers who raise animals live in poor countries without public health regulations, or work for large corporate enti- ties that can move their operations to places with weak regulations. To minimize the careless use of antibiotics around the world, we need multi-lateral coordination between states on some common standards for the use of antibiotics in animals.\n\n18.1", "n_tokens": 144, "kind": "text"}
{"chunk_id": "drug_resistance_book-305-1", "doc_id": "drug_resistance_book", "page": 305, "text": "Introduction\n\nImagine a world in which every time you tied your shoes, you contributed to a pro- cess that resulted in the unintended suffering and death of thousands of people you’ll never know.1 In this world, like ours, shoelaces are useful: they save time, are a little cheaper than using Velcro ties, and more convenient than wearing slip-on shoes. But when everyone ties their shoes, lots of people die, and many more suffer. This is a strange world to imagine, but it is a lot like the world we live in. The culprit isn’t tying shoelaces, of course, but consuming factory farmed meat. Factory farms are wicked places – one of the last bastions of legally sanctioned cruelty toward animals. But more than this, they are bad for human health.\n\n1 Parts of the introduction are reprinted from an article that first appeared in Compass, the annual magazine of the Kenan Institute for Ethics at Duke University (2017).\n\nJ. Anomaly (*) University of Pennsylvania, Philadelphia, PA, USA e-mail: anomaly@upenn.edu\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_18\n\n297", "n_tokens": 300, "kind": "text"}
{"chunk_id": "drug_resistance_book-306-0", "doc_id": "drug_resistance_book", "page": 306, "text": "298\n\nJ. Anomaly\n\nSome antibiotics are given to cattle and pigs to marginally speed up their growth. The biological mechanisms through which antibiotics promote growth aren’t well understood, but the use of antibiotics to promote growth does seem to work. More importantly, raising animals in densely packed conditions requires a steady dose of antibiotics to prevent infections that would otherwise run rampant.\n\nLike many practices, there are benefits as well as costs: meat from factory farms is cheaper than meat from farms with free-range animals, often about half the price. This is partly because factory farms allow animals to occupy less space, which makes their production cheaper, and this savings is passed on to consumers.\n\nApart from its obvious benefits, factory farming produces many costs (Anomaly 2015). In this essay, I will focus on the threat that our use of antibiotics in animal agriculture poses for human health. Contrary to popular opinion, the problem is not that antibiotics are passed along from animals to people who eat them, and that this is bad for our health. Instead, the problem is that the more antibiotics we give to livestock, the more we encourage the emergence and spread of antibiotic-resistant bacteria in a microbial environment shared by animals and people (Marshall and Levy 2011; Spellberg et al. 2016).", "n_tokens": 255, "kind": "text"}
{"chunk_id": "drug_resistance_book-306-1", "doc_id": "drug_resistance_book", "page": 306, "text": "Like all eukaryotic organisms, people pay a high price for sex: each child only shares half of her genes with each parent. But sexual reproduction seems to confer benefits by increasing variation in the immune system children inherit, thus making it more likely that some of them will survive the onslaught of parasites that continu- ally evolve novel ways of exploiting their hosts (Hamilton et al. 1990). As strange as sex is – each of two independent organisms swapping their genes to create a hybrid – the bacterial equivalent is even kinkier than a San Francisco night club. Bacteria reproduce by cloning themselves, but they evolve throughout their lives by promiscuously swapping genes with other bacteria and by extracting genes from the viruses that parasitize them. This allows them to adapt to new environments quickly: in a lethal environment, a small number of bacteria are likely to have some advan- tage over the trillions that die. And this advantage comes either from a random genetic mutation, or from the lateral transfer of genes from one bacterium to another. Some genes allow bacteria to fend off the antibiotics that plants, animals, and other bacteria use to destroy them. Many of these naturally occurring antibiotics have existed for billions of years, as part of an unending evolutionary arms race between host and parasite. Like their naturally occurring cousins, synthetic antibiot- ics made in a lab usually involve penetrating a bacterial cell wall and disrupting DNA", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-306-2", "doc_id": "drug_resistance_book", "page": 306, "text": "synthesis, or otherwise slowing or stopping bacterial reproduction.", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-306-3", "doc_id": "drug_resistance_book", "page": 306, "text": "All a bacterium needs to survive an antibiotic is some way to either block the penetration of the chemical with a thick cell wall, degrade it with enzymes, or pump it out if it penetrates its body. Once that happens, it’s off to the races. The lucky bacterium multiplies rapidly and spreads its resistance to other bacteria. When new resistant strains of bacteria emerge in animal agriculture, they are passed along to farmers who work with animals, workers who slaughter animals, consumers who", "n_tokens": 99, "kind": "text"}
{"chunk_id": "drug_resistance_book-307-0", "doc_id": "drug_resistance_book", "page": 307, "text": "18 Antibiotics and Animal Agriculture: The Need for Global Collective Action\n\neat meat, and people in our more general microbial environment (Laxminarayan et al. 2016).\n\nThe average person hosts about 40 trillion bacteria at any given time, and we constantly swap bacteria with each other and with the environment around us (Sender et al. 2016). So even though the overuse of antibiotics tends to affect those closest to the source of resistant bacteria – whether animals or people – over time, strains of bacteria that are resistant to antibiotics can spread through trade and travel among people, and through soil and streams around factory farms. And while reduc- ing the use of antibiotics does tend to reduce resistance, the decline of resistance does not happen immediately, since reservoirs of antibiotic-resistant genes tend to persist in bacterial plasmids for a long time (Andersson and Hughes 2010).\n\nFor more than a decade the European Union has banned antibiotics for growth promotion in farm animals, and tried to impose standards that increase animal wel- fare and reduce the need to use antibiotics. The US has begun to follow suit, driven by consumer demand for antibiotic-free meat, and FDA threats of regulation. But most developing countries are moving in the opposite direction, with explosive growth of antibiotic use in both people and animals in China, India, Pakistan, Egypt, and many sub-Saharan African countries (Van Boeckel et al. 2015).\n\n18.2", "n_tokens": 294, "kind": "text"}
{"chunk_id": "drug_resistance_book-307-1", "doc_id": "drug_resistance_book", "page": 307, "text": "Economic Models\n\nThe problem of antibiotic resistance is often framed by well-known economic mod- els like the prisoner’s dilemma, the tragedy of the commons, or the provision of public goods. All three models are useful in some contexts, but when they are not adequately qualified they can cast shade rather than light on the problem of resistance.\n\n18.2.1\n\nPrisoner’s Dilemma\n\nConsider first the prisoner’s dilemma (PD). In the original example, we are pre- sented with two prisoners who are suspected of armed robbery, but a District Attorney (DA) who only has enough evidence to prosecute them for the illegal pos- session of firearms. The prisoners are in separate jail cells, and the DA offers each of them a deal: if you snitch on your accomplice and he stays silent, you’ll get off scot free and he’ll be executed. If you both stay silent, you’ll each get one year in prison. If you both snitch, you’ll each get a decade in prison. The payoffs are as follows:\n\n299", "n_tokens": 225, "kind": "text"}
{"chunk_id": "drug_resistance_book-308-0", "doc_id": "drug_resistance_book", "page": 308, "text": "300\n\nJ. Anomaly\n\nOdin\n\nLoki Silence\n\nSilence 1 year/1 year Snitch\n\nFreedom/Death\n\nSnitch Death/Freedom 10 years/10 years\n\nIf the accomplices lack friendly feelings for one another, and if neither fears reprisals outside of prison, the rational move for each is to snitch, even if the socially optimal move is for both to stay silent. The PD is interesting because each player acting rationally produces an outcome that is worse for everyone.\n\nThe PD is a simple model that is frequently invoked to explain why rational agents act in ways that contribute to air pollution or species extinction even when each person would prefer to breath clean air or preserve biodiversity. Although most of the real-world games the PD is used to illustrate are complicated by the fact that there are more than two players, that players have asymmetric information or poorly formed preferences, and that they face uncertainty about whether (or how many times) the game will be repeated, the simplistic two player model is still of some use in visualizing problems like antibiotic resistance.\n\nConsider the following case. Each carnivore faces the choice to consume meat\n\nfrom factory farmed animals or humanely raised animals free from antibiotics.\n\nOdin\n\nHumanely raised Factory farmed\n\nLoki Humanely raised Factory farmed 2nd/2nd 1st/4th", "n_tokens": 265, "kind": "text"}
{"chunk_id": "drug_resistance_book-308-1", "doc_id": "drug_resistance_book", "page": 308, "text": "4th/1st 3rd/3rd\n\nThe payoff matrix indicates that each person does best by consuming factory farmed meat, that each does worst by consuming humanely raised meat (if the other does not), but that they both do better if they both consume meat from humanely raised rather than factory farmed animals. In the real world, if there were only two consumers and two producers, the effects of Loki’s consumption choices would not be big enough to adversely affect Odin’s welfare. But when we generalize to hun- dreds of millions of people, we get a case in which each person marginally increases the probability of antibiotic-resistant bacteria emerging and spreading, but each also saves a bit of money by consuming meat from factory farmed animals. As long as the benefit to each from buying factory farmed meat exceeds the costs associated with the alternative, the model predicts they will continue their socially suboptimal behavior.\n\nThere are several limitations of extending a two-person model to a many-person case. First, in the large number case we can treat other people’s actions as given, whereas in the small number case we might change their behavior by reasoning with them (Bowles and Gintis 2013). Second, in the large number case we may have to resort to using state power to incentivize socially optimal behavior, whereas in the small number case people are in a better position to create local solutions that", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-309-0", "doc_id": "drug_resistance_book", "page": 309, "text": "18 Antibiotics and Animal Agriculture: The Need for Global Collective Action\n\nexploit social norms and informal punishments to move from the Nash equilibrium to the Pareto optimum (Ostrom 2000).\n\nSimilar considerations apply to farmers choosing whether to raise their animals with or without antibiotics, which is a many-person prisoner’s dilemma in which most people reason parametrically (taking other’s actions as more-or-less given). While there is a growing market for antibiotic-free meat, so that some farmers find it profitable to reject factory farming, most consumers around the world either don’t know enough or care enough about the problem to entice farmers to reject antibiot- ics and raise their animals humanely.\n\n18.2.2", "n_tokens": 152, "kind": "text"}
{"chunk_id": "drug_resistance_book-309-1", "doc_id": "drug_resistance_book", "page": 309, "text": "Tragedy of the Commons\n\nMany have argued that our aggregate use of antibiotics – in hospital settings and animal agriculture – is analogous to the misuse of commonly owned resources. In the classic example of a commons tragedy, farmers lack private property rights and are forced to raise animals on a common plot of land. The farmers internalize the benefits from raising animals and selling their meat, but share the costs of grass and soil depletion. Consequently, in the absence of sufficient altruistic restraint, each farmer continues to add animals to the commons up to the point at which the per- sonal benefits equal the personal costs. To the extent that they ignore social costs, farmers add animals even if it makes everyone worse off than they would be if they agreed to a set of enforceable constraints.", "n_tokens": 157, "kind": "text"}
{"chunk_id": "drug_resistance_book-309-2", "doc_id": "drug_resistance_book", "page": 309, "text": "Assume, for example, that above some number for each animal added to a com- mon pasture, each farmer will get 10 utility points but the community will lose 20 utility points as the grass becomes overgrazed. If there are 10 farmers, each nets 8 utility points from adding another animal (+10 from selling the meat and − 2 from depleting grass and soil), and so they add animals until the commons is ruined. The typical solution to commons tragedies is to privatize plots of land, or (less effi- ciently) to set up enforceable limits with penalties for exceeding the limits. In small settings, these standards can be enforced by the court of public opinion, assuming farmers care about their reputation in the community. In large settings, standards are usually set by the state, and enforced with penalties for violating laws, or taxes and subsidies that attempt to bring about a socially optimal use of common resources.", "n_tokens": 190, "kind": "text"}
{"chunk_id": "drug_resistance_book-309-3", "doc_id": "drug_resistance_book", "page": 309, "text": "Is the use of antibiotics on factory farms a commons tragedy? Some suggest that it is (Hollis and Maybarduk 2015). Others are more cautious, arguing that it depends on assumptions that include how quickly alternative antibiotics and vaccines will be developed, and how accurately we can diagnose infections (McAdams 2017a). Just as there is no such thing as a precise carrying capacity for land (since we can develop chemical fertilizers to increase soil productivity, or genetically engineer animals to more efficiently turn grass into meat), so too there is no specific point at which using more antibiotics necessarily imposes net costs on people.\n\nAs with the Prisoner’s Dilemma, the commons tragedy model can help us con- ceptualize the incentives that generate the problem of antibiotic resistance. But it\n\n301", "n_tokens": 163, "kind": "text"}
{"chunk_id": "drug_resistance_book-310-0", "doc_id": "drug_resistance_book", "page": 310, "text": "302\n\nJ. Anomaly\n\ncan also be misleading. For example, suppose we develop better diagnostics. Rapid diagnostic tests can make broad-spectrum antibiotics last longer by helping us iden- tify the specific kind of infection plaguing a person or animal so that we can treat it with a narrow-spectrum antibiotic agent (McAdams 2017a). When better diagnos- tics are available to guide treatment in conjunction with extremely narrow-spectrum agents, David McAdams argues that “greater antibiotic use can in some cases decrease the selective pressure favoring resistant bacteria” (2017a, p. 6). Better diagnostics may also make it more profitable for companies to manufacture and conserve antibiotics if it leads physicians and farmers to more carefully use antibiot- ics to target specific infections (2017b). Using the wrong antibiotic often fails to treat the relevant infection, and it encourages resistance among all bacteria that the antibiotic affects. Using broad-spectrum antibiotics without a specific diagnosis is like carpet-bombing an entire city in order to kill a few soldiers. To the extent that we can target our enemies with precision strikes, there is less opportunity for col- lateral damage in the form of resistant strains of bacteria that grow in number as their susceptible compatriots are killed.", "n_tokens": 263, "kind": "text"}
{"chunk_id": "drug_resistance_book-310-1", "doc_id": "drug_resistance_book", "page": 310, "text": "In addition to rapid diagnostic tests, the invention of “adjuvants” (supplements that make antibiotics more effective by priming our immune system, or by blocking bacterial resistance) can extend the life of antibiotics (Wright 2016). Rapid diagnos- tics and effective adjuvants show that the collective consumption of antibiotics does not automatically create a commons tragedy. It all depends on how we use antibiot- ics, and this is in part a function of technology, and the incentives that physicians and farmers face as a result of public policies.\n\nNevertheless, the careless way in which antibiotics are currently used in animal agriculture outside of Europe probably is a commons tragedy. This is because farm- ers in most countries today simply ignore the social cost of using antibiotics in livestock, and many farmers fail to understand how using antibiotics in agriculture can lead to the rise of bacterial infections in people that are increasingly expensive, difficult, or impossible to treat.\n\n18.2.3", "n_tokens": 197, "kind": "text"}
{"chunk_id": "drug_resistance_book-310-2", "doc_id": "drug_resistance_book", "page": 310, "text": "Public Goods\n\nA final model frequently used to describe problems associated with our use of anti- biotics requires us to make a distinction. In economics, private goods are those that are consumed by individuals in ways that don’t involve significant externalities (costs or benefits borne by people external to an economic transaction). For exam- ple, when I buy a private good like a cup of coffee or a pair of eyeglasses, the costs or benefits imposed on other people are trivial. Public goods, by contrast, are con- sumed in common, so that we share the benefits of consumption. Public goods can be thought of as non-excludable positive externalities (Cowen 2008), though this is misleading in cases where the public good is experienced as a cost rather than a benefit to those who consume it.", "n_tokens": 168, "kind": "text"}
{"chunk_id": "drug_resistance_book-311-0", "doc_id": "drug_resistance_book", "page": 311, "text": "18 Antibiotics and Animal Agriculture: The Need for Global Collective Action\n\nAntibiotics themselves are not public goods, but to some extent the efficacy of antibiotics, and efforts made to move us toward the socially optimal use of antibiot- ics, are public goods. Similarly, efforts to eliminate infectious diseases are public goods (Selgelid 2007), since the reduction or eradication of a disease is shared by all people in a region, and potentially all people on the planet. By extension, reduc- ing the reckless use of antibiotics in agriculture is a public good. Although alterna- tive agricultural methods are more expensive, the enormous external costs of drug-resistant diseases that emerge from factory farming almost certainly exceed the benefits of cheaper meat (O’Neill et al. 2015).2", "n_tokens": 158, "kind": "text"}
{"chunk_id": "drug_resistance_book-311-1", "doc_id": "drug_resistance_book", "page": 311, "text": "Many people, including some economists, equate public goods problems with commons tragedies and prisoner’s dilemmas. This is a mistake, although it is under- standable since many commons tragedies and public goods problems can be use- fully modeled by the prisoner’s dilemma. But often public goods are better described as assurance games or coordination games (Hampton 1987), and this is good news for lawmakers and farming associations who are aware of the problem and want to converge on common standards that allow them to make a profit and minimize the risk of antibiotic resistance. One problem with preserving global public goods like the efficacy of antibiotics is that most people are unaware of the problem, since each plays a very small role in producing it. In other words, many people who might help preserve or produce public goods are rationally ignorant about the nature of the problem.\n\n18.3", "n_tokens": 179, "kind": "text"}
{"chunk_id": "drug_resistance_book-311-2", "doc_id": "drug_resistance_book", "page": 311, "text": "Moral Principles\n\nIgnorance of how the use of antibiotics in agriculture harms human health is ratio- nal in the economic sense, but it is not necessarily morally excusable (Anomaly 2015). Since the problem of AMR is difficult to understand, and since each act of consuming factory-farmed products contributes only imperceptibly to the problem, it makes perfect sense that consumers would ignore the problem and purchase cheap factory-farmed meat, rather than more expensive meat from farms that don’t use antibiotics.\n\nBut the fact that we can explain consumer ignorance does not absolve consumers of responsibility for contributing to the problem. As information about the private benefits and social costs of using antibiotics in farm animals becomes more widely available, consumers have an increasing responsibility to act on it by changing their purchasing habits and trying to persuade governments to make it harder to purchase meat from animals unnecessarily dosed with antibiotics. Alexander Fleming\n\n2 It may be that some use of antibiotics in agriculture is both individually beneficial for animals (who contract infections despite humane and prudent farming practices), and socially beneficial for people (who may be less likely to contract a bacterial infection an animal has). But the growing quantity of antibiotics used in farming today is likely to produce harms that far exceed these benefits.\n\n303", "n_tokens": 263, "kind": "text"}
{"chunk_id": "drug_resistance_book-312-0", "doc_id": "drug_resistance_book", "page": 312, "text": "304\n\nJ. Anomaly\n\nfamously warned that “the thoughtless person playing with penicillin is morally responsible for the death of the man who finally succumbs to infection with the penicillin-resistant organism.”3 One form of “playing with penicillin” is the use of it as a growth promoter on factory farms, or the more common use of it to prevent infections in the cramped and cruel conditions that characterize factory farms.\n\nA more nuanced version of Fleming’s admonition requires us to distinguish actual harms to discrete people from probabilistic harms to actual or potential peo- ple. Another way to put the point is to say that the harms of antibiotic resistance are “identity-independent” in the sense that the victims of AMR cannot be known ahead of time and, in some cases, are not yet born. While a single farmer (or consumer) misusing antibiotics can create or encourage a resistant strain that spreads to other people, generally the prevalence of resistant bacteria in the environment depends on how all of us act. By acting in ways that create genetic pollution in our microbial environment, we make it a little more likely that someone will suffer or die of a previously treatable infection.", "n_tokens": 254, "kind": "text"}
{"chunk_id": "drug_resistance_book-312-1", "doc_id": "drug_resistance_book", "page": 312, "text": "Many other pollution problems are structurally similar to antibiotic resistance. For example, each of us drives to work and produces the social costs of pollution and traffic congestion as a byproduct, while experiencing the private benefit of an enjoyable ride in our own car. There are also social benefits when each person drives, if driving contributes to a more efficient workforce that creates better goods at lower cost. Suppose the social costs of air pollution and traffic congestion exceed the individual benefits of driving. A common response is to impose a price on driv- ing by taxing fuel or charging user fees to encourage the efficient use of roads and the atmosphere. The underlying moral principles are that we should pay in propor- tion to the amount we contribute to the problem, and that if anyone’s liberties to pollute are restricted, then all us should face the same restrictions (Gaus 1999, p. 197).", "n_tokens": 182, "kind": "text"}
{"chunk_id": "drug_resistance_book-312-2", "doc_id": "drug_resistance_book", "page": 312, "text": "Similar arguments have been made for taxing antibiotics in medicine and agri- culture to discourage low-value use (Kades 2005; Anomaly 2013). But antibiotic resistance is much more complicated than air pollution or traffic congestion: in some cases we may want to subsidize rather than tax the use of antibiotics when people who can’t afford them are likely to spread infectious diseases to others (Selgelid 2007). Apart from taxes and subsidies, there is a vast literature on how to harness intellectual property rights, prescription requirements, basic science research funding, and shared surveillance to control the problem (O’Neill et al. 2016). What I now want to argue is that without more coordination between states, the problem of antibiotic resistance in agriculture will likely get worse, with dire con- sequences for human health in the coming century.\n\n3 http://www.fda.gov/NewsEvents/Speeches/ucm427312.htm", "n_tokens": 197, "kind": "text"}
{"chunk_id": "drug_resistance_book-313-0", "doc_id": "drug_resistance_book", "page": 313, "text": "18 Antibiotics and Animal Agriculture: The Need for Global Collective Action\n\n18.4\n\nGlobal Coordination\n\nThe provision of global public goods like conserving antibiotics and reducing infec- tious disease raises two problems: the free rider problem occurs when individual consumers, farmers, or states seek the gains of limited antibiotic use without paying the costs; the assurance problem occurs when each is willing to pay the cost of reducing unnecessary use, but lacks the assurance that others will abide by policies that constrain our collective use of antibiotics.\n\nThe first problem is difficult to overcome to the extent that self-interest domi- nates the actions of farmers in a market or of politicians in a government. But there is some evidence that most consumers who understand the problem are willing to pay higher prices for meat from animals not given antibiotics (Spellberg et al. 2016). Moreover, if people really understood the problems factory farms create they would likely be willing to pay significantly more for meat, since most people support taxes (or costly regulations) when they are reasonably sure the tax will be used to discour- age the problems associated with pollution (Kallbekken et al. 2011).", "n_tokens": 236, "kind": "text"}
{"chunk_id": "drug_resistance_book-313-1", "doc_id": "drug_resistance_book", "page": 313, "text": "Agricultural producers are also likely to be willing to comply with standards that limit antibiotic use provided other firms are also forced to internalize the cost of similar regulations or taxes. The fact that the assurance problem is often more seri- ous than the free rider problem in trying to elicit cooperation in many public goods games (Bowles and Gintis 2013) is good news for those who worry about the feasi- bility of states setting mutually beneficial standards.\n\nPart of the problem with antibiotics in agriculture is that as transportation costs decline, the market for animal meat becomes increasingly global: animal feed is produced in one country, animals are raised in another, and then meat is exported to a third country. Since producers in many countries are now in a position to operate industrial animal farms, unless all states set standards that limit antibiotic use, pro- ducers will tend to migrate to countries with the weakest regulations. There is already some evidence that this “race to the bottom” is happening as Chinese farms are producing meat in factory farms that use more confinement and antibiotics than farms in other countries. In fact, just as the US is beginning to move away from fac- tory farming due to consumer demand and threats of regulation by the US Food and Drug Administration, many of the most populous developing countries – including China, India, and Brazil – are embracing factory farming (O’Neill et al. 2015).", "n_tokens": 284, "kind": "text"}
{"chunk_id": "drug_resistance_book-313-2", "doc_id": "drug_resistance_book", "page": 313, "text": "A well-designed trade treaty between major exporters and importers of meat should recognize the problem of “leakage,” which occurs when one country sets relatively high environmental standards, and allows other countries with weaker standards to increase the production of similar goods in ways that simply changes where the pollution is emitted (Barrett 1999). In other words, any treaty worth implementing cannot reward free-riding countries whose firms are permitted to externalize the costs of their production, while firms in other countries internalize the costs of complying with policies that would make everyone better off if coun- tries complied with them.\n\n305", "n_tokens": 122, "kind": "text"}
{"chunk_id": "drug_resistance_book-314-0", "doc_id": "drug_resistance_book", "page": 314, "text": "306\n\nJ. Anomaly\n\nA second feature of an effective treaty to limit antibiotics in agriculture is a mini- mum participation clause to assure prospective signatories that unless a sufficient number of nations sign on, they will not be forced to pay additional production costs (Barrett 1999). This feature solves the assurance problem for firms and nations that are willing to comply with stricter production practices provided enough others do to produce the global benefits associated with restricting antibiotic use.\n\nA third feature of any multi-lateral agreement to restrict antibiotic use is that it would need to be flexible enough to allow countries to achieve collective goals in different ways. For example, some experts advocate setting targets for the per capita quantity of antibiotics that can be administered to animals. According to the British Review on Antimicrobial Resistance, pork producers in Denmark (the first country to ban antibiotics as growth promoters) use about 50 mg of antibiotics per kg of livestock in the country (O’Neill et al. 2015, p. 2).", "n_tokens": 201, "kind": "text"}
{"chunk_id": "drug_resistance_book-314-1", "doc_id": "drug_resistance_book", "page": 314, "text": "A flexible treaty would take something like this number as a benchmark that all countries must meet, but it would allow countries to achieve the relevant goal in different ways: by taxing antibiotics, placing a cap on total use, restricting antibiot- ics by requiring veterinary oversight, or some combination of these policies. Antibiotics deemed especially important for human use should probably be banned for use in agriculture by all countries. But what often matters is the quantity of anti- biotics used, not just the kind. This is especially true because plasmids that confer antibiotic resistance can be transferred between bacteria of different species, and can reduce the efficacy of different drugs than those administered by farmers (Marshall and Levy 2011).\n\nOne advantage of imposing “pollution taxes” or user fees on antibiotics in agri- culture is that, unlike regulations, governments have strong incentives to enforce them. Governments can use the revenue raised from taxes to finance vaccination programs that minimize the need to administer antibiotics. They might also fund basic science research that aims to develop new vaccines and diagnostics for infec- tious diseases, and to develop entirely new treatments like genetically engineered bacteriophage viruses (Bikard et al. 2014).", "n_tokens": 250, "kind": "text"}
{"chunk_id": "drug_resistance_book-314-2", "doc_id": "drug_resistance_book", "page": 314, "text": "Taxing socially costly activities like using antibiotics in agriculture also incentiv- izes farmers to find alternative ways to produce meat that minimize antibiotic resis- tance. These alternatives may include increasing the roaming space animals have, and decreasing the stress they face when forced to live in extreme confinement. A more promising alternative is to create “in vitro meat” made in a lab from embry- onic stem cells. This would avoid the need to raise animals at all, thus reducing untold amounts of suffering and potential public health problems.\n\nFinally, any agreement to restrict antibiotic use should be attractive enough for each participating country to be willing to enforce it. It is likely that offering bene- fits for compliance will be more effective than simply threats of sanctions for non- compliance. For example, it is in the interest of all nations that each nation monitors the outbreak and spread of infectious diseases, as well as novel patterns of antibiotic resistance. But sometimes only wealthier states have the budgets and technology to accomplish this. By sharing information and technology with developing countries, wealthier countries can both signal goodwill and deliver tangible benefits to other", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-315-0", "doc_id": "drug_resistance_book", "page": 315, "text": "18 Antibiotics and Animal Agriculture: The Need for Global Collective Action\n\ncountries they wish to comply with stricter controls on antibiotic use. This may act as a positive incentive for poor countries to do their part, even if the threat of sanc- tions for non-compliance with collectively beneficial restrictions is also important. Each nation faces its own challenges, including an electorate that is unlikely to fully understand the social benefits and costs of antibiotics, and factory farmers who are unlikely to welcome regulations that impose new costs on them. Governments can justify spending some money to ease the transition from factory farming tech- niques to alternatives that produce better consequences for the same reason they can justify compensating taxi cab drivers who were required to buy a costly permit from the state to drive a taxi, but who are now forced to compete with companies like Uber, whose drivers did not have to pay for the right to operate as a taxi service. In fact, if relatively wealthy governments offer temporary assistance to domestic firms to transition away from factory farming, and to relatively poor governments to com- ply with new restrictions, the move away from the reckless use of antibiotics may be easier to induce, and more fair from the standpoint of global distributive justice.", "n_tokens": 250, "kind": "text"}
{"chunk_id": "drug_resistance_book-315-1", "doc_id": "drug_resistance_book", "page": 315, "text": "References\n\nAndersson, Dan, and Diarmaid Hughes. 2010. Antibiotic resistance and its cost: Is it possible to\n\nreverse resistance? Nature 8: 260–271.\n\nAnomaly, Jonathan. 2013. Collective action and individual choice. Journal of Medical Ethics 39:\n\n752–756.\n\n———. 2015. What’s wrong with factory farming? Public Health Ethics 8 (3): 246–254. Barrett, Scott. 1999. Montreal vs Kyoto. In Global public goods: International cooperation for the\n\n21st century, ed. Inge Kaul et al. Oxford: Oxford University Press.\n\nBikard, David, et al. 2014. Exploiting CRISPR-Cas nucleases to produce sequence-specific anti-\n\nmicrobials. Nature Biotechnology 32: 1146–1150.\n\nBowles, Samuel, and Herbert Gintis. 2013. A cooperative species: Human reciprocity and its evo-\n\nlution. Princeton: Princeton University Press.\n\nCowen, Tyler. 2008. Public goods. The concise encyclopedia of economics. 2nd ed. http://www.\n\neconlib.org/library/Enc/PublicGoods.html.\n\nGaus, Gerald. 1999. Social philosophy. London: M.E. Sharpe Publishing. Hamilton, William, et al. 1990. Sexual reproduction as an adaptation to resist parasites. Proceedings\n\nof the National Academy of Science 87: 3566–3573.\n\nHampton, Jean. 1987. Free rider problems in the production of collective goods. Economics and", "n_tokens": 310, "kind": "text"}
{"chunk_id": "drug_resistance_book-315-2", "doc_id": "drug_resistance_book", "page": 315, "text": "Philosophy 3: 245–273.\n\nHollis, Aidan, and Peter Maybarduk. 2015. Antibiotic resistance is a tragedy of the commons that\n\nnecessitates global cooperation. Journal of Law, Medicine, and Ethics 43: 33–37.\n\nKades, Eric. 2005. Preserving a precious resource: Rationalizing the use of antibiotics. Northwest\n\nUniversity Law Review 99: 611–675.\n\nKallbekken, Steffen, et al. 2011. Do you not like Pigou, or do you not understand him? Journal of\n\nEnvironmental Economics and Management 62 (1): 53–64.\n\nLaxminarayan, Ramanan, et al. 2016. Antibiotic use and resistance in food animals. The Center for Disease Dynamics, Economics, and Policy. https://cddep.org/sites/default/files/india_abx_ report.pdf. Accessed 1 May 2017.\n\nMarshall, Bonnie, and Stuart Levy. 2011. Food animals and antimicrobials: Impacts on human\n\nhealth. Clinical Microbiology Reviews 24 (4): 718–733.\n\n307", "n_tokens": 226, "kind": "text"}
{"chunk_id": "drug_resistance_book-316-0", "doc_id": "drug_resistance_book", "page": 316, "text": "308\n\nJ. Anomaly\n\nMcAdams, David. 2017a. Resistance diagnosis and the changing epidemiology of antibiotic resis-\n\ntance. New York Academy of Sciences. 1388 (2017): 5–17.\n\n———. 2017b. Resistance diagnosis and the changing economics of antibiotic discovery. New\n\nYork Academy of Sciences. 1388 (2017): 18–25.\n\nO’Neill, Jim, et al. 2015. Antimicrobials in agriculture and the environment: Reducing unneces-\n\nsary use and waste. The Review on Antimicrobial Resistance. http://amr-review.org/.\n\n———. 2016. Tackling drug-resistant infections globally: Final report and recommendations. The\n\nReview on Antimicrobial Resistance. http://amr-review.org/.\n\nOstrom, Elinor. 2000. Collective action and the evolution of social norms. Journal of Economic\n\nPerspectives 14 (3): 137–158.\n\nSelgelid, Michael. 2007. Ethics and drug resistance. Bioethics 21 (4): 218–229. Sender, Ron, et al. 2016, August 19. Revised estimates for the number of human and bacterial cells\n\nin the body. PLOS Biology. https://doi.org/10.1371/journal.pbio.1002533.\n\nSpellberg, Brad, et al. 2016. Antibiotic resistance in humans and animals. Discussion paper for the National Academy of Medicine. Accessed May 2017. http://www.nam.edu/ antibiotic-resistance-in-humans-and-animals.\n\nVan Boeckel, T.P., et al. 2015. Global trends in antimicrobial use in food animals. Proceedings of", "n_tokens": 367, "kind": "text"}
{"chunk_id": "drug_resistance_book-316-1", "doc_id": "drug_resistance_book", "page": 316, "text": "the National Academy of Sciences 112 (18): 5649–5654.\n\nWright, Gerard. 2016. Antibiotic adjuvants: Rescuing antibiotics from resistance. Trends in\n\nMicrobiology 24 (11): 862–871.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 214, "kind": "text"}
{"chunk_id": "drug_resistance_book-317-0", "doc_id": "drug_resistance_book", "page": 317, "text": "Chapter 19 Technological Fixes and Antimicrobial Resistance\n\nNicholas B. King\n\nAbstract A ‘technological fix’ reduces the negative impact of a problem without addressing its underlying political, economic, or social causes. This chapter exam- ines antimicrobials’ central role in both the modern faith in technological fixes in medicine, and critiques of over-reliance on technological interventions that produce unintended consequences. The enduring appeal of technological fixes is rooted in their promise to provide simple, efficient, measurable, and effective solutions to complex problems; but this practically is purchased at the price of eliding important distributive concerns.\n\nKeywords Ethics · Public health · Infectious diseases · Social policy · History of science\n\n19.1", "n_tokens": 149, "kind": "text"}
{"chunk_id": "drug_resistance_book-317-1", "doc_id": "drug_resistance_book", "page": 317, "text": "Introduction\n\nIn October, 2003, The Bill and Melinda Gates Foundation (BMGF) announced the first 14 ‘Grand Challenges in Global Health,’ as part of an initiative to stimulate scientific research on diseases affecting less-developed nations. Grand Challenge #10 asked for applications that would help “discover drugs and delivery systems that minimize the likelihood of drug resistant microorganisms.” In the intervening years, combatting antimicrobial resistance has continued to be a priority for the BMGF, with at least 50 grants funded through initiatives aimed at ‘Creating Drugs and Delivery Systems to Limit Drug Resistance,’ and identifying ‘Novel Approaches to Characterizing and Tracking the Global Burden of Antimicrobial Resistance.’ Funded projects include efforts to crowdsource surveillance of antimicrobial resis- tance (AMR), investigating the role of metabolic pathways in M. tuberculosis\n\nN. B. King (*) McGill University, Montreal, QC, Canada\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_19\n\n309", "n_tokens": 260, "kind": "text"}
{"chunk_id": "drug_resistance_book-318-0", "doc_id": "drug_resistance_book", "page": 318, "text": "310\n\nN. B. King\n\nbacteria as a target for drug therapy, and identifying chemical entities that would act as ‘selection inverters’ to limit or reverse the development of AMR.\n\nGiven the problem’s scale and complexity, the importance of developing techno- logical solutions to improve surveillance and response to AMR might seem unas- sailable. However, soon after the initial announcement of the BMGF Grand Challenges, historian Anne-Emanuelle Birn published a sharp critique in The Lancet. Birn argued that, “in calling on the world’s researchers to develop innova- tive solutions targeted to ‘the most critical scientific challenges in global health’, the Gates Foundation has turned to a narrowly conceived understanding of health as the product of technical interventions divorced from economic, social, and political contexts”(Birn 2005, p. 515). In the area of AMR, Birn argued that:", "n_tokens": 187, "kind": "text"}
{"chunk_id": "drug_resistance_book-318-1", "doc_id": "drug_resistance_book", "page": 318, "text": "Three more Grand Challenges addressing drug resistance and the development of cures for latent and chronic infections are also short-sighted. While access to effective immunothera- pies for HIV/AIDS, tuberculosis, and other ailments has been appropriately termed a human right, integration of treatment with the well- established social and economic com- ponents of prevention surely merits at least one Grand Challenge. Here what deserves care- ful consideration are the factors associated with both HIV and multiple drug resistant tuberculosis: typically a combination of deprived social conditions—poor nutrition, over- crowded and unsanitary housing, economic insecurity, and inadequate health-care ser- vices—which lead to disease and can inhibit the taking of a complete course of medication (Birn 2005, p. 516).", "n_tokens": 165, "kind": "text"}
{"chunk_id": "drug_resistance_book-318-2", "doc_id": "drug_resistance_book", "page": 318, "text": "Noting that “it is easy to be seduced by technical solutions”(Birn 2005, p. 516), Birn questioned the BMGF’s assumption that the most pressing global health prob- lems can be solved through the application of innovative scientific and technologi- cal solutions that target proximate causes of disease, while ignoring more distal political, economic, or social determinants of health. She concluded with a call for integrating both narrow technological and wider social interventions, and cautioned that “the longer we isolate public health’s technical aspects from its political and social aspects, the longer technical interventions will squeeze out one side of the mortality balloon only to find it inflated elsewhere”(Birn 2005, p. 518).", "n_tokens": 154, "kind": "text"}
{"chunk_id": "drug_resistance_book-318-3", "doc_id": "drug_resistance_book", "page": 318, "text": "Birn’s general argument is commonplace in contemporary public health. These arguments frequently employ a critique of ‘technological fixes’ (or in Birn’s lan- guage, ‘technical solutions’) – attempts to solve problems through technological innovations or interventions, without attending to the social, economic, or political factors that may have contributed to the development of the problem in the first place. Over-reliance on the promise of technological fixes has long been controver- sial in public health, particularly since the widespread recognition of the importance of the social determinants of health. Critics contend that too much emphasis is placed on ‘downstream’ technical solutions to health problems whose root ‘upstream’ causes are not amenable to technological intervention.\n\nIn this chapter, I will use the idea of a ‘technological fix’ as a window into the moral economy of responses to AMR, paying special attention to questions of dis- tributive justice. Responding to antimicrobial resistance – which results from both a lack of appropriate medical technology and a complex web of behavioral, social, political, and economic factors – invites but also troubles the easy distinctions at the", "n_tokens": 235, "kind": "text"}
{"chunk_id": "drug_resistance_book-319-0", "doc_id": "drug_resistance_book", "page": 319, "text": "19 Technological Fixes and Antimicrobial Resistance\n\nheart of the technological fix idea, and confronts us with difficult decisions regard- ing how best to distribute social and economic resources.\n\n19.2\n\nTechnological Fixes\n\nThe idea of a technological fix arose within a context of postwar optimism that advances in science and technology could provide cheap and effective solutions to seemingly intractable social problems. While there were important precursors, one of the most important early popularizers of this view was Alvin Weinberg, a physi- cist and longtime director of the Oak Ridge National Laboratory. Weinberg had long advocated philosophical reflection and social awareness among scientists, particu- larly about the implications of ‘Big Science.’ During the 1960s, in a series of con- versations with colleagues, he developed the idea that at least some pressing problems that were largely seen as intrinsically social might be amenable to simple technological interventions (Johnston 2018), culminating in an influential 1966 speech, “Can Technology Replace Social Engineering?” which was printed in a number of periodicals, including the Bulletin of the Atomic Scientists.\n\nWeinberg argued that the causes of many pressing social problems of the day were intractably complex, and interventions targeting those causes are infeasible or impossible. He thus advocated remedies that can reduce or eliminate the harms generated by these problems, without addressing those causes:", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-319-1", "doc_id": "drug_resistance_book", "page": 319, "text": "There is a more basic sense in which social problems are much more difficult than are tech- nological problems. A social problem exists because many people behave, individually, in a socially unacceptable way. To solve a social problem one must induce social change – one must persuade many people to behave differently than they behaved in the past. One must persuade many people to have fewer babies, or to drive more carefully, or to refrain from disliking blacks. By contrast, resolution of a technological problem involves many fewer individual decisions (Weinberg 1991, p. 42).\n\nWeinberg identified technologies that had already ‘fixed’ social problems, including the intra-uterine device (a ‘one-shot’ form of birth control which requires a minimum of individual motivation), development of safer cars (which reduces traffic deaths without having to improve driver competence), and even the hydrogen bomb (a strong disincentive to war that does not require greater tolerance or under- standing). He proposed additional fixes, such as providing air conditioning to low- income households (to improve immediate personal comfort and potentially reduce rioting during hot summer months, without having to address the underlying social or economic causes of riots), and employing nuclear-powered desalination (which would eliminate water shortages without changing water consumer behavior).", "n_tokens": 264, "kind": "text"}
{"chunk_id": "drug_resistance_book-319-2", "doc_id": "drug_resistance_book", "page": 319, "text": "While Weinberg was an admitted optimist and a tireless promoter of technologi- cal fixes, in his 1966 speech he struck a conciliatory note with potential critics: Noting that “technological solutions to social problems tend to be incomplete and metastable, to replace one social problem with another,” he conceded that “we tech- nologists shall not satisfy our social engineers, who tell us that our Technological\n\n311", "n_tokens": 88, "kind": "text"}
{"chunk_id": "drug_resistance_book-320-0", "doc_id": "drug_resistance_book", "page": 320, "text": "312\n\nN. B. King\n\nFixes do not get to the heart of the problem; they are at best temporary expedients; they create new problems as they solve old ones” (Weinberg 1991, pp. 47–8). Answering the question posed in his title, Weinberg concluded that “technology will never replace social engineering…It is only by cooperation between technologist and social engineer that we can hope to achieve what is the aim of all technologists and social engineers – a better society, and thereby, a better life” (Weinberg 1991, p. 48).\n\nWeinberg’s hedging notwithstanding, his ideas about technological fixes met with immediate and sustained criticism; as early as 1970 the Oxford English Dictionary included wholly negative or ironic definitions of the term (Rosner 2004). Critics have mounted both practical and ideological objections. On the practical side, technological fixes provide at best short-term relief from the deleterious symp- toms of social problems, but fail to address their root causes; at worst, they oversim- plify intrinsically complex problems which they then fail to solve, and may introduce side effects that are worse than the problems they intend to solve. In a larger sense, the search for technological fixes is fundamentally reactionary in nature, encourag- ing society to seek cheap, quick, and partial solutions to holistic problems, while turning a blind eye to fundamental social and distributive injustices.", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-320-1", "doc_id": "drug_resistance_book", "page": 320, "text": "The transparent pursuit of technological fixes has had few defenders as vocal as Weinberg, and many detractors. This does not mean that the idea has fallen out of favor. Indeed, continued criticism is a sign of the enduring appeal of the idea of a technological fix, even if the term itself is not commonly used. For example, Evgeny Morozov’s 2013 book, To Save Everything, Click Here: The Folly of Technological Solutionism, criticizes the ‘there’s an app for that’ mentality of technological ‘solu- tionism’ in the internet age. Echoing earlier criticisms, Morozov argues that efforts to use internet-based technology to solve complex social problems – such as com- batting obesity through exercise-tracking apps rather than food regulation – encour- age us to define problems in terms of the technologies that might solve them, and discourage broader consideration of macro-level interventions (Winograd 2013).\n\n19.3", "n_tokens": 197, "kind": "text"}
{"chunk_id": "drug_resistance_book-320-2", "doc_id": "drug_resistance_book", "page": 320, "text": "Technological Fixes and Health\n\nTechnological fixes have been the subject of intense and sustained debate in the areas of public health and medicine. Advances in medical technology (e.g. vaccines, therapeutic drugs, surgical techniques, medical devices such as x-rays) play an undeniable role in diagnosing and curing disease, relieving suffering, increasing life expectancy, and improving population health. This fact alone would seem to justify continued investment of the BMGF Grand Challenges variety. Yet, beginning around the same time that Weinberg began evangelizing for technological fixes, crit- ics began to question a similar logic underlying increasing investment in medical technology.\n\nFirst, critics questioned whether medical advances played as great a role in health improvements as commonly believed. The classic statement of this critique is", "n_tokens": 161, "kind": "text"}
{"chunk_id": "drug_resistance_book-321-0", "doc_id": "drug_resistance_book", "page": 321, "text": "19 Technological Fixes and Antimicrobial Resistance\n\nThomas McKeown’s 1976 book, The Role of Medicine: Dream, Mirage, or Nemesis? McKeown argued that changes in political economy – including rising standards of living and better sanitation and nutrition – rather than specific therapeutic or preven- tive efforts, were responsible for the massive mortality declines of the ninteenth and early twentieth centuries (McKeown 1979). While the McKweown thesis has been hotly contested (Szreter 1988; Fairchild 1998; Colgrove 2002), it is now widely accepted that the contribution of technological innovation to historical improve- ments in health and longevity has been greatly overstated.", "n_tokens": 142, "kind": "text"}
{"chunk_id": "drug_resistance_book-321-1", "doc_id": "drug_resistance_book", "page": 321, "text": "Critics also pointed to the unintended consequences of medical technology. The classic statement (and the ‘Nemesis’ of McKeown’s title) is Ivan Illich’s 1975 book, Medical Nemesis: The Expropriation of Health. Illich criticized medicine’s role in the production of ‘iatrogenic’ illness, side effects of medical interventions that might often be worse than the original pathology they were intended to treat. He lamented the progressive “medicalization of life,” which left individuals and societ- ies ill-equipped to contend with normal aspects of human life including birth, pain, and death, as anything other than technologically-mediated pathology. And he objected to modern medicine’s “radical monopoly” on all aspects of health and disease, diverting economic and intellectual resources from other attempts to improve the human condition.", "n_tokens": 174, "kind": "text"}
{"chunk_id": "drug_resistance_book-321-2", "doc_id": "drug_resistance_book", "page": 321, "text": "Finally, critics contended that the pursuit of medical technology promoted a nar- row approach to health and illness, rather than the environmentally and socially holistic approach that is actually necessary. In his 1959 book, Mirage of Health: Utopias, Progress, and Biological Change, René Dubos – a microbiologist who as early as 1942 had predicted the emergence of bacterial resistance (Moberg 1996) – argued that attempts to create a world free of disease are bound to fail, “because paradise is a static concept while human life is a dynamic process” (Dubos 1996, p. 281). Modern medical technology is ill-equipped to address the evolutionarily dynamic biological and social worlds, and single-minded pursuit of technological innovation is a fool’s errand.\n\nIn the years since, the arguments mounted by McKeown, Illich, and Dubos have resonated with a wide variety of critics of technological fixes in clinical care, mod- ern medicine, and public health. They have found most purchase among proponents of the social determinants of health, who contend that the majority of the world’s inequalities in health result from political, economic, environmental, and social injustices, rather than lack of technological innovation. As the World Health Organization’s 2008 report, Closing the Gap in a Generation, argues:", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-321-3", "doc_id": "drug_resistance_book", "page": 321, "text": "Traditionally, society has looked to the health sector to deal with its concerns about health and disease. Certainly, maldistribution of health care – not delivering care to those who most need it – is one of the social determinants of health. But the high burden of illness responsible for appalling premature loss of life arises in large part because of the conditions in which people are born, grow, live, work, and age. In their turn, poor and unequal living conditions are the consequence of poor social policies and programmes, unfair economic arrangements, and bad politics. Action on the social determinants of health must involve the whole of government, civil society and local communities, business, global fora, and inter- national agencies. Policies and programmes must embrace all the key sectors of society not just the health sector (WHO Commission on Social Determinants of Health 2008, p. 1).\n\n313", "n_tokens": 184, "kind": "text"}
{"chunk_id": "drug_resistance_book-322-0", "doc_id": "drug_resistance_book", "page": 322, "text": "314\n\nN. B. King\n\n19.4\n\nTechnological Fixes in the Context of Antimicrobial Resistance\n\nIt is no accident that Dubos developed his theories of microbial ecology, and his broader critique of the ‘mirage’ of modern medicine, within the context of his early work on bacterial resistance (Moberg 1996). Antimicrobials appear at first glance to be a technological fix par excellence, in the sense that they are a simple and effective technical solution to a complex problem with biological, social, political, and eco- nomic determinants. Indeed, a recent article critiquing the pursuit of technological fixes in dementia cited antibiotics as the classic case of a technological fix with unintended consequences (Jongsma 2017).", "n_tokens": 153, "kind": "text"}
{"chunk_id": "drug_resistance_book-322-1", "doc_id": "drug_resistance_book", "page": 322, "text": "One could in fact argue that the apparent success of antibiotics is in large part responsible for a broader faith in technological fixes in medicine in the developed world. In 1967, during an oft-cited speech before American public health officials at the White House, U.S. Surgeon General William H. Stewart declared that it was time to close the book on infectious diseases and turn attention towards chronic health problems (Garrett 1994, p. 33). Stewart’s optimistic claim reflects a perennial American faith in the power of biomedical science to conquer disease, but it is also evidence of a significant transformation in the burden of disease during the past century. In what is often referred to as the “epidemiologic transition,” the proportion of deaths caused by infectious disease in the United States (and other industrialized nations) declined precipitously (Omran 1983). In 1900, infectious disease was responsible for 797 deaths per 100,000 population; by 1980, this figure had dropped to 36 deaths per 100,000 population. As mortality from infectious disease climbed, death rates for heart disease, various cancers, stroke, and accidents held steady or increased. In a dramatic reversal, chronic diseases replaced infectious ones as the leading killers in the United States. In 1900, 40% of deaths in the U.S. were caused by the eleven major infectious diseases (pneumonia, influenza, and tuberculosis alone accounting for more than 25% of all deaths), 16% by the three major chronic", "n_tokens": 299, "kind": "text"}
{"chunk_id": "drug_resistance_book-322-2", "doc_id": "drug_resistance_book", "page": 322, "text": "diseases (heart disease, cancer, and stroke), and 4% by accidents; by 1973, only 6% of deaths were caused by infectious diseases, 58% by chronic diseases, and 9% by accidents (Armstrong 1999).", "n_tokens": 47, "kind": "text"}
{"chunk_id": "drug_resistance_book-322-3", "doc_id": "drug_resistance_book", "page": 322, "text": "The social and institutional ramifications of the epidemiologic transition were profound. Deluged with dramatic stories of patients snatched from the brink of death by antibiotics such as streptomycin and penicillin (dubbed “yellow magic” by Reader’s Digest in 1943), Americans increasingly credited biomedical science for reducing the threat of infectious disease. This accelerated the transformation (or “narrowing”), underway since the early part of the century, of the focus of public health, from broad preventive measures towards clinical medicine, screening and the early detection of disease (Rosenkrantz 1974; Tomes 1998). This transformation was accompanied by changes in federal health expenditures as well: between 1950 and 1959, federal grants-in-aid declined from $45 million to $33 million, while", "n_tokens": 163, "kind": "text"}
{"chunk_id": "drug_resistance_book-323-0", "doc_id": "drug_resistance_book", "page": 323, "text": "19 Technological Fixes and Antimicrobial Resistance\n\nfunding for clinical and laboratory research jumped from $28 million in 1947 to $186 in 1957 (Fee 1994). The redirection of public and private funding from public health towards biomedical research would continue to accelerate into the 1980s, when it would be exacerbated by the dismantling of public health infrastructures in general under the pressure of Reagan-era budgetary constraints.\n\nEven as much of the institutional apparatus for addressing infectious disease was being dismantled, the public and the medical profession increasingly mirrored Stewart’s optimism regarding the threat of infectious disease. As historian Nancy Tomes notes, “With the array of drugs and vaccines available by 1965, the need to guard against contact infection understandably relaxed. Americans quickly came to believe that with a few soon-to-be-cured exceptions, modern medicine and public health had ‘conquered’ epidemic disease. Young physicians in the 1960s were advised, ‘Don’t bother going into infectious diseases,’ and to concentrate on cancer or heart disease instead” (Tomes 1998, p. 254) Americans increasingly came to see infectious disease as a thing of the past, and they were bolstered in this confidence by the lack of significant epidemics of communicable disease – a confidence only briefly shaken by the HIV/AIDS epidemic, at least until the discovery of antiretro- viral drugs.", "n_tokens": 281, "kind": "text"}
{"chunk_id": "drug_resistance_book-323-1", "doc_id": "drug_resistance_book", "page": 323, "text": "Yet one can argue whether antibiotics truly ‘fixed’ the problem of infectious disease. As already noted, while they are often given full credit for the decline of infectious disease in Europe and North America, antibiotics were introduced after the majority of mortality declines that are more correctly attributed to rising stan- dards of living, better nutrition, and basic public health preventive measures such as sanitation, vaccination, vector control, and provision of clean water (Szreter 1988; Cutler and Miller 2005). Moreover, social and economic factors continue to be major determinants of infectious disease (Semenza 2016). Even in high-income countries with well-functioning health care systems and access to a full range of antibiotics, poverty, social marginalization, and food and water quality continue to play a significant role in the incidence of infectious disease (King 2003; Semenza 2010). It remains to be seen whether, from a population perspective, investment in additional antimicrobials is the most effective or efficient way to reduce the burden of infectious disease.", "n_tokens": 214, "kind": "text"}
{"chunk_id": "drug_resistance_book-323-2", "doc_id": "drug_resistance_book", "page": 323, "text": "Whether or not antibiotics ‘fixed’ infectious disease, their introduction generated the unintended consequence of antimicrobial resistance. While it might seem logi- cal that a ‘technological’ problem (antimicrobials) demands a ‘technological’ solu- tion (more antimicrobials), as the other chapters in this volume illustrate, the causes of and solutions to antimicrobial resistance are more complicated. As with infec- tious disease, the proximate cause of antimicrobial resistance is biological – patho- gens develop resistance under the selective pressure exerted by use of antimicrobials – but underlying this proximate cause is a range of more distal deter- minants. These include, among others:\n\n315", "n_tokens": 160, "kind": "text"}
{"chunk_id": "drug_resistance_book-324-0", "doc_id": "drug_resistance_book", "page": 324, "text": "316\n\nN. B. King\n\nPhysician behavior – e.g., prescribing antibiotics for conditions caused by viruses (Sprenger 2015); engage in suboptimal practices such as use of monotherapy rather than combination therapy; and incorrect drug administration routes (Struelens 1998).\n\nPatient behavior – e.g., failure to complete full course of treatment; and self- medication, particularly in countries where antimicrobials are available over the counter.\n\nPoor hygiene, sanitation, and infection control in hospitals and other healthcare facilities, leading to cross-infection with multiple strains of bacteria (Aiello 2006; Struelens 1998).\n\nWidespread use – including misuse and overuse – of antimicrobials in agricul- ture (Levy 2014; Ventola 2015).", "n_tokens": 167, "kind": "text"}
{"chunk_id": "drug_resistance_book-324-1", "doc_id": "drug_resistance_book", "page": 324, "text": "Lack of development of new antimicrobials, which are less profitable than drugs for chronic conditions that are generally more expensive and used for much lon- ger periods of time (Brown and Wright 2016). Novel antibiotics will be introduced into the same social, political, and economic contexts that have contributed to the development of antibiotic resistance in the first place. Addressing these contexts would require, among other interventions: chang- ing the behavior of physicians and patients to encourage appropriate stewardship of antimicrobials; instituting and enforcing new sanitation and infection control proto- cols at healthcare facilities across the globe; reforming an agricultural system dependent upon cheap antibiotics; and changing the incentive structure of the phar- maceutical industry to ensure that need rather than profit drives drug research.", "n_tokens": 159, "kind": "text"}
{"chunk_id": "drug_resistance_book-324-2", "doc_id": "drug_resistance_book", "page": 324, "text": "Faced with a wide and seemingly insurmountable range of determinants, focus- ing on the development of new lines of antimicrobials through targeted research grants and incentive programs is attractive. Yet such a narrow pursuit would, ulti- mately, amount to little more than layering technological fixes on prior technologi- cal fixes. As Dubos noted a half-century ago, “Granted the obvious usefulness of sanitary practices, immunological procedures, and antimicrobial drugs, it does not necessarily follow that destruction of microbes constitutes the only possible approach to the problem of infectious disease, nor necessarily the best”(Dubos 1996, p. 53).\n\n19.5\n\nTechnological Fixes and Distributive Justice\n\nTechnological fixes have an enduring appeal. Part of this is practical: they appear to provide simple, efficient, measurable, and effective solutions to complex problems. However, the presumed practicality of these fixes conceals underlying moral and political assumptions, with important ramifications for distributive justice.", "n_tokens": 219, "kind": "text"}
{"chunk_id": "drug_resistance_book-325-0", "doc_id": "drug_resistance_book", "page": 325, "text": "19 Technological Fixes and Antimicrobial Resistance\n\nOne of Weinberg’s precursors was Richard L. Meier, a chemist and technological optimist who advocated the use of technological systems as a means of eliminating poverty and other social ills (Johnston 2018). It is worth noting an important distinc- tion between the little-known precursor and the widely-known successor: while Meier saw technology as a means of remedying distributive injustices, Weinberg saw it as a means for minimizing the harms of those injustices without addressing them. Indeed, in his influential 1966 essay, Weinberg’s primary example of a suc- cessful technological fix is the advances in mass production of goods that “enable[d] our capitalistic society to achieve many of the aims of the Marxist social engineer without going through the social revolution Marx viewed as inevitable” (Weinberg 1991, p. 43).\n\nThe distinction between Meier and Weinberg illustrates an often-hidden ethical component of the technological fix approach. Technological fixes generally reward the rich. This is partially by design: fixes are appealing precisely because they avoid social engineering that might upset the status quo, including extant inequalities. They require no hard questions about the justness of current distribu- tional procedures or outcomes, and they often expressly promise to reduce the negative consequences of extant inequalities without addressing the inequalities themselves.", "n_tokens": 302, "kind": "text"}
{"chunk_id": "drug_resistance_book-325-1", "doc_id": "drug_resistance_book", "page": 325, "text": "The concentration of benefits among the rich is also a consequence of the global economy of health research. Health-related technological innovations are most likely to occur in wealthy institutions – top research universities, multinational pharmaceutical companies and medical device manufacturers, highly-capitalized biotechnology startup companies – concentrated in high-income countries. Initiatives that target technological innovation, from BMGF research grants to tar- geted incentives for pharmaceutical development, thus overwhelming benefit wealthy individuals and institutions in wealthy countries. While it is true that these investments may eventually benefit others, in the short-term they simply circulate resources from rich donors to rich institutions in the global north, often in the name of benefitting the least advantaged.\n\nTechnological fixes may thus be ‘practical’ insofar as they provide an easily identifiable, targeted, and efficient strategy for distributing resources; but this prac- tically is purchased at the price of eliding important distributive concerns. In the context of antimicrobial resistance, we would do well to resist the urge to unthink- ingly pursue technological fixes, lest they contribute to precisely the inequalities that underlie the spread of infectious disease and the continued generation of anti- microbial resistance.\n\nAcknowledgments The author thanks Joy Tseng for research assistance in the preparation of this chapter.\n\n317", "n_tokens": 272, "kind": "text"}
{"chunk_id": "drug_resistance_book-326-0", "doc_id": "drug_resistance_book", "page": 326, "text": "318\n\nN. B. King\n\nReferences\n\nAiello, Allison E., Nicholas B. King, and Betsy Foxman. 2006. Antimicrobial resistance and the\n\nethics of drug development. American Journal of Public Health. 96(11):1910–1914.\n\nArmstrong, Gregory L., Laura A. Conn, and Robert W. Pinner. 1999. Trends in infectious dis- ease mortality in the United States during the 20th century. Journal of the American Medical Association 281:61–66.\n\nAnne-Emanuelle, Birn. 2005. Gates’s grandest challenge: Transcending technology as public\n\nhealth ideology. Lancet 366:514–519.\n\nBrown, E.D., and G.D. Wright. 2016. Antibacterial drug discovery in the resistance era. Nature\n\n529(7586):336–343.\n\nColgrove, James. 2002. The McKeown thesis: A historical controversy and its enduring influence.\n\nAmerican Journal of Public Health. 92(5):725–729.\n\nCutler, David. 2005. And miller, Grant. The role of public health improvements in health advances:\n\nThe twentieth-century United States. Demography 42(1):1–22.\n\nDubos, Rene. 1996. Mirage of health: Utopias, Progress, and biological change. New Brunswick:", "n_tokens": 279, "kind": "text"}
{"chunk_id": "drug_resistance_book-326-1", "doc_id": "drug_resistance_book", "page": 326, "text": "Rutgers University Press.\n\nFairchild, Amy L., and Gerald M. Oppenheimer. 1998. Public health nihilism vs. pragma- tism: History, politics, and the control of tuberculosis. American Journal of Public Health. 88:1105–1117.\n\nFee, Elizabeth. 1994. Public health and the state: The United States. In The history of public health\n\nand the modern state, ed. Dorothy Porter, 224–275. Amsterdam: Editions Rodopi B.V.\n\nGarrett, Laurie. 1994. The coming plague: Newly emerging diseases in a world out of balance.\n\nNew York: Farrar, Strauss and Giroux.\n\nJohnston, Sean F. 2018. Alvin Weinberg and the promotion of the technological fix. Technology\n\nand culture. 59(2).\n\nJongsma, Karin R., and Sand, Martin. 2017. The usual suspects: Why techno-fixing dementia is\n\nflawed. Medicine, health care, and philosophy. 20(1):119–130.\n\nKing, Nicholas B. 2003. The influence of anxiety: September 11th, bioterrorism, and American\n\npublic health. Journal of the History of Medicine and Allied Sciences. 58(4):433–448.\n\nLevy, Stuart B., and Marshall, B. 2014. Antibacterial resistance worldwide: Causes, challenges and\n\nresponses. Nature Medicine. 10(12 Suppl):S122–S129.\n\nMcKeown, Thomas. 1979. The role of medicine : Dream, mirage, or nemesis? Princeton, N.J.:\n\nPrinceton University Press.\n\nMoberg, Carol L. 1996. Rene Dubos: A harbinger of microbial resistance to antibiotics. Microbial\n\nDrug Resistance 2(3):287–297.\n\nOmran, Abdel R. 1983. The epidemiologic transition theory. A preliminary update. Journal of", "n_tokens": 388, "kind": "text"}
{"chunk_id": "drug_resistance_book-326-2", "doc_id": "drug_resistance_book", "page": 326, "text": "Tropical Pediatrics. 29:305–316.\n\nRosenkrantz, Barbara. 1974. ‘Cart before horse’: Theory, practice, and professional image in\n\nAmerican public health, 1870-1920. Journal of the History of Medicine. 55–73.\n\nRosner, Lisa. 2004. The technological fix: How people use technology to create and solve prob-\n\nlems. London: Routledge.\n\nSemenza, J.C., J.E. Suk, and S. Tsolova. 2010. Social determinants of infectious diseases: A public\n\nhealth priority. Euro Surveillance 15(27):1–3.\n\nSemenza, J.C., E. Lindgren, L. Balkanyi, L. Espinosa, M.S. Almqvist, P. Penttinen, et al. 2016. Determinants and drivers of infectious disease threat events in Europe. Emerging Infectious Diseases. 22(4):581–589.\n\nSprenger, M. 2015. How to stop antibiotic resistance? Here’s a WHO prescription.. Retrieved from\n\nhttp://www.who.int/mediacentre/commentaries/stop-antibioticresistance/en/\n\nStruelens, M.J. 1998. The epidemiology of antimicrobial resistance in hospital acquired infections:\n\nProblems and possible solutions. BMJ 317(7159):652–654.\n\nSzreter, Simon. 1988. The importance of social intervention in Britain’s mortality decline, c. 1850-1914: A re-interpretation of the role of public health. Social History of Medicine. 1:1–37.", "n_tokens": 350, "kind": "text"}
{"chunk_id": "drug_resistance_book-327-0", "doc_id": "drug_resistance_book", "page": 327, "text": "19 Technological Fixes and Antimicrobial Resistance\n\nTomes, Nancy. 1998. The gospel of germs: Men, women, and the microbe in American life.\n\nCambridge, MA: Harvard University Press.\n\nVentola, C.L. 2015. The antibiotic resistance crisis: Part 1: Causes and threats. Pharmacy &\n\nTherapeutics. 40(4): 277–283.\n\nWeinberg, Alvin M. 1991. Can Technology Replace Social Engineering. In Controlling Technology: Contemporary Issues, ed. W.B. Thompson. Buffalo, NY: Prometheus Books.\n\nWinograd, Terry. (July 1, 2013). What’s wrong with technological fixes?: Boston review. WHO Commission on Social Determinants of Health. 2008. Closing the gap in a generation: health equity through action on the social determinants of health. Final report of the Commission on the Social Determinants of Health. Geneva, Switzerland: World Health Organization, Commission on Social Determinants of Health.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.", "n_tokens": 299, "kind": "text"}
{"chunk_id": "drug_resistance_book-327-1", "doc_id": "drug_resistance_book", "page": 327, "text": "The images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n319", "n_tokens": 74, "kind": "text"}
{"chunk_id": "drug_resistance_book-328-0", "doc_id": "drug_resistance_book", "page": 328, "text": "Chapter 20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic Use\n\nJasper Littmann, Annette Rid, and Alena Buyx\n\nAbstract To reduce the effect of antimicrobial resistance and preserve antibiotic effectiveness, clinical practice guidelines and health policy documents call for the “rational use” of antibiotics that aims to avoid unnecessary or minimally effective antibiotic prescriptions. In this paper, we show that rational use programmes can lead to ethical conflicts because they place some patients at risk of harm – for exam- ple, a delayed switch to second-line antibiotics for community-acquired pneumonia is associated with increased fatality rates. Implementing the rational use of antibiot- ics can therefore lead to conflicts between promoting patients’ clinical interests and preserving antibiotic effectiveness for future use. The resulting ethical dilemma for clinicians, patients and policy makers has so far not been adequately addressed. We argue that existing guidance for acceptable risks in clinical research can help to define risk thresholds for the rational use of antibiotics. We develop an ethical framework that allows clinicians and policy-makers to evaluate policies for rational antibiotic use in six practical steps.", "n_tokens": 232, "kind": "text"}
{"chunk_id": "drug_resistance_book-328-1", "doc_id": "drug_resistance_book", "page": 328, "text": "This paper is an extended version of: Littmann J, Rid A, Buyx A: Tackling anti-microbial resis- tance: ethical framework for rational antibiotic use. European Journal of Public Health 2018; 28(2): 359–363. A fuller defense of our framework is provided in: Rid A, Littmann J, Buyx A: Evaluating the risks of public health programs: rational antibiotic use and antimicrobial resistance. Bioethics 2019; 33(7): 734-748.\n\nJ. Littmann National Institute of Public Health, Centre for Antimicrobial Resistance, Oslo, Norway\n\nInstitute for Ethics and History of Medicine, Technical University, Munich, Germany\n\nA. Rid Department of Bioethics, The Clinical Center, National Institutes of Health, Bethesda, MD, USA\n\nA. Buyx (*) Institute for Ethics and History of Medicine, Technical University, Munich, Germany e-mail: a.buyx@tum.de\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_20\n\n321", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-329-0", "doc_id": "drug_resistance_book", "page": 329, "text": "322\n\nJ. Littmann et al.\n\nKeywords Antimicrobial resistance · Medical ethics · Rational use of antibiotics · Research ethics · Rationing · Acceptable risk\n\n20.1\n\nIntroduction\n\nAntimicrobial resistance (AMR) has been described as one of the major threats to public health in the twenty-first century and sparked concerns about the possibility of a post-antibiotic era, in which many infections are no longer treatable (WHO 2014; General Assembly of the United Nations 2016; Davies et al. 2013). Such a development would not only have detrimental effects on patient care, but is also likely to significantly affect public health, agriculture, as well as economic and national security (PCAST 2014; O’Neill 2014; Adeyi et al. 2017; OECD 2018).\n\nOver the past few years, the challenge of AMR has increasingly been recognised by policy makers. The World Health Organization (WHO) developed a global action plan on AMR (WHO 2011, 2015), the United Nations General Assembly passed a declaration on the issue (General Assembly of the United Nations 2016) and the G20—a forum of the world’s major economies—has placed AMR on its agenda (Bundesministerium für Gesundheit 2011). In addition, considerable investments have been made to strengthen and incentivise the development of new antibiotics (Boucher et al. 2013; Drive-AB-12 2018; Rex 2014; Outterson et al. 2016a, b).", "n_tokens": 309, "kind": "text"}
{"chunk_id": "drug_resistance_book-329-1", "doc_id": "drug_resistance_book", "page": 329, "text": "Since one of the major causes of AMR is the overprescription and overconsump- tion of antibiotics, comprehensive response plans to preserve antibiotic effective- ness do not focus solely on the development of new drugs. They also include a wide range of measures, including surveillance, infection control and, crucially, the pro- motion of the “rational” use of antibiotics (WHO 2014). Rational use programmes primarily focus on avoiding unnecessary prescriptions of antibiotic treatments, for example in the context of viral respiratory infections. However, they also include practices that involve delaying or withholding access to antibiotics that are known to be beneficial. These practices can place some patients at risk of harm and thereby lead to conflicts between two important ethical goals: promoting patients’ clinical interests and preserving antibiotic effectiveness for future use.", "n_tokens": 165, "kind": "text"}
{"chunk_id": "drug_resistance_book-329-2", "doc_id": "drug_resistance_book", "page": 329, "text": "The ethical conflict between these goals has so far not been adequately addressed. In this paper, we describe programmes for rational antibiotic use and show when they require placing some patients at risk of harm for the benefit of managing the existing pool of effective antibiotics. We argue that ethical guidance on acceptable risks in clinical research can help to develop acceptable programmes for rational antibiotic use. Based on a recognized ethical framework for risk and risk-benefit evaluations in clinical research, we propose a novel framework that allows clini- cians and policy-makers to evaluate when rational antibiotic use is (or is not) ethi- cally justified.", "n_tokens": 127, "kind": "text"}
{"chunk_id": "drug_resistance_book-330-0", "doc_id": "drug_resistance_book", "page": 330, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\n20.2\n\nRational Use of Antibiotics\n\nThe promotion of “rational” antibiotic use – sometimes referred to as “prudent” or “appropriate” use – is a key component of many response plans to AMR (Bundesministerium für Gesundheit 2011; UK Department of Health 2013; Public Health Agency of Canada 2014; The White House 2014; Australian Department for Health 2015). The WHO provided the most widely cited definition of the rational use of medicines in general, which includes the rational use of antibiotics. According to WHO, this requires that “patients receive medications appropriate to their clinical need, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community” (WHO 1985). Elsewhere, the WHO defined appropriate antibiotic use as the “cost-effective use of antimicrobials which maximizes clinical therapeutic effect while minimizing drug- related toxicity and the development of antimicrobial resistance” (WHO 2011). Most concise is the definition provided by the Alliance for the Prudent Use of Antibiotics (APUA), which defines prudent use as “the right drug for the right con- dition for the right amount of time” (Wilson and Tan 2010).", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-330-1", "doc_id": "drug_resistance_book", "page": 330, "text": "Notwithstanding some differences in meaning, these definitions all delineate types of antibiotic use that are clearly “irrational”—that is, obvious instances of overuse or misuse where antibiotics are prescribed or taken even though they are not the appropriate treatment. For example, antibiotics are an appropriate treatment for “strep throat”, which is caused by a bacterium susceptible to certain antibiotics. However, they are not an appropriate treatment for most sore throats, which are caused by viruses against which antibiotics are not effective.", "n_tokens": 103, "kind": "text"}
{"chunk_id": "drug_resistance_book-330-2", "doc_id": "drug_resistance_book", "page": 330, "text": "There is a wide array of interventions designed to reduce antibiotic prescribing, and evidence suggests that restrictive measures, which limit the availability of anti- biotics, have a higher chance of success than information campaigns or educational interventions that teach prescribing clinicians about AMR (Charani et al. 2011; Davey et al. 2013). In many instances, such restrictions appear to be a promising and effective way of reducing antibiotic use. For instance, recent research has shown that antibiotic prescribing in primary care can be restricted substantially, without a negative effect on clinical outcomes, through a practice called delayed prescribing (Schuetz et al. 2009; Spurling et al. 2013; Little et al. 2014). Here patients for whom antibiotics are unlikely to be an appropriate treatment—say most patients with sore throats—receive a prescription that they can use at the pharmacy if their symptoms do not improve on their own within a few days. Receiving such a prescription gives patients reassurance, even though only few end up filling it. A Cochrane review concluded that delayed prescribing offers no additional risks to the patient, while offering similar patient satisfaction when compared to immediate prescribing (Spurling et al. 2013).\n\n323", "n_tokens": 259, "kind": "text"}
{"chunk_id": "drug_resistance_book-331-0", "doc_id": "drug_resistance_book", "page": 331, "text": "324\n\nJ. Littmann et al.\n\nSo understood, rational use of antibiotics is ethically justified because it pro- motes patients’ clinical interests while also preserving antibiotic effectiveness for future use. Not only are present patients spared the side effects of unnecessary treat- ment, avoiding such treatment also curbs the spread of antibiotic resistance and thereby helps to ensure that existing antibiotics remain effective to treat future patients. Indeed, because rational use so understood promotes the interests of pres- ent as well as future patients, clinicians and policy-makers are ethically required to ensure that patients use “the right drug for the right condition for the right amount of time” (Wilson and Tan 2010).\n\n20.3\n\nEthically Challenging Instances of Rational Use", "n_tokens": 152, "kind": "text"}
{"chunk_id": "drug_resistance_book-331-1", "doc_id": "drug_resistance_book", "page": 331, "text": "In addition to avoiding unnecessary antibiotic use, rational use programmes embrace practices that restrict access to antibiotics even when treatment would reduce a given patient’s health risk (Millar 2012). One example for this are programmes that ask clinicians to factor resistance thresholds in the community when they suggest antibiotic treatment to their patients. For example, clinical practice guidelines for treating community-acquired pneumonia recommend the use of macrolides—a par- ticular class of antibiotics—unless 25% or more of the relevant pathogens are resis- tant to macrolides in the given local community (Mandell et al. 2007). Only then should clinicians switch to more effective second-line drugs (Mandell et al. 2007).1 When considering the entire patient population, this is a sensible recommendation, since it is to be expected that macrolides—the first line of treatment—remains effective in most patients if resistance is below 25%. However, a delayed switch to second-line drugs negatively affects clinical outcomes in some patients, notably those with severe pneumonia. Some authors estimate that a similar guideline has carried a mortality risk of more than 1% for all patients in the past (Daneman et al. 2008). Rational use practices of this type effectively delay or withhold a proven beneficial antibiotic in order to curb the spread of antimicrobial resistance. This places some present patients at risk for the sake of future patients.", "n_tokens": 293, "kind": "text"}
{"chunk_id": "drug_resistance_book-331-2", "doc_id": "drug_resistance_book", "page": 331, "text": "In these and comparable cases, the rational use of antibiotics confronts clinicians with a trade-off between promoting their present patients’ best clinical interests and helping to maintain effective antibiotic treatments for future patients (Kollef and Micek 2014). This trade-off seems particularly stark for several reasons (Littmann et al. 2015; Littmann and Buyx 2018). First, it is difficult to measure the contribu- tion of any individual course of antibiotics to the emergence of AMR in a popula- tion, so that estimates about the benefits of rational use programmes are relatively uncertain. It seems likely, however, that delaying or withholding any given antibi- otic treatment makes no more than a very small contribution to curbing AMR and, in some cases, no contribution at all. For example, a patient might develop resistant\n\n1 Since the time of writing, an updated version of the consensus guidelines has superseded the cited work (Metlay et al. 2019).", "n_tokens": 204, "kind": "text"}
{"chunk_id": "drug_resistance_book-332-0", "doc_id": "drug_resistance_book", "page": 332, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\nbacteria but die before transmitting these to other people or the environment. As a result, rational use programmes that involve delaying or withholding antibiotic treatment are neither necessary nor sufficient for addressing AMR. Moreover, the benefits of preserving antibiotics may accrue to unknown people in the potentially distant future. By contrast, the benefits of antibiotic treatment for the present patient are much easier to measure and can therefore be predicted with greater certainty. Antibiotic treatment also has immediate benefits that accrue to known or “identi- fied” persons. These differences readily explain why a typical clinician who is tasked with delaying or withholding antibiotics from her present patients with the goal of tackling AMR would feel an acute ethical conflict (Cohen et al. 2015).", "n_tokens": 171, "kind": "text"}
{"chunk_id": "drug_resistance_book-332-1", "doc_id": "drug_resistance_book", "page": 332, "text": "Bioethicists have started to discuss this ethical conflict (Selgelid 2007; Battin et al. 2009; Millar 2012; Oczkowski 2017; Littmann and Buyx 2014; Littmann et al. 2015). However, at both the clinical and policy level, there is no ethical guidance on when rational use programmes that involve delaying or withholding antibiotics and hence compromise the best clinical interests of present patients are acceptable. Moreover, many policy documents lack explicit discussion of any ethical chal- lenges, and those that include ethical considerations are narrowly disease- and pathogen-specific (Bundesministerium für Gesundheit 2011; WHO 2011; Davies et al. 2013; Andreasen 2014). What is therefore needed is a more specific analysis of whether and when it is acceptable to restrict antibiotics use with the goal of curb- ing AMR, even when doing so poses risks to present patients and thereby compro- mises their best clinical interests.\n\n20.4\n\nThe Analogy to Clinical Research", "n_tokens": 207, "kind": "text"}
{"chunk_id": "drug_resistance_book-332-2", "doc_id": "drug_resistance_book", "page": 332, "text": "To address this question, it is helpful to consider more generally whether and when it is justified for clinicians not to promote the best clinical interests of their present patient. Standard professional guidance takes a relatively restrictive stance on this issue. For example, the World Medical Association states that clinicians owe their patients “complete loyalty”, and that they may place the interests of others above those of the patient only in “exceptional situations” (Williams 2015). However, closer analysis reveals many clinical practices that place the interests of other patients, individuals or society above the interests of a given present patient (Wendler 2010). Consider, for example, that clinicians routinely give vaccinations not to pro- tect the present patient, but to maintain herd immunity; that clinicians transplant kidneys from healthy individuals to patients with renal failure in order to enable these patients to live a better and longer life; and that clinicians allow younger col- leagues to gain experience and perform procedures for the first time, even though they know that this will result in higher complication rates for the present patient. Importantly, these practices are not only frequent, but ethically justified provided that a number of conditions are met (Wendler 2010). This finding raises the possibil- ity of evaluating the ethical acceptability of rational use programmes for antibiotics in comparison to other practices that involve", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-332-3", "doc_id": "drug_resistance_book", "page": 332, "text": "compromising the interests of individual patients for the benefit of others.", "n_tokens": 13, "kind": "text"}
{"chunk_id": "drug_resistance_book-332-4", "doc_id": "drug_resistance_book", "page": 332, "text": "325", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-333-0", "doc_id": "drug_resistance_book", "page": 333, "text": "326\n\nJ. Littmann et al.\n\nFor such comparisons to be both sound and useful, it is essential to identify com- parator practices that are relevantly similar to rational use programmes for antibiotics and widely considered to be acceptable (Sunstein 1993). Moreover, detailed ethical guidance on how to evaluate the given comparator practice should ideally exist. Clinical research fulfils all three desiderata, as the following paragraphs demonstrate.", "n_tokens": 89, "kind": "text"}
{"chunk_id": "drug_resistance_book-333-1", "doc_id": "drug_resistance_book", "page": 333, "text": "Clinical research is a subset of research with human participants that focuses on evaluating methods to prevent, treat or cure illness and disease, or on generating the knowledge necessary to develop such methods. One of the key characteristics of clinical research is that investigators expose participants to some risks for the poten- tial benefits of unknown patients in the potentially distant future. Clinician- investigators routinely perform research procedures that do not promote the best clinical interests of the present patient-participant, but serve solely to address research questions. In fact, the majority of clinical trials involve procedures that have no prospect of clinical benefit for participants but help to answer important research questions. For example, most clinical trials involve additional blood draws, biopsies or imaging procedures that would not be performed as part of routine clini- cal care, but serve to test the safety and efficacy of an investigational drug. Moreover, phase 1 trials with healthy individuals by definition have no prospect of clinical benefit. It is widely considered acceptable for clinician-investigators to perform these “net risk” procedures and trials—and thereby deviate from the general clinical norm of promoting the present patient’s best clinical interests—because clinical research generates knowledge with the potential to improve the health or care of future patients (WMA 2013; CIOMS 2016). That is, the potential benefits of", "n_tokens": 265, "kind": "text"}
{"chunk_id": "drug_resistance_book-333-2", "doc_id": "drug_resistance_book", "page": 333, "text": "clinical research for future populations are widely considered to justify that investigators expose patient-participants to some level of net research risk.", "n_tokens": 24, "kind": "text"}
{"chunk_id": "drug_resistance_book-333-3", "doc_id": "drug_resistance_book", "page": 333, "text": "Importantly, the potential benefits for future patients—or the so-called “social value” of the research—is generally seen as the fundamental justification for expos- ing participants to net research risks, not the participants’ informed consent. Participants’ consent is, of course, relevant for determining what levels of net research risk are acceptable in socially valuable research. Only small levels of net risk are acceptable when participants cannot give their own informed consent, for example in research involving children, or when obtaining participants’ consent is not feasible, for example in research on large datasets that were originally collected for clinical (and not for research) purposes. By contrast, greater net risks are accept- able when participants give their voluntary and informed consent. However, it is generally accepted—and for good reason in our view—that research without social value is not justified even when the research poses low net risks and participants consent (Wendler and Rid 2017). This underscores that the fundamental justifica- tion for exposing participants to net research risks lies in the potential benefits of clinical research for future patients.", "n_tokens": 221, "kind": "text"}
{"chunk_id": "drug_resistance_book-333-4", "doc_id": "drug_resistance_book", "page": 333, "text": "Restricting antibiotic use with the goal of curbing AMR is relevantly similar to clinical research in this important respect. Just like in research, clinicians expose the present patient to some risks of harm for the potential benefits of unknown patients in the potentially distant future. Moreover, what level of risk is acceptable arguably", "n_tokens": 62, "kind": "text"}
{"chunk_id": "drug_resistance_book-334-0", "doc_id": "drug_resistance_book", "page": 334, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…", "n_tokens": 17, "kind": "text"}
{"chunk_id": "drug_resistance_book-334-1", "doc_id": "drug_resistance_book", "page": 334, "text": "depends on whether the present patient consents to delaying or foregoing antibiotic treatment that would be in her best clinical interests. In clinical research, it is not certain that any given clinical trial generates findings that make a significant contri- bution to improving the health or care of future patients and populations. Moreover, the enrolment of any single patient-participant is uncertain to make a significant difference to the value of any given trial. Yet without sufficient overall participation, trials—and clinical research more generally—would fail. Rational use programmes that involve delaying or withholding antibiotics are similar in this respect. It is not only uncertain that such programmes will make a significant contribution to address- ing AMR, but restricting a single patient’s access to antibiotics may not lead to a measurable effect on the overall level of AMR. Yet reducing antibiotic prescriptions overall is a key component of strategies for curbing AMR and ensuring that bacte- rial infections can still be treated effectively in the future (Costelloe et al. 2010; Davies et al. 2013). Given this relevant similarity between clinical research and rational use programmes that delay or withhold antibiotics, and considering that it is widely accepted for clinician-investigators to impose some level of net risk on patient-participants for the potential benefit of future patients (Selgelid 2007; Kollef and Micek 2014), it should also be acceptable to", "n_tokens": 287, "kind": "text"}
{"chunk_id": "drug_resistance_book-334-2", "doc_id": "drug_resistance_book", "page": 334, "text": "impose comparable levels of risks on patients in order to preserve antibiotic effectiveness for future patients.2", "n_tokens": 19, "kind": "text"}
{"chunk_id": "drug_resistance_book-334-3", "doc_id": "drug_resistance_book", "page": 334, "text": "Moreover, there is a long-standing and nuanced debate about acceptable risk in clinical research. This does not only mean that our judgments about acceptable risks are relatively considered in the research context, but also that detailed ethical guid- ance in this area exists (WMA 2013; CIOMS 2016; Emanuel et al. 2008). Clinical research therefore fulfils the three desiderata for sound and helpful comparisons formulated above: it is relevantly similar to rational use programmes that delay or withhold antibiotics for the sake of curbing AMR; it is widely considered an accept- able exception from the general principle that clinicians should act in the best inter- ests of the present patient; and detailed ethical guidance on how to evaluate research risks, including net research risks, exists. This suggests that judgments about accept- able risk in clinical research can inform the ethical evaluation of rational use pro- grammes that impose risks on present patients with the goal of curbing AMR and safeguarding antibiotic effectiveness for future patients (Rid et al. 2019).\n\n20.5", "n_tokens": 218, "kind": "text"}
{"chunk_id": "drug_resistance_book-334-4", "doc_id": "drug_resistance_book", "page": 334, "text": "An Ethical Framework for Evaluating Rational Antibiotic Use\n\nFor clinician-researchers to justifiably impose risks on patient-participants in clini- cal research, a number of conditions must be met. Specifically, the research must be scientifically valid and socially valuable; the risks to participants have to be\n\n2 There are, of course, relevant dissimilarities between clinical research and rational use pro- grammes that involve delaying or withholding antibiotics. However, as we argue elsewhere in more detail, the similarities between the two clearly dominate the dissimilarities (Rid et al. 2019).\n\n327", "n_tokens": 123, "kind": "text"}
{"chunk_id": "drug_resistance_book-335-0", "doc_id": "drug_resistance_book", "page": 335, "text": "328\n\nJ. Littmann et al.\n\nminimised and reasonable in relation to the potential clinical benefits for them and/ or the social value of the research; and, when participants cannot or do not consent, any net risks to them should be no greater than minimal or, in cases of compelling social value, no greater than a minor increase over minimal risk (WMA 2013; CIOMS 2016).\n\nTo operationalise these conditions, one of the authors of this paper (AR) has developed a systematic framework for evaluating research risks and potential ben- efits based on prominent research ethics guidelines and literature (Rid and Wendler 2011). This framework can be usefully adapted to evaluate the risks of rational use programmes that involve delaying or withholding antibiotics from patients who could clinically benefit (Appendix). The framework is most useful for evaluating rational use programmes that do not require clinicians to obtain the patient’s informed consent for restricting antibiotics. In particular, the minimal risk threshold for research without informed consent (Rid 2014) provides much needed orienta- tion regarding acceptable levels of unconsented to net risks in the public health context. However, the framework could also help to evaluate rational use pro- grammes that would require the patient’s informed consent. Here, the debate about upper net risk limits in research with competent consenting adults is particularly informative (London 2006; Miller and Joffe 2009).", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-335-1", "doc_id": "drug_resistance_book", "page": 335, "text": "The framework sets out six steps for evaluating rational use programmes that involve delaying or withholding antibiotics. A hypothetical programme to restrict antibiotic use for lower respiratory tract infections (LRTIs) helps to illustrate how these steps would work in practice (Table 20.1, Ethical framework for rational anti- biotic use).", "n_tokens": 64, "kind": "text"}
{"chunk_id": "drug_resistance_book-335-2", "doc_id": "drug_resistance_book", "page": 335, "text": "The first step—ensure and enhance the programme’s social value—requires decision-makers to develop rational use programmes based on sound evidence and policy methods. This is to ensure that all programmes are rigorously developed and judged to be both feasible and effective. For example, the available data should sug- gest that delaying or withholding the given antibiotics for LRTIs has the potential to help curb AMR. Data should also be sufficient to estimate the risks of restricting the antibiotics for patients; if there is too much uncertainty regarding how likely patients will suffer harm, relevant data should first be gathered in a research study. For pro- grammes that meet these conditions, step one also requires conducting (and/or reviewing) observational research on their implementation. For example, how does restricted antibiotics use for LRTIs affect prescription rates, clinical outcomes, and antimicrobial resistance in the community? Such research serves to confirm that the given programme is indeed effective, while also expanding the existing knowledge of AMR. Evidence from accompanying observational research should inform regu- lar re-evaluations of the programme.", "n_tokens": 226, "kind": "text"}
{"chunk_id": "drug_resistance_book-335-3", "doc_id": "drug_resistance_book", "page": 335, "text": "The second step—identify the programme interventions—requires considering how the care of patients under the given rational use programme would differ from recommended standard care. Of course, the key difference would be that antibiotics are delayed or withheld under clearly specified circumstances. However, pro- grammes might also include supplementary, non-routine interventions that aim to reduce the risks of restricting antibiotic use. Importantly, these non-routine", "n_tokens": 82, "kind": "text"}
{"chunk_id": "drug_resistance_book-336-0", "doc_id": "drug_resistance_book", "page": 336, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\n329\n\nTable 20.1 Ethical framework for rational antibiotic use Step 1. Ensure and enhance the policy’s social value\n\nElements 1. Ensure that restricting antibiotics use for the given condition is based on sound evidence and policy methods\n\n2. Ensure that restricting antibiotics use for the given condition passes a minimum threshold of social value 3. Enhance the knowledge to be gained from the policy and use it to refine the policy\n\n2. Identify the policy interventions\n\n1. Identify the policy intervention and any supplementary (non-routine) interventions to protect patients", "n_tokens": 122, "kind": "text"}
{"chunk_id": "drug_resistance_book-336-1", "doc_id": "drug_resistance_book", "page": 336, "text": "Example Available data allow estimating the clinical and public health impact of restricted antibiotics use for lower respiratory tract infections Policy to restrict antibiotics use for lower respiratory tract infections is rigorously developed (policy analysis, stakeholder consultation, etc.) and judged to be feasible and effective Restricted antibiotics use for lower respiratory tract infections has the potential to address antimicrobial resistance, a major public health problem Initiate researcha to evaluate how restricted antibiotics use for lower respiratory tract infections affects prescription rates, clinical outcomes, antimicrobial resistance etc. and update policy as new evidence comes in Evaluate how the experience with restricting antibiotics use for lower respiratory tract infections can inform the management of antibiotics use for other conditions (e.g. urinary tract infection) Policy intervention: restricted antibiotics use for lower respiratory tract infections Supplementary interventions: provide relevant information to patients in writing (e.g. signs of worsening condition, next steps in this situation), provide 1-time respiratory therapy session to manage symptoms Exclude routine clinical interventions from analysis: provide relevant information verbally, provide supportive measures for lower respiratory tract infections (e.g. mucolytics, inhalation, pain medication) Could consider whether written patient information is essential", "n_tokens": 242, "kind": "text"}
{"chunk_id": "drug_resistance_book-336-2", "doc_id": "drug_resistance_book", "page": 336, "text": "2. Ensure that each supplementary intervention is essential for protecting patients\n\n(continued)", "n_tokens": 15, "kind": "text"}
{"chunk_id": "drug_resistance_book-337-0", "doc_id": "drug_resistance_book", "page": 337, "text": "330\n\nTable 20.1 (continued)\n\nStep 3. Evaluate and reduce the risks to patients\n\nElements 1. Evaluate the risks of the policy intervention and each supplementary intervention\n\n2. Reasonably reduce the risks\n\n4. Evaluate and enhance the potential benefits for patients\n\n1. Evaluate the potential clinical benefits of the policy intervention and each supplementary intervention\n\n5. Evaluate whether the interventions pose net risks\n\n2. Enhance the potential clinical benefits 1. Determine whether the risks of each individual intervention exceed the intervention’s potential clinical benefits (implies net risks): Would an informed clinician who is committed solely to promoting the patient’s clinical interests recommend the intervention? 2. Determine whether the unit of policy and supplementary interventions pose net risks: would an informed clinician recommend the unit of interventions?\n\nJ. Littmann et al.", "n_tokens": 158, "kind": "text"}
{"chunk_id": "drug_resistance_book-337-1", "doc_id": "drug_resistance_book", "page": 337, "text": "Example Restricting antibiotics use for lower respiratory tract infections poses risks (e.g. of increased complications such as pneumonia or empyema), which may require antibiotics and/or hospitalisation) Providing relevant information to patients in writing (rather than verbally) can cause mild anxiety Ensure that routine clinical interventions to treat lower respiratory tract infections are implemented (e.g. supportive measures) Ensure that serious harms, should they occur, are adequately managed at no financial cost to the patient (e.g. antibiotics and/or hospitalisation) and patients receive compensation for any lasting serious harms Actively monitor or exclude patient groups from policy who are at increased risk of complications or other serious harms (e.g. immunodeficiency) Instruct clinicians to exercise judgment in individual cases Reassure patients about written information sheet Restricting antibiotics use for lower respiratory tract infections spares patients the risks of treatment (e.g. diarrhea) 1-time respiratory therapy session helps to manage symptoms Consider complementing 1-time respiratory therapy session with educational material Informed clinician would not recommend withholding antibiotic treatment for lower respiratory tract infections or measures to manage the resulting risks (e.g. written information, active monitoring): net risks Informed clinician would recommend respiratory therapy session: no net risks", "n_tokens": 260, "kind": "text"}
{"chunk_id": "drug_resistance_book-337-2", "doc_id": "drug_resistance_book", "page": 337, "text": "Informed clinician would not recommend unit of interventions: potential clinical benefits of respiratory therapy session do not outweigh the risks of withholding antibiotic treatment and measures to manage the resulting risks\n\n(continued)", "n_tokens": 40, "kind": "text"}
{"chunk_id": "drug_resistance_book-338-0", "doc_id": "drug_resistance_book", "page": 338, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\nTable 20.1 (continued)\n\nStep 6. Evaluate whether the net risks are justified by the policy’s social value\n\nElements 1. Determine the level of cumulative net risk posed to patients 2. Determine whether the policy’s cumulative net risks fall within the general range of acceptable net risk: could judge in light of net risk limits in biomedical research, notably the “minimal risk”” threshold in research without informed consent for rational use programmes that do not require clinicians to obtain the patient’s informed consent and upper net risk limits in research for rational use programmes that require informed consent 3. Evaluate whether the given level of cumulative net risk is proportionate to the social value of implementing the policy: would an ideal social arbiter recommend the policy?\n\nExample Relatively small level of net risk from withholding antibiotic treatment and measures to manage the resulting risks Net risks from withholding antibiotic treatment for lower respiratory tract infections arguably falls within the range of acceptable net risk in clinical research (i.e. the net risks arguably fall below the minimal risk threshold)\n\nIdeal social arbiter may recommend the policy, given the importance of curbing antimicrobial resistance and the arguably minimal net risks to patients", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-338-1", "doc_id": "drug_resistance_book", "page": 338, "text": "The framework is adapted from an existing framework for risk-benefit evaluations in biomedical research (Rid and Wendler 2011; see Appendix for additional details). Example: hypothetical policy to restrict antibiotics use (delayed or no prescription) for lower respiratory tract infections without obtaining the patients’ informed consent aResearch to evaluate the impact of restricted antibiotics use for a given condition has to be judged based on standard ethical criteria for research (CIOMS 2016; WMA 2013)\n\ninterventions can carry their own risks. For example, if antibiotics for LRTIs were delayed or withheld, patients might be informed about signs of pneumonia or empyema (i.e. potential more serious complications of an initial infection) in writ- ing, rather than verbally as in standard practice, so as to ensure that they know when to seek expert advice and thereby reduce risks to them. However, receiving written information can itself cause concern among patients. It is therefore essential to iden- tify all programme interventions in order to comprehensively evaluate the risks that the given rational use programme poses to patients. As part of this step, the need for any supplementary interventions should also be scrutinized with a view to avoiding unnecessary risks. For example, do patients really require written information?\n\n331", "n_tokens": 254, "kind": "text"}
{"chunk_id": "drug_resistance_book-339-0", "doc_id": "drug_resistance_book", "page": 339, "text": "332\n\nJ. Littmann et al.\n\nStep three—evaluate and reduce the risks to patients—requires evaluating the risks of all programme interventions, including those of any supplementary inter- ventions, based on the available evidence. Moreover, all reasonable measures must be taken to reduce the risks to patients. For example, if written information about pneumonia and/or empyema is considered necessary, how can this information be conveyed in ways that reduce anxiety and stress for patients? Similarly, rational use programmes that involve delaying or withholding antibiotics need to ensure that patients who suffer serious harms are adequately treated at no financial cost. In the case of restricting antibiotics for LRTIs, for instance, it must be guaranteed that any collections of pus in the pleural cavity (i.e. empyemas) are promptly treated for free. Patients with any lasting serious harms should also receive compensation. Furthermore, patient groups at increased risk of experiencing serious harm—for example, patients with immune deficiency—should either be actively monitored or excluded from the programme. Guidelines should also instruct clinicians to exercise their judgment in individual cases.", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-339-1", "doc_id": "drug_resistance_book", "page": 339, "text": "Step four—evaluate and enhance the potential benefits for patients—requires evaluating based on the available evidence to what extent patients could benefit clinically from the given rational use programme. For example, not receiving anti- biotics for LRTIs means avoiding their side effects and reducing the risk of infection with Clostridium difficile—which is associated with antibiotic use and sometimes leads to a life-threatening infection of the colon—or resistant infection in future. Moreover, non-routine supplementary interventions can have potential clinical ben- efits for patients. For instance, if a one-time respiratory therapy session is intro- duced to help manage patients’ symptoms, this should be considered when evaluating the risks of the overall programme. Any supplementary interventions with potential clinical benefits for patients should also be targeted at groups who would benefit most, especially when they cannot be provided to all patients. For example, the one-time respiratory therapy session might be focused on patients who suffer from chronic pulmonary problems (provided they are not excluded from the programme for being at increased risk).", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-339-2", "doc_id": "drug_resistance_book", "page": 339, "text": "Step five—evaluate whether the interventions pose net risks to patients— requires judging, again based on the available evidence, whether the risks of each individual intervention exceed the intervention’s potential clinical benefits. If the answer to this question is yes, then the given intervention is said to pose “net risks” to the patient. One way of making this determination is to ask whether an “informed clinician” who is committed solely to the promoting the patients’ best clinical inter- ests would recommend that they undergo the intervention in question (Rid and Wendler 2011). If the clinician would recommend the intervention, it promotes the patients’ clinical interests and thus does not pose net risks. This implies that the intervention’s risk-benefit profile is acceptable and—assuming the requirements of the previous steps are satisfied—needs no further evaluation. If the clinician would be indifferent, then undergoing the intervention neither undermines nor promotes the patients’ clinical interests. Provided that including the intervention in the", "n_tokens": 197, "kind": "text"}
{"chunk_id": "drug_resistance_book-340-0", "doc_id": "drug_resistance_book", "page": 340, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…", "n_tokens": 17, "kind": "text"}
{"chunk_id": "drug_resistance_book-340-1", "doc_id": "drug_resistance_book", "page": 340, "text": "rational use programme is necessary to ensure its safety (step 2), this suggests that it has an acceptable risk-benefit profile. If the clinician would advise against the intervention, then it poses net risks that require further evaluation (step 6). For example, an informed clinician who is committed solely to promoting the patients’ best clinical interests would not recommend delaying or withholding antibiotics for LRTIs (at least where the expected benefit of antibiotic treatment outweighs the expected harms of adverse effects of antibiotics outlined above). This means that this intervention poses net risks whose acceptability needs to be considered further. Finally, step six—evaluate whether the net risks to patients are justified by the programme’s social value—serves precisely this purpose. It first requires determin- ing the cumulative level of net risk of the given rational use programme by adding the net risks of all its interventions. For example, restricting antibiotics for LRTIs likely poses a relatively small level of cumulative net risk from delaying or with- holding antibiotic treatment and providing patients with written information in order to manage the resulting risks. Evaluators must then judge whether the pro- gramme’s cumulative net risks fall within the general range of acceptable net risk to patients and, if the answer is yes, whether the risks are proportionate to the social value of implementing the programme.", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-340-2", "doc_id": "drug_resistance_book", "page": 340, "text": "With regard to the general range of acceptable net risk, there is a long-standing debate about this issue in clinical research that can inform judgements about the acceptability of rational use programmes. Debate has been most intense in the con- text of research involving participants who cannot give their own informed consent, such as children or patients with dementia. Many ethical guidelines and regulations, as well as many research ethicists, endorse a “minimal risk” threshold for such research in order to protect participants from excessive net research risks (Emanuel et al. 2008; WMA 2013; CIOMS 2016). The precise interpretation of this threshold remains contested. However, a recent analysis of the existing literature identifies several “lessons learned” that are equally pertinent for the evaluation of rational use programmes (Rid 2014). Specifically, the most convincing definitions of minimal risk refer to the two basic components of research risk, likelihood and magnitude of research harm. Further, these definitions distinguish different magnitudes of harm (e.g. small, moderate, serious) and set approximate likelihood thresholds for each magnitude of harm, where the likelihood thresholds are anchored with numeric information (e.g. 1 per 100,000) derived from risk comparisons. For example, if the risks of participating in a charity soccer game are considered acceptable, and this activity is thought to be relevantly similar to clinical research, data on the risks of", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-340-3", "doc_id": "drug_resistance_book", "page": 340, "text": "playing soccer can be used to anchor likelihood thresholds for different magnitudes of research harm. At present, comparator risks are best specified as the risks that average, healthy, normal individuals in different age groups face in riskier but still acceptable activities that are directed at benefiting others, such as playing soccer for charitable purposes in children. In practice, this implies that the most convincing definitions of the minimal risk threshold equate minimal net research risks with very low likelihoods of serious and moderate harm and modest likelihoods of small", "n_tokens": 106, "kind": "text"}
{"chunk_id": "drug_resistance_book-340-4", "doc_id": "drug_resistance_book", "page": 340, "text": "333", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-341-0", "doc_id": "drug_resistance_book", "page": 341, "text": "334\n\nJ. Littmann et al.\n\nharm (Rid 2014). Using this threshold as a preliminary guide for evaluating the acceptability of rational use programmes, net risks such as those reported for delay- ing antibiotics for LRTIs would seem to qualify as minimal. Specifically, if the two main complications—empyema and pneumonia—are classified as moderate harms, the up to 10% likelihood that they will occur (Schuetz et al. 2009) is broadly con- sistent with the likelihood of moderate harms observed in appropriate comparator risks (Rid et al. 2010).", "n_tokens": 123, "kind": "text"}
{"chunk_id": "drug_resistance_book-341-1", "doc_id": "drug_resistance_book", "page": 341, "text": "Similar arguments have been advanced in the debate about upper risk limits in research with competent consenting adults. Specifically, several authors suggest that these upper risk limits should be delineated in comparison to appropriate com- parators risks for competent adults, such as emergency medical assistance (London 2006; Miller and Joffe 2009). In rational use programmes that require clinicians to obtain informed consent for delaying or withholding antibiotics, the range of accept- able net risks could be evaluated based on what levels of risk are considered accept- able in research involving competent consenting adults. However, all current rational use programmes that we are aware of proceed without the patients’ informed con- sent (though individual doctors may discuss prescribing decisions with their patients and seek to understand patients’ preferences), so that the minimal net risk threshold is more pertinent. Moreover, although some ethical guidelines allow a “minor increase” above minimal risk in research without consent when it is not possible to gather the necessary data in a less risky manner and the social and scientific value of the research is compelling (CIOMS 2016), the minor increase over minimal risk threshold remains underspecified in the research ethics literature. We therefore would not recommend applying it systematically in the context of rational use programmes.", "n_tokens": 255, "kind": "text"}
{"chunk_id": "drug_resistance_book-341-2", "doc_id": "drug_resistance_book", "page": 341, "text": "With regard to judging whether the net risks of a given rational use programme are proportionate to the social value of implementing it, one way of making this judgment is to ask whether an “informed and impartial social arbiter” would recom- mend the programme in question after carefully considering the risks and potential benefits for all affected parties and giving everyone’s claims fair consideration, while treating like cases alike in similar areas of policy (Rid and Wendler 2011). This test provides no more than a heuristic to guide evaluators’ judgment; however, the idea of a social arbiter helps to ensure that rational use programmes are evalu- ated just like other programmes or policies that impose some level of risk on indi- viduals for the sake of realising an important social good—within clinical medicine, but also beyond. In the case of delaying or withholding antibiotics for LRTIs, the (arguably) minimal net risks that this programme involves for patients would seem proportionate to the importance of preserving antibiotic effectiveness and the potential of this programme to help curb AMR. Moreover, given that net risks are minimal, the programme could proceed without obtaining the patients’ informed consent.", "n_tokens": 246, "kind": "text"}
{"chunk_id": "drug_resistance_book-342-0", "doc_id": "drug_resistance_book", "page": 342, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\n20.6\n\nPotential Objections\n\nCritics might argue that there are less invasive strategies for curbing the spread of AMR that we should exhaust before delaying or withholding antibiotics in clinical medicine, such as eliminating unnecessary antibiotic treatments, reducing antibiotic use in farming, and investing more, and more effectively, into research on new anti- biotics. These other strategies should indeed be pursued with urgency, and there is little reason to believe that adopting rational use programmes would undermine them. However, given that AMR is now recognized as one of the major public health threats of the twenty-first century, it is essential to consider all approaches that could delay or prevent AMR in an ethically justifiable way. As this paper argues, rational use programmes that involve delaying or withholding antibiotics should become part of the conversation.", "n_tokens": 180, "kind": "text"}
{"chunk_id": "drug_resistance_book-342-1", "doc_id": "drug_resistance_book", "page": 342, "text": "It might also be objected that few such programmes would satisfy the minimal risk threshold known from the context of clinical research. At this point, it is diffi- cult to respond to this objection because few reliable data exist on patient outcomes when antibiotics are delayed or withdrawn. However, we have identified at least one case—restricting antibiotic use for LTRIs—where reasonable estimates suggest that the minimal risk threshold would be respected. As more data become available, more cases could follow. Moreover, our proposed ethical framework would also be helpful for evaluating rational use programmes that pose more than minimal risks to patients and therefore require obtaining their informed consent to participate. However, as mentioned, all current rational use programmes we are aware of pro- ceed without obtaining the patients’ informed consent, and we suspect this will stay the same in future. To be effective, rational use programmes need to be implemented as widely as possible—and in practice this is likely to be feasible only when patients are not asked to give their informed consent to having antibiotic treatment withheld or delayed. Given the considerable uncertainty about the social value of rational use programmes in terms of curbing AMR, and considering that such programmes are generally rolled out without requiring that clinicians obtain patients’ informed con- sent, we would argue that rational use programmes should pose no more than lim- ited net", "n_tokens": 270, "kind": "text"}
{"chunk_id": "drug_resistance_book-342-2", "doc_id": "drug_resistance_book", "page": 342, "text": "risks to patients until more evidence supports their social value.", "n_tokens": 11, "kind": "text"}
{"chunk_id": "drug_resistance_book-342-3", "doc_id": "drug_resistance_book", "page": 342, "text": "Finally, some might argue that the present argument rests on an ethical frame- work for risk-benefit evaluations in clinical research that is not universally accepted. In particular, prominent research ethicists hold that clinician-investigators should generally not delay or withhold established effective treatments from patient- participants in clinical trials (Weijer and Miller 2004). This argument is based on the idea that clinician-investigators continue to have clinical obligations in the research context, which make it unacceptable for them to act against the best clini- cal interests of patient-participants by depriving them of proven effective interven- tions. And, it might be argued, if it is not acceptable to delay or withhold proven interventions in the research context, then it is not acceptable to do the same in rational use programmes. However, it is important to see that this latter position is not universally accepted in research ethics. This is because it cannot explain why it\n\n335", "n_tokens": 192, "kind": "text"}
{"chunk_id": "drug_resistance_book-343-0", "doc_id": "drug_resistance_book", "page": 343, "text": "336\n\nJ. Littmann et al.\n\nis justified for clinician-investigators to pose any net research risks to patient- participants—for example, by performing research-specific blood draws or biopsies that have no prospect of clinical benefit. After all, these interventions by definition do not promote the best clinical interests of patient-participants (Miller and Brody 2003). The ethical framework for risk-benefit evaluations that forms the basis of the present paper avoids this problem. It justifies why some level of carefully evaluated net risk can be imposed to patient-participants, namely because clinical research has important social value. Moreover, the framework applies the same standards for acceptable net risk to all research interventions, whether or not net risks result from delaying or withholding effective treatments or from performing research proce- dures without a prospect of clinical benefit (Rid and Wendler 2011). Thus, the ethi- cal framework for risk-benefit evaluations in clinical research used here, while not universally accepted, is arguably more defensible than the existing alternatives.\n\n20.7", "n_tokens": 215, "kind": "text"}
{"chunk_id": "drug_resistance_book-343-1", "doc_id": "drug_resistance_book", "page": 343, "text": "Conclusion\n\nFor clinicians, rational use programmes can pose ethical conflicts when they involve delaying or withholding antibiotics and thereby compromise the clinical interests of their present patients for the sake of preserving antibiotic effectiveness for future patient populations. Such exceptions from the general norm that clinicians should always act in the best interests of the present patient need to be carefully developed and managed. In this paper, based on a comparison to clinical research, we pre- sented an ethical framework that enables an explicit and transparent evaluation of the net risks that rational use programmes can pose to patients in order to address AMR. Because these evaluations require judgments about complex empirical facts and normative questions, it is essential that rational use programmes be developed transparently and with the involvement of patients, clinicians and other relevant stakeholders. This involvement would not only improve the quality of deliberations, but also help to ensure the fairness and legitimacy of the resulting policies and their successful implementation.\n\nFinally, the rational use of antibiotics can only be one part of a comprehensive strategy to address the danger of AMR; other measures have to be pursued with equal urgency, including better infection control, comprehensive strategies to reduce antibiotics use in animals, and the development of new antibiotics.", "n_tokens": 243, "kind": "text"}
{"chunk_id": "drug_resistance_book-343-2", "doc_id": "drug_resistance_book", "page": 343, "text": "Acknowledgments We thank Jonathan Grant, Harald Schmidt, David Wendler, James Wilson and Peter West-Oram, as well as the editors of this volume, Euzebiusz (Zeb) Jamrozik and Michael Selgelid, for comments on earlier versions of this manuscript. AB’s and JL’s work was supported by the Deutsche Forschungsgemeinschaft (grant BU 2450/2-1).\n\nDisclaimer This work was completed as part of Annette Rid’s official duties as an employee of the NIH Clinical Center. However, the opinions expressed are the authors’s own. They do not rep- resent any position or policy of the National Institutes of Health, Public Health Service, or Department of Health and Human Services.", "n_tokens": 163, "kind": "text"}
{"chunk_id": "drug_resistance_book-344-0", "doc_id": "drug_resistance_book", "page": 344, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\ne l p m a x E\n\ne h t\n\ng n i t a m\n\ni t s e w o l l a\n\na t a d\n\ne l b a l i a v A\n\nf o\n\nt c a p m\n\ni\n\nh t l a e h\n\nc i l b u p\n\nd n a\n\nl a c i n i l c\n\nr e w o l\n\nr o f\n\ne s u\n\ns c i t o i b i t n a\n\ng n i t c i r t s e r\n\ns n o i t c e f n i\n\nt c a r t\n\ny r o t a r i p s e r\n\nr e w o l\n\nr o f e s u s c i t o i b i t n a t c i r t s e r o t y c i l o P\n\ny l s u o r o g i r\n\ns i\n\ns n o i t c e f n i\n\nt c a r t y r o t a r i p s e r\n\n, s i s y l a n a y c i l o p . g . e ( d e p o l e v e d\n\ne b o t d e g d u j d n a ) n o i t a t l u s n o c r e d l o h e k a t s\n\ne v i t c e f f e d n a e l b i s a e f\n\nr e w o l\n\nr o f\n\ne s u\n\ns c i t o i b i t n a\n\nd e t c i r t s e R\n\ne h t\n\ns a h\n\ns n o i t c e f n i\n\nt c a r t\n\ny r o t a r i p s e r\n\nl a i b o r c i m\n\ni t n a\n\ns s e r d d a\n\no t\n\nl a i t n e t o p\n\nm e l b o r p\n\nh t l a e h\n\n c i l b u p\n\nr o j a m a\n\n, e c n a t s i s e r\n\nw o h\n\ne t a u l a v e\n\no t\n\na h c r a e s e r\n\ne t a i t i n I\n\nr e w o l\n\nr o f\n\ne s u\n\ns c i t o i b i t n a\n\nd e t c i r t s e r\n\ns t c e f f a\n\ns n o", "n_tokens": 510, "kind": "text"}
{"chunk_id": "drug_resistance_book-344-1", "doc_id": "drug_resistance_book", "page": 344, "text": "i t c e f n i\n\nt c a r t\n\ny r o t a r i p s e r\n\n, s e m o c t u o l a c i n i l c\n\n, s e t a r\n\nn o i t p i r c s e r p\n\ne t a d p u\n\nd n a\n\n. c t e\n\ne c n a t s i s e r\n\nl a i b o r c i m\n\ni t n a\n\nn i\n\ns e m o c\n\ne c n e d i v e w e n\n\ns a\n\ny c i l o p\n\nh t i\n\nw e c n e i r e p x e\n\ne h t\n\nw o h\n\ne t a u l a v E\n\nr e w o l\n\nr o f", "n_tokens": 156, "kind": "text"}
{"chunk_id": "drug_resistance_book-344-2", "doc_id": "drug_resistance_book", "page": 344, "text": "e s u\n\ns c i t o i b i t n a\n\ng n i t c i r t s e r\n\nm r o f n i\n\nn a c\n\ns n o i t c e f n i\n\nt c a r t\n\ny r o t a r i p s e r\n\nr o f\n\ne s u\n\nc i t o i b i t n a\n\nf o\n\nt n e m e g a n a m e h t\n\nt c a r t\n\ny r a n i r u\n\n. g . e (\n\ns n o i t i d n o c\n\nr e h t o\n\n) n o i t c e f n i\n\ne b\n\ns t n e m e l E\n\ng n i t c i r t s e r\n\nt a h t\n\ne r u s n E\n\n. 1\n\nn e v i g\n\ne h t\n\nr o f\n\ne s u s c i t o i b i t n a\n\nd n u o s\n\nn o\n\nd e s a b\n\ns i\n\nn o i t i d n o c\n\ns d o h t e m y c i l o p\n\nd n a\n\ne c n e d i v e\n\ng n i t c i r t s e r\n\nt a h t\n\ne r u s n E\n\n. 2\n\nn e v i g\n\ne h t\n\nr o f\n\ne s u s c i t o i b i t n a\n\nm u m i n i m a\n\ns e s s a p\n\nn o i t i d n o c\n\ne u l a v\n\nl a i c o s\n\nf o\n\nd l o h s e r h t\n\no t\n\ne g d e l w o n k\n\ne h t\n\ne c n a h n E\n\n. 3\n\ny c i l o p\n\ne h t\n\nm o r f\n\nd e n i a g\n\ne s U c i t o i b i t n A\n\nl a n o i t a R r o f k r o w e m a r F\n\nl a c i h t E\n\ne s u\n\nc i t o i b i t n a\n\nd e t c i r t s e R\n\np e t S\n\ne l p m a x E\n\ns t n e m e l E\n\ne c n a h n e d n a e r u s n E\n\n. 1\n\nc fi i t n e i c s\n\nd e z i n g o c e r\n\ns e s u\n\ny d u t S\n\ns d o h t e m y d", "n_tokens": 510, "kind": "text"}
{"chunk_id": "drug_resistance_book-344-3", "doc_id": "drug_resistance_book", "page": 344, "text": "u t s\n\ne h t\n\ne r u s n E\n\n. 1\n\nl a i c o s\n\ns ’ y c i l o p\n\ne h t\n\ns d o h t e m\n\nd n u o s\n\ne r a\n\ne u l a v\n\ne l b a u l a v\n\na\n\ns e s s e r d d a\n\ny d u t S\n\na\n\ns e s s a p\n\ny d u t s\n\ne h t\n\ne r u s n E\n\n. 2\n\ns u o i r e s\n\na\n\ns i\n\nr e c n a c\n\nr e v i l\n\n: n o i t s e u q\n\nl a i c o s\n\nf o\n\nd l o h s e r h t\n\nm u m i n i m\n\nt s i x e\n\ns t n e m t a e r t\n\nw e f\n\nd n a\n\ne s a e s i d\n\ne u l a v", "n_tokens": 184, "kind": "text"}
{"chunk_id": "drug_resistance_book-344-4", "doc_id": "drug_resistance_book", "page": 344, "text": "e l b a l i a v a\n\ns n e m i c e p s\n\ne k a m d l u o C\n\no t\n\ne g d e l w o n k\n\ne h t\n\ne c n a h n E\n\n. 3\n\nh c r a e s e r\n\nr e h t o\n\nr o f\n\ny d u t s\n\ne h t\n\nm o r f\n\nd e n i a g\n\ne b\n\n: x i d n e p p A\n\nh c r a e s e r\n\nl a c i n i l\n\nC\n\np e t S\n\nd n a\n\ne r u s n E\n\n. 1\n\ne h t\n\ne c n a h n e\n\ne u l a v\n\nl a i c o s\n\ns ’ y d u t s\n\n) d e u n i t n o c (\n\n337", "n_tokens": 166, "kind": "text"}
{"chunk_id": "drug_resistance_book-345-0", "doc_id": "drug_resistance_book", "page": 345, "text": "338\n\ne s u\n\nc i t o i b i t n a\n\nd e t c i r t s e R\n\nh c r a e s e r\n\nl a c i n i l\n\nC\n\ne l p m a x E\n\ns t n e m e l E\n\np e t S\n\ne l p m a x E\n\ns t n e m e l E\n\np e t S\n\ns c i t o i b i t n a\n\nd e t c i r t s e r\n\n: n o i t n e v r e t n i\n\n y c i l o P\n\ny c i l o p\n\ne h t\n\ny f i t n e d I\n\n. 1\n\ny c i l o p\n\ne h t\n\ny f i t n e d I\n\n. 2\n\nd o o l b\n\n, g u r d\n\nl a n o i t a g i t s e v n I\n\n h c i h w e n i m r e t e D\n\n. 1\n\ne h t\n\ny f i t n e d I\n\n. 2\n\ns n o i t c e f n i\n\nt c a r t\n\ny r o t a r i p s e r\n\nr e w o l\n\nr o f\n\ne s u\n\ny n a\n\nd n a\n\nn o i t n e v r e t n i\n\ns n o i t n e v r e t n i\n\ny s p o i b\n\nr e v i l\n\n, n a c s T C\n\n, s w a r d\n\ne h t\n\ns s e r d d a\n\ns n o i t n e v r e t n i\n\nh c r a e s e r\n\ne d i v o r p\n\n: s n o i t n e v r e t n i\n\n y r a t n e m e l p p u S\n\n) e n i t u o r - n o n (\n\ny r a t n e m e l p p u s\n\n) d n u o s a r t l u\n\nh t i\n\nw\n\n(\n\nt c e t o r p\n\nr o\n\n) s ( n o i t s e u q y d u t s\n\ns n o i t n e v r e t n i\n\n n i\n\ns t n e i t a p\n\no t\n\n n o i t a m r o f n i\n\nt n a v e l e r\n\ns t n e i t a p t c e t o r p\n\no t\n\ns n o i t n e v r e t n i\n\n)", "n_tokens": 509, "kind": "text"}
{"chunk_id": "drug_resistance_book-345-1", "doc_id": "drug_resistance_book", "page": 345, "text": "1 s t c e j b u s\n\ns n g i s\n\nr e h t o\n\nd n a\n\nr e v e f\n\n h g i h\n\n. g . e (\n\ng n i t i r\n\nw\n\n n i\n\ne k a t\n\no t\n\ns p e t s\n\n, n o i t i d n o c\n\ng n i n e s r o w a\n\nf o\n\ny r o t a r i p s e r\n\ne m\n\ni t - 1\n\ne d i v o r p\n\n, ) n o i t a u t i s\n\ns i h t\n\ns\n\nm o t p m y s\n\ne g a n a m o t\n\n n o i s s e s\n\ny p a r e h t\n\ns n o i t n e v r e t n i\n\nl a c i n i l c\n\ne n i t u o r\n\ne d u l c x E", "n_tokens": 182, "kind": "text"}
{"chunk_id": "drug_resistance_book-345-2", "doc_id": "drug_resistance_book", "page": 345, "text": "t n a v e l e r\n\ne d i v o r p : s i s y l a n a m o r f\n\ne v i t r o p p u s\n\ne d i v o r p\n\n, y l l a b r e v\n\nn o i t a m r o f n i\n\nt c a r t\n\ny r o t a r i p s e r\n\nr e w o l\n\nr o f\n\ns e r u s a e m\n\n, n o i t a l a h n i\n\n, s c i t y l o c u m\n\n. g . e (\n\ns n o i t c e f n i\n\n) n o i t a c i d e m n i a p\n\nt n e i t a p n e t t i r\n\nw\n\nr e h t e h w\n\nl a i t n e s s e\n\nr e d i s n o c\n\nd l u o C\n\ns i\n\nn o i t a m r o f n i\n\ns i\n\nh c a e\n\nt a h t\n\ne r u s n E\n\n. 2\n\nn o i t n e v r e t n i\n\ny r a t n e m e l p p u s\n\ng n i t c e t o r p r o f\n\nl a i t n e s s e\n\n) 1 s t n e i t a p\n\nr e v i l\n\na\n\ng n i r e w s n a\n\nr e h t e h w\n\nr e d i s n o c\n\nd l u o C\n\nr o f\n\nt n a t r o p m\n\ni\n\ns i y s p o i b\n\n) s ( n o i t s e u q\n\ny d u t s\n\ne h t\n\nh c r a e s e r\n\ne r u s n E\n\n. 2\n\no t\n\ny l e k i l\n\ne r a\n\ns n o i t n e v r e t n i\n\nd n a\n\nt n a t r o p m\n\ni\n\nd l e i y\n\nn o i t a m r o f n i\n\ne v i t a c i l p u d - n o n\n\nJ. Littmann et al.", "n_tokens": 445, "kind": "text"}
{"chunk_id": "drug_resistance_book-346-0", "doc_id": "drug_resistance_book", "page": 346, "text": "e s u\n\nc i t o i b i t n a\n\nd e t c i r t s e R\n\nh c r a e s e r\n\nl a c i n i l\n\nC\n\ne l p m a x E\n\ns t n e m e l E\n\np e t S\n\ne l p m a x E\n\ns t n e m e l E\n\np e t S\n\n20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\nr e w o l\n\nr o f\n\ne s u\n\ns c i t o i b i t n a\n\ng n i t c i r t s e R\n\nf o\n\ns k s i r\n\ns e s o p\n\ns n o i t c e f n i\n\nt c a r t\n\ny r o t a r i p s e r\n\ne k i l\n\ns n o i t a c i l p m o c\n\nf o\n\ne s a e r c n i\n\n. e . i\n\ny a m h c i h w\n\n, a m e y p m e\n\nr o\n\na i n o m u e n p\n\n) n o i t a s i l a t i p s o h\n\nr o / d n a\n\ns c i t o i b i t n a\n\ne r i u q e r\n\no t\n\n n o i t a m r o f n i\n\nt n a v e l e r\n\ng n i d i v o r P\n\n) y l l a b r e v\n\nn a h t\n\nr e h t a r ( g n i t i r\n\nw n i\n\ns t n e i t a p\n\ny t e i x n a\n\nd l i\n\nm e s u a c\n\nt h g i m\n\ny r o t a r i p s e r\n\nr e w o l\n\ne n i t u o r\n\nt a h t\n\ne r u s n E\n\ne r a\n\nn o i t i d n o c\n\nt a e r t\n\no t\n\ns n o i t c e f n i\n\nt c a r t\n\n) s e r u s a e m e v i t r o p p u s\n\n. g . e (\n\nd e t n e m e l p m\n\ni\n\ny e h t\n\nd", "n_tokens": 458, "kind": "text"}
{"chunk_id": "drug_resistance_book-346-1", "doc_id": "drug_resistance_book", "page": 346, "text": "l u o h s\n\n, s\n\nm r a h\n\ns u o i r e s\n\nt a h t\n\ne r u s n E\n\no n t a\n\nd e g a n a m y l e t a u q e d a\n\ne r a\n\n, r u c c o\n\n. g . e (\n\nt n e i t a p\n\ne h t\n\no t\n\nt s o c\n\nl a i c n a n fi\n\nd n a\n\n) n o i t a s i l a t i p s o h\n\nr o / d n a\n\ns c i t o i b i t n a\n\ny n a\n\nr o f\n\nn o i t a s n e p m o c\n\ne v i e c e r\n\ns t n e i t a p\n\ns\n\nm r a h\n\ns u o i r e s\n\ng n i t s a l\n\nt n e i t a p\n\ne d u l c x e\n\nr o\n\nr o t i n o m y l e v i t c A\n\nd e s a e r c n i", "n_tokens": 215, "kind": "text"}
{"chunk_id": "drug_resistance_book-346-2", "doc_id": "drug_resistance_book", "page": 346, "text": "t a\n\ne r a\n\no h w y c i l o p m o r f\n\ns p u o r g\n\ns u o i r e s\n\nr e h t o\n\nr o\n\ns n o i t a c i l p m o c\n\nf o\n\nk s i r\n\n) y n e i c fi e d o n u m m\n\ni\n\n. g . e (\n\ns m r a h\n\nt n e m g d u j\n\ne s i c r e x e\n\no t\n\ns n a i c i n i l c\n\nt c u r t s n I\n\ns e s a c\n\nl a u d i v i d n i\n\nn i\n\nn e t t i r\n\nw\n\nt u o b a\n\ns t n e i t a p\n\ne r u s s a e R\n\nt e e h s\n\n n o i t a m r o f n i\n\n) d e u n i t n o c (\n\ne h t\n\nf o s k s i r\n\ne h t\n\ne t a u l a v E\n\n. 1\n\nh c a e\n\nd n a\n\nn o i t n e v r e t n i\n\ny c i l o p\n\nn o i t n e v r e t n i\n\n y r a t n e m e l p p u s\n\ns k s i r\n\ne h t\n\ne c u d e r\n\ny l b a n o s a e R\n\n. 2\n\ne c u d e r\n\nd n a e t a u l a v E\n\ns t n e i t a p\n\no t\n\ns k s i r\n\n. 3\n\ne h t\n\nr e p\n\n5 3 - 8\n\na\n\ns e s o p\n\ny s p o i b\n\nr e v i L\n\nx a r o h t o t a m e h\n\nf o\n\nk s i r\n\n0 0 0 , 0 0 1\n\nr e v i l\n\nr e h t e h w\n\nr e d i s n o c\n\nd l u o C\n\n1 - n o - 1\n\n h t i\n\nw\n\nr e f a s\n\ns i y s p o i b\n\ng n i r o t i n o m\n\n h c a e\n\nf o\n\ns k s i r\n\ne h t\n\ne t a u l a v E\n\n. 1\n\nn o i t n e v r e t n i\n\nh c r a e s e r\n\ne h t\n\ne c u d e r\n\ny l b a n o s a e R\n\n.", "n_tokens": 497, "kind": "text"}
{"chunk_id": "drug_resistance_book-346-3", "doc_id": "drug_resistance_book", "page": 346, "text": "2\n\ns k s i r\n\no t\n\nd n a\n\ne t a u l a v E\n\n. 3\n\ns k s i r\n\ne h t\n\ne c u d e r\n\ns t n a p i c i t r a p\n\n339", "n_tokens": 48, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-0", "doc_id": "drug_resistance_book", "page": 347, "text": "340\n\ne s u\n\nc i t o i b i t n a\n\nd e t c i r t s e R\n\nh c r a e s e r\n\nl a c i n i l\n\nC\n\ne l p m a x E\n\ns t n e m e l E\n\np e t S\n\ne l p m a x E\n\ns t n e m e l E\n\np e t S\n\nr e w o l\n\nr o f\n\ne s u\n\ns c i t o i b i t n a\n\ng n i t c i r t s e R\n\nl a i t n e t o p\n\ne h t\n\ne t a u l a v E\n\n. 1\n\nd n a e t a u l a v E\n\n. 4\n\ny a m\n\n: g u r d\n\nl a n o i t a g i t s e v n i\n\ny l n O\n\nl a i t n e t o p e h t\n\ne t a u l a v E\n\n. 1\n\nd n a\n\ne t a u l a v E\n\n. 4\n\ns e r a p s\n\ns n o i t c e f n i\n\nt c a r t\n\ny r o t a r i p s e r\n\n y c i l o p e h t\n\nf o s t fi e n e b\n\nl a c i n i l c\n\nl a i t n e t o p\n\n e h t\n\ne c n a h n e\n\nr e c n a c\n\ne c u d e r\n\nh c a e\n\nf o s t fi e n e b\n\nl a c i n i l c\n\ne h t\n\ne c n a h n e\n\n. g . e (\n\nt n e m t a e r t\n\nf o\n\ns k s i r\n\ne h t\n\ns t n e i t a p\n\nh c a e\n\nd n a\n\nn o i t n e v r e t n i\n\ns t n e i t a p\n\nr o f\n\ns t fi e n e b\n\nn o i t n e v r e t n i\n\nh c r a e s e r\n\ns t fi e n e b\n\nl a i t n e t o p\n\n) a e h r r a i d\n\n n o i t n e v r e t n i\n\ny r a t n e m e l p p u s\n\ns t n a p i c i t r a p\n\nr o f\n\ns p l e h\n\nn o", "n_tokens": 489, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-1", "doc_id": "drug_resistance_book", "page": 347, "text": "i s s e s\n\ny p a r e h t\n\ny r o t a r i p s e r\n\ne m\n\ni t - 1\n\ns\n\nm o t p m y s\n\ne g a n a m o t\n\nc i n o r h c\n\nh t i\n\nw s t n e i t a p\n\nn o\n\ns u c o f\n\nd l u o C\n\nl a i t n e t o p e h t\n\ne c n a h n E\n\n. 2\n\nr e v i l\n\nd e c n a v d a\n\nn o s u c o f\n\nd l u o C\n\nl a i t n e t o p\n\ne h t\n\ne c n a h n E\n\n. 2\n\ns\n\nm e l b o r p\n\ny r a n o m l u p\n\ns t fi e n e b\n\nl a c i n i l c\n\ns t n e i t a p\n\nr e c n a c\n\ns t fi e n e b\n\nl a c i n i l c", "n_tokens": 204, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-2", "doc_id": "drug_resistance_book", "page": 347, "text": "t o n\n\nd l u o w n a i c i n i l c\n\nd e m r o f n I\n\ns k s i r\n\ne h t\n\nr e h t e h w e n i m r e t e D\n\n. 1\n\nr e h t e h w e t a u l a v E\n\n. 5\n\nd l u o w n a i c i n i l c\n\nd e m r o f n I\n\ne h t\n\nr e h t e h w e n i m r e t e D\n\n. 1\n\ne t a u l a v E\n\n. 5\n\nc i t o i b i t n a\n\ng n i d l o h h t i\n\nw d n e m m o c e r\n\nn o i t n e v r e t n i\n\nl a u d i v i d n i\n\n h c a e\n\nf o\n\ne s o p s n o i t n e v r e t n i\n\ne h t\n\n: g u r d l a n o i t a g i t s e v n i\n\nd n e m m o c e r\n\nl a u d i v i d n i\n\n h c a e\n\nf o\n\ns k s i r\n\ne h t\n\nr e h t e h w\n\nt c a r t\n\ny r o t a r i p s e r\n\nr e w o l\n\nr o f\n\nt n e m t a e r t\n\ns ’ n o i t n e v r e t n i\n\ne h t\n\nd e e c x e\n\ns k s i r\n\nt e n\n\ns k s i r\n\nt e n\n\no n\n\ne h t\n\nd e e c x e\n\n n o i t n e v r e t n i\n\ne s o p\n\ns n o i t n e v r e t n i\n\ne h t\n\ne g a n a m o t\n\ns e r u s a e m d n a\n\ns n o i t c e f n i\n\ns t fi e n e b l a c i n i l c\n\nl a i t n e t o p\n\nt o n\n\nd l u o w n a i c i n i l c\n\nd e m r o f n I\n\nl a i t n e t o p\n\ns ’ n o i t n e v r e t n i\n\ns k s i r\n\nt e n\n\n, n o i t a m r o f n i n e t t i r\n\nw\n\n. g . e (\n\ns k s", "n_tokens": 510, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-3", "doc_id": "drug_resistance_book", "page": 347, "text": "i r\n\ng n i t l u s e r\n\nn a\n\nd l u o W\n\n: ) s k s i r\n\nt e n\n\ns e i l p m\n\ni (\n\nT C\n\n, s w a r d\n\nd o o l b d n e m m o c e r\n\nt e n\n\ns e i l p m\n\ni (\n\ns t fi e n e b\n\nl a c i n i l c\n\ns k s i r\n\nt e n\n\n: ) g n i r o t i n o m e v i t c a\n\n s i\n\n o h w n a i c i n i l c\n\nd e m r o f n i\n\ns k s i r\n\nt e n\n\n: y s p o i b\n\nr e v i l\n\n, n a c s\n\nd e m r o f n i n a", "n_tokens": 167, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-4", "doc_id": "drug_resistance_book", "page": 347, "text": "d l u o W\n\n: ) s k s i r\n\nd n e m m o c e r\n\nd l u o w n a i c i n i l c\n\nd e m r o f n I\n\ng n i t o m o r p\n\no t\n\ny l e l o s\n\nd e t t i\n\nm m o c\n\nd e t t i\n\nm m o c\n\ns i\n\n o h w n a i c i n i l c\n\ns k s i r\n\nt e n\n\no n\n\n: n o i s s e s\n\ny p a r e h t\n\ny r o t a r i p s e r\n\ns t s e r e t n i\n\nl a c i n i l c\n\ns ’ t n e i t a p e h t\n\n’ s t n e i t a p\n\ng n i t o m o r p\n\no t\n\ny l e l o s\n\n? n o i t n e v r e t n i\n\ne h t\n\nd n e m m o c e r\n\nd n e m m o c e r\n\ns t s e r e t n i\n\nl a c i n i l c\n\nt o n\n\nd l u o w n a i c i n i l c\n\nd e m r o f n I\n\nt i n u\n\n e h t\n\nr e h t e h w e n i m r e t e D\n\n. 2\n\n) 1 ? n o i t n e v r e t n i\n\ne h t\n\n: s n o i t n e v r e t n i\n\nf o t i n u\n\nd n e m m o c e r\n\ny r a t n e m e l p p u s\n\nd n a\n\n y c i l o p\n\nf o\n\ny r o t a r i p s e r\n\nf o\n\ns t fi e n e b\n\nl a c i n i l c\n\nl a i t n e t o p\n\n: s k s i r\n\nt e n e s o p\n\ns n o i t n e v r e t n i\n\ns k s i r\n\ne h t\n\n h g i e w t u o\n\nt o n\n\no d\n\nn o i s s e s\n\ny p a r e h t\n\nn a i c i n i l c\n\nd e m r o f n i\n\nn a\n\nd l u o w\n\nd n a\n\nt n e m t a e r t\n\nc i t o i b i t n a\n\ng n i d l o h h t", "n_tokens": 508, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-5", "doc_id": "drug_resistance_book", "page": 347, "text": "i\n\nw\n\nf o\n\nf o t i n u\n\ne h t\n\nd n e m m o c e r\n\ns k s i r\n\ng n i t l u s e r\n\ne h t\n\ne g a n a m o t\n\ns e r u s a e m\n\n? s n o i t n e v r e t n i\n\na\n\nn i\n\nd n a t s\n\ns y a w l a\n\ns n o i t n e v r e t n i\n\ny r a t n e m e l p p u s\n\nd n a\n\n y c i l o p\n\ne h T : n o s a e R\n\nA N\n\n/\n\nd n a\n\n, n a c s T C\n\n, s w a r d\n\nd o o l B\n\nf o\n\ny n a\n\nr e h t e h w e n i m r e t e D\n\n. 1\n\ne t a u l a v E\n\n. 6\n\ne h t", "n_tokens": 188, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-6", "doc_id": "drug_resistance_book", "page": 347, "text": "e s u a c e b\n\n) s n o i t n e v r e t n i\n\nf o\n\nt i n u ( ” y t i s s e c e n\n\ny c i l o p “ t c i r t s\n\nf o\n\nn o i t a l e r\n\nd e m u s e r p (\n\ng u r d\n\nl a n o i t a g i t s e v n i\n\na\n\nn i\n\n d n a t s\n\ns n o i t n e v r e t n i\n\ne h t\n\nt e n e h t\n\nr e h t e h w\n\ng n i t c e t o r p\n\nr o f\n\nl a i t n e s s e\n\nd e r e d i s n o c\n\ne r a\n\ns n o i t n e v r e t n i\n\ny r a t n e m e l p p u s\n\n) s e s o p r u p t n e s e r p\n\nr o f\n\ne u r t\n\nc fi i t n e i c s\n\nt c i r t s\n\nf o\n\nn o i t a l e r\n\nd e fi i t s u j\n\ne r a\n\ns k s i r\n\ne r o f e r e h t\n\ns i\n\np e t s\n\ns i h t\n\nf o\n\nt n e m e l e\n\nt s r fi\n\ne h T\n\n. ) 2\n\np e t s (\n\ns t s e r e t n i ’ s t n e i t a p\n\nf o\n\nt i n u (\n\ny t i n u\n\nr o\n\ny t i s s e c e n\n\nl a i t n e t o p\n\ne h t\n\ny b\n\nJ. Littmann et al.\n\n p e t s\n\ns u o i v e r p\n\ne h t\n\n n i\n\nd e d u l c n i\n\nn e e b s a h\n\nt n e m e l e\n\nd n o c e s\n\ne h T\n\n. y r a s s e c e n n u\n\n. ) 5\n\np e t s (\n\nd l u o w n a i c i n i l c\n\nd e m r o f n I\n\nf o\n\nt", "n_tokens": 450, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-7", "doc_id": "drug_resistance_book", "page": 347, "text": "i n u e v o b a\n\ne h t\n\nd n e m m o c e r\n\ne h t\n\nt a h t\n\ns e t a l u p i t s (\n\ns n o i t n e v r e t n i\n\ne h t\n\nf o s t fi e n e b\n\nl a c i n i l c\n\nl a i t n e t o p\n\ne h t\n\nt e s f f o\n\ng u r d l a n o i t a g i t s e v n i\n\nf o\n\ns k s i r\n\ne h t\n\nd n a\n\ns k s i r\n\nn w o\n\ns ’ g u r d\n\n) s n o i t n e v r e t n i\n\ny n a\n\nr e h t e h w e n i m r e t e D\n\n. 2\n\ne s o p s n o i t n e v r e t n i\n\nf o\n\ns t i n u\n\nd e m r o f n i n a\n\nd l u o w\n\n: s k s i r\n\nt e n", "n_tokens": 218, "kind": "text"}
{"chunk_id": "drug_resistance_book-347-8", "doc_id": "drug_resistance_book", "page": 347, "text": "e h t\n\nd n e m m o c e r\n\nn a i c i n i l c\n\n? s n o i t n e v r e t n i\n\nf o\n\n) s ( t i n u\n\nr e h t o\n\nf o\n\ns t fi e n e b\n\ns n o i t n e v r e t n i\n\n) n a c s T C d n a\n\ns w a r d\n\nd o o l b\n\ne h t", "n_tokens": 94, "kind": "text"}
{"chunk_id": "drug_resistance_book-348-0", "doc_id": "drug_resistance_book", "page": 348, "text": "e s u\n\nc i t o i b i t n a\n\nd e t c i r t s e R\n\nh c r a e s e r\n\nl a c i n i l\n\nC\n\ne l p m a x E\n\ns t n e m e l E\n\np e t S\n\ne l p m a x E\n\ns t n e m e l E\n\np e t S\n\n20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\nm o r f\n\n k s i r\n\nt e n\n\nf o\n\nl e v e l\n\nl l a m\n\ns\n\ny l e v i t a l e R\n\nf o l e v e l\n\ne h t\n\ne n i m r e t e D\n\n. 1\n\nr e h t e h w e t a u l a v E\n\n. 6\n\ne v i t a l u m u c\n\nf o\n\nl e v e l\n\ne l b a r e d i s n o C\n\nf o\n\nl e v e l\n\ne h t\n\ne n i m r e t e D\n\n. 1\n\ne t a u l a v E\n\n. 7\n\nd n a\n\nt n e m t a e r t\n\nc i t o i b i t n a\n\ng n i d l o h h t i\n\nw\n\no t\n\nd e s o p\n\nk s i r\n\nt e n\n\ne v i t a l u m u c\n\ne r a\n\ns k s i r\n\nt e n e h t\n\n y s p o i b\n\nr e v i l\n\ne h t\n\nm o r f\n\ns k s i r\n\nt e n\n\ne h t\n\n n i\n\n k s i r\n\nt e n\n\ne v i t a l u m u c\n\ne h t\n\nr e h t e h w\n\ns k s i r\n\ng n i t l u s e r\n\ne h t\n\ne g a n a m o t\n\ns e r u s a e m\n\ns t n e i t a p\n\ns ’ y c i l o p\n\ne h t\n\ny b\n\nd e fi i t s u j\n\n, e t u l o s b a\n\ny n a d d a\n\n: y d u t s\n\ns k s i r\n\nt e n g n i n i a m e r\n\ne u l a v\n\nl a i c o s\n\ns s e c x e\n\nd n a\n\n, t c e r i d n i\n\n, e v i t a l e r\n\ne h t\n\ny b\n\nd e fi", "n_tokens": 500, "kind": "text"}
{"chunk_id": "drug_resistance_book-348-1", "doc_id": "drug_resistance_book", "page": 348, "text": "i t s u j\n\ne r a\n\ns k s i r\n\nt e n\n\ne u l a v\n\nl a i c o s\n\ns ’ y d u t s\n\n c i t o i b i t n a\n\ng n i d l o h h t i\n\nw m o r f\n\ns k s i r\n\nt e N\n\ne h t\n\nr e h t e h w e n i m r e t e D\n\n. 2\n\ny l b a b o r p\n\ns k s i r\n\nt e n\n\ne v i t a l u m u C\n\ne h t\n\nr e h t e h w e n i m r e t e D\n\n. 2\n\nt c a r t\n\ny r o t a r i p s e r\n\nr e w o l\n\nr o f", "n_tokens": 159, "kind": "text"}
{"chunk_id": "drug_resistance_book-348-2", "doc_id": "drug_resistance_book", "page": 348, "text": "t n e m t a e r t\n\ns k s i r\n\nt e n\n\ne v i t a l u m u c\n\ns ’ y c i l o p\n\nf o e g n a r\n\nl a r e n e g\n\ne h t\n\n n i h t i\n\nw\n\nl l a f\n\ns k s i r\n\nt e n\n\ne v i t a l u m u c\n\ns ’ y d u t s\n\ne g n a r\n\ne h t\n\n n i h t i\n\nw s l l a f\n\ny l b a u g r a\n\ns n o i t c e f n i\n\nf o\n\ne g n a r\n\nl a r e n e g\n\ne h t\n\n n i h t i\n\nw\n\nl l a f\n\nh c r a e s e r\n\nr o f\n\nk s i r\n\nt e n\n\ne l b a t p e c c a\n\ne g n a r\n\nl a r e n e g\n\ne h t\n\n n i h t i\n\nw\n\nl l a f\n\nh c r a e s e r\n\nl a c i n i l c\n\n n i\n\n k s i r\n\nt e n\n\ne l b a t p e c c a\n\nf o\n\ne g d u j\n\nd l u o c\n\n: k s i r\n\nt e n\n\ne l b a t p e c c a\n\ns t n a p i c i t r a p t n e t e p m o c\n\nh t i\n\nw\n\nd l u o c\n\n: k s i r\n\nt e n\n\ne l b a t p e c c a\n\nf o\n\ny l b a u g r a\n\ns k s i r\n\nt e n\n\ne h t\n\n. e . i (\n\ne c i t c a r p\n\nd n a\n\nn i\n\ns t i\n\nm\n\ni l\n\n k s i r\n\n f o t h g i l\n\n n i\n\n k s i r\n\nt e n\n\nf o\n\nt h g i l\n\n n i\n\ne g d u j\n\n) d l o h s e r h t\n\n k s i r\n\nl a m i n i m e h t\n\nw o l e b\n\nl l a f\n\nh c r a e s e r\n\nl a c i d e m o i b\n\nl a c i d e m o i b\n\n n i\n\ns t i\n\nm\n\ni l\n\ne h t\n\ny l b a t o n\n\n, h c r a e s e r\n\n n i\n\nd l o h s e r h t\n\n” ” k s i r\n\nl a m i n", "n_tokens": 506, "kind": "text"}
{"chunk_id": "drug_resistance_book-348-3", "doc_id": "drug_resistance_book", "page": 348, "text": "i m “\n\nd e m r o f n i\n\nt u o h t i\n\nw h c r a e s e r\n\ne s u\n\nl a n o i t a r\n\nr o f\n\nt n e s n o c\n\nt o n\n\no d\n\nt a h t\n\ns e m m a r g o r p\n\n n i a t b o\n\no t\n\ns n a i c i n i l c\n\ne r i u q e r\n\nd e m r o f n i\n\ns ’ t n e i t a p\n\ne h t\n\nk s i r\n\nt e n\n\nr e p p u\n\nd n a\n\nt n e s n o c\n\nr o f\n\nh c r a e s e r\n\n n i\n\ns t i\n\nm\n\ni l\n\ns e m m a r g o r p\n\ne s u\n\nl a n o i t a r", "n_tokens": 173, "kind": "text"}
{"chunk_id": "drug_resistance_book-348-4", "doc_id": "drug_resistance_book", "page": 348, "text": "d e m r o f n i\n\ne r i u q e r\n\nt a h t\n\nt n e s n o c\n\ne h t\n\nd n e m m o c e r\n\ny a m\n\nr e t i b r a\n\nl a i c o s\n\nl a e d I\n\nn e v i g\n\ne h t\n\nr e h t e h w e t a u l a v E\n\n. 3\n\nd l u o w r e t i b r a\n\nl a i c o s\n\nl a e d I\n\ne h t\n\nr e h t e h w e t a u l a v E\n\n. 3\n\ng n i b r u c\n\nf o\n\ne c n a t r o p m\n\n i\n\ne h t\n\nn e v i g\n\n, y c i l o p\n\ns i\n\n k s i r\n\nt e n e v i t a l u m u c\n\nf o l e v e l\n\nd e m u s e r p (\n\ny d u t s\n\ne h t\n\nd n e m m o c e r\n\nt e n\n\ne v i t a l u m u c\n\nf o\n\nl e v e l\n\nn e v i g\n\ny l b a u g r a\n\ne h t\n\nd n a\n\ne c n a t s i s e r\n\nl a i b o r c i m\n\ni t n a\n\nl a i c o s\n\ne h t\n\no t\n\ne t a n o i t r o p o r p\n\n) s e s o p r u p t n e s e r p\n\nr o f\n\ne u r t\n\ne h t\n\no t\n\ne t a n o i t r o p o r p s i\n\nk s i r\n\ns t n e i t a p\n\no t\n\ns k s i r\n\nt e n l a m i n i m\n\ne h t\n\n g n i t n e m e l p m\n\n i\n\nf o\n\ne u l a v\n\ng n i t c u d n o c\n\nf o e u l a v\n\nl a i c o s\n\nl a i c o s\n\nl a e d i\n\nn a\n\nd l u o w\n\n: y c i l o p\n\nl a e d i\n\nn a\n\nd l u o w\n\n: y d u t s\n\ne h t\n\n? y c i l o p\n\ne h t d n e m m o c e r\n\nr e t i b r a\n\nd n e m m o c e r\n\nr e t i b r a\n\nl a", "n_tokens": 506, "kind": "text"}
{"chunk_id": "drug_resistance_book-348-5", "doc_id": "drug_resistance_book", "page": 348, "text": "i c o s\n\n? y d u t s\n\ne h t\n\n. e s u c i t o i b i t n a d e t c i r t s e r\n\nf o s k s i r e h t g n i t a u l a v e f o s e s o p r u p e h t\n\nr o f d e t p a d a s i\n\n) 1 1 0 2 r e l d n e W d n a d i R\n\n( h c r a e s e r\n\nl a c i n i l c n i\n\ns n o i t a u l a v e t fi e n e b - k s i r\n\nr o f k r o w e m a r f g n i t s i x e n a w o h s w o h s e l b a t e h T", "n_tokens": 179, "kind": "text"}
{"chunk_id": "drug_resistance_book-348-6", "doc_id": "drug_resistance_book", "page": 348, "text": ", n a c s T C a\n\n, s w a r d d o o l b f o s e i r e s\n\na\n\n, g u r d l a n o i t a g i t s e v n i\n\ne h t\n\nf o n o i t a r t s i n i m d a g n i v l o v n i\n\n, r e c n a c\n\nr e v i l\n\nr o f\n\nt n e m t a e r t\n\nl a n o i t a g i t s e v n i n a\n\nf o y d u t s 2 e s a h p l a c i t e h t o p y h : h c r a e s e r\n\nl a c i n i l c\n\nr o f\n\ne l p m a x E\n\nt c a r t\n\ny r o t a r i p s e r\n\nr e w o l\n\nr o f\n\ne s u\n\nc i t o i b i t n a\n\nf o\n\nt c i r t s e r\n\no t\n\n y c i l o p\n\nl a c i t e h t o p y h\n\n: e s u\n\nc i t o i b i t n a\n\nd e t c i r t s e r\n\nr o f\n\ne l p m a x E\n\n. ) ] 1 1 0 2\n\nr e l d n e W d n a\n\nd i R\n\n[\n\nm o r f\n\ns n o i t a c fi i d o m\n\nt u o h t i\n\nw n e k a t (\n\ny s p o i b\n\nr e v i l\n\na\n\nd n a\n\nt n e s n o c\n\nd e m r o f n i\n\n’ s t n e i t a p\n\ne h t\n\ng n i n i a t b o\n\nt u o h t i\n\nw s n o i t c e f n i\n\n) 3 1 0 2 A M W\n\n; 6 1 0 2 S M O C\n\nI\n\n(\n\nh c r a e s e r\n\nr o f\n\na i r e t i r c\n\nl a c i h t e\n\nd r a d n a t s\n\nn o\n\nd e s a b\n\nd e g d u j\n\ne b\n\nd l u o h s\n\nn o i t i d n o c\n\nn e v i g a\n\nr o f\n\ne s u\n\ns c i t o i b i t n a\n\nd e t", "n_tokens": 497, "kind": "text"}
{"chunk_id": "drug_resistance_book-348-7", "doc_id": "drug_resistance_book", "page": 348, "text": "c i r t s e r\n\nf o\n\nt c a p m\n\ni\n\ne h t\n\ne t a u l a v e\n\no t\n\nh c r a e s e R\n\n341", "n_tokens": 37, "kind": "text"}
{"chunk_id": "drug_resistance_book-349-0", "doc_id": "drug_resistance_book", "page": 349, "text": "342\n\nJ. Littmann et al.\n\nReferences\n\nAdeyi, O. et al. 2017. Drug-resistant infections: A threat to our economic future (vol. 2): final report. Washington, DC. World Bank Group. http://documents.worldbank.org/curated/ en/323311493396993758/final-report.\n\nAndreasen, M. 2014. Arbejdspapirer om antibiotikaresistens (Working papers on antibiotic resis-\n\ntance). Det Etiske Råd (Danish Ethics Council): Copenhagen.\n\nAustralian Department of Health. 2015. Responding to the threat of antimicrobial resistance:\n\nAustralia’s first national antimicrobial resistance strategy 2015–2019. Canberra.\n\nBattin, M.P., L.P. Francis, J.A. Jacobson, et al. 2009. The patient as victim and vector: Ethics and\n\ninfectious disease. New York: Oxford University Press.\n\nBoucher, H.W., G.H. Talbot, D.K. Benjamin, et al. 2013. 10 × ‘20 Progress—Development of new drugs active against gram-negative bacilli: An update from the Infectious Diseases Society of America. Clinical Infectious Diseases 56: 1685–1694.\n\nBundesministerium für Gesundheit. 2011. Deutsche Antibiotikaresistenz-Strategie [German anti-\n\nbiotic resistance strategy]. Berlin.\n\nCharani, E., R. Edwards, N. Sevdalis, et al. 2011. Behavior change strategies to influence anti- microbial prescribing in acute care: A systematic review. Clinical Infectious Diseases 53: 651–662.\n\nCohen, G., N. Daniels, and N. Eyal. 2015. Identified versus statistical lives: An interdisciplinary", "n_tokens": 387, "kind": "text"}
{"chunk_id": "drug_resistance_book-349-1", "doc_id": "drug_resistance_book", "page": 349, "text": "perspective. Oxford: Oxford University Press.\n\nCostelloe, C., C. Metcalfe, A. Lovering, et al. 2010. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: Systematic review and meta-analysis. BMJ 340: c2096.\n\nCouncil for International Organizations of Medical Sciences, World Health Organization. 2016. International Ethical for Health-related Research Involving Humans. Geneva. https://cioms. ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf. Accessed 26 Nov 2018. Daneman, N., D.E. Low, A. McGeer, et al. 2008. At the threshold: Defining clinically meaning- ful resistance thresholds for antibiotic choice in community-acquired pneumonia. Clinical Infectious Diseases 46: 1131–1138.\n\nDavey, P., E. Brown, E. Charani, et al. 2013. Interventions to improve antibiotic prescribing prac- tices for hospital inpatients. Cochrane Database of Systematic Reviews 30 (4): CD003543. Davies, S.C., J. Grant, and M. Catchpole. 2013. The drugs don’t work: A global threat. London:\n\nPenguin.\n\nDrive-AB. 2018. Driving reinvestment in research and development for antibiotics and responsible\n\nantibiotic use. http://drive-ab.eu. Accessed 26 Nov 2018.\n\nEmanuel, E., C. Grady, R.A. Crouch, et al. 2008. The Oxford textbook of clinical research ethics.", "n_tokens": 342, "kind": "text"}
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{"chunk_id": "drug_resistance_book-350-0", "doc_id": "drug_resistance_book", "page": 350, "text": "20 Tackling Anti-microbial Resistance: An Ethical Framework for Rational Antibiotic…\n\nLittmann, J., A. Rid, and A.M. Buyx. 2018. Tackling anti-microbial resistance: Ethical framework\n\nfor rational antibiotic use. European Journal of Public Health 28 (2): 359–363.\n\nLondon, A.J. 2006. Reasonable risks in clinical research: A critique and a proposal for the integra-\n\ntive approach. Statistics in Medicine 25 (17): 2869–2885.\n\nMandell, L., R. Wunderink, A. Anzueto, et al. 2007. Infectious Diseases Society of America/ American Thoracic Society: Consensus guidelines on the Management of Community- Acquired Pneumonia in adults. Clinical Infectious Diseases 44: 27–72.\n\nMetlay, J.P., G.W. Waterer, A.C. Long, et al. 2019. Diagnosis and treatment of adults with com- munity-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. American Journal of Respiratory and Critical Care Medicine 200 (7): e45–e67.\n\nMillar, M. 2012. Constraining the use of antibiotics: Applying Scanlon’s contractualism. Journal", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-350-1", "doc_id": "drug_resistance_book", "page": 350, "text": "of Medical Ethics 38: 465–469.\n\nMiller, F., and H. Brody. 2003. A critique of clinical equipoise. Therapeutic misconception in the\n\nethics of clinical trials. The Hastings Center Report 33 (3): 19–28.\n\nMiller, F.G., and S. Joffe. 2009. Limits to research risks. Journal of Medical Ethics 35: 445–449. Oczkowski, S. 2017. Antimicrobial stewardship programmes: Bedside rationing by another name? Journal of Medical Ethics 43 (10): 1–4. https://doi.org/10.1136/medethics-2015-102785. O’Neill, J. 2014. Review on antimicrobial resistance. Antimicrobial resistance: tackling a crisis for\n\nthe health and wealth of nations. London.\n\nOrganisation for Economic Co-Operation and Development (OECD). 2018. Stemming the super- bug tide: Just a few dollars more, OECD Health Policy Studies, OECD Publishing, Paris, https://doi.org/10.1787/9789264307599-en. Accessed 26 Nov 2018.\n\nOutterson, K., J.H. Rex, T. Jinks, et al. 2016a. Accelerating global innovation to address antibacte-\n\nrial resistance: Introducing CARB-X. Nature Reviews Drug Discovery 15: 589.\n\nOutterson, K., S.J. Hoffman, A. Ghafur, et al. 2016b. International cooperation to improve access\n\nto and sustain effectiveness of antimicrobials. Lancet 387: 296.\n\nPresident’s Council of Advisors on Science and Technology (PCAST). 2014. Report to the\n\nPresident on combating antimicrobial resistance. Washington: PCAST.\n\nPublic Health Agency of Canada. 2014. Antimicrobial resistance and use in Canada: a federal", "n_tokens": 410, "kind": "text"}
{"chunk_id": "drug_resistance_book-350-2", "doc_id": "drug_resistance_book", "page": 350, "text": "framework for action. Ottawa.\n\nRex, J.H. 2014. ND4BB: Addressing the antimicrobial resistance crisis. Nature Reviews\n\nMicrobiology 12: 231–232.\n\nRid, A. 2014. Setting risk thresholds in research: Lessons from the debate about minimal risk.\n\nMonash Bioethics Review 32 (1–2): 63–85.\n\nRid, A., and D. Wendler. 2011. A framework for risk-benefit evaluations in biomedical research.\n\nKennedy Institute of Ethics Journal 21 (2): 141–179.\n\nRid, A., E.J. Emanuel, and D. Wendler. 2010. Evaluating the risks of clinical research. Journal of the American Medical Association 304 (13): 1472–1479. https://doi.org/10.1001/jama.2010.1414. Rid, A., J. Littmann, and A. Buyx. 2019. Evaluating the risks of public health programs: Rational\n\nantibiotic use and antimicrobial resistance. Bioethics 33 (7): 734–748.\n\nSchuetz, P., M. Christ-Crain, R. Thomann, et al. 2009. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: The prohosp random- ized controlled trial. JAMA 302: 1059–1066.\n\nSelgelid, M.J. 2007. Ethics and drug resistance. Bioethics 21: 218–229. Spurling, G.K., C.B. Del Mar, and L. Dooley et al. 2013. Delayed antibiotics for respiratory infec-", "n_tokens": 356, "kind": "text"}
{"chunk_id": "drug_resistance_book-350-3", "doc_id": "drug_resistance_book", "page": 350, "text": "tions. In: Cochrane database of systematic reviews, ed: Cochrane, 30(4): CD004417.\n\nSunstein, C. 1993. On analogical reasoning. Harvard Law Review 106: 741–791. The White House. 2014. National strategy for combating antibiotic-resitant bacteria. Washington. UK Department of Health. 2013. UK five year antimicrobial resistance strategy 2013 to\n\n2018. London.\n\nWeijer, C., and P. Miller. 2004. When are research risks reasonable in relation to anticipated ben-\n\nefits. Nature Medicine 10 (6): 570–573.\n\n343", "n_tokens": 132, "kind": "text"}
{"chunk_id": "drug_resistance_book-351-0", "doc_id": "drug_resistance_book", "page": 351, "text": "344\n\nJ. Littmann et al.\n\nWendler, D. 2010. Are physicians always obligated to act in the patient’s best interests? Journal of\n\nMedical Ethics 36 (2): 66–70.\n\nWendler, D., and A. Rid. 2017. In defense of the social value requirement for clinical research.\n\nBioethics 31 (2): 77–86.\n\nWilliams, J. 2015. World Medical Association: Medical ethics manual, 3rd Edition 2015. Ferney-Voltaire Cedex: World Medical Association. https://www.wma.net/wp-content/ uploads/2016/11/Ethics_manual_3rd_Nov2015_en.pdf. Accessed 26 Nov 2018.\n\nWilson, M., and M. Tan. 2010. Raising awareness for prudent use of antibiotics in animals: Position paper of the global alliance for the prudent use of antibiotics (APUA). Rome: APUA. World Health Organization (WHO). 1985. The rational use of drugs, report of the conference of\n\nexperts. Geneva: WHO Press.\n\n———. 2011. Global strategy for containment of antimicrobial resistance. Geneva: WHO Press. ———. 2014. Antimicrobial resistance – global report on surveillance. Geneva: WHO Press. ———. 2015. Worldwide country situation analysis: response to antimicrobial resistance.", "n_tokens": 293, "kind": "text"}
{"chunk_id": "drug_resistance_book-351-1", "doc_id": "drug_resistance_book", "page": 351, "text": "Geneva: WHO Press.\n\nWorld Medical Association (WMA). 2013. Declaration of Helsinki: Ethical principles for medi- cal research involving human subjects. Helsinki. https://www.wma.net/policies-post/wma- declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed 26 Nov 2018.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 244, "kind": "text"}
{"chunk_id": "drug_resistance_book-352-0", "doc_id": "drug_resistance_book", "page": 352, "text": "Chapter 21 Solidarity and Antimicrobial Resistance\n\nSøren Holm and Thomas Ploug", "n_tokens": 18, "kind": "text"}
{"chunk_id": "drug_resistance_book-352-1", "doc_id": "drug_resistance_book", "page": 352, "text": "Abstract The concept of solidarity has received increasing attention in discussions about public health interventions, both as a possible justification for such interven- tions and as a possible motivating factors for individual action. This chapter pro- vides an analysis of whether thinking through a lens of solidarity is likely to be helpful in devising strategies and policies to combat antimicrobial resistance. It first provides a critical overview of recent accounts of solidarity and argues that solidar- ity must be understood as a group based concept. It then applies this conception of solidarity to individual use of antibiotics through a case study of the antibiotic treat- ment of moderate and severe acne where it is argued that solidarity based thinking is valuable within a context of shared decision-making. Issues of policy making are then discussed and it is argued that basing a policy on solidarity on the one hand constrains the methods chosen to pursue public health goals, but that on the other hand solidarity may provide a strong and durable motivation to comply with such a policy. The limits of solidarity are explored in the final section and it is concluded that 1) the concept of solidarity does have an important role to play in thinking about public health, 2) considerations of solidarity can help us shape the goals and methods of public health policies in the area of antibiotics, and 3) that it is likely that solidarity may also be helpful in thinking through", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-352-2", "doc_id": "drug_resistance_book", "page": 352, "text": "other contentious issues in pub- lic health.", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-352-3", "doc_id": "drug_resistance_book", "page": 352, "text": "Keywords Antibiotic resistance · Bioethics · Collective action · Solidarity\n\nS. Holm (*) Centre for Social Ethics and Policy, School of Law, University of Manchester, Manchester, UK\n\nCenter for Medical Ethics, Faculty of Medicine, University of Oslo, Oslo, Norway e-mail: soren.holm@manchester.ac.uk\n\nT. Ploug Centre for Applied Ethics and Philosophy of Science, Department of Communication, Aalborg University, Copenhagen, Denmark e-mail: ploug@hum.aau.dk\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_21\n\n345", "n_tokens": 179, "kind": "text"}
{"chunk_id": "drug_resistance_book-353-0", "doc_id": "drug_resistance_book", "page": 353, "text": "346\n\nS. Holm and T. Ploug\n\n21.1\n\nIntroduction\n\nAntibiotic resistance in bacteria, viruses and other pathogenic microorganisms is an increasing public health problem. The treatment of infectious diseases depends on the availability of effective antibiotics and modern surgery is only possible because post-operative infections can be effectively treated. It is therefore of the utmost importance to devise policies that can minimise and delay the emergence of resis- tance, as well as policies that promote the development of new classes of antibiotics. But developing such policies and ensuring compliance with them is a compli- cated problem. It is complicated by (1) the fact that the development of resistance is not only caused by misuse or overuse of antibiotics, (2) the possibility of resistant strains and resistance genes to spread rapidly in our globalised and interconnected world, and (3) the close connection between health system deficiencies in resource poor environments and the development of resistance (Daulaire et al. 2015).", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-353-1", "doc_id": "drug_resistance_book", "page": 353, "text": "Any use of antibiotics can lead to the selection of genetic variants that confer resistance to that antibiotic or class of antibiotics in microorganisms. Although proper use of antibiotics can minimise the emergence of such genetic variants it cannot completely prevent it, and there is some evidence that genes conferring resis- tance can be present even before the antibiotic is developed and used (Rolo et al. 2017a, b). Patients shed microorganisms during their treatment (e.g. approximately 1 × 1011 bacteria per gram of faeces), and the antibiotics themselves are also excreted in urine and faeces leading to selection for antibiotic resistance in bacteria in the sewer systems of health care institutions (Hansen et al. 2016).\n\nThis means that antibiotic resistance cannot be prevented merely by preventing misuse and overuse of antibiotics. In some circumstances we will also need to restrict proper use. We may, for instance have to restrict the use of an effective anti- biotic against a known microorganism which is sensitive to that antibiotic in con- texts where most of the cases of the illness in question are self-limiting. The cost of this will be that many patients will experience illness for longer than if they had been treated, and that some whose illness turn out not to be self-limiting may suffer more significant effects.", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-353-2", "doc_id": "drug_resistance_book", "page": 353, "text": "In this paper we will analyse to what extent the concept of ‘solidarity’ can help in (1) guiding personal and professional decision-making about the use of antibiot- ics, (2) designing and deciding on proper policies for minimising and delaying the emergence of resistance, and (3) maintaining support for and promoting compliance with anti-resistance policies. Solidarity is an old concept, but has recently experi- enced a resurgence in public health ethics.\n\nThe focus of the paper is on the use of antibiotics in human health care, and pri- marily on policies that aim to control the use of antibiotics in health care. There are significant issues concerning how to properly incentivise the development of new antibiotics and how to control the marketing of antibiotics, but these issues of ‘industrial policy’ are better analysed through the concepts of justice and injustice. Antibiotic use in veterinary medicine and in agriculture more generally, e.g. as growth promoters in animal husbandry is also outside the scope of this paper. These", "n_tokens": 213, "kind": "text"}
{"chunk_id": "drug_resistance_book-354-0", "doc_id": "drug_resistance_book", "page": 354, "text": "21 Solidarity and Antimicrobial Resistance\n\npractices contribute very significantly to the development and maintenance of anti- biotic resistance, but we simply do not have space to analyse them in depth within the solidarity framework.1\n\n21.2", "n_tokens": 46, "kind": "text"}
{"chunk_id": "drug_resistance_book-354-1", "doc_id": "drug_resistance_book", "page": 354, "text": "Solidarity and Public Health\n\nSolidarity is an old concept with roots in both moral theology and socialist/social democratic political philosophy. Both the authors of this paper are from Denmark and up until the mid-1990s ‘solidarity talk’ was common in Danish political dis- course and it is still common within the organised labour movement.\n\nThe concept of solidarity has recently been revived in public health ethics by Prainsack & Buyx and by Jennings & Dawson (Dawson and Jennings 2012, Jennings 2015, Jennings and Dawson 2015, Prainsack and Buyx 2011, 2016; see also Baylis et al. 2008).\n\nPrainsack & Buyx develop their conception of solidarity from the bottom up in their important book-length exploration of the concept, building on the concept of the solidaristic act defined in the following way:\n\nSolidarity is an enacted commitment to carry ‘costs’ (financial, social, emotional or other- wise) to assist others with whom a person or persons recognise similarity in a relevant aspect. (Prainsack and Buyx 2016, p. 52)\n\nBased on this definition they then distinguish three ‘tiers’ of solidarity:\n\n1. Interpersonal solidarity 2. Group solidarity 3. Contractual, Legal or Administrative Norms (or perhaps better ‘institutionalised solidarity’)\n\nAnd they define group solidarity as:", "n_tokens": 262, "kind": "text"}
{"chunk_id": "drug_resistance_book-354-2", "doc_id": "drug_resistance_book", "page": 354, "text": "… solidarity comprises manifestations of a shared commitment to carry costs to assist oth- ers with whom people consider themselves bound together through at least one similarity in a relevant respect (e.g. a shared situation, characteristic, or cause). (Prainsack and Buyx 2016, p. 55, emphasis in original)\n\nOther important features of their account are that they see solidarity as an inher- ently symmetrical relation, and thus distinct from asymmetrical relations like char- ity (p. 67); and that they claim that solidarity is a hybrid descriptive-normative concepts and that it is therefore “… suited neither to be framed nor applied in the way clearly deontic concepts such as human rights, or justice, can be.” (p. 93)\n\nWe agree with their analysis in many respects. It is very useful because it shows that although the concept of solidarity has a history which links it historically to socialist and social democratic political philosophy, it can be developed and used\n\n1 We do not even have space to consider whether or not human networks of solidarity can and should be extended to also encompass some or all animals.\n\n347", "n_tokens": 235, "kind": "text"}
{"chunk_id": "drug_resistance_book-355-0", "doc_id": "drug_resistance_book", "page": 355, "text": "348\n\nS. Holm and T. Ploug\n\nfor bioethical purposes without relying on any explicit or implicit socialist premis- es.2 However, the commitment to develop the conception from the bottom up, from the individual, isolated solidaristic act leads to some problematic conclusions.\n\nThe first problem is that it may not make sense to define a specific class of soli- daristic acts without reference to a motive grounded in group solidarity. Acts of beneficence or charity are often based on a recognition of ‘similarity in a relevant aspect’ between the agent and the beneficiary of the act, e.g. the ability to suffer or the ability to experience a certain kind of welfare benefit or the simple fact that the beneficiary is recognised as being a fellow human being; and beneficial acts based in justice are often built on the recognition that the agent and the recipient are simi- lar in the relevant sense of being moral agents subject to obligations of justice.", "n_tokens": 200, "kind": "text"}
{"chunk_id": "drug_resistance_book-355-1", "doc_id": "drug_resistance_book", "page": 355, "text": "The second problem is that it is far from obvious that relations of solidarity are, or have to be inherently symmetrical. Agents may perform solidaristic acts for other persons in the full knowledge that they can perform these acts because they have more power or more resources than those they assist, and that it is unlikely that they will need reciprocation. But, if the acts are motivated by solidarity and not by, for instance pity or a desire to do good works, then they should count as within the scope of solidarity. And even if the acts are performed with the expectation that they will be reciprocated if and when needed, that does not entail that the acts or the relationship is symmetrical at the time when the act is performed. If I, based on a motive of solidarity donate money to the striking workers during a long term strike, I may have an expectation that if ever I was participating in a long term strike some- one would, based on solidarity donate money to me and my fellow strikers, but that would not necessarily be an expectation that the money would come from the very same workers who are now on strike, and it could still involve the realisation that I am currently much better off than they are. A strict symmetry requirement would also entail that solidarity with future generations beyond the lifetime of the moral agent would be ruled out, simply because whereas I can do something for future generations, they cannot do anything for me.3", "n_tokens": 291, "kind": "text"}
{"chunk_id": "drug_resistance_book-355-2", "doc_id": "drug_resistance_book", "page": 355, "text": "It also cannot be definitional for acts of solidarity that they must involve net costs. Walking in the 1st of May parade with the other members of the blacksmiths’ labour union was, at least in years when the weather was good, a great source of joy for one of our grandfathers, but it was also an act of solidarity and identification with the union, its members and its causes, as well as with the larger network of labour unions.\n\nJennings & Dawson has a more traditional understanding of solidarity as a group\n\nconcept and identify three relational dimensions of solidarity:\n\nThe fundamental gesture or posture of solidarity is standing up beside. This posture has three relational dimensions: standing up for, standing up with, and standing up as. (p.32, emphasis in original)\n\n2 Whether that is sufficient to ensure that those socialist historical connotations will not be activated in the minds of readers or listeners when the term ‘solidarity’ is used is a different question. 3 Except, perhaps keeping my good reputation alive.", "n_tokens": 201, "kind": "text"}
{"chunk_id": "drug_resistance_book-356-0", "doc_id": "drug_resistance_book", "page": 356, "text": "21 Solidarity and Antimicrobial Resistance\n\nWe stand up for when we “assist or advocate for the other” (p 36). We stand up with when our solidarity requires us to enter “into the lifeworld of the other”; and we stand up as when there is “a yet stronger degree of identification between the agents of solidaristic support and the recipients of such support.” (p. 37). These three dimensions are not fundamentally different types of solidarity and they all draw their justification from the same conception of solidarity, but they point to dif- ferent levels of engagement and action. It is, for instance uncontroversial that health care professionals should in many circumstances stand up for the patient groups they serve, but their obligation to stand up with these patient groups only get acti- vated in certain contexts, and it is perhaps even rarer that they are required to stand up as with a patient group. But, the obligation to stand up as may be activated in more circumstances for health care professionals if the issue that requires solidaris- tic action is an issue affecting other health care professionals. In our analyses below of the implications of solidarity for individual and group actions and societal poli- cies in relation to antimicrobial resistance we use Jennings & Dawson’s three dimensions to indicate the level of engagement and commitment necessary for a particular kind of solidarity based action or policy to be likely to be effective.\n\n21.3", "n_tokens": 296, "kind": "text"}
{"chunk_id": "drug_resistance_book-356-1", "doc_id": "drug_resistance_book", "page": 356, "text": "Solidarity and Antimicrobial Resistance\n\nAntimicrobial resistance is a problem that may potentially affect each and every one of us. It may currently be a more significant problem in some areas of the world, but it is not geographically containable. In order to reduce the rate at which antimicro- bial resistance develops and spreads we also all have to be involved, since there is no use of antibiotics which does not promote resistance to some small degree.\n\nWe thus have a coordination problem. Each of us will in each instance where antibiotics can be prescribed personally benefit or potentially benefit by using anti- biotics more than is optimal seen from the point of an optimal, overall balance between use and development of resistance. Or to put it the other way around, slow- ing down the development of resistance will require each of us sometimes to suffer when that suffering could have been potentially reduced by the prescription of antibiotics.", "n_tokens": 182, "kind": "text"}
{"chunk_id": "drug_resistance_book-356-2", "doc_id": "drug_resistance_book", "page": 356, "text": "Coordination problems can, as discussed in other chapters of this book be solved in a variety of different ways, e.g. by changing the choice architecture and/or incen- tive structure. But some of these more structural solutions may either be illiberal in the sense that they reduce the option space available to individuals, even if none of the individual choices have any harmful consequences as individual choices, or they may create perverse incentives to try to circumvent restrictions in the choice archi- tecture. It is therefore worth considering whether there are alternative options.\n\nCan considerations of solidarity help to solve these coordination problems in a\n\nmore constructive way, and what is required for solidarity to be activated?\n\nIf we look at Jennings & Dawson’s three relational dimensions of solidarity it seems to be the case that even persons who have not realised that antimicrobial\n\n349", "n_tokens": 176, "kind": "text"}
{"chunk_id": "drug_resistance_book-357-0", "doc_id": "drug_resistance_book", "page": 357, "text": "350\n\nS. Holm and T. Ploug\n\nresistance is a problem for themselves can come to see that they ought to stand up for others in relation to antimicrobial resistance. They might, for instance decide to stand up for victims of extensively drug-resistant tuberculosis (XDR-TB) in sub- Saharan Africa, because they recognise some connection between themselves and the victims, even though they do not see themselves in any way threatened by XDR-TB.\n\nHowever, once persons have realised that they share in the problem of antimicro- bial resistance the two more intensely relational dimensions of solidarity can be activated, i.e. they can come to the realisation that they have to stand up with or as those who are threatened by antimicrobial resistance.\n\nThis does, potentially have different implications for ordinary persons /patients and for health care professionals. Ordinary persons can stand up with others in a number of ways in this context, they can advocate for policy changes, for research investment and for increased health care; and they can stand up as and take respon- sibility for their own use of antibiotics and encouraging others to do the same.", "n_tokens": 234, "kind": "text"}
{"chunk_id": "drug_resistance_book-357-1", "doc_id": "drug_resistance_book", "page": 357, "text": "Health care professionals have a wider range of actions available to them because of their roles as gatekeepers to antibiotics, experts in public debates, and trusted advisors to individual patients. But this also means that they have to bring two dif- ferent perspectives to bear, their personal perspective and their professional per- spective; and that they can be part of potentially different networks of solidarity (e.g. solidarity with other health care professionals in areas of the world where resistance is very prevalent).\n\nIt is important to note that activating solidarity in the context of antimicrobial resistance does not necessarily have to be based solely on the realisation that I and others share this particular similarity or vulnerability. Groups within which we feel and enact solidarity are often sustained by multiple, complexly intertwined per- ceived similarities (e.g. a national, regional or professional identity that engenders group solidarity is not just about one shared feature), and it may well be that the chance of successfully engendering ‘antimicrobial solidarity’ is much larger if it takes place within already existing networks of solidarity. Single similarity solidar- ity may in some instances be strong, but multi-similarity solidarity is often stronger, partly because it receives support from a multiplicity of motivating factors.", "n_tokens": 264, "kind": "text"}
{"chunk_id": "drug_resistance_book-357-2", "doc_id": "drug_resistance_book", "page": 357, "text": "It is likely that the most important and effective kind of solidaristic identification and action in relation to antimicrobial resistance is if enough people stand up as and take responsibility for their own use of antibiotics. What are the necessary condi- tions for this kind of solidarity to be engendered and for it to spread within already existing networks of solidarity? The first necessary precondition is, as mentioned above the realisation that antimicrobial resistance is not only a problem for others, it is also a problem for me and for others like me. However, for this to result in more than a sentiment of solidarity or a solidarity based call or activism for others to do something, I also need to know that there is something I can do personally in rela- tion to the use of antibiotics. Many people in the industrialised world have probably internalised three key messages about antibiotics during their own upbringing, and later as parents:", "n_tokens": 191, "kind": "text"}
{"chunk_id": "drug_resistance_book-358-0", "doc_id": "drug_resistance_book", "page": 358, "text": "21 Solidarity and Antimicrobial Resistance\n\n1. Don’t ask for antibiotics unnecessarily, e.g. when there is no bacterial infection 2. Take the antibiotics if they are offered by the doctor 3. Take the full course of antibiotics that is prescribed\n\n1. and 3. were traditionally backed up by the claim that this will help prevent the development of resistance, and 2. by the general idea that if a doctor offers a treat- ment option it must be good for you. However, 3. which has been a mainstay of antibiotic folk-knowledge for generations has now been repudiated by a group of scientist in a recent high profile paper where they claim that taking the full course actually promotes the development of resistance (Llewelyn et al. 2017). So, what knowledge do people now need to have in order to be able to act effec- tively in this context? They should still not ask for antibiotics when they are not necessary, but the concept of ‘not necessary’ may have to be further explicated so that we all understand that many bacterial infections are self-limiting and therefore not in need of antibiotic treatment, and also that pursuing treatment even when it is technically effective may bring about bad consequences for others to which we stand in a relation of solidarity.", "n_tokens": 271, "kind": "text"}
{"chunk_id": "drug_resistance_book-358-1", "doc_id": "drug_resistance_book", "page": 358, "text": "Let us briefly analyse a specific case study of antibiotic use through the lens of solidarity, i.e. the use of antibiotics in the treatment of acne (Acne vulgaris) in teen- agers and adolescents. Acne is a common disease and moderate and severe acne can lead to permanent scarring of the skin, as well as social and psychological problems in those affected by the condition (Hassan et al. 2009; Kellett and Gawkrodger 1999; Murray and Rhodes 2005). Oral antibiotics have for decades been used when topical treatments have been tried but turn out not to be effective and before the prescription of systemic isotretinoin or other retinoic acid analogues, since the reti- noic acid analogues have many and potentially severe side-effects (Nagler et al. 2016). There has, however been an increasing realisation that whilst this use of oral antibiotics is effective in many cases, it also leads to increasing antimicrobial resis- tance (Dreno et al. 2014; Sinnott et al. 2016). What implications do solidarity in terms of standing up with and as have for patients and doctors in this scenario? We will first focus on the patient-doctor encounter and then move on to the question of policy.", "n_tokens": 264, "kind": "text"}
{"chunk_id": "drug_resistance_book-358-2", "doc_id": "drug_resistance_book", "page": 358, "text": "In the patient-doctor encounter the enactment of solidarity is a matter for per- sonal and potentially shared decision-making. The doctor can and should advise the patient on the benefits and drawbacks of antibiotics and of other available treat- ments and the patient should make a decision based on an evaluation of how the different treatment options will affect his or her life and life plans. What solidarity brings to the table are two things, it provides the doctor with a license (and potential obligation) to appeal to the patients solidaristic motivations and it creates an obliga- tion for the patient to consider the choice through the lens of solidarity and not merely as an individual decision. This does not mean that the patient has to refuse antibiotics, or that the doctor has not to mention them as one of the treatment options. Acne is not a trivial disease, the side-effects of other available treatments are significant, and it is only the patient who can judge whether the sacrifice of for- going antibiotics is outweighed by the solidaristic public health benefits in terms of\n\n351", "n_tokens": 217, "kind": "text"}
{"chunk_id": "drug_resistance_book-359-0", "doc_id": "drug_resistance_book", "page": 359, "text": "352\n\nS. Holm and T. Ploug\n\nreducing the development of antibiotic resistance. It is also important to note that the doctor’s license to appeal to solidaristic motivations is not generated by the doc- tor’s professional role but by the fact that he or she stands with the patient in a mutual relation of solidarity and that they both recognise this.", "n_tokens": 75, "kind": "text"}
{"chunk_id": "drug_resistance_book-359-1", "doc_id": "drug_resistance_book", "page": 359, "text": "Things are more complicated at the policy level. The ‘spontaneous’ enactment of solidarity that we would wish to crystallise in policy arise in a situation where the doctor interpellates the patient as a person within a network of solidarity and encour- ages the patient to consider and enact solidarity in his or her decision-making, and where the patient enacts solidarity in a nuanced way by giving proper weight to the public health consequences of using antibiotics in his or her specific circumstances. This is tricky to implement as a policy and the main risks are that the doctor will be seen not as someone who stands with the patient and interpellates him or her in a network of solidarity, but as an agent of the state or the public health system, and that the patient will therefore not engage in solidaristic decision-making but per- ceive the situation as one where he or she is simply being asked or forced to sacrifice personal interests for some abstract conception of the public good. To avoid this problem the justification given for a policy, the way it is communicated to doctors and patients, and the way in which it is being implemented in health care will have to foreground solidarity considerations as the driving force behind the policy. A policy of simply banning the use of oral antibiotics for the treatment of acne is, for instance unlikely to sustain a solidarity based motivation for compliance.", "n_tokens": 279, "kind": "text"}
{"chunk_id": "drug_resistance_book-359-2", "doc_id": "drug_resistance_book", "page": 359, "text": "Consideration of the implications of solidarity can also guide the choice of meth- ods used to pursue public health goals in other areas. It has for instance been sug- gested in the literature that the active stigmatisation of the overweight and obese is an acceptable public health intervention, if there is evidence that it is effective (Callahan 2013); and there have been suggestions that targeted stigmatisation of farmers whose pigs carry multi-resistant bacteria is acceptable or perhaps even appropriate.4 But, if there are some obese people or some pig farmers within my circles of solidarity a choice of pursuing active stigmatisation to further public health goals becomes potentially problematic seen from the perspective of solidar- ity. These are people with whom I share important things and with whom I work on common projects and not people who should be harmed or ridiculed. And, given that standing up with or as them requires me to understand their lifeworld I may well come to understand why they act as they do. More generally considerations of solidarity enjoin us to choose supportive methods in our public health policies, and only resort to proscription when absolutely necessary.\n\n4 For a rejection of this view on other grounds than solidarity see Ploug et al. 2015.", "n_tokens": 255, "kind": "text"}
{"chunk_id": "drug_resistance_book-360-0", "doc_id": "drug_resistance_book", "page": 360, "text": "21 Solidarity and Antimicrobial Resistance\n\n21.4\n\nSolidarity as a Motivational Factor\n\nWe have argued above that considerations of solidarity can be useful in the design of policies to minimise and delay antibiotic resistance. But, building on the case study we need to consider solidarity as a motivating factor for action in more detail. We do not want to become embroiled in the interminable discussion about whether moral considerations necessarily motivate, or whether they only motivate when combined with a suitable desire. And, working with a concept like solidarity we do not need to become embroiled in that debate because realising that one has an obli- gation derived from or in solidarity straddles the cognitive/affective divide. Being in a relation of solidarity with a group is not a purely cognitive matter, but also a matter of felt identification. You don’t walk in the parade on the eighth of March, or partici- pate in a ‘Reclaim the Streets’ action purely on the basis of a dispassionate, rational assessment of your ethical obligations. You do it because you identify with the cause and with the group pursuing the cause.", "n_tokens": 238, "kind": "text"}
{"chunk_id": "drug_resistance_book-360-1", "doc_id": "drug_resistance_book", "page": 360, "text": "This motivating force of solidarity lead to and support individual solidaristic action, but it can also be an important factor in engendering support for policy change and maintaining support for policies once they are implemented. However, the mere fact that a policy builds on or crystallises an already existing, or a develop- ing solidarity based practice does not automatically mean that the support will transfer from the practice to the new context where what was previously a freely chosen action is now prescribed and must be performed (or proscribed and no lon- ger available).\n\nIn the design of policies we therefore need to be careful not to lose the connec- tion to solidarity as a motivating factor. The policy in a sense has to continue to speak to people and call them out in the language of solidarity and interpellate them as active participants in networks of solidarity.\n\nThis has implication both for how policies should be designed and how they should be communicated. We need to understand which networks of solidarity the relevant groups of citizens are embedded within, and design policies that appeal to those already existing networks.\n\n21.5", "n_tokens": 227, "kind": "text"}
{"chunk_id": "drug_resistance_book-360-2", "doc_id": "drug_resistance_book", "page": 360, "text": "The Extent and Limitations of Solidarity\n\nThere are a number of possible criticisms of the line of argument which has been pursued above. Here we want to look at two of them which are especially relevant in the context of antibiotic resistance since it is a global problem that needs global solutions.\n\nThe first possible criticism is that because we develop solidarity as a group con- cept, there will be some individuals and groups that are outside the solidarity group, that are Other than the ones included in our solidarity and who will be disadvan- taged by solidarity in the in-group. The second criticism is that it is implausible to\n\n353", "n_tokens": 129, "kind": "text"}
{"chunk_id": "drug_resistance_book-361-0", "doc_id": "drug_resistance_book", "page": 361, "text": "354\n\nS. Holm and T. Ploug\n\nthink that the solidarity of ordinary people could ever have a global scope (Holm 1993). Saints may aspire to global solidarity, but most of us restrict our solidarity to smaller and more local groups. Taken together these two criticisms imply that soli- darity is an unsuitable, and perhaps even pernicious concept on which to base a solution to a global public health problem.", "n_tokens": 86, "kind": "text"}
{"chunk_id": "drug_resistance_book-361-1", "doc_id": "drug_resistance_book", "page": 361, "text": "We take the second criticism to be empirically true. Few people manage to engender a state of ‘solidarity with the people of the world’5 in themselves (pace West-Oram and Buyx 2017). But perhaps that is not what is needed for solidarity to have global reach and be useful in supporting public health policies and initiatives. A global reach of local solidarity can come about in two ways. The simplest way is if local networks of solidarity are exhaustive in the sense that everyone is a member of at least one local network of solidarity, and if the results of solidarity in all, or perhaps just most of these networks contribute to a similar aim, i.e. in the present context the conservation of effective antibiotics through a reduction in the develop- ment of resistance. In this scenario a positive global outcome can be achieved by purely local action. Each local network of solidarity does not have to pursue an aim which is precisely identical to that of other networks. The second way in which local solidarity can have global reach is when we have local, but overlapping circles of solidarity that reach in an unbroken chain from people in the affluent north to people in the impoverished south. This may be sufficient to sustain the public health policies globally. In such a situation, persons may for instance accept policies restricting the use of antibiotics based on their solidarity with their fellow citizens in a particular country or region, but most of the people in that circle", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-361-2", "doc_id": "drug_resistance_book", "page": 361, "text": "of solidarity which is defined by local citizenship will also be in other overlapping circles of soli- darity based on other identifications like language, gender, profession etc. etc. Some of these overlapping circles may reach directly from the north to the south, there may for instance be solidarity among nurses or teachers or solidarity based on shared history. Others may be longer and involve more linking circles of solidarity but may never the less still be effective.", "n_tokens": 88, "kind": "text"}
{"chunk_id": "drug_resistance_book-361-3", "doc_id": "drug_resistance_book", "page": 361, "text": "The first criticism also contains an element of truth, but it is perhaps not as dam- aging to the use of solidarity as it initially seems. It is undoubtedly true that there are some circles of solidarity that are partly constituted by identifying a particular group of others as ‘the enemy’, or as the radical Other. Communist solidarity among workers for instance posits the violent struggle between the working class and the capitalist class as an inevitable historical fact. However, not all forms of solidarity have to work in that way, and most do not. Danish identity and solidarity among Danes, for instance originally relied on distinguishing Danes from Swedes and Germans and seeing those two groups as enemies. But, although Swedes and Germans are still the Other and instantiate all of the traits that are non-Danish and therefore not-ours, they are no longer the enemy. So whereas solidarity almost inev- itably expresses a form of partiality, which is partly what distinguishes it from thin\n\n5 ‘Solidaritet med verdens folk’ is a common slogan in left wing politics in the Nordic countries", "n_tokens": 217, "kind": "text"}
{"chunk_id": "drug_resistance_book-362-0", "doc_id": "drug_resistance_book", "page": 362, "text": "21 Solidarity and Antimicrobial Resistance\n\nconceptualisations of justice or utility maximisation, it may be a perfectly benign type of partiality.6\n\n21.6\n\nConclusion\n\nIn this paper we have argued for three main conclusions. First, that the concept of solidarity has an important role to play in analysing how individuals and groups can and should act in relation to the threat of antimicrobial resistances and that it is an important counterweight to pure self-interest. Second, that considerations of soli- darity can help us to shape both the goals and the methods of public health policies in order to make them long-term socially sustainable. And, third by implication that given that solidarity is helpful when thinking through one thorny issue in public health ethics and policy, it is likely to be helpful in other areas of public health ethics as well and that it therefore warrants continued attention from the public health (eth- ics) community.\n\nWe have also analysed the problems in moving from a voluntary practice sus- tained by solidarity to an official policy crystallising that practice as prescriptions and proscriptions and shown that careful design and communication is necessary not to lose the motivating force of solidarity when formulating policy.", "n_tokens": 254, "kind": "text"}
{"chunk_id": "drug_resistance_book-362-1", "doc_id": "drug_resistance_book", "page": 362, "text": "References\n\nBaylis, F., N.P. Kenny, and S. Sherwin. 2008. A relational account of public health ethics. Public\n\nHealth Ethics 1 (3): 196–209.\n\nCallahan, D. 2013. Obesity: Chasing an elusive epidemic. Hastings Center Report 43 (1): 34–40. Daulaire, N., A. Bang, G. Tomson, J.N. Kalyango, and O. Cars. 2015. Universal access to effec- tive antibiotics is essential for tackling antibiotic resistance. The Journal of Law, Medicine & Ethics 43 (S3): 17–21.\n\nDawson, A., and B. Jennings. 2012. The place of solidarity in public health ethics. Public Health\n\nReviews 34 (1): 65–79.\n\nDreno, B., D. Thiboutot, H. Gollnick, V. Bettoli, S. Kang, J.J. Leyden, A. Shalita, and V. Torres. 2014. Antibiotic stewardship in dermatology: Limiting antibiotic use in acne. European Journal of Dermatology 24 (3): 330–334.\n\nHansen, T.A., T. Joshi, A.R. Larsen, P.S. Andersen, K. Harms, S. Mollerup, E. Willerslev, K. Fuursted, L.P. Nielsen, and A.J. Hansen. 2016. Vancomycin gene selection in the microbi- ome of urban Rattus norvegicus from hospital environment. Evolution, Medicine, and Public Health 2016 (1): 219–226.\n\nHassan, J., S. Grogan, D. Clark-Carter, H. Richards, and V.M. Yates. 2009. The individual health burden of acne: Appearance-related distress in male and female adolescents and adults with back, chest and facial acne. Journal of Health Psychology 14 (8): 1105–1118.", "n_tokens": 421, "kind": "text"}
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{"chunk_id": "drug_resistance_book-363-1", "doc_id": "drug_resistance_book", "page": 363, "text": "London: Nuffield Council on Bioethics.\n\n———. 2016. Solidarity in biomedicine and beyond. Cambridge: Cambridge University Press. Rolo, J., P. Worning, J.B. Nielsen, R. Bowden, O. Bouchami, P. Damborg, L. Guardabassi, et al. 2017a. Evolutionary origin of the staphylococcal cassette chromosome mec (SCCmec). Antimicrobial Agents and Chemotherapy 61 (6): e02302–e02316.\n\nRolo, J., P. Worning, J.B. Nielsen, R. Sobral, R. Bowden, O. Bouchami, P. Damborg, et al. 2017b. Evidence for the evolutionary steps leading to mecA-mediated β-lactam resistance in staphylo- cocci. PLoS Genetics 13 (4): e1006674.\n\nSinnott, S.-J., K. Bhate, D.J. Margolis, and S.M. Langan. 2016. Antibiotics and acne: An emerging\n\niceberg of antibiotic resistance? British Journal of Dermatology 175 (6): 1127–1128.\n\nWest-Oram, P.G., and A. Buyx. 2017. Global health solidarity. Public Health Ethics 10 (2):\n\n212–224.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.", "n_tokens": 393, "kind": "text"}
{"chunk_id": "drug_resistance_book-363-2", "doc_id": "drug_resistance_book", "page": 363, "text": "The images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 73, "kind": "text"}
{"chunk_id": "drug_resistance_book-364-0", "doc_id": "drug_resistance_book", "page": 364, "text": "Chapter 22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\nNiels Nijsingh, D. G. Joakim Larsson, Karl de Fine Licht, and Christian Munthe\n\nAbstract This chapter charts and critically analyses the ethical challenge of assess- ing how much (and what kind of) evidence is required for the justification of inter- ventions in response antibiotic resistance (ABR), as well as other major public health threats. Our ambition here is to identify and briefly discuss main issues, and\n\nN. Nijsingh (*) Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, Gothenburg, Sweden\n\nDepartment of Philosophy, Linguistics and Theory of Science (FLoV), University of Gothenburg, Gothenburg, Sweden\n\nInstitute of Ethics, History and Theory of Medicine, Ludwig Maximilians Universität, Munich, Germany e-mail: niels.nijsingh@med.uni-muenchen.de\n\nD. G. J. Larsson Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, Gothenburg, Sweden\n\nDepartment of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden e-mail: joakim.larsson@fysiologi.gu.se\n\nK. de Fine Licht Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, Gothenburg, Sweden\n\nDepartment of Technology Management and Economics, Chalmers University of Technology, Gothenburg, Sweden e-mail: karl.licht@sp.se", "n_tokens": 320, "kind": "text"}
{"chunk_id": "drug_resistance_book-364-1", "doc_id": "drug_resistance_book", "page": 364, "text": "C. Munthe Centre for Antibiotic Resistance Research (CARe), University of Gothenburg, Gothenburg, Sweden\n\nDepartment of Philosophy, Linguistics and Theory of Science (FLoV), University of Gothenburg, Gothenburg, Sweden e-mail: christian.munthe@gu.se\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_22\n\n357", "n_tokens": 126, "kind": "text"}
{"chunk_id": "drug_resistance_book-365-0", "doc_id": "drug_resistance_book", "page": 365, "text": "358\n\nN. Nijsingh et al.\n\npoint to ways in which these need to be further advanced in future research. This will result in a tentative map of complications, underlying problems and possible challenges. This map illustrates that the ethical challenges in this area are much more complex and profound than is usually acknowledged, leaving no tentatively plausible intervention package free of downsides. This creates potentially over- whelming theoretical conundrums when trying to justify what to do. We therefore end by pointing out two general features of the complexity we find to be of particu- lar importance, and a tentative suggestion for how to create a theoretical basis for further analysis.\n\nKeywords Antibiotic resistance · Public health ethics · Precautionary principle · Complexity\n\n22.1", "n_tokens": 155, "kind": "text"}
{"chunk_id": "drug_resistance_book-365-1", "doc_id": "drug_resistance_book", "page": 365, "text": "Antibiotic Resistance\n\nAntibiotic resistance is emerging as one of our largest global challenges: more and more bacterial infections1 are becoming increasingly impervious to antibiotics, which increases morbidity, mortality and societal costs around the world.\n\nThe evolutionary principle that drives ABR is relatively simple: when popula- tions of bacteria are exposed to an antibiotic, strains that have acquired resistance to the drug (through mutations or through uptake of genetic material) are favoured over the sensitive ones. The emergence of ABR on a macro-scale is, however, noto- riously complex.2 One reason is that ABR is a global phenomenon with a variety of causes on different levels and in different contexts, some of which are poorly understood.\n\nThe most obvious cause of ABR is the use of antibiotics in humans, especially when antibiotics are used inappropriately (e.g. when overly broad antibiotics are used, or when a patient has no benefit from antibiotic treatment). The use of antibi- otics in animals, both for treatment and prevention of disease and for growth promo- tion, also contributes to the problem.3 Some bacteria have the ability to colonize both humans and domestic animals, and mobile genetic elements, such as resistance plasmids, often move across bacterial species. Hence, there are no firm barriers that", "n_tokens": 270, "kind": "text"}
{"chunk_id": "drug_resistance_book-365-2", "doc_id": "drug_resistance_book", "page": 365, "text": "1 We will limit ourselves here to antibiotic resistance. Antibiotic resistance is a sub-category of antimicrobial resistance, which also includes drug resistance in viruses, fungi and other microor- ganisms than bacteria. 2 World Health Organization (2014). The evolving threat of antimicrobial resistance: options for action. Geneva, Switzerland: World Health Organization. 3 Anomaly, J. (2020). Antibiotics and Animal Agriculture; The Need for Global Collective Action. In Ethics and Drug Resistance: Collective Responsibility for Global Public Health. Springer, Cham.", "n_tokens": 114, "kind": "text"}
{"chunk_id": "drug_resistance_book-366-0", "doc_id": "drug_resistance_book", "page": 366, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\nseparate the microflora of animals from that of humans. The external environment is another source of resistance, both as a transmission route for certain pathogens, for example through faecal contamination of water, and as a source for resistance genes that over time are recruited from harmless bacteria into pathogens, assisted by a selection pressure from antibiotics.4 The need to take into account the interconnec- tion between humans, animals and the external environment is often referred to as a “One Health perspective”.5\n\nClearly, there is an urgent need to address all of these causes of ABR and imple- ment interventions at different sites and different levels of organization. However, as we will see, securing the evidence required to establish both the effectiveness and the risks of such interventions, comes at a moral price. This raises in a straightfor- ward manner the question of what the criteria of evidence should be for the various interventions that aim to fight ABR. This question links the ethical justification of ABR interventions to debates around the ethics of risk and precaution. In other words, all ABR interventions pose the challenge of what quality of evidence for what balance of risks and possible benefits is required for such an intervention to be justified.\n\n22.2", "n_tokens": 268, "kind": "text"}
{"chunk_id": "drug_resistance_book-366-1", "doc_id": "drug_resistance_book", "page": 366, "text": "Precaution\n\nThe notion of precaution is central to much public health and environmental think- ing. Specifically, when faced with complex and potentially extremely threatening phenomena such as a pandemic, global warming or pollution, it makes sense both to act in response to them even if there is a lack of evidence, but also to proceed with caution when enacting precautionary measures to mitigate or prevent damage.\n\nScholars of the Precautionary Principle (PP) have worked to express this intu- ition more clearly, resulting in a generic criterion of justified decision-making and policy arrangements that can be expressed in the following way:\n\n... in the face of an activity that may produce great harm, we (or society) have reason to ensure that the activity is not undertaken, unless it has been shown not to impose too seri- ous risks.6\n\nThis criterion expresses three basic things: First, the idea that uncertain major threats may provide reason for action.7 Second, the contention that whatever such", "n_tokens": 208, "kind": "text"}
{"chunk_id": "drug_resistance_book-366-2", "doc_id": "drug_resistance_book", "page": 366, "text": "4 Bengtsson-Palme, Johan, and DG Joakim Larsson (2015). Antibiotic resistance genes in the envi- ronment: prioritizing risks. Nature Reviews Microbiology 13.6: 396–396. 5 Boden, L. & D. Mellor. (2020). Epidemiology and ethics of antimicrobial resistance in animals. In Ethics and Drug Resistance: Collective Responsibility for Global Public Health. Springer, Cham. 6 Munthe, Christian (2016). Precautionary principle. In: Ten Have (ed.) Encyclopedia of global bioethics. Dordrecht: Springer International Publishing. 7 Compare also: “uncertainty should not be a reason for inaction in the face of serious environmen- tal threats”. Daniel Steel calls this idea the ´meta-precautionary principle´. Note that the vagueness of this procedural meta-criterion allows PP to be applied in a large number of different contexts\n\n359", "n_tokens": 211, "kind": "text"}
{"chunk_id": "drug_resistance_book-367-0", "doc_id": "drug_resistance_book", "page": 367, "text": "360\n\nN. Nijsingh et al.\n\nactions are taken must not themselves impose too serious risks or new uncertain major threats, and, third, that we are required to demonstrate reasons both why responses to threats are motivated and why apparent threats may be accepted. The criterion expresses a generic formula, within which more specific PP versions, or specific precautionary policy suggestions, must fit in order to be justified. There are thus various ways to flesh out the idea that we have reason to take precautions in the face of major, but uncertain threats. As a version of PP is specified, it further delin- eates what can properly be considered responsible decision-making in such con- texts, not least regarding what is required more precisely to satisfy the requirement of demonstrating reasons for whatever precautionary action is suggested.8", "n_tokens": 166, "kind": "text"}
{"chunk_id": "drug_resistance_book-367-1", "doc_id": "drug_resistance_book", "page": 367, "text": "One basic assumption underlying PP is that there is a moral price to exposing people to risk, as well as to proceed with activities in the face of uncertain risks. However, there is also always a price to any precautionary intervention that aims to clarify uncertainties and to prevent or mitigate risks: these will always claim resources that could have been used for other worthwhile purposes, create risks of their own, and delay or stop possibly valuable activities. For that reason, sugges- tions for precautionary action need to be subjected to precautionary scrutiny too, and to be justified it needs to be demonstrated that they incur an acceptable price and level of precaution. Particularly in systemically complex situations, the emer- gence of risks and uncertainties on various levels raises complications concerning how to balance the type and severity of the various harms and uncertainties involved. A version of PP has to set standards concerning when precautionary action is required, and what is required of it in order to be responsible. Daniel Steel has recently explained this in terms of a ‘tripod’, consisting of a knowledge condition, a harm condition, and a suggested precautionary action.9 Variations of how this tri- pod is construed will affect the price of precaution, as well as the level of precaution enacted. A PP version thus needs to specify for (1) any suggested precautionary action, (2) what threat is sufficiently serious for such action to be defensible, and", "n_tokens": 316, "kind": "text"}
{"chunk_id": "drug_resistance_book-367-2", "doc_id": "drug_resistance_book", "page": 367, "text": "(3) what degree of uncertainty is acceptable for it. For example, in order to, say, justify taking expensive precautionary measures to curb ABR (1), there needs to be a sci- entifically plausible model (3) in which failure to introduce these measures leads to significant economic or health damage (2). Whether or not in a specific case the model leading to harm is ´plausible´ and the damage is ´significant´ of course requires further elaboration. In any justifiable specification of the ‘tripod’, it is nec- essary to balance in a responsible way the need for precautionary action against the price of precaution.", "n_tokens": 151, "kind": "text"}
{"chunk_id": "drug_resistance_book-367-3", "doc_id": "drug_resistance_book", "page": 367, "text": "Although details vary among authors, critical debate on what it takes to justify a PP version has led to a reasonably broad consensus on some minimal desiderata. These regard that a sound PP must not balance its required level and price of\n\nand on different levels of organization. See Steel, Daniel (2014). Philosophy and the precautionary principle. Cambridge University Press. 8 Munthe, Christian (2011). The price of precaution and the ethics of risk. Dordrecht: Springer. 9 Steel (2014).", "n_tokens": 108, "kind": "text"}
{"chunk_id": "drug_resistance_book-368-0", "doc_id": "drug_resistance_book", "page": 368, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\nprecaution arbitrarily (but according to a general principle that applies equally to all cases), that it needs to avoid so-called precautionary paradox, and that principle for responsible balancing of precautionary level and price must be proportional.10\n\nPP is arbitrary when it offers no good, generalizable reasons why a specific course of action is acceptable or not. If an appeal to PP is used to recommend inter- vention 1, but to prohibit intervention 2, it should be able to meaningfully distin- guish between the two measures and show how these are relevantly different. Note that the requirement to avoid arbitrariness also excludes treating the status quo with special regard: the fact that things are currently done in certain way is not in itself an argument for doing it that way.11 It also means that whatever requirements are set by the specification of the tripod in a PP, these apply both to uncertain threats in order to justify precautionary action, and to the uncertainties of these actions themselves.", "n_tokens": 230, "kind": "text"}
{"chunk_id": "drug_resistance_book-368-1", "doc_id": "drug_resistance_book", "page": 368, "text": "This links to the need to avoid ‘precautionary paradox’. PP can lead to paradox in two related ways: Either its requirements are so strong that it tends to ban all options in most situations, thereby undermining any capacity to guide decision- making.12 Or it issues inconsistent prescriptions by requiring and banning one and the same option.13 It has been a theme among critics to point out how simplistic versions of PP may easily become paradoxical in any or both of these ways.14", "n_tokens": 103, "kind": "text"}
{"chunk_id": "drug_resistance_book-368-2", "doc_id": "drug_resistance_book", "page": 368, "text": "The desideratum of proportionality follows from both of these requirements. In order to avoid paradox and arbitrariness, a justified version of PP must present a principle of responsible balancing of what level of precaution is required and what price of precaution is acceptable to pay that applies equally to all situations, as well as to all options in such situations. Any plausible version of PP will thus offer prin- cipled grounds for comparing suggested precautionary interventions, or the accep- tance of an uncertainty or a threat, to alternative options in a unified manner. Such a version will express an allegedly morally responsible way of balancing the required level and price of precaution. To justify a specific precautionary action in a situa- tion, it is therefore necessary to point how such a PP version supports it. As different situations vary with regard to what options are available, what stakes in terms of threats and prospects these actualise, and what knowledge is available with regard to these factors, one and the same precautionary intervention may therefore be", "n_tokens": 220, "kind": "text"}
{"chunk_id": "drug_resistance_book-368-3", "doc_id": "drug_resistance_book", "page": 368, "text": "10 Munthe, 2011, 2016; Munthe, C. (2017). Precaution and Ethics: Handling risks, uncertainties and knowledge gaps in the regulation of new biotechnologies. Berne: Swiss Federal Office for Buildings and Publications and Logistics (FOBL); Steel, (2014). 11 However, there may be good instrumental reasons to be cautious when implementing change in a situation of great uncertainty. We will return to that point later. 12 What Munthe (2011, ch. 2) has called decisional paralysis. 13 What Steel (2014) terms inconsistency. 14 Holm, Søren, and John Harris (1999). “Precautionary principle stifles discovery.” Nature 400.6743: 398–398. Sunstein, Cass R (2005). Laws of fear: Beyond the precautionary principle. Cambridge University Press. McKinney, WJ, & Hill, HH (2000). Of sustainability and precaution: The logical, epistemological, and moral problems of the precautionary principle and their implications for sustainable development. Ethics and the Environment, 5: 77–87.\n\n361", "n_tokens": 251, "kind": "text"}
{"chunk_id": "drug_resistance_book-369-0", "doc_id": "drug_resistance_book", "page": 369, "text": "362\n\nN. Nijsingh et al.\n\njustifiable in some situations, but not in others. This regards also what quality and type of information about risks and effectiveness we require, and how much of fur- ther investigation to mitigate uncertainties is needed in the light of that. Precautionary requirements will therefore be gradual rather than absolute, and context-dependent rather than rigid. Different situations will justify different levels of precaution, and different prices of precaution to attain such levels.15", "n_tokens": 106, "kind": "text"}
{"chunk_id": "drug_resistance_book-369-1", "doc_id": "drug_resistance_book", "page": 369, "text": "This regards not least the option of postponing a specific intervention in order to gather more evidence to ensure its effectiveness and responsibility. Possibly, this is the most common type of precautionary measure, familiar from standard regulation of drugs and the introduction of novel biotechnology.16 It is also easy to see how this type of precautionary action may often be justified on the basis of a defensible ver- sion of PP. However, knowledge is never perfect, and the option to further update the basis of information for assessing the effectiveness and riskiness of an interven- tion is ever present. So, when do we know enough? How much time and resources should we spend on making sure that what we do in order to invoke responsible precautionary response to dangers and uncertainties will not in fact worsen the situ- ation from a precautionary standpoint by invoking an unjustifiable price of precau- tion? This is a distinct ethical issue that becomes a particular challenge in the face of complex and drastic public health threats, such as ABR, where the price of delay- ing interventions is obvious, and costs and new risks of conducting research are salient. If we wait, the ABR problem continues to grow and increasingly threatens to overwhelm us, and if we experiment with interventions this will usually create new uncertainties and risks of harm. At the same time, unproven interventions may both escalate the ABR problem, and expand it to include severe policy failures.", "n_tokens": 317, "kind": "text"}
{"chunk_id": "drug_resistance_book-369-2", "doc_id": "drug_resistance_book", "page": 369, "text": "This takes us to the question of how these stakes, and options of collecting (or not col- lecting) evidence, should be assessed and evaluated.", "n_tokens": 31, "kind": "text"}
{"chunk_id": "drug_resistance_book-369-3", "doc_id": "drug_resistance_book", "page": 369, "text": "22.3\n\nEvidence\n\nTraditionally, guidelines for evidence basing and research in the area of medicine confine themselves to clinical trials of biomedical interventions, focusing mostly on the immediate somatic effects on individual patients.17 At the same time, as men- tioned, ABR (and most other public health) interventions greatly surpass that area, and mostly occur outside of immediate therapeutic action (although sometimes intended to affect it, e.g., those interventions that regard antibiotic prescription prac- tices). However, the recently revised guidelines by the Council for International Organizations of Medical Sciences (CIOMS) allow for a broader conception of\n\n15 Munthe, (2017). 16 Munthe (2011), p. 97. See also Munthe, (2017). 17 World Medical Association (2014). “World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.” The Journal of the American College of Dentists 81.3: 14", "n_tokens": 199, "kind": "text"}
{"chunk_id": "drug_resistance_book-370-0", "doc_id": "drug_resistance_book", "page": 370, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\n‘health research’, including the study of any intervention that aims to change health- related behaviour on both individual and institutional levels.18 This more inclusive conception clearly and significantly leaves room for the gauging of the proper amount of evidence for public health interventions.", "n_tokens": 67, "kind": "text"}
{"chunk_id": "drug_resistance_book-370-1", "doc_id": "drug_resistance_book", "page": 370, "text": "A starting point for this type of assessment is the recognition of the fact that all health research – not only on biomedical interventions – imposes risks on research subjects, while the projected aim is to gather more knowledge in the interest of sci- ence or society.19 A central tenet of research ethics therefore is that health research either has to plausibly benefit the research subject, or the societal benefit needs to be very large. In the new CIOMS guidelines, the latter is explicitly recognized in terms of the “social value” that may be attained by an intervention.20 Furthermore, consid- erations of promoting trust towards health professionals and the complexity of the ethical issues involved provide arguments to treat health research with a certain amount of caution.21 To this, we may add the precautionary considerations related in the preceding section: while a public health threat may be major and acute, any intervention meant to mitigate or prevent it may instead make it worse, or produce structural side effects that undermine other types of social goods. Therefore, the CIOMS frame is helpful to understand the question of evidence in public health interventions, such as the interventions aimed at fighting ABR.22 To establish whether the evidence is sufficient, we have to chart the types of harm and uncer- tainty for various interventions in order to determine whether the expected (social) value of the intervention outweighs the value of postponing the use of a", "n_tokens": 290, "kind": "text"}
{"chunk_id": "drug_resistance_book-370-2", "doc_id": "drug_resistance_book", "page": 370, "text": "new inter- vention to collect more solid information about it.", "n_tokens": 13, "kind": "text"}
{"chunk_id": "drug_resistance_book-370-3", "doc_id": "drug_resistance_book", "page": 370, "text": "This challenge is well illustrated by debates over suggested interventions in pub- lic health emergencies, such as Ebola.23 When, in 2014, the West African Ebola epidemic was finally recognized as a global threat, it was suggested to prevent\n\n18 Council for International Organizations of Medical Sciences (CIOMS) (2016). International Ethical Guidelines for Health-Related Research Involving Humans. Geneva, Switzerland: Council for International Organizations of Medical Sciences. http://www.cioms.ch (accessed July 28, 2017). Munthe, C., Nijsingh, N., de Fine Licht, K., & Joakim Larsson, D. G. (2019). Health-related Research Ethics and Social Value: Antibiotic Resistance Intervention Research and Pragmatic Risks. Bioethics, 33(3), 335–342. 19 Wilson, James, and David Hunter (2010). “Research exceptionalism.” American Journal of Bioethics 10.8: 45–54. 20 CIOMS (2016). 21 Wilson and Hunter (2010). 22 Attena, Francesco (2014). “Complexity and indeterminism of evidence-based public health: an analytical framework.” Medicine, Health Care and Philosophy 17.3: 459–465. 23 National Academies of Sciences, Engineering, and Medicine (2017). Integrating Clinical Research into Epidemic Response: The Ebola Experience. National Academies Press. An even more recent example is the Zika epidemic. See Edwards, Sarah JL (2016). “The precautionary paradox and Zika.” Research Ethics: 178–181.", "n_tokens": 339, "kind": "text"}
{"chunk_id": "drug_resistance_book-370-4", "doc_id": "drug_resistance_book", "page": 370, "text": "and Glenza, J. “Zika virus: Floridians fear ‘Pandora’s box’ of genetically altered mosquitos.” The Guardian, August 14, 2016: https://www.theguardian.com/us- news/2016/aug/14/florida- keys-zika-virus-genetically-modified-mosquitoes (accessed July 25, 2017).\n\n363", "n_tokens": 84, "kind": "text"}
{"chunk_id": "drug_resistance_book-371-0", "doc_id": "drug_resistance_book", "page": 371, "text": "364\n\nN. Nijsingh et al.\n\nfurther harm by ‘fast tracking’ new vaccines and experimental drugs, thus relaxing the demands of evidence required to introduce new medication.24 This suggestion was countered by public health officials, who argued that the epidemic should rather be controlled by means of proven public health policies, such as proper hygiene, surveillance and quarantine.25 Another issue that was debated was whether random- ized clinical trials could be justified in the context of an epidemic and the extent to which genuine equipoise could be presumed. In part, the answers to these questions depend on the relative risk to which the affected communities were exposed, in another part it depends on how we assess the gravity of uncertainties underlying the assessment of these risks and how we value the importance of acting on good evi- dence in view of those uncertainties. While the question on the evidence of interven- tions to counter ABR is similar to such debates, the issue of ABR also raises a new set of worries and topics for discussion. Specifically, whereas the Ebola crisis was unexpected and presented an acute emergency, ABR is – for now – slowly emerg- ing, albeit foreseen, but nevertheless posing a major and growing public health threat. Already a substantial amount of morbidity and mortality is attributed to ABR, but this number is likely to keep growing in a way well known to us.\n\n22.4", "n_tokens": 293, "kind": "text"}
{"chunk_id": "drug_resistance_book-371-1", "doc_id": "drug_resistance_book", "page": 371, "text": "Justifying Interventions\n\nSince the causes are varied, the fight against ABR takes place in different arenas. In this section, we distinguish between various groups of interventions. The first set concerns the development of new types of (or alternatives for) antibiotics. Second, we consider interventions that target the access to antibiotics by individuals. Third, various interventions aim to establish a larger degree of surveillance. Last, we bring together various institutional measures to attack the environmental health side of the ABR problem, such as the use of antibiotics in animals, as well as emissions of antibiotics. In accordance with the broad notion of ‘health research’ introduced in the former section, these interventions span a wide array of different actions and policies. As a consequence, we will consider many different levels and types of intervention; both on the scale of an individual patient–doctor interaction, as well as on the level of macro-economic interventions, institutional regulation and global health treaties. Varied though these interventions may be, they all share the charac- teristic of aiming to help curbing – or otherwise fighting – ABR. To what extent it can be demonstrated that they are effective in that regard, and to what extent they pose risks of their own, determines whether they can be responsibly introduced.", "n_tokens": 254, "kind": "text"}
{"chunk_id": "drug_resistance_book-371-2", "doc_id": "drug_resistance_book", "page": 371, "text": "Not all interventions in the fight against ABR are new. In fact, a number of important interventions intended to counter ABR belong to the classic public health\n\n24 Geisbert, Thomas W. (2015). “Emergency treatment for exposure to Ebola virus: the need to fast- track promising vaccines.” Jama 313.12: 1221–1222. 25 Rid, Annette, and Ezekiel J. Emanuel. (2014). “Ethical considerations of experimental interven- tions in the Ebola outbreak.” The Lancet 384.9957: 1896–1899.", "n_tokens": 120, "kind": "text"}
{"chunk_id": "drug_resistance_book-372-0", "doc_id": "drug_resistance_book", "page": 372, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\nrepertoire: screening, surveillance, quarantine, hygiene, and so on. Although they are not always uncontroversial, these interventions have been thoroughly tested and proven effective. Unfortunately, however, they will not suffice in addressing the problem of ABR.26 New methods will need to be explored, which raises the question how to determine which intervention is preferable; which offers greater relative benefit, and which poses fewer relative risks? The answer to that question depends on the evidence available to assess the various interventions. We have no ambition here to be complete in listing the possible, but aim to illustrate and map some major complexities that arise when balancing the level of precaution against the price of precaution.\n\n22.4.1", "n_tokens": 167, "kind": "text"}
{"chunk_id": "drug_resistance_book-372-1", "doc_id": "drug_resistance_book", "page": 372, "text": "Biomedical Interventions\n\nA fundamental problem in managing and fighting ABR is the lack of appropriate biomedical interventions. One aspect of this is the lack of truly new antibiotics. Although there is some progress in the development of novel antibiotics that affect Gram-positive bacteria (bacteria with a single outer cell wall),27 innovation for Gram-negative bacteria that has reached the market has for decades consisted only in variations of the same.28 In part, this can be attributed to the fact that developing new antibiotics is relatively unappealing from a business point of view. Therefore there is a widely recognized and urgent need to encourage academia and pharma- ceutical companies to develop new antibiotics, and to facilitate their introduction.29 So-called expedited programs to this effect have been launched, for example by the US Food and Drug Administration (FDA).30 Interventions included in such pro- grams are priority review, accelerated approval, and fast track (which can be combined).31 By promising a swifter, simplified and/or more relaxed process for licencing new therapies, such options both offer incentives to industry to invest in", "n_tokens": 226, "kind": "text"}
{"chunk_id": "drug_resistance_book-372-2", "doc_id": "drug_resistance_book", "page": 372, "text": "26 O’Neill, Jim (2014). Antimicrobial resistance: tackling a crisis for the health and wealth of nations. Review on antimicrobial resistance. 27 Wright, Gerard. (2015). “Antibiotics: An irresistible newcomer.” Nature 517.7535: 442–444. 28 See, e.g., University of Illinois at Urbana-Champaign. “Antibiotic breakthrough: How to over- come www.sciencedaily.com/ releases/2017/05/170510132012.htm (accessed July 6, 2017); WHO 2015. 29 World Health Organization, WHO. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: World Health Organization, 2017. Online access: http://www.who.int/medicines/publications/global-priority-list-antibiotic- resistant-bacteria/en (accessed July 28, 2017) 30 U.S. Department of Health and Human Services. Guidance for Industry. Expedited Programs for Serious Conditions – Drugs and Biologics. Washington: USDHHS, 2014. Online access: https:// www.fda.gov/downloads/drugs/.../ucm358301.pdf (accessed July 7, 2017). See for a more elabo- rate discussion: Munthe, C., & Nijsingh, N. (2019). Cutting red tape to manage public health threats: An ethical dilemma of expediting antibiotic drug innovation. Bioethics, 33(7), 785–791. 31 https://www.fda.gov/forpatients/approvals/fast/ucm20041766.htm (accessed July 28, 2017)\n\ngram-negative\n\nbacterial\n\ndefenses.”\n\nScienceDaily.\n\n365", "n_tokens": 388, "kind": "text"}
{"chunk_id": "drug_resistance_book-373-0", "doc_id": "drug_resistance_book", "page": 373, "text": "366\n\nN. Nijsingh et al.", "n_tokens": 11, "kind": "text"}
{"chunk_id": "drug_resistance_book-373-1", "doc_id": "drug_resistance_book", "page": 373, "text": "the development of new antibiotics, and speed up the introduction of successful fruits of such endeavours. Interventions of this sort appear attractive, considering the potential damage that lack of development and delay could cause, motivating a lower acceptable price of precaution than in the case a “normal” drug development context. At the same time, entirely new classes of antibiotics imply elevated uncer- tainties regarding effect and side effects, pointing to a need for more caution, and motivating a higher price of precaution. In addition, problems with regards to the control of prescription, use and transmission imply further uncertainties regarding the benefits of “expediting” new antibiotics. In particular, it creates a stark tension between the overall aim of ABR research and the needs of patients burdened by resistant infections. If a new compound is introduced in a setting where the men- tioned problems have not been mastered, resistance, though inevitable, can be expected to develop faster. As a result, there is a relative public health benefit to delay the discovery and introduction of new antibiotics while addressing the prob- lems of ensuring responsible use, and mitigating transmission of resistance. Still, earlier introduction may save lives and reduce morbidity of individuals. Therefore, it is less clear whether expedited programs for the introduction of new antibiotics should be at the top of the priority list. Unless they are combined with effective", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-373-2", "doc_id": "drug_resistance_book", "page": 373, "text": "measures to control usage and transmission, they introduce graver uncertainties of both negative side effects for patients, and of having the overall aim of managing the ABR problem undermined. Below, we will comment on interventions to manage this complexity of the ABR challenge.", "n_tokens": 53, "kind": "text"}
{"chunk_id": "drug_resistance_book-373-3", "doc_id": "drug_resistance_book", "page": 373, "text": "Another aspect of this challenge is that, if resources are concentrated to this effect, it may be possible to develop drugs to take in order to mitigate plasmid- mediated transmission of resistant bacteria from one patient to others. These could be taken by patients with resistant infections, but also patients who take antibiotics where this treatment may otherwise give rise to local resistance. This is a possible intervention that is still in a very early stage of exploration,32 which means there will be a long and expensive path to any possible actual treatment. At the same time, there is an obvious risk that no such success awaits at the other end – creating a severe uncertainty with regard to the actual worth of incentive schemes aimed at effecting such focused research and development endeavours. In addition, any suc- cessful treatment of this sort will create an ethical challenge in terms of exposing patients to the risk of side effects of the treatment without any sort of potential somatic benefit for these same patients. If it is successful, it will have an important general primary preventive effect of great public health value in the face of the ABR problem. If the introduction of such a drug would be “expedited”, this will at the same time increase the risk and uncertainty regarding negative side effects concen- trated only to those people taking the drug. Weighing these stakes has to be a part of striking the balance between what the acceptable price of precaution", "n_tokens": 291, "kind": "text"}
{"chunk_id": "drug_resistance_book-373-4", "doc_id": "drug_resistance_book", "page": 373, "text": "is to be when comparing incentive schemes.", "n_tokens": 8, "kind": "text"}
{"chunk_id": "drug_resistance_book-373-5", "doc_id": "drug_resistance_book", "page": 373, "text": "32 See, e.g., Buckner, Michelle, Maria Laura Ciusa, and Laura JV Piddock. (2018). “Strategies to combat antimicrobial resistance: anti-plasmid and plasmid curing.” FEMS microbiology reviews.", "n_tokens": 61, "kind": "text"}
{"chunk_id": "drug_resistance_book-374-0", "doc_id": "drug_resistance_book", "page": 374, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\nControlling use and transmission is less essential regarding therapeutic interven- tions where resistance development is not an apparent threat. Phage therapy (the therapeutic use of viral strains to attack bacteria) might fall into that category.33 The efficacy and safety of phage therapy has not been proven to the stage where it would fulfil current guidelines in Europe and the USA. However, it might be that these guidelines do not quite suffice in assessing the responsible introduction of phage therapy, e.g. since individually designed cocktails may be required for each patient, creating an impediment for designing controlled trials. Thus, phage therapy, or other innovative solutions that do not (as new antibiotic compounds) feed immedi- ately into the ABR development problem, may be a better target for “expedited programs” from an ABR standpoint – at least while we lack effective means to control use and transmission. On the other hand, accepting the higher degree of uncertainty, means lowering the level of required precaution, which may harm patients severely if experimental treatments turn out to be unsuccessful.", "n_tokens": 241, "kind": "text"}
{"chunk_id": "drug_resistance_book-374-1", "doc_id": "drug_resistance_book", "page": 374, "text": "A more general challenge posed by all types of expediting program interven- tions, is that they may inadvertently create incentives that give rise to negative dynamics regarding drug development. The basic problem is that any expedited program creates an incentive for industry to re-direct their research efforts in a way that shapes studies to be less stringent and clinically relevant than what they would otherwise have been. A well-known example of this is the acceptance of surrogate outcome variables (an essential part of accelerated approval interventions), which makes it economically attractive for companies to run studies measuring only these, meaning that there will be a structural dynamic change of clinical research efforts into paths with less potential or without demonstrating actual clinical value. Similarly, so-called compassionate use programs have recently come under fire for creating a structural incentive for industry to move more and more drug develop- ment out of the default review process, thus creating a generally decreasing level of safety and elevated uncertainty regarding effect. To be sure, expediting programs partly aim at having industry thus allocate their efforts and resources, however, if there is a structural negative dynamic on the general effectiveness of new drugs, this must be viewed as a relevant downside. For that reason, policy makers may want to consider other solutions to the issue of drug development, such as rewarding phar- maceutical", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-374-2", "doc_id": "drug_resistance_book", "page": 374, "text": "companies for developing new antibiotics, for example with exclusivity extensions, buyouts and entry prizes.34 Each of these interventions has the potential to offer incentives to the pharmaceutical companies, but also to pose risks to society", "n_tokens": 44, "kind": "text"}
{"chunk_id": "drug_resistance_book-374-3", "doc_id": "drug_resistance_book", "page": 374, "text": "33 De Vos, Daniel & Pirnay, Jean-Paul (2015). “Could viruses help resolve the worldwide antibiotic crisis?” AMR Control, 110. 34 Seth Seabury Neeraj Sood (2017, May 18). Toward A New Model For Promoting The Development Of Antimicrobial Drugs. Health Affairs Blog: http://healthaffairs.org/ blog/2017/05/18/toward-a-new-model-for-promoting-the-development-of-antimicrobial- drugs/(accessed July 28, 2017); Morel, Chantal M., and Elias Mossialos. “Stoking the antibiotic pipeline.” BMJ: British Medical Journal (Online) 340. Jim O’Neill (2014) has also suggested a ´pay or play´ principle, where pharmaceutical companies are required to either contribute or pay a fine.\n\n367", "n_tokens": 192, "kind": "text"}
{"chunk_id": "drug_resistance_book-375-0", "doc_id": "drug_resistance_book", "page": 375, "text": "368\n\nN. Nijsingh et al.\n\nand individuals, for instance a risk of social backlash.35 There are, of course, also large uncertainties regarding whether or not such actions would be money well spent. Returning to our main question concerning the evidence required for justifying various interventions that aim to offer incentives to develop new medicine, we see that a trade-off has to be made not just between individual and public interest, but also between various levels of uncertainty, and risks of structural negative dynamic effects. If faster development of antibiotics comes at the price of faster emergence of ABR for those same drugs, this raises the question on how to appreciate the urgency of the matter. In particular, it demands that we weigh current ABR against possible future ABR and the likelihood of developing alternatives for which ABR development is not an issue. There is both a danger of being retrospectively overly restrictive in the use of antibiotics when an alternative to the current drugs is found, as well as a danger of complacency based on the false reliance on such an alterna- tive. At the same time, we need to weigh into the balance the apparent but uncertain risk of incentive schemes being structurally counterproductive.\n\n22.4.2", "n_tokens": 251, "kind": "text"}
{"chunk_id": "drug_resistance_book-375-1", "doc_id": "drug_resistance_book", "page": 375, "text": "Prescription Practices\n\nSince the individual use of antibiotics is an important driver of ABR, interventions aiming to control the distribution of antibiotic drugs to individual patients are an important part of ABR policy. The proposed interventions include mandating pre- scription policies (in those countries where this is not already the case), various limitations to the type of antibiotics that are made available and improved access where antibiotics are currently lacking.\n\nIt is a received wisdom that the prescription system is an effective way of con- trolling the use of drugs. At the same time, the effectiveness on the system may vary, depending on numerous factors. For instance, antibiotic prescription practices across European regions vary considerably, linked to varying levels of institutional corruption.36 Such structural challenges can be assumed to multiply in countries where there is no system or culture of effective prescription for antibiotics. Given the widespread acceptance of the over-the-counter availability of antibiotics in such societies, not only among citizens, but also medical professionals, and sometimes policy makers, there is a recognised uncertainty as to the real impact of trying to create or toughen up such regulation.37", "n_tokens": 224, "kind": "text"}
{"chunk_id": "drug_resistance_book-375-2", "doc_id": "drug_resistance_book", "page": 375, "text": "35 Munthe et al. (2019). 36 Rönnerstrand, Björn, and Victor Lapuente. (2017). “Corruption and use of antibiotics in regions of Europe.” Health Policy 121.3: 250–256. 37 Radyowijati, Aryanti, and Hilbrand Haak (2003). “Improving antibiotic use in low-income coun- tries: an overview of evidence on determinants.” Social science & medicine 57.4 (2003): 733–744. Dreser, Anahí, et al. (2012). “Regulation of antibiotic sales in Mexico: an analysis of printed media coverage and stakeholder participation.” BMC public health 12.1: 1051.", "n_tokens": 158, "kind": "text"}
{"chunk_id": "drug_resistance_book-376-0", "doc_id": "drug_resistance_book", "page": 376, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\nWe meet here with a type of uncertainty that is entirely about how societies may react to attempted institutional change.38 Weighing into the mix economic, cultural and institutional factors of relevance, a more incremental change seems preferable. It provides opportunity to attend to the interests of various stakeholders, as well as taking the time for a society to adjust, in order to ease both the passing of regulation, and its effective implementation. However, that requires quite a bit of knowledge of such mechanics of overarching social change, and also uses time itself as a factor. This raises the question of how long is long enough to attempt establishing social change, and how much effort should be spent on securing the understanding of how to make such attempts work. Facing the ABR challenge, how high should the price of precaution due to delaying prescription regulative action be allowed to rise while attending to such uncertainties?", "n_tokens": 196, "kind": "text"}
{"chunk_id": "drug_resistance_book-376-1", "doc_id": "drug_resistance_book", "page": 376, "text": "For countries where a reasonably effective prescription practice is in place, unless a patient is critically ill, the first choice of antibiotics is often not the latest, most potent formula (with still limited resistance problems). Therefore, antibiotics prescribed usually bring a greater risk that the treatment will not cure the infection due to resistance. At the same time, this practice serves to protect the future integrity of “last line antibiotics” by minimising their use and thereby inhibiting the evolu- tionary drive towards resistance to them. Most commentators describe the payoff of these interventions in terms of public good, whereas risks of implementing them are considered to be carried by single individuals.39 However, matters are slightly more complex than that. First, although there is agreement that this intervention does delay resistance for broad-spectrum compounds, the magnitude of the effect is still uncertain. Second, since broad-spectrum antibiotics are more likely to drive resis- tance in the individual patient’s own gut flora,40 there is also a chance of individual benefit linked to prescription practice.", "n_tokens": 213, "kind": "text"}
{"chunk_id": "drug_resistance_book-376-2", "doc_id": "drug_resistance_book", "page": 376, "text": "We thus face a complex trade-off situation, where individual risks of suffering untreated infections must be balanced against the uncertain prospect that patients are protected against being infected by resistant bacteria, at the same time as the question remains whether this mix of risk and uncertain benefit for some individuals can be justified by a social benefit of uncertain magnitude. This also raises the ques- tion how much effort should be spent on making sure that the right balance is struck, for example by straightening out some of the important uncertainties.\n\nIn any case, agreeing that such a practice is indeed justified does not end the problem. We must also ask what intervention would actually effectively address it.", "n_tokens": 134, "kind": "text"}
{"chunk_id": "drug_resistance_book-376-3", "doc_id": "drug_resistance_book", "page": 376, "text": "38 The risk of incentive schemes for drug creation to produce unintended negative dynamics via their effect on industry in the former section also belongs to this type. 39 Littmann, Jasper, and A. M. Viens. (2015). “The ethical significance of antimicrobial resistance.” Public health ethics 8.3: 209–224. 40 This is phenomenon can be observed in urinary tract infections, for example. As the normal non- resistant invading bacteria of this flora are exterminated by the treatment, a very fertile living space is created for bacteria that are resistant against the drug used. Costelloe, Ceire, et al. (2010). “Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: system- atic review and meta-analysis.” Bmj 340: c2096.\n\n369", "n_tokens": 184, "kind": "text"}
{"chunk_id": "drug_resistance_book-377-0", "doc_id": "drug_resistance_book", "page": 377, "text": "370\n\nN. Nijsingh et al.", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-377-1", "doc_id": "drug_resistance_book", "page": 377, "text": "One idea, of course, is to make professional prescription guidelines for doctors to use. However, this introduces the uncertainty that doctors may fail to apply them, e.g., due to patient pressure, economic counter-incentives, or the mere inertness of habit. To address that, there is the option of allowing professionals less choice, for example by requiring application to a higher instance and proof of due cause for having a prescription green lighted. Such an intervention could consist of several levels of requirements, and for some antibiotics regular doctors may be stripped of all prescription rights. At the same time, being able to leave professional discretion to doctors in individual cases also has its value, and the more of rigid restriction is built into an intervention, the bigger the risk that individuals are harmed due to lack of (timely) access to treatment. However, rigid regulatory interventions clearly avoid the uncertainty with regard to the overall aims of delaying resistance develop- ment, as well as avoiding harmful individual prescriptions. To make this trade-off, it would be of great value to know more about the social dynamics creating the uncertainty around the effectiveness of prescription interventions, as well as how these might be complemented by additional institutional changes to mitigate the pressure on doctors from patients, and to remove economic counter-incentives.41 On the other hand, as we delay action, or apply overly cautious interventions", "n_tokens": 276, "kind": "text"}
{"chunk_id": "drug_resistance_book-377-2", "doc_id": "drug_resistance_book", "page": 377, "text": "with uncertain effectiveness while making sure what more exact variant would be best, the price of precaution is allowed to go up in terms present prescription practices being allowed to continue.", "n_tokens": 35, "kind": "text"}
{"chunk_id": "drug_resistance_book-377-3", "doc_id": "drug_resistance_book", "page": 377, "text": "This precautionary challenge is further complicated by the fact that there is an instrumental value to fine-tune prescription interventions so that treatment of infec- tion is optimized also under a restrictive prescription practice. The reason for this is that increased persistent infection can be expected to increase the future demand and consumption of antibiotics, thereby accelerating rather than mitigating resis- tance development in the long run.42 Depending on what current prescription prac- tices look like in specific societies, this may mean that an optimal prescription intervention should not only decrease prescription, but in some cases leave it as it is, and in yet other even improve the access to antibiotics. Considerations of fairness may add further reasons to a similar effect, and also the need of securing the legiti- macy of any policy in this area. After all, of what interest is the issue of ABR to anyone who is barred from accessing appropriate antibiotics in the first place? This further complicates the uncertainty about what exact intervention would be most effective. But it also adds a basic source of uncertainty with regard to how the moral stakes should be balanced in a measure of effectiveness. A sound precaution- ary solution therefore needs to acknowledge the latter point when striking the bal- ance between ensuring a desired level of precaution at an acceptable price of precaution, and allow both considerations of health promotion and fair", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-377-4", "doc_id": "drug_resistance_book", "page": 377, "text": "distribution of the population health.", "n_tokens": 6, "kind": "text"}
{"chunk_id": "drug_resistance_book-377-5", "doc_id": "drug_resistance_book", "page": 377, "text": "41 As such changes may involve drastic reform to entire health care and health insurance systems, the knowledge required is quite advanced and complicated to collect. 42 Daulaire, N., et al. (2015). “Universal access to effective antimicrobials: an essential feature of global collective action against antimicrobial resistance.” Journal of Law, Medicine & Ethics 43.2.", "n_tokens": 80, "kind": "text"}
{"chunk_id": "drug_resistance_book-378-0", "doc_id": "drug_resistance_book", "page": 378, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\n22.4.3\n\nSurveillance\n\nThe fight against ABR also requires enhanced possibilities of diagnosis and surveil- lance of resistant bacteria. Better diagnostic methods are in themselves unobjection- able as increased speed, precision and readiness in determining the cause of an infection limits the danger of squandering antibiotics. However, there will be trade- offs between increasing speed, increasing precision and financial costs and possibly the intrusiveness of the sample taking. Because of this, as well as the general uncer- tainties befalling any new measurement tool, there is once again a challenge to decide how much support for the reliability and validity of a new diagnostic tool has to be secured in order to start implementing it. The balance here, as before, includes assessing the value of more firm knowledge against the price of precaution in terms of delaying tools that may also offer opportunities for better surveillance in the face of the ABR threat. But it also includes the complications as more speedy introduc- tion will tend to increase one or the other of well-known downsides to such interventions.", "n_tokens": 239, "kind": "text"}
{"chunk_id": "drug_resistance_book-378-1", "doc_id": "drug_resistance_book", "page": 378, "text": "These complications become especially challenging as resistant infections or even carriership may often actualise restrictive communicable disease management measures, such as compulsory isolation, quarantine or mandatory life-style restric- tions. The implied tension between individual interest and collective good is par- ticularly salient when this involves asymptomatic carriers, who have nothing to benefit from being institutionalized.43 The issue is further complicated when we consider the possibility of false positives, where patients are wrongly identified as carrying resistant bacteria. As in the former section, this also links to a risk of undermining the legitimacy of ABR policies. Thus, while speedy introduction of diagnostic methods certainly has its potential upsides, it will increase uncertainties of a sort that in other areas are often taken to undermine health surveillance programs.\n\nAttempting to strike these several balances, we face the general problem of hav- ing the right idea concerning the moral stakes involved and a sound notion of what price of precaution to allow. In addition, increased complexities of how to assess the quality of available and attainable evidence for ambitious and complex public health interventions add another layer of uncertainty.44", "n_tokens": 238, "kind": "text"}
{"chunk_id": "drug_resistance_book-378-2", "doc_id": "drug_resistance_book", "page": 378, "text": "43 Weinstein, Robert A., Daniel J. Diekema, and Michael B. Edmond. (2007). “Look before you leap: active surveillance for multidrug-resistant organisms.” Clinical Infectious Diseases 44.8: 1101–1107. Nijsingh, N., Juth, N., Munthe, C., “The Ethics of Screening”, in: Quah, Stella R. International encyclopedia of public health. Academic Press, 2016. Nijsingh, N., Munthe, C., Lindblom, A., & Åhrén, C. (2020). Screening for multi-drug-resistant Gram-negative bacteria: what is effective and justifiable?. Monash bioethics review. 44 Attena, (2014).\n\n371", "n_tokens": 173, "kind": "text"}
{"chunk_id": "drug_resistance_book-379-0", "doc_id": "drug_resistance_book", "page": 379, "text": "372\n\nN. Nijsingh et al.\n\n22.4.4", "n_tokens": 16, "kind": "text"}
{"chunk_id": "drug_resistance_book-379-1", "doc_id": "drug_resistance_book", "page": 379, "text": "Environment and Animals\n\nA wide variety of ABR interventions relate to attempts to curb the emission of anti- biotics in the environment45 and their use in animals. We have grouped these together because of the potential risks of the interventions, which seem mostly economical. For example, attempts to enhance transparency of pharmaceutical companies46or banning of the use of antibiotics as a growth enhancer,47 or taxing consumer prod- ucts emanating from ABR driving practices, such as meat production,48 do not have direct health risks for humans. Compared to the possible economic damage of such interventions, the health risks of ABR may seem to clearly win out. However, there is still much uncertainty concerning the role of non-human use and pollution in the establishing of ABR and economic cost of interventions carry their own set of sec- ondary risks and uncertainties, which might be substantial indeed as the incurred costs become more significant.\n\nOne obvious uncertainty regards the effectiveness of systems of surveillance and control of emission rates in production or compound use in farming. These will include uncertainties and imprecisions of technical methods, but even more institu- tional uncertainties of the sort we have already discussed related to prescription and surveillance interventions. As already observed, straightening these uncertainties out includes coming to grips with very complex social circumstances, and may require quite a lot of time and resources.", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-379-2", "doc_id": "drug_resistance_book", "page": 379, "text": "On top of this, macro-economic ABR interventions targeting environmental emission may have adverse effects in themselves, both socially and economically, for instance, by discouraging pharmaceutical business and thereby restricting access to drugs generally. Consequently, we may legitimately ask which interventions are necessary, or reasonable, and which are disproportional, given the uncertain effects of current practices. Should, for instance, pharmaceutical companies be required to monitor and make sure antibiotics emission from manufacturing are very low?49 Or should regulation rather target the pricing of products, adding tax or extra cost in the procurement of drugs by public national health services? Or should some other", "n_tokens": 128, "kind": "text"}
{"chunk_id": "drug_resistance_book-379-3", "doc_id": "drug_resistance_book", "page": 379, "text": "45 Pruden, Amy, et al. “Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment.” Environmental health perspectives 121.8 (2013): 878. 46 Larsson, DG Joakim, and Jerker Fick. “Transparency throughout the production chain—a way to reduce pollution from the manufacturing of pharmaceuticals?.” Regulatory Toxicology and Pharmacology 53.3 (2009): 161–163. Nijsingh, N., Munthe, C., & Larsson, D. J. (2019). Managing pollution from antibiotics manufacturing: charting actors, incentives and disincentives. Environmental Health, 18(1), 95. 47 Laxminarayan, Ramanan, Thomas Van Boeckel, and Aude Teillant. (2015). “The economic costs of withdrawing antimicrobial growth promoters from the livestock sector.”. 48 Giubilini, Alberto, et al. (2017). “Taxing Meat: Taking Responsibility for One’s Contribution to Antibiotic Resistance.” Journal of Agricultural and Environmental Ethics 30.2: 179–198. 49 Bengtsson-Palme, Johan, and DG Joakim Larsson. (2016). “Concentrations of antibiotics pre- dicted to select for resistant bacteria: Proposed limits for environmental regulation.” Environment International 86: 140–149.", "n_tokens": 294, "kind": "text"}
{"chunk_id": "drug_resistance_book-380-0", "doc_id": "drug_resistance_book", "page": 380, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\ninstitutional intervention to similar effect be chosen, for example having high emis- sions in production reduce the calculated health benefit in the context of health technology assessment? In all these cases, should the link between detected emis- sion rates and such incentives be proportionally or more rigidly designed? If the former, according to what formula or proportionality, if the latter, on what grounds should thresholds be set? And what institutional arrangement would be effective to have whatever intervention is chosen to be effectively implemented? Similar ques- tions appear with regard to interventions aimed at creating incentives to reduce the use of antibiotics in farming.50", "n_tokens": 143, "kind": "text"}
{"chunk_id": "drug_resistance_book-380-1", "doc_id": "drug_resistance_book", "page": 380, "text": "All of this makes for a considerable difficulty in assessing the proper balancing of the level of precaution and its acceptable price. Surely, the urgency of mitigating major environmental practices that fuel antibiotic resistance development is a prior- ity. However, to find the right way of doing this requires quite a bit of very complex knowledge, and behind this need lurks the very real risk that a more speedy intro- duction of interventions is not only sub-optimal, but actually makes the problem worse. For instance, implementing any of the regulative interventions mentioned may mainly have the effect of having pharmaceutical and food production relocat- ing to areas where the regulative situation is even worse. Or secondary effects, e.g., in the form of drastically increased food prices may both undermine the legitimacy of ABR policies and create a public health threat of its own. On the other hand, it is well known that it takes considerable time to have large-scale operations such as drug production and farming change their longstanding ways, and in the light of that, applying interventions to address the environmental side of the ABR challenge is paramount.\n\n22.5", "n_tokens": 235, "kind": "text"}
{"chunk_id": "drug_resistance_book-380-2", "doc_id": "drug_resistance_book", "page": 380, "text": "Discussion\n\nWe have assessed interventions with regard to how much and what kind of evidence is needed when evaluating and implementing interventions in response to antibiotic resistance, a public health threat of immense proportions. The notion of responsible precautionary decision-making provides a basic and strong reason to act in response to this threat. However, determining what response to go for introduces complex problems of balancing what level of precaution to aim for and what price of precau- tion to pay, actualising much more difficult ethical challenges than what is often acknowledged.\n\nWe end this exploration by briefly addressing two issues that emerge when we consider the evidence for interventions that aim to fight antibiotic resistance, lead- ing into a final broad suggestion for future analyses to build on.\n\n50 Silley, Peter, and Bernd Stephan. (2017). “Prudent use and regulatory guidelines for veterinary antibiotics—politics or science?.” Journal of applied microbiology 123.6: 1373–1380.\n\n373", "n_tokens": 201, "kind": "text"}
{"chunk_id": "drug_resistance_book-381-0", "doc_id": "drug_resistance_book", "page": 381, "text": "374\n\nN. Nijsingh et al.", "n_tokens": 11, "kind": "text"}
{"chunk_id": "drug_resistance_book-381-1", "doc_id": "drug_resistance_book", "page": 381, "text": "First, there is the sheer size of the possible consequences of increased ABR. For example, there is a real question whether standards of treatment and diagnosis in research ethics and clinical ethics may need revision in light of a public health threat as significant to global wellbeing as ABR. Although one should be wary to discard too easily the frameworks that have proven to be of value throughout the years, the possible disruptive effects of ABR raise the issue to what extent these standards can be maintained, given the range of difficult choices we might face. At the same time, we have seen that many of the uncertainties posed by ABR interventions are not so much about having risks of undesirable side effects as such are typically conceived of when evaluating pharmaceuticals. Rather, the important uncertainties are about risks of outright counterproductivity due to social psychological and institutional dynamics, where apparently promising attempts to counter ABR may instead lure us into political, economic or psychological dead ends from which we are unable to get out. Social processes are typically slow, variably inert and intractable, which means also that they may be very difficult to reverse, and that doing so may require a lot of time. Given that interventions on all of the mentioned levels are probably necessary to reduce the risk of emerging resistance and that they are to a large extent interrelated, the standards of evidence should be set from an integrated,", "n_tokens": 287, "kind": "text"}
{"chunk_id": "drug_resistance_book-381-2", "doc_id": "drug_resistance_book", "page": 381, "text": "One Health perspective.", "n_tokens": 4, "kind": "text"}
{"chunk_id": "drug_resistance_book-381-3", "doc_id": "drug_resistance_book", "page": 381, "text": "This connects to the general observation that methods in response to ABR have to intervene on a variety of different levels, from the everyday practice of physicians to those affecting global structures. Interventions worthy of consideration therefore involve a myriad of different types and degrees of uncertainty and risks, which are also unevenly distributed across people, societies and time. Assessment of the evi- dence thus needs to consider a multi-layered mosaic of uncertainties and ethical dilemmas regarding the short- and long-term trade-off between individual interests and public health aims. This regards especially the issue of how much and what evidence to collect regarding the effectiveness of interventions, and their potential long-term legitimacy.", "n_tokens": 136, "kind": "text"}
{"chunk_id": "drug_resistance_book-381-4", "doc_id": "drug_resistance_book", "page": 381, "text": "These considerations may drive one to despair whether a responsible, measured approach to the issues at play here is at all feasible. One way of moving forward in the light of these considerations is to acknowledge that there are good – moral and precautionary – reasons to cut the Gordian knot: just as there is a question of how much to amass and ponder evidence and the proper resolution of ethical dilemmas, we must not get stuck forever in the precautionary conundrum. Moving along such a path, one primary consideration is then to assess the relative importance of avoid- ing harm and risk of harm that result from otherwise apparently effective interven- tion packages, while avoiding the pull of the enormity of the ABR challenge to lure us into policy deadlocks. In doing so, the complexity and close connections of the various risks offer strong grounds for putting the reversibility of potential adverse consequences at centre stage. Related to debates on the ethics of precaution, this links to different proposals on how to limit the scope of a precautionary principle,", "n_tokens": 220, "kind": "text"}
{"chunk_id": "drug_resistance_book-382-0", "doc_id": "drug_resistance_book", "page": 382, "text": "22 Justifying Antibiotic Resistance Interventions: Uncertainty, Precaution and Ethics\n\ne.g., in terms of de minimis risk, and, more specifically, to the importance of avoid- ing irreversible negative outcomes. This is not to say that this is a generally plausi- ble solution for all precautionary decision-making, but the peculiar complex challenges of assessing evidence for ABR interventions seem to add reasons for the fittingness of an approach that prioritises reversibility.51\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 271, "kind": "text"}
{"chunk_id": "drug_resistance_book-382-1", "doc_id": "drug_resistance_book", "page": 382, "text": "51 This research was supported by the UGOT Challenges Initiative at the University of Gothenburg; and by the Swedish Research Coucil, VR, contract no. 2014–40, for the Lund-Gothenburg Responsibility Project.\n\n375", "n_tokens": 45, "kind": "text"}
{"chunk_id": "drug_resistance_book-383-0", "doc_id": "drug_resistance_book", "page": 383, "text": "Chapter 23 Antimicrobial Footprints, Fairness, and Collective Harm\n\nAnne Schwenkenbecher\n\nAbstract This chapter explores the question of whether or not individual agents are under a moral obligation to reduce their ‘antimicrobial footprint’. An agent’s antimicrobial footprint measures the extent to which her actions are causally linked to the use of antibiotics. As such, it is not necessarily a measure of her contribution to antimicrobial resistance. Talking about people’s antimicrobial footprint in a way we talk about our carbon footprint may be helpful for drawing attention to the global effects of individual behaviour and for highlighting that our choices can collectively make a real difference. But can we be morally obligated to make a contribution to resolving a collective action problem when our individual contributions by them- selves make no discernible difference? I will focus on two lines of argument in favour of such obligations: whether a failure to reduce one’s antimicrobial footprint is unfair and whether it constitutes wrongdoing because it is harmful. I conclude by suggesting that the argument from collective harm is ultimately more successful.\n\nKeywords Political philosophy · Ethics · Public health · Antimicrobial resistance · Collective action problems\n\n23.1", "n_tokens": 250, "kind": "text"}
{"chunk_id": "drug_resistance_book-383-1", "doc_id": "drug_resistance_book", "page": 383, "text": "Introduction\n\nAnti-microbial resistance and a decline in anti-microbial efficacy are urgent collec- tive action problems. Who should act on this problem? According to the World Health Organisation’s recommendations, concerted action on this issue requires efforts from a diverse array of actors: patients, drug prescribers and dispensers, hospitals, policy makers, and food producers (WHO 2001: 68–70, see also Littmann and Viens 2015).\n\nA. Schwenkenbecher (*) Murdoch University, Perth, Western Australia e-mail: A.Schwenkenbecher@murdoch.edu.au\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_23\n\n377", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-384-0", "doc_id": "drug_resistance_book", "page": 384, "text": "378\n\nA. Schwenkenbecher\n\nIn this chapter I explore the idea of an ‘antimicrobial footprint’ and discuss whether or not individual agents are under a moral obligation to reduce theirs. Importantly, I am not suggesting that reducing our antimicrobial footprints by way of individual behavioural change is the best or most efficient way of decelerating antimicrobial resistance, since that is an empirical question. However, given that the WHO identified individual agents such as patients and prescribers as agents of change, it seems that individuals’ moral obligations deserve some discussion, which is why I will focus on those in this chapter. But before I do so, let me briefly point to another way in which individual agents are implicated in anti-microbial resis- tance: as consumers of products from animal industries. Notably, the aforemen- tioned WHO report treats the implications of our aggregate meat consumption as an issue for regulation, but not one for individual behavioural change. In contrast, my argument includes individual consumer choices amongst the options individuals have for addressing antimicrobial resistance.\n\nI will focus on two lines of argument for moral obligations to reduce one’s anti- microbial footprint: whether a failure to reduce it is unfair and whether it constitutes wrongdoing because it is harmful. I conclude by suggesting that the argument from collective harm is ultimately more successful.\n\n23.2", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-384-1", "doc_id": "drug_resistance_book", "page": 384, "text": "Antimicrobial Resistance as a Collective Moral Action Problem\n\nAntimicrobial resistance is a collective action problem in that it is the result of many different agents’ activities, it can only be solved by the concerted efforts of many different agents, and it seems rational for individual actors to free-ride because indi- vidual behavioural change (if taken in isolation) is neither responsible for the prob- lem’s occurrence nor could it ever remedy the problem.\n\nCrucially, too, antimicrobial resistance is the inevitable result of using antimicro- bials and thereby selecting microorganisms that are resistant to our drugs. Resistance will eventually emerge to any antimicrobial agent we use. This means that resis- tance as such is an effect that has to be factored into the ‘good’ that specific antimi- crobials provide. To put it differently, it is only a matter of time for any antimicrobial drug to lose its efficacy. To undermine the public good of antimicrobial efficacy is to reduce overall efficacy and to produce resistance at a faster-than-necessary rate. Some have warned that we might be in danger of losing this public good altogether one day – a worst-case scenario, which we are currently capable of preventing. In order to do that, we need to slow down the process of emerging resistance through a more limited and more considerate use of such drugs.", "n_tokens": 295, "kind": "text"}
{"chunk_id": "drug_resistance_book-384-2", "doc_id": "drug_resistance_book", "page": 384, "text": "But who is meant by ‘we’? Unsurprisingly, many call for global regulation or even the socialization of the use of antibiotics in order to delay the erosion of this good (Smith and Coast 2002; Anomaly 2010). And no doubt, regulators, policy- makers and industry leaders must be at the forefront of restricting the use of antimi- crobials in a way that secures their continued efficacy.", "n_tokens": 87, "kind": "text"}
{"chunk_id": "drug_resistance_book-385-0", "doc_id": "drug_resistance_book", "page": 385, "text": "23 Antimicrobial Footprints, Fairness, and Collective Harm\n\nBut what about ordinary people – individual agents who consume antibiotics either directly (as patients) or indirectly (as consumers of animal products) or who prescribe them (as medical doctors)? The ‘general community’ was identified by the WHO as a target of intervention (WHO 2001). The assumption behind that seems to be that individual members of the general community can jointly reduce resistance. If that is the case, does it follow that we ought to do something about reducing resistance?\n\nOne of the starting points for answering this question is to establish what causal relationship obtains between our use of antibiotics and emerging resistance. According to WHO authors, “the relationship between use and resistance is not a simple correlation” when it comes to antimicrobials. “Paradoxically, underuse through lack of access, inadequate dosing, poor adherence and sub-standard antimi- crobials may play as important a role as overuse” (WHO 2001: 15).", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-385-1", "doc_id": "drug_resistance_book", "page": 385, "text": "Further, it is not simply the case that those who are causally responsible for anti- microbial resistance are automatically morally responsible. That is, knowing how a problem came about, or which agent(s) caused it, does not necessarily tell us which agent(s) can be blamed for its occurrence or even who should fix it. Retrospective moral responsibility is often used synonymously with moral blameworthiness. The focus in this chapter will be on prospective – or forward-looking – moral responsi- bility in the sense of having a moral obligation to act or to bring about a certain outcome.\n\nClearly, any answer to the question of prospective moral obligations must be based on empirical data concerning which actions will really make a difference to antibiotic resistance. One of the great difficulties for making the case for moral obligations to change individuals’ behaviour lies in the fact that no individual (human) agent’s actions will make a measurable or perceptible difference to solving the problem. It is an issue on which only the aggregation and combination of count- less individual actions and enduring behavioural change will have a real impact.", "n_tokens": 227, "kind": "text"}
{"chunk_id": "drug_resistance_book-385-2", "doc_id": "drug_resistance_book", "page": 385, "text": "Both common-sense morality and traditional moral theory often struggle in deal- ing with collective moral action problems – cases where what is wrong or right cannot be determined by looking at individuals and their actions in isolation, but where instead these must be considered in conjunction or in aggregation. Increasingly, scholars are making an effort to rethink traditional ethical approaches with a view to better account for collective agents, actions and effects (May and Hoffman 1991; French and Wettstein 2006; French and Wettstein 2014; Hess et al. 2018). One of the early attempts to do so will be discussed further down: Derek Parfit proposed that we re-think our ‘moral mathematics’. According to Parfit, we need to revise our notions of wrong and right, harm and benefit regarding aggregate effects, where individual actions only make a significant difference in conjunction with countless actions of others (Parfit 1984). It is easy to see that such collective moral action problems abound: Apart from anti-microbial resistance, climate change, and overfishing are cases that come to mind.\n\nSo who should act on these problems? The most obvious response would be to point to states and state agents and the need for new policies and regulation. And there is no doubt that such agents are in principle best suited for dealing with such\n\n379", "n_tokens": 270, "kind": "text"}
{"chunk_id": "drug_resistance_book-386-0", "doc_id": "drug_resistance_book", "page": 386, "text": "380\n\nA. Schwenkenbecher\n\ncomplex large-scale problems. But there is a role for ‘ordinary citizens’ where gov- ernments fall short of doing what is required. Where climate change mitigation is concerned, for instance, the combined actions of individual agents can make a sig- nificant contribution to closing the so-called emissions gap, that is, the gap between the emission reductions countries have currently committed to and the reductions required for limiting global warming to a maximum of 2 °C (Dietz et al. 2009; Ostrom 2010; Wynes and Nicholas 2017).", "n_tokens": 125, "kind": "text"}
{"chunk_id": "drug_resistance_book-386-1", "doc_id": "drug_resistance_book", "page": 386, "text": "Whether or not anti-microbial resistance is a problem that can be fixed or improved through the aggregate effect of individual behavioural change by patients and doctors, consumers and producers is ultimately an empirical question. But, in line with the WHO Global Strategy for Containment of Antimicrobial Resistance, I will proceed on the assumption that collectively individual actors can make a sig- nificant difference. Can this ground an obligation for patients, doctors, consumers and producers to make a joint effort towards reducing the use of antibiotics? In the following, I will re-assess some of the philosophical arguments defending ascrip- tions of individual obligations in combating collective action problems. I will intro- duce the idea of an ‘antimicrobial footprint’ and discuss whether not contributing to the public good of antimicrobial efficacy is unfair and whether or not it constitutes harmful behaviour. I will conclude by suggesting that not reducing your antimicro- bial footprint (where it is possible for you to do so at an acceptable cost) is poten- tially wrong because it is harmful (even if your individual actions as such make no difference to antimicrobial resistance).\n\n23.3", "n_tokens": 243, "kind": "text"}
{"chunk_id": "drug_resistance_book-386-2", "doc_id": "drug_resistance_book", "page": 386, "text": "Antimicrobial Footprints\n\nLet me start by introducing a new concept: that of an antimicrobial footprint. An individual agent’s antimicrobial footprint would result from the extent to which her actions are causally linked to the use of antibiotics. The idea mirrors that of a carbon footprint, a measure which – however imperfect (Wright et al. 2011) – reflects the amount of greenhouse gases released into the atmosphere as a result of individuals’ actions. Importantly, it links global effects to individual behaviour and highlights that our choices can collectively make a real difference. It may be a helpful tool, then, to start talking about our antimicrobial footprint in a way we talk about our carbon footprint.\n\nWith regard to antibiotics, a person’s antimicrobial footprint would not necessar- ily be a measure of her contribution to resistance, but merely of her overall direct and indirect use. Direct use would involve using such drugs as a patient, prescriber or agricultural producer. Indirect use would involve the consumption of goods from animal industries that were produced by overusing antimicrobials. Our diet, then, plays a major role in accelerating resistance (Giubilini et al. 2017) (see also the chapter by Anomaly “Antibiotics and Animal Agriculture). It is important to note, though, that underuse of antibiotics also causally contributes to resistance, not just overuse.", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-387-0", "doc_id": "drug_resistance_book", "page": 387, "text": "23 Antimicrobial Footprints, Fairness, and Collective Harm\n\nTo reiterate, the anti-microbial footprint is – just like one’s carbon footprint – an imperfect measure. As mentioned above, the causal links between our use of antimi- crobials and resistance are not always straightforward. But the concept as such draws attention to an important fact – that every single one of us is causally and morally implicated in the problem of antimicrobial resistance.\n\nNote further that – just like with our carbon footprint – our antimicrobial foot- print will differ depending on our needs and circumstances. If we live in a climate which forces us to heat or cool our dwellings during major parts of the year in order to be healthy and safe then our carbon footprint will necessarily be greater than that of a person living in a milder climate. Likewise, if we suffer from health conditions that require the use of antibiotics we will necessarily have a greater antimicrobial footprint. Reducing our carbon footprint as well as reducing our antimicrobial foot- print must not involve unacceptable cost.", "n_tokens": 219, "kind": "text"}
{"chunk_id": "drug_resistance_book-387-1", "doc_id": "drug_resistance_book", "page": 387, "text": "But just like in the case of greenhouse gas emissions, there are many instances where we can reduce our antimicrobial footprint at an acceptable cost. First, research shows that patients often ask for such drugs (and are prescribed such drugs) when it would not have been necessary (WHO 2001, see also chapter by Oakley). If doctors can avoid prescribing such drugs and patients stop insisting on them where they are not needed this can make a significant difference for the better.\n\nAnother way to reduce one’s antimicrobial footprint at an acceptable cost (and with numerous co-benefits such as improved health) is to become vegetarian (or vegan) or at least to have a meat-reduced diet (or else to resort to game and fish caught in the wild). This is a factor that is missing from many public debates con- cerning antimicrobial resistance and also missing from the WHO report (2001) mentioned earlier.", "n_tokens": 193, "kind": "text"}
{"chunk_id": "drug_resistance_book-387-2", "doc_id": "drug_resistance_book", "page": 387, "text": "Let us assume for the sake of argument that a reasonable way of promoting the idea of antimicrobial footprint reductions can be found – one which does not unduly jeopardize individuals’ health and which promotes reductions that are truly effec- tive. Do we have moral obligations to reduce our antimicrobial footprint? Why would anyone have such an obligation? The question is a serious one: by them- selves, none of our individual antimicrobial footprint reductions would make a dif- ference to local, or regional, let alone global antimicrobial efficacy. I call this the impotence objection, or the no-effect-view. The issue is a familiar one: can we be morally obligated to make a contribution to resolving a collective action problem when our individual contributions make no discernible difference? The view that we cannot be obligated to perform an action if it makes no discernible positive differ- ence to a morally desirable outcome seems to be entailed by standard individualist act-consequentialism. The discussion of obligations to contribute to collective endeavours even where our individual actions make no perceptible difference is ongoing (Parfit 1984; Cullity 1995; Kagan 2011; Nefsky 2011; Schwenkenbecher 2014; Spiekermann 2014; Pinkert 2015).", "n_tokens": 286, "kind": "text"}
{"chunk_id": "drug_resistance_book-387-3", "doc_id": "drug_resistance_book", "page": 387, "text": "I will not rehearse all positions here, nor even the main ones, but instead focus on two solutions that appear particularly interesting and suitable to the kind of problem we are faced with and which move outside the standard act-consequentialist frame- work: the argument from unfairness and the argument from collective harm (for a\n\n381", "n_tokens": 69, "kind": "text"}
{"chunk_id": "drug_resistance_book-388-0", "doc_id": "drug_resistance_book", "page": 388, "text": "382\n\nA. Schwenkenbecher\n\ndifferent argument based on solidarity, see chapter by Holm and Ploug “Solidarity and Antimicrobial Resistance”). Most importantly, these solutions avoid the prob- lem of impotence or imperceptible effects by locating the wrongness of failing to contribute somewhere other than in the effects of one’s individual actions.\n\n23.4", "n_tokens": 83, "kind": "text"}
{"chunk_id": "drug_resistance_book-388-1", "doc_id": "drug_resistance_book", "page": 388, "text": "The Argument from Unfairness\n\nThe first of these arguments is about fairness: Under certain conditions, it is unfair not to contribute to schemes that we benefit from, regardless of the immediate effect of our free-riding, that is, regardless of whether or not we undermine the scheme or make people worse off by defecting. According to Garrett Cullity’s Principle of Fairness (Cullity 1995), if a person receives benefits from a scheme that satisfies the following conditions, it is unfair of her not to meet the requirements the scheme makes on those enjoying its benefits:\n\n(i) The practice of participation in the scheme represents a net benefit for her; (ii) Similarly, this practice does not make most others worse off either; (iii) She is not raising a legitimate moral objection to the scheme. (p. 18f,\n\nparaphrased)\n\nAccording to Cullity, the free-rider’s unfairness lies in giving herself objection- ably preferential treatment in such cases. The benefits she seeks to gain from free- riding “only exist because others who seek them take it upon themselves to contribute toward their production”. In other words, her choice to free-ride is moti- vated by the benefits that others provide, while she grants herself the privilege of enjoying those benefits without providing them (1995: 22–23).", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-388-2", "doc_id": "drug_resistance_book", "page": 388, "text": "In a later paper, Cullity specifies that unfair actions are failures of appropriate impartiality (Cullity 2008). Judgments about fairness and unfairness concern actions for which one particular way of being impartial is morally required (2008: 3). “Unfairness requires not just that the impartiality you fail to display would have been appropriate, but that it is the appropriate way of doing what ought to be done, as it ought to be done.” (2008: 5). Cullity gives the following general description of what is common to unfair actions: “Not Φ-ing is unfair when:\n\n(i) something ought, all things considered, to be done; (ii) doing it as it ought to be done requires a form of impartiality; (iii) Φ-ing is the appropriate form for that impartiality to take; and (iv) the failure of appropriate impartiality can contribute to a non-instrumental\n\nexplanation of the failure to do what ought to be done.” (ibid.)\n\nAccording to Cullity, then, what matters for assessing the wrongness of free- riding is not only whether there is an action that ought to be performed (or an out- come to be produced or a scheme to be implemented) but that there is a specific way in which this ought to be done, which requires people to apply some kind of impar- tial rule, rather than look to their own advantage. Doing “what ought to be done as", "n_tokens": 313, "kind": "text"}
{"chunk_id": "drug_resistance_book-389-0", "doc_id": "drug_resistance_book", "page": 389, "text": "23 Antimicrobial Footprints, Fairness, and Collective Harm\n\nit ought to be done” (ibid.) requires that individuals do not exempt themselves from contributing. That is, out of the two imperatives that bind agents in such cases – the imperative to produce the collective good and the imperative of distributive (or pro- cedural) justice – the free-rider violates the latter even where she cannot be said to clearly violate the former (because she does not jeopardize the collective outcome with her defection alone).\n\nHow does this relate to our specific problem of antimicrobial footprint reduc- tions? Let us assume that Cullity is correct in claiming that the above features char- acterise unfair actions. Is failing to reduce one’s antimicrobial footprint unfair? In order for that to be true, it would have to be the case that reducing or limiting anti- microbial resistance is something that all-things-considered ought to be done. Such a claim implies that it can be done at an acceptable overall cost. I think we can safely assume that both are the case.", "n_tokens": 234, "kind": "text"}
{"chunk_id": "drug_resistance_book-389-1", "doc_id": "drug_resistance_book", "page": 389, "text": "But what about doing it as it ought to be done? Is reducing our individual anti- microbial footprint the method by which we ought to combat anti-microbial resis- tance? Cullity rejects the idea that whenever a group ought to collectively act or produce a good, individual group members ought to be doing something to produce that good: “That would have odd implications for collective actions to which no one is contributing” (2008: 11). He thinks that it is not unfair if I do not unilaterally pursue a goal if there is no collectively agreed method for pursuing it (ibid.). Defecting (or exempting yourself from contributing to a collective good) is only unfair if there is such a method.\n\nAccording to Cullity, a collectively agreed method for addressing a collective action problem is in place where the required course of action was decided in a fair procedure. He makes two qualifications though: first, that sometimes decisions pro- duced by fair procedures can be bad and therefore need not to be respected. Second, that we may sometimes be obligated to respect the outcomes of procedures that though not perfectly fair are good enough. Unfortunately, Cullity does not specify what it means for a procedure to be good enough.", "n_tokens": 256, "kind": "text"}
{"chunk_id": "drug_resistance_book-389-2", "doc_id": "drug_resistance_book", "page": 389, "text": "It is not possible here to have a detailed discussion on fair (or good enough) pro- cedures for deciding on the production of collective goods. Regulation and legisla- tion – where they result from legitimate democratic procedures – should arguably count as such. What is crucial for Cullity’s procedural condition is the underlying rationale: that in order for a collective scheme to have legitimacy, in the sense that it gives individual agents binding reasons for playing their role therein, such a scheme must have been produced in the right way. If that is the case, then we as individual agents can be bound by rules (including laws) that are not of our own making and that we would in fact not have chosen ourselves. But these clarifications do not help with our current enquiry, since our focus is precisely on actions that are not called for by regulation and legislation, but on voluntary individual behavioural change that might be necessary while regulation and legislation fall short of reining in the problem.\n\nThis is the point where the fairness argument in favour of reducing our antimi- crobial footprint crumbles, I believe. It is quite unclear what kind of method or procedure would count as fair where aggregate individual behavioural changes to reduce our use of antimicrobials are concerned. Would it be enough for such changes\n\n383", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-390-0", "doc_id": "drug_resistance_book", "page": 390, "text": "384\n\nA. Schwenkenbecher\n\nto have been recommended by an authoritative, politically neutral global body such as the WHO or other expert panels? According to WHO, its Global Strategy for Containment of Antimicrobial Resistance report is the result of expert consultation, workshops and consensus meetings. It is doubtful that this is the kind of procedure Cullity had in mind. Moreover, even though the panel has made recommendations for individual behaviour change, it has not in fact proposed an outright ‘scheme’ for individual participation with clearly defined roles and contributory actions. For both of these reasons, it does not constitute the kind of collective agreement that gives potentially binding reasons to individual agents. In sum, the argument put forward by Cullity cannot support the idea that individuals ought to take on a share in reduc- ing antimicrobial resistance as a matter of fairness.\n\nA different and more promising approach might be built on an argument that antibiotic overuse or misuse is a way of wronging others in that it harms those who suffer its consequences. This argument relies on a notion of ‘collective’ harm – a relatively new concept that is increasingly gaining traction.\n\n23.5", "n_tokens": 239, "kind": "text"}
{"chunk_id": "drug_resistance_book-390-1", "doc_id": "drug_resistance_book", "page": 390, "text": "The Collective Harm Argument\n\nAccording to Elizabeth Cripps (2011), individual agents can be collectively respon- sible for harm brought about by their aggregate individual actions in some cases:\n\na person becomes one of a group collectively responsible for harm once her contribution exceeds the amount such that, were everyone contributing only to that level, there would be no harm (p. 181)\n\nIn order for a person to be thus responsible for harm, certain conditions have\n\nto be met:\n\n1. “individuals acted in ways which, in aggregate, caused harm, and which they were aware (or could reasonably be expected to have foreseen) would, in aggre- gate, cause harm (although each only intentionally performed his own act); 2. they were all aware (or could reasonably expected to have foreseen) that there were enough others similarly placed (and so similarly motivated to act) for the combined actions to bring about the harm; and\n\n3. the harm was collectively avoidable: by acting otherwise (which they could rea- sonably have done), the individuals making up the putative group could between them have avoided the harm.” (pp. 174f)\n\nThe crucial point to be noted is that in order to be weakly collective responsible (as Cripps puts it) for harm, individuals need to know (or be in a position to foresee) two things: (i) that if enough other people did what they do it will cause harm, and (ii) that there are enough other people doing what they do.", "n_tokens": 313, "kind": "text"}
{"chunk_id": "drug_resistance_book-390-2", "doc_id": "drug_resistance_book", "page": 390, "text": "Whether or not a large enough number of people are in this position vis-à-vis antimicrobial resistance is an empirical question. However, I suspect that these epis- temic conditions are not met when it comes to our antimicrobial footprint. The problem of antimicrobial resistance has much less presence in the media and public", "n_tokens": 71, "kind": "text"}
{"chunk_id": "drug_resistance_book-391-0", "doc_id": "drug_resistance_book", "page": 391, "text": "23 Antimicrobial Footprints, Fairness, and Collective Harm\n\ndiscourse than the problem of climate change and carbon footprint reductions, for instance.\n\nCripps’ criteria are clearly modelled on Derek Parfit’s (1984) conditions for col- lectively doing wrong or harming others. He, too, relies on an epistemic condition that is – currently – unlikely to be met where antimicrobial resistance is concerned:\n\n(C12) When (1) the outcome would be worse if people suffered more, and (2) each of the members of some group could act in a certain way, and (3) they would cause other people to suffer if enough of them act in this way, and (4) they would cause these people to suffer most if they all act in this way, and (5) each of them both knows these facts and believes that enough of them will act in this way, then (6) each of them would be acting wrongly if he acted in this way. (p. 81, my emphasis in bold)", "n_tokens": 215, "kind": "text"}
{"chunk_id": "drug_resistance_book-391-1", "doc_id": "drug_resistance_book", "page": 391, "text": "According to both Cripps and Parfit, then, we only act wrongly if we know about the effects of our own antimicrobial overuse or misuse and we are aware that enough others are engaged in this practice. Consequently, public awareness campaigns would make it the case that Cripps’ and Parfit’s conditions are met. Public knowl- edge – which obtains where most people know some proposition to be true and most people know that most people know – would turn harmless actions into harm. But still, on their accounts there is – currently – no harm or wrongdoing committed by many if not most of those who contribute to antimicrobial resistance. Also, for Cripps, weakly collective responsibility does not imply that any individual has direct duties to avert the (aggregate) harm. Instead such duties fall to the group, first and foremost. That is, even if we were collectively responsible for antimicrobial resistance we would not be required to individually reduce our antimicrobial foot- print on her account.", "n_tokens": 216, "kind": "text"}
{"chunk_id": "drug_resistance_book-391-2", "doc_id": "drug_resistance_book", "page": 391, "text": "Let me now turn to Judith Lichtenberg, who combines the unfairness argument and the argument from aggregate harm (2010): If we knowingly contribute to harms that “depend on the joint effects of many people’s actions” (p. 568) we accept that if a sufficient number of other persons act in the same way, these harms will occur. She thinks that to do so is wrong because it means to act unfairly: “In the case of aggregate harms, doing the right thing involves an appeal to the unfairness of acting inconsistently with how one thinks others ought to act.” (2010: 569). As I under- stand Lichtenberg, contributing to aggregate harms is not intrinsically wrong, but is wrong because it cannot be justified in rule-consequentialist terms or by way of universalizing. Similar to Cullity, she argues that the wrongness lies in exempting oneself from a rule that one should accept as morally optimal.", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-391-3", "doc_id": "drug_resistance_book", "page": 391, "text": "Note that Lichtenberg’s account is more demanding than Cripps’ and Parfit’s because it does not have as strong a knowledge condition. For the wrongness of contributing it does not matter whether or not an individual agent knows that enough others will perform the same action and harm will be thus caused in aggregation. It suffices for the individual to know that collectively we should adopt a rule prohibit- ing such actions. This is a more demanding account because it seems to require us (pro tanto, at least) to individually refrain from doing what is collectively subopti- mal. As I understand it, Lichtenberg’s rule, if applied to antimicrobial footprint reductions, would imply that avoidable antimicrobial overuse and misuse are instances of harming, from which we (pro tanto) ought to abstain.\n\n385", "n_tokens": 179, "kind": "text"}
{"chunk_id": "drug_resistance_book-392-0", "doc_id": "drug_resistance_book", "page": 392, "text": "386\n\nA. Schwenkenbecher\n\nIn response, one might argue that to demand – as Lichtenberg appears to do – that we individually do our part in a pattern that is collectively optimal is too strong a requirement. After all, sometimes it may be right to do what is collectively subop- timal if no one else does what is collectively optimal and our individual ‘sacrifice’ would be pointless. However, note that if Lichtenberg’s proposal is safe from this objection as long as it is understood as generating pro tanto obligations to avoid contributing to collective harm, that is, obligations that can be overridden by other, more important obligations. If the collective defection rate is too high, my pro tanto obligations may simply fail to become all-out obligations. That is, if not enough others contribute, I may not have an all-things-considered obligation to avoid col- lective harm.\n\n23.6", "n_tokens": 192, "kind": "text"}
{"chunk_id": "drug_resistance_book-392-1", "doc_id": "drug_resistance_book", "page": 392, "text": "Conclusion\n\nIn this chapter I discussed arguments in favour of a moral obligation to reduce one’s individual antimicrobial footprint. Despite the intuitive appeal of this idea, there exists no simple, straightforward defence of an obligation to change our individual behaviour. High levels of collective awareness and a genuine collective willingness to address the problem of anti-microbial resistance appear to be important precondi- tions for motivating (all-out) obligations for individuals to reduce their antimicro- bial footprint. It is one of the most frustrating aspects of collective action problems that it is precisely the publicly known lack of commitment to resolving them which seems to sustain and justify a (further) lack of commitment for all those who could potentially resolve it.\n\nAcknowledgements The author gratefully acknowledges the financial support received from the Oxford Martin School for this project as a Visiting Fellow to the program “Collective Responsibility for Infectious Diseases” (April – July 2017) as well as the extremely valuable feedback from col- leagues in the Oxford Martin School and the Uehiro Centre for Practical Ethics.\n\nReferences\n\nAnomaly, J. 2010. Combating resistance: The case for a global antibiotics treaty. Public Health\n\nEthics 3 (1): 13–22.\n\nCripps, E. 2011. Climate change, collective harm and legitimate coercion. Critical Review of", "n_tokens": 267, "kind": "text"}
{"chunk_id": "drug_resistance_book-392-2", "doc_id": "drug_resistance_book", "page": 392, "text": "International Social and Political Philosophy 14 (2): 171–193.\n\nCullity, G. 1995. Moral free riding. Philosophy and Public Affairs 24 (1): 3–34. ———. 2008. Public goods and fairness. Australasian Journal of Philosophy 86 (1): 1–21. Dietz, T., G.T. Gardner, J. Gilligan, P.C. Stern, and M.P. Vandenbergh. 2009. Household actions can provide a behavioral wedge to rapidly reduce US carbon emissions. Proceedings of the National Academy of Sciences 106 (44): 18452–18456.\n\nFrench, P.A., and H.K. Wettstein, eds. (2006). Special Issue: Shared intentions and collective\n\nresponsibility, Midwest Studies in Philosophy 30.", "n_tokens": 169, "kind": "text"}
{"chunk_id": "drug_resistance_book-393-0", "doc_id": "drug_resistance_book", "page": 393, "text": "23 Antimicrobial Footprints, Fairness, and Collective Harm\n\n———, eds. (2014). Special issue: Forward-looking collective responsibility, Midwest Studies in\n\nPhilosophy 38.\n\nGiubilini, A., P. Birkl, T. Douglas, J. Savulescu, and H. Maslen. 2017. Taxing meat: Taking responsibility for one’s contribution to antibiotic resistance. Journal of Agricultural and Environmental Ethics 30 (2): 179–198.\n\nHess, K.E., V.E. Igneski, and T.L.E. Isaacs. 2018. Collectivity: Ontology, ethics, and social justice.\n\nLondon: Rowman & Littlefield International.\n\nKagan, S. 2011. Do I make a difference? Philosophy & Public Affairs 39 (2): 105–141. Lichtenberg, J. 2010. Oughts and cans. Philosophical Topics 38 (1): 123–142. Littmann, J., and A.M. Viens. 2015. The ethical significance of antimicrobial resistance. Public\n\nHealth Ethics 8 (3): 209–224.\n\nMay, L., and S. Hoffman. 1991. Collective responsibility: Five decades of debate in theoretical\n\nand applied ethics. Rowman & Littlefield: Savage.\n\nNefsky, J. 2011. Consequentialism and the problem of collective harm: A reply to Kagan.\n\nPhilosophy & Public Affairs 39 (4): 364–395.\n\nOstrom, E. 2010. Polycentric systems for coping with collective action and global environmental\n\nchange. Global Environmental Change 20 (4): 550–557.\n\nParfit, D. 1984. Five mistakes in moral mathematics. Reasons and persons. Vol. 1, 55–83. Oxford:", "n_tokens": 372, "kind": "text"}
{"chunk_id": "drug_resistance_book-393-1", "doc_id": "drug_resistance_book", "page": 393, "text": "Clarendon Press.\n\nPinkert, F. 2015. What if I cannot make a difference (and know it). Ethics 125 (4): 971–998. Schwenkenbecher, A. 2014. Is there an obligation to reduce one’s individual carbon footprint?\n\nCritical Review of International Social and Political Philosophy 17 (2): 168–188.\n\nSmith, R.D., and J. Coast. 2002. Antimicrobial resistance: a global response. Bulletin of the World\n\nHealth Organization 80: 126–133.\n\nSpiekermann, K. 2014. Small impacts and imperceptible effects: Causing harm with others.\n\nMidwest Studies In Philosophy 38 (1): 75–90.\n\nWorld Health Organisation. (2001). WHO global strategy for containment of antimicrobial", "n_tokens": 168, "kind": "text"}
{"chunk_id": "drug_resistance_book-393-2", "doc_id": "drug_resistance_book", "page": 393, "text": "resistance.\n\nWright, L.A., S. Kemp, and I. Williams. 2011. ‘Carbon footprinting’: Towards a universally\n\naccepted definition. Carbon Management 2 (1): 61–72.\n\nWynes, S., and K.A. Nicholas. 2017. The climate mitigation gap: Education and government rec- ommendations miss the most effective individual actions. Environmental Research Letters 12 (7): 074024.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n387", "n_tokens": 261, "kind": "text"}
{"chunk_id": "drug_resistance_book-394-0", "doc_id": "drug_resistance_book", "page": 394, "text": "Chapter 24 Global Health Governance and Antimicrobial Resistance\n\nBelinda Bennett and Jon Iredell\n\nAbstract This chapter analyses the challenges and the adequacy of existing frame- works to provide a strong foundation to support global responses to antimicrobial resistance. Calls for global responses are indicative of a growing global commit- ment to seeking practical means of tackling the growing problem of antimicrobial resistance. While antimicrobial resistance is often conceptualised as an emergency, the application of the International Health Regulations, designed to govern responses to public health emergencies of international concern, remains unclear. Furthermore, there may be challenges for countries in developing and resourcing national approaches to address antimicrobial resistance. Clarity and agreement around defi- nitions of key concepts related to antimicrobial resistance will also be essential to antibiotic stewardship and development of policy in this area. Finally, improve- ments to health systems as a result of the Sustainable Development Goals may help to support improvements in public health and may play a role in global strategies to address antimicrobial resistance.\n\nKeywords Antimicrobial resistance · International Health Regulations · Sustainable Development Goals\n\n24.1", "n_tokens": 238, "kind": "text"}
{"chunk_id": "drug_resistance_book-394-1", "doc_id": "drug_resistance_book", "page": 394, "text": "Introduction\n\nAntimicrobial resistance (AMR) has been described as ‘a global health crisis,’ (Review on Antimicrobial Resistance 2015) ‘a slowly emerging disaster’ (Viens and Littman 2015), and ‘a complex global public health challenge’ (World Health\n\nB. Bennett (*) School of Law, Queensland University of Technology, Brisbane, Queensland, Australia e-mail: belinda.bennett@qut.edu.au\n\nJ. Iredell Department of Infectious Diseases, Westmead Hospital and University of Sydney, Sydney, NSW, Australia\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_24\n\n389", "n_tokens": 188, "kind": "text"}
{"chunk_id": "drug_resistance_book-395-0", "doc_id": "drug_resistance_book", "page": 395, "text": "390\n\nB. Bennett and J. Iredell", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-395-1", "doc_id": "drug_resistance_book", "page": 395, "text": "Organization 2014: xix). With AMR raising the possibility that we could soon be living in a ‘post-antibiotic era’ (World Health Organization 2014: ix) and with rec- ognition that AMR ‘threatens the sustainability of the public health response to many communicable diseases, including tuberculosis, malaria and HIV/AIDS’ (World Health Assembly 2014), there is increased international dialogue around the need to find practical global solutions for the looming crisis (Laxminarayan et al. 2013). Others have argued for the need for AMR strategies to address equitable access to medicines; conservation through stewardship and appropriate use of anti- microbials; and innovation to ensure the development of the new antimicrobials, as well as the importance of a binding legal framework addressing these issues (Hoffman, Outterson, Røttingen et al. 2015; Hoffman, Røttingen and Frenk 2015). Proposals have included a new international treaty (Hoffman, Outterson, Røttingen et al. 2015; Anomaly 2010), the establishment of an intergovernmental panel (Woolhouse and Farrar 2014), a range of policy options to support action on AMR (Hoffman, Caleo, Daulaire et al. 2015), and the use of the International Health Regulations as an existing framework for managing global health risks (Wernli et al. 2011). Such is the complexity of the challenge posed by AMR that national and regional approaches alone are unlikely to be effective solutions (Littman et al. 2020). Yet the complex nature of AMR presents", "n_tokens": 334, "kind": "text"}
{"chunk_id": "drug_resistance_book-395-2", "doc_id": "drug_resistance_book", "page": 395, "text": "considerable challenges for global health governance, and with recent global health crises revealing shortcomings in global health governance, there are clearly significant challenges associated with utilising existing frameworks to address the growing problem of AMR. This chapter analyses these challenges and the adequacy of existing frameworks to provide a strong foundation to support global action on AMR.", "n_tokens": 72, "kind": "text"}
{"chunk_id": "drug_resistance_book-395-3", "doc_id": "drug_resistance_book", "page": 395, "text": "24.2\n\nThe Rise of Drug Resistance\n\nSevere infection long ago overtook heart attacks in terms of likelihood of hospital admission in developed countries (Seymour et al. 2012). The ability to manage it is essential for intensive care, major surgery and transplantation services that are increasingly routine. Up to 20 million people each year are treated with mechanical ventilation in intensive care (Adhikari et al. 2010). Infection complicates about half of ICU admissions and is an important cause of death in the critically ill (Vincent et al. 2009).\n\nAntibiotics are a cornerstone of treatment of severe infection, with the risk of death increasing in the presence of antibiotic resistance (Review on Antimicrobial Resistance 2016a). In response to the steady rise in antibiotic resistance that began soon after the first introduction of antibiotics and has been quickly accelerating (Davies et al. 2013; Laxminarayan et al. 2013; Review on Antimicrobial Resistance 2016a: 10), experts call for international co-ordination of public policy solutions that include (i) better antibiotic controls in industry, agriculture and medicine (anti- microbial stewardship), and (ii) better surveillance and containment (infection con- trol) (Howard et al. 2013; Laxminarayan et al. 2013; Piddock 2012; Spellberg et al. 2008).", "n_tokens": 277, "kind": "text"}
{"chunk_id": "drug_resistance_book-396-0", "doc_id": "drug_resistance_book", "page": 396, "text": "24 Global Health Governance and Antimicrobial Resistance\n\n24.3", "n_tokens": 13, "kind": "text"}
{"chunk_id": "drug_resistance_book-396-1", "doc_id": "drug_resistance_book", "page": 396, "text": "A Global Approach to AMR?\n\nWith the recognition of the problems posed by growing AMR have come calls for a global approach to limiting the spread of AMR and its associated risks. In 2015 the World Health Assembly adopted a global action plan on antimicrobial resistance (World Health Organization 2015a; Ho and Lee 2020) and called on Member States to develop national actions plans on AMR and to ‘mobilize human and financial resources through domestic, bilateral and multilateral channels in order to imple- ment plans and strategies in line with the global action plan’ (World Health Assembly 2015). The global action plan included five strategic objectives:\n\n(1) to improve awareness and understanding of antimicrobial resistance; (2) to strengthen knowledge through surveillance and research; (3) to reduce the incidence of infection; (4) to optimize the use of antimicrobial agents; and (5) to ensure sustainable investment in countering antimicrobial resistance (World Health Organization 2015a: 1)\n\nThe World Health Assembly resolution was followed in 2016 by a declaration by the high-level meeting of the United Nations General Assembly on antimicrobial resistance. The declaration of the high-level meeting included committing to work nationally, regionally and globally to address AMR, and to mobilize funding and resources to support the development and implementation of national plans (United Nations General Assembly 2016).", "n_tokens": 288, "kind": "text"}
{"chunk_id": "drug_resistance_book-396-2", "doc_id": "drug_resistance_book", "page": 396, "text": "These calls for global action on antimicrobial resistance indicate a growing global commitment to seeking practical means of tackling the growing problem of antimicrobial resistance. As Wernli et al. have pointed out, this growing focus on AMR ‘also indicates that AMR has transformed into a global governance priority, which requires international co-operation’ (Wernli et al. 2017: 1). The policy dis- courses around AMR are also complex however, with Wernli et al. identifying five key policy frames that are evident in the debates around AMR, with each of these frames providing insights into AMR and the interdependencies between these pol- icy frames: (i) ‘AMR as a healthcare issue’; (ii) ‘AMR as a development issue,’ reflecting the burden of infectious diseases in low- and middle-income countries; (iii) the relationship between AMR and innovation, which recognises the impor- tance of research and development for new antibiotics; (iv) AMR as a global health security issue; and (v) AMR and the role of a One-Health approach to addressing AMR (Wernli et al. 2017).", "n_tokens": 251, "kind": "text"}
{"chunk_id": "drug_resistance_book-396-3", "doc_id": "drug_resistance_book", "page": 396, "text": "International cooperation will clearly play a key role in responding to AMR (Årdal et al. 2016). However, recent global health crises have revealed difficulties in ensuring effective responses to emerging public health crises, leaving the role of global health governance in leading responses to AMR unclear. The remainder of this chapter identifies four key areas that will present challenges for a global response to AMR: (i) the challenge of fitting responses to AMR within other global health governance frameworks that support urgent responses to health crises; (ii) the challenge of developing national and regional capacities to identify and respond to AMR; (iii) the challenge of developing common understandings and definitions of AMR; and finally (iv) the challenge of fitting AMR within the global priorities iden- tified by the Sustainable Development Goals.\n\n391", "n_tokens": 166, "kind": "text"}
{"chunk_id": "drug_resistance_book-397-0", "doc_id": "drug_resistance_book", "page": 397, "text": "392\n\nB. Bennett and J. Iredell\n\n24.4\n\nThe International Health Regulations, Global Health Governance and AMR\n\nAdopted to manage the international spread of infectious diseases, the International Health Regulations (2005) (IHR) (World Health Organization 2016a) could possi- bly provide a framework for improved surveillance and reporting of AMR. However, there has been debate over whether the scope of the IHR could include evolving events such as AMR or whether the IHR are more properly focused on emergency situations (Wernli et al. 2011; Kamradt-Scott 2011). It has been argued that AMR may, at least in some instances, fulfil two of the four IHR criteria for a ‘public health emergency of international concern’ (PHEIC) i.e. those relating to the seriousness of the public health impact of an event, and the potential for international spread of disease (Wernli et al. 2011: 3), with the remaining two IHR criteria being that the event is ‘unusual or unexpected,’ and that there is ‘a significant risk of international travel or trade restrictions’ (World Health Organization 2016a: Annex 2). It is cer- tainly the case that the IHR provide a strong normative scaffold for the shared expectations about how both states and the international community should respond to the international spread of disease (Davies et al. 2015), as well as clear processes for reporting progress.", "n_tokens": 303, "kind": "text"}
{"chunk_id": "drug_resistance_book-397-1", "doc_id": "drug_resistance_book", "page": 397, "text": "While patterns of AMR vary between countries (Review on Antimicrobial Resistance 2014), AMR certainly poses major risks to public health globally (World Health Organization 2015a). The focus of the IHR on managing global risks to public health, and the inclusion of consideration of whether there is ‘a significant risk of international spread’ as one of the criteria for determining whether events that may constitute a PHEIC should be notified to WHO (World Health Organization 2016a: Annex 2), provide a global perspective to the risks posed by spread of AMR. As it is now more than a decade since the revised IHR took effect in 2007, the IHR provide a familiar and well-established framework for the global community and, it has been argued that it may be possible to build on existing frameworks rather than building new ones (Wernli et al. 2011: 5). Yet these factors do not neces- sarily make the IHR an ideal mechanism for addressing AMR (Kamradt-Scott 2011), even though, with the global initiatives referred to above, global health gov- ernance seems set to play a key role in addressing AMR.", "n_tokens": 241, "kind": "text"}
{"chunk_id": "drug_resistance_book-397-2", "doc_id": "drug_resistance_book", "page": 397, "text": "Despite the promise that initially heralded the adoption of the revised IHR in 2005 (Fidler and Gostin 2006), recent global health crises have revealed significant shortcomings in contemporary global health governance including, inadequate capacity building of national health systems, a failure by countries to comply with the IHR 2005 through the imposition of trade and travel restrictions contrary to WHO recommendations, and a lack of funding to support an effective global response to global public health emergencies (Gostin et al. 2015, 2016; Moon et al.", "n_tokens": 107, "kind": "text"}
{"chunk_id": "drug_resistance_book-398-0", "doc_id": "drug_resistance_book", "page": 398, "text": "24 Global Health Governance and Antimicrobial Resistance\n\n2015; Ottersen et al. 2016). Furthermore, the suitability of the IHR as a mechanism for addressing AMR remains unclear, with the primary focus of the IHR being on the global capacity to deal with global public health emergencies (Kamradt-Scott 2011). With the IHR’s focus being on acute emergencies, rather than issues requir- ing sustained response over a prolonged period, their utility as a framework for coordinating global responses to AMR appears less certain (Wernli et al. 2017: 5; Kamradt-Scott 2011).\n\nWhile a new treaty may provide a clear mechanism for addressing the challenges posed by AMR (Anomaly 2010; Hoffman, Outterson, Røttingen et al. 2015), as has been noted, ‘Reaching such an ambitious legal agreement will take leadership, skill, and perseverance from a wide range of actors’ (Rochford et al. 2018: 1977). A treaty would also need to balance stewardship of antibiotics and innovation with recogni- tion of lack of access to antibiotics for many people, particularly in low and middle income countries (Padiyara et al. 2018: 3). Furthermore, as discussed below, the issue of capacity building remains an enduring challenge, particularly in low resource countries.\n\n24.5", "n_tokens": 281, "kind": "text"}
{"chunk_id": "drug_resistance_book-398-1", "doc_id": "drug_resistance_book", "page": 398, "text": "Building Capacity\n\nA further difficulty associated with using the IHR as a mechanism for addressing AMR is in the challenges faced by many countries to meet their IHR core capacity requirements (Davies et al. 2015: 126-132; World Health Organization 2015b). The IHR require Member States to develop core capacities within their national health systems to ‘detect, assess, notify and report events’ that are within the scope of the IHR (Article 5). These national capacities required by the IHR will provide an important step in building surveillance capacities for AMR (Wernli et al. 2011). Countries were required to achieve the core capacity requirements of the IHR by 2012 i.e. within 5 years of the IHR coming into force, with some extensions possi- ble, but many countries still had not achieved their core capacity requirements (World Health Organization 2016b). Although global collaboration (Goff et al. 2017) and regional networks may provide an additional mechanism for capacity building, particularly in developing regions (Bennett and Carney 2017), the chal- lenge of building strong public health systems remains a key one for global health (Gostin et al. 2016; Moon et al. 2015).", "n_tokens": 251, "kind": "text"}
{"chunk_id": "drug_resistance_book-398-2", "doc_id": "drug_resistance_book", "page": 398, "text": "In addition, although the World Health Assembly has urged its Member States to develop national action plans for antimicrobial resistance (World Health Assembly 2015), the results of 2013–2014 WHO survey showing that few countries reported having comprehensive national AMR plans (World Health Organization 2015c: 1), suggests that there may be considerable work to be done in many countries. More recently, a self-assessment survey of countries and their progress in\n\n393", "n_tokens": 90, "kind": "text"}
{"chunk_id": "drug_resistance_book-399-0", "doc_id": "drug_resistance_book", "page": 399, "text": "394\n\nB. Bennett and J. Iredell\n\ndeveloping and implementing national AMR plans also shows that considerable work remains, with only 60% of countries having a national multisectoral action plan on AMR, although a further 33% had plans in development (World Health Organization et al. 2018: 7). In addition, although 125 countries reported having awareness raising activities about AMR risks and human health, only 36 had cam- paigns in animal health (World Health Organization et al. 2018: 12). While 103 countries reported having a national surveillance system in humans, only 41 coun- ties had systematic data collection in animals, and most countries have no surveil- lance system in place in the plant and environment sectors (World Health Organization et al. 2018: 15).", "n_tokens": 163, "kind": "text"}
{"chunk_id": "drug_resistance_book-399-1", "doc_id": "drug_resistance_book", "page": 399, "text": "One key difficulty is that although the IHR require countries to develop their national capacities to deal with potential global public health emergencies that arise within their borders, poorer countries may have difficulty in finding the resources to support such capacity building (Gostin and Katz 2016: 276-277; Davies et al. 2015: 126-132), leaving many countries unable to achieve the capacities required by the IHR. There is renewed interest in developing sustainable mechanisms for global health financing, including financing of global public goods such as addressing anti- microbial resistance (Ottersen et al. 2017; Mendelson et al. 2016; Moon et al. 2017). Clearly there is a need for investment to address shared vulnerabilities in global health (Gostin 2017). Global commitments and the development of effective financ- ing mechanisms will be key to the development of effective responses to AMR. Without them we may see a repeat of the difficulties in building IHR core capacities, with poorer countries lacking the resources to develop their national capacities.\n\n24.6", "n_tokens": 213, "kind": "text"}
{"chunk_id": "drug_resistance_book-399-2", "doc_id": "drug_resistance_book", "page": 399, "text": "Understandings and Definitions\n\nUnderstandings of the mechanisms of development of AMR as well as definitions of key terms relating to infection and antimicrobial use are critical to effective pol- icy response for AMR. Even the term ‘antimicrobial resistance’ may be poorly understood (Mendelson et al. 2017). The two pillars of the health policy response to antimicrobial resistance relate to control of its spread (‘infection control’) and to reduction of inappropriate antibiotic use that promotes it (antimicrobial steward- ship) (Davies et al. 2013; Laxminarayan et al. 2013).\n\nMeasures of success and failure of public health policy are heavily contingent on definitions. The definition of ‘inappropriate prescribing’ remains poorly informed by research into antibiotic effects and is therefore regarded as a public policy research priority in the area of antibiotic resistance (Spellberg et al. 2011). Similarly, the definition of ‘severe infection’ or ‘sepsis’ is subject to major revision (Fullerton et al. 2017) and new definitions may alter the cohort included in this definition, especially at initial point of care where health policy must drive effective immediate responses (Fullerton et al. 2017).", "n_tokens": 252, "kind": "text"}
{"chunk_id": "drug_resistance_book-400-0", "doc_id": "drug_resistance_book", "page": 400, "text": "24 Global Health Governance and Antimicrobial Resistance\n\nThese definitional questions are of key importance to policy initiatives such as antibiotic stewardship. AMR is an example of the tragedy of the commons in which overconsumption of a common resource harms the common good (Hollis and Maybarduk 2015; Giubilini and Savulescu 2020). For this reason, stewardship and the preservation of key antimicrobials is an important strategy in addressing AMR (Laxminarayan et al. 2013). Yet the development of policy responses for AMR is a particular challenge as there is a need to limit inappropriate use of antibiotics, (which assumes well-developed understandings of ‘inappropriate prescribing’), while simultaneously ensuring equitable access to medicines (Laxminarayan et al. 2013, 2016; Padiyara et al. 2018; Selgelid 2007). An antibiotic that is harmful to the public health in terms of driving resistance in the longer term may be thought to have specific benefit to the individual for whom it is prescribed. This may lead to direct conflict between public health policy needs and the needs of an individual and means in turn that antimicrobial stewardship may be cast in a policing role.", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-400-1", "doc_id": "drug_resistance_book", "page": 400, "text": "These challenges may be described as ones of ‘understandings’ and of ‘defini- tions.’ To address these challenges additional funding is required to support research on the mechanisms for acquiring resistance to further our understandings of this important area. Agreed international standards for data collection on AMR (World Health Organization 2014) are also vital if surveillance is to be comprehensive and effective, making definitional issues ones of critical importance.\n\n24.7\n\nAMR and the Sustainable Development Goals (SDGs)", "n_tokens": 99, "kind": "text"}
{"chunk_id": "drug_resistance_book-400-2", "doc_id": "drug_resistance_book", "page": 400, "text": "When the Sustainable Development Goals (SDGs) (United Nations 2015) were adopted by the United Nations General Assembly in September 2015, AMR was not listed amongst the 17 goals, although it is mentioned in the SDG declaration (World Health Organization 2015d: 103). Nor was there the inclusion of a broader SDG goal on global health security, which might have also provided a focus for action on AMR (Kickbusch et al. 2015). However, this is not to suggest that the SDGs will be irrel- evant for global responses to AMR. For example, addressing antimicrobial resistance will clearly be important to achieving SDG3 (‘Ensure healthy lives and promote well-being for all at all ages’), while the goal of universal health coverage in SDG3.8 will help to ensure the existence of strong health systems (Gostin 2017: 194). International trade of animals or products, the complexity of addressing both over- consumption and lack of access to medicines, and the relevance of trade agreements and intellectual property arrangements to research and development for new antimi- crobials, all highlight the importance of considering the relevance of trade to the development of solutions to antimicrobial resistance (Hanefeld et al. 2017). Access to water and sanitation were also included as SDG6 (United Nations 2015). As the UK’s Review on Antimicrobial Resistance has noted, improved water and sanitation can help to reduce antibiotic consumption by helping to prevent infections that may then be treated", "n_tokens": 316, "kind": "text"}
{"chunk_id": "drug_resistance_book-400-3", "doc_id": "drug_resistance_book", "page": 400, "text": "with antibiotics (Review on Antimicrobial Resistance 2016a: 21-23;", "n_tokens": 17, "kind": "text"}
{"chunk_id": "drug_resistance_book-400-4", "doc_id": "drug_resistance_book", "page": 400, "text": "395", "n_tokens": 1, "kind": "text"}
{"chunk_id": "drug_resistance_book-401-0", "doc_id": "drug_resistance_book", "page": 401, "text": "396\n\nB. Bennett and J. Iredell\n\n2016b). The association between poor sanitation, infections and antibiotic use shows that broader public health goals and improvements can play an important role in global strategies to prevent AMR (Review on Antimicrobial Resistance 2016a; 2016b).\n\n24.8\n\nConclusion\n\nDeveloping effective mechanisms to address the growing threat of AMR will be essential to safeguarding public health into the future. To achieve this will require, amongst other things, strong mechanisms for global health governance to support coordinated programs and building of capacity at the national, regional and global levels. The commitments to the development of national plans for AMR along with suggestions for new financing mechanisms to support capacity building and the funding of global public goods reflect a promising prioritisation of AMR. Whether we can develop practical and effective means of addressing AMR remains to be seen.\n\nAcknowledgements Belinda Bennett gratefully acknowledges helpful discussions with Sara E Davies in the development of this chapter and Elizabeth Dallaston for her research assistance.", "n_tokens": 205, "kind": "text"}
{"chunk_id": "drug_resistance_book-401-1", "doc_id": "drug_resistance_book", "page": 401, "text": "References\n\nAdhikari, N.K.J., R.A. Fowler, S. Bhagwanjee, and G.D. Rubenfeld. 2010. Critical care and the\n\nglobal burden of critical illness in adults. The Lancet 375: 1339–1346.\n\nAnomaly, J. 2010. Combating resistance: The case for a global antibiotics treaty. Public Health\n\nEthics 3 (1): 13–22.\n\nÅrdal, C., K. Outterson, S.J. Hoffman, A. Ghafur, M. Sharland, N. Ranganathan, et al. 2016. International cooperation to improve access to and sustain effectiveness of antimicrobials. Lancet 387: 296–307.\n\nBennett, B., and T. Carney. 2017. Public health emergencies of international concern: Global,\n\nregional and local responses to risk. Medical Law Review 25 (2): 223–239.\n\nDavies, S.C., T. Fowler, J. Watson, D.M. Livermore, and D. Walker. 2013. Annual report of the Chief Medical Officer: Infection and the rise of antimicrobial resistance. Lancet 381 (9878): 1606–1609.\n\nDavies, S.E., A. Kamradt-Scott, and S. Rushton. 2015. Disease diplomacy: International norms\n\nand global health security. Baltimore: Johns Hopkins University Press.", "n_tokens": 297, "kind": "text"}
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{"chunk_id": "drug_resistance_book-403-3", "doc_id": "drug_resistance_book", "page": 403, "text": "Organization.\n\n———. 2015b. Implementation of the International Health Regulations (2005): Report of the Review Committee on second extensions for establishing national public health capacities and on IHR implementation (A68/22 Add.1).\n\n———. 2015c. Worldwide country situation analysis: Response to antimicrobial resistance.\n\nGeneva: World Health Organization.", "n_tokens": 75, "kind": "text"}
{"chunk_id": "drug_resistance_book-404-0", "doc_id": "drug_resistance_book", "page": 404, "text": "24 Global Health Governance and Antimicrobial Resistance\n\n———. 2015d. Health in 2015: From MDGs Millennium Development Goals to SDGs Sustainable", "n_tokens": 31, "kind": "text"}
{"chunk_id": "drug_resistance_book-404-1", "doc_id": "drug_resistance_book", "page": 404, "text": "Development Goals. Geneva: World Health Organization.\n\n———. 2016a. International Health Regulations (2005). 3rd ed. Geneva. ———. 2016b. Implementation of the International Health Regulations (2005): Annual report on the implementation of the International Health Regulations (2005). Report by the Director- General (WHA A69/20).\n\nWorld Health Organization, Food and Agricultural Organization of the United Nations, World Organisation for Animal Health. 2018. Monitoring global progress on addressing antimicro- bial resistance: Analysis report of the second round of results of AMR country self-assessment survey 2018.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n399", "n_tokens": 294, "kind": "text"}
{"chunk_id": "drug_resistance_book-405-0", "doc_id": "drug_resistance_book", "page": 405, "text": "Chapter 25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nCalvin W. L. Ho\n\nand Tsung-Ling Lee", "n_tokens": 29, "kind": "text"}
{"chunk_id": "drug_resistance_book-405-1", "doc_id": "drug_resistance_book", "page": 405, "text": "Abstract Recognizing that antimicrobial resistance (AMR) poses a serious threat to global public health, the World Health Organization (WHO) has adopted a Global Action Plan (GAP) at the May 2015 World Health Assembly. Underscoring that systematic misuse and overuse of drugs in human medicine and food production is a global public health concern, the GAP-AMR urges concerted efforts across gov- ernments and private sectors, including pharmaceutical industry, medical profes- sionals, agricultural industry, among others. The GAP has a threefold aim: (1) to ensure a continuous use of effective and safe medicines for treatment and preven- tion of infectious diseases; (2) to encourage a responsible use of medicines; and (3) to engage countries to develop their national actions on AMR in keeping with the recommendations. While the GAP is a necessary step to enable multilateral actions, it must be supported by effective governance in order to realize the proposed aims. This chapter has a threefold purpose: (1) To identify regulatory principles embed- ded in key WHO documents relating to AMR and the GAP-AMR; (2) To consider the legal and regulatory actions or interventions that countries could use to strengthen their regulatory lever for AMR containment; and (3) To highlight the crucial role of the regulatory lever in enabling other levers under a whole-of-system approach. Effective AMR containment requires a clearer understanding of how the regulatory lever could be implemented or", "n_tokens": 305, "kind": "text"}
{"chunk_id": "drug_resistance_book-405-2", "doc_id": "drug_resistance_book", "page": 405, "text": "enabled within health systems, as well as how it underscores and interacts with other levers within a whole-of-system approach.", "n_tokens": 29, "kind": "text"}
{"chunk_id": "drug_resistance_book-405-3", "doc_id": "drug_resistance_book", "page": 405, "text": "C. W. L. Ho (*) Faculty of Law, The University of Hong Kong, Hong Kong S.A.R., People’s Republic of China\n\nCentre for Medical Ethics and Law, Li Ka Shing School of Medicine and Faculty of Law, The University of Hong Kong, Hong Kong S.A.R., People’s Republic of China e-mail: cwlho@hku.hk\n\nT.-L. Lee Taipei Medical University, Taipei, Taiwan\n\nShuang-Ho Hospital, New Taipei City, Taiwan e-mail: tl265@georgetown.edu\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_25\n\n401", "n_tokens": 193, "kind": "text"}
{"chunk_id": "drug_resistance_book-406-0", "doc_id": "drug_resistance_book", "page": 406, "text": "402\n\nC. W. L. Ho and T.-L. Lee\n\nKeywords Global action plan · Governance · Regulation · Law/legal · Collective action · Stewardship\n\n25.1\n\nIntroduction", "n_tokens": 38, "kind": "text"}
{"chunk_id": "drug_resistance_book-406-1", "doc_id": "drug_resistance_book", "page": 406, "text": "Antimicrobial resistance (AMR) is widely recognized as a public health threat, responsible for 700,000 deaths worldwide. If the spread of antimicrobial resistance is left unaddressed, it could lead to 10 million additional annual deaths by 2050, according to an estimation by the World Bank. Facilitated by inappropriate uses of medicines to control the spread of infection for human and animal health, antimi- crobial resistance also poses long term threat to human development. The United Nations (UN) Secretary-General Ban Ki-Moon describes AMR as a “fundamental threat” to human development at a high-level UN meeting on drug-resistant bacteria (United Nations News Centre 2016). Likewise, recognizing the gravity of antimi- crobial resistance on global health, the then Director-General for the World Health Organization (WHO) Margaret Chan characterizes the rise of AMR as a “slow- motion tsunami” (Leatherby 2017). Without an effective global containment strat- egy, the World Bank warns, the economic impact of AMR makes it unlikely for the world to reach the sustainable development goals set for 2030 (World Bank 2017). Scientists have long known that microbes can become resistant to medicine. Alexander Fleming, the Nobel laureate for the discovery of penicillin, cautioned the world in his 1945 Nobel acceptance speech of the impending public health crisis (Fleming 1945, at p. 93): “… there is the danger that the ignorant man may easily under dose himself and by exposing his microbes", "n_tokens": 313, "kind": "text"}
{"chunk_id": "drug_resistance_book-406-2", "doc_id": "drug_resistance_book", "page": 406, "text": "to non-lethal quantities of the drug make them resistant.” Since the 1950s the WHO has identified AMR as a global threat, but little progress has been made in improving access to antimicrobi- als and maintaining their appropriate consumption and effectiveness. Likewise, lim- ited innovation in antimicrobials further compounds the challenge. For these reasons, a broad range of microorganisms have become more resistant to antimicro- bials in all parts of the world. An emerging concern is AMR for diseases which affect low and middle income countries (LMICs) disproportionately, such as tuber- culosis (TB), malaria and HIV (See Chaps. 2–4). Furthermore, with extensively drug-resistant to tuberculosis now identified in 105 countries, it further raises con- cerns of a future TB epidemic where limited treatment options are available.", "n_tokens": 185, "kind": "text"}
{"chunk_id": "drug_resistance_book-406-3", "doc_id": "drug_resistance_book", "page": 406, "text": "Even though the direct consequences of AMR on human health were beginning to be scientifically well-understood several decades ago, international efforts to address this problem did not begin till the late 1990s and 2000s. The WHO played a key role in catalysing international actions on the issue. It convened a series of consultative groups and expert workshop to assess, evaluate, and develop a series of recommendation for effective containment interventions to garner international attention. This work culminated in the report WHO Global Strategy for Containment", "n_tokens": 97, "kind": "text"}
{"chunk_id": "drug_resistance_book-407-0", "doc_id": "drug_resistance_book", "page": 407, "text": "25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nof Antimicrobial Resistance (World Health Organization 2001). Since this strategy was published, AMR has been discussed at several World Health Assembly meet- ings, resulting in the adoption of several resolutions such as WHA60.16 concerning the rational use of medicine and WHA62.15 on prevention and control of multidrug- resistant tuberculosis and extensively drug-resistant tuberculosis. At the 2015 World Health Assembly, member states endorsed a Global Action Plan on Antimicrobial Resistance (GAP-AMR; World Health Organization 2015a) – which calls for an effective One Health approach – and which was later endorsed through resolutions by the Food and Agriculture Organization of the United Nations (FAO) and World Organisation for Animal Health (OIE). In the same year, AMR was recognized as a threat to the world’s sustainability and human development at the UN level. In a landmark UN resolution guiding the global development plan for the next 15 years entitled Transforming our world: the 2030 Agenda for Sustainable Development (United Nations 2015), AMR is mentioned but not explicitly set out as a Sustainable Development Goals (SDGs) target. Most recently, the G20 summit reaffirmed the commitment to combat antimicrobial resistance (G20 Leaders’ Declaration 2017).", "n_tokens": 276, "kind": "text"}
{"chunk_id": "drug_resistance_book-407-1", "doc_id": "drug_resistance_book", "page": 407, "text": "These commitments, both within and outside of the high-level political setting of UN organs, underscore the growing political interest in AMR. Two distinct but interrelated factors explain the recent high-level political attention. First, national governments have a strong self-interest in mitigating the negative impacts of AMR on public health: the estimated economic cost for failing to address the issue would be £66 trillion in lost productivity to the global economy (Public Health England 2015). Second, AMR transcends national borders and exposes a global vulnerability which necessitates collective action at the international level. The shared vulnerabil- ity underpinning AMR was recently acknowledged by Tedros Adhanom, the WHO Director-General, in his address to the G20 summit. Urging the world to act, he underscored the interdependence of the world, noting “… vulnerability for one is vulnerability for all of us” (World Health Organization 2017a). German Chancellor Angela Merkel echoed this concern, depicting AMR as akin to a global health secu- rity issue of global collective responsibility (Scheuber 2017).", "n_tokens": 240, "kind": "text"}
{"chunk_id": "drug_resistance_book-407-2", "doc_id": "drug_resistance_book", "page": 407, "text": "This chapter has a threefold purpose: (1) To identify regulatory principles embed- ded in key WHO documents relating to AMR and the GAP-AMR; (2) To consider the legal and regulatory actions or interventions that countries could use to strengthen their regulatory lever for AMR containment; and (3) To highlight the crucial role of the regulatory lever in enabling other levers under a whole-of-system approach. In the section that follows, we consider how the WHO and other international bodies have systematically framed this global health issue as a collective action problem; initially by setting out the WHO GAP-AMR. But subsequently, it was quickly rec- ognised that a global plan would not be self-enabling and therefore a global frame- work has since been proposed by the UN to facilitate implementation by all member states. We set out what we consider to be the core principles that are embedded in the GAP-AMR and the global framework built around it. We then consider the regu- latory lever that member states need to establish and apply in order for these prin- ciples to effect change at the national level.\n\n403", "n_tokens": 234, "kind": "text"}
{"chunk_id": "drug_resistance_book-408-0", "doc_id": "drug_resistance_book", "page": 408, "text": "404\n\nC. W. L. Ho and T.-L. Lee\n\n25.2\n\nThe WHO and AMR\n\n25.2.1\n\nCollective Action Problem\n\nIlona Kickbusch and David Gleicher (World Health Organization 2012a, b) define global health as health issues which transcend national boundaries and governments and call for actions on the global forces and global flows that determine the health of people. As microbes are capable of penetrating national borders, national efforts are contingent upon, and vulnerable to external actions and forces. It is widely rec- ognised that a collective response is necessary to mitigate the negative consequences of AMR. As no country is capable of addressing the issue without some degree of mutual reliance on others to mount an effective response against AMR, the interde- pendency makes AMR containment a collective action problem.", "n_tokens": 171, "kind": "text"}
{"chunk_id": "drug_resistance_book-408-1", "doc_id": "drug_resistance_book", "page": 408, "text": "Some scholars go further and argue that the containment of AMR is a public good: the benefits from effective containment are enjoyed by all and there is no rivalry in consumption (Smith and Coast 2002). If this is correct, it could present a free rider problem: individual states lack incentive to take the necessary actions and instead, rely on others to act. Arguably, the free rider problem can be addressed through international law (Wernli et al. 2011; Review on Antimicrobial Resistance 2014). Steven Hoffman and Asha Behdinan (2016), Reinl (2016), Susan Rogers Van Katwyk et al. (2016), Christine Årdal et al. (2016), and Asha Behdinan et al. (2015), for instance, argue that countries can be encouraged to act if international law embeds incentives. While many international institutions are involved in addressing the threat posed by AMR, as a starting point, we focus the discussion on the WHO, particularly for its instrumental role in developing the GAP-AMR.\n\n25.2.2", "n_tokens": 219, "kind": "text"}
{"chunk_id": "drug_resistance_book-408-2", "doc_id": "drug_resistance_book", "page": 408, "text": "Global Action Plan\n\nRecognizing that systematic misuse and overuse of antimicrobial drugs in human medicine and food production puts every nation at risk, the overarching goal of the GAP-AMR is thus to ensure that the world is able to “treat and prevent infectious diseases with effective and safe medicines that are quality-assured, used in a respon- sible way, and accessible to all who need them” (World Health Organization 2015a, b, at p. 8). To achieve this goal, the GAP-AMR requires concurrent actions at the national and international levels. While the GAP-AMR is not technically binding, it seeks to harmonise practices across countries while affording regulatory flexibility. To assure policy coherence at the national and international levels, the GAP-AMR provides five objectives to guide and align national and international policy actions: (1) to improve awareness and understanding of AMR through effective communica- tion, education and training; (2) to strengthen the knowledge and evidence base through surveillance and research; (3) to reduce the incidence of infection through effective sanitation, hygiene and infection prevention measures; (4) to optimize the", "n_tokens": 242, "kind": "text"}
{"chunk_id": "drug_resistance_book-409-0", "doc_id": "drug_resistance_book", "page": 409, "text": "25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nuse of antimicrobial medicines in human and animal health; and (5) to develop the economic case for sustainable investment that takes account of the needs of all countries, and increases investment in new medicines, diagnostic tools, vaccines and other interventions. Member states are urged to have national action plans that are aligned with the GAP-AMR within 2 years of the endorsement of the action plan by the World Health Assembly.", "n_tokens": 100, "kind": "text"}
{"chunk_id": "drug_resistance_book-409-1", "doc_id": "drug_resistance_book", "page": 409, "text": "Moreover, because excessive human and animal use of antibiotics in multiple settings will have health, economic and security implications beyond national bor- ders, the GAP-AMR embraces a One Health approach towards AMR. Defined as a collaborative, multi-sectoral and trans-disciplinary, the One Health approach recog- nizes interconnection between people, animals, plants and the shared environment. This approach calls for sectorial coordination involving human and veterinary med- icine, agriculture, finance, environment, and consumers to optimal health outcomes. At the level of international health, horizontal coordination of different UN agencies occurs through the WHO. As the specialized public health agency within the UN agency, the WHO is charged with organizing international responses to shared health challenges, and this responsibility includes acting as “the directing and coor- dinating authority on international health work” (World Health Organization n. d.). The WHO works with the Strategic and Technical Advisory Group on AMR at the FAO and OIE to develop a framework for monitoring and evaluation of member states’ national action plans. Likewise, the FAO, OIE and World Bank are encour- aged to put in place and implement action plans in their respective fields. Notably, the regulatory functions bestowed on the WHO are broader in scope than any other international agency in the UN orbit.", "n_tokens": 273, "kind": "text"}
{"chunk_id": "drug_resistance_book-409-2", "doc_id": "drug_resistance_book", "page": 409, "text": "As of 2017, more than one third of WHO member states have completed their national action plans on AMR, and a further 62 are in the process of doing so. These national action plans provide a basis for an assessment of the resource needs at national and international levels. The WHO is tasked with publishing biennial prog- ress report on countries’ progress in implementing their national action plans. The progress report will also include an assessment of progress made by the FAO, OIE and WHO.\n\n25.2.3\n\nLimitations of the Global Action Plan\n\nTo be sure, the GAP-AMR provides a good starting point, but the plan lacks con- crete goals to compel action. Moreover, the WHO alone cannot be expected to solve the global AMR crisis. For instance, preserving antimicrobial medicines will require a global agreement as to what constitutes ‘appropriate use’. Likewise, new financ- ing mechanisms will be needed to incentivise global innovation in antimicrobial medicines. Thus, in the same resolution that endorsed the global action plan, the World Health Assembly (2015a, b) requested the Director-General to develop a global development and stewardship framework to support GAP-AMR in combat- ing AMR. Specifically, the Health Assembly requires the Director-General to (World Health Assembly 2015a, b, Request 7):\n\n405", "n_tokens": 278, "kind": "text"}
{"chunk_id": "drug_resistance_book-410-0", "doc_id": "drug_resistance_book", "page": 410, "text": "406\n\nC. W. L. Ho and T.-L. Lee\n\ndevelop, in consultation with Member States and relevant partners, options for establishing a global development and stewardship framework to support the development, control, dis- tribution and appropriate use of new antimicrobial medicines, diagnostic tools, vaccines and other interventions, while preserving existing antimicrobial medicines, and promoting affordable access to existing and new antimicrobial medicines and diagnostic tools, taking into account the needs of all countries, and in line with the global action plan on antimicro- bial resistance.\n\nThe global framework will build on the GAP-AMR, but with specific focuses on preservation of antimicrobial medicines and development of new antimicrobial medicines, diagnostic tools, vaccines and other interventions. According to a report issued by the FAO, OIE and WHO (Food and Agriculture Organization 2017, at p. 4), a global development and stewardship framework would have a threefold goal:\n\n1. Stewardship: Preserving antimicrobial medicines through a stewardship frame- work covering control, distribution and appropriate use;\n\n2. Research & Development: Developing of new health technologies for preventing and controlling antimicrobial resistance; and\n\n3. Access: Promoting affordable access to existing and new antimicrobial medi- cines and diagnostic tools.", "n_tokens": 274, "kind": "text"}
{"chunk_id": "drug_resistance_book-410-1", "doc_id": "drug_resistance_book", "page": 410, "text": "This framework further encapsulates key principles that have been expounded in earlier initiatives of the WHO. For the purposes of this chapter, we highlight three principles that are of especial pertinence to laws and regulations on pharmaceuti- cals, which are discussed in the section that follows (for a broader ethical discussion on AMR, see Haire, Chap. 3, this volume; Cheah et al., Chap. 4, this volume). Not necessarily in order of priority, these principles are:\n\n1. Rational and responsible use of antimicrobials", "n_tokens": 123, "kind": "text"}
{"chunk_id": "drug_resistance_book-410-2", "doc_id": "drug_resistance_book", "page": 410, "text": "At a practical level, the WHO defines rational use of medicines as patients receiv- ing medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community (World Health Organization 1985). This definition extends to the use of antimicrobials, where for instance, irrational use occurs when patients are prescribed and/or take antibiotics (intended to treat bacterial infection) when in fact they have a viral infection. As a matter of public policy, responsible use of antimicrobials is set out as a governing principle that should underpin national governments’ efforts to curb AMR. This principle requires governments to ensure that existing activities, capabilities and resources of health system are aligned to ensure patients receive the right dosage of antimicrobials at the right time, use them appropriately and benefit from the usage (World Health Organization 2012a, b).\n\n2. Equitable access to, and appropriate use of, existing and new antimicrobial medicines.\n\nThe GAP-AMR recognizes that all countries should have a national action plan on antimicrobial resistance that includes an assessment of resource needs. Moreover, recognizing the need to optimise the use of antimicrobial medicines in human and", "n_tokens": 264, "kind": "text"}
{"chunk_id": "drug_resistance_book-411-0", "doc_id": "drug_resistance_book", "page": 411, "text": "25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nanimal health, the WHO has updated its model list of essential medicine which categories antibiotics into three groups: access, watch and reserve. The access group include antibiotics (considered to have low resistance potential) recommended as first or second choice treatment options for common infections. This group of anti- biotics should be widely available at an affordable cost and of assured quality. The watch group of antibiotics are those generally considered as to have higher resis- tance potential but are recommended as for first or second choice treatment for limited number of indicators. The reserve group consists of ‘last-resort’ options, or tailored to highly specific patients and setting, and when other alternatives have already failed. International efforts are required in monitoring, reporting the uses of reserve antibiotics to preserve their effectiveness (World Health Organization 2017b, c).\n\n3. Transparency: Data Sharing, Collection and Evaluation", "n_tokens": 188, "kind": "text"}
{"chunk_id": "drug_resistance_book-411-1", "doc_id": "drug_resistance_book", "page": 411, "text": "Data sharing, collection and evaluation have been emphasised in order to pro- mote transparency and collaboration. A report by the WHO Secretariat on antimi- crobial resistance sets these responsibilities out concisely as (World Health Organization 2015a, at p. 11): “Publishing biennial progress reports, including an assessment of countries and organizations that have plans in place, their progress in implementation, and the effectiveness of action at regional and global levels; and including an assessment of progress made by the FAO, OIE and WHO in imple- menting actions undertaken within the organizations’ tripartite collaboration will also be included in these reports.”\n\nSignificantly, the call for a global development and stewardship framework was later reiterated at a high-level meeting on antimicrobial resistance at the UN level in 2016 (United Nations 2016). It was the only fourth time that the UN General Assembly convened a high-level meeting on a health issue. Previous meetings – HIV/AIDS, Ebola and non-communicable diseases – catalysed and mobilized polit- ical actions at the international level. The UN Political Declaration on antimicrobial resistance was adopted by all 193 member states, signalling a global commitment to combat antimicrobial resistance.", "n_tokens": 257, "kind": "text"}
{"chunk_id": "drug_resistance_book-411-2", "doc_id": "drug_resistance_book", "page": 411, "text": "In the discussion so far, we have considered the framing of AMR as a collective action problem the WHO and other international organisations. We have also briefly set out how the GAP-AMR and an enabling global framework have been con- structed in response to this problem. More importantly, we have attempted to iden- tify key principles that are embedded in the GAP-AMR, and in respect of which the global framework seeks to give expression to. For ease of reference, we refer to them generally as regulatory principles, because member states need to incorporate them – through laws and regulations – within their health systems. These laws and regulations collectively constitute a regulatory lever that will, at a basic level, enable member states to design, implement and manage policies (particularly pharmaceuti- cal oriented ones) toward responsible use and good stewardship of antimicrobials. These laws and regulations are considered in the next section of the chapter. We then explain why a sound regulatory lever within a whole-of-system approach is\n\n407", "n_tokens": 210, "kind": "text"}
{"chunk_id": "drug_resistance_book-412-0", "doc_id": "drug_resistance_book", "page": 412, "text": "408\n\nC. W. L. Ho and T.-L. Lee\n\ncritical to enable other levers (financial and information ones in particular) to oper- ate effectively in meeting global AMR objectives.\n\n25.3\n\nRegulatory Leverage for Responsible Use and Good Stewardship of Antimicrobials", "n_tokens": 61, "kind": "text"}
{"chunk_id": "drug_resistance_book-412-1", "doc_id": "drug_resistance_book", "page": 412, "text": "The prevalence of AMR is heavily influenced by the way that antimicrobials are consumed. It is now well established that overuse and underuse of antibiotics can lead to resistance (Jamrozik and Selgelid, Chap. 1, this volume). Even so, improper or imprudent use of antibiotics is deeply entrenched within health systems. In order for all member states of the WHO to meet their moral and political commitments set out under the GAP-AMR, it is critical for health systems to be strengthened on all fronts. Clearly the challenge of AMR is a complex one because it is influenced by many different factors and conditions. At the level of health systems, the relational dynamics between prescribers (or suppliers) of antibiotics and patients (or consum- ers), financial incentives, systemic commitments and characteristics, and the regula- tory environment, are arguably the key contributors to AMR. For the purposes of this chapter, we focus on the role of regulation (broadly applied to refer to both legislative and regulatory actions) and examine how it could be used to support the containment of AMR. Many countries do not have a substantially clear and system- atic legal and regulatory framework that is specifically directed at AMR (for exam- ple, Singh 2017). At a fundamental level, a clear regulatory position on responsible antimicrobial use that simultaneously prioritises effective antimicrobial stewardship is a pre-requisite to a coordinated response in policy decisions and actions across", "n_tokens": 311, "kind": "text"}
{"chunk_id": "drug_resistance_book-412-2", "doc_id": "drug_resistance_book", "page": 412, "text": "different domains within a health system. In addition, a variety of regulatory inter- ventions should be considered to enable, as well as promote, the use of structural (delivery arrangement), information and financial levers to encourage appropriate use and stewardship of antimicrobials. It is further important for the regulatory envi- ronment to be sufficiently open in allowing a combination of top-down and bottom- up actions within a whole-of-system approach.", "n_tokens": 95, "kind": "text"}
{"chunk_id": "drug_resistance_book-412-3", "doc_id": "drug_resistance_book", "page": 412, "text": "Policy discussions on effective stewardship of pharmaceuticals in health systems as a response to the problem of AMR predate the GAP-AMR. In a WHO report (Bigdeli et al. 2014) published ahead of the 2015 World Health Assembly, four main policy objectives with respect to medicines (and antimicrobials) in health systems have been identified as: (1) widely available high-quality medicinal products; (2) equitable access; (3) appropriate and safe use; and (4) affordability. Different policy actions and conditions are matched to each of the four policy objectives in the fol- lowing manner (Bigdeli et al. 2014, at p. 45):\n\n1. Ensuring availability of quality generic and innovative products:\n\nMonitoring product quality; • Prequalifying supplies and products;", "n_tokens": 167, "kind": "text"}
{"chunk_id": "drug_resistance_book-413-0", "doc_id": "drug_resistance_book", "page": 413, "text": "25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nNegotiating prices, quality, volume, and supply-chain security; • Promoting fair competition; • Engaging in risk sharing agreements; • Establishing patient access programmes;\n\n2. Improving Equitable Access:\n\nUnderstanding utilization profiles; • Assessing of care seeking behaviour and barriers to care; • Expanding provider networks; • Targeting policies and programmes to improve access for vulnerable populations;\n\n3. Encouraging Appropriate Use:\n\nImplementing and updating standard treatment guidelines; • Matching essential medicines and reimbursement lists to standard treatment guidelines;\n\nAssessing provider performance; • Managing care comprehensively; • Implementing and monitoring policies to encourage clinically appropriate and cost-effective use;\n\n4. Keeping cost affordable:\n\nMonitoring routine medicines expenditures by therapeutic area; • Evaluating health technologies and budget impact; • Assessing household medicines expenditure; • Implementing and monitoring policies and programmes to reduce waste and inappropriate use.", "n_tokens": 183, "kind": "text"}
{"chunk_id": "drug_resistance_book-413-1", "doc_id": "drug_resistance_book", "page": 413, "text": "Not surprisingly, these policy objectives are closely aligned with what we have identified to be regulatory principles that underscore the GAP-AMR. For instance, rational and responsible use, equitable access and transparency are all necessary conditions to ensure the availability of quality antimicrobials within a health sys- tem. However, these policy objectives and their attending actions and conditions inevitably compete in many ways. Price pressures could limit investment in gover- nance infrastructure, where such limitations are typically manifested in weak regu- latory capacity, information imbalance, lack of coordination among different stakeholders and perverse incentives whereby irresponsible use is directly supported by direct financial gain. Over time, these practices not only strain health systems by increasing needless consumption, cost and inefficiencies, but also accentuate the global threat of AMR. Within the paradigm of value-based practice, the problem of AMR highlights the urgent need to shift current low-value practices to high-value ones (Porter 2010; Elshaug et al. 2017). A low-value practice is an intervention where evidence suggests that it confers no or very little benefit (to a patient for instance). It also depicts any practice where risk of harm exceeds probable benefit, or where added costs of the intervention do not provide proportional added benefits.\n\n409", "n_tokens": 273, "kind": "text"}
{"chunk_id": "drug_resistance_book-414-0", "doc_id": "drug_resistance_book", "page": 414, "text": "410\n\nC. W. L. Ho and T.-L. Lee\n\nIn contrast, a high-value practice is one where evidence suggests it confers benefit on the intervention subject, or probability of benefit exceeds probable harm, or where the added costs of the intervention provide proportional added benefits rela- tive to alternatives. For instance, overprescribing that is incentivised, among other factors, by increased revenue for healthcare providers through greater pharmaceuti- cal sales is a low-value practice that continues to be sustained in many health systems.", "n_tokens": 115, "kind": "text"}
{"chunk_id": "drug_resistance_book-414-1", "doc_id": "drug_resistance_book", "page": 414, "text": "While it is beyond the scope of this chapter to address comprehensively the value implications of inappropriate use and poor stewardship of antimicrobials, our intent is to make explicit an implicit understanding that responding to the AMR challenge could be closely linked to addressing many on-going concerns relating to quality of care (World Health Organization 2016). The role and impact of regulation on qual- ity of care have been a longstanding concern among a variety of scholars in different quarters. With limited exception however (notably in the work on refining the work- ing definitions for substandard and falsified medical products (World Health Organization 2017c)), there has not been as much focus on the regulatory lever within health systems on containment of AMR as compared to the financial lever, for example. We hope to address this deficiency by proposing different tools and conditions that could make-up or compose the regulatory lever in relation to each of the four policy objectives identified by the WHO, as well as propose what we con- sider to be a sufficient open and responsive regulatory environment that could con- structively resolve tensions by focusing on higher-value practice when these objectives come into conflict.\n\n25.3.1", "n_tokens": 246, "kind": "text"}
{"chunk_id": "drug_resistance_book-414-2", "doc_id": "drug_resistance_book", "page": 414, "text": "Ensuring Quality\n\nA sufficiently robust and up-to-date legal and regulatory framework is necessary to control the quality, safety and efficacy of pharmaceuticals, including antimicrobials. Substandard or degraded antimicrobials, where dosage may be lower or less effec- tive, contribute to therapeutic failure and could thereby encourage the development of drug-resistant strain of pathogens. Similarly, counterfeit antimicrobials could have an adverse effect if the active ingredients include other types of antibiotics (and/or other drugs). In order for such a legal and regulatory framework to be robust, regulatory actions must include accreditation, audit and inspection for the purposes of controlling quality and assessing the safety and efficacy of antimicrobials. For instance, health systems that manufacture antimicrobials must have a legal and reg- ulatory framework to ensure that good manufacturing standards and practices are adhered to. It is not enough to only specify these requirements, but it is just as important for regulatory mechanisms to be in place that can effectively detect defi- ciencies or deviations from prescribed standards and practices.\n\nAppropriate laws and regulations are also needed to legitimise, implement and sustain policies and programmes that are directed at rational and appropriate antimi- crobial use. These policies and programmes generally relate to disease surveillance", "n_tokens": 270, "kind": "text"}
{"chunk_id": "drug_resistance_book-415-0", "doc_id": "drug_resistance_book", "page": 415, "text": "25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nand management, and standard treatment guidelines. More recently, various mea- sures have been introduced to incentivise the use of high value care through pay-for- performance programmes. These programmes reward healthcare providers for achieving quality, efficiency and “value” by increasing accessibility and appropriate use of drugs that are of proven efficacy. However, evidence of the effectiveness of such programmes are mixed in high-income countries and extremely limited in LMICs. From a regulatory standpoint, pay-for-performance programmes are not self-enabling everywhere but are likewise dependent on a supportive regulatory environment. Broadly speaking, appropriate legal or regulatory principles should be in place to ensure fair bargain, safety and (where appropriate) fair compensation, monitoring and data sharing.\n\nIn summary, the following legal and regulatory interventions should be consid- ered in advancing the policy goal of ensuring availability of quality (generic and innovative) antimicrobials:\n\nLaws and regulations on standards and practices that ensure quality level is achieved (e.g. good manufacturing standards and practices);", "n_tokens": 228, "kind": "text"}
{"chunk_id": "drug_resistance_book-415-1", "doc_id": "drug_resistance_book", "page": 415, "text": "Legally sanctioned practices for monitoring product quality and prequalifying supplies and products (e.g. through licensing, accreditation, audit and inspection); • Law and regulations that promote fair competition or that enable regulatory action to be taken against anti-competitive practices;\n\nLegally entrenching disease surveillance and management programmes; and • Set out legal and regulatory baseline and principles for risk sharing agreements and patient access programmes.\n\n25.3.2", "n_tokens": 86, "kind": "text"}
{"chunk_id": "drug_resistance_book-415-2", "doc_id": "drug_resistance_book", "page": 415, "text": "Improving Prescribing and Dispensing\n\nIn many LMICs, antimicrobials are sold over-the-counter without a prescription or otherwise dispensed by individuals who lack professional training or authority. Even where there may be laws or regulations that proscribe such practices, they may be poorly or inadequately enforced (Singh 2017; World Health Organization 2015b). For instance, accreditation and professional licensing may not specifically target adherence to standard treatment guidelines. Consequently, the failure to adhere to guidance on responsible antimicrobial prescription would not render the healthcare provider professionally accountable or otherwise legally empower a professional body to take remedial action. Responsible prescribing and dispensing practices could also be hampered by weak healthcare infrastructure, expectations of patients and perverse financial incentives. Access to rapid or reliable diagnostic tests may be limited in a low resource health system. This could in turn encourage healthcare providers to veer towards prescribing an antibiotic in order to ensure that the pros- pect of a bacterial infection is addressed even if there is no reliable diagnosis to that effect. Such a conservative approach could even be a cost effective response (in the short term) if the cost of the antibiotic is lower than to order a laboratory test to\n\n411", "n_tokens": 259, "kind": "text"}
{"chunk_id": "drug_resistance_book-416-0", "doc_id": "drug_resistance_book", "page": 416, "text": "412\n\nC. W. L. Ho and T.-L. Lee\n\nvalidate a diagnosis (World Health Organization 2015b). For this and other reasons, providers may feel obligated to prescribe – while patients may feel entitled to use – antimicrobials, as a quick treatment option. Patients may not be aware of what appropriate use of antimicrobials means, particularly where duration of medical consultation is limited, and could consider themselves to have received substandard care if they have not been prescribed an antibiotic. At a systemic level, financial incentives may encourage overprescribing of antimicrobials. Where pharmaceutical sales generate revenue for healthcare providers and institutions, there would be a perverse financial incentive to overprescribe. Such a practice may be exacerbated where pharmaceutical companies themselves enter into profit-sharing arrangements with these providers or institutions. Additionally, it is currently impossible to deter- mine the extent that antimicrobials are appropriately prescribed and consumed as there is a lack of reliable data across all health systems.", "n_tokens": 217, "kind": "text"}
{"chunk_id": "drug_resistance_book-416-1", "doc_id": "drug_resistance_book", "page": 416, "text": "Laws and regulations are necessary to prohibit over-the-counter sale of antimi- crobials while ensuring that patients continue to have access through appropriately trained and qualified healthcare professionals. In addition, requiring an appropriate amount of information to be indicated on packaging and to be shared as part of responsible prescribing practice could be given regulatory force. On the former, such a requirement could be taken up as a regulatory measure to ensure high-value or quality use of antimicrobials, particularly where full treatment courses are to be dispensed. Healthcare providers, institutions and professional associations have a crucial role to play in robust guideline development and implementation processes, filling evidence gaps with research, developing high-value practices, and leading or participating in efforts to shift from low-value to high-value practices. In many health systems, these stakeholders do not have sufficient or appropriate legal stand- ing to contribute constructively to policy measure that are directed at improving prescribing and dispensing practices (Singh 2017; World Health Organization 2015b). As noted earlier, professional associations that have an interest in ensuring that standard treatment guidelines are observed by their members may not have any regulatory authority to monitor and improve such practices. Where professional organisations have the capability and motivation to improve professional practices, appropriate", "n_tokens": 262, "kind": "text"}
{"chunk_id": "drug_resistance_book-416-2", "doc_id": "drug_resistance_book", "page": 416, "text": "laws and regulations could be facilitative of this in a manner that is transparent and accountable. The challenge of perverse financial incentives is per- haps more difficult to surmount, particularly if the health system concerned is com- mitted to particular structural arrangements or values. Legal or regulatory intervention could then be a platform for evaluation, discussion and change. For instance, legal and regulatory changes introduced by South Korea in 2000 to pro- hibit doctors from dispensing drugs have reduced inappropriate antibiotic prescrib- ing (Kwon 2003; Park et al. 2005).", "n_tokens": 120, "kind": "text"}
{"chunk_id": "drug_resistance_book-416-3", "doc_id": "drug_resistance_book", "page": 416, "text": "In summary, the following legal and regulatory interventions could be consid-\n\nered to improve prescribing and dispensing of antimicrobials:\n\nProhibit over-the-counter sale of antimicrobials; • Lend regulatory weight to standard treatment guidelines;", "n_tokens": 58, "kind": "text"}
{"chunk_id": "drug_resistance_book-417-0", "doc_id": "drug_resistance_book", "page": 417, "text": "25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nEmpower healthcare institutions and professional associations to improve pre- scribing and (where applicable) dispensing practices through means that include assessing provider performance;\n\nIntroduce regulation to ensure that care is managed comprehensively; • Laws and regulations that support implementing and monitoring policies to encourage clinically appropriate and cost-effective use of antimicrobials; and • Evaluate, remove or manage perverse financial incentives through appropriate laws and regulations.\n\n25.3.3", "n_tokens": 108, "kind": "text"}
{"chunk_id": "drug_resistance_book-417-1", "doc_id": "drug_resistance_book", "page": 417, "text": "Ensuring Appropriate, Affordable and Equitable Access\n\nThe policy goals of ensuring appropriate, affordable and equitable access to phar- maceuticals (including antimicrobials) are aligned with the WHO’s global health initiative on universal health coverage (UHC), broadly directed at promoting access for all to appropriate health services at affordable cost (World Health Assembly Resolution 2005; World Health Organization 2010a, b). Much discussion on UHC has focused on expanding populations covered by national payment systems, although comparatively little information exists on what pharmaceutical are pro- vided, whether they meet the healthcare needs of the population, and how health systems manage pharmaceuticals so that patients receive high-value services at costs that households and systems can afford. When the types of pharmaceuticals provided do not meet population needs, risk protection is inadequate and this does not prevent household impoverishment (Yip and Hsiao 2009; Parry 2012; Wagner et al. 2008).", "n_tokens": 192, "kind": "text"}
{"chunk_id": "drug_resistance_book-417-2", "doc_id": "drug_resistance_book", "page": 417, "text": "The economic burden of pharmaceuticals on households is high: they account for nearly half of household healthcare expenditures in 12 Asia-Pacific countries (Wagner and Ross-Degnan 2009) and for all healthcare expenses in four out of 10 households in 22 low- and 17 middle-income countries (Wagner et al. 2011). Pharmaceuticals also constitute a major source of inefficiencies in health systems. Of the ten leading sources of inefficiency in health systems identified in the 2010 World Health Report, pharmaceuticals account for the top three (World Health Organization 2010a). Underuse of generic products, use of substandard and coun- terfeit medicines, and inappropriate use of medicines waste scarce resources in sys- tems. The World Health Organization estimates that more than half of all medicines globally are prescribed, dispensed, or sold inappropriately (World Health Organization 2009). For instance, overuse of antibiotics to treat acute respiratory tract infections wastes resources and leads to use of higher cost second and third line antibiotics for drug resistant infections. In many LMICs, access to a qualified healthcare professional may cost patients more time and money when compared with inappropriately or illegally obtaining antibiotics over-the-counter or from an unauthorised vendor. To promote appropriate and affordable access, national antibi- otics policies and standard treatment guidelines must be supported by essential medicines lists or formularies that encourage", "n_tokens": 284, "kind": "text"}
{"chunk_id": "drug_resistance_book-417-3", "doc_id": "drug_resistance_book", "page": 417, "text": "rational and responsible use of", "n_tokens": 5, "kind": "text"}
{"chunk_id": "drug_resistance_book-417-4", "doc_id": "drug_resistance_book", "page": 417, "text": "413", "n_tokens": 2, "kind": "text"}
{"chunk_id": "drug_resistance_book-418-0", "doc_id": "drug_resistance_book", "page": 418, "text": "414\n\nC. W. L. Ho and T.-L. Lee\n\nantimicrobials. In addition, appropriate laws and regulations must be in place to ensure that the antimicrobial supply chain is secure in terms of their procurement, storage and sale (World Health Organization 2015b). These requirements extend to importation requirements and quality inspections for health systems that do not manufacture antimicrobials.\n\nThe use of antimicrobials in animals for food production or other purposes will also need to be carefully monitored and regulated. Whereas laws and regulations have conventionally been domain specific particularly in keeping regulations relat- ing to humans distinct from nonhuman animals, the One Health approach endorsed in the GAP-AMR highlights the need for a more comprehensive and coordinated approach across the food, veterinary and health sectors. Many countries have yet to establish a regulatory mechanism to enforce requirements for appropriate use of antimicrobials in animals. In addition, there is inadequate infrastructure for moni- toring and controlling the development of resistant pathogens in animals, their verti- cal transmission from one animal species to another, as well as zoonotic transmissions to humans.", "n_tokens": 239, "kind": "text"}
{"chunk_id": "drug_resistance_book-418-1", "doc_id": "drug_resistance_book", "page": 418, "text": "Above all, WHO policy documents and guidance (2010a, 2014, 2016, 2017a) have consistently emphasised the importance of promoting equity through greater stakeholder engagement and prioritising the worst off (or otherwise the most vul- nerable) in a given society. This could be especially important for decentralised health systems, where inequalities across regions may be great (see also Reid, Chap. 16, this volume). A related concern is that public awareness of appropriate antimicrobial use remains low in most, if not all, health systems. Even within healthcare institutions, infrastructure and human resources may not be adequately equipped to implement and manage infection prevention and control programmes. Equitable access as devised through paradigms such as “accountability for reason- ableness” (Daniels and Sabin 2002) is arguably more likely to enable and encourage relevant stakeholders – particularly the broader community – to be interested and proactively involved in national antibiotics policies and related infection prevention and control programmes. As we shall elaborate on below, an equitable regulatory lever is crucial in support bottom-up approaches to promoting high-value use of antimicrobials (Tang et al. 2016).\n\nIn summary, the following legal and regulatory interventions could be consid-\n\nered to ensure appropriate, affordable and equitable access to antimicrobials:", "n_tokens": 276, "kind": "text"}
{"chunk_id": "drug_resistance_book-418-2", "doc_id": "drug_resistance_book", "page": 418, "text": "Introducing laws and regulations that implement and sustain infection prevention and control programmes, including appropriate surveillance mechanisms, to understand utilisation profiles, assess care seeking behaviour and barriers to care, and improve access for vulnerable populations;\n\nRegulation could be the basis of public awareness campaigns and continuing education for stakeholders;\n\nLaws and regulations may be needed to support monitoring routine medicines expenditures by therapeutic area, evaluating health technologies and budget impact, and assessing household medicines expenditure;\n\nImplementing and monitoring policies and programmes to reduce waste and inappropriate use through appropriate regulations;", "n_tokens": 102, "kind": "text"}
{"chunk_id": "drug_resistance_book-419-0", "doc_id": "drug_resistance_book", "page": 419, "text": "25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nRequiring appropriate stakeholders’ involvement or contribution through regula- tion; and\n\nReduce the use of antibiotics as growth promoters in animals through laws and regulations.\n\n25.4\n\nRegulatory Lever Within a Whole-of-System Approach\n\nIn our discussion above, we have considered the different types of legal and regula- tory actions or tools that could constitute the regulatory lever, taking into account pharmaceutical policy goals and the GAP-AMR regulatory principles. We have also noted that the regulatory lever is but one of other levers that are available to policy- makers, two of such levers being financial and information. In this section, we broadly explain why the regulatory lever underscores the effectiveness of these two other levers within a “whole-of-system” approach that is directed at AMR contain- ment. By this approach, we adopt the WHO’s emphasis that focus should not be limited to a particular component of a health system – broadly defined to mean “all organizations, people and actions whose primary intent is to promote, restore and maintain health”- but to recognise that different systemic components are interre- lated and interact in ways that may be anticipated or unanticipated (World Health Organization 2010a; b, at p. 19).\n\n25.4.1", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-419-1", "doc_id": "drug_resistance_book", "page": 419, "text": "Financial Lever\n\nThe financial lever could be thought of as being constituted by financial schemes that include budget controls, tax and incentive arrangements, and also the policies and actions of healthcare purchasers or payers, particularly social insurers (Bigdeli et al. 2014). Ideally, financing schemes should be designed to support decision- making through provision of information on demographic characteristics, health- care needs and utilisation patterns of its users, and also of healthcare providers – particularly prescribing patterns and related costs. Implementers of financial schemes exert a degree of financial control over patients and healthcare providers in terms of what they pay for, and could shape patient demand through both financial and educational means. Additionally, financial incentives should encourage cost-effective prevention and care, while financial commitments should be directed at meeting infrastructural requirement, such as surveillance mechanisms that allow the use of international and local data on disease burden and utilisation patterns to signal potential inappropriate use patterns. In reality, financial interven- tions, like expenditure-focused policy instruments, tend to lack specificity and often have unintended effects. For instance, a cap on funding does not necessarily encour- age clinically appropriate use or otherwise reduce wasteful spending as a result of over-treatment.\n\n415", "n_tokens": 261, "kind": "text"}
{"chunk_id": "drug_resistance_book-420-0", "doc_id": "drug_resistance_book", "page": 420, "text": "416\n\nC. W. L. Ho and T.-L. Lee\n\nWithin a whole-of-system approach, the financial lever should be applied together with the regulatory lever to support the establishment of a sound informa- tion environment, by making available evidence-based clinical guidelines and eco- nomic assessments that include health technology assessment and budget impact. As we have noted above, this is crucial in overcoming the current challenge that too little information on monitoring and evaluation activities is available, primarily due to lack of mechanisms in many health systems to monitor antimicrobial prescription and use. While some information is available on how medicines are financed in these health systems, there is little information to reliably determine equitable access and appropriate use.\n\n25.4.2\n\nInformation Lever\n\nThe information lever of many health systems is disproportionately focused on price rather than on appropriate use and good stewardship. There is a need to review, revise and develop information systems to collect information that will enable policy- makers to target policies that improve prescribing practices, carry out audits and conduct education programmes. Such a system should also be able combine information from different parts of the healthcare system. Regular samples of paper- based facility prescribing and dispensing records can provide information on utili- zation to inform policy decisions (World Health Organization 2015b).", "n_tokens": 281, "kind": "text"}
{"chunk_id": "drug_resistance_book-420-1", "doc_id": "drug_resistance_book", "page": 420, "text": "Policies that ensure appropriate use of antibiotics in a manner that is effective, safe, equitable and efficient depend on the availability of information including population demographics, disease epidemiology, treatment approaches, and politi- cal and economic environments. Health systems will need to be capable of generat- ing routine, up-to-date information about the type of antibiotics that are needed by patients, which antibiotics are being used and how they are used across different patient populations within the health system, who prescribed them, whether they are clinically appropriate (such as in addressing the disease burden faced by the popula- tion) and the cost spent. Without such information, it will be difficult to determine if quality of care is provided. Ideally, information systems should capture details on the antibiotics use and expenditure, along with quality of care (such as the percent- age of primary care patients receiving antibiotics), and details of misuse. However, these details are usually not captured by data collection systems. For instance, where providers are paid through bundled-payment arrangements (whether case or episode-based), the information system may not be designed to capture data on the type and amount of antibiotics prescribed, since payment does not depend on such information. As we have noted above, appropriate laws and regulations could help bring about changes to information systems that prioritises AMR containment.", "n_tokens": 275, "kind": "text"}
{"chunk_id": "drug_resistance_book-420-2", "doc_id": "drug_resistance_book", "page": 420, "text": "Constant monitoring, feedback and evaluation are important to ensure that levers continue to achieve desired goals. Crucially, member states will need to ensure that the whole-of-system approach to AMR containment could be implemented bottom- up and top-down (Elshaug et al. 2017). Bottom-up actions require stakeholders who are not in any formal positions of authority to change practices that are within their", "n_tokens": 82, "kind": "text"}
{"chunk_id": "drug_resistance_book-421-0", "doc_id": "drug_resistance_book", "page": 421, "text": "25 Global Governance of Anti-microbial Resistance: A Legal and Regulatory Toolkit\n\nsphere of influence. Such stakeholders could be patients, clinicians, cooperatives and agricultural producers (see Schwenkenbecher, Chap. 23, this volume and Oakley, Chap.8 in this volume). In contrast, top-down actions have wider impact and the drivers of change typically include governments, professional bodies and third party payers. The use of the regulatory lever, along with other levers, should enable as well as facilitate a combination of both bottom-up and top-down actions to improve policies and practices relating to antibiotics access, use and stewardship.\n\n25.5", "n_tokens": 138, "kind": "text"}
{"chunk_id": "drug_resistance_book-421-1", "doc_id": "drug_resistance_book", "page": 421, "text": "Conclusion\n\nIn this chapter, we have considered how AMR containment has become a collective action problem, perhaps most comprehensively mapped out in the GAP-AMR. While the GAP-AMR itself lacks legal or regulatory force, there are at least three regula- tory principles that could be drawn from it. These regulatory principles in turn require countries to adopt a variety of legal and regulatory actions or interventions that may be necessary to strengthen their regulatory lever for AMR containment. We have attempted to explicate these legal and regulatory actions in terms of four phar- maceutical policy objectives that have been articulated in a number of WHO docu- ments and initiatives. Finally, we highlighted the crucial role of the regulatory lever in implementing the GAP-AMR, and also in enabling other levers under a whole- of- system approach.", "n_tokens": 170, "kind": "text"}
{"chunk_id": "drug_resistance_book-421-2", "doc_id": "drug_resistance_book", "page": 421, "text": "Policies on AMR in health systems need to be responsive to shifting contexts and goals. Such adaptations must be informed by the best available evidence of what works, for whom, how and why in a given situation. In addition, routine monitoring and periodic evaluations of the impacts are necessary, and they are further crucial to ensuring quality, appropriate use and good stewardship of antimicrobials. The regu- latory lever could and arguably should be applied to introduce, guide, scale-up, adapt, adjust or terminate policies on AMR containment. While it is not disputed that the regulatory lever is generally recognised to be important, there has been rela- tively little attention as to what it means in terms of laws and regulations that could be directed at AMR containment. If the GAP-AMR is to be effectively enabled, this lacuna that we have highlighted will require greater attention.", "n_tokens": 183, "kind": "text"}
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{"chunk_id": "drug_resistance_book-424-0", "doc_id": "drug_resistance_book", "page": 424, "text": "420\n\nC. W. L. Ho and T.-L. Lee\n\n———. 2010a. The world health report. Health systems financing: The path to universal cov- erage. Geneva: World Health Organization. Available at: http://www.who.int/whr/2010/en/ index.html.\n\n———. 2010b. Western Pacific Regional strategy for health systems based on the values of pri- mary health care. Available at: http://www.wpro.who.int/topics/health_systems/wpro_strat- egy_health_systems_primary_health_care.pdf.\n\n———. 2012a. Governance for health in the 21st century. Geneva: World Health Organization. http://www.euro.who.int/__data/assets/pdf_file/0019/171334/RC62BD01-\n\nAvailable Governance-for-Health-Web.pdf.", "n_tokens": 206, "kind": "text"}
{"chunk_id": "drug_resistance_book-424-1", "doc_id": "drug_resistance_book", "page": 424, "text": "at:\n\n———. 2012b. The pursuit of responsible use of medicines: Sharing and learning from country experiences. Geneva: World Health Organization. Available at: http://apps.who.int/iris/bit- stream/10665/75828/1/WHO_EMP_MAR_2012.3_eng.pdf.\n\n———. 2014. Making fair choices on the path to universal health coverage. Geneva: World Health Organization. Available at: http://www.who.int/choice/documents/making_fair_choices/en/. ———. 2015a. Global action plan on antimicrobial resistance. Geneva: World Health Organization. Available at: http://www.who.int.libproxy1.nus.edu.sg/antimicrobial-resistance/ publications/global-action-plan/en/.\n\n———. 2015b. Antimicrobial resistance in the Western Pacific Region: A review of surveillance and health systems response. Geneva: World Health Organization. Available at: http://www. wpro.who.int/entity/drug_resistance/documents/amr_wpr.pdf.\n\n———. 2016. Health care without avoidable infections: The critical role of infection prevention and control. Geneva: World Health Organization. Available at: http://apps.who.int.libproxy1. nus.edu.sg/iris/bitstream/10665/246235/1/WHO-HIS-SDS-2016.10-eng.pdf.\n\n———. 2017a. Health emergencies represent some of the greatest risks to the global economy and security: Remarks delivered by Dr Tedros Adhanom Ghebreyesus to G20 8 July 2017. Available at: http://www.who.int/dg/speeches/2017/g20-summit/en/.", "n_tokens": 410, "kind": "text"}
{"chunk_id": "drug_resistance_book-424-2", "doc_id": "drug_resistance_book", "page": 424, "text": "———. 2017b. Report of the 21st WHO expert committee on the selection and use of essential medicines. Geneva: World Health Organization. Available at: http://www.who.int/medicines/ publications/essentialmedicines/EML_2017_ExecutiveSummary.pdf?ua=1.\n\n———. 2017c. WHO global surveillance and monitoring system for substandard and falsified medical products. Geneva: World Health Organization. Available at: https://www.who.int/ medicines/regulation/ssffc/publications/gsms-report-sf/en/.\n\n———. n.d. About WHO: What we do. Available at: http://www.who.int/about/what-we-do/en/. Yip, Winnie, and William C. Hsiao. 2009. Non-evidence-based policy: How effective is China’s new cooperative medical scheme in reducing medical impoverishment? Social Science and Medicine 68: 201–209. https://doi.org/10.1016/j.socscimed.2008.09.066.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.", "n_tokens": 336, "kind": "text"}
{"chunk_id": "drug_resistance_book-424-3", "doc_id": "drug_resistance_book", "page": 424, "text": "The images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 73, "kind": "text"}
{"chunk_id": "drug_resistance_book-425-0", "doc_id": "drug_resistance_book", "page": 425, "text": "Chapter 26 The Super-Wicked Problem of Antimicrobial Resistance\n\nJasper Littmann, A. M. Viens, and Diego S. Silva\n\nKeywords Complex systems · Social policy · Bioethics · Political philosophy\n\nAntimicrobial resistance (AMR) – the progressive process by which microbes, such as bacteria, through evolutionary, environmental and social factors develop the abil- ity to become resistant to drugs that were once effective at treating them – is a threat from which no one can escape. It is one of the largest threats to clinical and global health in the twenty-first century – inflicting monumental health, economic and social consequences.1 All persons locally and globally, and even all future persons yet to come into existence, all suffer the shared, interdependent vulnerability to this threat that will have a substantial impact on all aspects of our lives. For example,", "n_tokens": 180, "kind": "text"}
{"chunk_id": "drug_resistance_book-425-1", "doc_id": "drug_resistance_book", "page": 425, "text": "1 J O’Neill, et al., Infection Prevention, Control and Surveillance: Limiting the Development and Spread of Drug Resistance (London: Review on Antimicrobial Resistance, 2016) https://amr- review.org/sites/default/files/Health%20infrastructure%20and%20surveillance%20final%20ver- sion_LR_NO%20CROPS.pdf (accessed September 29, 2017); President’s Council of Advisors on Science and Technology, Report To The President On Combating Antimicrobial Resistance (Washington: PCAST, 2014); World Health Organization, The Evolving Threat of Antimicrobial Resistance: Options for Action (Geneva: WHO Press, 2012); World Economic Forum, Global Risks 2013 – Insight Report, Eighth Edition (Geneva, 2013); S.C. Davies, J. Grant and M. Catchpole, The Drugs Don’t Work: A Global Threat (London: Penguin, 2013); O.O. Adeyi, et al., Drug- Resistant Infections: A Threat to Our Economic Future (Washington, DC: World Bank, 2017).\n\nJ. Littmann (*) Norwegian Institute of Public Health, Oslo, Norway e-mail: jasper.littmann@fhi.no\n\nA. M. Viens School of Global Health, York University, Toronto, Canada e-mail: amviens@yorku.ca\n\nD. S. Silva Sydney Health Ethics, School of Public Health, University of Sydney, Sydney, NSW, Australia e-mail: diego.silva@sydney.edu.au\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8_26\n\n421", "n_tokens": 412, "kind": "text"}
{"chunk_id": "drug_resistance_book-426-0", "doc_id": "drug_resistance_book", "page": 426, "text": "422\n\nJ. Littmann et al.\n\nwhile reliable data are hard to find, the European Centre for Disease Prevention and Control (ECDC) has conservatively estimated that, in Europe alone, AMR causes additional annual cost to health care systems of at least €1.5 billion, and is respon- sible for around 25,000 deaths per year. Furthermore, AMR significantly increases the cost of treating bacterial infections with an increase in length of hospital stays and average number of re-consultations, as well as the resultant lost productivity from increased morbidity.2 With a combined cost of up to $100 trillion to the global economy – pushing a further 28 million people into extreme poverty – this is one of the most pressing challenges facing the world.3 Most troublingly, if we do not suc- ceed in diminishing the progression of AMR, there is the very real potential for it to threaten common procedures and treatments of modern medicine, including the safety and efficacy of surgical procedures and immunosuppressing chemotherapy.4 Some experts are warning that we may soon be ushering in a post-antibiotic area.5\n\n26.1", "n_tokens": 238, "kind": "text"}
{"chunk_id": "drug_resistance_book-426-1", "doc_id": "drug_resistance_book", "page": 426, "text": "Challenges in Responding to AMR\n\nThere exists a multitude of policy responses to AMR at the local, national and inter- national levels.6 Unfortunately, their success to date has only been limited.7 This may partly be due to the fact that many microorganisms are highly adaptable and constantly evolving, thereby presenting a perpetual challenge to clinicians, research- ers, public health professionals and policy-makers.8 However, the formulation and", "n_tokens": 90, "kind": "text"}
{"chunk_id": "drug_resistance_book-426-2", "doc_id": "drug_resistance_book", "page": 426, "text": "2 L.L. Maragakis, E.N. Perencevich and S.E. Cosgrove, ‘Clinical and Economic Burden of Antimicrobial Resistance,’ Expert Review of Anti-infective Therapy 6(2008): 751–63; F. Alam, et al. ‘The additional costs of antibiotics and re-consultations for antibiotic-resistant Escherichia coli urinary tract infections managed in general practice,’ International Journal of Antimicrobial Agents 33(2009): 255–57; R. Smith and J. Coast, ‘The true cost of antimicrobial resistance,’ BMJ 2013; 346: f1493; Centers of Disease Control and Prevention, Antibiotic Resistance Threats in the United States, 2013 (Atlanta: Centers of Disease Control and Prevention, 2013) 3 J. O’Neill et al., Tackling Drug-Resistant Infections Globally: Final Report and Recommendations (London: Review on Antimicrobial Resistance, 2016), available at https://amr-review.org/sites/ default/files/160518_Final%20paper_with%20cover.pdf (accessed September 29, 2017). 4 A. Teillant, S. Gandra, D. Barter, D.J. Morgan, and R. Laxminarayan, ‘Potential burden of antibi- otic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study,’ Lancet Infectious Diseases 15(2015): 1429–37. 5 S.C. Davies, J. Grant and M. Catchpole, The Drugs Don’t Work: A Global Threat (London: Penguin, 2013). 6 World Health Organization, Global Strategy for Containment of Antimicrobial Resistance (Geneva: WHO, 2001); Infectious Diseases Society of America, ‘The 10 × ‘20 Initiative: Pursuing a", "n_tokens": 403, "kind": "text"}
{"chunk_id": "drug_resistance_book-426-3", "doc_id": "drug_resistance_book", "page": 426, "text": "Global Commitment to Develop 10 New Antibacterial Drugs by 2020,’ Clinical Infectious Diseases 8(2010): 1081–83; Bundesministerium für Gesundheit, Deutsche Antibiotikaresistenz- Strategie (Berlin, 2011); Department of Health, UK Five Year Antimicrobial Resistance Strategy 2013 to 2018 (London, 2013) 7 World Health Organization, Antimicrobial Resistance – Global Report on Surveillance (Geneva: WHO Press, 2014) 8 A.S. Fauci and D.M. Morens, ‘The Perpetual Challenge of Infectious Diseases,’ New England Journal of Medicine 366(2012): 454–61.", "n_tokens": 142, "kind": "text"}
{"chunk_id": "drug_resistance_book-427-0", "doc_id": "drug_resistance_book", "page": 427, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\nimplementation of effective polices are also compounded by the complexity of the challenge. This complexity pertains to the number of local, national and interna- tional stakeholders involved, the difficulty in establishing successful collaboration and coordination mechanisms across different policy areas, and the numerous inter- related drivers that make this a problem at the global scale.9", "n_tokens": 81, "kind": "text"}
{"chunk_id": "drug_resistance_book-427-1", "doc_id": "drug_resistance_book", "page": 427, "text": "The number of stakeholders who contribute to the emergence of AMR is extraor- dinarily large.10 Misuse and over-prescription of antibiotics, for example, are driven not only by health care professionals but also consumers – many of whom will not use antibiotics as instructed, often without being aware of the potential conse- quences of their actions.11 Other patient groups entirely lack access to appropriate antimicrobial treatment, especially in poorer or less developed settings.12 Where treatment is either unaffordable for many or infrastructure is lacking, people are more likely to self-medicate or buy counterfeit drugs through unofficial channels, increasing the chance that their drugs are less effective or unsuitable for treating the infection.13 Beyond human usage, the pervasive use of antibiotics outside of medical settings also remains a key source of resistance. Indeed, it is estimated that more antibiotics are given to animals than consumed by humans – and, in many instances, for non-therapeutic use.14 The wide use of antibiotics within agricultural, aquacul- ture, horticultural and animal farming industries all provide multiple opportunities for the increase incidence and prevalence of antibiotic-resistant bacteria.15\n\nAMR does not, therefore, squarely fall into a single policy domain and any effec- tive policy will require collaboration among a wide range of experts, such as clini- cians, veterinarians, microbiologists, pharmacologists, epidemiologists, lawyers,", "n_tokens": 299, "kind": "text"}
{"chunk_id": "drug_resistance_book-427-2", "doc_id": "drug_resistance_book", "page": 427, "text": "9 R. Laximinarayan, et al., ‘Antibiotic resistance - the need for global solutions,’ Lancet Infectious Diseases 13(2013): 1057–98. 10 W. Albrich, D. Monnet, S. Harbarth, ‘Antibiotic Selection Pressure and Resistance in Streptococcus pneumoniae and Streptococcus pyogenes,’ Emerging Infectious Diseases 10(2004): 514–17. 11 C.C. Butler, et al., ‘Understanding the culture of prescribing: qualitative study of general practi- tioners’ and patients’ perceptions of antibiotics for sore throat,’ BMJ 317(1998): 637–42; I. Björkman, et al., ‘Infectious disease management in primary care: perceptions of GPs.’ BMC Fam Pract, 12:1 (2011); N. Britten, ‘Patients’ expectations of consultations’, BMJ, 328 (2004):416–17 12 M. Mendelson, et al. ‘Maximising access to achieve appropriate human antimicrobial use in low- income and middle-income countries,’ Lancet 387(2015):188–98; R. Laxminarayan, et al., ‘Access to effective antimicrobials: a worldwide challenge,’ Lancet 387(2016): 168–175. 13 N. Gualde, Resistance: The human struggle against infection (New York: Dana Press, 2006); R. Laxminarayan and D.L. Heymann, ‘Challenges of drug resistance in the developing world,’ BMJ 344(2012): e1567. 14 J. O’Neill, et al., Antimicrobials in agriculture and the environment: reducing unnecessary use and waste (London: Review on Antimicrobial Resistance, 2016) https://amr-review.org/sites/ default/files/Antimicrobials%20in%20agriculture%20and%20the%20environment%20-%20", "n_tokens": 453, "kind": "text"}
{"chunk_id": "drug_resistance_book-427-3", "doc_id": "drug_resistance_book", "page": 427, "text": "Reducing%20unnecessary%20use%20and%20waste.pdf (accessed September 12, 2017). 15 Food and Agriculture Organization of the United Nations, Drivers, Dynamics and Epidemiology of Antimicrobial Resistance in Animal Production (Geneva: WHO, 2016); R.W. Meek RW, H. Vyas and L.J.V. Piddock, ‘Nonmedical Uses of Antibiotics: Time to Restrict Their Use?’ PLoS Biology 13(2015): e1002266. https://doi.org/10.1371/journal.pbio.1002266.", "n_tokens": 136, "kind": "text"}
{"chunk_id": "drug_resistance_book-427-4", "doc_id": "drug_resistance_book", "page": 427, "text": "423", "n_tokens": 2, "kind": "text"}
{"chunk_id": "drug_resistance_book-428-0", "doc_id": "drug_resistance_book", "page": 428, "text": "424\n\nJ. Littmann et al.", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-428-1", "doc_id": "drug_resistance_book", "page": 428, "text": "philosophers, economists and public health professionals.16 This requires high degrees of multi-sectorial integration, coordination and accountability mechanisms, for which existing policy-making structures are inappropriate or insufficient.17 This is further compounded by the fact that AMR has numerous interdependent biologi- cal and social drivers that make it a problem on the global scale. Expanding interna- tional travel, tourism and trade will continue to perpetuate resistance beyond current levels.18 As such, while national and regional policies can certainly impact on the prevalence of drug-resistant infections,19 the global dissemination of resistant bac- teria demonstrate why such localised efforts alone cannot be ultimately effective.20 As a result of all of these considerations, AMR also raises distinctive ethical issues, which must not only be accounted for in our policy and response activities, but will play an important role in supporting the numerous difficult choices involved in balancing the benefits and burdens associated with protecting antibiotic effective- ness and reducing the spread of drug-resistant infections.21 Our traditional norma- tive theories and principles, as developed in other infection prevention and control contexts, will be insufficient if mechanically applied as if it were just another prob- lem of infectious disease ethics. It will require careful attention to the morally- relevant features of what makes AMR a distinctive problem, and", "n_tokens": 273, "kind": "text"}
{"chunk_id": "drug_resistance_book-428-2", "doc_id": "drug_resistance_book", "page": 428, "text": "due care and context-specificity in the application of moral guidance and regulation. The ethical analysis required to shape and guide our policy response to the problem of AMR", "n_tokens": 33, "kind": "text"}
{"chunk_id": "drug_resistance_book-428-3", "doc_id": "drug_resistance_book", "page": 428, "text": "16 S.B. Levy, The Antibiotic Paradox (Cambridge, MA: Perseus Publishing, 2002). 17 R.D. Smith and J. Coast, ‘Antimicrobial resistance: a global response,’ Bulletin of the World Health Organization 80(2002): 126–133; R. Laxminarayan, et al., ‘Antibiotic resistance-the need for global solutions,’ Lancet Infectious Diseases 13(2013): 1057–98; C. Årdal, et al., ‘International cooperation to improve access to and sustain effectiveness of antimicrobials,’ Lancet 387(2015): 296–307; S. J. Hoffman and T. Ottersen, ‘Addressing Antibiotic Resistance Requires Robust International Accountability Mechanisms,’ The Journal of Law, Medicine and Ethics 43(2015): 53–64. 18 D.W. MacPherson, B.D. Gushulak and W.B. Baine, ‘Population Mobility, Globalization, and Antimicrobial Drug Resistance,’ Emerging Infectious Diseases 17(2009): 1727–1732; Z. S. Ahammad, et al., ‘Increased Waterborne blaNDM-1 Resistance Gene Abundances Associated with Seasonal Human Pilgrimages to the Upper Ganges River,’ Environmental Science & Technology 48(2014): 3014–3020; A.H. Holmes, L.S. Moore and A. Sundsfjord, ‘Understanding the mechanisms and drivers of antimicrobial resistance,’ Lancet 387(2016): 176–87. 19 For instance, as illustrated by the significant variation in the proportion of methicillin-resistant Staphylococcus aureus (MRSA) infections across European hospitals. See, e.g., European Centre for Disease Prevention and Control, Annual epidemiological report on communicable diseases in Europe (Stockholm: ECDC,", "n_tokens": 398, "kind": "text"}
{"chunk_id": "drug_resistance_book-428-4", "doc_id": "drug_resistance_book", "page": 428, "text": "2011). 20 I.N. Okeke and R. Edelman, ‘Dissemination of Antibiotic-Resistant Bacteria across Geographic Borders,’ Clinical Infectious Diseases 33(2001): 364–369; S.E. Majowicz, et al., ‘The Global Burden of Nontyphoidal Salmonella Gastroenteritis,’ Clin Infect Dis 50(2010): 882–89; L.S. Tzouvelekis, et al., ‘Carbapenemases in Klebsiella pneumoniae and Other Enterobacteriaceae: an Evolving Crisis of Global Dimensions,’ Clinical Microbiology Reviews. 25(2012): 682–707; Nicola K. Petty, et al. ‘Global dissemination of a multidrug resistant Escherichia coli clone,’ PNAS 111(2014): 5694–5699. 21 J. Littmann and A.M. Viens, ‘The Ethical Significance of Antimicrobial Resistance,’ Public Health Ethics 8(2015): 209–224.", "n_tokens": 227, "kind": "text"}
{"chunk_id": "drug_resistance_book-429-0", "doc_id": "drug_resistance_book", "page": 429, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\nalso necessitates thinking and theorizing that is able to incorporate and reflect the various biological, social, political and legal factors involved in the spread and con- trol of drug-resistant infections.", "n_tokens": 54, "kind": "text"}
{"chunk_id": "drug_resistance_book-429-1", "doc_id": "drug_resistance_book", "page": 429, "text": "In this paper, we will argue that the concept of super-wicked problems can pro- vide an apt description of the current situation regarding AMR, and that it will help us better understand some of the complex ethical challenges associated with AMR. Furthermore, framing AMR as a super-wicked problem will help to explain why at first glance, AMR appears to be so similar to other large policy challenges, such as climate change. However, we will argue that the structural similarity should not lead us to conclude that attempts to mitigate one super-wicked problem can simply be transferred to another. Instead, we suggest that the crucial feature of super-wicked problems is the need to change path dependency – a term we will explain more fully below – and that this change will likely require unique approaches, methods and tools for each super-wicked problem. To develop this argument, we will first introduce the ideas of super-wicked problems as a way to frame AMR. Second, we will argue that conceptualizing AMR as a super-wicked problem can help inform policy making by highlighting how our efforts should be focused. Finally, in sections four and five, we provide a potential way to move forward, and highlight key ethical issues that arise in this context.\n\n26.2", "n_tokens": 255, "kind": "text"}
{"chunk_id": "drug_resistance_book-429-2", "doc_id": "drug_resistance_book", "page": 429, "text": "Framing AMR as a Super-Wicked Problem\n\nThe concept of wicked problems, which has its origins in Rittel and Webber’s paper about planning theory, describes certain policy problems as complex challenges that do not respond to standard problem-solving mechanisms.22 Rittel and Webber sug- gest that the success of social policy in the 19th and early twentieth century was essentially the picking of low-hanging fruits, and that the policy challenges that societies are now facing are much more difficult to address.23 Inherent complexity (i.e., the overlapping and varied sources of influence or causes to a social problem that resist simple linear solutions),24 inter-relatedness with other policy fields, and several conflicting goals that might each be reasonably pursued, make some policy problems “wicked”. According to Rittel and Webber, these problems are not solv- able by traditional instruments of policy making, especially not by cost-benefit or\n\n22 H.W.J. Rittel and M.M. Webber, ‘Dilemmas in a General Theory of Planning,’ Policy Sciences 4:2 (1973): 155–69. 23 H.W.J. Rittel and M.M. Webber, ‘Dilemmas in a General Theory of Planning,’ Policy Sciences 4:2 (1973): 155–69. 24 M.C. Jackson, Systems Thinking: Creative Holism for Managers (West Sussex, UK: John Wiley and Sons, Ltd., 2003).\n\n425", "n_tokens": 304, "kind": "text"}
{"chunk_id": "drug_resistance_book-430-0", "doc_id": "drug_resistance_book", "page": 430, "text": "426\n\nJ. Littmann et al.\n\nsystem analysis, as these approaches cannot make sense of all dimensions of wicked problems.25\n\nWicked problems are characterized by the fact that proposed solutions cannot be judged as ‘right’ or ‘wrong’ but merely as more or less suitable, and they do not allow for a trial-and-error approach to policy-making. Instead, Rittel and Webber argue, wicked problems only allow policy-makers a single shot at solving the prob- lem – if this fails, the unsuccessful policy will have changed the original problem to such an extent its initial alternatives may no longer be viable contenders.26\n\nThe concept of wicked problems has been applied to a number of areas as diverse as coastal governance,27 liberal arts and design28 and, more recently, climate change. It has been argued, however, that the latter no longer presents a wicked, but a ‘super- wicked’ problem.29 Super-wicked problems provide an even greater challenge due to four additional complications that policy makers have to engage with. These cri- teria are:\n\n(i) Time for finding a solution to a policy challenge is running out; (ii) Those seeking to solve the problem are part of the cause; (iii) Central authorities to address the problem are either weak or non-existent; and (iv) Policy responses discount the future irrationally.30", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-430-1", "doc_id": "drug_resistance_book", "page": 430, "text": "The following section illustrates how these criteria can be applied to the case of AMR, why it should be viewed as a super-wicked problem and how each aspect of the problem raises important ethical concerns that must be factored into how we will be justified in responding to AMR as a super-wicked problem.\n\n26.2.1", "n_tokens": 67, "kind": "text"}
{"chunk_id": "drug_resistance_book-430-2", "doc_id": "drug_resistance_book", "page": 430, "text": "Criterion 1: Time Is Running Out\n\nSuper-wicked problems require drastic and urgent responses if they are not to become unsolvable policy dilemmas. In the case of AMR, it is evident that increas- ing drug resistance will exacerbate the existing challenge, which has led to concerns\n\n25 H.W.J. Rittel and M.M. Webber, ‘Dilemmas in a General Theory of Planning,’ Policy Sciences 4:2 (1973): 155–69. 26 H.W.J. Rittel and M.M. Webber, ‘Dilemmas in a General Theory of Planning,’ Policy Sciences 4:2 (1973): 155–69. 27 S. Jentoft and R. Chuenpagdee, ‘Fisheries and coastal governance as a wicked problem,’ Marine Policy 33(2009): 553–60. 28 R. Buchanan, ‘Wicked Problems in Design Thinking,’ Design Issues 8(1992): 5–21. 29 R. Lazarus, ‘Super wicked problems and climate change: restraining the present to liberate the future,’ Cornell Law Review 94(2009): 1153–234; K. Levin, et al., ‘Overcoming the tragedy of super wicked problems: constraining our future selves to ameliorate global climate change,’ Policy Sciences 45:2 (2012): 123–52. 30 K. Levin, et al., ‘Overcoming the tragedy of super wicked problems: constraining our future selves to ameliorate global climate change,’ Policy Sciences 45:2 (2012): 123–52.", "n_tokens": 337, "kind": "text"}
{"chunk_id": "drug_resistance_book-431-0", "doc_id": "drug_resistance_book", "page": 431, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\nabout a “post-antibiotic era”.31 There is thus, in short, an observable trend towards more complex cases of AMR, which will either be very difficult to treat or no longer respond to antibiotics at all.32 Indeed, for some infections, such as tuberculosis or gonorrhea, resistance to all common treatments can already be observed.33 As multi- and extensively drug resistant infections are being registered more and more fre- quently and with a lack of new antibiotics under development, the prospect of total antimicrobial resistance is no longer an abstract worst-case scenario.34 This not only signals the need to make exigent decisions about a large and serious risk of harm for individuals and populations, but also factoring in the ethics of acting under condi- tions of necessity, urgency and uncertainty – and how this may differ from policy responses taken under conditions of normalcy.35\n\n26.2.2", "n_tokens": 204, "kind": "text"}
{"chunk_id": "drug_resistance_book-431-1", "doc_id": "drug_resistance_book", "page": 431, "text": "Criterion 2: Those Seeking a Solution Are Part of the Problem\n\nAMR is a multi-factorial problem and often those involved in combating it also contribute to, or exacerbate it, in some important way:\n\nHealth care professionals, who in many countries act as gatekeepers for access to antibiotics, often prescribe more antibiotics than necessary, which can lead to higher prevalence of drug-resistant infections.36 There in an increasing number of studies, which indicate that a high proportion of prescriptions of antibiotics do not comply with scientific guidelines.37 Furthermore, appropriate infection", "n_tokens": 114, "kind": "text"}
{"chunk_id": "drug_resistance_book-431-2", "doc_id": "drug_resistance_book", "page": 431, "text": "31 N. Brown, ‘Dawn of the post-antibiotic age?’ BMJ 309(1994): 615; A.J. Alanis, ‘Resistance to Antibiotics: Are We in the Post-Antibiotic Era?’ Arch Med Res 36(2005): 687–705. 32 European Centre for Disease Prevention and Control, Antimicrobial resistance surveillance in Europe: Annual report of the European Antimicrobial Resistance Surveillance Network (EARS- Net) 2011 (Stockholm, 2012). 33 E. Alirol, et al., ‘Multidrug-resistant gonorrhea: A research and development roadmap to dis- cover new medicines,’ PLoS Med 14(2017): e1002366; World Health Organization, Treatment guidelines for drug-resistant tuberculosis, 2016 update (Geneva: WHO, October 2016 revision) http://apps.who.int/iris/bitstream/10665/250125/1/9789241549639-eng.pdf?ua=1&ua=1 (Accessed September 25, 2017). 34 European Centre for Disease Prevention and Control, The bacterial challenge: time to react (Stockholm, 2009). 35 See, e.g., A.M. Viens, ‘Normative Uncertainty and the Ethics of Risk Regulation in Emergency,’ in A. Alemanno (ed.), Governing Disasters: The Challenges of Emergency Risk Regulation (Edward Elgar Publishing, 2011), pp. 137–46; A.M. Viens, In Extremis: Morality in Times of Emergency (London: University of London PhD, 2012). 36 R.G. Finch, ‘Antibiotic resistance: a view from the prescriber,’ Nature Reviews Microbiology 2(2004): 989–94; V.I. Enne, ‘Reducing antimicrobial resistance in the community by restricting prescribing: can it be done?’ Journal of Antimicrobial Chemotherapy 65(2010):", "n_tokens": 421, "kind": "text"}
{"chunk_id": "drug_resistance_book-431-3", "doc_id": "drug_resistance_book", "page": 431, "text": "179–82. 37 K.E. Fleming-Dutra, A.L. Hersh and D.J. Shapiro, ‘Prevalence of Inappropriate Antibiotic Prescriptions Among US Ambulatory Care Visits, 2010–2011,’ JAMA 315(2016): 1864–1873. doi:https://doi.org/10.1001/jama.2016.4151.", "n_tokens": 82, "kind": "text"}
{"chunk_id": "drug_resistance_book-431-4", "doc_id": "drug_resistance_book", "page": 431, "text": "427", "n_tokens": 2, "kind": "text"}
{"chunk_id": "drug_resistance_book-432-0", "doc_id": "drug_resistance_book", "page": 432, "text": "428\n\nJ. Littmann et al.\n\nprevention and control can reduce the need for antibiotics in the first place – which is an area where improvements can be made too.38", "n_tokens": 36, "kind": "text"}
{"chunk_id": "drug_resistance_book-432-1", "doc_id": "drug_resistance_book", "page": 432, "text": "Pharmaceutical companies have steadily decreased research efforts into new antimicrobial drugs, despite mounting pressures on health care systems to intro- duce new and effective drugs. The lack of investment is, at least, partly caused by concerns over limited returns on investment due to advancing AMR.39 Margaret Chan, former World Health Organization (WHO) Director-General, recently alluded to this problem, when she rhetorically asked: “[f]rom an industry per- spective, why invest considerable sums of money to develop a new antimicrobial when irrational use will accelerate its ineffectiveness before the R&D investment can be recouped?”40 Recent advances in clinical research show that it may be possible to develop entirely new classes of antibiotics.41 However, the time frame for their development remains unclear and unless novel ways of financing are introduced, their prices are likely to be prohibitive for most patients in low and middle-income countries (LMICs). The industry perspective is that the invest- ment into new antibiotics is only financially feasible, if considerable lump sum payments, so-called market entry rewards, are paid out. These are usually esti- mated to have to be greater than $ 1 billion.42 Moreover, the antibiotic production process and discarded antibiotic-laced waste can also have a considerably nega- tive environmental impact that further perpetuates resistance.43", "n_tokens": 282, "kind": "text"}
{"chunk_id": "drug_resistance_book-432-2", "doc_id": "drug_resistance_book", "page": 432, "text": "38 J. O’Neill et al., Tackling Drug-Resistant Infections Globally: Final Report and Recommendations (London: Review on Antimicrobial Resistance, 2016), available at https://amr-review.org/sites/ default/files/160518_Final%20paper_with%20cover.pdf (accessed September 29, 2017). 39 C. Morel and E. Mossialos, ‘Stoking the antibiotic pipeline,’ BMJ 340(2010): c2115. 40 M. Chan, Secondary Antimicrobial Resistance in the European Union and the World (Geneva: World Health Organization, 2012), available at: http://www.who.int/dg/speeches/2012/ amr_20120314/en/ (accessed September 29, 2017). 41 L.L. Ling, et al., ‘A new antibiotic kills pathogens without detectable resistance,’ Nature 517(2015): 455–59. 42 R. Laxminarayan, P. Matsoso, S Pant, C. Brower, J.A. Røttingen, K. Klugman and S. Davies, ‘Access to effective antimicrobials: a worldwide challenge,’ Lancet 387(2016): 168–175; K. Outterson, et al., ‘Delinking Investment in Antibiotic Research and Development from Sales Revenues: The Challenges of Transforming a Promising Idea into Reality,’ PLOS Medicine 13(2016): e1002043. https://doi.org/10.1371/journal.pmed.1002043. 43 K.D. Brown, et al., ‘Occurrence of antibiotics in hospital, residential, and dairy effluent, munici- pal wastewater, and the Rio Grande in New Mexico,’ Science of the Total Environment 366(2006): 772–783; J. Fick, et al., ‘Contamination of surface, ground, and drinking water from pharmaceuti- cal production,’ Environ Toxicol Chem 28(2009): 2522–7; D.G.J. Larsson,", "n_tokens": 468, "kind": "text"}
{"chunk_id": "drug_resistance_book-432-3", "doc_id": "drug_resistance_book", "page": 432, "text": "‘Pollution from drug manufacturing: review and perspectives. Phil. Trans. R. Soc. B 369(2014): 20130571; Changing Markets Foundation, Superbugs in the Supply Chain: How Pollution from Antibiotics Factories in India and China is Fuelling the Global Rise of Drug-Resistant Infections (Utrecht: Changing Markets Foundation, 2016); R. Laxminarayan and R.R. Chaudhury, ‘Antibiotic Resistance in India: Drivers and Opportunities for Action,’ PLoS Medicine 3(2016): e1001974; C. Lübbert, et al., ‘Environmental pollution with antimicrobial agents from bulk drug manufacturing industries in Hyderabad, South India, is associated with dissemination of extended-spectrum beta-lactamase and carbapenemase-producing pathogens,’ Infection 45(2017): 479–491.", "n_tokens": 183, "kind": "text"}
{"chunk_id": "drug_resistance_book-433-0", "doc_id": "drug_resistance_book", "page": 433, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\nPatients who are prescribed antibiotics often fail to adhere to treatment recom- mendations. This problem is exacerbated in countries where antibiotics are avail- able for purchase over the counter, and patients may be unable to afford or have access to a health care professional who can prescribe and dispense the appropri- ate drug.44\n\nFood Producers and Sellers must continue to take significant steps to reduce the use of antibiotics as growth promoters and adopt practices that reduce the extent to which the food chain continues to be a key pathway for the transmission of resistant pathogens.45 We also need to ensure AMR surveillance systems include resistance levels in animal stocks and food systems.", "n_tokens": 148, "kind": "text"}
{"chunk_id": "drug_resistance_book-433-1", "doc_id": "drug_resistance_book", "page": 433, "text": "Governments and intergovernmental organizations still lack the requisite regula- tion and governance structures to address the complexity associated with AMR and remain focused on multilateral and bilateral agreements that were commonly used in the middle of the twentieth century.46 The various and complex interacting contributions to the spread of AMR make it difficult (though certainly not impossible) to attribute causal responsibility to past action, including a failure to act. This also raises important questions about how our policy response should hold individuals, groups and institutions morally responsi- ble for their complicity or causal contribution to AMR in any accountability mecha- nisms developed going forward.\n\n26.2.3\n\nCriterion 3: Central Authorities to Address the Problem Are either Weak or Non-existent\n\nThere is currently a lack of institutional structures that can meet the challenge of AMR effectively and at all policy levels. While international organizations, such as WHO or ECDC, have developed guidelines for prudent use of antibiotics, as well as", "n_tokens": 200, "kind": "text"}
{"chunk_id": "drug_resistance_book-433-2", "doc_id": "drug_resistance_book", "page": 433, "text": "44 M.B. Planta, ‘The Role of Poverty in Antimicrobial Resistance’ J Am Board Fam Med, 20:6 (2007):533–39; I.N. Okeke, A. Lamikanra, R. Edelman, ‘Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries,’ Emerging Infectious Diseases 5(1999): 18–27; D.J. Morgan, I.N. Okeke, R. Laxminarayan, E.N. Perencevich and S. Weisenberg, ‘Non-prescription antimicrobial use worldwide: a systematic review,’ The Lancet Infectious Diseases 11(2011): 692–701. 45 C. Verraes, et al., ‘Antimicrobial Resistance in the Food Chain: A Review,’ International Journal of Environmental Research and Public Health 10(2013): 2643–2669; T. P. Van Boeckel, et al., ‘Global trends in antimicrobial use in food animals,’ Proceedings of the National Academy of Sciences of the United States of America 112(2015): 5649–5654; T. P. Van Boeckel, et al. ‘Reducing antimicrobial use in food animals,’ Science 357(2017): 1350–1352. 46 A. C. Singer, et al. ‘Review of Antimicrobial Resistance in the Environment and Its Relevance to Environmental Regulators,’ Frontiers in Microbiology 7(2016):1728; Gabriel Birgand, et al., ‘Comparison of governance approaches for the control of antimicrobial resistance: Analysis of three European countries,’ Antimicrobial Resistance & Infection Control 7(2018): 28. More is written regarding the role of these stakeholders below, under criterion 3.\n\n429", "n_tokens": 389, "kind": "text"}
{"chunk_id": "drug_resistance_book-434-0", "doc_id": "drug_resistance_book", "page": 434, "text": "430\n\nJ. Littmann et al.\n\nprograms for co-operation and data sharing, their implementation lies with the respective national governments and adherence cannot be enforced.47 Failure to fol- low these recommendations is not necessarily a matter of ignorance or antipathy – in many instances countries may simply lack the control mechanisms, infrastructure, expertise, or resources to meet all requirements and recommendations of best- practice guidelines. It is also being increasingly recognized that poor governance and political corruption make major contributions to our inability to effectively respond to AMR.48 However, since drug resistance cannot be confined by national borders, these discrepancies and deficiencies in national health systems and policies inevitably threatens the effectiveness of antibiotics and control of drug-resistant infections, even in countries that strictly enforce measures to reduce and control the use of antibiotics and mitigate the spread of AMR. More recently, the United Nations has sought to address AMR more comprehensively across sectors and pol- icy areas, both by establishing a temporary interagency coordination group, and by strengthening the tripartite, a coordinating forum comprised of WHO, FAO, OIE, and UN Environment.49 Nevertheless, coordination between international mecha- nisms and national institutions remains a voluntary process, for which few dedi- cated resources are available.", "n_tokens": 261, "kind": "text"}
{"chunk_id": "drug_resistance_book-434-1", "doc_id": "drug_resistance_book", "page": 434, "text": "This raises important questions about, for instance, who should take ultimate responsibility for antimicrobial stewardship when there are no central authorities or where jurisdictions lack the resources or infrastructure to undertake stewardship activities in accordance with international recommendations.50 Indeed, the effect of the absence of authorities and resources in the face of the inherent complexity of global health governance has gained greater and greater traction in the global health arena. In particular, we are starting to see more of a role for formal and informal stakeholders (e.g., Wellcome Trust, Bill and Melinda Gates Foundation, World Bank, corporations) increasingly shaping and guiding global health activity through many channels – many of which are no longer transparent nor are the varied values and interests of these stakeholders always easy to fully comprehend.51 As such, the super-wicked problem of AMR sits within a much broader complex challenge that", "n_tokens": 174, "kind": "text"}
{"chunk_id": "drug_resistance_book-434-2", "doc_id": "drug_resistance_book", "page": 434, "text": "47 See e.g. the World Health Organization’s Global Action Plan on Antimicrobial Resistance (Geneva: WHO, 2015). 48 P. Collignon, et al., ‘Antimicrobial Resistance: The Major Contribution of Poor Governance and Corruption to this Growing Problem,’ PLoS One 10(2015): e0116746; B. Rönnerstrand and V. Lapuente, ‘Corruption and use of antibiotics in regions of Europe,’ Health Policy 121(2017): 250–256. 49 See World Health Organization, ‘Interagency Coordination Group on Antimicrobial Resistance (IACG), https://www.who.int/antimicrobial-resistance/interagency-coordination-group/en/ (accessed October 10, 2018), and World Health Organization, FAO, OIE, WHO – Tripartite Concept Note (Geneva: WHO, 2010) http://www.who.int/foodsafety/areas_work/zoonose/con- cept-note/en/ (accessed October 10, 2018). 50 B. Bennett and J. Iredell, “Global health governance and antimicrobial resistance” In Ethics and Drug Resistance: Collective Responsibility for Global Public Health. Springer, Cham. 51 C. Clinton and D. Sridhar, Governing Global Health (Oxford: Oxford University Press, 2017); J. Youde. Global Health Governance (Cambridge: Polity Press, 2012); Nora Kenworthy, Ross", "n_tokens": 320, "kind": "text"}
{"chunk_id": "drug_resistance_book-435-0", "doc_id": "drug_resistance_book", "page": 435, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\nis making sense of, and impacting, global health governance, thus amplifying and multiplying the complexity of addressing AMR.\n\n26.2.4", "n_tokens": 45, "kind": "text"}
{"chunk_id": "drug_resistance_book-435-1", "doc_id": "drug_resistance_book", "page": 435, "text": "Criterion 4: Current Policies Discount the Future Irrationally\n\nThere is a notable disparity between the enormous significance that antibiotics have in today’s health care systems and the lack of a comprehensive and realistically implementable global strategy to protect them as a resource for current and future generations.52 Indeed, while the impact of AMR on health outcomes today and in the future is increasingly recognized, there remains a lack of coordination and suf- ficient funding to address the problem. When the health ministers of the G20 coun- tries met for the first time in 2017, they declared “AMR has the potential to have a major negative impact on public health as well as on growth and global economic stability”.53 Other impact assessments have come to similar conclusions.54 Since modern medicine relies so heavily on antibiotics as a prophylactic for standard sur- gical procedures, the further progression of AMR would be detrimental not only for infectious disease policy, it would also affect the outcome of surgical care or the survival chances of cancer patients. In short, AMR has become a wider health sys- tem issue.55 It is therefore all the more surprising that current policies do not place greater emphasis on long-term strategies to preserve antibiotic effectiveness and best-case policy scenarios consist in the preservation of some level of antibiotic effectiveness in the short run, without a comprehensive replacement strategy for ineffective drugs.56", "n_tokens": 284, "kind": "text"}
{"chunk_id": "drug_resistance_book-435-2", "doc_id": "drug_resistance_book", "page": 435, "text": "Due to the complexity of the drivers of AMR, its costs are extremely difficult to assess, even if they are only measured locally or in the short run.57 A number of recent economic models have attempted to model the long-term costs, but due to the", "n_tokens": 53, "kind": "text"}
{"chunk_id": "drug_resistance_book-435-3", "doc_id": "drug_resistance_book", "page": 435, "text": "MacKenzie, and Kelley Lee (eds.), Case Studies on Corporations and Global Health Governance: Impacts, Influence and Accountability (Rowman & Littlefield, 2016). 52 M. Millar M, ‘Can antibiotic use be both just and sustainable... or only more or less so?’ Journal of Medical Ethics 37(2011): 153–7; L. Leibovici, M. Paul and O. Ezra, ‘Ethical dilemmas in anti- biotic treatment,’ Journal of Antimicrobial Chemotherapy 67(2012): 12–16. 53 Berlin Declaration of the G20 Health Ministers, Berlin 2017, p. 5 https://www.bundesgesund- heitsministerium.de/fileadmin/Dateien/3_Downloads/G/G20-Gesundheitsministertreffen/G20_ Health_Ministers_Declaration_engl.pdf (accessed on September 25, 2017). 54 O. Adeyi. et al., Drug-resistant infections: A threat to our economic future, Volume 2 (Washington, D.C: World Bank, http://documents.worldbank.org/curated/ en/323311493396993758/final-report 55 R. Smith and J. Coast, ‘The true cost of antimicrobial resistance,’ BMJ 346(2013): f1493. 56 A.J. Alanis, ‘Resistance to Antibiotics: Are We in the Post-Antibiotic Era?’ Arch Med Res 36(2005): 687–705. 57 D.H. Howard, R.D. Scott, ‘The Economic Burden of Drug Resistance,’ Clin Infect Dis 41(2005): S283-S86; R. Smith and J. Coast, ‘The true cost of antimicrobial resistance,’ BMJ 346(2013): f1493.\n\n2017),\n\navailable\n\nat\n\n431", "n_tokens": 417, "kind": "text"}
{"chunk_id": "drug_resistance_book-436-0", "doc_id": "drug_resistance_book", "page": 436, "text": "432\n\nJ. Littmann et al.\n\ncomplexity of AMR, they inevitably have to restrict their analysis to a select number of bacterial pathogens or consider a limited number of potential cost factors.58 As a result, existing cost models likely underestimate the long-term effects of AMR. However, even these conservative cost models, which – by their own admis- sion – systematically underestimate some of the costs associated with drug resis- tance, come to the conclusion that the cost of AMR (including resistance to antiviral drugs) may exceed $100 trillion in total GDP loss by 2050.59 What this shows quite clearly is that current efforts to address AMR are simply not proportionate to the magnitude of the challenge at hand.", "n_tokens": 157, "kind": "text"}
{"chunk_id": "drug_resistance_book-436-1", "doc_id": "drug_resistance_book", "page": 436, "text": "This also raises questions about the proportionality of our policy responses – in a moral and legal sense – in light of how it will be legitimate for us to act given the seriousness of the challenge faced. If the spread and magnitude of harm of AMR will be as predicted, what could be currently seen as a disproportionate response – for instance, what might be seen as overly paternalistic or coercive measures – may be seen to be justified as the problem worsens. Nevertheless, if the long game here is about keeping AMR at bay for as long as possible, should we actually have to wait until the problem gets much worse before we are justified in utilizing more paternal- istic or coercive measures to achieve the same goal? The moral and legal calculus involved – and the extent to which the legitimacy of our responses should be deter- mined in proportion to the risk of harm – could signal, for example, the develop- ment of new or more stringent stewardship obligations, the imposition of more risk on individuals (even without consent) and potential limitations on once established and uncontroversial entitlements and rights.60 The nature of super-wicked problems are such that we must consider not only what norms and values should advance particular social, medical and public health goals, but also how such norms and values can set constraints or limits on these goals.", "n_tokens": 283, "kind": "text"}
{"chunk_id": "drug_resistance_book-436-2", "doc_id": "drug_resistance_book", "page": 436, "text": "58 J. Taylor, et al., Estimating the economic costs of antimicrobial resistance: models and results (Cambridge, UK: RAND Europe, 2014); KPMG, The global economic impact of antimicrobial resistance (London: KPMG: 2014). 59 J. O’Neill et al., Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. (London: Review on Antimicrobial Resistance, 2016), available at https://amr-review.org/sites/ default/files/160518_Final%20paper_with%20cover.pdf (accessed September 29, 2017). 60 Gro Harlem Brundtland, who served three terms as Prime Minister of Norway and as Director- General of the World Health Organization from 1998 to 2003, maintained that “AMR is just as much about human rights and justice as it is about health” [http://blogs.bmj.com/bmj/2017/12/06/ gro-harlem-brundtland-new-who-guidelines-are-crucial-step-to-fighting-antimicrobial- resistance/]", "n_tokens": 246, "kind": "text"}
{"chunk_id": "drug_resistance_book-437-0", "doc_id": "drug_resistance_book", "page": 437, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\n26.3\n\nHow Conceptualizing AMR as a Super-Wicked Problem Can Inform Policy Making\n\nThe account of AMR as a super-wicked problem is not merely descriptive, but offers a framework for assessing the expected impact of policy making. Understanding AMR as a super-wicked problem underlines three important facts. First, it high- lights the tendency of current policies to focus on preserving antibiotic effective- ness, while failing to reduce the future need for antibiotics. Second, it explains why traditional instruments, such as cost-benefit analysis (CBA), are unsuited to deter- mining an appropriate policy response. Third, it helps bring to light how the com- plex interaction of ethical considerations will contribute to shaping which policy options will be viewed as acceptable.", "n_tokens": 167, "kind": "text"}
{"chunk_id": "drug_resistance_book-437-1", "doc_id": "drug_resistance_book", "page": 437, "text": "Many of the existing policies that address AMR (and a considerable portion of the academic literature) emphasize the need for new antibiotics, as well as the cost- effective and prudent use of available resources.61 The policy focus is thus on addressing problems on the supply side, and the creation of new resources, where a broad number of policy campaigns already exist.62 However, if AMR is understood as a super-wicked problem, it becomes apparent that such approaches – while a necessary contribution – will ultimately and inevitably fall short of the goal of effec- tively controlling AMR in the long run. Consideration must take place of the relative value of focusing on upstream versus downstream determinants of drug-resistant infections, and the extent to which values other than efficiency or innovation (e.g., health equity) should guide both which drivers of resistance we focus on as well as which preventive and therapeutic responses we should pursue.\n\nFraming AMR as a super-wicked problem should lead policy makers to place a much stronger emphasis on those policies, which – to paraphrase Levin et al. – gen- erate a shift in path dependencies.63 The concept of path dependencies explains current policies in light of their development of time, and as a result of earlier deci- sion.64 A given policy may therefore be more influenced by legacy decisions than by", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-437-2", "doc_id": "drug_resistance_book", "page": 437, "text": "61 E. Mossialos, et al, Policies and incentives for promoting innovation in antibiotic research (Copenhagen: European Observatory on Health Systems and Policies, 2008); T. Groves, ‘Back to basics with the three Rs,’ BMJ 344(2012); R. Laxminarayan and G.M. Brown, Economics of Antibiotic Resistance: A Theory of Optimal Use (Washington D.C. Resources for the Future, 2001); C. Morel and E. Mossialos, ‘Stoking the antibiotic pipeline,’ BMJ 340(2010): c2115. 62 L.D. Högberg, A. Heddini, and O. Cars, ‘The global need for effective antibiotics: challenges and recent advances’ Trends Pharmacol Sci 31(2010): 509–15. 63 K. Levin, et al., ‘Overcoming the tragedy of super wicked problems: constraining our future selves to ameliorate global climate change,’ Policy Sciences 45(2012): 123–52. 64 A more complete definition of path dependence is as follows: ‘Path dependence is the idea that decisions we are faced with depend on past knowledge trajectory and decisions made, and are thus limited by the current competence base. In other words, history matters for current decision-mak- ing situations and has a strong influence on strategic planning… A well-known example is the QWERTY layout for typewriters. Despite the fact that different keyboard layouts in modern com- puter keyboards would allow faster typing, the QWERTY layout prevails.’ Financial Times Lexicon http://lexicon.ft.com/Term?term=path-dependence (accessed September 30, 2017).\n\n433", "n_tokens": 366, "kind": "text"}
{"chunk_id": "drug_resistance_book-438-0", "doc_id": "drug_resistance_book", "page": 438, "text": "434\n\nJ. Littmann et al.\n\nthe current state of affairs and the latest available evidence. A shift in path depen- dencies is necessary once it has become apparent that the trajectory of earlier policy decisions is leading to an unsustainable outcome in the long run. In the case of cli- mate change, for example, such path dependency is exemplified by the widespread and continued reliance on fossil fuels.65 In the case of AMR, this path dependency is reflected by the reliance on antibiotics as not only a treatment against acute infec- tion, but also as a tool for infection prevention in both clinical and veterinary set- tings. This dependency is replicated in most current policies that focus on pulling on the same levers, which aim at either increasing the availability of antibiotics or decreasing the use of antibiotics. What is crucially missing is sufficient emphasis on infection prevention and control measures that reduce the need for antibiotics in the first place.", "n_tokens": 196, "kind": "text"}
{"chunk_id": "drug_resistance_book-438-1", "doc_id": "drug_resistance_book", "page": 438, "text": "Consequently, current policies do not offer a long-term fix to the problem of AMR and create, at best, a “faux paradigmatic change”, in which the implementa- tion of policy only makes small corrections to a previous policy failure temporari- ly.66 The most obvious example for a faux paradigmatic shift is the reliance on future developments of new antibiotics, which are effective against resistant bacte- ria. While such a development will provide significant short-term improvements, past experience suggests that bacteria will ultimately develop resistance to new classes of antibiotics, as well. Consequently, as Spellberg has observed, “we will never truly defeat microbial resistance; we can only keep pace with it.”67 In the absence of a realistic option for true paradigmatic change (i.e., a technological method to avoid the further emergence and spread of AMR altogether), it appears advisable to abandon ambitions to outpace the adaptation of microbes to new anti- biotics, and instead focus on the creation of incremental but transformative changes, which no longer follow the same policy trajectory and instead reduce the dependence on antibiotics. In particular, this new trajectory must have as a chief focus policy options that can be effectively implemented in LMICs.", "n_tokens": 260, "kind": "text"}
{"chunk_id": "drug_resistance_book-438-2", "doc_id": "drug_resistance_book", "page": 438, "text": "One analogy that summarizes this situation, and which has been used repeatedly to describe the problem at hand, is that of a “leaky bucket”.68 If we think of antibi- otic effectiveness as a resource contained in a bucket, the emergence of resistance is\n\n65 G. Unruh, ‘Understanding Carbon Lock-In,’ Energy Policy 28(2000): 817–30; P. Aghion, C. Hepburn, A. Teytelboym, and D. Zenghelis, Path dependence, innovation and the economics of climate change (London: Centre for Climate Change Economics and Policy Grantham Research Institute on Climate Change and the Environment, 2014) http://www.lse.ac.uk/GranthamInstitute/ wp-content/uploads/2014/11/Aghion_et_al_policy_paper_Nov20141.pdf (accessed September 29, 2017). 66 B. Cashore and M. Howlett, ‘Punctuating Which Equilibrium? Understanding Thermostatic Policy Dynamics in Pacific Northwest Forestry,’ Am J Pol Sci 51(2007): 532–51; K. Levin, et al. ‘Overcoming the tragedy of super wicked problems: constraining our future selves to ameliorate global climate change,’ Policy Sciences 45(2012): 123–52. 67 H.W. Boucher, et al. ‘Bad Bugs, No Drugs: No ESKAPE! An Update from the Infectious Diseases Society of America,’ Clin Infect Dis 48(2009): 1–2. 68 This analogy was originally proposed by Prof. Otto Cars, ReAct-Action on Antimicrobial Resistance, Uppsala University Sweden.", "n_tokens": 363, "kind": "text"}
{"chunk_id": "drug_resistance_book-439-0", "doc_id": "drug_resistance_book", "page": 439, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\nakin to holes in this bucket, slowly draining the effectiveness of available drugs. The development of a new drug would effectively add water to the leaking bucket. But, in the absence of a realistic option to develop antibiotics that avoid the subsequent emergence of resistance, this will only have a temporary effect and not address the underlying problem; namely, the holes in the bucket. Thus, not only are the antibiot- ics currently in clinical development not adequate to counter the increasing preva- lence of AMR, it is unlike they ever could be.69", "n_tokens": 124, "kind": "text"}
{"chunk_id": "drug_resistance_book-439-1", "doc_id": "drug_resistance_book", "page": 439, "text": "A second argument for framing AMR as a super-wicked problem is that this approach discourages a reliance on CBA in policy making. Super-wicked prob- lems – by their nature – are not easily solvable with standard CBA tools because they describe scenarios in which the cost of inaction will be very high, yet occur at some point in the distant future. Consequently, CBA will usually recommend an insufficiently large commitment of resources to address super-wicked problems because costs incurred today are pitted against benefits at a later stage for which neither magnitude nor time frame are known.70 As outlined earlier, existing cost- models for the assessment of the economic burden of AMR systematically underes- timate the true cost of AMR because, as Smith and Coast argue, “[none] considered the bigger picture – a world in which there are no effective antibiotics for situations where they are currently used routinely”.71 And where it has been attempted to take these wider costs into consideration, the complexity of AMR has usually forced analysts to restrict their models to pathogens and geographical regions for which reliable data exists.72 One response to this criticism of CBA in policy-making is to suggest that a bad estimate of cost is still better than no estimate at all. However, as Jamieson rightly points out, this response overlooks that whenever uncertainties about future developments are great, relying on the supposedly neutral judgment of a bad cost-estimate is a leap", "n_tokens": 296, "kind": "text"}
{"chunk_id": "drug_resistance_book-439-2", "doc_id": "drug_resistance_book", "page": 439, "text": "of faith – and it may prompt us to reach policy decisions that, in the long run, are far worse than the ones we might have considered had we not aimed for cost-efficiency based on unreliable or incomplete information.73", "n_tokens": 45, "kind": "text"}
{"chunk_id": "drug_resistance_book-439-3", "doc_id": "drug_resistance_book", "page": 439, "text": "A final argument for framing AMR as a super-wicked problem is that this approach provides a greater prominence on the importance of the values and norms that should inform what would make particular policy options more or less\n\n69 World Health Organization, Antibacterial Agents in Clinical Development: An Analysis of the Antibacterial Clinical Development Pipeline, including Tuberculosis (Geneva: World Health Organization, 2017). 70 R. Lazarus, ‘Super wicked problems and climate change: restraining the present to liberate the future,’ Cornell Law Review 94(2009): 1153–234. 71 R.D. Smith and J. Coast, ‘The true cost of antimicrobial resistance’. BMJ 2013; 346: f1493. Also cf. J. Coast and R.D. Smith, ‘Distributional Considerations in Economic Responses to Antimicrobial Resistance,’ Public Health Ethics 8(2015): 225–237. 72 See e.g. the RAND corporations cost model for O’Neill’s AMR review: https://www.rand.org/ pubs/research_reports/RR911.html (accessed September 29, 2017). 73 D. Jamieson, ‘Ethics, Public Policy and Global Warming,’ in S.M. Gardiner, et al. (eds.) Climate Ethics (Oxford: Oxford University Press, 2010), pp. 77–86. Also cf. A. Williams, ‘Cost- effectiveness analysis: is it ethical?’ Journal of Medical Ethics 18(1992): 7–11.\n\n435", "n_tokens": 321, "kind": "text"}
{"chunk_id": "drug_resistance_book-440-0", "doc_id": "drug_resistance_book", "page": 440, "text": "436\n\nJ. Littmann et al.", "n_tokens": 10, "kind": "text"}
{"chunk_id": "drug_resistance_book-440-1", "doc_id": "drug_resistance_book", "page": 440, "text": "acceptable.74 Through diminishing an analysis of the cost of AMR in primarily eco- nomic terms, it helps bring to light the non-economic costs and values involved in shaping which policy options will be viewed as acceptable. By emphasizing the need for shifts in path dependencies, and the resultant changes in our approaches and responses, it also emphasizes the need to re-evaluate the values and norms which underpinned our previous policies and activities. To put it another way, through framing AMR as a super-wicked problem, we not only acknowledge that previous approaches are unlikely to be sustainable in the long run, but we are also forced to ask what sort of values and norms could justify new policy options that would not only be effective but also ethical. This is all the more relevant because understanding AMR as more than a scientific or technical issue is a relatively new perspective. For most of the existence of antibiotics, their use has been primarily viewed as a medical or microbiological issue, and was governed accordingly. This means that value judgments were commonly only implicit and often incoherent. We have seen that these technical or medical matters do not exhaust all of the relevant considerations, and much of the decision-making and policy-making around AMR concerned matters that were inherently and inescapably ethical. Acting as an anti- microbial steward, for instance, often involves making moral judgments, promoting particular values and prioritising", "n_tokens": 290, "kind": "text"}
{"chunk_id": "drug_resistance_book-440-2", "doc_id": "drug_resistance_book", "page": 440, "text": "different aims – which are normative, and not merely technical, activities. In viewing AMR as a societal challenge, we can see the failings of earlier approaches that had not considered the normative significance this shift implies.", "n_tokens": 45, "kind": "text"}
{"chunk_id": "drug_resistance_book-440-3", "doc_id": "drug_resistance_book", "page": 440, "text": "26.4\n\nIncrementally Creating Transformative Shifts in Path Dependency: Alternative Strategies\n\nCreating transformative changes in path dependency will require adjustments on all types and levels of antibiotic use, and is unlikely to come in the shape of a single intervention. While there are no formulaic strategies to address wicked and super- wicked problems, different kinds of policy response will be suited to different time frames and address different aspects of the challenge that AMR presents. Nancy Roberts distinguishes between three possible approaches to super-wicked prob- lems: authoritative, competitive and collaborative strategies.75\n\n74 For different ways in which framing the problem of AMR can have ethical and political implica- tions, see, for instance, A.M. Viens and Jasper Littmann, ‘Is Antimicrobial Resistance a Slowly Emerging Disaster?’ Public Health Ethics 8(2015): 255–265. 75 N. Roberts, ‘Wicked Problems and Network Approaches to Resolution,’ Int Public Manag Rev 1(2000): 1–19.", "n_tokens": 209, "kind": "text"}
{"chunk_id": "drug_resistance_book-441-0", "doc_id": "drug_resistance_book", "page": 441, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\n26.4.1\n\nAuthoritative Strategies\n\nThese strategies involve a small number of decision-makers who develop policy solutions, which are then implemented by others. Such approaches require that decision-makers have the ability to enforce the implementation of their chosen strat- egy. The advantage of such a policy is that decision-making complexity is reduced, and policies can be implemented and adjusted relatively quickly. On the other hand, such approaches to solving super-wicked problems are likely to alienate a large proportion of stakeholders and they depend on the existence of power structures where they can be enforced.76 To this end, recent proposals for international legal frameworks and an intergovernmental panel have been put forward.77 However, the question how adherence at the local level could be controlled and, where necessary, enforced – let alone sufficiently resourced – make such centralized and costly pro- posals very difficult to implement. Authoritative strategies may therefore be of greater use at the national or regional level. At the global level, however, the current lack of adequate resource, governance and accountability structures, which could help to effectively implement them, is likely to limit their usefulness in addressing the challenge of AMR.\n\n26.4.2", "n_tokens": 255, "kind": "text"}
{"chunk_id": "drug_resistance_book-441-1", "doc_id": "drug_resistance_book", "page": 441, "text": "Competitive Strategies\n\nThese strategies let different stakeholders or corporations compete for the creation of (market-based) solutions and often lead to creative approaches to problem solv- ing.78 However, the commitment of stakeholders will largely depend on the strength of incentives to focus on a given policy area. In the case of AMR, the absence of sufficient market incentives has led to minimal investments into R&D for new anti- biotics, which lies well below a socially optimal level.79 Recent initiatives such as", "n_tokens": 99, "kind": "text"}
{"chunk_id": "drug_resistance_book-441-2", "doc_id": "drug_resistance_book", "page": 441, "text": "76 L. Briggs, ‘Tackling Wicked Problems – A Public Policy Perspective,’ in Contemporary Government Challenges (Australian Public Service Commission, 2007). 77 J. Anomaly, ‘Combating Resistance: The Case for a Global Antibiotics Treaty,’ Public Health Ethics 3(2010): 13–22; M. Woolhouse and J. Farrar, ‘Policy: An intergovernmental panel on anti- microbial resistance,’ Nature 509(2014): 555–557; Steven J. Hoffman, ‘An international legal framework to address antimicrobial resistance,’ Bulletin of the World Health Organization 93(2015): 66; S.J. Hoffman, J-A. Røttingen and J. Frenk, ‘International Law Has a Role to Play in Addressing Antibiotic Resistance,’ Journal of Law, Medicine & Ethics 43(2015): 65–67; A.D So, et al., ‘An integrated systems approach is needed to ensure the sustainability of antibiotic effective- ness for both humans and animals,’ J Law Med Ethics. 2015:43(Suppl 3):38–45; N. Gulati, et al., Using International Instruments to Address Antimicrobial Resistance (Ottawa: University of Ottawa Global Strategy Lab, 2016). 78 N. Roberts, ‘Wicked Problems and Network Approaches to Resolution,’ Int Public Manag Rev 1(2000): 1–19. 79 E. Mossialos, et al., Policies and incentives for promoting innovation in antibiotic research (Copenhagen: European Observatory on Health Systems and Policies, 2008).\n\n437", "n_tokens": 335, "kind": "text"}
{"chunk_id": "drug_resistance_book-442-0", "doc_id": "drug_resistance_book", "page": 442, "text": "438\n\nJ. Littmann et al.\n\nthe US Generating New Antibiotic Incentives Now (GAIN) Act or the European Innovative Medicines Initiative (IMI) are trying to address this, but even if success- ful, their overall budget does not permit any kind of paradigmatic shift to current antibiotic use policy.80 Other strategies which have been offered, such as antibiotic de-linkage schemes,81 health impact funds,82 public-private partnerships,83 innova- tion prizes84 and other mechanisms85 have mostly sought to replicate the old approach of developing new antibiotics in the hopes of outpacing resistance. While some AMR funding streams now include calls for projects in behavioral science, communication and education, their funding remains a miniscule fraction of what is currently being invested into drug development. From an ethical perspective, this creates additional problems. New drugs are likely to disproportionately benefit high-income countries (HICs), despite LMICs having the greatest burden of drug- resistant infections. Behavioural science research is also predominantly focused on HICs. We currently lack sufficient behaviour change research into what can be effectively achieved in regions with high levels of resistance and limited resources, e.g. some African countries, India, or countries in South East Asia. Competitive strategies are unlikely to change this as they are currently structured and incentivized.\n\n26.4.3", "n_tokens": 285, "kind": "text"}
{"chunk_id": "drug_resistance_book-442-1", "doc_id": "drug_resistance_book", "page": 442, "text": "Collaborative Strategies\n\nThese strategies involve a large number of stakeholders, especially in cases where responsibility and decision-making power are widely dispersed. While more diffi- cult to establish than top-down authoritative approaches, collaborative strategies are widely considered to be the most suitable approach to dealing with wicked and", "n_tokens": 56, "kind": "text"}
{"chunk_id": "drug_resistance_book-442-2", "doc_id": "drug_resistance_book", "page": 442, "text": "80 J.P. Roberts, ‘Incentives aim to boost antibiotic development,’ Nature Biotechnology 30:8 (2012):735. 81 C. Clift, et al. (eds.), Towards a New Global Business Model for Antibiotics: Delinking Revenues from Sales (London: Chatham House, 2015). 82 K. Outterson, T. Pogge and A. Hollis, ‘Combating Antibiotic Resistance Through the Health Impact Fund,’ in I. Glenn Cohen (ed.), The Globalization of Health Care: Legal and Ethical Issues (Oxford: Oxford University Press 2013), pp. 318–338. 83 For example, DRIVE-AB (Driving reinvestment in research and development and responsible antibiotic use), available from: http://drive-ab.eu; CARB-X (Combating antibiotic resistant bacte- ria biopharmaceutical accelerator), available from: http://www.carb-x.org 84 For example, the Longitude Prize, available at: https://longitudeprize.org; Antimicrobial Resistance Diagnostic Challenge, available at: https://dpcpsi.nih.gov/AMRChallenge. Also see J. Love and T. Hubbard, ‘The Big Idea: Prizes to Stimulate R&D for New Medicines,’ Chicago- Kent Law Review 82(2007): 1519–1554. 85 K. Outterson, J.H. Powers, G.W. Daniel, and M.B. McClellan, ‘Repairing the Broken Market for Antibiotic Innovation,’ Health Affairs 34(2015): 277–285; M.J. Renwick, D.M. Brogan and E. Mossialos, ‘A Systematic Review and Critical Assessment of Incentive Strategies for Discovery and Development of Novel Antibiotics,’ The Journal of Antibiotics 69(2016): 73–88; R.D. Smith, and J. Coast. ‘The economics of resistance through and", "n_tokens": 420, "kind": "text"}
{"chunk_id": "drug_resistance_book-442-3", "doc_id": "drug_resistance_book", "page": 442, "text": "ethical lens,’ In Ethics and Drug Resistance: Collective Responsibility for Global Public Health. Springer, Cham.", "n_tokens": 22, "kind": "text"}
{"chunk_id": "drug_resistance_book-443-0", "doc_id": "drug_resistance_book", "page": 443, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\nsuper-wicked problems, especially in the absence of a strong global planning authority to address the challenge.86 Collaborative strategies can and are already being used at different levels, from UN initiatives to regional local campaigns that focus on raising awareness or improve prescribing.87\n\nThese three strategies are not mutually exclusive and different approaches can and should be combined, where viable and appropriate. Viewing AMR as a super- wicked problem suggests that sustainable change is most likely to result from col- laborative strategies focusing on multiple drivers, yet the urgency with which a response to AMR must be found may necessitate, for example, the inclusion of competitive strategies to develop new drugs and authoritative strategies at the national level to enforce strict prescribing guidelines or prohibitions on using anti- biotics in farm animals as growth promoters. However, the critical reader will also notice that, for the most part, present efforts to address AMR can already be catego- rized as authoritative, competitive or collaborative strategies respectively. This begs a question as to whether framing AMR as a super-wicked problem can be of any further help in developing novel and effective strategies to combat drug resistance. In the paper’s penultimate section, we canvass a few potential ways in which the super-wicked problem frame can impact on current AMR policy going forward.", "n_tokens": 280, "kind": "text"}
{"chunk_id": "drug_resistance_book-443-1", "doc_id": "drug_resistance_book", "page": 443, "text": "26.5\n\nShifting Path Dependencies – The Way Forward\n\nUnderstanding AMR as a super-wicked problem itself does not, unfortunately, gen- erate a set of novel, easily implementable policy solutions. Yet, as outlined before, the complexity of AMR, as well as the countless factors that contribute to it, make one-stop solutions highly unlikely in the first place.\n\nWhile it does not offer any immediate solution to the problem, the understanding of AMR as a super-wicked problem may, however, achieve another goal – namely, to prompt a reconsideration of the relative importance of different responses to drug resistance. One of the most important insights of framing AMR as a super-wicked problem is that there is no technological fix we can engineer, nor any simple market- based solution that will avoid the impending scarcity of effective antibiotics in the future. Any responses that will help us keep AMR at bay in a significant way will involve a delicate balancing of benefits and burdens that will require difficult choices and restrictions to be imposed on individuals and populations. This insight is at odds with current research funding in the area of AMR, which is heavily skewed towards drug development.88 Moreover, given the global scale of the problem, success in one", "n_tokens": 255, "kind": "text"}
{"chunk_id": "drug_resistance_book-443-2", "doc_id": "drug_resistance_book", "page": 443, "text": "86 L. Briggs, ‘Tackling Wicked Problems - A Public Policy Perspectiv,’ in Contemporary Government Challenges (series) (Australian Public Service Commission, 2007). 87 For a selection of local initiatives see for example the ReAct Toolbox, https://www.reactgroup. org/toolbox/ 88 R. Kelly, et al., ‘Public funding for research on antibacterial resistance in the JPIAMR countries, the European Commission, and related European Union agencies: a systematic observational anal- ysis,’ The Lancet Infectious Diseases 16(2016): 431–440.\n\n439", "n_tokens": 129, "kind": "text"}
{"chunk_id": "drug_resistance_book-444-0", "doc_id": "drug_resistance_book", "page": 444, "text": "440\n\nJ. Littmann et al.\n\npart of the world will likely only be temporary, given the drivers brought and accel- erated by globalization. Framing AMR as such a fundamentally unsolvable policy challenge may appear to be defeatist. However, the point is not to admit defeat, but to focus on those interventions that may be of greatest use in the long run – even if we can never overcome the vicious cycle of bacterial resistance and antibiotic obso- lescence.89 It may come as good news at this stage that many potential candidates for such a strategy already exist, but have simply not have been implemented properly.", "n_tokens": 129, "kind": "text"}
{"chunk_id": "drug_resistance_book-444-1", "doc_id": "drug_resistance_book", "page": 444, "text": "The most obvious example in this context is infection control and prevention and water, sanitation and hygiene (WASH). While ultimately decisive for the control of nosocomial infections, hospital and healthcare hygiene and infection prevention have often appeared to be more of an afterthought in recent policy discussion. However, they remain of crucial importance for the prevention of infections, in both high- and low-income settings.90 Similarly, many of the ongoing efforts for the cre- ation of broader public awareness for the problem and causes of AMR have not yet achieved their desired goals.91 Education and hygiene measures are no silver bul- lets – and have their own issues with compliance and recalcitrance – but if AMR is understood as a super-wicked problem, these policies should receive much greater recognition as a crucial part of an effective AMR strategy. Indeed, these are just some of the many different behaviour change interventions – aimed at both professionals and the public – that should comprise a multipronged and diversified response to AMR.92 Of course, the success of such behavior change interventions will itself be dependent upon fixing even more fundamental problems plaguing global health, including poverty and extreme income inequality, since many", "n_tokens": 246, "kind": "text"}
{"chunk_id": "drug_resistance_book-444-2", "doc_id": "drug_resistance_book", "page": 444, "text": "89 A.E. Aiello, N.B. King and B. Foxman, ‘Ethical Conflicts in Public Health Research and Practice Antimicrobial Resistance and the Ethics of Drug Development,’ American Journal of Public Health, 96(2006): 1910–1914; B. Spellberg, J.G. Bartlett and D.N. Gilbert, ‘The Future of Antibiotics and Resistance,’ New England Journal of Medicine 368(2013): 299–302. 90 S. Harbarth, et al., ‘Antimicrobial resistance: one world, one fight!’ Antimicrobial Resistance and Infection Control 4(2015): 49 – https://doi.org/10.1186/s13756-015-0091-2; Peter Collingon, et al., ‘Anthropological and socioeconomic factors contributing to global antimicrobial resistance: a univariate and multivariable analysis,’ The Lancet Planetary Health 2018; 2: e398–405. Also World Health Organization, Guidelines on Sanitation and Health (Geneva: WHO, 2018). 91 Special Eurobarometer, Antimicrobial Resistance Report, May – June 2013 (Brussels: EU Directorate-General Communication, 2013). 92 See, for example, T. Edgar, S.D. Boyd and M.J. Palamé, ‘Sustainability for behaviour change in the fight against antibiotic resistance: a social marketing framework,’ Journal of Antimicrobial Chemotherapy 63(2009): 230–237; C.S. Lundborg and A.J. Tamhankar, ‘Understanding and changing human behaviour—antibiotic mainstreaming as an approach to facilitate modification of provider and consumer behaviour,’ Uppsala Journal of Medical Sciences 119(2014):125–133; Pubic Health England, Behaviour Change and Antibiotic Prescribing in", "n_tokens": 386, "kind": "text"}
{"chunk_id": "drug_resistance_book-444-3", "doc_id": "drug_resistance_book", "page": 444, "text": "Healthcare Settings: Literature Review and Behavioural Analysis (London: Public Health England, 2015); S. Tonkin- Crine, A.S Walker and C.C Butler, ‘Contribution of behavioural science to antibiotic stewardship,’ BMJ 2015; 350:h3413; K. Chaintarli et al., ‘Impact of a United Kingdom-wide campaign to tackle antimicrobial resistance on self-reported knowledge and behaviour change,’ BMC Public Health 16(2016):393.", "n_tokens": 108, "kind": "text"}
{"chunk_id": "drug_resistance_book-445-0", "doc_id": "drug_resistance_book", "page": 445, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\ntechnical and behavioral interventions are limited by adverse social, economic, and political contexts.93 Tackling AMR will require those working in global health to directly address injustices, however one conceives of justice. Here, for our pur- poses, any conception of justice will do since the problem of injustices in global health are theoretically overdetermined.94 In other words, practically speaking, tack- ling the levers that make AMR a super-wicked problem will have to include making real efforts to address global injustices for the various ways in which they contribute to the level of drug-resistant pathogens around the world.", "n_tokens": 141, "kind": "text"}
{"chunk_id": "drug_resistance_book-445-1", "doc_id": "drug_resistance_book", "page": 445, "text": "Finally, understanding AMR as a super-wicked problem and thereby as a global challenge that defies simple solutions by any one party suggests that a much greater part of our efforts must be directed towards increasing standards of access and qual- ity of prescribing in those regions where resources continue to be limited. We have not yet managed to ensure the provision of adequate access to antibiotics in many regions of the world, where the price of drugs is often prohibitive for patients and where over-the-counter sales have led to an unregulated and uncontrolled use of antibiotics.95 We are, therefore, faced with a situation in which we have to reduce the excessive use of antibiotics in some regions of the world while ensuring greater access in others.96 As Daulaire et al. maintain, ‘meaningful access is dependent on good stewardship and vice versa.’97 Nevertheless, this will require us to successfully confront and find answers to difficult distributive questions about when access should be increased or limited, and how to maintain sustainable fair access in a way that attempts to diminish the rate of AMR as long as possible. Stewardship to pro- tect the effectiveness of antibiotics presupposes a functioning healthcare and legal system with sufficient oversight to regulate antibiotic usage adequately. New drugs, especially against Gram-negative bacteria, are badly needed and if resistance against drugs of last resort (e.g., carbapenems, colistin) further increases, we are", "n_tokens": 308, "kind": "text"}
{"chunk_id": "drug_resistance_book-445-2", "doc_id": "drug_resistance_book", "page": 445, "text": "officially out of options for treatment. In many of the countries that require greater access, it is difficult to guarantee even the most basic stewardship mechanisms. As a result, there is a need to explore different ways of approaching antibiotic governance in a global setting as part of responding to this super-wicked problem that genuinely", "n_tokens": 63, "kind": "text"}
{"chunk_id": "drug_resistance_book-445-3", "doc_id": "drug_resistance_book", "page": 445, "text": "93 S. Gill and I. Bakker, ‘The global crisis and global health,’ in S. Benatar and G. Brock (eds.), Global Health and Global Health Ethics (Cambridge: Cambridge University Press, 2011), pp. 221–238. 94 See, for example, L. Reid “Antimicrobial resistance and social inequalities in health: consider- ations of justice” In Ethics and Drug Resistance: Collective Responsibility for Global Public Health. Springer, Cham, where the author provides an egalitarian argument toward this conclusion. 95 R. Laximinarayan, et al. ‘Antibiotic resistance – the need for global solutions,’ Lancet Infect Dis, 13:12 (2013): 1057–98. 96 G. Heyman, O. Cars, M.T. Bejarano, and S. Peterson, ‘Access, Excess, and Ethics—Towards a Sustainable Distribution Model for Antibiotics,’ Upsala Journal of Medical Sciences 119(2014): 134–141. 97 Nils Daulaire, et al., ‘Universal Access to Effective Antibiotics is Essential for Tackling Antibiotic Resistance,’ The Journal of Law, Medicine and Ethics 43(2015): 17–21 at 18.\n\n441", "n_tokens": 261, "kind": "text"}
{"chunk_id": "drug_resistance_book-446-0", "doc_id": "drug_resistance_book", "page": 446, "text": "442\n\nJ. Littmann et al.\n\nempowers local and regional stakeholders to shape the path dependencies that guide our response.\n\n26.6\n\nConclusion\n\nWhile AMR is a complex and arduous challenge, understanding it as a super-wicked problem does not mean it is intractable or that the multitude of drivers and stake- holders defy making substantial progress. The discussion of potential initiators of path dependency in this paper serves as an illustration of possible scenarios rather than as a comprehensive list of recommendations, but it highlights that recognizing AMR as a super-wicked problem would indeed have policy implications and should lead us to reconsider our values and priorities in responding to AMR.\n\nThis will also include a discussion of ethical norms and standards that should be met in addressing the problem of drug resistance. Given that AMR has only recently moved from being a purely clinical (or veterinary) problem into the realm of global challenges that require a broader societal response, there exists currently little research, and even less agreement on what the most important ethical issues in AMR are, and what we should do about them.98 Ethicists should weigh in on such complex and wicked problems,99 but they must also be aware of the fact that this is not an abstract problem, but already a health challenge on a global scale.", "n_tokens": 266, "kind": "text"}
{"chunk_id": "drug_resistance_book-446-1", "doc_id": "drug_resistance_book", "page": 446, "text": "Understanding AMR as a super-wicked problem is not merely a matter of cate- gorization. Instead, it should lead us to reconsider current policy approaches in light of their expected usefulness and likely success of implementation. New approaches to tacking AMR should seek to avoid replicating earlier patterns and problems of jumping between ‘one-best-way’ approaches or ‘one-size-fits-all’ interventions – both empirically and ethically. If AMR does indeed present a super-wicked prob- lem, policy efforts should be primarily directed at shifting path dependencies. As such, the aim is not ‘solving’ AMR but to make progress towards better mitigation and management through these shifts. Current policies, for instance, which promote infection prevention and control, antimicrobial stewardship and the development of new drugs, are a crucial contribution to curbing AMR because they prolong antibi- otic effectiveness and prevent infections in the first place. However, they are clearly insufficient as answers in the medium to long run, and should therefore only consti- tute a first step in initiating more fundamental changes to public health policy to reduce future dependence on antibiotics and more general social policy affecting the drivers of drug resistance.", "n_tokens": 256, "kind": "text"}
{"chunk_id": "drug_resistance_book-446-2", "doc_id": "drug_resistance_book", "page": 446, "text": "98 J. Littmann J and A.M. Viens, ‘The Ethical Significance of Antimicrobial Resistance,’ Public Health Ethics 8(2015): 209–224. 99 D.S. Silva, M.J. Smith MJ, and C.D. Norman, ‘Systems thinking and ethics in public health: a necessary and mutually beneficial partnership,’ Monash Bioethics Review 2018 Jun 13. doi: https:// doi.org/10.1007/s40592-018-0082-1. [Epub ahead of print].", "n_tokens": 125, "kind": "text"}
{"chunk_id": "drug_resistance_book-447-0", "doc_id": "drug_resistance_book", "page": 447, "text": "26 The Super-Wicked Problem of Antimicrobial Resistance\n\nFraming AMR as a super-wicked problem also emphasizes the importance of ongoing trends towards more integrated collaborations across sectors and research disciplines. It should help in creating greater awareness for the true scope of the problem we are faced with and the urgency with which we must address it.\n\nAcknowledgements The authors would like to thank James Wilson and Anthony Kessel for feed- back on an earlier draft of this paper.\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n443", "n_tokens": 259, "kind": "text"}
{"chunk_id": "drug_resistance_book-448-0", "doc_id": "drug_resistance_book", "page": 448, "text": "Index A Adeyi, O.O., 421 Albrich, W., 423 Allen, T., 195 Amartya Sen, 206 Animals, 5, 7, 8, 11, 13, 79–82, 91, 94, 322, 389–396, 402–410, 415–417, 421–443 Antimicrobial stewardship (AMS), 89–103 Attena, F., 363 109–118, 186, 188, 211, 216, 217, 227, 230, 232, 236, 266, 270, 280, 287, 297–307, 346, 358, 359, 364, 372–373, 378–380, 394, 395, 402, 403, 405, 407, 414, 415, 423, 429, 439 Annette, R., 364 Anomaly, J., 205, 297–307, 358 Antibiotic overprescribing, 137 Antibiotic resistance, 5–7, 90, 93, 112, 128, 135, 142, 225–228, 230–238, 297, 299–301, 303, 304, 306, 316, 324, 346, 347, 352, 353, 357–375, 379, 390, 394, 422–424, 427, 428, 433, 437, 438, 440, 441 B Ballon, P., 210 Barter, D., 422 Beckerman, K.P., 45 Bengtsson-Palme, Johan, 359, 372 Bennett, B., 389–396 Bernd Stephan, 373 Bioethics, 171, 178, 252, 359, 363 Blumenthal-Barby, J.S., 128 Boden, L., 110–118, 359 Britten, N., 130 Butler, C.C., 423 Buyx, A., 347 Byskov, M.F., 203–223 Antibiotics, 5–9, 11–13, 15, 20–26, 78–83, 89–103, 110, 111, 114, 115, 117, 126–137, 142–146, 149, 151, 184, 187–190, 192, 205, 225–238, 247, 253, 262, 268, 269, 271, 272, 280–284, 287–291,", "n_tokens": 508, "kind": "text"}
{"chunk_id": "drug_resistance_book-448-1", "doc_id": "drug_resistance_book", "page": 448, "text": "297–307, 314–316, 346, 349–352, 354, 358–359, 362, 364–373, 378–381, 384, 390, 391, 393–396, 405–408, 410–417, 423, 424, 427–431, 433–442 Antimicrobial resistance (AMR), 76–83, 90, 92, 94, 96, 102, 115–118, 142, 143, 146, 147, 151, 203, 258, 259, 262–265, 268, 271–273, 275, 303, 304, 309, 310,", "n_tokens": 142, "kind": "text"}
{"chunk_id": "drug_resistance_book-448-2", "doc_id": "drug_resistance_book", "page": 448, "text": "C Capabilities and growth stunting, 229–232, 234–238\n\nCarter I., 209 Catchpole, M., 422 Cheah, P.Y., 56–69 Ciusa, L.M., 366 Coast, J., 279–291, 424 Cocking, D., 129 Cognitive bias, 12, 126, 131, 135 Coker, R., 76–83 Coleman, C.H., 171–179\n\n© The Author(s) 2020 E. Jamrozik, M. Selgelid (eds.), Ethics and Drug Resistance: Collective Responsibility for Global Public Health, Public Health Ethics Analysis 5, https://doi.org/10.1007/978-3-030-27874-8\n\n445", "n_tokens": 163, "kind": "text"}
{"chunk_id": "drug_resistance_book-449-0", "doc_id": "drug_resistance_book", "page": 449, "text": "446 Collective action, 149, 286, 297–307, 370, 383, 403 Collective action problems, 6, 9, 12, 15, 377, 378, 380, 381, 383, 386, 403, 404, 407, 417 Collective responsibility, 149, 167, 358, 359, 385, 386, 403, 430, 438, 441 Collignon, P.J., 135 Complexities, 47, 65, 66, 158, 261, 289, 310, 363, 365, 366, 371, 374, 390, 395, 423, 425, 429–432, 435, 437, 439 Coomans, F., 156–168 Cosgrove, S.E., 422 Costelloe, C., 369 Cox, H., 156–168 Cripps, E., 384, 385 Crocker, D.A., 206, 207 Cullity, G., 382–385 D Daniel, J., 360 Daniels, N., 252 da-Shalit, A., 262 Data use, 67 Daulaire, N., 205, 370 Davies, S.C., 422 Dawson, A., 218, 221, 347–349 Day, N.P.J., 56–69 de Fine Licht, K., 358–375 De Vos, Daniel, 367 Denholm, J.T., 20–32 De-Shalit, A., 231 Diekema, d.J., 371 Discounting, 238, 286–287 Drug resistance, 4, 6, 7, 9–11, 13–15, 21, 25, 26, 39, 40, 42–47, 49, 50, 55–70, 79, 80, 92, 111–113, 117, 195, 309, 310, 390, 421, 423, 426, 430–432, 439, 442 E Easy rescue, 143, 144, 147–151 Economics, 9–10, 13, 59, 62, 63, 66, 67, 82, 83, 98, 118, 142, 156, 159, 162, 163, 166, 172, 174, 215, 219, 227, 229–231, 233, 235, 247, 248, 253, 260–271, 273, 275, 279–291, 299–303, 310,", "n_tokens": 510, "kind": "text"}
{"chunk_id": "drug_resistance_book-449-1", "doc_id": "drug_resistance_book", "page": 449, "text": "311, 313–316, 360, 369, 370, 372, 374, 402, 403, 405, 413, 416, 421, 431, 432, 434–436, 441 Edmond, M.B., 371 Edwards, S.J.L., 363 Eggleston, B., 132 Emanuel, E.J., 364 Index Entwistle, V.A., 209 Ethics, 23, 26, 31, 32, 55–70, 109–118,", "n_tokens": 113, "kind": "text"}
{"chunk_id": "drug_resistance_book-449-2", "doc_id": "drug_resistance_book", "page": 449, "text": "126–129, 132–134, 178, 280, 281, 284–291, 297, 316, 317, 355, 357–375, 386, 424, 427, 435, 441\n\nExternalities, 83, 145, 146, 280–282, 284, 286,\n\n287, 302\n\nF Fairness, 68, 81, 83, 173, 234, 238, 243–254,\n\n261, 370, 377–386\n\nFauci, A.S., 422 Favor, C., 205 Fick, J., 372 Foster, K., 151 Fox, J.G., 20–32 Francis, J.G., 243–254 Francis, L.P., 243–254 Free-riding, 281, 283–289, 305, 382\n\nG Gandra, S., 422 Geisbert, T.W., 364 Gilbert, G.L., 90–103 Gilbert, M., 204 Giubilini, A., 372 Glenza, J., 363 Global action plan, 116, 232, 236, 271, 322,\n\n391, 403–408, 430\n\nGovernance, 81, 102, 115, 389–396, 401–417,\n\n426, 429–431, 437, 441\n\nGrant, J., 422 Grill, K., 218, 221 Grundmann, H., 151 Gualde, N., 423\n\nH Haak, H., 368 Haire, B., 38–51 Harbarth, S., 423 Harris, R.J., 361 Hashiguchi, L., 76–83 Health inequalities, 167, 258–261, 264–267,\n\n269, 273, 274 Health justice, 258, 259, 261 Hill, H.H., 361 Ho, C.W.L., 402–417 Holm, S., 346–355 Holmes, O.W., 92 Huber, M., 209 Human rights, 48, 156–162, 166, 167, 172, 174, 176, 178, 310, 347, 432", "n_tokens": 450, "kind": "text"}
{"chunk_id": "drug_resistance_book-450-0", "doc_id": "drug_resistance_book", "page": 450, "text": "Index\n\nHunter, D., 363 Hursthouse, R., 129\n\nI Infection prevention and control, 77, 94, 111,\n\n115, 117, 178, 414, 424, 427–428, 434, 442\n\nInfectious diseases, 9, 10, 13, 20, 25, 42, 64,\n\n66, 90–93, 95, 110, 115, 135, 142, 144, 171–179, 186, 191, 197, 206, 210, 221, 226–235, 237, 238, 271, 285, 288, 291, 303–306, 314–317, 346, 371, 386, 392, 404, 422–424, 429, 431, 434, 439\n\nInternational Health Regulations, 232,\n\n390, 392–393\n\nIyer, K., 137\n\nJ Jamrozik, E., 4–15, 184–198 Jasper, L., 369 Jennings, B., 347–349 Joakim Larsson, D.G., 359, 372 Justice, 9, 129, 133–137, 205, 210, 211, 226,\n\n234, 252, 257–275, 281, 307, 310, 316–317, 346–348, 355, 383, 441\n\nJuth, N., 371\n\nK Kahneman, D., 131 Kerridge, I., 90–103 Khan, M., 76–83 King, N.B., 267, 309–317 Koch, R., 186 Krieger, H., 128 Krom, A., 221\n\nL Lamont, J., 205 Lapuente, V., 368 Larsson, D.G.J., 358–375 Law/legal, 63, 79, 80, 102, 129, 146, 158, 159, 162–165, 173–175, 190, 193, 286, 288, 347, 390, 393, 401–417, 425, 432, 437, 441\n\nLaxminarayan, R., 372, 422, 423 Lee, T.-L., 402–417 Levy, S.B., 424 Lichtenberg. J., 385 Littmann, J., 204, 205, 421–443 Liverani, M., 76–83 London, L., 156–168", "n_tokens": 501, "kind": "text"}
{"chunk_id": "drug_resistance_book-450-1", "doc_id": "drug_resistance_book", "page": 450, "text": "M Mar, C.D., 129 Mallon, M., 186 Maragakis, L.L., 422 Mason, P.H., 20–32 McAdams, D., 302 McKinney, W.J., 361 Medical virtues, 126, 129–134, 136 Medicine and Public Health, 315 Mellor, D., 110–118, 359 Mendelson, M., 111, 423 Michelle, B., 366 Milgram, S., 132 Millar, M., 225–238 Miller, D.E., 132 Monnet, D., 423 Morel, C.M., 367 Morens, D.M., 422 Morgan, D.J., 422 Mossialos, E., 367 Munthe, C., 197, 358–375\n\nN Nguyen, B., 20–32 Nijsingh, N., 197, 358–375 Norheim. O.F., 259 Nussbaum, M.C., 134, 204, 206, 209–216, 218, 222, 226–230, 234, 237\n\nO O’Neill, J., 289, 365, 367, 421–423 Oakley, J., 125–137 One health, 81, 94, 111–113, 117, 118, 359,\n\n374, 391, 403, 405, 414\n\nP Parfit, D., 379, 381, 385 Parker, M., 56–69 Perencevich, E.N., 422 Piddock, L.J.V., 366 Pirnay, J-P., 367 Ploug, T., 346–355 Political Philosophy, 347 Practical intelligence, 128, 132 Prah Ruger, J., 206 Prainsack, B., 347 Precautionary principle (PP), 359–362 Privacy, 10, 28, 67, 160, 190, 191, 244, 249,\n\n250, 261\n\nPrivate sectors, 77, 78, 80, 81, 162,\n\n275, 287 Pruden, A., 372\n\n447", "n_tokens": 459, "kind": "text"}
{"chunk_id": "drug_resistance_book-451-0", "doc_id": "drug_resistance_book", "page": 451, "text": "448 Public health, 4, 9–12, 14, 15, 20, 21, 26, 30, 31, 38, 39, 47, 48, 50, 58, 61, 63, 67, 69, 76, 78, 80, 82, 83, 111–113, 117, 135, 142, 143, 157–159, 162, 164, 165, 173, 176, 179, 184–187, 190, 191, 193–198, 203, 205, 208, 209, 220, 221, 229, 236, 243, 244, 246, 249, 252, 258, 263, 266–268, 270, 279, 297, 306, 310, 312–315, 346, 351, 352, 354, 355, 359, 362–364, 366, 368, 371, 373, 374, 389–396, 402, 403, 405, 422, 424, 429, 431, 432, 440, 442 Public health ethics, 12, 15, 185, 193–198, 346, 347, 355, 369, 424, 435, 436, 442 Public-goods, 144–147, 281, 283–284, 299, 302–303, 305, 394, 396 R Radyowijati, A., 368 Randall, A., 130 Rawls, J., 252 Redelmeier, D., 128, 136 Regulations, 9, 12, 79–83, 101, 112–114, 127, 236, 245, 254, 271, 272, 285, 287, 297, 299, 305–307, 312, 361, 362, 364, 368, 369, 372, 378, 379, 383, 406–408, 410–417, 424, 427, 429 Reid, L., 258–275 Rights-based approach, 156, 158, 159, 167 Robeyns, I., 206, 207 Rönnerstrand, B., 368 Ruff, C.C., 128, 136 Rump, B.O., 203–223 Russell, D.C., 132 S Saposnik, G., 128, 136 Saripanidas, S., 127 Scanlon, T.M., 148, 234, 237, 238 Schwenkenbecher, A.,", "n_tokens": 507, "kind": "text"}
{"chunk_id": "drug_resistance_book-451-1", "doc_id": "drug_resistance_book", "page": 451, "text": "377–386 Scientific progress, 156, 158–160, 162–167 Selgelid, M.J., 4–15, 190, 194, 195, 205 Sen, A., 226, 261 Seth Seabury Neeraj Sood, 367 Shawa, R., 156–168 Silley, P., 373 Silva, D.S., 421–443 Simpson, J.Y., 92 Singer, P., 148 Smith, R.D., 279–291, 424 Social justice, 228, 231 Social policies, 313, 425, 442 Index", "n_tokens": 126, "kind": "text"}
{"chunk_id": "drug_resistance_book-451-2", "doc_id": "drug_resistance_book", "page": 451, "text": "Solidarity, 233, 272, 273, 345–355, 382 Søren, H., 361 Southeast Asia, 56–58, 66, 68, 75–83 Stewardship, 12, 26, 77, 89–103, 127, 244,\n\n262, 316, 390, 393–395, 405–417, 430, 432, 441, 442 Strømme, E.M., 259 Sunstein, C.R., 361 Surveillance, 8, 10–15, 21, 23–25, 42, 49, 57–60, 65, 76–77, 80, 98, 99, 101, 103, 112, 116–118, 185, 187, 191, 197, 232, 243–246, 248, 251, 252, 254, 264, 304, 309, 310, 364, 365, 371, 372, 390–395, 404, 410, 411, 414, 415, 422, 427, 429\n\nSustainable Development Goals (SDG),\n\n273, 395\n\nT Teillant, A., 372, 422 Temkin, L.S., 260 Tobler, P.N., 128, 136 Toward, A., 367 Tuberculosis, 4, 5, 14, 19–32, 64, 65, 76, 127, 142, 156–168, 173, 177, 185, 229, 230, 249, 268, 309, 310, 314, 350, 390, 402, 403, 427, 435\n\nTversky, A., 131\n\nU Ukoumunne, O., 130\n\nV Van Boeckel, T.P., 372 Venkatapuram, S., 206 Verweij, M., 175, 203 Veterinary, 83, 93, 111, 112, 114–117, 271, 306, 346, 405, 414, 434, 442\n\nViens, A.M., 221, 369, 421–443\n\nW Watt, I.S., 209 Weinstein, R.A., 371 Wilson, J., 363 Wolff, J., 231, 261 Wright, G.D., 365\n\nZ Zowasi, H.M., 247", "n_tokens": 467, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-0-0", "doc_id": "final_ce_dental_caries", "page": 0, "text": "FDA Drug Topics: An Update on Transmucosal Buprenorphine and Dental Caries\n\nMark A. Liberatore, PharmD, RAC Commander, United States Public Health Service Deputy Director for Safety Division of Anesthesiology, Addiction Medicine, and Pain Medicine, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration", "n_tokens": 78, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-1-0", "doc_id": "final_ce_dental_caries", "page": 1, "text": "Learning Objectives\n\n1. Discuss the national opioid crisis, opioid use disorder, and available treatments\n\n2. Describe cases of dental caries with the use of transmucosal buprenorphine-containing products\n\n3. Review FDA’s framework for updating product labeling and explain FDA’s findings and the resulting regulatory action\n\n4. Summarize how healthcare providers can help mitigate these adverse events\n\nwww.fda.gov\n\n2", "n_tokens": 88, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-2-0", "doc_id": "final_ce_dental_caries", "page": 2, "text": "Presentation Outline\n\nBackground\n\nOpioid Crisis and Opioid Use Disorder • Overview and review of safety signal • Description of FDA regulatory framework • Action, communication, and reaction • Takeaways/Summary • Challenge Questions • Panel discussion and Q & A 3\n\nOpioid Crisis and Opioid Use Disorder • Overview and review of safety signal • Description of FDA regulatory framework • Action, communication, and reaction • Takeaways/Summary • Challenge Questions • Panel discussion and Q & A 3", "n_tokens": 97, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-3-0", "doc_id": "final_ce_dental_caries", "page": 3, "text": "www.fda.gov\n\nOPIOID CRISIS AND OPIOID USE DISORDER (OUD)\n\n4", "n_tokens": 20, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-4-0", "doc_id": "final_ce_dental_caries", "page": 4, "text": "Opioid Crisis • Opioid crisis declared a Public Health Emergency\n\non October 26, 2017\n\n“Crisis” is a broad term covering many aspects of the public health issue: – Misuse and Abuse – Addiction (Opioid Use Disorder (OUD)) – Overdose – Death\n\nwww.fda.gov\n\n5", "n_tokens": 63, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-5-0", "doc_id": "final_ce_dental_caries", "page": 5, "text": "Overdose Deaths\n\n107,941 drug\n\noverdose deaths occurred in 2022 – 32.6 deaths per 100,000 people – Age-adjusted rate quadrupled from 2002-2022\n\nfrom National Center on Health Statistics: https://www.cdc.gov/nchs/products/databriefs/db491.htm\n\nwww.fda.gov\n\n(SOURCE: National Center for Health Statistics, National Vital Statistics System, mortality data file)\n\n6", "n_tokens": 93, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-6-0", "doc_id": "final_ce_dental_caries", "page": 6, "text": "Current Landscape of Opioid-involved Deaths • Heroin\n\n2021 = 2.8/100k – 2022 = 1.8/100k • Natural & semi-synthetic\n\n2021 = 4.0/100k – 2022 = 3.5/100k\n\nMethadone\n\n2021 = 1.1/100k – 2022 = 1.0/100k\n\nSynthetic opioids other than methadone, which includes fentanyl, fentanyl analogs, and tramadol – 2002 = 0.4/100,000 – 2013 = 1.0/100,000 – 2022 = 22.7/100,000\n\nfrom National Center on Health Statistics: https://www.cdc.gov/nchs/products/databriefs/db491.htm\n\nwww.fda.gov\n\n(SOURCE: National Center for Health Statistics, National Vital Statistics System, mortality data file)\n\n7", "n_tokens": 188, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-7-0", "doc_id": "final_ce_dental_caries", "page": 7, "text": "Opioid Use Disorder (DSM-5)\n\nAt least 2 of the following within a 12-month period:\n\n1\n\nOpioids are often taken in larger amounts or over a longer period of time than intended.\n\nMild = 2-3\n\n2\n\nThere is a persistent desire or unsuccessful efforts to cut down or control opioid use.\n\n3\n\nA great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects.\n\nModerate = 4-5\n\n4\n\nCraving, or a strong desire to use opioids.\n\n5\n\nRecurrent opioid use resulting in failure to fulfill major role obligations at work, school or home.\n\nSevere 6 or more\n\n6\n\nContinued opioid use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of opioids\n\n7\n\nImportant social, occupational or recreational activities are given up or reduced because of opioid use.\n\n8\n\nRecurrent opioid use in situations in which it is physically hazardous\n\n9\n\nContinued use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by opioids.\n\n10\n\nTolerance, as defined by either of the following: (a) a need for markedly increased amounts of opioids to achieve intoxication or desired effect (b) markedly diminished effect with continued use of the same amount of an opioid\n\n11\n\nWithdrawal, as manifested by either of the following: (a) the characteristic opioid withdrawal syndrome (b) the same (or a closely related) substance are taken to relieve or avoid withdrawal symptoms 8\n\nwww.fda.gov\n\n* These criteria not considered for those individuals taking opioids under appropriate medical supervision.", "n_tokens": 354, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-8-0", "doc_id": "final_ce_dental_caries", "page": 8, "text": "Need\n\nUtility\n\nAvailability\n\nNeed for Treatment\n\nIn 2022, estimated six million people in the US had an opioid use disorder •Estimated 3.7% of US adults need OUD treatment\n\nMedications for the treatment of opioid use disorder (MOUD) decrease opioid- related mortality and overdose\n\nEvidence-based treatment is a pillar of the Department of Health and Human Services Overdose Prevention Framework\n\nThree FDA-approved treatments for OUD\n\nNaltrexone •Methadone •Buprenorphine\n\n9", "n_tokens": 101, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-9-0", "doc_id": "final_ce_dental_caries", "page": 9, "text": "Buprenorphine\n\nBrief regulatory history\n\n1982: Original approval for pain – 2002: Approval for OUD\n\nOften found in combination with naloxone • Available sublingual tablets and films\n\nTMB = transmucosal buprenorphine\n\nAlso as subcutaneous implant, extended-release injection – 2015: new formulations and dosing regimens approved for pain\n\nMechanism of Action\n\nPartial agonist a mu-opioid receptor – Antagonist at kappa receptor\n\nA New Era of OUD Treatment\n\nThe Drug Addiction Treatment Act of 2000 is no longer in effect\n\nAs of June 2023, all DEA- registered prescribers of controlled substances must complete 8 hours of training on MOUD\n\nThis greatly increases the number of possible prescribers and hopefully increases access\n\n10", "n_tokens": 150, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-10-0", "doc_id": "final_ce_dental_caries", "page": 10, "text": "SAFETY SIGNAL\n\nwww.fda.gov 11", "n_tokens": 8, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-11-0", "doc_id": "final_ce_dental_caries", "page": 11, "text": "How it Began... • Office of Surveillance and Epidemiology (OSE), Division of\n\nPharmacovigilance II (DPV II) monitors FDA’s Adverse Event Reporting System (FAERS) July 2018: A report was found of patient who experienced dental caries following the use of sublingual product containing buprenorphine/naloxone\n\nA disproportionality analysis published using WHO database hypothesized that products containing buprenorphine have a high disproportionality for dental caries\n\nOSE opened a tracked safety issue (known today as a Newly Identified Safety Signal (NISS)) and an investigation ensued\n\n12", "n_tokens": 142, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-12-0", "doc_id": "final_ce_dental_caries", "page": 12, "text": "Sublingual Buprenorphine • Can be used sublingually or buccal (but not per-oral)\n\nSublingual Administration Place one film under the tongue, close to the base on the left or right side. If an additional film is necessary to achieve the prescribed dose, place an additional film sublingually on the opposite side form the first film. Place the film in a manner to minimize overlapping as much as possible. The film must be kept under the tongue until the film is completely dissolved. If a third film is necessary to achieve the prescribed dose, place it under the tongue on either side after the first two films have dissolved.\n\nBuccal Administration Place one film on the inside of the right or left cheek. If an additional film is necessary to achieve the prescribed dose, place an additional film on the inside of the opposite cheek. The film must be kept on the inside of the cheek until the film is completely dissolved. If a third film is necessary to achieve the prescribed dose, place it on the inside of the right or left cheek after the first two films have dissolved.\n\n13", "n_tokens": 223, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-13-0", "doc_id": "final_ce_dental_caries", "page": 13, "text": "Key Findings from OSE/DPV-II Search\n\n486 Reports\n\n474 FAERS\n\n12 medical literature\n\n305 Cases Selected for Review\n\nMost common course of treatment of the tooth/teeth was “extractions/pulled/removed” which occurred in 71 instances • Many cases were reported by providers, provided extensive documentation, and demonstrated temporal association\n\n294 FAERS\n\n11 medical literature\n\n151 Cases Reported\n\nTreatment event\n\nWhile it has been reported that substance use disorders increase major oral health functional and esthetic problems associated with periodontal disease, caries, infections, and tooth loss, many cases found described severe dental issues in patients with no prior history of dental problems\n\n14", "n_tokens": 129, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-14-0", "doc_id": "final_ce_dental_caries", "page": 14, "text": "FAERS Case #1\n\n30-year-old male • Buprenorphine/naloxone SL film 8mg BID for OUD • PMH included addiction to oral pain meds, “impeccable teeth,” no concomitant medications • After 1 year of therapy, experienced severe tooth\n\ndecay with 15 dental caries\n\nTreatment with unspecified dental work • Treatment with buprenorphine/naloxone continued\n\n15", "n_tokens": 88, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-15-0", "doc_id": "final_ce_dental_caries", "page": 15, "text": "FAERS Case #2\n\n25-year-old female • Buprenorphine/naloxone SL film for OUD • PMH: mother reported daughter’s teeth were in “perfect condition” with no dental caries or dental problems\n\nAfter 1.5 years of therapy, experienced rapid deterioration of teeth (some began falling out)\n\nAfter 3 years, all teeth removed\n\n16", "n_tokens": 77, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-16-0", "doc_id": "final_ce_dental_caries", "page": 16, "text": "REVIEW OF SAFETY SIGNAL\n\nwww.fda.gov 17", "n_tokens": 10, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-17-0", "doc_id": "final_ce_dental_caries", "page": 17, "text": "Summary of Case Characteristics\n\n• Age:\n\n50% female\n\nMean: 41.8 years – Median: 36.2 years – Range: 18-71 years\n\nHCP reporting: 65/305 (~21%) • • Number of teeth: 182 Serious outcomes = 131\n\nTwo or more (e.g., “teeth”): 113 – “Majority”: 6 – “All”: 11\n\nFormulation reported: 238 – Film only: 143 – Tablet only: 48 – Tablet and Film: 47 Indication for use: 194 – Opioid Dependence: 173 – Pain: 28 Time to Diagnosis: 136 – Mean: 31.5 months – Median: 24.25 months – Range: 0.5-182 months\n\n18", "n_tokens": 145, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-18-0", "doc_id": "final_ce_dental_caries", "page": 18, "text": "FAERS Case #3\n\n53-year-old-male • Buprenorphine/naloxone SL film for OUD • PMH: chronic pain, open heart surgery • Denied history of dental caries • After initiating SL product, patient experienced 15 dental caries over a time period of ~2 years\n\nPatient had regular dental cleanings every 3 months • Diagnosed with dental caries at each 6-month visit while on the product\n\n19", "n_tokens": 90, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-19-0", "doc_id": "final_ce_dental_caries", "page": 19, "text": "FAERS Case #4\n\n34-year-old-female • Buprenorphine (single ingredient) SL tablet • Experienced “deterioration of tooth enamel and significant damage to teeth in the region of [product] dissolution”\n\nPMH: previous enrollment in methadone program, denial of continued use of “street” drugs\n\nDental exams every 6 months while on methadone • Teeth in “good condition” at time of switch to buprenorphine SL • After toothache developed between visits, dentist noticed patient’s “front teeth” all needing filling in the region where SL product was used\n\n20", "n_tokens": 120, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-20-0", "doc_id": "final_ce_dental_caries", "page": 20, "text": "Literature\n\nSuzuki, J., L. Mittal, and S. B. Woo. 2013. 'Sublingual buprenorphine and dental problems: a case series', Prim Care Companion CNS Disord, 15.\n\nMean age 34.4 years, predominantly white (91%), taking buprenorphine for a mean of 45.7 months (range 5-77) at a mean dose of 11.6mg/day (range, 2-20mg), took the medication a mean of 3.2 times per day.\n\nAverage of 8.9 minutes (range 1-30 min) to dissolve completely • Mean number of caries: 5.2 (range, 0-24) • Majority of subjects (54.5%) reported tooth pain\n\n21", "n_tokens": 162, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-21-0", "doc_id": "final_ce_dental_caries", "page": 21, "text": "Product-Specific Information*\n\nDRUG X adheres to the moist buccal mucosa and will completely dissolve after application, usually within 30 minutes\n\nMedian dissolve time of DRUG Y was 5 minutes while the median dissolve time of DRUG Z was 12.5 minutes\n\nMean in vivo dissolution time is 17.6 minutes for 8 mg tablet, 8.13 minutes for 2 mg tablet\n\nThe mean dissolution time (seconds) was 241 (cold beverage), 261 (hot beverage), 222 (room temperature water\n\nDissolution testing described combination\n\nproduct needing\n\n7 minutes to dissolve\n\n* Information listed is from different products\n\n22", "n_tokens": 117, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-22-0", "doc_id": "final_ce_dental_caries", "page": 22, "text": "Biological Plausibility\n\nhttps://www.microlit.us/the-role-of-ph-value-in-titration/\n\nBuprenorphine is stable in solution at a pH of 3.5-5.5\n\nDental caries can result from activity of acids on tooth structure – Normal pH of saliva is between 6.7 and 7.4 – When pH drops below 5.5, acid begins to erode enamel • Prolonged exposure to acidic environment would be expected to contribute to dental adverse events 23", "n_tokens": 107, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-23-0", "doc_id": "final_ce_dental_caries", "page": 23, "text": "REGULATORY FRAMEWORK\n\nwww.fda.gov 24", "n_tokens": 8, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-24-0", "doc_id": "final_ce_dental_caries", "page": 24, "text": "Food and Drug Administration Amendments Act of 2007 (FDAAA)\n\nSigned into law September 27, 2007 • Section 901 of the Act adds section 505(o)(4) to the Federal Food, Drug, and Cosmetic Act\n\nAuthorizes FDA to require safety labeling changes for the following products: – Prescription drugs with an approved NDA – Biological products with an approved BLA – Prescription drugs with an approved ANDA (if the reference\n\nlisted drug is not currently marketed)\n\n25", "n_tokens": 94, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-25-0", "doc_id": "final_ce_dental_caries", "page": 25, "text": "Regulatory Authority • 505(o)(4): FDA can require, and if necessary, order labeling changes if FDA becomes aware of New Safety Information that FDA believes should be included in the labeling of a drug. • What is “New Safety Information?”\n\n505-1(b) defines it as “information derived from a clinical trial, an adverse event report, a postapproval study, peer reviewed biomedical literature, data derived from postmarket risk identification and analysis system, or other scientific data deemed appropriate by FDA”\n\n26", "n_tokens": 107, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-26-0", "doc_id": "final_ce_dental_caries", "page": 26, "text": "What Can be Changed?\n\n(https://www.fda.gov/drugs/fdas-labeling-resources-human-prescription-drugs/prescribing-information-resources)\n\n27", "n_tokens": 41, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-27-0", "doc_id": "final_ce_dental_caries", "page": 27, "text": "Warnings and Precautions • Intended to identify and describe a\n\ndiscrete set of adverse reactions and other potential safety hazards that are serious or are otherwise clinically significant.\n\nTo include the adverse event in this section there should be reasonable evidence of a causal association, but a causal relationship need not have been definitively established.\n\n28", "n_tokens": 61, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-28-0", "doc_id": "final_ce_dental_caries", "page": 28, "text": "Serious or Otherwise Clinically Significant Serious\n\nOtherwise Clinically Significant\n\n• •\n\nDeath Life-threatening adverse event Inpatient hospitalization or prolongation of existing hospitalization A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly or birth defect\n\nBased on appropriate medical judgement, may jeopardize the patient and require medical or surgical intervention to prevent one of the outcomes in the above list\n\nIndication\n\nSeriousness relative to the disease or condition treated\n\nIncidence\n\nHigh absolute risk or rate of occurrence\n\nOther\n\nPotential serious outcome unless regimen is adjusted – Reaction that can be managed with appropriate patient selection, monitoring, and prevention or management is needed to avoid potentially serious outcome\n\nAn adverse reaction that can significantly affect patient compliance, particularly when noncompliance has potentially serious consequences\n\n29", "n_tokens": 155, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-29-0", "doc_id": "final_ce_dental_caries", "page": 29, "text": "FAERS Case #5\n\n36-year-old-female • SL buprenorphine/naloxone • Experienced rapid tooth loss over 14 months while on the product • Teeth became soft and brittle, chipped just by brushing or chewing soft foods\n\nHad X-rays 14 months before starting SL buprenorphine, “showed none of the insane damages (that) had happened to teeth”\n\nDentist stated never seen tooth decay like this • Did not have the means to have teeth fixed, would hide teeth when talking, most severely affected teeth were pulled\n\nOn unknown date, patient stopped taking SL buprenorphine/naloxone\n\n30", "n_tokens": 129, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-30-0", "doc_id": "final_ce_dental_caries", "page": 30, "text": "Causal Association?\n\nFactors\n\nFindings\n\n1. Frequency of Reporting\n\nHundreds of cases\n\n2. Adverse event rate in the drug treatment group exceeds the rate in the placebo and active-control group in controlled trials?\n\n(n/a, no clinical trial data found explored this adverse event)\n\n3. Evidence of a dose-response relationship\n\nPossibly, though cases may have been more closely tied to dosing frequency than dose\n\n4. Extent to which the adverse event is consistent with the pharmacology of the drug\n\nStrong biological plausibility for the sublingual dosage form\n\n5. Temporal association between drug administration and event\n\nCase descriptions often had reliable information on dental health prior to starting treatment\n\n6. Existence of dechallenge and rechallenge experience 7. Whether adverse event is known to be caused by related drugs\n\n6. Existence of dechallenge and rechallenge experience 7. Whether adverse event is known to be caused by related drugs\n\nYes and no...\n\n31", "n_tokens": 194, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-31-0", "doc_id": "final_ce_dental_caries", "page": 31, "text": "Caused by Related Drugs??? • Few cases involving other SL/transmucosal forms of\n\nopioids – Already labeled (note: different composition)\n\n305 cases of dental caries involving TMB\n\n28 of 305 implicated a brand name SL product indicated for pain – Notable as well that the dosing for this product is around 10x less than that of TMB for OUD\n\nZero cases involving buprenorphine depot (OUD) • Zero cases involving buprenorphine transdermal (Pain) 32", "n_tokens": 104, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-32-0", "doc_id": "final_ce_dental_caries", "page": 32, "text": "Regulatory Decision • These cases of dental caries were determined to be\n\nserious and otherwise clinically significant\n\nThe totality of evidence provided reasonable evidence of a causal association between the drug in this dosage form and the adverse event\n\nThis type of adverse event has implications for prescribing decisions and for patient management • A new Warnings and Precautions statement was\n\nwarranted\n\n33", "n_tokens": 71, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-33-0", "doc_id": "final_ce_dental_caries", "page": 33, "text": "REGULATORY ACTION\n\nwww.fda.gov 34", "n_tokens": 8, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-34-0", "doc_id": "final_ce_dental_caries", "page": 34, "text": "New Safety Information (NSI) • Section 505(o)(4) requires FDA provide NSI to require\n\nchanges – 305 cases – Evidence of rampant caries – 71/305 cases resulted in tooth extraction – Acknowledged that the presence of substance use disorder\n\nmay increase major oral health problems\n\n26/305 cases occurred in patients with no prior history of dental problems (well documented)\n\n28/305 cases occurred in patients taking the product for the pain indication\n\n35", "n_tokens": 90, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-35-0", "doc_id": "final_ce_dental_caries", "page": 35, "text": "Labeling – 5 Warnings and Precautions (first paragraph)\n\n5.x Dental Adverse Events\n\nCases of dental caries, some severe (i.e., tooth fracture,\n\ntooth loss), have been reported following the use of transmucosal buprenorphine-containing products. Reported events include cavities, tooth decay, dental abscesses/infection, rampant caries, tooth erosion, fillings falling out, and, in some cases, total tooth loss. Treatment for these events included tooth extraction, root canal, dental surgery, as well as other restorative procedures (i.e., fillings, crowns, implants, dentures). Multiple cases were reported in individuals without any prior history of dental problems.\n\n36", "n_tokens": 150, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-36-0", "doc_id": "final_ce_dental_caries", "page": 36, "text": "Labeling – 5 Warnings and Precautions (second paragraph)\n\nRefer patients to dental care services and encourage them\n\nto have regular dental checkups while taking TRADENAME. Educate patients to seek dental care and strategies to maintain or improve oral health while being treated with transmucosal buprenorphine-containing products. Strategies include, but are not limited to, gently rinsing teeth and gums with water then swallowing after TRADENAME has been completely dissolved in the oral mucosa. Advise patients to wait at least one hour after taking TRADENAME before brushing teeth[see Dosing and Administration (2.x), Information for patients (17), Medication Guide].\n\n37", "n_tokens": 134, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-37-0", "doc_id": "final_ce_dental_caries", "page": 37, "text": "Labeling – 2. Dosage and Administration\n\n2.1 Important Dosage and Administration Information • 2.2 Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose • 2.3 Induction • 2.4 Maintenance • 2.5 Method of administration\n\nAdvise patients to do the following after the product has completely dissolved in the oral mucosa: take a sip of water, swish gently around the teeth and gums, and swallow. Advise patients to wait for at least one hour after taking TRADENAME before brushing teeth [see Warnings and Precautions (5), Postmarketing experience (6.2), Information for Patients (17), and the Medication Guide]\n\n38", "n_tokens": 140, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-38-0", "doc_id": "final_ce_dental_caries", "page": 38, "text": "Labeling – 17 Information for Patients\n\nAdvise patients that, after TRADENAME has\n\ncompletely dissolved in the oral mucosa, to take a sip of water, swish it gently around their teeth and gums, and swallow. Advise patients to wait for at least one hour after taking TRADENAME before brushing teeth. • Refer patients to dental care services and encourage them to have regular dental checkups while taking TRADENAME. Instruct patients to inform their dentist that they have started therapy on TRADENAME\n\n39", "n_tokens": 98, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-39-0", "doc_id": "final_ce_dental_caries", "page": 39, "text": "Labeling – Medication Guide\n\nUnder “How should I take TRADENAME?”\n\nAfter TRADENAME is completely dissolved, rinse your mouth with water and swallow. Wait for at least one hour before brushing teeth.\n\nReport any problems with your teeth immediately to your provider and schedule an appointment with a dentist. Tell your dentist that you have started taking TRADENAME. 40", "n_tokens": 70, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-40-0", "doc_id": "final_ce_dental_caries", "page": 40, "text": "www.fda.gov\n\nCOMMUNICATIONS PLAN AND PUBLIC RECEPTION\n\n41", "n_tokens": 11, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-41-0", "doc_id": "final_ce_dental_caries", "page": 41, "text": "Communications\nPlan\n\nt|\n\nFDA warns about dental problems with\nbuprenorphine medicines dissolved in the\nmouth to treat opioid use disorder and\n\npain\n\nBenefits for use outweigh these risks and oral care can help\n\n| # share | > Post | in Linkeain | a Emon |B Prt |\n\n1-12-2022 FDA Drug Safety Communication\n\nfety\n\nDrug Safety Communication (PDF - 94 KB)\nWhat safety concern is FDA announcing?\nWhat is FDA doing?\nWhat is buprenorphine and how can it help me?\nWhat should patients and caregivers do?\nWhat should health care professionals do?\nWhat did FDA find?\nWhat is my risk?\nHow do I report side effects from buprenorphine?\n\nHow can I get new safety information on medicines I’m\nprescribing or taking?\n\nFacts about buprenorphine\n\nAdditional Information for Patients and Caregivers\nAdditional Information for Health Care Professionals\nData Summary\n\nReferences\n\nFDA\n\n42", "n_tokens": 189, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-42-0", "doc_id": "final_ce_dental_caries", "page": 42, "text": "Professional Uptake / Reception\n\nJ THE JOURNAL OF THE AMERICAN DENTAL ASSOCIATION\n\nOrally dissolving buprenorphine for opioid use disorder linked to\ncaries\n\nStuart L. Segelnick, DDS, MS 2 & - Mea A. Weinberg, DMD, MSD, RPh\n\n| |\\ ns Medscape\n\nThe Leading Voice of Nursing Since 19110\nNews > Medscape Medical News\n\nBUPRENORPHINE Orally Dissolving Buprenorphine Tied to Severe\nTooth Decay, FDA Warns\n© The labeling for transmucosal\nbuprenorphine products will January 13, 2022\npe ee World Y USElection Business¥ Markets Sustainability LegalY BreakingviewsV Technology V\ndrug may cause serious dental \"\nproblems such as tooth decay,\ncavities, oral infections, and Healthcare & Pharmaceuticals\ntooth loss. . °\n# Nurses and NPs should com- FDA flags risk of dental issues from use\nlete an oral history and as- oe eae .\neae of opioid addiction drug buprenorphine\nbeginning treatment. Patients\nshould be informed of these\npotential adverse effects and\nencouraged to receive regular\ndental care.\n\nAmerican Pharmacists Association\n\nFDA warns of dental problems associated with certain buprenorphine medications 43", "n_tokens": 251, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-43-0", "doc_id": "final_ce_dental_caries", "page": 43, "text": "Social Media Reaction\n\nhttps://www.reddit.com/r/suboxone/comments/s2nifc/warning_to_suboxonesubutex_users_just_got_an_fda/\n\n44", "n_tokens": 49, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-44-0", "doc_id": "final_ce_dental_caries", "page": 44, "text": "Etminan, Mahyar, Ramin Rezaeianzadeh, Abbas Kezouh, and Kevin Aminzadeh. 2022. 'Association Between Sublingual Buprenorphine-Naloxone Exposure and Dental Disease', JAMA, 328: 2269-71.\n\nBarus, R., F. Montastruc, C. de Canecaude, H. Bagheri, A. Sommet, and M. Lapeyre-Mestre. 2023. 'Sublingual/Buccal buprenorphine and dental problems: a pharmacovigilance study', Expert Opin Drug Saf, 22: 1283- 87.\n\nNew Science\n\n45", "n_tokens": 148, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-45-0", "doc_id": "final_ce_dental_caries", "page": 45, "text": "Summary\n\n1. The U.S. is still in an opioid overdose crisis, but treatments, like transmucosal buprenorphine for opioid use disorder are available\n\n2. FDA detected a signal involving transmucosal buprenorphine and dental caries, reviewed the scientific information\n\n3. FDA’s review off the safety signal determined that the dental caries were serious, otherwise clinically significant, and there was reasonable causal association between the drug and the event; thus a new Warnings and Precautions statement was added to TMB products, per FDA’s authority\n\n4. Healthcare providers can help by being aware of this adverse event, discussing with their patients, monitoring for such events, and encouraging regular dental checkups while on TMB. 46", "n_tokens": 154, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-46-0", "doc_id": "final_ce_dental_caries", "page": 46, "text": "Q&A\nPANEL\n\nwww.fda.gov 47", "n_tokens": 10, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-47-0", "doc_id": "final_ce_dental_caries", "page": 47, "text": "Q&A Panelists\n\nSamantha Cotter, PharmD, BCPS, FISMP Safety Evaluator Division of Pharmacovigilance Office of Surveillance and Epidemiology\n\nMonisha Billings, DDS, MPH, PhD Team Lead / Epidemiologist Safety, Policy, Research, and Initiatives Office of New Drugs - Immediate office\n\nZachary Illg, DO Medical Officer Division of Anesthesiology, Addiction Medicine, and Pain Medicine Office of New Drugs\n\n48", "n_tokens": 95, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-48-0", "doc_id": "final_ce_dental_caries", "page": 48, "text": "www.fda.gov\n\nReferences\n\nHaffajee, R. L., and R. G. Frank. 2018. 'Making the Opioid Public Health Emergency Effective', JAMA Psychiatry, 75: 767-68. Ciccarone, D. 2021. 'The rise of illicit fentanyls, stimulants and the fourth wave of the opioid overdose crisis', Curr Opin Psychiatry, 34: 344-50. American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition,. Washington, DC, American Psychiatric Association. Saunders, E. C. 2022. 'Flexible Buprenorphine/Naloxone Treatment Models: Safe and Effective in Reducing Opioid Use Among Persons With Prescription Opioid Use Disorder', Am J Psychiatry, 179: 699-701. Dowell D, Brown S, Gyawali S, et al. Treatment for Opioid Use Disorder: Population Estimates — United States, 2022. MMWR Morb Mortal Wkly Rep 2024;73:567–574. DOI: http://dx.doi.org/10.15585/mmwr.mm7325a1 Madden, Erin Fanning, Suzanne Prevedel, Timothy Light, and Sandra H. Sulzer. 2021. 'Intervention Stigma toward Medications for Opioid Use Disorder: A Systematic Review', Substance Use & Misuse, 56: 2181-201. Hanson GR, McMillan S, Mower K, Bruett CT, Duarte L, Koduri S, Pinzon L, Warthen M, Smith K, Meeks H and Trump B (2019) Comprehensive oral care improves treatment outcomes in male and female patients with high-severity and chronic substance use disorders. J Am Dent Assoc 150:591-601.\n\n49", "n_tokens": 388, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-49-0", "doc_id": "final_ce_dental_caries", "page": 49, "text": "www.fda.gov\n\nReferences\n\nSuzuki, J., L. Mittal, and S. B. Woo. 2013. 'Sublingual buprenorphine and dental problems: a case series', Prim Care Companion CNS Disord, 15. Hans, Rinki, Susan Thomas, Bharat Garla, Rushabh J. Dagli, and Manoj Kumar Hans. 2016. 'Effect of Various Sugary Beverages on Salivary pH, Flow Rate, and Oral Clearance Rate amongst Adults', Scientifica, 2016: 5027283. Guidance for Industry – Safety Labeling Changes – Implementation of Section 505(o)(4) of the FD&C Act, https://www.fda.gov/regulatory-information/search-fda-guidance- documents/safety-labeling-changes-implementation-section-505o4-federal-food-drug-and- cosmetic-act Guidance for Industry – Warnings and Precautions, Contraindications, Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/warnings-and- precautions-contraindications-and-boxed-warning-sections-labeling-human-prescription Suzuki, J., and E. M. Park. 2012. 'Buprenorphine/naloxone and dental caries: a case report', Am J Addict, 21: 494-5. Buprenorphine: Drug Safety Communication - FDA warns about dental problems with buprenorphine medicines dissolved in the mouth to treat opioid use disorder and pain, retrieved from: https://www.fda.gov/safety/medical-product-safety- information/buprenorphine-drug-safety-communication-fda-warns-about-dental-problems- buprenorphine-medicines. Posted January 12, 2022.\n\n50", "n_tokens": 400, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-50-0", "doc_id": "final_ce_dental_caries", "page": 50, "text": "www.fda.gov\n\nReferences\n\nEtminan, Mahyar, Ramin Rezaeianzadeh, Abbas Kezouh, and Kevin Aminzadeh. 2022. 'Association Between Sublingual Buprenorphine-Naloxone Exposure and Dental Disease', JAMA, 328: 2269-71. Barus, R., F. Montastruc, C. de Canecaude, H. Bagheri, A. Sommet, and M. Lapeyre-Mestre. 2023. 'Sublingual/Buccal buprenorphine and dental problems: a pharmacovigilance study', Expert Opin Drug Saf, 22: 1283-87. Segelnick, S. L. and M. A. Weinberg (2024). \"Orally dissolving buprenorphine for opioid use disorder linked to caries.\" J Am Dent Assoc 155(7): 561-564. Aschenbrenner, D. S. (2022). \"New Dental Warning for Buprenorphine.\" AJN The American Journal of Nursing 122(5): 18. Brooks, M. (2022). \"Orally Dissolving Buprenorphine Tied to Severe Tooth Decal, FDA Warns.\" from https://www.medscape.com/viewarticle/966562?form=fpf. Reuters (2022). \"FDA flags risk of dental issues from use of opioid addiciton drug buprenorphine.\" from https://www.reuters.com/business/healthcare-pharmaceuticals/fda- flags-risk-dental-issues-use-opioid-addiction-drug-buprenorphine-2022-01-12/ . Sartain, M. (2022). \"FDA warns of dental problems associated with certain buprenorphine medications.\" from https://www.pharmacist.com/Publications/Transitions/ArtMID/828/ArticleID/885/FDA-warns- of-dental-problems-associated-with-certain-buprenorphine-medications .\n\n51", "n_tokens": 466, "kind": "text"}
{"chunk_id": "final_ce_dental_caries-51-0", "doc_id": "final_ce_dental_caries", "page": 51, "text": "PAW U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 9, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-0-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 0, "text": "The State of Pharmaceutical Quality\n\nPatrizia Cavazzoni, M.D. Director Center for Drug Evaluation and Research Food and Drug Administration U.S. Department of Health and Human Services Presented at IPA 8th Global Pharmaceutical Quality Summit June 22, 2023", "n_tokens": 51, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-1-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 1, "text": "Quality Issues Lead to Drug)“ J =&\nShortages ¢ ~\n\nPercentage of Drugs Newly in Shortage by Reason, Calendar Years 2013-2017\n\nQuality Issues 62%\nUnknown\nIncrease in Demand\n\nNatural Disaster\n\nProduction Discontinuation\n\nMost drugs in shortage were experiencing supply disruptions, specifically quality issues.\nSource: Internal FDA Data", "n_tokens": 61, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-2-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 2, "text": "Early Notification is Key to Prevention\n\nThrough ongoing dialogue/work with industry the number of prevented shortages continues to grow, while new drug shortages remain flat\n\nDepending on the precipitating events, some drug shortages can endure for months to years (e.g., plant remediations and Agency approvals)\n\nThe earlier this work begins the greater the likelihood a shortage can be prevented, or the most severe impacts mitigated\n\nTotal Prevented US Drug Shortages Per Year1\n\nNumber of New US Drug Shortages Per Year1\n\n1. Annual Report on Drug Shortages for Calendar Year 2022", "n_tokens": 113, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-3-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 3, "text": "Manufacturing Capacity Shortfall\n\nFor critical drugs, there exists a US and global production capacity shortfall  This is particularly true for sterile injectable drugs  There are no current incentives for generic drug manufacturers to produce\n\nexcess over market demand (unlike other commodities)\n\nThis can lead to disruptions in supply which can ultimately result in shortages  Disruptions can be caused by unforeseen events:\n\no Hurricane Maria in Puerto Rico o Necessary compliance remediations o Geopolitical concerns\n\n Or financial pressures could lead to:\n\no Manufacturing site closures o Firm bankruptcies", "n_tokens": 107, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-4-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 4, "text": "Oncology Drug Shortages\n\n 16 drugs in shortage (as of May 2023)\n\namifostine injection, – azacitadine injection, – capecitabine tablets, – carboplatin injection, – cisplatin injection, – cytarabine injection, – dacarbazine injection, – dexamethasone injection\n\nfludarabine injection – fluorouracil injection – hydrocortisone injection – leucovorin injection – lutetium lu 177 vipovotide textraxeta injection – methotrexate injection – palifermin injection – streptozocin injection", "n_tokens": 126, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-5-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 5, "text": "ERVICE\npa SERVICES. 0\n. F\n\nC\n\n_ of HEAL Ty, ey\n%,\n\nevan\n\npatients will die\n\nBy Paul Goldberg\n\nPrve curative regimens containing\nplatinum-based drugs—cisplatin\nand carboplatin—have become large-\nly unavailable because ofa nationwide\ndrug shortage. The institutions that\nhave some supplies of cisplatin and car-\nboplatin are setting up algorithms for\nrationing their dwindling stocks, which\nusually means giving top priority to pa-\ntients treated with curative intent and\ndenying standard-of-care treatment to\nPatients who cannot be cured but who\ncanstill benefit from these drugs.\n\nGsplatinand carboplatin are old, gener-\nic drugs. Cisplatin was first described\nin medical literature in 1844 (The Can-\ncer Letter, April 28, 2023). Both cisplatin\nand carboplatin have been widely used\n‘since the 1970s. Since platinum drugs\nare thoroughly studied and are a sta-\nple in oncology, this means they are\noften present in regimens on both the\nexperimental and control arms of din-\nical trials.\n\nVia\n\nN\n~)\n~\n\neo )\n\nL\n\nEhe New Mork Cimes\n\nRising Rate of Drug Shortages Is\nFramed as a National Security Threat\n\nASenate homeland security committee examined growing health\n\ncare shortages amid reports of rationing within hospitals.\n\nges\n\nEhe New York Cimes\n\nDrug Shortages Near an All-Time\nHigh, Leading to Rationing\n\nA worrisome scarcity of cancer drugs has heightened concerns\nabout the troubled generic drug industry. Congress and the\nWhite House are seeking ways to address widespread supply\n\nproblems.", "n_tokens": 332, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-6-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 6, "text": "\n\n\n\n\n\nCritical Shortage of Cisplatin and Carboplatin\n\n1.8 million Americans are diagnosed with some form of cancer every year There are estimates that up to 500,000 patients possibly could have a stage and a diagnosis that would rely on a platinum agent The current shortages of cisplatin and carboplatin followed an inspection and identification of quality issues at one company’s facility\n\nShortages posted on FDA website in 2/23\n\nand 4/23. respectively The company shut down production leading to the current shortage. In addition, the shortage of cisplatin led to a ripple effect as demand for the second line treatment, carboplatin, increased but the manufacturers were not able to meet demand", "n_tokens": 139, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-7-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 7, "text": "Import Alerts\n\n A critical tool to keep violative, defective or potentially harmful drug products from reaching the U.S. market – China, Latin America most\n\nimport alerts in 2021\n\nRest of the World 5\n\nMany inspection refusal,704(a), non- compliance\n\nIndia 3\n\nLatin America 4\n\nSource: Office of Pharmaceutical Quality Report on the State of Pharmaceutical Quality: FY2021\n\nChina 4\n\nIndia 2\n\nEU & UK 1 China 1\n\nIA 66-40 (GMP-based) Inspection\n\nIA 66-40\n\n(GMP-based)\n\n704(a)(4)\n\nRest of the World 3\n\nLatin America 8\n\nEU & UK 1 EU & UK 1\n\nChina 7\n\nIA 66-78 (Testing-based) HS\n\nRest of the World 1\n\nLatin America 1\n\nIndia 2\n\nChina 5\n\nIndia 1\n\nIA 99-32 (Refusal-based) Inspection\n\nIA 99-32 (Refusal-based) 704(a)(4)", "n_tokens": 185, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-8-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 8, "text": "Inspections\n\nFDA continued mission-critical inspections throughout the public health emergency\n\nFDA has conducted domestic inspections at standard operational levels since October 2021​\n\nFDA resumed foreign facility surveillance inspections in March 2022, and resumed inspections in China with U.S.- based staff in April 2023​\n\nFDA continues to leverage a variety of tools for facility assessment, including remote assessments", "n_tokens": 67, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-9-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 9, "text": "Recurring Issues in Drug Manufacturing Compliance\n\nMicrobial contamination\n\nOphthalmic product contaminated with multi- drug resistant bacteria\n\nLack of data integrity, transparency, and record retention – Information must be accurate, reliable, and\n\nBurkholderia cepacia complex in non-sterile,\n\ncomplete\n\nwater-based drug products • Poor excipient quality and manufacturing controls – Diethylene glycol/ethylene glycol\n\ncontamination\n\nBenzene contamination (warning letter) – First CGMP Warning letter issued to excipient manufacturer\n\nRefusal of inspection; failure to respond to requests for records\n\nAppropriate remediation strategy and suitable timeframes are important\n\nInadequate controls related to: • Aseptic manufacturing • Cleaning and cross-contamination • Supply chain globalization & contract\n\nmanufacturing\n\nFacility design and maintenance • Out-of-specification result investigations", "n_tokens": 163, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-10-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 10, "text": "Sustainable Compliance\n\nFDA’s Current Good Manufacturing Practice (CGMP) requirements provide the foundation for a robust state of control and drug quality\n\nMaintaining ongoing CGMP compliance requires a proactive and prevention-focused quality system If the quality system at a facility is slow to address operations with excessive variability, this reactive • approach is a recipe for lapses in compliance and inconsistent pharmaceutical quality\n\nFigure A: This facility experiences lapses in control due to inconsistent adherence to CGMP and vacillates between acceptable and substandard quality.\n\nFigure B: This prevention-focused, CGMP-compliant facility yields consistently conforming medicines.\n\nCompliant\n\nCompliant\n\ntime\n\ntime\n\nNon-Compliant\n\nNon-Compliant", "n_tokens": 136, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-11-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 11, "text": "Critical Factors Associated with Sustainable Compliance\n\nSenior Management Oversight of Facilities\n\nEnsure ongoing suitability of operational design, control, and maintenance\n\nAllocate resources for production infrastructure upgrades when operations are deficient.\n\nTechnological capability directly impacts quality of outputs, and is central to sustainable compliance\n\nLifecycle Quality Signals and Root Cause Analysis\n\nImportant to have an effective system for implementing corrective actions and preventive actions\n\nA structured approach to the investigations is critical for understanding the root cause", "n_tokens": 87, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-12-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 12, "text": "Example of Transformation from OAI to Sustainable Compliance\n\nLarge, multinational manufacturer of generics\n\nProduces critical sterile drugs for vulnerable patients\n\nMultiple VAI inspections  emerging concerns conveyed during regulatory meetings, firm commits to systemic CGMP remediation\n\nIneffective remediation, recurring problems  Recalls, WL, 3rd party audit\n\nFirm made long term investments in transformational change. This required fundamental changes in the:\n\nQuality System: Key management changes. Improved quality system governance at site. Increased QA oversight of facility, process, and quality performance.\n\nFacility Design: Replaced old lines with modern processing lines. Converted low- capability inefficient facility to highly capable isolator technology.\n\nOutcome: Sustainable Compliance (approaching 10 years)", "n_tokens": 141, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-13-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 13, "text": "A Call to Action: Achieving Sustainable Compliance\n\n1. 2. Ensure strong quality management oversight\n\nIdentify and address current problems; implement long-term systemic remediation\n\n\"Walk the talk:” quality is top priority throughout organization • Accountability for quality\n\n3. Well-designed facilities, equipment, and processes • Upgrade to highly capable facilities and equipment • State of control vigilantly monitored\n\n4. Engineer quality system to proactively identify and remediate problems as they occur (FDA is not your quality system)\n\nPrompt attention to address emerging adverse trends and deviations\n\n Commitment to quality assurance creates the needed conditions for dependable supply for patients", "n_tokens": 124, "kind": "text"}
{"chunk_id": "global_pharmaceutical_quality_summit-14-0", "doc_id": "global_pharmaceutical_quality_summit", "page": 14, "text": "PY U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 10, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-0-0", "doc_id": "medicine_vaccine_book", "page": 0, "text": "Carlos M. Correa Reto M. Hilty Editors\n\nAccess to Medicines and Vaccines\n\nImplementing Flexibilities Under Intellectual Property Law", "n_tokens": 27, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-1-0", "doc_id": "medicine_vaccine_book", "page": 1, "text": "Access to Medicines and Vaccines", "n_tokens": 5, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-2-0", "doc_id": "medicine_vaccine_book", "page": 2, "text": "Carlos M. Correa (cid:129) Reto M. Hilty Editors\n\nAccess to Medicines and Vaccines\n\nImplementing Flexibilities Under Intellectual Property Law", "n_tokens": 32, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-3-0", "doc_id": "medicine_vaccine_book", "page": 3, "text": "Editors Carlos M. Correa South Centre Geneva, Switzerland\n\nReto M. Hilty Max Planck Institute for Innovation and Competition München, Bayern, Germany\n\nISBN 978-3-030-83113-4 https://doi.org/10.1007/978-3-030-83114-1\n\nISBN 978-3-030-83114-1\n\n(eBook)", "n_tokens": 84, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-3-1", "doc_id": "medicine_vaccine_book", "page": 3, "text": "© The Editor(s) (if applicable) and The Author(s) 2022. This book is an open access publication. Open Access This book is licensed under the terms of the Creative Commons Attribution 4.0 International License adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The images or other third party material in this book are included in the book’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the book’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher", "n_tokens": 297, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-3-2", "doc_id": "medicine_vaccine_book", "page": 3, "text": "remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.", "n_tokens": 18, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-3-3", "doc_id": "medicine_vaccine_book", "page": 3, "text": "(http://creativecommons.org/licenses/by/4.0/), which permits use,\n\nsharing,\n\nThis Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland", "n_tokens": 60, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-4-0", "doc_id": "medicine_vaccine_book", "page": 4, "text": "Preface\n\nThis book is an outcome of a partnership between the Max Planck Institute (MPI) for Innovation and Competition and the South Centre, which jointly organized a Global Forum on Intellectual Property, Access to Medicine and Innovation in Munich on 9– 10 December 2019.\n\nThe MPI is more than 50 years old, but it was less than 20 years ago that its research focus began to change quite fundamentally. In the first decades after its foundation, the Institute academically supported and accompanied efforts to achieve a certain standard of protection on the international level. At that time, there was hardly any consideration of the implications of the intellectual property system for countries at different levels of technological and economic development.", "n_tokens": 136, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-4-1", "doc_id": "medicine_vaccine_book", "page": 4, "text": "Much changed in the 1990s, however—not least with the creation of the WTO and the entry into force of the Agreement on Trade Related Aspects of Intellectual property Rights (the TRIPS Agreement) in 1994. One year later, in 1995, the South Centre was launched and began its work, at a time when it was becoming increas- ingly doubtful whether high standards of intellectual property protection would produce comparable benefits for all countries, regardless of their level of develop- ment. The South Centre published in 1997 ‘The TRIPS Agreement. A Guide for the South. The Uruguay Round Agreement on Trade-Related Intellectual Property Rights’, one of the first analysis of the ‘flexibilities’ allowed by the TRIPS Agree- ment, the main theme of the Global Forum referred to above.\n\nIt took a little more time before a differentiated view began to gain ground at the MPI, but a new era began in 2002 with a change in the management of the Institute. The question of how to avoid dysfunctional effects of IP rights in certain areas and contexts became more and more important.\n\nNaturally, these perspectives brought into focus countries whose development depended much more on policies other than strong intellectual property protection. How little their own industries benefitted from high protection standards became particularly obvious when primarily foreign rather than local companies used the domestic intellectual property system to protect their own inventions, creations, or trademarks.\n\nv", "n_tokens": 288, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-5-0", "doc_id": "medicine_vaccine_book", "page": 5, "text": "vi\n\nWhile in earlier years, the MPI’s activities in Asia or Latin America, for instance, were targeted at explaining the meaning and rationale of high standards of IP protection, the view became much more cautious under the new perspective. In the first instance, the Institute tried to understand the socio-economic context of a country, and supported local academics, but also legislators and national policymakers in the analysis and assertion of their specific needs.\n\nThis cautious approach to research activities and target-oriented support mean- while has become a tradition of the MPI, especially in Southeast Asia and partly in Africa. A new and special focus, however, now lies on Latin America. An initiative started there a few years ago with ‘Smart IP for Latin America’. Its purpose above all is to promote cooperation among the states concerned, but also to increase awareness for specific interests these countries may have and commonly defend. The topic of the Global Forum—access to medicine—is just one of many examples.", "n_tokens": 206, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-5-1", "doc_id": "medicine_vaccine_book", "page": 5, "text": "The South Centre, on its part, has worked extensively on intellectual property, particularly but not only in relation to access to medicines. As an intergovernmental organization of developing countries, it has focused on the analysis of the intellectual property system as it may affect development strategies, including the disciplines of the TRIPS Agreement and the standards of protection established pursuant to free trade agreements. A key area of work has been the extent to which that Agreement leaves policy space to implement intellectual property policies suited to different national scenarios in the developing world. The Global Forum jointly convened with the MPI gave the South Centre an opportunity to gather scholars and professionals of developed and developing countries to review current trends and advance in the understanding of the issues at stake with a focus in the area of intellectual property and medicines.", "n_tokens": 156, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-5-2", "doc_id": "medicine_vaccine_book", "page": 5, "text": "In this context, this book examines topics of particular relevance for shaping intellectual property regimes that take into account public health concerns. It pro- vides not only deep analyses but options for the interpretation of existing regulations or the adoption of new legislation that, being consistent with the TRIPS Agreement, can allow the judiciary and policy makers to take such concerns into account. In different chapters, the book addresses various dimensions of the flexibilities allowed under the TRIPS Agreement. Although there is a significant literature and statements on the subject, such as the ‘Declaration on Patent Protection. Regulatory Sovereignty under TRIPS’ elaborated under the auspices of the MPI,1 the book contains new reflections and examines recent developments in case law and legislation.\n\nThe covered issues include how the TRIPS Agreement can be interpreted to implement its flexibilities, the use of competition law to promote access to medi- cines, the role of cooperation in the examination of patent applications, patentability requirements, the impact of TRIPS plus provisions (such as the linkage between patents and drug regulatory approvals), the patentability in the area of CRISPR genome editing technologies, as well as an analysis of the scope of exceptions and limitations to exclusive rights provided for by the Agreement, such as the exhaustion\n\n1Available at https://www.mpg.de/8132986/Patent-Declaration.pdf.\n\nPreface", "n_tokens": 287, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-6-0", "doc_id": "medicine_vaccine_book", "page": 6, "text": "Preface\n\nvii\n\nof rights and parallel imports, compulsory licenses, the ‘Bolar exemption’, and procedural mechanisms like pre-grant oppositions. The implications of the protec- tion of test data are also examined.\n\nWhile celebrating the opportunity of working together in organizing the Global Forum, we hope that this book will assist policy makers and judges and provide new inputs for academic research. While, as mentioned, there is a differentiated impact of intellectual property rights depending on the level of development of the country where it applies, the reconciliation of such rights with public health interests, particularly in relation to access to medicines, is a matter of concern for all countries.\n\nGeneva, Switzerland München, Germany\n\nCarlos M. Correa Reto M. Hilty", "n_tokens": 148, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-7-0", "doc_id": "medicine_vaccine_book", "page": 7, "text": "Contents\n\nInterpreting the Flexibilities Under the TRIPS Agreement . . . . . . . . . . . Carlos M. Correa\n\nIntellectual Property Exhaustion and Parallel Imports of Pharmaceuticals: A Comparative and Critical Review . . . . . . . . . . . . Irene Calboli\n\nCompulsory Licenses and Government Use: Challenges and Opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yousuf A. Vawda\n\nAccess to CRISPR Genome Editing Technologies: Patents, Human Rights and the Public Interest . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Duncan Matthews\n\nBolar Exception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Viviana Munoz Tellez\n\nPatent Oppositions in India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 Sandeep Kanak Rathod\n\nProtection of Clinical Test Data and Public Health: A Proposal to End the Stronghold of Data Exclusivity . . . . . . . . . . . . . . 183 Ellen ‘t Hoen\n\nCourts and Pharmaceutical Patents: From Formalist Positivism to the Emergence of a Global Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Calixto Salomão Filho and Vitor Henrique Pinto Ido\n\nRobust Patent Examination or Deep Harmonization? Cooperation and Work Sharing Between Patent Offices . . . . . . . . . . . . . . . . . . . . . . . 241 Nirmalya Syam\n\n1\n\n31\n\n73\n\nix", "n_tokens": 421, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-8-0", "doc_id": "medicine_vaccine_book", "page": 8, "text": "x\n\nIntellectual Property Rights (IPRs), Competition Law and Excessive Pricing of Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 Mor Bakhoum The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities: Dealing with the Implementation Challenges . . . . . . . . . . . . . . . . . . . . . 297 Mohammed El Said\n\nPatent Linkages and Its Impact on Access to Medicines: Challenges, Opportunities for Developing Countries . . . . . . . . . . . . . . . . . . . . . . . . . 329 K. D. Raju\n\nContents", "n_tokens": 159, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-9-0", "doc_id": "medicine_vaccine_book", "page": 9, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\nCarlos M. Correa\n\nAbstract While the TRIPS Agreement provides for minimum standards of protec- tion of intellectual property, it leaves certain degree of policy space for WTO members, whether developed or developing countries, to implement the Agree- ment’s provisions in different manners, to legislate in areas not subject to the minimum standards under the Agreement, and to develop legal interpretations of such provisions to determine the scope and content of the applicable obligations. This paper focuses on some aspects of how panels and the Appellate Body of the WTO have interpreted said provisions. The paper also draws general conclusions for the implementation of TRIPS flexibilities, which are of crucial importance for the design of a pro-competitive intellectual property system and, in particular, for achieving public health objectives, as specifically recognized by the Doha Declara- tion on TRIPS and Public Health.", "n_tokens": 190, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-9-1", "doc_id": "medicine_vaccine_book", "page": 9, "text": "1 Introduction\n\nWhile the Agreement on Trade-Related Aspects of Intellectual Property Rights (‘the TRIPS Agreement’) has had a major impact in framing national laws on intellectual property rights (IPRs)—notably in developing countries—and has led to some degree of harmonization of such laws, it is not a uniform law on IPRs.\n\nOne the one hand, the TRIPS Agreement provides for minimum standards, thereby allowing the members of the World Trade Organization (WTO) to adopt broader protections.1 Many such ‘TRIPS-plus’ protections have been established through free trade agreements signed by the US and the European Union with\n\n1Article 1.1 of the TRIPS Agreement makes it clear, however, that no WTO member is obliged to grant such a broader protection. See, e.g., Correa (2020b), p. 21.\n\nC. M. Correa (*) South Centre, Geneva, Switzerland e-mail: director@southcentre.int\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_1\n\n1", "n_tokens": 260, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-10-0", "doc_id": "medicine_vaccine_book", "page": 10, "text": "2\n\nC. M. Correa\n\ndeveloping country partners.2 Examples of such TRIPS-plus protections include (in the area of patents) the extension of the patent term in order to compensate for delays in the grant of a patent or the marketing approval of a pharmaceutical product,3 data exclusivity,4 and what is known as ‘patent linkage’,5 among others. On the other hand, the TRIPS Agreement leaves some room for WTO members, whether developed or developing countries, to implement the Agreement’s pro- visions in different manners, to legislate in areas not subject to the minimum standards under the Agreement, and to develop legal interpretations of such pro- visions to determine the scope and content of the applicable obligations.", "n_tokens": 150, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-10-1", "doc_id": "medicine_vaccine_book", "page": 10, "text": "The possibility, and admissibility, of differences in the implementation of the provisions of the TRIPS Agreement are expressly recognized in Article 1.1 of the Agreement: “Members shall be free to determine the appropriate method of implementing the provisions of this Agreement within their own legal system and practice.” Competition law, which may be applied to control the acquisition or exercise of IPRs, is an example of the second situation in which the Agreement does not provide a binding standard.6 The room for different interpretations may result from the absence of definitions. One example is the lack of a definition of the concept of ‘invention,’ which differs among countries and allows WTO members not to grant patents, for instance, on developments without a technical effect (such as under European law), or to grant or not grant patents on genetic materials.7 In many cases, the space for different interpretations derives from general expressions or ambiguities in the text resulting from compromises reached in the negotiation of the Agreement. An outstanding example is the WTO members’ right to grant compul- sory licenses due to lack of working of a patent, an issue indirectly referred to in Article 27.1 of said Agreement.8 The task of the interpreter is particularly daunting terms such as “reasonably,” “unreasonably,”9 when the text “unjustifiable,”10 or “unjustifiably.”11\n\nincludes general", "n_tokens": 298, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-10-2", "doc_id": "medicine_vaccine_book", "page": 10, "text": "The actual policy space available under the TRIPS Agreement—beyond those areas not covered under the Agreement—depends, in the last instance, on the\n\n2See, e.g., Morin and Surbeck (2020). 3See, e.g., The Law Library of Congress, Global Legal Research Center (2016). Available from: https://www.loc.gov/law/help/patent-terms/patent-term-extensions-adjustments.pdf. 4Shaikh (2016). 5Son et al. (2018). Available from: https://doi.org/10.1186/s12992-018-0423-0. 6UNDP (2015b). Available from: https://www.undp.org/content/undp/en/home/librarypage/hiv- aids/using-competition-law-to-promote-access-to-medicine.html. 7Minn (2016). 8Article 27.1 in fine: “...patents shall be available and patent rights enjoyable without discrimina- tion as to the place of invention, the field of technology and whether products are imported or locally produced.” See, e.g., Correa (2005). See also below. 9A large number of provisions in the TRIPS Agreement uses these terms, e.g., Articles 8.2, 13, 15.5, 25.5, 26.2, 30. 31(b), 31(l), 34.2, 37, 1, 39.2(c), 41, 43. 10Article 4(d) of the TRIPS Agreement. 11Article 20 of the TRIPS Agreement.", "n_tokens": 367, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-11-0", "doc_id": "medicine_vaccine_book", "page": 11, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\ninterpretation of the Agreement’s provisions. This paper focuses on some aspects of how panels and the Appellate Body of the WTO have interpreted said provisions. It discusses, first, the concept of ‘TRIPS flexibilities’ and the possible types of such flexibilities as found in the legislation of developing and developed countries. Second, the paper discusses the references to such flexibilities in WTO jurispru- dence. Third, it briefly refers to some of the principles of interpretation that are relevant for the use of TRIPS flexibilities, including the value of dispute settlement rulings, the search for the ordinary meaning of the terms used, the context, and the object and purpose of the treaty. Fourth, it discusses the legal status of the Doha Declaration on the TRIPS Agreement and Public Health adopted at the 4th WTO Ministerial Conference in November 2001.12 There is no attempt in this paper to analyze the specific content of the rulings in TRIPS-related disputes; however, the paper does draw some general conclusions for the implementation of such flexibil- ities, which are of crucial importance for the design of a pro-competitive intellectual property system and, for achieving public health objectives (as specifically recognized by the Doha Declaration).13\n\nin particular,", "n_tokens": 283, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-11-1", "doc_id": "medicine_vaccine_book", "page": 11, "text": "2 Defining the TRIPS Flexibilities\n\nThe terminology used to refer to the policy space available for the implementation of the TRIPS Agreement has evolved. Expressions such as “room to maneuver,” “margins of freedom,” “safeguards,” and “margin of discretion” were used in the early studies and reports that identified various aspects of such space.14 Currently, the diversity of legislative options available under said Agreement is generally known as ‘TRIPS flexibilities.’\n\nThe term ‘flexibility’ appears in the Preamble (sixth paragraph) and in Article 66.1 of the TRIPS Agreement but it is used there with a broader meaning. It indicates that least-developed countries (LDCs) are not bound to comply with the TRIPS Agreement obligations (except Articles 3 through 5) during the transition period:\n\nIn view of the special needs and requirements of least-developed country Members, their economic, financial and administrative constraints, and their need for flexibility to create a viable technological base, such Members shall not be required to apply the provisions of this Agreement, other than Articles 3, 4 and 5, for a period of ...15", "n_tokens": 241, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-11-2", "doc_id": "medicine_vaccine_book", "page": 11, "text": "12Available from: https://www.who.int/medicines/areas/policy/tripshealth.pdf?ua¼1. Hereinafter, “the Doha Declaration.” 13See, e.g., Velásquez et al. (2020). https://www.southcentre.int/book-by-the-south-centre-2020/ #more-14014. 14Germán Velásquez (2013), p. 5. https://www.southcentre.int/wp-content/uploads/2013/05/ RP47_WTO-role-in-IP-and-access-to-medicines_EN.pdf. 15Emphasis added.\n\n3", "n_tokens": 164, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-12-0", "doc_id": "medicine_vaccine_book", "page": 12, "text": "4\n\nC. M. Correa\n\nThe terminology ‘TRIPS flexibilities’ does include the exemption for LDCs, but it also encompasses possible variations in the manner in which the TRIPS Agree- ment’s provisions are interpreted and implemented as they are applied to countries actually subject to them. Such terminology was used for the first time with this latter meaning in the context of the WTO in paragraph 4 of the Doha Declaration.16 Said paragraph states:\n\n4. We agree that the TRIPS Agreement does not and should not prevent Members from taking measures to protect public health. Accordingly, while reiterating our commitment to the TRIPS Agreement, we affirm that the Agreement can and should be interpreted and implemented in a manner supportive of WTO Members' right to protect public health and, in particular, to promote access to medicines for all. In this connection, we reaffirm the right of WTO Members to use, to the full, the provisions in the TRIPS Agreement, which provide flexibility for this purpose.17\n\nThe Declaration confirmed the availability of a number of flexibilities. Its adop- tion was a response to the concerns of developing countries about the obstacles they faced when seeking to implement measures to promote access to affordable medi- cines, without limitation to certain diseases, in the interest of public health.18", "n_tokens": 277, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-12-1", "doc_id": "medicine_vaccine_book", "page": 12, "text": "Since the adoption of the Doha Declaration, the concept of ‘TRIPS flexibilities’ has been referenced in a vast body of literature, especially (but not only) in relation to access to medicines,19 and in numerous resolutions of UN agencies20 and bodies, the Human Right Council including the World Health Organization (WHO), (HRC),21 and the UN Assembly, as well as in reports of the UN Special Rapporteur", "n_tokens": 90, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-12-2", "doc_id": "medicine_vaccine_book", "page": 12, "text": "16Paragraph 17 of the general Doha Ministerial Declaration states: “We stress the importance we attach to implementation and interpretation of the Agreement on Trade-Related Aspects of Intel- lectual Property Rights (TRIPS Agreement) in a manner supportive of public health, by promoting both access to existing medicines and research and development into new medicines and, in this connection, are adopting a separate Declaration.” https://www.wto.org/english/thewto_e/minist_e/ min01_e/mindecl_e.htm. 17Emphasis added. 18The Council for TRIPS convened special sessions (which were held in June, August, and September of 2001) to deal with the relationship between health and TRIPS. See, e.g., the sub- missions made by the European Communities and their Members States on the relationship between the provisions of the TRIPS Agreement and access to medicines, IP/C/W/280 (12 June 2001); and submissions by the African Group, Barbados, Bolivia, Brazil, Cuba, Dominican Republic, Ecuador, Honduras, India, Indonesia, Jamaica, Pakistan, Paraguay, Philippines, Peru, Sri Lanka, Thailand, and Venezuela on TRIPS and public health, IP/C/W/296 (29 June 2001). See also Council for TRIPS Special Discussion on Intellectual Property and Access to Medicines, IP/C/M/31 (10 July 2001). 19See, e.g., Velásquez et al. (2020). https://www.southcentre.int/book-by-the-south-centre-2020/ #more-14014. 20One of the first studies on TRIPS flexibilities was published by the UNCTAD (1996). https://", "n_tokens": 370, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-12-3", "doc_id": "medicine_vaccine_book", "page": 12, "text": "unctad.org/en/docs/ite1_en.pdf. 21On the relationship between the TRIPS Agreement and the human right to health, see, e.g., Sellin (2015). https://link.springer.com/article/10.1007/s40802-015-0047-5#Abs1.", "n_tokens": 80, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-13-0", "doc_id": "medicine_vaccine_book", "page": 13, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\non the Right to Health.22 For instance, the World Health Assembly (WHA) urged member states “to consider, whenever necessary, adapting national legislation in order to use to the full the flexibilities contained in the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS)”.23 The Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property24 explicitly referred to the flexibilities reaffirmed by the Doha Declaration, including the research exception (Element 2.4e), the transitional period for least-developed countries (LDCs) (Ele- ment 6.1b), and the regulatory exception or “Bolar exception” (Element 6.3a). A 2011 resolution adopted by the HRC, and subsequent resolutions on the matter, also noted the governments’ right to use, to the fullest extent, the provisions of the TRIPS Agreement, the Doha Declaration, and the WTO General Council Decision of 30 August 2003 in the context of the HIV/AIDS epidemic.25 Importantly, Goal 3. Target 3.b of the Sustainable Development Goals (SDGs), as adopted by the UN General Assembly, also refers to the TRIPS flexibilities:", "n_tokens": 261, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-13-1", "doc_id": "medicine_vaccine_book", "page": 13, "text": "Goal 3. Target 3.b: Support the research and development of vaccines and medicines for the communicable and noncommunicable diseases that primarily affect developing countries, provide access to affordable essential medicines and vaccines, in accordance with the Doha Declaration on the TRIPS Agreement and Public Health, which affirms the right of devel- oping countries to use to the full the provisions in the Agreement on Trade-Related Aspects of Intellectual Property Rights regarding flexibilities to protect public health, and, in particular, provide access to medicines for all.26\n\nThere is no agreed-upon definition of ‘TRIPS flexibilities.’ In accordance with a WIPO document, the term “flexibilities” means that there are “different options through which TRIPS obligations can be transposed into national law so that national interests are accommodated and yet TRIPS provisions and principles are complied with.”27 That concept implies that the legislative options made are com- patible with the TRIPS Agreement and, hence, fully legitimate. Although this remark may be deemed trite , it is important to make it in view of the reluctance of some developed countries to accept the use of such flexibilities, and even to exert pressures on or apply retaliatory trade sanctions against countries that do comply with the Agreement’s obligations. This position is well reflected in the continuous", "n_tokens": 287, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-13-2", "doc_id": "medicine_vaccine_book", "page": 13, "text": "22See, e.g., WHO, WIPO, and WTO (2012). https://www.wipo.int/edocs/pubdocs/en/global_ challenges/628/wipo_pub_628.pdf. 23WHA 56.27, “Intellectual property rights, innovation and public health” (28 May 2003). Avail- able from: https://apps.who.int/gb/archive/pdf_files/WHA56/ea56r27.pdf?ua¼1. For a list of WHO resolutions referring to intellectual property, see Germán Velásquez, Carlos M. Correa, and Vitor Ido, op. cit., pp. 73–75. 24Available from: https://www.who.int/phi/implementation/phi_globstat_action/en/. See, Germán Velásquez (2019). 25See, https://www.ohchr.org/EN/Issues/HIV/Pages/Documents.aspx. 26Resolution adopted by the General Assembly on 25 September United Nations General Assembly (2015), A/RES/70/1. https://www.un.org/ga/search/view_doc.asp?symbol¼A/RES/70/1& Lang¼E. 27WIPO (2010), p. 11. https://www.wipo.int/meetings/en/doc_details.jsp?doc_id¼142068.\n\n5", "n_tokens": 340, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-14-0", "doc_id": "medicine_vaccine_book", "page": 14, "text": "6\n\nC. M. Correa\n\nuse by the US of the Special Section 301 of the US Trade Act 1974,28 and in the European Commission Staff Working Document on the protection and enforcement of intellectual property rights in third countries.29\n\nThere are different types of TRIPS flexibilities. Some refer to the scope and extent of the substantive rights to be recognized under the Agreement,30 and others to the ways in which such rights can be enforced. One way of grouping flexibilities is also to take into account “the point in time at which Members may resort to them: (i) in the process of the acquisition of the right; (ii) defining the scope of the right; and (iii) when enforcing the right.”31 As noted in one report, those flexibilities\n\n...sometimes are made very explicit (as in the right of each WTO Member to choose its national regime of exhaustion of IP rights, hence allowing parallel imports), and in other instances follow from the use of general and open terms in TRIPS provisions (such as legitimate interests, justifiability, ordre public and morality) that WTO Member can – within the limits of accepted principles of treaty interpretation in public international law – interpret and implement in accordance with their public policy preferences.32", "n_tokens": 267, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-14-1", "doc_id": "medicine_vaccine_book", "page": 14, "text": "in interpreting and implementing the TRIPS Agreement, it would be an impossible task to identify all flexibilities. They can be found in all the areas covered by the Agreement, and they can be identified as new circumstances arise. Thus, the exception to copyright protection, which is of particular importance to ensure access to knowledge and preserve a robust public domain,33 needs to be considered in light of technological developments.34 WIPO’s Database on Flexibilities in the Intellectual Property Sys- tem35 provides information on just fourteen TRIPS flexibilities as provided for in the national laws of some countries, but the list is certainly much longer and their use in national laws and regulations more extensive. As noted, the type and use of such flexibilities have been widely explored, most particularly in relation to public health policies and access to medicines,36 in academic literature, numerous reports, and\n\nGiven the possible variations\n\nin national", "n_tokens": 194, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-14-2", "doc_id": "medicine_vaccine_book", "page": 14, "text": "regimes\n\n28See, e.g., Correa (2020a). 29European Commission (2020). https://trade.ec.europa.eu/doclib/docs/2020/january/tradoc_ 158561.pdf. 30The ‘scope’ of a right delimits the boundaries and defines its content; the ‘extent’ refers to the legal limitations on the exercise of the right. 31WIPO (2010), op. cit., p. 12. 32Ruse-Khan and Puutio (2017), p. 10. Available from: https://www.unescap.org/sites/default/files/ IPR%20Handbook.pdf. 33See, e.g., Geiger et al. (2013). https://digitalcommons.wcl.american.edu/cgi/viewcontent.cgi? article¼1041&context¼research. 34Eger and Scheufen (2012). https://www.researchgate.net/publication/280043122_The_past_and_ the_future_of_copyright_law_technological_change_and_beyond. 35Available from: https://www.wipo.int/ip-development/en/agenda/flexibilities/database.html. 36See, e.g., Germán Velásquez, Carlos M. Correa, and Vitor Ido, op. cit.", "n_tokens": 335, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-15-0", "doc_id": "medicine_vaccine_book", "page": 15, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\nother sources of information.37 Box 1 includes references to some of the flexibilities available in the field of public health.\n\nBox 1 Public health-related TRIPS flexibilities (1) Flexibility in the choice of patentability criteria, including for chemical entities and biologics—WTO members have considerable policy space to define what an ‘invention’ is and to apply rigorous standards of patentability to avoid the grant of patents that, without making a genuine technical contribution, may distort market competition.\n\n(2) Compulsory license—Widely recognized in the legislation of developed and developing countries—and granted since the adoption of the TRIPS Agreement by administrations or courts in countries such as Thailand, Ecuador, Indonesia, India, USA, Italy, and Germany—compulsory licenses may be necessary to correct market distortions (abuses of market power, unfair pricing, refusal to license, etc.).\n\n(3) Government use—In many cases governments may decide, consistently with the TRIPS Agreement, for non-commercial purposes, such as for ensuring the supply of essential medicines.\n\nto use patented inventions\n\n(4) Compulsory licenses for the supply of medicines to countries with a lack of or insufficient manufacturing capacity—Compulsory licenses exclusively for the export of medicines can be granted under the amend- ment introduced to the TRIPS Agreement in 2017 and the waiver adopted by WTO in 2003.", "n_tokens": 293, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-15-1", "doc_id": "medicine_vaccine_book", "page": 15, "text": "(5) Test data protection—The TRIPS Agreement (Article 39.3) requires WTO members to protect test data against unfair competition, which does not create exclusive rights. The Agreement is complied with if legislation on unfair competition is implemented to protect such data. (6) Exemptions) for LDCs—LDCs need not grant patents for pharmaceuti- cals and test data protection at least until 2033 under the extended transition period provided for under Article 66.1 of the TRIPS Agreement.\n\n(7) Parallel importation—Importing protected medicines from any country where they can be purchased cheaper than locally is consistent with the TRIPS Agreement.\n\n(8) Pre and post patent grant opposition—Procedures before patent offices third parties to contribute to the\n\nprovide for\n\nthe possibility for\n\n(continued)\n\n37See, e.g., Medicines Law & Policy, The TRIPS Flexibilities Database. Available from: http:// tripsflexibilities.medicineslawandpolicy.org/. See also, The Graduate Institute Geneva, Knowledge Portal on Innovation and Access to Medicines. https://www.knowledgeportalia.org/.\n\n7", "n_tokens": 237, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-16-0", "doc_id": "medicine_vaccine_book", "page": 16, "text": "8\n\nC. M. Correa\n\nBox 1 (continued)\n\nexamination process through ‘observations’ or ‘oppositions,’ whether before or after the grant of a patent, or both.\n\n(9) Use of competition law to address the misuse of IPRs—Competition law may be applied to correct market distortions created through the abuse of IPRs.\n\n(10) Bolar exception—‘Bolar exceptions’ are important to accelerate the entry of generic products and promote a dynamic market for medicines. (11) Research or experimentation exception—This exception allows research to be conducted by third parties on patented inventions, for instance, to improve on them or derive new inventions.\n\n(12) Disclosure requirement, particularly for biologics—The full and pre- cise disclosure of an invention is crucial for the patent system to perform its informational function. This is particularly relevant for biologicals, which cannot be described in the same way as medicines produced by chemical synthesis", "n_tokens": 193, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-16-1", "doc_id": "medicine_vaccine_book", "page": 16, "text": "(13) Flexibilities in enforcement of IP—Measures to enforce IPRs—such as reversal of the burden of proof, determination of infringement by equiv- alence and damages, and border measures—if overly broad, may distort competition by discouraging or preventing market entry and the avail- ability of generic medicines. Provisional injunctions need to be cau- tiously granted so as not to distort the market dynamics, generally after giving the alleged infringer an opportunity to articulate his defense. Permanent injunctions may be denied for public health reasons under certain circumstances.\n\n(14) Security exception—Compliance with obligations under the TRIPS Agreement can be suspended, inter alia, in cases of emergency in inter- national relations, such as in the case of a pandemic (Article 73 (b) of the Agreement).\n\nSource: adapted from South Centre, “A Public Health Approach to Intel- lectual Property Rights: Public Health Related Flexibilities in the TRIPS Agreement,” available from: https://ipaccessmeds.southcentre.int/wp-con tent/uploads/2018/12/Public-Health-Related-Flexibilities-in-the-TRIPS- Agreement.pdf.", "n_tokens": 263, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-16-2", "doc_id": "medicine_vaccine_book", "page": 16, "text": "Any WTO member can make use of the TRIPS flexibilities, as applicable, in order to attain public health or other public objectives and, in fact, both developed and developing countries have done so. Thus, the flexibility in the TRIPS Agreement permitted the US to maintain a double-novelty standard depending on whether the disclosure of the invention had taken place within or outside the territory of the US", "n_tokens": 82, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-17-0", "doc_id": "medicine_vaccine_book", "page": 17, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\n(35 USC section 102 (a)).38 In defending this flexibility, which has allowed for the misappropriation of genetic resources and traditional knowledge,39 the US held that in the TRIPS Agreement there was “no prescription as to how WTO Members define what inventions are to be considered ‘new’ within their domestic systems” and, hence, that its legislation was “perfectly consistent with the provisions of the TRIPS Agreement.”40 Another example in the US is the doctrine that allows US courts not to grant a permanent injunction despite the proven existence of an infringement of IPRs, in accordance with the precedent set by the US Supreme Court in the eBay vs. MercExchange case.41 There are also many examples in Europe42 where, for instance, the European Parliament’s Resolution of 2 March 2017 on EU options for improving access to medicines (2016/2057(INI)) emphasized “that the European Patent Office (EPO) and the Member States should only grant patents on medicinal products that strictly fulfil the patentability requirements of novelty, inventive step and industrial applicability, as enshrined in the European Patent Convention” (par- agraph 48).43 More recent examples are the amendments to the patent laws in Canada and Germany to address the COVID-19 emergency. Bill C 13 2020 of Canada,44 for instance, added a new section to the Patent Act implementing a new type of compulsory license for patents:", "n_tokens": 315, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-17-1", "doc_id": "medicine_vaccine_book", "page": 17, "text": "19.4 (1) The Commissioner shall, on the application of the Minister of Health, authorize the Government of Canada and any person specified in the application to make, construct, use and sell a patented invention to the extent necessary to respond to the public health emergency described in the application.", "n_tokens": 62, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-17-2", "doc_id": "medicine_vaccine_book", "page": 17, "text": "38According to this section, “[a] person shall be entitled to a patent unless the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for patent, or the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of the application for patent in the United States.” This rule was amended by the Leahy-Smith America Invents Act (2011). http://www.wipo.int/edocs/ lexdocs/laws/en/us/us219en.pdf. 39Reid (2019). https://digitalcommons.law.ou.edu/cgi/viewcontent.cgi?article¼1121& context¼ailr. 40See, Document IP/Q3/USA/1 (1 May 1998). As a result of the relative novelty requirement of the US, several patents were granted to researchers or firms relating to or consisting of genetic materials or traditional knowledge acquired in developing countries. See, e.g., Mgbeoji (2006). https://books. google.fr/books?id¼q4MIoBKy88MC&pg¼PA121&lpg¼PA121&dq¼biopiracy+us+patents& source¼bl&ots¼-ZBMOhXLLn&sig¼ACfU3U0DslCI-lxiwQuSmN-jeuuC-fafLQ&hl¼en& sa¼X&ved¼2ahUKEwitsrmu8N_pAhUSx4UKHe1_DHYQ6AEwEnoECAkQAQ#v¼onepage& q¼biopiracy%20us%20patents&f¼false. 41eBay Inc. v. MercExchange, L.L.C., 547 U.S. 388 (2006), https://www.supremecourt.gov/ opinions/05pdf/05-130.pdf. 42For the use of TRIPS flexibilities in relation to plant patents, see, e.g., Correa (2014).", "n_tokens": 509, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-17-3", "doc_id": "medicine_vaccine_book", "page": 17, "text": "https://", "n_tokens": 4, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-17-4", "doc_id": "medicine_vaccine_book", "page": 17, "text": "www.southcentre.int/wp-content/uploads/2014/11/RP55_Patent-Protection-for-Plants_EN.pdf. See also, Prifti (2015). 43Available from: https://www.europarl.europa.eu/doceo/document/TA-8-2017-0061_EN.html. 44Available from: https://www.parl.ca/DocumentViewer/en/43-1/bill/C-13/royal-assent.", "n_tokens": 122, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-17-5", "doc_id": "medicine_vaccine_book", "page": 17, "text": "9", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-18-0", "doc_id": "medicine_vaccine_book", "page": 18, "text": "10\n\nC. M. Correa\n\nIn Germany, an amendment to the Patent Act provided that an invention relating to medicinal products, including narcotics; the active ingredients, starting materials, and auxiliary materials for these products; medical devices; laboratory diagnostics; aids; personal protective equipment; and products for disinfection of the products shall be used in the interest of public welfare (“öffentliche Wohlfahrt”) or in the interest of the security of the Federation.45\n\n3 TRIPS Flexibilities in WTO Jurisprudence\n\nDespite the TRIPS Agreement being one of the most controversial components of the WTO system, and that it has given rise to a large number of proceedings under the Dispute Settlement Understanding, a relatively small number of cases has reached the phase of a panel or Appellate Body intervention.\n\nParadoxically, although the adoption of the TRIPS Agreement essentially was aimed at disciplining developing countries, who have been forced to make massive legislative changes to adapt to the Agreement’s high minimum standards,46 most disputes leading to the establishment of a panel have been against developed countries (two against the US,47 two against the European Communities and their Member States,48 two against Canada,49 and one against Australia50). Only two developing countries were subject to such procedures:51 India (two complaints", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-18-1", "doc_id": "medicine_vaccine_book", "page": 18, "text": "45Fuchs (2020). https://www.twobirds.com/en/news/articles/2020/germany/covid-19-new-german- legislation-to-fight-pandemic-may-affect-granted-patents. 46See, e.g., Correa (2011a). 47See, DS 160 Panel Report United States — Section 110(5) of US Copyright Act (2010); Appellate Body report DS 176 United States — Section 211 Omnibus Appropriations Act of 1998 (2002). 48See, DS 174 Panel Report European Communities — Protection of Trademarks and Geograph- ical Indications for Agricultural Products and Foodstuffs (2005); DS 290 Panel Report, European Communities — Protection of Trademarks and Geographical Indications for Agricultural Products and Foodstuffs (2005). 49See, Report of the WTO Panel, Canada—Patent Protection for Pharmaceutical Products, WT/DS114/R; Report of the Appellate Body, Canada—Term of Patent Protection, WT/DS170/ AB/R (2000). 50See Panel Report in DS435, 441, 458, 467, Australia — Certain Measures Concerning Trade- marks, Geographical Indications and Other Plain Packaging Requirements Applicable to Tobacco Products and Packaging (2018) (hereinafter, “Australia—Tobacco Plain Packaging”). The panel report was appealed by Honduras and the Dominican Republic (see, https://www.wto.org/english/ tratop_e/dispu_e/cases_e/ds441_e.htm). The report of the Appellate Body was issued on June 9, 2020 (WT/DS435/AB/R WT/DS441/AB/R). On the situation of the Appellate Body as a result of the US blockade to the appointment of new members, see, e.g., Danish and Aileen Kwa (2019).", "n_tokens": 410, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-18-2", "doc_id": "medicine_vaccine_book", "page": 18, "text": "Available from: https://www.southcentre.int/wp-content/uploads/2019/12/PB69_Crisis-at-the- WTO%E2%80%99s-Appellate-Body-AB-Why-the-AB-is-Important-for-Developing-Members_ EN-1.pdf. 51A violation to the TRIPS Agreement was incidentally invoked in the Indonesia-Autos case in relation to the protection of trademarks. The panel, however, found that the United States had not", "n_tokens": 117, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-19-0", "doc_id": "medicine_vaccine_book", "page": 19, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\nconcerning the implementation of Article 70.8, the so called “mailbox” provision)52 and China (criminal sanctions for copyright infringement and other issues).53 Only four developing countries (Indonesia, Cuba, Honduras, and the Dominican Repub- lic) have been complaining parties (against Australia in the tobacco plain packaging case) in WTO disputes under the TRIPS Agreement that have reached such stage.54 In other cases of disputes initiated against developing countries, no panel was established. One example was a complaint by the US against Argentina on patents and test data protection.55 A mutually agreed-upon solution was communicated to the Dispute Settlement Body (DSB) on 20 June 2002. However, the parties did not reach a common understanding on the interpretation of Article 39.3 of the TRIPS Agreement, nor on the application of Article 70.7.56 Argentina has not to date introduced the data exclusivity regime that the US claimed would remedy the (unproven) violation of Article 39.3. Another example, further discussed below, was the US challenge in January 2001 against Brazilian legislation that authorizes the granting of compulsory licenses and parallel imports in instances when patents are not worked.57 The dispute ended several months later when the US complaint was withdrawn.58", "n_tokens": 264, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-19-1", "doc_id": "medicine_vaccine_book", "page": 19, "text": "The panel and Appellate Body reports produced in relation to the disputes mentioned above have, in practice, addressed the policy space available under the TRIPS Agreement, but they have only occasionally referred to the concept of ‘flexibilities.’ In China—Intellectual Property Rights, for instance, third parties", "n_tokens": 59, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-19-2", "doc_id": "medicine_vaccine_book", "page": 19, "text": "demonstrated that Indonesia was in breach of its TRIPS obligations (Report of the WTO Panel, Indonesia—Certain Measures Affecting The Automobile Industry, WT/DS 54/R, WT/DS 55/R, WT/DS 59/R, WT/DS 64/R (1998), para. 11.1–11.43). 52See Report of the Appellate Body, India-Patent Protection for Pharmaceutical and Agricultural Chemical Products, WT/DS50/AB/R (1998) and Report of the WTO Panel, India—Patent Protec- tion for Pharmaceutical and Agricultural Chemical Products, WT/DS79/R (1998) (hereinafter, “India—Patents (US)”). 53See Panel Report in lDS362, China—Measures Affecting the Protection and Enforcement of Intellectual Property Rights (2009) (hereinafter, “China—Intellectual Property Rights”). 54Brazil requested the US consultations with regard to provisions of US legislation that limits the right to use or sell any federally-owned invention only to a licensee that agrees that any products embodying the invention or produced through the use of the invention will be manufactured substantially in the United States. See, United States—US Patents Code, WT/DS224/1 (7 February 2001). In DS 408, India complained about border measures imposed on the transit of medicines. See, European Union and a Member State—Seizure of Generic Drugs in Transit (2010). These cases were not ultimately pursued. 55Argentina—Patent Protection for Pharmaceuticals and Test Data Protection for Agricultural Chemicals, WT/DS171 (6 May 1999) and Argentina-Certain Measures on the Protection of Patents and", "n_tokens": 359, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-19-3", "doc_id": "medicine_vaccine_book", "page": 19, "text": "Test Data, WT/DS196 (30 May 2000). 56See, Notification of Mutually Agreed Solution According to the Conditions Set Forth in the Agreement (IP/D/18/Add.1, IP/D/22/Add.1). 57See, Brazil—Measures Affecting Patent Protection, Request for the Establishment of a Panel by the United States, WT/DS199/3 (9 January 2001). 58Brazil—Measures Affecting Patent Protection, Notification of Mutually Agreed Solution, WT/DS199/4, G/L/454, IP/D/23/Add.1 (19 July 2001).", "n_tokens": 143, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-19-4", "doc_id": "medicine_vaccine_book", "page": 19, "text": "11", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-20-0", "doc_id": "medicine_vaccine_book", "page": 20, "text": "12\n\nC. M. Correa\n\nalluded to the ‘flexibility’ allowed by the TRIPS Agreement in relation to the definition of ‘commercial scale.’59 The US noted, with respect to Article 1.1 of the Agreement, that the provision “only offers flexibility in how a Member implements TRIPS obligations and does not exempt a Member from full compliance with TRIPS obligations.”60 In this case the panel confirmed that the TRIPS Agreement does not mandate specific forms of legislation.61 In relation to the US claim that China did not comply with Article 61 of the TRIPS Agreement, it stated:\n\nThe Panel may not simply assume that a Member must give its authorities wide discretion to determine what is on a commercial scale in any given case, and may not simply assume that thresholds, including numerical tests, are inconsistent with the relative benchmark in the first sentence of Article 61 of the TRIPS Agreement. As long as a Member in fact provides for criminal procedures and penalties to be applied in cases of wilful trademark counterfeiting or copyright piracy on a commercial scale, it will comply with this obligation. If it is alleged that a Member's method of implementation does not so provide in such cases, that allegation must be proven with evidence...(para. 7.602).\n\nA few references to the ‘flexibilities’ allowed by the prohibition contained in Article 20 of the TRIPS Agreement can be found in the panel report in Australia— Tobacco Plain Packaging. For instance, the panel stated:", "n_tokens": 316, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-20-1", "doc_id": "medicine_vaccine_book", "page": 20, "text": "On their face, the explicit prohibitions contained in Article 20 of the TRIPS Agreement and Article 2.2 of the TBT Agreement respectively must be read and, absent a conflict, applied together. The principle of harmonious reading dictates that the flexibilities implicitly left by those prohibitions also need to be viewed together, without a priori giving precedence to one over, and to the exclusion of, the other.62\n\nThe panel in the same case also referred, as discussed below, to the Doha Declaration as a “re-affirmation by Members of the flexibilities provided in the TRIPS Agreement in relation to measures taken for the protection of public health”;63 the concept of TRIPS flexibilities was also alluded to, for example, by Brazil and Thailand as third parties64 and by the panel itself (para. 7.2407 and 7.2408). Interestingly, the Appellate Body in Australia—Tobacco Plain Packaging referred to the concept of Members’ ‘regulatory autonomy’ in encumbering the use of trademarks by special requirements under Article 20.65\n\n59See, China—Intellectual Property Rights, para. 7.484, 7.493, 7.597, and 7.678. 60Idem, para. 7.199. 61Para 7.602. 62Australia—Tobacco Plain Packaging, para. 7.100. 63Idem, para. 7.2408. 64Idem, para. 7.2391 and 2387. 65Appellate Body Report, op. cit., para. 6.697.", "n_tokens": 341, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-21-0", "doc_id": "medicine_vaccine_book", "page": 21, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\n4 Interpretation of the TRIPS Agreement66\n\nThis section considers some principles for and aspects of the interpretation of the TRIPS Agreement particularly relevant for the application of the TRIPS flexibilities.", "n_tokens": 46, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-21-1", "doc_id": "medicine_vaccine_book", "page": 21, "text": "4.1 Precedential Value of GATT/WTO Jurisprudence\n\nNeither the GATT nor the WTO jurisprudence have precedential value; however, even if unrelated to intellectual property, such jurisprudence may influence and provide guidance for future rulings on the TRIPS Agreement.67 One issue of particular relevance is whether jurisprudence on subjects other than those covered by this Agreement should be used to interpret it. The panel in India—Patent Protection for Pharmaceutical and Agricultural Chemical Products, for instance, held that although the TRIPS Agreement has a “relatively self-contained, sui generis status within the WTO,” it also was “an integral part of the WTO system, which itself builds upon the experience of over nearly half a century under the GATT 1947.”68 In United States—Section 110(5) of the U.S. Copyright Act, while the panel noted that caution was required when interpreting the TRIPS Agreement provisions in the light of precedents developed in GATT dispute settlement practice, it stated that\n\ngiven that the agreements covered by the WTO form a single, integrated legal system, we deem it appropriate to develop interpretations of the legal protection conferred on intellectual property right holders under the TRIPS Agreement which are not incompatible with the treatment conferred to products under the GATT, or in respect of services and service suppliers under the GATS, in the light of pertinent dispute settlement practice.69", "n_tokens": 282, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-21-2", "doc_id": "medicine_vaccine_book", "page": 21, "text": "The application of general GATT and WTO jurisprudence to cases involving the TRIPS Agreement would ignore the specificity of intellectual property issues and one major difference between the TRIPS Agreement and other WTO covered agreements: the former provides for disciplines on intellectual property rights, which are private rights,70 the exercise of which may restrain rather than facilitate international trade (as in the case of other WTO agreements). The private rights nature of intellectual property rights was highlighted in the panel report in China— Intellectual Property Rights:\n\n66This section is partially based on Carlos Correa, op. cit., 2005, which examines other aspects, such as the role of the negotiating history and the application of prior intellectual property conventions incorporated into the TRIPS Agreement;—,; see also Kennedy (2016). 67See, e.g., Flowers (2019), pp. 90–104. See also, Howse (2000). Available from: https:// onlinelibrary.wiley.com/doi/abs/10.1111/j.1747-1796.2000.tb00139.x. 68Para. 7.19. 69Para. 6.185. 70See, the Preamble to the TRIPS Agreement, fourth paragraph.\n\n13", "n_tokens": 258, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-22-0", "doc_id": "medicine_vaccine_book", "page": 22, "text": "14\n\nC. M. Correa\n\nViewed in context, the phrase “shall have the authority” does not require Members to take any action in the absence of an application or request. Therefore, a condition that authority shall only be available upon application or request seems to be assumed in much of Sections 2, 3 and 4 of Part III. This is consistent with the nature of intellectual property rights as private rights, as recognized in the fourth recital of the preamble of the TRIPS Agreement. Acquisition procedures for substantive rights and civil enforcement procedures generally have to be initiated by the right holder and not ex officio.71\n\nOne corollary of this, for instance, is that in contrast to the general GATT/WTO jurisprudence, the exceptions in the TRIPS Agreement need not to be read narrowly, but instead with the aim of achieving the objectives as defined in Article 7 (see below). Notably, intellectual property rights constitute exceptions in terms of Article XX(d) of GATT and, hence, their restrictive effects should not be augmented but mitigated through the interpretation of the scope and extent of the conferred exclu- sive rights.72 The exceptions to exclusive rights are crucial to preserve market dynamics and achieve a diversity of public interests; they are a key component of the TRIPS flexibilities.73", "n_tokens": 269, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-22-1", "doc_id": "medicine_vaccine_book", "page": 22, "text": "4.2 Ordinary Meaning\n\nThe GATT and WTO panels, as well as the WTO Appellate Body, have relied on the interpretive method codified by the Vienna Convention on the Law of the Treaties (VCLT). One of the basic steps for interpretation under Article 31 of the VCLT is the determination of the ‘ordinary meaning’ of the terms employed in the treaty, provided that “a special meaning shall be given to a term if it is established that the parties so intended” (Article 31.4). Many WTO panel and Appellate Body reports clearly indicate that such ordinary meaning is searched in the dictionary in order to clarify the scope and content of the relevant texts.74 Thus, the Appellate Body in EC – Chicken Cuts states: \"The Appellate Body observed that dictionaries are a useful starting point” for the analysis of 'ordinary meaning' of a treaty term, but they are not necessarily dispositive. The ordinary meaning of a treaty term must be ascertained according to the particular circumstances of each case. Importantly, the ordinary meaning", "n_tokens": 217, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-22-2", "doc_id": "medicine_vaccine_book", "page": 22, "text": "71Panel Report, lDS362, China—Measures Affecting the Protection and Enforcement of Intellec- tual Property Rights, op. cit., para 7.247. See also, para. 7.135. See also, para. 7.247, 7.135, 7.241, and 7.530; and Australia—Tobacco Plain Packaging, footnote 4472. 72See, e.g., Okediji (2017). 73Rodrigues Jr. (2012). https://www.researchgate.net/publication/288719106_The_general_excep tion_clauses_of_the_TRIPS_agreement_Promoting_sustainable_development. 74See, e.g., the elaboration DS 160 Panel Report, United States — Section 110(5) of US Copyright Act (2010); Appellate Body report DS 176, United States — Section 211 Omnibus Appropriations Act of 1998 (2002).", "n_tokens": 204, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-23-0", "doc_id": "medicine_vaccine_book", "page": 23, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\nof a treaty term must be seen in the light of the intention of the parties “as expressed in the words used by them against the light of the surrounding circumstances.”75\n\nIn China—Intellectual Property Rights, the panel observed that\n\nthe general rule of treaty interpretation in Article 31 of the Vienna Convention refers in paragraph 1 to the ordinary meaning of the terms of the treaty, read in context. Where the terms are a single term, or ordinarily used together, then the treaty interpreter should refer to the ordinary meaning of that single term, or of each term in the particular context of each other. This is a distinct exercise from that in paragraph 4 of Article 31 of the Vienna Convention which requires a “special meaning” to be given to a term if it is established that the parties so intended. No party to this dispute considers that a “special meaning” should be given to the phrase \"on a commercial scale,\" and nor does the Panel.76\n\nWhile the rule regarding the ordinary meaning seems clear, an important question relates to the temporal aspect of the interpretation, that is, whether panels and Appellate Body should rely on the meaning of a term at the time of negotiation or adoption of an agreement, or whether they would be authorized to apply an evolu- tionary approach, that is, to rely on the meaning of a term at the time of its interpretation. Two approaches exist on this issue:", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-23-1", "doc_id": "medicine_vaccine_book", "page": 23, "text": "...the principle of contemporaneity, according to which the terms of a treaty are to be interpreted according to the meaning which they possessed, or which would have been attributed to them, and in the light of current linguistic usage, at the time when the treaty was originally concluded. Opposed to that is the dynamic approach, very often also labelled ‘evolutionary’ interpretation, which seeks to establish the meaning of a treaty at the time of its interpretation.77\n\nIn Canada—Patent Protection for Pharmaceutical Products, the panel examined the status of the legislation at the time of the negotiation of the Agreement to determine the concept of “legitimate interest” as contained in Article 30:\n\nMoreover, the Panel believed that it was significant that concerns about regulatory review exceptions in general, although well known at the time of the TRIPS negotiations, were apparently not clear enough, or compelling enough, to make their way explicitly into the recorded agenda of the TRIPS negotiation. The Panel believed that Article 30’s “legitimate interests” concept should not be used to decide, through adjudication, a normative policy issue that is still obviously a matter of unresolved political debate.78", "n_tokens": 236, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-23-2", "doc_id": "medicine_vaccine_book", "page": 23, "text": "75Appellate Body Report in EC – Chicken Cuts, para. 175, quoting Appellate Body Report in US – Softwood Lumber IV, para. 59, and referring to Appellate Body Reports in US – Offset Act (Byrd Amendment), para. 248, and US – Gambling, para. 166, and quoting McNair (1961), p. 365. 76Para 7.558. 77Dörr and Schmalenbach (2012). Available from: https://link.springer.com/chapter/10.1007% 2F978-3-642-19291-3_34, para. 58 (emphasis in the original), para. 23 (emphasis in the original). On the importance of the principle of “contemporaneity” in treaty interpretation, see also, Brownlie (1998), p. 627. 78Canada—Patent Protection for Pharmaceutical Products, para. 7.82.\n\n15", "n_tokens": 200, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-24-0", "doc_id": "medicine_vaccine_book", "page": 24, "text": "16\n\nC. M. Correa\n\nThe WTO jurisprudence has adopted in some cases the evolutionary method of interpretation.79 In United States—Section 110(5) of the US Copyright Act, reference was made to the WIPO Copyright Treaty (WCT) adopted in 1996, 2 years after the TRIPS Agreement. The panel stated that the WCT should be viewed as “relevant to seek contextual guidance ... when developing interpretations that avoid conflicts within the overall multilateral copyright framework ...”80 Although it noted that the statement concerning WCT’s Article 10 adopted by the signatory parties did not fall under the Vienna Convention rules on a subsequent agreement on the same matter or subsequent practice, the recourse to a post-TRIPS treaty to interpret a provision of the TRIPS Agreement constitutes a troubling precedent as long as it may lead to interpretations unduly expanding the Agreement’s obligations. This is particularly the case in the light of technological developments and the increase of the level of protection beyond the standards of the TRIPS Agreement resulting from free trade agreements.81", "n_tokens": 219, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-24-1", "doc_id": "medicine_vaccine_book", "page": 24, "text": "It is also worth noting that article 71 of the TRIPS Agreement specifically provides for the TRIPS Council to review the Agreement “in the light of any relevant new developments, which might warrant modification or amendment of this Agree- ment,” thereby suggesting that any further ‘developments’ in intellectual property law need to be incorporated on the basis of WTO members’ consensus, rather than via interpretation.\n\n4.3 Context\n\nIn accordance with Article 31 of the VCLT, the terms in a treaty need to be considered taking their context into account. The preambles of WTO agreements have often been considered as the relevant context for the interpretation of particular provisions.82 In India–Patents (US), the Appellate Body referred to the Preamble of the TRIPS Agreement for the interpretation of Article 70.8(a): “The Panel’s inter- pretation here is consistent with the object and purpose of the TRIPS Agreement.” According to the Appellate Body, the object and purpose of the Agreement is, inter alia, “the need to promote effective and adequate protection of intellectual property rights.”83 References to the preamble were also made in China—Intellectual", "n_tokens": 241, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-24-2", "doc_id": "medicine_vaccine_book", "page": 24, "text": "79In United States – Import Prohibition of Certain Shrimp and Shrimp Products, WT/DS58/AB/R, para. 130 (1998), the Appellate Body held that certain terms in the WTO Agreements are not “static” but evolutionary, in relation to the term “exhaustible natural resources” as it appears in GATT Article XX(g) (para. 127, 130). 80United States—Section 110(5) of the U.S. Copyright Act, para. 6.70. 81See, e.g., Ruse-Khan (2017) (forthcoming, Netherlands Yearbook of International Law); Max Planck Institute for Innovation & Competition Research Paper, No. 18-02; University of Cambridge Faculty of Law Research Paper, No. 3/2018. https://ssrn.com/abstract¼3082718. 82See, e.g. Carlos Correa, op. cit., 2020, Chapter 1. 83See, https://www.wto.org/english/docs_e/legal_e/27-trips_02_e.htm.", "n_tokens": 236, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-25-0", "doc_id": "medicine_vaccine_book", "page": 25, "text": "Interpreting the Flexibilities Under the TRIPS Agreement", "n_tokens": 10, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-25-1", "doc_id": "medicine_vaccine_book", "page": 25, "text": "Property Rights.84 The Preamble of the Agreement on Technical Barriers to Trade was largely invoked as well by the panel in Australia—Tobacco Plain Packaging.85 for interpreting other provisions is crucial. One example is the interpretation of Article 27.1 in fine. As noted above, the US initiated a case against Brazil arguing that Article 68 of the Brazilian patent law, which authorizes the government to grant a compulsory license if the patent owner fails to work the patent, was inconsistent with Article 27.1 in fine of the TRIPS Agreement. In accordance to this provisions, “patents shall be available and patent rights enjoyable without discrimination as to the place of invention, the field of technology and whether products are imported or locally produced.” Key to addressing the US argument is identifying the context for the interpretation of this phrase in Article 27.1. In fact, this text incorporated a compromise reached, at the final stages of the negotiation of the Agreement, between developed and developing countries since the latter wanted to preserve the possibil- ity of granting compulsory licenses for the lack or insufficient working of a patent.86 Developing countries expressed the concern that Article 27.1 could be read in a way that restricts the use of compulsory licenses, for instance, on the grounds of lack of working, as specifically provided for under Article 5A of the Paris Convention for the Protection of Industrial Property. In fact, the “patent rights”", "n_tokens": 296, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-25-2", "doc_id": "medicine_vaccine_book", "page": 25, "text": "referred to in Article 27.1 are defined in Article 28.1, which only requires the granting of negative rights with regard to the exploitation of the invention, that is, the right to prevent third parties from using (without authorization) the patented invention. Hence, a proper interpretation of Article 27.1 read in conjunction with Article 28.1, based on the rules of the Vienna Convention, indicates that the products mentioned in Article 27.1 are infringing products, not the products of the patent owner itself, since patents only confer exclusionary and not positive rights. In other words, Article 27.1—if read in the context of Article 28 of the Agreement—forbids discrimination between infring- ing imported and infringing locally-made products, but it does not prevent the establishment of differential obligations with regard to non-infringing imported and locally-made products (i.e., products made or imported by the patent owner or with his/her consent). Hence, it does not outlaw compulsory licenses for lack of working.", "n_tokens": 217, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-25-3", "doc_id": "medicine_vaccine_book", "page": 25, "text": "The appropriate choice of\n\ntreaty provisions that provide the context\n\nThe principle of “effective interpretation” (or “l’effet utile”) requires that a treaty must be interpreted in such a way as to give meaning and effect to all the terms of the to Article 27.1 in fine. This treaty. This is certainly possible with respect non-discrimination clause may apply, for instance, to a case in which the rights enjoyed by patent owners differ depending on whether the alleged infringing goods have been locally produced or imported. For instance, Section 337 of the U.S. Tariff Act was found inconsistent with the GATT in United States—Section 337 of the\n\n84See, para. 7.135. 85See, e.g., para. 7.2398. 86UNCTAD and ICTSD (2005), p. 467. https://unctad.org/en/PublicationsLibrary/ictsd2005d1_en. pdf.\n\n17", "n_tokens": 205, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-26-0", "doc_id": "medicine_vaccine_book", "page": 26, "text": "18\n\nC. M. Correa\n\nTariff Act of 1930, since it accorded less favorable treatment to imported products challenged as infringing on US patents than the treatment accorded to similarly challenged products of United States origin.87\n\nAnother example in which the correct identification of the context for a provision may have decisive effects relates to Article 39.3, which has been interpreted by the US and the European Commission as requiring the grant of exclusive rights (‘data exclusivity’) with respect to test data for pharmaceuticals and agrochemical prod- ucts. This interpretation is clearly inviable in light of Article 39.1 which provides an essential contextual element and only requires protection against unfair commercial practices, which does not entail such exclusive rights.88\n\nIn engaging in the difficult task of clarifying the meaning of ‘unjustifiably’ in Article 20 of the TRIPS Agreement, the panel in Australia—Tobacco Plain Pack- aging elaborated on the context of that provision. It specifically alluded to the Preamble and Articles 7 and 8 of the Agreement:", "n_tokens": 229, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-26-1", "doc_id": "medicine_vaccine_book", "page": 26, "text": "We first note that the first recital of the preamble to the TRIPS Agreement expresses a key objective of the TRIPS Agreement, namely to “reduce distortions and impediments to international trade” and takes into account the need, on one hand, “to promote effective and adequate protection of intellectual property rights” and, on the other, “to ensure that measures and procedures to enforce intellectual property rights do not themselves become barriers to legitimate trade” (para. 7.2398).\n\nWe also consider that Article 7 entitled “Objectives” and Article 8 entitled “Principles” provide relevant context (para 7.2399).\n\nArticles 7 and 8, together with the preamble of the TRIPS Agreement, set out general goals and principles underlying the TRIPS Agreement, which are to be borne in mind when specific provisions of the Agreement are being interpreted in their context and in light of the object and purpose of the Agreement. As the panel in Canada – Pharmaceutical Patents observed in interpreting the terms of Article 30 of the TRIPS Agreement, “[b]oth the goals and the limitations stated in Articles 7 and 8.1 must obviously be borne in mind when doing so as well as those of other provisions of the TRIPS Agreement which indicate its object and purposes” (para. 7.2402).", "n_tokens": 266, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-26-2", "doc_id": "medicine_vaccine_book", "page": 26, "text": "The panel further elaborated on the ‘balance’ suggested by Articles 7 and 8.1 of the TRIPS Agreement and, in particular, on the fact that the Agreement did not intend to prevent WTO members from adopting measures to protect public interests, such as public health. It stated:\n\nArticle 7 reflects the intention of establishing and maintaining a balance between the societal objectives mentioned therein. Article 8.1, for its part, makes clear that the provisions of the TRIPS Agreement are not intended to prevent the adoption, by Members, of laws and regulations pursuing certain legitimate objectives, specifically, measures “necessary to protect public health and nutrition” and “promote the public interest in sectors of vital importance to their socio-economic and technological development,” provided that such measures are consistent with the provisions of the Agreement (para. 7.2403).\n\n87See, e.g., Haedicke (2000), p. 1774. 88See, e.g., Correa (2011b).", "n_tokens": 210, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-27-0", "doc_id": "medicine_vaccine_book", "page": 27, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\nArticle 8 offers, in our view, useful contextual guidance for the interpretation of the term “unjustifiably” in Article 20. Specifically, the principles reflected in Article 8.1 express the intention of drafters of the TRIPS Agreement to preserve the ability for WTO Members to pursue certain legitimate societal interests, at the same time as it confirms their recognition that certain measures adopted by WTO Members for such purposes may have an impact on IP rights, and requires that such measures be “consistent with the provisions of the [TRIPS] Agreement” (para. 7.2404).\n\nThe specific objectives expressly identified in Article 8.1 do not, in our view, necessarily exhaust the scope of what may constitute a valid basis for the “justifiability” of encum- brances on the use of trademarks under Article 20. However, their identification in Article 8.1 may shed light on the types of recognized “societal interests” that may provide a basis for the justification of measures under the specific terms of Article 20, and unquestionably identify public health as such a recognized societal interest (para. 7.2406).", "n_tokens": 271, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-27-1", "doc_id": "medicine_vaccine_book", "page": 27, "text": "In summary, while the Preamble and Articles 7 and 8 of the TRIPS Agreement provide the context for the interpretation of all its provisions, as suggested by the examples above, the careful choice of other specific provisions to examine the scope and extent of particular obligations is key to preserving the flexibilities under that agreement.", "n_tokens": 68, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-27-2", "doc_id": "medicine_vaccine_book", "page": 27, "text": "4.4 Object and Purpose\n\nAs noted, the interpretative method codified by the VCLT—as spelled out in Articles 31 and 32 of the VCLT—relies on the textual interpretation of treaty provisions. The reference, however, to the ‘object and purpose’ of the treaty as one of the elements for interpretation has been understood by some courts as leaving room to consider the ‘intention’ of the negotiating parties or to apply a teleological approach.89 It has been noted, for instance, that the European Court of Human Rights, “has developed its own version of these rules of interpretation—a version that tracks the three traditional approaches to treaty interpretation: the textual approach, the subjective approach, and the teleological approach.90 However, as noted by two commentators, The consideration of object and purpose finds its limits in the ordinary meaning of the text of the treaty. It may only be used to bring one of the possible ordinary meanings of the terms to prevail and cannot establish a reading that clearly cannot be expressed with the words used in the text.91\n\nThe quoted authors note in this regard the opinion in the Iran-US Claims Tribunal\n\nwhich pointed out:\n\nEven when one is dealing with the object and purpose of a treaty, which is the most important part of the treaty’s context, the object and purpose does not constitute an element", "n_tokens": 275, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-27-3", "doc_id": "medicine_vaccine_book", "page": 27, "text": "89Linderfalk (2007), p. 205. https://www.corteidh.or.cr/tablas/r32592.pdf. 90See, e.g., Dothan (2019), p. 765; iCourts Working Paper Series, No. 141. https://ssrn.com/ abstract¼3241331. 91Oliver Dörr and Kirsten Schmalenbach, op. cit., para 58.\n\n19", "n_tokens": 107, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-28-0", "doc_id": "medicine_vaccine_book", "page": 28, "text": "20\n\nC. M. Correa\n\nindependent of that context. The object and purpose is not to be considered in isolation from the terms of the treaty; it is intrinsic to its text. It follows that, under Article 31 of the Vienna Convention, a treaty’s object and purpose is to be used only to clarify the text, not to provide independent sources of meaning that contradict the clear text.92\n\nIn the case of the WTO agreements, adherence to the treaty text and avoiding ‘activism’ in the interpretation of their provisions is of utmost importance—as shown by recent debates on the functioning of the Appellate Body93—so as not to expand the Members’ obligations or create new ones, and to provide certainty to their trade relations.", "n_tokens": 150, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-28-1", "doc_id": "medicine_vaccine_book", "page": 28, "text": "Notably, under Article 4.2 of the Dispute Settlement Understanding (“DSU”), panels and the Appellate Body are mandated to ‘clarify’ the various WTO agree- ments, and in doing so they cannot add to or diminish the rights and obligations provided in such agreements. Moreover, Article 4.9 provides that the DSU does not prejudice a government's right to seek an ‘authoritative interpretation’ of any of those agreements from the Ministerial Conference or General Council of the WTO. Hence, the WTO attempts to introduce a difficult distinction between ‘clarification’ and ‘interpretation.’ The panels and Appellate Body reports regularly note, however, that they ‘interpret’ the provisions invoked by the members in accordance to the VLCT rules. This has indeed been the case in those disputes referring to the TRIPS Agreement.94\n\nHowever, although the literal interpretation is the basic rule of interpretation under Article 31 (1) of the VCLT as recognized in the Convention itself, in some cases the textual reading of a provision or a term thereof in its context may still leave ambiguity as to the legal meaning of a text. At this point, the identification of the ‘object and purpose’ of the treaty, conceived as part of the literal interpretation and not as a separate step, acquires particular importance. It is difficult to think of judgments that are absolutely neutral in terms of the policy objectives enshrined in the treaty.", "n_tokens": 304, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-28-2", "doc_id": "medicine_vaccine_book", "page": 28, "text": "Identifying the object and purpose of the TRIPS Agreement is different from characterizing the purpose of intellectual property rights, as the objectives pursued by governments with these rights, as well as the way of implementing them, may differ significantly, even while they comply with the standards of the Agreement and other applicable international treaties). There is no global, uniform system of intellectual property protection.\n\nIn Canada—Patent Protection for Pharmaceutical Products, the panel elaborated\n\non the policy objective of patent laws. It stated:\n\nThe normal practice of exploitation by patent owners, as with owners of any other intellec- tual property right, is to exclude all forms of competition that could detract significantly from the economic returns anticipated from a patent’s grant of market exclusivity ... Patent laws\n\n92Iran-United States Claims Tribunal, Federal Reserve Bank of New York v. Bank Markazi (n 19) para 58. 93See, e.g., Danish and Aileen Kwa, op. cit. 94See, e.g., M. Kennedy, op. cit., 2016.", "n_tokens": 230, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-29-0", "doc_id": "medicine_vaccine_book", "page": 29, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\nestablish a carefully defined period of market exclusivity as an inducement to innovation, and the policy of those laws cannot be achieved unless patent owners are permitted to take effective advantage of that inducement once it has been defined.95\n\nThis view seems to suggest that obtaining ‘economic returns’ as an ‘inducement to innovation’ is what underpins patent policies. It is not consistent with the purpose of the TRIPS Agreement as reflected in Articles 7 and 8. This approach overlooks that patents, as well as other intellectual property rights, can and should be designed and implemented to achieve public rather than private interests, including the diffusion of technical knowledge, technological progress, and access to the out- comes of innovation.96 Thus, in 1917, the US Supreme Court noted that “the primary purpose of that [patent] law is not to create private fortunes, but is to promote the progress of science and the useful arts.”97\n\nArticles 7 (‘Objectives’) and 8 (‘Principles’) of the TRIPS Agreement are key for the determination of the object and purpose of the Agreement, in conjunction, as discussed below, with the Doha Declaration as a subsequent agreement among the parties. Importantly, those provisions are not just hortatory provisions98 but have been incorporated—upon the demand of developing countries during the negotia- tions99—among the prescriptive provisions of the Agreement.", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-29-1", "doc_id": "medicine_vaccine_book", "page": 29, "text": "In Canada–Patent Term, the Appellate Body referred to the need to interpret Article 70.1 of the Agreement as having particular regard to the object and purpose of the treaty, but it eluded an interpretation and application of Articles 7 and 8:\n\n[W]e note that our findings in this appeal do not in any way prejudge the applicability of Article 7 or Article 8 of the TRIPS Agreement in possible future cases with respect to measures to promote the policy objectives of the WTO Members that are set out in those Articles. Those Articles still await appropriate interpretation.100\n\nThe Panel Report in Canada—Pharmaceutical Patents dealt more specifically with the question of the ‘object and purpose’ of the TRIPS Agreement. It relied to this end on Articles 7 and 8 for that determination, but in conjunction with other provisions of the Agreement. It stated:\n\nArticle 30’s very existence amounts to a recognition that the definition of patent rights contained in Article 28 would need certain adjustments. On the other hand, the three limiting conditions attached to Article 30 testify strongly that the negotiators of the Agreement did not intend Article 30 to bring about what would be equivalent to a renegotiation of the basic balance of the Agreement. Obviously, the exact scope of Article 30’s authority will depend on the specific meaning given to its limiting conditions. The words of those conditions must", "n_tokens": 285, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-29-2", "doc_id": "medicine_vaccine_book", "page": 29, "text": "95Canada—Patent Protection for Pharmaceutical Products, supra note 23, para. 7.55. 96See, paragraph 4 of the Doha Declaration. 97Motion Picture Patents Co. v. Universal Film Co. [1917] 243 U. S. 502. 98See, e.g., “TRIPS provisions as interpreted by the WTO dispute settlement organs”, Law Explorer. https://lawexplores.com/trips-provisions-as-interpreted-by-the-wto-dispute-settlement- organs/. 99See, Carlos Correa, op. cit., 2020, pp. 83–95. 100Appellate Body Report, Canada – Term of Patent Protection, WT/DS170/AB/R (18 September 2000), para. 101. https://www.wto.org/english/tratop_e/dispu_e/170abr_e.pdf.\n\n21", "n_tokens": 204, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-30-0", "doc_id": "medicine_vaccine_book", "page": 30, "text": "22\n\nC. M. Correa\n\nbe examined with particular care on this point. Both the goals and the limitations stated in Articles 7 and 8.1 must obviously be borne in mind when doing so as well as those of other provisions of the TRIPS Agreement which indicate its object and purposes.101\n\nIt is unclear what “other provisions of the TRIPS Agreement which indicate its object and purposes” are suggested by the panel. While there might be different perceptions about the object and purpose of the TRIPS Agreement—as the debates between developed and developing countries have shown during the negotiation and after the adoption of the TRIPS Agreement102—the panels and Appellate Body need to be guided by the text of the Agreement and not by the individual views of the members of those bodies.\n\nParagraph 5(a) of the Doha Declaration confirmed the importance of Articles", "n_tokens": 167, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-30-1", "doc_id": "medicine_vaccine_book", "page": 30, "text": "7 and 8 for the interpretation of the TRIPS Agreement:\n\nAccordingly and in the light of paragraph 4 above, while maintaining our commitments in the TRIPS Agreement, we recognize that these flexibilities include:\n\na. In applying the customary rules of interpretation of public international law, each provision of the TRIPS Agreement shall be read in the light of the object and purpose of the Agreement as expressed, in particular, in its objectives and principles.\n\nThe wording of this paragraph (“in particular”) suggests that while Articles 7 and 8 are determinant in defining the object and purpose of the Agreement, other pro- visions of the Agreement, as well as the preambular provisions, can also contribute to the determination of its object and purpose. Such may be the case, for instance, of Article 41.2 which states: “Procedures concerning the enforcement of intellectual property rights shall be fair and equitable ...” This provision makes it clear that one purpose of the Agreement is to ensure that the enforcement of intellectual property rights (as mandated in Part III of the Agreement) is ‘fair and equitable’ to all the parties concerned, and that it does not provide undue advantages to the right holders over third parties in judicial or administrative procedures, or vice versa.", "n_tokens": 257, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-30-2", "doc_id": "medicine_vaccine_book", "page": 30, "text": "An interesting elaboration on the object and purpose of the TRIPS Agreement based on Articles 7 and 8 was undertaken by the panel in Australia—Tobacco Plain Packaging.103 The panel largely relied on the Doha Declaration to address this issue. It noted:\n\nWe note in this respect that the Doha Declaration, adopted by Ministers on 14 November 2001, provides that, “[i]n applying the customary rules of interpretation of public interna- tional law, each provision of the TRIPS Agreement shall be read in the light of the object and purpose of the Agreement as expressed, in particular, in its objectives and principles” (para. 7.2407).\n\nWhile this statement was made in the specific context of a re-affirmation by Members of the flexibilities provided in the TRIPS Agreement in relation to measures taken for the protec- tion of public health, we note that paragraph 5 of the Doha Declaration is formulated in\n\n101See, Canada—Patent Protection for Pharmaceutical Products, supra note 23, para. 7.26. 102Shadlen (2004). Available from: https://link.springer.com/article/10.1007%2FBF02686283. 103Romero (2020b). Available from: https://www.southcentre.int/policy-brief-79-june-2020/.", "n_tokens": 287, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-31-0", "doc_id": "medicine_vaccine_book", "page": 31, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\ngeneral terms, inviting the interpreter of the TRIPS Agreement to read “each provision of the TRIPS Agreement” in the light of the object and purpose of the Agreement, as expressed in particular in its objectives and principles. As described above, Articles 7 and 8 have central relevance in establishing the objectives and principles that, according to the Doha Declara- tion, express the object and purpose of the TRIPS Agreement relevant to its interpretation (7.2408).\n\nThe Appellate Body essentially followed the panel’s views on this matter. It clarified, however, that the conclusions reached regarding the purpose of the TRIPS Agreement are supported by Articles 7 and 8, and that the analysis of the Doha Declaration reconfirmed the panel’s findings. It held:\n\nThe Panel also remarked that the societal interests referred to in Article 8 may provide a basis of the justification of measures under Article 20. Thus, we agree with Australia that, in any event, the reliance on the Doha Declaration was not of decisive importance for the Panel's reasoning since the Panel had reached its conclusions about the contextual relevance of Articles 7 and 8 of the TRIPS Agreement to the interpretation of Article 20 before it turned to the Doha Declaration. The Panel relied on the Doha Declaration simply to reconfirm its previous conclusions regarding the contextual relevance of Articles 7 and 8 of the TRIPS Agreement (6.658).", "n_tokens": 296, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-31-1", "doc_id": "medicine_vaccine_book", "page": 31, "text": "This analysis and the observations above show that the WTO case law has considered Articles 7 and 8, both as part of the context for interpretation and as defining elements of the object and purpose of the TRIPS Agreement. It confirms the relevance of said provisions for the interpretation of other provisions in the Agreement.\n\n4.4.1 Legal Weight of the Doha Declaration\n\nIn order to give authority to its argument regarding the relevance of Articles 7 and 8 for the interpretation of the TRIPS Agreement’s provisions, in Australia—Tobacco Plain Packaging specifically elaborated on the legal weight of the Doha Declaration. This is one of the most distinct (and welcome) contributions of this panel’s report, as it is the first time in which the normative effects of that Declaration have been considered in WTO jurisprudence.", "n_tokens": 166, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-31-2", "doc_id": "medicine_vaccine_book", "page": 31, "text": "the panel\n\nIn some WTO disputes prior to the Australia tobacco case, the issue of subsequent practices as an element for interpretation of the TRIPS provisions was very cau- tiously considered. Thus, in Canada—Patent Protection for Pharmaceutical Prod- ucts, the panel considered comparative law in order to determine whether the interest claimed as “legitimate” by the EC was a “widely recognized policy norm.”104 In United States—Section 110(5) of the US Copyright Act, the panel confirmed its conclusion with reference to examples of “state practice” of members of the Berne Union and WTO, but it warned that it “did not wish to express a view on whether these are sufficient to constitute ‘subsequent practice’ within the meaning of Article\n\n104Para.7.77.\n\n23", "n_tokens": 165, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-32-0", "doc_id": "medicine_vaccine_book", "page": 32, "text": "24\n\nC. M. Correa\n\n31(3)(b) of the Vienna Convention.”105 In China—Intellectual Property Rights, the panel rejected certain material submitted by China to prove a “subsequent practice” in the application of the TRIPS Agreement within the meaning of Article 31(3) of the Vienna Convention. The panel considered that it lacked “the breadth to constitute a common, consistent, discernible pattern of acts or pronouncements” and that “the content of the material does not imply agreement on the interpretation of Article 61 of the TRIPS Agreement.”106\n\nA key panel assertion in the referenced case against Australia is that the Doha Declaration must be considered a ‘subsequent agreement’ as defined in the VCLT.107 In accordance with Article 31.3(a) of the VCLT, “any subsequent agree- ment between the parties regarding the interpretation of the treaty or the application of its provisions” shall be taken into account, together with the context.108 It is worth noting that the International Law Commission adopted in its 2018 report “Draft Conclusions on Subsequent Agreements and Subsequent Practice in Relation to the Interpretation of Treaties”109 which, in accordance with one commentator, suggests a “subtle elevation of subsequent agreement and subsequent practice,” which would thereby become an integral part of the main rule of interpretation.110\n\nIn making reference to the Appellate Body ruling in US – Clove Cigarettes (para.\n\n262), the panel stated:", "n_tokens": 293, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-32-1", "doc_id": "medicine_vaccine_book", "page": 32, "text": "This paragraph of the Doha Declaration may, in our view, be considered to constitute a “subsequent agreement” of WTO Members within the meaning of Article 31(3)(a) of the Vienna Convention. As the Appellate Body has clarified:\n\nBased on the text of Article 31(3)(a) of the Vienna Convention, we consider that a decision adopted by Members may qualify as a “subsequent agreement between the parties” regarding the interpretation of a covered agreement or the application of its provisions if: (i) the decision is, in a temporal sense, adopted subsequent to the relevant covered agree- ment; and (ii) the terms and content of the decision express an agreement between Members on the interpretation or application of a provision of WTO law (para. 7.2409).\n\nThe panel’s view rebuts the United States Trade Representative' (USTR) opinion expressed upon the conclusion of the Doha Conference that the Doha Declaration merely was a “political declaration.”111 As noted by a commentator, “[d] istinguishing legal claims from non-legal or political claims, such as access to", "n_tokens": 232, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-32-2", "doc_id": "medicine_vaccine_book", "page": 32, "text": "105See, United States—Section 110(5) of the U.S. Copyright Act, para. 6.55, n. 68. 106Para. 7.581. 107For an early analysis on this subject, see, Correa (2002), p. 45. https://apps.who.int/iris/handle/ 10665/67345. 108See, e.g., Stefan Kadelbach (2018). http://www.qil-qdi.org/international-law-commission-and- role-of-subsequent-practice-as-a-means-of-interpretation-under-articles-31-and-32-vclt/. 109United Nations (2018). https://legal.un.org/ilc/reports/2018/english/a_73_10_advance.pdf. 110Tladi quent-agreements-and-subsequent-practice/. 111USTR Fact Sheet Summarizing Results from WTO Doha Meeting, 15 November 2001.\n\n(2018). https://www.ejiltalk.org/is-the-international-law-commission-elevating-subse", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-33-0", "doc_id": "medicine_vaccine_book", "page": 33, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\nessential medicines, can deprive them of their status as rights and thereby serve to legitimize an unjust status quo.”112\n\nThe panel further explored the legal status of the Doha Declaration under WTO law, noting that although being a ‘declaration,’ it was adopted by a consensus decision at the WTO Conference. The panel argued as follows:\n\nIn this instance, the instrument at issue is a “declaration,” rather than a “decision.” However, the Doha Declaration was adopted by a consensus decision of WTO Members, at the highest level, on 14 November 2001 on the occasion of the Fourth Ministerial Conference of the WTO, subsequent to the adoption of the WTO Agreement, Annex 1C of which comprises the TRIPS Agreement. The terms and contents of the decision adopting the Doha Declara- tion express, in our view, an agreement between Members on the approach to be followed in interpreting the provisions of the TRIPS Agreement. This agreement, rather than reflecting a particular interpretation of a specific provision of the TRIPS Agreement, confirms the manner in which “each provision” of the Agreement must be interpreted, and thus “bears specifically” on the interpretation of each provision of the TRIPS Agreement (7.2410).", "n_tokens": 273, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-33-1", "doc_id": "medicine_vaccine_book", "page": 33, "text": "This paragraph reiterates the characterization of the Doha Declaration as a ‘subsequent agreement’ under the VCLT and adds two important elements: its adoption ‘at the highest level’ and an agreement ‘on the approach’ to be followed in interpreting each provision of the Agreement. This ‘approach’ is reflected in paragraph 5(a) of the Declaration quoted above but also in the rest of the Declaration, particularly as it makes a clear case for protecting public health, a key public interest and a matter of respect and realization of human rights, in implementing the TRIPS Agreement.113\n\nThe panel’s analysis on the Doha Declaration does not aim, however, at asserting its legal value per se but its role as a confirmation that Articles 7 and 8 of the TRIPS Agreement provide both the context and define the object and purpose of the Agreement. The panel stated in this regard:\n\nThe guidance provided by the Doha Declaration is consistent, as the Declaration itself suggests, with the applicable rules of interpretation, which require a treaty interpreter to take account of the context and object and purpose of the treaty being interpreted, and confirms in our view that Articles 7 and 8 of the TRIPS Agreement provide important context for the interpretation of Article 20 (7.2411).", "n_tokens": 257, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-33-2", "doc_id": "medicine_vaccine_book", "page": 33, "text": "The analysis of the legal status of the Doha Declaration is one of the most significant contributions by the panel in Australia—Tobacco Plain Packaging. It supported the panel’s conclusion with respect to the justifiability of the plain packaging measures adopted by that country and, hence, their consistency with Article 20 of the TRIPS Agreement.114\n\n112Gathii fea2e7f4e97baf2f0f03.pdf. 113See, e.g., Carlos Correa, op cit., 2002; Velasquez, Correa, and Ido, op. cit, 2020; UNDP (2015a). https://www.undp.org/content/undp/en/home/librarypage/hiv-aids/doha10yearson.html. 114Romero (2020a). https://www.southcentre.int/research-paper-108-april-2020/.\n\n(2002), p. 315. https://pdfs.semanticscholar.org/a3a6/65016915476d1088\n\n25", "n_tokens": 244, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-34-0", "doc_id": "medicine_vaccine_book", "page": 34, "text": "26\n\nC. M. Correa\n\n5 Conclusions\n\nThe notion that the TRIPS Agreement is not a uniform law and that it allows WTO members some room to maneuver in interpreting and implementing the Agreement’s obligations is well established in the literature and numerous resolutions by UN agencies and bodies. The adoption of the Doha Declaration, and several rulings by panels and the Appellate Body, point in the same direction. An evolution is percep- tible in the WTO jurisprudence on the matter. In particular, the most recent panel report in Australia—Tobacco Plain Packaging shows the explicit acceptance of the concept of TRIPS flexibilities in WTO case law and their role in preserving the required policy space to pursue public policies such as public health. This is an important development that could provide the basis for a further step in that jurisprudence: the integration of human rights law, as a component of international law, in the analysis of the obligations imposed by that Agreement and of the leeway that states should preserve for the realization of such rights.115", "n_tokens": 208, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-34-1", "doc_id": "medicine_vaccine_book", "page": 34, "text": "The extent to which the TRIPS flexibilities can be implemented at the national level without the risk of trade retaliations depends on the way the Agreement’s provisions are interpreted by panels and the Appellate Body. Several issues need to be addressed in considering how such provisions should be interpreted, consistently with the interpretive method codified by the VCLT. While the search for the ordinary meaning of the terms used is a well-established methodology, divergences may exist with regard to whether they should be deemed as ‘static’ or ‘evolutionary.’ An evolutionary approach creates the risk of unduly expanding the obligations under the Agreement, as actively promoted by some developed countries through free trade agreements. The adequate determination of the context—beyond the Preamble and Articles 7 and 8—for interpretation of a particular provision is also important, as it may decisively influence the determination of the scope and extent of the obligation under the Agreement. Similarly, the understanding on the object and purpose of the Agreement plays an important role. The WTO jurisprudence seems to have firmly admitted that such a determination is to be based on said Articles 7 and 8.", "n_tokens": 236, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-34-2", "doc_id": "medicine_vaccine_book", "page": 34, "text": "The impact of the TRIPS Agreement on public health and, particularly, access to medicines has been one of the most sensitive issues since its adoption. This issue has been key in promoting debates and analyses on the TRIPS flexibilities (although they are also important in relation to other public interests, such as access to knowledge or food security). In this regard, the panel ruling in the case against Australia on plain packaging has confirmed the legal status of the Doha Declara- tion—seen by some as a merely political instrument—as a ‘decision’ taken by consensus that constitutes a ‘subsequent agreement’ among the WTO members. This is also an important development as it suggests that a pro-public health interpretation is not only tenable but also mandated, and confirms the room that\n\n115See, e.g., Sellin (2015), pp. 445–473. https://link.springer.com/article/10.1007/s40802-015- 0047-5.", "n_tokens": 216, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-35-0", "doc_id": "medicine_vaccine_book", "page": 35, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\ngovernments have to confidently adopt pro-public health measures without fearing the risk of costly and burdensome litigation under the DSU.", "n_tokens": 38, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-35-1", "doc_id": "medicine_vaccine_book", "page": 35, "text": "References\n\nBrownlie I (1998) Principles of public international law. p. 627 Correa C (2002) Implications of the Doha Declaration on the TRIPS agreement and public health. World Health Organization, Geneva, p 45. Available from https://apps.who.int/iris/handle/ 10665/67345\n\nCorrea C (2005) The TRIPS Agreement from the perspective of developing countries. In: Macrory P, Appleton A, Plummer M (eds) The World Trade Organization: legal, economic and political analysis. Springer, Berlin, p 2005\n\nCorrea C (2011a) Globalisation and intellectual property rights. The struggle of developing countries to influence TRIPS. In: Alam S, Klein N, Overland J (eds) Globalisation and the quest for social and environmental justice: the relevance of international law in an evolving World Order. Routledge, Milton Park\n\nCorrea C (2011b) Test data protection: rights conferred under the TRIPS Agreement and some effects of TRIPS-plus standards. In: Dreyfuss RC, Strandburg KJ (eds) The law and theory of trade secrecy. A handbook of contemporary research. Edward Elgar, Cheltenham\n\nCorrea C (2014) Patent protection for plants: legal options for developing countries. Research Paper No. 55. South Centre, Geneva. Available from https://www.southcentre.int/wp-content/uploads/ 2014/11/RP55_Patent-Protection-for-Plants_EN.pdf", "n_tokens": 316, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-35-2", "doc_id": "medicine_vaccine_book", "page": 35, "text": "Correa C (2020a) Special Section 301: US interference with the design and implementation of National Patent Laws. Research Paper 115. South Centre, Geneva. Available from https:// www.southcentre.int/research-paper-115-july-2020/\n\nCorrea C (2020b) Trade Related Aspects of Intellectual Property Rights. A commentary on the\n\nTRIPS Agreement, 2nd edn. Oxford University Press, p 21\n\nDanish and Aileen Kwa (2019) Crisis at the WTO’s Appellate Body (AB): why the AB is important for developing members. Policy Brief No. 69. South Centre, Geneva. Available from https:// www.southcentre.int/wp-content/uploads/2019/12/PB69_Crisis-at-the-WTO%E2%80%99s- Appellate-Body-AB-Why-the-AB-is-Important-for-Developing-Members_EN-1.pdf\n\nDörr O, Schmalenbach K (2012) Article 31. General rule of interpretation. In: Vienna Convention on the law of treaties – a commentary. Springer, Berlin. Available from https://link.springer. com/chapter/10.1007%2F978-3-642-19291-3_34\n\nDothan S (2019) The three traditional approaches to treaty interpretation: a current application to the European Court of Human Rights. Fordham Int Law J 42:765; iCourts Working Paper Series, No. 141. Available from: https://ssrn.com/abstract¼3241331", "n_tokens": 344, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-35-3", "doc_id": "medicine_vaccine_book", "page": 35, "text": "Eger T, Scheufen M (2012) The past and the future of copyright law: technological change and beyond”. In Liber Amicorum Boudewijn Bouckaert. Die Keure. Available from https://www. researchgate.net/publication/280043122_The_past_and_the_future_of_copyright_law_techno logical_change_and_beyond\n\nEuropean Commission (2020) Report on the protection and enforcement of intellectual property rights in third countries. Commission staff working document. Available from https://trade.ec. europa.eu/doclib/docs/2020/january/tradoc_158561.pdf\n\nFlowers Z (2019) The role of precedent and stare decisis in the World Trade Organization’s dispute\n\nsettlement body. Int J Legal Information 47(2):90–104\n\nFuchs S (2020) COVID-19: New German legislation to fight pandemic may affect granted German patents. Available from https://www.twobirds.com/en/news/articles/2020/germany/covid-19- new-german-legislation-to-fight-pandemic-may-affect-granted-patents\n\n27", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-36-0", "doc_id": "medicine_vaccine_book", "page": 36, "text": "28\n\nC. M. Correa\n\nGathii JT (2002) The legal status of the Doha Declaration on TRIPS and public health under the Vienna Convention of the Law of Treaties. Harv J Law Technol 15(2):315. Available from https://pdfs.semanticscholar.org/a3a6/65016915476d1088fea2e7f4e97baf2f0f03.pdf\n\nGeiger C, Gervais D, Senftleben M (2013) The three-step test revisited: how to use the test’s flexibility in national copyright law. PIJIP Research Paper Series. Available from https:// digitalcommons.wcl.american.edu/cgi/viewcontent.cgi?article¼1041&context¼research\n\nGermán Velásquez (2013) Access to medicines and intellectual property: the contribution of the World Health Organization. Research Paper No. 47. South Centre, Geneva, p 5. Available from https://www.southcentre.int/wp-content/uploads/2013/05/RP47_WTO-role-in-IP-and-access- to-medicines_EN.pdf\n\nGermán Velásquez (2019) Medicines and intellectual property: 10 years of the WHO global\n\nstrategy. Research Paper No. 100. South Centre, Geneva\n\nHaedicke M (2000) U.S. imports, TRIPS and Section 337 of the Tariff Act of 1930. Int Rev Indus", "n_tokens": 334, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-36-1", "doc_id": "medicine_vaccine_book", "page": 36, "text": "Property Copyright Law 31(7/8):1774\n\nHowse R (2000) The Canadian medicine panel: a dangerous precedent in dangerous times. J World Intellectual Property 3(4). Available from https://onlinelibrary.wiley.com/doi/abs/10.1111/j. 1747-1796.2000.tb00139.x\n\nKadelbach S (2018) The International Law Commission and role of subsequent practice as a means of interpretation under Articles 31 and 32 VCLT. Questions of International Law. Available from http://www.qil-qdi.org/international-law-commission-and-role-of-subsequent-practice-as- a-means-of-interpretation-under-articles-31-and-32-vclt/\n\nKennedy M (2016) WTO dispute settlement and the TRIPS agreement: applying intellectual\n\nproperty standards in a trade law framework. Cambridge University Press, Cambridge\n\nLinderfalk U (2007) On the interpretation of treaties: the modern international law as expressed in the 1969 Vienna Convention on the Law of Treaties. Springer, Berlin, p 205. Available from https://www.corteidh.or.cr/tablas/r32592.pdf\n\nMcNair (1961) The law of treaties. Clarendon Press, Oxford, p 365 Mgbeoji I (2006) Global biopiracy: patents, plants, and indigenous knowledge. UBC Press, Vancouver. Available from https://books.google.fr/books?id¼q4MIoBKy88MC& pg¼PA121&lpg¼PA121&dq¼biopiracy+us+patents&source¼bl&ots¼-ZBMOhXLLn& sig¼ACfU3U0DslCI-lxiwQuSmN-jeuuC-fafLQ&hl¼en&sa¼X&ved¼2ahUKEwitsrmu8N_ pAhUSx4UKHe1_DHYQ6AEwEnoECAkQAQ#v¼onepage&q¼biopiracy%20us%20pat ents&f¼false", "n_tokens": 464, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-36-2", "doc_id": "medicine_vaccine_book", "page": 36, "text": "Minn M (2016) Patenting of genetic research in Europe and the U.S.: a questionable future for diagnostic methods and personalized medicines. Biotechnology Law Report 38(2). Available from https://www.liebertpub.com/doi/10.1089/blr.2019.29108.mm\n\nMorin J-F, Surbeck J (2020) Mapping the new frontier of international IP law: introducing a TRIPs-\n\nplus dataset. World Trade Rev 19(1)\n\nOkediji RL (ed) (2017) Copyright law in an age of limitations and exceptions. Cambridge University Press, Cambridge. Available from https://books.google.fr/books? id¼3lpEDgAAQBAJ&pg¼PA241&lpg¼PA241&dq¼copyright+exception+interpretation +article+30+ruth&source¼bl&ots¼7MCIdWRbq7&sig¼ACfU3U2kCly0QaU- z P X h b 8 3 g b 8 Q c S F 8 U t w & h l ¼e n & s a ¼X & v e d ¼2 a h U K E w j U 4 N C b y - zpAhURnxQKHXg0AtoQ6AEwBHoECAkQAQ#v¼onepage&q¼copyright%20exception% 20interpretation%20article%2030%20ruth&f¼false\n\nPrifti V (2015) The breeder’s exception to patent rights – analysis of compliance with article 30 of\n\nthe TRIPS Agreement. Springer, Berlin\n\nReid J (2019) Biopiracy: the struggle for traditional knowledge rights. Am Indian Law Rev 34(1). Available from https://digitalcommons.law.ou.edu/cgi/viewcontent.cgi?article¼1121& context¼ailr\n\nRodrigues EB Jr (2012) The general exception clauses of the TRIPS agreement: promoting sustainable development. Cambridge University Press, Cambridge. Available from https://", "n_tokens": 451, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-37-0", "doc_id": "medicine_vaccine_book", "page": 37, "text": "Interpreting the Flexibilities Under the TRIPS Agreement\n\nwww.researchgate.net/publication/288719106_The_general_exception_clauses_of_the_ TRIPS_agreement_Promoting_sustainable_development\n\nRomero T (2020a) Public health and plain packaging of tobacco: an intellectual property perspec- tive. Research Paper No. 108. South Centre, Geneva. Available from: https://www.southcentre. int/research-paper-108-april-2020/\n\nRomero T (2020b) Articles 7 and 8 as the basis for interpretation of the TRIPS Agreement. Policy Brief No. 79. South Centre, Geneva. Available from https://www.southcentre.int/policy-brief- 79-june-2020/\n\nRuse-Khan HG (2017) From TRIPS to FTAs and back: re-conceptualising the role of a multilateral IP framework in a TRIPS-plus world. Forthcoming, Netherlands Yearbook of International Law; Max Planck Institute for Innovation & Competition Research Paper, No. 18-02; University of Cambridge Faculty of Law Research Paper, No. 3/2018. Available from: https://ssrn.com/ abstract¼3082718\n\nRuse-Khan HG, Puutio TA (2017) A handbook on negotiating development oriented intellectual property provisions in trade and investment agreements. UNESCAP, Bangkok, p 10. Available from https://www.unescap.org/sites/default/files/IPR%20Handbook.pdf\n\nSellin JA (2015) Does one size fit all? Patents, the right to health and access to medicines. Netherlands Int Law Rev 62:445–473. Available from https://link.springer.com/article/10. 1007/s40802-015-0047-5", "n_tokens": 386, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-37-1", "doc_id": "medicine_vaccine_book", "page": 37, "text": "Shadlen K (2004) Patents and pills, power and procedure: the north-south politics of public health in the WTO. St Comp Int Dev 39, 76–108. Available from https://link.springer.com/article/10. 1007%2FBF02686283\n\nShaikh OH (2016) Access to medicine versus test data exclusivity – Safeguarding flexibilities under\n\ninternational law. Springer, Berlin\n\nSon KB, Lopert R, Gleeson D, Lee TJ (2018) Moderating the impact of patent linkage on access to medicines: lessons from variations in South Korea, Australia, Canada, and the United States. Globalization and Health vol. 14. Available from https://doi.org/10.1186/s12992-018-0423-0 The Graduate Institute Geneva, Knowledge Portal on Innovation and Access to Medicines. Avail-\n\nable from: https://www.knowledgeportalia.org/. Last accessed 12 Feb 2021\n\nThe Law Library of Congress, Global Legal Research Center (2016) Patent Term Extensions and\n\nAdjustments\n\nTladi D (2018) Is the International Law Commission elevating subsequent agreements and subse- quent practice? EJIL:Talk! Available from https://www.ejiltalk.org/is-the-international-law- commission-elevating-subsequent-agreements-and-subsequent-practice/\n\nUNCTAD (1996) The TRIPS agreement and developing countries. Available from https://unctad.", "n_tokens": 327, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-37-2", "doc_id": "medicine_vaccine_book", "page": 37, "text": "org/en/docs/ite1_en.pdf\n\nUNCTAD & ICTSD (2005) Resource book on TRIPS and development. Cambridge University Press, Cambridge, p 467. Available from https://unctad.org/en/PublicationsLibrary/ ictsd2005d1_en.pdf\n\nUNDP (2015a) The Doha Declaration 10 years on and its impact on access to medicines and the right to health. Available from https://www.undp.org/content/undp/en/home/librarypage/hiv- aids/doha10yearson.html\n\nUNDP (2015b) Using competition law to promote access to medicine. Available from https://www. undp.org/content/undp/en/home/librarypage/hiv-aids/using-competition-law-to-promote- access-to-medicine.html\n\nUnited Nations (2018) Report of the International Law Commission (A/73/10, 2018). Available\n\nfrom https://legal.un.org/ilc/reports/2018/english/a_73_10_advance.pdf\n\n29", "n_tokens": 242, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-38-0", "doc_id": "medicine_vaccine_book", "page": 38, "text": "30\n\nC. M. Correa\n\nUnited Nations General Assembly (2015) A/RES/70/1. Available from https://www.un.org/ga/\n\nsearch/view_doc.asp?symbol¼A/RES/70/1&Lang¼E\n\nVelásquez G, Correa CM, Ido V (2020) Intellectual property, human rights and access to medicines: a selected and annotated bibliography, 3rd edn. South Centre, Geneva. Available from https:// www.southcentre.int/book-by-the-south-centre-2020/#more-14014\n\nWHO, WIPO, and WTO (2012) Promoting access to medical technologies and innovation - intersections between public health, intellectual property and trade. Available from https:// www.wipo.int/edocs/pubdocs/en/global_challenges/628/wipo_pub_628.pdf\n\nWIPO (2010) Patent related flexibilities in the multilateral legal framework and their legislative implementation at the national and regional levels, p 11. Available from https://www.wipo.int/ meetings/en/doc_details.jsp?doc_id¼142068\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.", "n_tokens": 357, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-38-1", "doc_id": "medicine_vaccine_book", "page": 38, "text": "The images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 73, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-39-0", "doc_id": "medicine_vaccine_book", "page": 39, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals: A Comparative and Critical Review\n\nIrene Calboli", "n_tokens": 18, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-39-1", "doc_id": "medicine_vaccine_book", "page": 39, "text": "Abstract This Chapter addresses the topic of intellectual property (IP) exhaustion in the context of the parallel trade of pharmaceuticals. These imports, which are controversial in general, are more complex with respect to pharmaceuticals, which require additional marketing and import authorizations. Nevertheless, individual countries remain free to accept these imports under the flexibility of Article 6 of the Agreement on Trade Related Aspects to Intellectual Property Rights (TRIPS Agreement). This Chapter reviews several national approaches—in developed, developing, and least developed countries (LDCs)—from the perspective of the exhaustion of patent rights as well as other IP rights. Through this review, it highlights that several countries today accept parallel trade. A large number of these countries are, however, developed countries, whereas several developing countries and LDCs instead prohibit parallel imports. This finding is perplexing, and the reasons for this restrictive approach are unclear as developing countries and LDCs need flexible policies and can largely benefit from parallel trade. In addition, despite the claim by the pharmaceutical industry that parallel trade would increase the price of medicines in these countries—as originator would increase prices due to the fear of parallel imports—medicines are sold at lower prices mostly because of governments’ pricing or after the expiration of patent protection. Based on this review, this Chapter concludes that", "n_tokens": 265, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-39-2", "doc_id": "medicine_vaccine_book", "page": 39, "text": "national legislations, which are not taking advantage of the flexibility in Article 6 of the TRIPS Agreement, may consider reviewing their policies and allow parallel imports.", "n_tokens": 32, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-39-3", "doc_id": "medicine_vaccine_book", "page": 39, "text": "I. Calboli (*) Texas A&M University School of Law, Fort Worth, TX, USA\n\nNanyang Business School, Nanyang Technological University, Singapore, Singapore\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_2\n\n31", "n_tokens": 97, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-40-0", "doc_id": "medicine_vaccine_book", "page": 40, "text": "32\n\n1 Introduction: The Relevance (and Resilience)\n\nof the Principle of Intellectual Property Exhaustion and Its Application to Pharmaceuticals\n\nIn this chapter, I explore the application of the principle of intellectual property (IP) exhaustion to the parallel imports of pharmaceuticals and the impact that different policies on exhaustion can have on these imports across selected jurisdic- tions. The legal treatment of IP exhaustion continues to represent one of the most debated and unresolved issues in international trade.1 In addition, the debate regard- ing IP exhaustion and pharmaceuticals reflects the more complex debate on access to medicines and public health, and how domestic policies on IP exhaustion can be used to implement the existing IP-related flexibilities provided in the international system.2 Several commentators have addressed this debate before, yet disagreements and uncertainty continue to characterize this important area of IP and international trade.", "n_tokens": 175, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-40-1", "doc_id": "medicine_vaccine_book", "page": 40, "text": "Moreover, domestic policies on IP exhaustion are not the only barrier to parallel imports of pharmaceuticals, as these imports are also subjected to national marketing approvals, in many import authorizations, and other formalities. In addition, instances, national governments exert price control on the sale of pharmaceuticals, in particular prescription medications. In other words, as commentators have noted, pharmaceuticals are traded, and parallel traded, in “distorted” markets due to the additional regulatory schemes and price control policies that apply to these products. National competition laws are also important in the context of parallel imports of pharmaceuticals, for example regarding excessive pricing or the validity of contrac- tual clauses to block the products’ redistribution after they have first been put into the market by the IP holders. Because of its limited scope, this Chapter only mentions and does not analyzes in detail this complex ecosystem of parallel trade in pharma- ceuticals.3 In practice, however, these factors remain very relevant, perhaps even more relevant than domestic policies on IP exhaustion in certain instances. In particular, in some countries, the actual impact of IP exhaustion on the admissibility of parallel imports of pharmaceuticals is certainly minimal, if not irrelevant due to the additional regulatory requirements and possible contractual limitations against these imports.", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-40-2", "doc_id": "medicine_vaccine_book", "page": 40, "text": "1For a detailed analysis and summary of the relevant debates, see the contributions in Calboli and Lee (2016). See also Ghosh and Calboli (2018); Fink 2004, p. 174); Maskus (2000), p. 1269; Abbott (1998), pp. 607–636; Abbott 2000) http://ssrn.com/abstract¼1921856; Heath (1997), p. 623; Jehoram (1996), p. 280; Hilke (1988), p. 75. 2For a discussion of the flexibilities and applications to pharmaceuticals and health care, see El-Said (2010). 3For a comprehensive review of all these aspects, see Abbott (2016), p. 145 [hereinafter Abbott, Parallel Trade in Pharmaceuticals]. See also Kyle (2007), p. 88 and Maskus (2001).\n\nI. Calboli", "n_tokens": 201, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-41-0", "doc_id": "medicine_vaccine_book", "page": 41, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nIn light of this, why then writing a chapter on this topic, if IP exhaustion may not matter, or matter considerably less than originally thought, for the admissibility of parallel imports of pharmaceuticals into national markets?", "n_tokens": 55, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-41-1", "doc_id": "medicine_vaccine_book", "page": 41, "text": "As I mentioned, the debate in this area remains complex and, even though domestic policies on IP exhaustion are not the only aspect to consider, these policies are still relevant, in particular when national governments are in favor of parallel imports and grant the pharmaceuticals the necessary marketing approvals and import authorizations. It is difficult to predict how often, in practice, national governments would approve these imports, but certainly in these instances domestic policies on exhaustion would make the difference in the legal treatment of the imports. Would these be treated as legitimate imports or IP infringements? Moreover, domestic policies on exhaustion not only can affect the imports of patented pharmaceuticals, but also generics. In particular, national rules on trademark exhaustion can be used to block parallel imports including of generics. While this may not affect countries with the ability to produce generics domestically, it could affect countries without manufacturing capacity. Instead, domestic policies favoring parallel imports could facilitate the supply of medicines at lower prices than branded versions, or even the supply of certain medicines altogether as originator companies often not directly distribute certain medicines in some countries.", "n_tokens": 221, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-41-2", "doc_id": "medicine_vaccine_book", "page": 41, "text": "The chapter proceeds as follows. Section 2 presents an overview of the principle of exhaustion in the context of international trade. This background leads to the discussion on the legal treatment of parallel imports of pharmaceuticals. Section 3 explores the domestic policies on patent exhaustion in selected developed and developing countries and elaborates on how different solutions—national, interna- tional, or regional exhaustion—impact the parallel trade of pharmaceuticals in these countries. Section 4 focuses on the impact of overlapping IP rights—notably trade- marks and copyrights in addition to patents—to the parallel trade of pharmaceuticals. This Section highlights how parallel imports can be affected by these overlaps, in particular when a country adopts international patent exhaustion, but practices national exhaustion for copyrights or trademarks. It also highlights that overlapping rights can block parallel imports when the imported products, albeit genuine, carry small quality differences from the products distributed into the importing countries by IP holders.4 Section 5 concludes and highlights that several developed countries adopt today more liberal policies on IP exhaustion, notably international exhaustion, than several developing and least developed countries (LDCs), which follow instead national exhaustion. This is certainly problematic for the latter countries and their access to pharmaceuticals.", "n_tokens": 240, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-41-3", "doc_id": "medicine_vaccine_book", "page": 41, "text": "4See, e.g. Calboli (2014a), p. 151 [hereinafter Calboli, Avoidable Effects]; Calboli (2011), p. 1241 [hereinafter Calboli, Market Integration] (addressing in details the legal treatment of quality differences in the context of trademark exhaustion).\n\n33", "n_tokens": 74, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-42-0", "doc_id": "medicine_vaccine_book", "page": 42, "text": "34\n\n2 Intellectual Property Exhaustion and Paralle Trade:\n\nGeneral Considerations and Application to Pharmaceuticals", "n_tokens": 16, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-42-1", "doc_id": "medicine_vaccine_book", "page": 42, "text": "The doctrine of IP exhaustion is crucial in IP theory, as it limits the rights of IP holders to control the distribution of the products they have put in the market after their first lawful release.5 This doctrine was developed in the nineteenth century to balance the rights of IP holders and to prevent the use of their IP rights against the lawful rights of retailers, second-hand dealers, and consumers to freely display, advertise, and resell the products they lawfully purchased in the market, even if those actions directly compete with the IP holders’ business activities in the same market.6 Generally, there are not major controversies regarding the application of this doctrine within national markets, at least regarding products whose quality has not been changed and are resold nationally.7 In contrast, controversy has tradition- ally characterized the debate over the application of the doctrine of exhaustion in the context of international trade. In particular, the legal treatment of the phenomenon of parallel imports—the imports of genuine products, imported into a country from unauthorized third party importers after their first authorized sale by the IP holders abroad8—is one of the few aspect of IP that has never been internationally harmo- nized and discussion over the admissibility into national markets of these products continue to date. The tension between the application of the principle IP exhaustion and the movement of products across national border, in general", "n_tokens": 276, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-42-2", "doc_id": "medicine_vaccine_book", "page": 42, "text": "and in the context of pharmaceuticals, is addressed in this Section.", "n_tokens": 13, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-42-3", "doc_id": "medicine_vaccine_book", "page": 42, "text": "2.1 The Principle of Intellectual Property Exhaustion\n\nin International Trade: An Overview\n\nProfessor Ghosh and I have extensively addressed the debates over the exhaustion doctrine and cross-border trade in our recent book, Exhausting Intellectual Property Rights: A Comparative Law and Policy Analysis.9 The surge in global trade over the past century has heightened these debates, driven primarily by the concerns\n\n5See, e.g., Ghosh and Calboli (2018), pp. 22–40. 6See Kohler (1900), p. 452. An English translation of Josef Kohler’s passages on exhaustion can be found in Heath (2014a), p. 419, 424. 7With the exception of the transfer of digital goods and self-replicating technologies—two recent phenomena that have been addressed by courts in several jurisdictions. See, e.g., Capitol Records, LLC v. ReDigi Inc., 934 F. Supp. 2d 640 (S.D.N.Y 2013); Case C-128/11, UsedSoft GmbH v. Oracle Int’l Corp., 2012 E.C.R. I-00000; Bowman v. Monsanto Co., 133 S.Ct. 1761 (2013); Case No. C-428/09, Monsanto v. Cefetra, 2010 E.C.R. I-09961. 8Ghosh and Calboli (2018), pp. 41–64. 9Id.\n\nI. Calboli", "n_tokens": 315, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-43-0", "doc_id": "medicine_vaccine_book", "page": 43, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...", "n_tokens": 12, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-43-1", "doc_id": "medicine_vaccine_book", "page": 43, "text": "expressed against and in favor of the arbitrage of consumer goods from low-cost to high-cost jurisdictions.10 Although IP holders are interested in the benefits of free trade in reducing manufacturing costs and decreasing tariffs, quotas, and other trade restrictions, they generally oppose parallel imports because of the competition the imports create in the high cost domestic markets and the resulting loss of profits in those markets.11 On the other side, supporters of parallel imports, including this author, point specifically to the inconsistency of the international IP system, which seeks harmonizing the IP system to eliminate barriers to trade and facilitate the registration and enforcement of IP rights worldwide, yet does not equally harmonize the free movement of products across jurisdictions to the same—in essence allowing IP rights to possibly operate as an invisible barrier to otherwise legitimate trade.12 The issue of IP exhaustion is not addressed in any of the agreements administered by the World Intellectual Property Organization (WIPO). Exhaustion, or lack of agreement thereof, is mentioned explicitly only in Article 6 of the Agreement on Trade Related Aspects to Intellectual Property Right (TRIPS Agreement), adopted under the auspices of the Word Trade Organization (WTO). The provision famously states that “nothing in this Agreement shall be used to address the issue of the exhaustion of intellectual property rights.”13 Accordingly, the choice of exhaustion", "n_tokens": 278, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-43-2", "doc_id": "medicine_vaccine_book", "page": 43, "text": "regimes depends on national decisions about desirable economic outcomes based on specific economic and trade-related factors, the size of national markets, the level of development, and possibly the pressure exerted foreign governments. Essentially, cross-border trade remains a form of national strategy, which may or may not include economic integration, and in which nation states maintain their political indepen- dence, while economic agents are permitted to engage in trade crossing their respective countries.14", "n_tokens": 94, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-43-3", "doc_id": "medicine_vaccine_book", "page": 43, "text": "10Parallel imports can be divided into two specified categories: passive and active parallel imports. See Fink (2004), pp. 171–188. The first category relates to the situation in which third party importers purchase products in one country and sell them in another. The second identifies the case of a foreign licensee, or authorized distributor abroad, who sell into the national market of the IP holders without her consent. The latter case is less frequent and is often prohibited through specific clauses in licensing agreements. 11For an excellent review of the economic studies on parallel imports, see Maskus (2016), p. 106 [hereinafter Maskus, Economic Perspective]. See also Saggi (2013), p. 131; Valletti and Szymanski (2006), p. 499; Valletti (2006), p. 314; Chen and Maskus (2005), p. 1; Malueg and Schwartz (1994), p. 187. 12See Ghosh and Calboli (2018), pp. 41–64. See also Calboli (2002), p. 47 (advocating for a change to international exhaustion in the EU). 13Agreement on Trade-Related Aspects of Intellectual Property Rights, April 15, 1994, Marrakesh Agreement Establishing the World Trade Organization, Annex 1C, Legal Instrument—Result of the Uruguay Rounds Vol. 31, 33 I.L.M. 83, 1869 U.N.T.S. 299 (1994), art. 6 [hereinafter TRIPS]. On the drafting of Article 6 of TRIPS, see Jehoram (1999), pp. 495, 508 (noting that this provision represents a compromise between two opposite approaches: “[t]he US Proposal [to introduce its own national system,] national exhaustion[,] and the", "n_tokens": 394, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-43-4", "doc_id": "medicine_vaccine_book", "page": 43, "text": "[pleas of] developing countries . . . for the opposite,” international exhaustion). See also Yusuf (2016) p. 23, 26; Taubman et al. (2012), pp. 18–20; Verma (1998), pp. 534, 539. 14Ghosh and Calboli (2018), pp. 44–48.", "n_tokens": 77, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-43-5", "doc_id": "medicine_vaccine_book", "page": 43, "text": "35", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-44-0", "doc_id": "medicine_vaccine_book", "page": 44, "text": "36", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-44-1", "doc_id": "medicine_vaccine_book", "page": 44, "text": "As it is generally known, countries follow one of three systems: national, regional, or international exhaustion.15 Under the principle of national exhaustion, IP holders’ rights are exhausted after the first sale of a good or batch of goods, but only if this first sale has occurred in the national territory.16 This regime is the least friendly for international trade and permits IP holders to stop parallel imports at the border or legitimately seize products after importation as IP infringements, even though these are genuine goods.17 Instead, under the principle of regional exhaus- tion, a compromising solution between the international and regional exhaustion, the rights of IP holders are exhausted after the first sale of a good or batch of goods, but only if the sale has occurred in one of the member countries of a regional organiza- tion following this principle as a common rule for all members.18 Under this system, the import of products originating from third countries from outside the region remains unlawful and can be stopped as infringement.19 Finally, under the principle of international exhaustion, IP holders’ rights to control the further distribution of a good or batch of goods exhaust after the first sale of the goods regardless of the country where this first sale has occurred.20 Undoubtedly the friendliest approach for international trade, under this system parallel imports are considered lawful in the country of importation, even though the country from which the", "n_tokens": 285, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-44-2", "doc_id": "medicine_vaccine_book", "page": 44, "text": "goods are imported may well apply a different system, i.e. national or regional exhaustion.21", "n_tokens": 20, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-44-3", "doc_id": "medicine_vaccine_book", "page": 44, "text": "National exhaustion should be contrasted with regional exhaustion, the rule that is currently established in the European Union (EU as extended to the European Economic Area, EEA)22 and the Organization Africaine pour la Propriete Intellectuelle (OAPI).23 What contrasts regional from national exhaustion is that regional exhaustion stems from the economic union of regions, but not necessarily the political union. Still, the principle is often the product of courts, treaties, or legislation.24 In the EU, for example, much of the credit for the system’s develop- ment is due to the EU Commission and the Court of Justice of the EU (CJEU).25", "n_tokens": 136, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-44-4", "doc_id": "medicine_vaccine_book", "page": 44, "text": "15Id. at 10–11. 16See Rothchild (2016), p. 226. See also Ghosh and Calboli (2018), pp. 10–11. 17Ghosh and Calboli (2018), pp. 10–11. 18On the development of this principle in the EU, see Beier (1990), p. 131; Jehoram (1992), p. 622. 19See, e.g., Calboli (2002), p. 47 [hereinafter Calboli, Trademark Exhaustion in the EU] (discussing the debate on the geographical extent of trademark exhaustion in the EU); Shea (1995), p. 463. 20Ghosh and Calboli (2018), pp. 10–11. 21Id. 22For a review, see Calboli (2019a), p. 22 [hereinafter Calboli, Comparing IP Exhaustion]. 23See Accord portant révision de l'Accord de Bangui du 2 mars 1977 instituant une Organisation Africaine de la Propriété Intellectuelle (Bangui (République centrafricaine), le 24 février 1999) [hereinafter Bangui Agreement]. 24Ghosh and Calboli (2018), pp. 63–64. 25See Jehoram (1992), p. 622; see also Beier (1990), p. 131. For example, the role of the Court of Justice of the EU (CJEU) was crucial in clarifying and enforcing the rule of regional trademark exhaustion in the EU. See Case C-335/96, Silhouette Int’l Schimed Gmbh & Co. KG v. Hartlauer Handelsgesellschaft mbH, 30 I.I.C. 920 (1998); Case-173/98, Sebago, Inc. v. GB-Unic SA,\n\nI. Calboli", "n_tokens": 412, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-45-0", "doc_id": "medicine_vaccine_book", "page": 45, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nMoreover, economic integration within the regional area generally arises prior to the decision among member states to adopt the rule of regional exhaustion.26 It could be argued (and this author believes) that, in a harmonized international trade system, in which international organizations administer treaties, international exhaustion could be the logical step following from national and regional exhaustion. However, the TRIPS Agreement—and accordingly international trade construct supervised by the WTO—makes exhaustion a matter of territoriality and national choice.27", "n_tokens": 108, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-45-1", "doc_id": "medicine_vaccine_book", "page": 45, "text": "In our book, Professor Ghosh and I discuss at length the complex set of policy debates in this area.28 We also highlight how a meaningful assessment of exhaustion policy needs to take into consideration economic implications, possibly through empirical analysis of the relationships among exhaustion policy, international trade, and IP. In this respect, we refer to several economic studies analyzing the effects of importation on market prices, consumers, producers, and importers.29 parallel Through empirical studies, prominent economists found that in some instances, price differences are due to marketing decisions by IP holders.30 These decisions reflect the seeking of price differences across countries to attract licensees and distributors in various jurisdictions that can take advantage of market conditions. In this scenario, parallel importers seek to take advantage of arbitrage possibilities arising from the ability to buy products at a low price and sell them at a high price, depending on the legal regime.31 In other instances, however, price differences can arise from decisions in separate countries independent from the marketing decisions of the IP holders, for example because of higher product demand due to consumer tastes or regulatory differences that translate into higher or lower prices depending on the nature of the regulation.32 The latter consideration is relevant regarding the", "n_tokens": 245, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-45-2", "doc_id": "medicine_vaccine_book", "page": 45, "text": "2 C.M.L.R. 1317 (1999); Joined Cases C-414-416/99, Zino Davidoff SA v. A & G Imports Ltd., Levi Strauss & Co. v. Tesco Stores Ltd., and Levi Strauss & Co. v. Costco Wholesale UK Ltd., 2001 E.C.R. I-8691. 26The principle of free movement of goods, for example, predates the adoption of the principle of regional exhaustion in the EU and was already enshrined into the Treaty of Rome in 1957. See Consolidated Version of the Treaty on the Functioning of the European Union, Mar. 30, 2010, 2010 O.J. (C 83) [hereinafter TFEU] as amended following the entering into force of the Treaty of Lisbon on December 1, 2009. Treaty of Lisbon, Dec. 13, 2007, 2007 O.J. (C 306). Several decisions were issued by the CJEU regarding the free movement of goods and the exercise of IP rights, before the official adoption of the principle of regional exhaustion. See Joined Cases 56 & 58/64, Costen & Grunding v. EC Comm’n, 1966 E.C.R. 299; Case 24/67, Parke Davis v. Centrafarm, 1968 E.C.R. 55; Case 40/70, Sirena v. Eda, 1971 E.C.R. 69; Case15/74, Centrafarm v. Sterling Drugs, [1974] E.C.R. 1147; Case 187/80, Merck & Co. v. Stephar, [1981] E.C.R. 2063. See also Saggi (2014), p. 125. 27Ghosh and Calboli (2018), pp. 63–64. 28Id. at 41–64. 29See Ganslandt and Maskus (2008), pp. 267–268; Ganslandt and Maskus (2004), p. 1035 [here- inafter Ganslandt and Maskus (2004)]; Roy and Saggi (2012), p. 262. 30Ganslandt and Maskus (2004), p. 29. 31Id. 32Id. See also Ghosh and Calboli (2018), pp. 48–51.\n\n37", "n_tokens": 505, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-46-0", "doc_id": "medicine_vaccine_book", "page": 46, "text": "38\n\ndiscussion of parallel imports in pharmaceuticals, which are subject to non IP-related regulations and whose price is often negotiated by governments and not private economic agents.33", "n_tokens": 32, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-46-1", "doc_id": "medicine_vaccine_book", "page": 46, "text": "Overall, looking at the spectrum of national solutions adopted on exhaustion and the various interests at stake, two observations can be derived from the existing studies. First, it seems the price differences of parallel imported products can be a social benefit for importers and, in several instances, for the importing countries. This could also be the case for parallel imported pharmaceuticals.34 Price differences do matter for how national legal regimes on exhaustion are implemented both in a particular country or region—that is, whether a country chooses national, regional, or international exhaustion.35 This first observation has implications for the second, notably that parallel importation is largely the result of price arbitrage arising from differences in prices. Importers see a profit-making opportunity and respond by buying low(er) and selling high(er). Here again, as empirical studies indicate, IP holders can nonetheless respond strategically to these importers either by pre-empting importation before it occurs through contractual clauses they can enforce through litigation36 or marketing strategies—such as applying small differ- ences in product quality in different countries or appealing to national tastes with varied products. IP holders can also lobby for changes in national laws favoring national exhaustion. Because of various strategic behaviors, the analysis of exhaus- tion is complicated and the policy responses become more challenging, as one size does not", "n_tokens": 277, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-46-2", "doc_id": "medicine_vaccine_book", "page": 46, "text": "fit all. The approach under Article 6 of the TRIPS Agreement attempts to allows flexibility for individual national responses within this complexity.37 How- ever, as explained in the next Section, a system of international exhaustion does promote free trade. In turn, this can lead to access to lowered prices products, or access to products that would not be sold in certain countries altogether.38", "n_tokens": 77, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-46-3", "doc_id": "medicine_vaccine_book", "page": 46, "text": "33See discussion infra Part 2.2. 34Ghosh and Calboli (2018), p. 49. 35Id. 36Id., at 49–50. 37Id. at 63–64. See also Maskus (2016), p. 106; Chiappetta (2016), p. 125. 38For a relevant empirical study of the impact of parallel imports (although limited in geographical scope), see National Economic Research Associates, The Economic Consequences of the Choice of Regime in the Area of Trademarks: Final Report for DG XV of the European Commission 76-100 (1999). But see Kanavos et al. (2004) (finding neutral welfare effects as most of the benefits from producers went to the parallel importers and not to consumers). See also Kanavos and Costa-i-Font (2005), pp. 758, 772–775. A similar conclusion is supported by Ganslandt and Maskus (2004), p. 1035 (finding the actual cost savings were small in a study of Sweden because the wholesale price reductions were not passed on to hospitals and patients, instead the retailers and parallel importers made larger margins).\n\nI. Calboli", "n_tokens": 257, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-47-0", "doc_id": "medicine_vaccine_book", "page": 47, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\n2.2 Patent Exhaustion and the Debate on Parallel Trade\n\nof Pharmaceuticals\n\nUnlike most products, pharmaceuticals “are developed, approved, manufactured, traded, and used under complex and demanding regulatory schemes.”39 For strictly regulated markets such as the U.S. or the EU, these regulatory schemes apply all the way from the time of production of the active pharmaceutical ingredients.40 Still, in all countries today, also developing countries, regulators must issue an official in the market.41 This marketing approval before the pharmaceuticals are put approval may vary in standards for “new” pharmaceuticals and “generic” versions of previously approved pharmaceuticals.42 For new medicines, elaborate lists of documents, including clinical trials and manufacturing, are necessary, while appli- cants for generics need to present details of the “bioequivalence” of the compound and manufacturing. Additionally, importers and distributors of pharmaceuticals are generally subject to import regulations and procedures for product recalling and other safety requirements.43", "n_tokens": 208, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-47-1", "doc_id": "medicine_vaccine_book", "page": 47, "text": "It is old news that bringing a new medicine to market is a costly and lengthy processes. On average, a successful drug costs over $1 billion to develop, and only one in several thousand compounds reaches the final approval stage.44 Since it is relatively uncomplicated and inexpensive to copy the molecules of a new drug, patents are a fundamental part of the industry for the exclusive rights granted through patents. One of the main factors for the industry to obtain the maximum profitability is also the possibility to sell the medicines at differentiated prices across different countries. However, price setting for pharmaceuticals does not depend entirely on the industry international pricing strategy. Instead, many national governments control the prices pharmaceuticals are sold at nationally and later control these prices within hospitals, pharmacies, and other distributors.45 Because of these negotiations, in countries offering national healthcare schemes, prescription medications are considerably less expensive than in other countries, while pricing of over the counter medications are left more to the market rules.46 In some instances, national compe- tition authorities have also determined when pricing was “excessive.”47 As noted before, this complex regulatory ecosystem makes it even more important, from the", "n_tokens": 237, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-47-2", "doc_id": "medicine_vaccine_book", "page": 47, "text": "39Abbott (2016), p. 145. 40Id. at 148–149. 41Id. 42Id. For the process of developing generics, see the contributions in Shargel and Kanfer (2014). 43Abbott (2016), pp. 149–150. 44The Drug Development Process, United States Food and Drug Administration, https://www.fda. gov/patients/learn-about-drug-and-device-approvals/drug-development-process. 45Abbott (2016), p. 150; Wasserman Rajec (2016), pp. 271, 283; Grabowski (2002), p. 533, 535. 46Abbott (2016), p. 150. 47See Abbott (2014), pp. 78–79.\n\n39", "n_tokens": 173, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-48-0", "doc_id": "medicine_vaccine_book", "page": 48, "text": "40\n\npharmaceutical industry’s viewpoint, that producers are able to prevent parallel trade from lower priced into higher priced markers.48\n\nA rule of national patent exhaustion is the most effective rule to facilitate national price discrimination and block parallel imports of pharmaceuticals on the basis of national patent enforcement.49 Representatives of the industry strongly support this rule. To justify their support, they have argued that price discrimination is advanta- geous not only for pharmaceutical producers, but also for developing countries, as this rule allows producers to set higher prices in more affluent markets while lowering prices in less affluent ones. This position has been supported by several economists.50 Supporters of this view have argued that parallel imports could lead to a price increase, and not a price reduction, in lower priced markets (and possibly to a reduction of the supply of pharmaceuticals altogether) precisely to prevent possible trade diversion by parallel importers of pharmaceuticals first sold in these markets.51 The industry also likes to point to the losses that parallel imports can bring to pharmaceutical companies and the fact that these losses would inevitably lead to less investments in R&D with consequential damage for pharmaceutical innova- tion.52 The argument has been made that parallel imports also harbour counterfeited products, which are certainly a growing threat for public health, especially in developed countries.53", "n_tokens": 269, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-48-1", "doc_id": "medicine_vaccine_book", "page": 48, "text": "These positions have been largely rebutted, however, by proponents of interna- tional patent exhaustion and convincingly.54 Supporters of international exhaustion have highlighted that it is difficult to assess whether price discrimination effectively benefits low income countries since many drugs are not sold at all in these coun- tries55 or they are sold for a small section of the affluent population at the same price as in higher-priced markets. Simply put, the assertions of the industry in this respect are speculative, as there are no data comparing the prices of the same pharmaceu- ticals in developed and developing countries, on a large scale and for a considerable number of products. Similarly, it has been correctly stressed that the industry has not presented compelling evidence that it would suffer severe losses and, in turn, these in R&D. Instead, supporters of international losses would affect reinvestment the industry spends large sums on the advertising and exhaustion noted that", "n_tokens": 201, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-48-2", "doc_id": "medicine_vaccine_book", "page": 48, "text": "48See Bale Jr (1999), p. 637 (arguing for the pharmaceutical industry). 49See supra Sect. 2.1. 50See Bale Jr (1999), p. 648 (noting that “[t]he threat of parallel trade takes away any incentive of vaccine and pharmaceutical patent holders to make significant concessions to poorer countries”). See also Varian (1985), p. 870; see also Schwartz (1990), p. 1259; Singham (2000), pp. 363, 407. 51Bale Jr (1999), p. 637. 52Id. See also Danzon (1998), p. 293. 53See, e.g., Delepierre et al. (2012), p. 247; Kelesidis et al. (2007), p. 214; Harper and Gellie (2006). 54See, e.g. Abbott (2007) (providing of a detailed and very convincing rebuke to the various arguments called by the pharmaceutical industry in favour of national exhaustion and price discrimination) [hereinafter Abbott, Economic and Social Welfare]. See also Owoeye (2015), p. 359; Kumar Rai and Jagannathan (2012), p. 53. 55Abbott (2007), p. 8.\n\nI. Calboli", "n_tokens": 291, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-49-0", "doc_id": "medicine_vaccine_book", "page": 49, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\npromotion of “lifestyle” (highly profitable) drugs rather than reinvesting all their profits in R&D.56 The argument about fake medicines is increasingly important as the size of counterfeited medicines in developing countries has become a true issue.57 This argument is not directly related to parallel imports, however, and again no evidence has been brought that parallel importers—who are subject to strict import controls and regulations no less than other imported medicines—are necessarily linked to the increase of counterfeited medical products in national markets.58", "n_tokens": 123, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-49-1", "doc_id": "medicine_vaccine_book", "page": 49, "text": "Accordingly, despite the pressure against parallel imports on the part of the industry, it cannot be disputed that parallel imports of pharmaceuticals can have beneficial effects for importing countries in terms of prices and access to pharma- ceuticals. In particular, imports of lower priced pharmaceuticals can increase access to medicines and, in turn, assist both patients and national governments in saving costs, as several pharmaceuticals are provided through publicly funded health pro- grams.59 Certainly, for this advantage to be true, the cost savings from the lower point price of the medicines should be shared between importers, retailers, hospitals, and ultimately patients and cannot be pocked only by the importers and the distrib- utors.60 In this respect, the role of national governments remains crucial, as govern- ments retain regulatory control on the importation of paralleled imported pharmaceuticals. Governments should (and generally do) exercise price control for these pharmaceuticals in order to impose that importers share the savings obtained through the arbitrage of the pharmaceuticals across different national markets.61 It is individual countries—above all developing countries and thus advisable that LDCs—use the flexibility provided under Article 6 of the TRIPS Agreement and practice the type of domestic exhaustion that best suits national needs in terms of access to pharmaceuticals, thus international exhaustion.62", "n_tokens": 271, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-49-2", "doc_id": "medicine_vaccine_book", "page": 49, "text": "Opponents of parallel imports tried to argue soon after the adoption of the TRIPS Agreement that Article 28 grants patent holders the right to “prevent third parties from making, using, offering for sale, selling or importing” a product and thus it\n\n56Id., at 8-9 (noting that “[this argument is based on the premise that higher levels of income will lead to increased investments in R&D ... [but] originator companies on average invest about 15% of their gross income on R&D.]” Instead, it is noted that “[t]he industry spends a substantially higher percentage of income on advertising, promotion and administration. Much of the advertising and promotion costs are spent on “lifestyle” drugs such as Viagra. Considerable R&D spending is directed to lifestyle products and minor variations on existing therapies (so-called “me too” drugs).”). 57United Nations Interregional Crime and Justice Research Institute, Counterfeit Medicines and Organised Crime (2012). 58Abbott (2007), pp. 9–10. 59See Ho (2011), p. 91. 60But see Kanavos and Costa-i-Font (2005), pp. 772–775; Ganslandt and Maskus (2004), p. 1035. 61Abbott (2007), pp. 9–10. 62See Musungu and Cecilia (2006).\n\n41", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-50-0", "doc_id": "medicine_vaccine_book", "page": 50, "text": "42\n\nlimits the application of Article 6.63 This argument was rebuked, however, and a footnote in Article 28 confirms explicitly that the provision of Article 28 is subject to Article 6.64 This point was further addressed by the Declaration on the TRIPS Agreement and Public Health at the WTO Ministerial Conference held in Doha in 2001.65 The Doha Declaration focused on accessed to health and reinforced the right of WTO members to take measures to protect public health, including issuing compulsory licenses. In particular, paragraph 5(d) of the Doha Declaration clarified that countries can adopt international exhaustion to allow the parallel importation of lower-priced medicines for public health purposes under Article 6 of the TRIPS Agreement and this cannot be challenged under the WTO dispute settlement system.66", "n_tokens": 158, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-50-1", "doc_id": "medicine_vaccine_book", "page": 50, "text": "One controversial point remained after the Doha Declaration: whether pharma- ceuticals produced under compulsory licences could be imported into foreign coun- tries. These imports may represent the only option for access to medicines for some of the LDCs, which cannot effectively avail themselves of compulsory licensing for lack of manufacturing capacity. In fact, most LDCs are still not obliged to implement pharmaceutical patents and clinical trial data protection, as the TRIPS Council agreed in 2015 to extend the waiver, which was set to expire on January 1, 2016, until 2033.67 Hence, manufacturing capacity is the highest barrier in these countries. However, Article 31(f) of the TRIPS Agreement does not explicitly allow parallel imports of compulsory licensed medicines. Instead, the provision allows compulsory", "n_tokens": 155, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-50-2", "doc_id": "medicine_vaccine_book", "page": 50, "text": "63TRIPS, supra note 13, Art. 28. See Bale Jr (1999), pp. 641–648. See also Kodak SA v Jumbo- Markt AG, 4C. 24/1999/rnd, Dec. 7, 1999 (the Swiss Federal Supreme Court stated that: “Article 28 of the TRIPS Agreement gives the patent holder the right to prevent third parties from selling and importing patented products”.). 64TRIPS, supra note 13, Art. 28 fn 6 (“this right [i.e. the right of importation], like all other rights conferred under this Agreement in respect of the use, sale, importation or other distribution of goods, is subject to the provisions of Article 6.”). De Carvalho (2010), p. 173. 65See Abbott (2002), p. 469. For a detailed review of the TRIPS Agreement and public health, see Musungu (2016), p. 489. See also t’Hoen (2002), p. 27; Coriat and Orsenigo (2014); Velásquez et al. (2020). 66Declaration on the TRIPS Agreement and Public Health (14 November 2001), Doc. WT/ MIN (01)/DEC/2 (20 Nov. 2001) (“5(d)The effect of the provisions in the TRIPS Agreement that are relevant to the exhaustion of intellectual property rights is to leave each Member free to establish its own regime for such exhaustion without challenge, subject to the MFN and national treatment provisions of Articles 3 and 4.”). 67Council for TRIPS, Extension of the Transitional Period Under Article 66.1 of the TRIPS Agreement for Least Developed Country Members for Certain Obligations With Respect to Pharmaceutical Products, IP/C/73 (Nov. 6, 2015). See also Daniel Benoliel & Timothy John Chirwa, The", "n_tokens": 409, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-50-3", "doc_id": "medicine_vaccine_book", "page": 50, "text": "Impact of Pharmaceutical Patents on Health Expenditures in Least-Developed Countries, unpublished paper available at http://law.haifa.ac.il/images/Publications/ BenolielChirwa.pdf (comparing LDCs in OAPI with other LDCs and noting that patents are not a primary obstacle to access to medicines in LDCs, as opposed to several other factors such as: rational selection and use of drugs, affordable prices, unsustainable and inadequate funding, and Reliable health and supply systems).", "n_tokens": 105, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-50-4", "doc_id": "medicine_vaccine_book", "page": 50, "text": "I. Calboli", "n_tokens": 5, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-51-0", "doc_id": "medicine_vaccine_book", "page": 51, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nlicencing to be granted “predominantly” for the domestic market.68 Finally, in 2003, WTO members agreed to facilitate LDCs to import medicines made under compul- sory licensing if they are unable to manufacture the medicines themselves. This resulted in the adoption of Article 31bis of the TRIPS Agreement in 2005.69 The provision became effective in January 2017, after a sufficient number of countries ratified the provision,70 even though the provision has not been invoked by any LDCs in the context of parallel imports of compulsory licensed pharmaceuticals to date.\n\n3 National Solutions to Patent Exhaustion and Parallel", "n_tokens": 138, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-51-1", "doc_id": "medicine_vaccine_book", "page": 51, "text": "Trade of Pharmaceuticals\n\nBecause of the flexibility of Article 6 of the TRIPS Agreement, countries worldwide can decide their national policy on patent exhaustion autonomously between national, international, or regional exhaustion. Some countries also apply a differ- entiated approach to the exhaustion of pharmaceuticals. In the following Section, I review the domestic policies of selected countries in various continents.71 This information is necessarily limited due to the impossibility to comprehensively address all countries’ policies in this Chapter. In addition, as mentioned above, the analysis does not extend to the national requirements each country applies regarding the regulatory schemes for the marketing approval and import authorization for the parallel imports of pharmaceuticals, which again remain a fundamental aspect of imports of medicines (both by originator companies and parallel importers).", "n_tokens": 155, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-51-2", "doc_id": "medicine_vaccine_book", "page": 51, "text": "3.1 Selected Jurisdictions in Asia\n\nSeveral countries in Asia72 follow a regime of international exhaustion related to patent rights. This choice can be explained by the fact that several countries in Asia are still developing countries or LDCs. For example, the two largest countries in Asia, India and China, both practice international patent exhaustion. India’s\n\n68TRIPS Agreement, supra note 13, Art. 31(f). 69Id., Art. 31bis. See Abbott (2005), p. 317; Abbott and Reichman (2007), p. 921. 70Zaheer Abbas and Riaz (2017), p. 451. 71For detailed overview in this respect, see World Intellectual Property Organization, Standard Committee on Patents Electronic Forum, Questionnaire on Exceptions and Limitations of Patent Rights, the database administered by the WIPO’s Standing Committee on Patents https://www. wipo.int/scp/en/exceptions/ [hereinafter WIPO, Questionnaire on Patent Exceptions]. 72Even if partially outdate now, a relevant resource for Asia is still Parallel Imports in Asia (Heath 2004).\n\n43", "n_tokens": 237, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-52-0", "doc_id": "medicine_vaccine_book", "page": 52, "text": "44\n\napproach is based on Section 107A of the Indian Patent Act, as amended in 2002, which provides that “[f]or the purpose of this Act, (b) importation of patented products by any person from a person who is duly authorized under the law to produce and sell or distribute the product, shall not be considered as an infringement of patent rights”.73 In China, Article 69 of the Chinese Patent Law provides that the following shall not be deemed to be patent right infringement “(1) after a patented product or a product directly obtained by using the patented method is sold by the patentee or sold by any unit or individual with the permission of the patentee, any other person uses, offers to sell, sells or imports that product.”74 Previously, under the rule of the Patent Law of China of 1985, the applicable rule was national patent exhaustion. This was changed, however, with the entry into force of new 2008 Patent Law, which provides for international patent exhaustion.75", "n_tokens": 202, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-52-1", "doc_id": "medicine_vaccine_book", "page": 52, "text": "Out of the ten members of the Association of South East Asian Nations (ASEAN),76 three countries also practice international exhaustion. In particular, Cambodia follows international patent exhaustion under its Law on the Patents, Utility Model Certificates and Industrial Designs,77 even though Cambodia does not currently provide patent protection for pharmaceuticals under the TRIPS Council’s waiver for LDCs. International exhaustion is also adopted under the Patents Act of Malaysia78 and the Intellectual Property Law of Vietnam.79 Other ASEAN coun- tries, such as Brunei,80 Lao PDR81 (also an LDC), and Thailand82 do not have a specific rule on patent exhaustion. In these countries, whether the parallel importa- tion of genuine products sold overseas with the proprietors’ consent constituted infringement may depend on the contents of the contracts signed between the parties concerned. In Myanmar, a new Patent Law has been adopted in 2019, which is currently pending for approval, even though it remains unclear how the principle of", "n_tokens": 206, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-52-2", "doc_id": "medicine_vaccine_book", "page": 52, "text": "73Patents (Amendment) Act, 2002, No. 38, Acts of Parliament, 2002 (India). See also Ghosh and Calboli (2018), pp. 108–109; Pai (2016), pp. 324, 327; Gopalakrishnan and Agitha (2012), p. 229; Basheer and Kochupillai (2009), p. 63. 74Patent Law of the People’s Republic of China (promulgated by the Standing Comm. Nat’l People’s Cong., Dec. 27, 2008, effective Oct. 1, 2009) CN028 (China). See also Yu (2004), pp. 25–38. 75See Yu and Yin (2016), pp. 308, 311. See also Ghosh and Calboli (2018), p. 109. 76For a discussion on ASEAN, including the principle of exhaustion and free movement, seeCalboli (2019b), pp. 363–391. 77Law on Patents, Utility Models and Industrial Designs, Art. 44 (Cambodia). 78Patents Act 1983, as amended by the Patents (Amendment) Act 2006, § 58A (Malay.). 79Law on Intellectual Property (No. 50/2005/QH11 of Nov. 29, 2005), art. 125(2)(b) (Viet.). 80Constitution of Brunei Darussalam, Patents Order, Art. 83(3) (2011) (Brunei). 81Lao People’s Democratic Republic Intellectual Property Laws (Law No. 01/NA of 20 Dec. 2011) (Lao PDR) [hereinafter Lao PDR Law]. 82Patent Act B.E. 2522, as amended by the Patent Act (No. 2) B.E. 2535 and the Patent Act (No. 3) B.E. 2542 (Thai.).\n\nI. Calboli", "n_tokens": 412, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-53-0", "doc_id": "medicine_vaccine_book", "page": 53, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\npatent exhaustion is addressed in the new law. Myanmar can also be exempted from implementing patent protection for pharmaceuticals until 2033 (as an LDC).83", "n_tokens": 44, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-53-1", "doc_id": "medicine_vaccine_book", "page": 53, "text": "Other Asian countries follow a hybrid system. In particular, the 2016 Patent Law of Indonesia84 grants patent owners the exclusive right to prohibit other parties from “importing” the patented products or the products derived from the patented prod- ucts.85 Yet, this provision does not apply, explicitly, to the imports of patented pharmaceuticals that have been lawfully marketed outside Indonesia and have been imported into Indonesia by third parties.86 Similarly, the Philippine Intellectual Property Code87 includes the right to oppose unauthorized imports,88 but again this provision does not apply to the imports of pharmaceuticals.89 Singapore also follows a hybrid approach, but opposite to the approach adopted by Indonesia and the Philippines. Notably, Singapore does not allow imports of patented pharmaceu- ticals if the products have not been previously sold or distributed in Singapore by the patent owner or with her consent.90 After the products have been marketed in Singapore by the originator companies, imports are theoretically allowed. However, also after the first released in the Singaporean market by the patent holders, imports can still be blocked when the pharmaceuticals have been parallel imported because of a breach in the contract between the patent holder and her licensees, including outside Singapore.91 As parallel imports are often the results of genuine products diverted from their original distributors into the distribution channels of parallel importers,", "n_tokens": 270, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-53-2", "doc_id": "medicine_vaccine_book", "page": 53, "text": "this principle effectively nullifies the possibility to parallel imports pharmaceuticals into Singapore. This principle was introduced after the US-Singapore trade agreement. On the other side, Singapore practices interna- tional patent exhaustion for all other products.92", "n_tokens": 48, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-53-3", "doc_id": "medicine_vaccine_book", "page": 53, "text": "then parallel\n\nThe remaining largest economies in Asia, Japan and Korea, do not have a specific statutory policy on patent exhaustion, and their respective case law has led to diverging position. In Japan, courts have largely recognized international patent exhaustion.93 In particular, the Supreme Court stated that enforcing Japanese patents would not be consistent with international trade, even though the Court did not\n\n83At this time, the author could not locate the pending draft of the 2019 Patent Law (Myanmar), as the draft is not published not available in any known database. 84Law of the Republic of Indonesia No. 13 of July 28, 2016, on Patents (Indon). 85Id. at art. 19(1)-(2) and art. 160. 86Id. at art. 167. This exception is based directly on the need to “to ensure a reasonable price and satisfy the justice of a pharmaceutical product is necessary for human health.” Id. at Explanation to art. 167. 87Intellectual Property Code, Rep. Act 8293, as amended by Rep. Act 10372 (Phil). 88Id. at § 72. 89Id. 90Patents Act (Ch. 221, 2005 Rev. Ed.) § 66(3)(a) (Sing.). 91Id. at §§ 66(3)(b) & (c). 92Id. at § 66(2)(g). 93Heath (2004), p. 51.\n\n45", "n_tokens": 309, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-54-0", "doc_id": "medicine_vaccine_book", "page": 54, "text": "46\n\ndirectly acknowledge that Japan practices international exhaustion. The Court rec- ognized the patent owner could prohibit the importation of goods through contrac- tual restrictions and by indicating on the product that the patented item is not intended for sale in Japan.94 In Korea, the Patent Act also does not elaborate on the issue of patent exhaustion and judicial decisions led to an opposite interpreta- tion—national exhaustion. This position makes of Korea one of the few Asian countries choosing national patent exhaustion and it probably consistent with the level of technological development of the country95 (even though the same could be said for Japan). However, in 1981, precisely in a case related to the imports of Italian pharmaceuticals from Switzerland into Korea, the Seoul District Court said the foreign sale had also exhausted the rights in Korea.96 Still, the court fell short of explaining the reasoning for the decision in that case and no later case confirmed nor denied this position. It thus remains unclear if this decision changed the general view in favor of national patent exhaustion in Korea, or if it could be supported that also Korea decided through caselaw to follow a differentiated regime for the exhaustion of pharmaceuticals (international) versus other patented products (national).97", "n_tokens": 247, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-54-1", "doc_id": "medicine_vaccine_book", "page": 54, "text": "3.2 Canada, United States, Australia, and New Zealand\n\nToday, international patent exhaustion is the system of choice also in Canada and the U.S., based on judicial precedents.98 Specifically in Canada, in the 1998 decision in Eli Lilly & Co v Novopharm Ltd., the Supreme Court confirmed that, when a patentee sells a patented product, the rights of the products exhaust as long as the seller did not impose any restrictions on the subsequent distribution.99 Thus, the key inquiry in Canada is today not where the goods were first sold, whether in or outside Canada, but whether the products were sold with or without restrictions.100\n\nThe U.S. follows a very similar position. Notably, the traditional interpretation on patent exhaustion was recently changed in favor of international exhaustion by the 2017 Supreme Court decision Impression Products v. Lexmark.101 Like in several other countries, the U.S. Patent Act does not elaborate on the geographical extent of the exhaustion of a patented product, or a product embodying patented process, after\n\n94Id. at. 52–58. 95Byung-Il (2004), p. 73. 96Id. at 76–77 (citing the decision of the Seoul District Court in the case Ildong Pharmacie v. Farmatalia Carlo Erba S.p.A., Mar. 14, 1981). 97Id. at 77. 98See Calboli, Comparing IP Exhaustion, supra note 22, at 32. 99Eli Lilly & Co. v. Novopharm Ltd., [1998] 2 S.C.R. 129. 100Id. 101Impression Prods., Inc. v. Lexmark Int’l, Inc., 581 U.S. 1523 (2017). See Ghosh and Calboli (2018), pp. 88–102.", "n_tokens": 391, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-54-2", "doc_id": "medicine_vaccine_book", "page": 54, "text": "I. Calboli", "n_tokens": 5, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-55-0", "doc_id": "medicine_vaccine_book", "page": 55, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nthe first sale of the products. In the past decades, several decisions by U.S. courts adopted the position that the sale of an article in a foreign country does not exhaust the U.S. patent.102 In its February 2016 decision in the Lexmark case, the U.S. Court of Appeals for the Federal Circuit repeated this position. However, to the disbelief of many in the U.S., the Supreme Court reversed and stated that the first sale of products anywhere in the world exhausted the rights also in the U.S. Still, the Court did not exclude that contractual restrictions could prevent the import of gray market goods after the decision in Lexmark.103 Thus, also in the U.S., the key inquiry may still be whether the products were sold with or without restrictions. Moreover, regardless of the change in national policy, the imports of pharmaceuticals remain subjects to the US regulatory schemes and the impact of Lexmark on these imports is, in practice, non-existing.", "n_tokens": 216, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-55-1", "doc_id": "medicine_vaccine_book", "page": 55, "text": "On the other side, Australia follows a less trade friendly national policy and favors national patent exhaustion. Also in Australia, however, the Patents Act does not specifically address the issue.104 Notably, the Patent Act states that patent holders have exclusive rights to exploit their inventions in Australia.105 The defini- tion of “exploitation” is provided in the Patent Act and includes importation, similar to the TRIPS Agreement and other national laws.106 This leads to the interpretation that Australia practices national exhaustion. Patent law in Australia is also constrained by the obligations under the Australia–United States trade agreement, whose Article 17.9.4 states that “Each Party shall provide that the exclusive right of the patent owner to prevent importation of a patented product, or a product that results from a patented process, without the consent of the patent owner shall not be limited by the sale or distribution of that product outside its territory, at least where the patentee has placed restrictions on importation by contract or other means.”107 Similarly to Australia, also New Zealand does not allow parallel importation of patented products.108 Here again, we have a hybrid system, however, as the Crown has the authority to order parallel importation of pharmaceuticals under the Medi- cines Act of 1981, notwithstanding the Patents Act.109 Of course, provided that the products are in line with the requirements imposed under the country’s regulatory", "n_tokens": 286, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-55-2", "doc_id": "medicine_vaccine_book", "page": 55, "text": "schemes and import authorizations.", "n_tokens": 6, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-55-3", "doc_id": "medicine_vaccine_book", "page": 55, "text": "102See Ghosh and Calboli (2018), at 88-102 (citing Boesch v. Graff, 133 U.S. 697 (1890); Jazz Int’l Trade Comm’n, 264 F.3d 1094 (Fed. Cir. 2001); Lexmark Int'l, Photo Corp. v. Inc. v. Impression Prods. Inc., 816 F.3d 721, 771 (Fed. Cir. 2016)). 103Impression Products, Inc. v. Lexmark Int’l, Inc., 581 U.S. 1523 (2017). 104See Ghosh and Calboli (2018), pp. 107–108. 105Patents Act 1990 s 13 (Austl.). 106Id. at Schedule 1 (Austl.). 107Free Trade Agreement, U.S.-Austl., May 18, 2004, art. 17.9.4. 108See Ghosh and Calboli (2018), pp. 107–108; Susy Frankel, Test Tubes for Global Intellectual Property Issues: Small Market Economies 178 (2015). 109Frankel, supra note 108, at 178 (citing Section 32A of the Medicines Act 1981, introduced by the Medicines Amendment Act 1989). See also Patents Act, pt 2 (N.Z.).\n\n47", "n_tokens": 292, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-56-0", "doc_id": "medicine_vaccine_book", "page": 56, "text": "48\n\n3.3 Selected Jurisdictions in Latin America\n\nLike in Asia, most countries in Latin America follow the principle of international patent exhaustion. There are important exceptions, however, to this rule.\n\nThe first exception is Mexico, which is surprising as both its partner members in the North American Free Trade Agreement (NAFTA), Canada and the U.S., follow now international patent exhaustion. Instead, Mexico practices national exhaustion. Also, in Mexico, no specific language related to the exhaustion of patent rights is found under the Mexican law. The Mexican Industrial Property Law clarifies, however, that the rights conferred by a patent cannot be asserted against “any person who markets, acquires or uses the patented product or the product obtained by means of the patented process, after said product has been lawfully placed on the mar- ket.”110 In the absence of a provision stating the opposite, the majoritarian interpre- tation of the wording “the market” is that it only includes “national market.”111", "n_tokens": 212, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-56-1", "doc_id": "medicine_vaccine_book", "page": 56, "text": "National patent exhaustion is also the system adopted in Brazil. This position is particularly perplexing in light of Brazil’s role in the parallel importation of phar- maceuticals in the 1990s. Notably, Article 43 of Law 9.279 of 1996 provides national regarding products “manufactured in accordance with a process or product patent that has been placed on the internal market directly by the patent holder or with his consent.”112 However, under Article 68(4) of the same law, if the exploitation of the patent (and use of the trademark) is made through importation of the product—that is, in the case where the products are not manufactured in Brazil, third parties are allowed to import these products after they have put them into the “market”, which is interpreted in this instance as anywhere in the world.113 Accordingly, in this case, parallel imports are admitted in Brazil.114\n\nexhaustion for patent\n\nand trademark rights\n\nOn the other side, Chile follows a system of international patent exhaustion as per Article 49(5) of Law No. 19.039, according to which a “patent shall not confer the right to prevent third parties from marketing the patent protected product, which such parties have acquired lawfully after that product has been lawfully introduced into the market of any country by the right owner or by a third party with the owner’s", "n_tokens": 276, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-56-2", "doc_id": "medicine_vaccine_book", "page": 56, "text": "110Mexican Industrial Property Law, art. 22. Ley de la Propiedad Industrial, Diario Oficial de la Federación [D.O.F.] 27-06-1991, amended by D.O.F. 02-08-1994 (Mex.). 111See Correa and Correa (2016), p. 206. 112Lei No. 9.279, de 14 de Mayo de 1996, art. 43(4) (Braz.) [hereinafter Brazilian IP Law]. 113Id., at art. 68(4). See also Correa and Correa (2016), p. 206. 114This provision finds its origin of the requirement of “local manufacture obligation” for patent holders that was originally provided under Brazilian law. As this requirement could have been challenged as incompatible with Article 27(1) of the TRIPS Agreement, the 1996 Law abolished the rule. Yet, Article 68(1), under the rubric “Compulsory Licensing,” provides that the following can grant a decision of issuing compulsory licensing: “I. failure to work the subject matter of a patent on the territory of Brazil, failure to manufacture or incomplete manufacture of the product or failure to completely use a patented process, except for failure to work due to lack of economic viability, in which case importing shall be admitted. Brazilian IP Law, supra note 112, at art. 68(1).\n\nI. Calboli", "n_tokens": 311, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-57-0", "doc_id": "medicine_vaccine_book", "page": 57, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nconsent.”115 As reported, legislative debates found this solution necessary “to provide a balance between the ... right holders and ... the citizens”116 Argentina also adopts international exhaustion, according to Article 36(c) of Law No. 24.481 (consolidated text, 1996) on Patents and Utility Models and subsequent amendments “The right conferred by a patent shall not have any effect against: (c) Anyone acquiring, using, importing or in any way marketing the patented product or the product obtained by means of the patented process, after said product has been lawfully placed on the market in any country.”117\n\nThe four members of the Andean Community—Bolivia, Ecuador, Colombia, and Peru—also practice international exhaustion.118 Article 54 of Decision 486 of the Commission of the Andean Community establishes that the patent shall not confer the right “to proceed against a third party making commercial use of a product protected by a patent once that product has been introduced into the commerce of any country by the owner or another person authorized by the right holder or with economic ties to that patent owner.”119 Notwithstanding, the imports of these products can be further restricted by national laws providing for the import autho- rizations and other formalities.", "n_tokens": 270, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-57-1", "doc_id": "medicine_vaccine_book", "page": 57, "text": "3.4 European Union and Switzerland\n\nFree movement of goods, including of pharmaceuticals, is allowed in the EU/EEA under the rule of regional exhaustion. Articles 34 and 36 of the Treaty on the the European Union (TFEU)—originally then the Treaty Functioning of Establishing the European Economic Community (EEC Treaty)—are the applicable provisions to the exhaustion of patented goods within the EU. Notably, the distri- bution of a patented good by the consent of the patent owner into the market of any EU Member State exhausts the rights of distribution within the EU.120 Exhaustion does not apply, however, if the product is a patented pharmaceutical manufactured", "n_tokens": 134, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-57-2", "doc_id": "medicine_vaccine_book", "page": 57, "text": "115Law No. 19.039 on Industrial Property of 1991, art. 49(5) (Chile). This provision has not been modified in the various amendment and updates of Law 19.039 that have been adopted since 1991. 116World Intellectual Property Organization, Standard Committee on Patents Electronic Forum, Questionnaire on Exceptions and Limitations of Patent Rights, Chile, Exhaustion of Rights, https:// www.wipo.int/scp/en/exceptions/replies/chile.html#Q8. 117Law No. 24.481, Oct. 23, 1995, art. 36(c), [LV-C] A.D.L.A. 2948 (as amended by Law No. 24.572 [LV-E] A.D.L.A. 5892 (Arg.) [hereinafter Argentine Patent Law]. See also Correa and Correa (2016), p. 202. 118Decision No. 486 Establishing the Common Industrial Property Regime, Sept. 14, 2000, art. 54, WIPO CAN012, https://wipolex.wipo.int/en/text/223717 (Andean Community). 119Id. 120See Stothers (2007); Case15/74, Centrafarm v. Sterling Drugs, [1974] E.C.R. 1147; Case 187/80, Merck & Co. v. Stephar, [1981] E.C.R. 2063.\n\n49", "n_tokens": 327, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-58-0", "doc_id": "medicine_vaccine_book", "page": 58, "text": "50\n\nfor the purpose of marketing approval rather than for commercialization.121 Articles 34 and 36 also apply regardless of possible contractual limitations against further distribution of patented products. In particular, these limitations may be in conflict with Article 34 if they restrict or prevent importation into and distribution in another Member State.\n\nAn additional exception to the principle of free movement is found in the Act of Accession 2003122 of new members from Eastern Europe, which provides that IP holders can rely on the “Specific Mechanism” and prevent the import and marketing of pharmaceuticals from new EU Member States into other EU Members States in which they have protection.123 The reason for this exception was because patent protection and supplementary protection certificate (SPC) for pharmaceuticals was implemented later in time in these countries and at the time of accessions, several drugs were patented in the Western EU Member States but could no longer be patented in these countries. The “Specific Mechanism” additionally provides importers should demonstrate to the authorities in charge of issuing the permission to import they have notified the patent or SPC holder no less than a month earlier.124 In 2005, the “Specific Mechanism” was later extended to Bulgaria and Romania, and in 2012 to Croatia.125", "n_tokens": 258, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-58-1", "doc_id": "medicine_vaccine_book", "page": 58, "text": "The only case in this area, Merck v. Sigma,126 confirmed nonetheless a pro-exhaustion stance by the CJEU’s interpretation of the provision. In particular, even though the Court accepted the Specific Mechanism provides for a specific derogation to the principle of free movement, it also stated that importers do not have “an obligation to obtain the express prior consent” from the rights holders.127 Instead, rights holders have one month to oppose the imports and if they do not “take advantage of that period,” importers “may legitimately apply to the competent authorities for authorisation to import the product and, where appropriate, import", "n_tokens": 139, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-58-2", "doc_id": "medicine_vaccine_book", "page": 58, "text": "121Case C-316/95, Generics v. Smith Kline & French Laboratories, [1997] E.C.R. I-3929. 122Act of Accession of Cyprus, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Malta, Poland, Slovenia and Slovakia, Apr. 16, 2003, 2003 O.J. (L236) 33 [hereinafter Specific Mecha- nism]. See Heath (2014b), p. 399; Stothers (2016), pp. 169, 178. 123Specific Mechanism, supra note 122. 124Id. Critically, in general, over this type of differentiated systems, see Jerome Reichman, Ruth Okediji, Ioannis Lianos, Robin Jacob, Christopher Stothers, The WTO Compatibility of a Differ- entiated International Exhaustion Regime Proposed by the Eurasian Economic Community, A Consultancy Report, Research Paper Series, Skolkovo-HSE International Laboratory for Law & Development (on file with author). 125Act of Accession of Bulgaria and Romania, 2005 O.J. (L157) 203, Annex V.1; Act of Accession of Croatia 2012 O.J. (L112) 21, Annex IV.1. 126Case C-539/13, Merck Canada Inc. v. Sigma Pharmaceuticals plc, [2015] R.P.C. 30. The importer provided advanced notification to Merck of its intention to import pharmaceuticals from Poland, where protection did not apply. Merck did not respond and the products were imported into the U.K. Merck objected and parallel imports were blocked. When Merck also sought damages, the issue was referred to the CJEU. See Stothers (2016), at 179. 127Case C-539/13, Merck Canada, ¶ 28.\n\nI. Calboli", "n_tokens": 401, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-59-0", "doc_id": "medicine_vaccine_book", "page": 59, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nand market it.”128 This should not be read as the rights holders have “forfeited the right to rely on the Specific Mechanism.”129 They simply cannot “obtain compen- sation for the loss” due to the imports “which he failed to oppose” in time,130 but remain “free to oppose future importation and marketing of the pharmaceutical product protected by the patent or SPC.”131", "n_tokens": 100, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-59-1", "doc_id": "medicine_vaccine_book", "page": 59, "text": "Not an EU Member State, Switzerland’s example is worth noting as part of the European region. Until 2008, Swiss law applied national exhaustion to patents. The rule was then changed in favour of regional patent exhaustion and Switzerland now practices regional exhaustion with the countries members of the EU/EEA.132 How- ever, pharmaceuticals are still subject to national patent exhaustion in Switzerland, and parallel imports of pharmaceuticals first put into the market in a foreign country, including in the EU/EEA, cannot enter into the country. To be precise, Article 9 (a) paragraph 5 indicates that the principle of regional exhaustion does not apply and the consent of the holder of the patent of a product “is reserved” in the instances in which the price the product “in Switzerland or in the country in which they are placed” has been “fixed by the state.”133 This principle applies directly to prescrip- tion pharmaceuticals and all the medicines that are subjected to price control by national government. However, in the law, this principle is not directly referred to pharmaceuticals, but to all patented products that could be subject to price control.", "n_tokens": 229, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-59-2", "doc_id": "medicine_vaccine_book", "page": 59, "text": "3.5 Selected Jurisdictions in Africa\n\nAccess to medicines is a priority for most countries in Africa, the continent with the largest number of LDCs worldwide,134 all of which are users of pharmaceuticals coming from foreign countries.135 National practice on patent exhaustion varies\n\n128Id. at ¶ 31. 129Id. at ¶ 32. 130Id. 131Id. 132Federal Act on Patents for Inventions (SR 232.14 LBI) art. 9a (inserted by No I of the Federal Act of June 22, 2007 (AS 2551 (2009); BBl 1 (2006)), as amended by No I of the Federal Act of Dec. 19, 2008, in force since July 1, 2009 (AS 2615 (2009); BBl 303 (2008)) (Switz.). 133Id. at art. 9a, ¶ 5 LBI (“Irrespective of the provisions of paragraphs 1–4, the consent of the proprietor of the patent for the placing on the market of patent-protected goods is reserved if their price in Switzerland or in the country in which they are placed on the market is fixed by the state.”). See also Kyle (2009), p. 339, 345 (noting that, on the other side, “Switzerland treats copyrights and trademarks as internationally exhausted.”). 134See United Nations, Committee for Development, List of Least Developed Countries, https:// (listing www.un.org/development/desa/dpad/wp-content/uploads/sites/45/publication/ldc_list.pdf the 47 countries currently categorized as LDCs). 135Vawda and Shozi (2020); dos Santos and Lowé Gnintedem (2018), pp. 592, 593–594; Ncube (2016), p. 110.\n\n51", "n_tokens": 389, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-60-0", "doc_id": "medicine_vaccine_book", "page": 60, "text": "52\n\nacross countries in the continent, however, with some countries practicing interna- tional exhaustion, while others national or regional exhaustion. The laws of several countries also remain silent on the issue.136\n\nFor example, the following countries do not seem to have a clear position on the issue as of today: Congo, Egypt, Nigeria, Swaziland, Angola, Lesotho, and Malawi.137 South Africa’s position is also unclear, even though several commenta- tors support it following international exhaustion. In the late 1990s, South Africa implemented regulations authorizing parallel importation of medicines protected by patents and trademarks,138 but the South African Patents Act remains unclear as to whether the doctrine of exhaustion of rights applies nationally or internationally.139 Well-known by experts in this area, South Africa wanted to authorize parallel importation of retroviral pharmaceuticals for AIDS in the 1990s.140 It was precisely in this occasion that patent holders argued that international exhaustion was pre- cluded by Article 28 of the TRIPS Agreement.141 The case was eventually dropped, but the ensuing criticism led to the adoption of the Doha Declaration.142", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-60-1", "doc_id": "medicine_vaccine_book", "page": 60, "text": "International patent exhaustion is instead directly adopted in the law of several countries in Africa. These countries include Ghana, which changed its previous regime of national patent exhaustion with the revision of the Patent Act in 2003, whose Section 11(4)(a) now states that “[t]he rights conferred under the patent shall not extend to acts in respect of articles which have been put on the market in any country by the owner of the patent or with the owner's consent.”143 Similarly, Article 43(1) of the 2012 Industrial Property Act of Namibia provides that “[t]he following acts do not constitute an infringement of the rights under a patent, namely: a) acts of importation of patented inventions which have been put on the market in any territory or country by the owner of the patent or with his or her authorization.”144 Kenya also explicitly permits the parallel imports of patented pharmaceuticals under the Industrial Property Act 2001, replacing the Industrial Property Act 1989, which prohibited parallel imports. Notably, Article 58(2) now recites, “[t]he rights under the patent shall not extend to acts in respect of articles which have been put on the market in Kenya or in any other country or imported into Kenya.”145 Additional", "n_tokens": 251, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-60-2", "doc_id": "medicine_vaccine_book", "page": 60, "text": "136Id. at 31–32. In general, see also McKeith (2013), p. 287. 137See WIPO, Questionnaire on Patent Exceptions (in which the respective countries may indicated that there is no clear national position of the issue). 138Abbott (2016), pp. 146–147. 139Id. 140See (Tayler 2004, p. 117). 141See supra Section 1.2. 142Id. 143Patents Act No. 657 (2003), § 11(4)(a) (Ghana). Vawda and Shozi (2020), p. 32. 144Industrial Property Act No. 1 (2012), § 42(1)(a) (Namibia). Vawda and Shozi (2020), p. 32. 145Industrial Property Act No. 3 (2001), § 58(2), as amended up to Act No. 11 (2017) (Kenya).\n\nI. Calboli", "n_tokens": 212, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-61-0", "doc_id": "medicine_vaccine_book", "page": 61, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\ncountries that explicitly follow international patent exhaustion are: Botswana,146 Burundi,147 Liberia,148 Seychelles,149 Sierra Leone,150 Zambia,151 Zanzibar,152 and Zimbabwe.153\n\nTo the contrary, the following countries provide for national exhaustion: Mada- gascar, Mozambique, Rwanda, Sao Tome and Principe, South Sudan, and Uganda.154 This choice is, at best, puzzling as all the countries in this list are LDCs.155 Even though these countries may not protect pharmaceuticals with patents at this time because of the TRIPS Council’s waiver—thus the impact of a national exhaustion regime ultimately does not affect imports of pharmaceuticals—this system can affect parallel imports of other products currently patented in these countries. Moreover, a system of national exhaustion may protect the business interests of the foreign patent holders more than the national interests, as most patents are filed by foreigners in the countries in question.156 Another country practicing national exhaustion is Morocco under Article 55(d) of the Patent Law of 2000.157 The provision was repeated in the US-Morocco FTA in 2004,158 in which both the U.S. and Morocco subscribed to this position. As the U.S. later changed its national rule to international patent exhaustion,159 Morocco could also consider a change in policy for public health reasons.", "n_tokens": 281, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-61-1", "doc_id": "medicine_vaccine_book", "page": 61, "text": "Finally, regional exhaustion is the system practiced by the seventeen members of the Organisation Africaine de la Propriété Intellectuelle (OAPI): Benin, Burkina Faso, Cameroon, Central African Republic, Chad, Comoros, Congo, Côte d’Ivoire, Gabon, Guinea, Equatorial Guinea, Mali, Mauritania, Niger, Guinea Bissau, Sene- gal, and Togo. Its seat is in Yaoundé, Cameroon. In particular, OAPI operates a", "n_tokens": 100, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-61-2", "doc_id": "medicine_vaccine_book", "page": 61, "text": "146Industrial Property Act No. 8 (2010), § 25(1)(a) 2010 (Botswana). Vawda and Shozi (2020), p. 32 (recounting that Botswana utilized this flexibility when it declared HIV/AIDS a national emergency in 2000 and began importing cheaper ARV drugs). 147Industrial Property Law No. 1 (2009), art. 57 (Burundi). 148Liberia Intellectual Property Act, § 13.11(b) (2016) (Liberia). 149The Patents and Industrial Design Act, § 19 (2012) (Seychelles). 150Patents and Industrial Design Act, § 23(1)(a) (2012) (Sierra Leone). 151Patents Act No. 40 (2016) § 76 (Zam). 152Industrial Property Act No. 4 (2008) § 11(4)(a)(i) (Zanzibar). 153Patents Act [Chapter 26:03], § 24A (amended by Act 9 of 2002) (Zimbabwe). 154Vawda and Shozi (2020), p. 32. 155See United Nations, supra note 134. 156See Graff and Pardey (2019) (for a survey of patent filing by foreigner and local inventors in Africa). 157Law No. 17-97 on the Protection of Industrial Property, art. 55 (Morocco). 158United States-Morocco Free Trade Agreement, 15 June 2004, 44 I.L.M. 544, art. 15.9 (“4. Each Party shall provide that the exclusive right of the patent owner to prevent importation of a patented product, or a product that results from patented process, without the consent of the patent owner shall not be limited by the sale or distribution of that product outside its territory”). 159Impression Prods., Inc. v. Lexmark Int’l, Inc., 581 U.S. 1523 (2017). See Ghosh and Calboli (2018), pp. 88–102.\n\n53", "n_tokens": 440, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-62-0", "doc_id": "medicine_vaccine_book", "page": 62, "text": "54\n\nunitary system for patents and OAPI member states do not have individual national laws. The Revised Bangui Agreement of February 1999 is the applicable patent law for all member states.160 Article 8(1)(a) of Annex I provides that “The rights deriving from the patent shall not extend: (a) to acts in relation to subject matter brought on to the market on the territory of a member State by the owner of the patent or with his consent.”161 It should be noted, however, that even though thirteen of OAPI members states (excluding Cameroon, Congo, Côte d’Ivoire, and Gabon) are LDCs, the rights granted under the Bangui Agreement include pharmaceutical patents (as per Article 27 of the TRIPS Agreement).162 Accordingly, LDCs in OAPI are de facto excluded from taking advantage of the existing TRIPS Council’s waiver for patent protection for pharmaceuticals.163 Moreover, these countries are bound by a system of regional exhaustion and not international exhaustion, whereas international exhaustion could likely a more favorable approach for all OAPI member states.164\n\n4 Overlapping Intellectual Property Rights and Parallel", "n_tokens": 229, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-62-1", "doc_id": "medicine_vaccine_book", "page": 62, "text": "Trade of Pharmaceuticals\n\nIn addition to patents, other IP rights can affect parallel trade, even when countries practice international patent exhaustion. This situation can arise when countries practice national exhaustion for trademark, copyright, or design rights.165 In general, overlapping IP rights can apply to a product in its entirety or to different parts or features of it.166 An example of the former is the overlapping trademark and copyright protection that can apply to the shape of a perfume bottle, the décor of a store, or the pictorial logo affixed to the packaging of consumer products, including pharmaceuticals.167 An example of the latter is the cumulation of patent, trademark, and copyright protection that can cumulate on a pharmaceutical, the first protecting the compound/product and/or process of making the compound, the second protecting the shape and/or color of the pill made with the patented compound and", "n_tokens": 174, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-62-2", "doc_id": "medicine_vaccine_book", "page": 62, "text": "160Bangui Agreement, supra note 23. 161Id. at Art. 8(1)(a). See also Kongolo (2000), p. 717. 162Bangui Agreement, supra note 23, art. 2. 163Deere (2008), p. 240. 164Vawda and Shozi (2020), pp. 32–33. In addition, the same regime of regional exhaustion applies to trademarks, which may result in blocking, as possible trademark infringement, also trademarked generic medicines from foreign countries. See Calboli and Visser (2020), p. 102. 165See Calboli, Avoidable Effects, supra note 3; Ginsburg and Calboli (2020), p. 434. In this chapter, I do not focus on design rights, which nonetheless may remain a relevant area of investigation, even this overlap may be less relevant, in practice, due to the limited duration of design rights, which is generally comparable, or shorter in time than patents rights. 166Ginsburg and Calboli (2020), p. 434; Derclaye and Leistner (2011); Moffat (2004), p. 1473. 167Ginsburg and Calboli (2020), p. 434.\n\nI. Calboli", "n_tokens": 275, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-63-0", "doc_id": "medicine_vaccine_book", "page": 63, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nthrough the patented process, and the third being the written instructions accompa- nying the medicines’ packaging, or the decoration of the packaging itself.168 The problematic effects of these overlaps and their application to parallel imports is addressed in this Section.\n\n4.1 Overview of Overlapping Rights and Enforcement", "n_tokens": 72, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-63-1", "doc_id": "medicine_vaccine_book", "page": 63, "text": "of Copyright to Parallel Imports\n\nOverlapping IP protection can apply simultaneously or sequentially. In the first case, two or more rights protect the same product at the same time. For example, a pictorial logo or the shape or color of a product—be this product a chocolate, liquor, or a pharmaceutical—can simultaneously enjoy trademark protection as distinctive signs and possibly copyright protection as independent artistic works, in addition to the protection the product may enjoy under patent or design law.169 Likewise, the labels, instructions, and other literary parts of a products could be protected under copyright in addition to the protection that the products enjoys under patent law. Instead, in the second case, two or more types of protection apply to the same product at different times. For instance, the patent or design granted on a product, or copyright protection on its shape or logo, are set to be limited in time. Instead, trademark protection on a product’s logo and possibly shape or color can continue time limits.170 Whether they are used simultaneously or sequentially, without overlapping rights can prolog and/or enhance the scope of protection of the inter- ested products.", "n_tokens": 229, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-63-2", "doc_id": "medicine_vaccine_book", "page": 63, "text": "In the context of pharmaceuticals, overlapping protection is often sought for different parts of the medicines or their packaging during or after patent protection. For example, in addition to protecting the names of the pharmaceuticals as marks, trademark registrations are often granted for the shape, colors, and other distinctive features of the medicines.171 Similarly, logos and decorative or distinctive elements", "n_tokens": 70, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-63-3", "doc_id": "medicine_vaccine_book", "page": 63, "text": "168Id. 169Id. For a detailed list of examples, see Calboli (2014b), p. 52 [hereinafter Calboli, Overlapping Rights]. For examples of overlapping protection between trademarks and patents, in particular applied to pharmaceuticals, see the cases cited infra in Part IV.B. See also Calboli (2020), p. [hereinafter Calboli, Trademark Protection for Medicines]. See also the contributions in Overlapping Intellectual Property Rights (Neil Wilkof & Shamnad Basheer eds., 2012. 170Ginsburg and Calboli (2020), p. 434. For famous cases in the U.S., see Frederick Warne & Co. v. Book Sales, Inc., 481 F. Supp. 1191, 1196 (S.D.N.Y. 1979); Walt Disney Prods. v. Air Pirates, 581 F.2d 751 (9th Cir. 1978) (finding that both copyright and trademark permissible on Disney comic book characters); Universal City Studios v. J.A.R. Sales, Inc., 216 U.S.P.Q. 679 (C.D. Cal. 1982) (discussing the protection of the “E.T.” motion picture character). 171For several relevant examples in the U.S., see U.S. Trademark Registration Nos. 2,593,407 (Pfizer Inc.; Viagra pill; diamond shape and color blue); 2,625,335 (Glaxo Group; Flovent HFA inhaler; tethered cap, mouthpiece covering shape, edge shapes); 2,679,181 (Gilead Sciences, Inc.; Viread pill; almond shape and color blue); 3,812,561 (Glaxo Group; Advair diskus inhaler; unique\n\n55", "n_tokens": 407, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-64-0", "doc_id": "medicine_vaccine_book", "page": 64, "text": "56\n\napplied to the packaging, or the labels, product instructions, or similar features of the pharmaceuticals could be protected as copyrighted works.172\n\nThe justification for overlapping IP rights rests on several elements: the broad definition of protectable subject matter (the item to be protected and the individual scope of protection of the type of products or individual product features); the lack of a comprehensive normative system prohibiting the possibility to cumulate separate types of IP protection in the same product, or different features of the same product; and the lack of a comprehensive system prohibiting, as misuse or abuse of rights, the enforcement of IP protection outside the traditional scope of protection.173 Even though national variations subsist regarding the treatment of overlapping rights in individual nations, overlapping IP protection is generally accepted.174 Some exclu- sions apply regarding the protection of the functional elements and additional protection under trademarks or copyright.175 Still, in most countries, there are no", "n_tokens": 197, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-64-1", "doc_id": "medicine_vaccine_book", "page": 64, "text": "round design, color purple, color white, and wave patterns); 5,018,105 (Gilead Sciences, Inc.; Harvoni pill; diamond shape, light-orange color, and identification number); 5,018,106 (Gilead Sciences, Inc.; Sovaldi pill; oval shape, light-yellow color, and identification number); 5,030,567 (Gilead Sciences, Inc.; Truvada pill: oblong shape, color blue, word engraving); 5,298,494 (Eli Lilly and Co.; Olumiant pill; color light pink, oval/oblong shape, and word engraving); 5,435,196 (Teva Respiratory; AirDuo RespiClick inhaler; colors yellow and white); 5,614,245 (Glaxo Group; Seretide evohaler; color purple Pantone Matching System 2587). See also Calboli, Trademark Protection for Medicines, supra note 170. 172In the U.S., for example, the following are registered: U.S. Copyright Registration Nos. TX0004141715 (Pfizer, Inc.; Zyrtec (certirizine Hydrochloride) tablets for oral use; copyright registration for the product label); TX0004065039 (Abbott Laboratories; Advera, Specialized, complete nutrition, clinically proven effective nutritional management; copyright registration for the product label); TX0004068652 (Abbott Laboratories: Pedialyte oral electrolyte maintenance solution; copyright registration for the product label); TX0004862188 (Novartis Crop Protection, Inc.: AAtrex 4L herbicide : CGA 7L38BB 052 : 2/12 gallons, US standard measure: copyright registration for the directions for use and conditions of sale and warranty); TX0001650844 (Merck & Company, Inc.: Clinoril", "n_tokens": 433, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-64-2", "doc_id": "medicine_vaccine_book", "page": 64, "text": "(selindac/ M S D:), copyright registration for the product information summary); TX0001135773 (Merck & Company, Inc.: Cosmegen (dactinomycin, M S D), actinomycin D, injection; copyright registration for the product label). 173See Calboli (2014b), p. 58. 174For example, in 2013, the United Kingdom eliminated the prohibition of cumulating copyright and design protection. The Enterprise and Regulatory Reforms Act 2013 extended copyright protection also to artistic works that have been reproduced more than 50 times. See Enterprise and Regulatory Reforms Act 2013, § 74 (U.K.) http://www.legislation.gov.uk/ukpga/2013/24/ section/74/enacted. 175In the U.S., see TrafFix Devices v. Mktg. Displays, 532 U.S. 23, 32 (2001); see also McKenna (2012), pp. 823, 824 (advocating for a broader application of the doctrine of functionality and prohibiting overlaps). In the EU, see Case C-299/99, Philips v. Remington, 2002 E.C.R. I-05475, ECLI:EU:C:2002:377; Case C-48/09, Lego Juris v. OHIM, 2010 E.C.R. I-08403, ECLI:EU: C:2010:516; Case C-30/15, Simba Toys v. European Union Intellectual Property Office (EUIPO), 2016 EUR-Lex-62014TJ0687, ECLI:EU:C:2016:849. See also the contributions in The Protection of Non-Traditional Trademarks: Critical Perspectives (Irene Calboli & Martin Senftleben eds., 2018).", "n_tokens": 400, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-64-3", "doc_id": "medicine_vaccine_book", "page": 64, "text": "I. Calboli", "n_tokens": 5, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-65-0", "doc_id": "medicine_vaccine_book", "page": 65, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nbright line rules also in this respect and the decision frequently falls with the courts.176\n\nTo date, several national decision related to overlapping rights in the context of parallel imports have focused on the mutual overlap between copyright or trademark rights, the use of copyright for incidental product features,177 and the overlap between patent and trademark rights.178 In the reminder of this section, I address the overlap between copyright and trademarks and the use of copyright on incidental feature, including the use copyright protection against generic pharmaceuticals. The use of copyright in this context is particularly pernicious. Copyright protection applies without the need of registration or other formalities across all members of the Berne Convention for the Protection of Literary and Artistic Works, which makes its enforcement with respect to pharmaceuticals both inexpensive and appli- cable worldwide without the need to market the product in the countries where protection is sought. Trademark protection is also useful, but is based on national registration and/or national use. Moreover, marks are deemed abandoned after a few years of non-use. Still, trademark protection’s primary advantage remains the poten- tial for perpetual protection as trademarks can be renewed for an unlimited number of times while copyright also expires.179", "n_tokens": 257, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-65-1", "doc_id": "medicine_vaccine_book", "page": 65, "text": "The overlap between trademark and copyright protection came to the attention of the courts first in Australia, a country practicing international trademark exhaustion but national copyright exhaustion.180 In 1986, however, this strategy went too far when the parallel imports of liqueur bottles were stopped based on infringement of the copyright in the labels affixed to the bottles.181 Considerable criticism followed this decision, and in turn the Australian Parliament deliberated to introduce Section 44C into the Copyright Act to prevent similar situations in the future. The new provision specifically prohibits against invoking copyright protection (and national copyright exhaustion) in the context of parallel imports. The provision reads that “[t]he copyright in a work a copy of which is, or is on, or embodied in, a non-infringing accessory to an article is not infringed by importing the accessory with the article”182—“accessory” being defined as: labels, packaging, containers,", "n_tokens": 196, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-65-2", "doc_id": "medicine_vaccine_book", "page": 65, "text": "176Australia, Singapore, and other parts of the Commonwealth practice a demarcation between copyright and design protection regarding artistic works that are reproduced in series. In particular, creators generally lose copyright protection in artistic works when the works are industrially applied (more than 50 copies of the work are made) or when the work is registered, or could be registered, as a design (the owner must then rely on the Designs Act). See, e.g., Copyright Act 1968 (Cth) §§ 75, 77, and 77A (Austl.); Singapore Copyright Act of 1987, §§ 69, 70, and 74 (2006) (Sing.). 177See Calboli (2014b). 178See infra discussion and cases cited in Part IV.B. 179Ginsburg and Calboli (2020), p. 434. 180See, e.g., Calboli and LaFrance (2013), p. 1. 181R A & A Bailey & Co. Ltd. v. Boccaccio Pty. Ltd. (1986) 6 IPR 279. 182Copyright Amendment Act (No. 1) 1998 (Cth.) [Austl.] (amending § 10(1) and adding ss. 44C, 112C).\n\n57", "n_tokens": 274, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-66-0", "doc_id": "medicine_vaccine_book", "page": 66, "text": "58\n\ninstructions, warranties, “or other information,” as well as instructional sound recording or films, “provided with the article.”183", "n_tokens": 31, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-66-1", "doc_id": "medicine_vaccine_book", "page": 66, "text": "IP holders played a similar game in the U.S. and Canada, until the respective Supreme Courts called it off. In the U.S., the 2013 decision in Kirtsaeng v. Wiley and Sons184 clarified that the Copyright Act provides for a system of international exhaustion. Previously, however, the majority of courts supported that the combined reading of Section 109(a) and Section 602(a)(1) of the Copyright Act prescribed national copyright exhaustion.185 Before Kirtsaeng, IP holders used copyright imports of otherwise legitimate products—famous protection to block parallel examples were shampoos bottles186 and sports watches.187 Similarly, Canada prac- tices international trademark exhaustion and national copyright exhaustion.188 In Euro-Excellence, Inc. v. Kraft Canada, Kraft sued an importer for copyright infringement for the importation of chocolate bars.189 The Supreme Court found the imports to be lawful, however, even though it reached its decision “on contrac- tual grounds.”190 In 2013, Professor Mary LaFrance and I191 proposed a legislative provision be implemented in the U.S. similar to the amendment approved in Australia in order to prohibit the enforcement of a claim for copyright infringement on “accessory copyright.”192 A revision of copyright law to this extent would prevent misuses of copyright law to block the parallel imports of otherwise legiti- mate products, in particular when the claim for copyright infringement refers to accessories or nonessential parts of the", "n_tokens": 306, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-66-2", "doc_id": "medicine_vaccine_book", "page": 66, "text": "products.193 Even though the US currently applies international exhaustion both for patents and copyrights, a similar", "n_tokens": 20, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-66-3", "doc_id": "medicine_vaccine_book", "page": 66, "text": "183Id. In 2003, the Australian legislature expanded this list, and added that a “computer program,” “electronic literary or music item,” or “sound recording” that is part of or combined with imported articles are also “accessories. Copyright Amendment (Parallel Importation) Act 2003 (Cth.) [Austl.]. See Polo/Lauren Co. LP v. Ziliani Holdings Pty. Ltd. [2008] 75 I.P.R. 143 (F.C.A.) (applying the provisions and finding that parallel imports of polo shirts were not infringing). See Ghosh and Calboli (2018), pp. 148–152. 184Kirtsaeng v. John Wiley & Sons, Inc., 133 S. Ct. 1351, 1358 (2013). 185For a detailed reconstruction of doctrine of copyright exhaustion in the U.S., see Calboli (2014c), p. 75; Ghosh and Calboli (2018), p. 116. 186Quality King Distribs., Inc. v. L’Anza Research Int’l, Inc., 523 U.S. 135 (1998). 187Costco Wholesale Corp. v. Omega, S.A., 131 S. Ct. 565 (2010). 188See Ghosh and Calboli (2018), p. 122. 189Euro-Excellence Inc. v. Kraft Canada Inc., [2007] 3 S.C.R. 20, 2007 SCC 37. 190Id. 191Calboli and LaFrance (2013), p. 1. 192Id. at 266-72 (referring also to the relevant case law in Australia). 193See supra note 172 listing examples of copyright registration for medicines in the U.S. For an to enforce copyright against a generic pharmaceuticals producer, see example of attempt SmithKline Beecham Consumer Healthcare, L.P. v. Watson Pharms., Inc. 211 F.3d 21 (2d Cir. 2000) (holding that copyright liability does not attach to the use by the seller of a generic", "n_tokens": 450, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-66-4", "doc_id": "medicine_vaccine_book", "page": 66, "text": "medicine of the label of the same medicine by the originator company, the Nicorette gum, after the generic seller had obtained FDA approval to sell the medicine).", "n_tokens": 34, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-66-5", "doc_id": "medicine_vaccine_book", "page": 66, "text": "I. Calboli", "n_tokens": 5, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-67-0", "doc_id": "medicine_vaccine_book", "page": 67, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\namendment would prevent the opportunity for future strategic overlaps, should the law again be amended toward a system of national exhaustion.\n\nlaw have been acknowledged in the U.S. and Australia, for example, even though this use was not with respect to parallel imports of genuine products but to block the introduction to market of generics nationwide. In 2000, the U.S., an originator company attempted to block the distribution of a generic claiming copyright infringement on the FDA-approved labelling that the generic manufactured used. This claim was rejected by the court based on the fact that the Hatch-Waxman Act requires the use of the “same” labelling and accordingly this requirement trumps the possibility to claim copyright infringement on pharmaceutical labels. Still, the court stated that copyright protection could be used, not regarding labels, but other materials such as advertis- ing.194 Similarly, in Australia, in 2008, an originator company claimed copyright infringement against a generic producer because of the reproduction of the legally required product information of the medicine. This claim was eventually also rejected and led to adoption of another amendment in Australia: the Therapeutic Goods Legislation Amendment (Copyright) Bill 2011, which was passed in 2001 and introduced Section 44BA to the Copyright Act.195", "n_tokens": 263, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-67-1", "doc_id": "medicine_vaccine_book", "page": 67, "text": "Attempts by the pharmaceutical\n\nindustry to use copyright\n\nIn Norway, however, the pharmaceutical industry attempted to claim copyright infringement against parallel imports within the EU/EEA. This attempt was also rejected.196 Notably, the Norwegian Medicines Control Agency had provided notice to the industry that it would allow parallel importers to use the official Summaries of Product Characteristic (SPCs) given by originator companies for the purpose of seeking the importing authorization for intra EEA parallel imports. Astra Norge sued the Norwegian government on the claim that this infringed its copyright in the SPCs. The court of first instance ruled in favor of Astra Norge, but the court of appeal referred asked to the EFTA court if this decision would violate the EU Directive on marketing authorizations.197 In conclusion, the EFTA Court ruled that indeed a finding of copyright infringement would represent a measure having equivalent", "n_tokens": 184, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-67-2", "doc_id": "medicine_vaccine_book", "page": 67, "text": "194SmithKline Beecham, 211 F.3d 21. See Tsien (2014), p. 334, 366. 195Therapeutic Goods Legislation Amendment (Copyright) Bill 2011 (Cth) [Austl.] (adding s. 44BA). According to the new provision the copyright infringement cannot be invoked: “2 ...: (a) supplying, in Australia, some or all of any product information that is approved... in relation to medicine; (b) reproducing, in Australia, [this] information . . .; (c) publishing, in Australia, [this] information . . .; (d) communicating, in Australia, [this] information . . .; (e) adapting, in Australia, [this] information . . .; to the extent that the supply, reproduction, publication, communication or adaptation is for a purpose related to the safe and effective use of the medicine referred to in paragraph (a).” Moreover, “3. An act done in Australia that is ancillary or incidental to a supply, reproduction, publication, communication or adaptation referred to in subsection (2) is not an infringement of any copyright . . .” I am grateful to Luigi Palombi for pointing me to this specific amendment. 196This is reported by Stothers (2007), p. 426 (citing the decision Case E-1/98 Norway v. Astra Norge [1998] EFTA Court Reports 140). 197Id.\n\n59", "n_tokens": 321, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-68-0", "doc_id": "medicine_vaccine_book", "page": 68, "text": "60\n\neffect to a quantitative restriction and a disguised restriction to EU/EEA trade.198 Once again, the principle of free movement in the EEA prevailed over the attempt to use copyright (or other IP rights) to block intra EU/EEA parallel trade. Ultimately these various attempts demonstrate that IP holder always try to use multiple avenues to pursue their interests, the enforcement of copyright to features of the packaging or information annexed to the medicines being also one of these avenues.\n\n4.2 Enforcement of Trademark Rights to Parallel Imports", "n_tokens": 104, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-68-1", "doc_id": "medicine_vaccine_book", "page": 68, "text": "of Pharmaceuticals\n\nIn addition to (attempting to) enforce copyright protection, an additional avenue to attempt to block the parallel imports of pharmaceuticals, and products in general, is the enforcement of trademark protection for products that may still be protected by patents or whose patent protection has expired.\n\nThe advantage of this overlap is obvious when the country of importation practices international exhaustion for patents but national exhaustion for trademarks, as the imports can then be blocked as a trademark infringement. For example, amongst the countries analyzed in Part III, several of the countries practicing international patent exhaustion have no clear policy in the area and apply instead national trademark exhaustion.199 This is the case, for example in LDCs in ASEAN, Cambodia and Lao PDR,200 which block parallel imports under trademark law. Also in Thailand, which does not have an express position on trademark exhaustion in general, it has been noted that trademark law can be invoked to block the imports of pharmaceuticals not imported directly by the trademark holders.201 Another country practicing national trademark exhaustion is Brazil, with the exception of the instance where the trademark holder has not restricted in licensing agreements against parallel imports into Brazil or does not have a licensee in Brazil.202 Unfortunately,", "n_tokens": 237, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-68-2", "doc_id": "medicine_vaccine_book", "page": 68, "text": "198Id. 199Ghosh and Calboli (2018), p. 65. See also Grigoriadis (2014). 200See Law Concerning Marks, Trade Names and Acts of Unfair Competition of the Kingdom of Cambodia, Art. 11(c) (Cambodia); Lao PDR Law, supra note 81, at art. 57(3) lit. 1. 201See Lifescience Asia-Pacific Network, A Comparative Overview of Distribution and Marketing of Drugs in Asia-Pacific:, p. 49. https://corrs.com.au/site-uploads/images/PDFs/Insights/article-IP- comparative-overview-of-distribution-and-marketing-of-drugs-across-asia-pacific.pdf (noting that, in Thailand, “parallel imports are not permitted in the pharmaceutical sector because it is mandatory for a company to preliminarily obtain an import license and product registration locally” and that “the FDA will not accept an application for a product with a trademark that is identical to other products in the Thai market, unless this product has the same manufacturer and the manufacturer has given its authorization to use and sell the product.”). 202Brazilian IP Law, supra note 112, Art. 132 (III). See also Grigoriadis (2014), pp. 457–458 (highlighting that Brazil practices national trademark exhaustion even though it is a Member State of Mercosur, which establishes the principle of international exhaustion under Article 13 of the\n\nI. Calboli", "n_tokens": 332, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-69-0", "doc_id": "medicine_vaccine_book", "page": 69, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\ninformation is not readily available at this time regarding the position several African countries, in particular LDCs, adopt on trademark exhaustion. Still, there are no doubts the effect of the limitations invoked under a system of national exhaustion are very relevant, as they can contribute to effectively blocking medicines from entering the countries allowing these imports under patent law.", "n_tokens": 78, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-69-1", "doc_id": "medicine_vaccine_book", "page": 69, "text": "IP holders have invoked trademark law to block the parallel imports also within regions that practice regional exhaustion, notably in the EU. However, the CJEU resisted the IP overlaps game and, in most instances, ruled in favor of parallel imports. As mentioned above, free movement of goods is one of the fundamental freedoms of the EU, and the CJEU long made it clear that the exercise of IP rights cannot trump free movement. Moreover, the CJEU designed the principle “mutual recognition” according to which Member States should accept “the sale in [their] territory of a product lawfully produced and marketed in another Member” even when the “technical or quality requirements ... differ from those imposed on [their] domestic products.”203 In other words, genuine products of materially different quality cannot be blocked within the EU/EEA as long as they comply with national standards, which today have largely been replaced with EU standards. However, in the EU cases in question, parallel importers repackaged the pharmaceuticals—thus, the products carried differences in quality not because the trademark holder had produced them as such, but because the importers had altered the quality of the packaging. Yet, the CJEU still allowed the imports.204", "n_tokens": 252, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-69-2", "doc_id": "medicine_vaccine_book", "page": 69, "text": "In particular, the CJEU supported trademark rights could not be enforced against repackaged parallel imported medicines when “the repackaging did not adversely affect the original condition of the product” and that “the trade mark owner receives prior notice of the marketing of the repackaged product.”205 In Bristol-Myers Squibb v. Paranova,206 the Court created a specific list of conditions for the repackaging and stated that: (1) it should be necessary to market the product in the country of importation; (2) does not affect the original condition of the product inside the packaging; (3) clearly states who repackaged the product and the name of the manufacturer; (4) does not damage the reputation of the trademark or of its holder; and (5) the importer gives notice to the trademark holder before the repackaged", "n_tokens": 180, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-69-3", "doc_id": "medicine_vaccine_book", "page": 69, "text": "Protocol on Harmonization of Norms on Intellectual Property in Mercosur in Matters of Trade- marks, Indications of Source and Appellations of Origin adopted in 1995). 203Commission Communication No. C 256/2, Communication from the Commission concerning the consequences of the judgment given by the Court of Justice on 20 Feb. 1979 in Case 120/78, 1980 O.J. (C 256) 2, 2–3 (EC). The CJEU developed the principle of “mutual recognition” in Case 120/78, Rewe-Zentral AG v. Bundesmonopolverwaltung fur Branntwein, 1979 E.C.R. 649 (Cassis de Dijon). 204See Stothers (2016), pp. 171–175. 205Hoffmann-La Roche v Centrafarm, 1978 E.C.R at 1166. See Stothers (2016), pp. 171–172. 206Joined Cases 427, 429 & 436/93, Bristol-Myers Squibb v. Paranova 1996 E.C.R. I-3457. See Stothers (2016), pp. 172–173.\n\n61", "n_tokens": 249, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-70-0", "doc_id": "medicine_vaccine_book", "page": 70, "text": "62\n\nproduct is put for sale, and, on demand, supplies her with a specimen.207 In addition, the CJEU ruled that even changing the mark on the packaging (with the mark used by trademark holders in the country of importation) was not grounds to prohibit parallel imports if the trademark holders deliberately used different marks in differ- ent EU countries.208 This constituted, according to the Court, a “disguised restriction on trade between Member States” under the rule of Article 36 of the Treaty209 as long as210 the mark’s replacement is “objectively necessary”211 and not only for “the parallel importer . . . to secure a commercial advantage.”212 Still, despite these supportive rulings regarding parallel imports of pharmaceuticals, the CJEU also ruled a decade ago the unauthorized repackaging and relabeling of genuine products may constitute “legitimate reasons” against parallel trade within the EU/EEA when this may lead to consumer confusion or provoke unfair detriment to a mark’s reputation.213", "n_tokens": 211, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-70-1", "doc_id": "medicine_vaccine_book", "page": 70, "text": "Using trademark protection can prove useful to block parallel imports not only when a country practices national exhaustion but also when it follows a system of international trademark exhaustion.214 Notably, under the rule of several national trademark laws—the U.S., Canada, India, China, Korea, Singapore, amongst others—IP holders can oppose parallel imports under a regime of international exhaustion when the quality of the imported products is different of those sold nationally, even if the products are genuine and were first marketed by IP holders in foreign markets.215 This principle is based on the idea trademarks indicate to", "n_tokens": 117, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-70-2", "doc_id": "medicine_vaccine_book", "page": 70, "text": "207Several cases followed from these “BMS conditions,” which frequently were resolved in favor of importers. See Stothers (2016), p. 172 (citing C-143/00, Boehinger parallel Ingelheim v. Swingward, 2002 E.C.R. I-3759; Case C-348/04, Boehinger Ingelheim v. Swingward, 2002 E.C.R. I-3759, as applied by the English Court of Appeal in [2008] EWCA (Civ) 83; Joined Cases C-400/09 and C-207/10, Orifarm v. Merck Sharp & Dohme, 2011 E.C.R. I-7063). As we have seen in Section III regarding the Specific Mechanism, the requirement to notify the originator of the pharmaceuticals remains, however, an important condition to fulfil by parallel importers. Courts have rules that failure to notify will result in finding of infringement. See Id. at 173 (citing Hollister v. Medik Ostomy Supplies, [2012] EWCA (Civ) 1419, [2012] W.L.R 327 (Eng.)). 208Case 3/78, Centrafarm BV v. American Home Prods. Co., 1978 E.C.R. 1823. 209Id. at 1841–1842. 210Case C-379/97, Pharmacia & Upjohn v. Paranova, 1999 E.C.R. I-6927. 211Id. at I – 6967–6969. 212Id. See Stothers (2016), pp. 174–175 (citing Specialty Euro. Pharm. v. Doncaster Pharms. Ltd., [2015] EWCA (Civ) 54, [69], [2015] W.L.R.). 213Case C-59/08, Copad, SA v. Christian Dior Couture SA, 2009 E.C.R I- 03421 (stating that a trademark owner may oppose the unauthorized sale of luxury goods to discount stores by a licensee if the sale could damage the reputation of the mark). See Calboli, Reviewing Trademark Exhaustion, supra note 10, at 261–262. 214See, e.g.,", "n_tokens": 506, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-70-3", "doc_id": "medicine_vaccine_book", "page": 70, "text": "Calboli (2011), p. 1241; LaFrance (2013), p. 45. 215Ghosh and Calboli (2018), p. 65; Grigoriadis (2014).", "n_tokens": 46, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-70-4", "doc_id": "medicine_vaccine_book", "page": 70, "text": "I. Calboli", "n_tokens": 5, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-71-0", "doc_id": "medicine_vaccine_book", "page": 71, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nconsumers origin and consistent quality.216 Accordingly, consumers could be con- fused when they rely on the mark affixed to the paralleled imported products, but these products are “materially different” in quality.217 Small quality differences often apply to products marketed in different countries because of national standards or producers’ choices (or marketing partitioning strategy by IP holders).218 In some countries, like the U.S. and Singapore, this rule is mitigated by the use of dis- claimers—in other words, the products can still be lawfully imported as long as the importers properly labels the products indicating their origin and quality dispelling the risk of consumer confusion.219 Yet, in an action for infringement, it is up to national courts to decide the extent they could find these disclaimers weigh against a likelihood of consumer confusion. Courts in the U.S., for example, have interpreted the concept of “material differences” broadly, to include a large set of product features and accessories and have blocked parallel imports accordingly.220", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-71-1", "doc_id": "medicine_vaccine_book", "page": 71, "text": "In summary, it is not surprising that the pharmaceutical industry considers trademark protection as an important avenue to block parallel imports even though the courts have frequently denied their claims. Considering the expansion of trade- mark protection, that can protect today the packaging but also the color and shape of several pharmaceuticals, and the length that this protection grants due to the possi- bility to renew the protection indefinitely, we will certainly continue to see more activity in this respect.", "n_tokens": 95, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-71-2", "doc_id": "medicine_vaccine_book", "page": 71, "text": "216See Landes and Posner (1987), pp. 265–266 (“[T]rademark law . . . can best be explained on the hypothesis that the law is trying to promote economic efficiency.”); see also Economides (1988), p. 523, 526; Kratzke (1991), pp. 199, 205. 217See Schechter (1927), p. 813, 818 (“The true functions of the trademark are, then, to identify a product as satisfactory and thereby to stimulate further purchases by the consuming public.”); Sanders and Maniatis (1993), p. 406. 218Calboli (2011), p. 1271. 219Tariff Act, 19 U.S.C. § 1307 (1930). “This product is not a product authorized by the United States trademark owner for importation and is physically and materially different from the autho- rized product.” The disclaimer must be “designed to remain on the product until the first point of sale to a retail customer in the United States.” 19 C.F.R. § 133.23(b). 220In the US, for example, see Societe Des Produits Nestle S.A. v. Casa Helvetia, Inc., 982 F.2d 633, 639 n.7 (1st Cir. 1992) ; Lever Bros. Co. v. U.S., 877 F.2d 101, 103, 108 (D.C. Cir. 1989); Dial Corp. v. Encina Corp., 643 F. Supp. 951, 952 (S.D. Fla. 1986); Ferrero U.S.A., Inc. v. Ozak Trading, Inc., 753 F. Supp. 1240, 1243, 1247 (D.N.J.), aff’d, 935 F.2d. 1281 (3rd Cir. 1991); El Greco Leather Prods. Co. v. Shoe World, Inc., 806 F.2d 392 (2d Cir. 1986).\n\n63", "n_tokens": 471, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-72-0", "doc_id": "medicine_vaccine_book", "page": 72, "text": "64\n\n5 Conclusion: A Call for a Wider Application\n\nof the Flexibility of Article 6 of the TRIPS Agreement in Developing and Least Developed Countries\n\nIn the light of the above, what conclusions could be derived from the comparative review offered by this chapter regarding domestic policies on patents exhaustion and the application of overlapping IP right to the parallel imports of pharmaceuticals?", "n_tokens": 66, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-72-1", "doc_id": "medicine_vaccine_book", "page": 72, "text": "At the outset, the analysis elaborated in this chapter confirms that the national treatment of the principle of IP exhaustion remains a highly complex legal question across different jurisdictions. This is even more true regarding pharmaceuticals considering how many countries apply differentiated rules or have recently changed their national laws to address these imports. As I anticipated in the Introduction, this review also confirms that the principle of IP exhaustion remains a relevant tool for countries’ international trade policies, including for trade in pharmaceuticals. In turn, it is still important to engage in scholarly discussions on this area, even though other factors—from marketing approvals, to import authorizations, or contractual restric- tions—can affect the admissibility of these imports into national markets. For example, domestic policies providing for national exhaustion can become the ultimate barrier against parallel imports of pharmaceuticals in the instances in the necessary regulatory approvals which national governments do grant (or recognize specific foreign approvals) to these products. To the contrary, domestic policies on international exhaustion would become the decisive factor to permit these imports into national markets. In addition to patent exhaustion, domestic policies on trademark or copyright exhaustion can also be used as effective barrier to the parallel imports of pharmaceuticals, including generics.", "n_tokens": 250, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-72-2", "doc_id": "medicine_vaccine_book", "page": 72, "text": "More specifically, the comparative review presented in this chapter highlights that, twenty-five years after the adoption of the TRIPS Agreement, a number of national governments are using more actively the flexibility offered by Article 6 of the TRIPS Agreements in order to frame national solutions on the application of the principle of IP exhaustion in ways that best fit their international and domestic trade- related interest. Several countries, developing and developed countries, have under- gone specific revisions of their national laws in this respect, and the interpretation of the principle of exhaustion has been debated at large by national courts in the past several decades. In general, both national legislators and judges seem to have acquired a better understanding of the possible applications of this principle. National and international economic studies have also been prepared to assist policy makers in determining the economic implications of legislative choices in this area. Interestingly, several developed countries, including the US and Canada, have changed their national policies from national to international patent exhaustion— even though parallel imports may still be blocked in several countries through (enforceable) contractual restrictions and, with respect to pharmaceuticals, by the mentioned regulatory requirements.", "n_tokens": 232, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-72-3", "doc_id": "medicine_vaccine_book", "page": 72, "text": "To the contrary, legislative or judicial reforms in favour of more liberal policies on IP exhaustion are still not the case for several developing countries and LDCs.\n\nI. Calboli", "n_tokens": 35, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-73-0", "doc_id": "medicine_vaccine_book", "page": 73, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...", "n_tokens": 12, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-73-1", "doc_id": "medicine_vaccine_book", "page": 73, "text": "Instead, as noted in this chapter, several of these countries continue to follow a system of national patent exhaustion. For example, this position is followed by several LDCs in Africa. Several developing countries and LDCs even allow for the enforcement of overlapping IP rights in their jurisdictions. As noted in this chapter, the LDCs countries members of OAPI follow a system of regional exhaustion, which remains more restrictive than international exhaustion. These findings, and the limited use of the flexibility of Article 6 of the TRIPS Agreement in these countries, are the most problematic conclusions from the comparative review in this chapter. The reasons for these choices are difficult to identify as the legislative history of these laws cannot be easily reconstructed, but most likely range from the lack of expertise of national legislators, to the lack of economic studies regarding these countries, or the absence of, or low quality technical assistance, or the pressure of foreign governments and business interests, including trade-offs accepted as part of trade agreements or foreign direct investments. Regardless of the reasons, these national policies are problematic as they undermine the possibility, for these coun- tries, to import less costly products, including pharmaceuticals. In the case of pharmaceuticals, these national policies could essentially amount to block these countries from accessing life saving medicines for their citizens.", "n_tokens": 265, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-73-2", "doc_id": "medicine_vaccine_book", "page": 73, "text": "Simply put, it is almost paradoxical, and quite problematic, that several developed countries currently apply less restrictive IP exhaustion policies than a number of developing countries and LDCs, whereas the former have larger economic capabil- ities and access to products than the latter.", "n_tokens": 54, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-73-3", "doc_id": "medicine_vaccine_book", "page": 73, "text": "The last conclusion that can be derived from the comparative review in this chapter is the relevance of IP overlaps in this debate, in particular when countries practice different type of exhaustion—national instead of international. In particular, it is clear that only when countries practice international exhaustion for all IP rights overlapping IP protection cannot interfere with the general admissibility of parallel imports in that country—at least from the perspective of the enforcement of IP rights. As a result, pharmaceutical companies have attempted to invoke copyright and trademark rights to block the further circulation of their products or to block the introduction to market of generics. In the EU, in particular, companies have invoked both copyrights, and most frequently trademark protection to try to block the parallel trade of their products within the EU since the late 1970s. As mentioned in this chapter, copyright could be used to protect the packaging, the logos, and the instructions of the medicine. Likewise, trademark rights are granted today not just for the marks affixed to the pharmaceutical packaging, but also on the pills, the devices necessary to inhale the medicines, etc.", "n_tokens": 221, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-73-4", "doc_id": "medicine_vaccine_book", "page": 73, "text": "This finding, certainly not new but not frequently raised in the debate of scholars, which are experts on patents and pharmaceuticals, is also problematic. In particular, the enforcement of these additional rights can easily nullify the effects of domestic policies on international patent exhaustion, should countries practice national trade- mark or copyright exhaustion. The same applies, as this chapter illustrates, when IP holders can invoke differences in the quality of the products, even in the case of domestic policies providing for international exhaustion. Again, calling upon these rights may become a last resort for the pharmaceutical industries—which still\n\n65", "n_tokens": 118, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-74-0", "doc_id": "medicine_vaccine_book", "page": 74, "text": "66\n\nheavily relies on regulatory schemes to control the international distribution of pharmaceuticals—and courts seem to have rarely supported these claims. Yet, these disputes may not be representative of the number of claims actually used in cease and desists letters to parallel importers and distributors of these products nationally. As it is known, very few disputes reach the courts, due to the time and legal fees involved. Instead, most disputes are settles in highly secretive and nontransparent out-court proceedings where dubious claims and weak rights— such as copyright and trademark protection for pharmaceuticals—can be validated by the parties in the settlements. Ultimately, this large numbers of rights simply offers more arrows that IP holders to throw against parallel imports, and we can be sure that, should the occasion arise, the arrows will be used with full force.", "n_tokens": 164, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-74-1", "doc_id": "medicine_vaccine_book", "page": 74, "text": "References\n\nAbbott FM (1998) First report (final) to the Committee on International Trade law of the interna- tional law association on the subject of parallel importation. J Int Econ Law 1(4):607–636 Abbott FM (2000) Second Report (Final) to the Committee on International Trade Law of the International Law Association on the Subject of the Exhaustion of Intellectual Property Rights and Parallel Importation. 69th Conference of the International Law Association. http://ssrn.com/ abstract¼1921856\n\nAbbott FM (2002) The Doha declaration on the TRIPS agreement and public health: lighting a dark\n\ncorner at the WTO. J Int Econ Law 5:469\n\nAbbott FM (2005) The WTO medicines decision: world pharmaceutical trade and the protection of\n\npublic health. Am J Int Law 99(2):317\n\nAbbott FM (2007) Parallel importation: economic and social welfare dimensions. International\n\nInstitute for Sustainable Development\n\nAbbott FM (2014) Anti-competitive behaviours and the remedies available for redress. UNDP", "n_tokens": 219, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-74-2", "doc_id": "medicine_vaccine_book", "page": 74, "text": "Competition Guidelines, pp 78–79\n\nAbbott FM (2016) Parallel trade in pharmaceuticals: trade therapy for market distortions. In: Calboli I, Lee E (eds) Research handbook on intellectual property exhaustion and parallel imports. Edward Elgar, Cheltenham, p 145\n\nAbbott FM, Reichman J (2007) The Doha round public health legacy: strategies for the production and diffusion of patented medicines under the amended TRIPS provisions. J Int Econ Law 10 (4):921\n\nAgreement on Trade-Related Aspects of Intellectual Property Rights, April 15, 1994, Marrakesh Agreement Establishing the World Trade Organization, Annex 1C, Legal Instrument—Result of the Uruguay Rounds Vol. 31, 33 I.L.M. 83, 1869 U.N.T.S. 299 (1994)\n\nBale HE Jr (1999) The conflicts between parallel trade and product access and innovation: the case\n\nof pharmaceuticals. J Int Econ Law 1:637\n\nBasheer S, Kochupillai M (2009) TRIPS, patents and parallel imports in India: a proposal for\n\namendment. Indian J Intell Prop Law 2:63\n\nBeier F-K (1990) Industrial property and the free movement of goods in the internal European\n\nmarket. I.I.C. 21(4):131\n\nBenoliel D, Chirwa TJ. The Impact of Pharmaceutical Patents on Health Expenditures in Least- Developed Countries, unpublished paper available at http://law.haifa.ac.il/images/Publications/ BenolielChirwa.pdf\n\nByung-Il K (2004) Parallel imports in Korea. In: Heath C (ed) Parallel Imports in Asia. Kluwer Law\n\nInternational, p 73\n\nI. Calboli", "n_tokens": 356, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-75-0", "doc_id": "medicine_vaccine_book", "page": 75, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...", "n_tokens": 12, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-75-1", "doc_id": "medicine_vaccine_book", "page": 75, "text": "Calboli I (2002) Trademark exhaustion in the European Union: community-wide or international?\n\nThe Saga continues. Marq Intell Prop Law Rev 6:47\n\nCalboli I (2011) Market integration and (the limits of) the first sale rule in North American and\n\nEuropean Trademark Law. Santa Clara Law Rev 51:1241\n\nCalboli I (2014a) The (avoidable) effects of territorially different approaches to trademark and copyright exhaustion. In: Calboli I, Lee E (eds) Trademark protection and territoriality chal- lenges in a global economy. Edward Elgar, p 151\n\nCalboli I (2014b) Overlapping rights: the negative effects of trademarking creative works. In: Gervais DJ, Frankel S (eds) The evolution and equilibrium of copyright in the digital age, p 52 Calboli I (2014c) The United States Supreme Court’s decision in Kirtsaeng v. Wiley & Sons: an\n\n“Inevitable” step in which direction? Int Rev Intell Prop Compet Law 45:75\n\nCalboli I (2019a) The intricate relationship between intellectual property exhaustion and free movement of goods in regional organizations: comparing the EU/EEA, NAFTA, and ASEAN. Queen Mary J Intell Prop 9(1):22\n\nCalboli I (2019b) The ASEAN way or no way? A closer look at the absence of a common rule on intellectual property exhaustion in ASEAN and the impact on the ASEAN market. Univ Pa Asian Law Rev 14(363):363–391\n\nCalboli I (2020) Beyond patents: the problems of non-traditional trademark protection for medi-\n\ncines and heath technologies. Int Rev Intell Prop Compet Law 51:1", "n_tokens": 366, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-75-2", "doc_id": "medicine_vaccine_book", "page": 75, "text": "Calboli I, LaFrance M (2013) The case for a legislative amendment against “accessory copyright” for Gray market products: what can the U.S. learn from Singapore and Australia?, Singapore J Legal Stud 2013:1\n\nCalboli I, Lee E (eds) (2016) Research handbook on intellectual property exhaustion and parallel\n\nimports. Edward Elgar\n\nCalboli I, Senftleben M (eds) (2018) The protection of non-traditional trademarks: critical perspec-", "n_tokens": 105, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-75-3", "doc_id": "medicine_vaccine_book", "page": 75, "text": "tives. Oxford University Press\n\nCalboli I, Visser C (2020) Regional trademark protection: comparing regional organizations in Europe, Africa, South East Asia, and South America. In: Calboli I, Ginsburg JC (eds) Cam- bridge handbook on international and comparative trademark law. Cambridge University Press, p 102\n\nChen Y, Maskus KE (2005) Vertical pricing and parallel imports. J Int Trade Econ Dev 14:1 Chiappetta V (2016) Working towards international harmony on intellectual property exhaustion (and substantive law). In: Calboli I, Lee E (eds) Research handbook on intellectual property exhaustion and parallel imports. Edward Elgar, p 125\n\nCoriat B, Orsenigo L (2014) IPRs, Public Health and the Pharmaceutical Industry: Issues in the Post-2005 TRIPS Agenda. In: Cimoli M, Dosi G, Maskus KE, Okediji RL, Reichman JH (eds) Intellectual property rights legal and economic challenges for development\n\nCorrea CM, Correa JI (2016) Parallel imports and the principle of exhaustion of rights in Latin America. In: Calboli I, Lee E (eds) Research handbook on intellectual property exhaustion and parallel imports. Edward Elgar, p 206\n\nCouncil for TRIPS, Extension of the Transitional Period Under Article 66.1 of the TRIPS Agree- ment for Least Developed Country Members for Certain Obligations With Respect to Pharma- ceutical Products, IP/C/73 (Nov. 6, 2015)", "n_tokens": 314, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-75-4", "doc_id": "medicine_vaccine_book", "page": 75, "text": "Danzon PM (1998) The economics of parallel trade. Pharmacoeconomics 13:293 De Carvalho NP (2010) The TRIPS Regime of Patents Rights 173 Declaration on the TRIPS Agreement and Public Health (14 November 2001), Doc. WT/ MIN(01)/\n\nDEC/2 (20 Nov. 2001)\n\nDeere C (2008) The Implementation Game: the TRIPS Agreement and the Global Politics of\n\nIntellectual Property Reform in Developing Countries 73, 240\n\nDelepierre A et al (2012) Update on counterfeit antibiotics worldwide; Public health risks.\n\nMedecine et Maladies Infectieuses 42:247\n\nDerclaye E, Leistner M (2011) Intellectual property overlaps: a European perspective. Hart\n\n67", "n_tokens": 153, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-76-0", "doc_id": "medicine_vaccine_book", "page": 76, "text": "68\n\nI. Calboli\n\ndos Santos F, Lowé Gnintedem PJ (2018) Regional frameworks for protection of intellectual property in Africa. In: Oyewunmi A et al (eds) Intellectual property law, practice and manage- ment: perspectives from Africa, pp 592, 593–594\n\nEconomides NS (1988) The economics of trademarks. Trademark Rep 78(523):526 El-Said MK (2010) Public Health Related TRIPS-plus Provisions in Bilateral Trade Agreements: A Policy Guide for Negotiators and Implementers in the WHO Eastern Mediterranean Region 200–04\n\nEnterprise and Regulatory Reforms Act 2013, § 74 (U.K.). http://www.legislation.gov.uk/ukpga/\n\n2013/24/section/74/enacted\n\nFederal Act on Patents for Inventions (SR 232.14 LBI) art. 9a (inserted by No I of the Federal Act of June 22, 2007 (AS 2551 (2009); BBl 1 (2006)), as amended by No I of the Federal Act of Dec. 19, 2008, in force since July 1, 2009 (AS 2615 (2009); BBl 303 (2008)) (Switz.)\n\nFink C (2004) Entering the jungle of intellectual property rights exhaustion and parallel imports. In: Fink C, Maskus KE (eds) Intellectual property rights and development: lessons from recent economic research, p 174\n\nGanslandt M, Maskus KE (2004) Parallel imports and the pricing of pharmaceutical products:\n\nevidence from the European Union. J Health Econ 23:1035\n\nGanslandt M, Maskus KE (2008) Intellectual property rights, parallel imports, and strategic", "n_tokens": 363, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-76-1", "doc_id": "medicine_vaccine_book", "page": 76, "text": "behavior. In: Maskus KE (ed) Intellectual property, growth, and trade. pp 267–268\n\nGhosh S, Calboli I (2018) Exhausting intellectual property rights: a comparative law and policy\n\nanalysis. Cambridge University Press\n\nGinsburg JC, Calboli I (2020) Overlapping copyright and trademark protection in the United States: more protection and more fair use? In: Ginsburg JC, Calboli I (eds) Cambridge handbook on international and comparative trademark law. Cambridge University Press, p 434\n\nGopalakrishnan NS, Agitha TG (2012) Indian patent system: the road ahead. In: Shimanami R\n\n(ed) The future of the patent system, p 229\n\nGrabowski H (2002) Patents and New Product Development in the Pharmaceutical and Biotech- nology Industries. In: Smith CG, O’Donnell JT (eds) The process of new drug discovery and development, 2nd edn. p 533, 535\n\nGraff GD, Pardey PG (2019) Inventions and patenting in Africa: empirical trends from 1970 to\n\n2010. J World Intell Prop 23(4)\n\nGrigoriadis LG (2014) Trade marks and free trade: a global analysis. Springer Harper J, Gellie B (2006) Counterfeit Medicines: Survey Report Heath C (1997) Parallel imports and international trade. I.I.C. 28:623 Heath C (2004) Parallel Imports in Japan. In: Heath C (ed) Parallel Imports in Asia. Kluwer Law\n\nInternational, p 51\n\nHeath C (2014a) Exhaustion and patent rights. In: Bagley M, Okediji R (eds) Patent law in global", "n_tokens": 349, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-76-2", "doc_id": "medicine_vaccine_book", "page": 76, "text": "perspective. Oxford University Press, p 419, 424\n\nHeath C (2014b) Patent rights and the “Specific Mechanism” to prevent parallel imports. I.I.C\n\n45:399\n\nHilke JC (1988) Free trading or free-riding: an examination of the theories and available empirical\n\nevidence on Gray market imports. World Compet Law Econ Rev 31:75\n\nHo CM (2011) Access to Medicine in the Global Economy: Intnational Agreements on Patents and\n\nRelated Rights 91\n\nJehoram HC (1992) Harmonising intellectual property law within the European community.\n\nI.I.C. 23:622\n\nJehoram HC (1996) International exhaustion versus importation right: a murky area of intellectual\n\nproperty law. G.R.U.R. Int 4:280\n\nJehoram HC (1999) Prohibition of parallel\n\nimports through intellectual property rights.\n\nI.I.C. 30:495, 508\n\nKanavos P et al (2004) The economic impact of pharmaceutical parallel trade in European Union Member States: a stakeholder analysis, Special Research Paper, London School of Economics", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-77-0", "doc_id": "medicine_vaccine_book", "page": 77, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nKanavos P, Costa-i-Font J (2005) Pharmaceutical parallel trade in Europe: stakeholder and com-\n\npetition effects. Econ Policy 758:772–775\n\nKelesidis T et al (2007) Counterfeit or substandard antimicrobial drugs: a review of the scientific\n\nevidence. J Antimicrobial Chemotherapy 60:214\n\nKohler J (1900) Handbuch des Deutschen Patentrechts. Mannheim, p 452 Kongolo T (2000) The new OAPI agreement as revised in February 1999: complying with TRIPS. J\n\nWorld Intell Prop 3:717\n\nKratzke WP (1991) Normative economic analysis of trademark law. Memphis State Univ Law Rev\n\n21(199):205\n\nKumar Rai R, Jagannathan S (2012) Parallel imports and unparallel laws: an examination of the exhaustion doctrine through the lens of pharmaceutical products. Info Comms Technol Law 21:53\n\nKyle M (2009) Parallel trade in pharmaceuticals: firm responses and competition policy. In: Hawk BE (ed) International antitrust law & policy: Fordham competition law, Juris Publishing, pp 339, 345\n\nKyle MK (2007) Pharmaceutical price controls and entry strategies. Rev Econ Stat 89:88 LaFrance M (2013) Wag the dog: using incidental intellectual property rights to block parallel\n\nimports. Mich Telecomm Technol Law Rev 20:45\n\nLandes WM, Posner RA (1987) Trademark law: an economic perspective. J Law Econ 30\n\n(265):265–266\n\nMalueg DA, Schwartz M (1994) Parallel imports, demand dispersion, and international price", "n_tokens": 363, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-77-1", "doc_id": "medicine_vaccine_book", "page": 77, "text": "discrimination. J Int Econ 37:187\n\nMaskus KE (2000) Parallel imports. World Econ 23:1269 Maskus KE (2001) Parallel imports in pharmaceuticals: implications for competition and prices in\n\ndeveloping countries: final report. World Intellectual Property Organization\n\nMaskus KE (2016) Economic Perspectives on Exhaustion and Parallel Imports. In: Calboli I, Lee E (eds) Research handbook on intellectual property exhaustion and parallel imports. Edward Elgar, p 106\n\nMcKeith S (2013) Pharmaceutical patents in developing nations: parallel importation and the\n\ndoctrine of exhaustion. Afr J Legal Stud 6:287\n\nMcKenna M (2012) (Dys)functionality. Houston Law Rev 48:823, 824 Moffat VR (2004) Mutant copyrights and backdoor patents: the problem of overlapping intellectual\n\nproperty protection. Berkeley Technol Law J 19:1473\n\nMusungu S, Cecilia Oh (2006) The use of flexibilities in TRIPS by developing countries: can they\n\npromote access to medicines?, WHO Study on IPRs, Innovation and Public Health\n\nMusungu SF (2016) The TRIPS agreement and public health. In: Correa CM, Yusuf AA (eds) Intellectual property and international trade: trips agreement, 3rd edn. Kluwer Law Interna- tional, p 489\n\nNational Economic Research Associates, The Economic Consequences of the Choice of Regime in the Area of Trademarks: Final Report for DG XV of the European Commission 76-100 (1999) Ncube CB (2016) Intellectual property policy, law and administration in Africa. Exploring Conti-", "n_tokens": 327, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-77-2", "doc_id": "medicine_vaccine_book", "page": 77, "text": "nental and Sub-regional Co-operation, p 110\n\nOverlapping Intellectual Property Rights (2012) Wilkof N, Basheer S (eds) Owoeye O (2015) Access to medicines and parallel trade in patented pharmaceuticals. E.I.P.R. 37\n\n(6):359\n\nPai Y (2016) The hermeneutics of the patent exhaustion Doctrine in India. In: Calboli I, Lee E (eds) Research handbook on intellectual property exhaustion and parallel imports. Edward Elgar, pp 324, 327\n\nReichman J, Okediji R, Lianos I, Jacob R, Stothers C. The WTO Compatibility of a Differentiated International Exhaustion Regime Proposed by the Eurasian Economic Community, A Consul- tancy Report, Research Paper Series, Skolkovo-HSE International Laboratory for Law & Development (on file with author)\n\n69", "n_tokens": 181, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-78-0", "doc_id": "medicine_vaccine_book", "page": 78, "text": "70\n\nRothchild JA (2016) Exhaustion of intellectual property rights and the principle of territoriality in the United States. In: Calboli I, Lee E (eds) Research handbook on intellectual property exhaustion and parallel imports. Edward Elgar, p 226\n\nRoy S, Saggi K (2012) Equilibrium parallel imports and international market structure. J Int Econ\n\n87:262\n\nSaggi K (2013) Market power in the global economy: the exhaustion and protection of intellectual\n\nproperty. Econ J 123:131\n\nSaggi K (2014) Regional exhaustion of intellectual property. Int J Econ Theory 10:125 Sanders AK, Maniatis SM (1993) A consumer trade mark: protection based on origin and quality.\n\nE.I.P.R. 11:406\n\nSchechter FI (1927) The rational basis of trademark protection. Harv Law Rev 40(813):818 Schwartz M (1990) Third-degree price discrimination and output: generalizing a welfare result. Am\n\nEcon Rev 80:1259\n\nShargel L, Kanfer I (eds) (2014) Generic drug product development: solid oral dosage forms, 2nd\n\nedn. CRC Press\n\nShea N (1995) Does the first trade marks directive allow international exhaustion of rights?,\n\nE.I.P.R. 10:463\n\nSingham SA (2000) Competition policy and the stimulation of innovation: TRIPS and the interface between competition and patent protection in the pharmaceutical industry. Brooklyn J Int Law 26:363, 407\n\nStothers CM (2007) Parallel Trade in Europe: Intellectual property. Competition and Regulatory", "n_tokens": 331, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-78-1", "doc_id": "medicine_vaccine_book", "page": 78, "text": "Law\n\nStothers CM (2016) The European internal market: exhaustion plus. In: Calboli I, Lee E (eds) Research Handbook on intellectual property exhaustion and parallel imports. Edward Elgar pp 169, 178\n\nt’Hoen E (2002) TRIPS, pharmaceutical patents, and access to essential medicines: a long way from\n\nSeattle to Doha. Chicago J Int Law 3:27\n\nTaubman A, Wager H, Watal J (2012) A handbook on the WTO TRIPS Agreement, pp 18–20 Tayler Y (ed) (2004) Battling HIV/AIDS: a decision maker’s guide to the procurement of medicines\n\nand related supplies, World Bank, p 117\n\nThe Drug Development Process, United States Food and Drug Administration, https://www.fda. Accessed\n\ngov/patients/learn-about-drug-and-device-approvals/drug-development-process. 10 March 2021\n\nTsien AY (2014) Legal and legislative hurdles to generic drug development approval, and market- ing. In: Shargel L, Kanfer I (eds) Generic drug product development: solid oral dosage forms, 2nd edn. 334, 366\n\nUnited Nations, Committee for Development, List of Least Developed Countries, https://www.un.\n\norg/development/desa/dpad/wp-content/uploads/sites/45/publication/ldc_list.pdf\n\nUnited Nations Interregional Crime and Justice Research Institute, Counterfeit Medicines and", "n_tokens": 309, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-78-2", "doc_id": "medicine_vaccine_book", "page": 78, "text": "Organised Crime (2012)\n\nValletti TM (2006) Differential pricing, parallel trade, and the incentive to invest. J Int Econ 70:314 Valletti TM, Szymanski S (2006) Parallel trade, international exhaustion and intellectual property\n\nrights: a welfare analysis. J Indus Econ 54:499\n\nVarian HR (1985) Price discrimination and social welfare. Am Econ Rev 75:870 Vawda YA, Shozi B (2020) Eighteen years after Doha: an analysis of the use of public health\n\nTRIPS flexibilities in Africa. South Centre\n\nVelásquez G, Correa CM, Pinto Ido VH 2020) Intellectual property, human rights and access to\n\nmedicines: a selected and annotated bibliography, 3rd edn\n\nVerma SK (1998) Exhaustion of intellectual property rights and free trade—Article 6 of the TRIPS\n\nagreements. I.I.C. 29:534, 539\n\nWasserman Rajec SR (2016) Regulatory Responses to International Patent Exhaustion. In: Calboli I, Lee E (eds) Research handbook on intellectual property exhaustion and parallel imports. Edward Elgar, pp 271, 283\n\nI. Calboli", "n_tokens": 245, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-79-0", "doc_id": "medicine_vaccine_book", "page": 79, "text": "Intellectual Property Exhaustion and Parallel Imports of Pharmaceuticals:...\n\nWIPO, Questionnaire on Patent Exceptions (in which the respective countries may indicated that\n\nthere is no clear national position of the issue)\n\nWorld Intellectual Property Organization, Standard Committee on Patents Electronic Forum, Questionnaire on Exceptions and Limitations of Patent Rights, the database administered by the WIPO’s Standing Committee on Patents. https://www.wipo.int/scp/en/exceptions/\n\nWorld Intellectual Property Organization, Standard Committee on Patents Electronic Forum, Questionnaire on Exceptions and Limitations of Patent Rights, Chile, Exhaustion of Rights, https://www.wipo.int/scp/en/exceptions/replies/chile.html#Q8\n\nYu X (2004) Exhaustion and Parallel Imports in China. In: Heath C (ed) Parallel Imports in Asia.", "n_tokens": 171, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-79-1", "doc_id": "medicine_vaccine_book", "page": 79, "text": "Kluwer Law International, pp 25–38\n\nYu X, Yin C (2016) Development of Patent Exhaustion in Mainland China. In: Calboli I, Lee E (eds) Research handbook on intellectual property exhaustion and parallel imports. Edward Elgar, pp 308, 311\n\nYusuf AA (2016) TRIPS: background, principles and general provisions. In: Correa CM, Yusuf AA (eds) Intellectual property and international trade: trips agreement, 3rd edn. Kluwer Law International, pp 23, 26\n\nZaheer Abbas M, Riaz S (2017) Compulsory licensing and access to medicines: TRIPS amendment\n\nallows export to least-developed countries. J Intell Prop Law Prac 12(6):451\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n71", "n_tokens": 313, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-80-0", "doc_id": "medicine_vaccine_book", "page": 80, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nYousuf A. Vawda\n\nAbstract The compulsory licensing and government use flexibility is potentially the most powerful tool available under the TRIPS Agreement, as amplified by the Doha Declaration, to advance public health objectives. Yet, many lower and middle income countries have shown an apparent reluctance to both incorporate them into their national legislation and then utilise them—except in a relatively small number of cases. This contribution analyses the circumstances surrounding this phenome- non. It outlines the context, historical roots of compulsory licensing and its inclusion on the TRIPS Agreement, recent examples of its utility including in two sub-Saharan countries affected by HIV/AIDS, and offers some recommendations. Among the propositions advanced are that the use of such flexibilities is not an insurmountable problem (as the case of Zimbabwe illustrates) and that in the longer term, public health objectives are best advanced by, among others, amending the TRIPS Agree- ment to exempt health technologies from the ambit of intellectual property protec- tion, and new, alternative models for rewarding innovation in this field of technology being introduced.", "n_tokens": 239, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-80-1", "doc_id": "medicine_vaccine_book", "page": 80, "text": "1 Introduction\n\nThis paper is a contribution to the debate on the role of compulsory licensing and government use to promote access to medicines, and is situated within the context of the universally accepted right of access to health care and medicines.1 These are two types of authorisation issued to either third parties or the government itself to make use of a patented invention without the consent of the patent holder, under defined circumstances.\n\n1For present purposes, the term ‘medicines’ includes pharmaceutical and biologic products, vac- cines, diagnostics and related technologies.\n\nY. A. Vawda (*) School of Law, University of KwaZulu-Natal, Durban, South Africa e-mail: vawday@ukzn.ac.za\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_3\n\n73", "n_tokens": 213, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-81-0", "doc_id": "medicine_vaccine_book", "page": 81, "text": "74\n\nY. A. Vawda\n\nlaw unequivocally establishes access to healthcare as a fundamental right,2 this right has achieved recognition mostly in theory. The consistent prioritisation by states and multinational corporations of enforcement of intellectual property (IP) rights over promoting access to medicines, has resulted in health technologies becoming increasingly inaccessible. This is largely because of the monopoly pricing of many life-saving medicines—which has rendered them unaffordable and endangered public goods.3 Such an indictment has been met by the proponents of strong IP protection with the counterclaim that certain provisions in international instruments secure IP protection as a human right. They often cite, in support, the recognition in the ICESCR of the right to the ‘protection of the moral and material interests resulting from any scientific, literary or artistic production of which he is author’.4 However, this sub-article must not be read in isolation, and is counterbalanced by another, which recognises everyone’s right ‘to enjoy the benefits of scientific progress and its applications’5 which, it is argued, must trump any IP claims.\n\nDespite the fact\n\nthat", "n_tokens": 239, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-81-1", "doc_id": "medicine_vaccine_book", "page": 81, "text": "international\n\nThis tension between IP protection and access to health has been the subject of a number of international commissions and, most recently, the UN Secretary-Gen- eral’s High Level Panel on Access to Medicines in 2016.6 One of the Panel’s key recommendations directly references the need for adoption and use of compulsory licensing legislation:\n\nGovernments should adopt and implement legislation that facilitates the issuance of com- pulsory licenses. Such legislation must be designed to effectuate quick, fair, predictable and implementable compulsory licenses for legitimate public health needs, and particularly with regards to essential medicines. The use of compulsory licensing must be based on the provisions found in the Doha Declaration and the grounds for the issuance of compulsory licenses left to the discretion of governments.7\n\nIt is in this context that compulsory licences and government use provisions in IP law are advanced as both important safeguards against abusive practices by IP rights holders, and enablers of the public’s right to access medicines at affordable prices. In theory, the compulsory licence and government use flexibility is one of the most powerful tools available under the 1994 WTO Agreement on Trade Related", "n_tokens": 228, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-81-2", "doc_id": "medicine_vaccine_book", "page": 81, "text": "2For example, in the Universal Declaration of Human Rights https://www.ohchr.org/EN/UDHR/ Documents/UDHR_Translations/eng.pdf (UDHR), the International Covenant on Economic Social and Cultural Rights https://www.ohchr.org/Documents/ProfessionalInterest/cescr.pdf (ICESCR), and a host of other international and regional instruments. 3Vawda and Baker (2013). http://www.scielo.org.za/scielo.php?script¼sci_arttext&pid¼S1996- 20962013000100004#top119. 4UDHR, art 27(2) and ICESCR art 15(1)(c). 5ICESCR, art 15(1)(b). 6United Nations (2016), http://www.unsgaccessmeds.org/final-report. 7United Nations (2016), recommendation 2.6.1 (b). In addition, recommendation 2.6.1 (c) urges the revision and adoption of the paragraph 6 decision.", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-82-0", "doc_id": "medicine_vaccine_book", "page": 82, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nAspects of Intellectual Property Rights (TRIPS Agreement)8 (as amplified by the Doha Declaration9) to advance public health objectives. This is because is removes the patent holder’s exclusive right to work the patent. Despite these options having been recognised internationally since as far back as the Paris Convention in 188310 (as elaborated below), and more recently in Article 31 of the TRIPS Agreement, and with increasing use particularly in the wake of the HIV/AIDS pandemic, many lower and middle income countries (LMICs) have shown an apparent reluctance to fully engage with these mechanisms. They have firstly, not universally incorporated these and other flexibilities into their national legislation and, secondly, where they are available in their legislation, failed or refused to utilise them—except in a relatively small number of cases.11", "n_tokens": 180, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-82-1", "doc_id": "medicine_vaccine_book", "page": 82, "text": "“The lack of appropriate national legislation for the full implementation of such flexibilities remains one of the greatest difficulties for some developing countries. At the international level, there is a need to improve the legal and technical assistance offered to these countries with respect to intellectual property and public health. In the 16 years since the Doha Declaration, technical assistance has been insufficient or inappropriate.”12 This comment highlights the twin problems of the failure to incorporate the flexibilities in national legislation, and the lack of sufficient and, importantly, appropriate technical assistance.\n\nThere are of course multiple other difficulties to be surmounted. They include: political and economic pressures by countries which house IP-rich industries not to use the flexibilities;13 the lack of political will by the governments of LMICs, as well as of some regional IP organisations;14 the lack of technical, legal and regulatory capacity to process such applications; and the legal and judicial culture existent in", "n_tokens": 211, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-82-2", "doc_id": "medicine_vaccine_book", "page": 82, "text": "8Trade-Related Aspects of Intellectual Property Rights [WTO] https://www.wto.org/english/docs_ e/legal_e/27-trips_03_e.htm. 9Declaration on the TRIPS agreement and public health [WTO] https://www.wto.org/english/ thewto_e/minist_e/min01_e/mindecl_trips_e.htm. 10As elaborated below in Sect. 2. 11See, for example, Ellen ‘t Hoen, The Global Politics of Pharmaceutical Monopoly Power. Drug patents, access, innovation and the application of the WTO Doha Declaration on TRIPS and Public Health (2009) https://www.msfaccess.org/sites/default/files/MSF_assets/Access/Docs/ACCESS_ book_GlobalPolitics_tHoen_ENG_2009.pdf. 12Correa and Velasquez (2019) South Centre Research Papers 85 https://www.southcentre.int/wp- content/uploads/2019/04/RP85_Access-to-Medicines-Experiences-with-Compulsory-Licenses- and-Government-Use-The-Case-of-Hepatitis-C_EN.pdf. 13This problem was most recently highlighted in the case of Colombia’s attempts to issue a compulsory licence on imatinib, as indicated by its Minister of Health to a meeting of the World Health Assembly. See WIPO (2017) WIPO Standing Committee on the Law of Patents https:// www.wipo.int/edocs/mdocs/scp/en/scp_27/scp_27_6.pdf, 3. 14Sangeeta Shashikant, “The African Regional Intellectual Property Organization (ARIPO) Proto- col on Patents: Implications for Access to Medicines” [2014] South Centre Research Paper No 56, 6.\n\n75", "n_tokens": 422, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-83-0", "doc_id": "medicine_vaccine_book", "page": 83, "text": "76\n\nY. A. Vawda\n\nmany countries whose intellectual property law has its genesis in the period of colonialism.15\n\nThis paper’s sights are more modest. It reviews the distinct responses of two countries caught in the epicentre of the HIV/AIDS pandemic in sub-Saharan Africa (namely Zimbabwe and South Africa), to understand their respective approaches to the use of compulsory licensing and government use and the barriers that need to be confronted, and to explore some future directions for policy and legal reform in this thematic area.", "n_tokens": 108, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-83-1", "doc_id": "medicine_vaccine_book", "page": 83, "text": "2 Historical and Conceptual Roots\n\nA compulsory licence is an authorisation granted by a government allowing third parties to produce a patented product or to utilise a patented process without the consent of the patent holder, and which use will not amount to an infringement of the patent. The grant of a compulsory licence constitutes a proactive governmental intervention when market forces result in a disequilibrium between the objectives of rewarding innovation and ensuring social and economic welfare.16 They ‘ensure an efficient operation of innovation markets by avoiding the risk that patents themselves become barriers to invention and innovation ... (and) ... (a)s policy tools, compulsory licences help to ensure that patent protection remains properly balanced with other socio-economic interests.’17\n\nThe first iteration of the term ‘compulsory licence’ in an international instrument is to be found in the Paris Convention of 188318 which, although it does not itself define the term, provides for its grant ‘to prevent the abuses which might result from the exercise of the exclusive rights conferred by the patent, for example, failure to work.’19 The earliest recorded references to compulsory licences are found in the Venice Patent Law of 1474.20 This was followed by the UK Statute of Monopolies of 1623 and has, over the past few centuries, been received into the national laws of many jurisdictions.21 In similar vein, ‘government use’ or ‘crown use’ is a grant by", "n_tokens": 296, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-83-2", "doc_id": "medicine_vaccine_book", "page": 83, "text": "15Vawda (2018) South Centre Research Papers 90, 16–18. 16For a history of the evolution of intellectual property, compulsory licences and related issues, see May and Sell (2006). 17Max Planck Institute (2014), p. 9 https://www.mpg.de/8133454/Patent-Declaration1.pdf. 18Paris Convention for the Protection of Industrial Property of March 20, 1883 https://www.wipo. int/edocs/lexdocs/treaties/en/paris/trt_paris_001en.pdf. 19Paris Convention for the Protection of Industrial Property of March 20, 1883, art 5A(2). 20See Editorial and-Thailand-2.html. 21Correa (1999) Trade-Related Agenda, Development and Equity, Working Papers https://www. iatp.org/sites/default/files/Intellectual_Property_Rights_and_the_Use_of_Co.pdf. accessed 26 January 2020. For a background of the use of compulsory licensing in other jurisdictions, see Ellen ‘t Hoen, The Global Politics of Pharmaceutical Monopoly Power. Drug patents, access,\n\n(2012) http://thailawforum.com/articles/Trips-and-access-to-medicines-India-", "n_tokens": 279, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-84-0", "doc_id": "medicine_vaccine_book", "page": 84, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nthe government, to itself or other entities or contractees acting on behalf of govern- ment, to make use of a patented product or process without the consent of the patent holder. Its origin is frequently attributed to UK law.22 In both instances of compul- sory licences and government use, a royalty is required to be paid to the patent holder.23 In the case of compulsory licences, prior negotiation for a voluntary licence on reasonable commercial terms and within a reasonable period of time is also a requirement.24 This requirement is waived in cases of national emergency or other circumstances of extreme urgency, or in cases of public non-commercial use (gov- ernment use)25 or to remedy a practice that has been determined after a judicial or administrative process to be anti-competitive.26", "n_tokens": 172, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-84-1", "doc_id": "medicine_vaccine_book", "page": 84, "text": "The availability and use of compulsory licensing in the pharmaceutical sector was apparently limited during the early twentieth century, as many countries excluded such products from patentability.27 Nonetheless, there are examples of its use in industrialised countries, for example, early instances of use in Canada28 resulted in some of the lowest prices for medicines, while in the UK29 the ‘crown use’ pro- visions have been effectively deployed to secure generic medicines for the National Health Service. The US,30 too, has a long history of government use licences under 28 U.S.C. section 1498, especially for federal programmes involving defence equip- ment as well as medicines. In terms of this expeditious provision, the government was able to procure cheaper generic drugs in the 1960s at less than 1% of their list price together with a reasonable royalty.31 And recently, during the 2001 anthrax", "n_tokens": 183, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-84-2", "doc_id": "medicine_vaccine_book", "page": 84, "text": "innovation and the application of the WTO Doha Declaration on TRIPS and Public Health (2009), 41–44. 22Patents, Designs, and Trade Marks Act of 1883, s 27(2) https://archive.org/stream / patentsdesignsa01britgoog/patentsdesignsa01britgoog_djvu.txt. 23Trade-Related Aspects of Intellectual Property Rights [WTO], art 31(h) requires the payment of ‘adequate remuneration’. 24Trade-Related Aspects of Intellectual Property Rights [WTO], art 31(b). 25Trade-Related Aspects of Intellectual Property Rights [WTO], art 31(b). 26Trade-Related Aspects of Intellectual Property Rights [WTO], art 31(k). 27Ellen ‘t Hoen, The Global Politics of Pharmaceutical Monopoly Power. Drug patents, access, innovation and the application of the WTO Doha Declaration on TRIPS and Public Health (2009), 40. 28Ellen ‘t Hoen, The Global Politics of Pharmaceutical Monopoly Power. Drug patents, access, innovation and the application of the WTO Doha Declaration on TRIPS and Public Health (2009), 41. 29Ellen ‘t Hoen, The Global Politics of Pharmaceutical Monopoly Power. Drug patents, access, innovation and the application of the WTO Doha Declaration on TRIPS and Public Health (2009), 42. 30Ellen ‘t Hoen, The Global Politics of Pharmaceutical Monopoly Power. Drug patents, access, innovation and the application of the WTO Doha Declaration on TRIPS and Public Health (2009), 43. 31Brennan et al. (2016) “A Prescription for Excessive Drug Pricing: Leveraging Government Patent Use for Health (2016), p. 275", "n_tokens": 371, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-84-3", "doc_id": "medicine_vaccine_book", "page": 84, "text": "https://yjolt.org/sites/default/files/kapczynski_18yjolt275_gk_0_0. pdf.", "n_tokens": 38, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-84-4", "doc_id": "medicine_vaccine_book", "page": 84, "text": "77", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-85-0", "doc_id": "medicine_vaccine_book", "page": 85, "text": "78\n\nY. A. Vawda\n\nscare, Canada and the US were willing to consider invoking this flexibility, as has Italy on a number of occasions on anti-trust grounds.32", "n_tokens": 40, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-85-1", "doc_id": "medicine_vaccine_book", "page": 85, "text": "3 The TRIPS Framework\n\nArticle 31 (a) to (l) of the TRIPS Agreement provides for the grant of compulsory licences provided certain conditions are satisfied and procedures followed. These are: (cid:129) Each case must be considered on its individual merits; (cid:129) The proposed user must have made a prior attempt to obtain a voluntary licence from the right holder on reasonable commercial terms, which attempt has not been successful within a reasonable period of time. This requirement is waived (1 ) in the cases of national emergency or other circumstances of extreme urgency, or in cases of public non-commercial use, although the right holder must be notified; and (2) where a compulsory licence has been granted to remedy anti-competitive practices;\n\n(cid:129) The scope and duration of use is limited to the purpose for which the use was authorised and such authorisation shall be terminated if and when the circum- stances which led to the use cease to exist and are unlikely to recur, subject to the legitimate interests of the licensee being protected;\n\n(cid:129) The use is non-exclusive, and is non-assignable except with that part of the\n\nenterprise or goodwill which enjoys such use;\n\n(cid:129) The use is to be predominantly for the supply of the domestic market, except when the compulsory licence is issued to remedy anti-competitive practices. (There is now an additional exception for countries with little or no manufactur- ing capacity under Article 31bis);", "n_tokens": 312, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-85-2", "doc_id": "medicine_vaccine_book", "page": 85, "text": "(cid:129) The patent holder must be paid adequate remuneration for such use taking into account the economic value of the authorisation, but compensation may be adjusted downwards when a compulsory licence is issued to remedy anti- competitive practices;\n\n(cid:129) The legal validity of any decision relating to the authorisation of the use, as well as the amount of remuneration, is subject to judicial or other independent review by a “distinct higher authority” in that country; and\n\n(cid:129) The right holder of a second patent that cannot be exploited without infringing the first patent may receive a licence if the second invention involves an important technical advance of considerable economic significance in relation to the first invention. In such instances, the owner of the first patent shall be entitled to a cross-licence to the second invention on reasonable terms, and the use authorised\n\n32Ellen ‘t Hoen, The Global Politics of Pharmaceutical Monopoly Power. Drug patents, access, innovation and the application of the WTO Doha Declaration on TRIPS and Public Health (2009), 41–42.", "n_tokens": 226, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-86-0", "doc_id": "medicine_vaccine_book", "page": 86, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nin the licence on the first invention shall not be assigned without assignment of the second patent.\n\nArticle 31 of the TRIPS Agreement does not specify or otherwise limit the grounds upon which licences can be granted. This clarification was one of the key outcomes of the Doha Declaration, namely that each country has the right to grant compulsory licences, to determine the grounds on which to grant them, and to determine what constitutes an emergency or other circumstances of extreme urgency, notably public health crises with no restrictions as to disease coverage or frequency of use.33 In addition, the TRIPS Council was mandated to find a solution to the problem encountered by countries with insufficient or no manufacturing capacity in their potential use of the compulsory licensing provisions of Article 31.34 Finally, the Declaration reiterated the freedom of countries to adopt the exhaustion regime of their choice (in order to facilitate parallel importation).35", "n_tokens": 191, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-86-1", "doc_id": "medicine_vaccine_book", "page": 86, "text": "In the wake of the HIV/AIDS pandemic, and buoyed by the Doha Declaration’s pro-public health interpretation of the TRIPS Agreement, a significant number of developing countries and LDCs afflicted by this crisis issued a combination of compulsory licences and government use orders to facilitate the acquisition of antiretroviral medicines (ARVs) and, occasionally, medicines for other conditions. Such countries include Brazil, Ecuador, Eritrea, Ghana, India, Indonesia, Malaysia, Mozambique, Thailand, Zambia and Zimbabwe.36 Further discussion of such use is undertaken below.\n\nCompulsory licences are generally available on a variety of grounds, most notably in relation to patents where the patentee is found to have abused its rights in one manner or another, for example, by excessive pricing, refusals to license, or failure to work, but also where the government wants to ensure alternate sources of medicines supply, to facilitate co-formulations, or even to promote local production. Countries might also consider including judicial licences as an alternative remedy to interdicts in claims of infringement.37", "n_tokens": 224, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-86-2", "doc_id": "medicine_vaccine_book", "page": 86, "text": "33Doha Declaration paragraphs 4b and 4c. 34The solution proposed and now codified in Article 31bis entails onerous procedural requirements on both importing and exporting countries, and has been used only once. See Correa (2019) South Centre Policy Brief N0 57 https://www.southcentre.int/wp-content/uploads/2019/01/PB57_Will- the-Amendment-to-the-TRIPS-Agreement-Enhance-Access-to-Medicines_EN-1.pdf. 35Doha Declaration paragraph 4d. 36See Khor (2014), p. 24. 37See, for example, United Nations Development Programme (2013), p. 39 https://www.undp.org/ content/dam/undp/library/hivaids/English/using_law_to_accelerate_treatment_access_in_south_ africa_undp_2013.pdf accessed 26 January 2020. This option is discussed in some detail below in the section ‘The South Africa case’. (See also, further discussion on judicial licences below).\n\n79", "n_tokens": 243, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-87-0", "doc_id": "medicine_vaccine_book", "page": 87, "text": "80\n\nY. A. Vawda\n\nTable 1 Use of flexibilities against type. Adapted from Medicines Law and Policy (note 38)\n\nFlexibility utilised or intended TRIPS Art 31 (compulsory licensing, public non-commercial use) Doha Declaration Para 7 (LDC pharmaceutical transition period provision) TRIPS Art 30 (patent exception) Doha Declaration Para 5(d) (parallel importation) TOTAL\n\nNumber of uses 105 46 3 1 155\n\n4 A Scan of the Use of TRIPS Flexibilities\n\nThe most comprehensive data currently available on the use of flexibilities are those compiled by Medicines Law and Policy.38 It records some 155 instances of the use of various TRIPS flexibilities since 2001 in 82 countries across the spectrum of WTO classification (least developed countries, developing countries, high-income countries).\n\nIn terms of the relevant flexibility invoked, the majority (105) were in respect of compulsory licensing and government use, followed by the LDC pharmaceutical transition period provision (46), which provides a total waiver from recognizing or enforcing pharmaceutical patents and data protections (Table 1).\n\nA recent update by the South Centre records further uses of compulsory licensing in Russia, in 2019, and Israel, in 2020, the latter in the wake of the COVID-19 pandemic.39\n\nIt is evident that the compulsory licensing and government use flexibility is most favoured by countries seeking to enhance access to medicines, with some of them invoking a public health emergency as the basis for their decision.40", "n_tokens": 312, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-87-1", "doc_id": "medicine_vaccine_book", "page": 87, "text": "Thailand and Ecuador feature as the countries which have made the most frequent use of TRIPS flexibilities, in some 11 instances each. Thailand’s example of government use licences is instructive for the manner in which it marshalled the synergies among evidence-based research and analysis, public mobilisation by civil society, and leadership by politicians and policy makers to ‘move the mountain’.41 The effects of the licences issued between 2006 and 2007 on the prices of various medicines have been substantial. The price for the ARV efavirenz dropped by more than 7 times, and lopinavir/ritonavir by 3 times; for the anti-platelet clopidogril by 50 times; and for the anti-cancer drugs docetaxel and letrazole by 24 and 70 times\n\n38Medicines Law and Policy, “The TRIPS Flexibilities Database” http://tripsflexibilities. medicineslawandpolicy.org/. 39See South Centre, “Compulsory Licences and Government Use of Patented Medicines: Pre- cedents Relevant to Address COVID-19” https://ipaccessmeds.southcentre.int/covid-19-pandemic/. 40See Khor (2014). Of the 12 countries surveyed Ghana, Mozambique, Eritrea and Zimbabwe premised their licences on the emergency ground. 41Wibulpolprasert et al. (2011) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180369/.", "n_tokens": 337, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-88-0", "doc_id": "medicine_vaccine_book", "page": 88, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nrespectively.42 Indonesia is another country with multiple uses, having issued compulsory licences for the supply of ARVs on 3 occasions.43\n\nAccording to the TRIPS Flexibilities Database, 40 of the 46 instances of the use of flexibilities by LDCs related to the LDC transition provision. With the exception of Bangladesh44 there does not appear to be any instances of the use of this flexibility prior to the Doha Declaration. It is therefore significant that there has been a surge in the use of this flexibility post-Doha. Additionally, in terms of the most recent extension of the waiver until 2033, the exemption relates not only to pharmaceutical patents, but also to data protection, mailbox obligations and market exclusivity.45", "n_tokens": 168, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-88-1", "doc_id": "medicine_vaccine_book", "page": 88, "text": "Reference has been made to the lack of appropriate technical advice to countries, when formulating their IP laws, in relation to their use of public health flexibilities. In this regard, the situation of the African Regional Intellectual Property Organisa- tion (ARIPO) is instructive. A 2014 study on the ARIPO Protocol on Patents46 revealed that the effective use of TRIPS flexibilities by countries in the East African Community (EAC), for example, has been constrained by the workings of ARIPO, which processes the majority of patent applications for that region. Further, that its current modus operandi ‘does not facilitate the full use of TRIPS flexibilities and instead erects patent barriers to the importation and local production of affordable medicines.’47 A recent analysis by Baker of the ARIPO-commissioned ‘Compara- tive Study of the Industrial Property Laws of ARIPO Member States’ (Comparative Study) criticises it for ‘its failure to address the vast majority of TRIPS flexibilities’ that are available to its members.48 These include, among others: the lack of substantive discussion on stringent patentability standards; on the full range of allowable non-inventions and exclusions; on research and education, as well as other exceptions permitted under TRIPS Article 30; on disclosure requirements; on the prerogative of governments to define the grounds for compulsory licences; and on the use of competition policy to address abuse of patents.", "n_tokens": 306, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-88-2", "doc_id": "medicine_vaccine_book", "page": 88, "text": "42Khor (2014), p. 13. 43Medicines Law and Policy, “The TRIPS Flexibilities Database”. 44See Gay (2018) https://www.researchgate.net/publication/325206579_Pharmaceutical_Dreams_ TRIPS_and_drugs_policy_in_Bangladesh. 45UN Committee for Development Policy (2015) https://www.un.org/ldcportal/wto-drugs-patent- waiver-for-ldcs-extended-until-2033/. 46Shashikant (2014) South Centre Research Paper No 56 https://www.southcentre.int/wp-content/ uploads/2014/11/RP56_The-ARIPO-Protocol-on-Patents_ENl.pdf. 47Shashikant (2014) South Centre Research Paper No 56, 45. 48Baker (n.d.) “A Full description of WTO TRIPS Flexibilities Available to ARIPO Member States and a Critique of ARIPO’s Comparative Study Analyzing and Making Recommendations Concerning Those Flexibilities [2019] http://kelinkenya.org/wp-content/uploads/2019/05/ARIPO- Member-States-obligations-and-flexibilities-under-the-WTO-TRIPS-Agreement-March-2019.pdf.\n\n81", "n_tokens": 302, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-89-0", "doc_id": "medicine_vaccine_book", "page": 89, "text": "82\n\nY. A. Vawda\n\n5 A Tale of Two Countries\n\nThis section will focus on two case examples from Southern Africa, regarding neighbouring countries heavily affected by the HIV/AIDS pandemic, and their respective approaches to the use of compulsory licensing and government use for access to medicines.", "n_tokens": 58, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-89-1", "doc_id": "medicine_vaccine_book", "page": 89, "text": "5.1 The Zimbabwean Case\n\nZimbabwe’s compulsory licensing regime presents an interesting legal framework. The primary statute is the Patents Act,49 which has undergone three rounds of amendments (in 2001, and twice in 2002) to make it TRIPS-compliant. The Act contains, in addition to provisions for compulsory licensing and government use, special provisions for government use during particular emergencies.\n\nIn addition, there is extensive resort to secondary legislation, such as statutory letters or instruments, to support this framework. Statutory instruments are a form of legislation which allow the provisions of an Act of Parliament to be subsequently brought into force without Parliament having to pass a new Act. They are derived from UK law, Zimbabwe having been a former British colony. The Statutory Instrument or Government Notice is thus a form of delegated or subsidiary legisla- tion.50 In Zimbabwe, an Act of Parliament may delegate power to a relevant Minister to make statutory instruments51 within the scope, and for the purposes, of the particular Act, provided they are consistent with that Act, as well as the Declaration of Rights in Chapter 4 of the country’s Constitution.52\n\nIt should be noted that the range of flexibilities incorporated into the Patents Act includes provisions for: compulsory licensing53 and government use;54 parallel importation;55 early working exception (‘test batches’);56 pre-grant opposition to", "n_tokens": 278, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-89-2", "doc_id": "medicine_vaccine_book", "page": 89, "text": "49Patents (Amendment) Act, 1987 Chapter 26:03 (amended by Acts 26/1971, 39/1973 (ss. 39 and 52), 42/1976 (s. 15), 39/1979, 15/1981, 29/1981, 41/1983, 12/1986 (s. 13), 11/1991 (s. 17), 20/1994 (s. 7), 22/2001, 9/2002, 14/2002.) 50Statutory Instruments (2008), UK House of Commons Information Office Factsheet L7 Legisla- tive Series https://www.parliament.uk/documents/commons-information-office/l07.pdf. 51Delegated or Subsidiary Legislation (undated) Zimbabwe Legal Information Institute https:// zimlii.org/content/delegated-or-subsidiary-legislation. 52Constitution of Zimbabwe Amendment (No 20) Act (2013). See also, Declaration of Rights (2013), Zimbabwe Human Rights Commission. http://www.zhrc.org.zw/your-rights/. 53Patents (Amendment) Act, 1987 Chapter 26:03, ss 30A and 31. 54Patents (Amendment) Act, 1987 Chapter 26:03, ss 34 and 35. 55Patents (Amendment) Act, 1987 Chapter 26:03, s 24A. 56Patents (Amendment) Act, 1987 Chapter 26:03, s 24B.", "n_tokens": 316, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-90-0", "doc_id": "medicine_vaccine_book", "page": 90, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\npatents on a wide range of grounds;57 and revocation on substantially the same grounds as those for opposition to the grant of a patent.58\n\nExemptions are granted from patenting of diagnostic, therapeutic or surgical methods of treatment; plants, animals, micro-organisms, and essentially biological processes for their production.59\n\nThe requirements of novelty, inventive step and industrial applicability for the grant of a patent are included as grounds for pre-grant opposition should they not be satisfied, but the Act does not address the patentability criteria in any detail, and does not specifically exclude new uses, or new compounds, combinations or admixtures of a known substance from patenting. Neither are there any exceptions for educa- tional, research, experimental and other uses. A ‘relative novelty’ standard is applicable, as the Act requires that the invention was ‘not known or used in Zimbabwe.’60", "n_tokens": 200, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-90-1", "doc_id": "medicine_vaccine_book", "page": 90, "text": "5.1.1 Compulsory Licences\n\nThe grounds for compulsory licences are limited to: (1) dependent patents,61 and (2) several grounds for ‘abuse of patent’, such as: non-working; failure to meet demand on reasonable terms; refusal to license; and any anti-competitive abuse.62 In the second set of instances, an applicant has to demonstrate that he or she has not been able to obtain a licence on reasonable terms within 6 months of a request for a voluntary licence, and on the ground that the reasonable requirements of the public with respect to the invention have not been or will not be satisfied.63 The circum- stances which will satisfy the latter criterion are deemed to have occurred if:\n\n(cid:129)\n\n(cid:129)\n\n(cid:129)\n\nthe invention, though capable of being worked in Zimbabwe, is not being worked on a commercial scale and there is no satisfactory reason for non-working; such working is being prevented by the importation of the patented article by the patentee or associated persons, namely, persons claiming under him, or directly or indirectly purchasing from him, or against whom he is not taking legal action for infringement; the demand for the patented article in Zimbabwe is not being met to an adequate extent and on reasonable terms;64", "n_tokens": 267, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-90-2", "doc_id": "medicine_vaccine_book", "page": 90, "text": "57Patents (Amendment) Act, 1987 Chapter 26:03, s 17. 58Patents (Amendment) Act, 1987 Chapter 26:03, s 45. 59Patents (Amendment) Act, 1987 Chapter 26:03, s 2A. 60Patents (Amendment) Act, 1987 Chapter 26:03, s 2(2)(a). 61Patents (Amendment) Act, 1987 Chapter 26:03, s 30A. 62Patents (Amendment) Act, 1987 Chapter 26:03, s 31. 63Patents (Amendment) Act, 1987 Chapter 26:03, s 31(1). 64See also footnote 84, and accompanying text. In this regard, it is submitted that the reference to ‘reasonable terms’ could well include ‘unreasonable pricing’ of a medicine, particularly in the context of the socio-economic conditions in a particular country.\n\n83", "n_tokens": 182, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-91-0", "doc_id": "medicine_vaccine_book", "page": 91, "text": "84\n\nY. A. Vawda\n\n(cid:129) by the refusal to grant a licence on reasonable terms, trade or industry in Zimbabwe, or that of any persons trading or the establishment of any new trade or industry in Zimbabwe is being prejudiced, and it is in the public interest that licence(s) be granted; trade, industry, or any person(s) engaged therein are being prejudiced by unfair conditions attached by the patentee to the purchase, hire, license or use of the patented article or use or working of the patented process;\n\n(cid:129)\n\n(cid:129) any restrictive condition (such as being in restraint of trade or contrary to public policy) has been inserted into a licensing contract for the sale, lease or use of any article or process protected by the patent; and\n\n(cid:129) a practice by the patent holder has been determined after a judicial or adminis- trative process to be anti-competitive, in which case the requirement for prior negotiation for a voluntary licence is waived.65", "n_tokens": 213, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-91-1", "doc_id": "medicine_vaccine_book", "page": 91, "text": "The procedure for the application for a compulsory licence is relatively workable. It entails a fully motivated application to the Registrar of Patents in the manner prescribed by the Act; permits the patentee or other person to oppose it; and after consideration of all the submissions, the Registrar may grant the application on appropriate terms, or refuse it.66 Decisions of the Registrar may be appealed before the Intellectual Property Tribunal.67 This entails an essentially administrative pro- cedure with recourse to appeal before a quasi-judicial Tribunal.\n\nIn addition, the Act apparently also permits a presumptive licence where a patent is in force in respect of a substance capable of being used as food or medicine or in their production.68 This ‘necessity’ premise is plausible where the invention is a medicine or other public necessity that is not available to the general public or a significant group of patients. The relevant tribunal shall on application, grant a presumptive licence subject to payment of a reasonable and affordable royalty. Other inventions falling into this category include the process for producing such substances, inventions capable of being used as surgical or curative devices, or in the protection of the environment, or those capable of substantially improving the technological, social and economic development of the country.69", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-91-2", "doc_id": "medicine_vaccine_book", "page": 91, "text": "5.1.2 Government Use\n\nBy far the strongest flexibility in the Act relates to government use and the special provisions as to State use during an emergency. The essence of this use provision is that ‘any department of state or any person authorized in writing by the Minister\n\n65Patents (Amendment) Act, 1987 Chapter 26:03, ss 31(1), 31(6) and 31(6a). 66Patents (Amendment) Act, 1987 Chapter 26:03, ss 31(1) to 31(5). 67Patents (Amendment) Act, 1987 Chapter 26:03, s 69. 68Patents (Amendment) Act, 1987 Chapter 26:03, s 32(1)(a). 69Patents (Amendment) Act, 1987 Chapter 26:03, s 32(1).", "n_tokens": 171, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-92-0", "doc_id": "medicine_vaccine_book", "page": 92, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\n(of Justice, Legal and Parliamentary Affairs) may make, use or exercise any inven- tion disclosed in any specification lodged at the Patent Office for the service of the State in accordance with this section.’70 Section 34(1) is TRIPS-plus to the extent it requires agreement with the patent holder on the terms and conditions of the use,71 and appears to contradict section 34(5) (which requires that the patent holder need only be informed). It elaborates that the authority may be given either before or after the patent grant, or either before or after the acts for which the authority is given are done, that is, the authority is retrospective in this regard, presumably with an emergency in mind. Secondly, the authority may be given to any person, whether or not he or she is authorised directly or indirectly by the patentee to make, use, exercise or vend the invention.72 The patentee need only be informed timeously and be furnished with any information required, unless it would be contrary to the public interest to do so.73", "n_tokens": 231, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-92-1", "doc_id": "medicine_vaccine_book", "page": 92, "text": "The Act additionally includes ‘Special provisions as to State use during emer- gency’74 in terms of which the State and authorised parties shall have the power to make, use, exercise and vend the invention for purposes deemed by the Minister necessary or expedient to achieve a number of identified public interest purposes. In the case of access to pharmaceutical inventions, the relevant provisions relate to the following needs: the maintenance, and securing a sufficiency, of supplies and services essential to both the life and well-being of the community; promoting the productivity of industry, commerce or agriculture; fostering and directing exports and reducing imports of any classes, from all or any countries and for redressing the balance of trade; or generally, ensuring that the whole resources of the community are available for use, and are used, in a manner best calculated to serve the interests of the community.75\n\nEmploying this framework, the Zimbabwean government issued what appears to be the first government use licence on medicines in the post-Doha era.76 The licence invokes the following legal provisions:\n\n1. Section 34 of the Patents Act which is the enabling provision for the government use licence (Use of patented inventions for service of the State).", "n_tokens": 254, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-92-2", "doc_id": "medicine_vaccine_book", "page": 92, "text": "70Patents (Amendment) Act, 1987 Chapter 26:03, s 34(1). 71Patents (Amendment) Act, 1987 Chapter 26:03, s 34(2). TRIPS Article 31(b) waives this condition in cases of national emergency or other circumstances of extreme urgency, or of public non-commercial use. 72Patents (Amendment) Act, 1987 Chapter 26:03, ss 34(4)(a) and (b). 73Patents (Amendment) Act, 1987 Chapter 26:03, s 34(5). 74Patents (Amendment) Act, 1987 Chapter 26:03, s 35. 75Patents (Amendment) Act, 1987 Chapter 26:03, ss 35(1)(b), (c), (d), (e) and (f). 76Cecilia (2006) Int. J Intellectual Property Management Vol 1 Nos 1/2, 22-36 https://www. researchgate.net/publication/247835566_Compulsory_licences_Recent_experiences_in_develop ing_countries.\n\n85", "n_tokens": 232, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-93-0", "doc_id": "medicine_vaccine_book", "page": 93, "text": "86\n\nY. A. Vawda\n\n2. Section 35 of the Patents Act which enables the declaration of an emergency to override, in this case, antiretroviral patents (Special provisions as to State use during emergency).\n\n3. General Notice 240 of 2002: Declaration of Period of Emergency for an initial period of 6 months commencing 24 May 2002 (reproduced below).\n\n4. Statutory Instrument 32 of 2003, extending the period of emergency for a further 5 years (from January 2003 to December 2008).\n\nGeneral Notice 240 of 2002 PATENTS ACT [CHAPTER 26:03]\n\nDeclaration of Period of Emergency (HIV/AIDS) Notice 2002 IT is hereby notified that the Minister of Justice, Legal and Parliamentary Affairs has, in terms of section 34 as read with section 35 of the Patents Act [Chapter 26:03] made the following notice:\n\n1. This notice may be cited as the Declaration of Period of Emergency (HIV/AIDS) Notice, 2002.\n\n2. In view of the rapid spread of HIV/AIDS among the population of Zimbabwe, the Minister hereby declares an emergency for a period of six months, with effect from the date of promulgation of this notice, for the purpose of enabling the State or a person authorised by the Minister under section 34 of the Act (a) to make or use any patented drug, including any antiretroviral drug, used in the treatment of persons suffering from HIV/AIDS or HIV/AIDS related conditions;\n\n(b) to import any generic drug used in the treatment of persons suffering from HIV/AIDS or HIV/AIDS-related conditions.", "n_tokens": 327, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-93-1", "doc_id": "medicine_vaccine_book", "page": 93, "text": "P. A. CHINAMASA Minister of Justice, Legal and Parliamentary Affairs.\n\n24-5-002\n\nOnce the extended period of emergency had been proclaimed, several companies applied for authorisation to supply antiretrovirals, with a locally-registered company Varichem Pharmaceuticals [Pvt] Ltd being granted authority to ‘produce antiretro- viral or HIV/AIDS-related drugs and supply three-quarters of its produced drugs to State-owned health institutions’ at prices that ‘shall be fixed subject to price control mechanisms to be determined by the Minister.’77 Subsequently, another local company Datlabs, and a local agent Omahn, were authorised to import ARVs from Indian companies Ranbaxy and Cipla, respectively. The authorisation did not\n\n77As quoted in Cecilia (2006), p. 26.", "n_tokens": 171, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-94-0", "doc_id": "medicine_vaccine_book", "page": 94, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nspecify the rate of royalty payable, but it appears that the rate offered was 4% of the value of the generic medicines actually delivered.78\n\n5.1.3 Lessons\n\nThe provisions discussed above represent an expeditious mechanism to enable access to medicines in the context of a declared public health emergency. A number of important lessons may be drawn from this example.\n\nFirstly the importance of effective enabling legislation, so that clear guidelines are available in the law to institute the use of this flexibility, supplemented by detailed mechanisms in the regulations.\n\nSecondly, an expedient administrative rather than judicial procedure, both for the issuance of a compulsory licence, as well as the operation of the government use licence. It is vital that such a procedure is time-saving and cost-effective.\n\nThirdly, various other access-friendly considerations were tied in with this public health flexibility, namely: advancing the industrial policy objective of promoting local production; cost-saving measures such as the use of generic medicines; and the employment of price controls to make the medicines affordable to the State.", "n_tokens": 225, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-94-1", "doc_id": "medicine_vaccine_book", "page": 94, "text": "However, medicines prices generally continue to be high in both the private and public sectors in Zimbabwe, with one study showing that public sector prices were higher than average prices for medicines in seven other African countries,79 although subsequent public sector prices for essential medicines have declined.80 Since the establishment of the Unitaid Medicines Patent Pool, and the inclusion in its coverage of all WHO-recommended ARVs, all sub-Saharan African countries are included in the category of eligible countries, rendering the use of flexibilities superfluous for such medicines. However, as there are no such licensing arrangements for a range of other highly-priced essential medicines, the need to utilise TRIPS flexibilities continues to exist.81\n\n78Ibid. 79See Gavaza et al. people_pay_for_medicines_in_Zimbabwe. 80Marume et al. (2018), https://www.ajol.info/index.php/cajm/article/view/164302. 81Hoen et al. (2018), https://joppp.biomedcentral.com/articles/10.1186/s40545-018-0157-7.\n\n(2009), https://www.researchgate.net/publication/51704733_The_prices_\n\n87", "n_tokens": 278, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-95-0", "doc_id": "medicine_vaccine_book", "page": 95, "text": "88\n\nY. A. Vawda\n\n5.2 The South African Case\n\n5.2.1 Legal Framework\n\nDespite the existence of relevant provisions in over a century of patent legislation,82 not a single compulsory licence has been granted on a pharmaceutical-related patent in South Africa.83 The existing legislation provides for compulsory licences in cases of (1) dependent patents,84 and (2) abuse of patents. In the latter case, the following permissible grounds are enumerated: (cid:129) The patented invention is not being worked in the country on a commercial scale", "n_tokens": 116, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-95-1", "doc_id": "medicine_vaccine_book", "page": 95, "text": "or to an adequate extent;\n\n(cid:129) The demand for the patented article is not being met to an adequate extent and on reasonable terms; (One proposed policy option available in this regard is that ‘a price charged by the patent holder that bears no reasonable relation to the marginal or average variable cost of manufacturing the item shall be deemed unreasonable.’)85\n\n(cid:129) The refusal to license on reasonable terms prejudices trade, industry or agriculture in the country, and it is in the public interest that a licence be granted; and (cid:129) The demand is being met by importation and the price charged is excessive in\n\nrelation to the price charged in countries of manufacture.86 The government use provision states that ‘a Minister of State may use an invention for public purposes on such conditions as may be agreed upon with the patentee, or in default of agreement on such conditions as are determined by the commissioner (of patents) on application by or on behalf of such Minister and after hearing the patentee.’87 The requirement of ‘on such conditions as may be agreed upon with the patentee’ is, of course, TRIPS-plus in that TRIPS Article 31 (b) expressly waives this requirement in certain circumstances, in particular for public non-commercial use.\n\nFor reasons that are explored more fully below, which include the problem of AIDS denialism, pressure from the US government and the legal difficulties of", "n_tokens": 293, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-95-2", "doc_id": "medicine_vaccine_book", "page": 95, "text": "82Patents Act No 57 of 1978, s 56 provides a limited number of grounds for the issuance of compulsory licences, and s 4 permits government use (albeit still requiring prior agreement on the terms). 83See, for example: Vawda (2018), https://www.southcentre.int/wp-content/uploads/2018/12/ RP90_Compulsory-Licensing-Jurisprudence-in-South-Africa-Do-We-Have-Our-Priorities-Right_ EN-1.pdf; Yousuf A Vawda (2013), “Country Case Study: South Africa. In Correa (2013) https:// www.southcentre.int/wp-content/uploads/2016/05/Bk_2013_Pharmaceutical-innovation_EN.pdf. 84Patents Act 57 of 1978, s 55. 85See United Nations Development Programme (2013), p. 68. 86Patents Act 57 of 1978, ss 56(a), (c), (d) and (e) respectively. 87Patents Act, s 4.", "n_tokens": 238, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-96-0", "doc_id": "medicine_vaccine_book", "page": 96, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nsucceeding in compulsory licensing applications,88 advocates of access to medicines have had to seek other flexibilities to advance their cause.\n\nIt has been said that the key to successful rights litigation is both the framing of access issues as human rights claims, as well as having this framing embedded in domestic law.89 Although South African treatment activists have been successful in framing their access to health care and medicines campaigns in terms of human rights norms, they have been less successful in having this paradigm inserted in IP contests in the courts.90 Sometimes presented as the use of compulsory licensing in South Africa,91 the most successful use of a TRIPS flexibility in the country was the invocation of competition law and policy to challenge excessive prices and refusal to licence key ARVs. In the first 2002 Hazel Tau case, after the Competition Commis- sion found probable violations and prior to the Competition Tribunal considering the Commission’s request to grant anti-competition compulsory licences, the patent holders settled by granting licences to multiple generic companies allowing sales throughout the region, thus increasing affordable access to medicines.92 The second case, in 2007, involved a complaint against another company on the grounds of refusal to licence.93 Here again, the company negotiated voluntary licences, with similar results.94", "n_tokens": 265, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-96-1", "doc_id": "medicine_vaccine_book", "page": 96, "text": "In this instance, not only was the general framing in terms of human rights norms evident, but the legislation in terms of which the complaint had been lodged was expressly grounded in transformative and rights-based terms:\n\nThe people of South Africa recognise:\n\nThat apartheid and other discriminatory laws and practices of the past resulted in excessive concentrations of ownership and control within the national economy, weak enforcement of anti-competitive trade practices. and unjust restrictions on full and free participation in the economy by all South Africans.\n\nThat\n\nthe economy must be open to greater ownership by a greater number of", "n_tokens": 116, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-96-2", "doc_id": "medicine_vaccine_book", "page": 96, "text": "South Africans.\n\n88See Sects. 5.2.2, 5.2.3 and 5.2.4 below. 89See, for example: Land (2013) https://www.academia.edu/10455316/Human_Rights_Frames_ in_IP_Contests?email_work_card¼view-paper; and Berger and Kapczynski (2009) Human Rights Advocacy Stories https://papers.ssrn.com/sol3/papers.cfm?abstract_id¼1323522. 90See discussion below in respect of the approach of South African courts to employing a human rights lens in IP disputes, despite having a strong Bill of Rights in its Constitution. 91See Medicines Law and Policy, “The TRIPS Flexibilities Database”. 92Hazel Tau and Others v GlaxoSmithKline and Boehringer Ingelheim (Competition Commission) Case No 2002Sep226, in which patients and civil society organisations complained to the Compe- tition Commission that the named pharmaceutical companies had abused their dominant position in the ARV market, refused to license an essential facility, and engaged in excessive pricing. The Commission found against the companies, and its request to the Competition Tribunal was to order compulsory licences. As indicated, the dispute was settled prior to this hearing with the companies agreeing to grant several voluntary licences for the medicines involved. 93Treatment Action Campaign v MSD (Pty) Ltd & Another (November 2007) Competition Com- mission of South Africa. 94United Nations Development Programme (2013), pp. 93–95.\n\n89", "n_tokens": 339, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-97-0", "doc_id": "medicine_vaccine_book", "page": 97, "text": "90\n\nY. A. Vawda\n\nThat credible competition law, and effective structures to administer that law are\n\nnecessary for an efficient functioning economy.\n\nThat an efficient, competitive economic environment, balancing the interests of workers, owners and consumers and focussed on development, will benefit all South Africans.95\n\nThis legal text is significant in that it situates competition law in the context of South Africa’s history, distorted by apartheid, and outlines a developmental path to the application of competition law in the country.\n\n5.2.2 AIDS Denialism\n\nThe unfortunate chapter of AIDS denialism in South Africa’s lack of response to the pandemic and the resultant avoidable and unnecessary deaths has now been well documented.96 In the context of the government’s questioning of the connection between HIV and the resulting disease syndrome as well as the efficacy of ARVs and other medicines having rendered the question of treatment highly controversial, prospects for the use of compulsory licences were remote.", "n_tokens": 211, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-97-1", "doc_id": "medicine_vaccine_book", "page": 97, "text": "5.2.3 US Pressure\n\nEarly legal challenges and threats against South Africa, Brazil and Thailand on proposed and purported use of compulsory licences have also been well documented.97 In addition, over the past two decades, the US has threatened many countries contemplating such use and routinely placed them on its Special 301 Reports under the US Trade Act of 1974. As commentators have noted, while such threats are usually bluster, it has not stopped some countries (such as India and Brazil) from backing down.98 No doubt, such threats have a chilling effect on countries seeking to preserve their trade relations with the US.\n\nThe use of TRIPS flexibilities has increasingly come under attack in recent bilateral and regional trade agreements involving the US. In particular, the US has sought to constrain the use of compulsory licensing by, for example, limiting the", "n_tokens": 170, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-97-2", "doc_id": "medicine_vaccine_book", "page": 97, "text": "95Competition Act No 89 of 1998, Preamble. The emphasis here is on the final sentence. for example, Nattrass (2005) https://www.sahistory.org.za/sites/default/files/nattrass_ 96See, hivaids_policy.pdf; and Geffen and Cameron (2009) Centre for Social Science Research Aids and Society Research Unit, CSSR Working Paper No 257 https://open.uct.ac.za/bitstream/item/ 22585/Geffen_deadly_hand_denial_2009.pdf?sequence¼1. 97See, for example: Oxfam (2001), https://oxfamilibrary.openrepository.com/bitstream/handle/ 10546/620381/bn-access-to-medicines-south-africa-010201-en.pdf?sequence¼1&isAllowed¼y; Ooms Reichman (2009) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893582/. 98Baker (2018) https://healthgap.org/dont-be-afraid-of-compulsory-licenses-despite-us-threats-spe cial-301-reports-1998-2017-listing-concerns-but-taking-little-action/.\n\nand Hanefeld (2019) https://www.bmj.com/content/bmj/365/bmj.l2098.full.pdf;\n\nand", "n_tokens": 347, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-98-0", "doc_id": "medicine_vaccine_book", "page": 98, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\ngrounds in cases of public non-commercial use, or of national emergency or other circumstances of extreme urgency (as in the Australia-US Free Trade Agreement).99 This strategy ‘has been characterised by a progressive “ratcheting up” of IP protections for pharmaceuticals, with provisions intended to prolong monopolies, support high prices and frustrate market entry of generic medicines—all of which undermine access to affordable medicines.’100\n\nto:\n\nremedying anti-competitive practices, or\n\nIn South Africa, neither the government nor the judiciary appears to have had any appetite for compulsory licences, despite the declarations of its representatives at global fora.101\n\nPrevious calls by civil society and generic manufacturers on the government to implement the provisions of the Patents Act to this end have gone unheeded.102 Currently, patient groups are again engaging the government to issue compulsory licences in respect of newer ARVs, and drugs for use in the treatment of cancer and tuberculosis.103\n\n5.2.4", "n_tokens": 209, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-98-1", "doc_id": "medicine_vaccine_book", "page": 98, "text": "Judicial Deference\n\nAn analysis of compulsory licence applications on pharmaceutical and chemical products before the Commissioner of Patents (High Court) or the Supreme Court of Appeal of South Africa during the period 1978 - 2018 revealed that not a single compulsory licence had been issued, nor has one been issued since the advent of patent legislation in the country in the early twentieth century.104\n\nIn summary, the case analysis highlighted the following lines of reasoning\n\nadopted by the courts in rejecting such applications: (cid:129) The failure on the part of the applicant to discharge the evidentiary burden that the\n\npatent had been abused.105\n\n(cid:129) The concept of working a patent included exploitation, which was interpreted\n\nwidely enough to entail working by importation.106\n\n99See Lopert and Gleeson (2013), pp. 199–223 http://onlinelibrary.wiley.com/doi/10.1111/jlme. 12014/abstract. 100Lopert and Gleeson (2013), p. 199. 101See, for example, WIPO (2016) https://www.wipo.int/edocs/mdocs/scp/en/scp_25/scp_25_6. pdf. 102See, for example, Oxfam (2001), pp. 2–3. 103See Medicins Sans Frontieres (2015) https://www.msf.org/south-africa-should-override-patent- key-hiv-medicine-after-widespread-stock-out-problem; and Fix the Patent Laws Campaign (2019) https://www.fixthepatentlaws.org/. 104Vawda (2018), p. 90. 105Syntheta (Pty) Ltd v Janssen Pharmaceutica NV & Another 1999 (1) SA 85 SCA. 106Sanachem (Pty) Ltd v British Technology Group PLC 1992 BP 276 (CP).\n\n91", "n_tokens": 413, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-99-0", "doc_id": "medicine_vaccine_book", "page": 99, "text": "92\n\nY. A. Vawda\n\n(cid:129) With regard to the amount of remuneration, that it was not unreasonable to charge\n\na royalty which the trade would carry.107\n\n(cid:129) Regarding negotiating reasonable terms for a licence, the court required evidence\n\nindicating, with reasonable precision, what reasonable terms are.108\n\n(cid:129) That a charge of unreasonable terms is not established merely on proof that the compulsory licensing applicant can sell the same sort of article at a lower price.109\n\nAbsent from this formalistic reasoning were any considerations of the level of development of the country, the socio-economic status of the majority of it popula- tion, or the impact of the price of the medicines on access to health care.", "n_tokens": 152, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-99-1", "doc_id": "medicine_vaccine_book", "page": 99, "text": "Of significance is the manner in which the courts have approached the dispute between the patent holder and patent challenger. Thus, in an application (Aventis)110 for, among others, a temporary interdict (injunction) based on an infringement claim against a generic drug manufacturer, the court refused, despite being requested, to consider the impact of the interdict on the supply of medicines and adjudicate the case through the lens of the Constitution and its Bill of Rights.111 It further took a rather narrow view on the question of awarding damages (royalties) as an alternative to the interdict, holding that this would be tantamount to granting a compulsory licence. Article 44.2 of the TRIPS Agreement permits this option and there is now strong precedent for the granting of judicial, royalty-bearing licences instead of injunctions from the US Supreme Court.112 Even though the court in Aventis acknowledged that the issue of patent validity (which had been challenged) still stood to be determined in revocation proceedings, it refused to accept this less restrictive means of resolving an interim dispute, and appears to have disregarded the social value of the alleged infringing product in its considerations.", "n_tokens": 241, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-99-2", "doc_id": "medicine_vaccine_book", "page": 99, "text": "There are several other instances of what appear to be deference towards the interests of patent holders. One relates to the anomalous practice in infringement proceedings that, even if it were found that the invention was not patentable, it would remain valid absent a counterclaim for revocation.113 The effect of this approach is that in infringement proceedings, even if the defence of invalidity is successful thereby defeating an infringement claim, the patent remains on the register, and the proprietor can sue others on the patent.\n\nAnother instance where the prerogatives of the patent holder are prioritised are the so-called interlocutory applications for amendments to patent specifications, where the court has relieved the applicant (the patent holder) of the burden of\n\n107Sanachem (Pty) Ltd v British Technology Group PLC 1992 BP 276 (CP). 108Afitra (Pty) Ltd and Another V Carlton Paper of SA (Pty) Ltd 1992 BP 331 (CP). 109Afitra (Pty) Ltd and Another V Carlton Paper of SA (Pty) Ltd 1992 BP 331 (CP). 110Cipla Medpro v Aventis Pharma (139/12); Aventis Pharma SA v Cipla Life Sciences (138/12) [2012] ZASCA 108 (26 July 2012). 111Constitution of the Republic of South Africa (1996). 112eBay Inc. v MercExchange, L.L.C. 547 U.S. 388 (2006). See also the Indian High Court decision of Hoffman La Roche v. Cipla & Anr, IA No. 642/2008 in CS (OS) No, 89.2008. 113Strix Ltd v Nu-World Industries (Pty) Ltd 2016 (1) SA 387 (SCA).", "n_tokens": 388, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-100-0", "doc_id": "medicine_vaccine_book", "page": 100, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nproviding full reasons for the amendment.114 The Bateman judgment cites with approval another decision (Kimberly-Clark),115 despite the fact that the latter deci- sion in fact adopts the opposite approach. In addition, this court adopted the approach that ‘it is in the public interest that patents should be rectified or validated by way of amendment’116 without having regard to the impact of the continuing validity of the patent on the broader public interest. Any appreciation of the notion of ‘access’ as a public interest in relation to an essential product, facility or service is absent.\n\nIt is therefore contended that the very architecture of the patent landscape, the rather limited grounds on which an application for a compulsory licence may be brought, combined with the overly formal approach to judicial interpretation and adjudication, including an apparent deference to patent holders over the general public, may be responsible for the dearth of such applications, and hence the lack of their grant. It must be noted in passing that generic manufacturers are unlikely to apply for compulsory licences unless there are sufficient commercial prospects, given that the South African pharmaceuticals market is relatively small. And, as regards those medicines covered by the Medicines Patent Pool, South Africa is already benefiting from this initiative.117", "n_tokens": 271, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-100-1", "doc_id": "medicine_vaccine_book", "page": 100, "text": "5.2.5 New IP Policy Phase I\n\nIn 2018 after a protracted civil society-led campaign,118 the South African Cabinet approved a new IP policy, premised on public health,119 in recognition of the abject failure of the present system to adequately meet the need of the general public to access affordable medicines. The IP Policy draws its inspiration from the Constitu- tion of South Africa, and recognises that ‘there is a need for a comprehensive IP Policy that will promote a holistic, balanced and coordinated approach to IP that is mindful of the many obligations mandated under the South African Constitution.’ The policy expressly recognises the need to reform the regime as it relates to compulsory licences, both in terms of their scope and procedure for application, as well as for the establishment of guidelines for expedited government use.120\n\n114Bateman Equipment Ltd and Another v The Wren Group (Pty) Ltd 2000 (1) SA 649 (SCA). 115Kimberly-Clark of South Africa (Pty) Ltd formerly Carlton Paper of South Africa (Pty) Ltd v Proctor & Gamble (Pty) Ltd (A488/96) [1998] ZASCA 39. 116Bateman Equipment Ltd and Another v The Wren Group (Pty) Ltd 2000 (1) SA 649 (SCA). 117See footnote 80 and accompanying text. 118Baker (2015-16), pp. 309–343 documents the origins of such a campaign. 119Republic of South Africa (2018) https://www.thedti.gov.za/news2018/IP_Policy2018-Phase_I. pdf. 120Republic of South Africa (2018), p. 28.\n\n93", "n_tokens": 366, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-101-0", "doc_id": "medicine_vaccine_book", "page": 101, "text": "94\n\nY. A. Vawda\n\n6 Compulsory Licensing Options Under TRIPS\n\nAs indicated,121 the TRIPS Agreement does not limit the grounds upon which licences can be granted. The robust discourse over the last two decades around the use of TRIPS flexibilities and, in particular compulsory licensing, had provided policy-makers, legislators and advocacy groups with a panoply of options to con- sider122 in relation to various aspects of this flexibility: broad grounds, easy-to-use procedures, and royalty guidelines and rates that are not so onerous that they frustrate generic competition and hence access to affordable medicines.", "n_tokens": 129, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-101-1", "doc_id": "medicine_vaccine_book", "page": 101, "text": "6.1 Expanded Grounds for Compulsory Licences\n\nThe expanded grounds for the issuance of compulsory licences that may be consid- ered are: (cid:129) The patent is not worked or not fully worked in the country by the patent holder including that the invention is not available to the public at a reasonably afford- able price; or that it has not been worked locally other than by importation and the patent holder fails to demonstrate that it is not economically or technologically feasible to manufacture it in whole or in part in the country;\n\n(cid:129) The patent is worked by the patent holder or licensee in a form and by means that\n\nare harmful to or abusive of the public interest;\n\n(cid:129) The price charged by the patent holder bears no reasonable relation to the marginal or average variable cost of manufacturing the item and is deemed to be unreasonable;\n\n(cid:129) The patent can be worked locally on a feasible economy of scale and may benefit the general public; or through a licence granted for importation where it is considered advantageous to do so;", "n_tokens": 223, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-101-2", "doc_id": "medicine_vaccine_book", "page": 101, "text": "(cid:129) There is an emergency or other urgent matter of national interest, in which case prior negotiation for a licence on reasonable commercial terms is not required; (cid:129) There is a risk of supply interruptions of essential products such as medicines; (cid:129) There is a need to promote local production and technology transfer; (cid:129) There is any other public interest or public health need; (cid:129) The patent holder has been found to have engaged in an anti-competitive practice; (cid:129) Where the invention, being a medicine or other public necessity, is not available to the general public or a significant group of patients, the relevant tribunal is\n\n121See Sect. 3 above. 122These options are drawn primarily from United Nations Development Programme (2013), pp. 57–71; Baker and Vawda (2017), pp. 40–60 https://www.fixthepatentlaws.org/submission-by- university-of-kwazulu-natal-affiliated-academics-on-sa-draft-intellectual-property-policy/.", "n_tokens": 239, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-102-0", "doc_id": "medicine_vaccine_book", "page": 102, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nenabled to grant, on application, a presumptive licence subject to a reasonable and affordable royalty;\n\n(cid:129) Where the country lacks sufficient capacity to produce a medicine patented in that country, a compulsory licence may be issued for the importation of the product; and conversely for a compulsory licence to be issued in the manufacturing country where that medicine is under patent, for the purpose of supplying a country with insufficient manufacturing capacity, in terms of a streamlined, easy-to-use procedure. Alternatively, to adopt Article 31bis of the TRIPS Agree- ment and the Annex to it;\n\n(cid:129) The grant of a judicial licence in cases alleging infringement, as a satisfactory and\n\nless restrictive alternative to the grant of an interdict or injunction;\n\n(cid:129) Where it is not possible to execute the licence granted on any of the foregoing grounds based on patent disclosures alone, a compulsory licence may be granted on otherwise confidential manufacturing know-how, subject to prior negotiation, payment of reasonable royalty, and non-exclusivity and non-assignability; and (cid:129) Where a product is already on the market while the patent application regarding a needed invention (such as a medicine to respond to an epidemic) is still pending, a provisional compulsory licence may be granted to take effect when the relevant patent/s are granted.", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-102-1", "doc_id": "medicine_vaccine_book", "page": 102, "text": "6.2 Government Use\n\nWith regard to government use licences, these need to be expeditious and easy to implement. The following formulation has been proposed:123 (cid:129) Any properly designated public official or government contractor, domestic or foreign, receiving the authorisation or consent of the government of a country, may make public, non-commercial use of a patent.\n\n(cid:129) No prior negotiation with the patent holder is required, it being necessary only to\n\npromptly notify the holder of such use.\n\n(cid:129) For the purposes of this provision, the use or manufacture of an invention described in and covered by a patent granted in the country by a contractor, sub-contractor, or any person, firm or corporation for the government and with the authorisation or consent of the government, shall be construed as use for that country.\n\n123Baker and Vawda (2017), pp. 47–49.\n\n95", "n_tokens": 197, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-103-0", "doc_id": "medicine_vaccine_book", "page": 103, "text": "96\n\nY. A. Vawda\n\n6.3 Adequate Remuneration\n\nAs regards remuneration of the right holder, TRIPS Article 31(f) requires adequate remuneration based on the economic value of the licence in the country issuing it. The following formulation has been proposed:124 (cid:129) Remuneration Guidelines shall specify a normal royalty of 4% of wholesale cost, with an upward adjustment of no more than 2% based on disclosed, extraordinary research and development costs or therapeutic breakthrough in the case of pharmaceuticals. The rate could be adjusted downwards by the same margin based on the use of public funds in the research, or if the holder has already recovered significantly more than its research and development costs as adjusted for risk and opportunity costs.\n\n6.4 Procedures for Compulsory Licensing Applications\n\nAs indicated, procedures for compulsory licensing should be expeditious and easy- to-use. Expedited administrative procedures, rather than judicial processes, which are both more time-consuming and expensive, should be used. The TRIPS Agree- ment requires judicial process only in relation to independent administrative review in respect of the legal validity of a licence and the amount of remuneration.125 The following formulation has been proposed:126 (cid:129) Examination of an application for a compulsory licence shall be conducted by the", "n_tokens": 268, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-103-1", "doc_id": "medicine_vaccine_book", "page": 103, "text": "relevant authority or tribunal.\n\n(cid:129) The relevant authority or tribunal shall by notice summon the patent holder and applicant to hear their evidence and opinions, and shall stipulate time periods for the submission of evidence, opinions and other matter.\n\n(cid:129) Should the patent holder not respond to the notice within 2 months, the patent holder will be presumed to have no objection to the issuance of the compulsory licence.\n\n6.5 Collaboration and Cooperation in the Issuance of CLs\n\nFinally, there are significant benefits to cooperation between countries on the issuance of compulsory licences. Groups of developing countries could, for exam- ple, pool their procurement needs and coordinate the proposed use of compulsory\n\n124Baker and Vawda, “Submission by University of KwaZulu-Natal-Affiliated Academics”, 56–58. 125TRIPS Agreement, art 31(i) and (j). 126Baker and Vawda (2017), pp. 58–60.", "n_tokens": 210, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-104-0", "doc_id": "medicine_vaccine_book", "page": 104, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nlicences for selected medicines, thereby generating sufficient economies of scale to make it viable for generic manufacturers to enter those markets.127\n\nAn interesting variant of this approach is that permitted by Article 31bis of\n\nTRIPS:\n\nWith a view to harnessing economies of scale for the purposes of enhancing purchasing power for, and facilitating the local production of, pharmaceutical products: where a developing or least developed country WTO Member is a party to a regional trade agreement ... at least half of the current membership of which is made up of countries presently on the United Nations list of least developed countries, the obligation of that Member under Article 31(f) shall not apply to the extent necessary to enable a pharmaceutical product produced or imported under a compulsory licence in that Member to be exported to the markets of those other developing or least developed country parties to the regional trade agreement that share the health problem in question. It is understood that this will not prejudice the territorial nature of the patent rights in question.128\n\nThus, for example, all member states of the Southern African Development Community can benefit from this collaborative and pooled procurement mechanism, as 9 of the 15 members are LDCs,129 or those of the East African Community as well, with 4 of its 5 WTO-member states being LDCs.", "n_tokens": 271, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-104-1", "doc_id": "medicine_vaccine_book", "page": 104, "text": "A strong case has been made that, for African countries to make optimal use of compulsory licensing, they must develop strong manufacturing capacity in the pharmaceutical sector. This is imperative because, as the emerging economies in Asia have begun ‘to implement a more protectionist intellectual property framework, Africa is ill-advised to continue relying on generic manufacturers in Asia for access to affordable pharmaceuticals.’130 The African Union’s Pharmaceutical Manufactur- ing Plan for Africa131 has increasingly been promoting national and regional col- laboration in order to achieve greater self-sufficiency and a sustainable supply of pharmaceuticals for the continent.\n\n6.6 A Compulsory Licensing Facility\n\nAnother novel proposal to address the inadequate and uncoordinated use of com- pulsory licensing is that of the establishment of a compulsory licensing facility or consortium (CL Facility).132 In a submission to the UN Secretary-General’s High\n\n127See Reichman (2009), pp. 247–263. 128TRIPS Agreement, art 31bis 3. 129Hoen et al. (2018). 130Owoeye (2014), pp. 92, 217 http://www9.who.int/bulletin/volumes/92/3/13-128413/en/. 131African Union (2012), https://apps.who.int/medicinedocs/documents/s20186en/s20186en.pdf. 132See Baker (2016a) http://www.unsgaccessmeds.org/inbox/2016/2/27/brook-baker?rq¼brook% 20baker; Baker (2016b) http://www.unsgaccessmeds.org/inbox/2016/2/26/z73kpodxk4jw96mhqe 2tivq0sd1g3v.\n\n97", "n_tokens": 396, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-105-0", "doc_id": "medicine_vaccine_book", "page": 105, "text": "98\n\nY. A. Vawda\n\nLevel Panel on Access to Medicines, the aims of the proposed CL Facility are stated as being to: (cid:129) undertake a series of analyses on all possible options for compulsory licences, the conditions and circumstances of their use, and their implications for access to medicines;\n\n(cid:129) develop and support the implementation of model legislation effectuating the optimal use of compulsory licences and government use orders; provide technical and advocacy assistance for their adoption and use both nationally and regionally (to enable aggregated markets to sustain production and access to medicines).", "n_tokens": 120, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-105-1", "doc_id": "medicine_vaccine_book", "page": 105, "text": "7 Conclusion\n\nDeveloping countries and LDCs, particularly, face many challenges with both the domestication and also the implementation of TRIPS flexibilities, including com- pulsory licences and government use. Many of these are not insurmountable, such as the need for political will, the ability to resist trade and political pressures, and the engagement of appropriate technical assistance. In some instances, such as in South Africa, there is the additional reluctance of the judicial system to apply access-friendly interpretations of IP law in line with its Constitution and Bill of Rights.\n\nIn the two case studies presented here, the prospects for the use of compulsory licensing and government use are not encouraging. Although Zimbabwe used this flexibility in the instances cited more than 10 years ago, it has not done so since then. In South Africa, it has never been used despite many compelling circumstances and strong appeals. There is great expectation that the new IP Policy, once legislated, ought to clear the path for easy use of these forms of licensing. Thereafter it will be entirely up to the political will of government to act on the legislation.", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-105-2", "doc_id": "medicine_vaccine_book", "page": 105, "text": "The current COVID-19 pandemic has brought into sharp relief the inequality that exists both among countries of the world, and within them. Access to any vaccines and other therapies that may be developed cannot be guaranteed, because they are likely to be protected by various forms of intellectual property rights, and hence only be available at a high cost. In this context, compulsory licensing and government use remain an important option for, particularly, developing and least developed coun- tries to ensure access to such health technologies.", "n_tokens": 104, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-106-0", "doc_id": "medicine_vaccine_book", "page": 106, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nReferences\n\nCases\n\nSouth Africa\n\nAfitra (Pty) Ltd and Another V Carlton Paper of SA (Pty) Ltd 1992 BP 331 (CP) Bateman Equipment Ltd and Another v The Wren Group (Pty) Ltd 2000 (1) SA 649 (SCA) Cipla Medpro v Aventis Pharma (139/12); Aventis Pharma SA v Cipla Life Sciences (138/12)\n\n[2012] ZASCA 108 (26 July 2012)\n\nHazel Tau and Others v GlaxoSmithKline and Boehringer Ingelheim (Competition Commission)\n\nCase No 2002Sep226\n\nKimberly-Clark of South Africa (Pty) Ltd formerly Carlton Paper of South Africa (Pty) Ltd v\n\nProctor & Gamble (Pty) Ltd (A488/96) [1998] ZASCA 39\n\nSanachem (Pty) Ltd v British Technology Group PLC 1992 BP 276 (CP) Strix Ltd v Nu-World Industries (Pty) Ltd 2016 (1) SA 387 (SCA) Syntheta (Pty) Ltd v Janssen Pharmaceutica NV & Another 1999 (1) SA 85 SCA Treatment Action Campaign v MSD (Pty) Ltd & Another (November 2007) Competition Commis-\n\nsion of South Africa\n\nUSA\n\neBay Inc. v MercExchange, L.L.C. 547 U.S. 388 (2006)\n\nIndia\n\nHoffman La Roche v. Cipla & Anr, IA No. 642/2008 in CS (OS) No, 89.2008 (India)\n\nStatutes and Statutory Instruments\n\nInternational\n\nDeclaration on the TRIPS agreement and public health [WTO]. https://www.wto.org/english/\n\nthewto_e/minist_e/min01_e/mindecl_trips_e.htm. Accessed 23 Feb 2021\n\nInternational Covenant on Economic Social and Cultural Rights. https://www.ohchr.org/", "n_tokens": 428, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-106-1", "doc_id": "medicine_vaccine_book", "page": 106, "text": "Documents/ProfessionalInterest/cescr.pdf. Accessed 23 Feb 2021\n\nParis Convention for the Protection of Industrial Property of March 20, 1883. https://www.wipo.int/\n\nedocs/lexdocs/treaties/en/paris/trt_paris_001en.pdf. Accessed 23 Feb 2021\n\nTrade-Related Aspects of Intellectual Property Rights [WTO]. https://www.wto.org/english/docs_\n\ne/legal_e/27-trips_03_e.htm. Accessed 23 Feb 2021\n\nUniversal Declaration of Human Rights. https://www.ohchr.org/EN/UDHR/Documents/UDHR_\n\nTranslations/eng.pdf. Accessed 23 Feb 2021\n\n99", "n_tokens": 158, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-107-0", "doc_id": "medicine_vaccine_book", "page": 107, "text": "100\n\nY. A. Vawda\n\nUnited Kingdom\n\nPatents, Designs, and Trade Marks Act of 1883, s 27(2) https://archive.org/stream /\n\npatentsdesignsa01britgoog/patentsdesignsa01britgoog_djvu.txt. Accessed 23 Feb 2021\n\nStatutory Instruments (2008) UK House of Commons Information Office Factsheet L7 Legislative Series https://www.parliament.uk/documents/commons-information-office/l07.pdf. Accessed 23 Feb 2021\n\nSouth Africa\n\nConstitution of the Republic of South Africa, 1996 Patents Act No 57 of 1978\n\nZimbabwe\n\nConstitution of Zimbabwe Amendment (No 20) Act, 2013 Declaration of Rights (2013) Zimbabwe Human Rights Commission. http://www.zhrc.org.zw/your-\n\nrights/. Accessed 23 Feb 2021\n\nBooks\n\nCorrea CM (ed) (2013) Pharmaceutical innovation, incremental patenting and compulsory licens- ing. South Centre, Geneva. https://www.southcentre.int/wp-content/uploads/2016/05/Bk_ 2013_Pharmaceutical-innovation_EN.pdf. Accessed 23 Feb 2021\n\nKhor M (2014) Compulsory license and “Government Use” to promote access to medicines: some\n\nexamples. Third World Network 24\n\nMay C, Sell SK (2006) Intellectual property rights: a critical history. Lynne Rienner Publishers,\n\nBoulder\n\nContributions to Edited Books\n\nVawda YA (2013) Country case study: South Africa. In: Correa CM (ed) Pharmaceutical innova- tion, incremental patenting and compulsory licensing. South Centre, Geneva. https://www. southcentre.int/product/pharmaceutical-innovation-incremental-patenting-and-compulsory- licensing/. Accessed 23 Feb 2021", "n_tokens": 385, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-107-1", "doc_id": "medicine_vaccine_book", "page": 107, "text": "Journal Articles\n\nBaker BK (2015-16) International collaboration on IP and access to medicines: the birth of the\n\nS. Africa fix the patents law campaign. NYLS Law Rev 60:309–343 Brennan H et al (2016) A prescription for excessive drug pricing: leveraging", "n_tokens": 57, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-108-0", "doc_id": "medicine_vaccine_book", "page": 108, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nCecilia O (2006) Compulsory licences: recent experiences in developing countries. Int. J Intellect Property Manag 1(1/2):22–36. https://www.researchgate.net/publication/247835566_Compul sory_licences_Recent_experiences_in_developing_countries. Accessed 23 Feb 2021\n\nGovernment Patent Use for Health (2016) Yale J Law Technol 18: 275 https://yjolt.org/sites/\n\ndefault/files/kapczynski_18yjolt275_gk_0_0.pdf. Accessed 23 Feb 2021\n\nHoen E’t et al (2018) Patent challenges in the procurement and supply of generic new essential medicines and lessons from HIV in the Southern African Development Community (SADC) region. J Pharm Policy Practice. https://joppp.biomedcentral.com/articles/10.1186/s40545-018- 0157-7. Accessed 23 Feb 2021\n\nLopert R, Gleeson D (2013) The high price of ‘Free’ trade: US trade agreements and access to medicines. J Law Med Ethics 41(1):199–223. http://onlinelibrary.wiley.com/doi/10.1111/jlme. 12014/abstract. Accessed 23 Feb 2021\n\nOoms G, Hanefeld J (2019) Threat of compulsory licences could increase access to essential Accessed\n\nmedicines. 23 February 2021\n\nBMJ.\n\nhttps://www.bmj.com/content/bmj/365/bmj.l2098.full.pdf.\n\nReichman JH (2009) Compulsory licensing of patented pharmaceutical inventions: evaluating the J Law Med Ethics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893582/.", "n_tokens": 415, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-108-1", "doc_id": "medicine_vaccine_book", "page": 108, "text": "options. Accessed 23 Feb 2021\n\nVawda YA, Baker BK (2013) Achieving social justice in the human rights/intellectual property debate: Realising the goal of access to medicines. Afr Human Rights Law J. http://www.scielo. org.za/scielo.php?script¼sci_arttext&pid¼S1996-20962013000100004#top119. Accessed 23 Feb 2021", "n_tokens": 95, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-108-2", "doc_id": "medicine_vaccine_book", "page": 108, "text": "Online Journals\n\nBerger JM, Kapczynski A (2009) The story of the TAC case: the potential and limits of socio- economic rights litigation I South Africa. Human Rights Advocacy Stories. https://papers.ssrn. com/sol3/papers.cfm?abstract_id¼1323522. Accessed 23 Feb 2021\n\nCorrea CM (1999) Intellectual property rights and the use of compulsory licences: options for developing countries. South Centre, Geneva, Trade-Related Agenda, Development and Equity, Working Papers https://www.iatp.org/sites/default/files/Intellectual_Property_Rights_and_the_ Use_of_Co.pdf. Accessed 23 Feb 2021\n\nCorrea CM (2019) Will the amendment to the TRIPS agreement enhance access to medicines?” South Centre Policy Brief N0 57 https://www.southcentre.int/wp-content/uploads/2019/01/ PB57_Will-the-Amendment-to-the-TRIPS-Agreement-Enhance-Access-to-Medicines_EN-1. pdf. Accessed 23 Feb 2021\n\nCorrea CM, Velasquez G (2019) Access to medicines: experiences with compulsory licenses and government use – the case of Hepatitis C. South Centre Research Papers 85. https://www. southcentre.int/wp-content/uploads/2019/04/RP85_Access-to-Medicines-Experiences-with- Compulsory-Licenses-and-Government-Use-The-Case-of-Hepatitis-C_EN.pdf. Accessed 23 Feb 2021", "n_tokens": 344, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-108-3", "doc_id": "medicine_vaccine_book", "page": 108, "text": "Editorial (2012) Compulsory licensing: background. Thailand J Law Policy. http://thailawforum. com/articles/Trips-and-access-to-medicines-India-and-Thailand-2.html. Accessed 26 Jan 2020 Gavaza P et al (2009) The prices people pay for medicines in Zimbabwe. Central Afr J Med. https:// www.researchgate.net/publication/51704733_The_prices_people_pay_for_medicines_in_Zim babwe. Accessed 23 Feb 2021\n\nGay D (2018) Pharmaceutical dreams: TRIPS and drugs policy in Bangladesh” https://www. researchgate.net/publication/325206579_Pharmaceutical_Dreams_TRIPS_and_drugs_policy_ in_Bangladesh. Accessed 23 Feb 2021\n\n101", "n_tokens": 172, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-109-0", "doc_id": "medicine_vaccine_book", "page": 109, "text": "102\n\nY. A. Vawda\n\nGeffen N, Cameron E (2009) The deadly hand of denial: Governance and politically-instigated denialism in South Africa”, Centre for Social Science Research Aids and Society Research Unit, CSSR Working Paper No 257 https://open.uct.ac.za/bitstream/item/22585/Geffen_deadly_ hand_denial_2009.pdf?sequence¼1. Accessed 23 Feb 2021\n\nLand M (2013) Human Rights Frames in IP Contests (uncorrected proof). Oxford University Press, Oxford. https://www.academia.edu/10455316/Human_Rights_Frames_in_IP_Contests?email_ work_card¼view-paper . Accessed 23 Feb 2021\n\nMarume A et al (2018) Price and availability survey of essential medicines in the Harare province, Zimbabwe. Central African J Med. https://www.ajol.info/index.php/cajm/article/view/164302. Accessed 23 Feb 2021\n\nShashikant S (2014) The African Regional Intellectual Property Organization (ARIPO) Protocol on patents: implications for access to medicines” South Centre Research Paper No 56 https://www. southcentre.int/wp-content/uploads/2014/11/RP56_The-ARIPO-Protocol-on-Patents_ENl.pdf. Accessed 23 Feb 2021\n\nVawda YA (2018) Compulsory licensing jurisprudence in South Africa: do we have our priorities right?” South Centre Research Papers 90 https://www.southcentre.int/wp-content/uploads/ 2018/12/RP90_Compulsory-Licensing-Jurisprudence-in-South-Africa-Do-We-Have-Our-Prior ities-Right_EN-1.pdf. Accessed 23 Feb 2021", "n_tokens": 396, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-109-1", "doc_id": "medicine_vaccine_book", "page": 109, "text": "Wibulpolprasert S, et al (2011) Government use licences in Thailand: The power of evidence, civil movement and political leadership” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180369/. Accessed 23 Feb 2021\n\nCommand Articles and Law Commission Reports\n\nAfrican Union (2012) Pharmaceutical Manufacturing Action Plan for Africa Business Plan, https://\n\napps.who.int/medicinedocs/documents/s20186en/s20186en.pdf. Accessed 23 Feb 2021\n\nMax Planck Institute (2014) Declaration on Patent Protection: Regulatory Sovereignty under\n\nTRIPS, 9 https://www.mpg.de/8133454/Patent-Declaration1.pdf. Accessed 23 Feb 2021 Oxfam (2001) South Africa vs. the Drug Giants – A Challenge to Affordable Medicines. Oxfam Background Briefing February 2001 https://oxfamilibrary.openrepository.com/bitstream/han dle/10546/620381/bn-access-to-medicines-south-africa-010201-en.pdf?sequence¼1& isAllowed¼y. Accessed 23 Feb 2021\n\nRepublic of South Africa (2018) Intellectual Property Policy of the Republic of South Africa Phase I https://www.thedti.gov.za/news2018/IP_Policy2018-Phase_I.pdf. Accessed 23 Feb. 2021 UN Committee for Development Policy (2015) WTO drugs patent waiver for LDCs extended until https://www.un.org/ldcportal/wto-drugs-patent-waiver-for-ldcs-extended-until-2033/.", "n_tokens": 372, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-109-2", "doc_id": "medicine_vaccine_book", "page": 109, "text": "2033 Accessed 23 Feb 2021\n\nUnited Nations (2016) Secretary-general’s high level panel on access to medicines report: promot- ing innovation and access to health technologies. http://www.unsgaccessmeds.org/final-report. Accessed 23 Feb 2021\n\nUnited Nations Development Programme (2013) Using law to accelerate treatment access in South Africa: an analysis of patent. Compet Med Law 39. https://www.undp.org/content/dam/ undp/library/hivaids/English/using_law_to_accelerate_treatment_access_in_south_africa_ undp_2013.pdf. Accessed 23 Feb 2021\n\nWIPO (2016) Standing Committee on the Law of Patents, Twenty-Fifth Session. https://www.wipo.\n\nint/edocs/mdocs/scp/en/scp_25/scp_25_6.pdf. Accessed 23 Feb 2021\n\nWIPO (2017) Constraints Faced by Developing Countries and Least Developed Countries (LDCs) in Making Full Use of Patent Flexibilities and Their Impacts on Access to ffordable Especially Essential Medicines for Public Health Purposes in Those Countries: Supplement to Document", "n_tokens": 254, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-110-0", "doc_id": "medicine_vaccine_book", "page": 110, "text": "Compulsory Licenses and Government Use: Challenges and Opportunities\n\nSCP/26/5 WIPO Stnding Committee on the Law of Patents https://www.wipo.int/edocs/mdocs/ scp/en/scp_27/scp_27_6.pdf, 3. Accessed 23 Feb 2021\n\nWebsites and Blogs\n\nBaker B (2016a) Health gap submission to the UNSG’s high level panel on access to medicines (unsgaccessmeds.org) http://www.unsgaccessmeds.org/inbox/2016/2/27/brook-baker?\n\n(1) rq¼brook%20baker. Accessed 23 Feb 2021\n\nBaker B (2016b) Submission to UN Secretary-General’s High Level Panel on Access to (unsgaccessmeds.org) http://www.unsgaccessmeds.org/inbox/2016/2/26/", "n_tokens": 204, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-110-1", "doc_id": "medicine_vaccine_book", "page": 110, "text": "Medicines”(2) z73kpodxk4jw96mhqe2tivq0sd1g3v. Accessed 23 Feb 2021\n\nBaker B (2018) Don’t Be Afraid of Compulsory Licenses Despite US Threats: Special 301 Reports 1998-2017 – Listing Concerns But Taking Little Action” (HealthGap) https://healthgap.org/ dont-be-afraid-of-compulsory-licenses-despite-us-threats-special-301-reports-1998-2017-list ing-concerns-but-taking-little-action/. Accessed 23 Feb 2021\n\nBaker BK (n.d.) A Full Description of WTO TRIPS Flexibilities Available to ARIPO Member States and a Critique of ARIPO’s Comparative Study Analyzing and Making Recommendations Concerning Those Flexibilities. https://www.bu.edu/gdp/files/2020/05/ARIPO-Member-States- obligations-andflexibilities-under-the-WTO-TRIPS-Agreement-March-2019.pdf\n\nBaker BK, Vawda YA (2017) Submission by University of KwaZulu-Natal-Affiliated Academics on The Draft Intellectual Property Policy of the Republic of South Africa Phase 1”, 40–60. https://www.fixthepatentlaws.org/submission-by-university-of-kwazulu-natal-affiliated-aca demics-on-sa-draft-intellectual-property-policy/. Accessed 23 Feb 2021\n\nFix the Patent Laws Campaign (2019) Minister Mkhize must ensure access to cancer medicine that WHO now considers ‘essential’”. https://www.fixthepatentlaws.org/. Accessed 23 Feb 2021 Medicines Law and Policy, “The TRIPS Flexibilities Database” http://tripsflexibilities.", "n_tokens": 401, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-110-2", "doc_id": "medicine_vaccine_book", "page": 110, "text": "medicineslawandpolicy.org/. Accessed 23 February 2021\n\nMedicins Sans Frontieres (2015) South Africa should override patent on key HIV medicine after widespread stock out problem: Press Release https://www.msf.org/south-africa-should- override-patent-key-hiv-medicine-after-widespread-stock-out-problem. Accessed 23 Feb 2021 Nattrass N (2005) “AIDS Policy in Post-Apartheid South Africa” (SA History Online) https://www.\n\nsahistory.org.za/sites/default/files/nattrass_hivaids_policy.pdf. Accessed 23 Feb 2021\n\nOwoeye OA (2014) Compulsory patent licensing and local drug manufacturing capacity in Africa”. Bulletin of the WHO, 92, 217 http://www9.who.int/bulletin/volumes/92/3/13-128413/en/ Accessed 23 Feb 2021\n\nRecommendations Concerning Those Flexibilities (2019). http://kelinkenya.org/wp-content/ uploads/2019/05/ARIPO-Member-States-obligations-and-flexibilities-under-the-WTO-TRIPS- Agreement-March-2019.pdf. Accessed 23 Feb 2021\n\nSouth Centre, “Compulsory Licences and Government Use of Patented Medicines: Precedents to Address COVID-19” https://ipaccessmeds.southcentre.int/covid-19-pandemic/.\n\nRelevant Accessed 23 Feb 2021\n\nZimbabwe Legal Information Institute, “Delegated or Subsidiary Legislation” (undated) https:// zimlii.org/content/delegated-or-subsidiary-legislation. Accessed 23 Feb 2021, Chapter 4\n\n103", "n_tokens": 373, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-111-0", "doc_id": "medicine_vaccine_book", "page": 111, "text": "104\n\nY. A. Vawda\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 173, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-112-0", "doc_id": "medicine_vaccine_book", "page": 112, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and the Public Interest\n\nDuncan Matthews\n\nAbstract While detailed debates are underway about the scientific and ethical implications of genome editing, this chapter argues that greater attention should be paid to the patent policy issues that these technologies raise. The chapter argues that WTO Members need to consider urgently the implications of patenting genome editing inventions for human rights and the public interest, taking into account Article 27.2 of the TRIPS Agreement, which provides that Members may exclude from patentability inventions, the prevention within their territory of the commercial exploitation of which is necessary to protect ordre public or morality. Furthermore, while genome editing has great potential to transform healthcare and the wellbeing in society across a broad range of scientific fields, the granting of patent rights for these technologies will have profound implications for affordability and access, particu- larly for people living with chronic lifelong illnesses and for future generations not yet born who are at risk of inheriting preventable medical conditions from their parents. The chapter argues that WTO Members need to consider carefully the impact of granting of genome editing patents, balancing the need to reward inventorship while at the same time having regard to implications for affordability, access and the enjoyment of fundamental human rights.", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-112-1", "doc_id": "medicine_vaccine_book", "page": 112, "text": "1 Introduction\n\nGenome editing technologies hold great potential for scientific research and society. They provide fast, efficient, precise and relatively inexpensive tools to modify the cells of any living organism. Using genome editing techniques, cells of the body (somatic cells) can be modified, potentially curing patients of chronic, lifelong illnesses. Editing the genome of human embryos can also modify the germline identity of human beings, eradicating hereditary diseases in new-born babies and creating resistance to life-threatening conditions for future generations. There is also\n\nD. Matthews (*) Queen Mary University of London, London, UK e-mail: d.n.matthews@qmul.ac.uk\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_4\n\n105", "n_tokens": 210, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-113-0", "doc_id": "medicine_vaccine_book", "page": 113, "text": "106\n\nD. Matthews\n\ngreat potential for non-human uses of genome editing technologies. New varieties of plants can be developed that are disease resistant or have a higher crop yield, while new breeds of farmed animals or marine life can be introduced into the food system in order to offer a broader range of options to consumers and to contribute positively to food security.\n\nThe great potential of genome editing is due to the fact that it offers a relatively simple tool to change any organism’s deoxyribonucleic acid (DNA). This allows genetic material to be added, removed or altered in particular locations in the genome. Genome editing technologies can be divided into four types: zinc finger nucleases (TALENs), meganucleuses and CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats). All four work by inducing a natural cellular repair mechanism designed to repair breakages in DNA but the first three are considered more difficult, less precise and more time-consuming process than CRISPR.\n\n(ZFNs),", "n_tokens": 217, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-113-1", "doc_id": "medicine_vaccine_book", "page": 113, "text": "transcription activator-like effector nucleases\n\nSince 2012, CRISPR has been used in combination with Cas9 (CRISPR associ- ated protein number 9, which plays a vital role in the natural immunological defence system of the body) to guide and cut DNA, and therefore alter, a cell’s genome. It does not fundamentally differ from the previously known genome editing technol- ogies but the additional advantages of the CRISPR-Cas9 system lie in its ability to provide a faster, cheaper, more accurate and more efficient method than other previously known genome editing techniques.1 For instance, if there is a mutation in the genome, CRISPR-Cas9 makes it possible to search, delete and even replace it.2 A simple analogy would be with a word processor document, whereby the author can search for, delete and replace a typographical error.3\n\nYet genome editing raises new challenges in terms of how governance systems regulate technologies and involves key public policy imperatives, particularly those of human rights, fair and equitable access to the benefits of this new technologies’ use, and how governance systems can act in the public interest.", "n_tokens": 247, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-113-2", "doc_id": "medicine_vaccine_book", "page": 113, "text": "In the patent policy debate on genome editing technologies thus far, preliminary studies have already been undertaken into the patentability of CRISPR-Cas9 inven- tions under United States (U.S.) law,4 while claims have been made that patent law in Europe is already fit for purpose.5 Elsewhere, various studies have examined the extent that licensing practices can enable or impede research,6 how patent-holding\n\n1See also National Institutes of Health (NIH), U.S. National Library of Medicine, Your Guide to Understanding Genetic Conditions: What Are Genome Editing and CRISPR-Cas9? https://ghr.nlm. nih.gov/primer/genomicresearch/genomeediting 2The human genome is about 300 billion letters long and, so far, scientists have identified approximately 6000 mutations. 3This analogy with word processing was used, for example, in the presentation by Feng Zhang (Broad Institute) at the Program on Science, Technology and Society Workshop on Editorial Aspirations: Human Integrity at the Frontiers of Biology, 26–28 April 2017, Harvard University. 4Deborah (2017), p. 408; Hannah Mosby (2018), p. 579. 5All European Academies (ALLEA) (2016). 6Sherkow (2017a), p. 565; McMahon (2020) op. cit. n 6.", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-114-0", "doc_id": "medicine_vaccine_book", "page": 114, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\nuniversities grant exclusive licences to private companies which stand in as surro- gates for the institutions themselves,7 and how ethical licensing can be used as a tool of privately driven governance,8 with evidence that the private governance function of patents is often overlooked.9 Other studies have advocated using international law to facilitate agreement on the governing principles,10 particularly to identify appro- priate limitations to the CRISPR toolkit.11 Elsewhere research exemptions have been advocated as mechanisms to guarantee freedom to operate alongside patent pools, clearing houses and compulsory licences in order to help to facilitate access to patented genome editing technologies.12\n\nRather less attention has been paid to the extent that patents for genome editing technologies can be considered barriers to affordable healthcare that infringe the fundamental rights, particularly the right to health.13 Greater attention needs to be paid to the extent that the patent issues that CRISPR-based therapies raise can have adverse implications for public health.14", "n_tokens": 207, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-114-1", "doc_id": "medicine_vaccine_book", "page": 114, "text": "Fair and equitable access to healthcare in the context of the right to health is underpinned by the fundamental principle that everyone should have access to the health services they need, when and where they need them, without suffering financial hardship.15 This principle takes as its legal basis Article 25.1 of the Universal Declaration of Human Rights, 1948, which states explicitly that “([E] veryone has the right to a standard of living adequate for the health and well-being of himself and his family, including food, clothing, housing and medical care...” and by Article 12.1 of the United Nations International Covenant on Economic, Social and Cultural Rights, which states that “[T]he States parties to the present Covenant recognize the right of everyone to the enjoyment of the highest attainable standard of physical and mental health”.16\n\nThis chapter will argue that, in debates about the inter-relationship between patents, fair and equitable access to human genome editing, greater attention needs to be paid to human rights approaches, taking into account the public interest. As such the patent system needs to be considered carefully from a human rights perspective when the governance of genome editing is scrutinised. This human", "n_tokens": 246, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-114-2", "doc_id": "medicine_vaccine_book", "page": 114, "text": "7Contreras and Sherkow (2017), p. 698. 8Guerrini et al. (2017), p. 22. 9McMahon (2020), p. 161. 10Tsung-Ling (2019), p. 1. 11Sadie (2019), p. 1. 12Van Overwalle et al. (2006), p. 143. 13For a general discussion see on the relationship between patents, access to healthcare and the right to health see Matthews (2015), pp. 496–512. 14For a preliminary study see Sherkow (2017b), p. 667. 15Health is a fundamental human right. Statement by Dr Tedros Adhanom Ghebreyesus, WHO Director-General, 10 December 2017: https://www.who.int/mediacentre/news/statements/funda mental-human-right/en/. 16For further discussion see Matthews (2010), pp. 118–139.\n\n107", "n_tokens": 214, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-115-0", "doc_id": "medicine_vaccine_book", "page": 115, "text": "108\n\nD. Matthews\n\nrights approach to the study of patents for genome editing technologies is under- developed and, the chapter will argue, must take place if governance institutions are to understand fully the impact of granting of genome editing patents, balancing the need to reward inventorship with affordability, access and the enjoyment of funda- mental human rights.\n\nIn order to address these issues, the chapter will first provide an explanation of the human genome and how CRISPR-Cas9 genome editing works, highlighting the huge potential genome editing of the germline identity of humans for individuals and for society. The chapter will then turn attention to recent patenting controversies, highlighting the genome editing patent disputes that have already taken place in the U.S. and Europe.", "n_tokens": 150, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-115-1", "doc_id": "medicine_vaccine_book", "page": 115, "text": "Observed through the lens of recent patent disputes in the U.S. and Europe, the chapter will argue that World Trade Organisation (WTO) Members need to pay greater consideration of the patent policy implications of genome editing. Such consideration is imperative in order to ensure that the granting of private rights can be accommodated on an equitable basis, balanced alongside the need to avoid unnecessary risk (including ordre public and morality exceptions under patent law), taking into account human rights principles, meeting public expectations, ensuring fair and equitable access, and acting in the public interest with regard to these potentially transformational healthcare technologies.\n\nBy way of limitation, it should be stated from the outset that this chapter is concerned primarily with editing the human germline, given that this specific application of genome editing technologies accords most closely with (and has most immediacy for) concerns about the patent policy implications in terms of the impacts on society outlined above. While it should be acknowledged that many of the issues considered in this chapter apply equally to somatic therapeutic uses (the cells of the body that are not involved in reproduction) and to agricultural or fisheries food production, germline applications will remain the chapter’s primary focus.", "n_tokens": 247, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-115-2", "doc_id": "medicine_vaccine_book", "page": 115, "text": "2 The Human Genome\n\nThe human genome is contained in 23 pairs of chromosomes (22 autosomes and 1 pair of sex chromosomes) in a sequence of paired chemical bases that are held together in the long molecules of DNA that are present in almost all the cells of the body. The genome is the complete set of genes—regions of the DNA molecule of varying length that usually encode proteins that perform distinct biological func- tions—together with interspersed non-coding regions that regulate when the genes are expressed.17\n\n17Nuffield Council on Bioethics, Genome Editing and Human Reproduction: Social and Ethical Issues (2018), p. 7.", "n_tokens": 132, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-116-0", "doc_id": "medicine_vaccine_book", "page": 116, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\nAlthough all people have similar sets of genes, no two people have exactly the same genome. Even the genomes of “identical” (monozygotic) twins may differ owing to errors in DNA replication and somatic mutations, as well as acquired differences in their epigenomes.18 Some of the genomic differences between people produce differences in their appearance or in their physiology (known as their “phenotype”), while others have no observable effects. Although genomic differ- ences can be highly significant for the expression of disease-related and other characteristics, many of the differences between people that are observable or medically significant arise from the combined effects of genetic, environmental and biographical factors. The Nuffield Council on Bioethics, for instance, has pointed out that environmental factors can cause changes in genes that may increase susceptibility to cancers.19", "n_tokens": 206, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-116-1", "doc_id": "medicine_vaccine_book", "page": 116, "text": "From time to time, inherited genomic variations result in disease or confer a predisposition to disease. This usually comes about due to small changes in the genome, which may be transmitted to future generations. These changes can affect the production of proteins in cells, as well as the regulatory regions of genes or genes that encode a ribonucleic acid (RNA) product. Inherited genetic conditions include life-limiting conditions such as Duchenne muscular dystrophy and cystic fibrosis. Genetic conditions are also significant causes of infertility, pregnancy loss and neonatal death.20 Additionally, even the same genetic mutation can differ signifi- cantly in terms of the way it is manifested in the people affected (their “phenotype”) and the consequences that this may have for the length or quality of their lives. This is because the function of some genes can be modified by other genes, as well as by environmental factors. In the case of single gene disorders, such as Huntingdon’s Disease, it is therefore possible that multiple variants in the same genome affect the associated phenotype. These are sometimes referred to as “modifier genes”.21", "n_tokens": 251, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-116-2", "doc_id": "medicine_vaccine_book", "page": 116, "text": "Thus far, over 10,000 single gene disorders have been identified which are associated with an alteration in a region of a single gene that affects the biological function of that gene product. Individually, single gene disorders are usually rare, but collectively they affect at least one in every hundred people born worldwide. Since they can be inherited and because of the way humans have evolved, migrated and", "n_tokens": 79, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-116-3", "doc_id": "medicine_vaccine_book", "page": 116, "text": "18The epigenome is a multitude of chemical compounds that can tell the genome what to do. The human genome is the complete assembly of DNA (deoxyribonucleic acid)-about 3 billion base pairs—that makes each individual unique. DNA holds the instructions for building the proteins that carry out a variety of functions in a cell. The epigenome is made up of chemical compounds and proteins that can attach to DNA and direct such actions as turning genes on or off, controlling the production of proteins in particular cells. When epigenomic compounds attach to DNA and modify its function, they are said to have “marked” the genome. These marks do not change the sequence of the DNA. Rather, they change the way cells use the DNA’s instructions. The marks are sometimes passed on from cell to cell as cells divide. They also can be passed down from one generation to the next. Source: National Human Genome Research Institute, Epigenomics Fact Sheet: https://www. genome.gov/about-genomics/fact-sheets/Epigenomics-Fact-Sheet. 19Nuffield Council on Bioethics (2018), op. cit. n 17, 7. 20Zorrilla and Yatsenko (2013), p. 1; Hyde and Schust (2015), p. 5; Wojcik et al. (2018), p. 20. 21Nuffield Council on Bioethics (2018), op. cit. n 17, 8.\n\n109", "n_tokens": 319, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-117-0", "doc_id": "medicine_vaccine_book", "page": 117, "text": "110\n\nD. Matthews\n\nmixed or, in some cases, become geographically isolated, some genetic disorders tend to be associated with particular ethnic groups.\n\nAn example is the blood disorder beta thalassaemia, which occurs more com- monly among people of Mediterranean origin; another is sickle cell disease, which is more prevalent in Afro-Caribbean groups. In Europe, one of the most widely known single gene disorders is cystic fibrosis, which arises in children of parents who each have an altered copy of the cystic fibrosis transmembrane conductance regulator gene when the child inherits both mutated alleles. While many genetic disorders are now well understood, many rare genetic disorders have not yet been defined in terms of the genetic mutation responsible.22", "n_tokens": 155, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-117-1", "doc_id": "medicine_vaccine_book", "page": 117, "text": "The Nuffield Council on Bioethics has highlighted the practical consequences of the diffusion of genomics. On the one hand, there will be increasing emphasis in health care on prevention and public health and, on the other, the development of increasingly ‘personalised’ (and therefore differentiated) medicine. This suggests that, as greater awareness of individuals’ susceptibility to illness becomes known through the diffusion of genomics, new obligations will arise for public authorities to provide improved societal conditions (for example, higher-quality environmental standards, such as improved air quality, and equitably provided healthcare). Impor- tantly, knowledge about genomics also raises the question of responsibility on individuals not only for adapting their own behaviour and choosing a suitable lifestyle and a suitable material and social environment, but also, potentially, for selecting a genotype that will be expressed in their future children.23", "n_tokens": 181, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-117-2", "doc_id": "medicine_vaccine_book", "page": 117, "text": "Debates about “designer babies” resulting from genetic interventions into pre-implantation embryos in an attempt to influence the traits that resulting children will have are not new.24 However, these debates have been brought more sharply into focus by the relative ease with which CRISPR genome editing techniques can alter the germline identity of human beings. The National Academies of Sciences, Engineering and Medicine 2017 Report on Human Genome Editing, for instance, draws the distinction between restorative intervention that can alleviate suffering caused by genetically inherited diseases on the one hand, and interventions that improve bodily condition or function beyond what is needed to restore or sustain health, such as enhanced sports prowess, on the other hand.25\n\n22Nuffield Council on Bioethics (2018), op. cit. n 17, 8. 23Nuffield Council on Bioethics (2018), op. cit. n 17, 13. 24See, for instance, Bonnie Steinbock, Designer babies: choosing our children’s genes, The Lancet (11 October 2008); Jonietz (2003). 25The National Academies of Sciences, Engineering and Medicine, Human Genome Editing: Science, Ethics and Governance, 2017, Consensus Study Report, 145.", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-118-0", "doc_id": "medicine_vaccine_book", "page": 118, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...", "n_tokens": 16, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-118-1", "doc_id": "medicine_vaccine_book", "page": 118, "text": "3 The CRISPR-Cas9 Genome Editing Technique\n\nThe transformative potential of CRISPR-Cas9 first came to public attention in 2012 following the publication of a seminal paper published in Science by Jennifer Doudna of University of California Berkeley, Emmanuelle Charpentier, at that time based at Umeå University in Sweden, and their collaborators.26 The Science paper demonstrated that CRISPR-Cas9 can be used to cut and (possibly) edit DNA in vitro. Doudna and Charpentier, and also Feng Zhang and George Church at the Broad Institute (an independent research institute that evolved from a decade of research collaborations among scientists at Harvard University and the Massachu- setts Institute of Technology), became the names most closely associated with CRISPR-Cas9, while the parallel work of Virginijus Šikšnys was also recognised along with that of Doudna and Charpentier with their joint award of the Kavli Prize in Nanoscience in 2018.\n\nCRISPR-Cas9 was adapted from a naturally occurring genome editing in the bacterial immune system. The bacterial immune system captures snippets of DNA from invading viruses and uses them to create DNA segments known as CRISPR arrays.27 The CRISPR arrays allow the bacteria to remember the viruses and, if the viruses attack again, the bacteria produce RNA segments from the CRISPR arrays to target virus DNA. The bacteria then use Cas9 or a similar enzyme to cut the DNA apart, which disables the virus.28", "n_tokens": 306, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-118-2", "doc_id": "medicine_vaccine_book", "page": 118, "text": "In the context of CRISPR-Cas9 gene editing in the laboratory, bio-scientists are able to create a small piece of RNA with a short “guide” sequence that attaches (binds) to a specific target sequence of DNA in a genome. The RNA also binds to the Cas9 enzyme and guides it to the targeted location. The Cas9 enzyme then cuts the DNA at the targeted location so that the genome editing can take place.29 As such, CRISPR-Cas9 has enabled precisely targeted alterations to be performed on DNA sequences in living cells. Working like genetic scissors, the Cas9 nuclease opens both strands of the targeted sequence of DNA to introduce the modification to knock-out the mutation. In this way, genome editing is in effect the ability to develop one-shot genome editing medical treatments.30 It is being explored in research on a wide variety of diseases, including single-gene disorders such as cystic fibrosis, haemophilia, Huntingdon’s disease and sickle cell anaemia, with possible", "n_tokens": 218, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-118-3", "doc_id": "medicine_vaccine_book", "page": 118, "text": "26Jinek et al. (2012), p. 816. 27National Institutes of Health (NIH), op. cit. 1. 28National Institutes of Health (NIH), op. cit. 1. 29The underlying mechanism of CRISPR had also been described previously in Archaea by Francisco Mojica in 1993, who is later said to have coined the term ‘CRISPR’ in correspondence with a colleague (see: Mojica et al. 1993, pp. 613–621; Davies and Mojica 2018, p. 5) and earlier in bacteria by Ishino and colleagues (see: Ishino et al. 1987, pp. 5429–5433), while the conjunction of CRISPR and CRISPR associate nucleases (CRISPR-Cas) was identified as a proto-immune system from 2007 (see: Barrangou et al. 2007, pp. 1709–1712). 30Feng Zhang (Broad Institute), op. cit. n 3.\n\n111", "n_tokens": 219, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-119-0", "doc_id": "medicine_vaccine_book", "page": 119, "text": "112\n\nD. Matthews\n\napplications including plant, microbial, animal and human genetic interventions.31 Genome editing also holds promise for the treatment and prevention of complex diseases such as cancer, heart disease, mental illness and human immunodeficiency virus (HIV) infection.32\n\nIn order to allow access to embryos for the purpose of editing them, these would be created in a laboratory using a method of in vitro fertilisation (IVF). Perhaps the most plausible application for this would be cases in which the variant predisposed whoever had it to a clinically recognised disease. In this case, it would be necessary to know before the embryo was created that there was a likelihood of it inheriting the disease-causing variant, such as by screening the prospective parents. For instance, individuals might have been alerted to the possible presence of the variant through having an affected relative and through screening.", "n_tokens": 180, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-119-1", "doc_id": "medicine_vaccine_book", "page": 119, "text": "However, it is important to recognise the uncertainty that continues to exist about the technical efficacy of the procedures currently available. Of particular concern in this regard is whether CRISPR-Cas9 systems faithfully cleave their intended geno- mic target without uncontrolled cutting of other sequences (“off-target events”) in ways that would make them unsafe for clinical use. The Nuffield Council on Bioethics has also pointed to uncertainty over whether the HDR pathway can be recruited to produce the desired genome change at sufficiently high frequencies for effective clinical use or, if so, how.33\n\nThere are widespread concerns that CRISPR-based genome editing may result in unintended effects in terms of both off-target effects and mutations of human embryos and of incidental editing.34 Kosicki, Tomberg and Bradley, for example, found DNA damage that included deletions of thousands of DNA bases, including at spots far from the edit.35 In some instances deletions can silence genes that should be active and, in other instances, activate genes that should be silent, including cancer- causing genes.36", "n_tokens": 239, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-119-2", "doc_id": "medicine_vaccine_book", "page": 119, "text": "31See also Nordberg et al. (2018), pp. 36–83: 37. 32National Institutes of Health (NIH), op. cit., n 1. 33Nuffield Council on Bioethics (2018), op. cit. n 17, 36. Homology directed repair (HDR) is a naturally occurring nucleic acid repair system that can be used to modify genomes in many organisms, including humans. HDR is initiated by the presence of double strand breaks (DSBs) in DNA. 34For the US Food and Drug Administration (FDA), off-target effects would usually be assessed in relation to toxicity of a drug. How the off-target effects of gene editing can be assessed is less clear, given that mutations will perhaps occur two or three generations later. 35Kosicki et al. (2018), p. 765. 36Sharon Begley, ‘Potential DNA damage from CRISPR has been “seriously underestimated” study finds’, 16 July 2018, STAT News: https://www.statnews.com/2018/07/16/crispr-potential- dna-damage-underestimated/.", "n_tokens": 250, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-120-0", "doc_id": "medicine_vaccine_book", "page": 120, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\n4 Lulu and Nana: The Chinese Genome-Edited Twins\n\n“Immune from HIV”\n\nWidespread public awareness of the possible negative implications and controver- sies associated with the use of genome editing to edit the human germline identity became the focus of global attention in November 2018 when a Chinese researcher at the Southern University of Science and Technology of China in Shenzhen, Dr. He Jiankui, revealed at the Second International Summit on Human Genome Editing in Hong Kong that, as a result of his research, he had implanted into a female patient embryos that had been edited to disable the genetic pathway HIV uses to infect cells and twins had been born whose embryonic genomes had been edited.37 Dr. He claimed to have disabled a gene called CCR5, which encodes a protein that allows HIV to enter cells. Dr. He was seeking to mimic a mutation that is present in about 6–8% of the population and which helps to protect them from HIV infection.\n\nConcerns were raised in the scientific community that Dr. He might have inad- vertently caused mutations in other parts of the genome, which could have unpredictable health consequences.38 If the gene has been disabled, the twin girls born with CCR5 disabled could be vulnerable to other diseases. CCR5, for instance, is already thought to help people fight off, for example, the effects of West Nile virus.39", "n_tokens": 306, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-120-1", "doc_id": "medicine_vaccine_book", "page": 120, "text": "Dr. He was widely condemned by the global scientific community for violating long-standing scientific principles and ethical norms through the application of his research. Subsequently, on 21 January 2019, the Southern University of Science and Technology in Shenzhen announced that Dr. He had been dismissed from his post following an investigation by the Guangdong Health Ministry.40 By the end of 2019 a court in Shenzhen had found He and two collaborators guilty of conducting illegal medical practices when they had forged ethical review documents and misled doctors into unknowlingly implanting gene-edited embryos into two women.41\n\n37Cyranoski and Ledford (2018), pp. 607–608, https://www.nature.com/articles/d41586-018- 07545-0. 38Most recently, see Antonio Regalado, MIT Technology Review, December 3, 2019: https://www. technologyreview.com/s/614764/chinas-crispr-babies-read-exclusive-excerpts-he-jiankui-paper/. 39Cyranoski and Ledford (2018) op. cit. 37. 40Cyranoski and Ledford (2018) op. cit. 37. 41Normile (2019).\n\n113", "n_tokens": 270, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-121-0", "doc_id": "medicine_vaccine_book", "page": 121, "text": "114\n\nD. Matthews\n\n5 Patenting the CRISPR-Cas9 Genome Editing\n\nBreakthrough\n\nDoudna, Charpentier and their collaborators were named as co-inventors for U.S. Patent Application No. 13/842,859, filed by the University of California, the University of Vienna and Charpentier on 15 March 2013, with a priority date of 25 May 2012 when the original provisional application was filed at the US Patent and Trademark Office (USPTO). The patent application was particularly broad in scope, listing 155 claims to the general CRISPR technology.42\n\nZhang and Church’s Broad Institute patent application to the USPTO, US Patent No. 8,697,359, was filed later with a priority date of 12 December 2012, seven months after the Doudna, Charpentier and collaborators’ priority date. The Broad Institute patent was nevertheless deemed eligible for a special accelerated examina- tion track and the patent was issued by the USPTO on 15 April 2014.43\n\nThe USPTO granted the key patent over the foundational CRISPR technology to the Broad Institute following interference proceedings with the University of California.", "n_tokens": 241, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-121-1", "doc_id": "medicine_vaccine_book", "page": 121, "text": "The outcome of the USPTO Patent Trial and Appeal Board (PTAB), rendering judgment that there was no interference-in-fact between the claims in interference between the University of California and the Broad Institute.44 Broad persuaded the PTAB that the parties claim patentably distinct subject matter, rebutting the pre- sumption of interference. Broad convinced the PTAB that its claims, which were all limited to CRISPR-Cas9 systems in a eukaryotic environment, are not drawn to the same invention as the University of California’s, the latter which were all directed to CRISPR-Cas9 systems not restricted to any environment.\n\nSpecifically, the evidence showed the PTAB that the invention of such systems in eukaryotic cells would not have been obvious over the invention of CRISPR-Cas9 systems in any environment, including in prokaryotic cells or in vitro, because the ordinary skill in the art would not have reasonably expected a CRISPR-Cas9 system to be successful in a eukaryotic environment.45\n\nThe PTAB terminated interference proceedings upon accepting Broad’s argu- ment that its claims pertaining to eukaryotic cells are sufficiently distinct from the University of California’s claims for use in any environment, meaning there was no “interference in fact,” a threshold requirement rooted in 37 C.F.R. § 41.203(a).", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-121-2", "doc_id": "medicine_vaccine_book", "page": 121, "text": "42See also Feldman (2016), p. p. 401. 43See also Jacob S. Sherkow, The CRISPR Patent Interference Showdown Is on: How Did We Get Here and What Comes Next? Stanford Law School Law and Biosciences Blog: https://law.stanford. edu/2015/12/29/the-crispr-patent-interference-showdown-is-on-how-did-we-get-here-and-what- comes-next/. 44USPTO Patent Interference No. 106,048. Decisions on Motions 37 C.F.R. § 41.125(a). 45Cyranoski and Ledford (2018) op. cit. 37, 2. See also Kevin Noonan, ‘CRISPR Interference Parties Propose Motions’, Patent Docs Patent Law Blog, 1 August 2019: https://www.patentdocs. org/2019/08/crispr-interference-parties-propose-motions.html.", "n_tokens": 210, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-122-0", "doc_id": "medicine_vaccine_book", "page": 122, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\nThe University of California’s claims had been based on inventions made by Doudna, Charpentier and their collaborators. As discussed above, their breakthrough research in 2012 had demonstrated that CRISPR-Cas9 can be used to cut and (possibly) edit DNA in vitro. However, the USPTO decided that this did not extend to editing genomes in advanced, or eurkaryotic cells, and as such the Broad Institute’s invention was not obvious having regard to the prior art.\n\nThough the PTAB did not cancel or finally refuse any claims when terminating the interference, its decision triggered speculation that UC might eventually take U.S. rights to use in prokaryotes, with Broad taking them in eukaryotes.\n\nThe equivalent application by the Broad Institute for European patent was filed at the European Patent Office (EPO) but, on 23 March 2018, the EPO Opposition Division (OD) found that the priority claim is not valid and revoked the patent for lack of novelty. The case was then referred to the EPO Board of Appeal (BoA), which issued its preliminary comments in preparation for Oral Proceedings on 4 November 2019 (T 0844/18).", "n_tokens": 263, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-122-1", "doc_id": "medicine_vaccine_book", "page": 122, "text": "The key issues for the Oral Proceedings were whether the priority claim of the Broad Institute patent EP2771468 was valid and whether the EPO had the power to decide on entitlement to priority. The patentees appealed the OD Decision and the Oral Proceedings before EPO Board of Appeal 3.3.08 on this critical issue com- menced on 13 January 2020.\n\nThe opponents to the Broad Institute argued successfully that the EPO is com- petent to priority and bound to do so by Article 87 of the European Patent Conven- tion (EPC), and that the OD decision was in line with the large body of EPO case law on priority. The EPO case law provides that the right to claim priority from an earlier application according, as set out in Article 87 EPC which itself is derived from Article 4 of the Paris Convention on the Protection of Industrial Property (1967), is afforded to the applicant of the earlier application and to no other party. As such, the applicant (or applicants) must be the same as the original filing. The Broad Institute's European patent EP2771468 was based on a Patent Cooperation Treaty (PCT) filing (WO2014204729) claiming priority from a number of US provisional applications. One of the US provisionals named an inventor-applicant who was not named on the PCT application.", "n_tokens": 286, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-122-2", "doc_id": "medicine_vaccine_book", "page": 122, "text": "The two earliest priority documents that the Broad Institute was seeking to rely on at the EPO from 12 December 2012 and 2 January 2013 named Luciano Marraffini of Rockefeller University as an inventor-applicant. Marraffini was not an applicant on the later patent and had not assigned priority rights to the Broad Institute. In fact, until mid-2017 the Broad Institute and Rockefeller University were in an inventorship dispute over a number of early CRISPR patents.46 The ‘468 patent was thus revoked in view of an invalid priority claim.\n\n46Allen & Overy, Broad Institute CRISPR-Cas9 Patent Revoked in Europe, https://www. allenovery.com/en-gb/global/news-and-insights/publications/broad-institute-crispr-cas9-patent- revoked-in-europe.\n\n115", "n_tokens": 173, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-123-0", "doc_id": "medicine_vaccine_book", "page": 123, "text": "116\n\nD. Matthews\n\nOf particular note in this case, was the impressive array of prominent experts who provided expert opinions on behalf of the Broad Institute, including former UK Supreme Court President The Rt. Hon. Lord Neuberger, former UK Lord of Appeal in Ordinary judge The Rt. Hon. Lord Hoffmann, Matrix Chambers barrister Philippe Sands, Emeritus Scientific Member of the Max-Planck-Institute for Innovation and Competition Prof. Dr. Joseph Straus, former chair of an EPO Board of Appeal Dr. Ursula Kinkeldey and Swiss Federal Patent Court Judge Dr. Tobias Bremi.47 This list of experts attests to the significance that the Broad Institute placed on the value of the patent at stake and the significance of the legal issue in question.\n\nDespite expectations that the Board of Appeal would refer questions on priority arising in the case to the EPO Enlarged Board of Appeal, in fact the Board of Appeal decided it could sufficiently answer all questions on priority and, as such, upheld the findings of the Opposition Division and dismissed the case on grounds that there was already substantial and consistent body of EPO case law on the matter of priority under Article 87 EPC. Broad will also face further oppositions to EP3009511, which is directed to CRISPR-Cpf1 (now called Cas12a) systems.48", "n_tokens": 286, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-123-1", "doc_id": "medicine_vaccine_book", "page": 123, "text": "At the time of writing, the EPO has so far granted three European patents, all to the University of California, the University of Vienna and Emmanuelle Charpentier, and related to “Methods and compositions for RNA-directed target DNA modifica- tion and for RNA-directed modulation of transcription”.\n\nThe first European patent granted to the Regents of the University of California, the University of Vienna and Emmanuelle Charpentier (EP2800811), concerning the basic CRISPR method, was granted on 7 April 2017.49 It claims a DNA-targeting RNA that comprises a targeting sequence and, together with a modifying polypep- tide, provides for site-specific modification of a target DNA and/or a polypeptide associated with the target DNA. Opposition Proceedings at the EPO were filed subsequently by seven parties, with oral proceedings taking place on 5–7 February 2020. The outcome of the EPO Opposition Proceedings was, taking account of the amendments made by the patent proprietor during the opposition proceedings, the patent and the invention to which it relates were found to meet the requirements of the EPC.50", "n_tokens": 239, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-123-2", "doc_id": "medicine_vaccine_book", "page": 123, "text": "47Amy Sandys, EPO Revokes Broad Institute Patent – But it’s just the beginning for CRISPR-cas, JUVE Patent, 17 January 2020. 48Jef Akst, UC Berkeley Receives CRISPR Patent in Europe, Scientist (March 24, 2017), https:// www.the-scientist.com/?articles.view/articleNo/48987/title/UC-Berkeley-Receives-CRISPR- Pat ent-in-Europe/. 49EP2800811: https://register.epo.org/application?number¼EP13793997&tab¼main (accessed 1 December 2019). 50Art. 53(c) and Rule 28 objection raised by only one of several opponents against EP2800811. The Opposition Division’s provisional opinion was fairly dismissive of the Article 53(c) and Rule 28 objections.", "n_tokens": 191, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-124-0", "doc_id": "medicine_vaccine_book", "page": 124, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\nThe second European patent, with claims that are directed to compositions and uses of a chimeric version of the Cas9 protein, most often associated with use in regulation of gene expression as opposed to direct editing of the genetic code itself, was granted on 26 January 2018.51 Opposition proceedings against the grant of the second European patent have been initiated by four parties, while the most recent European patent for a CRISPR-related invention, which claims methods and com- positions of using CRISPR-Cas9 to modify DNA and regulate gene activity in eukaryotic cells, including kits to carry out such work, was granted on 1 March 2019, with the first opponent filing an EPO Opposition almost immediately on 1 April 2019.52 At the time of writing, the date for oral proceedings relating to the second and third European patents granted to the Regents of the University of California et al has yet to be set and, overall, this is likely to be a lengthy process.\n\n6 Excluding Genome Editing Technologies from", "n_tokens": 217, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-124-1", "doc_id": "medicine_vaccine_book", "page": 124, "text": "Patentability\n\nWhat is surprising about the cases related to CRISPR-Cas9 genome editing that have been considered thus far at the USPTO and EPO is the lack of consideration of the necessity test in decisions to grant patents on these foundational technologies. The Agreement on Trade-Related Aspects of Intellectual Property (the TRIPS Agree- ment) introduces a “necessity test” to assess whether protection of an overriding social interest is justified.53 Specifically, Article 27.2 permits World Trade Organi- sation (WTO) Members to “exclude from patentability inventions, the prevention within their territory of the commercial exploitation of which is necessary to protect ordre public or morality, including to protect human, animal or plant life or health or to avoid serious prejudice to the environment, provided that such exclusion is not made merely because the exploitation is prohibited by their law”.\n\nAs is often stressed, a patent is a grant of exclusive rights but not in itself an authorisation to exploit the patented invention. The latter can be regulated by separate legislation provided this is consistent with Article 27.2, including on grounds that it is necessary to protect human, animal or plant life or health or to avoid serious prejudice to the environment.54 The flexibility of WTO Members to exclude patents, for example on inventions related to genome editing technologies, therefore is provided for explicitly in the TRIPS Agreement.", "n_tokens": 285, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-124-2", "doc_id": "medicine_vaccine_book", "page": 124, "text": "The TRIPS flexibilities contained in Article 27.2 reflect the “necessity test” under the evolving jurisprudence of the WTO whereby the national regulatory autonomy constitutes a core principle for WTO Members which are entitled to pursue their\n\n51EP3241902: https://register.epo.org/application?number¼EP17163434&tab¼main. 52EP3401400: https://register.epo.org/application?number¼EP18152360. 53See also UNCTAD-ICTSD Project on IPRs and Sustainable Development (2005), p. 378. 54Ibid., page 382–383.\n\n117", "n_tokens": 145, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-125-0", "doc_id": "medicine_vaccine_book", "page": 125, "text": "118\n\nD. Matthews\n\ndomestic policy objectives and choose the means for their fulfilment, provided they do not entail protectionist ends.55 The necessity test also underpins the principles set out in Article 8.1 of the TRIPS Agreement, whereby “Members may, in formulating or amending their laws and regulations, adopt measures necessary to protect public health and nutrition, and to promote the public interest in sectors of vital importance to their socio-economic and technological development, provided that such mea- sures are consistent with the provisions of this Agreement.”\n\nThe scope of Article 8.1 was elaborated on by the WTO Dispute Settlement Panel Report in Canada—Patent Protection of Pharmaceutical Products, whereby the prohibition on discrimination as to the field of technology contained in Article 27.1 of TRIPS “does not limit the ability to target certain products in dealing with certain of the important national policies referred to [in Article 8.1].”56 The Panel therefore confirmed that there is considerable scope for WTO Members to include in national legislation exclusions based on measures necessary to protect health and to promote the public interest as set out in the permissible ordre public or morality exceptions set out in Article 27.2 of TRIPS.", "n_tokens": 250, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-125-1", "doc_id": "medicine_vaccine_book", "page": 125, "text": "With regard to the application of the TRIPS flexibilities available under Articles 8.1 and 27.2 of TRIPS in the U.S., it is widely understood that there are no restrictions on patentable subject matter under Section 101 of the U.S.C., and hence no immediate grounds for the USPTO to refuse CRISPR-Cas9 genome editing patents using Article 27.2 type ordre public or morality exceptions to patentability. This legal position was subject to confirmatory judgment by the U.S. Supreme Court in Diamond v. Chakrabarty, with the seminal conclusion that statutory subject matter under 101 includes “everything under the sun that is made by man”.57", "n_tokens": 146, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-125-2", "doc_id": "medicine_vaccine_book", "page": 125, "text": "The situation differs in Europe, where the patentability of inventions related to the editing of germline genomes is already restricted in EPC countries, exceptions to patents being directly linked and based on the logic of inserting public policy mechanisms in patent law.58 When these public policy mechanisms are applied to the grant of patents in the field of the life sciences, and particularly in reproductive medicine and genetic engineering, the debate has been controversial for decades.59 Article 53(a) of the EPC sets out a general ordre public and morality exception whereby “European patents shall not be granted in respect of ... inventions the publication or exploitation of which would be contrary to ‘ordre public’ or morality, provided that the exploitation shall not be deemed to be contrary merely because it is prohibited by law or regulation in some or all of the Contracting States”.\n\nThe meaning of ordre public in the context of Article 53(a) EPC has since been elaborated by the EPO Technical Board of Appeal in the T356/93 decision as\n\n55Kapterian (2010), pp. 89–127; Salinas Alcaraz (2015), pp. 77–99. 56Canada – Patent Protection of Pharmaceutical Products, Report of the Panel, WT/DS114/R, 17 March 2000, paragraph 7.92. 57Diamond v. Chakrabarty 447 U.S. 303 (1980). 58Nordberg et al. (2018) op. cit. n 31, 40. 59For a wider discussion see Ingrid SchneiderLL (2019), pp. 263–287.", "n_tokens": 331, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-126-0", "doc_id": "medicine_vaccine_book", "page": 126, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\nfollows: “It is generally accepted that the concept of ‘ordre public’ covers the protection of public security and the physical integrity of individuals as part of society. This concept encompasses also the protection of the environment. Accord- ingly, under Article 53(a) EPC, inventions the exploitation of which is likely to breach public peace or social order (for example, through acts of terrorism) or to seriously prejudice the environment are to be excluded from patentability as being contrary to ‘ordre public’.”60\n\nIn the same T 356/93 decision, the EPO Technical Board of Appeal elaborated on the meaning of “morality” under Article 53(a) EPC as follows: “The concept of morality is related to the belief that some behaviour is right and acceptable whereas other behaviour is wrong, this belief being founded on the totality of the accepted norms which are deeply rooted in a particular culture. For the purposes of the EPC the culture in question is the culture inherent in European society and civilisation. Accordingly, under Article 53(a) EPC, inventions the exploitation of which is not in conformity with the conventionally accepted standards of conduct pertaining to this culture are to be excluded from patentability as being contrary to morality.”", "n_tokens": 269, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-126-1", "doc_id": "medicine_vaccine_book", "page": 126, "text": "The EPO Guidelines for Examination on Article 53(a) EPC also elaborate on how the test should be applied: “Any invention the commercial exploitation of which would be contrary to ‘ordre public’ or morality is specifically excluded from patentability. The purpose of this is to deny protection to inventions likely to induce riot or public disorder, or to lead to criminal or other generally offensive behaviour ... Anti-personnel mines are an obvious example. This provision is likely to be invoked only in rare and extreme cases. A fair test to apply is to consider whether it is probable that the public in general would regard the invention as so abhorrent that the grant of patent rights would be inconceivable. If it is clear that this is the case, objection should be raised under Art. 53(a); otherwise not...”.61\n\nIn the EU law context there are explicit links with the ordre public and morality exceptions of Article 53(a) EPC by means of the 1998 Biotechnology Directive.62 The Directive includes, in Articles 5 and 6, provisions which can be interpreted as having the aim of preserving European fundamental values and human rights norms in patent law.63", "n_tokens": 245, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-126-2", "doc_id": "medicine_vaccine_book", "page": 126, "text": "Article 5 of the Biotechnology Directive focuses on the human body which, at various stages of its formation and development, and the simple discovery of one of its elements, including the sequence or partial sequence of a gene, cannot constitute patentable inventions. Nevertheless, Article 5 goes on to state that an element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a\n\n60EPO Technical Board of Appeal in Plant Genetic Systems/Glutamine synthetase inhibitors T356/ 93 [1995] EPOR 357. 61Guidelines for Examination in the EPO C-IV, 4.1. 62Directive 98/44 of the European Parliament and of the Council of 6 July 1998 on the Legal Protection of Biotechnological Inventions. 63Schneider, op. cit. n 58.\n\n119", "n_tokens": 180, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-127-0", "doc_id": "medicine_vaccine_book", "page": 127, "text": "120\n\nD. Matthews\n\npatentable invention, even if the structure of that element is identical to a natural element, provided that the industrial application of a sequence or a partial sequence of a gene is disclosed in the patent application.\n\nThe sixteenth recital to the Biotechnology Directive indicates that the logic of Article 5 is “respect for the fundamental principles safeguarding the dignity and integrity of the person”, asserting that “it is important to assert the principle that the human body, at any stage in its formation or development, including germ cells and the simple discovery of one of its elements or one of its products, including the sequence or partial sequence of the human gene, cannot be patented”.64\n\nArticle 6(1) of the Biotechnology Directive then goes on to require that “inven- tions shall be considered unpatentable where their commercial exploitation would be contrary to ordre public or morality”, while Article 6(2) sets out a non-exhaustive list of examples of biotechnological inventions that are excluded from patentability on moral grounds, including (a) “processes for cloning human beings”, (b) “processes for modifying the germ line genetic identity of human beings”, and (c) “uses of human embryos for industrial or commercial purposes”.", "n_tokens": 259, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-127-1", "doc_id": "medicine_vaccine_book", "page": 127, "text": "Nevertheless, Article 6(1) of the Biotechnology Directive should be read in conjunction with Recital 42, which states that “... in any case such exclusion does not affect inventions for therapeutic or diagnostic purposes which are applied to the human embryo and are useful to it”. Whether genome editing techniques comprising processes for modifying the germline genetic identity of human beings constitute inventions for “therapeutic” purposes within the meaning of Recital 42 therefore remains uncertain and is yet to be clarified by the EPO or its Boards of Appeal.\n\nIn this regard, it should be noted that although the EPO, as an organisation constituted by the EPC, is not subject to the treaties and legislation of the EU, the EPO Administrative Council adopted all the articles of the Biotechnology Directive into its own legal order via the implementing rules of the EPC, with Articles 5 and 6 of the Biotechnology Directive comprising Rules 28 and 29 of the EPC.65", "n_tokens": 189, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-127-2", "doc_id": "medicine_vaccine_book", "page": 127, "text": "Consequently, Rule 28 of the Implementing Regulations to the EPC imports the Article 6(2)(b) provision of the Biotechnology Directive into EPO examination practice whereby “Under Article 53(a) EPC European patents shall not be granted ... in respect of biotechnological (b) processes for modifying the germ line genetic identity of human beings...”. The possibility that Recital 42 of the Biotechnology Directive could over-ride the exception to the patentability of genome editing technologies for processes related to modifying the germline genetic identity of human beings therefore remains remote before the EPO.\n\ninventions which,\n\nin particular, concern:\n\n64See also Schellekens and Vantsiouri (2013), p. 190: https://www.tandfonline.com/doi/abs/10. 5235/17579961.5.2.190, who elaborate on the concept of human dignity and refer to Marco Olivetti’s commentary on Article 1 of the EU Charter of Fundamental Rights, in which he ‘discerns human beings becoming mere objects in medical or biological practices as an example of an affront to dignity’ (Olivetti 2010, p. 7). 65See also Schneider, op. cit., n 58, 264.", "n_tokens": 266, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-128-0", "doc_id": "medicine_vaccine_book", "page": 128, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\nRule 29 of the Implementing Regulations is also directly relevant to genome editing technologies relating to the human germline given that it states, in Rule 29.1, that “[t]he human body, at the various stages of its formation and development, and the simple discovery of one of its elements, including the sequence or partial sequence of a gene, cannot constitute patentable inventions”.\n\nNevertheless, the debate remains ongoing as to whether the exclusions to patent- ability encompassed in Articles 5 and 6 of the Biotechnology Directive and, by association, Rules 28 and 29 of the Implementing Regulations to the EPC embody the precautionary principle as enshrined in Article 191 of the Treaty on the Func- tioning of the European Union (TFEU) which aims at ensuring a higher level of environmental protection through preventative decision-taking in the case of risk. In practice, the scope of the principle is far wider and covers also consumer policy, as well as EU legislation concerning food and human, animal and plant health.66 Whether the precautionary principle should (or could) also be taken into account by patent granting authorities when determining whether a European patent should be issued remains, as yet, unresolved.67", "n_tokens": 267, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-128-1", "doc_id": "medicine_vaccine_book", "page": 128, "text": "As demonstrated by the foregoing discussion, the European patent system there- fore comprises a fairly comprehensive toolkit to enable patent examiners to assess what types of inventions should be excluded from patentability on grounds that they are considered socially undesirable and/or violate human dignity.68 This has a perceptible impact on the drafting of CRISPR-related patent applications to the EPO, with disclaimers such as “non-human’, “human germline not modified” or “wherein the cells are not germ cells”.69\n\nSpecifically, although European patent claims to the “composition” or “vector system” (that is to say a DNA molecule used as a vehicle to artificially carry foreign genetic material into another cell) are regularly being granted by the EPO, on grounds that they are considered to fall outside the Rule 28(b) exception, there is significant evidence of amendments to the claims in genome editing European patent applications which explicitly exclude use of a process for modifying the germline genetic identity of human beings.70", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-128-2", "doc_id": "medicine_vaccine_book", "page": 128, "text": "66European Commission, Communication (COM(2000) 1 final) on the Precautionary Principle: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri¼LEGISSUM%3Al32042. 67See, for instance, Reynolds (2013), p. 95; Nordberg et al. (2018), op. cit. 31, 49–50, noting that in its most simple formulation the Precautionary Principle may seem to ignore the costs of not continuing a line of research and development and finding that, while a broadly precautionary approach to regulation of gene editing is justified, it is important that it is interpreted in a way that avoids a disproportionate (and potentially incoherent) focus on possible harm. Nordberg et al. (2018) op. cit. n 31, sum up that CRISPR-Cas9 and the future of gene-editing technology can potentially produce enormous benefits to humans, but the uncertainty about possible harm that may result from large-scale gene editing means that a precautionary approach is advisable to policy decisions that respect a proportionality constraint on acceptable precautions. 68See also Schneider, op. cit. n 58, 267. 69See also Schneider, op. cit. n 58, 283. 70Sherkow and Thomas Scott (2019), p. 97 North Carolina Law Review 1497, discusses the strategy of keeping some of the most significant information about vectors secret while patenting only certain aspects.\n\n121", "n_tokens": 338, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-129-0", "doc_id": "medicine_vaccine_book", "page": 129, "text": "122\n\nD. Matthews\n\nA practical example of limitations to claim language introduced by the EPO Examining Division is the aforementioned Broad Institute European patent EP2771468, which was subject to Oral Proceedings at the EPO in January 2020. The Broad Institute patent contained amended claim language relating to “Use of the composition of claim 1, or the vector system of claim 2 or any claim dependent thereon for genome engineering, provided that said use is not a method for treatment of the human or animal body by surgery or therapy, and provided that said use is not a process for modifying the germline genetic identity of human beings” [emphasis added]. This amended claim language is, of course, consistent with both Rule 28 of the Implementing Regulations to the EPC and Article 6(2)(b) the Biotechnology Directive.\n\nIndications that limiting claim language into European patents for CRISPR technologies is being established as office practice at the EPO is supported by closer examination of the Regents of the University of California, University of Vienna, Emmanuelle Charpentier European patent EP2800811. The University of California et al patent contains similar amended language to the Broad Institute ‘468 patent. Specifically, the ‘811 patent at claims 20 and 21 states: “provided that said method is not a method of modifying the germ line identity of a human being” [emphasis added], this wording being upheld during EPO Oral Proceedings on 5-7 February 2020.", "n_tokens": 301, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-129-1", "doc_id": "medicine_vaccine_book", "page": 129, "text": "It is certainly significant that the limiting claim language to the ‘468 and ‘811 patents are very similar, indicating a practice for the EPO Examining Division to insert Rule 28 type language in all such cases. The approach taken in the ‘468 and ‘811 patents is also consistent with findings of the All European Academies (ALLEA) Statement on Patent-Related Aspects of CRISPR-Cas Technology which, in 2016, considered the principles enshrined in the EU Biotechnology Directive and the Implementing Regulations of the EPC, as applied in the patent grant practice of the EPO to inventions related to CRISPR technology, fit for purpose and flexible enough to take account of future regulatory developments.\n\nSuch limitations on patent claims (or refusal to grant a patent based on morality exceptions) have raised concerns that such a policy may result in a chain reaction of overall reduction in the various types of incentives to innovate and invest in the areas of research concerned.71 No doubt such concerns will continue to be raised and limitations to claim language for European patents related to genome editing tech- nologies will remain under close scrutiny in the future.\n\n71See, for instance, Nordberg et al. (2018), op. cit. n 31, 51.", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-130-0", "doc_id": "medicine_vaccine_book", "page": 130, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\n7 International Human Rights Law and Genome Editing\n\nWe now turn in this chapter to the implications of granting patents relating to genome editing in terms of the enjoyment of internationally binding human rights. The applicable international and legally binding instrument dealing specifically with the protection of human rights in the biomedical field is the Oviedo Convention.72 The Oviedo Convention draws on the principles established by Article 1 of the Universal Declaration on Human Rights (UDHR) of 1948, which affirms that “[a]ll human beings are born free and equal in dignity and rights.”\n\nAs the Nuffield Council on Bioethics has acknowledged, dignity is an important concept that links human beings to the possession of a human genome and, at the same time, elevates the being of individual humans above the given.73 Dignity also plays a restraining role. For example, the UNESCO Declaration on Science and the Use of Scientific Knowledge affirms specifically that both “scientific research and the use of scientific knowledge should respect human rights and the dignity of human beings.”74", "n_tokens": 250, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-130-1", "doc_id": "medicine_vaccine_book", "page": 130, "text": "The Oviedo Convention aims to protect the dignity and identity of all human beings and guarantee everyone, without discrimination, respect for their integrity and other rights and fundamental freedoms with regard to the application of biology and medicine. It set out fundamental principles applicable to daily medical practice and is regarded as establishing basic patient’s rights. It also deals with biomedical research, genetics and transplantation of organ and tissues.75\n\nSpecifically, Article 13 of the Oviedo Convention (entitled ‘Interventions on the human genome’) prohibits germline modification: “An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants.”\n\nArticle 13 therefore establishes two key principles. First, that any genome modification (in research or in treatment) should have as its aim a benefit for human health. It does not permit genome modifications that are for other purposes. For example, it does not permit attempts to enhance human characteristics beyond normal functioning or for welfare purposes not related to health. For those states in which the Oviedo Convention is in force, Article 13 therefore limits, but does not prohibit, genome editing involving human embryos for research purposes. Second,", "n_tokens": 271, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-130-2", "doc_id": "medicine_vaccine_book", "page": 130, "text": "72Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No 164). 73Nuffield Council on Bioethics (2018), op. cit. n 17, 124. 74UNESCO Declaration on Science and the Use of Scientific Knowledge (1999), Preamble, para. 19. The UNESCO Declaration on Bioethics and Human Rights asserts that the “ethical issues raised by the rapid advances in science and their technological applications should be examined with due respect to the dignity of the human person...”. 75Oviedo Convention and its Protocols, Council of Europe, opened for signature on 4 April 1997, Oviedo, Spain: https://www.coe.int/en/web/bioethics/oviedo-convention.\n\n123", "n_tokens": 191, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-131-0", "doc_id": "medicine_vaccine_book", "page": 131, "text": "124\n\nD. Matthews\n\nthe aim must not be to introduce changes that can be passed on to future generations; that is, interventions that lead to the birth of children with a modified genome.76\n\nOn the face of it, Article 13 of the Oviedo Convention appears to prohibit heritable genome editing interventions although, according to the Nuffield Council on Bioethics, not without some ambiguity.77 However, it has been argued persua- sively that the Convention does not veto genetic editing for basic research purposes, but only its clinical application on human embryos to be transferred into the womb.78 This argument is supported by the strict textual interpretation of the Convention, given that Article 13 states explicitly that “An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants” [emphasis added].", "n_tokens": 195, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-131-1", "doc_id": "medicine_vaccine_book", "page": 131, "text": "The prohibition introduced by Article 13 of the Oviedo Convention therefore appears limited to interventions seeking to modify the human genome only where this introduces modifications into the genome of descendants. As such, the wording of Article 13 can be interpreted as giving sufficient room for basic research into preventive, diagnostic or therapeutic purposes.79 Nevertheless, it should also be borne in mind that the explanatory report to the Convention refers explicitly to the need to “protect the dignity and identity of all human beings”,80 underpinned by the guiding principle of the primacy of the human being.81\n\nAlthough the Oviedo Convention is the only international legal instrument that explicitly addresses heritable genetic modification, even those countries that have not signed or ratified the Convention, including the UK and Germany, have taken it into account in framing their domestic provisions in many areas of biomedicine such as patient rights, consent and privacy, the protection of biomedical research partic- ipants or living donors and in relation to applications of biomedicine such as genetics.82", "n_tokens": 226, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-131-2", "doc_id": "medicine_vaccine_book", "page": 131, "text": "76See also Nuffield Council on Bioethics (2018), op. cit. n 17, 117. 77Nuffield Council on Bioethics (2018), op. cit. 17, 124. 78de Mignuel Beriain et al. (2019), p. 226. 79Ibid, 229. 80‘In every case, any intervention which aims to modify the human genome must be carried out for preventive, diagnostic or therapeutic purposes. Interventions aimed at modifying genetic charac- teristics not related to a disease or to ailment are prohibited. As long as somatic cell gene therapy is currently at the research stage, its application can be allowed only if it complies with the standards of protection provided for in Article 15 and the following Articles’. Paragraph 90, Explanatory Report to the Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedi- cine’, Oviedo, 4.IV.1997, European Treaty Series No. 164, Council of Europe: https://rm.coe.int/ 16800ccde5. See also Nordberg (2018), pp. 54–92: 77. 81The whole Convention, the aim of which is to protect human rights and dignity, is inspired by the principle of the primacy of the human being, and all its articles must be interpreted in this light’. Paragraph 22, Explanatory Report to the Convention, ibid. 82See also Nuffield Council on Bioethics (2018) op. cit. n 17, 116.", "n_tokens": 350, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-132-0", "doc_id": "medicine_vaccine_book", "page": 132, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\nElsewhere, in the scientific community, the wider debate on whether there should be a complete ban on gene editing technologies continues and remains largely polarised.83 Central to this wider debate are arguments that the Oviedo Convention, as currently worded, prioritises human rights and human dignity over the interests of scientific endeavour and technological needs.84 This emphasis on human rights and human dignity is consistent with Article 3 of the EU Charter of Fundamental Rights, which protects the right to respect for a person’s physical and mental integrity.85 Paragraph 1 of the Charter asserts that “everyone has the right to respect for his or her physical and mental integrity”, while paragraph 2 sets out a not exhaustive list of acts that must be respected in particular in the fields of medicine and biology, namely: (a) the free and informed consent of the person concerned, according to the pro- cedures laid down by law; (b) the prohibition of eugenic practices, in particular those aiming at the selection of persons; (c) the prohibition on making the human body and its parts as such a source of financial gain; and (d) the prohibition of the reproductive cloning of human beings.\n\n8 International Initiatives on the Regulation", "n_tokens": 274, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-132-1", "doc_id": "medicine_vaccine_book", "page": 132, "text": "and Governance of Gene Editing\n\nInternational initiatives lead by the scientific community have also played an important role to play in framing the debate on access to gene editing technologies and allaying fears of a eugenic future.86 Persistent calls have been made for an international moratorium on gene editing.87 In March 2015, many of the eminent scientists working at the cutting-edge of CRISPR research co-authored a statement published in Science magazine calling for a moratorium on germline cell editing.88 Elsewhere, the US National Academies of Science and National Academy of Medicine Human Gene-Editing initiative, designed to inform decision-making related to recent advances in human genome-editing research, has been a particularly", "n_tokens": 141, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-132-2", "doc_id": "medicine_vaccine_book", "page": 132, "text": "83See, for example, the counter arguments in Sykora and Caplan (2017), pp. 1871–1872, who argue that the debate cannot occur while scientists and clinicians forge ahead with germline modifications and disregard the views, interests and concerns of the many communities to whom germline modification matters; and Baylis and Ikemoto (2017), pp. 2084–2085. 84Baylis and Ikemoto (2017) ibid 2084. 85Charter of Fundamental Rights of the European Union (2010/ C 83/389: https://eur-lex.europa.eu/ LexUriServ/LexUriServ.do?uri¼OJ:C:2010:083:0389:0403:en:PDF. 86Nordberg et al. (2018), op. cit. n 31, 39. 87See, for example, Schneider, above, n 58, 281, citing Baltimore et al. (2015a), pp. 36–38; Lanphier et al. (2015), pp. 410–411; Leopoldina Nationale Akademie der Wissenschaften, The Opportunities and Limits of Genome Editing (2015): https://www.leopoldina.org/en/publications/ detailview/publication/chancen-und-grenzen-des-genome-editing-2015/; Reich et al. (2015). 88Baltimore et al. PMC4394183/.\n\n(2015b), pp. 365–338: https://www.ncbi.nlm.nih.gov/pmc/articles/\n\n125", "n_tokens": 358, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-133-0", "doc_id": "medicine_vaccine_book", "page": 133, "text": "126\n\nD. Matthews\n\nvaluable venue for international dialogue.89 The First International Summit on Gene Editing took place in Washington DC on 1-3 December 2015, hosted by the National Academy of Sciences and the National Academy of Medicine and co-hosted by the Chinese Academy of Sciences and the UK Royal Society. The Summit convened experts from around the world to discuss the scientific, ethical, and governance issues associated with human gene-editing research. A Second International Summit on Human Genome Editing took place in Hong Kong on 27–29 November 2018, hosted by the Academy of Sciences of Hong Kong in collaboration with the UK Royal Society, the US National Academy of Sciences and the US Academy of Medicine.\n\nSubsequently, on 13 August 2019, the first public meeting on the International Commission on the Clinical Use of Human Germline Genome Editing took place in Washington DC, hosted by the National Academy of Sciences, with the second meeting of the Commission taking place in London on 14–15 November 2019 and hosted by the Royal Society.", "n_tokens": 204, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-133-1", "doc_id": "medicine_vaccine_book", "page": 133, "text": "The World Health Organization (WHO) is also playing an increasing active role in coordinating global policy responses to CRISPR genome editing worldwide. On 14 December 2018 the WHO announced the establishment of an 18-member multi- disciplinary Expert Advisory Committee on the Governance and Oversight of Human Genome Editing to examine the scientific, ethical, social and legal chal- lenges associated with human genome editing (both somatic and germ cell).90 The committee sought to identify regulatory and governance gaps, concerns about inappropriate use of human genome editing technologies and concerns regarding rogue clinics exploiting regulatory gaps in some parts of the world. On 29 August 2019 the WHO expert advisory committee announced that it had approved the first phase of a new global registry to track research on human genome editing, using the International Clinical Trials Registry Platform (ICTRP), a WHO entity.91", "n_tokens": 173, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-133-2", "doc_id": "medicine_vaccine_book", "page": 133, "text": "On 12 July 2021 the WHO Expert Advisory Committee on the Governance and Oversight of Human Genome Editing published its final reports entitled Human Genome Editing: A Framework for Governance and Recommendations. The Com- mittee’s Framework for Governance elaborates why a governance role for patents can be significant, acknowledging that patent holders may find themselves with a reasonable amount of influence over how a technology develops. Likewise, the Committee's Recommendations recognise the practical considerations in terms of relevant patent holders perhaps being unwilling to limit the use of their inventions, and the unequal geographic distribution of patent holders given the location of current patent applications relevant to human genome editing. To implement these\n\n89National Academies of Sciences Human Genome Editing Initiative: https://nationalacademies. org/gene-editing/index.htm. 90Global health ethics: Human Genome editing, World Health Organization: https://www.who.int/ ethics/topics/human-genome-editing/en/. 91WHO Launches Global Registry on Human Genome Editing, World Health Organization, 29 August 2019: https://www.who.int/news-room/detail/29-08-2019-who-launches-global-regis try-on-human-genome-editing.", "n_tokens": 263, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-134-0", "doc_id": "medicine_vaccine_book", "page": 134, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\nactions, the specific Recommendations of the Committee are: first, in collaboration with other international institutions, such as the World Intellectual Property Orga- nization (WIPO), the WTO and its TRIPS Agreement, that the WHO should encourage relevant patent holders to help ensure equitable access to human genome editing interventions; second, that the WHO should encourage industry to work with resource-constrained countries to build capacity to take advantage of human genome interventions; and, third, that the WHO should convene a meeting of those holding or applying for patents relevant to human genome editing, industry bodies, interna- tional organisations such as WIPO and the WTO, and those involved in establishing or running relevant patent pools to explore the potential for the adoption of appro- priate ethical licensing requirements.", "n_tokens": 180, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-134-1", "doc_id": "medicine_vaccine_book", "page": 134, "text": "WHO Expert Advisory Committee’s Recommendations on intellectual property comprise one of eight core themes on the governance of human genome editing and have been subject to careful analysis by patent scholars (including the author of this chapter). This patent scholars’ analysis builds upon and elaborates the Committee’s work, in particular by calling for wider public debate about the role of “ordre public” or morality exceptions to patentability in the area of genome editing or considering promoting post-grant governance through the use of research exceptions or compul- sory licences.92\n\nThe WHO has also called for a moratorium, emphasising that countries should not allow any further work on human germline genome editing in human clinical applications until the technical and ethical implications have been properly consid- ered.93 Such further work is considered, at this time, to be inconsistent with the principle of responsible stewardship of science.94", "n_tokens": 183, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-134-2", "doc_id": "medicine_vaccine_book", "page": 134, "text": "9 Concluding Remarks\n\nCRISPR genome editing interventions have great potential to edit the germline human identity in a manner which will eliminate diseases, improve public health and contribute positively to welfare in society. Yet genome editing also poses unique and unprecedented challenges: scientific, regulatory and ethical. The potential uses of these technologies to alter the human germline raise a number of fundamental issues for society. Editing of the human genome will influence the characteristics of\n\n92Matthews et al. (2021). 93WHO Launches Global Registry on Human Genome Editing, World Health Organization, 29 August 2019: https://www.who.int/news-room/detail/29-08-2019-who-launches-global-regis try-on-human-genome-editing. 94Presentation by Robin Lovell Badge (Francis Crick Institute, UK), member of the WHO expert advisory committee on developing global standards for governance and oversight of Human Genome editing at the Second Meeting of the International Commission on the Clinical Use of Human Germline Genome Editing, London, 14 November 2019. Available at: https://royalsociety. org/topics-policy/projects/genetic-technologies/international-commission/.\n\n127", "n_tokens": 254, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-135-0", "doc_id": "medicine_vaccine_book", "page": 135, "text": "128\n\nD. Matthews\n\nfuture generations in ways that may well be considered ethically unacceptable given the unknown risks of off-target effects. Ensuring that institutions are appropriately equipped to accommodate this new technology is essential for the future governance and regulation of gene editing technologies, of which the patent system forms a crucial component part.\n\nThe risks, benefits and ethical reasoning for exclusions to patentability need to be considered carefully by the policy community, based on inputs from all stake- holders, including patient groups, the scientific community and also those engaged in patent law and policy. As has been argued convincingly, it is only through public policy engaging multiple stakeholders and the interdisciplinary academic commu- nity that dialog proceeds in a manner that is conducive to the future development of this ground-breaking technology.95 This imperative applies to the patent system as much as it does to other levers of governance and regulation.", "n_tokens": 188, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-135-1", "doc_id": "medicine_vaccine_book", "page": 135, "text": "In this context, WTO Members should pay careful attention to the patent policy implications of genome editing technologies, particularly for inventions relating to altering the germline identity of human beings. Strong arguments can be made in favour of encouraging such inventions in terms of eradicating hereditary diseases in new-born babies and creating resistance to life-threatening conditions for future generations. Such uses of genome editing technologies may well be considered consistent with fundamental human rights, particularly the right to dignity, of future generations under Article 13 of the Oviedo Convention.\n\nNonetheless, WTO Members must balance decisions about permitting the patenting of this transformational technology and the possibilities of eradicating, for example certain hereditary diseases from society, with the possibilities of nega- tive impacts when deciding to permit patents on altering the germline identity of human beings. The extent of off-target effects for future generations, effects that are ancillary to the intended genome alteration, are not yet known or fully understood. The shadow of eugenics experiments conducted in Europe during the middle of the last century remains strong. Human rights, particularly those enshrined in Article 13 of the Oviedo Convention, must be given primacy at all costs.", "n_tokens": 245, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-135-2", "doc_id": "medicine_vaccine_book", "page": 135, "text": "The patent system can, and should, play an important role in this process. As we have seen in this chapter, Article 27.2 of the TRIPS Agreement establishes a “necessity test” and encompasses the TRIPS flexibility that WTO Members may exclude from patentability within their territory inventions, the commercial exploi- tation of which could be considered contrary to ordre public and morality, including to protect human animal or plant life or to avoid serious prejudice to the environ- ment, provided that such exclusion is not made merely because the exploitation is prohibited by their law.\n\nThe approach now being taken by the EPO is instructive in this respect. By eschewing an approach based on rejecting CRISPR-based patent applications out- right in favour of a more nuanced approach when considering the European patent claim language of genome editing technologies with the potential to alter the\n\n95Nordberg et al. (2018) op. cit. n 31, 46.", "n_tokens": 199, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-136-0", "doc_id": "medicine_vaccine_book", "page": 136, "text": "Access to CRISPR Genome Editing Technologies: Patents, Human Rights and...\n\ngermline identity of human beings, the EPO has retained limits on patentability within the established EPC norms on exclusions to patentability. This chapter has set out how the European patent tradition of exclusions to patentability based on ordre public and morality is well-established by virtue of Article 53(a) EPC, Articles 5 and 6 of the Biotechnology Directive and Rule 28 of the Implementing Regulations to the EPC. The chapter has also demonstrated how the EPO is now paying due regard to these provisions by requiring amended claim language for European Patents relating to genome editing technologies. Other WTO Members should take note of this approach and, it is suggested by this chapter, follow suit. This is imperative in order to ensure that the granting of private patent rights can be accommodated on an equitable basis, balanced alongside the need to avoid unnecessary risk (including the morality exception under patent law), take account of human rights, meet public expectations, and act in the public interest with regard to this potentially transfor- mational healthcare technology.", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-136-1", "doc_id": "medicine_vaccine_book", "page": 136, "text": "This chapter has set out some of the risks, advantages, ownership issues, ethics and access problems related to genome editing. We saw in this chapter that the right to health carries with it the expectation that everyone should have access to the health services they need, when and where they need them, without suffering financial hardship. This is particularly pertinent given the global context in which access to health care technologies needs to be evaluated. Different IP regimes and the national legislation of different countries express different ethical values.96 The world is now only at the beginning of this new healthcare debate and patent systems will be central to how we conceptualise and resolve these public policy problems. Without doubt, given the rapid pace of genome editing science and its wide applications, greater consideration of these crucial issues within the global patent policy community is urgently required if governance institutions are to adequately take into account the impact of granting of genome editing patents, balancing the need to reward inventorship with affordability, access and the enjoyment of funda- mental human rights in the public interest.\n\nAcknowledgements With thanks to Emanuela Gambini for invaluable research assistance and insights, and to Phil Hinchliffe, Abbe Brown, Jacob S Sherkow and two anonymous referees for their helpful comments and suggestions. The opinions and any errors in the chapter remain the author’s own.", "n_tokens": 272, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-136-2", "doc_id": "medicine_vaccine_book", "page": 136, "text": "References\n\nAkst J (2017) UC Berkeley Receives CRISPR Patent in Europe. Scientist (March 24, 2017), https:// www.the-scientist.com/?articles.view/articleNo/48987/title/UC-Berkeley-Receives-CRISPR- Patent-in-Europe/ (Last accessed 16 February 2021)\n\n96Nuffield Council on Bioethics (2018), op. cit. 17, xvi.\n\n129", "n_tokens": 97, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-140-1", "doc_id": "medicine_vaccine_book", "page": 140, "text": "and development. Cambridge University Press, p 378\n\nUNESCO Declaration on Science and the Use of Scientific Knowledge (1999), Preamble, para. 19 Van Overwalle G, van Zimmeren E, Verbeure B, Matthijs G (2006) Models for facilitating access to\n\npatents on genetic inventions. Nat Rev Genet 7:143\n\nWHO Launches Global Registry on Human Genome Editing, World Health Organization, 29 August 2019.: https://www.who.int/news-room/detail/29-08-2019-who-launches-global- registry-on-human-genome-editing (Last accessed 17 February 2021)\n\nWojcik MH, Schwartz Inbar Yamin TS, Edward HL, Genetti CA, Towne MC, Agrawal PB (2018) Genetic disorders and mortality in infancy and early childhood: delayed diagnosis and missed opportunities. Genet Med, p 20\n\nZorrilla M, Yatsenko AN (2013) ‘The Genetics of Infertility’ Current Status in the Field, Current", "n_tokens": 222, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-140-2", "doc_id": "medicine_vaccine_book", "page": 140, "text": "Genetic Medicine Reports, 1\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n133", "n_tokens": 171, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-141-0", "doc_id": "medicine_vaccine_book", "page": 141, "text": "Bolar Exception\n\nViviana Munoz Tellez\n\nAbstract This chapter discusses the exemption from liability of patent infringement for activities related to regulatory approval for medicines, also known as the “regulatory review” or “Bolar” exception. The Bolar exception supports the market entry of generics by allowing the use of a patented invention by a third party without the consent of the patent holder for the sole purpose of obtaining regulatory approval. This constitutes an important defense for generic manufacturers when undertaking activities such as studies and trials to provide the information required by regulatory agencies. In this regard, the Bolar exception can respond to a public policy objective of facilitating market entry of generics to support competition and exerting downward pressure on prices for medicines. The Bolar exception is included in many country patent laws and is compatible with international legal instruments regarding patent law.", "n_tokens": 165, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-141-1", "doc_id": "medicine_vaccine_book", "page": 141, "text": "1 Exceptions to Patent Rights\n\nA patent grants the patent holder the exclusive right to exclude others from making, using, importing, and selling the patented innovation for a limited period of time.1 Most, if not all, patent laws exclude certain matter from patentability, and also limit the rights of patent holders by way of exceptions.2 These have the important function\n\n1The TRIPS Agreement states that the available term of protection must expire no earlier than 20 years from the date of filing the patent application. In some jurisdictions the term may be extended, for example in the United States through Patent Term Adjustment (PTA) and Patent Term Extension (PTE). The extended exclusivity delays generic competition that can negatively affect access to medical products in the trading partners, and pressures patent offices to examine patent applications more expediously. Patent term extensions are often requirements in regional trade agreements involving the United States and European Union. See Correa (2017). 2Bently (2011), pp. 315–347.\n\nV. Munoz Tellez (*) South Centre, Geneva, Switzerland e-mail: Munoz@southcentre.int\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_5\n\n135", "n_tokens": 296, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-142-0", "doc_id": "medicine_vaccine_book", "page": 142, "text": "136\n\nV. Munoz Tellez\n\nof defining spaces of freedom of action, wherein obtaining permission from patent right holders is not required.\n\nInternational patent law as regulated by the World Trade Organization (WTO) Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS)3 contains an overall obligation for members of the WTO to grant patents for inven- tions that meet the criteria of patentability4 in all fields of technology. Nonetheless, certain exclusions from patentable inventions are permitted.5\n\nExceptions allow activities that would otherwise be considered patent infringe- ment. They may remove liability for infringing patent rights, by deeming certain acts as non-infringing (as is the case of the Bolar exception analysed in this chapter). WTO members have greater freedom to introduce exceptions to the rights of patent holders in their legal systems, as compared to exclusions from patentable subject matter. Rather than defining the exceptions, the TRIPS Agreement allows Members to develop limited exceptions so long as these comply with certain conditions.6 Exceptions that can be found in many jurisdictions are exceptions for private, non-commercial use, or to promote research or experimentation.7 Generally, the Bolar exception can be considered to be a specific type of experimental use exception.", "n_tokens": 264, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-142-1", "doc_id": "medicine_vaccine_book", "page": 142, "text": "Members have discretion to decide what exceptions to establish, consistent with the TRIPS Agreement. This has the advantage of allowing countries to determine what exceptions are most relevant to their evolving domestic priorities and various policy considerations. These may include, to confine the patent right for the subject matter that it was intended, and for protecting third party rights and the public interest.8 Exceptions to patent rights may be stipulated in legislation or judicially created—developed through case law. Domestic exceptions can however be chal- lenged under the WTO Dispute Settlement Understanding (DSU). There has so far been a single instance of a challenge to exceptions that limit patent rights, in the", "n_tokens": 133, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-142-2", "doc_id": "medicine_vaccine_book", "page": 142, "text": "3Agreement on Trade-related Aspects of Intellectual Property Rights of 1994; being Annexe 1C to the Agreement Establishing the World Trade Organization, April 15, 1994 (hereafter “TRIPS Agreement”). 4TRIPS Article 27.1 states that “...patents shall be available for any inventions...in all fields of technology, provided that they are new, involve an inventive step and are capable of industrial application.” The TRIPS Agreement does not define “invention” and “technology” and does not determine how patentability requirements should be applied. This is an important area of policy space for WTO members to define the appropriate contours of their patent laws in accordance to meeting the objectives of the patent system and against other objectives such as public health policy. See Correa (2014). 5The permissible exclusions are defined in the TRIPS Article 27.2 and Article 27.3. 6TRIPS Article 30 states that “Members may provide limited exceptions to the exclusive rights conferred by a patent, provided that such exceptions do not unreasonably conflict with a normal exploitation of the patent and do not unreasonably prejudice the legitimate interests of the patent owner, taking account of the legitimate interests of third parties.” 7See Correa (2005). 8Dreyfuss (2018), p. 8.", "n_tokens": 289, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-143-0", "doc_id": "medicine_vaccine_book", "page": 143, "text": "Bolar Exception\n\npanel Canada-Pharmaceutical Patents case.9 The panel decision is not a binding precedent for Members in developing their exceptions that are compatible with the TRIPS Agreement. Moreover, given that the decision was not appealed, the Appel- late Body did not provide its own interpretation.10", "n_tokens": 57, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-143-1", "doc_id": "medicine_vaccine_book", "page": 143, "text": "2 Rationale for the Bolar Exception\n\nWhen the patent monopoly expires, the patent ceases be a legal obstacle for a competitor to produce and commercialize the protected product or use the protected process. However, other market barriers may remain. Pharmaceutical products must meet regulatory requirements for authorization to be placed on the market. The patent status of the originator product can impede the competitor from being able to start work to meet regulatory requirements in order to be able to place the product on the market once the originator patent expires. Unless such work is permitted during the patent term, by an exception. Without the Bolar exception, or a broad experi- mental use exception that includes acts to provide information for regulatory approval, the competitor will not be able to prepare for regulatory approval until the patent expiry. This means that, as obtaining the marketing approval for a generic11 medicine takes time, the patent monopoly for the originator is practically extended further in time than originally conceived. In recognition of this problem- atic, the Bolar exception is present in many national jurisdictions.\n\nA review of the process of market authorization for medical products is presented below, prior to discussing in more detail examples of how the Bolar exception is crafted in various jurisdictions.", "n_tokens": 254, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-143-2", "doc_id": "medicine_vaccine_book", "page": 143, "text": "9World Trade Organization (2000) 10Mercurio and Tyagi note that the Appellate Body has supported a broad interpretation of exceptions based on the Appellate Body Report, European Communities—Measures Concerning Meat and Meat Products (Hormones), ¶ 104, WT/DS26/AB/R, WT/DS48/AB/R (Jan. 16, 1998), (“[M]erely characterizing a treaty provision as an ‘exception’ does not by itself justify a ‘stricter’ or ‘narrower’ interpretation of that provision than would be warranted by examination of the ordinary meaning of the actual treaty words, viewed in context and in the light of the treaty’s object and purpose, or, in other words, by applying the normal rules of treaty interpretation.”). Mercurio and Tyagi (2010), 262, footnote 68. 11In this chapter the term generics is used to describe chemical, small molecule medicinal products that are structurally and therapeutically equivalent to an originator product. Generics are inter- changeable with an originator product.\n\n137", "n_tokens": 223, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-144-0", "doc_id": "medicine_vaccine_book", "page": 144, "text": "138\n\nV. Munoz Tellez\n\n2.1 Marketing Authorization of Medical Products\n\nGovernments have an important role in formulating laws and regulations to define and control the national market in medical products in the interest of public health.12 The national medicine regulatory authority aims to protect public health by ensuring that a product is safe, efficacious and of good quality before it reaches a patient. Thus, national medicine regulatory authorities around the world subject pharmaceu- tical products to premarketing evaluation and marketing authorization to ensure that they conform to required standards.13 The marketing approval system is applied in accordance to national law. All medicines have to be authorized before they can be marketed. The manufacturers of any medicine, whether it is a brand-name originator or a generic,14 need to comply with the requirements. A granted marketing autho- rization is valid in the geographical territory in which it is applied for.15", "n_tokens": 189, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-144-1", "doc_id": "medicine_vaccine_book", "page": 144, "text": "The specific regulatory requirements for a medical product to be marketed may vary. For chemically synthesized pharmaceuticals, regulatory authorities generally require that generic products demonstrate the same bioavailability and often bio- equivalence of the generic medicine to a reference product. Producing a full dossier, including showing the results of pre-clinical tests and clinical trials to show safety and efficacy of the product, can require significant investment and time. In the case of requests for approval for local production of medicines or import of medicines already marketed and approved in third countries, requirements of local clinical trials may be waived. Hence, if a medical product is a generic of a reference medical product, it may receive an abridged process for compliance with the premarketing evaluation and marketing authorization.\n\nMarketing approval or licensure of biologics—referring to medical products that are made from living organisms-, and biosimilars16 may be subject to specific and more stringent requirements. There is significant divergence on approaches being", "n_tokens": 217, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-144-2", "doc_id": "medicine_vaccine_book", "page": 144, "text": "12See World Health Organization (1999). 13See World Health Organization (2011). 14A generic medicine is an equal substitute for an already marketed brand-name drug and is not protected by a patent in force. Generics are generally commercialized under a non-proprietary name. Pharmaceutical substances and active pharmaceutical ingredients are given unique, non-proprietary, generic International Nonproprietary Names (INN). A generic may also be marketed under its own brand name. 15However, many national regulatory authorities have entered into harmonization initiatives or mutual recognition agreements. For example, in the European Union there are different authoriza- tion routes and some medicines go through a centralised marketing authorisation valid in all EU member States. 16Another term used for example by the WHO is “similar biotherapeutic products”, to refer to a biological product which is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product.", "n_tokens": 202, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-145-0", "doc_id": "medicine_vaccine_book", "page": 145, "text": "Bolar Exception\n\ntaken by regulatory agencies in this area and debate are ongoing on the current guidance by the World Health Organization (WHO) on the matter.17\n\n2.2 Relationship of Patent Protection, Marketing\n\nAuthorization and Supplementary Legal Protection\n\nThe relationship between patent protection and marketing authorization of medical products at first would appear to be very weak. All medical products are subject to regulatory requirements, regardless of their patent status. Moreover, in accordance to patent law, once patent protection expires, competitors should have free entry. However, in practice, questions of marketing authorization and patent protection for medical products have become more intertwined, as policy makers juggle in balancing between innovation and competition incentives, under pressure from a wide range of stakeholders.\n\nIn principle, the patent status of the originator medical product should be irrele- vant for purposes of the regulatory requirements for approval of generics or biosimilars. However, some countries have adopted a patent linkage regime to link the grant of marketing approval by a regulatory authority with the patent status of an originator medical product.18 This system poses the additional burden on the regu- latory authority to review whether there may be a patent infringement before it will issue marketing approval for a new product and creates new restrictions for the registration of generic and biosimilar products.", "n_tokens": 265, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-145-1", "doc_id": "medicine_vaccine_book", "page": 145, "text": "In addition, patent term extensions may be available in some jurisdictions under the rationale of compensating for delays in examination or simply because the product is subject to regulatory review. These provisions, generally incorporated in free trade agreements entered into by the USA and the European Union,19 result in further delays of generic and biosimilar market entry.\n\nThe increased laxity in the criteria applied in patent examination in some juris- dictions also enables the pharmaceutical industry to employ strategic patenting tactics such as “evergreening” to artificially extend the patent term for profitable medical products.20 Moreover, in some jurisdictions, the patent incentive for inno- vation is now supplemented with other legal exclusivities that support the originator\n\n17See Velásquez (2018). See also on challenges on advancing biosimilars, Vaca and Gómez (2020), Kang et al. (2020). 18Patent linkage is not an international obligation, but often requested by the United States in free trade agreement negotiations and as part of unilateral trade pressures. See Mercurio (2017), pp. 97–122, and Correa (2020). 19See Daniel Opoku Acquah, Revisiting the Question of Extending the Limits of Protection of Pharmaceutical Patents and Data Outside the EU – The Need to Rebalance, Research Paper 127, December 2020, South Centre, https://www.southcentre.int/wp-content/uploads/2020/12/RP- 127.pdf. 20See Ducimetière (2019). Gurgula (2019). I-Mak (2018).\n\n139", "n_tokens": 349, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-146-0", "doc_id": "medicine_vaccine_book", "page": 146, "text": "140\n\nV. Munoz Tellez\n\nin delaying entry of generics or biosimilars after the patent term expiry, including data and market exclusivity21 and supplementary protection certificates.22\n\nOn the other hand, in order to promote competition, regulatory authorities may provide abbreviated pathways for the approval of generics and more recently, for biosimilars. The policy rationale of the Bolar exception, where available in national patent laws, also aims to lower product development costs, expedite regulatory approval and ease market entry.\n\nIn this sense, the balance between innovation and competition no longer rests solely on the design and implementation of the patent system—but on the myriad of other related instruments that are crafted to respond to the variety of interests involved and overall complex ecosystem of medical product development, procure- ment and supply.\n\n2.3 Role of Generic and Biosimilar Competition in Promoting", "n_tokens": 186, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-146-1", "doc_id": "medicine_vaccine_book", "page": 146, "text": "Access\n\nMedicine prices decrease significantly after patent expiry.23 The increased use of generic medicines is an important measure for cost-containment in pharmaceutical procurement. Generics increase competition and lower prices for medicines that improve access and lower medicine purchase expenditures for governments, to sustain their healthcare systems. This is of particular relevance today in the context of rising drug spending, affected by high prices for some medicines, in particular of biologics such as monoclonal antibodies, notably in low and middle income coun- tries where in addition to limited government budgets for public procurement, out- of-pocket purchases are high.\n\nIn the United States, the top twelve grossing medicines, mostly biologicals, have increased by 68% from 2012 to 2018 and cost $96 billion to health insurers, government payers, and consumers in 2017 alone.24 A recent US FDA report from December 2019 compared medicines that had initial generic entry between 2015 and 2017 and found that the median price of generics relative to brands is 40%.25 In Europe, pioneer in biosimilar registration and the largest market for global biosimilar", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-146-2", "doc_id": "medicine_vaccine_book", "page": 146, "text": "21See Correa (2013), pp. 16-/173. 22The experience with these new exclusivities or sui generis IPRs for regulated products has also led to the adoption of new exceptions. See Seuba (2019), pp. 876–886, https://doi.org/10.1093/ jiplp/jpz108. 23Vondeling et al. pmid:30019138. 24I-Mak Report, Overpatented, Overpriced: how excessive pharmaceutical patenting is extending monopolies and driving up drug prices, 2018. http://www.i-mak.org/wp-content/uploads/2018/08/ I-MAK-Overpatented-Overpriced-Report.pdf. 25The calculations use average manufacturer prices. Conrad and Lutter (2019).\n\n(2018), pp. 653–660. https://doi.org/10.1007/s40258-018-0406-6", "n_tokens": 228, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-147-0", "doc_id": "medicine_vaccine_book", "page": 147, "text": "Bolar Exception\n\nsales, biosimilar competition has significantly reduced prices for biologicals.26 Nonetheless, the overall market penetration of biosimilars remains low, though expiration of patent and exclusivities of the originator biologics is increasing oppor- tunities for further savings.27 Currently 61 biosimilars have been approved in Europe since the establishment of the regulatory framework for registration of biosimilars in 2005.28 India is the largest provider of generic medicines globally, occupying a 20% share in global supply by volume, and with increasing capacity for production of biosimilars.29\n\nThe extent of the cost-saving potential from switching from originators to generic products may nonetheless vary among countries depending on, among other factors, differences in the timing of patent expiries, the type of generic medicine pricing policies they apply,30 dispensing practices, the market share of generic medicines. Expanding biosimilar uptake presents additional challenges, including the extensive litigation actions by biopharmaceutical manufacturers, the need for greater accep- tance by physicians and patients of biosimilars as safe and effective alternatives to reference-biologic products.", "n_tokens": 247, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-147-1", "doc_id": "medicine_vaccine_book", "page": 147, "text": "On a more global level, the role of generics in increasing access is evident in relation the HIV/AIDS pandemic. The decline in mortality rates between the mid 1990s to early 200s is attributable in large part to the expanded access to generic antiretrovirals (ARVs), mostly produced in India, that greatly reduced prices and allowed for treatment expansion. In Brazil, with the production of local generic ARVs, the prices fell by more than 70% in four years. By 2000, AIDS mortality rate in Brazil had been halved and HIV-related hospital admissions had fallen by 80%.31", "n_tokens": 127, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-147-2", "doc_id": "medicine_vaccine_book", "page": 147, "text": "3 History of the Bolar Exception\n\nPatents and other exclusivities constitute barriers to market access for generics and biosimilars. The Bolar exception is a tool within patent law that supports market entry of generics and biosimilars, by allowing manufacturers to prepare these products in advance of the expiration of the originators’ patents.\n\nThe history of the Bolar Exception is well documented. It stems from US Congress reaction to the US Court of Appeals Federal Circuit 1984 decision in\n\n26Gabi Journal Editor Biosimilars Markets (2020), pp. 90–92. https://doi.org/10.5639/gabij.2020. 0902.015. 27OECD/European Union (2018), https://doi.org/10.1787/health_glance_eur-2018-en. 28European Medicines Agency, https://www.ema.europa.eu/en/medicines/. 29https://www.investindia.gov.in/sector/pharmaceuticals. 30The various policies include free-pricing systems (i.e. US) versus price-regulated systems (i.e. EU), reference pricing, price competition and discounts, and tendering procedures. Reimburse- ment policies may also affect final generic price. 31UNAIDS (2008), p. 113.\n\n141", "n_tokens": 295, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-148-0", "doc_id": "medicine_vaccine_book", "page": 148, "text": "142\n\nV. Munoz Tellez", "n_tokens": 6, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-148-1", "doc_id": "medicine_vaccine_book", "page": 148, "text": "Roche Products v Bolar Pharmaceutical Co. where it was held that the experimental use doctrine did not protect the “limited use of a patented drug for testing and investigation strictly related to US Food and Drug Administration (FDA) drug approval requirements” and found that Bolar’s experimental use in this case had definite, cognizable, and not insubstantial commercial purposes.32 The Generic Pharmaceutical Industry Association (GPIA) had shown in its amicus curiae that various generics had been tested prior to patent expiry, and argued that the decision essentially allowed originator manufacturers to retain market exclusivity for their products beyond the duration of the patent terms because generic manufacturers could not even start developing and seeking approval for competing generic prod- ucts until after the originator patent expired.33 Soon after, the US Congress passed the Drug Price Competition and Patent Term Restoration Act of 1984, better known as the Hatch-Waxman Act, 35 U.S.C. § 271(e) (2003). The Hatch-Waxman Act made significant changes to US patent law with the aim to encourage innovation in the pharmaceutical industry while facilitating the speedy introduction of lower-cost generic medicines, thereby attempting to get a compromise between the interests of the research based and generic segments of the industry. Among the changes introduced, was the Bolar exception codified as 35 U.S.C. § 271(e)(1) that reversed Roche v Bolar court of appeals decision:", "n_tokens": 312, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-148-2", "doc_id": "medicine_vaccine_book", "page": 148, "text": "It shall not be an act of infringement to make, use or sell a patented invention ... solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.\n\nJudicial interpretations of 271(e)(1) have given a broad reading of the subject matter (i.e. originators, biologics, generics, biosimilars, medical devices) and per- mitted the coverage of a range of activities under the exemption.34\n\nMany countries have subsequently introduced a similar regulatory review excep-\n\ntion in their patent laws, as will be discussed further in section 5 below.\n\n4 Consistency with Article 30 of the TRIPS Agreement\n\nA WTO dispute settlement panel examined the regulatory review provision of the Patent Act of Canada in the Canada–Pharmaceuticals Patent case35 and confirmed that it conforms with the TRIPS Agreement. The panel found that there was no conflict with a normal exploitation of the patent (Article 28.1 of the TRIPS\n\n32Roche Products v Bolar Pharmaceutical Co., 733 F.2d.858 (Fed.Cir.1984) at 863. 33Krulwich (1985), pp. 519–525. Retrieved December 20, 2020, from http://www.jstor.org/stable/ 26658803. 34See Noonan (2015), p. a020800. Published 2015 Mar 16. https://doi.org/10.1101/cshperspect. a020800. 35Ibid, at 9.", "n_tokens": 338, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-149-0", "doc_id": "medicine_vaccine_book", "page": 149, "text": "Bolar Exception\n\nAgreement) and that it was justified under Article 30 of the TRIPS Agreement (exceptions).\n\nThe Canada Patent Act, Section 55.2(1) reads: “It is not an infringement of a patent for any person to make, construct, use or sell the patented invention solely for uses reasonably related to the development and submission of information required under any law of Canada, a province or a country other than Canada that regulates the manufacture, construction, use or sale of any product.”\n\nThe panel held that the provision was justified under Article 30 by meeting all of the three cumulative criteria: it is a “limited” exception, not unreasonably interfering with the normal exploitation of the patent, and not unreasonably prejudicing the rights of the patent holder, taking into account the legitimate interests of third parties.36\n\nIn the WTO Council for Trade Related Aspects of Intellectual Property Rights (TRIPS Council)37 and at the World Intellectual Property Organization,38 countries have continued to exchange on the rationale for inclusion of the exception in their laws as a mean to balance the private interests of patent right holders and public interest, and experiences in its use.\n\n5 Crafting National Legal Frameworks for the Bolar", "n_tokens": 253, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-149-1", "doc_id": "medicine_vaccine_book", "page": 149, "text": "Exception\n\nThe Bolar Exemption is recognized in various national patent laws, generally with the aim to support entry of competitor products upon patent expiry of the originator product. A WIPO study from 2018 indicates that at least 65 countries and two regional instruments provide for a Bolar exception.39 While the objective of the Bolar exception is the same—to avoid delays in market entry for competitor products—there can be significant divergences among national approaches, includ- ing on scope and implementation.\n\nIn fact, for the design of a Bolar exception, there can be numerous alternative approaches. Professor Correa has advanced that “the broader the formulation of the exception in terms of covered products, sources of samples, type of trials allowed,", "n_tokens": 154, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-149-2", "doc_id": "medicine_vaccine_book", "page": 149, "text": "36The panel found that the stockpiling provision in the Canadian Patent Act is inconsistent with TRIPS Agreement Article 28.1, as it did not satisfy the first condition of TRIPS Agreement Article 30 because it is not a “limited exception.” 37WTO document IP/C/M/88/Add.1, Minutes of the TRIPS Council, 12 April 2018, Agenda item 12: Intellectual Property and Public Interest, Regulatory Review exception, https://docs.wto.org/ dol2fe/Pages/SS/directdoc.aspx?filename¼q:/IP/C/M88A1.pdf&Open¼True. 38WIPO draft reference document on the exception regarding acts for obtaining regulatory approval from authorities (second draft), document SCP/28/3, https://www.wipo.int/edocs/mdocs/scp/en/ scp_28/scp_28_3.pdf. The document is kept open for future discussion by the Standing Committee on Patents. 39Ibid, at 35.\n\n143", "n_tokens": 231, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-150-0", "doc_id": "medicine_vaccine_book", "page": 150, "text": "144\n\nV. Munoz Tellez\n\ntime to undertake them, and geographical scope, the more competitive environment is ensured that will benefit consumers, health providers and other public agencies.”40 The policy choice for designing a broader Bolar exception is more favourable to the objective of promoting competition.\n\nSeveral countries, such as the United Kingdom and Ireland, have in recent years amended their patent laws to broaden the scope of the Bolar exception. The extension of the Bolar exception has also been under consideration in the EU41 given the divergences in current implementation throughout the member States and in the context of how a future Unified Patent Court (UPC) may apply the Bolar exception.42 A study by the Max Planck Institute for Innovation and Competition prepared for the European Commission recommended that the EU member States adopt a broader than the minimum standard currently provided for under Art. 27 (d) UPCA, in following the national Bolar exceptions in Germany, Ireland, Italy, France, among other EU member States.43 The economic impacts of extending the Bolar exception in the EU to cover any medicines (not limited to products following an abridged marketing authorisation only), have been estimated as cost savings from patent screening of up to €23-€34.2 million per year.44", "n_tokens": 263, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-150-1", "doc_id": "medicine_vaccine_book", "page": 150, "text": "In order to well define the Bolar exception, it may be preferable to design it as a specific exception, as opposed to inclusion as part of a general research or experi- mental exception.\n\nThe Bolar exception can be crafted to cover all regulated products, including but not limited to health-related products for human use, such as medicines and medical devices. Other regulated products covered in some Bolar exceptions include veter- inary medicines and plant protection products.\n\nThe scope of the activities should be clearly defined. These should relate to obtaining marketing approval for generics and biosimilars, but may also extend for acts relating to medical devices (as provided for in the US) and innovative medicines (for example to carry out health technology assessments as in the Bolar exception in the UK Patents Act).\n\nIt is not necessary to restrict the user of the Bolar exception to the party that would be requesting the marketing authorization. It can also include acts by third parties involved in supplying materials to a company to run tests and trials related to obtaining marketing authorization for a generic or biosimilar.", "n_tokens": 229, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-150-2", "doc_id": "medicine_vaccine_book", "page": 150, "text": "40Correa (2016). 41The Bolar exception was introduced in Article 10(6) of the Directive 2004/27/EC of 31 March 2004, https://eur-lex.europa.eu/legal-content/EN/TXT/?uri¼CELEX:32004L0027. 42The establishment of the unitary patent system and UPC may follow if the Agreement on a Unified Patent Court (UPCA) enters into force. The UPCA Article 27(d) contains the Bolar Exception: “The rights conferred by a patent shall not extend to ...the acts allowed pursuant to Article 13(6) of Directive 2001/82/EC or Article 10(6) of Directive 2001/83/EC in respect of any patent covering the product within the meaning of either of those Directives”. 43Max Planck Institute for Innovation and Competition, Study on the legal aspects of supplemen- tary protection certificates in the EU, European Union, 2018, pp. 338–361. 44Charles River Associates (2016).", "n_tokens": 232, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-151-0", "doc_id": "medicine_vaccine_book", "page": 151, "text": "Bolar Exception\n\nA clear definition of the scope of the permitted acts is one of the critical aspects of a Bolar exception so as to provide legal certainty of the safeguards it provides against patent infringement and to the rights of patent holders. Acts that are related to obtaining marketing approval that should be covered include studies, trials and experiments required for obtaining marketing approval in the country, as well as for obtaining marketing approval in other countries. As noted earlier, third party activity for the company seeking marketing approval, such as delivery of an Active Pharmaceutical Ingredient (API) to carry out tests or trials when the company is unable to produce the API in-house, can also be included.45", "n_tokens": 138, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-151-1", "doc_id": "medicine_vaccine_book", "page": 151, "text": "6 India Bolar Exception: Recent Developments\n\nThe design and implementation of the Bolar exception is of particular relevance in countries that have domestic production capacity for generics and biosimilars. The Bolar exception in Indian legislation is of special interest, as India, as noted, is a global leader in the global supply of affordable generic and biosimilar products. The Bolar exception contributes to a favorable environment for the generic and biosimilar industry in India to develop and expand.\n\nThe Indian patent act in Section 107A includes a broad Bolar exception. It reads: “any act of making, using, selling or importing a patented invention solely for uses reasonably related to the development and submission of information required under any law in India, or in a country other than India, shall not be considered as infringement of patent rights.”46\n\nThe exception applies to any regulated sector, and extends to acts done for submission of information not only in India but in any other country. The scope of acts covered can include the manufacture of the patented protected product, export of an API or finished formulation by a generic company, conduct of clinical trials, or import of the API or formulation by a third party to support relevant regulatory approvals in India or other countries.", "n_tokens": 253, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-151-2", "doc_id": "medicine_vaccine_book", "page": 151, "text": "While the Section. 107A is clearly worded, there has been significant litigation with respect to this provision, and, accordingly the Indian judiciary has provided important interpretation of its scope. A recent case tested in particular the definition of “selling” and determined that it allows export of a patented product for generation or submission of information for seeking regulatory approval in India or other countries, without such export constituting an act of patent infringement. A Division Bench of the Delhi High Court held that export for the purpose of conducting development/clinical studies and trials is within the ambit of the Indian Bolar\n\n45The Dusseldorf Court of Appeal in 2013 (docket no. I-2 U 68/12, Astellas v Polharma) referred a preliminary ruling on this question to the European Court of Justice (ECJ), but the ECJ did not issue a judicial pronouncement as Astellas withdrew action against Polpharma. 46https://indiankanoon.org/doc/151051886/.\n\n145", "n_tokens": 218, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-152-0", "doc_id": "medicine_vaccine_book", "page": 152, "text": "146\n\nV. Munoz Tellez\n\nexception.47 The Court established an indicative list of factors to determine whether the export is ‘reasonably related’ to the research purpose or not.\n\nThe court also clarified that section 107A is not to be treated as an exception to section 48 of Indian Patent Act: “Its history of interpretation by TRIPS, the discus- sion in the Parliamentary Joint Committee Report, all clearly point to its being a special provision that deals with the rights of the patented invention for research purposes.”48\n\nThe relationship of the Bolar exception with the terms of a compulsory license was also considered by the court. As noted by Indian delegation to the WTO, “Bolar exceptions have an important link with compulsory licensing. The absence of the Bolar exceptions can severely affect the ability of a country to effectively utilize compulsory license provisions when considered necessary.”49", "n_tokens": 175, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-152-1", "doc_id": "medicine_vaccine_book", "page": 152, "text": "In Bayer Corporation and Ors. v. Union of India and Ors., Bayer had filed a suit for infringement of Patent against Natco, a generic producer. During the pendency of the suit, Natco obtained a compulsory license for the same patent for the territory of India. Bayer filed a writ petition in the High Court of Delhi seeking a direction to the Custom Authorities to seize the consignments for export of the products covered by the compulsory license (CL) manufactured by Natco, on grounds that the export violated the terms of the CL. The Court passed an interim order to restrain Natco from the export. In parallel, Natco requested and obtained permission to export 1 kg of API to China to conduct clinical studies and trials for regulatory purposes. Bayer considered that the API sale was an infringement of the patent in violation of the CL terms. Natco argued that it was covered by the Bolar exemption as the export was for regulatory purposes.50 In its decision the Court noted that “it is..of the opinion that Natco’s status as compulsory licensee did not place it under any additional statutory bar from exporting the product, as long as the underlying condition in Section 107A was satisfied”.51", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-152-2", "doc_id": "medicine_vaccine_book", "page": 152, "text": "7 Conclusions\n\nPolicy makers can apply different approaches to address the competing interests of promoting innovation and the discovery of new medicines while at the same time fostering competition through the development and market entry of lower cost\n\n47Delhi High Court decision pronounced on 22 April 2019 on Bayer Corporation vs Union Of India & Ors. and Bayer Intellectual Property GMBH & Anr. v. Alembic Pharmaceuticals Ltd.RFA(OS) (COMM) 6/2017, https://indiankanoon.org/doc/85364944/. 48Ibid, para 89. 49Ibid at 35, para 435, page 53. 50For further analysis of the arguments made by Bayer and Natco, see Rathod (2017), available at https://doi.org/10.2139/ssrn.2971521. 51Ibid at 45, para 94.", "n_tokens": 181, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-153-0", "doc_id": "medicine_vaccine_book", "page": 153, "text": "Bolar Exception\n\ngeneric and biosimilar products. The policy approach should be in line with public health policies, i.e. to support access to medicines for all, and informed by the domestic context of the pharmaceutical industry.\n\nWithout the regulatory review or “Bolar” exception, competitive products such as generics and biosimilars would not be able to enter the market for prolonged periods following patent expiry of originator products. The safeguard against patent infringement for acts covered by the Bolar exception supports the regulatory approvals for generics and biosimilars without delay. Policy choices to expand the term of patent protection, introduce test data exclusivity or patent linkage can have the effect of increasing barriers for generic and biosimilar market entry.\n\nA broad and well-defined Bolar exception, as described in this chapter, is suited to the objective of promoting timely regulatory approval for generics and biosimilars to lower costs for health systems and improve access to medicines.\n\nReferences\n\nAgreement on Trade-related Aspects of Intellectual Property Rights of 1994; being Annexe 1C to\n\nthe Agreement Establishing the World Trade Organization, 15 April 1994\n\nBently L (2011) Exclusions from patentability and exceptions to patentees’ rights: taking excep-\n\ntions seriously. Curr Leg Probl 64:315–347\n\nCharles River Associates (2016) Assessing the Economic Impacts of the exemption provisions", "n_tokens": 288, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-153-1", "doc_id": "medicine_vaccine_book", "page": 153, "text": "during patent and SPC protection in Europe, European Commission\n\nConrad R, Lutter R (2019) U.S. Food and Drug Administration Generic Competition and Drug Prices: New Evidence Linking Greater Generic Competition and Lower Generic Drug Prices. https://www.fda.gov/media/133509/download\n\nCorrea C (2005) The international dimension of the research exception. SIPPI (Project on Science and Intellectual Property in the Public Interest), The American Association for the Advancement of Science, Washington, DC. http://sippi.aaas.org/Pubs/Correa_International%20Exception.pdf Correa C (2013) Protection of data submitted for the registration of pharmaceutical products: trips requirements and “TRIPS-Plus” provisions. In: Intellectual Property and Access to Medicines. South Centre and World Health Organization, pg. 16-/173. https://www.southcentre.int/wp- content/uploads/2016/05/Bk_2013_IP-and-Access-to-Medicines_EN.pdf\n\nCorrea CM (2014) Tackling the Proliferation of Patents: How to avoid undue limitations to competition and the public domain. Research Paper 52, South Centre, 2014 https://www. southcentre.int/wp-content/uploads/2014/09/RP52_Tackling-the-Proliferation-of-Patents-rev_ EN.pdf\n\nCorrea CM (2016) The Bolar exception: legislative models and drafting options. Research Paper 66, South Centre. https://www.southcentre.int/wp-content/uploads/2016/03/RP66_The-Bolar- Exception_EN1.pdf\n\nCorrea CM (2017) Intellectual Property in the Trans-Pacific Partnership: Increasing the Barriers for", "n_tokens": 392, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-153-2", "doc_id": "medicine_vaccine_book", "page": 153, "text": "the Access to Affordable Medicines. Research Paper 62R, South Centre\n\nCorrea CM (2020) Special Section 301:US Interference with the Design and Implementation of National Patent Laws, Research Paper 115. South Centre, July 2020. https://www.southcentre. int/research-paper-115-july-2020/\n\nDelhi High Court decision pronounced on 22 April 2019 on Bayer Corporation vs Union Of India & Ors. and Bayer Intellectual Property GMBH & Anr. v. Alembic Pharmaceuticals Ltd.RFA(OS) (COMM) 6/2017. https://indiankanoon.org/doc/85364944/\n\n147", "n_tokens": 136, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-154-0", "doc_id": "medicine_vaccine_book", "page": 154, "text": "148\n\nV. Munoz Tellez\n\nDreyfuss RC (2018) Justine Pila intellectual property law: an anatomical overview. In: The Oxford\n\nhandbook of intellectual property law. Oxford University Press, p 8\n\nDucimetière C (2019) Second Medical Use Patents – Legal Treatment and Public Health Issues, Research Paper 101. South Centre, December 2019. https://www.southcentre.int/research- paper-101-december-2019/\n\nEuropean Medicines Agency., https://www.ema.europa.eu/en/medicines/ Gabi Journal Editor Biosimilars Markets: US and EU compared, Generics and Biosimilars Initiative\n\nJournal (GaBI Journal). 2020;9(2):90–92. https://doi.org/10.5639/gabij.2020.0902.015\n\nGurgula O (2019) The ‘obvious to try’ method of addressing strategic patenting: How developing countries can utilise patent law to facilitate access to medicines. Policy Brief 59, April 2019, South Centre. https://www.southcentre.int/policy-brief-59-april-2019/#more-12341\n\nI-Mak, Overpatented, overpriced: how excessive pharmaceutical patenting is extending monopolies and driving up drug prices, 2018. http://www.i-mak.org/wp-content/uploads/2018/08/I-MAK- Overpatented-Overpriced-Report.pdf\n\nI-Mak Report Overpatented, Overpriced: How Excessive Pharmaceutical Patenting is Extending Monopolies and Driving up Drug Prices. http://www.i-mak.org/wp-content/uploads/2018/08/I- MAK-Overpatented-Overpriced-Report.pdf\n\nKang HN, Thorpe R, Knezevic I et al (2020) Regulatory challenges with biosimilars: an update", "n_tokens": 427, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-154-1", "doc_id": "medicine_vaccine_book", "page": 154, "text": "from 20 countries. Ann N Y Acad Sci. https://pubmed.ncbi.nlm.nih.gov/33222245/\n\nKrulwich A (1985) Statutory reversal of Roche v. Bolar: what you see is only the beginning of what you get. Food Drug Cosmetic Law J 40(4):519–525. http://www.jstor.org/stable/26658803 Max Planck Institute for Innovation and Competition (2018) Study on the legal aspects of\n\nsupplementary protection certificates in the EU. European Union, pp 338–361\n\nMercurio B (2017) Patent linkage regulations. In Mercurio B, Kim D (eds) Contemporary issues in\n\npharmaceutical patent law. Routledge, pp 97–122\n\nMercurio B, Tyagi M (2010) Treaty interpretation in WTO dispute settlement: the outstanding question of the legality of local working requirements. Minnesota J Int Law. 262, footnote 68 Noonan KE (2015) The role of regulatory agencies and intellectual property: Part I. Cold Spring Harb Perspect Med. 5(7):a020800. Published 2015 Mar 16. https://doi.org/10.1101/cshperspect. a020800\n\nOECD/European Union (2018) Health at a Glance: Europe 2018: State of Health in the EU Cycle. OECD Publishing, Paris/European Union, Brussels. https://doi.org/10.1787/health_glance_eur- 2018-en", "n_tokens": 333, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-154-2", "doc_id": "medicine_vaccine_book", "page": 154, "text": "Panel Report Canada – Patent Protection of Pharmaceutical Products WT/DS114/R, 17 March\n\n2000. https://www.wto.org/english/tratop_e/dispu_e/7428d.pdf\n\nRathod S (2017) The Curious Case of India’s Bolar Provision. SSRN https://doi.org/10.2139/ssrn.\n\n2971521\n\nRoche Products v Bolar Pharmaceutical Co., 733 F.2d.858 (Fed.Cir.1984) at 863 Seuba X (2019) The export and stockpiling waivers: new exceptions for supplementary protection certificates. J Intellect Prop Law Pract 14(11):876–886. https://doi.org/10.1093/jiplp/jpz108 UNAIDS: The First Ten Years, Joint United Nations Programme on HIV/AIDS (UNAIDS) 2008, p\n\n113\n\nVaca C, Gómez C (2020) The Controversy around technical standards for similar biotherapeutics: barriers to access and competition. Pharmacoepidemiol Drug Safety. https://doi.org/10.1002/ pds.5100\n\nVelásquez G (2018) The international debate on generic medicines of biological origin, Policy Brief No. 50, South Centre, https://www.southcentre.int/wp-content/uploads/2018/08/PB50_The- International-Debate-on-Generic-Medicines-of-Biological-Origin_EN.pdf\n\nVondeling GT, Cao Q, Postma MJ, Rozenbaum MH (2018) The impact of patent expiry on drug prices: a systematic literature review. Appl Health Econ Health Policy 16:653–660. https://doi. org/10.1007/s40258-018-0406-6 pmid:30019138\n\nWIPO. draft reference document on the exception regarding acts for obtaining regulatory approval from authorities (second draft), document SCP/28/3, https://www.wipo.int/edocs/mdocs/scp/en/", "n_tokens": 475, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-155-0", "doc_id": "medicine_vaccine_book", "page": 155, "text": "Bolar Exception\n\nscp_28/scp_28_3.pdf. The document is kept open for future discussion by the Standing Com- mittee on Patents\n\nWorld Health Organization (1999) Marketing authorization of pharmaceutical products with special reference to multisource (generic) products: a manual for a drug regulatory authority. World Health Organization. https://apps.who.int/iris/handle/10665/65175\n\nWorld Health Organization (2011) Marketing authorization of pharmaceutical products with special reference to multisource (generic) products: a manual for National Medicines Regulatory Authorities (NMRAs), 2nd edn. World Health Organization. https://apps.who.int/iris/handle/ 10665/44576", "n_tokens": 154, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-155-1", "doc_id": "medicine_vaccine_book", "page": 155, "text": "World Trade Organization (2000) Canada – Patent Protection of Pharmaceutical Products, Report\n\nof the Panel, WT/DS114/R, 17 March 2000\n\nWTO document IP/C/M/88/Add.1, Minutes of the TRIPS Council, 12 April 2018, Agenda item 12: Intellectual Property and Public Interest, Regulatory Review exception. https://docs.wto.org/ dol2fe/Pages/SS/directdoc.aspx?filename¼q:/IP/C/M88A1.pdf&Open¼True\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n149", "n_tokens": 287, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-156-0", "doc_id": "medicine_vaccine_book", "page": 156, "text": "Patent Oppositions in India\n\nSandeep Kanak Rathod\n\nAbstract Pre-grant and post-grant oppositions filed in India by civil society and generic companies have been instrumental in visibly increasing access of drugs to the public—both in terms of earlier generic entry and also cheaper prices due to such generic competition. This paper looks at the significant pharmaceutical patent oppo- sitions in India during the last 15 years. It focuses on some unique aspects connected to each of these oppositions and tracks how these oppositions helped in securing earlier access to generic drugs. The last part of the paper analyses patent opposition pendency statistics and notes that increasing pendency numbers, over the last few years, is a matter of deep concern as it could impact access to drugs, in future.", "n_tokens": 161, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-156-1", "doc_id": "medicine_vaccine_book", "page": 156, "text": "1 Introduction\n\nPatent oppositions by civil society organisations and generic pharmaceutical com- panies have been instrumental in increasing access of drugs to the public—by preventing patent evergreening and bringing in earlier generic drug entry as well as increasing competition in the pharmaceutical sector leading to cheaper prices due to such generic entry. Over the years, various commentators have written on Indian patent oppositions—from different legal and policy perspectives.1\n\nIn this paper, the author analyses key pharmaceutical patent oppositions in the last one and half decade and shares certain lesser discussed angles of these oppositions. The paper is divided in two parts. The first part discusses important pharmaceutical patent oppositions pertaining to drugs across disease categories and looks at how legal arguments have progressed moving beyond the simplistic statutory arguments as well as how certain strategies that are beyond the opposition framework can lead to successful results even when an opposition is not filed.\n\n1Below are some papers that have looked at patent oppositions in India from different perspectives: Amin (2010); Ho (2011); Ali (2016); Serrano and Burri (2019), pp. 275–294.\n\nS. K. Rathod (*) Mumbai, India\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_6\n\n151", "n_tokens": 300, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-157-0", "doc_id": "medicine_vaccine_book", "page": 157, "text": "152\n\nS. K. Rathod\n\nThe second part of the paper looks at the current opposition pendency statistics and what these statistics mean for oppositions for the times to come. Before proceeding further, it is important to note that India, like many developing countries, has a healthcare system where individuals pay a very large proportion of healthcare expenses from their pocket.2 This reality combined with a large population, means that the drug access mechanism becomes that much more strained and every attempt at increasing drug access needs to be seen not only in the limited framework of intellectual property (IP) but in the broader framework of living in a resource constrained country.", "n_tokens": 128, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-157-1", "doc_id": "medicine_vaccine_book", "page": 157, "text": "India has a long history of patent law, going back to the 1850s.3 The present patents regime in India is enshrined within the Patents Act, 19704 (‘the 1970 Act’) that was enacted after repealing the Indian Patents and Designs Act 1911. After independence in 1947, India set up committees to look at the 1911 Act and these committees noted the stage of economic development in India, the relevance of patents to a country that was then not an industrially developed nation and what possible changes could be made to the 1911 Act. The Ayyangar Committee Report5 also noted the disparities resulting from the 1911 Act and how certain steps were necessary to completely rewrite the statute. Importantly, this Report recommended moving to a ‘process claims’ only regime for certain sectors6 and was the foundation for the 1970 Act.\n\nThe 1970 Act allowed only process patents within the drug/pharmaceuticals and food domain, until 2005. Changes were made in stages to the 1970 Act in 1999, 2002 and 2005 as a part of India’s commitments to the Trade Related Aspects of Intellectual Property Agreement (TRIPs Agreement) and India restarted issuing product patents for pharmaceuticals and allied sectors from 2005.\n\n2As per the National Health Accounts (NHA) estimate for 2014–15, Out-of-Pocket Expenditure (OPE) per person, per year in India, is Rs. 2394, which comes out to be 63% of the total health expenditure.\n\nReference: <https://www.downtoearth.org.in/dte-infographics/india_s_health_crisis/index.", "n_tokens": 327, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-157-2", "doc_id": "medicine_vaccine_book", "page": 157, "text": "html>.\n\nThe World Bank data also gives a similar figure (of 62.4% as OPE—latest data pertained to year 2017): <https://data.worldbank.org/indicator/SH.XPD.OOPC.CH.ZS?end¼2017&locations¼IN& start¼2000&view¼chart>. 3The ‘background’ section has been adopted from author’s earlier article: Compulsory licences on pharmaceutical patents in India: A short article. Journal of Generic Medicine, 13(3), 108–113. doi:10.1177/1741134317691804. 4A copy of the statute is available at the Indian Patent Office’ website: <http://www.ipindia.nic.in/ acts-patents.htm>. 5‘Report on the revision of the patents law’ by Justice N. Rajagopala Ayyangar; released in September 1959 and available at <http://www.ipindia.nic.in/writereaddata/Portal/Images/pdf/ 1959-_Justice_N_R_Ayyangar_committee_report.pdf>. 6The Report discussed the background and rationale for moving from product claims to a process claims only regime for certain sectors, extensively—Refer Paragraphs 56 through 102 of the Report.", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-158-0", "doc_id": "medicine_vaccine_book", "page": 158, "text": "Patent Oppositions in India\n\nOriginally, oppositions came in the prosecution framework only once—i.e. after a patent application had already been examined and accepted by the Patent Office i.e. India allowed filing oppositions against ‘applications accepted for grant’. India modified its patent opposition system in 2005 and created provisions for two types of oppositions—pre-grant opposition against a published application and post-grant opposition against a granted patent. In the earlier system, oppositions came in the prosecution framework only once—i.e. after a patent application had already been examined and accepted by the Patent Office. The modification thus allowed an opposition to be filed at an earlier stage of the prosecution framework as well as after the grant of patent.\n\nAccordingly, a patent application can now be opposed under section 25(1) by filing a representation with the Patent Office. This is also normally called as a ‘pre- grant opposition’. A granted patent can be opposed under section 25(2) by filing an opposition. This is normally called as a ‘post-grant opposition’. It needs to be filed within 12 months from the date of publication of such grant. A patent can also be sought to be revoked under section 64 and the Government can revoke patents on policy considerations under section 66.\n\nThere are four main players within the patent opposition framework as applied to", "n_tokens": 289, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-158-1", "doc_id": "medicine_vaccine_book", "page": 158, "text": "pharmaceutical inventions: (cid:129) The Government—Ministry of Commerce & Industry, Government of India (which is ultimately responsible for the functioning of the Patent Office and grant of patents), the Ministry of Health and Family Welfare (responsible for health framework) and the Ministry of Chemicals and Fertilizers (that houses the Department of Pharmaceuticals); Innovator companies filing patents for their products (Applicants);\n\n(cid:129) (cid:129) Generic companies seeking to launch drugs as soon as possible (Opponents); and (cid:129) Civil society/Non-governmental organisations (also termed as ‘NGOs’) working at the grassroots on access to medicines and patient rights and who oppose patent applications/patents for ensuring drug access (hence, also Opponents).\n\nEach of these players are important stakeholders and have different priorities/ goals within the patent system but each of them must play their roles with integrity and efficiency to create a system that balances drug access and health with encour- aging an intellectual property (IP) rights framework to reward innovators.", "n_tokens": 223, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-158-2", "doc_id": "medicine_vaccine_book", "page": 158, "text": "The paper discusses 14 oppositions (both pre-grant and post-grant) that relate to important drugs that are needed by a large patient population. Oppositions for niche drugs are excluded. In most of the cases, companies had launched a generic version of the product, while the opposition proceedings were on-going and hence if the oppositions would have failed, it would have negatively impacted generic drug access.\n\nAs we trace these pharmaceutical oppositions, we note that many of the early oppositions filed in 2005–2015 were centered mainly around the statutory arguments\n\n153", "n_tokens": 112, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-159-0", "doc_id": "medicine_vaccine_book", "page": 159, "text": "154\n\nS. K. Rathod\n\nfrom S.37 (which excludes from patentability certain inventions and is titled ‘What are not inventions’) and mostly around S.3(d) of the Patents Act (that bars grant of patents to new form of known substances or mere use of known processes).\n\nOpponents have, over the years, moved beyond basing their case on S.3(d) alone and have gone to draft and win oppositions based on more complex arguments like lack of inventive step, obvious to try, anticipatory disclosures from markush claim8 filings etc. Just like the opposition arguments moved beyond 3(d), so have the patent examiners, for examination of pharmaceutical claims.\n\nPublished empirical research9 covering patent applications having priority dates between 2000 and 2012 advises that while examiners are invoking S. 3(d) more over time, but when they do so, it still tends to be in conjunction with novelty and inventive step objections. But effective use of S.3 and its implementation is an open question. A later paper10 covering pharmaceutical patents granted between 2009 and 2016 argues that the Examiners at the Patent Office have not been implementing S.3 framework to its fullest and that more than 70% of such patents were in contravention of the anti-evergreening framework of S.3.", "n_tokens": 281, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-159-1", "doc_id": "medicine_vaccine_book", "page": 159, "text": "Hence, while one can try and imagine what would have happened in these 13 cases in absence of these oppositions; the undeniable fact is these pharmaceutical oppositions have expanded drug access for multiple important drugs—not just for Indian patients but also for patients from other countries that are dependent on Indian generic drugs.\n\nWithin this scenario, increasing pendency statistics for oppositions, over the last\n\nfew years, is a matter of deep concern as it could negatively impact drug access.\n\n2 Patent Oppositions in India", "n_tokens": 101, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-159-2", "doc_id": "medicine_vaccine_book", "page": 159, "text": "2.1 Gleevec Opposition\n\nAny paper on Indian patent oppositions can move forward only by starting from the Imatinib Mesylate Beta polymorph form opposition. Imatinib (brand name Gleevec)\n\n7Section 3 of the Patents Act, 1970, is titled—‘What are not inventions’. Section 3 is a ‘deeming’ fiction—it prohibits grant of patents to certain categories of inventions and is part of the chapter titled ‘Inventions not patentable’. Thus, these inventions, in absence of this section would have been patentable. Text of S.3 is available at https://indiankanoon.org/doc/874310/. Within S.3, S. 3(d), 3 (e) and 3(i) have special importance as they relate to pharmaceutical inventions. 8A ‘Markush’ claim recites a list of alternatively useable members and can cover millions of compounds in a single claim. This can, at times, go much beyond actual embodiments exemplified in the patent specification. For a general discussion on what are markush claims, please refer https:// www.uspto.gov/web/offices/pac/mpep/s2117.html. 9Sampat and Shadlen (2018), p. e0194714. 10Ali et al. (2018).", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-160-0", "doc_id": "medicine_vaccine_book", "page": 160, "text": "Patent Oppositions in India\n\nTable 1 Imatinib opposition\n\nDrug: Therapeutic area: Nature of patent filing in India: Application # Date & links to opposition decision:\n\nImatinib Anti-cancer/Oncology Beta crystalline polymorph of drug—Imatinib Mesylate 1602/MAS/1998 25/Jan/2006 Natco: <https://indiankanoon.org/doc/1352538/> Cipla: <https://indiankanoon.org/doc/1740470/> Hetero: <https://indiankanoon.org/doc/1629598/> CPAA: <https://indiankanoon.org/doc/994049/> 17/July/2018\n\nExpiry, if patent would have been granted: Opponent(s):", "n_tokens": 174, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-160-1", "doc_id": "medicine_vaccine_book", "page": 160, "text": "Unique points:\n\nCancer Patients Aid Association (CPAA) Companies: Hetero, Cipla, Natco Evidence submission, obviousness, disclosure versus claim scope and S.3(d)\n\nis a Novartis drug used in treatment of certain cancers (such as acute lymphoblastic leukemia, chronic myeloid leukemia, gastrointestinal stromal tumors etc.).\n\nThis opposition battle went all the way up to the Supreme Court of India11 where besides looking at the S.3(d) interpretation, the Court also made way for some very interesting case-law on inventive step, rejecting Novartis’ arguments on disclosure v/s claim scope.\n\nFiling details in Table 1: The Indian Imatinib opposition saga starts after the grant of an exclusive market- ing right (EMR) in December 2003 by the Patent Office to Novartis on its application for Beta polymorph of Imatinib Mesylate.\n\nEMRs12 were the predecessors of ‘pharmaceutical product patent claims’. EMRs were brought into the statute book in 1999 as an interim mechanism to afford product patent type protection, after the United States’ filed an action against India at the World Trade Organisation’s Dispute Settlement Body in 1997.13 These EMRs could be granted only upon satisfying certain criteria and were to cease upon grant of product patent to the EMR holder, in due course.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-160-2", "doc_id": "medicine_vaccine_book", "page": 160, "text": "The drug ‘Imatinib’, including its salts forms was invented at Novartis in 1993 and patents were filed for it in many countries. This patent was not filed in India since India did not allow product patent status for pharmaceutical products, in 1993.\n\n11Novartis AG v. Union of India & Ors. [2013] INSC 369. https://www.globalhealthrights.org/wp- content/uploads/2013/04/SC-2013-Novartis-AG-v.-Union-of-India.pdf. 12EMRs were bought in via the 1999 amendment and covered in Chapter IVA (Sections 24A through F) of the Patents Act. The EMR chapter was removed in the 2005 amendment that reintroduced product patents for pharmaceuticals. 13Refer Nupur Maithani and Priyanka Vyas, ‘India: Exclusive Marketing Rights Revisited in India’ available at https://www.mondaq.com/india/patent/73894/exclusive-marketing-rights-revisited-in- india.\n\n155", "n_tokens": 230, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-161-0", "doc_id": "medicine_vaccine_book", "page": 161, "text": "156\n\nS. K. Rathod\n\nNovartis’ own experiments in 1996 had shown that there was no difference in efficacy between Imatinib and Imatinib Mesylate salt. It filed the Indian patent application for the Beta crystalline polymorph of Imatinib Mesylate in July 1998 and sought an EMR for the same from the Indian Patent Office, in March 2002. This 1998 patent filing was two steps away from the original 1993 invention—a move from Imatinib base to Imatinib Mesylate and then a move from Imatinib Mesylate to making a Beta crystalline polymorph of the same.\n\nMeanwhile, Novartis had launched the drug in United States in 2001 and in India in April 2002. It got the EMR in December 2003. Some generic companies also launched the drug in India after Novartis’ launch, but before the grant of EMR. There was a huge difference between Novartis’ price and the price charged by generic companies.\n\nBased on this EMR, in early 2004, Novartis went ahead with filing of infringe- ment suits at two Courts—the Madras High Court (seven cases) and the Bombay High Court (three cases). The Madras High Court granted injunction(s) in favour of Novartis against such generic launches but the Bombay High Court did not grant injunctions. Multiple generic companies and civil society groups filed pre-grant oppositions against the pending application.", "n_tokens": 310, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-161-1", "doc_id": "medicine_vaccine_book", "page": 161, "text": "While journal articles have discussed nuances of the later court battles that came after the pre-grant opposition—including the Madras High Court14 decision(s), the Intellectual Property Appellate Board decision15 (IPAB) and the Supreme Court’s decision,16 but there is very little written material on the actual pre-grant decision. While the Opponents raised multiple grounds, two key questions raised were related to (i) S.3(d) and (ii) assessment of obviousness. S.3(d) brings in an additional question of examination when claims relate to new forms of known substances—in this case, claimed ‘beta polymorph of imatinib mesylate’ was a new form of known substance—Imatinib and its salts and would be eligible for patent only if the beta polymorph passed the framework of S.3(d) i.e. a patent could be granted only if the beta polymorph differed significantly in properties with regard to efficacy when compared to Imatinib or its known salts. The obviousness assessment for these claims was focused on the question of how making polymorphs of a known drug or its salt forms could be considered obvious to a person skilled in the art.", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-161-2", "doc_id": "medicine_vaccine_book", "page": 161, "text": "There is a notion that the opposition proceeding was superficial and did not give Novartis a fair chance to adduce evidence/data that it could not have put in the original patent specification. This notion is not based on facts. Actually, the Patent Controller (Mr. Rengaswamy), at first instance, had afforded an opportunity to Novartis to show the merits of the beta polymorphic form. Novartis could only the relative show that\n\nin bioavailability—i.e.\n\nthere was a 30% improvement\n\n14Basheer and Reddy (2008), pp. 131–155. 15The IPAB’s decision was analysed here: https://spicyip.com/2009/07/breaking-news-novartis- loses-glivec.html. 16The Supreme Court decision has been discussed below: (i) Ragavan (2013). http://works.bepress. com/srividhya_ragavan/156/. (ii) Attaran (2014), pp. 477–479. (iii) Grebe and Low (2017).", "n_tokens": 245, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-162-0", "doc_id": "medicine_vaccine_book", "page": 162, "text": "Patent Oppositions in India\n\nbioavailability of Imatinib Mesylate in the beta crystalline form versus Imatinib free base (and not Imatinib Mesylate salt)—but could not show any specific therapeutic advantage of the beta crystalline form over Imatinib Mesylate itself. A salt form of a drug (regardless of its polymorphic form) would normally have increased bioavail- ability over a drug in its base form.\n\nImportantly, in his decision, the Controller noted that ‘... also the difference in bioavailability may be due to the difference in their solubility in water’ and he held: ... As regards efficacy, the specification itself states that wherever ß-crystals are used the imatinib free base or other salts can be used. The present patent specification does not bring out any improvement in the efficacy of the ß-crystal form over the known substances rather it states the base can be used equally in the treatment of diseases or in the preparation of pharmacological agents wherever the ß-crystal is used. Even the affidavit submitted on behalf of the Applicant does not prove any significant enhancement of known efficacy. It is found that this patent application claims only a new form of a known substance without having any significant improvement in efficacy. Hence I conclude that the subject matter of this application is not patentable...", "n_tokens": 314, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-162-1", "doc_id": "medicine_vaccine_book", "page": 162, "text": "Had these oppositions not been filed and Controller Rengaswamy not considered these key questions viz. (i) S.3(d) framework for assessing patentability arguments for new forms of a known substance and (ii) the law of obviousness for pharmaceu- tical inventions—then theoretically, the EMR and subsequent product patent would have sustained and possibly blocked generic launch until July 2018. While this opposition used S.3(d) extensively, the jurisprudence that developed from the Patent Office all the way up to the Supreme Court went a lot beyond the plain S.3 (d) argument.\n\nLet’s focus on some things that had their genesis from this set of pre-grant opposition(s). The filing of the pre-grant oppositions became the foundation for the later battles that led to the following important consequences: (cid:129) Securing earlier and consistent availability of generic version—from 2003 onwards and much before July 2018 (which would have been the expiry for the granted patent—thus earlier generic availability by a margin of 15 years);\n\n(cid:129) Bringing in a framework for examining obviousness while assessing pharmaceu-", "n_tokens": 244, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-162-2", "doc_id": "medicine_vaccine_book", "page": 162, "text": "tical inventions;\n\n(cid:129) Creating jurisprudence on the concept of efficacy in pharmaceutical inventions and the difference between bioavailability and therapeutic efficacy (S.3(d)); (cid:129) Laid the foundation for the Supreme Court to note that there cannot be a difference between what is disclosed in the patent specification versus what is claimed in the patent’ claims. This last point will again be in focus in the coming years—as Markush disclo- sures versus specific compound patent claim invalidation litigations are now pend- ing the Indian Courts.\n\nAs noted earlier, literature has discussed extensively about the later high court, IPAB and Supreme Court battles of Imatinib. However, it is Controller Rengaswamy who was the first adjudicator/judge and made an important contribution that later\n\n157", "n_tokens": 184, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-163-0", "doc_id": "medicine_vaccine_book", "page": 163, "text": "158\n\nS. K. Rathod\n\nTable 2 Valganciclovir opposition\n\nDrug: Therapeutic area: Nature of patent filing in India: Patent/Application # Dates of decision(s):\n\nExpiry, if patent remained granted: Opponent(s):\n\nUnique points:\n\nValganciclovir Anti-viral Compound (L-valinate ester of Ganciclovir) IN207232 (from 959/MAS/1995) 2nd Pre-grant: 30/Jan/2009 Post-grant: 30/April/2010 and again on 01/July/2015 27/July/2015 Indian Network of People Living with HIV/AIDS (INP+); Companies: Matrix; Ranbaxy; Cipla and Bakul Pharma. Ambit of ‘Person interested’ to file post-grant opposition, Obvious to try and S.3(d).\n\nbecame the cornerstone for access saga.\n\nIndia’s pharmaceutical patent opposition/drug", "n_tokens": 199, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-163-1", "doc_id": "medicine_vaccine_book", "page": 163, "text": "2.2 Valcyte Opposition\n\nGanciclovir was approved as a drug in 1988. Roche later filed a patent application for a modification of Ganciclovir—i.e. it claimed the L-valinate ester of Ganciclovir (Valganciclovir, brand name: Valcyte). This drug is used in the treatment of adults in preventing infection with cytomegalovirus (CMV) that may occur after an organ transplant (heart, kidney, or pancreas). It is also used to treat CMV infection of the eye in adults with acquired immunodeficiency syndrome (AIDS). See Table 2.\n\nThis application saw the opposition fight in multiple rounds at the pre-grant stage and then a strongly contested post-grant opposition stage as well. And in the midst of this, there were rounds to the Madras High Court and the Supreme Court too.\n\nIn the first round, only a single short pre-grant opposition was filed by civil society groups (NGOs) in July 2006. The Controller rejected this opposition in November 2007 summarily and proceeded to process the grant of the patent. The civil society groups then moved the Madras High Court (HC) challenging this patent arguing that their pre-grant opposition was not heard by the patent controller. In December 2008, the HC asked the Patent Office to review its decision.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-163-2", "doc_id": "medicine_vaccine_book", "page": 163, "text": "Roche decided to move the Supreme Court contesting the HC order17 which then directed the Patent Controller to consider the pre-grant opposition and dispose the case by 31/Jan/2009. The Patent Controller heard the matter again and through his decision dated 30/Jan/2009, rejected the NGOs’ pre-grant opposition. Accordingly, the first set of pre-grant oppositions (in 2 rounds) did not succeed and a patent was granted to Roche.\n\n17https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/sc-asks-chen nai-patent-office-to-hear-roche/printarticle/4213952.cms.", "n_tokens": 149, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-164-0", "doc_id": "medicine_vaccine_book", "page": 164, "text": "Patent Oppositions in India\n\nMeanwhile, Cipla had launched a generic version of the product in September 2008 and Roche filed a patent infringement suit. Subsequently, NGOs and multiple generic companies filed post-grant oppositions.\n\nWhile the post-grant opposition was fought on multiple grounds including (a) S.3 (d) barred patenting of ‘new’ ester form of a known substance ‘ganciclovir’, in absence of enhanced efficacy and (b) an important obviousness argument was also bought in by a generic company (Matrix) which argued that making a valinate ester of a drug like Ganciclovir was obvious when seen from prior art construct of making a valinate ester of a drug like Aciclovir (an ‘obvious to try’ framework!Acicyclovir to its valinate ester—Valacyclovir approach would prompt a person to attempt to make the valinate ester—Valganciclovir—from Ganciclovir since these are similar drugs chemically and the underlying problem to be solved was similar)—this obviousness argument was eventually accepted by the Controller.", "n_tokens": 238, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-164-1", "doc_id": "medicine_vaccine_book", "page": 164, "text": "Apart from the science aspects noted above, a lesser known but key aspect in the post-grant stage was whether civil society groups had a ‘standing’ (‘locus’) to file a post-grant opposition as the Patents Act states that only a ‘person interested’ could file a post-grant opposition. Hence whether a non-manufacturing entity (like a civil society group) could come within the scope of ‘person interested’, thus having ‘locus-standi’ to file a post-grant opposition was, till then, an open question. To this question, the Controller specifically ruled that civil society groups came within the ambit of ‘person interested’. This ruling expanded the scope of entities that could file a post-grant opposition and consequently civil society groups were now free to file post-grant oppositions.\n\nThe Controller, in the final Valcyte decision, not only revoked the granted patent and secured generic production, but also helped in expanding the ambit of the term ‘person interested’ and demonstrated how an ‘obvious to try’ argument could be effectively implemented for assessing patentability of alternative forms of known substances.\n\nRoche appealed the post-grant rejection from the Patent Office to the IPAB, which remanded the matter back to the Controller. In July 2015, the Controller revoked this patent a second time,18 which reconfirmed the earlier decision, includ- ing ‘obvious to try’ framework and the standing of civil society organisations to file post-grant oppositions as ‘person interested’.", "n_tokens": 321, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-164-2", "doc_id": "medicine_vaccine_book", "page": 164, "text": "2.3 Herceptin Opposition\n\nTrastuzumab (brand name: Herceptin) is a biologic drug (a monoclonal antibody) from Roche/Genentech, used primarily in the treatment of breast cancer. Roche had one Indian patent that covered a particular formulation of this drug. Roche had— over the years—filed multiple divisional applications from this original filing,\n\n18https://spicyip.com/2015/07/valganciclovir-patent-revoked.html.\n\n159", "n_tokens": 111, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-165-0", "doc_id": "medicine_vaccine_book", "page": 165, "text": "160\n\nS. K. Rathod\n\ncreating a series of pending divisional filings—each of which would have normally required filing separate oppositions, to secure launch of any generic product. Each of the three divisional filings suffered from individual procedural defects which meant that these were incorrect filings and should have not been allowed to remain in the system, in the first place.\n\nA generic company (Glenmark) had filed a post-grant opposition against the granted patent, but that opposition never saw any traction at the Patent Office. Glenmark had also filed a pre-grant opposition against the first divisional application (1638), but this opposition too never reached the stage of a formal hearing.\n\nSince late 2012, an NGO (‘Campaign for Affordable Trastuzumab’) had been working to increase access to Trastuzumab and was talking to the Government for the same.19 In March 2013, the Health Ministry had even recommended issuance of a compulsory license against the formulation patent20 but no compulsory license was issued on this patent.", "n_tokens": 216, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-165-1", "doc_id": "medicine_vaccine_book", "page": 165, "text": "In February 2013, a generic company had (Mylan Laboratories) bought the issue of all three divisional filings being incorrect in law, to the notice of the Patent Office by means of detailed letters. Consequently, the Patent Office invited Roche to explain its divisional filings. Roche did not attend the meetings in July 2013 and subsequently the Patent Office rejected the divisional filings.21 Roche had kept all of above Indian filings, active, from 2000 through July 2013.\n\nIn August 2013, Roche also abandoned its main patent22 (by opting to not pay renewal fee), but not before asserting23 that “This decision takes into account the strength of the particular rights and the IP (intellectual property) environment in India in general.” Roche statement excluded any mention about Roche’s rationale for originally filing and then abandoning these divisional filings or why it suddenly abandoned its main granted patent, for no specific reason.\n\nGlobal media reports around the matter—led the Indian Patent Office to do something that it had never done (and has not done since). The Patent Office put out a press release (noted in Table 3) which systematically mentioned the defects in each of the Roche’ divisional filings.", "n_tokens": 254, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-165-2", "doc_id": "medicine_vaccine_book", "page": 165, "text": "Roche’s decision to originally prosecute and later abandon the Indian formulation patent as well as file and later abandon the multiple divisional applications (all of which it had kept alive for many years)—must be also seen in a broader context of corresponding filings outside India. While the above actions were going in India during 2012–13, Roche had been fighting an intense battle with Hospira (a generic company) first at the EPO (since 2006) and later also at the UK Courts for\n\n19http://www.pharmabiz.com/NewsDetails.aspx?aid¼77303&sid¼1. 20Refer Compulsory Licenses article, noted earlier, at pages 111 and 113. 21https://www.livemint.com/Companies/TBQxokHyVTMGozu78o6CSL/India-partly-revokes- Roche-cancer-drug-patent.html. 22https://www.ft.com/content/b8c9cf06-0676-11e3-9bd9-00144feab7de. 23https://www.reuters.com/article/us-roche-herceptin-india/roche-gives-up-on-india-patent-for- breast-cancer-drug-idUSBRE97F08220130816.", "n_tokens": 309, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-166-0", "doc_id": "medicine_vaccine_book", "page": 166, "text": "Patent Oppositions in India\n\nTable 3 Trastuzumab opposition\n\nDrug: Therapeutic area: Nature of patent filing in India: Patent/Application #\n\nDate & Link: Expiry date, for the granted patent: Unique points:", "n_tokens": 47, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-166-1", "doc_id": "medicine_vaccine_book", "page": 166, "text": "Trastuzumab Oncology (Breast cancer) Formulation for Trastuzumab\n\n1. Original: IN/PCT/2000/391/KOL (matured into a patent IN205534) 2. 1638/KOLNP/2005—first divisional application (child); 3. 3272/KOLNP/2008—second divisional application (i.e. first grandchild); 4. 3273/KOLNP/2008—third divisional application (i.e. second grandchild) Government Press Release dated 05/Aug/2013 (Krishnan 2013) 03/May/2019\n\nFiling of multiple divisional applications; Patent Office dismissed the applications on procedural grounds\n\ncounterpart of this formulation patent. In October 2010, the EPO, in a first instance ruling, ruled this formulation patent (EP1308455), invalid. As of 2013, when Roche abandoned the Indian patent, its appeal against the invalidity decision, was pending at the EPO. In April 2014,24 the UK Patents Court, ruled the UK counterpart of the formulation patent as being invalid.\n\nThe author submits that while these abandonment/rejection results were achieved outside of the standard ‘oppositions’ framework, it must be noted that ‘out of the box’ actions/petitions can also achieve path-breaking results, even before/without filing an opposition. The Patent Office’s decision of removing these incorrect divisional application filings and Roche’ abandonment of the sole granted patent removed the need for filing multiple oppositions to the applications as well as the granted patent and thus cleared the way for launch of the world’s first biosimilar Trastuzumab, in India in early 2014.25", "n_tokens": 355, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-166-2", "doc_id": "medicine_vaccine_book", "page": 166, "text": "2.4 Zykadia Opposition\n\nCeritinib (brand name: Zykadia) is a Novartis drug used for treatment of lung cancer. This relatively recent post-grant opposition decision against Ceritinib compound patent is a short and interesting decision. See Table 4.\n\nNatco had launched an ‘at risk’ generic version of Ceritinib in India, prior to this opposition decision. Novartis also has a patent infringement suit pending against\n\n24[2014] EWHC 1094 (Pat), https://www.bailii.org/ew/cases/EWHC/Patents/2014/1094.html. 25https://www.thehindubusinessline.com/companies/mylan-launches-first-trastuzumab-biosimilar- in-india/article23122107.ece.\n\n161", "n_tokens": 190, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-167-0", "doc_id": "medicine_vaccine_book", "page": 167, "text": "162\n\nS. K. Rathod\n\nTable 4 Ceritinib opposition\n\nDrug: Therapeutic area: Patent/Application # Opponent: Dates of decision(s): Expiry, if patent remains standing: Unique points:\n\nCeritinib Oncology IN276026 (from 3951/DELNP/2009) Natco Pharma 16/Aug/2019 08/Dec/2026\n\nAnticipation—Markush disclosure versus specific compound; Lack of inventive step and S.3(d)\n\nNatco at the Delhi High Court. The opposition decision allowed Natco to continue to be present in market, but with the risk of payment of damages in future.\n\nFor the opposition, Natco used 3 main arguments—lack of novelty (anticipation),\n\nlack of inventive step and not an invention u/s 3(d).\n\nFor anticipation, Natco argued that two separate prior document(s): IN232653 (application # 2241/CHENP/2005, coming from WO2004080980) and IN240560 (application # 553/CHENP/2006, coming from WO2005016894)—both disclosed Markush26 group of compounds which individually destroyed novelty for Ceritinib molecule i.e. one would get/find the Ceritinib molecule in either of these documents, if one used the right substitutions. WO2005016894 had been cited in the original prosecution but time, had allowed the claims during examination.\n\nthe Controller, at", "n_tokens": 318, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-167-1", "doc_id": "medicine_vaccine_book", "page": 167, "text": "that\n\nThe Opponent also used these 2 documents and additionally 4999/KOLNP/2007 (coming from WO2007006926) to argue that the Ceritinib molecule lacked an inventive step.\n\nFinally, the Opponent also argued that the Patentee did not provide any in vivo efficacy data for Ceritinib in comparison to compounds disclosed in these 2 docu- ments and hence it failed the threshold of S.3(d) as Ceritinib would be a new form of known compounds in either of these filings.\n\nThe Controller’s approval of the Markush filing destroying the novelty of later specific compounds in his decision is very interesting to this author since there are many other compound patent filings which fall in this template of an earlier Markush patent disclosing a large number of compounds and a later specific patent filing for the compound. This decision could potentially imply that the earlier broad Markush patent disclosures can be used to invalidate later specific compound patent filings. Note: The Patentee filed an appeal against the Controller’s revocation decision, at the IPAB. In July 2020, the IPAB has issued a ‘stay’ on the Controller’s revocation order27 as an interim order in the appeal proceedings.\n\n26Refer earlier note for definition of ‘Markush’ claims. 27A copy of the IPAB Order is available at https://ipab.gov.in/ipab_orders/delhi/MP.NO.8.2019- OA.20.2019.PT.DEL.pdf.", "n_tokens": 341, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-168-0", "doc_id": "medicine_vaccine_book", "page": 168, "text": "Patent Oppositions in India\n\n2.5 The Viread Oppositions\n\nTenofovir Disoproxil Fumarate (brand name: Viread) is used in treatment of AIDS and Hepatitis B. Gilead had filed a bunch of patent applications related to its Viread IP portfolio for—Tenofovir Disoproxil (ester) and the final product—Tenofovir Disoproxil Fumarate (salt form of the ester). Tenofovir had been invented years earlier by a Czech scientist28 and later Gilead + UC San Francisco carried out additional work. Finally, Gilead developed the salt form that finally became the block-buster HIV drug.", "n_tokens": 150, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-168-1", "doc_id": "medicine_vaccine_book", "page": 168, "text": "Some interesting facets to the Gilead Viread Indian patent portfolio:\n\n(cid:129) Gilead filed a large number of divisional filings from the 2 original filings—\n\neventually turning into multiple ‘children’/‘grandchildren’ filings.\n\n(cid:129) Multiple companies, civil society and patient groups filed pre-grant oppositions in 2006 and onwards against most of these filings, over the years, including the divisional filings.\n\n(cid:129) Gilead secured a process patent in 2004 (IN190780 from the 1998 Fumarate filing) and later went on to complete a series of bilateral licenses with multiple Indian generic companies for making and supplying Tenofovir and its combina- tion products for HIV for multiple countries, including India.\n\nWhile many Indian companies went ahead with the royalty bearing license agreements around 2007, companies like Cipla did not take the license and contin- ued with the opposition. It is worth nothing that except the original process grant, Gilead lost out in the compound oppositions—on both the ester and salt patent application series. Gilead also modified the license structure when it was argued that the original bilateral license template covered language that would stop companies from opposing Gilead’ patents—a position that was specifically barred in Indian patent law. Table 5 summarizes the tenofovir opposition.", "n_tokens": 289, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-168-2", "doc_id": "medicine_vaccine_book", "page": 168, "text": "Over the years, Gilead has transformed its TDF licensing program from bilateral licenses to eventually moving onto the Medicine Patent Pool (MPP) multi-lateral license platform. The number of countries has also modified over the years with some critics arguing that the licenses exclude important middle income countries from the license ambit.29\n\nIt must always be remembered that Gilead’ first interaction in India was the genesis of many later developments—mass pharmaceutical patent licensing, market segmentation and targeted exclusion of generics from middle income countries,\n\n28https://www.latimes.com/business/la-fi-gilead-timeline-20160527-snap-story.html. 29https://www.bizjournals.com/sanfrancisco/blog/biotech/2011/07/gilead-hiv-aids-quad-india- africa.html.\n\n163", "n_tokens": 192, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-169-0", "doc_id": "medicine_vaccine_book", "page": 169, "text": "164\n\nS. K. Rathod\n\nTable 5 Tenofovir opposition\n\nDrug: Therapeutic area: Nature of patent filings in India: Patent/Application #\n\nOpponents:\n\nExpiry, if granted:\n\nTenofovir HIV Prodrug of Tenofovir & Salt of above prodrug (a) Tenofovir Disoproxil—an ester prodrug of tenofovir (2076/DEL/ 1997) (b) Tenofovir Disoproxil Fumarate (TDF)—a salt form of Tenofovir Disoproxil (896/DEL/2002—this itself came as a divisional applica- tion from 2174/DEL/1998) Indian Network of People Living with HIV/AIDS (INP+) Delhi Network of People Living with HIV/AIDS (DNP+) Cipla Ltd. 25/July/2017 for the ester form and 24/July/2018 for the salt form Filing of multiple divisional applications, S.3(d)\n\nUnique points:\n\nexpanding license program for later drugs to gain market acceptance (Gilead loaded a lot of its later drugs onto the TDF license).\n\nObservers opine that the Gilead licensing program is a fairly successful program for most stakeholders. The MPP platform’s30 status today as the major licensing platform covering HIV, Hepatitis and other drugs—is arguably due to Gilead’s early move to that platform. The MPP platform has now become a template for most of later HIV drug licenses and Gilead and many other companies extensively license their IP across multiple drug categories, mostly for developing and least developed countries.", "n_tokens": 342, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-169-1", "doc_id": "medicine_vaccine_book", "page": 169, "text": "2.6 Kaletra Opposition\n\nWe now look at another opposition worth noting—this too was not a routine opposition against compounds, salts or polymorphs. This was an opposition against Abbotts’ (now Abbvie) application covering its formulation technology platform to make heat stable tablets of various HIV drugs (see Table 6). Abbott’s product (brand name Kaletra) was originally a soft gelatin capsule containing a fixed-dose of 2 drugs—Lopinavir and Ropinavir, used in the treatment of HIV. The new platform made it possible to make solid oral tablet formulation, instead of the earlier soft gelatin capsules. The earlier capsule had some limitations in terms of storage/ handling etc.\n\nThis opposition is extremely significant from a drug access perspective since the underlying technology platform is the basis for supply of heat stable formulations of\n\n30For list of available drug patent licenses on the MPP platform, visit: https://medicinespatentpool. org/what-we-do/global-licence-overview/licences-in-the-mpp/.", "n_tokens": 228, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-170-0", "doc_id": "medicine_vaccine_book", "page": 170, "text": "Patent Oppositions in India\n\nTable 6 Ritonavir and Lopinavir opposition\n\nDrug: Brand: Therapeutic area: Nature of filings in India: Formulation platform to make heat stable tablets of various drugs Application #", "n_tokens": 42, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-170-1", "doc_id": "medicine_vaccine_book", "page": 170, "text": "Ritonavir and Lopinavir Kaletra Anti HIV\n\n1. 339/MUMNP/2006 and its 2 divisionals: 2. 726/MUMNP/2009 and 3. 2474/DELNP/2009. 30/Dec/2010 Matrix Laboratories Limited, I-MAK, Cipla Ltd. and Okasa Pvt. Ltd. 23/Aug/2024 Filing of multiple divisional applications, obviousness.\n\nDate of decision: Opponents: Expiry, if granted: Unique points:\n\nvarious HIV drugs—which is how multiple drugs can be given in tablet form across many high temperature countries (especially as the African countries have a very high presence of HIV-AIDS). This technology platform allowed making heat stable tablets of the drug Ritonavir (and additional drugs) dissolved within a polymer versus the earlier generation soft gelatin capsules that were not heat stable and hence, had this application been granted in India, it would have given Abbott/Abbvie a monopoly on the entire heat stable platform which today covers all Ritonavir based combinations—e.g., Ritonavir + Lopinavir, Ritonavir + Atazanavir etc. Abbvie also uses this platform today for its Hepatitis drug tablets.\n\nCompanies had launched generic versions of combination tablet in India and other countries during the time the opposition was going on. So, the opposition paved the way for securing continued marketing of multiple heat stable drug formulations in India and other developing countries.", "n_tokens": 305, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-170-2", "doc_id": "medicine_vaccine_book", "page": 170, "text": "There were multiple arguments used including anticipation (including Abbott’s own poster presentations and previous patent filings as anticipating the claimed invention). While the opponents lost out arguments under S.3(d), S.3 tablet (e) [admixture of known substances] and insufficient description, the Patent Office went ahead and rejected the application on the grounds of anticipation and lacking an inventive step, in late 2010.\n\nOne key fact that is not well known publicly is that the Applicant also filed multiple divisionals during the prosecution—including on the day of the parent application’s opposition hearing. Interestingly, the Applicant filed not one divisional but two divisionals—at two different branches of the Patent Office in two different cities. Eventually, these divisionals were abandoned but not before the fact of the divisional filings in different cities was highlighted to the Controller.31\n\n31For more information on the various divisional filings, refer:“Ever-greening: A status check in selected countries” (Journal of Generic Medicines (2010) 7, 227–242. DOI: 10.1057/jgm.2010.14).\n\n165", "n_tokens": 242, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-171-0", "doc_id": "medicine_vaccine_book", "page": 171, "text": "166\n\nS. K. Rathod\n\nTable 7 Atazanavir Sulphate opposition\n\nDrug: Therapeutic area: Nature of filing in India: Application # Date of decision Expiry, if granted: Opponents: Unique points:\n\nAtazanavir Sulphate Anti HIV Process to make the Sulphate salt/crystals from Atazanavir 6425/DELNP/2006 20/Dec/2010 03/May/2015 Matrix Laboratories, Cipla Ltd. Obvious to try, insufficiency of disclosure and S.3(d)", "n_tokens": 110, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-171-1", "doc_id": "medicine_vaccine_book", "page": 171, "text": "2.7 Reyataz Opposition\n\nThe next opposition is worth noting against a Bristol Myers’ patent application for a commercially relevant process to make the Sulphate salt of Atazanavir. Bristol Myers’ sells an oral formulation of Atazanavir Sulphate under the brand name: Reyataz.\n\nThis decision is important because it highlights the position that generic compa- nies keep a keen watch on not only the product/salt applications but also track and file detailed and strong oppositions against commercially sensitive process invention claims. Indian companies had launched generic version of this drug much before the opposition was finally adjudicated.\n\nApart from the standard approach for arguing obviousness (i.e. the process to make unique crystals of Atazanavir Sulphate from Atazanavir) based on prior art of Atazanavir and state of art, an interesting obviousness argument used here was that a process to make the Sulphate salt of an anti-coagulant drug (Clopidogrel to Clopidogrel Bisulphate) could lead to claims for making the Sulphate salt of Atazanavir, as lacking an inventive step. This was another ‘obvious to try’ argument by bringing in analogous prior art related to a different drug, but from overall field of developing synthetic processes for crystals of drugs. This ‘obvious to try’ argument, along with the other arguments, succeeded at the Patent Office. See Table 7.", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-171-2", "doc_id": "medicine_vaccine_book", "page": 171, "text": "2.8 Combivir Opposition\n\nfor an oral fixed-dose combination of Combivir Lamivudine and Zidovudine, used in the treatment of HIV infection. NGOs had filed a pre-grant opposition (see Table 8) this filing in March 200632 at the Kolkata Patent Office, stating the drug was not a new invention.\n\nis Glaxo’s brand product\n\n32https://www.msf.org/patent-application-aids-drug-opposed-first-time-india.", "n_tokens": 115, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-172-0", "doc_id": "medicine_vaccine_book", "page": 172, "text": "Patent Oppositions in India\n\nTable 8 Combivir opposition\n\nDrug: Therapeutic area: Application # Link Expiry, if granted: Opponents:\n\nFixed dose combination of two existing drugs: Zidovudine and Lamivudine Anti-HIV\n\n2044/CAL/1997 A copy of the opposition as filed, is available here 29/Oct/2017\n\nUnique point:\n\nIndian Network for People Living with HIV/AIDS and the Manipur Network of Positive People Applicant abandoned after civil society opposition\n\nAfter this opposition, Glaxo withdrew its patent application in Aug 200633 in India and Thailand34 and this removed the threat of a patent infringement suit against generic companies, in these 2 countries. The withdrawal meant that further opposi- tions were not required. Combivir was not the only Glaxo HIV/AIDS medical product that was opposed and this later resulted in more patent application(s) being abandoned by Glaxo.\n\n2.9 Trizivir Opposition\n\nTrizivir is an oral fixed-dose combination of 3 drugs—Lamivudine, Zidovudine and Abacavir Sulphate by Glaxo, used for the treatment of HIV infection. In October 2007, Glaxo withdrew its Indian application for Trizivir, after an opposition (see Table 9) was filed. Glaxo stated35 that “the company’s move is in public interest and is part of its policy of routine review of patent applications.”", "n_tokens": 301, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-172-1", "doc_id": "medicine_vaccine_book", "page": 172, "text": "2.10 Ziagen Opposition\n\nZiagen is a Glaxo product for the treatment of HIV, consisting Abacavir Sulphate. Glaxo abandoned its patent application for the Hemisulphate salt of Abacavir, after an opposition (see Table 10) was filed.\n\nPer the author’s checks, Indian companies had launched generic version of the\n\nabove 3 Glaxo’ medicines even before the abandonment actions by Glaxo.\n\n33https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/gsk-with draws-patent-application-for-aids-drug/articleshow/1912871.cms. 34http://www.twn.my/title2/intellectual_property/info.service/twn.ipr.info.090603.htm. 35https://www.livemint.com/Home-Page/kx90Ckvbspy4ApeAOxPFZP/GSK-withdraws-Trizivir- patent-application-8216in-public-i.html.\n\n167", "n_tokens": 248, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-173-0", "doc_id": "medicine_vaccine_book", "page": 173, "text": "168\n\nS. K. Rathod\n\nTable 9 Trizivir opposition\n\nDrug: Therapeutic area: Application # Expiry, if granted: Opponent: Unique point:\n\nCombination of 3 drugs: Lamivudine, Zidovudine and Abacavir Sulphate Anti-HIV IN/PCT/00/00521 26/April/2019 Cipla Ltd. Applicant abandoned after pre-grant opposition\n\nTable 10 Abacavir Sulphate opposition\n\nDrug: Therapeutic area: Application # Opponent: Expiry, if granted: Copy of decision: Unique point:\n\nAbacavir Sulphate Anti-HIV 872/CAL/98 Indian Network of People Living with HIV/AIDS (INP+) 14/May/2018 Image, here. Applicant abandoned after civil society opposition\n\n2.11\n\nIsentress Opposition\n\nMerck had filed a patent application for the Potassium salt of Raltegravir. Merck sells this product under the brand ‘Isentress’.\n\nCipla has been selling a generic version of Raltegravir in India, for the last few years. Three separate pre-grant oppositions (see Table 11) were filed against this application. The first opposition was filed in 2011 and the last one in late 2018. The oppositions did not see any traction for many years. When the Patent Office finally called all parties for a hearing in Aug 2020, Applicant (Merck) sent a letter—less than a week before hearing date—stating that they were not interested in pursuing the application, any further.", "n_tokens": 318, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-173-1", "doc_id": "medicine_vaccine_book", "page": 173, "text": "2.12 Sanofi TB Drugs Oppositions\n\nSanofi had filed two patent applications in India pertaining to anti-tuberculosis drug formulations for therapies known as 3HP and 3RH. The two applications covered two different formulations of known TB 2 drugs (Isoniazid and Rifapentine). One application covered a film coated formulation and the other application covered a dispersible (pediatric) formulation of the 2 drugs.\n\nCivil society groups have been advocating to Sanofi on these patents. They filed oppositions (see Tables 12 and 13) in November 2019—first in India and then in", "n_tokens": 129, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-174-0", "doc_id": "medicine_vaccine_book", "page": 174, "text": "Patent Oppositions in India\n\nTable 11 Raltegravir Potassium opposition\n\nDrug: Therapeutic area: Nature of filing in India: Application # Expiry, if granted: Opponents:\n\nRaltegravir Potassium Anti HIV Potassium salt of Raltegravir; crystals of the salt 4187/DELNP/2007 02/Dec/2025 Indian Network for People Living with HIV/AIDS, Delhi Network of Positive People and Mylan Laboratories Limited Applicant abandoned after civil society opposition\n\nUnique point:\n\nTable 12 Isoniazid and Rifapentine opposition\n\nDrug: Therapeutic area: Application # Expiry, if granted: Opponent:\n\nDispersible combination formulation of Isoniazid and Rifapentine Anti-Tuberculosis IN201637002758 22/July/2034 Delhi Network of People Living with HIV/AIDS (DNP+)\n\nTable 13 Isoniazid and Rifapentine opposition (different formulation)", "n_tokens": 190, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-174-1", "doc_id": "medicine_vaccine_book", "page": 174, "text": "Drug: Therapeutic area: Application # Expiry, if granted: Opponent:\n\nFilm coated combination formulation of Isoniazid and Rifapentine Anti-Tuberculosis IN201637002757 22/July/2034 Delhi Network of People Living with HIV/AIDS (DNP+)\n\nThailand36 and have also written letters asking Sanofi to abandon the patent families. After the oppositions were filed, Sanofi withdrew both application families in many countries. The application families were first withdrawn at the EPO, then Indonesia37 and later in India38 (February 2020). In August 2020, Sanofi formally confirmed that it was abandoning all patent filings relating to these 2 applications.39\n\nAs noted in the multiple instances above, many patent applicants, especially from the HIV domain, abandon their secondary patent applications (i.e. those related to process, salt or crystal forms) once they face pre-grant oppositions or once civil society groups start a public action on such drugs. It can be argued that the such later", "n_tokens": 214, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-174-2", "doc_id": "medicine_vaccine_book", "page": 174, "text": "36https://www.treatmentactiongroup.org/statement/sanofi-withdraws-two-patent-applications-on- life-saving-tuberculosis-prevention-drugs-in-europe-and-in-indonesia/. 37https://www.rouse.com/magazine/news/sanofis-tb-patents-dispute-overflows-to-indonesia/? tag¼indonesia. 38Refer information tweeted at: <https://twitter.com/achayansz/status/1245229743521370112>. 39Refer Sanofi’s letter dated 04/August/2020, to Treatment Action Group, available at: <https:// www.treatmentactiongroup.org/wp-content/uploads/2020/08/tag_otmeds_sanofi_patent_with drawals_RESPONSE.pdf>.\n\n169", "n_tokens": 207, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-175-0", "doc_id": "medicine_vaccine_book", "page": 175, "text": "170\n\nS. K. Rathod\n\nTable 14 Remdesivir opposition\n\nDrug: Therapeutic area: Patents #\n\nPetitioner(s)\n\nOpponent: Copy of request letter:\n\nRemdesivir CoVid-19 IN275967 (from 7068/DELNP/2010) IN332280 (from IN201727012821) (i) Cancer Patients Aid Association (CPAA) (ii) Campaign for Access to Affordable Medicines, Diagnostics and Devices, India (CAMeD-India) + Third World Network (India) (iii) LowCost Standard Therapeutics Copy of the Request letter dated 09/April/2020 is available at the CPAA website Copy of the Third World Network letter dated 13/May/2020 is available at their website.\n\nabandonment action is due to the patent applicant assessing the strength of its filing versus the legal arguments put forth by the pre-grant opponents [e.g. obviousness and S.3(d)] and the potential negative press related to drug access issues.", "n_tokens": 213, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-175-1", "doc_id": "medicine_vaccine_book", "page": 175, "text": "2.13 Veklury Opposition\n\nThe CoVid-19 pandemic has bought many drugs and issues surrounding drug access and patents, in the public limelight, at a scale, hitherto unseen. Gilead has at least 4 patents/patent applications pertaining to Remdesivir (Gilead brand: Veklury), in India. Amidst the global medical crisis, in April 2020, the Cancer Patients Aid Association (‘CPAA’) and later Third World Network (both being civil society organizations) asked the Government of India to revoke Gilead’s granted Indian patent(s).\n\nA post-grant opposition under section 25(2) was filed by a not-for-profit civil society organisation—LowCost Standard Therapeutics—on the patent (IN332280) in June 2020 (see Table 14). The petitions/letters did not opt for filing the standard post-grant opposition(s) under S.25(2) but sought revocation of the patent(s) under S.66 (‘Revocation of patent in public interest’40).\n\nCPAA filed the request for revoking one patent (IN332280) with the Ministry of Chemicals and Fertilizers as well as the Health Secretary for the Government of India.\n\n40Text of S.66 is available at <https://indiankanoon.org/doc/441313/>. It states:", "n_tokens": 302, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-175-2", "doc_id": "medicine_vaccine_book", "page": 175, "text": "66 Revocation of patent in public interest. –\n\nWhere the Central Government is of opinion that a patent or the mode in which it is exercised is mischievous to the State or generally prejudicial to the public, it may, after giving the patentee an opportunity to be heard, make a declaration to that effect in the Official Gazette and thereupon the patent shall be deemed to be revoked.", "n_tokens": 82, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-176-0", "doc_id": "medicine_vaccine_book", "page": 176, "text": "Patent Oppositions in India\n\nThe Campaign for Access to Affordable Medicines, Diagnostics and Devices, India (CAMD-India) and Third World Network (India) jointly wrote a separate request calling for revocation of two patents (IN275967 and IN332280) with the Department of Promotion of Industry and Internal Trade (DPIIT) (within the Min- istry of Commerce & Industry, Government of India).\n\nThe DPIIT supervises the functioning of the Patent Office. None of the Govern- ment ministries/departments have made any public statement on these letters as of end July, 2020. In July 2020, the Patent Office asked Gilead to respond to the LowCost Standard’ opposition. Gilead filed its reply in Oct 2020. A final hearing on the Opposition has not yet been scheduled.\n\nStarting May 2020, Gilead has signed voluntary licenses for manufacture and sale of Remdesivir in 127 countries (including India), with multiple companies (nine companies as of end July 202041) on a ‘zero royalty’ basis, until the disease remains a pandemic. These bilateral licenses are a change in Gilead’s strategy from the HIV multi-lateral licenses on the MPP platform. The Remdesivir license text is not available in the public domain.", "n_tokens": 273, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-176-1", "doc_id": "medicine_vaccine_book", "page": 176, "text": "3 Pendency of Oppositions in the Indian Patent Office\n\nOppositions can only help in increasing access if they are adjudicated in a timely and transparent fashion. So, while in the earlier section, we saw the monumental impact that pre-grant and post-grant oppositions had on drug access, it would be remiss if we do not look at some current ground realities.\n\nThe Government has over the last few years, multiple times, shown that it is focused towards higher number of patent grants42 but the author believes that adjudication of oppositions has been very slow at the Indian Patent Office, over the years.\n\nWe have two sources for numbers—the first are the annual reports published by the Patent Office. The Report for year ending March 2020 is not available on IPO site as of end December 2020. The CIPAM website43 is the second source for some of the numbers. A few years ago, Prashant Reddy (an Indian IP lawyer) tried to find out44 the exact number of oppositions pending at the Indian Patent Office, using the information request pathway, but the exercise did not yield relevant results. The 2020 Numbers are courtsey SpicyIP website.", "n_tokens": 250, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-176-2", "doc_id": "medicine_vaccine_book", "page": 176, "text": "41Gilead’s website discusses its Remdesivir licensing program here: <https://www.gilead.com/ purpose/advancing-global-health/covid-19/voluntary-licensing-agreements-for-remdesivir>. 42https://m.economictimes.com/news/economy/indicators/grant-of-patents-up-12-per-cent-during- april-december-fy19-dpiit/articleshow/68317795.cms. 43http://cipam.gov.in/iptrends/#patent. 44For a detailed article on his exercise, do read his note at the SpicyIP blog, available here: <https:// spicyip.com/2017/12/rtis-reveal-tardy-record-keeping-practices-at-the-ipo-no-records-of-pending- patent-oppositions-113857-trademark-oppositions-pending-5533-rectifications.html>.\n\n171", "n_tokens": 234, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-177-0", "doc_id": "medicine_vaccine_book", "page": 177, "text": "172 S. K. Rathod\n\nThe Patent Office has done a commendable job in terms of increasing the size of\nthe Examiner cadre, increasing the number of applications examined, reducing the\npendency of period taken to examine and grant a patent, but a deeper check reveals\nthe potential opposition pendency numbers and that presents an alarming picture.\n\nAs will noted, the data is not complete. And even for items where the IPO releases\nnumbers, there are internal inconsistencies.\n\n3.1 Pre-grant Oppositions\n\n* Post 2008-09, specific data for cumulative pre-grant oppositions pending at end\nof every year is not given in the Patent Office’ Annual Reports. Hence, we do not\nknow the number pre-grant oppositions pending on a cumulative basis, as per\nthe IPO.\n\n* For the latest 12-year period (FY 2007-8 through FY 2019-20), cumulatively\n~3600 pre-grant oppositions have been filed while the cumulative disposal\nnumber is ~950 oppositions. This means, potentially, 64% pre-grant oppositions\nare, as yet, undecided as per my calculations (see Fig. 1).\n\n* The number of ‘new’ pre-grant oppositions filed annually for last few years has\nbeen below 300 (with a sudden upward spike from FY 2018-19: 426 and going to\na massive 800 in FY 2019-20). This trend, when considered with the larger\nincrease in number of patent applications filed each year, would still imply that on\na percentage basis, a lesser number of applications are now being opposed,\neach year.\n\n¢ The annual pre-grant opposition disposal rate has not kept pace with trend of\nincreased patent application filings or the number of examiners inducted, nor has\n\nPre-grant opposition data\n\nES) eS SS Y ss S \\ we YY\n\nx\nor am a a OY\n\\ a aa SY sy Sy\nr PS FS §\n\nv v v\n\nNumber of Pre-grant Oppositions filed in period\nNumber of Pre-grant Oppositions disposed in period\n\nFig. 1 Pre-grant opposition data 2007-2020", "n_tokens": 433, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-178-0", "doc_id": "medicine_vaccine_book", "page": 178, "text": "Patent Oppositions in India\n\nit matched the pace of increase in new opposition filings. The disposal rate for year 2018–19 shows a sudden, huge upward unexplained spike: 399 and then a fall back to 67. This fall is in line with earlier trend of close to 100 or less pre-grant disposals annually. The one-time surprise figure of 399 pre-grant dis- posals in FY 2018–9 is an unexplainable mystery.\n\n(cid:129) For the same period, upon adding the numbers for pre-grant oppositions filed and reducing the annual pre-grant oppositions disposed (3607 less 947 equals 2660) and assuming that at least some of the pre-grant oppositions are duplicates against a single patent application or some oppositions may have been withdrawn, I believe that at least 1300+ unique pre-grant total oppositions are still pending.\n\n3.2 Post-grant Oppositions\n\n(cid:129) As at end of FY 2019–20, per the IPO, only 99 post-grant oppositions are pending on a cumulative basis. This differs drastically from my calculation (184)—which is based on simple addition/subtraction.\n\n(cid:129) For the latest 12 year period (FY 2007–8 through FY 2019–20), based on my calculation, cumulatively 310 post-grant oppositions have been filed while the cumulative disposal number is 126 oppositions (see Fig. 2).\n\n(cid:129) Around 10 post-grant oppositions are being disposed, annually for the last few", "n_tokens": 336, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-178-1", "doc_id": "medicine_vaccine_book", "page": 178, "text": "years.\n\n(cid:129) The number of ‘new’ post-grant oppositions filed annually for last few years has been below 20 (with a sudden upward rise in last 2 years—28 each for last\n\nPost-grant opposition data\n\n350\n\n300\n\n250\n\n200\n\n150\n\n100\n\n50\n\n0\n\n2007-08 2008-09 2009-10 2010-11 2011-12 2012-13 2013-14 2014-15 2015-16 2016-17 2017-18 2018-19 2019-20\n\nPendency information as per Annual Reports (This number differs from mathematical difference)\n\nPendency at year end: cumulative filed less cumulative disposed)\n\nNumber of Post-grant Oppositions disposed in period\n\nNumber of Post-grant Oppositions filed in period\n\nFig. 2 Post-grant opposition data 2007–2020\n\n173", "n_tokens": 157, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-179-0", "doc_id": "medicine_vaccine_book", "page": 179, "text": "174\n\nS. K. Rathod\n\n2 years)—which when considered with the large increase in number of patents granted, would again imply that on a percentage basis, comparatively lesser number of post-grant oppositions are now being filed every year.\n\n(cid:129) As per IPO annual report data, annual post-grant opposition pendency figure was below 170 for last few years. This high pendency number is also a cause of concern. However, the IPO data for pending post-grant opposition at year end is not completely understanding. For instance, for FY 2019-18: 193 pending and then for 2019–20 only 99 pending, but the IPO did not dispose 100 odd post-grant oppositions in FY 2019–20—so there is some confusion as to how the 193 pen- dency figure went down to only 99.\n\n(cid:129) The difference in the calculated pending cumulative post-grant oppositions 184 at end of FY 2019–20 versus the pending cumulative post-grant oppositions as per IPO (99)—cannot be easily explained but could possibly be due to some cases of multiple oppositions to a single patent or expiry of some patents before disposal, where no disposal decision was issued.", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-179-1", "doc_id": "medicine_vaccine_book", "page": 179, "text": "The number of patents granted has moved to approx. 25,000 grants for year ending March 2020 while the number of applications examined moved impressively by approx. 7 times (from ~11,700 to ~80,000+), with an approx. 3 times increase in the Examiner cadre (163 to 449). Within these numbers, the contentious proceedings disposal pendency as mentioned by IPO (from 23 in 2007–8 (17 pre-grants + 6 post- grants) to ~74 in 2019–20 (67 pre-grants + 7 post-grants) continues to remain a cause of concern.", "n_tokens": 126, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-179-2", "doc_id": "medicine_vaccine_book", "page": 179, "text": "3.3 Pendency at the Intellectual Property Appellate Board\n\n(IPAB)\n\nAppeals from IPO (for most items) needed to be filed at the IPAB. As of mid-2019, approx. 617 Patent cases were pending with IPAB.45 Even after starting various advertising initiatives on the importance of IP, it is glaring that the Government was consistently not able to keep the requisite bench strength at the IPAB, including the chairperson or the technical member (patents) at the IPAB.\n\nAs per a calculation done on SpicyIP, an Indian IP blog, ‘in its 17 years of existence, the IPAB has not had a Chairperson for a cumulative total of 1130 days’.46 The position of the Chairperson of the IPAB (i.e. the judicial member) was vacant for quite a long time and so the Supreme Court granted a fresh term in December\n\n45Year wise pendency data is not available for the IPAB. These numbers have come from a court case: refer para 7 in Mylan Laboratories Limited v. Union of India <https://indiankanoon.org/doc/ 58294410/>. 46https://spicyip.com/2020/04/the-case-for-shutting-down-the-intellectual-property-appellate- board-ipab.html.", "n_tokens": 278, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-180-0", "doc_id": "medicine_vaccine_book", "page": 180, "text": "Patent Oppositions in India\n\n2019 to the already retired judicial member.47 In a similar pattern, the position of the technical member (patents) was vacant since May 2016 and so, in July 2019, the Delhi High Court had then asked the technical member (plant variety protection) to look at the patent responsibilities.48\n\nThese judicial interventions show that recruitment of the senior-most IPAB functionaries was not done in time even when the government was aware of the normal tenure of such functionaries. Note: A new technical member (patents) was finally appointed in July 2020 and the process of recruiting a new chairperson (judicial member) to replace the current chairperson’s whose extended term was to end in September 2020, had started.49\n\n3.4", "n_tokens": 150, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-180-1", "doc_id": "medicine_vaccine_book", "page": 180, "text": "Impact of Pendency\n\nThe pendency number and dismal disposal for each component—pre-grant opposi- tions, post-grant oppositions and IPAB cases—is very worrying. The adjudication of pending oppositions (both pre-grant oppositions and post-grant oppositions) is a continuing challenge for the Patent Office. The rise in pre-grant disposals for 2018–19 needs to be understood and expanded upon. While the number of exam- iners at the Patent Office has trebled in the 3-year period, the numbers of controllers becoming Assistant or Deputy Controllers has not jumped by that percentage. It is the Controller who is at the center of managing the pre-grant and post-grant opposition process and finally adjudicating on the opposition and this could also be a reason for slower disposal.", "n_tokens": 178, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-180-2", "doc_id": "medicine_vaccine_book", "page": 180, "text": "The IPAB pendency position, for both proceedings and personnel, brings in a bigger question on the Government’s willingness to work towards a quick and efficient IP dispute disposal system. Undecided oppositions/IPAB revocations mean that generic companies may not have the confidence to undertake at risk launches, due to the threat of damages. Likewise, delay in clearing pre-grant oppositions also hurts patent applicants as it chips away at the term of any future patent available to the applicant and at same time, keeps a sword hanging on opponents for years. The IPO’s leadership must examine the pendency and should incentivize examiners and Controllers for faster adjudication of contentious pro- ceedings. Examiners and Controllers today are assessed based on examinations and grants and if opposition adjudication can be kept as an independent performance target which can lead to faster professional growth inside the IPO, it could act as an incentive for proceedings being completed faster.\n\n47https://images.assettype.com/barandbench/2019-12/829f572d-5ff5-421d-8a2ba10cc8d07727/ Supreme_Court___IPAB_Chairman_Order.pdf. 48Mylan, Ibid. 49Refer SpicyIP post: https://spicyip.com/2020/08/breaking-news-controller-generals-office- agrees-with-our-petition-for-scrapping-the-intellectual-property-appellate-board.html.\n\n175", "n_tokens": 335, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-181-0", "doc_id": "medicine_vaccine_book", "page": 181, "text": "176\n\nS. K. Rathod\n\nClearly, the present system for managing and adjudicating oppositions/IPAB matters, including timely recruitment, needs a major overhaul with time-bound proceedings and decision issuance being implemented for faster adjudication of oppositions. Urgent and immediate actions need to be undertaken by the Govern- ment to bring in requisite personnel, reduce pendency and increase disposal of oppositions and IPAB matters.", "n_tokens": 91, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-181-1", "doc_id": "medicine_vaccine_book", "page": 181, "text": "4 Conclusion\n\nThe pre-grant and post-grant oppositions filed by civil society organisations and generic companies—over the years have been instrumental in earlier launch of drugs, thereby increasing access of drugs not only for the Indian population—but also allowed export of drugs to other countries.\n\nThe filing (and winning) of these oppositions have been the pivot for earlier generic entry of many life-saving drugs. Oppositions have been instrumental in competitively priced generics. These oppositions not only led to generic products in India but also in a whole host of developing and least developed countries.\n\nAs we saw, the Indian oppositions have moved beyond the simple arguments of\n\nS.3(d) to more complex arguments and have seen fair bit of success.\n\nFinally, the increasing pendency of oppositions over the last few years is a matter of deep concern and the current trend seems to imply that unless the Government strengthens the system by bringing in requisite number of personnel, the pendency numbers will not come down, substantially, in the near term.\n\nAuthor’s Note The Indian opposition saga has been one of achieving path-breaking results through sheer advocacy and fighting spirit of the civil society organisations (NGOs). The massive efforts undertaken by these NGOs over the years in litigating against corporates with huge budgets must to be applauded, for the results achieved.", "n_tokens": 280, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-181-2", "doc_id": "medicine_vaccine_book", "page": 181, "text": "The author is deeply indebted to friends from the civil society and generic companies who willingly shared anecdotes and facts from these opposition battles. Most of them chose to remain anonymous for the purposes of this paper. The author thanks (in alphabetical order)—Swaraj Barooah, (Late) Shamnad Basheer, Adv. Julie George, Adv. Rajeshwari Hariharan, Adv. Feroz Ali Khader, Ms. Leena Menghaney, Adv. Guruswamy Nataraj and\n\n(continued)", "n_tokens": 117, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-182-0", "doc_id": "medicine_vaccine_book", "page": 182, "text": "Patent Oppositions in India\n\nProf. Bhaven Sampat for discussions over the years and friends who have reviewed draft versions of this paper.\n\nThe present paper is based on a talk given by the author at the invitation of the South Centre and the Max Planck Institute for Innovation and Competition at the ‘Global Forum on Intellectual Property, Access to Medicines and Innovation’ held at Munich in Dec 2019. The author thanks the South Centre team—Dr. Carlos Correa, Dr. German Velasquez, (and its wonderful Dr. Viviana Munoz and Mr. Nirmalya Syam) and Professor Dr. Reto M. Hilty at the Max Planck Institute for Innovation and Competition, for the opportunity.\n\nConflict Declaration/Disclaimer The author has been employed within the generic pharmaceutical industry for 18 plus years and was professionally involved in some of the opposition cases, discussed in this paper. The paper is based on information available in public domain as of 31/Dec/2020 and discussions with multiple stakeholders, over many years. All website links have been last accessed on the same date.\n\nErrors, if any, are the sole responsibility of the author. The views, obser- vations and submissions presented in this paper are entirely personal and should not be attributed or construed to reflect the views of the author’s present or past employer(s).\n\n177", "n_tokens": 281, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-183-0", "doc_id": "medicine_vaccine_book", "page": 183, "text": "178\n\n0 2 0 2 – 9 1 0 2\n\no t\n\n8 0 – 7 0 0 2\n\nd o i r e P e h t\n\nr o f\n\na t a D y c n e d n e P n o i t i s o p p O\n\n: x e n n A\n\ny c n e d n e P\n\ny c n e d n e P\n\n: d n e\n\nr a e y\n\nt a\n\nf o\n\nr e b m u N\n\nf o\n\nr e b m u N\n\n: d n e\n\nr a e y\n\nt a\n\nf o\n\nr e b m u N\n\nf o\n\nr e b m u N\n\ne v i t a l u m u c\n\nt n a r g - t s o p\n\nt n a r g - t s o p\n\ne v i t a l u m u c\n\nt n a r g - e r p\n\nt n a r g - e r p\n\ny c n e d n e P\n\ns s e l\n\nd e l fi\n\ns n o i t i s o p p o\n\ns n o i t i s o p p o\n\ns s e l\n\nd e l fi\n\ns n o i t i s o p p o\n\ns n o i t i s o p p o\n\ns t n e t a P\n\ns n o i t a c i l p p A\n\nt n e t a P\n\nr e p\n\ns a\n\nn o i t a m r o f n i\n\ne v i t a l u m u c\n\n n i\n\nd e s o p s i d\n\n n i\n\nd e l fi\n\ne v i t a l u m u c\n\n n i\n\nd e s o p s i d\n\n n i\n\nd e l fi\n\nd e t n a r g\n\nd e n i m a x e\n\ns r e n i m a x e\n\na s t r o p e r\n\nl a u n n a\n\nd e s o p s i d\n\nd o i r e p\n\nd o i r e p\n\nd e s o p s i d\n\nd o i r e p\n\nd o i r e p\n\nr a e Y\n\n6 1 3 , 5 1\n\n1 5 7 , 1 1\n\n3 6 1\n\ns a w a t a d\n\ny c n e d n e P\n\n8 2\n\n6\n\n4 3\n\n7 4\n\n7 1\n\n4 6\n\n8 0 – 7 0 0 2\n\ne h t\n\nn i\n\nn e v i g\n\nt o n\n\nt r o p e r\n\nl a u n n a\n\n’\n\nO P", "n_tokens": 504, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-183-1", "doc_id": "medicine_vaccine_book", "page": 183, "text": "I\n\n1 6 0 , 6 1\n\n6 9 2 , 0 1\n\ns e s a c\n\nt n a r g - t s o p 2 2 1\n\n2 9\n\n7\n\n1 7\n\n1 6 1\n\n9 3\n\n3 5 1\n\n9 0 – 8 0 0 2\n\nt n a r g - e r p\n\n7 3 3\n\nd n a\n\nd e n i a m e r\n\ns e s a c\n\ng n i d n e p\n\n8 6 1 6\n\n9 6 0 6\n\ns e s a c\n\nt n a r g - t s o p 6 4 1\n\n6 1 1\n\n4\n\n8 2\n\n2 3 2\n\n2 3\n\n3 0 1\n\n0 1 – 9 0 0 2\n\nt n a r g - e r p\n\nt o n — y c n e d n e p\n\n; g n i d n e p\n\nd e n o i t n e m\n\n9 0 5 7\n\n8 2 0 , 1 1", "n_tokens": 181, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-183-2", "doc_id": "medicine_vaccine_book", "page": 183, "text": "s e s a c\n\nt n a r g - t s o p 5 4 1\n\n5 1 1\n\n0 3\n\n9 2\n\n7 0 5\n\n9 1\n\n4 9 2\n\n1 1 – 0 1 0 2\n\n: g n i d n e p\n\nt o n — t n a r g - e r p\n\nd e n o i t n e m\n\n1 8 3 4\n\n1 3 0 , 1 1\n\ns e s a c\n\nt n a r g - t s o p 5 5 1\n\n5 2 1\n\n6 1\n\n6 2\n\n9 8 6\n\n1 1\n\n3 9 1\n\n2 1 – 1 1 0 2\n\nt n a r g - e r p\n\n; g n i d n e p\n\nt o n — y c n e d n e p\n\nd e n o i t n e m\n\nS. K. Rathod\n\n) d e u n i t n o c (", "n_tokens": 176, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-184-0", "doc_id": "medicine_vaccine_book", "page": 184, "text": "Patent Oppositions in India\n\ns t n e t a P\n\nd e t n a r g\n\n6 2 1 4\n\ns n o i t a c i l p p A\n\nd e n i m a x e\n\n8 6 2 , 2 1\n\nt n e t a P\n\ns r e n i m a x e\n\ny c n e d n e P\n\nr e p\n\ns a\n\nn o i t a m r o f n i\n\na s t r o p e r\n\nl a u n n a\n\ns e s a c\n\nt n a r g - t s o p 2 6 1\n\nt n a r g - e r p\n\n; g n i d n e p\n\nt o n — y c n e d n e p\n\ny c n e d n e P\n\n: d n e\n\nr a e y\n\nt a\n\ne v i t a l u m u c\n\ns s e l\n\nd e l fi\n\ne v i t a l u m u c\n\nd e s o p s i d\n\n2 3 1\n\nf o\n\nr e b m u N\n\nt n a r g - t s o p\n\ns n o i t i s o p p o\n\n n i\n\nd e s o p s i d\n\nd o i r e p\n\n7\n\nf o\n\nr e b m u N\n\nt n a r g - t s o p\n\ns n o i t i s o p p o\n\n n i\n\nd e l fi\n\n d o i r e p\n\n4 1\n\ny c n e d n e P\n\n: d n e\n\nr a e y\n\nt a\n\ne v i t a l u m u c\n\ns s e l\n\nd e l fi\n\ne v i t a l u m u c\n\nd e s o p s i d\n\n7 1 9\n\nf o\n\nr e b m u N\n\nt n a r g - e r p\n\ns n o i t i s o p p o\n\n n i\n\nd e s o p s i d\n\nd o i r e p\n\n4 3\n\nf o\n\nr e b m u N\n\nt n a r g - e r p\n\ns n o i t i s o p p o\n\n n i\n\nd e l fi\n\n d o i r e p\n\n2 6 2\n\nr a e Y\n\n3 1 – 2 1 0 2\n\nd e", "n_tokens": 454, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-184-1", "doc_id": "medicine_vaccine_book", "page": 184, "text": "n o i t n e m\n\n7 2 2 4\n\n5 1 6 , 8 1\n\ns e s a c\n\nt n a r g - t s o p\n\n1 6 1\n\n1 3 1\n\n9\n\n8\n\n8 7 1 1\n\n8 4\n\n9 0 3\n\n4 1 – 3 1 0 2\n\nt n a r g - e r p\n\nt o n — y c n e d n e p\n\n; g n i d n e p\n\nd e n o i t n e m\n\n8 7 9 5\n\n1 3 6 , 2 2\n\ns e s a c\n\nt n a r g - t s o p 4 6 1\n\n4 3 1\n\n5\n\n8\n\n8 5 3 1\n\n7 6\n\n7 4 2\n\n5 1 – 4 1 0 2\n\nt n a r g - e r p\n\nt o n — y c n e d n e p\n\n; g n i d n e p\n\nd e n o i t n e m\n\n6 2 3 6\n\n1 5 8 , 6 1\n\n2 3 1", "n_tokens": 194, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-184-2", "doc_id": "medicine_vaccine_book", "page": 184, "text": "s e s a c\n\nt n a r g - t s o p 0 6 1\n\n0 3 1\n\n0 1\n\n6\n\n0 6 5 1\n\n8 8\n\n0 9 2\n\n6 1 – 5 1 0 2\n\nt n a r g - e r p\n\n; g n i d n e p\n\nt o n — y c n e d n e p\n\nd e n o i t n e m\n\n7 4 8 9\n\n7 6 9 , 8 2\n\n8 5 4\n\ns e s a c\n\nt n a r g - t s o p 0 6 1\n\n0 3 1\n\n2 1\n\n2 1\n\n8 4 7 1\n\n8 1\n\n6 0 2\n\n7 1 – 6 1 0 2\n\nt n a r g - e r p\n\n; g n i d n e p\n\nt o n — y c n e d n e p\n\nd e n o i t n e m\n\n5 4 0 , 3 1\n\n0 3 3 , 0 6\n\n2 7 5\n\ns e s a c\n\nt n a r g - t s o p 0 7 1\n\n0 4 1\n\n8\n\n8 1\n\n0 0 9 1\n\n8 0 1\n\n0 6 2\n\n8 1 – 7 1 0 2\n\nt n a r g - e r p\n\nt o n — y c n e d n e p\n\n; g n i d n e p\n\nd e n o i t n e m\n\n179\n\n) d e u n i t n o c (", "n_tokens": 276, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-185-0", "doc_id": "medicine_vaccine_book", "page": 185, "text": "180\n\ny c n e d n e P\n\ny c n e d n e P\n\n: d n e\n\nr a e y\n\nt a\n\nf o\n\nr e b m u N\n\nf o\n\nr e b m u N\n\n: d n e\n\nr a e y\n\nt a\n\nf o\n\nr e b m u N\n\nf o\n\nr e b m u N\n\ns t n e t a P\n\ns n o i t a c i l p p A\n\nt n e t a P\n\nr e p\n\ns a\n\ny c n e d n e P\n\nn o i t a m r o f n i\n\ne v i t a l u m u c\n\ns s e l\n\nd e l fi\n\ne v i t a l u m u c\n\nt n a r g - t s o p\n\ns n o i t i s o p p o\n\n n i\n\nd e s o p s i d\n\nt n a r g - t s o p\n\ns n o i t i s o p p o\n\n n i\n\nd e l fi\n\ne v i t a l u m u c\n\ns s e l\n\nd e l fi\n\ne v i t a l u m u c\n\nt n a r g - e r p\n\ns n o i t i s o p p o\n\n n i\n\nd e s o p s i d\n\nt n a r g - e r p\n\ns n o i t i s o p p o\n\n n i\n\nd e l fi\n\nd e t n a r g\n\nd e n i m a x e\n\ns r e n i m a x e\n\na s t r o p e r\n\nl a u n n a\n\nd e s o p s i d\n\nd o i r e p\n\nd o i r e p\n\nd e s o p s i d\n\nd o i r e p\n\nd o i r e p\n\nr a e Y\n\n3 8 2 , 5 1\n\n6 2 4 , 5 8\n\n9 4 4\n\nt n a r g - t s o p\n\n3 9 1\n\n3 6 1\n\n5\n\n8 2\n\n7 2 9 1\n\n9 9 3\n\n6 2 4\n\n9 1 – 8 1 0 2\n\ns e s a c\n\nn o i t i s o p p o\n\n.\n\n g n i d n e p\n\nd e n i a m e r\n\nt n a r g - e r P\n\n:\n\nE T O N\n\nn e p n o i t", "n_tokens": 473, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-185-1", "doc_id": "medicine_vaccine_book", "page": 185, "text": "i s o p p o\n\ne r a\n\ns e r u g fi\n\ny c n e d\n\ny l e t a r a p e s\n\nn e v i g\n\nt o n\n\ns t r o p e r\n\nl a u n n a\n\ne h t n i\n\n.\n\n 9 0 – 8 0 0 2\n\ne c n i s\n\n6 3 9 4 2\n\n8 8 0 , 0 8\n\ny l n o\n\n,\n\nO P I\n\nr e p\n\ns A\n\n4 8 1\n\n7\n\n8 2\n\n0 6 6 2\n\n7 6\n\n0 0 8\n\n0 2 – 9 1 0 2\n\ns n o i t i s o p p o\n\n9 9\n\nt a g n i d n e p d e n i a m e r\n\nh c r a\n\nM\n\nf o\n\nd n e\n\ne h t\n\na\n\ns i\n\ne r e h T\n\n.\n\n 0 2 0 2\n\nr e f f i d e l b a e c i t o n\n\ne h t\n\nn e e w t e b\n\ne c n e\n\nr e b m u n", "n_tokens": 207, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-185-2", "doc_id": "medicine_vaccine_book", "page": 185, "text": "d e t a l u c l a c\n\na t a d O P I\n\nd n a\n\n4 8 1\n\nf o\n\ne b\n\nd l u o c\n\nt i\n\n— 9 9\n\nf o\n\nt a p f o\n\nt n u o c c a\n\nn o\n\n,\n\nd e r i p x e\n\ng n i v a h\n\ns t n e\n\ng n i e b\n\ns n o i t i s o p p o\n\nS. K. Rathod\n\nr o\n\ne v i t a l u m u c\n\ns i\n\nt i\n\nr e h t e h w — O P I\n\nr o f\n\n. c t e\n\nn o i t a l u c l a c\n\nn w a r d h t i\n\nw\n\nf o\n\nd o h t e m\n\nt o n\n\no d\n\ne w s a\n\nd e l i c n o c e r\n\ne b\n\nt o n n a c\n\na t a d\n\nt u b\n\n—\n\ne c n e r e f f i d\n\nl a c i t a m e h t a m m o r f\n\ns r e f f i d\n\nr e b m u n\n\ns i h T a\n\n. l a c i t a m e h t a m y l e r e m", "n_tokens": 254, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-186-0", "doc_id": "medicine_vaccine_book", "page": 186, "text": "Patent Oppositions in India\n\nReferences\n\nAli F (2016) Open prosecution: towards ex ante validation of patents. Available at SSRN: https://\n\nssrn.com/abstract¼2755189 or https://doi.org/10.2139/ssrn.2755189\n\nAli F, Rajagopal S, Raman VS, John R (2018) Pharmaceutical patent grants in India: how our safeguards against evergreening have failed, and why the system must be reformed. Available at <https://accessibsa.org/media/2018/04/Pharmaceutical-Patent-Grants-in-India.pdf>\n\nAmin T (2010) Re-visiting the patents and access to medicines dichotomy: an evaluation of TRIPS In: Aginam O, implementation and public health safeguards in developing countries. Harrington J, Yu P (eds) Global governance of HIV/AIDS: intellectual property and access to essential medicines. Edward Elgar. SSRN: https://ssrn.com/abstract¼1573723 or https://doi. org/10.2139/ssrn.1573723\n\nAttaran A (2014) A modest but meaningful decision for Indian Drug Patents (August 9, 2014).\n\nLancet 384:477–479. Available at SSRN: https://ssrn.com/abstract¼2747623\n\nBasheer S, Reddy P (2008) “Ducking” TRIPS in India: a saga involving Novartis and the legality of\n\nSection 3(d). Natl Law School India Rev 20(2):131–155\n\nEWHC 1094 (Pat), available at https://www.bailii.org/ew/cases/EWHC/Patents/2014/1094.html Financial Times, Roche drops patent for Herceptin in India. https://www.ft.com/content/b8c9cf06-\n\n0676-11e3-9bd9-00144feab7de", "n_tokens": 435, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-186-1", "doc_id": "medicine_vaccine_book", "page": 186, "text": "Gilead, Voluntary Licensing Agreements for Remdesivir. <https://www.gilead.com/purpose/\n\nadvancing-global-health/covid-19/voluntary-licensing-agreements-for-remdesivir>\n\nGrant of patents up 12 per cent during April-December FY’19: DPIIT, 8 March 2019. https://m. economictimes.com/news/economy/indicators/grant-of-patents-up-12-per-cent-during-april- december-fy19-dpiit/articleshow/68317795.cms\n\nGrebe E, Low M (2017) The global movement around the Imatinib Mesylate case and its roots in the AIDS movement (April 23, 2017) Revised version of CSSR Working Paper No. 349. Available at SSRN: https://ssrn.com/abstract¼2546392\n\nHo CM (2011) Freedom under TRIPS: India as an example. In: Access to medicine in the global economy: international agreements on patents and related rights. Oxford University Press, Loyola University Chicago School of Law Research Paper No. 2011-025. Available at SSRN: https://ssrn.com/abstract¼1921583\n\nKrishnan V (2013) Roche lost Herceptin patent due to procedural problems, 13 Aug 2013. https:// www.livemint.com/Companies/TBQxokHyVTMGozu78o6CSL/India-partly-revokes-Roche- cancer-drug-patent.html\n\nMelody Petersen A history of Gilead’s biggest HIV drug, 29 May 2016. https://www.latimes.com/", "n_tokens": 370, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-186-2", "doc_id": "medicine_vaccine_book", "page": 186, "text": "business/la-fi-gilead-timeline-20160527-snap-story.html\n\nMSF, Patent application for AIDS drug opposed for first time in India, Press Release 30 March\n\n2006. https://www.msf.org/patent-application-aids-drug-opposed-first-time-india Mylan Laboratories Limited v. Union of India. https://indiankanoon.org/doc/58294410/ Mylan launches first Trastuzumab biosimilar in India, 4 February 2014. https://www. thehindubusinessline.com/companies/mylan-launches-first-trastuzumab-biosimilar-in-india/arti cle23122107.ece\n\nNick Redfearn Sanofi’s TB patents dispute overflows to Indonesia, Rouse, 29 January 2020. https:// www.rouse.com/magazine/news/sanofis-tb-patents-dispute-overflows-to-indonesia/? tag¼indonesia\n\n[2013] INSC 369. Available at: <https://www. globalhealthrights.org/wp-content/uploads/2013/04/SC-2013-Novartis-AG-v.-Union-of-India. pdf>\n\nNovartis AG v. Union of\n\nIndia & Ors.\n\n181", "n_tokens": 308, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-187-0", "doc_id": "medicine_vaccine_book", "page": 187, "text": "182\n\nS. K. Rathod\n\nRagavan S (2013) The patent failure of Novartis with Gleevec, Note on Novartis v. Union of India Judgment. Wegner’s Writings (Blog by Hal Wegner). Available at: http://works.bepress.com/ srividhya_ragavan/156/\n\nRathod SK (2010) Ever-greening: a status check in selected countries. J Generic Med 7(3):227–242.\n\nhttps://doi.org/10.1057/jgm.2010.14\n\n‘Report on the revision of the patents law’ by Justice N. Rajagopala Ayyangar; released in September 1959 and available at <http://www.ipindia.nic.in/writereaddata/Portal/Images/pdf/ 1959-_Justice_N_R_Ayyangar_committee_report.pdf>\n\nReuters, Roche gives up on India patent for breast cancer drug, 16 August 2013. https://www. reuters.com/article/us-roche-herceptin-india/roche-gives-up-on-india-patent-for-breast-cancer- drug-idUSBRE97F08220130816\n\nSampat BN, Shadlen KC (2018) Indian pharmaceutical patent prosecution: the changing role of\n\nSection 3(d). PLoS ONE 13(4):e0194714. https://doi.org/10.1371/journal.pone.0194714\n\nSerrano O, Burri M (2019) TRIPS implementation in developing countries: likely scenarios to 2025. In: Elsig M, Hahn M, Spilker G (eds) The shifting landscape of global trade governance. Cambridge University Press, pp 275–294. Available at SSRN: https://ssrn.com/ abstract¼3380246\n\nThe Business Journals, Gilead boosts low-cost HIV drug deal in developing countries, 12 July 2011. https://www.bizjournals.com/sanfrancisco/blog/biotech/2011/07/gilead-hiv-aids-quad- india-africa.html", "n_tokens": 480, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-187-1", "doc_id": "medicine_vaccine_book", "page": 187, "text": "The Economic Times, GSK withdraws patent application for AIDS drug, 21 August 2006. https:// economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/gsk-withdraws-pat ent-application-for-aids-drug/articleshow/1912871.cms\n\nThe Economic Times, SC asks Chennai patent office to hear Roche, https://economictimes. indiatimes.com/industry/healthcare/biotech/pharmaceuticals/sc-asks-chennai-patent-office-to- hear-roche/printarticle/4213952.cms\n\nThe Office of the Controller General off Patents, Designs, Trade Marks And Geographical Indica- tions, Annual Report 2018-19. http://www.ipindia.nic.in/writereaddata/Portal/Images/pdf/ IP_India_Annual_Report_2019_Eng.pdf\n\nThird World Network, GSK withdraws Combivir patent application from India and Thailand, 12 September 2006. http://www.twn.my/title2/intellectual_property/info.service/twn.ipr.info. 090603.htm\n\nTreatment Action Group Sanofi Withdraws Two Patent Applications on Life-Saving Tuberculosis Prevention Drugs in Europe and in Indonesia, 22 January 2020. https://www. treatmentactiongroup.org/statement/sanofi-withdraws-two-patent-applications-on-life-saving- tuberculosis-prevention-drugs-in-europe-and-in-indonesia/", "n_tokens": 339, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-187-2", "doc_id": "medicine_vaccine_book", "page": 187, "text": "USPTO, Markish Claims https://www.uspto.gov/web/offices/pac/mpep/s2117.html\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 200, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-188-0", "doc_id": "medicine_vaccine_book", "page": 188, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the Stronghold of Data Exclusivity\n\nEllen ‘t Hoen\n\nAbstract Test data demonstrating the efficacy, safety and quality of a medicine is required by drug regulatory agencies before a new treatment obtains marketing approval and can be made available to patients. Because test data can be costly and time-consuming to produce, certain countries have ‘data exclusivity’ regimes that restrict use of test data to the originator company for a period of time. Generic and biosimilar companies rely on originator test data to obtain marketing approval for generic products, so data exclusivity periods can delay entry of lower-cost treatments to the market. While data exclusivity is not required by the World Trade Organization, countries such as the United States and the European Union often push their stronger data exclusivity provisions on other countries through free trade agreements (FTAs). While a small number of countries have waivers to data exclusivity for cases of emergency or other public health need, most do not. This can hamper the timely and affordable availability of needed medicines. Waivers to data exclusivity should be included in legislation to protect public health, and other ways to protect test data against unfair commercial use should be explored.\n\n1 Introduction: Test Data and Efficacy, Safety and Quality", "n_tokens": 281, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-188-1", "doc_id": "medicine_vaccine_book", "page": 188, "text": "of Medicines\n\nAssuring the efficacy, safety and quality of medicines—be it of originator products or generic medicines—is an important public function meant to protect the health of consumers and patients. This function is performed by national or regional medi- cines regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), using the data that is submitted to the agency by companies that seek to obtain a marketing authorisation for a medicinal product. For new medicines, medicines regulatory agencies require drug companies to submit test data that demonstrates efficacy, safety and quality of the medicine\n\nE. ‘t. Hoen (*) Medicines Law & Policy, Amsterdam, The Netherlands e-mail: ellenthoen@medicineslawandpolicy.net\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_7\n\n183", "n_tokens": 228, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-189-0", "doc_id": "medicine_vaccine_book", "page": 189, "text": "184\n\nE. ‘t. Hoen\n\nbefore granting marketing authorisation. Generating such data can be time- consuming and costly, particularly when it involves a new chemical entity or a new biologic medicine. As a result, test data is often protected against use by others. The TRIPS Agreement (Article 39.3) requires the protection of certain kinds of test data against unfair commercial use but does not require to provide exclusive rights to such data. In certain jurisdictions the protection of test data takes the form of data exclusivity; data exclusivity means that the use of the test data is exclusive to the originator company for a certain period of time. In practical terms, this means that during the data exclusivity period a generic version of the product cannot be registered by the regulatory agency.\n\n2 Generic and Biosimilar Medicine Marketing Approval", "n_tokens": 172, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-189-1", "doc_id": "medicine_vaccine_book", "page": 189, "text": "and the Use of Test Data\n\nA generic company applying for marketing authorisation for a generic product has to demonstrate that its product is bioequivalent to the originator product. Importantly, the generic applicant is not required to generate its own clinical efficacy and safety data. The generic applicant can rely on the clinical test data that was submitted by the original applicant, and which is on file with the regulatory agency. Applicants for biosimilar medicines (generic biologic medicines) have to demonstrate biosimilarity (analogue to bioequivalence for biologic medicines) and can also rely on the safety and efficacy experience gained with the reference medicine.1 This avoids unneces- sary repetition of clinical trials already carried out with the reference medicine.\n\nData exclusivity regimes delay the use of existing test data by generic and biosimilar companies in seeking marketing approval for their medicines for as long as the data exclusivity period holds.2", "n_tokens": 203, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-189-2", "doc_id": "medicine_vaccine_book", "page": 189, "text": "Data exclusivity does not prohibit the generic or biosimilar company from generating its own clinical efficacy data, but this is costly and, in most cases, would raise serious ethical issues. Such tests would involve carrying out randomised controlled clinical trials in which an already proven effective treatment is withheld from part of the study participants who receive the comparator or placebo product. In reality, generic companies do not carry out such trials. Therefore, a data exclusivity regime creates strong monopolies that are automatically granted, quietly enforced by the medicines regulatory system and often without exceptions or limitations.\n\n1European Medicines Agency and the European Commission, Biosimilars in the EU: Information guide for healthcare professionals (European Medicines Agency, 2019) https://www.ema.europa. eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf. 2Technopolis (15 June 2018a). https://www.technopolis-group.com/report/effects-of-supplemen tary-protection-mechanisms-for-pharmaceutical-products/.", "n_tokens": 246, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-190-0", "doc_id": "medicine_vaccine_book", "page": 190, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the...\n\n3 Rationale for Data Exclusivity\n\nThe notion behind data exclusivity is that the production of clinical test data—by running, for example, clinical trials—requires significant investments. Protecting such test data against use by generic and biosimilar companies is thus seen as a means to encourage medical research and development (R&D). The rationale behind data exclusivity is similar to the rationale behind patents and other pharmaceutical market exclusivities: the assumption that the protection of the research and devel- opment investments that companies make by providing exclusive rights is needed and sufficient to stimulate innovation.", "n_tokens": 153, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-190-1", "doc_id": "medicine_vaccine_book", "page": 190, "text": "3.1 Data Exclusivity and Patents\n\nThere are important differences between data exclusivity regimes and patents. Data exclusivity is granted automatically and enforced through the regulatory system; the holders of the rights, mostly drug companies, do not have to apply or provide evidence of eligibility. Patent applications, by contrast, are examined before market exclusivities are granted; rights holders must demonstrate their product meets patentability criteria such as novelty, usefulness and inventive step. Most medicines laws that provide for data exclusivity do not provide for a waiver of it should it be necessary for public interest grounds to suspend the exclusivity. For patents, com- pulsory licences and other measures to circumvent exclusivity can be sought when there is a public health need (see also Sect. 6).\n\nData exclusivity rights exist independently of patents, can overlap with patents and can also exist where patents do not. Data exclusivity is also different from patents in that there is no international obligation to provide data exclusivity.\n\n3.2 Data Exclusivity’s Effectiveness in Stimulating", "n_tokens": 238, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-190-2", "doc_id": "medicine_vaccine_book", "page": 190, "text": "Innovation\n\nWhether data exclusivity is an effective or necessary measure to stimulate innovation is questionable at best. A publication by Dutch research group Technopolis, pre- pared upon request of the Dutch government that looked at pharmaceutical exclu- sivity incentives available to industry in the EU3 concluded “this study cannot provide any evidence on whether, or to what extent, the impacts of these exclusiv- ities and protections align with the intended objectives.” In 2009, the US Federal Trade Commission (FTC) concluded that a lengthy exclusivity period of\n\n3Technopolis (May 2018b) http://www.technopolis-group.com/wp-content/uploads/2018/06/2718- Technopolis-report-on-supplementary-protection-mechanisms.pdf.\n\n185", "n_tokens": 170, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-191-0", "doc_id": "medicine_vaccine_book", "page": 191, "text": "186\n\nE. ‘t. Hoen\n\n12–14 years is unnecessary to promote innovation by biologic drug manufacturers. The FTC considered existing incentives (patents and market-based pricing) to be sufficient to support biologic innovation.4 In 2016, the EU Council decided to carry out an assessment of the various pharmaceutical incentive mechanisms contained in EU regulations with a view “to strengthen the balance in the pharmaceutical systems in de EU and its Member States.” This review is ongoing but preliminary reports indicate that evidence is ambiguous at best.5,6,7\n\n4 History of Data Exclusivity\n\n4.1 Data Exclusivity in the United States\n\nData exclusivity was first introduced in the US in 1984 when the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the “Hatch-Waxman Amendments” was adopted. The act provided several types of exclusivities to innovators, in addition to patents, as a trade-off for provisions to make market entry of generics easier and quicker.8 The US provides 5 years of data exclusivity for small molecule new chemical entities; 3 years for a new indication of a previously approved medicine; and 4 years for biologics, complemented by a parallel 12-year market exclusivity.9", "n_tokens": 270, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-191-1", "doc_id": "medicine_vaccine_book", "page": 191, "text": "4.2 Data Exclusivity in the European Union\n\nThe EU introduced data exclusivity in 1987. Directive 87/21/EEC initially provided for 6 years of data exclusivity for most medicines, and 10 years for biotechnology products, both measured from the date of first marketing approval. Member states\n\n4Federal Trade Commission (June 2009) https://www.ftc.gov/sites/default/files/documents/reports/ emerging-health-care-issues-follow-biologic-drug-competition-federal-trade-commission-report/ p083901biologicsreport.pdf. 5Council of the EU, ‘Council conclusions on strengthening the balance in the pharmaceutical systems in the EU and its Member States’ (17 June 2016) https://www.consilium.europa.eu/en/ press/press-releases/2016/06/17/epsco-conclusions-balance-pharmaceutical-system/. 6Copenhagen Economics, Study on the economic impact of supplementary protection certificates, pharmaceutical incentives and rewards in Europe (European Commission, May 2018) https://ec. europa.eu/health/sites/health/files/human-use/docs/pharmaceuticals_incentives_study_en.pdf. 7https://medicineslawandpolicy.org/useful-resources/briefs/. 8Lietzan (2016), p. 91 https://pdfs.semanticscholar.org/2fdb/0784f6fb314cf99063933cb6bfbfae6a7091. pdf. 9U.S. Federal Trade Commission (FTC, June 2009). https://www.ftc.gov/reports/emerging-health- care-issues-follow-biologic-drug-competition-federal-trade-commission-report.", "n_tokens": 410, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-192-0", "doc_id": "medicine_vaccine_book", "page": 192, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the...\n\ncould extend data exclusivity to 10 years if they considered this was “in the interest of public health.” Member states had different views as to when an extension to 10 years was justified, which led to a variation in exclusivity periods throughout the EU. In 2004, the EU data exclusivity rules were further harmonised and extended to 8 years of data exclusivity, plus two additional years of market exclusivity during which generic companies can prepare and apply for their marketing approval using test data but not market the product. An additional 1 year of market exclusivity can be obtained by the originator company for a new indication with significant added clinical benefit.10 The new EU exclusivity regime became known as the 8+2+1 rule. The EU data exclusivity regime is the most generous in the world.\n\n4.3 Protection of Test Data and the Rules of the World Trade", "n_tokens": 218, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-192-1", "doc_id": "medicine_vaccine_book", "page": 192, "text": "Organization\n\nDuring the Uruguay Round negotiations on intellectual property, the option of making data exclusivity an explicit obligation under the Agreement on Trade- Intellectual Property Rights (TRIPS Agreement)11 was Related Aspects of discussed, but the TRIPS negotiators explicitly rejected language that would have required granting exclusive rights to test data, opting for the more general text of Article 39.3,12 which reads as follows:\n\nMembers, when requiring, as a condition of approving the marketing of pharmaceutical or of agricultural chemical products which utilize new chemical entities, the submission of undisclosed test or other data, the origination of which involves a considerable effort, shall protect such data against unfair commercial use. In addition, Members shall protect such data against disclosure, except where necessary to protect the public, or unless steps are taken to ensure that the data are protected against unfair commercial use.", "n_tokens": 172, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-192-2", "doc_id": "medicine_vaccine_book", "page": 192, "text": "The WTO TRIPS Agreement contains an obligation of WTO members to protect certain kinds of test data against unfair commercial use, but does not create an obligation to provide data exclusivity. TRIPS data protection against unfair com- mercial use is required only where that data is related to a new chemical entity and required as a condition of marketing approval, was previously undisclosed, and required considerable effort to generate. Importantly, TRIPS does not stipulate a time period for this protection. This is further evidence of the absence of a data exclusivity obligation.\n\n10Directive 2004/27/EC on the Community code relating to medicinal products for human use [2004] OJ L136/34. 11Agreement on Trade-Related Aspects of Intellectual Property Rights (Apr. 15, 1994) (hereinafter TRIPS Agreement). 12The World Health Organization (WHO), the World Intellectual Property Organization (WIPO) and the World Trade Organization (WTO), WHO (2012), p. 64. https://www.wipo.int/policy/en/ global_health/trilateral_cooperation.html.\n\n187", "n_tokens": 236, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-193-0", "doc_id": "medicine_vaccine_book", "page": 193, "text": "188\n\nE. ‘t. Hoen\n\nTRIPS also does not preclude the use of test data for the regulatory approval of a competing product, which, as some have argued, does not fall within the definition of ‘unfair commercial use’.13,14,15 This position was reiterated by the developing country members of the WTO in 2001 at the Doha Ministerial Conference, where they stated that article 39.3 of TRIPS “does not require granting ‘exclusive rights’ to the owner of the data” and that it “does permit a national competent authority to rely on data in its possession to assess a second and further applications, relating to the same drug, since this would not imply any ‘unfair commercial use’.”16 TRIPS also does not require WTO members to extend protection to data that is in the public domain.17\n\nThe obligation to protect test data against ‘unfair commercial use’ does not yet apply to least developed country members (LDCs) of the WTO, who do not need to implement pharmaceutical-related aspects of the TRIPS agreement until 2033 or until they cease to be LDCs.18\n\nToday, most WTO members, outside the EU or the United States, do not provide data exclusivity. A survey of MedsPaL,19 a database of select medicines patent and exclusivity status, shows that only around 16 middle-income countries provide data exclusivity. Data exclusivity regimes often find their origin in trade agreements with the EU or the US that were negotiated outside of the WTO (see Sect. 5).", "n_tokens": 323, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-193-1", "doc_id": "medicine_vaccine_book", "page": 193, "text": "In conclusion, the TRIPS Agreement gives countries considerable latitude as to\n\nhow they want to implement test data protection.\n\n13Reichman (2009), p. 17. 14Timmermans (2007), p. e2. 15Commission on Intellectual Property Rights, Innovation and Public Health, Public Health, Innovation and Intellectual Property Rights (World Health Organization, 2006). 16‘TRIPS Council Discussion on Access to Medicines: Developing Country Group’s Paper’ (World Trade Organization, 20 June 2001) IP/C/W/296, paras 39–40. https://www.wto.org/english/tratop_ e/trips_e/paper_develop_w296_e.htm. 17Correa (2002). https://www.southcentre.int/wp-content/uploads/2019/02/Bk_2002_Protection- of-Data-Submitted-for-Pharmaceuticals-Registration_EN.pdf. 18The Council for Trips Extension of the Transition Period Under Article 66.1 of the Trips Agreement for Least Developed Country Members for Certain Obligations with Respect to Phar- maceutical Products (6 November 2015), World Trade Organization IP/C/73. 19‘MedsPaL: The Medicines Patents and Licences Database’. https://www.medspal.org.", "n_tokens": 284, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-194-0", "doc_id": "medicine_vaccine_book", "page": 194, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the...\n\n5 Data Exclusivity in Free Trade Agreements (FTAs)\n\nThe obligation to grant data exclusivity to the originator company in the US and the EU goes beyond the requirement of the TRIPS Agreement20 for the protection of undisclosed test data against unfair commercial use. Both the US and the EU seek to globalise their data exclusivity norms through trade agreements, including in WTO accession agreements with other countries or in bilateral agreements or trading blocs, by demanding from their trading partners that they introduce or expand data exclusivity.\n\nIn recent FTAs there has been some roll back of the demands related to data exclusivity. In 2018, after the withdrawal of the US, the 11 remaining parties to the Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP, formerly the TPP) suspended the IP chapter, including its various market exclusivity obligations. The US-Mexico-Canada Agreement (USMCA) initially contained a provision that bound parties to 5-year exclusivity for small molecules, 3 years for new clinical information (new use of a known medicine), and 10-years for biologics. In 2019, driven by the debate on high drug prices in the US, the provision for 10-year exclusivity for biologics was removed from the USMCA.", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-194-1", "doc_id": "medicine_vaccine_book", "page": 194, "text": "6 Data Exclusivity and TRIPS Flexibilities\n\nThe TRIPS Agreement includes a number of flexibilities that are relevant for public health. Data exclusivity can form a serious barrier to the effective use of such flexibilities for the purpose of accessing lower priced medicines. In particular, the effectiveness of compulsory licensing—a mechanism whereby a government grants third parties or itself the right to use a patented innovation without the consent of the patent holder—may be muted by data exclusivity.\n\n6.1 Compulsory Licensing and Government Use in Drug\n\nProcurement\n\nWhen a government grants itself the right to make use of a patented innovation through a compulsory licence, this is often called ‘government use’, or ‘public non-commercial use’.21 Such compulsory licences can be particularly useful in\n\n20During the Uruguay Round negotiations, the option of making data exclusivity an explicit obligation under the TRIPS Agreement was discussed, but negotiators instead adopted the general wording of the current Article 39.3. See: WTO, WIPO, and the WHO (n 10). 21This chapter will further use the term ‘compulsory licence’ to refer to both compulsory licences and government use or public non-commercial use of a patent.\n\n189", "n_tokens": 260, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-195-0", "doc_id": "medicine_vaccine_book", "page": 195, "text": "190\n\nE. ‘t. Hoen\n\npublic procurement of medicines to access lower-priced medicines from generic competitors.\n\nThe government is free to determine the grounds for granting a compulsory licence. Some countries’ domestic laws include specific provisions such as ‘high prices’ of medicines, or a ‘lack of access to medicines’. For example, French patent law authorises government use upon request by the minister of health when medi- cines are ‘only available to the public in insufficient quantity or quality or at abnormally high prices.’22\n\nIn 2001 the WTO Doha Declaration on the TRIPS agreement and Public Health23 provided a welcome clarification of the flexibilities24 contained in the TRIPS Agreement for the purpose of public health and specifically ‘to promote access to medicines for all’.25 Against the background of trade pressure on low- and middle- income countries that contemplated the use of compulsory licensing and other TRIPS-flexibilities, the Doha Declaration took away any doubts about the legality of such measures. Subsequently, low- and middle-income countries have used TRIPS flexibilities on a large scale in particular but not exclusively to facilitate the supply of low-cost generic medicines used for the treatment of HIV.26", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-195-1", "doc_id": "medicine_vaccine_book", "page": 195, "text": "6.2 Data Exclusivity and Compulsory Licensing\n\nCountries that have a data exclusivity regime may find providing more affordable access to a patent-protected medicine through a compulsory licence is hindered if the originator company’s product benefits from data exclusivity. While a compulsory licence may open the possibility of providing generic versions of a medicine that is still patent protected, data exclusivity may prevent the registration of such generic medicines and therefore still block their entry into the market.\n\n22Code de la propriété intellectuelle (version consolidée au 9 octobre 2016) Article L613-16. 23Declaration on the TRIPS agreement and public health (14 November 2001) WT/MIN(01)/DEC/ 2. https://www.wto.org/english/thewto_e/minist_e/min01_e/mindecl_trips_e.htm (hereinafter Doha Declaration). 24The term ‘flexibilities’ is used to describe limitations and exceptions to exclusive rights that countries can deploy for reasons of public interest. See also: WIPO, ‘Meaning of Flexibilities’. http://www.wipo.int/ip-development/en/agenda/flexibilities/meaning_of_flexibilities.html. 25Doha Declaration (n 22). 26Hoen (2016).", "n_tokens": 309, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-196-0", "doc_id": "medicine_vaccine_book", "page": 196, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the...\n\n191\n\n6.3 Remedies to Data Exclusivity Barriers and Compulsory", "n_tokens": 33, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-196-1", "doc_id": "medicine_vaccine_book", "page": 196, "text": "Licensing\n\nSome countries have introduced waivers to data exclusivity, which can be invoked to ensure that the regulatory authority can proceed with the registration of a generic product produced or imported under a compulsory licence. Countries that have such data exclusivity waivers include Malaysia, Chili and Colombia.27\n\nSection 5 of the Malaysia 2011 Directive of Data Exclusivity,28 entitled Non-Application of Data Exclusivity, provides that Nothing in the Data Exclusivity shall:\n\n(i) apply to situations where compulsory licenses have been issued or the implementation of any other measures consistent with the need to protect public health and ensure access for all; or\n\n(ii) prevent the Government from taking any necessary action to protect public health, national security, non-commercial public use, national emergency, public health crisis or other extremely urgent circumstances declared by the Government.\n\nIn Chile, Article 91 of Law 19.996, as amended in 2012,29 provides that test data\n\nexclusivity shall not be applied: (b) Where, for reasons of public health, national security, public non-commercial use, national emergency or other circumstances of extreme urgency declared by the compe- tent authority, it is justified to terminate the protection referred in Article 89’ [on test data exclusivity].\n\n(c) The pharmaceutical or agrochemical product is the subject of a compulsory license in", "n_tokens": 282, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-196-2", "doc_id": "medicine_vaccine_book", "page": 196, "text": "conformity with the provisions of this law.\n\nIn Colombia, Article 4 of Decree 2085 of 2002 on data exclusivity provides that, ‘The protection referred to in this Decree does not apply in the following cases [...] c) where necessary to protect the public, as qualified by the Ministry of Health’.\n\nIn the absence of such a waiver, countries have found it difficult to make effective\n\nuse of compulsory licensing. See Box 1.\n\nBox 1: Case of Romania and Malaysia In 2015 the World Health Organization (WHO) set the target of eliminating hepatitis C (HCV) as a public health threat by 2030. To reach this goal, prevention and treatment are necessary. People infected with HCV need a 12-week course of antiviral treatment. In countries that cannot access generic supply of HCV medicines, the price of the originator product may be a barrier to reaching the elimination target.\n\nIn 2016, the government of Romania contemplated use of a compulsory licence for sofosbuvir, an essential medicine for the treatment of HCV.\n\n(continued)\n\n27Hoen et al. (2017). https://joppp.biomedcentral.com/articles/10.1186/s40545-017-0107-9. 28https://npra.gov.my/images/reg-info/DataEx/Directive_on_DE.pdf. 29http://www.wipo.int/edocs/lexdocs/laws/en/cl/cl042en.pdf.", "n_tokens": 337, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-197-0", "doc_id": "medicine_vaccine_book", "page": 197, "text": "192\n\nE. ‘t. Hoen\n\nBox 1 (continued) Sofosbuvir was only available from the originator company at a price of around 50,000 euro for a 12-week treatment.30 However, EU data exclusivity for the product will not expire before 2022. This means that, even with a compulsory licence, the registration of a generic version of sofosbuvir would be prohibited until the EU market exclusivity for sofosbuvir expires at the earliest in 2024. Romania, like any other EU Member State, cannot give effect to a compulsory licence during the data and market exclusivity terms.\n\nthat date.31 Further,\n\nIn contrast, when Malaysia issued a compulsory licence for sofosbuvir in 201732 it was not hampered to register the generic product due to its legal waiver to data exclusivity (see Sect. 6.3).", "n_tokens": 192, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-197-1", "doc_id": "medicine_vaccine_book", "page": 197, "text": "6.4 Data Exclusivity Waivers in FTAs\n\nThe US does not have an explicit exception to data exclusivity for medical products. However, the consequence of data exclusivity for the effective use of TRIPS flexibilities was recognised in 2007 when the New Trade Policy in the US explicitly authorised a public health exception to data/market exclusivity in the event of a compulsory licence or other public health need. This flexibility in implementing data exclusivity was included in several US developing-country FTAs, including with Colombia, Panama, and Peru. This implementation flexibility reads:\n\nFor pharmaceutical products, Article 16.10.2(e)(i) provides an exception to the data exclu- sivity obligations for measures to protect public health in accordance with the Declaration on the TRIPS Agreement and Public Health (WT/MIN(01)/DEC/2) (the ‘Doha Declaration’). Thus, where a Party issues a compulsory licence in accordance with Article 31 of the TRIPS Agreement and the Doha Declaration, the data exclusivity obligations in Chapter Sixteen will not prevent the adoption or implementation of such a public health measure. In addition, in a case in which there is no patent on the pharmaceutical product, and, therefore, no need to issue a compulsory licence, the data exclusivity obligations in Chapter Sixteen will not prevent the adoption or implementation of such a measure.33", "n_tokens": 295, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-197-2", "doc_id": "medicine_vaccine_book", "page": 197, "text": "Certain trade agreements the EU is a party to establish that, in regard to test data, parties may provide exceptions to exclusivity for reasons of public interest and for\n\n30Paun (2016) http://www.politico.eu/pro/high-drug-prices-romania-changes-patents-hepatitis/. 31European Medicines Agency, ‘Marketing authorization’ Europa http://www.ema.europa.eu/ema/ index.jsp?curl¼pages/regulation/general/general_content_001595.jsp& mid¼WC0b01ac0580b18a3d#. 32Hoen (2018) https://medicineslawandpolicy.org/2018/04/the-power-of-trips-flexibilities-in-medi cines-procurement/. 33Office of the U.S. Trade Representative, Statement of Administration Action (2007) https://ustr. gov/archive/assets/Trade_Agreements/Bilateral/Peru_TPA/PTPA_Implementing_Legislation_ Supporting_Documentation/asset_upload_file194_15341.pdf.", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-198-0", "doc_id": "medicine_vaccine_book", "page": 198, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the...\n\nemergency situations. An example is the EU–Peru Agreement. Article 231 (4) pro- vides that ‘[t]he Parties may regulate exceptions for reasons of public interest, situations of national emergency or extreme urgency, when it is necessary to allow access to those data to third parties.’34 The implication of this is that the EU and Peru, both party to this agreement, may provide and use data exclusivity waivers to ensure effective use of compulsory licence. The waiver may also be relevant for non-patented products that still have a monopoly in the market because of data exclusivity. To take advantage of this provision, the party countries would need to provide for a data exclusivity waiver in their regulations.", "n_tokens": 168, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-198-1", "doc_id": "medicine_vaccine_book", "page": 198, "text": "6.5 EU Medicines Regulation and Compulsory Licensing\n\nEU law does not yet provide a safety valve to data exclusivity to allow registration of a competitor product in the EU. This became apparent during the h5n1 virus (avian influenza) outbreak in 2006, when the threat of a shortage of the antiviral oseltamivir (Tamiflu) signalled the need for an emergency compulsory licence in countries that wanted to ensure sufficient stockpile of the antiviral medicine. The European Generic Association had inquired as to the options under EU law to provide generic oseltamivir for epidemic preparedness purposes, but the European Commission informed them that:35\n\nNational emergency provisions in an EU Member State may allow the granting of a compulsory patent licence which would allow a generic or other company to use the patented product in the Member State in question.\n\nHowever, the Community pharmaceutical acquis does not currently contain any provi- sion allowing the waiver of the rules on data exclusivity and marketing protection periods described above in the case of a national or an EU-wide emergency.", "n_tokens": 229, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-198-2", "doc_id": "medicine_vaccine_book", "page": 198, "text": "Before expiry of the data exclusivity and marketing protection periods provided for by the European pharmaceutical legislation, applicants for a generic marketing authorisation have to either (1) provide the relevant authority with the required documentation on pre- clinical tests and clinical trials or (2) confirm that the marketing authorisation holder has consented to the use of the required documentation by the applicant.\n\nThe Commission response confirms the lack of public health safeguards in European pharmaceutical legislation. Even in cases of an urgent need or emergency situations, no data exclusivity waiver exists that can be applied by EU member states.\n\n34Trade Agreement between the European Union and its Member States, of the one part, and Colombia and Peru, of the other part [2012] L354/3. 35European Commission, from the European Commission to Mr. Greg Perry, EGA-European Generic Medicines Association on the subject of Tamiflu application and data exclusivity in an emergency compulsory license situation’ (Brussels, 2006) http://www.cptech.org/ ip/health/dataexcl/ec-de-tamiflu.pdf.\n\n‘Letter\n\n193", "n_tokens": 246, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-199-0", "doc_id": "medicine_vaccine_book", "page": 199, "text": "194\n\nE. ‘t. Hoen\n\n6.6 EU Data Exclusivity Waiver and Compulsory Licence\n\nfor Export\n\nThe one waiver to data exclusivity in the EU is only foreseen in cases of compulsory licensing for manufacturing a product for export outside the EU but not to enable effective use of compulsory licensing or other measures to protect public health within EU member states.36,37 Article 18 of the EU Regulation addresses the situation in which the applicant for a compulsory licence to manufacture medicines in an EU Member State for export outside the EU may use the scientific opinion procedure of the European Medicines Agency38,39 or any similar national procedures intended exclusively for markets outside the EU. These scientific opinions provide a benefit/risk analysis of a medicine, designed to facilitate registration in importing countries.40 The procedure provides waivers to data exclusivity rules necessary to obtain such opinions from the EMA or national authorities.41\n\n6.7 Data Exclusivity Waivers in Voluntary Patent Licences\n\nThe need to provide data exclusivity waivers to ensure effective availability of generic medicines is often recognised in voluntary licences. For example, all Med- icines Patent Pool42 (MPP) licences include a data exclusivity waiver to facilitate", "n_tokens": 263, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-199-1", "doc_id": "medicine_vaccine_book", "page": 199, "text": "36Regulation 816/2006 on Compulsory Licensing of Patents Relating to the Manufacture of Pharmaceutical Products for Export to Countries with Public Health Problems [2006] OJ L157/1. 37This regulation implements the WTO ‘August 30, 2003 decision’, which provided a waiver to the TRIPS Article 31(f) requirement that production under a compulsory licence be predominantly for the domestic market. This restriction hampered the use of compulsory licensing by countries that were dependent on the importation of medicines. The 30 August 2003 waiver became a permanent amendment of the TRIPS Agreement in 2017 (see: WTO, ‘WTO Members Welcome Entry Into Force of Amendment to Ease Access to Medicines’ (30 January 2017) https://www.wto.org/ english/news_e/news17_e/heal_30jan17_e.htm. 38Article 58 of Regulation (EC) No 726/2004. 39Committee for Medicinal Products for Human Use (CHMP) (European Medicines Agency, 17 November 2005). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guide line/2009/09/WC500003883.pdf. 40European Medicines Agency, ‘Medicines for use outside the European Union’. https://www.ema. europa.eu/en/human-regulatory/marketing-authorisation/medicines-use-outside-european-union. 41Regulation (EC) No 816/2006 of the European Parliament and of the Council of 17 May 2006 on compulsory licensing of patents relating to the manufacture of pharmaceutical products for export to countries with public health problems. Article 18(2) reads: “If a request for any of the", "n_tokens": 373, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-199-2", "doc_id": "medicine_vaccine_book", "page": 199, "text": "above procedures concerns a product which is a generic of a reference medicinal product which is or has been authorised under Article 6 of Directive 2001/83/EC, the protection periods set out in Article 14 (11) of Regulation (EC) No 726/2004 and in Articles 10(1) and 10(5) of Directive 2001/83/EC shall not apply”. 42Medicines Patent Pool http://www.medicinespatentpool.org/.", "n_tokens": 96, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-200-0", "doc_id": "medicine_vaccine_book", "page": 200, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the...\n\nregulatory approval of generics manufactured by MPP licensees in the territories that grant test data exclusivity. For instance, Guatemala is included in the territory of the MPP licences with ViiV Healthcare for paediatric formulations of dolutegravir (DTG) and for adult formulations of DTG and abacavir (ABC), both treatments for HIV. The licences specifically state that:\n\nViiV shall provide any Sublicensee with NCE [New Chemical Entity] exclusivity or other regulatory exclusivity waivers to the extent required by the applicable regulatory authorities in order to manufacture or sell Product in the Territory in accordance with the terms of the Sublicence. ViiV shall further provide to any Sublicensee such consents which it has the legal capacity to give as are necessary to enable such Sublicensee to perform its obligations.43\n\nBox 2: Data Exclusivity Waiver in Voluntary Licences: The Case of Guatemala The HIV treatment formulations of DTG 50 mg and ABC/DTG/3TC 600/50/ 300 mg are protected by test data exclusivity in Guatemala until 11 November 2020 and 29 November 2021 respectively.44 However, MPP licensees will be able to register and market generic versions of these formulations in Guate- mala before the expiration of these rights, based on the waiver included in the MPP licence agreements.\n\nDrug company Gilead has included the following waiver of data exclusivity", "n_tokens": 331, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-200-1", "doc_id": "medicine_vaccine_book", "page": 200, "text": "in its licence agreements for HCV treatment sofosbuvir:\n\nGilead agrees to provide Licensee with NCE Exclusivity, or other regulatory exclu- sivity, waivers as may be required by the applicable regulatory authorities in order to manufacture or sell Product in the Territory, provided such manufacture and sale by Licensee is compliant with the terms and conditions of this Agreement. Licensee agrees not to pursue or obtain regulatory exclusivity on any Product in any country within the Territory.45\n\nEven though Gilead obtained test data exclusivity for sofosbuvir 400 mg until 14 July 2021 in Guatemala, for instance, Gilead licensees should not be barred from registering and selling generic versions of sofosbuvir 400mg during this data exclusivity period in Guatemala, which is included in the license territory.\n\n43Medicines Patent Pool, ‘Products Licensed: ViiV’ https://medicinespatentpool.org/what-we-do/ global-licence-overview/licences-in-the-mpp/?patent_holder¼2718 Link Does Not Work. 44Medicines Patent Pool, ‘MedsPaL The Medicines Patent and Licences Database’. https://www. medspal.org. 45Gilead Sciences (15 September 2014) https://www.gilead.com/~/media/files/pdfs/other/2014_ original_hcv_licensing_agreement.pdf?la¼en.\n\n195", "n_tokens": 314, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-201-0", "doc_id": "medicine_vaccine_book", "page": 201, "text": "196\n\nE. ‘t. Hoen\n\n6.8 Public Health Measures, Data Exclusivity\n\nand Competition Law\n\nSome scholars have argued that the issuance of a compulsory licence for public interest reasons creates the obligation for the patent holder to provide a waiver to data exclusivity.46 A company holding a dominant position in the market that denies access to the data held by the regulatory authority in the case of a compulsory licence is likely to be viewed as abusive under competition law since national authorities have already decided that the public interest requires an additional product on the market. However, enforcing this position will likely lead to protracted legal pro- cedures and delays in the availability of the medicine for which the compulsory licence was requested.", "n_tokens": 147, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-201-1", "doc_id": "medicine_vaccine_book", "page": 201, "text": "6.9 EU Law Needs an Explicit Data Exclusivity Waiver\n\nIt would be desirable to introduce explicit data and market exclusivity waivers in national legislation. This is particularly important in the EU, now that European countries have indicated that they lack the negotiating power to obtain good results in price negotiations with pharmaceutical companies concerning patented products and several EU countries are exploring the use of compulsory licensing to strengthen this position.47\n\nThe following amendment to the EU medicines regulation would introduce a waiver to data exclusivity similar to the one contained in the Regulation on com- pulsory licensing for export:48,49\n\nThe protection periods set out in article 14 (11) of Regulation 726/2004 shall not apply in cases where it is necessary to allow access to and the use of pharmaceutical test data to register a generic of a reference medicinal product, which is or has been authorised under article 6 of Directive 2001/83/EC, for reasons of public interest including public health, in case of compulsory licensing of patents, including for public non-commercial use, and in situations of national emergency or extreme urgency.", "n_tokens": 223, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-201-2", "doc_id": "medicine_vaccine_book", "page": 201, "text": "46Junod (29 January 2019) https://www.publiceye.ch/fileadmin/doc/Medikamente/ValerieJunod_ Legal-Analysis-CL_20190129.pdf. 47Rumney (Public Finance International, 16 January 2017). https://www.publicfinancefocus.org/ news/2017/01/drug-manufacturers-have-too-much-power-price-negotiations-says-oecd. 48Regulation (EC) No 816/2006 of the European Parliament and of the Council of 17 May 2006 on compulsory licensing of patents relating to the manufacture of pharmaceutical products for export to countries with public health problems. 49Hoen et al. (2017).", "n_tokens": 158, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-202-0", "doc_id": "medicine_vaccine_book", "page": 202, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the...\n\n7 Conclusion and Recommendations\n\nThe TRIPS Agreement provides much flexibility for WTO members to design a test data protection regimes conducive to public health.\n\nWhere possible, countries should refrain from implementing data exclusivity and instead use the flexibility offered to them in the TRIPS agreement to provide data protection for certain types of data only and without granting exclusive rights to the originator of the data.\n\nSafeguards need to be in place to ensure that data remains available for legitimate public health functions including the assessment of efficacy and safety of needed products. Countries that have a data exclusivity regime should have the option to use waivers to data (and market) exclusivity for effective use of measures such as compulsory licensing, to protect public health.", "n_tokens": 173, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-202-1", "doc_id": "medicine_vaccine_book", "page": 202, "text": "There are different ways in which undisclosed test data can be protected, includ- ing: protecting it against dishonest commercial practices, but allowing its use to register a generic product,50 permitting generic reliance on the test data but with compensation to the entity that originally generated the data.51 Countries should consider replacing data exclusivity regimes with data protection regimes that acknowledge the investment made to generate data but do not allow the investor to exclude others from using the data. Under a data compensation regime, the registration of a generic medicine or biosimilar medicine is considered fair commer- cial use. The originator company that made the investment that was needed to generate the data will receive adequate remuneration for the use of the data but cannot prevent its necessary use by the medicines agency to perform its public health duties. The data compensation regime could be proposed as an alternative to data exclusivity demands in trade negotiations.", "n_tokens": 188, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-202-2", "doc_id": "medicine_vaccine_book", "page": 202, "text": "References\n\nAgreement on Trade-Related Aspects of Intellectual Property Rights (Apr. 15, 1994) Marrakesh Agreement Establishing the World Trade Organization, Annex 1C, The Legal Texts: The the Uruguay Round of Multilateral Trade Negotiations 320 (1999), 1869 Results of U.N.T.S. 299, 33 I.L.M. 1197 (1994)\n\nCode de la propriété intellectuelle (version consolidée au 9 octobre 2016) Article L613-16 Commission on Intellectual Property Rights, Innovation and Public Health, Public Health, Innova-\n\ntion and Intellectual Property Rights (World Health Organization, 2006)\n\nCommittee for Medicinal Products for Human Use (CHMP), ‘Guideline on Procedural Aspects Regarding a CHMP Scientific Opinion in the Context of Cooperation with the World Health Organisation (WHO) for the Evaluation of Medicinal Products Intended Exclusively for Mar- kets Outside the Community’ (European Medicines Agency, 17 November 2005). http://www.\n\n50Correa (2002). 51For example, in the US, Knowledge Ecology International has proposed a cost sharing model. See for details: Sanjuan et al. (2006), p. 1.\n\n197", "n_tokens": 251, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-203-0", "doc_id": "medicine_vaccine_book", "page": 203, "text": "198\n\nE. ‘t. Hoen\n\nema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003883. pdf. Last accessed 23 Feb 2021\n\nCopenhagen Economics, Study on the economic impact of supplementary protection certificates, pharmaceutical incentives and rewards in Europe (European Commission, May 2018). https:// ec.europa.eu/health/sites/health/files/human-use/docs/pharmaceuticals_incentives_study_en. pdf. Last accessed 22 Feb 2021\n\nCorrea CM (2002) Protection of data submitted for\n\nthe registration of pharmaceuticals: implementing the standards of the TRIPS Agreement. South Centre, Geneva. http://apps.who. int/medicinedocs/en/d/Jh3009ae/. Last accessed 23 Feb 2021\n\nCouncil of the EU (17 June 2016) Council conclusions on strengthening the balance in the pharmaceutical systems in the EU and its Member States. https://www.consilium.europa.eu/ en/press/press-releases/2016/06/17/epsco-conclusions-balance-pharmaceutical-system/. Last accessed 22 Feb 2021\n\nDeclaration on the TRIPS agreement and public health (14 November 2001) WT/MIN(01)/DEC/2", "n_tokens": 282, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-203-1", "doc_id": "medicine_vaccine_book", "page": 203, "text": "https://www.wto.org/english/thewto_e/minist_e/min01_e/mindecl_trips_e.htm\n\nEuropean Commission, ‘Letter from the European Commission to Mr. Greg Perry, EGA-European Generic Medicines Association on the subject of Tamiflu application and data exclusivity in an emergency compulsory license situation’ (Brussels, 2006). http://www.cptech.org/ip/health/ dataexcl/ec-de-tamiflu.pdf. Last accessed 23 Feb 2021\n\nEuropean Medicines Agency, ‘Marketing authorization’ Europa http://www.ema.europa.eu/ema/ index.jsp?curl¼pages/regulation/general/general_content_001595.jsp& mid¼WC0b01ac0580b18a3d#. Last accessed 23 February 2021\n\nEuropean Medicines Agency, ‘Medicines for use outside the European Union’ https://www.ema. europa.eu/en/human-regulatory/marketing-authorisation/medicines-use-outside-european- union. Last accessed 23 Feb 2021\n\nEuropean Medicines Agency and the European Commission, Biosimilars in the EU: Information guide for healthcare professionals (European Medicines Agency, 2019). https://www.ema. europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en. pdf. Last accessed 22 Feb 2021\n\nFederal Trade Commission (June 2009) Emerging health care issues: follow-on biologic drug competition. https://www.ftc.gov/sites/default/files/documents/reports/emerging-health-care- issues-follow-biologic-drug-competition-federal-trade-commission-report/ p083901biologicsreport.pdf. Last accessed 22 Feb 2021", "n_tokens": 406, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-203-2", "doc_id": "medicine_vaccine_book", "page": 203, "text": "Gilead Sciences, ‘Licence Agreement’ (15 September 2014). https://www.gilead.com/~/media/ files/pdfs/other/2014_original_hcv_licensing_agreement.pdf?la¼en. Last accessed 23 Feb 2021 Hoen E’t (2016) private patents and public health: changing intellectual property rules for access to\n\nmedicines. AMB Press, Health Action International, The Netherlands\n\nHoen E, ‘The Power of TRIPS Flexibilities in Medicines Procurement’ (Medicines Law & Policy, 9 April 2018). https://medicineslawandpolicy.org/2018/04/the-power-of-trips-flexibilities-in- medicines-procurement/. Last accessed 23 Feb 2021\n\nHoen E‘t FM, Boulet P, Baker BK (2017) Data exclusivity exceptions and compulsory licensing to promote generic medicines in the European Union: a proposal for greater coherence in European pharmaceutical legislation. JOPPP 10. https://joppp.biomedcentral.com/articles/10.1186/ s40545-017-0107-9. Last accessed 23 Feb 2021\n\nJunod V, ‘Legal analysis: the interface between patent protection and data exclusivity – the issue of compulsory licensing in the public interest under Swiss Law’ (Public Eye, 29 January 2019). https://www.publiceye.ch/fileadmin/doc/Medikamente/ValerieJunod_Legal-Analysis-CL_ 20190129.pdf. Last accessed 23 Feb 2021", "n_tokens": 342, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-203-3", "doc_id": "medicine_vaccine_book", "page": 203, "text": "Law No. 19.996 revising Law No. 19.039 on Industrial Property. http://www.wipo.int/edocs/\n\nlexdocs/laws/en/cl/cl042en.pdf. Last accessed 23 February 2021\n\nLietzan E (2016) The myths of data exclusivity (University of Missouri School of Law). Lewis h t t p s : / / p d f s . s e m a n t i c s c h o l a r . o r g / 2 f d b /\n\nC l a r k L a w R e v 0784f6fb314cf99063933cb6bfbfae6a7091.pdf. Last accessed 22 February 2021\n\n2 0 : 9 1 .", "n_tokens": 169, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-204-0", "doc_id": "medicine_vaccine_book", "page": 204, "text": "Protection of Clinical Test Data and Public Health: A Proposal to End the...\n\nMedicines Law & Policy, How the ‘Oxford’ Covid-19 vaccine became the ‘AstraZeneca’ Covid-19 vaccine. https://medicineslawandpolicy.org/useful-resources/briefs/. Last accessed 22 February 2021\n\nMedicines Patent Pool, MedsPaL: The Medicines Patents and Licences Database https://www.\n\nmedspal.org. Last accessed 23 February 2021\n\nMedicines Patent Pool. http://www.medicinespatentpool.org/. Last accessed 23 February 2021 Medicines Patent Pool ‘Products Licensed: ViiV’. https://medicinespatentpool.org/what-we-do/ global-licence-overview/licences-in-the-mpp/?patent_holder¼2718. Link Does not Work Office of the U.S. Trade Representative, Statement of Administration Action (2007). https://ustr. gov/archive/assets/Trade_Agreements/Bilateral/Peru_TPA/PTPA_Implementing_Legislation_ Supporting_Documentation/asset_upload_file194_15341.pdf. Last accessed 23 Feb 2021 Paun C (16 March 2016) ‘Skyhigh drug prices made Romania mull unusual path’ Politico, http:// accessed\n\nwww.politico.eu/pro/high-drug-prices-romania-changes-patents-hepatitis/. 23 Feb 2021\n\nLast\n\nRegulation 816/2006 on Compulsory Licensing of Patents Relating to the Manufacture of Pharma- ceutical Products for Export to Countries with Public Health Problems [2006] OJ L157/1 Reichman JH (2009) The international legal status of undisclosed clinical trials data: from private to", "n_tokens": 377, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-204-1", "doc_id": "medicine_vaccine_book", "page": 204, "text": "public goods? Marquette Intellect Property Law Rev 13:17\n\nRumney E, ‘Drug manufacturers have too much power in price negotiations, Says OECD’ (Public Finance International, 16 January 2017). https://www.publicfinancefocus.org/news/2017/01/ drug-manufacturers-have-too-much-power-price-negotiations-says-oecd. Last accessed 23 Feb 2021\n\nSanjuan JR, Love J, Weissman R (2006) Protection of pharmaceutical test data: a policy proposal’", "n_tokens": 113, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-204-2", "doc_id": "medicine_vaccine_book", "page": 204, "text": "KEI Research Paper 2006:1\n\nTechnopolis (15 June 2018a) Effects of supplementary protection mechanisms for pharmaceutical products. https://www.technopolis-group.com/report/effects-of-supplementary-protection- mechanisms-for-pharmaceutical-products/. Last accessed 22 Feb 2021\n\nTechnopolis (May 2018b) Effects of supplementary protection mechanisms for pharmaceutical products. http://www.technopolis-group.com/wp-content/uploads/2018/06/2718-Technopolis- report-on-supplementary-protection-mechanisms.pdf. Last accessed 22 Feb 2021\n\nThe Council for Trips Extension of the Transition Period Under Article 66.1 of the Trips Agreement for Least Developed Country Members for Certain Obligations with Respect to Pharmaceutical Products (6 November 2015), World Trade Organization IP/C/73\n\nTimmermans K (2007) Monopolizing clinical trial data: implications and trends. PLoS Med 4:e2 U.S. Federal Trade Commission, 'Emerging Health Care Issues: Follow-on Biologic Drug Com- petition' (FTC, June 2009). https://www.ftc.gov/reports/emerging-health-care-issues-follow- biologic-drug-competition-federal-trade-commission-report. Last accessed 22 Feb 2021\n\nWHO (2012) WTO, WIPO Trilateral Study Promoting Access to Medical Technologies and Innovation, 64 https://www.wipo.int/policy/en/global_health/trilateral_cooperation.html. Last accessed 22 February 2021\n\n‘Meaning of Flexibilities’ http://www.wipo.int/ip-development/en/agenda/flexibilities/\n\nWIPO,", "n_tokens": 358, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-204-3", "doc_id": "medicine_vaccine_book", "page": 204, "text": "meaning_of_flexibilities.html. Last accessed 23 February 2021\n\nWTO, ‘WTO Members Welcome Entry Into Force of Amendment to Ease Access to Medicines’ (30 January 2017). https://www.wto.org/english/news_e/news17_e/heal_30jan17_e.htm. Last accessed 23 Feb 2021\n\nWTO ‘TRIPS Council Discussion on Access to Medicines: Developing Country Group’s Paper’ (World Trade Organization, 20 June 2001) IP/C/W/296, paras 39–40. https://www.wto.org/ english/tratop_e/trips_e/paper_develop_w296_e.htm. Last accessed 23 Feb 2021\n\n199", "n_tokens": 163, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-205-0", "doc_id": "medicine_vaccine_book", "page": 205, "text": "200\n\nE. ‘t. Hoen\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 173, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-206-0", "doc_id": "medicine_vaccine_book", "page": 206, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the Emergence of a Global Law\n\nCalixto Salomão Filho and Vitor Henrique Pinto Ido\n\nAbstract This article seeks to repurpose the relation between courts and IP law, avoiding describing them as a purely neutral and unidimensional process whereby ‘courts apply IP law’. Based on two cases from Brazil (Trastuzumab and Sofosbuvir), the article argues that the role of courts in implementing TRIPS flexibilities is in itself a factor that determines or at least influences the behavior of actors in the field. As such, courts are not arenas, but actors that influence compe- tition and restructure markets. This pushes for the recognition that patent use and patent abuse, including practices in patent filings such as evergreening and sham litigation, are legal phenomena that ought to be regulated differently by law. Instead of formalist positivism, law should be more thoughtful of socio-economic conse- quences and of existing contexts. This aims at addressing economic structures rather than reinforcing them in cases pertaining to pharmaceutical patents.", "n_tokens": 242, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-206-1", "doc_id": "medicine_vaccine_book", "page": 206, "text": "The article concludes by proposing an interpretation of IP law which is integrated with competition law principles, both oriented towards, and based on, public interest provisions. Overall, the article posits that this is a better framework than regarding IP and competition law as ‘complementary’ and to address issues of how courts may be the two legal fields. misused by economic actors due to fragmentation of Furthermore, such endeavors are part of an emerging body of what some could even call “global law”; in this case, it means a nod for the transnational implications of national IP cases beyond its original realm.\n\nC. S. Filho (*) · V. H. P. Ido Faculty of Law, University of São Paulo, São Paulo, Brazil\n\nSouth Centre, Geneva, Switzerland\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_8\n\n201", "n_tokens": 219, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-207-0", "doc_id": "medicine_vaccine_book", "page": 207, "text": "202\n\nC. S. Filho and V. H. P. Ido\n\n1 Introduction\n\nCourts are prominent actors in the implementation of intellectual property (IP) law. 1 Apart from being enforcers of the existing law, they also delineate the contours of IP protection, including the definition of patentability criteria, scope of protection of IPRs, exclusions of patentable subject and conditions for enactment of injunctions. 2 This is an intrinsic characteristic of how IP law is conceived and how it operates, rather than a process of politicization of courts or an expansion of their role beyond their competence. 3 By doing so, courts inevitably affect competition and play a major role in the implementation of TRIPS in national jurisdictions, often with transnational consequences.\n\nScholarship’s attention on the role of judicial and quasi-judicial courts in IP has risen, 4 including advocates for courts to be the best suited for balancing IP policies 5 and ample discussions on specialized IP courts. 6 Judicial enforcement of IP has become a common, yet very questionable, variable for assessing what is understood as the level of IP protection in a given country. 7 It has also deserved emerging", "n_tokens": 234, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-207-1", "doc_id": "medicine_vaccine_book", "page": 207, "text": "1 While judges in some jurisdictions may be typically more prominent in such role—such as common law systems, which give more importance on precedents—, the last decades saw an unquestionable rise in the number of courts dealing with IP. This process has both a geographical dimension and an institutional one. Geographically, there has been a “globalization” of jurisdictions deciding upon IP and pharmaceutical cases. Institutionally, there has been a stark expansion of actors deciding IP cases, such as quasi-judicial independent IP appellate bodies, competition authorities’ decisions and IP specialized courts. 2 They are not the only relevant actors, as administrative border agents, police officers and others all concretely decide on issues such as what is a counterfeit. Nonetheless, courts have a specifically defining role as they provide the basis for the applicability of laws and regulations “on the ground”. 3 In this sense, when adjudicating IP cases, judges do not create, but rather apply, law. The issue is that this process is by default not a mere formalistic endeavor, and the exact details of IP law necessarily depend upon such interpretation. In many jurisdictions, where public considerations are directly embedded into IP law, this adjudication cannot be dissociated from a broader spectrum of public principles, including health and socio-economic development. Acknowledging this particu- lar feature of IP law is not the same as advocating for courts to disregard", "n_tokens": 297, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-207-2", "doc_id": "medicine_vaccine_book", "page": 207, "text": "precedents, decide against the law or over-expanding their own competence. As this paper will point out in more detail, the refusal to acknowledge such role, including when courts do not rule, is in itself a factor that impacts competition, generates judicial uncertainty and compromises the whole IP system. Also please see Sect. 2 of this article for a more comprehensive argument on the role of courts in IP. 4 For a comprehensive overview of developed countries, see Geiger et al. (2018). 5 Burk and Lemley (2013) (on the specific case of the USA, acknowledging its failures and considering that courts are the most suitable for patent law reform by adopting different interpre- tations according to different industries). 6 de Werra (2016). Published in: Specialised Intellectual Property Courts - Issues and Challenges, Global Perspectives for the Intellectual Property System, Issue Number 2: CEIPI-ICTSD. 2016, p. 15-41. Available at SSRN: https://ssrn.com/abstract¼2761209 (drawing positive and negative arguments for their implementation, noting that they cannot be recommended in all circumstances). 7 In those cases, “judicial enforcement” simply means the enforcement of pro-IP holder interests, without the inclusion of public interest provisions. As such, these rankings may wrongly give the impression that enforcement of IP means exclusively the protection of private rights. It is not a", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-208-0", "doc_id": "medicine_vaccine_book", "page": 208, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nimportance by the WIPO, the South Centre and other international organizations as key players in implementing IP norms, each with a distinct approach. 8\n\nIn particular, the consequences of court rulings to access to medicines is a sensitive topic, particularly if decisions are taken prioritizing exclusively IP holder interests. A single court ruling (or sometimes lack thereof) may have huge conse- quences for public policies and the realization of rights, as IPRs may pose major barriers to competition and access to essential products. As such, it makes sense to craft a more comprehensive analysis of the role of courts in implementing or not the in-built TRIPS flexibilities 9 across jurisdictions.\n\nThis article seeks to repurpose the relation between courts and IP law, avoiding describing them as a purely neutral and unidimensional process whereby ‘courts apply IP law’. According to this view, the main issue of concern would be how to provide specific technical knowledge on IP for judges. Instead, this article aims at exposing that jurisdictional practices are themselves an element to interpret TRIPS flexibilities, as courts reshape markets and the extension of patent monopolies even when they decide not to take action. In this sense, courts apply IP and by doing so they are also mutually influenced by the market structures. define markets;", "n_tokens": 292, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-208-1", "doc_id": "medicine_vaccine_book", "page": 208, "text": "surprise that they are used as pressure tools for developing countries to adopt more stringent standards of protection. In reality, the process of enforcement is supposed to be a balancing between private and public interests and should be seen as an important policy space for countries to enact IP policies that are coherent with other goals such as public health and industrial development (see Li and Correa (2009). For the use of rankings, see, for instance, “create”, the U.S. Chamber Interna- tional IP Index, which includes numerous indicators on enforcement. The 2018 edition included new indicators, which “cover important evolving areas of IP rights, such as injunctive-style relief through the disabling of infringing content online, as well as the practical operation of a given national IP system. As the Index evolves, it is only natural that a greater focus be placed on the operational aspects of a national IP system. The new indicators seek to measure national efforts at coordinating IP rights enforcement”, among others (https://www.theglobalipcenter.com/wp- content/uploads/2018/02/GIPC_IP_Index_2018.pdf). Similarly, the International Property Rights Index (associated to the Property Rights Alliance, an explicitly pro-property organization) includes indicators such as “judicial independence”, “rule of law”, “protection of intellectual property rights” and “perception of IP protection” (https://www.internationalpropertyrightsindex.org/about). These rankings also find a", "n_tokens": 326, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-208-2", "doc_id": "medicine_vaccine_book", "page": 208, "text": "notable echo in older and criticizable views of the “Law and Finance literature”, which evaluated jurisdictions according to their capacity to secure private rights (See La Porta et al. (1998), pp. 1113–155). 8 The World Intellectual Property Organization (WIPO), for instance, has created its WIPO Judicial Institute (https://www.wipo.int/about-wipo/en/activities_by_unit/index.jsp?id¼1022). Technical including the European Patent Office assistance provided by many multilateral (EPO), the European Commission, the United States Patent and Trademark Office (USPTO) and the JPO (Japanese Patent Office) have reportedly increased attention to judges, offering trainings that often mirror their understandings of IP law to other jurisdictions. An example is the interna- tionalization of doctrines that are originally European, such as the “Swiss claims” or the need to protect “Markush claims” for pharmaceuticals. Other institutions seek an alternative approach, such as the South Centre, which focuses its activities on the full implementation of TRIPS flexibilities in relation to IP law (https://ipaccessmeds.southcentre.int/). 9 For an overview of the notion of TRIPS flexibilities and their implementation, see Correa (2016); see also Deere (2008).", "n_tokens": 300, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-208-3", "doc_id": "medicine_vaccine_book", "page": 208, "text": "institutions,\n\n203", "n_tokens": 3, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-209-0", "doc_id": "medicine_vaccine_book", "page": 209, "text": "204\n\nC. S. Filho and V. H. P. Ido\n\nFurthermore, other actors play crucial roles, including civil society organizations and lobbying economic pressures, 10 and dealing with them is another important dimen- sion of the role of courts. In summary, it means a broader understanding of their role, which is embedded in certain structures of thinking and socio-economic implications and pressures. As we wish to propose, this framework allows a different legal assessment of what in practice courts do and what economic consequences their own behavior bear. For instance, when a court does not rule or takes too long to rule an IP case, this in itself likely generates more judicial uncertainty than the content of the decision. Despite differences in how this understanding reverberates in concrete IP cases, a general takeaway is that this requires a different interpretation of IP law, as per below.", "n_tokens": 176, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-209-1", "doc_id": "medicine_vaccine_book", "page": 209, "text": "The structure of the article is as follows: after this overview, it provides some inputs for the reasons why courts, while implementing TRIPS flexibilities, can be considered to be channels of “structural change”. This serves as a theoretical premise to the analysis. It is followed by an assessment of the consequences of the legal utilization—both directly and indirectly—of a narrative that treats intellectual prop- erty protection as necessary for innovation. 11 This normative argument serves as a de facto tool for impeding evidence-based discussions on the competitive implica- tions of IP in concrete cases. In short, the threat of decreased innovation is used, even if sometimes implicitly, to impede a more balanced and real consideration of rights and interests involved in IP law.", "n_tokens": 156, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-209-2", "doc_id": "medicine_vaccine_book", "page": 209, "text": "It then exemplifies the overall argument above through the comparison of two cases in Brazil. They share the similarity of dealing with access to medicines curbed by high prices (due to, among other reasons, intellectual property rights), albeit with different profiles, courts and arguments. In both, the role of courts is paramount, not only as the ones defining the interpretation of legal principles and rules in IP law with regards to demands of access to medicines, but also as setters of expectations for competitors and society at large. Both medicines have been subject to patent disputes in the country, in a way that IP is not necessarily the only issue to be considered, but certainly a relevant one. The first case refers to a litigation that questioned prices on the selling of cancer biological medicine Trastuzumab to Brazilian public entities, particularly in light of a stark price discrimination between regular public purchases", "n_tokens": 184, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-209-3", "doc_id": "medicine_vaccine_book", "page": 209, "text": "10 The number of institutions, arenas and players engaging with the topic of IP has grown immensely since the TRIPS Agreement was enacted. In the IP and public health field, key actors include civil society organizations (such as Médécins sans Frontières—MSF Access Campaign) and industry representatives (International Federation of Pharmaceutical Manufacturers & Associ- ations—IFPMA). New organizations (such as the Medicines Patent Pool—MPP) have been created and also shape and influence the very interpretation and implementation of IP. The existing framework of global IP law and access to medicines is in many senses dependent on the work of these organizations. See Hein and Moon (2013) and Matthews (2011). 11 While the specialized literature has a lot of divergence, the transplantation of this discussion into a legal argument in IP cases tends to over-expand the scope of protection of patents in particular. Therefore, by shedding light on the possibility of another kind of relation, that of innovation that arises precisely from more access (to knowledge), and not from more monopolies (patents and other IPRs), it is possible to reassess the role of IP in legal rulings.", "n_tokens": 245, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-210-0", "doc_id": "medicine_vaccine_book", "page": 210, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nand purchases to enforce judicial decisions. The second case deals with the procure- ment of hepatitis C medicine Sofosbuvir and the price differentiation after a patent was granted and later suspended, which is evidence for possible anti-competitive excessive pricing and/or abuse of dominant position.\n\nFinally, the text provides some theoretical conclusions on the relation between courts and IP. It firstly proves that the role of courts in implementing TRIPS flexibilities is in itself a factor that determines or at least influences the behavior of actors in the field. As such, courts are not arenas, but actors that influence compe- tition and restructure markets. This pushes for the recognition that patent use and patent abuse, including practices in patent filings such as evergreening and sham litigation, are legal phenomena that can be at least partly regulated differently by law. In fact, by shedding light and putting all pieces of this interaction together, there is a need for a different interpretation of IP law. Theoretically, it means a law that is more thoughtful of socio-economic consequences and of existing contexts, which aims at addressing economic structures rather than reinforcing them.", "n_tokens": 258, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-210-1", "doc_id": "medicine_vaccine_book", "page": 210, "text": "The article concludes by proposing an interpretation of IP law which is integrated with competition law principles, both oriented towards, and based on, public interest provisions. Overall, we argue that this is a better framework than regarding IP and competition law as ‘complementary’ and to address issues of how courts may be misused by economic actors due to fragmentation of the two legal fields. Moreover, this interpretation is derived from international law, from the theoretical foundations of IP and competition laws, and from the historical development of substantive national provisions—and not a mere theoretical speculation. Furthermore, such endeavors are part of an emerging body of what some could even call “global law”; in this case, it means a nod for the transnational implications of national IP cases beyond its original realm.\n\n2 Assessing the Role of Courts in TRIPS Flexibilities As", "n_tokens": 168, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-210-2", "doc_id": "medicine_vaccine_book", "page": 210, "text": "Forms of Structural Change\n\nIn previous works, the authors have argued that the strong interplay between economic power and law are so pervasive that structural interventions are needed in order to prevent law from becoming a mere instrument of economic interests, and to instead promote broader societal goals. 12 A “neo-structuralist” approach 13 means that individual, moral(istic), and even institutional explanations are insufficient and even sometimes misleading. Therefore, efforts to ensure the full implementation of TRIPS flexibilities need to rely on a legal interpretation that is structural in the sense of taking into account the role of economic structures of pharmaceutical monopolies and ready to counter their negative consequences when needed. The approach\n\n12 Salomão Filho (2013a) and Salomão Filho and Ido (2019). 13 Salomão Filho (2015).\n\n205", "n_tokens": 177, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-211-0", "doc_id": "medicine_vaccine_book", "page": 211, "text": "206\n\nC. S. Filho and V. H. P. Ido\n\ngenerally proposes that, willingly or not, legal interpretation will either be accepting of the status quo (adopting compensatory mechanisms at most) or transformative in a structural way. This analysis provides some inputs for a legal proposal for the role of courts to be less formalistic—in its intimate, self-referred and negative connota- tion—and more mindful about structural intervention through the application of public values. Whether courts wish to acknowledge this role or not, adjudicators will invariably perform it.", "n_tokens": 121, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-211-1", "doc_id": "medicine_vaccine_book", "page": 211, "text": "Specifically on the topic of TRIPS flexibilities, achieving broad access to med- icines for all knowingly demands structural reforms in the current R&D model for pharmaceuticals, a high-level policy commitment by governments to act boldly, and a major rethinking in the behavior of companies. 14 None of this is primarily a task of any courts around the world; none is exclusively a legal enterprise. Indeed, judges and decision-makers should operate within the realm of existing laws and have, in the majority of circumstances, a limited role for structural change. This is all true. However, it should equally be stressed that structural change is a task that includes courts and includes legal thinking. Legal interpreters need to rely, even if partly, on philosophical foundations and legal theories for the interpretation of concrete cases. Judges and adjudicators reflect certain viewpoints and distinct ideologies even if they do not acknowledge so. 15", "n_tokens": 196, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-211-2", "doc_id": "medicine_vaccine_book", "page": 211, "text": "Both considerations seem particularly relevant to IP and access to medicines, where notions of innovation, public interest and limits of monopolies are deeply intertwined and even part of ordinary legal arguments on IP. 16 Considering how the implementation of IP norms around the world since the TRIPS Agreement has been the result of a push by developed countries and their industries, 17 courts that adopt a formalist and limited approach will invariably reproduce the notion that IP needs to be expanded at all costs. This disregards that TRIPS flexibilities, including a focus on technological development and public health, are all primarily legal and legiti- mate tools. As such, if courts would strictly “follow the law”, they should enforce the", "n_tokens": 142, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-211-3", "doc_id": "medicine_vaccine_book", "page": 211, "text": "14 For a critical overview of the current R&D model, see Velásquez (2020). 15 For a compelling general critique, see Kennedy (1997); for an example of how courts may incorporate neoliberal values despite claims of impartiality, see Sanghera (2015), available at: https://www.opendemocracy.net/en/odr/unmasking-central-asias-neoliberal-judges/; for how a community of adjudicators and lawyers defines certain arguments in international arbitration and assumes a central role for a transnational legal order, see Dezalay and Garth (1996). 16 Examples would include the interpretation of the common clause on exception of patentability due to “public order”, dependent not only on an understanding of what “public order” means, but also how it is applicable in an analysis of a patent application. For an overview, see Bently (2011), pp. 315–347. Real cases show the need for courts to decide on multiple elements at once when faced with concrete cases, from patentability of living organisms to the limits posed by religious and morality laws to alleged obscene patent applications (see, for instance, Pankhuri and Shamnad (2018), available at: https://spicyip.com/2018/08/the-morality-of-sexual-pleasure-patent-office- training.html). 17 Sell (2003).", "n_tokens": 309, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-212-0", "doc_id": "medicine_vaccine_book", "page": 212, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nvalidity of TRIPS flexibilities, and be particularly aware of the socio-consequences to the public interest of patents and other intellectual property rights. 18 In other words, courts have the potential of de facto limiting the policy space of a country, and it is no surprise that so much effort is now given to the role of courts as part of the international economic architecture. 19\n\nIn developing countries, these considerations are even more evident for two reasons: on one hand, the material conditions of access to medicines are generally worse; 20 on the other, the majority of such countries contain constitutional and legal provisions that advocate for implementation of socio-economic rights (such as health) and development goals, often in more directive and transformative ways than the counterparts in industrialized economies. 21\n\nTherefore, courts’ stance on TRIPS flexibilities is of utmost importance, such as the position towards the validity of stringent patentability criteria for pharmaceuti- cals and the use of competition law to address anti-competitive practices in IP and health cases. Courts do not need to be “advocates” nor political actors to applying IP", "n_tokens": 242, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-212-1", "doc_id": "medicine_vaccine_book", "page": 212, "text": "18 This can be traced back to the very foundation of intellectual property law scholarship, such as that of Italian Tulio Ascarelli, with profound repercussions to Brazilian commercial law, among others. For Ascarelli (1970), p. 276. 19 Apart from intellectual property and TRIPS flexibilities, such considerations could be extended to multiple realms, such as international investment law (particularly investor-state dispute settle- ment—ISDS) and business and human rights litigation for environmental disasters, in which both pro-private biases and formalist views on jurisdictions and conflict of laws effectively lead to transnational economic deregulation. For notes on the impact of courts’ rulings in international economic governance, see Muir-Watt et al. (2019) (for a compilation of cases that redefine the boundaries of public and private, and highlight the increasing interdependence between national and international jurisdictions); and for a more theoretical account, Muir-Watt (2016), pp. 347–428. (“despite the contemporary juridification of international politics, private international law has contributed very little to the global governance debate, remaining remarkably silent before the increasingly unequal distribution of wealth and authority in the world. [...] According to the genealogy of private international law depicted here, the discipline has developed, under the aegis of the liberal divides between law and politics and between the public and the private spheres, a", "n_tokens": 303, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-212-2", "doc_id": "medicine_vaccine_book", "page": 212, "text": "form of epistemological tunnel-vision, actively providing immunity and impunity to abusers of private sovereignty.); see also Zumbansen (2012), pp. 899–925. 20 See the final report of the United Nations Secretary-General High-Level Panel on Access to Medicines (2016) for some considerations. The language agreed as part of the Sustainable Devel- opment Goals (SDGs), especially SDG 3 on health, should also be stressed: “Target 3.b.Support the research and development of vaccines and medicines for the communicable and non-communicable diseases that primarily affect developing countries, provide access to affordable essential medicines and vaccines, in accordance with the Doha Declaration on the TRIPS Agreement and Public Health, which affirms the right of developing countries to use to the full the provisions in the Agreement on Trade-Related Aspects of Intellectual Property Rights regarding flexibilities to protect public health, and, in particular, provide access to medicines for all.”. There is broad consensus on the need of specific, and often bolder action, in the context of developing countries. 21 See, for instance, the constitutional provisions that have been deemed, among other terms, “transformative” and “social”, including those of Brazil (1988), South Africa, (1996), Colombia (1991), Bhutan (2008) and India (1950), just to name a few remarkable examples. See, for theoretical discussions: Uprimny (2011); Bonilla Maldonado (2013); Mendes (2013), 272p; Iyer (2019), pp.", "n_tokens": 343, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-212-3", "doc_id": "medicine_vaccine_book", "page": 212, "text": "359–385; Hailbronner (2017), pp. 527–565.", "n_tokens": 20, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-212-4", "doc_id": "medicine_vaccine_book", "page": 212, "text": "207", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-213-0", "doc_id": "medicine_vaccine_book", "page": 213, "text": "208\n\nC. S. Filho and V. H. P. Ido\n\nlaw in a manner that is consistent with broader societal goals such as ensuring access to medicines. However, they sometimes refrain from doing so on such grounds. As we have noted before, the mere lack of decision is also a crucial feature in the lack of their implementation. 22 In this context, advocates for judicial adjudication as a purely neutral and technical process do not address the negative impact this very stance has or might have on access to medicines.\n\n3 Access and Innovation in Legal Discourse: From\n\nOpposition to Coexistence\n\nThere is one economic narrative that has profoundly influenced the debate on IP and access to medicines: the rhetoric whereby IP is an enabler of innovation, to the extent which it provides incentives for inventors, and therefore is also a prerequisite for access to future technologies. 23 In short, no access without IP. Importantly, this has been often converted into a self-standing legal argument, either underpinned or explicitly referred to, in multiple cases, without further consideration of historical and empirical circumstances of the real markets they address.\n\nThe objective of this section is not to delve deeply into the broader debate on IP and innovation, and how IP affects access to the outcomes of future and existing", "n_tokens": 261, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-213-1", "doc_id": "medicine_vaccine_book", "page": 213, "text": "22 The argument is also valid in the other direction: sometimes, measures taken by courts (such as investigations) have an indirect effect that is sufficient for social results. For instance, in the Hazel Tau case (2003), when the South African Competition Commission publicly announced that would sanction pharmaceutical company Glaxo-Smith-Klein (GSK) for the abuse of the exercise of its patent rights by charging excessive prices, a settlement was reached and no decision was taken. For an overview, see Knowledge Ecology International (KEI). CPTech’s 2003 reports for the RSA Competition Commission, in Hazel Tau et al. v GSK, Boehringer, et al. Available at: https://www. keionline.org/competition/2003-hazel-tau-tac. 23 For example, the director-general of the International Federation of Pharmaceutical Manufac- turers & Associations (IFPMA), Thomas Cueni, noted in a Financial times article on 17 May 2020 that “Patents, and IP more generally, are the main reason that there is such a strong innovation base to work from to find solutions” (Cueni, Thomas. Intellectual property is not a hindrance but a help to end Covid-19, Financial Times, available at: https://www.ft.com/content/e82dd07c-95c5-11ea- 899a-f62a20d54625). Another example of the utilization of this rhetoric is found in the official stance of the United States Trade Representative (USTR)’s Special 301 report of April 2020 “To promote affordable healthcare for American patients today and innovation to preserve access to the", "n_tokens": 362, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-213-2", "doc_id": "medicine_vaccine_book", "page": 213, "text": "cutting-edge treatments and cures that they deserve tomorrow, USTR has been engaging with trading partners to ensure that U.S. owners of IP have a full and fair opportunity to use and profit from their IP, including by promoting transparent and fair pricing and reimbursement systems”, available at: https://ustr.gov/sites/default/files/2020_Special_301_Report.pdf. Similarly, in a publi- cation by the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), it is noted that “A robust, time-limited system of patent protection is proven to facilitate development of, and access to, innovative pharmaceutical products and processes. In particular, a well- functioning patent protection system is a prerequisite for attracting finance for costly pharmaceu- tical research, given its high failure rates, by ensuring that successful innovation is rewarded”. Gawel (2016), pp. 45–53.", "n_tokens": 205, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-214-0", "doc_id": "medicine_vaccine_book", "page": 214, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\ninnovation, but to note how the conversion of this narrative into a legal argument is highly problematic. According to this view, less IP protection would necessarily lead to less innovation and therefore less access. This means that protecting IP would always be, according to this particular narrative, in the public interest. 24 Accord- ingly, if IPRs are to be anyhow limited or restricted—even when they were wrong- fully granted in the first place—this argument will consider that innovation will be hampered and, as a final result, access will be compromised. 25\n\nHowever, this assumption is remarkably questionable. For one, the role of IP in fostering innovation is far from clear. 26 Some markets are innovative and creative despite the lack of exclusivity rights, 27 and in many cases, IP is simply detrimental to innovation. A number of evidence-based studies propose that the barriers created", "n_tokens": 195, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-214-1", "doc_id": "medicine_vaccine_book", "page": 214, "text": "24 In this sense, it performs the same functional role that theories on IP as natural rights once had. Treating IP as a natural right tends to maximize its protection. Conversely, treating IP as a temporary monopoly granted by the State requires a public interest justification based on the incentives provided by it. The “IP as channel of innovation” argument leads to the same maximi- zation of IP as natural rights without needing to give away the notion that IP only exist to provide market incentives. It creates an overarching and somehow incontestable argument to consider that IP should always be expanded (in order to “achieve innovation”). This leads to very pragmatic consequences on the role of courts in IP law. When courts adopt fully this latter myth, the balancing of private and public interests in IP becomes a de facto imbalance gearing towards the private interest only. It becomes a tool for an adjudication that is incapable of properly taking into account public needs in the protection of IP. For a comprehensive critical analysis of patent law and history, which could include a reflection on the very adequacy of the “public and private balancing in IP”, see Pottage and Sherman (2010). 25 One such example is found among opposers of compulsory licensing, despite their recognition as a legal and legitimate tool under multiple international law instruments, including the WTO Doha Declaration on Public Health (2001). For instance, in a preliminary ruling on a class action", "n_tokens": 301, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-214-2", "doc_id": "medicine_vaccine_book", "page": 214, "text": "in Brazil requesting the compulsory licensing of medicine Kaletra (lopinavir/ritonavir) due to high prices, the judge considered that “issuing a compulsory license would trigger retaliation by the developed world and possible shortages of the drug, while the very capacity of domestic industry to produce the medicine in Brazil was also called into question”. See Costa et al. (2008). In a similar sense: “Patents benefit society in a number of ways, and although their specific role in each industry is unique, they are generally recognized for their ability to spur innovation. In the pharmaceutical industry, for example, patents are essential to motivating and directing future innovation, which generates new and better medicines for all. [...] The promise of immediate and improved access to brand name HIV/AIDS drugs is definitely alluring, but issuing or threatening a compulsory license has consequences. Compulsory licenses not only reduce foreign investment, they also impose costs related to litigation, safety, and efficacy.” Borowski (2009). http://ir.law.fsu.edu/lr/vol36/iss2/6. 26 Boldrin and Levine have famously argued against patents: “The case against patents can be summarized briefly: there is no empirical evidence that they serve to increase innovation and productivity, unless productivity is identified with the number of patents awarded – which, as evidence shows, has no correlation with measured productivity”. Boldrin and Levine (2013), pp. 3–22. Moreover, the importance", "n_tokens": 331, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-214-3", "doc_id": "medicine_vaccine_book", "page": 214, "text": "given to the number of patents as a measure of innovation has been challenged not only as inaccurate, but also representative of a process of financial speculation of patents as credits and even as financial assets. For such critique, see Kang (2020). 27 For an overview, see Darling and Perzanowski (2017). For a specific case, see Lemos and Castro (2012), on the tecnobrega music style in Northern Brazil as an example of an open business model which relies its success on the sharing of music without enforcement of copyrights.", "n_tokens": 119, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-214-4", "doc_id": "medicine_vaccine_book", "page": 214, "text": "209", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-215-0", "doc_id": "medicine_vaccine_book", "page": 215, "text": "210\n\nC. S. Filho and V. H. P. Ido\n\nby IP serve not as catalysts, but hinderances, of innovation. 28 Notions of “patent trolls” and “patent thickets”, where strategic patenting filing leads to an overlap of multiple IP rights that unfairly block competition, have become a major issue for contemporary markets. 29 As economist Joseph Stiglitz noted, following the US Supreme Court Myriad Genetics case (2013), which defined that isolated genes cannot be patented, “innovation has been accelerated, leading to better diagnostic tests [...] at much lower costs.” 30 Accordingly, it is possible to argue that markets without patents may be equally or even more innovative than those with IP protec- tion and simultaneously also conducive to better access conditions.\n\nFurthermore, for many accounts, IP has been historically an inefficient incentive at best. 31 The development processes of the overwhelming majority of now indus- trialized countries were based on copying strategies, national industrialization and the creation of innovation ecosystems that include know-how and skilled profes- sionals. In fact, IP has been deemed a limitation to development and innovation in most cases. 32 The innovation landscapes of highly innovative countries in current", "n_tokens": 260, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-215-1", "doc_id": "medicine_vaccine_book", "page": 215, "text": "28 See Heller (2010); Heller et al. (1998), pp. 698–701. For some, this means an IP system that does not deliver what it originally promises: “Intellectual Property rights are becoming increasingly badly configured in the developed world, leading to a stifling of innovation, distortions in the direction of innovation, and a reduction in the benefits which accrue from any innovation that occurs. Many of these failures arise because there is, especially under currently prevalent IPR regimes, no clear relationship between the social returns to innovation and the private returns. The proliferation of me-too drugs, the increase in patent hold-ups and similar excesses buttress the argument that the IPR system in the developed world is poorly configured.” Baker et al. (2017), available at: http://ip-unit.org/wp-content/uploads/2017/07/IP-for-21st-Century-EN.pdf. 29 See Matthews and Gurgula (2016). Queen Mary School of Law Legal Studies Research Paper No. 233/2016. Available at SSRN: https://ssrn.com/abstract¼2779014. 30 Stiglitz (2017), available at: https://www.theguardian.com/business/2017/oct/18/intellectual- property-laws-demand-a-21st-century-solution. 31 “Both theory and the preponderance of historical evidence suggest that development, at least in its initial stages, is best promoted by a weaker intellectual property regime than reflected in TRIPS, or at the minimum a markedly different regime.” Baker et al. (2017), available at: http://ip-unit.org/", "n_tokens": 377, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-215-2", "doc_id": "medicine_vaccine_book", "page": 215, "text": "wp-content/uploads/2017/07/IP-for-21st-Century-EN.pdf. 32 See, for instance, the landmark book Schiff (1971). Irregular or protection exclusively for nationals was also a feature in the United States, Germany and the United Kingdom. The studies on the socio-economic transformation of Japan, and then the Asian Tigers and more recently China, also prominently play a crucial role in a developmental State process that had little to do with the protection of foreign IP, relying instead on imitation and adaptation processes, at least in its earlier stages. For instance, Japan provided protection for national applicants but low protection for foreigners in the decades after WW2—a strategy later emulated by other late industrializing regions with high levels of innovation, such as South Korea and Taiwan. This is all relatively well-known and increasingly defended as means to assess even current practices by the very same players that actively put pressure in the international arena for developing countries to adopt higher standards of IP protection against what they have done in the past and also what they continue on doing. See, for instance, Chang (2002) and Amsden (2001).", "n_tokens": 238, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-216-0", "doc_id": "medicine_vaccine_book", "page": 216, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\ntimes are also not reliant on IP alone, 33 even if the extent of its impact is debatable. In fact, even among its strong defenders, there is a general consensus that IP is not necessarily conducive to innovation at all times, 34 and that in particular the effects of patents differ between industrialized and developing countries. 35 An example of the detrimental consequences to access without accruing any benefits of innovation is the early implementation of the TRIPS Agreement in Brazil in 1996, which can be contrasted with the relative positive experience of India. 36", "n_tokens": 132, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-216-1", "doc_id": "medicine_vaccine_book", "page": 216, "text": "33 Highly innovative countries do not adopt a laissez-faire approach and contain enormous funding for basic research, different research grants and direct investments alike. Examples include massive investments by DARPA and BARPA US agencies. For an assessment of the role of the State in innovation and the economy more broadly, see Mazzucato (2013). 34 See, for instance, Fink and Raffo (2019). 35 IP may possibly serve as an incentivizing mechanism in industrialized countries with a robust pharmaceutical industry already in place, with proper financial mechanisms, large public grants in early stages of research and research institutions and universities with large capacity and expertise. It will however not produce such an effect in countries with different profiles, and the historical global evidence in developing countries seems very clear in that regard. In summary, the already contested effects of IP towards innovation are even less compelling in the Global South, precisely where issues of access have been the most pressing and negative. The fact that HIV treatments were effectively rendered available in African countries around 10 years after they were available, leading to the unnecessary death of literally millions of lives, is no overstatement. For some broad considerations, see Cimoli et al. (2014). For a defense of the idea that prices should necessarily be lower in developing countries, and dissociated from any notion of compensation for investments, see Salomão Filho", "n_tokens": 288, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-216-2", "doc_id": "medicine_vaccine_book", "page": 216, "text": "(2007), pp. 160–161. 36 Brazil and India are among the very few countries in the Global South which have developed solid national generic industries (public and private). In both countries, the creation and consoli- dation of national pharmaceutical industries took place in the absence of IP incentives in the mid-twentieth century. In fact, similarly to the majority of the Global South, laws had been amended as to remove pharmaceutical patents from its national laws, a clear industrial and developmental policy measure. While the lack of IP was definitely not the only element that enabled the rise of pharmaceutical industries, they were seen as a clear barrier to the development of emerging industries. In Brazil, public laboratories such as Farmanguinhos and Butantã Institute play a crucial role in ensuring manufacturing of vaccines and medicines at affordable prices, as well as world- known R&D and public health research. India was able to consolidate the largest generic pharma- ceutical market of the world and is still lauded as a prime example of success, deemed the “pharmacy of the [developing] world”. Nonetheless, despite relatively comparable benchmarks, the implementation of TRIPS led Brazil and India to remarkably different paths. While Brazil opted to enact an Industrial Property Law in 1996, not fully enjoying the crucial TRIPS flexibility to only recognize pharmaceutical patents in 2001, India used it fully until the latest possible deadline in its case (2005). A", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-216-3", "doc_id": "medicine_vaccine_book", "page": 216, "text": "major promise of the proponents of the Industrial Property Law of 1996 in Brazil was the need to “modernize” the national system and “promote investments and innovation”. Yet, the granting of pharmaceutical patents in Brazil is overwhelmingly composed of foreign applicants, and combined with the lack of other policy incentives for the national industry, the result was a major negative impact in terms of its industrial capacity. It also has no signs of innovation output growth at all in the pharmaceutical sector. In fact, the new patent system created disincentives for generic companies due to their legal risks: as almost all of those benefitting from patents were foreign applicants, the investment in R&D in Brazil for pharmaceuticals actually declined and many generic firms are said to have become particularly conservative in their business practices, delaying competition even further. Even if the majority of the Indian companies are not lead innovators in the", "n_tokens": 180, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-216-4", "doc_id": "medicine_vaccine_book", "page": 216, "text": "211", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-217-0", "doc_id": "medicine_vaccine_book", "page": 217, "text": "212\n\nC. S. Filho and V. H. P. Ido\n\nFinally, there are also particular issues with any direct association between IP and innovation in legal thinking. The TRIPS Agreement and many national laws note that IP requires a constant balancing between public and private, the public value pertaining to access to medicines being one of paramount importance. 37 Patents are granted taking into account the public interest related to the disclosure of the invention and competition; they are an exceptional, limited and temporary legal bundle of exclusivity rights granted by the State solely in, and to the extent which it favors, the public interest. 38 As a consequence, the impediments created by IP as barriers to access should always be taken into account in the interpretation of concrete cases more prominently.", "n_tokens": 155, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-217-1", "doc_id": "medicine_vaccine_book", "page": 217, "text": "Indeed, the pharmaceutical sector is a particular and very sensitive case. On one hand, R&D investments are higher than most other industries, and risks are larger, with few successful products out of a much larger pipeline of candidates. On the other, in this field, there is much more public investment in R&D (in many cases the main investment is public not private) because its products are or at least should be essential goods, as they directly relate to health, sometimes as a life or death dilemma. Perhaps curiously, these arguments have been utilized to sustain opposite views: both the need for less or no patents (prioritizing access) and for more patents (prioritizing innovation). In light of the overview above, the problem with the debate framed in such a way is that it reinforces a questionable direct relation between IP, innovation and access.\n\nMany have empirically exposed, for instance, that the enactment of compulsory licensing has not had detrimental effects to foreign investment and has not undermined innovation overall, 39 and successful cases have drastically reduced prices and therefore enhanced access to medicines. Additionally, the global com- munity increasingly acknowledges that a model based only on patent protection is", "n_tokens": 240, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-217-2", "doc_id": "medicine_vaccine_book", "page": 217, "text": "pharmaceutical field, they have proven remarkably successful in ensuring access to medicines worldwide. Its economic importance to the country is also huge. See, for comparisons and analyses of the political economy of such countries, Shadlen (2017) and Vanni (2020). 37 Articles 7 and 8, TRIPS Agreement: “Article 7 Objectives.The protection and enforcement of intellectual property rights should contribute to the promotion of technological innovation and to the transfer and dissemination of technology, to the mutual advantage of producers and users of technological knowledge and in a manner conducive to social and economic welfare, and to a balance of rights and obligations Article 8. Principles 1. Members may, in formulating or amending their laws and regulations, adopt measures necessary to protect public health and nutrition, and to promote the public interest in sectors of vital importance to their socio-economic and technological development, provided that such measures are consistent with the provisions of this Agreement. 2. Appropriate measures, provided that they are consistent with the provisions of this Agreement, may be needed to prevent the abuse of intellectual property rights by right holders or the resort to practices which unreasonably restrain trade or adversely affect the international transfer of tech- nology”. For the effective implications of this tension in various countries and situations, see Dreyfuss and Rodríguez-Gavarito (2014). 38 In light of these", "n_tokens": 278, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-217-3", "doc_id": "medicine_vaccine_book", "page": 217, "text": "considerations, it makes sense to conceive IP in terms of bundles of rights instead of an absolute and unitary right. 39 For example, Inthira et al. (2011), p. 7:28.", "n_tokens": 44, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-218-0", "doc_id": "medicine_vaccine_book", "page": 218, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nnot the best incentive for innovation in the pharmaceutical sector, and alternatives exist. 40 For example, Amy Kapczynski compellingly describes the open science network of the Global Influenza Surveillance and Response System (GISRS), where “a global influenza virus-sharing network that has for decades produced critically important information goods, at significant expense, and in a loose-knit group—all without recourse to IP”, 41 which both responds better to societal health needs and does not treat innovation and access as a trade-off.", "n_tokens": 133, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-218-1", "doc_id": "medicine_vaccine_book", "page": 218, "text": "The global initiatives seeking the development and subsequent “equitable and affordable” access to Covid-19 vaccines and treatment, treating them as “global public goods” and as a “people’s vaccine”, 42 with support by key actors such as the European Union and China, have highlighted the needs for collaborative efforts. Unprecedented funding and multiple actions have been taken, including the creation of the voluntary WHO Covid-19 Technology Access Pool on the basis of a proposal by Costa Rica, 43 public international pledges for more resources, 44 as well as private pledges for making IP-protected technologies related to Covid-19 free of charge. 45 It highlights a possible new approach to global pharmaceutical R&D, not based on competition, but rather on intense sharing of information, which may produce faster and much more accessible outcomes in terms of health products.", "n_tokens": 171, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-218-2", "doc_id": "medicine_vaccine_book", "page": 218, "text": "40 It is not a surprise that calls for a renewed R&D model for pharmaceuticals are a constant demand in international discussions. See, for instance, Velásquez and Seuba (2011) (calling for a mandatory international agreement on pharmaceutical R&D at the World Health Organizaation); Stiglitz and Jayadev (2010), pp. 217–226 (“promoting prizes over patents; directing innovation toward socially beneficial outputs by adopting some form of value-based pricing; publicly funding clinical trials to reduce conflicts of interest while reducing costs; and actively managing frontier technologies to maximize positive social spillovers”). Proposals on prizes are among the most common alternative, the proposed Health Impact Fund—HIF (https:// at healthimpactfund.org/). Nowadays, alternative R&D models do exist for neglected diseases, such as the successful non-profit organization Drugs for Neglected Diseases Initiative (DNDi), which has already achieved approved medicines for neglected diseases under substantially lower R&D costs if compared to large transnational pharmaceutical firms for most diseases (https://www.dndi.org/). CEPI—Coalition for Epidemic Preparedness Innovation (https://cepi.net/), founded in 2017, may also serve as an alternative model for financing future vaccines, including for Covid-19. It is currently funded by industrialized countries and charities such as Bill and Melinda Gates Founda- tion and the Wellcome Trust. Unlike DNDi, the exact access conditions in case of a", "n_tokens": 328, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-218-3", "doc_id": "medicine_vaccine_book", "page": 218, "text": "successful candidate are however yet unclear and subject to debates. 41 Kapczynski (2017) Available at: https://scholarship.law.cornell.edu/clr/vol102/iss6/3. 42 For an analysis of the debate and how it has been partly incorporated (albeit with major limitations) into the 73rd World Health Assembly Resolution “Response to Covid-19” in 2020, see Syam et al. (2020). 43 See WHO COVID-19 Technology Access Pool (C-TAP): https://www.who.int/emergencies/ diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/covid-19-tech nology-access-pool. 44 See European Commission Press Release. “Coronavirus Global Response: €7.4 billion raised for universal access to vaccines”. 4 May 2020, available at: https://ec.europa.eu/commission/ presscorner/detail/en/ip_20_797. 45 See Open Covid Pledge: https://opencovidpledge.org/.", "n_tokens": 242, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-218-4", "doc_id": "medicine_vaccine_book", "page": 218, "text": "least\n\nin academia. See, for instance,\n\n213", "n_tokens": 10, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-219-0", "doc_id": "medicine_vaccine_book", "page": 219, "text": "214\n\nC. S. Filho and V. H. P. Ido\n\nAgain, in this sense, a more efficient approach that may achieve more innovation and broader access. 46\n\nFinally, a caveat to the association between IP and innovation refers to the real costs of R&D, which are deeply non-transparent, and where, as noted before, the role of public funding is pivotal. 47 It challenges once again the assumption of a necessary trade-off, rendering explicit instead the possibility of achieving a coexistence between access and innovation. More transparency on the pharmaceutical sector could enable courts to rely not on the general, abstract notion that IP is conducive to innovation, and instead make an empirical assessment of, for instance, how much public funding the medical product received or not, how the final net pricing has been fixed, and the exact socio-economic repercussions of a patent or other IP to the market. This would mean a better balance between private and public interest in IP and access to medicines.\n\nIn summary, this section aimed at presenting two important points for adjudica-\n\ntors dealing with IP and access to medicines to consider:\n\n1. arguments that entangle the protection of IP with innovation and access are an improper interpretation legal technique, which disregards the socio-economic and developmental implications of IP as much as it tends to limit the role of the public interest in IP. 48", "n_tokens": 293, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-219-1", "doc_id": "medicine_vaccine_book", "page": 219, "text": "2. access and innovation are not a necessary trade-off: under many (and perhaps most) circumstances, collaborative and deeply competitive markets are more inventive and also provide better access conditions. As a conclusion, adjudication in IP and access to medicines calls for an evidence- based and thoughtful analysis of what is really at stake in a particular case. From a legal point of view, the broader pharmaceutical sector regulation can be interpreted", "n_tokens": 87, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-219-2", "doc_id": "medicine_vaccine_book", "page": 219, "text": "46 For a proposal, see Mazzucato and Torreele (2020), available at: https://www.project-syndicate. org/commentary/universal-free-covid19-vaccine-by-mariana-mazzucato-and-els-torreele-2020-04. 47 While pharmaceutical companies may insist some of this information is trade secret (therefore legally protected), much of this data is actually not. A landmark Resolution at the 72nd World Health Assembly (WHA/72.8) agreed on the need for more transparency in the pharmaceutical industry, including net prices, but falling short of including specific commitments to the transpar- ency of R&D costs. Moreover, much attention has been given to the role of public funding in pharmaceutical innovation, particularly in earlier stages, which is neither recognized nor reflected in safeguards in terms of affordability and accessibility for the very public that financed it in the first place. For an overview of existing literature, see Vieira and Moon (2019), available at: https://www. knowledgeportalia.org/public-funding-of-r-d; Vieira and Moon (2020), available at https://www. knowledgeportalia.org/cost-of-r-d. 48 Rather than conclusive remarks on the relation between intellectual property and innovation—or more precisely, the multiple relations between IP, access and innovation—, the crucial point to be made is that courts have no clear evidence to decide based only on the premise that IP is a necessary element to achieve innovation. However, this is exactly how many courts are inclined to argue;", "n_tokens": 349, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-219-3", "doc_id": "medicine_vaccine_book", "page": 219, "text": "or, at least, by exacerbating the role of IP in innovation without a proper balance with public interests related to access, courts will also be inclined to maximize IP protection in the detriment of all other stakeholders, patients included. Therefore, as a conclusion, it is necessary to disentangle IP and innovation as separate categories, with a direct impact to legal interpretation.", "n_tokens": 77, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-220-0", "doc_id": "medicine_vaccine_book", "page": 220, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nin a way that secures both access and innovation, and not as a trade-off as a departing point. The following section attempts to exemplify how a legal rationale in that sense could take place, and what may happen when this is not taken into account. By doing so, it will also be possible to reflect on what role do courts have in TRIPS flexibilities' implementation.", "n_tokens": 100, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-220-1", "doc_id": "medicine_vaccine_book", "page": 220, "text": "4 Trastuzumab High Price Litigation in Brazil\n\nTrastuzumab (sold under brand name Herceptin) is a groundbreaking medicine for the treatment of breast cancer, listed as essential medicines by the World Health Organization (WHO). 49 Breast cancer is a disease that kills thousands of persons, especially women, yearly around the world. In Brazil alone, 53.680 cases were reported in 2013, and more than 56.000 in 2014. Trastuzumab was developed by Genentech, a pharmaceutical company based in San Francisco, United States, which later licensed to Swiss pharmaceutical 50 company F. Hoffmann-La Roche (hence- forth Roche) for US$40 million upfront, later sharing royalties with Genentech. 51 In practice, Roche is the owner of patents related to the drug and manages them. According to a Forbes article on 28 August 2019, Trastuzumab “is the leader in the breast cancer drugs space with annual sales of around $7 billion”, accounting for about 15% of the overall profits of Roche yearly. 52\n\nGiven how essential the medicine is 53 and its very high prices overall, various concerns about access to Trastuzumab have been highlighted in multiple jurisdic- tions around the world by civil society organizations. The production cost of the medicine is reported to be around US$240 for a 1-year supply. 54 Nonetheless, as reported by Médécins sans Frontières in 2017, Trastuzumab’s annual prices were set at around US$ 38 365 for the private sector and US$ 15 735 for the public sector in", "n_tokens": 330, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-220-2", "doc_id": "medicine_vaccine_book", "page": 220, "text": "49 World Health Organization (2019). 50 Grupo Direito e Pobreza (Law and Poverty Group) (2014). 51 Hu et al. (2020). 52 Forbes (2019), available at: https://www.forbes.com/sites/greatspeculations/2019/08/28/can- roches-blockbuster-drug-herceptins-sales-grow/#62da696a42e5. 53 In fact, from a competition perspective, all cancer drugs are essential in terms of the demand side, given the severity of the disease. As it is literally a matter of death or life, the equilibrium point between offer and demand is drastically influenced by a hugely inelastic demand. This means that structurally such drugs tend to be highly priced under purely market conditions, and therefore particular attention to potential competitive abuses is necessary. In other words, this means a careful assessment of pricing and how offer takes place. 54 See Hoen (2019) Strong call for transparency on medicine prices, cost of R&D at WHO Fair Pricing Forum. Medicines Law and Policy https://medicineslawandpolicy.org/2019/04/strong-call- for-transparency-on-medicine-prices-cost-of-rd-at-who-fair-pricing-forum/.\n\n215", "n_tokens": 280, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-221-0", "doc_id": "medicine_vaccine_book", "page": 221, "text": "216\n\nC. S. Filho and V. H. P. Ido\n\nSouth Africa, where patents will only expire in 2033. 55 Brazil, as we will expose in more details, prices were also extremely high: unaffordable for patients and unsustainable for the public budget. It is further relevant to note that the basic patent of Trastuzumab has expired in many other countries, including the USA. In both USA and Europe, there are already biosimilar versions available in the markets, which contributes to reducing prices. In Brazil, due to the patent extension term for cases of backlog of patent applications (provided for by Article 40, sole paragraph, of the Industrial Property Law (Law 9279/1996) and currently pending constitution- ality ruling at the Federal Supreme Court 56), the patent will not expire until 16 June 2028. 57\n\nHowever, even the lack of patent is no guarantee of reduced prices per se. In India, where patent oppositions had been filed, Roche withdrew patent applications on Trastuzumab. Still, the company has relied on litigation against biosimilar pro- ducers through India's drug regulatory body, which effectively enables Roche to be the sole provider of the medicine in the country as well. 58 This has been taken to the Indian Competition Commission as a possible abusive conduct for stalling the approval of generic drugs. 59", "n_tokens": 290, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-221-1", "doc_id": "medicine_vaccine_book", "page": 221, "text": "These facts are important evidence to highlight that high prices of Trastuzumab are not only caused by its uniqueness, as there are already biosimilar medicines available in international markets, and that the balancing between profits and health seem to be radically unaligned. The similarity of high prices around the world further denotes a tendency of monopoly pricing and abuse of patent.\n\nThe medicine was registered by the Brazilian regulatory agency ANVISA as early as 1999 and was incorporated as a treatment provided for by the public health", "n_tokens": 105, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-221-2", "doc_id": "medicine_vaccine_book", "page": 221, "text": "55 See MSF Global day of action against Roche’s inhumanity #RocheGreedKills. Press Release, 6 February 2017 https://msfaccess.org/global-day-action-against-roches-inhumanity- rochegreedkills. 56 Direct Unconstitutionality Claim (ADIN 5529). The judgment is expected to scrutinize whether the mentioned Article 40, Sole Paragraph of the Industrial Property Law is constitutional or not. It provides an extension of patent terms due to patent backlog by establishing that a patent has a minimum term of 10 years of protection. Since the general term is 20 years, any patent application procedure that lasts longer than 10 years leads to an extension in the overall term of protection. However, the competition effects of such extensions are dramatic. The strongest interpretation of Brazilian constitutional legal system and the majority of commentators seems to note that such legal provision is unconstitutional—similar to provisions on pipeline patents, also not yet judged by the Brazilian STF. In this sense, it becomes clear how it is important to acknowledge how the lack of action by the court—in such cases by refraining from deciding—is a central piece in the under- standing of their role in the implementation of patents in Brazil, and how they negatively affect the implementation of TRIPS flexibilities. 57 According to the analysis by the Law and Poverty Research Group, University of São Paulo, the first known patent that refers to Trastuzumab was filed on 3 November 2008; its unionist", "n_tokens": 311, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-221-3", "doc_id": "medicine_vaccine_book", "page": 221, "text": "priority dates back to 16 June 2008. See Grupo Direito e Pobreza (Law and Poverty Group) (2014), p. 6. 58 See MSF Access Campaign Global day of action against Roche’s inhumanity #RocheGreedKills (2017), https://msfaccess.org/global-day-action-against-roches-inhumanity-rochegreedkills. 59 Competition Commission of India. Case No. 68 of 2016—Roche—Mylan Biocon CCI Order 68 of 2016.", "n_tokens": 113, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-222-0", "doc_id": "medicine_vaccine_book", "page": 222, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nsystem SUS in 2012. Cancer prevention, detection, treatment and control are all covered by the public health system. Nonetheless, diminishing prices was a condi- tion for effective access to take place after its incorporation as a registered medicine paid by the SUS. During that occasion, and discounted taxes, prices of Trastuzumab were 62% higher than international price average and 115% of the lowest reported international price (surprisingly or not, in the United States). 60\n\nPublic procurement bids were conducted by the Ministry of Health in order to generate economies of scale, later distributing to State Health Secretaries under Brazilian federalist system. After direct negotiations with Roche, prices were reduced from R$7.860,26 per dose, charged in 2007, to R$3.446,89 in 2012 (without taxes, prices in Brazilian Real). However, State Health Secretaries have also been obliged through individual health claims, to provide Trastuzumab. This is a conse- quence of Brazil’s widespread “judicialization of health”, which enables individuals to go to courts demanding specific medicines and treatments, also obliging public entities to provide them regardless of costs in the majority of cases. 61 In practice, this means that there were two main routes for access to Trastuzumab: via the general", "n_tokens": 292, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-222-1", "doc_id": "medicine_vaccine_book", "page": 222, "text": "60 Grupo Direito e Pobreza (Law and Poverty Group) (2014). 61 This is a direct translation from the Portuguese “judicialização da saúde”, or “judicialización” in Spanish. Brazil's legal system is characterized by an ample recognition of the right to health, including universal health system, the SUS, which are both constitutionally protected (Articles 6 and 196, Federal Constitution of Brazil, 1988). This has been interpreted as a direct constitutional mandate which allows thousands of individual claims for medicines and treatments to reach courts, which have been in general granted in almost all cases, even experimental treatments and no matter the costs. The process has been also identified in other Latin American countries, particularly Colombia, Argentina and Costa Rica. In common, public budgets are overwhelmed by such claims, which are in certain cases a very large proportion of overall budgets. In 2019 and 2020, two landmark rulings by the Supreme Federal Court (STF), the country’s highest judicial instance, drastically reduced such claims as to avoid an overburden for health systems, in light of the recognition that individual claims affected the social realization of health rights. For a critical overview, see Kapczynski (2019), available at: http://humanityjournal.org/issue10-1/the-right-to- medicines-in-an-age-of-neoliberalism/. She notes that “The budgetary impact of the right to med- icines cases has unsurprisingly been significant. According to government figures,", "n_tokens": 332, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-222-2", "doc_id": "medicine_vaccine_book", "page": 222, "text": "from 2010–2016, the federal government spent 4.4 billion reais ($1.4 billion) to comply with judicial decisions, with most of this going to provide medicines.49 This sum has risen sharply over time, along with the number of cases.50 In 2016 alone, the federal government spent 1.2 billion reais ($400 million) to satisfy judicial mandates.51 The bulk of suits for access to medicines arises at the state level, where data are harder to come by. But analysis has found that states and municipalities may be spending anywhere from 3 to 10 per cent of their health budgets to satisfy right to health cases, and as much as 22 per cent of their medicines budgets to fulfill judgments mandating access to medicines.”. She further notes the impact of patents as one of the main causes for such high costs: “Why are the medicines involved, or more accurately, some of the medicines involved, so pro- foundly expensive? It is common ground that the “exponential growth in costs” in Brazil “can be explained by a high concentration of cases demanding expensive patented drugs.”81 Almost 80 per cent of the total sum spent by the federal government to satisfy judgments for medicines in 2011 was spent on just 20 medicines, for fewer than 0.05 per cent of litigants”. For a concern about the possibly deceptive and anti-distributive character of such claims, see Wang (2015), p. 617; for a defender of its counter-hegemonic potential as a grassroots instrument for the poor, despite its shortcomings, see Biehl", "n_tokens": 331, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-222-3", "doc_id": "medicine_vaccine_book", "page": 222, "text": "et al. (2016).", "n_tokens": 7, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-222-4", "doc_id": "medicine_vaccine_book", "page": 222, "text": "217", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-223-0", "doc_id": "medicine_vaccine_book", "page": 223, "text": "218\n\nC. S. Filho and V. H. P. Ido\n\nTable 1 Unity prices of Trastuzumab before July 2012 (in Brazilian Real—BRL)\n\nTrastuzumab 440 mg vial\n\nBrazil CMEDa PFb (with taxes) R$ 9.417,81\n\nCMED PF (without taxes) R$ 7.640,60\n\nCMED PF (without taxes and CAPc) R$ 5.969,60\n\nLowest price\n\nUSA R$ 3.555,67\n\nInternational Average R$ 4.728,98\n\nInternational Median R$ 4.832,21\n\naCMED is the acronym for “Câmara de Regulação do Mercado de Medicamentos” (Chamber of Regulation of Medicine Market), the Brazilian federal regulatory agency responsible for monitoring prices and establishing caps according to the prices of selected markets around the world, including the United States bPF is “Preço de Fábrica” (Manufacturer’s price) cCAP is “Coeficiente de Aplicação de Preço” (Price Application Coefficient, in Portuguese) is a mandatory minimum discount applied for medicine purchases by public administration entities, such as the Ministry of Health Recommendation Report by CONITEC/SUS—Trastuzumab for Treatment of Initiatial Stage Breast Cancer—July 2012, p. 16", "n_tokens": 279, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-223-1", "doc_id": "medicine_vaccine_book", "page": 223, "text": "universal public healthcare system and via individual court litigation. If this, on one hand, may pressurize public entities to provide better healthcare services and avoid individual claims, on the other hand, this dual system creates strong inequalities in terms of who may access medicines and when (often with “shortcuts”). An often- disregarded issue regarding this topic is how this system may also present an opportunity for abusive pricing conducts and patent abuses. In the specific case of Trastuzumab, Roche provided the medicine under a price agreed by the public bid, but refused to sell Trastuzumab for the same price in individual healthcare litigation cases, charging instead R$7.192,00—more than double the negotiated with the Ministry of Health. Further evidence shows that similar higher pricing occurred for all purchases not related to the centralized procurement, i.e., all individual litigations (Table 1). 62\n\nIn light of this data, the Law and Poverty Research Group of the University of São Paulo (USP) produced a comprehensive report on the prices charged by Roche on Trastuzumab, reporting the figures above. It then filed in June 2014 a “representa- tion” (i.e. a form of denunciation mechanism) for the Federal Public Ministry of Brazil, the authority mandated with the protection of collective rights in the country and general overseer of the public interest. 63", "n_tokens": 295, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-223-2", "doc_id": "medicine_vaccine_book", "page": 223, "text": "The research group noted that the price differentiation between markets is a case of abuse of dominant position, a doctrine of competition law but applicable more broadly to this case also, and further noting a case of excessive pricing given the\n\n62 Grupo Direito e Pobreza (Law and Poverty Group) (2014). 63 Grupo Direito e Pobreza (Law and Poverty Group) (2014).", "n_tokens": 79, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-224-0", "doc_id": "medicine_vaccine_book", "page": 224, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nexistence of market power by Roche. The company in this case was apt to discrim- inate between consumers without justification, leading to an overprice. 64 According to the legal document, they are in violation of the constitutional economic order and of a conduct of arbitrary profits (Articles 170 and 173, §§4 and 5 of Brazilian Federal Constitution). In this sense, although some arguments are usually found only in competition/antitrust law, the case dealt with civil torts.\n\nFinally, the average price charged in Brazil above the international average was utilized as grounds for another evidence of abusive conduct, according to Brazilian law. This takes into account precisely the monopolistic power of Roche in an international context, with discretion to charge higher prices in jurisdictions where, at least in theory, prices should be lower. With these elements, the research group's representation requested the launch of an investigation by the Federal Public Min- istry, demanding damages in the benefit of the public, the compulsory licensing of Trastuzumab, the immediate parallel import of biosimilars and for all conditions for local manufacturing to be available.", "n_tokens": 251, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-224-1", "doc_id": "medicine_vaccine_book", "page": 224, "text": "Indeed, the Federal Public Ministry welcomed the document and later filed a collective claim (“Inquérito Civil n. 1.16.000.000699/2015-87”, which proposed the civil public action) against Roche in 2016, replicating the arguments above and further considering that, while within the boundaries of the maximum regulated prices by CMED, they were still abusive due to the stark differentiation. 65 Notably, prices were much up to three times higher than those in the United States, and more than double of the international average. The decision to pursue a judicial litigation in the dissatisfaction with the laboratory’s formal was rooted, among others, response. The Federal Public Ministry requested all purchases to be equated with the centralized public procurement price, and requested a compulsory licensing to be issued and the immediate authorization for parallel imports.\n\nIn August 2018, however, the Federal Court of the Federal District (Brasilia) responsible for the case agreed with Roche that there was no demonstration of price abuse nor illegal conduct, since Roche had brought justifications. 66 As a conclusion, the whole situation described above remained unchanged. While there was an appeal", "n_tokens": 235, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-224-2", "doc_id": "medicine_vaccine_book", "page": 224, "text": "64 For a more thorough analysis of market power, and the use of the Lerner Index doctrine borrowed from competition law, see Salomão Filho (2013b), p. 152. 65 The existence of a regulation on medicine prices does not remove it from the scope of potential abusive practices regarding prices, an argument that was inaccurately explored by Roche. In reality, the price regulation (not a direct price fixing) cannot be used to shield liability from abusive pricing. It means that the Judiciary should acknowledge that there is potential abusive conduct in charging excessive prices of medicines, even if they are regulated. Furthermore, CEMED’s methodology is criticized for establishing excessively high price caps, which would also prove the point. 66 Among the arguments of the defendant, Roche argued that logistics costs are much higher when destined to a specific litigation, unlike the larger public procurements. Indeed, the relatively more complex molecule (being a biological drug) and specific needs for storages do pose difficulties regarding its manufacturing and logistics. The weakness of the argument is demonstrated by the fact that Roche sells other drugs in different places in Brazil with no such regional differences— showing therefore that the difference in price is in effect due to market power and illegal price discrimination.\n\n219", "n_tokens": 261, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-225-0", "doc_id": "medicine_vaccine_book", "page": 225, "text": "220\n\nC. S. Filho and V. H. P. Ido\n\nfiled against such decision, taking the case to the Appeals' Federal Court and pending final decision, some members within the Federal Public Ministry (claimant) opposed the continuation of this litigation.\n\nMeanwhile, Roche also joined a Partnership for Productive Development (PPD) with the Ministry of Health, securing transfer of technology for national laboratories Tecpar and Axis, while guaranteeing a market (following this agreement, 40% of all purchases by SUS would come from Roche). In theory, PPDs would lower prices, even if higher than direct competition. However, once again, prices went up, which led to another proceeding in August 2019, this time by the Union Audits Court (“Tribunal de Contas da União”), a quasi-judicial administrative court responsible for auditing public expenses, for abusive pricing. 67 This case is still pending at the conclusion of this paper.", "n_tokens": 197, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-225-1", "doc_id": "medicine_vaccine_book", "page": 225, "text": "From this description, a few preliminary comments can be made. In this particular case, the existence of patent protection over Trastuzumab was the defining feature that permitted Roche Brazil to charge monopolistic prices, putting the public health sector in an extremely unequal position (having one sole provider of a product with an extremely inelastic demand). If generics to Trastuzumab were available, individ- ual litigations could also purchase from the alternative providers, and the bargaining power of Roche towards the Brazilian public sector would be much more limited. Moreover, it is possible to conceptualize this behavior in relation to public purchases and court rulings as an abuse of patent rights under Brazilian competition law: although often disregarded, the way market players may benefit economically from legal uncertainty, multiple case filings and lack of competitors should be under the scrutiny of competition and IP law alike, not only as background facts, but as evidences. All in all, this is equally an important call for the inclusion of responsibilities of companies in litigations of public interest such as those related to access to medicines.", "n_tokens": 230, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-225-2", "doc_id": "medicine_vaccine_book", "page": 225, "text": "What is the direct result of this federal judicial ruling? The maintenance of the status quo and an implicit legitimization of Roche’s pricing practices. Also, while the new investigation at the Union Audits Court is unrelated to the previous one, it allows other reflections, including what is the relation between them and what are the possible legal impacts of one investigation in the other. The fact that this case has been framed as a “non-patent” issue or which has perceived the market monopoly power conferred by a patent as ancillary at best is the result of the limited under- standing pointed out in the Introduction: failing to acknowledge the role of courts in individual litigations to enhancing the power stemming from a patent in this partic- ular web of details, the ultimate result does not properly apply the public interest requirements of Brazilian IP and competition laws.\n\nFinally, even though a preliminary analysis could possibly focus on the role of the individuals involved in the litigation, this description highlights in fact that the\n\n67 Junqueira (2019). Available at https://www1.folha.uol.com.br/cotidiano/2019/08/investigacao- do-tcu-aponta-sobrepreco-em-remedio-para-cancer-e-leva-a-desabastecimento.shtml.", "n_tokens": 285, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-226-0", "doc_id": "medicine_vaccine_book", "page": 226, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nfunctioning of the IP system is extremely reliant on the role of courts. 68 As stated before, this is less about individual biographies of adjudicators/attorneys/business- people and more about a judicial system based on silos and typically reluctant to commit to applying law in a more comprehensive manner, even in light of such socio-economic circumstances. This has been moreover a case where a hesitant and absent role of the Judiciary to address IP and access to medicines issues has directly impacted the possibility of implementing access to medicines policies, even if at first glance this seems to not be a case on patents or competition. Importantly, the argument of how price differentiation by Roche was only being possible due to the complex web of various litigations had indeed been brought to courts, but the decisions overall preferred to interpret the facts in a much more limited way.", "n_tokens": 187, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-226-1", "doc_id": "medicine_vaccine_book", "page": 226, "text": "5 The Sofosbuvir Case in Brazil\n\nSofosbuvir—sold under the brand name Sovaldi by pharmaceutical multinational company Gilead Sciences—is a key medicine for the treatment of Hepatitis C, for decades an incurable disease. It has been deemed a long-waited game changer for the treatment of the disease. The utilization of direct-acting antivirals (DAAs) such as Sofosbuvir, in combination with other drugs, 69 is able to provide a cure in a very high percentage of cases (over 95%), and also contains a drastic reduction of collateral effects in comparison with the most utilized treatment for decades until then, based on inter-venous use of Interferon. Since its launch, Sofosbuvir has been a major commercial success for Gilead around the world, with estimations of billions of dollars in profits, largely superseding its overall investments in R&D by any possible account. 70\n\nThe major global concern on Sofosbuvir has been the fact that it is extremely costly in developed countries and in the majority of middle-income countries. It has been reported that the 12-week treatment has cost up to US$84.000 in the United States. In countries with generic offer, such as those coming from Egyptian generic company Pharco Pharmaceuticals, the same treatment can be provided for as low as US$300. 71 Importantly, Egypt did not grant the patent on Sofosbuvir, and Gilead", "n_tokens": 307, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-226-2", "doc_id": "medicine_vaccine_book", "page": 226, "text": "68 See Sect. 2 for some inputs on this topic. 69 Combinations include sofosbuvir with ledipasvir, velpatasvir, simeprevir and/or dataclasvir. Dataclasvir is patented by Bristol Meyer Squibb (BMS), while ledipasvir and velpatasvir have also been patented by Gilead. Other companies similarly have DAAs placed in markets and more are in the pipeline of new drugs. 70 According to an estimation by Hep C Coalition, a patient's of hepatitis C advocacy group, in the period 2013–2018 the drug generated a profit of around US$25.8 billion. Nonetheless, access to Sofosbuvir globally was still extremely reduced due to pricing, patents and registration delays. See: https://hepcoalition.org/news/press-releases/article/hepatitis-c-cure-sofosbuvir-turns-5-years-old- the-vast-majority-of-people-still?lang¼en#nb1. 71 See: https://www.dndi.org/2018/media-centre/press-releases/new-affordable-hepatitis-c-combi nation-treatment-shows-97-cure-rate/.\n\n221", "n_tokens": 275, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-227-0", "doc_id": "medicine_vaccine_book", "page": 227, "text": "222\n\nC. S. Filho and V. H. P. Ido\n\nhas offered a much lower price of US$900 per treatment, since Pharco Pharmaceu- ticals was also able to produce it. 72 The real beneficiaries were consumers and the public health sector of Egypt, which could have access to a full treatment at substantially lower prices than the majority of countries in the world. Importantly, the fact that prices are so dramatically different around the world is another evidence that pricing is a process that is disentangled from innovation processes. 73", "n_tokens": 118, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-227-1", "doc_id": "medicine_vaccine_book", "page": 227, "text": "Gilead established a large international scheme of voluntary licenses for certain Indian generic companies to produce and export Sofosbuvir at very low prices to least developed countries (LDCs). 74 However, middle-income countries (including Brazil) were not part of the scheme at all. Such agreements also prevent competition with non-licensee generic producers, and also impede exports to territories not covered by the licenses. Thus the majority of world population in need remained excluded from this beneficial scheme. 75 For those countries, the medicine remained an extremely pricy drug, and likely even more in countries with weaker health systems. This led Sofosbuvir to be at the central stage of global efforts for reduction of prices, campaigns for affordable and equitable access, and different attempts by governments to reduce prices, including the issuance of a compulsory license in Malaysia. 76 Patent oppositions have been filed in multiple countries, including Argentina, Brazil, Morocco, Egypt, Ukraine, Malaysia, India, China, Russia, the United States, Vietnam and in the European Patent Office (EPO), 77 some with successful outcomes to have a patent claim rejected or limited.\n\nWith millions of hepatitis C patients, Brazil incorporated DAAs as part of the universal public health system and opted in 2014 to negotiate prices of Sofosbuvir", "n_tokens": 270, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-227-2", "doc_id": "medicine_vaccine_book", "page": 227, "text": "72 Correa and Velásquez (2018). 73 While net prices do relate to numerous variables, including logistic costs, costs of APIs (active pharmaceutical ingredient), taxation, volume of purchases, reimbursement schemes, and others, these stark price differences between countries were mostly related to patents. The fact that Gilead Sciences as a transnational corporation group (despite separate legal entities) had the monopolistic power to discretionarily charge higher prices across jurisdictions shows this even more clearly. Medicine prices covered by patents are ultimately influenced by patents (therefore, by a monopoly), and not related to innovation. This is yet another caveat to the logic described in the previous section, to which a patent and its exercise, including the economic benefits arising from it, would be at least partly justifiable due to the innovation provided. What economic evidence shows, however, is that if prices and patents were really related to innovation, prices should be at least somewhat similar in the world, which does not happen at all. As such, this is a clear case of what antitrust law considers to be a monopoly pricing. 74 Hill et al. (2016), pp. 28–31. 75 Gilead. Chronic Hepatitis C Treatment Expansion – Generic Manufacturing for Developing Countries. Available at: https://www.gilead.com/-/media/files/pdfs/other/hcv-generic-agreement- fast-facts-11-15-17.pdf. 76 Press Statement Minister of Health 20th September 2017 – Implementation of the Rights of", "n_tokens": 328, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-227-3", "doc_id": "medicine_vaccine_book", "page": 227, "text": "Government for Sofosbuvir Tablet to Increase Access for Hepatitis C Treatment in Malaysia. Available at: https://kpkesihatan.com/2017/09/20/press-statement-minister-of-health-20th-septem ber-2017-implementation-of-the-rights-of-government-for-sofosbuvir-tablet-to-increase-access- for-hepatitis-c-treatment-in-malaysia/. 77 See https://www.patentoppositions.org/en/drugs/sofosbuvir.", "n_tokens": 125, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-228-0", "doc_id": "medicine_vaccine_book", "page": 228, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nwith Gilead directly. While a positive initiative that prevented prices from being even higher, Sofosbuvir sold for the public health system through public procure- ment mechanisms was estimated to be up to 52 times more expensive than generic versions available in other countries, according to GTPI, a Brazilian civil society organization. 78 From the outset until the present moment, while lower than the maximum charged in the United States, prices in Brazil were substantially higher than countries with generic availability such as Egypt and Malaysia (following its compulsory license).", "n_tokens": 124, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-228-1", "doc_id": "medicine_vaccine_book", "page": 228, "text": "Multiple patent applications had been filed by Gilead at INPI, the Brazilian IP office. In February 2017, Fiocruz files a pre-grant opposition to the main patent application (PI0809654-6). MSF Brazil, GTPI/REBRIP, and other organizations would follow. From the very beginning, the patent applications were controversial: in March 2017, ANVISA denied the prior approval (“anuência prévia”) to the the National Council of Health (“Conselho Nacional de patent. 79 In March, Saúde”) issued a technical-political recommendation against the patent and called for attention to public health needs. However, in May 2017, a preliminary injunction questioned ANVISA’s decision and it was therefore, according to the Brazilian legal system, legally bound to grant its prior approval—with the possibility of this decision to be upheld or overruled in later stages. In practice, the court ruled that the prior approval should be granted.", "n_tokens": 209, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-228-2", "doc_id": "medicine_vaccine_book", "page": 228, "text": "In its pre-grant opposition on the same patent application, GTPI/REBRIP, argued that it did not meet patentability criteria, but also further noted that the patent application in question referred to an essential drug, and therefore its granting would lead to violation of the right to health of Brazilian population. While this explicit public interest argument was not utilized, the INPI released on 19 April 2018 a preliminary technical examination report against the patent. While not legally binding, it signaled that the patent would not be granted. On 5 June 2018, ANVISA gave the regulatory approval for the generic drug to be produced locally by a Farmanguinhos-Fiocruz and Blanver (a generic company) partnership. It was largely expected that the patent would not be granted at this point. In June 2018, daclatasvir, dimeprevir and sofosbuvir were incorporated in the Brazilian SUS; they were expected to be distributed freely and universally by December 2018.\n\nOn 18 September 2018, in an unexpected decision, INPI granted the patent on one of the 126 substances filed, having denied 125 others and reversing its own", "n_tokens": 235, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-228-3", "doc_id": "medicine_vaccine_book", "page": 228, "text": "78 Grupo de Trabalho da Propriedade Intelectual (GTPI). Brazil is excluded from license authoriz- ing production of generic medicine for hepatitis C. Available at: http://deolhonaspatentes.org/ media/file/GTPI_statement_Gilead_license_sofosbuvir.pdf. 79 The prior approval was an innovation of the Brazilian Patent system whereby the regulatory agency ANVISA conducts an analysis of the patent application for pharmaceuticals, granting or not its “prior approval” before the INPI analysis. The interaction between the two agencies and the mandate of ANVISA have been hotly debated. In early times, ANVISA would conduct a full patentability criteria analysis and its decision was binding; this was later replaced to be an analysis of public health implications of the technology patent application, but no veto power per se is recognized as of now.\n\n223", "n_tokens": 188, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-229-0", "doc_id": "medicine_vaccine_book", "page": 229, "text": "224\n\nC. S. Filho and V. H. P. Ido\n\npreliminary technical examination. The main compound was not patented, but still, the decision was met with outcry and major discontent by civil society and patient groups. Although in principle generics could be produced if they did not infringe this limited patent, any generics reaching markets, in this case, would be subject to costly and limiting litigation. This risk is substantially higher in Brazil for generic compa- nies given the fact that damages for patent infringement are necessarily set at the highest possible amount, which hinders competition. 80 Subsequently, the generic medicine was legally and effectively blocked from entering the markets and Gilead enjoyed a legal monopoly due to its new patent.", "n_tokens": 150, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-229-1", "doc_id": "medicine_vaccine_book", "page": 229, "text": "Shortly thereafter, on 20 September 2018, Marina Silva, a former environment Minister and presidential candidate filed a federal lawsuit against the INPI decision in order to annul the patent, based on arguments of public health and on the precarity of the patent application, citing, among others, precedents in other countries. 81 The federal judge in Brasilia accepted the arguments and issued a preliminary injunction suspending the effects of the patent. 82 During this period, it can be said that there was a competition period, whereby patents were not a barrier to competition and the generic version was able to be commercialized and be part of public bids of Sofosbuvir-based treatments. The price reached an all-time low of R$64,84 (also see graphic below for the comparison).\n\nIn November 2018, combination medicines containing Sofosbuvir were procured at an emergency procedure by the Ministry of Health. Gilead filed a claim to impede its distribution due to patent infringement. In this context, a decision in favor of Gilead is taken but later overruled. 83 In December 2018, the preliminary ruling in Brasilia was overruled and the patent on Sofosbuvir is once again valid, leaving Gilead to wait for its patent letter to start enforcing it. It is noteworthy to mention that the decision by the Federal Court in Brasilia—1st Region was taken on procedural grounds and was therefore not based on substantive patentability requirements. 84", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-229-2", "doc_id": "medicine_vaccine_book", "page": 229, "text": "Following the previous decision, a decision by a Rio de Janeiro Federal Court in December 2018 suspends, under request of Gilead, PDP between Blanver and\n\n80 See Articles 44, §1, 208 and 209 of the Brazilian Industrial Property Law. For an assessment of how this maximalist set of norms impacts competition by greatly increasing the risks for generic companies, see Gabriela et al. (2018), Fiocruz & Escola Nacional de Saúde Pública Sergio Arouca, pp. 122–139. 81 Silva, Marina. Petição Inicial de Ação Popular (Statement of Claims of Popular Lawsuit). 82 Ação Popular n. 1019631-97.2018.4.01.3400. Judgement on 23 September 2018. (“acknowledge that the INPI, by not facing explicitly the arguments that the patent application here questioned was not in tune with the social, technological and economic interest of the country (from the point of view of the Program to Combat Hepatitis C, maintained by the SUS), it disrespected its constitu- tional obligation to preventively oversee national sovereignty and public interest, in the exact extent of art. 5O, XXIX, Federal Constitution, and arts. 2 and 18, I, from Law n. 9.279/96”; free translation). 83 See https://oglobo.globo.com/sociedade/em-nova-batalha-de-patentes-remedio-para-tratamento- da-hepatite-pode-ser-barateado-23584500. 84 See https://www.jota.info/paywall?redirect_to¼//www.jota.info/tributos-e-empresas/saude/juiz- revoga-liminar-que-quebrava-patente-de-remedio-contra-hepatite-c-21122018.", "n_tokens": 424, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-230-0", "doc_id": "medicine_vaccine_book", "page": 230, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nFiocruz/Farmanguinhos for the production of generic Sofosbuvir until final decision on patent is taken. 85 This effectively suspended the generic in Brazil. Also in December 2018, Gilead commits to reducing prices in public procurement. 86 How- ever, still much higher than the generic version. Gilead received its patent in mid-January 2019. In February 2019, Gilead won major public procurements of Sofosbuvir in Brazil.\n\nThis intricate description of events means temporally the occurrence of three", "n_tokens": 124, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-230-1", "doc_id": "medicine_vaccine_book", "page": 230, "text": "main phases:\n\n1. a de facto monopoly, when there was only a patent application and Gilead was the sole provider of Sofosbuvir; 87\n\n2. a short competitive market period where the recently granted patent was suspended due to a preliminary injunction based on public interest provisions, and the generic version was able to enter the market;\n\n3. a legal monopoly phase after the patent was reinstated, with only Gilead again in the market. 88\n\nIt should also be highlighted the number of legal actions taken by all parties, but in particular Gilead, which utilized various different legal tools, including infringe- ment claims of its then suspended patent and attempts to nullify public procurement bids that would have competition. Furthermore, while indeed the patent granted to Sofosbuvir is not on its basic compound and some generics could theoretically still be produced, in practice, some of the public bids are only available to Gilead. In short, the current situation at the time of writing is of full legal and de facto monopoly for the patent holder (Table 2).", "n_tokens": 216, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-230-2", "doc_id": "medicine_vaccine_book", "page": 230, "text": "The most decisive feature of this case, however, deals with the prices charged after the patent was reinstated, as they were substantially higher than those from the competition phase, but also from the original de facto monopoly situation. According to another report by the Law and Poverty Research Group, there was a spike of up to 1421.55% between the competition market period in mid (prices as low as R$64,84 on average) and the later patented phase (R$986,57 on average),", "n_tokens": 103, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-230-3", "doc_id": "medicine_vaccine_book", "page": 230, "text": "85 Case n. 050277092320184025101, Federal Court of 2nd Region, Rio de Janeiro. 86 See SBAC (2019) http://www.sbac.org.br/blog/2018/11/28/dona-de-patente-que-barra-generico- contra-hepatite-c-promete-desconto-a-governo/. 87 As noted in footnote 80, in Brazil, patent applications provide a very strong market power in comparison to other countries. This is partly related to the legal provision that establishes damages for patent infringement (including patent applications) at the maximum possible level in favor of the patent holder (Articles 208 and 209, Industrial Property Law)—with retroactive effects (Article 44, §1 of the same Law), which greatly discourages competitors from entering markets. Brazilian legal doctrine in patent law has also similarly sustained a view that patent applications are deserving of an almost, if not equivalent, level of protection as granted patents. Due to this specificity, the possibility for Gilead to charge a monopolistic price even before the granting of a patent is much clearer than it would be in many other jurisdictions. 88 See Grupo Direito e Pobreza (2019).\n\n225", "n_tokens": 267, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-231-0", "doc_id": "medicine_vaccine_book", "page": 231, "text": "226\n\nC. S. Filho and V. H. P. Ido\n\nTable 2 (Extract from Law and Poverty Research Group report) Effect of Introduction of Generic Sofosbuvir (Blanver/Farmanguinhos) in National Market\n\nEffect of Introduction of Generic Sofosbuvir (Blanver/Farmanguinhos) in Brazilian Market\n\n2,983.458\n\nR$ 986,57\n\n2,708.328\n\nR$ 639,29\n\nR$ 639,29\n\nR$ 256,34\n\nR$ 179,41\n\n1,140.272\n\nR$ 190,59\n\n949.800\n\nR$ 64,84\n\n1.588\n\n4,420 420\n\n700\n\n2015\n\n2016\n\n2017\n\n01/01/2018 ate 02/07/2018\n\n02/07/2018 ate 31/12/2018\n\n01/01/2019 Ate 16/01/2019\n\n16/01/2019 ate 22/06/2019\n\nSofosbuvir units sold by Gilead to the Brazilian State during the period Average unitary price of Sofosbuvir sold by Gilead during the period\n\nrepresenting an overwhelming extra budget toll for the public sector. 89 Furthermore, between the legal monopoly phase in 2019 (patented market) and the de facto monopoly from 2015-2018, there is also a major difference in pricing. For instance, in 2016, where a large number of Sofosbuvir units were purchased, the average unit price was R$179,41, compared to R$986,57 charged in 2019 during the new patent monopoly.", "n_tokens": 315, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-231-1", "doc_id": "medicine_vaccine_book", "page": 231, "text": "This complex intertwinement in the case calls for antitrust scrutiny. In light of the situation, a group of nine different Brazilian civil society organizations, representing both patient, consumer and human rights groups, as well as the Public Defenders of Brazil, filed a joint formal notification to the competition authority (CADE 90) in order to request the launch of an investigation for abusive anti-competitive practices (both excessive pricing as abuse of dominant position and abuse of patents) and asking for adequate remedies to be taken, including issuing a compulsory licensing\n\n89 Grupo Direito e Pobreza (2019). Importantly, Even though they refer to different public entities, as noted in the case of Trastuzumab, from a competition perspective, this is the same relevant market (public national health market, as essentially all procurements discussed here are made by the public sector, even if sometimes via different entities—e.g. Ministry of Health and Health Departments of States of Municipalities). The research also aggregated not only Sofosbuvir (Sovaldi), but also a combination of medicines: Harvoni (Sofosbuvir + ledipasvir) and Epclusa (sofosbuvir + velpatasvir). 90 CADE—Conselho Administrativo de Defesa Econômica (Brazilian Administrative Council for Economic Defence).", "n_tokens": 285, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-232-0", "doc_id": "medicine_vaccine_book", "page": 232, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nfor Sofosbuvir on the grounds of an anti-competitive conduct (Article 31k of TRIPS and Art. 38, IV, “a” of Brazilian Competition Law, Law 12.529/2011).\n\nA preliminary administrative investigation was indeed launched by CADE, but the case remains open. It might reach the Administrative Tribunal Council, which decides upon antitrust cases in Brazil. At first impression, there seems to be more space for a competition authority to address the case than judicial courts. 91 How- ever, the relatively more flexible administrative procedure under competition law and the stronger pressures on administrative bodies by government and interested private companies (patent holders) make the results uncertain. This is especially the case at a time in which pharmaceutical industries effectively threaten countries with possible delays in the supply of Covid-19 related medicines (Gilead’s voluntary licensing of Remdesivir, which excludes middle-income countries—including Bra- zil—is an example 92). Despite the yet inconclusive outcome of this preliminary investigation by CADE, the subsequent steps are largely dependent on how the institution decides to perform or not such role.\n\n6 Theoretical Conclusions on the Role of Courts in IP Based", "n_tokens": 260, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-232-1", "doc_id": "medicine_vaccine_book", "page": 232, "text": "on the Concrete Cases\n\nThe two cases reveal a number of issues on the interconnectedness between IP protection and the role of courts. A different kind of interpretation on the role of the Judiciary and other courts (including competition authorities’ adjudication bodies and regulatory bodies, when applicable) with regards to patent protection may thus be enabled. This section aims at presenting some theoretical conclusions drawn partly from the cases discussed and examples presented. a) Courts can reshape markets (and are also influenced by them). As such, patents and patent use or abuse can be seen mainly as a legal phenomenon and their scope depends on the enforcement given to the monopoly in different jurisdictions.", "n_tokens": 136, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-232-2", "doc_id": "medicine_vaccine_book", "page": 232, "text": "91 For instance, given their broad mandate, their relative reduced number (if compared to judicial courts), and the transnational characteristics of most cases (which impact and deal with conducts/ structures in multiple jurisdictions), most competition authorities are equipped for joint interna- tional investigations, work through the sharing of information and to adopt a comparative approach in terms of arguments and remedies deployed. In this sense, they are more accustomed to use case law from other jurisdictions as direct and indirect basis for their own judgements. From an international economic law perspective, it is also true that there is also more policy space for competition authorities to pursue objectives than IP courts. Also, CADE has been one of the first authorities to particularly address an abusive conduct case pertaining to IP, which is the sham litigation case by pharmaceutical company Eli Lily (Administrative Proceeding N. 08012.011508/ 2007-91, from June 2015). 92 Bermudez and Prabhala (2020). Gilead: o Brasil excluído no enfrentamento da pandemia. Available at: http://www.cee.fiocruz.br/?q¼node/1176.\n\n227", "n_tokens": 251, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-233-0", "doc_id": "medicine_vaccine_book", "page": 233, "text": "228\n\nC. S. Filho and V. H. P. Ido\n\nFirstly, courts affect competition. Instead of purely arenas where legal arguments meet in search of a ruling that clarifies the law, they are rather active actors that end up determining the behavior of the parties involved in an IP dispute, even when adjudicators refuse to recognize this role. In other words, judicial rulings and courts are a factor that influences the economic behavior of patent holders, competitors and governments.", "n_tokens": 103, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-233-1", "doc_id": "medicine_vaccine_book", "page": 233, "text": "As a consequence, they may in an intended or unintended manner expand the patent monopoly’s effective scope. For instance, if companies are aware of the extreme success rates of individual health litigation cases, such as it was the case of Trastuzumab in Brazilian courts, and that there is no scrutiny for the prices charged to the public sector in order to enforce judicial orders, this means that the patent monopoly is enhanced exorbitantly. It becomes an implicit authorization to charge any price, even if likely anti-competitive. Similarly, if companies know that their litigation practices and their price discrimination (between different entities in a same jurisdiction and/or across different countries) are to be considered lawful from a competition law perspective, such as what has been argued in the ongoing Sofosbuvir case before the competition authority (CADE), they also see their patent monopoly reinforced, allowing them to pretty much shield themselves from antitrust suits. The monopoly legally granted by a patent is not supposed to be so overarching and comprehensive. However, it may become so due to courts. The conclusion is that access to drugs is directly restrained.", "n_tokens": 230, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-233-2", "doc_id": "medicine_vaccine_book", "page": 233, "text": "In general, it is not possible to disregard the impact of courts; the absence of the Judiciary decision is also often the main feature to expand patent monopolies. The absence of rulings from the Brazilian Constitutional Court (STF) on patent matters sincetheenactmentofthe1988Constitutionandthe1996IndustrialPropertyLawuntil a May 2021 decision which ruled automatic patent term extensions unconstitutional is a present and dangerous example of this absenteeism. Therefore, in short, courts can reshape markets (and are also influenced by them). As such, patents and patent use or abuse can be seen mainly as a legal phenomenon and their scope depends on the enforcement given to patent rights and its flexibilities in different jurisdictions. b) “IP as crucial to innovation” wrongly becomes a legal argument, which ham-", "n_tokens": 181, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-233-3", "doc_id": "medicine_vaccine_book", "page": 233, "text": "pers access\n\nSecondly, rhetorical and economic narratives have direct legal consequences when turned into arguments deployed or accepted by courts. By applying as a given fact that maximal IP protection will lead to more innovation (therefore, according to this view, IP protection per se is in the public interest), courts impede an evidence-based assessment of concrete cases, preferring to rely on a pre-set definition. Most laws themselves do not define the specific trade-off related to patents, access and innovation, and invariably will require robust interpretation by courts in practical terms.\n\nThis means that there will be no real balancing between, for instance, the effects for competition or the impacts on prices and consequential increase in medicine prices, and the protection of a certain patent claim. Furthermore, an analysis of even “technical” aspects, such as patentability criteria, will tend to be informed and biased", "n_tokens": 185, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-234-0", "doc_id": "medicine_vaccine_book", "page": 234, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nby a tendency towards the granting of a patent—similarly to the notion adopted by some IP offices that patent applicants are “clients”, and not public offices working for the public interest.\n\nThe economic narrative that equals IP with more innovation tends to overly expand the scope of protection of IP from a temporary monopoly granted by the State (quasi-public right, for some) to a naturalized and almost absolute right. 93 This, in a sense, is an effect of IP protection on the role of courts. This narrative has been implicitly seen in the two cases analyzed, especially through the arguments provided for by the law firms representing the pharmaceutical companies in Brazil. This is the main conventional stream of argumentation in pharmaceutical patent litigation and legislative debates around the world. 94\n\nc) Anti-monopoly and IP law share public principles. As such, principles of competition/anti-monopoly law should be directly applicable to patents (neither as exemption nor complement)\n\nThirdly, apart from an IP interpretation that is more sensitive to the socio- economic implications of IPRs, there is a case to be made about the applicability of principles of anti-monopoly laws to patents. 95 This should not be seen as an", "n_tokens": 261, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-234-1", "doc_id": "medicine_vaccine_book", "page": 234, "text": "93 Oftentimes, the defense of TRIPS flexibilities mirrors the way the IP system is usually conceived: a tension between public and private interest, the public being the interest of society at large to benefit from more creations and inventions and access to them, and the private being the incentive/ recognition of the inventor/author to benefit, particularly economically, from it. The access to medicines debate, in that sense, is normally portrayed as a defense of more public interest to the relative detriment of the private interest of the IP holder. When put under those terms, the IP debate is defined as a permanent imbalance and a constant pursue of the balance between public and private. However, this should not necessarily be the case. The disaggregated framing of the question allows for different considerations. An essential point often not referred to in the IP scholarship is the impact of TRIPS flexibilities to the protection of IP. The flexibilities are neither an annulment nor an attempt to impede the exercise of legitimate IPRs. When patents proliferate and are granted under lax patentability criteria, it is well-established that this leads to the granting of numerous patents to non-inventions (i.e. patent applications that do not fit the novelty or non-obviousness, inventive step and industrial application requirements). Conceptually speaking, they should not be granted in the first place. This means that, from the outset, patents are not synonyms of inventions. However,", "n_tokens": 318, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-234-2", "doc_id": "medicine_vaccine_book", "page": 234, "text": "if the patents granted to non-inventions are never subject to legal scrutiny—for instance, through post-grant oppositions or through judicial rulings that invalidate patents—they will be legally enforced. 94 Another good example of how this comes about is in the anxieties surrounding the likelihood of international investment arbitration panels based on the measures taken by States with regards to Covid-19 IP-protected technologies, which may cause hugely detrimental effects to certain coun- tries, show how deeply engrained the “IP as innovation” approach is. Similarly, as noted by James Love, “companies will be able to claim that anything that reduces the price reduces incentives to invest in more rapid development, and litigate that issue.” See, Karlin-Smith (2020) https://www. politico.com/news/2020/03/05/coronavirus-drug-industry-prices-122412. 95 See, for example, FTC v. Actavis US Supreme Court Case. In this case of a pay-for-delay agreement, the court acknowledged that competition law should be applied to patents. This is different from the previous US interpretation: before that, decision courts largely considered that a behavior that falls within the subject matter of the patent would be lawful, even if it had a negative", "n_tokens": 268, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-234-3", "doc_id": "medicine_vaccine_book", "page": 234, "text": "229", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-235-0", "doc_id": "medicine_vaccine_book", "page": 235, "text": "230\n\nC. S. Filho and V. H. P. Ido\n\nexception or as a complement to the legal discipline of patents and other IPRs, but as an integral part of the meaning of IP: there is no IP without competition, even if it may sound paradoxical at first.\n\nIn practice, in relation to the Trastuzumab civil federal case in Brazil, this would lead to the recognition that the stark price differentiation between the price of public procurement and the price charged resulting from a judicial ruling against the State is so high that it should have been considered illegal. To do so, an application of principles of competition law, in particular a discipline of abuse of dominant position, would have been in our view sufficient to prove the case. The doctrine of competition law abuse of dominant position should definitely be applicable to this case, even if it was being ruled by an instance outside of the Brazilian competition law system. This would be arguably also the case in other jurisdictions. Conversely, for the Sofosbuvir competition case, the differences in the historical series of prices, and between the de facto monopoly, the legal monopoly (patent protection) and the competition situations (with generic drugs available in the market), highlight another anti-competitive practice based on both excessive pricing (price demonstrated through price discrimination) and abuse of patent power. 96 As noted before, this case is still pending as of the conclusion of this paper.", "n_tokens": 297, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-235-1", "doc_id": "medicine_vaccine_book", "page": 235, "text": "While at first the difference in courts (federal judicial court and competition authority) would seem to lead to completely different legal reasonings and rationale of distinct bodies of law, in reality the similarity of cases denotes that the disciplines of IP and competition law—and also in tune with public interest provisions and fundamental rights—are or should be in fact in a path of merger. An IP court cannot dismiss competition law as much as a competition body should not ignore IP provisions; although they may have different organizing structures, and are usually seen as targeting different goals, they have increasingly similar objectives and intertwinements. Integrated principles and integrated disciplines does not mean conflating all norms, arguing that IP and competition law are the same (they are not), but it does mean passing from essentially private law spheres to a way of interpreting law that should be based on public principles, particularly in light of the demand that it should not reproduce socio-economic structures as natural entities, but instead seek to regulate them for their economic power, as we have argued before", "n_tokens": 210, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-235-2", "doc_id": "medicine_vaccine_book", "page": 235, "text": "effect on the market and could be considered anti-competitive. This highlights that even in a country so adamantly protective of patent rights, such as the United States, the possibility of applying patent law to competition law exists. 96 There seems to be a proven argument in favor of an abuse of patent as an illicit anti-competitive conduct. This is a clear recognition under Brazilian law, but it is also a hypothesis clearly delineated by the TRIPS Agreement and therefore part of the national law of almost every jurisdiction around the world. Furthermore, even though the majority of pharmaceutical IP-related cases in antitrust bodies deals with “excessive pricing”, such doctrine is neither the only nor the sine qua non legal argument to elicit the anti-competitive conduct. In other words, the illegality is not (only) in a price deemed excessive, but in the utilization of a legal monopoly position (the patent) in an abusive manner. Therefore the need to identify the two conducts.", "n_tokens": 197, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-236-0", "doc_id": "medicine_vaccine_book", "page": 236, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nin different occasions. 97 Both are informed by and conceptualized under public interest law more than bearers of private interests. This also means that the cases described above would have required a different kind of interpretation that ade- quately addresses competition impacts of IP protection both directly and indirectly— including the role of courts as such. As many have argued in terms of the evolution of both disciplines (IP and competition law), the trend towards a broader consider- ation of interests, consequences and stakeholders denotes a process of “publicization” of private law, rather than the opposite. 98 d) There is an emerging global (case) law of TRIPS flexibilities based on screening and transparency. The role of courts is not dissociated from, but rather based on, an interaction between academia, NGOs and other actors.", "n_tokens": 184, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-236-1", "doc_id": "medicine_vaccine_book", "page": 236, "text": "Finally, a few notes should be made on how an emerging body of decisions taken by courts around the world has become a crucial feature for TRIPS flexibilities much beyond their own initial scope. Courts are increasingly required to navigate distinct “fields of law” and take into account other jurisdictions—both for the impact of their decisions and as sources of legal arguments. 99 There is also a “screening” process between courts. 100 Some national decisions have direct transnational repercussions, such as a ruling on the legality of parallel exports, which will impact countries which import or export medicines to that jurisdiction. An antitrust decision may deem illegal a conduct based on abusive exercise of IPRs, and may impose restrictions and sanctions that affect the outcomes of patent litigations in judicial courts.", "n_tokens": 161, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-236-2", "doc_id": "medicine_vaccine_book", "page": 236, "text": "97 See Sect. 2. 98 Salomão Filho (2015). 99 While IP law seems to be tightly related to national jurisdictions and international treaties only, the increasing prominence of international licensing agreements in IP, the introduction of IP in investment arbitration panels and the interplay between different actors discussed in this paper as “pharmaceutical patent activism” highlight that courts need to navigate this much more complex landscape, both public and private, both national and transnational at the same time. This is at least partly applicable to this analysis. It also deals with other phenomena. For instance, in the field of constitutional law and international human rights law, some have referred to this as “courts' dialogue”, whereby interpretation of certain rights and case law of regional human rights bodies such as the European Court of Human Rights and the American Court of Human Rights may influence each other, as well as national constitutional courts. Even if the expression may not be always accurate to describe constitutional practices, the possibility of cross- referencing based on sharing of experiences and case law. This does not compromise the sover- eignty or the independence of courts, as evidently all such arguments and data needs to be assessed according to national laws and real cases. Instead, it provides more transparency and avenues for a better coordination between different societal actors, which may have the positive effect of increasing", "n_tokens": 273, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-236-3", "doc_id": "medicine_vaccine_book", "page": 236, "text": "accountability. 100 Positive screening is an expression most commonly found in the investment world of stock such as exchanges, whereby investors positively value companies with commitments environmentally-sound operations and human rights protection, among others. Here, the notion of “screening” is borrowed broadly from corporate governance in a critical way, where reputational costs and examples set by peers in a given market are an increasingly important form of informal governance.", "n_tokens": 81, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-236-4", "doc_id": "medicine_vaccine_book", "page": 236, "text": "it does signal\n\n231", "n_tokens": 4, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-237-0", "doc_id": "medicine_vaccine_book", "page": 237, "text": "232\n\nC. S. Filho and V. H. P. Ido\n\nthere are indirect consequences, which cannot be underestimated either. Landmark rulings such as the USA Supreme Court Myriad Genetics Case 101 and the Indian Supreme Court Novartis Case 102 have been immensely discussed, read in law classrooms and utilized by courts around the world that in theory would not be bound anyhow by such decisions. Others have this emerging potential, such as the Kenyan High Court decision that, based on the right to health, struck down a law with a concept of “counterfeit” which ended up including safe and high-quality generic drugs. 103 In this sense, they are a real source of law for other courts.", "n_tokens": 143, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-237-1", "doc_id": "medicine_vaccine_book", "page": 237, "text": "But\n\nin other cases,\n\nSimilarly, pharmaceutical patent applications also have a transnational dimen- sion. Pharmaceutical companies file patents around the world, sometimes translating the content of application claims without proper adaption to national laws. 104 Civil society groups and generic competitors counter applications of key medicines through patent oppositions in one jurisdiction, such as India, which then become the basis for subsequent oppositions in other countries. This can be deemed a form of “patent activism”. 105 The cases of Trastuzumab and Sofosbuvir, as previously noted in their respective descriptions, have both been subject to scrutiny and advocacy by patients’ groups, and the dialogue between different actors and jurisdictions is a key feature for understanding the conducts and strategies deployed in Brazil.", "n_tokens": 153, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-237-2", "doc_id": "medicine_vaccine_book", "page": 237, "text": "101 United States Supreme Court (2013), Assoc. for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013) (on patentability of an isolated gene). 102 On constitutionality of Section 3(d) of the Indian Patent Act which establishes a robust inventive step requirement. For instance, Siva Tambisetty notes that “The decision in Novartis v UOI heralds a post-TRIPS coming of age for many jurisdictions like India, including Thailand, Brazil, Malaysia and Indonesia. There is an urgent need to build up legitimate legal standards, tests and principles around domestic patent legislation that do not replicate the predicament around patentability standards that several jurisdictions face”. See Tambisetty, Siva. Novartis v. Union of India and the Person Skilled in the Art: A Missed Opportunity. LSE Law, Society and Economy Working Papers 2/2014. For Ahmed Abdel-Latif, the case was the first time a decision by a developing country court was so intensely scrutinized, and could bear consequences to other countries, see Abdel-Latif (2013), available at https://www.ip-watch.org/2013/04/15/the-novartis-decision-a-tale- of-developing-countries-ip-and-the-role-of-the-judiciary/. Similarly, see Bennett (2014), p. 535 and its possible impacts. 103 For a comment, see Kapczynski (2019). 104 As patents are territorial, patent applications also need to be filed in multiple jurisdictions. Multiple streamlined and/or joint systems do exist, such as the WIPO-administered Patent Coop- eration Treaty", "n_tokens": 368, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-237-3", "doc_id": "medicine_vaccine_book", "page": 237, "text": "(PCT) system and regional patent systems such as the ones enabled by the European Patent Office and the OAPI—Organisation Africaine de la Propriété Intellectuelle. 105 See, for instance, the work of Médécins sans Frontières—Access Campaign, ITPC—International Treatment Patients Coalition, Third World Network (Malaysia), Lawyer’s Collective (India), GTPI—Grupo de Trabalho da Propriedade Intelectual (Brazil, for only a few examples of organiza- tions working specifically on this field. Furthermore, a database such as that of the Medicine Patent Pool's Medspal, the compilation of TRIPS flexibilities by the Medicines Law & Policy, or the compilation of compulsory licensing experiences such as that organized by the South Centre, are good examples that may be utilized by any courts around the world. For a comparison between India, Brazil and Nigeria (with a relative lack of “patent activism” in the latter), see Vanni (2020).", "n_tokens": 216, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-238-0", "doc_id": "medicine_vaccine_book", "page": 238, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nTheoretically, these and other cases may be understood as part of global and transnational law, 106 which may help to elucidate how specific courts are part of global economic governance, even as national decisions. As such, adjudicators are key actors in the consolidation of a global law of TRIPS flexibilities based on the sharing of positive experiences, transnational advocacy, international solidarity and in the benefit of developing countries. 107 It should include not only finalized cases, but also legal proceedings initiated but not prosecuted, injunctions granted or not, negotiations and settlements, and activists campaigns. Furthermore, developing countries have an ever-growing importance in IP jurisprudence. 108 The current Covid-19 pandemic and its multifaceted international reaction has a clear potential to accelerate and foster this process.", "n_tokens": 186, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-238-1", "doc_id": "medicine_vaccine_book", "page": 238, "text": "7 Concluding Remarks\n\nThis article sought to repurpose the relation between courts and the implementation of intellectual property. It argues for a shift from limited and uni-dimensional, i.e. “courts apply IP law neutrally”, through which courts define the contours of IP law and are also mutually influenced by IP arguments, theories and stakeholders, all and each with specific socio-economic impacts. Access to medicines is a field where these considerations become more evident.\n\nto broad and multi-dimensional,\n\nIt proposed two main arguments. Firstly, that courts have an enormous impact on the implementation of TRIPS flexibilities. While they are and should not be the only variable in place, any efforts for advancing or curbing the flexibilities involves courts. In particular, tribunals shape markets, even when—and maybe particularly when—adjudicators decide to refrain from broader consideration of circumstances", "n_tokens": 192, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-238-2", "doc_id": "medicine_vaccine_book", "page": 238, "text": "106 Again, as examples, refer to Muir-Watt, Horatia, 2013; Zumbansen, Peer, 2011. Sometimes, influences also come from non-state actors, such as arbitration panels, non-governmental entities such as ISO, ICANN and FIFA, and transnational private contracts. In private international law, notions of global law, transnational law and private ordering have been used to characterize a legal political economy—both from a descriptive and a normative point of view—that is not exclusively based on national and international law, but multiple normative setters. 107 The theoretical framework of a decentralized and collective construction of a global/transna- tional law in IP means two things: on the normative side, that no single entity, no single individual and no single country should define the effective norms and policies of the whole world; on a descriptive point of view, that all players have an important role, and that this interplay between academia, civil society organizations, international organizations and judicial/administrative authorities is essential to construct a robust account of TRIPS flexibilities through example and mutual screening. 108 Abbott, Drahos and Correa have argued that the world patent order was to be changed by the innovation and development of IP in developing countries, with a particular nod to the role of China, Brazil and India. This hypothesis can be now taken further to include the specific case law of these and other jurisdictions alike. Abbott et al.", "n_tokens": 308, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-238-3", "doc_id": "medicine_vaccine_book", "page": 238, "text": "(2012).", "n_tokens": 4, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-238-4", "doc_id": "medicine_vaccine_book", "page": 238, "text": "233", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-239-0", "doc_id": "medicine_vaccine_book", "page": 239, "text": "234\n\nC. S. Filho and V. H. P. Ido\n\nand socio-economic impact of their own decisions. For this reason, the role of courts itself (e.g. a ruling or a lack thereof) has competition impacts and should be taken into account in legal interpretation.\n\nSecondly, that a specific narrative which associates IP protection with fostering innovation is misleading, as it establishes an incorrect trade-off between access to health products and innovation. Since it is widely deployed by courts without further consideration, this narrative turned into legal argument is particularly problematic for over-expanding the effective protection of IP without a balance with the public interest. Thus, it should not be accepted as a juridical category or narrative.\n\nThe description of the cases of Trastuzumab and Sofosbuvir in Brazil serve as examples of how these different pieces come together, even if sometimes indirectly and not explicitly. Many other rulings can and should be described under those lenses. This article may present a framework for further analyses that include, rather than ignore, the specific role of courts and their respective arguments on TRIPS flexibilities.", "n_tokens": 236, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-239-1", "doc_id": "medicine_vaccine_book", "page": 239, "text": "A general conclusion is that this set of elements justifies a legal interpretation that is mindful of structures such as patents, including their effects on societies and the need for them to be reformed, rather than exclusively based on an allegedly formalist interpretation of laws. Such laws, as described above, already enable the restructuring of patent interpretation according to TRIPS flexibilities. This could be deemed a “neo-structuralist” approach to patent law. 109 These cases also lead to the recognition that IP and competition laws should be both interpreted jointly according to integrated public interest principles. 110\n\nFinally, the article posited that the increasing cross-referencing of courts and the transnational characteristics of IP and competition laws may be described—both descriptively and normatively—as an emerging global law of TRIPS flexibilities, based on screening and transparency. The reaction to the Covid-19 pandemic has the potential to accelerate this process. This is where other actors, including civil society and governments, through for instance patent oppositions, transparency of R&D costs and limitation of anti-competitive abuses, play a crucial role.\n\nReferences\n\nAbbott FM, Correa CM, Drahos P (2012) Emerging markets and the World Patent Order. Edward", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-239-2", "doc_id": "medicine_vaccine_book", "page": 239, "text": "Elgar, Cheltenham\n\nAbdel-Latif A (15 April 2013) The Novartis decision: a tale of developing countries, IP, and the role of the judiciary, intellectual property watch, Available at https://www.ip-watch.org/2013/04/15/ the-novartis-decision-a-tale-of-developing-countries-ip-and-the-role-of-the-judiciary/\n\nAção Popular n. 1019631-97.2018.4.01.3400. Judgement on 23 September 2018\n\n109 Salomão Filho (2015). 110 Salomão Filho (2015).", "n_tokens": 139, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-240-3", "doc_id": "medicine_vaccine_book", "page": 240, "text": "intellectual property. NYU Press, New York\n\nde Werra J (23 March 2016) Specialised intellectual property courts - issues and challenges. Published in: specialised intellectual property courts - issues and challenges, global perspectives for the intellectual property system, Issue Number 2: CEIPI-ICTSD. 2016, pp 15–41. Available at SSRN: https://ssrn.com/abstract¼2761209\n\nDeere C (2008) The implementation game: the TRIPS agreement and the global politics of\n\nintellectual property reform in developing countries. Oxford University Press, Oxford\n\nDezalay Y, Garth B (1996) Dealing in virtue: international commercial arbitration and the con-\n\nstruction of a transnational legal order. University of Chicago Press, Chicago\n\nDNDi (12 April 2018) New affordable hepatitis C combination treatment shows 97% cure rate. DNDi, https://www.dndi.org/2018/media-centre/press-releases/new-affordable-hepatitis-c-com bination-treatment-shows-97-cure-rate/\n\nDreyfuss RC, Rodríguez-Gavarito C (2014) Balancing wealth and health: the battle over intellectual\n\nproperty and access to medicines in Latin America. Oxford University Press, Oxford\n\n235", "n_tokens": 256, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-241-0", "doc_id": "medicine_vaccine_book", "page": 241, "text": "236\n\nC. S. Filho and V. H. P. Ido\n\nEuropean Commission Press Release. “Coronavirus Global Response: €7.4 billion raised for universal access to vaccines”. 4 May 2020, available at: https://ec.europa.eu/commission/ presscorner/detail/en/ip_20_797\n\nFink C, Raffo J (2019) What role for intellectual property in industrial development. In: Correa C, Seuba X (eds) Intellectual property and development: understanding the interfaces. Springer, Berlin\n\nForbes (28 August 2019) Can Roche’s blockbuster drug Herceptin’s sales grow?, Available at: https://www.forbes.com/sites/greatspeculations/2019/08/28/can-roches-blockbuster-drug- herceptins-sales-grow/#62da696a42e5\n\nGabriela CC, Marcela V, da Costa Dorneles RF, Vianna MNS (2018) Medicamentos em situação de exclusividade financiados pelo Ministério da Saúde: Análise da Situação Patentária e das Compras Públicas. Fiocruz & Escola Nacional de Saúde Pública Sergio, Arouca, pp 122–139 Gawel CR (2016) Patent protection as a key driver for pharmaceutical innovation. Pharm Policy Law 18:45–53, in Valverde, J.L.; Pisani, Eduardo, The Globalisation of the Pharmaceutical Industry, 2016\n\nGeiger C, Nard CA, Seuba X (2018) Intellectual property and the judiciary. Edward Elgar,", "n_tokens": 356, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-241-1", "doc_id": "medicine_vaccine_book", "page": 241, "text": "Cheltenham\n\nGilead (November 2017) Chronic hepatitis C treatment expansion – generic manufacturing for developing countries, Available at: https://www.gilead.com/-/media/files/pdfs/other/hcv- generic-agreement-fast-facts-11-15-17.pdf\n\nGrupo de Trabalho da Propriedade Intelectual (GTPI). Brazil is excluded from license authorizing production of generic medicine for hepatitis C. Available at: http://deolhonaspatentes.org/ media/file/GTPI_statement_Gilead_license_sofosbuvir.pdf\n\nGrupo Direito e Pobreza (2019) Abuso de Direito Patentário e Prática de Preços Abusivos no Caso\n\nHepatite C e Sofosbuvir\n\nGrupo Direito e Pobreza (Law and Poverty Group) (10 June 2014) University of São Paulo.\n\nRepresentation to the Federal Public Ministry of Brazil against Roche\n\nHailbronner M (2017) Transformative constitutionalism: not only in the global South. Am J Comp\n\nLaw 65(3):527–565\n\nHein W, Moon S (2013) Informal norms in global governance: human rights, intellectual property\n\nrules and access to medicines. Routledge, Milton Park\n\nHeller M (2010) Gridlock economy: how too much ownership wrecks markets, stops innovation,\n\nand costs lives, Michael Heller. Basic Books, New York\n\nHeller, Michael & Eisenberg, Rebecca. Heller, M. A.; Eisenberg, R. (May 1998). Can patents deter", "n_tokens": 333, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-241-2", "doc_id": "medicine_vaccine_book", "page": 241, "text": "innovation? The anticommons in biomedical research Science 280 (5364): 698–701\n\nHepatitis C cure (6 December 2018) Sofosbuvir, turns 5 years old: the vast majority of people still have not been treated, hepCoalition, https://hepcoalition.org/news/press-releases/article/ hepatitis-c-cure-sofosbuvir-turns-5-years-old-the-vast-majority-of-people-still?lang¼en#nb1 Hill A, Simmons B, Gotham D, Fortunak J (2016) Rapid reductions in prices for generic sofosbuvir\n\nand daclatasvir to treat hepatitis C. J Virus Erad 2(1):28–31\n\nHoen E (2019) Strong call for transparency on medicine prices, cost of R&D at WHO fair pricing forum. Medicines Law and Policy. https://medicineslawandpolicy.org/2019/04/strong-call-for- transparency-on-medicine-prices-cost-of-rd-at-who-fair-pricing-forum/\n\nHu Y, Eynikel D, Boulet P et al (2020) Supplementary protection certificates and their impact on access to medicines in Europe: case studies of sofosbuvir, trastuzumab and imatinib. J Pharma- ceutical Policy Practice 13:1\n\nInthira Y, Adun M, Sripen T, Chaisiri K, Yot T (2011) Government use licenses in Thailand: an\n\nassessment of the health and economic impacts. Global Health 7:28\n\nIyer V (2019) Constitution-making in Bhutan: a complex and Sui Generis experience. Chin J Comp\n\nLaw 7(2):359–385", "n_tokens": 388, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-241-3", "doc_id": "medicine_vaccine_book", "page": 241, "text": "Juiz revoga liminar que quebrava patente de remédio contra hepatite C. https://www.jota.info/ paywall?redirect_to¼//www.jota.info/tributos-e-empresas/saude/juiz-revoga-liminar-que- quebrava-patente-de-remedio-contra-hepatite-c-21122018. LINK DOES NOT WORK", "n_tokens": 107, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-242-0", "doc_id": "medicine_vaccine_book", "page": 242, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nJunqueira D (17 August 2019) Investigação do TCU aponta sobrepreço em remédio para câncer e leva a desabastecimento. Folha de São Paulo, Available at https://www1.folha.uol.com.br/ cotidiano/2019/08/investigacao-do-tcu-aponta-sobrepreco-em-remedio-para-cancer-e-leva-a- desabastecimento.shtml\n\nKang HY (2020) Patents as assets: intellectual property rights as market subjects and objects. In: Birch K, Muniesa F (eds) Turning things into assets: new lineaments in the study of technoscientific capitalism. MIT Press, Cambridge\n\nKapczynski A (2017) Order without intellectual property law: open science in influenza. Cornell\n\nLaw Rev 102:1539. Available at: https://scholarship.law.cornell.edu/clr/vol102/iss6/3\n\nKapczynski A (26 April 2019) The right to medicines in an age of neoliberalism. Humanity Journal, available at: http://humanityjournal.org/issue10-1/the-right-to-medicines-in-an-age-of- neoliberalism/\n\nKarlin-Smith S (2020) How the drug industry got its way on the coronavirus. Politico, https://www.", "n_tokens": 342, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-242-1", "doc_id": "medicine_vaccine_book", "page": 242, "text": "politico.com/news/2020/03/05/coronavirus-drug-industry-prices-122412\n\nKennedy D (1997) A critique of adjudication (fin de siècle). Harvard University Press, Cambridge Knowledge Ecology International (KEI). CPTech’s 2003 reports for the RSA Competition Com- mission, in Hazel Tau et al. v GSK, Boehringer, et al. Available at: https://www.keionline.org/ competition/2003-hazel-tau-tac\n\nLemos R, Castro O (2012) Tecnobrega. O Pará Reinventando o Negócio da Música (Tecnobrega.\n\nPará reinventing the Music Business). Hunter Books, Nashville\n\nLi X, Correa C (eds) (2009) Intellectual property enforcement – international perspectives. Edward\n\nElgar & South Centre, Northampton\n\nMatthews D (2011) Intellectual property, human rights and development, the role of NGOs and\n\nsocial movements. Edward Elgar, Cheltenham\n\nMatthews D, Gurgula O (12 May 2016) Patent strategies and competition law in the pharmaceutical sector: implications for access to medicines. Queen Mary School of Law Legal Studies Research Paper No. 233/2016. Available at SSRN: https://ssrn.com/abstract¼2779014\n\nMazzucato M (2013) The entrepreneurial state: debunking public vs. private sector myths. Anthem", "n_tokens": 303, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-242-2", "doc_id": "medicine_vaccine_book", "page": 242, "text": "Press, London\n\nMazzucato M, Torreele E (27 April 2020) How to develop a COVID-19 vaccine for all. project syndicate, Available at: https://www.project-syndicate.org/commentary/universal-free-covid19- vaccine-by-mariana-mazzucato-and-els-torreele-2020-04\n\nMendes CH (2013) Constitutional courts and deliberative democracy, vol 1, 1st edn. Oxford\n\nUniversity Press, Oxford, p 272\n\nMSF Access Campaign Global day of action against Roche’s inhumanity #RocheGreedKills (6 February 2017) Press release, https://msfaccess.org/global-day-action-against-roches- inhumanity-rochegreedkills\n\nMuir-Watt H (2016) Private international law beyond the Schism. Transnational Legal Theory\n\n2, 2011(3):347–428\n\nMuir-Watt H, Arroyo D, Bíziková L, de Oliveira AB (2019) Adjudication without frontiers: the\n\nglobal turn in private international law. Edward Elgar, London\n\nOpen Covid Pledge: https://opencovidpledge.org/ Pankhuri A, Shamnad B (13 August 2018) The morality of sexual pleasure: patent office training? Spicy IP, Available at: https://spicyip.com/2018/08/the-morality-of-sexual-pleasure-patent- office-training.html\n\nLa Porta R, Lopez-de-Silanes F, Shleifer A, Vishny RW (1998) Law and finance. J Political Econ\n\n106(6):1113–1155\n\nPottage A, Sherman B (2010) Figures of invention: a history of modern patent law. Oxford", "n_tokens": 382, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-242-3", "doc_id": "medicine_vaccine_book", "page": 242, "text": "University Press, New York\n\nPress Statement Minister of Health 20th September 2017 – Implementation of the Rights of Government for Sofosbuvir Tablet to Increase Access for Hepatitis C Treatment in Malaysia. Available at: https://kpkesihatan.com/2017/09/20/press-statement-minister-of-health-20th-\n\n237", "n_tokens": 72, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-243-0", "doc_id": "medicine_vaccine_book", "page": 243, "text": "238\n\nC. S. Filho and V. H. P. Ido\n\nseptember-2017-implementation-of-the-rights-of-government-for-sofosbuvir-tablet-to- increase-access-for-hepatitis-c-treatment-in-malaysia/\n\nReport of the United Nations Secretary-General High-Level Panel on Access to Medicines (2016) Salomão Filho C (2007) Direito industrial, direito da concorrência e licenciamento compulsório. In: Basso M et al (eds) Direitos de Propriedade Intelectual & Saúde Pública. O acesso universal aos medicamentos anti-retrovirais no Brasil. IDCID, São Paulo, pp 160–161\n\nSalomão Filho C (2013a) A legal theory of economic power – implications for social and economic\n\ndevelopment. Edward Elgar, Cheltenham\n\nSalomão Filho C (2013b) Direito Concorrencial. Malheiros, São Paulo, p 152 Salomão Filho C (2015) Teoria Crítico-Estruturalista do Direito Comercial. Marcial Pons, São\n\nPaulo\n\nSalomão Filho C, Ido VHP (2019) Global corruption and economic power. In: Horatia MW, Diego A, Lucia B, de Oliveira AB (eds) Adjudication without frontiers: the global turn in private international law. Edward Elgar, London\n\nSanghera B (6 November 2015) Unmasking Central Asia’s neoliberal judges. Open democracy, Available at: https://www.opendemocracy.net/en/odr/unmasking-central-asias-neoliberal- judges/\n\nSBAC (2019) Medicamento contra hepatite C terá descontó para o governo. http://www.sbac.org. br/blog/2018/11/28/dona-de-patente-que-barra-generico-contra-hepatite-c-promete-desconto-a- governo/", "n_tokens": 449, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-243-1", "doc_id": "medicine_vaccine_book", "page": 243, "text": "Schiff E (1971) Industrialization without National Patents: the Netherlands, 1869-1912; Switzer-\n\nland, 1850–1907. Princeton University Press, Princeton\n\nSell SK (2003) Private power, public law: the globalization of intellectual property rights. Cam-\n\nbridge University Press, Cambridge\n\nShadlen K (2017) Coalitions and compliance: the political economy of pharmaceutical patents in\n\nLatin America. Oxford University Press, Oxford\n\nSilva M. Petição Inicial de Ação Popular (Statement of Claims of Popular Lawsuit) Stiglitz J (19 October 2017) Wealth before health? Why intellectual property laws are facing a counterattack. The Guardian, available at: https://www.theguardian.com/business/2017/oct/18/ intellectual-property-laws-demand-a-21st-century-solution\n\nStiglitz J, Jayadev A (2010) Medicine for tomorrow: some alternative proposals to promote socially\n\nbeneficial research and development in pharmaceuticals. J Generic Med 7(3):217–226\n\nSyam N, Alas M, Ido VHP (2020) The 73rd World Health Assembly and resolution on COVID-19: quest of global solidarity for equitable access to health products. Policy Brief No. 78. South Centre, Geneva\n\nTambisetty S. Novartis v. Union of India and the Person Skilled in the Art: A Missed Opportunity.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-243-2", "doc_id": "medicine_vaccine_book", "page": 243, "text": "LSE Law, Society and Economy Working Papers 2/2014\n\nUnited States Supreme Court (2013) Assoc. for Molecular Pathology v. Myriad Genetics, Inc.,\n\n569 U.S. 576 (on patentability of an isolated gene)\n\nUnited States Trade Representative (USTR)'s Special 301 report of April 2020. Available at: https://\n\nustr.gov/sites/default/files/2020_Special_301_Report.pdf\n\nUprimny R (2011) The recent transformation of constitutional law in Latin America: trends and\n\nchallenges. Texas Law Rev 89(7):1587–1609\n\nVanni A (2020) Patent games in the Global South: pharmaceutical patent law-making in Brazil,\n\nIndia and Nigeria. Bloomsbury, London\n\nVelásquez G (2020) Rethinking R&D for pharmaceutical products after the novel coronavirus\n\nCOVID-19 shock. Policy Brief, No. 75. South Centre, Geneva\n\nVelásquez G, Seuba X (2011) Rethinking global health: a binding convention for pharmaceutical\n\nproducts. Research Paper No. 42. South Centre, Geneva\n\nVieira M, Moon S (2019) Research synthesis: public funding of pharmaceutical R&D. Graduate Institute, Global Health Centre, Geneva, available at: https://www.knowledgeportalia.org/ public-funding-of-r-d", "n_tokens": 286, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-244-0", "doc_id": "medicine_vaccine_book", "page": 244, "text": "Courts and Pharmaceutical Patents: From Formalist Positivism to the...\n\nVieira M, Moon S (2020) Research synthesis: costs of pharmaceutical R&D. Graduate Institute, Global Health Centre, Geneva, available at https://www.knowledgeportalia.org/cost-of-r-d Wang DWL (2015) Right to health litigation in Brazil: the problem and the institutional responses.", "n_tokens": 85, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-244-1", "doc_id": "medicine_vaccine_book", "page": 244, "text": "Human Rights Law Rev 15:617\n\nWHO COVID-19 Technology Access Pool (C-TAP): https://www.who.int/emergencies/diseases/ novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/covid-19-technol ogy-access-pool\n\nWorld Health Organization (2019) WHO model list of essential medicines, 21st List Zumbansen P (2012) Transnational law, evolving. In: Smits J (ed) Encyclopedia of comparative\n\nlaw, 2nd edn. Edward Elgar, pp 899–925\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n239", "n_tokens": 293, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-245-0", "doc_id": "medicine_vaccine_book", "page": 245, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work Sharing Between Patent Offices\n\nNirmalya Syam", "n_tokens": 23, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-245-1", "doc_id": "medicine_vaccine_book", "page": 245, "text": "Abstract Patent laws and regulations in many countries have utilized the flexibility available under the WTO TRIPS Agreement to apply nationally appropriate stan- dards to define the patentability criteria of novelty, inventive step and industrial applicability, in order to ensure the grant of high-quality patents for genuine inven- tions. Robust search and examination are crucial for the application of this flexibility to ensure the grant of patents for genuine inventions, e.g., for secondary pharma- ceutical patent applications which could lead to patent evergreening and adversely impact access to medicines by restraining generic competition. However, limited examination resources of patent offices have been stretched by the tremendous surge in the number of patent applications to be processed, leading to delays and backlogs. This has led patent offices to prioritize efficient and speedy processing of patent applications with their limited resources by using the search and examination work of other patent offices, sometimes to the extent of granting a patent on the basis of a corresponding grant by another patent office. This chapter discusses how work sharing has been driven by the major patent offices as part of a global patent harmonization agenda, both within the WIPO Patent Cooperation Treaty and through technical assistance and cooperation with other patent offices, and suggests how patent offices in developing countries could best harness the advantages of work sharing,", "n_tokens": 291, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-245-2", "doc_id": "medicine_vaccine_book", "page": 245, "text": "particularly in a South-South cooperation framework, while safeguarding the ability to apply in practice the patentability requirements under their national laws through a robust search and examination of patent claims.", "n_tokens": 36, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-245-3", "doc_id": "medicine_vaccine_book", "page": 245, "text": "1 Introduction\n\nPatent examination is one of the most critical tools available to a country to ensure that patents are granted for genuine inventions that satisfy the patentability require- ments under the law of a country. Patent examination practices adopted by a patent\n\nN. Syam (*) South Centre, Geneva, Switzerland e-mail: syam@southcentre.int\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_9\n\n241", "n_tokens": 133, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-246-0", "doc_id": "medicine_vaccine_book", "page": 246, "text": "242\n\noffice plays a crucial role in the application of this important tool. Almost over the past four decades, patent offices all over the world have entered into collaborative relationships with each other that has effectively led to the creation of a global web of collaboration networks between patent offices. These networks have evolved in parallel to the pursuit of normative initiatives to harmonize substantive and proce- dural aspects of patent law in multilateral forums such as the World Intellectual Property Organization (WIPO) or in bilateral or regional trade agreements. While the normative patent harmonization agenda has been resisted, the administrative cooperation between patent offices has received relatively less attention. This chap- ter examines how the various kinds of cooperative work sharing arrangements that have evolved between patent offices can impact the ability of a patent office to conduct robust search and examination in accordance with their applicable national law and policy, and the opportunities and challenges that arise from the cooperation between patent offices.", "n_tokens": 200, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-246-1", "doc_id": "medicine_vaccine_book", "page": 246, "text": "2 Patent Examination: A Critical TRIPS Flexibility\n\nRigorous examination of patent applications to determine whether they satisfy the general patentability requirements of novelty, inventive step and industrial applica- bility is the core function of patent offices in most countries. The decision by a patent office to grant patents should be based on as thorough an examination of the patent application as possible to ensure that only claims that fully meet the patentability requirements under the national law are allowed. An erroneously granted patent would remain valid unless it is successfully challenged before a judicial authority or a tribunal.1 Thus, the patent offices are expected to act as gatekeepers of the patent system and ensure that patents of questionable validity are not granted.2\n\nEven while recognizing the possibility of grant of patents in all fields of technol- ogy as required under the TRIPS Agreement, countries can have different thresholds of novelty, inventive step and industrial applicability in relation to specific fields of technology, such as pharmaceuticals. Thus, the outcome of a patent application can vary from one country to another, depending on the standard of patentability thresholds that are applied. The provisions of the World Trade Organization’s (WTO) Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS) provide the flexibility to WTO members to apply rigorous standards of", "n_tokens": 275, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-246-2", "doc_id": "medicine_vaccine_book", "page": 246, "text": "1Invalidation of a patent can take several years of litigation, during which period the patent can still be enforced, and involve investment of substantial technical and financial resources which may be difficult to access or afford, particularly in developing countries. Correa (2014a). 2Ibid, p. 2; the number of patent applications and grants have increased significantly in many countries without a corresponding genuine increase in innovation due to the application of low requirements of patentability.\n\nN. Syam", "n_tokens": 109, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-247-0", "doc_id": "medicine_vaccine_book", "page": 247, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\npatent examination to ensure that only genuine inventions that meet high thresholds of patentability criteria are granted a patent.3\n\nPatent examination practices pursed by national or regional patent offices are often based on the application of legal fictions.4 The adoption of some of these legal fictions by a patent office in its approach to the examination of a patent claim may be based on rules, regulations, bye-laws, guidelines or office practices. These may be also influenced by the adoption of treaty obligations for patent cooperation, technical assistance provided by influential patent offices, or administrative collaboration arrangements between patent offices based on memoranda of understanding (MOU) for such collaboration. Thus, even where the national law of a country lays down very strict requirements of patentability, its application can be signifi- cantly impacted by the practices followed by the patent office with regard to examination of patent applications.5", "n_tokens": 209, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-247-1", "doc_id": "medicine_vaccine_book", "page": 247, "text": "This situation demonstrates the need for not only establishing appropriate thresh- olds of patentability under the patent law, but also the important role that patent examiners play in applying the law. Patent offices in developing countries face challenges that impact the rigorous application of the patentability thresholds. These challenges include limited human resources for patent examination, high examiner attrition rates, surge in the number of patent applications in different technical fields, backlogs of pending applications,6 and meeting expectations to increase efficiency through expedited disposal of patent applications while ensuring the robustness of the patents granted.7 Patent offices in developing countries are thus required to make policy choices that essentially entail trade-offs between these challenges. Depending on the policy choice that is prioritised, these could adversely impact the ability of the patent offices to meet the other challenges.8 In the face of", "n_tokens": 185, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-247-2", "doc_id": "medicine_vaccine_book", "page": 247, "text": "3Article 27.1 of the TRIPS Agreement requires patents to be granted in all fields of technology without discrimination as long as the patent applications satisfy the patentability criteria of novelty, inventive step and industrial applicability. However, WTO members can apply their own definitions of these criteria, and in doing so, can differentiate between fields of technology. See Correa (2012). 4The boundaries of patentability of claimed inventions have been stretched through the adoption of a number of legal fictions. For example, it is assumed that a fictional ‘person skilled in the art’ against whose level of knowledge the inventiveness or non-obviousness of a claim is to be determined, is a person of ordinary knowledge to whom even trivial developments would appear to be inventive. However, there is no obligation under any international agreement to apply such legal fictions. Correa (2014b). 5One study found that in spite of stricter thresholds of patentability established under the patent law in India, in some instances the Indian patent office has granted patent claims that had been rejected in the US and EU in spite of the application of liberal thresholds of patentability. Chaudhuri et al. (2010); a recent study found a 72% error rate in the grant of secondary pharmaceutical patent applications in India, in spite of the high threshold established under the Indian patent law (Ali et al. 2018). 6However, sometimes backlogs in processing patent applications could also lead", "n_tokens": 319, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-247-3", "doc_id": "medicine_vaccine_book", "page": 247, "text": "to withdrawal of patent applications and save the resources of a patent office. 7Cruz and Olivos (2019). 8See Shadlen (2013), p. 87.", "n_tokens": 40, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-247-4", "doc_id": "medicine_vaccine_book", "page": 247, "text": "243", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-248-0", "doc_id": "medicine_vaccine_book", "page": 248, "text": "244\n\nthese conflicting policy priorities, patent offices often prioritise patent examination speed and use of limited human resources over ensuring the quality of granted patents.9\n\nPatent offices can respond to these challenges by increasing human resources for patent examination,10 use of automation technologies or by leveraging the search and examination capacity of other national or regional patent offices. Of these, automation and reliance on the work products of other patent offices can also drive, and in turn thrive, under a globally harmonized patent system. Reliance on automation and outsourcing of search and examination work to other patent offices, depending on the nature and extent of the use of automation and outsourcing, can have an impact on the outcome of the patent examination in terms of the examination standards and practices applied. In the context of pharmaceutical patent applications, if such reliance leads to the application of lower patentability requirements that liberally allow the grant of secondary patent claims, it can have a detrimental impact on access to medicines.11", "n_tokens": 208, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-248-1", "doc_id": "medicine_vaccine_book", "page": 248, "text": "3 Approaches to Patent Harmonisation\n\nWhile patent laws are territorially limited in scope, the policy space for designing national patent law is circumscribed by the obligations of a State under applicable international IP treaties from the Paris Convention12 to the TRIPS Agreement, as well as additional obligations incurred under bilateral or regional free trade agree- ments. Certain IP treaties like the Patent Law Treaty (PLT) and the Patent Cooper- ation Treaty (PCT) administered by WIPO also impose procedural obligations which must be followed by patent offices. These can apply to both the formality require- ments in patent applications as well as to the timelines and other procedures to be followed. The scope of these treaties can also expand to shape the search and examination processes followed by national patent offices.", "n_tokens": 163, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-248-2", "doc_id": "medicine_vaccine_book", "page": 248, "text": "9Ibid, p. 88. 10It is reported that the Indian Patent Office has substantially reduced backlogs by hugely augmenting its human resources, alongside amendments of processing timelines and use of ICT tools to better leverage its internal examination capacities. The Brazilian Patent and Trademark Office has also substantially reduced backlogs through a increasing the number of patent examiners in parallel to accelerating examination of patent applications in specific sectors and utilizing prior art search conducted by other offices on corresponding applications. See, e.g., Jayakumar (2017) and Nunes and Romano (2019). 11See, e.g., European Commission (2009), pp. 385–390 (describing how strategic patenting is used by pharmaceutical companies to block the entry of generic competition). 12See generally, Dhavan (1990), p. 131 (tracing the historical evolution of the Paris Convention, its evolution towards greater protection for the patentee and less regulatory authority for member States, and the marked absence of any attempt to properly examine the public interest).\n\nN. Syam", "n_tokens": 226, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-249-0", "doc_id": "medicine_vaccine_book", "page": 249, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nBesides the pursuit of a normative approach, collaboration between patent offices can also be used as a means of promoting harmonization. Such collaborations can be non-binding and persuasive in nature, in the form of technical assistance or work- sharing arrangements between patent offices. Patent office practices can acquire the force of a customary norm13 over a long period of time.\n\n3.1 Normative Approaches\n\nMuch of the focus on patent harmonisation has been on norm-setting processes that aim to advance harmonisation of substantive aspects of patent law. Soon after the establishment of WIPO in 1967 developing countries unsuccessfully moved pro- posals to reform the Paris Convention. These attempts were countered through attempts by the WIPO secretariat to advance proposals for a complementary treaty to the Paris Convention, some of the provisions of which were eventually transposed into the TRIPS Agreement in the WTO.14 Some of the other provisions of this draft treaty were reflected in the text of the PLT that was negotiated in WIPO after the adoption of the WTO TRIPS Agreement, as well as in the Substantive Patent Law Treaty (SPLT) which was unsuccessfully negotiated in the WIPO Standing Com- mittee on the Law of Patents (SCP) till 2005.15", "n_tokens": 271, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-249-1", "doc_id": "medicine_vaccine_book", "page": 249, "text": "The SPLT negotiations were part of an agenda being pursued in WIPO that regarded full and deep harmonisation of national laws relating to patentability as essential to the larger end “... to give national and regional patent authorities access to a common operational platform that permits them to cooperate, exchange infor- mation, share resources, and reduce duplication of their work.”16 This initiative, known as the WIPO Patent Agenda, also suggested exploration of other mechanisms in addition to deep substantive harmonisation, including “... not repeating work done elsewhere ...” to free up resources for the “... promotion of innovation, development of IP management skills, and other areas where active engagement may be required to realize the benefits of the patent system.”17 Rationalisation of resource use, with a major emphasis on reducing duplication by fully or partially relying on the work done by other offices either through formal treaty arrangements", "n_tokens": 192, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-249-2", "doc_id": "medicine_vaccine_book", "page": 249, "text": "13If States act in a certain consistent manner on a given subject matter over a period of time, it is assumed under the general principles of international law that they are acting in such a manner because they have a sense of a legal obligation, and hence such practice can be regarded as a rule of customary international law. If a majority of States believe that such a customary norm cannot be persistently objected to, it can acquire the status of a peremptory norm of international law, that would be binding on all States. Baker (2010), p. 173. 14Syam (2019), p. 18. 15Ibid. 16Assemblies of the member States of WIPO (2002). 17Ibid [10].\n\n245", "n_tokens": 151, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-250-0", "doc_id": "medicine_vaccine_book", "page": 250, "text": "246\n\nor through informal cooperation, was suggested as a matter of critical importance for both patent offices as well as patent applicants.18\n\nThis element of the WIPO patent agenda has continued to be pursued both within and outside of WIPO, even after the SPLT negotiations have been abandoned. Instead of treaty making, norm-setting on enabling reliance on the work of other patent offices is pursued through discussions on using soft law instruments such as amendment of the PCT Regulations and Administrative Instructions, or through the pursuit of exploratory discussions of patent office practices that draw from initiatives pursued in the form of cooperation between patent offices outside the framework of any WIPO treaty.\n\n3.2 Persuasive Approaches\n\nMore than normative approaches, persuasive approaches have become the principal mode of promoting greater use of the work of other patent offices. The major mode of such persuasive approach has been the delivery of technical assistance and other forms of cooperation between patent offices, which have built confidence and reliance in the technical capacities, systems and work products of the patent offices from developed countries that provide such assistance and cooperation.19 In some instances, patent offices that have received such assistance and cooperation have also agreed to fully recognise the patents granted by other patent offices without subjecting the same to further examination.20", "n_tokens": 280, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-250-1", "doc_id": "medicine_vaccine_book", "page": 250, "text": "3.2.1 Technical Assistance\n\nTechnical assistance is a very critical feature of cooperation between patent offices. The United States Patents and Trademarks Office (USPTO), the Japanese Patent Office (JPO) and the European Patent Office (EPO)—collectively known as the Trilateral Offices—act as the “...global hub of co-operation and convergence in patent administration.”21 Technical assistance to patent offices in developing coun- tries has been a mode for the Trilateral Offices to introduce their technical systems for exchanging information and for search and examination of applications to the recipient offices. Indeed, such technical assistance has been delivered even before the adoption of the TRIPS Agreement.22 The delivery of technical assistance to\n\n18Ibid [12]–[32]. 19Drahos (2008a), p. 151. 20Text to n 25. 21Drahos (2008a), p. 6. 22Ibid. For example, the 1995 annual report of the EPO which tacitly admits that its technical assistance to the ASEAN countries was driven by the objective of easing the process of prosecution\n\nN. Syam", "n_tokens": 245, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-251-0", "doc_id": "medicine_vaccine_book", "page": 251, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nadvance the economic interests of patent applicants from Europe still continues. The 2017 annual report of the EPO states that “Joint projects with our member states and patent offices from other regions are key to developing an efficient, quality-based international patent system. Tools and services developed by the EPO are often at the heart of these projects.”23", "n_tokens": 88, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-251-1", "doc_id": "medicine_vaccine_book", "page": 251, "text": "One of the focus areas of cooperation for the EPO has been to enable recognition of European patents in foreign countries by concluding validation agreements with the EPO. The EPO has concluded validation agreements with the patent offices of Cambodia, Georgia, Moldova, Morocco, and Tunisia.24 Pursuant to these validation agreements, a patent applicant may request that their patent applications filed or granted in the EPO be extended to these countries. Thus, where an applicant makes such a request to the EPO, the patent application filed in the EPO is recognised as a national patent application in the country with which a validation agreement has been concluded, and provisional protection is granted in that country. Subsequently, if the patent is granted in the EPO, it would have the same effect as a national patent in that country.25 The validation requests in third countries can be made in respect of any application filed directly in the EPO as well as any international patent applica- tion filed under the PCT which subsequently entered the national phase in EPO region (European phase). The EPO is also negotiating similar validation agreements with some other countries and regional patent offices such as Brunei, Jordan, Lao PDR, the OAPI and Angola. According to the EPO, other countries in Asia have also “... signaled their interest in evaluating the possibility to enter into a validation agreement with the EPO.”26", "n_tokens": 289, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-251-2", "doc_id": "medicine_vaccine_book", "page": 251, "text": "Countries concluding such validation agreements can, in effect, limit the flexi- bility that they have under the TRIPS Agreement to apply strict standards of patentability to limit or restrict frivolous patents on pharmaceutical products27 granted by patent offices like the EPO, that apply patentability standards that are very liberal and allow some of the claims that could be rejected under a strict approach.28 It should be noted that the examination processes do not allow patent offices to reach “definitive judgments on patentability” of a claim,29 but rather weigh the balance of probability of a claim being patentable, without necessarily being absolutely certain.30 If overly broad secondary pharmaceutical patents receive\n\nof patent applications of European origin filed in those countries, through training of examiners, by incorporating search and examination results from other offices into the patent grant procedures of the patent offices that are given training, and automation of systems of patent administration. 23European Patent Office (2017). 24European Patent Office (n.d.) 25See, e.g., European Patent Office (2016). 26European Patent Office (2017). 27't Hoen (2020). 28Correa (n 4), pp. 13–16. 29Ibid, pp. 2–3. 30Ibid, p. 3.\n\n247", "n_tokens": 290, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-252-0", "doc_id": "medicine_vaccine_book", "page": 252, "text": "248\n\nvalidation outside the EPO pursuant to the validation agreements with EPO, such patents can have a negative impact on public health and access to medicines.\n\n3.2.2 Quality of Patents\n\nCooperation arrangements between patent offices have been justified as a necessity in order to improve the quality of patents.31 In this context, some national patent offices have focused on initiatives such as “... raising the threshold of inventive step, reducing the cost to examiners of rejecting an application, and reducing opportunities for applicants to manipulate the application process.”32 However, at the multilateral level, the discussion on quality of patents has largely focused on enhancing “productive efficiency”33 in the examination process of patent offices rather than on strengthening the thresholds of patentability criteria applied in the examination process.", "n_tokens": 170, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-252-1", "doc_id": "medicine_vaccine_book", "page": 252, "text": "In the WIPO SCP developed countries have advanced several proposals for developing a work programme on “quality of patents” focusing on enhancing examination resources of patent offices through technical infrastructure develop- ment, improvement of patent office administrative processes, and exploring how patent offices can cooperate and collaborate in conducting search and examination work in order to improve patent granting processes.34 The proposals essentially focus on using information technology solutions to build search and examination capacity, exchange information on the quality of patent office processes based on feedback given to patent offices by applicants, and identify ways in which search and examination processes can be improved.35 Pursuant to this, the SCP has exchanged information and shared experiences on work-sharing programmes among patent offices and use of external information for search and examination.36", "n_tokens": 163, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-252-2", "doc_id": "medicine_vaccine_book", "page": 252, "text": "31See, Drahos (2008b). 32Ibid, p. 508. See generally, Correa (n 1), pp. 3–21 (describing legal and policy measures taken by various countries, including major developed countries, to reduce the proliferation of patents). 33Drahos (2008b), p. 508 (explaining how the backlog of patent applications beyond their search and examination capacity has driven the Trilateral offices to explore means to reduce pendency and ensure timely and expedited disposal of patent applications. Long-standing cooperation with the Trilateral Offices has also imbibed the quest for productive efficiency in the patent offices from developing countries). 34See, e.g., WIPO (Standing Committee on the Law of Patents) (2011) and Proposal by the delegation of Denmark (2011). 35Ibid. 36See, e.g., WIPO (Standing Committee on the Law of Patents) (2013a), Proposal by the delega- tions of the Republic of Korea, the United Kingdom and the United States of America regarding work sharing between offices in order to improve efficiencies of the patent system (2014), Proposal by the delegation of the United States of America on the study of worksharing (2015), and Proposal by the delegations of the Czech Republic, Kenya, Mexico, Singapore and the United Kingdom (2018).\n\nN. Syam", "n_tokens": 307, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-253-0", "doc_id": "medicine_vaccine_book", "page": 253, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nIn 2016, the twenty-fourth session of the SCP agreed to undertake a survey on how WIPO member States understood “quality of patents” and implementation of cooperation and collaboration between patent offices on search and examination of patent applications. The most frequently mentioned cooperation arrangements in responses to the survey37 were the following: access to documents/databases/search systems of other offices; use of search and examination products from other offices; collaborative search and examination initiatives; carrying out search and examina- tion for other offices; exchange of examiners with other patent offices; training on search and examination by other patent offices.", "n_tokens": 148, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-253-1", "doc_id": "medicine_vaccine_book", "page": 253, "text": "4 PCT Reforms\n\nAn important vehicle for promoting cooperation between patent offices all over the world is the PCT administered by WIPO. The PCT essentially allows the filing of an international patent application in the place of multiple national patent applications. The international patent application can designate countries where national phase entry of the application may be sought by the applicant after a preliminary review of the application (not an examination) by patent offices which are recognised as PCT International Search and Examination Authorities (International Authorities). This review is called the PCT international search and examination or the “international phase.”38 In the international phase, all PCT applications go through a mandatory international prior art search with the applicants having an option to also seek an international preliminary examination report after the international search report is produced. Upon national phase entry, the patent application filed under PCT is treated as a national patent application and examined as such by the relevant national patent office. The reports produced during the international phase are available to the national offices for reference, but it is not binding on them to rely on those reports in making their decision on a patent application.", "n_tokens": 233, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-253-2", "doc_id": "medicine_vaccine_book", "page": 253, "text": "37WIPO (Standing Committee on the Law of Patents) (2017) and Responses to the questionnaire on the term “Quality of Patents” and cooperation between patent offices in search and examination (part 2) (2017). 38The PCT international phase timelines allowed a patent applicant to delay the start of national processing of an international patent application. Under the Paris Convention, a patent must be filed in a country within 12 months from the date of first filing of the application in another country. Under PCT, while the international application must be filed within this 12-month period, the national phase entry can be delayed to 30 months from the priority date. This was done to enable an applicant to assess the viability of obtaining patent protection in a territory for a claimed invention before actually pursuing national search and examination. See Mossinghof (1999) (explaining that this was particularly important for pharmaceutical companies by enabling them to file a patent on a promising drug and then using the opportunity of delayed national examination in designated countries to assess the viability of pursing a national patent in a country based on factors as such clinical trial outcomes).\n\n249", "n_tokens": 237, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-254-0", "doc_id": "medicine_vaccine_book", "page": 254, "text": "250\n\nThough the reports produced in the PCT international phase are not binding upon national offices, this system also allows patent offices that produce the international search and examination report in their capacity as International Search and Exam- ination Authority (ISEA) to influence the national examination of that application in a developing country.39 As explained by the WIPO secretariat, one advantage of the PCT system is that “... the search and examination work of patent offices can be considerably reduced or virtually eliminated ... (emphasis added).”40\n\nThe accession of developing countries to the PCT has been made an obligation in various bilateral or regional free trade agreements.41 However, while a large number of developing countries have acceded to the PCT, the system is predominantly used by applicants from a few countries.42 Moreover, the international search and exam- ination under the PCT system is conducted only by a few patent offices, and the majority of the international search and examination reports are produced by the EPO acting as an international search authority.43 At the same time, many develop- ing countries that have joined the PCT system lack capacity in conducting substan- tive examination, though they have witnessed significant increase in the number of patent applications filed in their countries through the PCT route.44", "n_tokens": 277, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-254-1", "doc_id": "medicine_vaccine_book", "page": 254, "text": "Developed countries have consistently pursued the objective of eliminating the need for search and examination of patent applications in the national phase in WIPO discussions on reforming the PCT system.45 The PCT system that was established in 1970 has been significantly transformed today through incremental reforms", "n_tokens": 57, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-254-2", "doc_id": "medicine_vaccine_book", "page": 254, "text": "39Drahos (2008a). 40WIPO, ‘Patent Cooperation Treaty (“PCT”) (1970)’ (wipo.int) <http://www.wipo.int/pct/en/ treaty/about.html> accessed 9 May 2020. 41For example, article 18.7 of the Comprehensive and Progressive Trans-Pacific Partnership Agreement makes ratification or accession to the PCT a mandatory obligation for all countries that are party to the treaty. Government of Canada, ‘Consolidated TPP Text – Chapter 18 – Intellectual Property’ (international.gc.ca) https://www.international.gc.ca/trade-commerce/trade- agreements-accords-commerciaux/agr-acc/tpp-ptp/text-texte/18.aspx?lang¼eng. 42May (2007), p. 49. 43According WIPO statistics, more than 70% of International Search Reports under PCT between 2000 to 2018 have been issued by EPO, USPTO and JPO. Though the number of International Search Reports from China and South Korea have significantly increased in recent years, the EPO, USPTO and JPO continue to produce more than 65% of these reports between 2015 to 2018. See World Intellectual Property Organization (n.d.). 44See, e.g., Shashikant (2014), pp. 17–21 (pointing out that most patent applications in the African Regional Intellectual Property Office (ARIPO) are filed through the PCT route while the ARIPO has a capacity of 12 patent examiners, and that ARIPO relies heavily on the results of the PCT or foreign search and examination results and on the EPO guidelines). 45See, e.g., WIPO (Committee on Reform of the Patent Cooperation Treaty) (2001) (proposal to make PCT", "n_tokens": 409, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-254-3", "doc_id": "medicine_vaccine_book", "page": 254, "text": "search and examination binding on PCT Contracting Parties while simplifying PCT procedures for patent applicants); WIPO (Patent Cooperation Treaty (PCT) Working Group) (2018), (proposal by the WIPO secretariat to amend the PCT Regulations to enable national patent offices to delegate their national office functions to the office of any other PCT Contracting State or an intergovernmental organisation); also see, Rathod and Ali (2018).", "n_tokens": 99, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-254-4", "doc_id": "medicine_vaccine_book", "page": 254, "text": "N. Syam", "n_tokens": 4, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-255-0", "doc_id": "medicine_vaccine_book", "page": 255, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nintroduced through amendments to the Rules, Regulations and Administrative Instructions through which the PCT system operates.\n\nSeveral proposals have been advanced by developed countries to discourage duplication of international phase work under the PCT system in the national phase, encourage collaborative search and examination or work sharing between patent offices, or enable national search and examination to be dispensed with at the option of a PCT Contracting Party. The US had submitted a proposal at the PCT Union Assembly of WIPO in 2000 for reform of the PCT in two stages—first, simplifying certain procedures and aligning the PCT with the PLT, followed by a comprehensive overhaul of the PCT system.46 This proposal had received broad support from most developed countries.\n\nThe US proposal was transmitted to the PCT Union Assembly by the WIPO secretariat with a recommendation to establish a special body that should consider the proposal along with other possible proposals and report to the PCT Union Assembly.47 The PCT Union Assembly established an ad hoc Committee on Reform of the PCT. The committee met in two sessions from 2001 to 2002 and discussed a number of proposals from WIPO member States and observers.48", "n_tokens": 251, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-255-1", "doc_id": "medicine_vaccine_book", "page": 255, "text": "46WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2000a), (the proposal pointed to the need to simplify PCT procedures and converge PCT and patent office practices to the extent possible to facilitate obtaining worldwide patent protection through simplified application, preferably in electronic format, and minimize the distinction between international and national processing of the patent applications. Eventually, the proposal envisaged adopting procedures that would enable substantive rights to be granted through the PCT. More specifically, the changes proposed to the PCT system in the first stage included the following: elimination of the concept of designation of PCT Contracting Parties in respect of which an international patent application is filed, thus making an international application applicable to all PCT Contracting Parties and relieving the applicant from paying the designation fees; eliminating residency and nationality requirements for filing international patent applications, thus enabling any person regardless of residence or nationality to file a PCT application in any patent office of a PCT Contracting Party; aligning PCT filing date requirements to the PLT; aligning PCT rules on filing of missing parts in an application to the rules in the PLT; enabling an applicant to request supplementary search and examination from multiple International Search Authorities; subjecting all PCT applications to a preliminary international examination following", "n_tokens": 277, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-255-2", "doc_id": "medicine_vaccine_book", "page": 255, "text": "the international search report; enabling further delaying of national phase entry of an application at the option of the applicant; combining search and examination processes; and, facilitating electronic publication of the application and transmis- sion of search and examination results. The comprehensive reforms envisaged were regional consolidation of international search and examination authorities; eliminating the distinction between national and international applications to avoid duplication of processing the application in the international and national phases; making positive examination results from certain PCT international search and examination authorities binding on Contracting States; and, allowing for further deferment of national phase entry of an international application at the option of the applicant). 47WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2000b). 48See, WIPO (2001) (for the proposals made by the Austria, Australia, Canada, Cuba, the Czech Republic, Denmark, EPO, France, India, Israel, Japan, Republic of Korea, the Netherlands, Spain, Slovakia, Switzerland, Turkey, the UK and the USA).", "n_tokens": 211, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-255-3", "doc_id": "medicine_vaccine_book", "page": 255, "text": "251", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-256-0", "doc_id": "medicine_vaccine_book", "page": 256, "text": "252\n\n4.1 Working Group on PCT Reforms\n\nThe Working Group on Reform of the Patent Cooperation Treaty was established by the PCT Union Assembly49 pursuant to the recommendation of the ad hoc commit- tee. In its first two sessions in 2001 and 2002, the working group discussed the issues that were identified for further examination by the committee. The WIPO secretariat prepared draft proposals50 based on the recommendations of the working group and submitted the same to the committee at its second session in 2001. These proposals were broadly focused on three issues: improved coordination of international search and international preliminary examination under the PCT and the time limit for national phase entry; the concept and operation of the designation system; and changes related to the PLT.\n\n4.1.1 Establishment of a Written Opinion on Patentability to Accompany the International Search Report", "n_tokens": 169, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-256-1", "doc_id": "medicine_vaccine_book", "page": 256, "text": "On the recommendation of the committee, the PCT Union Assembly amended the PCT Regulations to the effect that a patent office could act as an International Search Authority or an International Preliminary Examination Authority under the PCT if it also held an appointment in the other capacity.51 This amendment effectively allowed the same patent office to act as both the search and the examining authority in the international phase. This also enabled the expansion of the role of the International Search Authority through another amendment to the PCT Regulations to require them to issue in addition to the International Search Report—that would identify prior art documents in their order of relevance in relation to the claims made in the international patent application—a Written Opinion on whether the claims satisfy the patentability requirements in the light of the prior art revealed in the international search. This fundamentally changed the international search phase in the PCT to include a written opinion in the nature of a first examination report (FER) on the patent application. If an international preliminary examination under chapter II of the PCT was not requested by the applicant, the International Bureau of WIPO was required to prepare an International Preliminary Report on Patentability (IPRP) based on the Written Opinion of the International Search Authority (WOISA).52 Thus, even if the applicant does not exercise the option of seeking an international preliminary", "n_tokens": 268, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-256-2", "doc_id": "medicine_vaccine_book", "page": 256, "text": "examination following the international search report and publication of the application, national offices today receive not just a search report but also an", "n_tokens": 26, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-256-3", "doc_id": "medicine_vaccine_book", "page": 256, "text": "49WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2001). 50See, WIPO (Committee on Reform of the Patent Cooperation Treaty (PCT)) (2002) and WIPO International Patent Cooperation Union (2002a, b, c, d). 51WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2002). 52WIPO (Committee on Reform of the PCT), PCT/R/2/7 (n 51) [10].\n\nN. Syam", "n_tokens": 111, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-257-0", "doc_id": "medicine_vaccine_book", "page": 257, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nIPRP on whether the application prima facie meets the patentability criteria. Deeper harmonisation of patent examination procedures was thus set in motion.\n\n4.1.2 Automatic Designation of all PCT Contracting Parties\n\nfor National Phase Entry\n\nThe PCT Union Assembly also approved amendments to the PCT Regulations53 to make the filing of a PCT application automatically applicable for national phase entry in all PCT Contracting Parties.54 Thus, applicants are no longer required to designate national or regional patent offices for national phase entry and pay associated fees.\n\n4.1.3 Establishment of an Optional Supplementary International", "n_tokens": 133, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-257-1", "doc_id": "medicine_vaccine_book", "page": 257, "text": "Search\n\nThe committee recommended to continue future discussions on PCT reforms in the mode of the working group directly reporting to the PCT Union Assembly on the basis of the proposals submitted and future proposals. Several proposals relating to the reform of the PCT system were discussed in this working group in nine sessions held from 2001 to 2007.\n\nThe third session of the working group discussed the outstanding proposals relating to PCT reforms.55 These included proposals relating to further improvement of the international search and examination system, for instance, to allow the applicants to opt for supplementary or top-up search.56 The fourth session of the working group discussed an options paper on the future development of the inter- national search and examination system, which suggested that the possibility of considering substantive revisions to the PCT for allowing search or examination by multiple authorities, introducing a supplementary search, a “top-up” search for new documents during the international examination, or even allowing a re-examination", "n_tokens": 189, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-257-2", "doc_id": "medicine_vaccine_book", "page": 257, "text": "53WIPO (International Patent Cooperation Union (PCT Union) Assembly), ‘Report’ (n 52). 54WIPO (Committee on Reform of the PCT), PCT/R/2/6 (n 51). 55WIPO (Working Group on Reform of the Patent Cooperation Treaty (PCT)) (2002a). The proposals were categorized into two groups based on whether the proposal would require an amendment of the treaty. Increasing reliance by national offices on the international search reports and IPERs, electronic transmission of search and examination results, establishment of regional patent offices as ISA, and technical assistance were among the issues that were deemed to not require any treaty amendment to be implemented. The working group also discussed whether the treaty itself should be revised, and the possible ways of undertaking its revision. It also recommended to the PCT Union Assembly to amend the PCT Regulations to allow the applicants to file for correction or addition of a priority claim in the international application within a stipulated time period. 56See, WIPO (Working Group on Reform of the Patent Cooperation Treaty (PCT)) (2002b).\n\n253", "n_tokens": 235, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-258-0", "doc_id": "medicine_vaccine_book", "page": 258, "text": "254\n\nby the International Authority after national phase entry of the application.57 It was also suggested that the international examination report could also indicate whether the application included subject matter on which there is variance in national laws concerning their patentability.58 It was assumed that this would facilitate non-duplication of search and examination at the national phase on subject matter regarding which the application of the patentability criteria was relatively harmo- nized in practice. It is pertinent to note here that such harmonisation was being pursued by the Trilateral Offices through their technical assistance and cooperation programmes with national and regional patent Offices of several countries.", "n_tokens": 128, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-258-1", "doc_id": "medicine_vaccine_book", "page": 258, "text": "The WIPO secretariat suggested that States that did not have their own search and examination systems, or wished to reduce duplication of search and examination done by other offices, or to have a system for validation of patents in certain cases, could consider adoption of an optional protocol to register patents based on national phase entry accompanied by the international search and examination report, or allow the applicant to amend the application in case of a negative international examination report so as to enter the national phase with a positive report on patentability, or seek a re-examination at the international phase even after national phase entry.59 The working group requested the WIPO Director-General to under- take consultations on these options.60", "n_tokens": 141, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-258-2", "doc_id": "medicine_vaccine_book", "page": 258, "text": "At the sixth session of the working group, the WIPO secretariat submitted a proposal for amendments to certain rules under the PCT Regulations to allow the applicants to request for a supplementary international search by other International Search Authorities in order to obtain a more thorough search report, and also to request for an updated or “top-up” search during the international preliminary examination.61 Following extended discussions over the next three sessions of the working group, consensus could not be reached. However, the 2007 PCT Union Assembly agreed to a proposal by France62 and a related joint proposal by Japan and Spain63 to amend the PCT Regulations to allow the applicants to make a request for a supplementary international search.64\n\n57See, WIPO (Working Group on Reform of the Patent Cooperation Treaty (PCT)) (2003a). 58Ibid [18]. 59WIPO (Working Group on Reform of the Patent Cooperation Treaty (PCT)) (2003b). 60WIPO (Working Group on Reform of the Patent Cooperation Treaty (PCT)) (2003c). 61WIPO (Working Group on Reform of the Patent Cooperation Treaty (PCT)) (2004). 62WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2007a). 63WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2007b). 64WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2007c).\n\nN. Syam", "n_tokens": 304, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-259-0", "doc_id": "medicine_vaccine_book", "page": 259, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\n4.2 New PCT Working Group\n\nThe WIPO secretariat presented a report on the PCT reforms process to the 2007 PCT Union Assembly which noted that the working group had addressed all the issues on its agenda relating to the reform of the PCT and had reached agreement on amending the PCT Regulations on some of those issues.65 However, it also noted that there would be an ongoing need for minor changes to the PCT Regulations in relation to certain proposals. It thus recommended the Assembly to formally declare the end of the mandate of the Committee on Reform of the PCT and the working group.66 The Assembly agreed to a proposal by the WIPO secretariat to establish a new working group to do preparatory work on matters that would be considered by the Assembly in future.67 This new working group—known as the PCT Working Group—has been meeting annually since 2008 with a broad mandate to discuss any matter which requires consideration of the PCT Union Assembly.", "n_tokens": 207, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-259-1", "doc_id": "medicine_vaccine_book", "page": 259, "text": "Discussions continued in the new PCT Working Group on promoting greater reliance on the International Search and Examination reports under the PCT system based on a preliminary discussion paper by the WIPO secretariat on enhancing the value of international search and preliminary examination under the PCT.68 The discussion paper pointed to existing mechanisms within the PCT which can deliver similar benefits as work sharing mechanisms outside the PCT system, with the advantage of being more effective and being able to reach out to a larger audience. The paper raised certain questions for further consideration in order to improve the implementation or use of those mechanisms. The WIPO secretariat is of the view that any deficiency within the PCT system is primarily due to the way in which the system has been used sub-optimally by national offices, including International Authorities, and this could be addressed within the PCT system without engaging in any new PCT reform exercise.69 At the request of the working group the WIPO secretariat produced another study on how to make the content of the international preliminary examination report more useful for the purpose of patentability assess- ment by national offices, and how to improve the international examination process itself.70", "n_tokens": 240, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-259-2", "doc_id": "medicine_vaccine_book", "page": 259, "text": "The second session of the working group also discussed a number of other proposals aimed at deeper reform of the PCT. These included a roadmap proposed by the WIPO secretariat on the work that could be undertaken to facilitate a greater use of the PCT system by national patent offices, including International Authorities, with a focus on reduction or elimination of unnecessary duplication of search and examination work undertaken in the international phase when the application enters\n\n65WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2007d). 66Ibid. 67WIPO (International Patent Cooperation Union (PCT Union) Assembly) (n.d.). 68WIPO (Patent Cooperation Treaty (PCT) Working Group) (2008). 69Ibid [3]. 70WIPO (Patent Cooperation Treaty (PCT) Working Group) (2009a).\n\n255", "n_tokens": 179, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-260-0", "doc_id": "medicine_vaccine_book", "page": 260, "text": "256\n\nthe national phase, greater use of work-sharing mechanisms developed outside the PCT system, and with the objective of ensuring high quality of granted patents while at the same time reducing the backlog of pending patent applications.71 The working group also discussed other related proposals by the Republic of Korea for a three- track PCT system72 and a proposal by the US for comprehensive PCT reform.73\n\nThe proposal by the WIPO secretariat on a roadmap for PCT reforms was discussed extensively through the session. The roadmap aimed to achieve a number of milestones74 which included reaching agreement on establishing a second written opinion prior to the issuance of a negative international examination report so as to allow the applicant the opportunity to amend the claims, including a “top-up” search in the international examination phase for prior art that may not have been available at the time of the international search done earlier, and establishing a third party observation system in the international phase.\n\nSome developing countries were particularly concerned that the proposals in the roadmap as well as the related proposals on work sharing and comprehensive PCT reform effectively promoted harmonization of national patent examination practices,", "n_tokens": 234, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-260-1", "doc_id": "medicine_vaccine_book", "page": 260, "text": "71WIPO (Patent Cooperation Treaty (PCT) Working Group) (2009b). 72WIPO (Patent Cooperation Treaty (PCT) Working Group) (2009c) (the Korean proposal sought to introduce amendments to the timelines in the PCT international search and examination phase to give the applicants the option to request for either accelerated examination, regular examination or deferred examination). 73WIPO (Patent Cooperation Treaty (PCT) Working Group) (2009d) (the US proposal suggested the establishment of a new PCT (PCT II) which would allow the applicant to submit prior art document along with the application, which would then be searched by two Authorities, and an international preliminary report on patentability would be established by a third International Authority, which would also receive third party observations. A positive international report on patentability would automatically form the basis for the grant of a national patent, unless a national office expressly rejects the report within a specified period). 74WIPO (Patent Cooperation Treaty (PCT) Working Group), PCT/WG/2/3 (n 71). The roadmap aimed to achieve the following milestones to improve the PCT system: (1) obtain a commitment from offices acting as International Search Authorities to not repeat the search done by them at the international phase when the application enters the national phase in the same office; (2) work towards elimination of reservations, notifications and declarations of incompatibility to the PCT, PCT Regulations", "n_tokens": 322, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-260-2", "doc_id": "medicine_vaccine_book", "page": 260, "text": "and Administrative Instructions in order to ensure a consistent effect of the international patent applications in all Contracting States; (3) reaching an agreement that all International Authorities will issue at least one written opinion prior to the issuance of a negative international preliminary report on patentability, at least in cases where the applicant has provided a substantive response to the written opinion of the International Search Authority; (4) develop a system of third party observations on novelty and inventive step to be made available to the International Preliminary Examination Authorities and designated offices; (5) including a “top- up” search in international preliminary examination on patentability; (6) eliminating unnecessary processing of an application through both the national as well as the PCT route and exploring the reasons why applicants use different routes for filing the same application; (7) establish a pilot project on collaborative search and examination by testing models allowing examiners from at least 3 different offices to work on the same application to establish a common international search report or written opinion; and, (8) undertake discussion in the working group on measures that could be undertaken to ensure that procedures and fee structures are appropriate to encourage use of the PCT system in a manner which is efficient and beneficial for all applicants and offices.", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-260-3", "doc_id": "medicine_vaccine_book", "page": 260, "text": "N. Syam", "n_tokens": 4, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-261-0", "doc_id": "medicine_vaccine_book", "page": 261, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nwhich could limit the ability of national Offices to undertake search and examination of patent applications entering the national phase through the PCT route.75 The working group agreed to undertake further discussion on the proposals based on an assessment of the need for any change in the PCT system in the light of existing problems and challenges facing the system, while ensuring that the freedom of Contracting States to prescribe, interpret and apply substantive conditions of patent- ability, and without seeking substantive harmonization or harmonization of national search and examination procedures.76\n\nThus, the third session of the PCT Working Group discussed a report77 by the WIPO secretariat analysing the functioning of the PCT system and the problems and challenges it faced. The Working Group endorsed the recommendations made in the report related to backlogs and improving the quality of granted patents,78 timeliness in the international phase,79 the quality of international search and preliminary", "n_tokens": 198, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-261-1", "doc_id": "medicine_vaccine_book", "page": 261, "text": "75WIPO (Patent Cooperation Treaty (PCT) Working Group) (2009e). 76Ibid [94]. 77WIPO (Patent Cooperation Treaty (PCT) Working Group) (2010a). The report advanced a number of recommendations to address the following challenges relating to the PCT system— assisting patent offices to address the problem of backlogs in processing patent applications and in improving the quality of granted patents; enhancing the actual and perceived quality of international search and examination in the PCT; creating incentives for the applicants to use the PCT system efficiently; addressing skills and manpower shortage in patent offices; addressing the need for access to effective search systems for national offices; addressing cost and accessibility of the PCT system for applicants; addressing the consistency and availability of safeguards in the form of reservations, notifications or declarations of incompatibility to the PCT, the regulations and administrative instructions; provision of technical assistance; and use of PCT information for technology transfer. 78Ibid [143], [146], [149]. These recommendations are the following: (1) Offices which act as International Authorities should take steps to improve the actual and perceived quality of the reports they establish under the PCT system to ensure that they provide content that designated and elected offices wish to take into account; (2) designated and elected offices should review the content of ISRs and IPRPs and make recommendations for their", "n_tokens": 310, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-261-2", "doc_id": "medicine_vaccine_book", "page": 261, "text": "improvement; (3) the International Bureau of WIPO and the International Authorities should review the proposals for changes in the content of ISRs and IPRPs and report back to the next session of the Working Group; (4) the exercise should in no way affect the right of designated and elected offices to use the ISRs and IPRPs as they see fit in accordance with their national laws and policies; (5) national offices which conduct search and examination in the national phase should consult with the International Bureau of WIPO on ways of making their national reports available to other national Offices and the International Bureau should ensure making these reports available through WIPO’s PATENTSCOPE database; (6) the Interna- tional Bureau of WIPO should make available a system of allowing third party observations on published international applications. The Working Group also recommended that the Chief Econ- omist of WIPO should undertake a study to analyse the root causes behind the surge in patent applications and the consequent heavy load on the international patent system. 79Ibid [152]. One of these recommendations required International Authorities to ensure they have adequate resources to conduct the expected number of international search and preliminary exam- ination in addition to their national work and give appropriate priority to international work in case of backlogs to ensure timely availability of the results to the other national offices.", "n_tokens": 284, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-261-3", "doc_id": "medicine_vaccine_book", "page": 261, "text": "257", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-262-0", "doc_id": "medicine_vaccine_book", "page": 262, "text": "258\n\nexamination,80 incentives for applicants to effectively use the system,81 skills and manpower shortages,82 access to effective search systems,83 cost and other accessi- bility issues,84 consistency and availability of safeguards,85 technical assistance, PCT information and technology transfer.86 The Working Group also discussed a", "n_tokens": 63, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-262-1", "doc_id": "medicine_vaccine_book", "page": 262, "text": "80Ibid [165], [170]. These recommendations were the following: (1) International Authorities should develop internal quality management systems in accordance with the quality framework under the International Search and Preliminary Examination Guidelines, with the objective of developing high quality ISRs and IPRPs; (2) International Authorities should seek ways to effectively search documentation in other languages; (3) national offices whose national patent collections are not readily available in electronic form should consider digitizing them; (4) the international Bureau should coordinate the development of a centralized system for designated offices to give feedback to International Authorities; (5) International Authorities should recognise the quality of their own work and not routinely conduct more than a “top-up” search for the same application in the national phase; (6) International Authorities should seek to make more informa- tion available relating to search strategies so that designated offices can easily assess the scope of the international search conducted; (7) International Authorities should seek to cite documents from a wide range of sources where possible; (8) International Authorities should encourage examiners to give good explanation of the relevance of cited documents, especially where the examiner considers there is lack of inventive step. 81Ibid [176]. These recommendations were the following: (1) the International Bureau and national offices should", "n_tokens": 273, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-262-2", "doc_id": "medicine_vaccine_book", "page": 262, "text": "recommend applicants to prepare their applications in good time and conduct their own prior art search before drafting their claims; (2) International Authorities should offer appli- cants a good opportunity for dialogue with the examiner during the international preliminary examination, least one written opinion before establishing a negative IPRP; (3) Contracting States should consider possible incentives which could be introduced at the international or national level to encourage applicants to file higher quality applications and have defects corrected in the international phase. 82Ibid [181]. National offices which are able to offer training in search and substantive examination were encouraged to coordinate their activities in order to provide complementary training. 83Ibid [185]. The International Bureau and Contracting States were encouraged to seek practical and affordable ways for national offices to develop online searching capabilities. 84Ibid [193]. The International Bureau and Contracting States were recommended to consider ways in which procedures could be simplified for applicants without needing to change national laws; review the level of fees for different types of applicants; review the PCT Applicant’s Guide to ensure that it is updated and provides information that is useful and easy to understand; ensure while updating the PCT online systems that the language, interfaces and associated help reduce the need to consult the PCT Regulations by the users. 85Ibid", "n_tokens": 268, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-262-3", "doc_id": "medicine_vaccine_book", "page": 262, "text": "[198]. Contracting States were recommended to review their notifications of incompatibility with the PCT Regulations and Administrative instructions and seek to determine whether they can withdraw the notifications of incompatibility. 86Ibid. The following recommendations were adopted: (1) when requesting technical assistance in the context of the PCT offices and Contracting States should ensure that the purpose of the request is clear and that the International Bureau is aware of the related national policies and ensure that the advice, training and systems which are delivered take the needs and national policies properly into account; (2) a study be conducted by the International Bureau to look into the issue of coordination of technical assistance for developing countries under Article 51 of the PCT; (3) that the interna- tional Bureau work with national offices to deliver effective patent status information; (4) a system of promoting licensing of patented technologies should be established enabling patentees to indicate their willingness to out license their patented technologies; (5) that the International Bureau", "n_tokens": 214, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-262-4", "doc_id": "medicine_vaccine_book", "page": 262, "text": "including at\n\nN. Syam", "n_tokens": 6, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-263-0", "doc_id": "medicine_vaccine_book", "page": 263, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nproposal by the WIPO secretariat for establishing a third-party observation system in the PCT and recommended that the WIPO secretariat should begin the development of such a system87 which has been operational since July 2012.\n\nIn the following sessions of the working group, some of PCT International Authorities reported on implementation of pilot projects between them on collabo- rative search and examination88 as well as integration of existing work sharing mechanisms outside the PCT system with the PCT. The PCT Regulations and Administrative instructions were also further amended to require International Preliminary Examination Authorities to conduct a mandatory “top-up” search for additional prior art that may not have been available at the time of conducting the international search.89 Subsequent sessions of the PCT have continued to discuss proposals on work sharing within the PCT system and share experiences of work sharing arrangements between national offices as well as pilot projects within the PCT system.", "n_tokens": 200, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-263-1", "doc_id": "medicine_vaccine_book", "page": 263, "text": "5 Work Sharing Arrangements Between Patent Offices\n\nSince the 1980s, the Trilateral Offices have entered into MOUs which have effec- tively made them “... the global hub of co-operation and convergence in patent administration.”90 An integral part of this cooperation between the Trilateral Offices, which have been gradually extended to include other patent offices, has been the exploration of various work sharing arrangements relating to different aspects of the work of a patent office, involving two or more patent offices. The possibility of integration of such work sharing arrangements inside the PCT system is also being discussed in the PCT Working Group of WIPO. The WIPO SCP discussions on quality of patents have also focused on sharing experiences of such work sharing arrangements.\n\nWork sharing arrangements have typically evolved through cooperation between patent offices over time through an incremental approach, led by the few major patent offices that process the bulk of the world’s patent applications. Such cooper- ation leverages the use of information and communications technologies (ICT) through digitization of patent documents, machine translation, electronic exchange of priority documents as well as search and examination reports. From mere exchange of information and reports, the work sharing arrangements can develop", "n_tokens": 260, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-263-2", "doc_id": "medicine_vaccine_book", "page": 263, "text": "undertake a follow up study on how effectively the PCT system has functioned in terms of disseminating technical information and facilitating access to technology and technical assistance to developing countries. 87WIPO (Patent Cooperation Treaty (PCT) Working Group) (2010b). 88WIPO (Patent Cooperation Treaty (PCT) Working Group) (2012). 89WIPO (Patent Cooperation Treaty (PCT) Working Group) (2013). 90Drahos (2008a).\n\n259", "n_tokens": 98, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-264-0", "doc_id": "medicine_vaccine_book", "page": 264, "text": "260\n\nfurther to include greater cooperation wherein offices agree to make use, sometimes to the best possible extent, the work products of other offices. The emphasis, as discussed previously, is on increasing productive efficiency through speeding up the search and examination process.", "n_tokens": 55, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-264-1", "doc_id": "medicine_vaccine_book", "page": 264, "text": "5.1 Trilateral Cooperation\n\nThe EPO, JPO and the USPTO have implemented a number of work sharing arrangements between them under the Trilateral Cooperation that was launched in 1983 in order to deal with the dramatic increase in the number of patent application filings impacting the Trilateral Offices.91 The initial area of cooperation was focused on digitization of all patent documents issued after 1920 and creating a common database of such documents. This was further expanded in subsequent years by the Trilateral Offices to develop a network for exchanging priority documents, an electronic exchange format for priority documents and a common patent application format.92\n\nDigitization, creation of technology specialized databases, and creation of a common ICT architecture facilitated electronic filing of applications and the conduct of paperless electronic search. However, the Trilateral Cooperation was not limited to facilitating exchange of documents. A number of comparative studies conducted by the Trilateral Offices on examination practices and the application of patentability criteria resulted in the harmonization of patent examination practices in various emerging technology fields, and also led to efforts to revise the PCT international search and examination guidelines.93", "n_tokens": 231, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-264-2", "doc_id": "medicine_vaccine_book", "page": 264, "text": "The Trilateral Offices have also explored a number of projects for collaborative search and examination on a common patent application. In 2007 the USPTO and JPO launched a pilot project called “New Route” under which a national or regional patent application filed in either of the offices is deemed to be an application in the other office, and the search and examination results produced by the office of first filing can be used by the office of second filing in their own search and examination of the application. The applicant is also provided additional time, similar to that available under the PCT, to decide on whether to pursue the application in the other office, based on the search and examination results in the office of first filing.94 The Trilateral Offices also agreed to undertake a pilot project known as the “Triway Pilot Programme” from 2008 to 2009, wherein all three offices agreed to conduct their own prior art search on a corresponding national application filed in all three offices\n\n91Trilateral (n.d.-a). 92Trilateral (n.d.-b). 93See Trilateral (n.d.-c). 94See, Trilateral, ‘New Route’ (trilateral.net) https://www.trilateral.net/projects/worksharing/new- route/new-route_index.\n\nN. Syam", "n_tokens": 300, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-265-0", "doc_id": "medicine_vaccine_book", "page": 265, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nand share the search results with each other in a timely manner.95 In 2008, the Trilateral Offices also launched a pilot project on Strategic Handling of Applications for Rapid Examination (SHARE) under which each office agreed to give procedural priority to examining applications for which it is the office of first filing, with the understanding that the office of second filing would use the search and examination results of the office of first filing to the maximum extent practicable.96\n\n5.2\n\nIP5 Cooperation", "n_tokens": 125, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-265-1", "doc_id": "medicine_vaccine_book", "page": 265, "text": "With the emergence of the patent offices of China (CNIPA) and South Korea (KIPO) among the leading patent offices in the world alongside the EPO, JPO and the USPTO, a similar framework of cooperation as among the Trilateral Offices has been established to include the CNIPA and KIPO.97 This group is known as the IP5. The IP5 cooperation is particularly significant because almost 80% of the total patent applications in the world and almost 95% of the international patent applications under the PCT are processed by the IP5 offices.98 The IP5 was launched in 2007 as a forum for cooperation among the leading five patent offices with a focus on “the elimination of unnecessary duplication of work among the offices, enhancement of patent examination efficiency and quality, and guarantee of the stability of patent right.”99 In 2017, the IP5 expanded their vision to cooperate on “Patent harmoniza- tion of practices and procedures, enhanced work-sharing, high-quality and timely search and examination results, and seamless access to patent information to pro- mote an efficient, cost-effective and user-friendly international patent landscape.”100 It should be noted, as discussed in the previous section, that around the same time as the IP5 was launched, similar initiatives focused on promoting work sharing with a focus on elimination of “unnecessary duplication” was also being pursued in the WIPO discussions on PCT reforms. This means that when the proposals for reforms in the PCT international", "n_tokens": 331, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-265-2", "doc_id": "medicine_vaccine_book", "page": 265, "text": "phase were advanced in the PCT working group discus- sions, the patent offices that handled almost the entire workload of the PCT inter- national phase work were largely aligned to the proposed reforms. Reform of the PCT system is an integral part of the work of the IP5 which has also initiated a pilot project on collaborative search and examination of international applications under the PCT. The IP5 group’s perspectives and initiatives on quality management systems and work sharing arrangements are also discussed for possible integration in the PCT system.", "n_tokens": 109, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-265-3", "doc_id": "medicine_vaccine_book", "page": 265, "text": "95Hu (2017). 96Neppel (2012). 97Ibid. 98fiveIPoffices (n.d.). 99Ibid. 100Ibid.\n\n261", "n_tokens": 40, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-266-0", "doc_id": "medicine_vaccine_book", "page": 266, "text": "262\n\nOne of the areas of cooperation among the IP5 offices is harmonization of patent classification systems among the IP5 offices as well as revision of the International Patent Classification (IPC) system administered by WIPO, to align the same to the Cooperative Patent Classification (CPC) system of the IP5 and to introduce new classifications in fast moving emerging technology areas.101 Such cooperation is also part of the Trilateral Cooperation discussed above.\n\nAnother major area of focus for the IP5 has been the “Global Dossier” project which seeks to offer, in a single portal, free and secure access to the dossier information on all applications in the same patent family that have been filed in the IP5 offices. The Global Dossier information has been expanded and linked with the WIPO Centralized Access to Search and Examination (CASE) system to include dossier information on patent applications under the same family filed in other patent offices outside the IP5 group.102\n\nBeyond the creation and expansion of systems to facilitate sharing of dossier information and conducting collaborative search and examination, the IP5 have also been exploring harmonisation of patent office practices within the IP5 in respect of patent application and grant procedures. It is possible that as the office practices are harmonised within the IP5, these could be extended through bilateral cooperation arrangements by the any of the IP5 offices to other patent offices across the world.", "n_tokens": 307, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-266-1", "doc_id": "medicine_vaccine_book", "page": 266, "text": "5.3 The Vancouver Group\n\nIn 2008, the IP offices of Australia, Canada and the United Kingdom (UK) formed a collaboration arrangement between them known as the Vancouver Group, with a similar focus as the IP5 and parallel discussions in WIPO on elimination of unnec- essary duplication and ensuring more effective work sharing. Mutual exploitation of the work of each office with regard to patent search and examination has been a priority area of the collaboration between the Vancouver Group offices. Thus, the Vancouver Group has agreed on a set of principles on the basis of which mutual exploitation can be undertaken. These include relying on the grant of patent or the search and examination report of another Vancouver group office where possible, taking self-initiative for such work sharing without requiring the applicant to make a request, and utilizing the WIPO CASE system for the same.103\n\n101fiveIPoffices, ‘Classification (Working Group 1)’ (fiveipoffices.org) https://www.fiveipoffices. org/activities/class. 102WIPO (n.d.-a). 103See, Vancouver Group (n.d.).\n\nN. Syam", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-267-0", "doc_id": "medicine_vaccine_book", "page": 267, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\n5.4 PROSUR\n\nPROSUR is a regional collaboration initiative launched in 2010 between IP offices of 13 Latin American countries.104 The PROPSUR initiative seeks to enhance efficiency and quality in the search, examination and decision-making processes of the participating IP offices through the exchange of data and information systems. The primary focus of the PROSUR countries is on exchange of information and opinions on patent applications, which can be available as a reference for the other participating offices in the conduct of their own search and examination.105 The information is shared among the PROSUR countries using ICT such as WIPO CASE and the electronic platform for collaborative examination (e-PEC) created by the patent offices of Argentina and Brazil.", "n_tokens": 165, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-267-1", "doc_id": "medicine_vaccine_book", "page": 267, "text": "5.5 ASPEC\n\nIn 2009 the nine member States of the Association of South-East Asian Nations (ASEAN) launched a regional patent work sharing programme called the ASEAN Patent Examination Cooperation (ASPEC).106 Similar to PROSUR, ASPEC allows IP offices from ASEAN Member States to utilise search and examination results on a corresponding application in other ASEAN Member States. In 2019, applicants were also given the possibility of requesting utilizing the ASPEC mechanism to use international search and examination reports produced under the PCT in relation to a corresponding application by an International Authority within the ASPEC partic- ipating countries.\n\n5.6\n\nIP BRICS\n\nThe IP offices of Brazil, Russia, India, China and South Africa (BRICS) launched a cooperation among the BRICS IP offices in 2012. In 2013 the IP BRICS agreed to a roadmap for cooperation.107 The areas of cooperation agreed upon in this forum include exchange of IP office staff and examiner trainings, exchange of examination related patent information data and IP documentation exchange and sharing, and\n\n104The countries that are represented in PROSUR are Argentina, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Ecuador, El Salvador, Nicaragua, Panama, Paraguay, Peru, and Uruguay. See, PROSUR (n.d.). 105Castillo (2012). 106ASEAN Intellectual Property Portal (n.d.). 107IP BRICS (2013).\n\n263", "n_tokens": 304, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-268-0", "doc_id": "medicine_vaccine_book", "page": 268, "text": "264\n\npatent processes and procedures.108 As part of this cooperation, annual meetings of the heads of the BRICS IP offices have been held since 2013, and 2 patent examiner trainings have been organized till date.109 Studies to explore examination practices and procedures relating to specific kinds of patent claims, such as Markush claims110 relating to pharmaceutical patents, have also been proposed.111", "n_tokens": 81, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-268-1", "doc_id": "medicine_vaccine_book", "page": 268, "text": "5.7 Patent Prosecution Highway\n\nThe Patent Prosecution Highway (PPH) is the most extensive work sharing arrange- ment outside the PCT system. The PPH is a collaboration framework between participating patent offices in which an applicant receiving a positive determination on the patentability of a claim can make a request for accelerated examination of the corresponding claim in another participating patent office by using the search and examination results from the first office. According to the USPTO, an examiner will generally examine the application within 2–3 months of the PPH examination request being granted,112 though there is no maximum time-period within which the examination should be done by the office conducting the accelerated processing. The processing time would obviously vary from one patent office to another relative to the number of applications they have to examine, with offices with a lower number of applications processing PPH accelerated search and examination faster than offices with higher number of applications.113\n\nThe PPH began in 2006 as a pilot project between the USPTO and the JPO within the framework of the Trilateral Cooperation. Within a decade, the PPH has expanded to include a large number of national and regional patent offices, including from developing countries, into some form of a PPH agreement. The PPH agreements are", "n_tokens": 269, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-268-2", "doc_id": "medicine_vaccine_book", "page": 268, "text": "108IP BRICS (n.d.-a). 109IP BRICS (n.d.-b). 110Markush claims are patent claims on a general chemical formula that includes a wide range of possible alternative chemical compounds. Drafting a Markush claim enables a patent applicant to claim through a single application a patent covering several alternative compounds that could be used. However, applications with Markush formulas only provide a few examples of possible alternative compounds while claiming a much broader range of such possible compounds without actually disclosing those compounds in the application. Thus, patents granted on Markush formulas “... allow the patentee to control a large number of compounds that have not been actually obtained..., but only theoretically inferred from their possible equivalence with other compounds covered by the general formula.” Correa (n 4), pp. 16–17. 111IP BRICS, ‘Patent Processes and Procedure – Procedures for patent examination involving Markush claims’, http://www.ipbrics.org/secondpage/project/d004.html. 112USPTO (n.d.-a). 113For instance, in 2019 the average pendency from a PPH request by the applicant to the final decision in the second office was 1.3 months in Australia and 18.4 months in the U.S. See, Patent Prosecution Highway Portal Site, ‘Statistics’(jpo.go.) https://www.jpo.go.jp/e/toppage/pph-portal/ statistics.html.\n\nN. Syam", "n_tokens": 333, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-269-0", "doc_id": "medicine_vaccine_book", "page": 269, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nin the nature of memorandum of understanding or collaboration agreements between patent offices and not legal treaties. Hence, implementation of the PPH mechanism does not require amendment of the national law and can be done merely through administrative regulations or bye laws that patent offices are allowed to adopt within the framework of the national patent law.", "n_tokens": 79, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-269-1", "doc_id": "medicine_vaccine_book", "page": 269, "text": "The PPH became a permanent mechanism between the USPTO and JPO at the end of the pilot period and was extended as a pilot project in 2008 between the USPTO and the EPO. In 2009, the EPO agreed to undertake a pilot PPH project with the JPO. Thus, the PPH was seeded and began to develop several shoots of bilateral PPH collaboration within the Trilateral Offices. The USPTO114 and the JPO have also concluded several bilateral PPH agreements with other IP offices outside the Trilateral. In 2014, the pilot project on a PPH mechanism between the IP5 offices was launched by attempting leverage fast track patent examination procedures already in place at the IP5, marking further expansion of the PPH. Existing bilateral PPH arrangements that had been established between the offices within the Trilateral and the IP5 group were integrated under this IP5 PPH project.115 In the same year, three offices from the IP5—JPO, KIPO and the USPTO—launched a “Global PPH” (GPPH) pilot project along with 23 other national and regional patent offices—Australia, Canada, UK (the Vancouver Group), Austria, Colombia, Den- mark, Estonia, Finland, Germany, Hungary, Iceland, Israel, New Zealand, Norway, the Nordic Patent Institute, Peru, Poland, Portugal, the Russian Federation, Singa- pore, Spain, Sweden, the Visegrad Patent Institute.116 Both the IP5 PPH and the GPPH allow participating offices to use all the search and examination work products of the office of first filing or examination among the participating", "n_tokens": 351, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-269-2", "doc_id": "medicine_vaccine_book", "page": 269, "text": "patent offices, including search and examination reports and written opinions produced by them as International Authorities under the PCT. In parallel with these initiatives, more countries are increasingly being brought within the ambit of the PPH through bilateral PPH agreements. Currently, more than 50 national or regional patent offices are part of the PPH network through a slew of bilateral or global PPH agreements. Even where a patent office is a party to the PPH network through some form of PPH agreement, the extent to which offices use the PPH system can vary, with some offices using the PPH more widely than others. For example, under bilateral PPH agreements, the PPH route is only available to the patent applicants from the respective parties, and there can be a maximum limit on the number of applicants who can make use of this route. The PPH agreement could be limited to certain specific technology sectors while excluding other sectors with sensitive public", "n_tokens": 200, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-269-3", "doc_id": "medicine_vaccine_book", "page": 269, "text": "114The USPTO has bilateral PPH agreements with the IP offices of Brazil, Chile, the Czech Republic, the Eurasian Patent Office, Mexico, Nicaragua, the Philippines, Nicaragua, Saudi Arabia, and the Taiwan Intellectual Property Office. USPTO (n.d.-b). 115WIPO (Standing Committee on the Law of Patents) (2013b). 116Ibid.\n\n265", "n_tokens": 87, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-270-0", "doc_id": "medicine_vaccine_book", "page": 270, "text": "266\n\ninterest concerns, such as pharmaceuticals.117 However, like most work sharing schemes, the PPH has also expanded through a gradual and incremental approach. Therefore, the extension of existing PPH arrangements that are limited to specific technology sectors could be extended to incrementally include processing of patent applications in other technology sectors.\n\n6 Opportunities and Challenges\n\nPatent cooperation and work sharing between patent offices presents both opportu- nities and challenges for patent offices. For resource constrained national patent offices, work sharing can be an attractive mechanism to ensure timely processing of patent applications. Use of ICT, digitization, automation, machine translation, etc. have made work sharing an attractive and realistic proposition. At the same time, work sharing could present the risk of trade-offs being made by patent offices in favour of efficient, accelerated and timely completion of search and examination work, over ensuring robustness of the search and examination itself. The risk of such trade-off is much more where work sharing arrangements apply to fields of technol- ogy, such as pharmaceuticals, where there can be significant variance between the patentability thresholds under the applicable national law.", "n_tokens": 251, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-270-1", "doc_id": "medicine_vaccine_book", "page": 270, "text": "6.1 South-South Cooperation\n\nWhile a number of patent offices in developing countries have bilateral MOUs on cooperation with patent offices in developed countries, cooperation between patent offices of developing countries has been very limited. Exploring work sharing or collaboration between patent offices among developing countries on the basis of South-South cooperation could be explored further. Work sharing arrangements like PROSUR and ASPEC enable patent offices in Latin America and the ASEAN to utilise their search and examination results on corresponding patent applications in their respective offices. Beyond formal work sharing agreements, patent offices in developing countries could also cooperate to undertake examiner exchange programmes, sharing of sector specific guidelines on patent examination, sharing of search and examination reports, objections or questions raised in first examination reports (FER), results of pre-grant opposition proceedings, and information on post- grant revocation or grant of any compulsory license on a patent. For instance, initiatives similar to the project proposed by INPI of Brazil under the IP BRICS\n\n117E.g., Intellectual Property India (n.d.) (limiting PPH requests to 100 applications per year and excluding pharmaceutical patent applications from the scope of PPH under the bilateral PPH between the Indian Patent Office and the Japanese Patent Office).\n\nN. Syam", "n_tokens": 275, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-271-0", "doc_id": "medicine_vaccine_book", "page": 271, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\ncooperation to undertake a study on examination procedures on patent applications containing Markush formulas with the objective of standardizing examination guidelines relating to such claims, could be further explored by other developing country patent offices and also be extended to include other forms of secondary patent claims made in the pharmaceutical sector.\n\nIt is critical that patent offices in developing countries engage in cooperation among them within a South-South framework not only in form but also in terms of policy orientation. The focus of South-South patent cooperation should be on harnessing the resources of their national and regional patent offices to ensure that those resources could be deployed efficiently to ensure robust examination of patent applications. To persuade the patent offices to collaborate with this orientation, it would be necessary to utilise existing forums of South-South cooperation such as IBSA,118 MERCOSUR,119 UNASUR, the regional economic communities (REC) in Africa,120 as well as regional cooperation forums in Asia to provide guidance to the respective national and regional patent offices of their member States, to cooperate in pursuit of this objective.", "n_tokens": 238, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-271-1", "doc_id": "medicine_vaccine_book", "page": 271, "text": "A priority area of focus in this regard should be on the examination of pharma- ceutical patent applications with the objective of enabling patent offices to fully utilise the flexibilities available under the TRIPS Agreement with regard to the differential application of the patentability criteria of novelty, inventive step and industrial applicability by taking into account the specificities of the technological sector. Thus, patent offices from developing countries can collaborate to share experience and knowledge and develop tools such as patent examination guidelines to enable the conduct of search and examination of pharmaceutical patent applica- tions by applying rigorous standards. Objections or clarificatory questions raised in FERs by applying such rigorous standards could be shared through appropriate ICT tools with other patent offices for their reference. Other offices could consider whether similar questions could be raised in the context of the requirements under their national law or regulations. High quality FER objections can result in the withdrawal or abandonment of frivolous applications.", "n_tokens": 208, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-271-2", "doc_id": "medicine_vaccine_book", "page": 271, "text": "118See, e.g., India-Brazil-South Africa Dialogue Forum (Second Summit of Heads of State/Gov- ernment) (2007) (agreeing to work towards a trilateral initiative on cooperation in the field of IP including capacity building and human resource development). 119See,Velásquez (2015)(referring tothe MERCOSUR healthministers’ declaration of2December 2009 calling for development and application of patentability criteria in view of proliferation of low quality patents and particularly to adopt criteria to protect public health through patentability guidelines). 120See, e.g., East African Community (2013); see generally, Vawda and Shozi (2020).\n\n267", "n_tokens": 148, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-272-0", "doc_id": "medicine_vaccine_book", "page": 272, "text": "268\n\n6.2 Safeguarding and Utilising TRIPS Flexibilities\n\nWhile South-South cooperation could be explored in the area of patent search and examination as a means of strengthening the implementation of robust patent examination standards, a critical challenge for patent offices from developing coun- tries in respect of patent cooperation or work sharing arrangements with the major patent offices such as the Trilateral or IP5 offices will be to effectively retain and safeguard the capacity to conduct such robust search and examination. Technical assistance programmes, examiner exchanges can expose and orient patent examiners from developing countries not only to the search tools, systems and techniques, but also to certain perspectives through which patent claims could be deemed to satisfy the criteria of patentability in a flexible way. For example, though under a strict interpretation a selection patent claim could be considered to be not novel as it is previously disclosed in an earlier application, patent examiners receiving technical assistance from the EPO could consider such claims to be permissible.121 Therefore, developing countries must ensure that patent examiners are exposed to trainings that offer different perspectives, and expose them to the development and public policy implications of the possible approaches that could be taken to interpret the patent- ability of a claim.", "n_tokens": 252, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-272-1", "doc_id": "medicine_vaccine_book", "page": 272, "text": "With regard to work sharing collaborations such as the PPH that go beyond merely offering access to search and examination results of one office to another but encourage reliance on the reports produced by an office of first filing or examination, developing countries should exercise caution. A prudent approach in this respect, which some developing countries have taken,122 is to limit such work sharing arrangements to exclude particularly sensitive fields of technology such as pharma- ceuticals, and limit the number of applications to be processed under such arrangements.", "n_tokens": 112, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-272-2", "doc_id": "medicine_vaccine_book", "page": 272, "text": "6.3 Use of Technology\n\nDigitization, ICT, machine translation, etc. have immensely aided patent offices to stay connected and share information rapidly and securely. While continuing to expand the use of such technologies to enable access to more information to conduct\n\n121A selection patent claim is a secondary patent claim on a specific compound that is selected from the broad range of compounds that have been claimed earlier through a Markush formula, on the basis of a legal fiction that is followed by some patent offices influenced by the EPO, that the compound being claimed as selected from the range under a Markush formula, was not specifically disclosed under the earlier patent claim based on the Markush formula. In this way, selection patent claims have been a major route for effectively extending the term of a patent by claiming a specific selection of a compound as the term of the original patent claim nears its expiry. See Correa (n 4), p. 17. 122E.g., Intellectual Property India (n.d.).\n\nN. Syam", "n_tokens": 228, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-273-0", "doc_id": "medicine_vaccine_book", "page": 273, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nmore comprehensive search and examination, facilitate electronic filing of patent applications, communication between the patent office and the applicants during the search and examination, as well as receiving oppositions or third party observations, there is need for caution with regard to use technologies to the decision-making itself. A number of patent offices have undertaken projects to use artificial intelli- gence (AI) and machine learning for patent classification as well as patent search. However, AI and machine learning tools can be used to even conducting the patent examination itself.123 Therein lies the risk for developing countries, particularly those which fully rely on the decisions of foreign patent offices, such as under the validation agreements with the EPO.\n\n6.4 Administrative Law Oversight", "n_tokens": 171, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-273-1", "doc_id": "medicine_vaccine_book", "page": 273, "text": "The global network of patent offices is a reality. If utilized appropriately, collabo- ration between patent offices can certainly provide efficiency gains for the conduct of the business of patent offices. At the same time, patent offices also have a regulatory role to play in the public interest by ensuring as far as possible that patents of questionable validity are not granted. The patent cooperation and work sharing arrangements that patent offices engage in with their counterparts from other coun- tries obviously have a bearing on this function. However, these arrangements are often implemented as pilot projects, as cooperation activities under MOUs. At most, implementation of these activities would involve a revision of the regulations, rules or guidelines developed by the patent office as subordinate rules under the frame- work of the patent law enacted by the legislature. Thus, implementation of principles of administrative law can be crucial to ensure that the functions of the patent office as a sentinel of the public interest through the conduct of robust search and examination to decide on the grant of a patent in accordance with the national law is safeguarded, while attempting to secure speed and efficiency in disposal of the workload of patent offices through mutual collaboration. Thus, patent offices should be required to undertake sufficient public consultations prior to engaging in collaborative work sharing arrangements, as well as when considering expansion of the", "n_tokens": 289, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-273-2", "doc_id": "medicine_vaccine_book", "page": 273, "text": "scope of such collaborations. Legislative oversight should also be exercised to ensure that collab- orations between patent offices are effectively enabling, and not limiting, the imple- mentation of the substantive patentability criteria under the national law.", "n_tokens": 49, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-273-3", "doc_id": "medicine_vaccine_book", "page": 273, "text": "123EPO is developing business solutions using Machine Learning and AI to manage patent files at various degrees of implementation: Automatic annotation of patent literature; Automatic detection of problem/solution in patent document; Automatic detection of exclusion from patentability. See generally, WIPO (n.d.-b).\n\n269", "n_tokens": 64, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-274-0", "doc_id": "medicine_vaccine_book", "page": 274, "text": "270\n\n7 Conclusion", "n_tokens": 3, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-274-1", "doc_id": "medicine_vaccine_book", "page": 274, "text": "Rigorous examination of a patent application to determine whether a patent claim satisfies the requirements of novelty, inventive step and industrial applicability, and sufficiently discloses the best enabling mode of working the claimed invention, is the most important role of a patent office. This makes it critical that patent offices are able to perform this role well by ensuring that the patentability thresholds as defined under the national law and the public policy objectives that inform the law, are given effect to in the process of interpretation of the patentability of a technical patent claim. Thus, how a patent examiner views a claim matters. The perspective of the examiner can be influenced by technical assistance or administrative collaboration arrangements between patent offices. Patent offices in developing countries also face challenges, such as limited human resources for patent examination, surge in the number of patent applications in different technical fields, associated backlogs, and the pressure to speedily dispose the applications. These challenges can impact the rigorous application of the patentability thresholds as patent offices have to make a choice of prioritizing between speed and efficiency in completing the search and examination work and robustness of the examination. Increasing human resources for search and examination, use of automation technologies and leveraging the search and examination capacity and work products of other patent offices are", "n_tokens": 284, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-274-2", "doc_id": "medicine_vaccine_book", "page": 274, "text": "possible approaches being deployed by patent offices to address this challenge.", "n_tokens": 14, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-274-3", "doc_id": "medicine_vaccine_book", "page": 274, "text": "Digitization and use of ICT systems has enabled offices to collaborate in conducting search and examination work more easily. However, this has also enabled the major patent offices such as the Trilateral Offices and the IP5 to play an influential role in influencing the work of other patent offices. Indeed, work sharing has been explicitly recognized as part of an agenda of achieving a harmo- nized global patent system. While the negotiations for a Substantive Patent Law Treaty was unsuccessful in WIPO, soft law reforms of the PCT system has been undertaken through an incremental approach, and work sharing arrangements devel- oped by the major patent offices outside the PCT system are also being promoted both in terms of their integration to the PCT through pilot projects (such as the PCT-PPH pilot project by EPO) as well as experience and best practices sharing sessions on “quality of patents” in the WIPO SCP discussions.", "n_tokens": 203, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-274-4", "doc_id": "medicine_vaccine_book", "page": 274, "text": "The nature of collaborations between patent offices vary. While some patent offices have entered into agreements to outsource search and examination work to the more resourceful patent offices or recognise within their territories the patents granted by another office (such as under the EPO validation agreements), other offices may collaborate merely to share information and documents relating to prior art, and search and examination results. Many patent offices have also agreed to engage in projects such as the PPH with one or more countries wherein they agree to not only share the search and examination results, but to use the search and examination results on a claim by one office to accelerate the examination of the claim in the other office. While engaging in such arrangements, patent offices in developing countries should ensure that the flexibility available to them under the\n\nN. Syam", "n_tokens": 179, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-275-0", "doc_id": "medicine_vaccine_book", "page": 275, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nTRIPS Agreement to apply the patentability criteria as defined under the national law and policy is effectively safeguarded. Some patent offices have excluded sensitive sectors such as pharmaceuticals from their PPH agreements and have limited the number of applications to. Which the accelerated procedure could apply. However, it is possible that over time the PPH agreements could be expanded to include technology sectors that are currently excluded and could also be extended to patent applications from more countries. Patent offices in developing countries should also ensure that patent examiners are exposed to trainings that offer different perspectives on how patent claim could be interpreted differently by application of the patent- ability criteria under a strict or relaxed standard.", "n_tokens": 151, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-275-1", "doc_id": "medicine_vaccine_book", "page": 275, "text": "Patent cooperation and work sharing presents both opportunities and challenges for patent offices. Patent offices in developing countries could engage in cooperation with each other in a South-South framework to undertake examiner exchange programmes, sharing of sector specific guidelines on patent examination, sharing of search and examination reports, objections or questions raised in first examination reports (FER), results of pre-grant opposition proceedings, and information on post- grant revocation or grant of any compulsory license on a patent. South-South cooperation should be undertaken with a focus on enabling patent offices to utilise their resources for ensuring robust examination of patent applications. A priority area of focus in this regard should be on the examination of pharmaceutical patent applications.", "n_tokens": 149, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-275-2", "doc_id": "medicine_vaccine_book", "page": 275, "text": "Finally, cooperation between patent offices typically take place in the form of projects implemented under MOUs, which are undertaken in exercise of the admin- istrative discretion that patent offices have. While exercising such discretion, it would be pertinent for patent offices to also assess the implications of such cooper- ation on their regulatory function of ensuring grant of robust patents in the public interest. It would this be pertinent to undertake public consultations and also exercise legislative oversight by application of the principles of administrative law, to ensure that cooperation that patent offices enter into in exercise of their discretionary powers, are exercised in the public interest and do not impede the attainment of the public policy objectives that inform the patent law.", "n_tokens": 153, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-275-3", "doc_id": "medicine_vaccine_book", "page": 275, "text": "References\n\nAli F, Rajagopal S, Raman VS, John R (2018) Pharmaceutical patent grants in India: how our safeguards against evergreening failed, and why the system must be reformed. accessibsa.org, 2018. https://accessibsa.org/media/2018/04/Pharmaceutical-Patent-Grants-in-India.pdf. Accessed 24 Feb 2021\n\nASEAN Intellectual Property Portal (n.d.) What is ASPEC? https://www.aseanip.org/Services/ ASEAN-Patent-Examination-Co-operation-ASPEC/What-is-ASPEC. Accessed 24 Feb 2021 Assemblies of the Member States of WIPO (2002) WIPO patent agenda: options for development of the international patent system, 19 August 2002, A/37/6 [9]. https://www.wipo.int/edocs/ mdocs/govbody/en/a_37/a_37_6.pdf. Accessed 24 Feb 2021\n\n271", "n_tokens": 214, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-276-0", "doc_id": "medicine_vaccine_book", "page": 276, "text": "272\n\nBaker R(R)B (2010) Customary international law in the 21st century: old challenges and new debates. Eur J Int Law 21(1):173. https://doi.org/10.1093/ejil/chq015. Accessed 24 Feb 2021 Castillo S (2012) The PROSUR approach to patents: shared information, independent decisions. American University Intellectual Property Brief. http://www.ipbrief.net/2012/07/28/the-prosur- approach-to-patents-shared-information-independent-decisions/. Accessed 24 Feb 2021\n\nChaudhuri S, Park C, Gopakumar KM (2010) Five years into the product patent regime: India’s response. United Nations Development Programme, 2010. https://www.undp.org/content/dam/ aplaws/publication/en/publications/hiv-aids/five-years-into-the-product-patient-regime-indias- response/Five%20years%20into%20the%20product%20patent%20regime-India%20Response. pdf. Accessed 24 Feb 2021\n\nCorrea CM (ed) (2012) A guide to pharmaceutical patents. South Centre, Geneva. https://www. southcentre.int/wp-content/uploads/2016/05/Bk_2012_A-Guide-to-Pharmaceutical-Patents_ EN.pdf. Accessed 24 Feb 2021\n\nCorrea CM (2014a) Tackling the proliferation of patents: how to avoid undue limitations to competition and the public domain. Research Paper No. 52, South Centre, Geneva, 9. https:// www.southcentre.int/wp-content/uploads/2014/09/RP52_Tackling-the-Proliferation-of-Pat ents-rev_EN.pdf. Accessed 24 Feb 2021", "n_tokens": 414, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-276-2", "doc_id": "medicine_vaccine_book", "page": 276, "text": "Revisited’. J Indian Law Inst 32(2):131\n\nDrahos P (2008a) “Trust Me”: patent offices in developing countries. Am J Law Med 34(2–3):151.\n\nhttps://doi.org/10.1177/009885880803400205. Accessed 24 Feb 2021\n\nDrahos P (2008b) Regulating patent offices: countering pharmaceutical hegemony. SCRIPTed 5 501. https://script-ed.org/wp-content/uploads/2016/07/5-3-Drahos.pdf. Accessed 24 Feb 2021 East African Community (2013) EAC regional intellectual property policy on the utilisation of public health-related WTO-TRIPS flexibilities and the approximation of National Intellectual Property Legislation. https://ipaccessmeds.southcentre.int/wp-content/uploads/2019/12/ EACTRIPSPolicy.pdf. Accessed 24 Feb 2021\n\nEuropean Commission (2009) Pharmaceutical sector inquiry: final report (8 July 2009), pp 385–390. https://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/staff_working_ paper_part1.pdf. Accessed 24 Feb 2021\n\nEuropean Patent Office (2016) Validation of European patents in Morocco (MA). Official Journal EPO, 29 January 2016. https://www.epo.org/law-practice/legal-texts/official-journal/2016/01/ a5.html. Accessed 24 Feb 2021\n\nEuropean Patent Office (2017) Working with our partners worldwide. https://www.epo.org/about- us/annual-reports-statistics/annual-report/2017/highlights/worldwide-influence.html. Accessed 24 Feb 2021\n\nEuropean Patent Office (n.d.) Validation states (EPO). https://www.epo.org/about-us/foundation/", "n_tokens": 435, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-276-3", "doc_id": "medicine_vaccine_book", "page": 276, "text": "validation-states.html. Accessed 24 Feb 2021\n\nfiveIPoffices (n.d.) About IP5 co-operation. https://www.fiveipoffices.org/about. Accessed 24 Feb\n\n2021\n\nHu W (2017) International patent rights harmonisation: the case of China. Routledge India-Brazil-South Africa Dialogue Forum (Second Summit of Heads of State/Government) (2007) Tshwane Declaration, Tshwane 17 October 2007. http://www.ibsa-trilateral.org/images/2nd_ IBSA_Summit_Declaration_-_Tshwane_2007.pdf. Accessed 24 Feb 2021\n\nIntellectual Property India (n.d.) Procedure guidelines for Patent Prosecution Highway (PPH). http://www.ipindia.nic.in/writereaddata/Portal/News/591_1_PPH_Procedure_Guideline_com bined_20191128_final.pdf. Accessed 24 Feb 2021\n\nN. Syam", "n_tokens": 216, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-277-0", "doc_id": "medicine_vaccine_book", "page": 277, "text": "Robust Patent Examination or Deep Harmonization? Cooperation and Work...\n\nIP BRICS (2013) BRICS Intellectual Property Offices Cooperation Roadmap. http://www.ipbrics. org/secondpage/aboutus/2013Roadmap%20final%20version%20signed%20IP-BRICS_2013. pdf. Accessed 24 Feb 2021\n\nIP BRICS (n.d.-a) Projects. http://www.ipbrics.org/secondpage/project.html. Accessed 24 Feb\n\n2021\n\nIP BRICS (n.d.-b) Meetings. http://www.ipbrics.org/secondpage/meeting.html. Accessed 24 Feb\n\n2021\n\nJayakumar PB (2017) We can clear the patent backlog within next two years. Business Today, 23 April 2017, Delhi. https://www.businesstoday.in/magazine/features/we-can-clear-the-patent- backlog-within-next-two-years/story/249173.html. Accessed 24 Feb 2021\n\nMay C (2007) The World intellectual Property Organization: resurgence and the development\n\nagenda. Routledge, p 49\n\nMossinghof GJ (1999) LECTURE: World Patent System Circa 20XX A.D. Yale J Law Technol 1 (1):2. https://digitalcommons.law.yale.edu/cgi/viewcontent.cgi?referer¼https://www.google. com/&httpsredir¼1&article¼1071&context¼yjolt. Accessed 24 Feb 2021\n\nNeppel C, Rutz B, Carmichael G, Karachalios K, Elahi S, McGinley C (2012) The future of IP in Europe. In: Shimanami R (ed) The future of the patent system. Edward Elgar, Cheltenham Nunes RD, Romano RS (2019) Brazil’s patent backlog days are numbered. Managing IP, 23 September 2019. https://www.managingip.com/article/b1kbm141jmzzwm/brazils-patent- backlog-days-are-numbered. Accessed 24 Feb 2021", "n_tokens": 470, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-277-1", "doc_id": "medicine_vaccine_book", "page": 277, "text": "Proposal by the delegation of Denmark (20 October 2011) SCP/17/7 https://www.wipo.int/edocs/\n\nmdocs/scp/en/scp_17/scp_17_7.pdf. Accessed 24 Feb 2021\n\nProposal by the delegation of the United States of America on the study of worksharing, 20 November 2015, SCP/23/4. https://www.wipo.int/edocs/mdocs/scp/en/scp_23/scp_23_4. pdf. Accessed 24 Feb 2021\n\nProposal by the delegations of the Czech Republic, Kenya, Mexico, Singapore and the United Kingdom, 18 June 2018, SCP/28/8. https://www.wipo.int/edocs/mdocs/scp/en/scp_28/scp_28_ 8.pdf. Accessed 24 Feb 2021\n\nProposal by the delegations of the Republic of Korea, the United Kingdom and the United States of America regarding work sharing between offices in order to improve efficiencies of the patent system, 22 January 2014, SCP/20/11 Rev. https://www.wipo.int/edocs/mdocs/scp/en/scp_20/ scp_20_11_rev.pdf. Accessed 24 Feb 2021\n\nPROSUR (n.d.) About us. http://prosur.org/quienes-somos/. Accessed 24 Feb 2021 Rathod SK, Ali F (2018) Inside views: deference, not delegation! - WIPO PCT negotiations. Intellectual Property Watch, 17 June 2018. http://www.ip-watch.org/2018/06/17/deference- not-delegation-wipo-pct-negotiations/#_ftn1. Accessed 24 Feb 2021\n\nResponses to the questionnaire on the term “Quality of Patents” and cooperation between patent offices in search and examination (part 2), 2 June 2017, SCP/26/4. https://www.wipo.int/edocs/ mdocs/scp/en/scp_26/scp_26_4.pdf. Accessed 24 Feb 2021", "n_tokens": 485, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-277-2", "doc_id": "medicine_vaccine_book", "page": 277, "text": "Shadlen KC (2013) The patent policy trilemma. Journal fur Entwicklungspolitik 29(2):87 Shashikant S (2014) The African Regional Intellectual Property Organization (ARIPO) Protocol on Patents: implications for access to medicines. Research Paper No. 56, South Centre, 17–21. https://www.southcentre.int/wp-content/uploads/2014/11/RP56_The-ARIPO-Protocol-on-Pat ents_ENl.pdf. Accessed 24 Feb 2021\n\nSyam N (2019) Mainstreaming or dilution? Intellectual property and development in WIPO. Research paper no. 95, South Centre, Geneva, p 18. https://doi.org/10.2139/ssrn.3559643 't Hoen E (2020) The expanding reach of the European Patent Office. Good for health? Medicines Law & Policy, 18 March 2020. https://medicineslawandpolicy.org/2020/03/the-expanding- reach-of-the-european-patent-office-good-for-health/. Accessed 24 Feb 2021 Trilateral (n.d.-a) About us. https://www.trilateral.net/about. Accessed 24 Feb 2021 achievements. Trilateral\n\n(n.d.-b) Significant\n\nhttps://www.trilateral.net/about/achievements.\n\nAccessed 24 Feb 2021\n\n273", "n_tokens": 321, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-278-0", "doc_id": "medicine_vaccine_book", "page": 278, "text": "274\n\nTrilateral (n.d.-c) The 30th anniversary: a brief history of the trilateral cooperation. https://www.jpo. Accessed\n\ngo.jp/news/kokusai/nichibeiou/document/nitibeiou_meeting_30/pamphlet.pdf. 24 Feb 2021\n\nUSPTO (n.d.-a) Patent Prosecution Highway: frequently asked questions. https://www.uspto.gov/ Accessed", "n_tokens": 99, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-278-1", "doc_id": "medicine_vaccine_book", "page": 278, "text": "sites/default/files/documents/FAQ%20for%20PPH%20final-%2004192018.pdf. 24 Feb 2021\n\nUSPTO (n.d.-b) Patent Prosecution Highway (PPH) – fast track examination of applications, uspto. gov. https://www.uspto.gov/patents-getting-started/international-protection/patent-prosecution- highway-pph-fast-track. Accessed 24 Feb 2021\n\nVancouver Group (n.d.) Technical infrastructure for improved international collaboration on search and examination. https://www.wipo.int/export/sites/www/patents/en/topics/worksharing/pdf/ vancouver_group.pdf. Accessed 24 Feb 2021\n\nVawda YA, Shozi B (2020) Eighteen years after Doha: an analysis of the use of public health TRIPS flexibilities in Africa. Research paper no. 103, South Centre, Geneva. https://www. southcentre.int/wp-content/uploads/2020/02/RP103_Eighteen-Years-After-Doha-An-Analysis- of-the-Use-of-Public-HealthTRIPS-Flexibilities-in-Africa_EN.pdf. Accessed 24 Feb 2021 Velásquez G (2015) Guidelines on patentability and access to medicines. Research paper no. 61, South Centre, Geneva, p 30. https://www.southcentre.int/wp-content/uploads/2015/03/ RP61_Guidelines-on-Patentability-and-A2M_EN.pdf. Accessed 24 Feb 2021\n\nWIPO (2001) PCT Union – Committee on Reform of the Patent Cooperation Treaty (PCT). wipo. https://www.wipo.int/meetings/en/details.jsp?meeting_id¼4306.\n\n21–25 May int, Accessed 24 Feb 2021\n\n2001.\n\nWIPO (n.d.-a) WIPO CASE – Centralized Access to Search and Examination, wipo.int. https://\n\nwww.wipo.int/case/en/. Accessed 24 Feb 2021", "n_tokens": 471, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-278-2", "doc_id": "medicine_vaccine_book", "page": 278, "text": "WIPO (n.d.-b) Index of AI initiatives in IP offices. https://www.wipo.int/about-ip/en/artificial_\n\nintelligence/search.jsp. Accessed 24 Feb 2021\n\nWIPO (Committee on Reform of the Patent Cooperation Treaty (PCT)) (2002) Language of the international application and translations, 31 May 2002, PCT/R/2/3. https://www.wipo.int/ edocs/mdocs/pct/en/pct_r_2/pct_r_2_3.pdf. Accessed 24 Feb 2021\n\nWIPO (Committee on Reform of the Patent Cooperation Treaty) (2001) Reform of the PCT: proposals by the United States of America, 23 March 2001, PCT/R/1/2. http://www.wipo.int/ edocs/mdocs/pct/en/pct_r_1/pct_r_1_2.pdf. Accessed 24 Feb 2021\n\nWIPO (International Patent Cooperation Union (PCT Union) Assembly) (2000a) Reform of the Patent Cooperation Treaty, 18 August 2000, PCT/A/29/3. https://www.wipo.int/edocs/mdocs/ govbody/en/pct_a_29/pct_a_29_3.pdf. Accessed 24 Feb 2021\n\nWIPO (International Patent Cooperation Union (PCT Union) Assembly) (2000b) Report, 3 October 2000, PCT/A/29/4. https://www.wipo.int/edocs/mdocs/govbody/en/pct_a_29/pct_a_29_4- main1.pdf. Accessed 24 Feb 2021\n\nWIPO (International Patent Cooperation Union (PCT Union) Assembly) (2001) Report, 3 October 2001, PCT/A/30/7. https://www.wipo.int/edocs/mdocs/govbody/en/pct_a_30/pct_a_30_7.pdf. Accessed 24 Feb 2021\n\nWIPO (International Patent Cooperation Union (PCT Union) Assembly) (2002) Report, 1 October 2002, PCT/A/31/10.", "n_tokens": 498, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-278-4", "doc_id": "medicine_vaccine_book", "page": 278, "text": "WIPO (International Patent Cooperation Union (PCT Union) Assembly) (2007a) Supplementary international search: proposed amendments of the PCT regulations, 17 August 2007, PCT/A/36/ 7. https://www.wipo.int/edocs/mdocs/govbody/en/pct_a_36/pct_a_36_7.pdf. Accessed 24 Feb 2021\n\nWIPO (International Patent Cooperation Union (PCT Union) Assembly) (2007b) Supplementary international search: proposed amendments of the PCT regulations, 19 September 2007, PCT/A/ 36/7Add. https://www.wipo.int/edocs/mdocs/govbody/en/pct_a_36/pct_a_36_7_add.pdf. Accessed 24 Feb 2021\n\nN. Syam", "n_tokens": 184, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-279-1", "doc_id": "medicine_vaccine_book", "page": 279, "text": "WIPO (International Patent Cooperation Union (PCT Union) Assembly)\n\n(2007c) Report, 12 November 2007, PCT/A/36/13 [153]. https://www.wipo.int/edocs/mdocs/govbody/en/pct_ a_36/pct_a_36_13.pdf. Accessed 24 Feb 2021\n\nWIPO (International Patent Cooperation Union (PCT Union) Assembly) (2007d) Reform of the PCT, 23 July 2007, PCT/A/36/1. https://www.wipo.int/pct/en/texts/articles/a36.html. Accessed 24 Feb 2021\n\nWIPO (International Patent Cooperation Union (PCT Union) Assembly) (n.d.) PCT/A/36/13 (n 64)\n\n [134]\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group) (2008) Enhancing the value of interna- tional search and preliminary examination under the PCT, 21 April 2008, PCT/WG/1/3. https:// www.wipo.int/edocs/mdocs/pct/en/pct_wg_1/pct_wg_1_3.pdf. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group) (2009a) Enhancing the value of inter- national search and preliminary examination under the PCT: making international preliminary examination more useful, 14 April 2009, PCT/WG/2/6. https://www.wipo.int/edocs/mdocs/pct/ en/pct_wg_2/pct_wg_2_6.pdf. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group) (2009b) The future of the PCT, 3 April https://www.wipo.int/edocs/mdocs/pct/en/pct_wg_2/pct_wg_2_3.pdf.\n\n2009, PCT/WG/2/3. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group) (2009c) Three track PCT system, 24 April 2009, PCT/WG/2/11.", "n_tokens": 500, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-279-3", "doc_id": "medicine_vaccine_book", "page": 279, "text": "WIPO (Patent Cooperation Treaty (PCT) Working Group) (2009d) Comprehensive proposal for PCT reform, 24 April 2009, PCT/WG/2/12. https://www.wipo.int/edocs/mdocs/pct/en/pct_wg_ 2/pct_wg_2_12.pdf. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group) (2009e) Report, 24 July 2009, PCT/WG/ 2/14 [24]. https://www.wipo.int/edocs/mdocs/pct/en/pct_wg_2/pct_wg_2_14.pdf. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group) (2010a) The need for improving the functioning of the PCT system, 5 May 2010, PCT/WG/3/2. https://www.wipo.int/edocs/mdocs/ pct/en/pct_wg_3/pct_wg_3_2.pdf. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group) (2010b) Report, 18 June 2010, [139]. https://www.wipo.int/edocs/mdocs/pct/en/pct_wg_3/pct_wg_3_\n\nPCT/WG/3/14 Rev. 14_rev.pdf. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group). Progress report on the Collaborative Search and Examination (CS&E) Second Pilot Project, 14 May 2012, PCT/WG/5/9. https:// www.wipo.int/edocs/mdocs/pct/en/pct_wg_5/pct_wg_5_9.pdf. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group). Summary by the Chair, 24 May 2013, https://www.wipo.int/edocs/mdocs/pct/en/pct_wg_6/pct_wg_6_23.pdf.", "n_tokens": 503, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-279-4", "doc_id": "medicine_vaccine_book", "page": 279, "text": "PCT/WG/6/23. Accessed 24 Feb 2021\n\nWIPO (Patent Cooperation Treaty (PCT) Working Group) (2018) Delegation of designated or elected office functions, 11 April 2018, PCT/WG/11/7. https://www.wipo.int/edocs/mdocs/pct/ en/pct_wg_11/pct_wg_11_7.pdf. Accessed 24 Feb 2021\n\nWIPO (Standing Committee on the Law of Patents) (2011) Revised proposals from the delegations of Canada and the United Kingdom, 19 October 2011, SCP/17/8. https://www.wipo.int/edocs/ mdocs/scp/en/scp_18/scp_18_ref_scp_17_8.pdf. Accessed 24 Feb 2021\n\nWIPO (Standing Committee on the Law of Patents) (2013a) Work sharing programs between patent offices and use of external information in search and examination, 4 December 2013, SCP/20/8. https://www.wipo.int/edocs/mdocs/patent_policy/en/scp_20/scp_20_8.pdf. Accessed 24 Feb 2021\n\nWIPO (Standing Committee on the Law of Patents) (2013b) Work-sharing programs among patent offices and use of external information for search and examination, 4 December 2013, SCP/20/ 8. https://www.wipo.int/edocs/mdocs/patent_policy/en/scp_20/scp_20_8.pdf. Accessed 24 Feb 2021\n\nWIPO (Standing Committee on the Law of Patents) (2017) Responses to the questionnaire on the term “Quality of Patents” and cooperation between patent offices in search and examination\n\n275", "n_tokens": 399, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-280-2", "doc_id": "medicine_vaccine_book", "page": 280, "text": "WIPO (Working Group on Reform of the Patent Cooperation Treaty (PCT)) (2004) Improving the quality of international searches, 6 April 2004, PCT/R/WG/6/9. https://www.wipo.int/edocs/ mdocs/pct/en/pct_r_wg_6/pct_r_wg_6_9.pdf. Accessed 24 Feb 2021\n\nWIPO International Patent Cooperation Union (2002a) Missed time limit for entering the national https://www.wipo.int/edocs/mdocs/pct/en/pct_r_2/pct_r_2_4.pdf.\n\nphase, Accessed 24 Feb 2021\n\n31 May\n\n2002.\n\nWIPO International Patent Cooperation Union (2002b) Right of priority and priority claims, 5 June 2002, PCT/R/2/5. https://www.wipo.int/edocs/mdocs/pct/en/pct_r_2/pct_r_2_5.pdf. Accessed 24 Feb 2021\n\nWIPO International Patent Cooperation Union (2002c) Automatic indication of all designations possible under the PCT; related proposals: elections; international filing fee; “communication on request” system, 7 June 2002, PCT/R/2/6. https://www.wipo.int/edocs/mdocs/pct/en/pct_r_2/ pct_r_2_6.pdf. Accessed 24 Feb 2021\n\nWIPO International Patent Cooperation Union (2002d) Enhanced international search and prelim- inary examination system, 7 June 2002, PCT/R/2/7. https://www.wipo.int/edocs/mdocs/pct/en/ pct_r_2/pct_r_2_7.pdf. Accessed 24 Feb 2021\n\nWorld Intellectual Property Organization (n.d.) IP Statistics Data Center (WIPO). https://www3.", "n_tokens": 439, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-280-3", "doc_id": "medicine_vaccine_book", "page": 280, "text": "wipo.int/ipstats/index.htm. Accessed 24 Feb 2021\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\nN. Syam", "n_tokens": 187, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-281-0", "doc_id": "medicine_vaccine_book", "page": 281, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing of Medicines\n\nMor Bakhoum\n\n1 Introduction\n\nThis chapter wrestles with the interface between Intellectual Property Rights (IPRs), competition law and access to medicines. It emphasizes the important role that competition law may play, in addition to the internal IP flexibilities, in order to foster access and dissemination of medical products. Of course, competition law could also be considered as a flexibility within the TRIPS agreement. In our analysis, we consider competition law separately given its role in creating competitive markets within which IP products are commercialized. Relying on the recent case law in the EU, in Italy and in South Africa on the application of competition law in the pharmaceutical sector, with a focus on the prohibition of excessive pricing of pharmaceuticals, this paper argues that TRIPS flexibilities are an important regula- tory tool to control prices and to foster access to medicines. However, in certain circumstances, IP flexibilities are operational only within a competitive market that is guaranteed by a functioning competition law.", "n_tokens": 216, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-281-1", "doc_id": "medicine_vaccine_book", "page": 281, "text": "Section 2 of the paper, which sets the stage, discusses the interface between TRIPS and Competition Policy and the enforcement orientation of competition law in the pharmaceutical sector since the entry into force of the TRIPS Agreement. This section presents the TRIPS competition-related provisions and their approach as a flexibility instrument. In addition to serving as a technology transfer instrument,1 TRIPS competition-related provisions may also be used in order to foster access to medicines. In this regard, this section emphasises the IP-related restrictions of\n\n1See for discussion, Ullrich (2005), pp. 727–756.\n\nM. Bakhoum (*) UVS Doctoral School, Université Virtuelle du Sénégal (UVS), Dakar, Senegal\n\nMax Planck Institute for Innovation and Competition, Munich, Germany e-mail: mor.bakhoum@uvs.edu.sn\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_10\n\n277", "n_tokens": 238, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-282-0", "doc_id": "medicine_vaccine_book", "page": 282, "text": "278\n\nM. Bakhoum\n\ncompetition in the pharmaceutical sector that can affect access to medicines. The discussion is informed by both the findings of the 2009 and 107 EU reports on the pharmaceutical sector and the case law on reverse payment settlements in the EU and the US.\n\nSection 3 of the paper focuses on the recent trends of competition law enforce- ment in the pharmaceutical sector with the emerging case law on excessive (high) pricing of pharmaceuticals. The discussion is informed by the Aspen Case on excessive pricing decided by the Italian competition authority and the ongoing investigations against Aspen in the EU and in South Africa.\n\nSection 4 deals with excessive pricing of pharmaceuticals in relations to IP flexibilities. It showcases that creating competitive pharmaceuticals markets by dealing with IP related restrictions of competition is in most cases important for TRIPS flexibilities to be operational. In addition to emphasizing the role of compe- tition law enforcement as a complement to the TRIPS flexibilities, the section outlines situations where competition law enforcement is warranted.\n\nSection 5 concludes with policy recommendation on how to align IP flexibilities\n\nand competition law enforcement in order to foster access to pharmaceuticals.\n\n2 TRIPS and Competition Policy: Orientations", "n_tokens": 243, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-282-1", "doc_id": "medicine_vaccine_book", "page": 282, "text": "and Enforcement Trends in the Pharmaceutical Sector\n\nThis section discusses three aspects: first, from a conceptual point of view, the interface between IP and Competition Law, second, TRIPS and Competition Policy with a reminder of TRIPS’ approach to competition law and, third, the enforcement trends of competition law in the pharmaceutical sector since the entry into force of the TRIPS Agreement.\n\n2.1 The Interface Between IPRs and Competition Law\n\nThe interplay between IP and competition law is dynamic. The IP system provides, in theory incentives for innovation and the development of cultural markets. How- ever, IPRs do not operate in a vacuum. IPRs are exercised and commercialized in markets that are mostly regulated. As a market regulatory tool, competition law determines the framework within which IPRs are commercialized. However, the potential of competition law to serve as a market regulatory tool differs from country to country. Hence, competition law is still not implemented everywhere and in developing countries, strong enforcement is lacking. Competition law used to be approached as a regulatory instrument that limits the exercise of IPRs. This “con- ventional” and conflicting approach of the interface between IPRs and competition", "n_tokens": 234, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-283-0", "doc_id": "medicine_vaccine_book", "page": 283, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...\n\nlaw is exemplified by the TRIPS competition-related provisions2 which are designed as a limit to the exercise of IPRs. This approach of the interface between IPRs and competition law is not in line with the approach of the relationship between IP and competition law as being complementary.3", "n_tokens": 76, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-283-1", "doc_id": "medicine_vaccine_book", "page": 283, "text": "The protection granted by the IP system to the right holders is not a reward as such. IP protection provides only to the right holder an opportunity to extract a reward from the market4 by commercializing its invention. The development and successful commercialisation of new technologies and products is closely related to the competitiveness of the markets within which they are commercialized. Hence, in most cases, the markets conditions determine whether a new technology is success- ful or not. With regards to the flexibilities within the IP system, building competitive markets is also a precondition for their operability. Of course, in complement to using competition law as a regulatory tool, using IP flexibilities participate to building competitive markets. Hence, as we shall see in this chapter, anticompetitive behaviours may hinder the build-in flexibilities of the IP system. With regards to access to pharmaceuticals, which is the focus of this paper, a number of anticom- petitive behaviours (limitation of compulsory licensing, limitation of parallel import, or extension of the duration of the patent-reverse payment settlements) that affect the competitiveness of the pharmaceutical markets, and may affect the IP flexibilities that are crucial to access to pharmaceuticals.\n\n2.2 TRIPS and Competition Law: Competition Law", "n_tokens": 267, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-283-2", "doc_id": "medicine_vaccine_book", "page": 283, "text": "as Flexibility Tool\n\nTRIPS is the first international instrument that recognizes the possibility to police the exercise of IPRS. TRIPS prohibits IPR-related restrictions of competition. Articles 8, 31 (k) and 40 of TRIPS, which are usually referred to as the TRIPS competition- related provisions, are largely conceived as legal tools to monitor the exercise of IPR (s) based on competition considerations.5 Competition law is part of the flexibility tools of the IP system. Competition related provisions within TRIPS are part of the general architecture of the Agreement and they provide a necessary balance to potential abusive exercise of IPRS. They should be read as part of the rights recognized to IP owner, and, also, their limits.\n\nThe competition-related provisions in the TRIPS were a result of a compromise between developed and developing countries during the negotiation of the TRIPS agreement.6 Developing countries which feared a monopolistic exercise of IPRs\n\n2Which focus on technology transfer. See for discussion, Ullrich (2005), pp. 727–756. 3Bakhoum and Gallego (2016), p. 9, see specially reference in fn. 33. 4See Ullrich and Heinemann (2007), p. 146. 5Bakhoum and Gallego (2016). 6Ullrich (2005), pp. 727–756.\n\n279", "n_tokens": 279, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-284-0", "doc_id": "medicine_vaccine_book", "page": 284, "text": "280\n\nM. Bakhoum\n\nmanaged to have provisions on competition law included in order to mitigate potential abuses in the exercise of IPRs.\n\nInitially, competition law in TRIPS was associated with technology transfer.7 In licensing agreements, competition law was considered as an instrument that protects the weaker licensee party against potential abuses of the IP right holder. As a consequence, TRIPS provides a detailed treatment of anticompetitive practises in licensing agreements.8\n\nThe reach of TRIPS competition related provisions is, however, not only limited to technology transfer. In additional to facilitating technology transfer, TRIPS competition related provisions can be read as an innovation policy tool.9\n\nWith regards to access to pharmaceuticals/medical products, TRIPS competition- related provisions may also be used as an access to medicines tool. This approach is proven by the increased reliance on competition law in the pharmaceutical industry since the entry into force of the TRIPS agreement.10 Competition enforcement is a complement to the IP flexibilities11 stricto sensu.", "n_tokens": 200, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-284-1", "doc_id": "medicine_vaccine_book", "page": 284, "text": "TRIPS does not create a binding international framework that obliges signatory members to apply competition law to IP-related restrictions of competition. The effectiveness of using competition law as a flexibility tool in the pharmaceutical sector depends on the institutional framework of each country. Unlike in IP law, there is no binding multilateral instrument that regulates competition law.12 The use of competition law as a flexibility tool is optional. Member States are given leeway to define their own policies when it comes to applying their competition law to IP-related restrictions.\n\nThis situation creates an imbalance from an international perspective. On the one hand, there is a harmonization, from the top, of the protection of IPRs. On the other hand, the use of competition law is ‘deregulated’ and left to the choice of each member to define its own policy. This “deregulation” of competition law enforce- ment has consequences, especially for developing countries, when applying com- petition law in the pharmaceutical sector.\n\n7Ullrich (2005), pp. 727–756. 8Article 40 TRIPS reads: “1. Members agree that some licensing practices or conditions pertaining to intellectual property rights which restrain competition may have adverse effects on trade and may impede the transfer and dissemination of technology.", "n_tokens": 266, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-284-2", "doc_id": "medicine_vaccine_book", "page": 284, "text": "2. Nothing in this Agreement shall prevent Members from specifying in their legislation licensing practices or conditions that may in particular cases constitute an abuse of intellectual property rights having an adverse effect on competition in the relevant market. As provided above, a Member may adopt, consistently with the other provisions of this Agreement, appropriate measures to prevent or control such practices, which may include for example exclusive grantback conditions, conditions preventing challenges to validity and coercive package licensing, in the light of the relevant laws and regulations of that Member”. 9Bakhoum and Gallego (2016). 10See infra, enforcement trends in the pharmaceuticals sector. See also, European Commission (2009–2017) https://ec.europa.eu/competition/sectors/pharmaceuticals/report2019/report_en.pdf. 11See, Berger (2006), p. 182. 12Drexl (2004), pp. 419–457.", "n_tokens": 192, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-285-0", "doc_id": "medicine_vaccine_book", "page": 285, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...\n\n2.3 Enforcement Trends of Competition Law\n\nin the Pharmaceutical Sector\n\nIPRs have expanded both in quantity and quality since the entry into force of the TRIPS agreement. New types of technologies, works and trademarks have been found eligible for protection;13 rights holders have been granted new exclusive prerogatives;14 the terms of protection for certain subject matter have been extended;15 and enforcement mechanisms and remedies have been strengthened and taken on an increasingly punitive character.16\n\nFrom an international perspective, we notice a proliferation of the so-called TRIPS-Plus agreements through bilateral and regional trade agreements. As a result, standards of IPR protection of developed countries have been transferred to devel- oping countries without due regard for the socio-economic, political and social context of the latter.17 This development reduces the policy space of developing countries to use TRIPS flexibilities, to foster access to pharmaceuticals.\n\nincluding in order", "n_tokens": 202, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-285-1", "doc_id": "medicine_vaccine_book", "page": 285, "text": "In reaction to the enhanced protection of IPRs through the TRIPS-Plus agree- ments there is a parallel push on how to best use the flexibilities embodied within TRIPS. The development in the framework of Doha with the Doha Declaration on IP and public health and subsequent article 31bis, which took over a decade to be implemented, to allow WTO members to issue compulsory licenses for export are prime examples of this development.18 Parallel to harnessing the use of TRIPS flexibilities, competition law enforcement is increasingly taking place in developed countries with mature competition law system and in some developing countries South Africa is an example of a developing countries pushing for a proactive enforcement of competition law in the pharmaceutical sector.\n\nAnticompetitive behaviours in the pharmaceutical sector may affect both inno- vation and access to medicines. The 2009 Pharmaceutical Sector Inquiry Report of the European Commission and the subsequent enforcement report of 2017 have", "n_tokens": 186, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-285-2", "doc_id": "medicine_vaccine_book", "page": 285, "text": "13See e.g. Directive 96/9/EC of the European Parliament and of the Council of 11 March 1996 on the legal protection of databases, OJ L 77, 27 March 1996, pp. 20–28. 14In the copyright field, for example, new forms of digital infringement related to the protection of technological protection measures have been created; see e.g. Directive 2001/29/EC of the European Parliament and of the Council of 22 May 2001 on the harmonization of certain aspects of copyright and related rights in the information society, OJ L 167, pp. 10–19. 15See e.g. Directive of the European Parliament and of the Council of 27 September 2011 amending Directive 2006/116/EC on the term of protection of copyright and certain related rights, OJ L 265, 11 October 2011, pp. 1–5; Sonny Bono Copyright Term Extension Act, Pub. L. No.105-298, 112 Stat. 2827 (1998). 16See e.g. Directive 2004/48/EC of the European Parliament and of the Council of 29 April 2004 on the enforcement of intellectual property rights, OJ L 195, 2 June 2004, pp. 16–25. 17For an overview and analysis of the most significant free trade agreements (FTAs) see Roffe (2014), pp. 17–40. 18Bakhoum and Gallego (2016).\n\n281", "n_tokens": 297, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-286-0", "doc_id": "medicine_vaccine_book", "page": 286, "text": "282\n\nM. Bakhoum\n\nidentified patenting strategies that block the development of competing medicines by reducing the incentives of other originator companies to continue their own R&D efforts.19 With regards to access, patenting strategies may also delay competition by generics.20 In 2007, the European Commission started an investigation against Boehringer Ingelheim after a competing pharmaceutical company had raised con- cerns that Boehringer’s patent applications would have the potential of blocking its competing medicines. The case was settled between the companies.21\n\nSince the entry into force of the TRIPS agreement, there is an increased scrutiny by competition authorities of behaviours in the pharmaceutical sector that negatively impact the timely entry of generics.22 In the EU, since the publication of the sector inquiry report on the pharmaceutical sector in 2009 there is an increased scrutiny of these practises.23\n\nWith regard to the interface between IP and Competition law, three different types of conducts may be identified: Category one concerns practices that are within the ambit of the patent system (Italian Pfizer, AstraZeneca) and involve the misuse of the patent and regulatory system which may impact innovation and access. Category two concerns behaviors that are outside of the boundaries of the patent system (such as ever-greening) while category 3 comprises practices half-way between the other two categories (pay for delay cases, FTC v Actavis, Lundbeck).24", "n_tokens": 300, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-286-1", "doc_id": "medicine_vaccine_book", "page": 286, "text": "19European Commission (2009), pp. 16 and 19. http://ec.europa.eu/competition/sectors/ pharmaceuticals/inquiry/staff_working_paper_part1.pdf.", "n_tokens": 44, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-286-2", "doc_id": "medicine_vaccine_book", "page": 286, "text": "Generally, the Sector Inquiry Report is concerned with two different sets of strategic patenting practices: on the one hand, those which aim at extending the exclusivity period to delay market entry of generics, and on the other hand, those whose objective is to block substitutive innovations by competitors. Regarding the later, blocking patents can be applied for either to broaden the applicant’s own field of activity (defensive blocking patents) or to limit the scope of action of competitors (aggressive blocking patents); see Ullrich (2013), pp. 244 and 248. 20The Commission and the two European courts have confirmed the application of Article 102 of the Treaty on the Functioning of the European Union (TFEU) to a strategic use of patent procedures aimed at delaying generic entry in the Astra Zeneca case; see Commission Decision of 15 June 2005 relating to a proceeding under Article 82 of the EC Treaty and Article 54 of the EEA Agreement, Case COMP/A.37.507/F3 – Astra Zeneca, http://ec.europa.eu/competition/antitrust/cases/dec_ docs/37507/37507_193_6.pdf (accessed 23 October 2014); GC, Case T-321/05, Astra Zeneca v. Commission, [2010] ECR 2010 II-2805; CJ, Case C-457/10 P, Astra Zeneca v. Commission, [2012] ECR I-770. On the relevance of the Astra Zeneca rulings for the assessment of blocking patents see Drexl (2013), pp. 312 et seq. 21See European Commission, Press Release of 6 July 2011, IP/11/842. http://europa.eu/rapid/press- release_IP-11-842_en.htm. 22See the different", "n_tokens": 398, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-286-3", "doc_id": "medicine_vaccine_book", "page": 286, "text": "cases discussed in this paper: See Case T-472/13, Lundbeck v. Commission, infra, box n(cid:1) 1; Case C-142/18, J&J et al. vs. Commission (“Fentanyl”), infra, box n(cid:1) 2; Case U.S. Supreme Court No. 12-416, FTC v. Actavis, infra, box 3; Case T-691/14, Servier and others v. Commission (still pending). 23See Contribution by the European Commission, UNCTAD Roundtable on The Role of Compe- tition in the Pharmaceutical Sector and its Benefits for Consumers. https://unctad.org/system/files/ non-official-document/CCPB_7RC2015_RTPharma_EC_en.pdf. 24Such distinction was made by Gallasch (2015). http://unctad.org/meetings/en/Presentation/ CCPB_7RC2015_PRES_RTPharma_Gallasch_en.pdf.", "n_tokens": 248, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-287-0", "doc_id": "medicine_vaccine_book", "page": 287, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...\n\nIn addition to “traditional” types of anticompetitive behaviours that affect phar- maceutical markets (cartels, bid rigging, and boycotts are conventional behaviours that aim to fix prices and earn monopoly profits), a particular type of anticompetitive agreement in the pharmaceutical industry has drawn the attention of competition law enforcers in recent years: the practice commonly known as a “pay for delay” agreement or, since it often involves a payment from the patentee to the alleged infringer, a “reverse payment” settlement agreement. Basically, it concerns situa- tions where a brand-name pharmaceutical company, as patent holder, and a generic producer, agree to settle either a patent infringement suit or a dispute concerning the validity of the patent under terms that require, firstly, the generic manufacturer not to produce and/or to distribute the patented product until the expiration of the patent, and secondly, the patent holder to “compensate” the generic company for staying out of the market.", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-287-1", "doc_id": "medicine_vaccine_book", "page": 287, "text": "Both in the United States and in Europe, the competition agencies and national/ regional courts have perceived such arrangements as an attempt to allocate markets and preserve monopolistic conditions25 and have condemned them as clear viola- tions of competition law.26 In the United States the Supreme Court has already had the opportunity to pronounce on the legal assessment of this kind of patent settlements.27\n\nIn July 2013, the European Commission fined Lundbeck and several producers of generic medicines for delaying generic market entry of Citalopram.28 In December", "n_tokens": 110, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-287-2", "doc_id": "medicine_vaccine_book", "page": 287, "text": "25Announcing the Commission’s decision on the Servier case, then Competition Commissioner Joaquín Almunia stated “Servier had a strategy to systematically buy out any competitive threats to make sure that they stayed out of the market. Such behavior is clearly anti-competitive and abusive. Competitors cannot agree to share markets or market rents instead of competing, even when these agreements are in the form of patent settlements. Such practices directly harm patients, national health systems and taxpayers”. See European Commission, Press Release of 9 July 2014, IP/14/799. http://europa.eu/rapid/press-release_IP-14-799_en.htm. 26In Europe, see European Commission, Press Release of 19 June 2013, IP/13/563 (Antitrust: Commission fines Lundbeck and other pharma companies for delaying market entry of generic medicines). http://europa.eu/rapid/press-release_IP-13-563_en.htm?locale¼en; Press Release of 10 December 2013, IP/13/1233 (Antitrust: Commission fines Johnson & Johnson and Novartis € 16 million for delaying market entry of generic pain-killer fentanyl). http://europa.eu/rapid/press- release_IP-13-1233_en.htm; Press Release of 9 July 2014, IP/14/799 (Antitrust: Commission fines Servier and five generic companies for curbing entry of cheaper versions of cardiovascular medicine). http://europa.eu/rapid/press-release_IP-14-799_en.htm. All press releases accessed 23 October 2014. At the time of writing this contribution, no public version of these decisions was yet available. For", "n_tokens": 377, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-287-3", "doc_id": "medicine_vaccine_book", "page": 287, "text": "an overview of the FTC’s practice see Cook (2001), pp. 437 et seq. (commenting particularly on In re Schering-Plough Corp., 136 F.T.C. 956 (2003); FTC v. Watson Pharm., Inc., 611 F. Supp. 2d 1081 (C.D. Cal. 2009) and FTC v. Cephalon, Inc., 551 F. Supp 2d 21 (D.D.C. 2008)). 27See Actavis decision. 28Press release Commission: http://europa.eu/rapid/press-release_IP-13-563_en.htm?locale¼en Information of General Court upon time of completion not available (July 2015).", "n_tokens": 169, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-287-4", "doc_id": "medicine_vaccine_book", "page": 287, "text": "283", "n_tokens": 1, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-288-0", "doc_id": "medicine_vaccine_book", "page": 288, "text": "284\n\nM. Bakhoum\n\n2013, the Commission fined Novartis and J&J29 which concluded an agreement whose aim was to delay the market entry of cheaper generic version of Fentanyl, a painkiller. This was a straightforward pay-for-delay case as it did not involve any patent dispute or litigation.\n\nIn the US, the Actavis decision of the Supreme Court30 sets the legal standard for the appreciation of pay-for-delay cases. After a discrepancy of decisions from lower courts, the Supreme Court concluded that the rule of reason should be applied to reverse payment settlements.\n\n3 Excessive Pricing of Pharmaceuticals: An Emerging\n\nEnforcement Trend\n\nThree aspects are discussed in this section: first, pricing of pharmaceuticals and IPRs, second, the case law on excessive pricing, third, the competition related issues raised by the case law on excessive pricing.", "n_tokens": 177, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-288-1", "doc_id": "medicine_vaccine_book", "page": 288, "text": "3.1 Pricing of Pharmaceuticals and IPRs\n\nIPRs affect the pricing of pharmaceuticals. The IP system has two dimensions: On the one hand, it regulates the conditions of acquisition of IPRs. On the other hand, it allows the right holder to exercise the exclusivity of the right conferred, by, for instance setting a given price for IP embodied products such as pharmaceuticals. Hence, an important right of IPRs holders is the freedom of pricing of IP embodied products. Freedom of pricing of pharmaceuticals is part of the exclusivity the IPRs holder enjoys. However, freedom of pricing pharmaceutical, as a right, is not absolute. It should be exercised in accordance with the principles of the market. Hence, pricing of pharmaceuticals should not be anticompetitive.\n\nFrom a competition law perspective, a core principle of the market economy and competition is the freedom of the pharmaceutical companies to set the prices of their products. Freedom of pricing pharmaceuticals is an expression of the general freedom of contract (freedom to enter into business dealings) which also is a tenet of the market economy.31 When an IPR is involved, contractual freedom may be exercised through licensing agreements. Sometimes, as part of the general IP policy", "n_tokens": 244, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-288-2", "doc_id": "medicine_vaccine_book", "page": 288, "text": "29See press release of Commission: http://europa.eu/rapid/press-release_IP-13-1233_en.htm; full text of judgment available at http://ec.europa.eu/competition/antitrust/cases/dec_docs/39685/ 39685_1976_7.pdf. 30570 U.S. 133 S. Ct. 2233 (2013). Judgment of the US Supreme Court available at: http://www. supremecourt.gov/opinions/12pdf/12-416_m5n0.pdf. 31For discussion on freedom of contract and competition law, see, Bakhoum (2018), pp. 157–186.", "n_tokens": 156, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-289-0", "doc_id": "medicine_vaccine_book", "page": 289, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...\n\nand the need to prevent potential abuse exercise of IPRs, freedom of contract, and of pricing, may be limited in order to protect the competitiveness of the markets and consumers. Contractual freedom and the freedom to set prices should not lead to anticompetitive practices that could take a form of high pricing of pharmaceuticals. High pricing is considered, in some competition law, as a form of abuse of dominant position.\n\n3.2 Overview of the Case Law on Excessive Pricing", "n_tokens": 110, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-289-1", "doc_id": "medicine_vaccine_book", "page": 289, "text": "of Pharmaceuticals\n\nExcessive pricing is considered a type of abuse of dominant position in number of jurisdictions. This is the case in the EU and some of its Member States. In South Africa also high pricing is considered an abuse of dominant position. If in principle, this form of prohibition is recognized, in practice, competition authorities have been very reluctant in dealing with excessive pricing cases.\n\nRecently, however, high pricing of pharmaceuticals has attracted the attention of competition authorities with a number of cases in the UK, the EU and in South Africa. In the EU, the Aspen case on excessive pricing decided by the Italian Competition Authority has attracted significant attention. Ongoing investigations both in the EU and in South Africa illustrate what could be considered as an emerging enforcement trend on the application of competition law in the pharma- ceutical sector.\n\nThe Italian Aspen case illustrates how important it is to have competitive markets in order to make TRIPS flexibilities operational. In this case, the Italian Competition Authority fined Aspen for infringing Article 102 (a) of the TFEU. The Italian Competition Authority considered that Aspen “had fixed unfair prices with increases up to 1500%”.32 It results from the facts that Aspen had acquired an off-patent cancer drug package from GlaxoSmithKline. The antitumor drugs are considered life-saving and irreplaceable especially in the treatment of children and elderly patients.", "n_tokens": 290, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-289-2", "doc_id": "medicine_vaccine_book", "page": 289, "text": "After acquiring the rights on the drugs, Aspen initiated “negotiations with the Italian Medicines Agency (Agenzia Italiana del Farmaco - AIFA) with the sole aim to obtain a high increase in prices, even in the absence of any necessary economic justifications”.33 An important factual element in the Aspen case is that there was a public procurement with the authorities purchasing directly the drugs from Aspen. Aspen used aggressive negotiation strategy with the Italian Medicines Agency and\n\n32See Press release on the Aspen case, 14/10/2016, available at: http://www.agcm.it/en/newsroom/ press-releases/2339-a480-price-increases-for-cancer-drugs-up-to-1500-the-ica-imposes-a-5-mil lion-euro-fine-on-the-multinational-aspen.html. For discussion of the case, see also, Lanza and Sfasciotti (2018), pp. 382–388. 33See Press release on the Aspen case, op. cit.\n\n285", "n_tokens": 227, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-290-0", "doc_id": "medicine_vaccine_book", "page": 290, "text": "286\n\nM. Bakhoum\n\nthreaten to interrupt supply to the Italian market.34 As a consequence of its negoti- ation strategy Aspen obtained extremely high prices ranging between 300% and 1500% of the initial levels.35\n\nTwo aspects were considered by the Italian Competition Authority when assessing the excessiveness of the prices charged by Aspen. It first considered the disproportion between price and cost. Second, it considered additional aspects such as the “specific context and behavioural factors, such as: the inter-temporal compar- ison of prices, the absence of economic justifications for the increase, the absence of any extra-economic benefits for patients, the nature of Comos’s drugs, the charac- teristics of the Aspen group, and the damage caused to the National Health System (Sistema Sanitario Nazionale – SSN)”.36", "n_tokens": 190, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-290-1", "doc_id": "medicine_vaccine_book", "page": 290, "text": "Similar investigations on excessive pricing have been opened by other competi- tion authorities. In 2017 the EU Commission opened its first formal investigation on excessive pricing against Aspen for life saving cancer medicines.37 The facts of the ongoing case are the same as the facts in the Aspen Italian case. The medicines in question were off-patent and Aspen acquired them after their patents had expired. As in the Italian case, “Aspen has imposed very significant and unjustified prices increases of up to several hundred percent (...)”.38 Moreover, “Aspen has threatened to withdraw the medicines in question in some Member States and has actually done so in certain cases”.39\n\nIn the UK, the Competition and Markets Authority (CMA) in 2016 fined Pfizer, Inc. (Pfizer) and Flynn Pharma Limited (Flynn) for charging excessive price for an anti-seizure drug. The CMA found that both Pfizer and Flynn were dominant in their respective markets of manufacturing and distribution of Epanutin and had signifi- cantly improved their cost-profit margins by increasing the sale price by 2600%.\n\nIn South Africa, the South African Competition Authority had opened investiga- tions against Roche, Pfizer and Aspen on high pricing.40 The Commission men- tioned that Roche has and “continue[s] to engage in excessive pricing, price discrimination and/or exclusionary conduct in the provision of breast cancer med- icine in South Africa”.41 The Commission added that “as a result of exorbitant", "n_tokens": 328, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-290-2", "doc_id": "medicine_vaccine_book", "page": 290, "text": "34See Press release on the Aspen case, op. cit. 35See Press release on the Aspen case, op. cit. 36See Press release on the Aspen case, op. cit. 37European Commission, Press Release, Antitrust: Commission opens formal investigation into Aspen Pharma’s pricing practices for cancer medicines, May 15, 2017, http://europa.eu/rapid/press- release_IP-17-1323_en.htm. 38May 2017 European Commission, Press Release, Antitrust: Commission opens formal investi- gation into Aspen Pharma’s pricing practices for cancer medicines, May 15, 2017. 39May 2017 European Commission, Press Release, Antitrust: Commission opens formal investi- gation into Aspen Pharma’s pricing practices for cancer medicines, May 15, 2017. 40Media release, South African Competition Commission, 13 June 2017, available at: http://www. compcom.co.za/wp-content/uploads/2017/01/International-pharmaceutical-companies-investi gated-for-cancer-medicine-prices.pdf. 41Media release, South African Competition Commission, 13 June 2017, op. cit.", "n_tokens": 260, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-291-0", "doc_id": "medicine_vaccine_book", "page": 291, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...\n\nprices, most breast cancer patients in both the private and the public sectors are unable to get treatment”.42 The investigation against Pfizer relates also to excessive pricing of lung cancer medication. According to the Commission, “Pfizer is the only lung cancer treatment medication known as xalkori crizotinib in provider of South Africa”.43 The investigation seems to be based on the fact that lung cancer treatment is unaffordable in South Africa given the high prices that the consumers are unable to afford. A Parallel investigation to the ongoing investigation in the EU is open against Aspen. The Investigation is based on a “reasonable suspicion that Aspen has and continues to engage in excessive pricing in the provision of certain cancer medicines (...)”.44", "n_tokens": 171, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-291-1", "doc_id": "medicine_vaccine_book", "page": 291, "text": "In the context of South Africa, the open investigations are in line with the earlier trend of the Commission to investigate anticompetitive practices in the pharmaceu- tical sector. A complaint was lodged before the South African Competition Com- mission against GlaxoSmithKline South Africa (Pty) Ltd (“GSK”) & Boehringer Ingelheim (Pty) (“BI”),45 (hereinafter GSK/BI case), initially for high pricing, but then the Commission extended the investigation to include an alleged violation of Section 8(b) and (c) of the Competition Act, which deals respectively with the essential facilities doctrine and exclusionary conduct.46 The Competition Commis- sion concluded its investigation with a finding that GSK and BI abused their dominant position by charging excessive prices, refusing to grant access to essential facilities to a competitor and engaging in exclusionary conduct. The matter did not come before the Competition Tribunal, as GSK and BI accepted a settlement, which resulted in a drastic reduction in the prices of the pharmaceuticals in South Africa. What can be learned from the Aspen Italian case and the ongoing investigations\n\non excessive pricing of pharmaceuticals?\n\n3.3 Competition and IP Issues Raised by the Case Law", "n_tokens": 259, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-291-2", "doc_id": "medicine_vaccine_book", "page": 291, "text": "on Excessing Pricing of Pharmaceuticals\n\nA number of lessons can be learned from the case law on excessive pricing of pharmaceuticals. There is an IP dimension and a competition law dimension in the analysis.\n\n42Media release, South African Competition Commission, 13 June 2017, op. cit. 43Media release, South African Competition Commission, 13 June 2017, op. cit. 44Media release, South African Competition Commission, 13 June 2017, op. cit. 45The case was settled. For discussion of the background of the case, see, Berger (2004), pp. 197–201. The Commission’s comments on the case at: South African Competition Commission Newsletter, edition.15, pp. 1–2. http://www.compcom.co.za/assets/Uploads/AttachedFiles/ MyDocuments/March-04-Newsletter.pdf. 46For a discussion of the case, see Ngobese and Mncube (2011).\n\n287", "n_tokens": 203, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-292-0", "doc_id": "medicine_vaccine_book", "page": 292, "text": "288\n\nM. Bakhoum\n\n3.3.1\n\nIP, Patent Term and Excessive Pricing of Pharmaceuticals\n\nThe case law on excessive pricing raises a number of issues that question the rationale of the IP system regarding access to pharmaceuticals.", "n_tokens": 45, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-292-1", "doc_id": "medicine_vaccine_book", "page": 292, "text": "The Italian Aspen case is not about IPRs and an abuse of a monopoly by a right holder during the protection term. It is true that pharmaceuticals are involved in the case. However, the pharmaceuticals patents for the cancer drugs had already expired when Aspen acquired them. As a consequence, IPRs cannot be invoked in order to justify the high prices charged by Aspen. The rationale of the IP system according to which the right holder has the exclusivity to commercialize its products at “monop- oly price” is not applicable in this case. Aspen had acquired the pharmaceuticals at the end of the protection period. At the end of the exclusivity term, Aspen could still charge prices that are even higher than the prices of the pharmaceuticals when the patents were into force. The behavior of Aspen contradicts the very rationale of the IP system according to which price competition by generics should, in principle, drive the prices of pharmaceuticals down. Hence, at the end of the patent term, the rationale of the IP system that generic competition should take place and drive the prices down is not operational in this case. This is an important aspect of the Aspen Italian case. In Fact, the prices of the pharmaceuticals when the patents were in force were lower than the prices charged by Aspen when the drugs were off-patent.", "n_tokens": 269, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-292-2", "doc_id": "medicine_vaccine_book", "page": 292, "text": "Price competition by generics does not necessarily follow the end of the exclu- sivity period. For price competition by generics to take place the market conditions have to be attractive enough for generic companies to enter the market at the end of the patent term. If there is not price competition at the end of the exclusivity period, the patent holder still can charge high prices.\n\nAnother important element of the analysis is that the drugs had not been devel- oped by Aspen. The usual justification of the recognition of the right of the IP holder to charge high prices is the investment made for the development of the IP embodied product. In this case, this rationale does not justify the high prices charged post- patent term. In fact, in the Italian Aspen case, the cancer drugs are produced by third party companies without any mobilization of resources by Aspen. To the contrary, the production costs of the medicines have considerably decreased over time.47 The increase of prices could not be justified by any costs since Aspen did not make any additional investment nor did it face any increase of production costs. Aspen did not make any improvement on the medicines and their related services.48\n\n47See Lanza and Sfasciotti (2018), p. 386. 48Ibid.", "n_tokens": 264, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-293-0", "doc_id": "medicine_vaccine_book", "page": 293, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...\n\n3.3.2 Competition Law and Excessive Pricing of Pharmaceuticals:\n\nMarket Conditions and Pricing\n\nMarket Power, Size of the Market and High Pricing", "n_tokens": 43, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-293-1", "doc_id": "medicine_vaccine_book", "page": 293, "text": "The structure of a given market and its competitive conditions influence prices. If a market is open with low entry barriers and substitute products or services are available, there is a likelihood that the prices become competitive. If to the contrary, a market is very small, only one undertaking offers a service or product, and there is no substitute, there is a likelihood to have dominance and market power which allow the undertaking to charge high prices. In pharmaceuticals markets, this may happen even for off-patent drugs. In the Aspen case, for example, the small size of the market of the pharmaceuticals involved afforded Aspen market power and allowed it to charge high prices. Blood cancer drugs in the case “has a small incidence on the population and the specific categories of patients treated with Aspen’s drugs further restrict the market size”.49 The small size of the market for blood cancer drug afforded Aspen sufficient power to bargain for high prices with the Italian Medicines Agency. Aspen’s market power allowed it to charge high prices without fear of losing market shares. Compared to the prices of the pharmaceuticals when the patents were in force, the prices increased from 300% to 1500%. The prices of the patented medicine were more affordable than the prices of the same medicine off-patent. This price increase was only possible because the market was not competitive and Aspen did not face any competition constraints that obliged it to reduce its prices.", "n_tokens": 288, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-293-2", "doc_id": "medicine_vaccine_book", "page": 293, "text": "Market power allows an undertaking to behave into the market without taking into account actual or potential competition. It allows, for instance, an undertaking to set prices without fear of losing market share. The negotiation strategy adopted by Aspen confirms its market power. Using its market power, Aspen adopted an aggressive negotiation strategy and threatened to interrupt the supply of the Italian market.50 Aspen was able to use its superior bargaining power since it has market power and did not face any competition. As pointed out, “the absence of any medical alternative for the cure of the weakest fringe of patients made them non-substitutable (essential) for the NHS, thereby depressing AIFA’s bargaining power in the nego- tiation with the company”.51\n\nAbsence of Substitutability and High Pricing of Pharmaceuticals\n\nThe concept of substitutability is used in competition law analysis in order to determine whether two products or services belong to the same market. It allows\n\n49Ibid. 50Ibid. 51Lanza and Sfasciotti (2018), p. 386.\n\n289", "n_tokens": 222, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-294-0", "doc_id": "medicine_vaccine_book", "page": 294, "text": "290\n\nM. Bakhoum\n\nthe competition authorities to define the relevant market and thereby determine whether a given undertaking enjoys a dominant position. If a market is small and there is no substitute for a given product, there is a strong likelihood that the undertaking offering the product will be found dominant. However, as a reminder, the simple fact of being dominant is not prohibited. Only abusive behavior resulting from a dominant position, such as charging excessive prices, is prohibited.\n\nIn the Aspen Italian case, Aspen’s market power was reinforced by the absence of alternative medicines in the market. Hence, no substitutable drugs existed in the market for the category of patients in Aspen’s market. This absence of substitutabil- ity of Aspen’s pharmaceuticals limit the ability of the consumers to turn to substitute products when prices become high. No substitute existed for the pharmaceuticals involved in the case which are used to treat severe oncological diseases for children and elderly people. In other words, consumers could not shift to alternative phar- maceuticals that have similar therapeutic virtues when the prices become high. Given the absence of substitute pharmaceuticals, the Italian Medical Agency did not have a choice but to accept the prices charged by Aspen.", "n_tokens": 250, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-294-1", "doc_id": "medicine_vaccine_book", "page": 294, "text": "Consumer Choice/Behavior (Rationality) and the Specificity of Pharmaceuticals\n\nWhat has been termed as “consumer rationality”52 is also an element to be consid- ered when pharmaceuticals are involved in a given case. Hence, if life saving drugs are involved, consumer behavior may be different. For life saving pharmaceuticals, in the absence of alternative drugs, consumers have a strong willingness to pay, no matter how high the prices are. Consumer rationality that commands consumers to seek alternative, more affordable, sources of supply when prices become high is not strong in the case of pharmaceuticals. If life saving drugs are involved, and there is no substitute, consumer rationality becomes absent.\n\nFrom a contract law perspective, an argument can be made that since consumers are willing to pay competition authorities should not intervene in the contract relationships. However, the absence of substitute medicines and the uneven bargaining powers53 between consumers and Aspen, which has market power, should limit the freedom of contract.\n\nThe combined factors which are Aspen’s market power, the lack of alternative products (substitute) and the absence of consumer rationality allowed Aspen to impose high prices on consumers.\n\n52Ibid. 53For discussion on freedom of contract and competition law, see, Bakhoum (2018).", "n_tokens": 256, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-295-0", "doc_id": "medicine_vaccine_book", "page": 295, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...", "n_tokens": 16, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-295-1", "doc_id": "medicine_vaccine_book", "page": 295, "text": "The Issue of the Determination of an Excessive Price\n\nCompetition authorities have been very reluctant to deal with excessive pricing given the issues raised by the assessment of high pricing. What amounts to an excessive price is a first hurdle that makes competition law intervention difficult. Whether dealing with excessive pricing is a form of regulation by competition authorities is another issue. By dealing with excessive pricing, competition author- ities can be seen as price regulators. Regulating prices is not in principle the role of competition authorities. If from a theoretical point of view dealing with excessive pricing raises a number of issues, a number of competition laws still consider high pricing as a form of abuse of dominant position. A firm with a dominant position may charge excessive prices without the risk of market entry of competitors and thus without the risk of competition. How to determine high prices? What is the relation between the economic value of a product or service and high prices?\n\nExcessive pricing may be assessed in relation to costs. In the Aspen case, the\n\nItalian Competition Authority applied the following method: – An estimation of excessiveness based on “percentage gross margin” – A profitability analysis—based on an approximation of the economic value of the drugs which takes into account all overall costs of making and commercializing the drug—compared to actual prices charged.54", "n_tokens": 263, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-295-2", "doc_id": "medicine_vaccine_book", "page": 295, "text": "The cost price analysis was the main approach of the Italian Competition Author- ity in determining excessive pricing: As pointed out, “ICA’s investigation on the unfair practice was carried out through a two-phase test that measured the dispro- portion between prices and costs. The unreasonableness of the mentioned dispro- portion resulted indicative of unfair prices also in the light of specific context and behavioural factors, such as: the inter-temporal comparison of prices, the absence of economic justifications for the increase, the absence of any extra-economic benefits for patients, the nature of Comos’s drugs, the characteristics of the group Aspen and the damage caused to the National Health System (Sistema Sanitario Nazionale – SSN)”.55\n\nAlthough Aspen did not incur any additional costs, it has substantially increased the prices. As indicated, there was “no investment to be recovered, no risk assump- tion by Aspen, no dry hole; no owned production facility, no freeze of financial resources by Aspen; no need to promote the drugs, no promotional costs to be recovered; no actual competitor, due to the absence of substitutability”.56 From a cost perspective, Aspen did not bring forth additional arguments that justify the increase of prices.\n\n54See, Lanza and Sfasciotti (2018), p. 385. 55See Press release on the Aspen case, op. cit. 56See, Lanza and Sfasciotti (2018).\n\n291", "n_tokens": 321, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-296-0", "doc_id": "medicine_vaccine_book", "page": 296, "text": "292\n\nM. Bakhoum\n\n4 Excessive Pricing of Pharmaceuticals and TRIPS", "n_tokens": 13, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-296-1", "doc_id": "medicine_vaccine_book", "page": 296, "text": "Flexibilities: Lessons from the Excessive Prices Cases\n\nA number of lessons can be learned from the case law on excessive pricing, especially the Italian Aspen case in relation to the rationale of the IP system and Competition law as a flexibility tool.\n\nAlthough pharmaceuticals were involved in the Aspen case, one can argue that the case raised only competition law issues. Since the patents of the cancer drugs involved in the Aspen case had already entered the public domain when Aspen acquired them, the behavior of Aspen could not be considered as an abuse of IPRs. The exclusivity afforded to the right holder of the pharmaceuticals ended with the patent term. The subsequent price increase at the end of the patent period could not, in principle, be considered an abuse of IPRs since the patented pharmaceutical has entered the public domain. However, in practice, the right holder of the off-patent pharmaceuticals continued to enjoy a de facto exclusivity and was able to charge high prices. Hence, although the pharmaceuticals involved in the Aspen case were no longer patented, the prices were not reduced. Such situation is not in line with the very rationale of the IP system according to which at the end of the patent term generic competition should kick in and drive the prices down. Similar to the reverse payment settlement cases that delay the entry in the market of generics, an abuse of dominant position post patent term may also slow the competition by generics.", "n_tokens": 287, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-296-2", "doc_id": "medicine_vaccine_book", "page": 296, "text": "Price reduction of pharmaceuticals is not automatic at the end of the patent term. There is a close link between the competitiveness of the market post patent and the reduction of prices at the end of the patent term. Whether prices of pharmaceuticals would be reduced at the end of the exclusivity period depends on the competitive- ness of the market. If the market is open and competitive at the end of the exclusivity period with a possibility of entry of generics, prices may be reduced. However, generic entry is not automatic either. Generic entry takes place only if the market is attractive and that there is a strong likelihood to have return on investment. In the Italian Aspen case, there was no competition by generics despite the absence of patents attached to the drugs. Absent generic competition, the right holder continues to enjoy a de facto exclusivity and to be able to charge high prices. If a given market is small enough so that a pharmaceutical company enjoys a monopoly position, it can continue to charge excessive prices even at the end of the exclusivity period.", "n_tokens": 217, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-296-3", "doc_id": "medicine_vaccine_book", "page": 296, "text": "Substitutability and consumer choice are important for price reduction of phar- maceuticals to take place. Absence of substitute and consumer choice, a patent owner may continue to have market power and to charge high prices at the end of the patent protection. This is a de facto extension of the exclusivity rights. Patent protection does not necessarily create market dominance. However, market domi- nance may exist after the expiration of the exclusivity period if there is no compe- tition in the market. Under certain market conditions at the expiration of the exclusivity period (market power, absence of substitute, no generic competition, price inelasticity, strong willingness of consumers to pay) the IP owner may still charge monopoly prices without fear of losing market shares.", "n_tokens": 166, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-297-0", "doc_id": "medicine_vaccine_book", "page": 297, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...\n\nThe Aspen case showcases how important it is to create competitive markets and to protect/promote competition in pharmaceuticals markets through a strong com- petition law enforcement. When IP flexibilities and the very rationale of the IP system are not operational at the end of the exclusivity period, competition law can be used as a tool to correct the anticompetitive behavior and to complement the IP system. As already pointed out, the design of TRIPS which have a competition law dimension as a flexibility tool gives to Member States the possibility to create strong competition law institutions in complement to the IP related flexibilities stricto sensu.\n\nIt also results from the Aspen case that under certain circumstances, access is more guaranteed (and prices are lower) during the exclusivity period, when the patent is still into force. This is the case when the flexibilities are fully applicable during the exclusivity period. It is possible during the patent term to use the flexibilities of the IP system such as issuing compulsory licenses. This possibility does not exist at the end of the exclusivity period.", "n_tokens": 249, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-297-1", "doc_id": "medicine_vaccine_book", "page": 297, "text": "There is a close link between the operability of the rationale of the IP system and its flexibilities and the market conditions. As highlighted in the discussion in this paper, having competitive markets participate to the operability of the core principles of the IP system and its flexibilities.\n\n5 Conclusions\n\nCompetition law enforcement is a complement of the IP system and its flexibilities. IP and competition law are two regulatory instruments that both have their potential and limits. IP affords rights. Competition law defines the framework for the com- mercialization. The freedom of IP owners to determine the price of pharmaceuticals should be exercised while respecting the market (competition) rules.\n\nThe IP system and its flexibilities of the IP system have intrinsic limitations that affect their operability. They may not, in some situations, have the expected effect on access to pharmaceuticals. The Doha declaration and article 31bis of the TRIPS agreements illustrate the difficulties to use the IP system in order to foster access to pharmaceuticals. There exist also some limits related to the scope of the IP system and its flexibilities. The IP system does not address the behavior of right holders that may affect prices of pharmaceuticals after the expiration of the patent term. Post patent term abusive behavior are beyond the reach of the IP system. In such situations, as illustrated by the Aspen case, only competition law may help reinstate the balance of the IP system.", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-297-2", "doc_id": "medicine_vaccine_book", "page": 297, "text": "The scope of application of competition law is more extended than the application of the IP flexibilities. Competition law polices the behaviors of market participants. It addresses practices when IPRs are into force and at the end of the protection term. Competition law is applicable when patented and off-patent products are involved such as in the Aspen case. Competition authorities are required to evidence a clear breach of the rules of the markets (e.g. cartels, abuse of dominance) and a clear\n\n293", "n_tokens": 101, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-298-0", "doc_id": "medicine_vaccine_book", "page": 298, "text": "294\n\nM. Bakhoum\n\nframework of analysis is provided by the law. The evolution of competition enforce- ment in the pharmaceuticals sector since the entry into force of the TRIPS agreement has illustrated an evolutive approach that could have a positive impact of competi- tion law enforcement on access to pharmaceuticals. The cases discussed in the UE, in Italy and in South Africa illustrate this trend to use a proactive role of competition law as an access to pharmaceuticals tools.\n\nBut competition law application in the pharmaceuticals sector is not without its issues: enforcement of competition law to IP related restrictions may be problematic. Hence, an argument can be made that strong enforcement may chill investment in R&D and innovation. However, in addition to access, competition law takes into account the innovation parameters when applied to IP related restrictions. With regards to pharmaceuticals patents, the question of the balance between access and innovation raises issues. Can lower prices of pharmaceuticals (access) and innova- tion (bringing new pharmaceuticals into the market) be aligned? Does one want lower prices of pharmaceuticals or is innovation more important?", "n_tokens": 220, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-298-1", "doc_id": "medicine_vaccine_book", "page": 298, "text": "In cases involving charging high prices post patent term, as it was the case in Aspen, the innovation argument cannot be strongly supported. One could argue that in post patent term cases, after the expiration of the patent, the incentives to innovate argument should not be considered since the exclusivity rights have expired. The patent holder has already reaped the benefits and rewards of the invention. However, one also should take account of the argument that even after the expiration of the patent, strong enforcement of competition law and regulation of prices may affect R&D incentives.\n\n(cid:129)\n\n(cid:129)\n\n(cid:129)\n\nFour different situations can be contemplated: If the flexibilities within the IP system work and may be used in order to enable the reduction of prices, one could consider that there may not be an access problem even if IP protection exists. IP flexibilities may work but anticompetitive conduct restricts their positive impact on prices and access. If for instance IP flexibilities are not operational because of anticompetitive practices, one could argue that there is a case for competition law intervention. If IP flexibilities do not work the question arises as to whether there is a case for competition law to correct the shortcomings.", "n_tokens": 271, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-298-2", "doc_id": "medicine_vaccine_book", "page": 298, "text": "(cid:129) No IP flexibilities because IP protection expired: one could argue that there is a case also for competition law intervention as illustrated by the Aspen case. IPRs could no longer be an obstacle to competition law intervention.\n\nThe discussions of the paper is largely based on the case law in developed jurisdictions. However, developing and LDC countries can learn a lot from the approach of developed countries of using competition law as an external flexibility in order to foster access to medicine during the patent term and after the expiration of the patent. South Africa is making efforts in that direction. Developing countries with limited competition culture and resources still face the challenge of enforcing their competition law to restrictions of competition affecting access to medicines. Though the lack of challenges is an issue, it is crucial for policy makers and enforcer", "n_tokens": 166, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-299-0", "doc_id": "medicine_vaccine_book", "page": 299, "text": "Intellectual Property Rights (IPRs), Competition Law and Excessive Pricing...\n\nto encourage the application of competition law in the pharmaceutical sector in combination to the TRIPS flexibilities.\n\nReferences\n\n570 U.S. 133 S. Ct. 2233 (2013). Judgment of the US Supreme Court available at: http://www.\n\nsupremecourt.gov/opinions/12pdf/12-416_m5n0.pdf. Accessed 24 Feb 2021\n\nBakhoum M (2018) Abuse without dominance in competition law: abuse of economic dependence and its interface with abuse of dominance. In: Di Porto F, Podszun R (eds) Abusive practices in competition law (ASCOLA Competition Law series). Edward Elgar Publishing, Cheltenham, UK; Northampton, MA, USA, pp 157–186\n\nBakhoum M, Gallego BC (2016) TRIPS and competition rules: from transfer of technology to innovation policy. In: Ullrich H, Hilty RM, Lamping M, Drexl J (eds) TRIPS plus 20 – from trade rules to market principles, p 9\n\nBerger J (2004) Advancing public health by other means: using competition policy, pp 197–201 Berger J (2006) Advancing public health by other means: using competition policy. In: Roffe P, Tansey G, Vivas-Eugui D (eds) Negotiating health: intellectual property and access to medicine. Earthscan, London, p 182", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-299-1", "doc_id": "medicine_vaccine_book", "page": 299, "text": "infra, box n(cid:1)\n\nCase T-472/13, Lundbeck v. Commission,\n\nJ&J et al. vs. Commission (“Fentanyl”), infra, box n(cid:1) 2; Case U.S. Supreme Court No. 12-416, FTC v. Actavis, infra, box 3\n\n1; Case C-142/18,\n\nCase T-691/14, Servier and others v. Commission (still pending) Cook A (2001) Pharmaceutical patent litigation settlements: balancing patent & antitrust policy\n\nthrough institutional choice. Mich Telecommun Technol Law Rev 17(2):417–458\n\nDirective 2001/29/EC of the European Parliament and of the Council of 22 May 2001 on the harmonization of certain aspects of copyright and related rights in the information society, OJ L 167, pp 10–19\n\nDirective 2004/48/EC of the European Parliament and of the Council of 29 April 2004 on the\n\nenforcement of intellectual property rights, OJ L 195, 2 June 2004, pp 16–25\n\nDirective 96/9/EC of the European Parliament and of the Council of 11 March 1996 on the legal", "n_tokens": 249, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-299-2", "doc_id": "medicine_vaccine_book", "page": 299, "text": "protection of databases, OJ L 77, 27 March 1996, pp 20–28\n\nDirective of the European Parliament and of the Council of 27 September 2011 amending Directive 2006/116/EC on the term of protection of copyright and certain related rights, OJ L 265, 11 October 2011, pp. 1–5; Sonny Bono Copyright Term Extension Act, Pub. L. No.105–298, 112 Stat. 2827 (1998)\n\nDrexl J (2004) International competition policy after Cancún: placing a Singapore issue on the\n\nWTO development agenda. World Compet 27(3):419–457\n\nDrexl J (2013) Astra Zeneca and the EU sector inquiry: when do filings violate competition law? In: Drexl J, Lee N (eds) Pharmaceutical innovation, competition and patent law – a trilateral perspective. Edward Elgar, Cheltenham, pp 290–322\n\nEuropean Commission (2009) Pharmaceutical Sector Inquiry – Final Report. http://ec.europa.eu/ competition/sectors/pharmaceuticals/inquiry/staff_working_paper_part1.pdf. Accessed 24 Feb 2021, pp 16 and 19\n\nEuropean Commission, Competition enforcement in the pharmaceutical sector (2009–2017), avail- able at: https://ec.europa.eu/competition/sectors/pharmaceuticals/report2019/report_en.pdf European Commission, Antitrust: Commission welcomes improved market entry for lung disease treatments. Press Release of 6 July 2011, IP/11/842. http://europa.eu/rapid/press-release_IP-11- 842_en.htm. Accessed 24 Feb 2021", "n_tokens": 345, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-299-3", "doc_id": "medicine_vaccine_book", "page": 299, "text": "European Commission, Press Release, Antitrust: Commission opens formal investigation into Aspen Pharma’s pricing practices for cancer medicines, 15 May 2017. http://europa.eu/rapid/ press-release_IP-17-1323_en.htm. Accessed 24 Feb 2021\n\n295", "n_tokens": 61, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-300-0", "doc_id": "medicine_vaccine_book", "page": 300, "text": "296\n\nM. Bakhoum\n\nEuropean Commission, Press Release of 10 December 2013, IP/13/1233 (Antitrust: Commission fines Johnson & Johnson and Novartis € 16 million for delaying market entry of generic pain- killer fentanyl). http://europa.eu/rapid/press-release_IP-13-1233_en.htm. Accessed 24 Feb 2021 European Commission, Press Release of 19 June 2013, IP/13/563 (Antitrust: Commission fines Lundbeck and other pharma companies for delaying market entry of generic medicines). http:// europa.eu/rapid/press-release_IP-13-563_en.htm?locale¼en. Accessed 24 Feb 2021\n\nEuropean Commission, Press Release of 9 July 2014, IP/14/799 (Antitrust: Commission fines Servier and five generic companies for curbing entry of cheaper versions of cardiovascular medicine). http://europa.eu/rapid/press-release_IP-14-799_en.htm. Accessed 24 Feb 2021 Gallasch S (2015) Pharmaceutical antitrust: use but with caution, contribution Keynote Speech at UNCTAD Roundtable on The Role of Competition in the Pharmaceutical Sector and its Benefits for Consumers, 8 July 2015 http://unctad.org/meetings/en/Presentation/CCPB_7RC2015_ PRES_RTPharma_Gallasch_en.pdf. Accessed 24 Feb 2021\n\nLanza EM, Sfasciotti PR (2018) Excessive price abuses: the Italian Aspen case. J Eur Compet Law\n\nPract 9(6):382–388\n\nMedia release, South African Competition Commission, 13 June 2017., available at: http://www. compcom.co.za/wp-content/uploads/2017/01/International-pharmaceutical-companies-investi gated-for-cancer-medicine-prices.pdf", "n_tokens": 422, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-300-1", "doc_id": "medicine_vaccine_book", "page": 300, "text": "Ngobese M, Mncube L (2011) Competition policy in South Africa’s pharmaceutical sector:\n\nbalancing competition and innovation (unpublished)\n\nPress release on the Aspen case, 14/10/2016. http://www.agcm.it/en/newsroom/press-releases/ 2339-a480-price-increases-for-cancer-drugs-up-to-1500-the-ica-imposes-a-5-million-euro-fine- on-the-multinational-aspen.html\n\nRoffe P (2014) Intellectual property chapters in free trade agreements: their significance and systemic implications. In: Drexl J, Grosse Ruse-Khan H, Nadde-Phlix S (eds) EU bilateral trade agreements and intellectual property: for better or worse? Springer, Berlin, p 17 et seq Ullrich H (2005) Expansionist intellectual property protection and reductionist competition rules: a TRIPS perspective. In: Maskus KE, Reichman JH (eds) International public goods and transfer of technology under a globalized intellectual property regime, pp 727–756\n\nUllrich H (2013) Strategic patenting by the pharmaceutical industry: towards a concept of abusive practices of protection. In: Drexl J, Lee N (eds) Pharmaceutical innovation, competition and patent law – a trilateral perspective. Edward Elgar, Cheltenham, pp 241–272", "n_tokens": 298, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-300-2", "doc_id": "medicine_vaccine_book", "page": 300, "text": "Ullrich H, Heinemann A (2007) Die Anwendung der Wettbewerbsregel auf die Verwertung von Schutzrechten und sonst geschützten Kenntnissen. In: Immenga U, Mestmäcker E-J (eds) Wettbewerbsrecht, Band I. EG/Teil 2, Kommentar zum Europäischen Kartellrecht, p 146 UNCTAD Roundtable on The Role of Competition in the Pharmaceutical Sector and its Benefits for Consumers, Geneva, 6-10 July 2015. https://unctad.org/system/files/non-official-document/ CCPB_7RC2015_RTPharma_EC_en.pdf\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.", "n_tokens": 335, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-301-0", "doc_id": "medicine_vaccine_book", "page": 301, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities: Dealing with the Implementation Challenges\n\nMohammed El Said", "n_tokens": 27, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-301-1", "doc_id": "medicine_vaccine_book", "page": 301, "text": "Abstract Improving the health and well-being of society is a priority to many governments. One essential element within this debate focuses on the accessibility and affordability of medicines for patients. Although interest in this area has persisted for decades, the recent shift in this field is manifested by this now being treated as a global concern, rather than as a regional or a national one. Patients in both developed and developing countries alike are facing the same challenges and are under an increased pressure to access and afford treatment. The recently published UN High Level Panel for Access to Medicines Report explicitly stated its view of ‘access to medicines, vaccines, diagnostics and related health technolo- gies as a serious, multidimensional global problem, with challenges that affect all people and all countries....the High-Level Panel recognizes that the costs of health technologies are rising globally and are being felt by individuals and by public and private insurance schemes in both wealthy and resource-constrained countries alike’ (UN Secretary General High Level Panel, ‘The United Nations Secretary-General High-Level Panel on Access to Medicines Report: Promoting Innovation and Access to Health Technologies’, (September 2016), 12. https://apps.who.int/medicinedocs/ documents/s23068en/s23068en.pdf.). This thinking represents a fundamental depar- ture from the previous approach which classified the problem related to access to medicines as one mainly", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-301-2", "doc_id": "medicine_vaccine_book", "page": 301, "text": "attributed to developing and least developed nations. It is within this debate that the role of intellectual property protection in general and by way of the rise of TRIPS-Plus agreements and their impact on accessibility and affordability of medicines takes centre stage.", "n_tokens": 47, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-301-3", "doc_id": "medicine_vaccine_book", "page": 301, "text": "The author would like to thank Professor Graham Dutfield for his valuable feedback and insights on this chapter. The usual disclaimer applies.\n\nM. El Said (*) School of Justice, UCLAN, Preston, UK e-mail: mel-said@uclan.ac.uk\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_11\n\n297", "n_tokens": 121, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-302-0", "doc_id": "medicine_vaccine_book", "page": 302, "text": "298\n\nM. El Said\n\n1 Introduction\n\nThere are many factors which impacts the access to medicines debate. Government policy, industrial development, demography, manufacturing capabilities, market conditions and procurement and tax regimes are some factors. However, for some time, the role of intellectual property monopolies especially patents granted to innovator drug companies to protect their research and development (R&D) invest- ments and provide market exclusivity by restricting competition became an integral part of this debate.1 This chapter will look at various factors affecting the accessi- bility and affordability debate and will focus on the role of intellectual property protection in that process. It will provide useful examples of the positive impact arising from the use of the TRIPS flexibilities and on the other hand will explain the dangers affiliated with adopting TRIPS-Plus regimes in this regard. It will also provide examples of practises and strategies which would limit the impact of TRIPS-Plus commitments under national laws.\n\n2 Expensive Medicines: National Implications and Global", "n_tokens": 208, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-302-1", "doc_id": "medicine_vaccine_book", "page": 302, "text": "Challenges\n\nThe price of medicines has been on a steady increase for some years. In the US, prices for branded prescription drugs doubled in five years between the period of 2011–2016.2 Further, it was projected that the prices of medicines in the US will increase on average 5.8% in 2020.3 More than 13% of Americans—about 34 million people—say a friend or family member recently passed away in the last five years after being unable to afford treatment for a condition while 58 million adults report inability to pay for needed drugs in the past year, according to a new poll from Gallup and West Health.4 A recent study in the UK found that total National Health Service (NHS) spending on medicines in England has grown from £13 billion in 2010/11 to £17.4 billion in 2016/17—an average growth of around 5% a year. The", "n_tokens": 180, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-302-2", "doc_id": "medicine_vaccine_book", "page": 302, "text": "1It should be highlighted that there are also other regulatory regimes and intellectual property exclusivities—apart from patents—aimed towards extending protection including those protecting use of test data, various regulatory linkages, and also trademarks covering not just names but also shapes and colours. 2MSF (2016). http://apps.who.int/medicinedocs/documents/s23020en/s23020en.pdf. 3In 2019 more than 50 companies raised the prices on hundreds of drugs in the US by an average of more than 6%, according to the analysis. Hopkins explains that the price of rheumatoid arthritis treatment Humira, the world’s top-selling drug, was raised by 7.4%. Similarly, heparin products— which are generic blood thinners typically administered in hospitals—prices rose by 15%. For more see Hopkins (2020) <https://www.marketwatch.com/story/drug-prices-rise-58-on-average-in- 2020-2020-01-02>. 4Gallup and West Health (2019). https://news.gallup.com/poll/268094/millions-lost-someone- couldn-afford-treatment.aspx?version¼print.", "n_tokens": 273, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-303-0", "doc_id": "medicine_vaccine_book", "page": 303, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nsame study concludes, ‘These figures are uncertain due to gaps in data, but the rate of increase is substantially faster than for the total NHS budget over the same period’.5 With the prevalance of the COVID 19 pandamic, pressure on national health providers have reached unprecedented levels.", "n_tokens": 83, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-303-1", "doc_id": "medicine_vaccine_book", "page": 303, "text": "The year 2019 was phenomenal in terms of setting new high records in medicines prices. In March 2019, the United States Food and Drug Administration (USFDA) approved the most expensive medicine in history up to date called Zolgensma (priced at $2.125 million), a medicine used for a rare disorder that destroys a baby’s muscle control and kills nearly all of those with the most common type of the disease within a couple of years. Other more commonly used medicines’ prices have also been notably high. For example, a 2018 WHO report on cancer medicines concluded that is unaffordable for many patients. A course of standard treatment for early stage HER2 positive breast cyclophosphamide, docetaxel, (doxorubicin, trastuzumab) would cost about 10 years of average annual wages in India and South Africa and 1.7 years in the United States of America. The costs associated with other medical care and interventions (such as surgical interventions and radio- therapy) and supportive care (such as anti-emetics and haematopoietic growth factors) would make overall care even more unaffordable. Even with insurance coverage, patients living with cancer in many countries have reported financial stress, to the extent that they may lower the treatment dose, partially fill prescriptions or even forego treatment altogether’.6 In France, in December 2015, the Ligue contre le cancer—which spends around €38 million ($43 million) a year on cancer research, making it the largest French non-governmental", "n_tokens": 324, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-303-2", "doc_id": "medicine_vaccine_book", "page": 303, "text": "funder of cancer R&D—condemned cancer drug prices as ‘exorbitant, unfair and unbearable’ and warned that if unabated, price inflation for new drugs posed a direct threat to the French medical system7 while others have expressed that “economic considerations significantly influence and, in some instances, take precedence over the scientific evidence” with relation to French Guidelines on antiretroviral therapy treatment.8", "n_tokens": 97, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-303-3", "doc_id": "medicine_vaccine_book", "page": 303, "text": "‘in the absence of\n\ninsurance coverage, cancer\n\ntreatment\n\ncancer\n\nNewly developed hepatitis C drugs’ prices have also raised eyebrows. The efficient drug Sovaldi was launched at a list price of $84,000 for a standard twelve-week treatment course, or about $1000 a pill. At the most recent average net price of $45,000 per patient for all sofosbuvir-based products in the US, it would cost $135 billion dollars to treat the estimated three million people with chronic hepatitis C in the US—over one third of total annual spending on all prescription drugs in the US.9 In the UK, the list price for a 12-week course of sofosbuvir was\n\n5The King’s Fund (2018) https://www.kingsfund.org.uk/sites/default/files/2018-04/Rising-cost-of- medicines.pdf. 6WHO (2018), p. xi https://apps.who.int/iris/bitstream/handle/10665/277190/9789241515115-eng. pdf?sequence¼1&isAllowed¼y. 7Sciences Avenir with AFP (2015). http://www.sciencesetavenir.fr/sante/cancer/20151216. OBS1499/la-ligue-contre-le-cancer-denonce-les-prixexorbitants-des-medicaments-innovants.html. 8Raffi and Reynes (2014), p. 1158. 9I-MAK (2017).\n\n299", "n_tokens": 347, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-304-0", "doc_id": "medicine_vaccine_book", "page": 304, "text": "300\n\nM. El Said\n\nnearly £35,000 (excluding VAT) and double that for a 24-week course.10 Notwith- standing the high price, in early 2015 sofosbuvir was recommended for funding based on its cost effectiveness. However, because of the budget impact of the treatment, in the following months the NHS England delayed consistent provision of sofosbuvir, instead phasing introduction through the use of quotas and prioritising patients with the most severe need.11 From 2012 to 2019, the average price of AbbVie’s rheumatoid-arthritis drug Humira climbed from $19,000 a year to $60,000 a year.12", "n_tokens": 144, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-304-1", "doc_id": "medicine_vaccine_book", "page": 304, "text": "The effects of this are felt in both developed and developing countries. Greater number of patients are now unable to afford medicines while governmental health budgets are struggling to cater for the needs of its citizens, a situation made worse during the COVID 19 pandamic. Henceforth, patients in the developing countries are lacking essential medicines and lifesaving treatments, diabetics have died in the US due to high price of insulin while the Dutch government has had to suspend its acquisition of the immune-oncology drug Keytruda (despite the fact that it helped in its development) because it was too expensive.13 The NHS in the UK—a wealthy country which, unlike the United States, has a publicly funded and all-inclusive health service with considerable bargaining power—is having to ration the supply of cancer drugs due to financial restrictions on treatment14 while waiting times for those actually offered the treatment are far too lengthy.15", "n_tokens": 185, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-304-2", "doc_id": "medicine_vaccine_book", "page": 304, "text": "3 Unequal Investment and More Monopoly\n\nThe problem which high prices of medicines poses should not be viewed in isolation of other contributing factors engulfing this debate. One issue which ranks high within this context is the challenge of inadequate funding for diseases primarily affecting the financially underprivileged or for which the opportunities to make large and long-term profits are considered by the industry to be limited.\n\nGrowing criticism has been made regarding the deficiency of the global regime in finding solutions to long standing diseases (or as some refer to as neglected\n\n10Boseley (2015) https://www.theguardian.com/society/2015/jan/16/sofosbuvir-hepatitis-c-drug- nhs. 11Gornall et al. (2016), p. 4117. 12Entis (2019). 13The Economist (2019). 14Donnelly (2015). The article further identifies that in total, 17 cancer drugs for 25 different indications will no longer be paid for in future in the UK. 15According to January 2019 NHS England data, almost 25% of cancer patients didn’t start treatment on time despite an urgent referral by their primary care doctor. This represents the worst performance since records began in 2009. For more see Pipes (2019). https://www.forbes. com/sites/sallypipes/2019/04/01/britains-version-of-medicare-for-all-is-collapsing/ #4c6ebeb736b8.", "n_tokens": 326, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-305-0", "doc_id": "medicine_vaccine_book", "page": 305, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\ndiseases) or the unequal distrbution of COVID 19 vaccines as an example. One visible area of concern is that related to the development of new antibiotics, an issue the WHO have classified as a global challenge in recent years. According to WHO, “No major new class of antibiotics has been discovered since 1987 and too few antibacterial agents are in development to meet the challenge of multidrug resis- tance.”16 One of the main issues related to lack of investment and R&D in this field is attributed to the industry’s fear that resistance to these drugs would develop even- tually hence eliminate the usefulness of the drug rapidly which may explain why most major pharmaceutical companies have stopped research in this area, a situation that has been described as a “serious market failure” and “a particular cause for concern”.17", "n_tokens": 200, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-305-1", "doc_id": "medicine_vaccine_book", "page": 305, "text": "In a recently published two reports, the WHO warned about the adverse effects of the declining private investment and lack of innovation in the development of new antibiotics. The WHO further highlighted how this is also undermining efforts to combat drug-resistant infections and diseases. The WHO reports found that the 60 products currently in development (50 antibiotics and 10 biologics) bring little benefit over existing treatments and very few target the most critical resistant bacteria (Gram-negative bacteria).18 The Chairman of the UK Review on Antimi- crobial Resistance warned recently that, if left unaddressed, drug-resistant infections could be responsible for the deaths of some ten million people a year by 2050, and $100 trillion in economic damage.19\n\nOther neglected diseases also share similar challenges and evident lack of invest- ment and innovation. For example, a 2002 analysis of new chemical entities developed between 1975 and 1999 found that only 1.1% were actually treatments devoted to tuberculosis (TB) and tropical diseases, despite them causing 11.4% of the global disease burden.20 Although the years between 2000 and 2011 witnessed some improvement whereby of the 850 new therapeutic products registered, 4.4% were for neglected diseases.21 However, according to the same study, only 4 of the 336 new chemical entities brought to the market during the same period were for neglected diseases (including malaria)—just 1.2% of the total.", "n_tokens": 289, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-305-2", "doc_id": "medicine_vaccine_book", "page": 305, "text": "16WHO (2015), p. 5 http://apps.who.int/iris/bitstream/10665/193736/1/9789241509763_eng.pdf. However, it was announced in late 2019 that a new antibiotic for drug-resistant tuberculosis— pretomanid was finally approved by the FDA. Interestingly, the drug was developed by the non-profit TB Alliance rather (2019) https:// medcitynews.com/2019/08/new-antibiotic-for-drug-resistant-tuberculosis-scores-fda-approval/. 17Ibid, 11. 18The two WHO reports cited below also found that research and development for antibiotics is primarily driven by small- or medium-sized enterprises with large pharmaceutical companies continuing to exit the field. For more see WHO (2017) https://apps.who.int/iris/bitstream/handle/ 10665/258965/WHO-EMP-IAU-2017.11-eng.pdf?sequence¼1, and WHO (2019) https://apps. who.int/iris/bitstream/handle/10665/330290/WHO-EMP-IAU-2019.12-eng.pdf. 19O’Neill (2015). 20Trouiller et al. (2002), p. 2188. 21Pedrique et al. (2013), p. 371.\n\nthan the industry. For more see Dearment\n\n301", "n_tokens": 322, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-306-0", "doc_id": "medicine_vaccine_book", "page": 306, "text": "302\n\nM. El Said\n\nTB which is the biggest infectious disease killer in the world today is another case in point, whereby the death toll alone in 2014 was 1.5 million lives. Until very recently, no new drug was introduced for nearly 50 years.22 Furthermore, the last treatment—largely inadequate due to its side effects—developed for Chagas disease (leading cause of infectious heart disease in Latin America) was over 40 years ago. Ebola also placed the global treatment regime under security. Médecins Sans Frontières (MSF) who often operates within the disease-stricken countries further states that the ‘fact that MSF frontline health workers lacked a treatment or a vaccine for Ebola virus as the outbreak engulfed Guinea, Sierra Leone and Liberia in 2014 is a poignant illustration of this problem. But the problem of inadequate or non-existent treatments and vaccines was a challenge for MSF long before 2014’.23 Notably, it was only in late 2019, it was announced that a new vaccine was approved in the US and EU for Ebola.24", "n_tokens": 214, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-306-1", "doc_id": "medicine_vaccine_book", "page": 306, "text": "4 The Double Taxation of Society\n\nOne of the strongest criticisms against pharmaceutical companies is the way they engage in business activities and R&D operations. It is vital to acknowledge that innovator pharmaceutical companies need incentives to protect their investments. Yet to what extent that should be sought at the expense of public health policy concerns is questionable. The high prices of medicines does not only have a negative effect regarding accessibility, but have also attracted criticism due to the fact that a vast number of medicine discoveries and some of the subsequent drug development, or indeed much of it in some cases, was funded by tax payers. The situation is made worse by anticompetitive behaviour of some of these companies.\n\nIt is no secret that the governmental levels of financial and technical support for biomedical innovations are considerable. The public sector makes substantial con- tributions to research and development upfront, through grants, subsidies and tax credits. In fact, some studies suggest that 30% of the estimated $240 billion yearly total global investment across all health R&D comes from the public sector.25", "n_tokens": 215, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-306-2", "doc_id": "medicine_vaccine_book", "page": 306, "text": "Several cases illustrate this, including Truvada. The drug was initially developed and patented by the US government after the Centers for Disease Control and Prevention (CDC) received $50 million in federal grants in addition to $7 million from the Bill and Melinda Gates Foundation in 2015. However, the government did not receive any income and no improvement in terms of accessibility rates was observed (it is believed that less than 10 percent of the 1.1 million people who should be on treatment are receiving it) despite the fact that Gilead Sciences the maker of the\n\n22See MSF (2016). 23See MSF (2016), p. 8. 24For more see Herder et al. (2020), pp. 1–14. 25Røttingen et al. (2013), p. 1286, also see MSF (2016).", "n_tokens": 175, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-307-0", "doc_id": "medicine_vaccine_book", "page": 307, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\ndrug earned $3 billion in sales in 2018 prompting the US government to initiate legal action against Gilead.26\n\nfour decades, 153 new FDA-approved drugs, vaccines, or new indications for existing drugs were discov- ered through research carried out in public sector research institutions (PSRIs). It was reported that these drugs included 93 small-molecule drugs, 36 biologic agents, 15 vaccines, 8 in vivo diagnostic materials, and 1 over-the-counter drug. More than half of these drugs have been used in the treatment or prevention of cancer or infectious diseases.27\n\nMoreover, a study found that during the past", "n_tokens": 148, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-307-1", "doc_id": "medicine_vaccine_book", "page": 307, "text": "Similar trends are observed elsewhere outside the US. In 2017, campaigners in the UK claimed that the NHS spent more than £1 billion on drugs developed from publicly funded research in 2016. A report published by campaign groups Global Justice Now and Stop Aids claimed that UK tax payers and patients worldwide are being denied the medicines they need, despite the public sector playing a pivotal role in the discovery of new medicines. It concluded that ‘In many cases, the UK taxpayer effectively pays twice for medicines: first through investing in R&D, and then by paying high prices for the resulting medicine once ownership has been transferred to a private company.’28 The report cites several examples of drugs which received public funding but now are out of the reach of majority of patients. For example, the report explains how Alemtuzumab was originally developed at Cambridge University and first approved for the treatment of B-cell chronic lym- phocytic leukaemia (B-CLL). Cambridge scientists then led further investigations of its usefulness, at a smaller dosage, in treating multiple sclerosis (MS). Sanofi Genzyme, who had acquired the rights to the drug, removed it from the market as a B-CLL medicine and re-launched it as a medicine for MS. The Report verifies that ‘At the time of withdrawal there was speculation that the exercise was motivated by commercial reasons. When it was used off-label (i.e. used for a non-licenced purpose) for MS prior to being withdrawn from the", "n_tokens": 317, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-307-2", "doc_id": "medicine_vaccine_book", "page": 307, "text": "market, the price in the UK was around £2,500 per MS treatment course in 2012’. In 2017, it costs was £56,000 per treatment course—a 22-fold increase.29", "n_tokens": 41, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-307-3", "doc_id": "medicine_vaccine_book", "page": 307, "text": "On the other hand, several anticompetitive practises have had a far-reaching impact on prices. Even when there are opportunities to reduce prices, we find that this is not taken advantage of (and even intentionally delayed). A recent study found that of the more than 1600 generic drugs approved by the FDA since January 2017, more than 700—or 43 per cent—are not for sale in the US.30\n\n26Rowland (2019). 27Stevens et al. (2011), p. 535. 28Global Justice Now and Stop AIDS (2017), p. 7. https://www.globaljustice.org.uk/sites/default/ files/files/resources/pills-and-profits-report-web.pdf. 29Ibid at 10. 30Mole (2019) https://arstechnica.com/science/2019/02/drug-companies-are-sitting-on-generics- 43-of-recently-approved-arent-for-sale/.\n\n303", "n_tokens": 225, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-308-0", "doc_id": "medicine_vaccine_book", "page": 308, "text": "304\n\nM. El Said\n\nDelaying tactics have also incurred huge costs on society. One study estimates that the American health system is poised to incur $55 billion during the next 15 years on three drugs (related cancer and hepatitis C treatment) alone due to patents blocking and delaying the entry of generic competition on these drugs only. Product lifecycle management, whereby branded companies obtain unmerited pat- ents to delay competition,31 is the primary strategy identified and evaluated by this study. The study also highlights that another related strategy is “pay-for-delay” whereby branded companies pay generics to stay off the market for some time.32", "n_tokens": 132, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-308-1", "doc_id": "medicine_vaccine_book", "page": 308, "text": "5 More Pharmaceutical Patents, Weaker Innovation\n\nAn equally troubling development which has contributed to the increase in medi- cines prices and extended monopoly patent terms in recent years is the increase in the number of drug patents granted, particularly those ‘inventions’ which are of a low and inferior quality, or as may be referred to as frivolous/trivial patents. This process is leading to what is referred to as the ‘evergreening’ of drugs.33\n\nThis development may be explained by looking at some national statistics in this regard. For example, it was found that between the years 2006 and 2016, the number of drug patents granted in the US doubled. The granted patents were mainly dedicated to accumulating patents not for new medicines but rather for small changes to existing ones, which allows them to build and extend monopolies, block", "n_tokens": 168, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-308-2", "doc_id": "medicine_vaccine_book", "page": 308, "text": "31It should be noted that the product lifecycle management starts at the development and regulatory approval stages and extends beyond the expiry of the granted patent. Notably, drug manufacturers do not only rely on patent protection when devising their lifecycle strategies. For example, reliance on trademark protection and branding is also vital in providing effective means to secure and maintain a strong market position. For more on this see Dutfield (2020). file:///C:/Users/melsaid/ Downloads/Not_Just_Patents_and_Data_Exclusivity_Th.pdf. 32I-MAK identifies the following three multi-billion-dollar drugs as having questionable patents that are providing excess exclusivity periods:\n\n(cid:129) Revlimid® (lenalidomide): Unmerited patents enable a minimum exclusivity period from 2019 through 2028. Payers are projected to spend $45 billion in excess costs for the drug within this period, prior to the first generic product entering the market.\n\n(cid:129) Sovaldi® (sofosbuvir): Unmerited patents will prevent competition from now through 2034, when final patents held by Gilead Sciences expire on the drug. Payers are projected to incur $10 billion in excess costs.\n\n(cid:129) Gleevec® (imatinib): In the one-year period from 2015–16, approximately $700 million dollars in excess costs were passed onto payers as a result of a pay-for-delay deal cut by Novartis to a generic company in exchange for delaying the entry of generic imatinib.", "n_tokens": 351, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-308-3", "doc_id": "medicine_vaccine_book", "page": 308, "text": "For more see I-MAK (2017).\n\n33The majority of these patents focuses on developing so-called ‘me-too’ drugs—medicines which have only small clinical advantages over existing drugs, but which can be patented and bring substantial profits. The effects of evergreening vary but the primary impact would be to extend the monopoly term granted to patents. For more see Kesselheim et al. (2006), p. 1637.", "n_tokens": 92, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-309-0", "doc_id": "medicine_vaccine_book", "page": 309, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\ncompetition and drive prices up.34 Moreover, on the 12 best-selling drugs in the US, drug makers have filed an average of 125 patent applications and have been granted an average of 71 patents for each.35 Another study found that 74 applications have been filed on Lantus (it is a man-made form of a hormone (insulin) that is produced in the body which works by lowering levels of glucose (sugar) in the blood) only in the US, which have the potential to delay competition for 37 years.36 This kind of “over patenting” blocks competition and enables pharmaceutical companies more freedom to regulate the pricing market of medicines.37\n\nElsewhere the findings are similar. A study in Australia found an average of 49 secondary patents granted for each of the 15 highest-cost drugs over a 20-year period. One-quarter of these secondary patents were believed to be evergreening patents.38 The Office of Patented Medicines and Liaison at the Therapeutic Products Directorate of Health Canada estimates that 44% of the 419 medicines on the Patent Register are covered by more than one patent.39", "n_tokens": 246, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-309-1", "doc_id": "medicine_vaccine_book", "page": 309, "text": "Moreover, an EU investigation concluded in 2008 that out of the 219 molecules in the sample under the investigation, originator and generic companies identified at least 1300 patent-related out of court contacts and disputes concerning the launch of generic products in the period 2000 to 2007. The vast majority of disputes were initiated by the originator companies, which most often invoked their primary patents, e.g. by sending warning letters. In this respect the inquiry finds that individual medicines are protected by up to nearly 100 product-specific patent families, which can lead to up to 1300 patents and/or pending patent applications across the Member States. Despite the lower number of underlying patent families based on European Patent Office (EPO) applications, looking from a commercial perspective, ‘a challenger may, in the absence of a European Community patent, need to analyse and possibly confront the sum of all existing patents and pending patent applications in those Member States in which the generic company wishes to enter’.40", "n_tokens": 204, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-309-2", "doc_id": "medicine_vaccine_book", "page": 309, "text": "34Amin and Kesselheim (2012), p. 2286. 35I-MAK (2018a) http://www.i-mak.org/wp-content/uploads/2018/08/I-MAK-Overpatented- Overpriced-Report.pdf. 36I-MAK (2018b). http://www.i-mak.org/wp-content/uploads/2018/10/I-MAK-Lantus-Report- 2018-10-30F.pdf. 37Amin and Kesselheim examined patents granted for two HIV drugs (ritonavir and lopinavir/ ritonavir) and found that Abbott owned 82 secondary patents and had a further 26 pending applications in the US, all of which involved small variations on the original patents for these drugs. They found that these evergreening patents could delay generic competition for 19 years beyond the date from which generic entry would have been anticipated. For more see Amin and Kesselheim (2012). 38Christie et al. (2013), p. e60812. 39Office of Patented Medicines and Liaison (2005). 40EU Commission (2008), p. 10. https://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/ communication_en.pdf.\n\n305", "n_tokens": 290, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-310-0", "doc_id": "medicine_vaccine_book", "page": 310, "text": "306\n\nM. El Said\n\nElsewhere, another analysis found of the 1015 new drugs and indications approved in France between 2004 and 2013, only 6.3% offered a clear therapeutic advantage, almost none were considered breakthroughs, and the majority (69.3%) offered no clear therapeutic benefit or were prematurely approved even though their clinical evaluation showed them to be more harmful than beneficial.41 A second analysis found that 85 to 90% of new products approved over the last four decades have provided only limited benefits.42 A third study that looked not just at registered products, but specifically at new chemical entities and new biologics, found that the majority of those launched in the UK between 2001 and 2012 were only “slightly innovative” and only a quarter (26%) were believed to be “highly innovative”.43\n\nRather than using the patent regime as an incentive to innovate and recoup investment for worthy inventions, ‘evergreening’ tactics and practises are in fact blocking accessibility and weakening innovation capabilities by undermining the true foundations of the patent regime and turning it into monopoly creator with no positive contribution to society’s needs.44\n\n6 Increased IP Standards: From TRIPS-Minus", "n_tokens": 253, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-310-1", "doc_id": "medicine_vaccine_book", "page": 310, "text": "to TRIPS-Plus\n\nThe global regulation of intellectual property rights is a relatively modern concept. Prior to the creation of the World Trade Organization (WTO) in 1996, countries had considerable policy space and full discretion in designing their national intellectual property legal regimes in accordance with their development stage and national priorities.45 As such, a large number of countries did not award legal protection to patents related to drugs and pharmaceutical products.46\n\nThis was no longer the case with the creation of the WTO. The Agreement on Trade Related Aspects of Intellectual Property Rights (the TRIPS Agreement)47 obligated member states to provide legal protection for inventions in all technolog- ical fields including pharmaceutical products. This was an important development whereby for the first time in history, countries lost the ability to regulate their\n\n41Prescrire International (2005), pp. 68, 71. 42Light and Warburton (2016), p. 34. 43Ward et al. (2014), p. 6235. 44Drahos (2010). 45See generally Machlup and Penrose (1950), p. 1. 46See El Said (2010). 47See the Agreement on Trade-Related Aspects of Intellectual Property Rights, Apr. 15, 1994, Marrakesh Agreement Establish the World Trade Organization, Annex 1C, 1869 U.N.T.S. 299 [hereinafter TRIPS Agreement] (listing the limitations on use of intellectual property by third parties authorized by the government).", "n_tokens": 304, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-311-0", "doc_id": "medicine_vaccine_book", "page": 311, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nnational intellectual property regimes freely and in accordance with their national development plans.\n\nReaching consensus regarding the TRIPS agreement was not a simple act. The intellectual property negotiations during the Uruguay Round of Trade Negotiations were amongst the most contentious and complex. As such and in order to strike a balance between the rights of users and intellectual property holders on the one hand, and the society on the other, several ‘flexibilities’ were introduced within TRIPS in order to curtail the negative impact which may arise from excessive intellectual property protection and at the same time to enable countries to deal with their public health challenges and emergencies.", "n_tokens": 143, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-311-1", "doc_id": "medicine_vaccine_book", "page": 311, "text": "6.1 The Flexibilities Explained\n\nThe TRIPS ‘flexibilities’ may best be explained as options available to member states allowing them to comply with the TRIPS Agreement requirements and at the same time maximise the implementation space available to them in accordance with their priorities.48 Following are some examples of the health-related flexibilities available under the agreement to member states: – Transitional periods. According to the WTO, least developed countries (LDCs) are given an extended transition period to protect intellectual property under the WTO’s TRIPS Agreement. This is in recognition of their special requirements and status, their economic, financial and administrative constraints, and the need for flexibility so that they can create a viable technological base. Several exten- sions of the transition period were provided by the TRIPS Council. The last 6th of November 2016 Council decision extends until January 2033 the period during which key provisions of the WTO’s intellectual property agreement, the TRIPS Agreement, do not apply to pharmaceutical products in LDCs.49 This means LDCs can choose whether or not to protect pharmaceutical patents and clinical trial data before 2033. The decision also keeps open the option for further extensions beyond that date.50", "n_tokens": 250, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-311-2", "doc_id": "medicine_vaccine_book", "page": 311, "text": "48There is a general differentiation in the literature between expressly provided safeguards, limitations/exceptions and countervailing legal principles and objectives on the one hand, and vague terminology on the other hand where there are provisions and omissions whose scope is subject to a wide range of interpretations in accordance with national and international legal regimes. For more see El Said (2010). 49See the Council for Trade-Related Aspects of Intellectual Property Rights, Extension of the Transition Period under Article 66.1 of the TRIPS Agreement for Least Developed Country Members for Certain Obligations with Respect to Pharmaceutical Products, Decision of the Council for TRIPS of 6 November 2015. 50In 2019, Uganda notified the African Regional Intellectual Property Organisation (ARIPO) that it is exercising its right as a least-developed country by stating that pharmaceutical inventions are not\n\n307", "n_tokens": 167, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-312-0", "doc_id": "medicine_vaccine_book", "page": 312, "text": "308\n\nM. El Said\n\nCompulsory licensing. A tool through which the state authorizes a third party to exploit patented inventions, generally against a specified royalty paid to the patent holder provided that several conditions set under the TRIPS Agreement (Article 31) are complied with. The objective behind this is to curtail anti- competitive behaviour and ensure the transfer of technology and dissemination of knowledge.51\n\nGovernment use exceptions. A tool which grants the state the right to use the patent without obtaining the consent of the patent holder for the purpose of public interest, including public health necessities. Although government use conditions are similar to compulsory licensing, government use exceptions provide an added advantage by fast-tracking the process, through granting the government the right to use the pharmaceutical patent without the need for prior negotiations with the owner.\n\nParallel importation. This tool gives the option to member states to obtain patented products when they are lawfully available in a foreign market at a lower price, thus enabling countries to shop for cheaper patented products. This requires as a prerequisite that a country adopt an exhaustion regime suitable to its needs and priorities.52", "n_tokens": 224, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-312-1", "doc_id": "medicine_vaccine_book", "page": 312, "text": "Exceptions to patents rights. Article 30 of TRIPS provides that members “may provide limited exceptions to the exclusive rights conferred by a patent, provided that such exceptions do not unreasonably conflict with a normal exploitation of the patent and do not unreasonably prejudice the legitimate interests of the patent owner, taking account of the legitimate interests of third parties.”53 However, the above provision does not define the scope of the permissible exceptions thus awarding member countries some considerable discretion to operate. Examples of these exceptions include the Bolar exception54 and the research and experimental use exception.\n\nStandards of patentability. Under TRIPS, patent protection must be granted for products and processes which are new, involve an inventive step and are indus- trially applicable.55 However, each of these are not defined and can be interpreted", "n_tokens": 170, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-312-2", "doc_id": "medicine_vaccine_book", "page": 312, "text": "eligible for patent protection in the country. See ‘t Hoen (2019). https://medicineslawandpolicy.org/ 2019/10/uganda-tells-aripo-no-more-patents-for-pharmaceuticals/. 51The special compulsory licensing system in the amended TRIPS Agreement, and the earlier 2003 waiver decision, (sometimes called the “Paragraph 6 System” because it refers to paragraph 6 of the Doha Declaration) only deals with compulsory licences to produce medicines expressly for export purposes. 52See TRIPS Agreement, Article 6. 53See TRIPS Agreement, Art. 30. 54This important exception facilitates the production and introduction of generic medicines into the market on the date of patent expiry. Accordingly, this exception permits the use of an invention for the purpose of obtaining approval of a generic product before the patent actually expires and without having to obtain the patentee’s approval. The WTO ruled that the use of this exception is TRIPS-compliant. For more see the WTO (2000). 55See TRIPS Agreement, Art. 27.", "n_tokens": 221, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-313-0", "doc_id": "medicine_vaccine_book", "page": 313, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nand applied by member states in accordance with their national priorities and objectives. For example, TRIPS do not specify the patenting of new uses of known products, including pharmaceutical drugs, thus allowing member coun- tries the possibility of rejecting these new uses for lack of novelty, inventive step or industrial applicability.\n\nOther procedural flexibilities. Another identified policy tool that may be used to improve the quality of granted patents and limits “evergreening” is pre-grant and post-grant patent oppositions, in addition to patent revocation proceedings. These methods have been used at different times in a wide range of developed and developing countries. Such proceedings enable interested parties to bring claims before the patent office on the basis that a particular patent does not meet local requirements.", "n_tokens": 184, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-313-1", "doc_id": "medicine_vaccine_book", "page": 313, "text": "6.2 Putting the Flexibilities into Use\n\nWe now have a considerable body of literature and empirical research dedicated to the benefits of utilising the TRIPS Agreement’s flexibilities under national laws. Despite this, some would still argue that the use ‘of the TRIPS flexibilities has been sporadic and limited’56 and that more could still be achieved in this regard.57\n\nA much widely affiliated issue with the use of the flexibilities is the issue related to the impact of generic drugs entry into the market and the savings achieved as a result. In many cases, in curtailing ‘evergreening’ and in opposing low quality patents. As such, it is common to see medicine prices dropping substantially (ranging between 30–90 percent in some cases) when generic medicines enter a market following the expiry of a patent.58\n\nthis is enabled by the flexibilities effect\n\nCompulsory licensing is the most used flexibility in this regard.59 There is no scarcity of evidence with relation to the positive impact compulsory licensing has had upon improving access to medicines. Malaysia was one of the latest countries to issue a “government use” compulsory license to obtain much cheaper version of a generic version of the famously known hepatitis C medicine Sofosbuvir in September 2017. It is believed that compulsory license issuance have enabled treatment cost at RM1000 to RM1200 ($240–$285) for 12 weeks course, compared to RM300,000 (approx. $72,000) which was the cost of treatment with the patented", "n_tokens": 327, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-313-2", "doc_id": "medicine_vaccine_book", "page": 313, "text": "56‘t Hoen et al. (2018), pp. 185–193. 57For more see El Said (2014), p. 60. 58See El Said (2010). 59See number of compulsory licenses issued in ‘t Hoen et al. (2018), p. 188. However, it should be kept in mind that the ability to use compulsory licensing is not an available option to all countries equally but is rather more relevant to those which possess manufacturing capabilities.\n\n309", "n_tokens": 100, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-314-0", "doc_id": "medicine_vaccine_book", "page": 314, "text": "310\n\nM. El Said\n\nversion and prior to issuance of the license.60 Moreover, it was reported that between 2013 and 2017, the Ecuadorian Institute of Intellectual Property (IEPI) issued ten compulsory licences for various medications including antiretroviral drugs.61 According to health officials in Ecuador, the compulsory licenses granted between 2013 and 2014, generated the potential for savings of 23 per cent to 99 per cent.62 Similar findings may also be found in the case of other compulsory licenses issued by Thailand, India, Indonesia, Brazil and Columbia.63\n\nOne of the other important flexibilities available to countries is related to the issue of patentability standards. As highlighted, member countries have a wide discretion and freedom to apply and define the patentability criteria of an invention under their national regime. As such, India has applied a strict patentability criteria aimed towards limiting the number of frivolous or secondary pharmaceutical patents granted.64 Although we cannot measures the direct price impact this will have on medicines nevertheless it is believed that the utilisation of this flexibility have a substantial impact in preventing patent abuses and the granting of low quality patents (anti-evergreening strategy).65 Other countries such as China and Philippines are following a similar approach to the Indian one in this regard.66", "n_tokens": 268, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-314-1", "doc_id": "medicine_vaccine_book", "page": 314, "text": "Egypt provides an interesting case as well. The country is home to the highest rate of HCV infections in the world. The Egyptian’s Patent Office practise won praise couple of year ago when it rejected one of Sofosbuvir patent applications through its application of a strict patentability criteria. This allowed a local generic producer to produce the drug for less than $200 per 12-week treatment.67", "n_tokens": 85, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-314-2", "doc_id": "medicine_vaccine_book", "page": 314, "text": "60For more see Ling (2019). http://english.astroawani.com/malaysia-news/using-compulsory- licence-affordable-medicines-200558. 61The issued compulsory license were for three ARV medicines namely Ritonavir+Lopinavir and Lamivudine+Abacavir, for Etoricoxib (Arcoxia® for the treatment of diseases with acute pains); Mycophenolate Sodium (MYFORTIC) used in the treatment of reception of kidney transplants; sunitinib, an anticancer drug used for the treatment of carcinoma renal cells (CRC) and gastroin- testinal stromal tumours (GISTs); and finally Certolizumab, used to counteract rheumatoid arthritis. See Correa and Velásquez (2019), p. 16. https://www.southcentre.int/wp-content/uploads/2019/04/ RP85_Access-to-Medicines-Experiences-with-Compulsory-Licenses-and-Government-Use-The- Case-of-Hepatitis-C_EN-1.pdf. 62Ibid, 18. 63For more see El Said (2016), p. 374. 64See Chatterjee (2013). https://www.ip-watch.org/2013/04/01/novartis-loses-patent-bid-lessons- from-indias-3d-experience/. 65See Sampat and Shadlen (2017), p. 693. 66Other countries are increasingly following India’s patentability path. The Philippines patent law, as amended in 2008, introduced a section similar to the Indian 3(d) section (although less stringent than India’s Patent Act).177\n\nChina has reformed its Patent Act in 2008 and 178. See Patent Law (promulgated by the Standing Comm. Nat’l People’s Cong., Mar. 12, 1984, rev’d Dec. 27, 2008), art. 22. For more see El Said (2016). 67Velasquez (2019), p. 108.", "n_tokens": 467, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-315-0", "doc_id": "medicine_vaccine_book", "page": 315, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nParallel importation is another flexibility already used by several countries with positive results. For example, six African countries (Ghana, Kenya, Mauritius, Namibia, South Africa and Zimbabwe) have incorporated an international exhaus- tion regime in their laws, allowing parallel imports from anywhere in the world. More specifically, Kenya has actively and effectively used parallel importation to improve access to antiretroviral medications.68\n\nOpposition procedures have been applied usefully and efficiently in several countries. This issue is posed to gain more importance due to the increased volume of pharmaceutical patents granted worldwide. To give a glimpse, it is believed that current estimates suggests that at least 27% of current patents would be found invalid by US courts due to low quality.69", "n_tokens": 179, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-315-1", "doc_id": "medicine_vaccine_book", "page": 315, "text": "There are many more examples of the use of the flexibilities by both developed and developing countries which this chapter will not delve into. However, a number of observations could be made about the efficient and successful use and implemen- tation of these flexibilities under national regimes. First, the need for a proactive national legislature is fundamental for the success of this process. Although these flexibilities are available under the international intellectual property regime, their implementation would not take place directly without legislating—in details—them under national laws and regulations. Second, awareness about the existence of these flexibilities is vital for their utilisation. Thirdly, the need for an engaged public, national entities and active civil society is essential for the success of this process as demonstrated by many thus far. Lastly, independent and highly trained judiciary is vital in the process of implementation and interpretation of these flexibilities under national legal frameworks.", "n_tokens": 205, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-315-2", "doc_id": "medicine_vaccine_book", "page": 315, "text": "6.3 The Shift Towards TRIPS-Plus\n\nThe TRIPS Agreement was subsequently used as a platform for further regulation of intellectual property rights globally. Although the initial understanding of develop- ing countries was that TRIPS would put an end to unilateralism and coercion in the regulation and enforcement of intellectual property by developed countries particu- larly the United States, that vision turned out to be misguided. Within a short period of time following the creation of the TRIPS Agreement, a new generation of bilateral and regional Free Trade Agreements (FTAs) started to emerge, with a far-reaching WTO-Plus agenda.\n\nWith relation to intellectual property, FTAs often contained dedicated chapters incorporating extensive intellectual property provisions which often include TRIPS- Plus obligations going beyond those required by the TRIPS Agreement. These\n\n68UNAIDS (2011), p. 15. https://www.unaids.org/sites/default/files/media_asset/JC2260_DOHA %2B10TRIPS_en_0.pdf. 69Miller (2012). https://papers.ssrn.com/sol3/papers.cfm?abstract_id¼2029263.\n\n311", "n_tokens": 247, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-316-0", "doc_id": "medicine_vaccine_book", "page": 316, "text": "312\n\nM. El Said\n\nTRIPS-Plus obligations restricted the available policy space of member states and gradually eliminated the options and flexibilities available to them under the TRIPS Agreement.70 Although the full impact of these TRIPS-Plus agreements is yet to materialise, we already have a considerable and rather frightening understanding— as will be explained in the next part of this chapter—about the negative impact these agreements have on affordability and accessibility to medicines.\n\n6.4", "n_tokens": 93, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-316-1", "doc_id": "medicine_vaccine_book", "page": 316, "text": "Impact and Examples of TRIPS-Plus Obligations\n\nBefore looking into the negative impact of TRIPS-Plus, it would be helpful to understand how do FTAs increase intellectual property protection levels beyond the TRIPS standards? An important objective of TRIPS-Plus obligations is to limit the use of the flexibilities available under the international intellectual property regime thus making it more difficult to utilise such flexibilities. There are a number of areas where this may take place with relevance to patents and public health. These include the following examples: – Expanding the scope of pharmaceutical patents and creating new drug\n\nmonopolies: this is achieved through a number of ways such as:\n\n(cid:129) (cid:129) (cid:129) minor variations on old medicines, new and second uses, and71 (cid:129) Further extension of protection to biological products which include vaccines, blood and blood components, and gene therapies in addition to other forms of protection.\n\nlowering the patentability standards, requiring patents be available for surgical and treatment methods,\n\nExtension of monopolies by extending patent terms if review at the patent office or regulatory authority failed completion within a certain period of time.\n\nRisk facilitating patent abuse by requiring countries to condition marketing approval on patent status (patent linkage).", "n_tokens": 265, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-316-2", "doc_id": "medicine_vaccine_book", "page": 316, "text": "Protection and Extension of “data exclusivity”: by providing at least 5 years exclusivity for information related to new products and 3 more in cases of new uses for old medicines—even when that information is disclosed and available in the public domain. More recent FTAs have also provided 10 years of “effective market protection” for biologics.72\n\nProhibition/restriction pre-grant oppositions—forbid challenges to weak or invalid patents until after they have been granted.\n\n70See Drahos (2001), p. 791 and El Said (2005), pp. 53–66. 71For more on this from an EU perspective please see Dutfield (2017), p. 453. 72Ney (2019). https://www.centerforbiosimilars.com/contributor/joshua-ney/2019/08/exclusivity- for-biologic-products-under-the-usmca-what-is-changing-and-what-happens-next.", "n_tokens": 213, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-317-0", "doc_id": "medicine_vaccine_book", "page": 317, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...", "n_tokens": 22, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-317-1", "doc_id": "medicine_vaccine_book", "page": 317, "text": "Regulate the decisions to reimburse new drugs: this gives drug companies new rights to challenge decisions on reimbursements if not favourable as currently proposed under the Transatlantic Trade and Investment Partnership (TTIP). – Require new forms of intellectual property enforcement–grant: customs authorities detaining shipments, including in-transit shipments, suspected of non-criminal trademark/copyright/patent infringements; require mandatory injunc- tions for alleged intellectual property infringements; raise damages amounts, etc. – Introducing Investor-State Dispute Settlement (ISDS) procedures: this leads to bypassing the WTO’s multilateral dispute settlement procedure and opting for a more pro-investment one. This development has been highly controversial as this grant private investors considerable power, especially big multinational corporations, to claim high amounts of money of compensation from investor sympathetic tribunals. Indirectly, this questions the impact of these claims on states’ power to regulate in the public interest, in order to safeguard public health priorities. Other flaws of the ISDS system include the lack of consistency in decision making and the huge costs incurred. There is now growing evidence that the threat of using these ISDS procedure is enough to obligate countries to change their policies.73 Countries at minimum should avoid entering into FTAs that contain TRIPS-plus obligations that can impact on pharmaceuticals price or", "n_tokens": 272, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-317-2", "doc_id": "medicine_vaccine_book", "page": 317, "text": "availability. Where countries have undertaken TRIPS-plus commitments, all efforts should be made to mitigate the negative impact of these commitments on access to treatment by using to the fullest extent possible, remaining public health related flexibilities available.", "n_tokens": 49, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-317-3", "doc_id": "medicine_vaccine_book", "page": 317, "text": "The thus far realised impact of TRIPS-Plus obligations on public health and access to medicines is frightening upon both developed and developing nations.75 In one of the first studies ever conducted on the impact of TRIPS-Plus obligations, a 2007 Oxfam study on the effect of the US-Jordan FTA found that since 2001 (which is the year the FTA was signed with the US), the prices of medicines in Jordan have increased by 20% (this led to price increases between two and ten-fold for key medicines to treat cardiovascular disease and cancer), and data protection provisions has resulted in delaying generic drugs entry for 79% of medicines newly launched between the years 2002 and 2006.76 The study estimates that the availability of\n\n73For instance, in 2016; and Ukraine de-registered a generic hepatitis C medicine after Gilead indicated that it would pursue arbitration. For more see Gleeson et al. (2019), p. 78. 74UNDP and UNAIDS (2012) https://www.unaids.org/sites/default/files/media_asset/JC2349_ Issue_Brief_Free-TradeAgreements_en_0.pdf. 75See El Said (2010). 76Oxfam (2007), p. 5 https://oxfamilibrary.openrepository.com/bitstream/handle/10546/114080/ b p 1 0 2 - a l l - c o s t s - n o - b e n e fi t s - t r i p s - 2 1 0 3 0 7 - e n . p d f % 3 B j s e s s i o n i d % 3D089750820CF675173F0C3204C369D63F%3Fsequence%3D1. Also see El Said (2006), p. 501.\n\n313", "n_tokens": 402, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-318-0", "doc_id": "medicine_vaccine_book", "page": 318, "text": "314\n\nM. El Said\n\ngeneric equivalents would have reduced Jordan’s expenditure on medicines by $6.3 and $22 million between mid-2002 and 2006.77 The study also shows that no real know-how transfer has occurred in the country despite the rhetoric that FTAs would in fact encourage the flow of know-how and Foreign Direct Investment (FDI).\n\nAlthough the 2007 Oxfam study was conducted under less than 5 years of the FTA implementation, we came a long way since then in terms of assessing and understanding the impact of FTAs on accessibility and affordability of medicines. More and more studies are affirming and exposing the negative impact of these obligations on public health and access to medicines.\n\nAmin and Keselheim conducted a study on the impact of ‘evergreening’ resulting from the granting of secondary patents. The authors concluded that secondary patents could extend market exclusivity and thus delay generic competition from entering the market for many years. The study identified 108 patents related to two HIV medicines (ritonavir (Norvir) and lopinavir/ritonavir (Kaletra)) which impact could delay generic competition until at least 2028. This is a twelve years additional period after the expiration of the patents on the drugs’ base compounds and thirty- nine years after the first patents on ritonavir were filed.78", "n_tokens": 287, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-318-1", "doc_id": "medicine_vaccine_book", "page": 318, "text": "For instance, research by Lexchin concluded that extension of legal protection in data protection for biologics have resulted in increase in spending in drug expendi- ture in Canada. He estimated the lost savings from data protection extension to range from $0 to $305.8 million.79 Another study in Australia found:80\n\nAt the time that the EOT [extension of the term] was introduced, the annual cost to the Pharmaceutical Benefit Scheme (PBS) was estimated to grow from $6 million in 2001-02 to $160 million in 2005-06. This cost arises because there is a delayed entry to the PBS of cheaper generic drugs. The estimate for 2012-13 is around $240 million in the medium term and, in today’s dollars, around $480 million in the longer term. The total cost of the EOT to Australia is actually about 20 per cent more than this, because the PBS is only one source of revenue for the industry.\n\nAnother study conducted by the Australian Generic Medicines Industry Associ- ation analysed the costs to the health system for 39 PBS-listed medicines for which generic competition was delayed after the patent on the active pharmaceutical ingredient expired, as a result of secondary patenting found that in the 12 months to November 2012, the cost of delayed generic launch was calculated at $37.8–$48.4 million.81 This estimate does not include subsequent price reductions due to price", "n_tokens": 293, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-318-2", "doc_id": "medicine_vaccine_book", "page": 318, "text": "77Oxfam, Ibid. 78See Amin and Kesselheim (2012). 79Lexchin (2019), p. 10. 80Harris et al. (2013), p. vi https://www.ipaustralia.gov.au/sites/default/files/2013-05-27_ppr_ final_report.pdf?acsf_files_redirect. The Report found that about 58% of new molecules listed on the PBS from 2003 to 2010 received extensions of term. Of the term extensions granted since 1999, 47% received the full 5 years.18 The cost of these extensions to the PBS in 2012–13 was estimated at about $240 million in the medium term and about $480 million in the longer term. 81Gleeson et al. (2015), p. 306.", "n_tokens": 179, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-319-0", "doc_id": "medicine_vaccine_book", "page": 319, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\ndisclosure. Another study estimated the costs of patent extensions to the PBS in 2012–13 at about $240 million in the medium term and about $480 million in the longer term.82 It was also found that data protection had no impact on the levels of pharmaceutical investment in the country as highlighted with the case of the US FTA with Jordan.\n\nThere has been much more work conducted recently in terms of alerting to the negative impact of the highly controversial Trans-Pacific Partnership Agreement (TPPA) agreement in this regard.83 The TPPA which is widely promoted as a “model for 21st century trade agreements” is a comprehensive trade and investment deal covering many areas including trade, investment, labour and intellectual prop- erty rights in in addition to its investor-state dispute settlement procedure.84 Brook concludes that ‘Provisions in the Intellectual Property (IP) Chapter of TPP lengthen, broaden, and strengthen patent-related monopolies on medicine and erect new monopoly protections on regulatory data as well. IP Chapter enforcement provisions also mandate injunctions preventing medicines sales, increase damage awards, and expand confiscation of medicines at the border’.85", "n_tokens": 256, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-319-1", "doc_id": "medicine_vaccine_book", "page": 319, "text": "In comparing the TPPA with similar agreements, a study found that the US- Mexico-Canada Agreement’s (USMCA) intellectual property chapter is closely based on the corresponding chapter of the TPPA, but includes 10 years of “effective market protection” for biologics in addition to including a broader definition of biologics, potentially expanding the array of drugs which will be eligible for this longer period of exclusivity, longer than the period negotiated in the TPPA.86 For Canada, this will increase the period of market protection for biologics by 2 years; two studies of the potential impact on pharmaceutical expenditure (using different methods and based on different assumptions) have estimated the savings foregone at between CDN$0 and $305.8 and up to CDN$169 by 2029.87", "n_tokens": 170, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-319-2", "doc_id": "medicine_vaccine_book", "page": 319, "text": "7 What Could Be Done and What Is Done?\n\nAs explained, we have a considerable wealth of empirical research about the positive impact of TRIPS flexibilities use and the negative impact of TRIPS-Plus obligations on the health care and access to medicines regimes in several developed and developing countries. However, it has been more difficult to observe how countries\n\n82Harris et al. (2013). 83The Office of the U.S. Trade Representative (USTR) issued a letter in 2019 to signatories of the Trans-Pacific Partnership Agreement that the United States has formally withdrawn from the agreement. 84The TPP is the first trade agreement to include provisions on pharmaceuticals that are, or contain, biologics, compounds produced through biological processes and which are used primarily for treating cancer and immune conditions. 85Baker (2016), p. e1001970. 86Swanson (2019). https://www.nytimes.com/2019/03/21/us/politics/nafta-drug-prices.html. 87Gleeson et al. (2015).\n\n315", "n_tokens": 237, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-320-0", "doc_id": "medicine_vaccine_book", "page": 320, "text": "316\n\nM. El Said\n\nwith TRIPS-Plus regimes have in fact attempted to utilise the remaining policy space available to them in order to mitigate the negative impact these TRIPS-Plus rules have on their national health care regimes. This is so primarily due to the difficulty in observing national practises and the lack of international jurisprudence arising from disputes about the implementation of these obligations (or rather about if such an implementation was in line with international norms or otherwise) under national frameworks.\n\nIn addition, it should be realised from the outset that the effect of TRIPS-Plus commitments will vary from each country and will depend on many factors, including market side, pharmaceutical protection capacity, development of legal regime, judiciary and so forth.\n\nNevertheless, and despite the above-mentioned difficulties, by looking into several cases, we have been able to observe some important contributions in this regard. The important aspect in this case is to continue applying and implementing a nationally creative thinking and interpretive policy aimed towards limiting the negative impact of the committed TRIPS-Plus rules. Following are examples of a number of national experiences of how countries attempted to limit the negative impact arising from TRIPS-Plus obligations.", "n_tokens": 242, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-320-1", "doc_id": "medicine_vaccine_book", "page": 320, "text": "7.1 Australia\n\nOne of the countries which have taken several serious steps in this field is Australia. This is because the country has agreed to a TRIPS-Plus obligations regime arising from the US-Australia FTA88 which had a huge cost on the national health budget and the accessibility and affordability of medicines. Accordingly, in 2013,89 the Australian legislator (following national consultation) introduced a number of reforms aimed towards mitigating the effects of the ‘evergreening’ of patents starting with applying a stricter patentability criteria by removing any geographical limita- tion upon the common general knowledge and by removing the requirement for a prior art document to be “ascertained”.90 The effect of this is to require a higher and more consistent inventive step standard for Australian patents granted in the country. Another area tackled by the Australian legislator is the issue of patent term extension granted in order to compensate for the delays during marketing approval as dictated under the FTA with the US.91 To start with, the 2013 Patent Law reform\n\n88The US-Australia Free Trade Agreement (US-AUS FTA) signed in 2004. 89Intellectual Property Laws Amendment (Raising the Bar) Act 2012 No. 35, 2012 as amended. Start date15 April 2013, hereafter the 2013 Patent Law. 90Dixon (2017). 91See US-AUS FTA, Art.17.9.8(b) states:", "n_tokens": 293, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-320-2", "doc_id": "medicine_vaccine_book", "page": 320, "text": "[E]ach Party shall make available an adjustment of the patent term to compensate the patent owner for unreasonable curtailment of the effective patent term as a result of the marketing approval process.", "n_tokens": 39, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-321-0", "doc_id": "medicine_vaccine_book", "page": 321, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nattempted to limit the possibilities of allowing patent term extension by further confining such type of extensions to certain and specific categories of products related to patents claiming new active ingredients or formulations only.92\n\nMoreover, the Australian 2013 Patent Law reform imposes additional substantive conditions specifically applicable for the extension of patent duration for “pharma- ceutical substances.” Based on this, the extension of the term is possible only if either or both of the following conditions are satisfied:93\n\n(a) one or more pharmaceutical substances per se must in substance be disclosed in the complete specification of the patent and in substance fall within the scope of the claim or claims of that specification;\n\n(b) one or more pharmaceutical substances when produced by a process that in substance be involves the use of recombinant DNA technology, must disclosed in the complete specification of the patent and in substance fall within the scope of the claim or claims of that specification. In addition, both of the following conditions must be satisfied in relation to at\n\nleast one of those pharmaceutical substances:\n\n(a) goods containing, or consisting of, the substance must be included in the", "n_tokens": 273, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-321-1", "doc_id": "medicine_vaccine_book", "page": 321, "text": "Australian Register of Therapeutic Goods;\n\n(b) the period beginning on the date of the patent and ending on the first regulatory\n\napproval date for the substance must be at least 5 years.\n\n(4) The term of the patent must not have been previously extended under this Part.\n\nMeaning of first regulatory approval date.\n\nMore reforms were introduced with relation to opposition procedures as well. As such, detailed and expansive opposition grounds against patent term extension procedures were included under the 2013 Patent Law reform. Accordingly, Article 78 of the Patent Law states:\n\nIf the Commissioner grants an extension of the term of a standard patent, the exclusive rights of the patentee during the term of the extension are not infringed:\n\n(a) by a person exploiting:\n\n(i) a pharmaceutical substance per se that is in substance disclosed in the complete specification of the patent and in substance falls within the scope of the claim or claims of that specification; or\n\n(ii) a pharmaceutical substance when produced by a process that involves the use of recombinant DNA technology, that is in substance disclosed in the complete specification of the patent and in substance falls within the scope\n\n92See El Said (2016). 93See Patents Act 1990 (Cth) ch 6 pt 3 s 70 sub-divs (2)-(3) (Austl).\n\n317", "n_tokens": 278, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-322-0", "doc_id": "medicine_vaccine_book", "page": 322, "text": "318\n\nM. El Said\n\nof the claim or claims of that specification; for a purpose other than therapeutic use; or\n\n(b) by a person exploiting any form of the invention other than:\n\n(i) a pharmaceutical substance per se that is in substance disclosed in the complete specification of the patent and in substance falls within the scope of the claim or claims of that specification; or\n\n(ii) a pharmaceutical substance when produced by a process that involves the use of recombinant DNA technology, that is in substance disclosed in the complete specification of the patent and in substance falls within the scope of the claim or claims of that specification.\n\nPatent linkage is another TRIPS-Plus issue whereby Australia’s approach may provide some valuable lessons for others. Article 17.10.4 (in the Intellectual Property chapter) of the US-AUS FTA provides for an attenuated or ‘weak’ form of patent linkage with relation to two aspects as explained by Son et al:94\n\n(a) measures in the marketing approval process to prevent a third party from marketing a product during the term of a patent without the consent of the patent owner; and\n\n(b) no provision for the owner to be notified of a marketing approval request made during the term of a patent. This wording provided scope for Australia to implement a patent linkage mechanism in a very different way to the United States.", "n_tokens": 296, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-322-1", "doc_id": "medicine_vaccine_book", "page": 322, "text": "In addition, the Australian regime excludes from protection patents covering (1) the drug substance, (2) the drug product including composition and formulation, and (3) the approved use from the patent linkage mechanism.95 Penalties for providing false or misleading information, however, are disproportionately higher for a patent holder certificate than for a generic producer certificate. Moreover, Australia’s Pharmaceutical Benefit Scheme (PBS) imposes automatic and irrevers- ible price cuts on medicines as soon as competing versions enter the market, this often incentivise generic companies to launch faster at risk, and innovator companies must pursue preliminary injunctions in order to resolve patent disputes.96 At the same time, since 2012, Australia’s Department of Health has pursued market-sized pecuniary damages (on top of those sought by the generic company) aimed at compensating for a delay in the PBS price reduction that would have been applied to a patented medicine during the period of a provisional enforcement measure.97 However, there is no corresponding mechanism for the government to compensate\n\n94Son et al. (2018), p. 101. 95Son et al. (2018), p. 101. 96GIPC (2019). https://www.theglobalipcenter.com/wp-content/uploads/2019/09/GIPC-Linkage- Zoom-In-Report.pdf. 97Australian Government Department of Health (2016). http://www.pbs.gov.au/industry/pricing/ price-disclosure-spd/price-disclosure-operational-guidelines-06-2016.pdf.", "n_tokens": 353, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-323-0", "doc_id": "medicine_vaccine_book", "page": 323, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\n319\n\ninnovators for the aforementioned losses if an infringing product prematurely.98\n\nis launched\n\nAlthough such reforms are vital, they should not be viewed as the only solutions to the accessibility of medicines challange and therefore the intellectual property regime should be viewed as one of several components and government strategies— one element of an eco-system—in this regard which would improve accessibility and affordability of medicines. For an example, in February 2019, the Australian gov- ernment signed a five-year deal with pharmaceutical companies, involving a lump sum payment of about $ 766 million for an unlimited five-year supply of the most advanced Hepatitis C (HCV) drugs.99 This innovative approach which has been called the “subscription” or “Netflix” model, have reduced the per-patient costs of these cutting-edge treatments by roughly 85% in the country.100", "n_tokens": 202, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-323-1", "doc_id": "medicine_vaccine_book", "page": 323, "text": "7.2 Chile\n\nChile also proved an interesting case of a developing country which adopted a TRIPS-Plus regime as a result of signing an FTA with the US in 2006 (the US-Chile FTA). Following a rigorous national debate with relation to the negative effect of data exclusivity and patent linkage included under the FTA, the Chilean government amended the patent law by limiting the availability of data protection under its national law to those pharmaceutical products that have been marketed in the national territory in the year after the grant of marketing approval and therefore if the drug was not marketed within a year, the test data submitted for approval purposes will not be protected.101 The rationale behind such a requirement is to encourage early registration of drugs after first registration abroad, so that the period of protection for the pharmaceutical test data starts early.\n\nIn addition, the law excluded several elements from the scope of protection.\n\nAccordingly, article 91 of the Chilean law states:\n\nThe protection of this Paragraph shall not apply when:", "n_tokens": 202, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-323-2", "doc_id": "medicine_vaccine_book", "page": 323, "text": "98GIPC (2019). 99The government also announced an investment of more than 1 Billion USD to enable universal access to HVC treatment. See Velásquez (2017). https://www.southcentre.int/wp-content/uploads/ 2017/05/RP77_Access-to-Hepatitis-C-Treatment-A-Global-Problem_EN-2.pdf. 100Moon and Erickson (2019), p. 607. Furthermore, the State of Louisiana announced in January 2019 that it was pursuing a similar approach for HCV. For more see Crisp (2019) https://www. theadvocate.com/baton_rouge/news/politics/article_614e4f42-1523-11e9-8c90-4fcb305d17e8. html. 101Law No. 19,039 art. 90, September 30, 1991 (modified on December 1, 2005 by Law 19,996, which classifies active ingredients as new chemical entities if they have not been marketed in the country prior to the health registration or authorization application). See also Biadgleng and Maur (2011), p. 20.", "n_tokens": 266, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-324-0", "doc_id": "medicine_vaccine_book", "page": 324, "text": "320\n\nM. El Said\n\n(a) The owner of the test data referred to in Article 89 has engaged in forms of conduct or practices declared as contrary to free competition in direct relation to the use or exploitation of that information, according to the final decision of the free competition court.\n\n(b) For reasons of public health, national security, non-commercial public use, national emergency or other circumstances of extreme urgency declared by the competent authority, ending the protection referred to in Article 89 shall be justified.\n\n(c) The pharmaceutical or chemical-agricultural product is the subject of a compul-\n\nsory license, according to what is established in this Law.\n\n(d) The pharmaceutical or chemical-agricultural product has not been marketed in the national territory after 12 months from the health certificate or clearance granted in Chile.\n\n(e) The pharmaceutical or chemical-agricultural product has a health certificate\n\nFurthermore, Chile implemented the linkage obligation established by the US-Chile FTA through the provision of information to the patent owner about a third party intending to commercialize a product with similar characteristics to one that is already patented.102\n\nThe aim of these measures is to explore whatever policy space remains available\n\nto the country in order to restrict the application of data exclusivity.", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-324-1", "doc_id": "medicine_vaccine_book", "page": 324, "text": "7.3 What Others Are Doing and How They Are Doing It?\n\nThere are many examples of interpretations and flexibility use taking place regularly in different parts of the globe.103 These developments are either legislative, admin- istrative or judicial in nature. Calls are made for countries to take advantage of the remaining policy space in this regard and share their experiences with others. Following are some non-exhaustive recommendations.\n\nSeveral recommendations were made more with connection to data exclusivity obligations. As a result, it is advisable for those regimes’ committing to TRIPS-Plus data exclusivity provisions not to grant protection unless a specific application is made (within a specific period—no more than 6 months—of time after the first approval in the world of a medicine) and where certain conditions are met. Countries\n\n102Correa remarks that on September 2nd, 2002 the Quinta Sala from the I Corte de Apelaciones (I Court of Appeals, Fifth Chamber) of Chile ruled that the Instituto de Salud Publica, which issues sanitary registries, ‘had no power whatsoever to either deny a marketing approval or to acknowl- edge rights derived from a patent’. See Correa (2017). https://www.southcentre.int/wp-content/ uploads/2017/02/RP74_Mitigating-the-Regulatory-Constraints-Imposed-by-Intellectual-Property- Rules-under-Free-Trade-Agreements_EN-1.pdf. See also Chandler (2010), https://papers.ssrn.com/ sol3/papers.cfm?abstract_id¼1602883. 103See Correa (2017).", "n_tokens": 368, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-325-0", "doc_id": "medicine_vaccine_book", "page": 325, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nmay also charge for these applications and require annual maintenance fee (such as those applicable to trademarks). In addition, detailing when protection will terminate is recommended. Correa suggests the following situations as examples:104 – When the right-holder or a person authorised by him does not commercialise the approved product in a manner sufficient to supply the demand within a period (e.g. twelve months) from the date of approval for commercialisation or when the commercialisation is interrupted, for more than x consecutive months (e.g. six months), except in cases of force majeure or government’s acts that prevent such commercialisation.\n\nFor public interest reasons such as national security, emergency or circumstances of extreme urgency that justify the termination of the period of exclusivity. – When, as a result of administrative or judicial procedures, it is determined that the right-holder has abused his rights, for example, through practices declared as anticompetitive. Keeping health out of the FTA agenda is one right step in this regard. We can observe some positive steps taken in this area. The recently concluded FTA between Australia and Peru have explicitly excluded public health measures and/or specific health programs from its scope. Article 8. 16 of the FTA states:105", "n_tokens": 288, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-325-1", "doc_id": "medicine_vaccine_book", "page": 325, "text": "Nothing in this Chapter shall be construed to prevent a Party from adopting, maintaining or enforcing any measure otherwise consistent with this Chapter that it considers appropriate to ensure that investment activity in its territory is undertaken in a manner sensitive to environmental, health or other regulatory objectives.\n\nCompulsory licensing in TRIPS agreements is stated with ambiguous wording such as ‘national emergency’, ‘other circumstances of extreme urgency’, and ‘public non-commercial use’. To deal with this ambiguity, active interpretations of these terms should be persued. In this context, the Thai experience is noteworthy. The legislator there defined public non-commercial use as ‘nutrition and public health service’ and ‘protection of natural the legislater interpreted the non-use of a patent as ‘insufficient use of a patent due to the high price’ and ‘severe shortage of food and drugs’.106\n\nresources and environment’. Also,\n\nIt is worth noting that the above referred to examples should not emanate from separate national initiatives but rather as a part of a more comprehensive approach dealing with public health challenges within these countries. As seen, several developed countries acknowledge today the negative consequences to TRIPS-Plus rules on public health and have taken steps to rectify the situation. Developing countries should follow suit and take serious notice of such implications.", "n_tokens": 267, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-325-2", "doc_id": "medicine_vaccine_book", "page": 325, "text": "104Correa (2017). 105See the Australian Government Department of Foreign Affairs and Trade. Chapter 8: Invest- ment. Peru-Australia Free Trade Agreement. https://www.dfat.gov.au/trade/agreements/in-force/ pafta/Pages/peru-australia-fta.aspx. 106Kuanpoth (2006), p. 149.\n\n321", "n_tokens": 86, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-326-0", "doc_id": "medicine_vaccine_book", "page": 326, "text": "322\n\nM. El Said\n\n8 Final Thoughts\n\nThe world is at a crossroads. At the time of completion of this chapter, the world was struggling in confronting the outbreak pandemic of the Corona virus (Covid-19). Although several vaccines are available today, the daily loss of life is having grave ramifications for the global economic and public health regimes. These outbreaks are not new, however how we deal with them will depend on our ability to access and grant funding for those working around the clock to find a cure. The intellectual property regime needs reorientation to become truly an incentive rather than an impediment to accessibility and treatment.", "n_tokens": 135, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-326-1", "doc_id": "medicine_vaccine_book", "page": 326, "text": "Some final thoughts could be made here with relation to supressing the impact of TRIPS-Plus conditions on access to medicines within the framework of trade and investment agreements. First, comprehensive assessment of the health impact of FTAs and TRIPS-Plus commitments should be undertaken by policy makers and negotiators. This should take place before an agreement is entered into. Second, public and stakeholder engagement and collaboration is needed and should be a priority. A national intellectual property committee with authorities and mandates should be tasked with implementing a balanced national intellectual property Agenda. Alternative and new business models for research and development are needed to achieve better pricing of medicines. Push, pull and pooling strategies should be given more thought and experimented with in this regard.107 Finally, transparency in drug pricing is pivotal to ensure that (i fair compensation is granted to those who invest in finding medical solutions to diseases, and (ii affordable drug prices are applied so that patients can afford them. The 2019 World Health Assembly’s resolution supporting greater public disclosure of prices for medicines and other health products is a step in the right direction.108", "n_tokens": 221, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-326-2", "doc_id": "medicine_vaccine_book", "page": 326, "text": "The legal recommendation stands today the same as before; governments should resist accepting and introducing TRIPS-Plus obligations even if others do so. At the same time, those who committed to such obligations should undertake a thorough review in order to identify areas where they can still utilise the TRIPS Flexibilities. We may not be able to stop the spread of TRIPS-Plus commitments around the globe; however, we should try and do our best to slow down the process of eroding the remaining policy space.\n\n107See Suleman et al. (2020), p. 368. See also more generally the UN Secretary General High-Level Panel (n 1). 108Fletcher stone-resolution-on-price-transparency/.\n\n(2019). https://www.healthpolicy-watch.org/world-health-assembly-approves-mile", "n_tokens": 179, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-327-0", "doc_id": "medicine_vaccine_book", "page": 327, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nReferences\n\nAgreement on Trade-Related Aspects of Intellectual Property Rights, Apr. 15, 1994, Marrakesh", "n_tokens": 43, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-327-3", "doc_id": "medicine_vaccine_book", "page": 327, "text": "Council for Trade-Related Aspects of Intellectual Property Rights, Extension of the Transition Period under Article 66.1 of the TRIPS Agreement for Least Developed Country Members for Certain Obligations with Respect to Pharmaceutical Products, Decision of the Council for TRIPS of 6 November 2015\n\nCrisp E (2019) Louisiana moves ahead with subscription model to pay for hepatitis C drugs for thousands. The Advocate (10 January 2019). https://www.theadvocate.com/baton_rouge/news/ politics/article_614e4f42-1523-11e9-8c90-4fcb305d17e8.html. Accessed 3 Mar 2021\n\nDearment A (2019) New antibiotic for drug resistant tuberculosis scores FDA approval. MedCity News (15 August 2019). https://medcitynews.com/2019/08/new-antibiotic-for-drug-resistant- tuberculosis-scores-fda-approval/. Accessed 3 Mar 2021\n\nDixon G (2017) Has “Raising the Bar” actually raised the bar on inventive step? Shelston (2 March 2017). https://shelstonip.com/insights/publications/has-raising-the-bar-actually-raised-the-bar- on-inventive-step/. Accessed 3 Mar 2021\n\n323", "n_tokens": 272, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-328-0", "doc_id": "medicine_vaccine_book", "page": 328, "text": "324\n\nM. El Said\n\nDonnelly L (2015) Thousands of cancer patients to be denied treatment. common drugs for breast, bowel, prostate, pancreatic and blood cancer will no longer be funded by the NHS following sweeping cutbacks. The Telegraph (4 September 2015)\n\nDrahos P (2001) BITS and BIPS: bilateralism in intellectual property. J World Intellect Prop 4:791 Drahos P (2010) The global governance of knowledge: patent offices and their clients. Cambridge", "n_tokens": 103, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-328-2", "doc_id": "medicine_vaccine_book", "page": 328, "text": "the future. Manchester J Int Econ Law 11(1):60\n\nEl Said M (2016) TRIPS-Plus, public health and performance-based rewards schemes options and supplements for policy formation in developing and least developed countries. Am Univ Int Law Rev 31(3):374\n\nEntis L (2019) Why does medicine cost so much? Here’s how drug prices are set. TIME (19 April\n\n2019)\n\nEU Commission (2008) Executive Summary of the Pharmaceutical Sector Inquiry Report (Report, 2008). https://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/communication_en. pdf. Accessed 3 Mar 2021, p 10\n\nFletcher E (2019) World health assembly approves milestone resolution on price transparency. Health Policy Watch (25 May 2019). https://www.healthpolicy-watch.org/world-health- assembly-approves-milestone-resolution-on-price-transparency/. Accessed 3 Mar 2021\n\nGallup and West Health (2019) Millions in U.S. lost someone who couldn't afford treatment. Gallup (13 November 2019). https://news.gallup.com/poll/268094/millions-lost-someone-couldn- afford-treatment.aspx?version¼print\n\nGIPC (2019) Providing certainty and predictability: how patent linkage mechanisms help innova- tors, follow-on manufacturers and patients. GIPC. https://www.theglobalipcenter.com/wp- content/uploads/2019/09/GIPC-Linkage-Zoom-In-Report.pdf. Accessed 3 Mar 2021", "n_tokens": 348, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-328-3", "doc_id": "medicine_vaccine_book", "page": 328, "text": "Gleeson D, Moir H, Lopert R (2015) Costs to Australian taxpayers of pharmaceutical monopolies and proposals to extend them in the Trans-Pacific Partnership Agreement. Med J Aust 202 (6):306 citing Generic Medicines Industry Association. Public response to the 2013 Pharma- ceutical Patents Review, Sydney: GMiA, 2013: 11\n\nGleeson D, Lexchin J, Labonté R, Townsend B, Gagnon M-A, Kohler J, Forman L, Shadlen K (2019) Analysing the impact of trade and investment agreements on pharmaceutical policy: provisions, pathways and potential impacts. Glob Health 15(1):78\n\nGlobal Justice Now and Stop AIDS (2017) Pills and profits how drug companies make a killing out of public research (Report, October 2017). https://www.globaljustice.org.uk/sites/default/files/ files/resources/pills-and-profits-report-web.pdf. Accessed 3 Mar 2021, p 7", "n_tokens": 224, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-329-0", "doc_id": "medicine_vaccine_book", "page": 329, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nGornall J, Hoey A, Ozieranski P (2016) A pill too hard to swallow: how the NHS is limiting access\n\nto high priced drugs. Br Med J 354:4117\n\nHarris T, Nicol D, Gruen N (2013) Pharmaceutical Patents Review Report. Commonwealth of Australia, Canberra, p vi. https://www.ipaustralia.gov.au/sites/default/files/2013-05-27_ppr_ final_report.pdf?acsf_files_redirect. Accessed 3 Mar 2021\n\nHerder M, Graham J, Gold R (2020) From discovery to delivery: public sector development of the\n\nrVSV-ZEBOV Ebola vaccine. J Law Biosci:1–14\n\n‘t Hoen E (2019) Uganda tells ARIPO: no more patents for pharmaceuticals. Medicine Law and Policy (8 October 2019). https://medicineslawandpolicy.org/2019/10/uganda-tells-aripo-no- more-patents-for-pharmaceuticals/. Accessed 3 Mar 2021\n\n‘t Hoen E, Veraldi J, Toebes B, Hogerzeil H (2018) Medicine procurement and the and the use of the flexibilities in the agreement on trade-related aspects of intellectual property rights, 2001- 2016. Bull World Health Organ 96(3):185–193\n\nHopkins JS (2020) Drug prices rise 5.8% on average in 2020. Market Watch (2 January 2020) https://www.marketwatch.com/story/drug-prices-rise-58-on-average-in-2020-2020-01-02 I-MAK (2017) America’s overspend: how the pharmaceutical patent problem is fuelling high drug prices (Report, October 2017). https://www.i-mak.org/americas-overspend/. Accessed 3 Mar 2021", "n_tokens": 434, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-329-1", "doc_id": "medicine_vaccine_book", "page": 329, "text": "I-MAK (2018a) Over-patented, overpriced: how excessive pharmaceutical patenting is extending monopolies and driving up drug prices (Report, August 2018). http://www.i-mak.org/wp- content/uploads/2018/08/I-MAK-Overpatented-Overpriced-Report.pdf. Accessed 3 Mar 2021 I-MAK (2018b) Lantus (Insulin Glargine) (Report, 2018). http://www.i-mak.org/wp-content/\n\nuploads/2018/10/I-MAK-Lantus-Report-2018-10-30F.pdf. Accessed 3 Mar 2021\n\nKesselheim A, Fischer M, Avorn J (2006) Extensions of intellectual property rights and delayed adoption of generic drugs: effects on Medicaid spending: what are the cost implications of generic substitution for three commonly prescribed drugs? Health Aff 25(6):1637\n\nKuanpoth J (2006) Patents and access to medicines in Thailand: the DDL case and beyond. Intellect\n\nProp Q 2:149\n\nLexchin J (2019) Increase in drug spending in Canada due to extension of data protection for\n\nbiologics: a descriptive study. Health Policy 14(3):10\n\nLight D, Warburton R (2016) Demythologizing the high costs of pharmaceutical research.", "n_tokens": 302, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-329-2", "doc_id": "medicine_vaccine_book", "page": 329, "text": "BioSocieties 6(1):34\n\nLing CY (2019) Using compulsory licence for affordable medicines. Astro Awani (9 March, 2019). http://english.astroawani.com/malaysia-news/using-compulsory-licence-affordable-medi cines-200558. Accessed 3 Mar 2021\n\nMachlup F, Penrose E (1950) The patent controversy in the nineteenth century. J Econ Hist 10(1):1 Miller S (2012) Where’s the innovation?: An analysis of the quantity and qualities of anticipated and obvious patents, 2 (10 February 2012). https://papers.ssrn.com/sol3/papers.cfm?abstract_ id¼2029263. Accessed 3 Mar 2021\n\nMole B (2019) MIA drugs — drug companies are sitting on generics—43% of recently approved aren’t for sale. ars Technica (2 September 2019). https://arstechnica.com/science/2019/02/drug- companies-are-sitting-on-generics-43-of-recently-approved-arent-for-sale/. Accessed 3 Mar 2021\n\nMoon S, Erickson E (2019) Universal medicine access through lump-sum remuneration —\n\nAustralia’s approach to hepatitis C. North Engl J Med 380:607\n\nMSF (2016) Lives on the edge: time to align medical research and development with people’s\n\nhealth needs (May 2016)\n\nNey J (2019) Exclusivity for biologic products under the USMCA: what is changing, and what happens next? Biosimilars (14 October 2019). https://www.centerforbiosimilars.com/contribu tor/joshua-ney/2019/08/exclusivity-for-biologic-products-under-the-usmca-what-is-changing- and-what-happens-next. Accessed 3 Mar 2021\n\nO’Neill J (2015) Buy back or pay forward? Project Syndicate (6 May 2015)\n\n325", "n_tokens": 438, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-330-0", "doc_id": "medicine_vaccine_book", "page": 330, "text": "326\n\nM. El Said\n\nOffice of Patented Medicines and Liaison (2005) Therapeutic products directorate statistical report\n\n2004: patented medicines (notice of compliance) regulations (2005, Health Canada)\n\nOxfam (2007) All costs, no benefits: how TRIPS-Plus intellectual property rules in the US-Jordan FTA Affect Access to Medicines 7 (Oxfam Int’l, Briefing Paper No. 102, 2007). https:// oxfamilibrary.openrepository.com/bitstream/handle/10546/114080/bp102-all-costs-no-bene fits-trips-210307-en.pdf%3Bjsessionid%3D089750820CF675173F0C3204C369D63F% 3Fsequence%3D1. Accessed 3 Mar 2021, p 5\n\nPatent Law (promulgated by the Standing Comm. Nat’l People’s Cong., Mar. 12, 1984, rev’d Dec.\n\n27, 2008), art. 22\n\nPedrique B, Strub-Wourgaft N, Some C, Olliaro P, Trouiller P, Ford N (2013) The drug and vaccine landscape for neglected diseases (2000-11): a systematic assessment. Lancet Global Health 6 (1):371\n\nPipes S (2019) Britain’s version of ‘Medicare for all’ is struggling with long waits for care. Forbes (1 April 2019). https://www.forbes.com/sites/sallypipes/2019/04/01/britains-version-of-medi care-for-all-is-collapsing/#4c6ebeb736b8. Accessed 3 Mar 2021\n\nPrescrire International (2005) A review of new drugs in 2004: floundering innovation and increased\n\nrisk-taking. Prescrire International 14:68, 71\n\nRaffi F, Reynes J (2014) Antiretroviral Treatment French Guidelines 2013: economics influencing", "n_tokens": 448, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-330-1", "doc_id": "medicine_vaccine_book", "page": 330, "text": "science. J Antimicrob Chemother 69:1158\n\nRøttingen J, Regmi S, Eide M, Young A, Viergever R, Årdal C (2013) Mapping of available health research and development data: what’s there, what’s missing, and what role is there for a global observatory? Lancet 382:1286\n\nRowland C (2019) An HIV treatment cost taxpayers millions, the government patented it, but a\n\npharma giant is making billions. Washington Post (27 March 2019)\n\nSampat B, Shadlen K (2017) Secondary pharmaceutical patenting: a global perspective. Res Policy\n\n46(3):693\n\nSciences Avenir with AFP (2015) The league against cancer denounced the “exorbitant” prices for innovative medicines (16 December 2015). http://www.sciencesetavenir.fr/sante/cancer/ 20151216.OBS1499/la-ligue-contre-le-cancer-denonce-les-prixexorbitants-des-medicaments- innovants.html\n\nSon K-B, Lopert R, Gleeson D, Lee T-J (2018) Moderating the impact of patent linkage on access to medicines: lessons from variations in South Korea, Australia, Canada, and the United States. Glob Health 14(6):101\n\nStevens A, Jensen J, Wyller K, Kilgore P, Chatterjee S, Rohrbaugh M (2011) The role of public-\n\nsector research in the discovery of drugs and vaccines. N Engl J Med 364:535", "n_tokens": 349, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-330-2", "doc_id": "medicine_vaccine_book", "page": 330, "text": "Suleman F, Low M, Moon S, Morgan S (2020) New business models for research and development with affordability requirements are needed to achieve fair pricing of medicines. BMJ:368 Swanson A (2019) Drug company protection are latest stumbling block for NAFTA rewrite. New York Times (New York, 21 March 2019). https://www.nytimes.com/2019/03/21/us/ politics/nafta-drug-prices.html. Accessed 3 Mar 2021\n\nThe Economist (2019) The global battle over high drug prices: western countries, as well as poor\n\nones, are demanding transparency in the cost of drugs. The Economist (21 May 2019)\n\nThe King’s Fund (2018) The rising cost of medicines to the NHS: what’s the story? (Briefing, April 2018). https://www.kingsfund.org.uk/sites/default/files/2018-04/Rising-cost-of-medicines.pdf Trouiller O, Olliaro P, Torreele E, Orbinski J, Laing R, Ford N (2002) Drug development for neglected diseases: a deficient market and a public-health policy failure. Lancet 359:2188 UN Secretary General High Level Panel (2016) The United Nations Secretary-General High-Level Panel on Access to Medicines Report: Promoting Innovation and Access to Health Technologies (September 2016), p 12. http://www.unsgaccessmeds.org/final-report. Accessed 3 Mar 2021 UNAIDS (2011) DOHA+10 TRIPS flexibilities and access to antiretroviral therapy: lessons from the past, opportunities for the future, p 15. https://www.unaids.org/sites/default/files/media_ asset/JC2260_DOHA%2B10TRIPS_en_0.pdf. Accessed 3 Mar 2021", "n_tokens": 415, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-331-0", "doc_id": "medicine_vaccine_book", "page": 331, "text": "The Impact of ‘TRIPS-Plus’ Rules on the Use of TRIPS Flexibilities:...\n\nUNDP and UNAIDS (2012) The potential impact of free trade agreements on public health. https:// www.unaids.org/sites/default/files/media_asset/JC2349_Issue_Brief_Free-TradeAgreements_ en_0.pdf. Accessed 3 Mar 2021, p 5\n\nVelásquez G (2017) Access to hepatitis C treatment: a global problem. Research Paper No. 77, South Centre, Geneva. https://www.southcentre.int/wp-content/uploads/2017/05/ RP77_Access-to-Hepatitis-C-Treatment-A-Global-Problem_EN-2.pdf. Accessed 3 Mar 2021 Velasquez G (2019) Seeking remedies for access to medicines and intellectual property: recent developments. South Centre, Geneva, p 108. https://www.southcentre.int/wp-content/uploads/ 2019/11/Bk_2019_Seeking-Remedies-for-Access-to-Medicines-and-Intellectual-Property_EN. pdf\n\nWard D, Slade A, Genus T, Martino O, Stevens A (2014) How innovative are new drugs launched in the UK? A retrospective study of new drugs listed in the British National Formulary (BNF) 2001-2012. BMJ 4(10):6235", "n_tokens": 318, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-331-1", "doc_id": "medicine_vaccine_book", "page": 331, "text": "WHO (2015) Global action plan on antimicrobial resistance, p 5. http://apps.who.int/iris/bitstream/\n\n10665/193736/1/9789241509763_eng.pdf. Accessed 3 Mar 2021\n\nWHO (2017) Antibacterial agents in clinical development: an analysis of the antibacterial clinical development pipeline, including tuberculosis (Report, Geneva, 2017). https://apps.who.int/iris/ bitstream/handle/10665/258965/WHO-EMP-IAU-2017.11-eng.pdf?sequence¼1. Accessed 3 Mar 2021\n\nWHO (2018) Pricing of cancer medicines and its impacts: a comprehensive technical report for the World Health Assembly Resolution 70.12 (Technical Report, 2018), p xi. https://apps.who.int/ iris/bitstream/handle/10665/277190/9789241515115-eng.pdf?sequence¼1&isAllowed¼y WHO (2019) Antibacterial agents in preclinical development: an open access database (WHO, Geneva). https://apps.who.int/iris/bitstream/handle/10665/330290/WHO-EMP-IAU-2019.12- eng.pdf. Accessed 3 Mar 2021\n\nWTO (2000) Canada—patent protection of pharmaceutical products. Geneva, WTO Dispute Panel", "n_tokens": 310, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-331-2", "doc_id": "medicine_vaccine_book", "page": 331, "text": "Report, WT/DS114/1\n\nOpen Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n327", "n_tokens": 176, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-332-0", "doc_id": "medicine_vaccine_book", "page": 332, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges, Opportunities for Developing Countries", "n_tokens": 17, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-332-1", "doc_id": "medicine_vaccine_book", "page": 332, "text": "K. D. Raju\n\nAbstract Linking patent protection to generics’ regulatory approvals is a heated topic of discussions and a friction point among countries proposing higher protection for patented drugs. Patent linkage has been pushed through bilateral and regional agreements outside of the WTO system. It is widely understood that patent linkage is implemented to delay the market entry of generic medicines. It is argued here that developing countries are not obliged to take up TRIPs plus patent-linkage obligations.\n\nA list of approved drugs and their therapeutic equivalence can be published by every country. The patent information can also be published to be made known to everybody. Regulatory mechanisms and patent protection should be kept in separate parallel tracks. Any attempt to link the two streams to prevent the registration of generics based solely on alleged patent infringement would negatively affect access to medicines worldwide.\n\nPatent linkage provisions are TRIPS-plus commitments, as there is no such obligation under the WTO TRIPS Agreement. The analysis of 16 countries which provide for patent linkage shows that it is, in most cases, a resulting commitment from regional trade agreements or bilateral agreements. Patent linkage provisions are not acceptable to the developing world, and any attempt to introduce these will affect the accessibility and affordability of generic medicines in the developing world.", "n_tokens": 251, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-332-2", "doc_id": "medicine_vaccine_book", "page": 332, "text": "K. D. Raju (*) Rajiv Gandhi School of Intellectual Property Law, Indian Institute of Technology, Kharagpur, Kharagpur, West Bengal, India e-mail: kdraju@rgsoipl.iitkgp.ac.in\n\n© The Author(s) 2022 C. M. Correa, R. M. Hilty (eds.), Access to Medicines and Vaccines, https://doi.org/10.1007/978-3-030-83114-1_12\n\n329", "n_tokens": 116, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-333-0", "doc_id": "medicine_vaccine_book", "page": 333, "text": "330\n\nK. D. Raju\n\n1 Introduction\n\nAccess to essential medicines is a developmental challenge to developing countries under the WTO Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPs).1 Accessibility, affordability, and availability of medicines (medicines and drugs are interchangeably used in this paper hereinafter) are the prime objectives of any developing country’s public health policy.2 Access to drugs is vital in the background that, after food, the second-largest household expenditure is on medi- cation, and this is paid out of pocket in these countries due to a lack of sufficient public health programs. Many countries drafted their medicines policies keeping this issue in mind. The challenging problem is that pandemics’ growing burden in developing and least developed countries raised a high demand for cost-effective medicines. Countries like India have previously met this increased demand by providing low-cost generic drugs to the world and helping them fight pandemics.3 Developing and developed countries alike have realized the importance of generic drugs in healthcare.4 The European Generics Medicines Association (EGA) formed “Medicines for Europe” in the year 2000 to support the generic and biosimilar industry, which supplies 67% of all medicines in Europe.5", "n_tokens": 255, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-333-1", "doc_id": "medicine_vaccine_book", "page": 333, "text": "Developing countries face challenges in the form of TRIPs-plus obligations imposed on them through various means, mainly bilateral and regional trade agree- ments. The availability and accessibility of medicines will be affected by policy choices, such as adopting a patent linkage. Patent linkage refers to the system or process by which a country links drug-marketing approval to the status of the patent (s) corresponding to the originator’s patented product.6", "n_tokens": 88, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-333-2", "doc_id": "medicine_vaccine_book", "page": 333, "text": "1WHO (2011–2016), available at https://apps.who.int/iris/bitstream/handle/10665/207519/ 9789290615705_eng.pdf. 2Ravikant et al. (2013), pp. 316–322. 3India recently sent an anti-malarial drug, Hydroxychroloquine, to 55 countries hit with Corona- virus. This drug is identified by the US Food and Drug Administration as a possible drug to treat Covid-19 disease, though its safety and efficacy are not yet established. See India Today, New Delhi, April 17, 2020, https://www.indiatoday.in/india/story/india-sending-hydroxychloroquine- 55-coronavirus-hit-countries-1667786-2020-04-17. Later the accepted the Solidarity Trial’s Inter- national Steering Committee recommendation to discontinue the trial’s hydroxychloroquine and lopinavir from the treatment of COVID-19 patients. See WHO (2020). https://www.who.int/ emergencies/diseases/novel-coronavirus-2019/advice-for-public/myth-busters? gclid¼EAIaIQobChMIjoGlirH06wIVhzMqCh3ISAVnEAAYASABEgKMz_D_BwE. 4European Generic Medicines Association (2009). https://www.medicinesforeurope.com/wp- content/uploads/2016/03/Market_Barriers_Report_FINAL_update_How_to_Increase_Patient_ Access_to_Generic_Medicines.pdf. 5Medicines for Europe, https://www.medicinesforeurope.com/medicines-for-europe/. 6https://www.wipo.int/export/sites/www/meetings/en/2007/lifesciences/sym_regulation/lss3_ge_ 07_ferrite.pdf.", "n_tokens": 456, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-334-0", "doc_id": "medicine_vaccine_book", "page": 334, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nThe present IP regime in 164 countries are under the WTO’s7 TRIPs Agreement concluded in 1995. Every WTO member country has to implement minimum standard of intellectual property at the domestic level according to TRIPs provisions. Article 1 of the Agreement stipulates, “Members may, but shall not be obliged to, implement in their law more extensive protection than is required by this Agree- ment.”8 Hence, it is clear that members are not obliged to implement higher standards than prescribed in the TRIPs agreement.9\n\nThe basic concept of patent protection is that once the patent term is over (presently 20 years under the TRIPS agreement), the product would be in the public domain and freely used, including for commercial purposes.10 This eclipse of patent protection is supposed to increase consumer welfare, and society would be better off from evergreening protection. Pharmaceutical regulatory approval is entirely differ- ent from patent protection. Moreover, it differs from country to country based on domestic legislation. Linking such regulatory and marketing approval to the origi- nator’s patent status would affect the generic drug industry at large and accessibility and affordability.", "n_tokens": 243, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-334-1", "doc_id": "medicine_vaccine_book", "page": 334, "text": "Patent linkage involves linking the marketing approval of generic drugs with the originator drug’s patent status and refusing to allow marketing approval until the patent is expired.11 The United States (US) first introduced the concept through the Hatch Waxman Act, 1984.12 This law provides for protecting the interest of patent holders through linking patent status of originators’ drugs and their regulatory approval in the “Orange Book.”13 Thus, a generic drug would not get marketing approval if it would potentially infringe one or more patents listed in the Orange Book. The US patent linkage system can be seen as a ploy by the patent holder to delay the entry of generic drugs in the market.14 However, the originator industry argues that this will help them prevent anticipated patent infringement and promote innovation and investment by giving inventors more certainty over their patent rights.15 However, generic manufacturers argue that TRIPs plus commitment under- mines the rapid approval of generic medicines. Besides, most countries’ drug regulatory authorities need not inform the inventors about the application for marketing approval or the actual approval of a generic version of patented drugs. Early working allows immediate marketing at the end of the patent period, equips the", "n_tokens": 242, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-334-2", "doc_id": "medicine_vaccine_book", "page": 334, "text": "7Presently, the World Trade Organization has 164 member countries, which constitute 99 percent of the world trade. 8Article 1 of the TRIPS Agreement. https://www.wto.org/english/docs_e/legal_e/27-trips.pdf. 9Ibid. 10Correa (2016). 11Mirandah (2012), p. 50. 12https://www.congress.gov/bill/98th-congress/senate-bill/01538. 13Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. https://www. accessdata.fda.gov/scripts/cder/ob/index.cfm. 14Son et al. (2018), p. 101. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201583/. 15Ellis (2019). https://geneva-network.com/article/patent-linkage/.\n\n331", "n_tokens": 220, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-335-0", "doc_id": "medicine_vaccine_book", "page": 335, "text": "332\n\nK. D. Raju\n\ngeneric companies to provide cheap drugs in developing countries without delay.16 This early working limited exception under Article 30 of the TRIPs Agreement does not infringe patented drug owners’ rights. Nonetheless, there is a concerted effort to introduce a link between the patent status of drugs and the regulatory approval of generic medicines in the recent past through regional and bilateral trade agreements. This paper argues that linking a generic drug’s market approval to its branded equivalent’s patent status is detrimental to access to medicines in developing coun- tries and least developed countries. It is argued that India and other developing countries should not statutorily link patent protection with marketing approvals of generic drugs, which is well beyond the TRIPs obligations. The backdoor entry of these provisions through regional trade agreements should be prevented to allow the production of cheap drugs for the developing world.", "n_tokens": 174, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-335-1", "doc_id": "medicine_vaccine_book", "page": 335, "text": "This paper analyses the legal regimes adopted to implement drug-related patent- linkage provisions, enforcement, and standard practices of 21 jurisdictions.17 The legal system of patent linkage countries (15 in number) and non-patent linkage countries (6 countries) is analyzed mainly in South-east Asian countries to under- stand these countries’ legal obligations and its implications in access to medicines. The Indian experience is examined carefully, along with compulsory licensing practice. Important judicial decisions are also analyzed to understand its effect on access to drugs. The paper concludes that linking patent rights with marketing approvals for generic medicines has far-reaching adverse consequences in develop- ing countries’ access to drugs. Patent linkage has an incentive for extending monop- oly rights beyond 20 years of the patent term and will negatively affect generic drugs’ entry after the expiry of patent rights. It is relevant to note that only 15 countries implemented patent linkage directly among the WTO Members,18 but regional trade agreements have patent linkage provisions, and their adoption will increase the number.19 All the countries with direct patent linkage provisions are included for a better understanding of the provisions.", "n_tokens": 233, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-335-2", "doc_id": "medicine_vaccine_book", "page": 335, "text": "16See Chapter 5. 17This include the US, EU, Canada, Australia, Japan, South Korea, China, Taiwan, Russia, Ukraine, Thailand, Philippines, Singapore, Malaysia, Indonesia, Vietnam, Thailand, Jordan, UAE, Peru and India. 18US, Canada, Japan, Australia, South Korea, China, Taiwan, Russia, Ukraine, Philippines, Singapore, Jordan, Mexico, UAE and Peru. 19Townsend et al. https://www.bilaterals.org/IMG/pdf/ssrn-id2850294.pdf.", "n_tokens": 118, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-336-0", "doc_id": "medicine_vaccine_book", "page": 336, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\n2 Perspectives on Patent Linkage\n\n2.1 US\n\nIn the US, patent linkage is included in the Drug Price Competition and Patent Term Restoration Act, 1984 (Hatch Waxman Act) to regulate the generic industry. Patent extensions are also allowed in the US for up to five years for qualifying patents.20 The patented drug must not have been infringed until expired or held invalid. However, the legislation also provides some benefits for the generic industry.21\n\nThe Act has passed with an objective of hassle-free approvals to generic drugs and unnecessary disputes with branded and patented drugs. Unfortunately, the multinational drug companies exploit the loopholes in the Act in favor of them to extend the patent protection.", "n_tokens": 161, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-336-1", "doc_id": "medicine_vaccine_book", "page": 336, "text": "In the US, the generic drug approval is linked to pioneer drug patents under the Hatch Waxman Act, 1984 through Orange Book, certification process, and a limited 180-day generic market exclusivity period for first generic applicants who challenge the validity of the patent or claim it would not be infringed under the Act’s Paragraph IV certificate system. Under the “patent linkage” provisions, the new drug applica- tion should include patent details, and the FDA reflects the existence of patents as part of the approval process for specific drug applications. If a valid patent exists, marketing approval will not be granted to a generic drug until the patent has expired or declared invalid by competent authorities. This generic marketing approval is “linked” to the expiration of the patented drug. Such patent information can be published in “Orange Book.” This Book lists approved drugs, discontinued drugs, and patent and exclusivity information. It is argued that the patent linkage system\n\n20West and Allison Hoppert. https://www.oblon.com/A11960/assets/files/News/125.pdf. 21They can be summarized as follows:\n\n(cid:129) Generic drugs need not prove their safety and efficacy but must demonstrate the product’s bioequivalence to the original patented drug. This will reduce the cost and delay of clinical trials of generic medicines.", "n_tokens": 303, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-336-2", "doc_id": "medicine_vaccine_book", "page": 336, "text": "(cid:129) Generic drugs are granted 180 days of exclusivity limited to the first generic entrant who files a paragraph IV certification and thereby challenges the patent’s validity or claims that it will not be infringed.\n\n(cid:129) Abbreviated New Drug Application (ANDA) applicant is not required to produce independent evidence of the generic drug’s safety and effectiveness. He has to prove also that the generic drug is bio-equivalent to reference listed drug (RLD). If the applicant submits a paragraph I or II certification, the patent in question will not delay ANDA approval. If the applicant submits a paragraph III certification, the applicant agrees to wait until the relevant patent has expired before seeking the ANDA’s final approval.\n\n(cid:129)\n\n(cid:129)\n\n(cid:129) Paragraph IV certification does not survive the expiry of a listed patent. In making paragraph IV certification, the generic drug maker says he believes that the patented drug is invalid, not infringed, or unenforceable. If the NDA holder brings a suit for infringement, the FDA can’t approve it for 30 months or whenever the court determines the issue.\n\n(cid:129)\n\n333", "n_tokens": 272, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-337-0", "doc_id": "medicine_vaccine_book", "page": 337, "text": "334\n\nK. D. Raju\n\nincreased the efficiency and productivity of the research and development sector of a generic company and patent holder company. However, generic drug approvals are vital for developing countries in curing pandemics.\n\nStudies have revealed that generic drug approval applications were late by 30 months due to patent linkage provisions and the infringement litigation.22 These infringement cases increase the cost of drugs, and the generics lost the right to enter the market during the stay period. S.156 provides for patent term extension up to five years if certain conditions are met like any patent term adjustment granted under section 154(b).23", "n_tokens": 129, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-337-1", "doc_id": "medicine_vaccine_book", "page": 337, "text": "The Act’s misuse includes “reverse payments” from originator companies to generic companies during the 180 days exclusive period not to enter the market. This is popularly known as the “pay-for-delay” program adopted by the originator companies. The FTC has taken a strong exception to this anti-competitive practice and believes that such practices are per-se illegal. To stop this practice, Congress passed the Medicare Prescription Drug Improvement Modernization Act, 2003. This Act stipulates that within ten days of reverse settlements, companies to register such settlements with FTC.24 As per the FTC estimate, consumers lost $3.5billion higher drug cost every year due to this “pay-for-delay” tactics of the originator compa- nies.25 But in some cases like in In re Tamoxifen Citrate Antitrust Litig.,26 the Second Circuit rejected the per se rule and held that reverse payment settlements do not violate anti-trust laws if they fall within the exclusionary zone of the patent. But the US Supreme Court, in a landmark judgment, FTC v. Actavis,27 held that the pay-for-delay practice of originator companies for settling patent disputes with generics and delay in entering the market could have significant anti-competitive effects and violate anti-trust laws.28", "n_tokens": 278, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-337-2", "doc_id": "medicine_vaccine_book", "page": 337, "text": "Patent linkage is similar to that of the branded drug companies’ pay-for-delay program to delay the entry of generics into the market. Thus access to cheaper medicines is denied in developed and developing countries if patent linkage or similar provisions are implemented.\n\nOther tactics used by the originator companies, including asking the FDA to take action on any ANDA application under “Citizen Petition” provision, will likely delay the generic version of drugs. FDA has to take a decision not longer than 150 days. Again, this will delay the generic entry for another 150 days, and\n\n22Winkler et al. (2018). https://www.finnegan.com/en/insights/requirements-benefits-and-possible- consequences-of-listing-patents-in-fdas-orange-book.html. 23Merc & Co.Inc v. High Tech Pharmaceuticals Inc,, US Court of Appeals No. 2006-1401, decided on March 29, 2007. 24Meagher (2017), p. 589. Available at: https://brooklynworks.brooklaw.edu/bjcfcl/vol11/iss2/12. 25Pay for Delay, Federal Trade Commission. https://www.ftc.gov/news-events/media-resources/ mergers-competition/pay-delay. 26466 F.3d 187, 228 (2d Cir. 2006). 27570 US. 136, 2013. 28Decided on June 17, 2013, https://www.supremecourt.gov/opinions/12pdf/12-416_m5n0.pdf.", "n_tokens": 348, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-338-0", "doc_id": "medicine_vaccine_book", "page": 338, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\noriginators can file multiple, successive petitions. Another methodology adopted by the branded companies is “product hopping” or “forced Switch schemes.” These are branded companies’ strategies to come up with alternative versions of the medicine shortly before the patent expiry with the effect of withdrawing the existing product registration, which might be thwarted registration of the generic equivalent. A patient who is using a particular branded medicine has the least possibility of switching to a new generic drug; instead, continue with the altered version of the branded drug. Thus, they were compelled to use essentially the same medicine with the same company for a higher price; this maintains the originator company’s monopoly for a more extended period than prescribed. Since the decision in Actavis by the US Supreme Court, the number of pay-for-delay cases has been decreased.29\n\n2.2 EU", "n_tokens": 188, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-338-1", "doc_id": "medicine_vaccine_book", "page": 338, "text": "The EU does not follow the patent linkage system. But at any time, the patent holder can get an injunction against any infringement throughout Europe. EU believes that any tinkering with the bolar provision through patent linkage will delay the entry of generic drugs into the European market.30 EU directives do not prohibit experimenting with any patented drug during the patent term and generating test data, which can be submitted to the regulatory authorities for marketing approval.31 EU’s Pharmaceutical Sector Inquiry preliminary report of November 28, 2008, accounts that 700 patent litigations were filed to prevent or delay the entry of registered generic drugs into the market.32\n\nThe European Medicines Agency is responsible for the marketing approvals of a generic drug in the EU.33 Article 81, Regulation No.EC726/200434 and Article 126 of Directive EC 2001/83 laying down community procedures for authorization of medicinal products.35 EU believes that patent linkage provisions are beyond the TRIPs obligations and not desirable in the EU. The bolar rule is strictly implemented", "n_tokens": 207, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-338-2", "doc_id": "medicine_vaccine_book", "page": 338, "text": "29Michael Carrier FTC v. Actavis: Where We Stand After 5 Years, 18 June 2018. 30Article 10.6. of Directive 2001/83/EC as amended). 31Data Exclusivity/Patent Linkage in the Context of EU Generic and Biosimilar Applications. Presentation by Suzette Kox at the WIPO Life Sciences Symposium: Intellectual Property and Life Sciences Regulation, 16 November 2017. https://www.wipo.int/export/sites/www/meetings/en/ 2007/lifesciences/sym_regulation/lss3_ge_07_kox.pdf. 32European Commission (2008). https://ec.europa.eu/competition/sectors/pharmaceuticals/inquiry/ preliminary_report.pdf. 33European Medicines Agency Generic and Hybrid Medicines. https://www.ema.europa.eu/en/ human-regulatory/marketing-authorisation/generic-hybrid-medicines. 34https://ec.europa.eu/competition/sectors/pharmaceuticals/archive/4_Regulator_framework.pdf. 35https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2004_726/reg_2004_726_ en.pdf.\n\n335", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-339-0", "doc_id": "medicine_vaccine_book", "page": 339, "text": "336\n\nK. D. Raju\n\nin the EU through Article 10.6 of Directive 2001/83/EC as amended.36 Generic companies are applying for marketing approval to demonstrate that it is bioequiva- lent to the originator product. For that, the generic companies can refer to the test data submitted by the originator companies. The test data provided by the originator firms will get data exclusivity period for eight years, but during the additional two-year market exclusivity provision, generic producers can early work and apply for marketing approval.37 Moreover, the EU practices a maximum of five years of extension based on the Supplementary Protection Certificate (SPC). Sub- mission of generic biosimilar applications only possible after the data exclusivity period.38", "n_tokens": 166, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-339-1", "doc_id": "medicine_vaccine_book", "page": 339, "text": "In 2012, the European Commission39 formally asked Italy to remove patent linkage provisions outlined in Law No 30 of 2005 (the IP Code), namely paragraph 1-bis of Article 68 containing a clear patent linkage., which harm and delay the entry of generic medicines in the market.40 The provision allows generic drug manufac- turers to start the drug registration process only during the “last year” of the patent or supplementary protection certificate’s validity. The Italian provision violated Article 10 of Directive 2001/83/EC in the community code relating to medicinal products. In 2012, Law No. 27/2012 made the Italian law in compliance with the EU Regulation. Now the marketing authorization application for a generic drug can be filed more than one year before the patent or supplementary protection certificate expiry. But manufacture, import, or sale of the drug would be considered as an infringement. But Law No. 189/2012 excluded generic drugs from the National Health Care Service. It means that generic drugs cannot be listed for reimbursement until the patent is expired. But in the name of secondary patents, the generics have to wait until its expiry as well.41\n\nOn 1 July 2019, Regulation UE 2019/933 introduced some amendments to the previous Regulation (EC) 469/2009 concerning the SPC, setting forth a waiver", "n_tokens": 283, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-339-2", "doc_id": "medicine_vaccine_book", "page": 339, "text": "36https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_ 2001_83_cons_2012_en.pdf. 37Medicines and Law Policy (2019). https://medicineslawandpolicy.org/wp-content/uploads/2019/ 06/European-Union-Review-of-Pharma-Incentives-Data-Exclusivity.pdf. 38Data Exclusivity/Patent Linkage in the Context of EU Generic and Biosimilar Applications. Presentation by Suzette Kox at the WIPO Life Sciences Symposium: Intellectual Property and Life Sciences Regulation, 16 November 2017. https://www.wipo.int/export/sites/www/meetings/en/ 2007/lifesciences/sym_regulation/lss3_ge_07_kox.pdf. 39Daniela Ampollini (Trevisan & Cuonzo) (2011). http://patentblog.kluweriplaw.com/2011/04/08/ patent-linkage-infringement-proceedings-by-the-european-commission-against-italy/. 40Intellectual Property Watch (2012). https://www.ip-watch.org/2012/01/31/european-commis sion-orders-italy-to-drop-patent-linkage-delaying-generics/. 41Decision of the Regional Administrative Court of Rome on January 2018 (T.A.R. Lazio, sez. III, - Roma, 19 January 2018, No 662).", "n_tokens": 374, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-340-0", "doc_id": "medicine_vaccine_book", "page": 340, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nunder certain conditions to export such manufactured drugs outside the EU jurisdictions.42\n\nOther EU countries like Hungary, Portugal, and Czech are trying to establish different kinds of linkages with patents.43 Italy and Belgium have restrictions on the reimbursement by National Health Service on drugs that infringe third-party patents. In Hungary and Egypt, declarations of non-infringement are sought by applicants at the time of filing.\n\nThe introduction of patent linkage would increase litigation frequency in patent enforcement and delay generics’ entry in the EU market.44 The EU Council of Ministers expressed concern over very high, unsustainable drug prices in the EU.45 The FDA style patent linkage cannot be implemented in the EU because there is no single patent in the entire EU jurisdiction. Instead, it is a bundle of patents filed in the European Patent Office (EPO). However, in the Italy case, the European Commission made it clear that patent linkage delays the entry of generic medicines and a clear abuse of the EU regulatory system.46 Patent linkage is considered illegal in the EU under Regulation (EC) No 726/2004 and Directive (EC) No 2001/83).47", "n_tokens": 259, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-340-1", "doc_id": "medicine_vaccine_book", "page": 340, "text": "2.3 Canada\n\nIn 1993 Canada first adopted a patent linkage system closely patterned on US law. These regulations were adopted to ensure that the early exception is not abused by generic drug applicants seeking to sell their products during the patent term. Notice of compliance provisions is similar to that of the Hatch – Waxman Act. Canada also keeps a Patent Book like Orange Book. Notice of allegation (NOA) and notice under Paragraph IV of the HW Act are similar. The statutory stay of approval in Canada is 24 months, and it is 30 months in the US. In 2017, significant amendments were made to the Patented Medicines (Notice of Compliance) Regulations1993 align with Canada’s the (PM-NOC-amended)\n\nto\n\nobligations", "n_tokens": 156, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-340-2", "doc_id": "medicine_vaccine_book", "page": 340, "text": "under\n\n42https://practiceguides.chambers.com/practice-guides/patent-litigation-2020/italy/trends-and- developments#:~:text¼The%20European%20Union%20does%20not,advance%20of%20the% 20patent%20expiration. 43Research Report on Establishing System of Linking New Drug Application and Patent Protection, BIPI Research (2016) No. 002. http://www.theglobalipcenter.com/wp-content/uploads/2017/03/ full-report-E.pdf. 44European Generic Medicines Association (2008). 45Catherine Drew (2017). https://www.pinsentmasons.com/out-law/analysis/eu-unlikely-to-fol low-us-with-patent-linkage-system-says-expert. 46Intellectual Property Watch (2012). 47Pharmaceutical Sector Inquiry – Preliminary Report, Fact Sheet “Regulatory Framework”. https://ec.europa.eu/competition/sectors/pharmaceuticals/archive/4_Regulator_framework.pdf.\n\n337", "n_tokens": 258, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-341-0", "doc_id": "medicine_vaccine_book", "page": 341, "text": "338\n\nK. D. Raju\n\nCanada-European Union Comprehensive Economic (CETA).48 The changes in the amendments can be summarized below:\n\nand Trade Agreement\n\n1. The Minister of Health was given the power to maintain the Patent Register. 2. Generic or bio-similar manufacturers are required to serve a notice of allegation (NOA).\n\n3. All NOAs need to include a searchable electronic copy of the second person’s drug submissions and copies of documents to be submitted.\n\n4. First-person cannot seek a prohibition order against the Minister of Health. 5. First-person, who brings an action under the law, will be able to renounce the 24-month stay.\n\n6. An un-successful action for patent infringement under the law, the second person will be able to sue all the plaintiffs for section 8 damages.49\n\nIt is worth noting that Canada introduced a Bolar exception provision in 1991.50 Section 55.2 of the Act provides for two exceptions to patent infringement. These are “early working” and “stockpiling” exceptions. EU filed a case in the WTO dispute settlement against this provision. In the year 2000, the Panel held that the early working provision did not violate the TRIPs agreement.51 However, the Panel held that the manufacturing and stockpiling of drugs in the last six months of the patent expiry term violate the Agreement. Later on, the stockpiling provision was repealed.", "n_tokens": 294, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-341-1", "doc_id": "medicine_vaccine_book", "page": 341, "text": "2.4 Australia\n\nAustralia effectively implemented patent linkage through Section 26B of the Ther- apeutic Goods Act 1989 and AUSFTA and consequent legislation, the US Free Trade Agreement Act, 2004. The generic companies seeking marketing approval must provide a patent certificate stating that the generic did not infringe any originator drug patents and notice the patentee.\n\nIf the generic drug infringes, no marketing approval will be granted. Moreover, an injunction will be issued, which will delay generic entry for another three years.52 The Australian courts are generally in favor of patentees, and permanent injunctions are usually granted to the originators.53\n\n48https://laws-lois.justice.gc.ca/eng/regulations/sor-93-133/index.html. 49White et al. linkage-regulations-get-long-await. 50Correa (2016). 51WT/DS114/R. 52Palombi (2014). http://theconversation.com/its-time-to-fix-the-free-trade-bungle-on-the-cost-of- medicines-32574. 53Managing IP (2019). https://www.managingip.com/Article/3865388/Australia-Protecting-phar maceutical-market-share-in-Australia.html.\n\n(2017). https://www.osler.com/en/resources/regulations/2017/canada-s-patent-", "n_tokens": 330, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-342-0", "doc_id": "medicine_vaccine_book", "page": 342, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nThe patent linkage provision is included under Section 26B of the Therapeutic Goods Act 1989.54 An applicant seeking marketing approval of a generic or biosimilar medicine must certify either that:\n\n(i) it will not market the drug in a manner that would infringe a valid patent or; (ii) It has notified the rights holder of their intention to market the drug before the", "n_tokens": 99, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-342-1", "doc_id": "medicine_vaccine_book", "page": 342, "text": "patent term expiry.55\n\nHowever, Australia claims that there is no administrative patent linkage in the country—after the potentially infringing applicant’s notice, the patent holder must sue to protect its rights.56 Permanent injunctions are an effective way for originators to prevent generics from entering the market. The Australian High Court considered the question in Aktiebolaget Hassle v. Alphapharm Pty. Ltd.57 Evergreening and linkage of the patent were discussed by the Court in this case and discussed how the patent owners use a regulatory process to extend their blockbuster drugs patent term for rent-seeking. The linkage-form of evergreening is the new method developed by the drug companies following the US Hatch – Waxman legislation. The companies try their luck in other jurisdictions even though there are no patent linkage provisions in Australia.58 The Astra group filed a patent infringement case against a generic drug manufacturer, Alphapharm, who started importing the drug to the Australian market at the end of the patent term. Justice Kirby, in his judgment, observed the tactics of the originators to delay the generic entry even after the patent term, in its most persuasive words:", "n_tokens": 246, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-342-2", "doc_id": "medicine_vaccine_book", "page": 342, "text": "The strategies that large pharmaceutical manufacturers have employed to avoid such generic competition, which include the use of intellectual property law, have been detailed else- where. They are attracted to the attention and response of the Federal Trade Commission in the United States. Such battles have had their counterparts in many other countries. They present serious issues for the developing world...in its interpretation of the legislation, and in identifying the proper approach to the ultimate factual determination of obviousness called for by that statute, this Court should avoid creating fail-safe opportunities for unwarranted extensions of monopoly protection that are not sustained by law.59\n\nAUSFTA, Article 17.10.04, provides that the branded drug manufacturer would be informed of an anticipated product.60 The regulatory process and marketing approval for generic pharmaceuticals would be connected with patent infringement status through this provision. It is also required to notify the patent holder of any", "n_tokens": 181, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-342-3", "doc_id": "medicine_vaccine_book", "page": 342, "text": "54Australian Government, About the Australian therapeutic goods legislation. https://www.tga.gov. au/about-australian-therapeutic-goods-legislation. 55Son et al. (2018). 56DrugPatentWatch Patent linkage: Balancing patent protection and generic entry https://www. drugpatentwatch.com/blog/patent-linkage-resolving-infringement/. 57(2062) HCA 59, 12 December 2002. 58Faunce and Lexchin (2007). https://anzhealthpolicy.biomedcentral.com/articles/10.1186/1743- 8462-4-8. 59Aktiebolaget Hassle v. Alphapharm Pty Ltd, 212 CLR 411, para 101 2002. 60Faunce and Lexchin (2007).\n\n339", "n_tokens": 181, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-343-0", "doc_id": "medicine_vaccine_book", "page": 343, "text": "340\n\nK. D. Raju\n\ngeneric marketing approval application.61 Originators have used the preliminary injunction route for successfully stalling the entry of generics in the market. The high degree of proof is with the generic industry to prove that they are not violating any patents. Besides, AUSFTA provision 17.10.4(b) required that the patent holder be notified of a generic marketing approval application. This provision is criticized as an attempt to delay the entry of generic medicines in the Australian market.62\n\n2.5", "n_tokens": 107, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-343-1", "doc_id": "medicine_vaccine_book", "page": 343, "text": "Japan\n\nEven though Japan directly did not implement the patent linkage system, the de-facto patent linkage system was implemented through a government regulation to approve generic drugs.63 During the active patent validity period, no generic approval will be granted.64 The patent linkages are secured in two stages of regula- tory approval and drug price listing.65 If there is a delay in getting marketing approval of the patented drug, the duration can be stretched for a period of up to five years.66\n\nAfter an amendment to the Patent Act in 2018, the patentee can claim patent extension if it is granted after five years of application. The patent extension term will mostly depend upon the period in which the originator is unable to use the patented drug during a marketing approval process. Japan also keeps a US-style Orange Book67 and patent linkage.68 The Minister will not approve any generic drug when a patent right prevents the generic drug from being marketed.69 However, under the price regulation system, the drug prices in Japan are determined by the state.", "n_tokens": 213, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-343-2", "doc_id": "medicine_vaccine_book", "page": 343, "text": "Any dispute between originator drug manufacturers and generic manufacturers\n\nmust be reported to the Ministry of Health, Labor and Welfare.\n\n61AUSFTA Article 17.10.4(b). 62Faunce and Lexchin (2007). 63IP Litigation in Life Sciences – Costs, Duration and Enforceability in Japan. Presentation by Yoichi Okumura, Global Head of IP, Takeda Pharmaceutical Company Limited. WIPO Conference on IP Dispute Resolution in Life Science, 22 May 2015. https://www.wipo.int/export/sites/www/ amc/en/docs/basel2015_okumura.pdf. 64Abe (2019). https://www.managingip.com/Article/3888280/Japan-What-impact-do-generic- drugs-have-on-the-Japanese-market.html. 65https://system.jpaa.or.jp/patent/viewPdf/3066. 66Law No. 145 of 1960. 67Approved Drug Products with Therapeutic Equivalence Evaluations. 68Notification No. 0605001 of the Economic Affairs Division, Health Policy Bureau of 2009 and Notification No. 0605014 of the Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau of the Ministry of Health, Welfare and Labour of 2009. 69Koizumi et al. (2011). https://www.amt-law.com/asset/res/news_2011en_pdf/110225_2055.pdf.", "n_tokens": 325, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-344-0", "doc_id": "medicine_vaccine_book", "page": 344, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nthe Patent Act 2006 (Amended).70 Tests conducted during the patent term for submission to the regula- tory approval is not an infringement under the Japan patent law.71\n\nJapan allows\n\nexperimentation exemption under\n\nPrice competition between originator drug and generic drug is significantly less in Japan due to state price control. Reverse payments are considered as an anti- competitive activity in Japan. Unlike the US, the ANDA 180-day exclusivity to the first filer is not available in Japan. All these measures show that patent linkage is not so intense that compared to the US. Nevertheless, Japan is a party to the RCEP Agreement and may be forced entirely to implement patent linkages if these are included in the final agreement.", "n_tokens": 168, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-344-1", "doc_id": "medicine_vaccine_book", "page": 344, "text": "2.6 South Korea\n\nSouth Korea is another country that implemented the patent linkage system, in line with the US Hatch-Waxman Act of 1984. This was done through a back door of the US – Korea Bilateral Free Trade Agreement signed in 2007,72 entered into force in 2012 (Article 18.9.5 – IP Chapter).73 The amendment introduced the patent list and the notification system. In addition to that, the government implemented a nine- month stay on marketing approval and nine-month first generic exclusivity in 2015. It was reported that the amendment increased the number of patent challenges as well as marketing approvals related litigations.74 According to the Agreement, Korea agreed to the following additional commitments over and above the TRIPs agreement: (cid:129) Extended patent term to compensate for the patent prosecution delays from the\n\nKorean Intellectual Property Office and other regulatory review delays.\n\n(cid:129) Data exclusivity should be granted for efficacy information submitted to support a\n\nprior approved drug (three years) or newly approved drug (five years).\n\n(cid:129) Patent linkage provision informing patentees of an applicant’s identity before\n\ngranting marketing approval of a generic drug.\n\n(cid:129) Marketing approval will not be granted for a generic drug without the original", "n_tokens": 271, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-344-2", "doc_id": "medicine_vaccine_book", "page": 344, "text": "patent owner’s consent during the valid patent period.\n\nThe South Korean Pharmaceutical Affairs Act permits clinical test data submitted by originators to be used by generic drug manufactures seeking marketing approval. Korean patent listing is also strictly policed by MFDS, and it allows Korean generic\n\n70www.japaneselawtranslation.go.jp. 71Ono Pharmaceuticals Co., Ltd. v. Kyoto Pharmaceuticals Industries, Ltd. Judgment dated 16 April 1999. 72Son et al. (2019). 73See Raley (2019a), pp. 459–492. 74Son and Lee (2017), pp. 1169–1178.\n\n341", "n_tokens": 134, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-345-0", "doc_id": "medicine_vaccine_book", "page": 345, "text": "342\n\nK. D. Raju\n\nmanufacturers to institute administrative hearings before the patent hearing. The branded companies must petition MFDS for the stay of generic drug sales, and the stay lasts for nine months, but the branded manufacturers to obtain a stay of generic drug FDA approval for up to 30 months like in the US.75 South Korea also provides patent term extension up to five years for pharmaceuticals and agrochemicals. South Korea is a part of RCEP negotiations. The leaked Korean RCEP draft on IP provides for patent term extension for unreasonable delays in granting patents. Unreasonable delay is defined as the delay for more than four years from the date of filing of the application or three years after the request for examination of the application, whichever is later [Article X.D.1.4(a)].76", "n_tokens": 168, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-345-1", "doc_id": "medicine_vaccine_book", "page": 345, "text": "2.7 China\n\nThe Administrative Measures for Drug Registration 2002 provides for the protection of patent rights related to drugs. The applicant has to prove the patent status and declare that it did not infringe on any patents. Attempts were made in 2005 and 2007 to include patent linkage provisions but are never happened until 2017.\n\nIn 2017, the Chinese Communist Party proposed reforms in the medical device approval system and issued Reform Opinion (Order No. 55) to implement the US model patent linkage system in drug regulation.77 China implemented “bolar exemp- tion” provisions through patent amendments laws in 2008, known as the “Naked Bolar Exemption.”78 Article 16 of “Opinion on Deepening Approval and Review System Reform and Encouraging Innovation of Drug and Medical Apparatus” of 2017 describes the patent linkage system in China. It includes notifying the relevant patentee of the generic drug and patent term adjustment system’s marketing approval process. The long term review process and delays will be compensated through a reasonable extension of the patent period. However, the Chinese new Drug Admin- istration Law, 2019, took effect from December 1, has a patent linkage provision.79 The new law provides for a nationwide drug marketing authorization holder sys- tem.80 The Chinese model of Orange book now has more than 131 drugs as well.81\n\nOrder 55 provides for the following:", "n_tokens": 278, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-345-2", "doc_id": "medicine_vaccine_book", "page": 345, "text": "75Raley (2019b). 76Townsend et al. https://www.bilaterals.org/IMG/pdf/ssrn-id2850294.pdf. 77Chen and Shi (2017), pp. 1484–1487. 78Article 69. 79China IPR (2021). https://chinaipr.com/category/patent-linkage/. 80Global Legal Monitor (2019). https://www.loc.gov/law/foreign-news/article/china-drug-adminis tration-law-revised/. 81Zhang et al. linkage/.\n\n(2018). http://patentblog.kluweriplaw.com/2018/04/03/china-establish-patent-", "n_tokens": 176, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-346-0", "doc_id": "medicine_vaccine_book", "page": 346, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\n1. A generic drug applicant shall notify the known patents at the time of drug filing. 2. If the drug applicant challenges a patent, it should declare that his drug does not infringe on any patent.\n\n3. The patent owner should start patent infringement proceeding within 20 days after the drug filing.\n\n4. The CFDA has the discretion to make the application pending for 24 months before drug approval.\n\n5. If there is no judicial remedy within the waiting period of 24 months, CFSA can\n\n6. If there is any infringement suit after the generic drug’s approval, it will be subject to the judicial decision’s outcome.\n\n6. If there is any infringement suit after the generic drug’s approval, it will be subject to the judicial decision’s outcome.\n\nOn 15th January 2020, China and the US signed an Economic and Trade Agreement to ease trade between the countries required to build a patent linkage and patent term restoration system in China.82 Article 1.12 of the agreement provides for patent extensions in case of unreasonable delays while examining the patent application and delays in marketing approvals. The excessive delay means more than four years from filing or three years from requesting examination. The patent validity can be extended by a maximum of five years in case of marketing approval delays.83 China was an active participant in the RCEP negotiations on patent linkage.84", "n_tokens": 295, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-346-1", "doc_id": "medicine_vaccine_book", "page": 346, "text": "2.8 Taiwan\n\nTaiwan has implemented a patent linkage system from 20 August 2019 following the amended Pharmaceutical Affairs Act. A new chapter of “Patent Linkage of Western Pharmaceuticals” was added to the law.85 The new generic drug manufac- turers seeking marketing approval of generic drugs has to submit a declaration that the new drug is not patented, or the patent has expired, or the approval must be given after the expiry of the patent, or the patent on the new drug is not valid or not infringed by the generic drug. Patent listing has to be made through online systems under the Taiwan Food and Drug Administration (TFDA). Patentees to upload information about originator drugs within 45 days form the approval of the TFDA.\n\n82BRIEF—China progressing drug-related patent laws, The Pharma Letter, 22 April 2020. https:// www.thepharmaletter.com/in-brief/brief-china-progressing-drug-related-patent-laws. 83Reddie & Grose LLP (2020) https://www.reddie.co.uk/2020/01/23/what-does-the-us-china- trade-deal-mean-for-pharmaceutical-patent-holders/. 84Li and Tong (2018), pp. 270–280. See also https://www.bilaterals.org/IMG/pdf/ssrn-id2850294. pdf. 85Reddie & Grose LLP (2020) https://www.reddie.co.uk/2020/01/23/what-does-the-us-china- trade-deal-mean-for-pharmaceutical-patent-holders/.\n\n343", "n_tokens": 366, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-347-0", "doc_id": "medicine_vaccine_book", "page": 347, "text": "344\n\nK. D. Raju\n\nThe originator can file infringement suits within this period and delay a generic drug’s approval for up to 12 months.86\n\n2.9 Russia\n\nPresently there is a positive trend towards the implementation of linkage in Russia. The Russian Civil Code provides a patent owner to file a claim to cease any activities that infringe the patent, including marketing approvals for the generics. Infringing activities include offering to sale, producing, storing, or distributing a general medicine. Threatening of infringement, obtaining marketing approvals, and regis- tering maximum sales price provided that the relevant patent is used to manufacture the generic. The marketing authorization will be canceled if the generic is not presented in the Russian market for three or more years. If the generic drug is already in the market, the originators try to get a judgment from the court in their favor and refer the matter to the Ministry of Healthcare for canceling the marketing approval.", "n_tokens": 194, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-347-1", "doc_id": "medicine_vaccine_book", "page": 347, "text": "Russia is a member of the Eurasian Economic Union (EAEU) rules, which entered into force in 2017. The EAEU rules stipulate that the application for generic marketing approval must include information on patents covered and a statement to the effect that the medicine does not infringe on any parties’ intellectual property rights. Submission of inaccurate information is a ground for revocation of marketing approval of the generics. From the year 2021, national legislation has to include all obligations under EAEU rules, including patent linkage. In April 2019, Russia launched state registration of drugs and pending applications before MoH.87\n\nIn a 2018 Judgement by the Russian Intellectual Property Court dated 24 April 2018, it was held that preparations to launch a generic drug three years before the expiry of the patent constitutes a threat of patent infringement.88 This decision overrules an earlier position that Russian law does not recognize generic drugs’ registration during the patent validity term as an act of infringement (Art. 1359 (2) of the Russian Civil Code.89\n\nThe MoH has prepared an amendment to the Law on Drugs, which states that “any company seeking to register a new drug (original or generic) shall indicate all patents and trademarks relevant for this new drug. Another obligation is to warrant that registration of this new drug would not infringe any third party’s intellectual rights, under the risk of penalties.”90", "n_tokens": 283, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-347-2", "doc_id": "medicine_vaccine_book", "page": 347, "text": "86Celebrating the Start of Patent Linkage, Taiwan Business TOPICS, 9 September 2019. https:// topics.amcham.com.tw/2019/09/celebrating-patent-linkage/. 87https://grls.rosminzdrav.ru/StatementRUInfo.aspx. 88Case No. А41-85807/2016. http://www.lidings.com/eng/legalupdates2?id¼388. 89Decision of the Supreme Commercial Court in case No. A40-65668/2008, dated 06.16.2009. 90Malakhov (2019).", "n_tokens": 145, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-348-0", "doc_id": "medicine_vaccine_book", "page": 348, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...", "n_tokens": 16, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-348-1", "doc_id": "medicine_vaccine_book", "page": 348, "text": "2.10 Ukraine\n\nIn Ukraine, Article 9 of the Ukrainian Law on Medicines and Drugs, 199691 pro- vides that marketing approval of a generic drug before the expiration of the origi- nator’s drug patent may be considered a violation of the patent owner’s rights. Medicinal products shall be allowed only after registration with the Ministry of Health (MoH).92 A generic applicant has to file a guarantee that the generic drug is not infringing any patented drugs. Patent infringement is a ground for the cancella- tion of marketing approval of generic drugs.\n\nArticle 34 of the Ukrainian Law on the Protection of Rights to Inventions93 provides that the manufacturing and selling of generic drugs before the expiration of the originator drug’s patent may be considered patent infringement. But it is not clear whether an application for marketing approval itself violates a patent or is regarded as an infringement. However, at the same time, a valid patent is not a guarantee for refusing a marketing approval for a generic drug by the MoH. As the patent linkage is not fully implemented in Ukraine, the originator patent owners have to monitor the marketing approvals and subsequently file patent infringement suits against generic drug applicants and cancel the marketing approval and issuance of an injunction.94 It is also to note that in Ukraine, there is no bolar provision available in any legislation for the early production of the generic drug before the expiry of the patent term.", "n_tokens": 299, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-348-2", "doc_id": "medicine_vaccine_book", "page": 348, "text": "Ukrainian law provides that the applicant for marketing approval must submit a sample of medicine to state regulatory bodies as part of the marketing authorization procedure. Production of such a sample of the drug itself will also be considered as patent infringement without any difference, whether it was just a non-commercial medicine production or not.95\n\nThe Ukrainian Supreme Court made vital observations on disputes between originator and generic drug manufacturers in Merck Sharp & Dohme Corp v. Aurobindo Pharma Limited., and granted injunctions against the generic manu- facturers.96 The court of appeal clarified that state registration of the pharmaceutical, as well as any preparatory actions without the actual placing of the product on the market, are not included in the concept of “use” of a patented invention within the", "n_tokens": 161, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-348-3", "doc_id": "medicine_vaccine_book", "page": 348, "text": "91No. 123/96BP, 4 April 1996. 92https://www.wto.org/english/thewto_e/acc_e/ukr_e/WTACCUKR139_LEG_8.pdf. 93LAW OF UKRAINE on the Protection of Rights to Inventions and Utility Models https:// ukrpatent.org/i_upload/file/law-special-1.pdf. 94H.Lundbeck A/S v.Farmak JSC, http://reyestr.court.gov.ua/Review/3683167. In this case the patent holder, Lundbeck, brought a claim because Farmak started the procedure to prepare the launch of a generic medicine while the patent was still in force. The court issued an injunction against, inter alia, the production, sale and offering for sale and the launch of the marketing authorization process. 95H. Lundbeck A/S v Chemo Iberica, S.A., http://www.reyestr.court.gov.ua/Review/10026637. 96Ukraine: Interim injunctions in pharma cases, Vasil Kisil & Partners. Lexology https://www. lexology.com/library/detail.aspx?g¼0eb0c844-233d-4988-9774-efffe9ebcabd.\n\n345", "n_tokens": 310, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-349-0", "doc_id": "medicine_vaccine_book", "page": 349, "text": "346\n\nK. D. Raju\n\nmeaning of Article 28(2) of the Law of Ukrainian Law, “On Protection of Rights to Inventions and Utility Models.” The Supreme Court dismissed the Court of Appeal’s order and upheld the ruling of the court of the first instance that refused to prohibit Aurobindo pharma from placing the drug on Ukraine’s market.97 Mostly the courts are in granting injunctions against marketing approval of generic medicines and favor originator companies.98", "n_tokens": 99, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-349-1", "doc_id": "medicine_vaccine_book", "page": 349, "text": "2.11 Thailand\n\nPresently there are no patent linkage laws applicable in Thailand. However, in 2017, Thailand constituted a committee to monitor various agencies, including the Food and Drug Administration (FDA) and 15 other governmental agencies. It establishes a clear linkage between agencies involved in the enforcement of IP, especially the Department of Intellectual Property (DIP) and FDA, indirectly.99\n\nThe FDA imposed a condition that all applicants of a new drug must fill a form listing all existing patents. Section 80 is included in the draft 2018 amendment to the Drug Act 1967.100 This is a mandatory requirement from generic drug manufacturers to find out possible infringement.101 Thailand wants to be part of the 11 member TPP agreement, but the discussions stalled due to the COVID-19 pandemic.102 The Pharmaceutical Affairs Act was amended and taken effect from 13 October 2019.103 Amendment to Section 80 provides for a “new drug or a new traditional drug applicant would be required to include documents showing patent/petty patent rights (Patent Information) or rights related to traditional Thai medicinal wisdom for regulatory approval of a drug.”104 This will formalize a system since 2008; the FDA has required that all applicants for a new drug fill out a form listing all of their", "n_tokens": 252, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-349-2", "doc_id": "medicine_vaccine_book", "page": 349, "text": "97Judgment dated 14 August 2018. (http://reyestr.court.gov.ua/Review/75896089). 98Polikarpov (2015). http://patentblog.kluweriplaw.com/2015/02/19/bolar-provision-in-ukraine- fiction-or-reality/. 99https://www.tilleke.com/resources/ip-linkage-thai-government%E2%80%99s-efforts-connect- agencies. 100Baker McKenzie, Thailand: Proposed Addition to Drug Act - Move Towards Patent Linkage Concept. https://www.lexology.com/library/detail.aspx?g¼f19da913-6e8d-4498-8d4e- 8b5f53da695e. 101Bangkok Post 80%99s-efforts-connect-agencies. 102Bangkok Post, February 17, 2020. https://www.bangkokpost.com/business/1859454/thailand- to-decide-on-trade-pact-around-april-japan-minister. 103Drug Act (No. 6), B.E. 2562 (AD 2019). https://www.lexology.com/library/detail.aspx? g¼8f66805c-64eb-49e1-87cc-25f6c716feb0. 104Baker McKenzie, Thailand: Proposed Addition to Drug Act.\n\n(2017). https://www.tilleke.com/resources/ip-linkage-thai-government%E2%", "n_tokens": 368, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-350-0", "doc_id": "medicine_vaccine_book", "page": 350, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nexisting patents.105 The Patent Act allows the patent owner to take criminal and civil actions against infringers. The penalty for infringement is not more than two years imprisonment or a fine up to THB 400,000.106\n\n2.12 Philippines\n\nThe Philippines removed the patent linkage system in 2006. The Government Order permits acceptance of product registration without verifying whether there is a relevant patent. However, the FDA shall comply with any court order. An originator cannot prevent a generic drug manufacturer from getting a Certificate of Product Registration (CPR). The innovator must file a civil, criminal, or administrative case and get an injunction against CPR issuance. The Intellectual Property Code provides provisions for patent infringement. Criminal action is available only for repeated infringers. Philippines will be affected by the RCEP agreement, which is pending for approval from India. Then patent linkage will be implemented throughout these countries.107", "n_tokens": 208, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-350-1", "doc_id": "medicine_vaccine_book", "page": 350, "text": "2.13 Singapore\n\nAfter entering a free trade agreement with the US and both countries, Singapore introduced a patent linkage system, and both countries implemented it from January 1, 2004.108 The system allows the patent owners to monitor the generic drug marketing application and imposes mandatory disclosures.109 Patent linkage pro- visions are incorporated in Regulation 23(2) of the Health Products (Therapeutic Products) Regulations 2016 (‘TPR’). The Health Science Authority (HAS) of Singapore administers regulation on drug approval. Registration of any therapeutic product needs a declaration to the effect that no patent is infringed. The applicant must also declare that (1) the patent owner has given consent to the launch of the generic version; (2) the patent is invalid; or (3) the patent will not be infringed by acts relating to the therapeutic product.\n\n105https://www.tilleke.com/sites/default/files/2017_Apr14_IP%20Linkage_The%20Thai%20Gov ernment%E2%80%99s%20Efforts%20to%20Connect%20Agencies.pdf. 106McKenzie (2019). https://www.bakermckenzie.com/en/insight/publications/guides/global- guide-to-patent-linkage. 107Mirandah (2012), p. 50. https://www.lexology.com/library/detail.aspx?g¼73ee9ee5-1873-457e- b24f-8af6e96721ff. 108United States – Singapore Free Trade Agreement. https://wits.worldbank.org/GPTAD/PDF/ archive/US-Singapore.pdf. 109https://www.tilleke.com/resources/ip-linkage-thai-government%E2%80%99s-efforts-connect- agencies.\n\n347", "n_tokens": 423, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-351-0", "doc_id": "medicine_vaccine_book", "page": 351, "text": "348\n\nK. D. Raju\n\nFiling of the false information is an offense with a fine and imprisonment of up to 12 months. If a generic company applies for marketing approval in the last 18 months of the patent’s life, to be granted after the patent period’s expiry, the marketing approval process will continue. Upon notice to the patentee, the marketing approval can be stalled for 45 days (notice period). The HAS may register the therapeutic product without further notice to the patent’s proprietor if no Order or Declaration has been made at the end of 30 months after the date of the application for the Order or Declaration. The patent holders get a 30-month stay of approval of any product license upon applying for the necessary Order or Declaration. This prolonged delay of up to 31.5 months in total leads to uncertainty among generic manufacturing seeking marketing approval and the patentee.110 A person who made a false decla- ration shall be liable for conviction to a fine of (cid:2)SGD 20,000 and/or imprisonment for a term (cid:2)12 months. The result of marketing approval in such cases will depend upon the court decision.", "n_tokens": 242, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-351-1", "doc_id": "medicine_vaccine_book", "page": 351, "text": "In AstraZeneca AB (SE) v. Sanofi-Aventis Singapore Pte. Ltd, the High Court discussed delaying originator drug makers’ tactics.111 This case was examined under the Medicines Act, which was replaced by the TPR, 2016. Sanofi has applied for marketing approval for film-coated tablets comprising rosuvastatin and a stabilizer. Sanofi declared that the product would not infringe AstraZeneca’s Singapore Patent No.SG89993 (993), because of a different combination. AstraZeneca argued that its patents are infringed, and hence, a 30-month stay in the application process is applicable. Sanofi was forced to disclose its composition of their product under the court order. High Court observed that the 30 months’ objective is to settle the dispute before the product enters the market. However, this provision may be misused for delaying the entry of drugs by the originators and, therefore, have the effect of delaying public access to competitors’ products. The Court concluded that “By way of a parenthetical concluding observation, where a claim has serious consequences to the public and a defendant’s legitimate business, as a matter of good practice, the plaintiff should be required to give proper particulars of its claim” to save a considerable amount of time, energy and expense.112", "n_tokens": 287, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-351-2", "doc_id": "medicine_vaccine_book", "page": 351, "text": "What kind of information could be disclosed to the patentee during marketing approval is also under discussion in Millaneium Pharmaceuticals, Inc. v. Drug Houses of Australia Pte Ltd.113 Millennium Pharmaceuticals owns two patents in Singapore nos. SG 151322 and SG 182998, which are the process for manufacturing bortezomib. Drug Houses of Australia (DHA) obtained marketing approval of bortezomib, an anti-cancer drug in Singapore. The declaration filed as a part of the marketing approval process was never made available, and Millenium was not\n\n11030 months stay period and 45 days notice period. 111[2013] SGHCR 7. 112AstraZeneca AB (SE) v Sanofi-Aventis Singapore Pte Ltd [2013] SGHCR 7 https://www. supremecourt.gov.sg/docs/default-source/module-document/judgement/2013-sghcr-7.pdf. 113(2018) SGHC 149 (First Instance); Appeal (2019) SGCA 31.", "n_tokens": 221, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-352-0", "doc_id": "medicine_vaccine_book", "page": 352, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nserved notice about the application and thus prevented from commencing litigation under the TPR.\n\nMillennium argued before the High Court that failing to declare the patents and lack notice is in violation of laws, and the patents are infringed and a consequent injunction restraining DHA from infringing patents. The court held that generic companies must declare all patents which could be considered relevant to the product in question. The High Court sided with Millenium and confirmed that the defendant had made a misleading statement. In this case, generic companies would be compelled to disclose process patents formulation patents related to the generic to be granted marketing approval.114\n\nSingapore provides data-exclusivity for five years from the dare of the original marketing approval. HAS will not grant authorization for a generic drug based on the actual test data without the originator company’s approval. Patent term extensions and adjustments are available in Singapore, similar to that of the US. Patent term adjustments are possible only due to a delay in prosecution by the Singapore Patent Office.", "n_tokens": 226, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-352-1", "doc_id": "medicine_vaccine_book", "page": 352, "text": "The patent linkage regime in Singapore is in favor of originator companies. The generic drug manufacturers have to inform the innovator of any possibility of infringing the patent, and consequent litigation prolongs the entry of generics in the market. Failure to inform about the possible patent infringement will lead to the cancellation of the marketing approval and even criminal sanctions.115", "n_tokens": 76, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-352-2", "doc_id": "medicine_vaccine_book", "page": 352, "text": "2.14 Malaysia\n\nPresently, there is no patent linkage in Malaysia. The exclusive use of the patentee is protected under section 36 of the Patent Act 1983. The drug regulatory body has no power to contravene the rights of the patentee. The generic marketing approval cannot be considered as an excuse for infringement.\n\nIn March 2018, Malaysia signed the Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP), and the agreement is entered into force on 30 December 2018. Chapter 18 of the CPTPP provides a patent linkage system. However, the CPTPP has not yet been ratified by Malaysia,116 and technically there is no patent linkage in Malaysia. However, the Drug Control Authority (DCA) monitors newly approved drugs when patent holders commence infringement\n\n114Khoo and Lucas (2020). https://www.mondaq.com/patent/927960/patent-linkage-in-singapore- better-to-be-safe-than-sorry. 115Lexology (2020). https://www.lexology.com/library/detail.aspx?g¼3f5760db-39a8-47fd-8d86- 95de83072e36. 116Trans-Pacific Partnership Agreement (TPP) & Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) https://fta.miti.gov.my/index.php/pages/view/71#:~: text¼Malaysia%20is%20still%20evaluating%20the,Prime%20Minister%20and%20his% 20Cabinet.\n\n349", "n_tokens": 366, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-353-0", "doc_id": "medicine_vaccine_book", "page": 353, "text": "350\n\nK. D. Raju\n\nproceedings against marketers and manufacturers of generic medicines. However, according to Section 37(1A) of the Patent Act 1983, no action can be taken against the generic companies registering the drug, and no commercial activities in Malaysia before the patent expiry. Nevertheless, if the generic manufacturers manufacture the drug and stockpile, advertise, originators can file an “imminent infringement” suit against the company under Section 59(2) of the Patent Act. This provision is similar to that of the US, and the originators can sue the generic manufacturer before the expiry of the patent.\n\nThe originator companies can monitor the notifications published by the National Pharmaceutical Regulatory Agency (NPRA) related to a new drug product that has been approved. The legal proceeding can be commenced against the generic drug manufacturers those who infringe any patents. The generic companies can register their products during the validity of the patent. However, other than registration, no commercial activity is allowed. Evidence of patent infringement can be obtained through an Anton Piller Order.117 The court will issue such an order only when the originator producer prima facie case against the infringer.", "n_tokens": 244, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-353-1", "doc_id": "medicine_vaccine_book", "page": 353, "text": "There is no criminal punishment for infringements; only civil action can be initiated before the “IP High Court” bench. The remedies available are permanent injunction, impounding of the infringed products (Discovery Order), and compen- sation by way of damages.\n\nIn Ranbaxy (M) Sdn. Bhd. v. EI Du Pont Nemours and Co.,118 the Court of Appeal of Malaysia upheld a decision of the High Court of Malaysia relating to patent infringement. The Generic manufacturer Ranbaxy argued that the regulatory approval granted by the National Pharmaceutical Control Board (NPCB) means that the manufacturing and sale of a patented pharmaceutical product are valid and not an infringement. The plaintiff obtained regulatory approval in Malaysia to manufacture and market a pharmaceutical drug known as COVANCE containing potassium losartan. The defendant alleged infringement of one of the claims. The court further held that the patent claim’s description sufficiently and adequately described or taught the invention and supported the invention, and there is sufficient disclosure to understand the patent. The Court of Appeal found that the appellant to have infringed the patent.119 The court rejected the argument of linking regulatory approval with the patent rights of originators in this case.120 A study on the impact", "n_tokens": 267, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-353-2", "doc_id": "medicine_vaccine_book", "page": 353, "text": "117An Anton Piller Order is a form of civil search warrant which allows the plaintiff to enter the defendant’s premises and conduct a search. It takes the name from the famous case of Anton Piller KG v. Manufacturing Processes Ltd., [1976] 1 All. E.R. 779, [1976] Ch. 55, [1976] 2 W.L.R. 162, [1975] EWCA Civ 12. 1182011, 1 AMCR 857. 119Court of Appeal upholds a drug-related patent infringement claim, International Law Office, 12 November 2012 https://www.internationallawoffice.com/Newsletters/Intellectual-Property/Malaysia/Shook-Lin- Bok-Kuala-Lumpur/Court-of-Appeal-upholds-a-drug-related-patent-infringement-claim. 120Pharmaceutical Association of Malaysia www.phama.org.my.", "n_tokens": 197, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-354-0", "doc_id": "medicine_vaccine_book", "page": 354, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nof patent linkage on Malaysia by Rafiq Idris reveals that patent linkage will increase Malaysia’s drug cost.121\n\n2.15 Vietnam\n\nIn Vietnam, also, there are no declared patent linkage provisions. Even though the Drug Administration of Vietnam (DAV) is notified about the potential infringement, a generic drug’s marketing approval will not be stopped. The marketing approval will be withdrawn after a suit for infringement is successful. Usually, preliminary injunctions have not been granted in infringement cases.122 Article 126 of the Vietnam Intellectual Property Law, 2005 amended in 2009 and 2019. Using the patent for personal, non-commercial purposes, for research, evaluation, analysis, and testing, is not considered patent infringement under Article 125(2) of the IP Act. Article 13.4 of Circular 44/2014/TT-BYT, the DAV, is obligated to revoke the marketing approvals in case of any patent infringement. Drugs can be imported without any license or marketing approvals under “special import quota.” A patentee can seek revocation of such quota on the strength of a conclusion of infringement from a competent body.", "n_tokens": 252, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-354-1", "doc_id": "medicine_vaccine_book", "page": 354, "text": "In 2015, the Ministry of Science and Technology (MOST) conducted a raid in a generic manufacturers facility in South Vietnam, on a complaint from an American patentee. The patentee was aware of the generic drug’s entry in 2014 for treating diabetes and filed a possible patent infringement against the manufacturer who got a marketing approval. MOST ceased hundreds of finished tablets and raw materials. A cease and desist order was also passed against the manufacturer, along with revoking marketing approvals. This case shows an effective administrative action from originator drug manufacturers during a valid patent period.123\n\n2.16\n\nIndonesia\n\nPresently there is no patent linkage system in Indonesia. In Indonesia, BPOM Regulation No. 3/2011 deals with the registration of drugs. It allows registration of generic drugs and issues distribution licenses, which will take effect only after the patent period expires. Criminal actions can be taken against the infringers, including search, seizure, and closing infringers’ business. Infringement is punishable with\n\n121Idris (2016), pp. 1672–1676. 122Managing IP (2017). https://www.managingip.com/article/b1kbpj5jsl30y6/vietnam-improving- pharmaceutical-ip-protection. 123Le and Mai (2015), pp. 57–58. https://www.tilleke.com/sites/default/files/2015_Apr_Pharma_ Maze_Patent_Enforcement_Vietnam.pdf.\n\n351", "n_tokens": 314, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-355-0", "doc_id": "medicine_vaccine_book", "page": 355, "text": "352\n\nK. D. Raju\n\nfour years of imprisonment and a fine up to IDR 1 billion. The patent holder may file civil proceedings as well for damages.\n\n2.17\n\nJordan\n\nMarketing approval is not provided for pharmaceutical products during the period of patent validity. Since the WTO accession in 1999 was amended in 2001,124 Jordan maintained a patent registration corresponding to a patent. Before enacting the patent law in 1999, consistent with the TRIPs agreement, Jordan was a heaven of copycat drugs infringing patents.125 In 2002, the Minister of Health clarified that there would be no acceptance of dossiers for generics’ marketing approval during the patent period. An application for a new drug marketing approval will be accepted by the Ministry only if the new drug produced by the domestic manufacturer is “similar but not the same as a patented one.”126\n\nlinkage system and prevented generics’", "n_tokens": 184, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-355-1", "doc_id": "medicine_vaccine_book", "page": 355, "text": "2.18 Mexico\n\nIn Mexico, the Mexican Institute of Industrial Property (IMPI)127 and the Federal Commission for Protection against Health Risks (COFEPRIS)128 work together to avoid granting marketing approvals for allopathic drugs which may infringe a patent in force. IMPI established a system of publication of patents through special Gazette listing patents and their non-proprietary names (INN). The linkage system is established under Article 167 bis of the Health Supplies Regulation and Article 47 bis of the Industrial Property Regulations in 2003. An application for marketing approval to COFEPRIS relating to “substances or active ingredients” are obligated to indicate whether they are the patent holder or licensee of the existing patent.129 If the applicant is not the patentee or the licensee, they must provide a declaration, under oath, that the application for marketing approval does not infringe the patent holder’s rights. The COFEPRIS works with IMPI for ten days to determine the product’s", "n_tokens": 205, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-355-2", "doc_id": "medicine_vaccine_book", "page": 355, "text": "124Jordan, Patents of Invention Law, Law No. 32 for the Year 19991 (and its amendment by: Temporary Law No. 71 for the Year 2001). https://www.sabaip.com/wp-content/uploads/2018/04/ Jordan-Patent-Law.pdf. 125Armouti and Nsour (2018). http://www.hjil.org/wp-content/uploads/Nsour-FINAL.pdf. 126report.nat.gov.tw. 127https://www.gob.mx/impi/, accessed on September 30, 2020. 128https://www.gob.mx/cofepris/, accessed on September 30, 2020. 129By Jorge (2019). https://www.southcentre.int/wp-content/uploads/2019/07/PB64_The-USMCA-must-be-amended- to-ensure-access-to-affordable-drugs-in-Mexico_EN-1.pdf.", "n_tokens": 240, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-356-0", "doc_id": "medicine_vaccine_book", "page": 356, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\npatent status for a pending marketing application. If a patent is listed in the Gazette, the Ministry of Health has not provided marketing approval for a new product that would infringe the patent.130\n\n2.19 United Arab Emirates (UAE)\n\nIn UAE, Pharmaceutical patent registration is governed by Federal Law No. 17 of 2002 (as amended by Federal Law No. 31 of 2006) (Patent Law) and Ministry of Health Decree No. 404 of 2000 (Patent Resolution). The Drug Control Department (DCD) of the Ministry of Health (MOH) reviews applications for pharmaceuticals’ marketing exclusivity under the Patent Resolution.131\n\nApplications for generic drugs will be accepted 12 months before the expiry of UAE patent protection provided that the application does not contain any informa- tion relating to the patentee, which is protected under Article 36 of the TRIPS agreement.132\n\nThe UAE Ministry of Health133 Resolution provides that the Ministry deny marketing approval for a product that would infringe an existing patent in UAE or the country of import of that drug. The Ministry will either reject the application or keep abeyance of the application until the patent term expires. This system provided patent infringements by generic drugs infringing patents.134\n\n3 Patent Linkage Provisions in Regional and Bilateral\n\nTrade Agreements", "n_tokens": 279, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-356-1", "doc_id": "medicine_vaccine_book", "page": 356, "text": "3.1 CPTPP\n\nThe Trans-Pacific Partnership (TPP) agreement was dropped after the US refused to participate in the negotiations in 2017. TPP minus the US lead to the Comprehensive and Progressive Agreement for Trans-Pacific Agreement (CPTPP) agreement, a free trade agreement between 11 countries in the Asia-Pacific Region. The countries involved are New Zealand, Australia, Brunei Darussalam, Canada, Chile, Japan,\n\n130Moeller IP, Patent Linkage in Mexico. https://www.moellerip.com/patent-linkage-in-mexico/. 131https://www.firstconsulting.com. 132 Aljurf and Murray (2018). https://content.next.westlaw.com/Document/ I81997321b69811e698dc8b09b4f043e0/View/FullText.html?contextData¼(sc.Default)& transitionType¼Default. 133United Arab Emirates Ministry of Health and Prevention, Health Legislation. https://www. mohap.gov.ae/en/Aboutus/Pages/PublicHealthPolicies.aspx. 134http://www.theglobalipcenter.com/wp-content/uploads/2018/02/United_Arab_Emirates.pdf.\n\n353", "n_tokens": 312, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-357-0", "doc_id": "medicine_vaccine_book", "page": 357, "text": "354\n\nK. D. Raju\n\nMalaysia, Mexico, Peru, Singapore, and Viet Nam. Article 18.53 requires that the generic manufacturer notify the patent holder about the marketing of such a phar- maceutical product. The provision allows patent owners to intervene to prevent the marketing approval issuing and avoids the chance of infringing their patents.135 CPTPP came into force for the first six countries, Canada, New Zealand, Australia, Japan, Mexico, and Singapore, on December 30, 2018. On January 14, 2019, it came to force for Viet Nam.136 Canada, Australia, Japan, and Singapore have patent linkage provisions; others have to include provisions once they ratify the agreement. Peru signed the CPTPP in 2018 and agreed to implement the patent linkage provisions.\n\n3.2 US – Peru FTA\n\nThe US-Peru Free Trade Agreement, which entered into force in 2009, Article 16.10.4, provides patent linkage. The generic drug will undergo a bioequivalence test before getting marketing approval. Notice to the patent holder is mandatory for getting marketing approval for the generic drug. The marketing approval will be deferred until the patent has expired, or sufficient time has to be given for adjudi- cating the dispute on the status of the patent. Un-authorized marketing of the product is prohibited before the expiry of the patent. Legislative decree of Peru 1075 imposed penalties and sanctions on a party deliberately provide false information to the regulatory authorities.137", "n_tokens": 313, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-357-1", "doc_id": "medicine_vaccine_book", "page": 357, "text": "3.3 AUSFTA\n\nThe Australia-US Free Trade Agreement (AUSFTA) 2005 provides for patent linkage (Article 17.10.4 – IP Chapter). There are measures in the marketing approval process to prevent others from marketing a product during the patent term without the patent owner’s consent. The owner will be informed of a marketing approval application.138 In Aktiebolaget Hassle v. Alphapharm Pty Limited., the High Court\n\n135https://www.mfat.govt.nz/assets/Trans-Pacific-Partnership/Text/18.-Intellectual-Property-Chap ter.pdf. 136https://www.international.gc.ca/trade-commerce/trade-agreements-accords-commerciaux/agr- acc/cptpp-ptpgp/index.aspx?lang¼eng. 137Kiliç and Maybarduk (2011). https://www.citizen.org/wp-content/uploads/comparative_analy sis_of_the_u.s._intellectual_property_proposal_and_peruvian_law.pdf. 138Australian Government, Australia–United States Free Trade Agreement, Chapter Seventeen – Intellectual Property Rights. https://www.dfat.gov.au/about-us/publications/trade-investment/australia-united-states-free-trade- agreement/Pages/chapter-seventeen-intellectual-property-rights.", "n_tokens": 319, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-358-0", "doc_id": "medicine_vaccine_book", "page": 358, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nof Australia observed that pharmaceutical manufacturers had employed many ways to delay the generic competition. It held that “the court should avoid creating fail- safe opportunities for unwarranted extensions of monopoly protection that are not sustained by law.”139\n\n3.4 RCEP\n\nNegotiations for a Regional Comprehensive Economic Partnership (RCEP), as launched in 2013, involved ASEAN member states and six of its trading partners, including; China, India, Japan, Australia, New Zealand, and South Korea. In November 2019, India decided to pull out of the negotiations citing its internal economic concerns, mainly the trade deficit with China. The RCEP was signed in November 2020. The IP chapter does not provide for patent linkage. An earlier leaked draft of the RCEP agreement140 had patent linkage provisions for “prevention of marketing pharmaceutical products infringing effective patent.”141 This provision sought to tie the marketing approval process to the patent validity, originators extension of the patent, and delay in the entry of generics. It would create a burden on the regulatory authorities to look into the validity of the patent. Presently, most of the countries do not have patent term extension provisions. But the draft included a patent extension provision both in Japan and South Korea’s drafts.142", "n_tokens": 272, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-358-1", "doc_id": "medicine_vaccine_book", "page": 358, "text": "3.5 KOREA - US FTA\n\nThe U.S.-Korea Free Trade Agreement (KORUS FTA) entered into force on March 15, 2012.143 Under Article 18.9.5 of the agreement provides that when a non-originator of a pharmaceutical product applies for marketing approval, the patent owner must be notified of the identity of the person making such a request. The government must make administrative arrangements to see that no marketing approvals will be granted without the patent owner’s consent. Patent linkage for biologics and generics was included in the Korean Pharmaceutical Affairs Act, amended in 2015 following obligations under the KORUS FTA. It is similar to that of the US provisions, provides for notice to the patent owner not less than\n\n139Aktiebolaget Hassle v Alphapharm Pty Ltd., 212 CLR 411, para 101. 2002. 140Weatherall (2016). 141https://www.bilaterals.org/IMG/pdf/ssrn-id2850294.pdf. 142Bouchard et al. (2010), pp. 174–227. 143U.S. - Korea Free Trade Agreement. https://ustr.gov/trade-agreements/free-trade-agreements/ korus-fta.\n\n355", "n_tokens": 273, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-359-0", "doc_id": "medicine_vaccine_book", "page": 359, "text": "356\n\nK. D. Raju\n\n180 days before the first marketing date of the bio-similar. Korea followed the US system as it is and is severely criticized in Korea.144\n\n4 Indian Scenario\n\nIndia does not presently provide for patent linkage under its patent law. The Indian drug industry is one of the largest in the world, with 20 percent (value)145 in all generics and accounts for 75 percent of the Indian market share.146 The US is the prime destination of Indian generic exports. In 2008, the Department of Pharmaceu- ticals started a program in the name of “Jan Aushadhi” (medicine for people) shops to made available unbranded generic drugs available to the poor people in the country at a reasonable and affordable price. Until June 30, 2019, 5300+ “Pradhan Mantri Bhartiya Janaushadhi Kendras” are functional spread over 35 States/UTs of our country.147 Under the umbrella of “Bureau of Pharma PSUs of India,” more than 900 drugs and 154 surgical & consumables covering almost all major therapeutic groups have been supplying.", "n_tokens": 233, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-359-1", "doc_id": "medicine_vaccine_book", "page": 359, "text": "The prime objective of Draft Pharmaceutical Policy, 2017148 of India, declares, “making essential drugs accessible at affordable prices to the common masses.” To fulfill the policy objective, the Government has come out with a price regulation mechanism through the National List of Essential Medicines. The National Health Policy, 2017 also emphasizes affordability as one of the fundamental principles.149 The policy’s goal is to “achieve the highest possible level of good health and well- being for all Indians through a preventive and promotive healthcare orientation in all developmental policies.” These policy objectives cannot be achieved without a vibrant generic drug industry.\n\nThe Government of India’s Pharma Vision 2020150 aims to make India a global leader in end-to-end- drug manufacturing. The export of pharma products is expected to reach $20 billion by 2020 and the total market to the tune of USD$55 billion.151 India supplies 20 percent of the global generic drug demand.152 It is more", "n_tokens": 201, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-359-2", "doc_id": "medicine_vaccine_book", "page": 359, "text": "144Laurenza (2015), pp. 439–442. 145http://www.uniindia.com/generic-drugs-holds-70-pc-market-share-in-pharmaceutical-sector-in- india/south/news/1512004.html. 146Indian Generic Drug Market Outlook 2020, September 2015. https://www.rncos.com/Market- Analysis-Reports/Indian-Generic-Drug-Market-Outlook-2020-IM779.htm. 147http://janaushadhi.gov.in/mesgceo.aspx. 148http://www.indiaenvironmentportal.org.in/files/file/draft%20pharmaceutical%20policy% 202017.pdf. 149https://mohfw.gov.in/sites/default/files/9147562941489753121.pdf. 150India Pharma 2020: Propelling access and acceptance, realising true potential https://online.wsj. com/public/resources/documents/McKinseyPharma2020ExecutiveSummary.pdf. 151Ibid. 152Press Information Bureau (2018). https://pib.gov.in/newsite/PrintRelease.aspx?relid¼186696.", "n_tokens": 312, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-360-0", "doc_id": "medicine_vaccine_book", "page": 360, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nimportant to note that Indian pharmaceutical firms supply over 80 percent of the antiretroviral drugs used internationally to combat AIDS (Acquired Immune Defi- ciency Syndrome). The Indian industry provides even 30 percent of the US generic drug market.153 Any changes in the global and regional policies will severely affect the Indian generic industry. There is a direct correlation between generic drugs and price affordability. However, there is a conflict of interest between patented drug manufacturers and the generic drug industry, and allegation of patent infringements are common in many cases. It is alleged that the originator drug industry is charging exorbitant prices on their patented drugs, which is no match to their investments. In India, the Madras High Court in the famous Novartis case discussed this issue.154", "n_tokens": 180, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-360-1", "doc_id": "medicine_vaccine_book", "page": 360, "text": "4.1 Drugs and Cosmetics Act, 1940\n\nRule 122E (Drugs & Cosmetics Rules) 1945 defines “new drug”. A generic drug has not been defined in the Act nor Rules. The Central Drugs Standards Control Organization (CDSCO) under the Directorate General of Health Services is respon- sible for the approval of drugs in India. The objective of the Act is to examine the safety and security of drugs that are manufactured and imported. There is no interlinkage between the Drugs and Cosmetics Act and Patent Act 2005. Grant of a patent by the Patent Controller General of India has no impact on whether or not marketing approval should be granted. Patents can be opposed by pre-grant [section 25(1)], and post-grant [section 25(1) (t)] opportunities, or even it can be canceled (Section 64). The Drugs Controller of India (DCGI) under the Drugs and Cosmetics Act, 1940, is the statutory authority to grant manufacturing and marketing approval. However, none of the legislations in India neither permits nor intends to provide patent linkage.", "n_tokens": 225, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-360-2", "doc_id": "medicine_vaccine_book", "page": 360, "text": "4.2 Bristol Myers Squibb v. Hetero Drugs Ltd. – 2008\n\nThe petitioner successfully got an ex-party injunction against the Hyderabad-based Hetero Drugs, which effectively linked patent status with marketing approval of the generic version of the originator drug, in this case, Dasatinib, a cancer drug. The Delhi High Court granted an injunction against the defendant and restrained generic company from “manufacturing, selling, distributing advertising, exporting, offering for sale or in any manner dealing directly or indirectly in any product infringing the plaintiff’s patent...” The court also observed that the DCGI must see that such approvals are not infringing any patent. The court held that “It is expected that the\n\n153https://www.ibef.org/industry/pharmaceutical-india.aspx. 154Raju (2009), pp. 7–32.\n\n357", "n_tokens": 188, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-361-0", "doc_id": "medicine_vaccine_book", "page": 361, "text": "358\n\nK. D. Raju\n\nDrugs Controller while performing statutory functions will not allow any party to infringe any laws and if the drug for which the defendants have sought approval is in breach of the patent of the plaintiffs, the approval ought not to be granted to the defendant.” This judgment created unrest and concerns in the generic industry. Unfortunately, this is far beyond the court’s jurisdiction without adequately exam- ining the Drugs and Cosmetics Act’s provisions about the mandate of the DCGI. It is not the duty of the DCGI to enforce the patent rights in India. Its mandate is to ensure the safety and quality of the drugs sold or imported into India. This will automati- cally stall India’s generics’ approval process during the patent term, which is a derogation from the bolar provision contained in Section 107A of the Patent Act.", "n_tokens": 179, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-361-1", "doc_id": "medicine_vaccine_book", "page": 361, "text": "There is no linkage in India, and neither the Patent Act nor the Drugs and Cosmetics Act has provisions for connecting this. The court tried to implement patent linkage, which is not envisaged, nor the legislature intended to include in the concerned laws during its drafting. The court has attempted to fill the gap, which is never existed. The costly originator medicines are a severe threat to needy patients in India. On one side, the foreign companies argue for patent linkage, and on the other hand, the generic companies and non-governmental organizations working in access to medicines are objecting to the patent linkage. This decision caused unrest in the well established generic industry in India. The court had delivered this judgment when the DCGI was not even a party to the dispute. Effectively this judgment made patent policing by the court without any legislative sanctions.", "n_tokens": 172, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-361-2", "doc_id": "medicine_vaccine_book", "page": 361, "text": "4.3 Bayer - Cipla Case\n\nIn Bayer v. Cipla, Union of India and Others, 2009,155 the Supreme Court held that submission of clinical data for getting marketing approval is not an infringement of the originator. Bayer has filed a case against Cipla, an Indian generic manufacturer in the High Court of Delhi, alleging that “sorafenib,” is a spurious drug, which is an imitation of the originator patented drug “Sorafenib tosylate.” A single Judge of the court dismissed the petition in August 2009, rejecting Bayer’s argument that infer- ring drug agencies’ role in patent policing or enforcement is unacceptable. Bayer appealed before the Division Bench of the High Court, and the judgment was delivered by the court in February 2010,156 upholding the position of the single judge in this case and refused to issue a restraint order against the grant of marketing approval to Cipla for its generic drug “Soranib.” Bayer filed a Special Leave Petition (SLP)157 before the Supreme Court, which decides the case in December 2010, upholding the decision of the Delhi High Court.\n\n155WP(C) No. 7833/2008. 156LPA 443/2009-9 February 2010. 157Special Leave to Appeal (CIVIL) No. 6540/2010.", "n_tokens": 279, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-362-0", "doc_id": "medicine_vaccine_book", "page": 362, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nIt is interesting to know that Bayer argued that S.2 of the Drugs and Cosmetics Act (DCA) read with S.48 of the Patent Act provides for inbuilt provision for “patent linkage.” The marketing approval granted under S.2 shall not derogate any other legislation, i.e., Patent law S.48, patentee’s rights. Bayer argued that patent linkage could be inferred from the joint reading of Section 2 of the Drugs and Cosmetic Act and Section 48 of the Patent Act. On the other hand, Cipla clearly said that submitting information to the drug regulatory is not an infringement of the patent. The Drugs Controller, given the regulatory approval to Cipla based on the drug, was safe, effective, and not an act of “making, using, offering for sale, selling or importing” the petitioner’s patented product.158 Section 107A(a) is known as the Indian “Bolar” provision, permits any drug manufacturer to experiment with any patented drug to generate data that could then be submitted to a drug control authority. The aim of the rule is that ensuring the immediate entry of generic drugs on patent expiration. “Spurious drug” is defined under section 17B of the Drugs Act, which does not include a generic version of any medicines. The court rejected Bayer’s argument that Rule 122B(1)(b) of the Drugs Rules, read with Form 44, and the data required (Appendix 1 to Schedule Y) intends patent linkage.", "n_tokens": 335, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-362-1", "doc_id": "medicine_vaccine_book", "page": 362, "text": "To suggest that patent linkage is established only because an entry in Form 44 asks the applicant to indicate the drug’s patent status is to misconstrue the provisions as they stand. A form in an appendix to a statutory rule (in this case, the DCR) cannot be understood contrary to the statute’s scheme. Court agreed with the respondent’s contention that the Drug Controller General of India’s (DCGI) office is not equipped to deal with patents’ validity. The office and functions of DCGI are governed under the Drugs and Cosmetics Act (DCA) and not under the Patents Act. The court observed that “spurious drugs” and “generic drugs” are two different concepts. The court found that patent linkage is a “TRIPs plus” obligation, and TRIPs do not deal with the concept of patent linkage.\n\nThe court concluded that patent linkage could not be read into the provisions of the Drugs and Cosmetics Act and Patent Act, and such systems are undesirable for the Indian context. Some of the other observations are very pertinent, as follows: (cid:129) Policing of patent rights is not the duty of the regulators. (cid:129) Patent rights are private rights, and they cannot be mix with public rights. (cid:129) Patent linkage will undermine the “Bolar” provision. (cid:129) Article 27 of the TRIPs Agreement requires that patents are made available without discrimination by the field of technology, patent linkage only specific to the pharmaceutical industry alone.", "n_tokens": 323, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-362-2", "doc_id": "medicine_vaccine_book", "page": 362, "text": "The Court elaborately discussed the objectives of the two legislations. Delhi High Court when dismissing the petition and imposed a cost of Rs. 6,75,000/- payable in equal shares to the Union of India and Cipla for vexatious and luxury litigation. The Supreme Court held that there is no room for patent linkage in India, and no such system could be encompassed into the existing Indian laws. Some scholars argue\n\n158Mittal (2010), pp. 187–196.\n\n359", "n_tokens": 103, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-363-0", "doc_id": "medicine_vaccine_book", "page": 363, "text": "360\n\nK. D. Raju\n\nthat denial of patent linkage in India is a negative development, and the availability of life-saving drugs must be ensured through compulsory licenses, not through giving parallel approval to generic drug manufacturing by DCGI.\n\nAccess to life-saving drugs in developing countries is essential and an essential public interest topic in India. Adopting patent linkage, either legislatively or judi- cially, would severely affect the generic drug industry in India.", "n_tokens": 92, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-363-1", "doc_id": "medicine_vaccine_book", "page": 363, "text": "5 Conclusions\n\nThe objective of patent rights is to give incentives to the innovator for further research and development. This protection is for a limited period, 20 years, as fixed under the TRIPs agreement. Presently, 164 WTO members are subscribed to this agreement and obliged to implement at the domestic level since 1995. The protection of patent rights is inevitable to promote innovation in the pharmaceutical sector. At the same time, generic medicines also play a crucial role in pharmaceutical innovation, especially affordability and accessibility in developing and developed countries. But an inappropriate extension of the monopoly rights beyond the per- mitted period of 20 years must be considered an abuse of the patent system. Patent linkage is how the country allows linking marketing approval of the generic drug with the originator drug’s patent status. The practice requires that generic companies applying for marketing approval must prove that they are not violating any valid patent. Under the arrangement, national regulatory authorities should prevent the registration and marketing of generic pharmaceuticals.", "n_tokens": 198, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-363-2", "doc_id": "medicine_vaccine_book", "page": 363, "text": "Originally, patent linkage introduced through the Hatch-Waxman Act 1984 in the US intended to encourage the manufacture of generic drugs without infringing any patents and to promote innovation in the pharmaceutical industry. However, there were no many takers of patent linkage provisions in other countries. The declared objective of the law is to facilitate the entry of generic drugs in the US market. But it is turned out to be a barrier for the generic companies to get regulatory approvals by filing an ANDA.\n\nFor the last 36 years, since the introduction of the patent linkage in the US, approximately 15 countries have adopted patent linkage provisions. Precisely, these provisions are pushed through regional or bilateral trade agreements by the US. There is no obligation under the TRIPs agreement to implement patent linkage. Originator companies argue that patent linkage is a rational means of ensuring patent rights and regulatory agencies not helping patent infringement. However, the objec- tive of patent law and regulatory approvals are different, and their functions are dissimilar. Patent linkage is not mentioned in the TRIPS agreement at all. The US has made the patent linkage provision to create a second tier of protection for a patent monopoly. Patent rights are private rights and have to be enforced privately, and it cannot be implemented through government regulatory authorities.", "n_tokens": 267, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-363-3", "doc_id": "medicine_vaccine_book", "page": 363, "text": "The passive approach to free trade agreements and IP standard setting is evident. Most of the bilateral trade agreements include IP chapters. The TRIPs flexibilities are", "n_tokens": 32, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-364-0", "doc_id": "medicine_vaccine_book", "page": 364, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nbreathing space for many developing and least developed countries, including India. Eroding these flexibilities will kill the golden goose who produces a significant chunk of the generic medicines for the developing world. Patent law requires enforcement of patent rights, but linkage inappropriately uses regulatory authorities to prevent infringement. These authorities may not be competent enough to deter- mine patents’ validity, and their mandates are different. Marketing regulatory pro- cedures should not be subject to patent law. Only the courts can decide if the patent is infringed or not after adducing sufficient evidence, and it is not the duty nor expertise of the regulators to do it.", "n_tokens": 158, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-364-1", "doc_id": "medicine_vaccine_book", "page": 364, "text": "EU does not support the idea of patent linkage because it will adversely affect the implementation of the bolar provision to manufacture generics and biosimilars in advance of patent expiry. However, Patent term extension is already granted in the EU in the form of supplementary protection certificates (SPC) on a national basis. It is alleged that patent linkage’s main objective is to extend the patent term by delaying generic medicines’ entry. A centralized “Orange book” also is missing in the EU. In the Italian patent linkage provision case, the European Commission made it clear that patent linkage delays generic medicines’ entry and a clear abuse of the EU regulatory system. It is also noticed that the originators are misusing the system by filing frivolous litigations against the generic industry. In 2007, 20 such cases were filed by the originators against generics and regulators in Portugal.159\n\nCanada amended the Patent Act in 2017 and introduced patent linkage pro- visions. The patent register is available similar to that of the “orange book” in the US. However, 180 days exclusivity period is absent for the generic manufacturers to challenge the patent. The statutory stay of generic is for 24 months less than the US period of 30 months.", "n_tokens": 262, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-364-2", "doc_id": "medicine_vaccine_book", "page": 364, "text": "Japan also implemented patent linkage in the country. The patent linkages are secured in two stages of regulatory approval and drug price listing. During the active patent period, no generic approvals will be granted. Patent extension up to five years is available.\n\nlinkage through AUSFTA and consequent domestic legislation. South Korea also implemented patent linkage through the US – Korea Bilateral Free Trade Agreement. China effectively implemented linkage through the Chinese new Drug Administration Law in 2019. On 15th January 2020, China and the US signed an Economic and Trade Agreement to effectively imple- ment patent linkage provisions. These provisions are similar to that of the US provisions under 35 U.S.C.§.154(b). Chinese Taipei (Taiwan) also added patent linkage provisions to the Pharmaceutical Affairs Act in 2019. The linkage provisions have close similarities with Chinese provisions.\n\nAustralia implemented a patent\n\nThailand effectively implemented patent linkage through “Drug Patent Approval Linkage” in 2019. Brunei, Singapore, New Zealand, and Chile signed the Trans- Pacific Partnership (TPP) in 2006, and patent linkage is introduced through this\n\n159https://www.medicinesforeurope.com/wp-content/uploads/2009/06/EGA-IP_Barriers_web.pdf.\n\n361", "n_tokens": 274, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-365-0", "doc_id": "medicine_vaccine_book", "page": 365, "text": "362\n\nK. D. Raju\n\nagreement. Singapore’s judicial decisions made it clear that the courts favor more excellent protection to the patentees and already implemented patent linkage.\n\nEven though Malaysia claims there is no patent linkage system, but it effectively implemented the CPTPP. The High Court and Court of Appeal of Malaysia held that the regulatory approval is nothing to do with any authorization to work on the patent. It means that in Malaysia, there is still room for the generic industry to get marketing approval.\n\nIt is interesting to note that regional trade agreements are taking the main stage in implementing the patent linkage provisions. AUSFTA and US-Peru FTA also have patent linkage provisions. Patent linkage provisions were also proposed in RCEP. These TRIPs-plus provisions could substantially increase generic medicines’ costs in the countries and threaten access to essential drugs in most states.", "n_tokens": 176, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-365-1", "doc_id": "medicine_vaccine_book", "page": 365, "text": "There is no patent linkage in India so far, and the courts are made it clear that these two systems cannot be connected. Indian courts actively prevented patent linkage successfully. The Satwant Reddy Committee Report in 2006 suggested the gradual adoption of patent linkage in India. However, the Indian scenario is unique, and it is the warehouse of generic medicines. Nevertheless, the jurisprudence from India gives mixed feelings. In the Bristol Myers Squibb dispute, Delhi High Court held that the Drug Controller General, when granting marketing approval to the generic drug, must see that no valid patent is infringed.\n\nOn the other hand, in Bayer v. Cipla, the same Delhi High Court (another bench) held that patent rights are private rights, and patent rights policing is not the regulators’ duty. Court also observed that linkage would undermine the bolar exemption granted under the TRIPs agreement. The dispute has gone to the Division Bench of the High Court and Supreme Court of India but confirmed the first ruling in favor of generic drugs in India.\n\nHowever, the story in Roche Ltd. & Anr. v. Cipla is protracted litigation for almost a decade. Initially, the case was in favor of Cipla and lost the dispute up to the Supreme Court. Nevertheless, the second phase of the dispute was absolutely in favor of Roche. The case reached the Supreme Court in 2017 again and finally settled out of court.", "n_tokens": 293, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-365-2", "doc_id": "medicine_vaccine_book", "page": 365, "text": "Later, Roche filed a series of suits against Indian generic pharmaceutical compa- nies like Glenmark Pharma, Reddy’s Lab, Natco Pharma, Innova Pharma, Cipla, Aureate Healthcare, BDR Pharma, Oncare Lifesciences, Accuracare Pharmaceuti- cals, and Metrix. This shows the ill intentions of the originator companies for using litigation as a coercive measure in India.\n\nLinking patent rights with regulatory and marketing approvals will have unde- sirable results in developing countries and have a negative effect on access to medicines in developing and least developed countries. Patent linkage introduces a significant obstacle to the timely availability of generic medicines. With this analysis of many countries’ linkage provisions, it is clear that while some developed coun- tries adopt these provisions, many do not, and imposing this in the developing countries like SAARC has an everlasting negative impact on the availability and accessibility of generic drugs. The comparative analysis of the patent regimes of different jurisdictions reveals no unanimity about patent linkage’s importance or", "n_tokens": 235, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-366-0", "doc_id": "medicine_vaccine_book", "page": 366, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nutility. Enforcement of regional trade agreements with patent linkage provisions will change this scenario. Patent linkage provisions will be used as a restrictive measure upon drug development in the developing nations. This provision favors multina- tional pharmaceutical companies those who want to extend their patent term for maximum exploitation.\n\n5.1 Suggestions\n\n(cid:129) TRIPS-plus obligations such as patent linkage should not be imposed on devel-\n\noping countries.\n\n(cid:129) Pre-emptive patent infringement suits only delay the entry of generic drugs, and such infringement suits may not be entertained by courts when public interest is involved.\n\n(cid:129) The role of licensing or regulatory authority and patent granting authority has to be separated. Regulatory officers cannot make an informed decision about the applicability of the patented drug and generic drugs. It must leave it to the court to decide the status.\n\n(cid:129) TRIPs plus patent linkage obligations should not be imposed on developing", "n_tokens": 213, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-366-1", "doc_id": "medicine_vaccine_book", "page": 366, "text": "countries through regional trade agreements.\n\n(cid:129) Originator companies can very well file patent infringement suits even without patent linkage provisions and seek to enforce their private rights through courts. (cid:129) Patent infringement suits must be based on good faith. Hefty fines should be imposed on companies who file frivolous litigations to delay marketing approvals of generics.\n\n(cid:129) Administrative procedures may be simplified, transparent, and a national registry\n\nshould list all new drug applications.\n\n(cid:129) Declaration of non-infringement can be taken for generic approvals to avoid\n\nunnecessary litigations.\n\n(cid:129) The originator company should disclose all its patent registrations for products/\n\nprocess while filing the regulatory approval.\n\n(cid:129) The patent application status should not be a ground for refusal, suspension, or\n\nprevention of marketing approvals.\n\n(cid:129) Patent linkage is an administrative procedure and nothing to do with the concept of patent protection. But some of the countries like Hungary made a provision for declaring the patent status when applying for marketing approval of the generic. (cid:129) Reject all efforts to introduce patent linkage in any form in developing countries.\n\n363", "n_tokens": 253, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-367-0", "doc_id": "medicine_vaccine_book", "page": 367, "text": "364\n\nK. D. Raju\n\nReferences\n\nAbe T (2019) Japan: what impact do generic drugs have on the Japanese market? Managing IP Asia Pacific https://www.managingip.com/Article/3888280/Japan-What-impact-do-generic-drugs- have-on-the-Japanese-market.html. Accessed 8 Mar 2021\n\nAktiebolaget Hassle v. Alphapharm Pty Ltd, 212 CLR 411, para 101 2002 Aljurf S, Murray M (2018) Pharmaceutical IP and competition law in the United Arab Emirates: o v e r v i e w . h t t p s : / / c o n t e n t . n e x t . w e s t l a w . c o m / D o c u m e n t / I81997321b69811e698dc8b09b4f043e0/View/FullText.html?contextData¼(sc.Default)& transitionType¼Default. Accessed 8 Mar 2021\n\nAnton Piller KG v. Manufacturing Processes Ltd., [1976] 1 All. E.R. 779, [1976] Ch. 55, [1976]\n\n2 W.L.R. 162, [1975] EWCA Civ 12\n\nArmouti W, Nsour M (2018) Data exclusivity for pharmaceuticals in free trade agreements: models in selected United States free trade agreements. http://www.hjil.org/wp-content/uploads/Nsour- FINAL.pdf. Accessed 8 Mar 2021\n\nArticle 1 of\n\nthe TRIPs Agreement. https://www.wto.org/english/docs_e/legal_e/27-trips.pdf.", "n_tokens": 383, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-368-0", "doc_id": "medicine_vaccine_book", "page": 368, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nMalaysia/Shook-Lin-Bok-Kuala-Lumpur/Court-of-Appeal-upholds-a-drug-related-patent- infringement-claim. Accessed 8 Mar 2021\n\nDaniela Ampollini (Trevisan & Cuonzo) (2011) Patent linkage? Infringement proceedings by the European Commission against Italy, Kluwer Patent Blog. http://patentblog.kluweriplaw.com/ 2011/04/08/patent-linkage-infringement-proceedings-by-the-european-commission-against- italy/. Accessed 5 Mar 2021\n\nData Exclusivity/Patent Linkage in the Context of EU Generic and Biosimilar Applications. Presentation by Suzette Kox at the WIPO Life Sciences Symposium: Intellectual Property and Life Sciences Regulation, 16 November 2017. https://www.wipo.int/export/sites/www/ meetings/en/2007/lifesciences/sym_regulation/lss3_ge_07_kox.pdf. Accessed 5 Mar 2021 Decided on June 17, 2013., https://www.supremecourt.gov/opinions/12pdf/12-416_m5n0.pdf.\n\nAccessed 5 Mar 2021\n\nDecision of the Regional Administrative Court of Rome on January 2018 (T.A.R. Lazio, sez. III, -\n\nRoma, 19 January 2018, No 662)\n\nDecision of the Supreme Commercial Court in case No. A40-65668/2008, dated 06.16.2009 Draft Pharmaceutical Policy – 2017. http://www.indiaenvironmentportal.org.in/files/file/draft%\n\n20pharmaceutical%20policy%202017.pdf. Accessed 8 Mar 2021\n\nDrug Act", "n_tokens": 392, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-368-2", "doc_id": "medicine_vaccine_book", "page": 368, "text": "europa.eu/competition/sectors/pharmaceuticals/inquiry/preliminary_report.pdf. 5 Mar 2021\n\nEuropean Generic Medicines Association (2008) Patent-related barriers to market entry for generic medicines in the European Union. http://www.ieis.org.tr/ieis/assets/media/EGA%20-%20IP_ Barriers_web.pdf. Accessed 5 Mar 2021\n\nEuropean Generic Medicines Association (2009) A Report by the EGA Economics Committee, 2009. https://www.medicinesforeurope.com/wp-content/uploads/2016/03/Market_Barriers_ Report_FINAL_update_How_to_Increase_Patient_Access_to_Generic_Medicines.pdf. Accessed 5 Mar 2021\n\nEuropean Medicines Agency Generic and Hybrid Medicines. https://www.ema.europa.eu/en/ human-regulatory/marketing-authorisation/generic-hybrid-medicines. Accessed 5 Mar 2021 Faunce TA, Lexchin J (2007) “Linkage” pharmaceutical evergreening in Canada and Australia. Aust N Z Health Policy 4(8). https://anzhealthpolicy.biomedcentral.com/articles/10.1186/1743- 8462-4-8. Accessed 8 Mar 2021\n\nGlobal Legal Monitor (2019) China: Drug Administration Law Revised. https://www.loc.gov/law/\n\nforeign-news/article/china-drug-administration-law-revised/. Accessed 8 Mar 2021\n\nGovernment of Canada, Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP). https://www.international.gc.ca/trade-commerce/trade-agreements-accords- commerciaux/agr-acc/cptpp-ptpgp/index.aspx?lang¼eng. Accessed 8 Mar 2021\n\nH. Lundbeck A/S v Chemo Iberica, S.A., http://www.reyestr.court.gov.ua/Review/10026637.", "n_tokens": 439, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-368-3", "doc_id": "medicine_vaccine_book", "page": 368, "text": "Accessed 8 Mar 2021\n\nH. Lundbeck A/S v. Farmak JSC., http://reyestr.court.gov.ua/Review/3683167. Accessed 8 Mar\n\n2021\n\nhttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_\n\n2001_83_cons_2012_en.pdf. Accessed 5 Mar 2021\n\nhttps://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2004_726/reg_2004_726_en.\n\npdf. Accessed 5 Mar 2021\n\nhttps://grls.rosminzdrav.ru/StatementRUInfo.aspx. Text in Russian? https://mohfw.gov.in/sites/default/files/9147562941489753121.pdf\n\n365", "n_tokens": 220, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-369-0", "doc_id": "medicine_vaccine_book", "page": 369, "text": "366\n\nK. D. Raju\n\nhttps://practiceguides.chambers.com/practice-guides/patent-litigation-2020/italy/trends-and-devel- opments#:~:text¼The%20European%20Union%20does%20not,advance%20of%20the% 20patent%20expiration\n\nhttps://system.jpaa.or.jp/patent/viewPdf/3066. Text in Foreign Language https://www.congress.gov/bill/98th-congress/senate-bill/01538. Accessed 5 Mar 2021 https://www.mfat.govt.nz/assets/Trans-Pacific-Partnership/Text/18.-Intellectual-Property-Chapter.\n\npdf\n\nhttps://www.tilleke.com/resources/ip-linkage-thai-government%E2%80%99s-efforts-connect-\n\nagencies\n\nhttps://www.tilleke.com/sites/default/files/2017_Apr14_IP%20Linkage_The%20Thai%20Govern-\n\nment%E2%80%99s%20Efforts%20to%20Connect%20Agencies.pdf\n\nhttps://www.wipo.int/export/sites/www/meetings/en/2007/lifesciences/sym_regulation/\n\nlss3_ge_07_ferrite.pdf\n\nhttps://www.wto.org/english/thewto_e/acc_e/ukr_e/WTACCUKR139_LEG_8.pdf Idris R (2016) Patent linkage: possible impact on Malaysia’s access to medicines. Scholars J Appl\n\nMed Sci 4(5C):1672–1676\n\nIndia Brand Equity Foundation (IBEF). https://www.ibef.org/industry/pharmaceutical-india.aspx.\n\nAccessed 8 Mar 2021\n\nIndia Pharma 2020: Propelling access and acceptance, realising true potential. https://online.wsj. Accessed\n\ncom/public/resources/documents/McKinseyPharma2020ExecutiveSummary.pdf. 8 Mar 2021", "n_tokens": 482, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-369-1", "doc_id": "medicine_vaccine_book", "page": 369, "text": "India Today, New Delhi, April 17, 2020. https://www.indiatoday.in/india/story/india-sending-\n\nhydroxychloroquine-55-coronavirus-hit-countries-1667786-2020-04-17\n\nIndian Generic Drug Market Outlook 2020, September 2015. https://www.rncos.com/Market- Analysis-Reports/Indian-Generic-Drug-Market-Outlook-2020-IM779.htm. Accessed 8 Mar 2021\n\nIntellectual Property Watch (2012) European Commission orders Italy to drop patent linkage delaying generics. https://www.ip-watch.org/2012/01/31/european-commission-orders-italy- to-drop-patent-linkage-delaying-generics/. Accessed 5 Mar 2021\n\nIP Litigation in Life Sciences – Costs, Duration and Enforceability in Japan. Presentation by Yoichi Okumura, Global Head of IP, Takeda Pharmaceutical Company Limited. WIPO Conference on IP Dispute Resolution in Life Science, 22 May 2015. https://www.wipo.int/export/sites/www/ amc/en/docs/basel2015_okumura.pdf. Accessed 8 Mar 2021\n\nJapanese law Translation. www.japaneselawtranslation.go.jp. Accessed 8 Mar 2021 Jordan, Patents of Invention Law, Law No. 32 for the Year 19991 (and its amendment by: Temporary Law No. 71 for the Year 2001). https://www.sabaip.com/wp-content/uploads/ 2018/04/Jordan-Patent-Law.pdf. Accessed 8 Mar 2021", "n_tokens": 349, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-369-2", "doc_id": "medicine_vaccine_book", "page": 369, "text": "Jorge MF (2019) The USMCA must be amended to ensure access to affordable drugs in Mexico. Policy Brief No. 64, South Centre. https://www.southcentre.int/wp-content/uploads/2019/07/ PB64_The-USMCA-must-be-amended-to-ensure-access-to-affordable-drugs-in-Mexico_EN-1. pdf. Accessed 8 Mar 2021\n\nKhoo KH, Lucas M (2020) Singapore: patent linkage in Singapore – better to be safe than sorry, Mondaq. https://www.mondaq.com/patent/927960/patent-linkage-in-singapore-better-to-be- safe-than-sorry. Accessed 8 Mar 2021\n\nKiliç B, Maybarduk P (2011) Comparative analysis of the United States’ TPPA Intellectual Property Proposal and Peruvian Law, Public Citizen, October 2011. https://www.citizen.org/ wp-content/uploads/comparative_analysis_of_the_u.s._intellectual_property_proposal_and_ peruvian_law.pdf. Accessed 8 Mar 2021\n\nKoizumi S, Yamanouchi M, Eagan JA (2011) Recent changes concerning regulatory protections for pharmaceutical companies in Japan. https://www.amt-law.com/asset/res/news_2011en_pdf/ 110225_2055.pdf. Accessed 8 Mar 2021\n\nLaurenza EC (2015) The scope of ‘patent linkage’ in the US-South Korea Free Trade Agreement and the potential effects on international trade agreements. Eur J Risk Regul 6(3):439–442", "n_tokens": 368, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-370-0", "doc_id": "medicine_vaccine_book", "page": 370, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nLAW OF UKRAINE on the Protection of Rights to Inventions and Utility Models. https://", "n_tokens": 34, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-370-1", "doc_id": "medicine_vaccine_book", "page": 370, "text": "ukrpatent.org/i_upload/file/law-special-1.pdf. Accessed 8 Mar 2021\n\nLe LX, Mai LD (2015) The pharma maze: patent enforcement\n\nin Vietnam. Intellect Prop Mag:57–58. https://www.tilleke.com/sites/default/files/2015_Apr_Pharma_Maze_Patent_ Enforcement_Vietnam.pdf. Accessed 8 Mar 2021\n\nLexology (2020) Singapore’s patent linkage scheme and its effects on marketing approval for generic drugs. https://www.lexology.com/library/detail.aspx?g¼3f5760db-39a8-47fd-8d86- 95de83072e36. Accessed 8 Mar 2021\n\nLi W, Tong T (2018) Studies of legal issues related to the implementation of the patent linkage system in China. Biotechnol Law Rep 37:270–280. https://doi.org/10.1089/blr.2018.29090.wl Malakhov B (2019) Russia: on a slow boat to patent linkage? Kluwer Patent Blog. http://patentblog. kluweriplaw.com/2019/05/22/russia-on-a-slow-boat-to-patent-linkage/. Accessed 8 Mar 2021 Managing IP (2017) Vietnam: improving pharmaceutical IP protection. https://www.managingip. com/article/b1kbpj5jsl30y6/vietnam-improving-pharmaceutical-ip-protection. Accessed 8 Mar 2021\n\nManaging IP (2019) Australia: protecting pharmaceutical market share in Australia. https://www. managingip.com/Article/3865388/Australia-Protecting-pharmaceutical-market-share- in-Australia.html. Accessed 5 Mar 2021\n\nMcKenzie B (2019) Global guide to patent linkage. https://www.bakermckenzie.com/en/insight/\n\npublications/guides/global-guide-to-patent-linkage. Accessed 8 Mar 2021", "n_tokens": 447, "kind": "text"}
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{"chunk_id": "medicine_vaccine_book-370-3", "doc_id": "medicine_vaccine_book", "page": 370, "text": "Accessed 8 Mar 2021\n\nOno Pharmaceuticals Co., Ltd. v. Kyoto Pharmaceuticals Industries, Ltd. Judgment dated 16 April\n\n1999\n\nOrange Book: Approved drug products with therapeutic equivalence evaluations. https://www.\n\naccessdata.fda.gov/scripts/cder/ob/index.cfm. Accessed 5 Mar 2021\n\nPalombi L (2014) It’s time to fix the free trade bungle on the cost of medicines, The Conversation. http://theconversation.com/its-time-to-fix-the-free-trade-bungle-on-the-cost-of-medi cines-32574. Accessed 5 Mar 2021\n\nPatented Medicines (Notice of Compliance) Regulations. https://laws-lois.justice.gc.ca/eng/\n\nregulations/sor-93-133/index.html. Accessed 5 Mar 2021\n\nPay for Delay, Federal Trade Commission. https://www.ftc.gov/news-events/media-resources/\n\nmergers-competition/pay-delay\n\nPharmaceutical Association of Malaysia www.phama.org.my\n\n367", "n_tokens": 235, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-371-0", "doc_id": "medicine_vaccine_book", "page": 371, "text": "368\n\nK. D. Raju\n\nPharmaceutical Sector Inquiry – Preliminary Report, Fact Sheet “Regulatory Framework”. https://\n\nec.europa.eu/competition/sectors/pharmaceuticals/archive/4_Regulator_framework.pdf\n\nPolikarpov A (2015) “Bolar provision” in Ukraine: fiction or reality? Kluwer Patent Blog. http://\n\npatentblog.kluweriplaw.com/2015/02/19/bolar-provision-in-ukraine-fiction-or-reality/. Accessed 8 Mar 2021\n\nPress Information Bureau (2018) Government of India Make India the international capital for Generic Medicines: Vice President, 21 December 2018. https://pib.gov.in/newsite/PrintRelease. aspx?relid¼186696. Accessed 8 Mar 2021\n\nRaju KD (2009) Interpretation of Section 3(d) in the Indian Patent Act 2005: a case study of\n\nNovartis. Indian J Intellect Prop Law 2:7–32\n\nRaley KT (2019a) The South Korean patent linkage system: a model for reforming the United States\n\nHatch–Waxman Act. Emory Int Law Rev 33:459–492\n\nRaley KT (2019b) The South Korean patent linkage system: a model for reforming the United States Hatch–Waxman Act. Emory Int Law Rev 33(3). https://law.emory.edu/eilr/content/ volume-33/issue-3/comments/south-korean-patent-linkage-reforming-hatch-waxman-act.html. Accessed 8 Mar 2021\n\nRavikant, Raju, Padmavati (2013) The impact of patent linkage on marketing of generic drugs. J", "n_tokens": 366, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-371-1", "doc_id": "medicine_vaccine_book", "page": 371, "text": "Intellect Prop Rights 18:316–322\n\nReddie & Grose LLP (2020) What does the US-China trade deal mean for pharmaceutical patent holders? https://www.reddie.co.uk/2020/01/23/what-does-the-us-china-trade-deal-mean-for- pharmaceutical-patent-holders/. Accessed 8 Mar 2021\n\nResearch Report on Establishing System of Linking New Drug Application and Patent Protection, BIPI Research (2016) No. 002. http://www.theglobalipcenter.com/wp-content/uploads/2017/ 03/full-report-E.pdf. Accessed 5 Mar 2021\n\nSon K-B, Lee T-J (2017) The trends and constructive ambiguity in international agreements on\n\nintellectual property and pharmaceutical affairs. Global Public Health 13:1169–1178\n\nSon K-B et al (2018) Moderating the impact of patent linkage on access to medicines: lessons from variations in South Korea, Australia, Canada and the United States. Global Health 14:101. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201583/. Accessed 5 Mar 2021\n\nSon K-B et al (2019) Does the patent linkage system prolong effective market exclusivity? Recent evidence from the Korea-U.S. Free Trade Agreement in Korea. Int J Health Serv 49(2). https:// doi.org/10.1177/0020731418822237. Accessed 8 Mar 2021\n\nTaiwan International Patent and Law Office (2019) Taiwan FDA completes draft of enforcement rules for Western pharmaceuticals patent linkage. https://www.tiplo.com.tw/en/tn_in.aspx? mnuid¼1284&nid¼46776. Accessed 8 Mar 2021", "n_tokens": 406, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-371-2", "doc_id": "medicine_vaccine_book", "page": 371, "text": "Townsend B, Gleeson D, Lopert R. The regional comprehensive economic partnership, intellectual property protection and access to medicines. https://www.bilaterals.org/IMG/pdf/ssrn- id2850294.pdf. Accessed 5 Mar 2021\n\nTrans-Pacific Partnership Agreement (TPP) & Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP) https://fta.miti.gov.my/index.php/pages/view/71#:~: text¼Malaysia%20is%20still%20evaluating%20the,Prime%20Minister%20and%20his% 20Cabinet. Accessed 8 Mar 2021\n\nU.S. - Korea Free Trade Agreement. https://ustr.gov/trade-agreements/free-trade-agreements/korus-\n\nfta. Accessed 8 Mar 2021\n\nUkraine: Interim injunctions in pharma cases, Vasil Kisil & Partners. Lexology. https://www. lexology.com/library/detail.aspx?g¼0eb0c844-233d-4988-9774-efffe9ebcabd. Accessed 8 Mar 2021\n\nUnited Arab Emirates Ministry of Health and Prevention, Health Legislation. https://www.mohap.\n\ngov.ae/en/Aboutus/Pages/PublicHealthPolicies.aspx. Accessed 8 Mar 2021\n\nUnited News of India (2019) Generic drugs holds 70 pc market share in pharmaceutical sector in India. http://www.uniindia.com/generic-drugs-holds-70-pc-market-share-in-pharmaceutical-sec tor-in-india/south/news/1512004.html. Accessed 8 Mar 2021", "n_tokens": 387, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-372-0", "doc_id": "medicine_vaccine_book", "page": 372, "text": "Patent Linkages and Its Impact on Access to Medicines: Challenges,...\n\nUnited States – Singapore Free Trade Agreement. https://wits.worldbank.org/GPTAD/PDF/\n\narchive/US-Singapore.pdf. Accessed 8 Mar 2021\n\nWeatherall K (2016) RCEP IP Chapter Leaked 15 Oct 2015 - Weatherall Section by\n\nSection Comments in Brief Working paper (2016), University of Sydney\n\nWest FJ, Allison Hoppert B. Extending the life of a patent in the United States. https://www.oblon.", "n_tokens": 113, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-372-1", "doc_id": "medicine_vaccine_book", "page": 372, "text": "com/A11960/assets/files/News/125.pdf. Accessed 5 Mar 2021\n\nWhite B et al (2017) Canada’s Patent Linkage Regulations get long-awaited makeover, OSLER. https://www.osler.com/en/resources/regulations/2017/canada-s-patent-linkage-regulations-get- long-await. Accessed 5 Mar 2021\n\nWHO (2011–2016) Regional Framework for Action on Access to Essential Medicines in the Western Pacific (2011-2016). https://apps.who.int/iris/bitstream/handle/10665/207519/ 9789290615705_eng.pdf. Accessed 5 Mar 2021\n\nWHO (2020) Coronavirus disease (COVID-19) advice for the public: Mythbusters, 23 November 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public/ myth-busters?gclid¼EAIaIQobChMIjoGlirH06wIVhzMqCh3ISAVnEAAYASABEgKMz_ D_BwE. Accessed 5 Mar 2021\n\nWinkler AM, David Weingarten M, Cyr SK (2018) Requirements, benefits, and possible conse- quences of listing patents in FDA’s Orange Book. July 3, 2018, BNA’s Pharmaceutical Law & Industry Report. https://www.finnegan.com/en/insights/requirements-benefits-and-possible-con sequences-of-listing-patents-in-fdas-orange-book.html. Accessed 5 Mar 2021\n\nZhang H, Li R, Min D, Yuxin J (2018) China is to establish patent linkage, Kluwer Patent Blog. http://patentblog.kluweriplaw.com/2018/04/03/china-establish-patent-linkage/. Accessed 8 Mar 2021", "n_tokens": 426, "kind": "text"}
{"chunk_id": "medicine_vaccine_book-372-2", "doc_id": "medicine_vaccine_book", "page": 372, "text": "Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.\n\nThe images or other third party material in this chapter are included in the chapter’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.\n\n369", "n_tokens": 167, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-0-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 0, "text": "G R x+BIOSIMS\n\nUnderstanding Regulatory Expectations for Post- Approval Changes in ANDAs\n\nOlugbenga “Gbenga” Okubadejo, PharmD Division Director, DRBPM III (Post Marketing Activities) Office of Program and Regulatory Operations Office of Pharmaceutical Quality Center for Drug Evaluation and Research Food and Drug Administration\n\nNovember 10th, 2021\n\n| VIR T UAL CONFERE NCE\n\n| NO VEMBER 8-10, 2021\n\n# G R x+BIOSIMS\n\n1\n\n| G R x+BIOSIMS.ORG", "n_tokens": 110, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-1-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 1, "text": "Pharmaceutical Quality\n\nA quality product of any kind consistently meets the expectations of the user.\n\nwww.fda.gov\n\n2", "n_tokens": 22, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-2-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 2, "text": "Pharmaceutical Quality\n\nA quality product of any kind consistently meets the expectations of the user.\n\nDrugs are no different.\n\nwww.fda.gov\n\n3", "n_tokens": 27, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-3-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 3, "text": "Patients expect safe and effective medicine with every dose they take.\n\nwww.fda.gov\n\n4", "n_tokens": 18, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-4-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 4, "text": "Pharmaceutical quality is\n\nassuring every dose is safe and effective, free of contamination and defects.\n\nwww.fda.gov\n\n5", "n_tokens": 24, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-5-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 5, "text": "It is what gives patients confidence in their next dose of medicine.\n\nwww.fda.gov\n\n6", "n_tokens": 19, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-6-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 6, "text": "Communication Expectations and Best Practices\n\nwww.fda.gov\n\n7\n\n7", "n_tokens": 12, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-7-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 7, "text": "OUTLINE\n\nForm FDA 356h • Supplement Cover Letter • Module 3 • Drug Master File facility related changes • Drug Substance Manufacturing Process Changes • Facility related changes • Nitrosamine Risk Assessment Reports • Submission Status Inquiries • Grouped Supplements • Priority Review Requests • Secure Email • Post Marketing Inquiries\n\n8", "n_tokens": 56, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-8-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 8, "text": "FORM FDA 356h\n\nUse Updated version (08/18) - https://www.fda.gov/media/72649/download • Address status (i.e. pending, active, inactive, and withdrawn) for all facilities within your application and not limited to the submission\n\nUpdate with subsequent submissions •\n\nInclude all relevant manufacturing facilities associated with the application. See FDA Guidance for Industry: Identification of Manufacturing Establishments in Applications Submitted to CBER and CDER, Questions and Answers for information on which facilities need to be included on Form 356h and other sections of the supplemental application\n\nAll Manufacturing/Packaging/Testing sites used by the referenced Drug Master File (DMF)\n\n9", "n_tokens": 137, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-9-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 9, "text": "FORM FDA 356h\n\nDrug Substance Manufacturing Facilities including the following;\n\nCritical Intermediate manufacturing facilities – Routine/Skip Testing facility used for release and stability specifications – Micronization Facilities – Sterilization Facilities\n\nField 24 – Indicate if the product proposed within the submission is a combination product [e.g., drug-device, drug-biological product, drug-device-biological product, see 21 CFR 3.2(e)]. https://www.fda.gov/combination-products/about-combination- products\n\n10", "n_tokens": 107, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-10-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 10, "text": "SUPPLEMENT COVER LETTER\n\nClearly identify the overall proposed change classification as either CBE-0, CBE-30, or PAS. For multiple changes, a summary table listing each changes and the classification with justification for each\n\n11", "n_tokens": 41, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-11-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 11, "text": "SUPPLEMENT COVER LETTER • All proposed changes in the entire submission (including all facility\n\nchanges which will be noted in module 3)\n\nAny referenced Drug Master File (DMF)? Include the DMF #\n\nIs submission based on a specific DMF amendment? Reference the DMF amendment letter to the agency or submission date in the cover letter\n\nAre there other previously pending, recent, or approved submissions with the same/similar proposed change(s)? Include the information\n\nFor PAS submission based on CBE denied to PAS reference the FDA communication\n\n12", "n_tokens": 108, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-12-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 12, "text": "MODULE 3", "n_tokens": 2, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-13-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 13, "text": "MODULE 3\n\nSection of the common technical document (CTD) regulatory submissions format that contains all the required quality information and data corresponding to the registration of a pharmaceutical product. Includes requirements for presenting manufacturing, characterization, drug substance controls, stability characteristics, descriptions and compositions of pharmaceuticals, and other essential information.\n\nAll intended CMC changes should be accompanied with information in this module and not only limited to description of changes in the cover letter\n\nIf an excipient is considered critical to the drug product performance, the testing facilities should be listed under this module\n\n14", "n_tokens": 109, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-14-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 14, "text": "Drug Master File Facility Related Changes\n\nAgency will consider all facilities that are listed in a DMF apply to the referencing ANDA application(s) unless explicitly stated in the DMF Letter of Authorization (LOA) that only certain facilities will be used by the referencing application\n\nAddition of critical DMF intermediates and testing sites which impact your application requires submission of a supplement\n\nPrior to submitting supplement for DMF related changes such an alternate API source, etc. communicate with DMF holder to inquire about status of their DMF to avoid delays or unexpected outcomes especially prior to submitting Complete Response deficiencies. This also includes cGMP status of their manufacturing sites.\n\n15", "n_tokens": 140, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-15-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 15, "text": "DRUG SUBSTANCE MANUFACTURING PROCESS CHANGES\n\nSubmissions should include Certificate of Analysis (CoA) for both the Drug Substance and Drug Product Manufacturer\n\nIf either is missing an Information Request will be issued and this may potentially delay filing classification\n\n16", "n_tokens": 41, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-16-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 16, "text": "Facility Related Changes • Awareness of most recent cGMP surveillance classification for the proposed\n\nfacility from business partners\n\nResource: FDA Inspection Database: https://www.fda.gov/inspections- compliance-enforcement-and-criminal-investigations/inspection-classification- database\n\no Not all inspections are included in the database. Inspections conducted by States, pre-approval inspections, mammography facility inspections, inspections waiting for a final enforcement action, and inspections of nonclinical labs are not included. Inspections of nonclinical labs are available at Nonclinical Laboratories Inspected under Good Laboratory Practices.\n\no The results show final classifications of No Action Indicated (NAI), Voluntary\n\nAction Indicated (VAI), Official Action Indicated (OAI) for each project area within an inspection.\n\n17", "n_tokens": 159, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-17-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 17, "text": "NITROSAMINE RISK ASSESSMENT REPORTS\n\nThe risk assessment reports, and any risk determined therein, are generally not\n\nassessed in application evaluation In accordance with the Guidance for Industry Control of Nitrosamine Impurities in Human Drugs (final, February 2021), risk assessment reports should not be submitted to the Agency for review but should be retained so that these documents are available upon request from a manufacturing site.\n\nHowever, where nitrosamines are detected, changes implemented to prevent or reduce nitrosamine impurities in active pharmaceutical ingredients and drug products should be reported in accordance with 21 CFR 314.420(c) and changes to approved applications as required under 21 CFR 314.70 and 314.97 and pending applications under 21 CFR 314.60 and 314.96\n\n18", "n_tokens": 157, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-18-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 18, "text": "Submission Status Inquiries\n\nAll CBE grant determinations, 30 days from the FDA receipt date\n\nCompletion of CBE assessments, generally 6-10 months from FDA receipt date (except for drug shortage or Public Health Emergency situations)\n\nPrior Approval Supplements, Acknowledgement Letter issued generally no later than day 30 from FDA receipt date\n\n19", "n_tokens": 60, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-19-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 19, "text": ") S A P ( S E N I L E M I T\n\nSubmission Type Standard PAS or PAS Major Amendments\n\nPriority PAS or PAS Major Amendments\n\nStandard and Priority PAS Minor Amendments\n\nGeneral Expected Completion 6-10 months depending on preapproval inspection requirements 4-10 months depending on preapproval inspection requirements, submission of complete and accurate Pre- Submission Facility Correspondence (PFC) 3 months\n\n20", "n_tokens": 79, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-20-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 20, "text": "Grouped Supplements\n\nRefer to MAPP 5015.6 Rev 1 – Office of Pharmaceutical Quality Review of Grouped Product Quality Supplements\n\nIdentical CMC post-approval changes that affect multiple approved applications\n\nTwo or more supplements reviewed and processed using the procedures and assigned to same assessment team\n\nThe supporting data necessary for the review of the CMC changes should be the same for each of the grouped supplements\n\n21", "n_tokens": 74, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-21-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 21, "text": "Grouped Supplements\n\nAny supplement that provides for the same CMC changes but necessitates the review of data that is unique to that supplement (e.g., product specific data) should not be grouped – However, should be mentioned in the cover letter\n\nThe cover letter for the supplements should clearly state the purpose of the proposed CMC changes and indicate that the supplement is one of multiple submissions for the same change\n\nSubmit cover letter and module 3 information to each supplement within the group\n\n22", "n_tokens": 96, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-22-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 22, "text": "PRIORITY REVIEW REQUESTS\n\nMAPP 5240.3 Rev. 5 – Office of Generic Drugs Prioritization of the Review of Original ANDAs, Amendments, and Supplements\n\nFDA will only consider a request for priority review when (1) the cover letter to the submission clearly states “Priority Review Requested” and references the ANDA number; (2) the basis for the request is consistent with this MAPP; (3) the applicant clearly and briefly states the basis for the request, including the prioritization factor(s); and (4) the applicant includes sufficient supporting documentation for the request\n\nIf a Complete Response Letter is issued, the resubmission needs to follow the same process if you desire a priority review\n\n23", "n_tokens": 143, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-23-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 23, "text": "SECURE EMAIL\n\nFDA communications via unsecure email cannot include commercial confidential information (e.g. application numbers or information, trade secrets, manufacturing, or patient information). Therefore, sponsors/applicants should establish secure email with FDA to allow for informal communications that may include commercial confidential information\n\nThis applies to all applicants and DMF holders\n\nUnsecure email leads to communication delays\n\nIf you have not already established secure email with the FDA and would like to set it up, send an email request to SecureEmail@fda.hhs.gov\n\n24", "n_tokens": 109, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-24-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 24, "text": "POST-MARKETING INQUIRIES\n\nManufacturing (CMC) Supplements: Contact the Project Owner OGD RPM or OPQ RBPM who issued the Acknowledgement Letter\n\nControlled Correspondence: Inquiries concerning CMC post-approval submission requirements that are not covered by CDER post-approval changes guidance and are not specific to an abbreviated new drug application (ANDA) should be submitted via a Standard Controlled Correspondence using the CDER Direct NextGen Collaboration Portal\n\nInquiries about CMC post-approval submission requirements which do not qualify as controlled correspondence and not covered under any of the CDER post-approval guidances: CDER-OPQ-Inquiries@fda.hhs.gov\n\n25", "n_tokens": 130, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-25-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 25, "text": "POST-MARKETING INQUIRIES\n\nLabeling Supplements: - genericdrugs@fda.hhs.gov\n\nANDA Transfer of Ownership, Withdrawal and Consolidation are managed by the Office of Generic Drugs - genericdrugs@fda.hhs.gov\n\n26", "n_tokens": 49, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-26-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 26, "text": "Lhanh youl\n\nwww.fda.gov 27", "n_tokens": 11, "kind": "text"}
{"chunk_id": "olugbengaokubadejoAAM2021-27-0", "doc_id": "olugbengaokubadejoAAM2021", "page": 27, "text": "AY U.S. FOOD & DRUG\n\nADMINISTRATION", "n_tokens": 10, "kind": "text"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-0-1", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 0, "text": "Center for Drug Evaluation and Research - Compliance Central with FDA Center Compliance Directors: Part 1\n\nDonald D. Ashley, JD\n\n2017 FDLI Enforcement, Litigation, and Compliance Conference: For the Drug, Device, Food, and Tobacco Industries\n\nDecember 6, 2017\n\nFooter text: www.fda.gov\n\nThis slide contains no charts, tables, diagrams, or other images.", "n_tokens": 73, "kind": "vision"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-1-1", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 1, "text": "CDER Office of Compliance Overview\n\nThe image is a title-style slide with a white background. The title \"CDER Office of Compliance Overview\" appears in large blue letters across the top, with \"CDER Office of Compliance\" on the first line and \"Overview\" on the second line.\n\nBelow the title is an illustration of pharmaceutical items on a light gray surface. From left to right and back to front:\n- A syringe lying horizontally, with a clear barrel and a green plunger/hub and needle extending to the right. The barrel has the printed label \"High Quality?\"\n- Several white oval tablets stacked in the background on the left.\n- A large capsule with a blue end and white body, angled upward, with the printed word \"Effective?\" running along it.\n- A red and white capsule lying on the right, with the printed word \"Safe?\" on its white section.\n\nThe slide includes the website \"www.fda.gov\" in blue text in the bottom left corner.", "n_tokens": 205, "kind": "vision"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-3-1", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 3, "text": "Responsibility Throughout Lifecycle\n\nThis is a diagram showing which FDA offices hold responsibility at each stage of a drug's lifecycle. Four column headings run across the top from left to right: PREAPPROVAL, APPROVAL, POSTMARKET, and CUSTOMER DISTRIBUTION. Dashed vertical lines separate these stages. Several blue chevron arrows run left to right across the stages, and a gold arrow sits below a horizontal black line.\n\nPREAPPROVAL stage, first blue arrow: \"OSI\" with the bullets \"Animal studies,\" \"Human clinical trials,\" and \"Good Laboratory Practice.\"\n\nAPPROVAL stage, blue arrow: \"OMQ & OSI\" with the bullets \"GMP inspections,\" \"Generic drug bioequivalence,\" and \"Human clinical trials.\"\n\nPOSTMARKET stage, blue arrow: \"OMQ, OSI & OUDLC\" with the bullets \"PMR, REMS, and PADE,\" \"GMP inspections,\" and \"Labeling Requirements.\"\n\nCUSTOMER DISTRIBUTION stage, lower blue arrow: \"ODSIR\" with the bullets \"Import/Export Compliance,\" \"Recalls/Shortages,\" \"Supply Chain Integrity,\" and \"DSCSA.\"\n\nBelow the black horizontal line, the label \"Outside the Normal Lifecycle\" appears in blue text. A large gold arrow spans the full width beneath it, labeled \"ODSIR & OUDLC\" with the bullets \"Internet Pharmacies and Counterfeit Drugs\" and \"Marketed Unapproved Drugs, OTC Drug Compliance, Health Fraud, and Compounding.\"\n\nThe footer in the lower left reads \"www.fda.gov.\"", "n_tokens": 335, "kind": "vision"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-8-1", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 8, "text": "Concept of Operations (\"ConOps\")\n\nThe slide is a text-only bulleted list with no charts, tables, diagrams, or images beyond the FDA logo and slide number, which are omitted here. The bullets read:\n\nEnsures consistency, efficiency and transparency\n\nAdvances strategic alignment by creating clear roles and responsibilities\n\nImproves operational capacity by enhancing collaboration\n\nMeets User Fee commitments\n\nImproves timeline for actions\n\nThe footer shows the website www.fda.gov.", "n_tokens": 87, "kind": "vision"}
{"chunk_id": "2017_FDLI_Compliance_Central_Presentation-14-1", "doc_id": "2017_FDLI_Compliance_Central_Presentation", "page": 14, "text": "THANK YOU\n\nThis slide has a white background with the bold black title \"THANK YOU\" centered in the middle. It contains no charts, tables, diagrams, or other images. Footer text in the lower left reads \"www.fda.gov\".", "n_tokens": 51, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-0-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 0, "text": "OGD UPDATE: Welcome to much more than GDUFA II\n\nThe slide is a title slide with no charts, tables, diagrams, or images beyond the FDA logo, which is omitted as instructed.\n\nPresenter text below the title:\nKathleen Uhl, MD\nDirector, Office of Generic Drugs\nCDER/FDA\n\nEvent text below the presenter details:\nAAM GRx+Biosims Conference\nSeptember 7, 2017", "n_tokens": 81, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-1-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 1, "text": "Disclaimer\n\nThis slide contains two bulleted statements of text and no charts, tables, diagrams, or images.\n\nThe first bullet reads: \"This presentation reflects the views of the speaker and do not reflect official FDA, HHS, or other government opinion or policy.\"\n\nThe second bullet reads: \"I have nothing to disclose.\"", "n_tokens": 68, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-3-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 3, "text": "OUTLINE\n\nThis slide is a text-only agenda with no charts, tables, diagrams, or other images. It lists five numbered items:\n\n1. Status of Generic Drug Program\n2. OGD Accomplishments\n3. GDUFA II\n4. Non-GDUFA activities\n5. Closing Comments", "n_tokens": 57, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-4-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 4, "text": "STATUS OF GENERIC DRUG PROGRAM\n\nThis slide has no charts, tables, diagrams, or images beyond the title text. The slide is otherwise blank white space.", "n_tokens": 30, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-7-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 7, "text": "GENERIC DRUG PROGRAM\nProgram Data/Analytics\n\nBullet text:\nFDA's generic drug program is in \"Steady State\" (Steady State is bold and underlined).\nAll ANDA submissions have GDUFA goals, as of 8/1/18.\nSub-point: \"Bridging\" of GDUFA I pre-Year 3 ANDAs - COMPLETE (COMPLETE is bold and underlined).\n\nDiagram: Two pairs of meshing gears, separated by a pink parallelogram with the italic text \"input/output\" in the center. The diagram is not a chart, has no axes, units, or numbers.\nLeft gear pair: A large gear on the left and a small gear on the right, meshed together. The label \"Input\" is above the large gear and \"Output\" is above the small gear. Curved blue arrows above each gear show their rotation direction.\nRight gear pair: A small gear on the left and a large gear on the right, meshed together. The label \"Input\" is above the small gear and \"Output\" is above the large gear. Curved blue arrows above each gear show their rotation direction.\n\nAttribution text at bottom: \"This Photo by Unknown Author is licensed under CC BY-SA,\" with \"This Photo\" and \"CC BY-SA\" as hyperlinks.", "n_tokens": 272, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-11-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 11, "text": "GENERIC DRUG PROGRAM\nOngoing Challenges\n\nThe slide contains a numbered list of three items, followed by a concluding statement in larger text:\n\n1. Large number of RTRs\n2. Low first cycle approvals\n3. In general, multiple review cycles to AP/TA\n\nInefficient and leads to a huge amount of re-work for FDA and applicants alike\n\nThere are no charts, tables, diagrams, or other images on this slide.", "n_tokens": 86, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-13-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 13, "text": "TOP 3 REASONS* FOR RTR\n\nThis slide contains a single table with one column headed \"DEFICIENCY\" and three numbered rows:\n1. Inadequate Stability\n2. Inadequate Dissolution\n3. Impurities\n\nFootnote at the bottom of the slide: \"* Analysis of FY2017 Year 5 cohort: 168 RTRs on 1,320 ANDAs.\"", "n_tokens": 70, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-19-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 19, "text": "GDUFA I ANDAs*\n\nFigure 1: Application Status for GDUFA I ANDAs. This is a pie chart with five slices, each labeled with a status and a count. No axis labels, units, or legend are shown; the labels sit beside each slice.\n\nSlice labels and counts:\n- 1st Cycle Approval, 594 (blue slice, upper right)\n- 2nd Cycle Approval, 691 (red slice, right)\n- 3rd or Above Cycle Approval, 265 (green slice, lower right)\n- Complete Response, 1376 (purple slice, bottom left)\n- Under Review, 1111 (teal slice, upper left)\n\nA bracket on the right side of the chart groups the first three approval slices and is labeled \"AP = 1550.\"\n\nBelow the chart, the text \"Off FDA's Books\" appears under the Complete Response and Under Review area.\n\nFootnote text: \"*Data as of 5/31/2018, Data Source: ANDAs originally submitted during GDUFA I, internal FDA database. Data generated by CDER/OTS/OB, Jingyu (Julia) Luan, PhD, Jing Han, PhD, and Stella Grosser, PhD.\"", "n_tokens": 243, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-23-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 23, "text": "GDUFA\n\nThis slide is a flowchart made of three text boxes connected by two downward block arrows. Reading top to bottom:\n\n1. \"GDUFA\" (plain bold text at the top), with a downward arrow below it.\n2. A pink rectangular box containing: \"TRANSFORM THE PROGRAM\", then \"and\" in smaller text, then \"PERFORM WHILE TRANSFORM\". A second downward arrow follows.\n3. A box outlined in red containing \"NEED TO BUILD A QUALITY SYSTEM\" in dark blue text.\n\nFooter text at the bottom left reads: \"Slide from Uhl Presentation October 2014, GPhA Fall Technical Conference\", with \"October 2014\" underlined.", "n_tokens": 139, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-24-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 24, "text": "GDUFA\n\nThis slide is a simple flow diagram with three stacked elements connected by two large blue downward arrows.\n\nAt the top is the text \"GDUFA,\" with a downward arrow beneath it.\n\nNext is a pale pink rectangular box containing: \"TRANSFORM THE PROGRAM,\" then \"and\" in smaller type, then \"PERFORM WHILE TRANSFORM.\" A second downward arrow leads from this box to the bottom element.\n\nAt the bottom, inside a red-outlined rectangle, is \"FDA BUILT A QUALITY SYSTEM,\" with the word \"BUILT\" underlined. Below it, in italics, is \"Exemplary drug regulatory program.\"", "n_tokens": 128, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-25-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 25, "text": "OGD ACCOMPLISHMENTS\n\nThis slide is a section title slide. It contains the title \"OGD ACCOMPLISHMENTS\" in large bold black capital letters, centered horizontally in the middle of a plain white background. There are no charts, tables, diagrams, or other images on the slide.", "n_tokens": 54, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-28-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 28, "text": "OGD ACCOMPLISHMENTS\n\nImplemented new pre-ANDA program for complex generic drug products per GDUFA II\n– 68 pre-ANDA meeting requests*\n• Double the pre-GDUFA II number\n• 100% grant/deny within 30 days\n• 100% granted meetings within 120 days\n\n* Data as of 8/8/18\n\nThe slide contains no charts, tables, diagrams, or images other than the FDA logo and slide number, which are omitted.", "n_tokens": 90, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-30-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 30, "text": "OGD ACCOMPLISHMENTS\n\nOrange Book Updates\nAddition of patent submission date\nReceiving/processing one-time marketing status updates for products in the active section (FDARA requirement)", "n_tokens": 31, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-39-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 39, "text": "GDUFA II (clarifications)\n\nThis slide has no charts, tables, diagrams, or other images beyond the text. The slide contains the title \"GDUFA II\" with the subtitle \"(clarifications)\" in bold black text on a white background, centered in the upper-middle area. The remainder of the slide is blank.", "n_tokens": 76, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-44-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 44, "text": "GDUFA II\n\n\"Goals\" or \"Commitment\" letter:\nhttp://www.fda.gov/downloads/forindustry/userfees/genericdruguserfees/ucm525234.pdf\n\nPLEASE READ!", "n_tokens": 51, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-45-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 45, "text": "NON-GDUFA ACTIVITIES\n\nThis slide has a white background with the title \"NON-GDUFA ACTIVITIES\" centered in large bold black capital letters. It contains no charts, tables, diagrams, or other images. The U.S. Food & Drug Administration logo appears in the upper right corner, which is omitted from this description.", "n_tokens": 68, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-50-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 50, "text": "CLOSING COMMENTS\n\nThe slide has a white background with the words \"CLOSING COMMENTS\" in large, bold, black capital letters, centered horizontally in the upper-middle portion of the slide. The rest of the slide is blank. It contains no charts, tables, diagrams, or other images.", "n_tokens": 57, "kind": "vision"}
{"chunk_id": "AAMGRxBiosimsSept2018_UHL-52-1", "doc_id": "AAMGRxBiosimsSept2018_UHL", "page": 52, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images, and no other text, numbers, or labels are visible.", "n_tokens": 32, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-0-1", "doc_id": "AAMkeynoteChoe2021", "page": 0, "text": "Association for Accessible Medicines GRx+Biosims 2021\n\nOFFICE OF GENERIC DRUGS\nKEYNOTE\nSally Choe, Ph.D.\nDirector, Office of Generic Drugs\nCenter for Drug Evaluation and Research\nU.S. Food and Drug Administration\nNovember 9, 2021", "n_tokens": 48, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-1-1", "doc_id": "AAMkeynoteChoe2021", "page": 1, "text": "Generic Drug Access\n\nThis slide contains a circular cycle diagram with four blue segments, each connected by gray curved arrows that run clockwise around the circle. The segments, starting at the top left and moving clockwise, read:\n\nCOVID-19 (top left)\nComplex Generics (top right)\nFDA Partnerships (bottom right)\nGDUFA II Successes (bottom left)\n\nThe diagram has no axes, units, legend, numbers, or other data beyond these four labels.", "n_tokens": 92, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-3-1", "doc_id": "AAMkeynoteChoe2021", "page": 3, "text": "GDUFA II Commitments\n\nThe slide has four blue rectangular boxes arranged in a two-by-two grid. There are no charts, tables, or numerical data.\n\nTop left box: ANDA original applications\nTop right box: ANDA prior approval supplements\nBottom left box: Controlled Correspondence\nBottom right box: Product-Specific Guidance\n\nThe footer shows the website www.fda.gov.", "n_tokens": 76, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-4-1", "doc_id": "AAMkeynoteChoe2021", "page": 4, "text": "Increasing Generic Drug Access\n\nThe slide has three horizontal blue banners, each with a small photo on the left and a text label on the right.\n\nBanner 1: The photo shows a close-up of rows of small glass vials or bottles with paper labels. The text reads \"670+ full approvals.\"\n\nBanner 2: The photo shows a glass vial or bottle with a metal cap, set against a blurred background. The text reads \"90+ first generics.\"\n\nBanner 3: The photo shows a large assortment of colorful pills, tablets, and capsules in many colors. The text is underlined and reads \"Milestone 100+ cumulative Competitive Generic Therapy (CGT) approvals.\"\n\nFooter: The website \"www.fda.gov\" appears at the bottom left.", "n_tokens": 158, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-6-1", "doc_id": "AAMkeynoteChoe2021", "page": 6, "text": "Product-Specific Guidances (PSGs)\n\nLeft side, text bullets:\nScientific advice to assist generic drug product development.\nSub-point: Revisions driven by science and research.\n135 PSGs in FY21.\nSub-points: 53 (39%) PSGs for complex products. 20 PSGs provided a more efficient BE approach.\nNew PSG snapshot infographic.\n\nRight side, screenshot of an FDA web page titled \"Product-Specific Guidances for Generic Drug Development.\" Social share buttons (Share, Tweet, LinkedIn, Email, Print) appear at the top. A blue button reads \"Search Product-Specific Guidances for Generic Drug Development.\" The body text reads: \"To further facilitate generic drug product availability and to assist the generic pharmaceutical industry with identifying the most appropriate methodology for developing drugs and generating evidence needed to support ANDA approval, FDA publishes product-specific guidances describing the Agency's current thinking and expectations on how to develop generic drug products therapeutically equivalent to specific reference listed drugs.\" Next paragraph: \"Increased transparency on product-specific guidances gives applicants seeking to develop generic drugs a better opportunity to efficiently allocate resources. The agency aims to ensure that policies and regulations – and scientific standards – keep pace with the science of equivalence. Improving patient access to high quality and affordable medicines supports FDA's mission to advance the public health.\" Next paragraph, cut off at the bottom: \"The agency routinely posts and revises product-specific guidances. FDA always seeks feedback and considers all...\" A thumbnail of the \"FDA Product-Specific Guidance Snapshot\" infographic appears on the right, with blue, orange and dark panels. Its small text is not legible. A caption below it reads \"FDA Product Specific Guidance Snapshot (PDF 150KB).\"\n\nFooter: www.fda.gov", "n_tokens": 382, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-7-1", "doc_id": "AAMkeynoteChoe2021", "page": 7, "text": "Complex Generics\n\nThe slide has three photographs in a row, with no charts, tables, diagrams, or readable text beyond the title and the website.\n\nLeft image: Several glass ampoules and vials, some with clear liquid and others with colored liquids in green, blue, yellow, and amber tones. The ampoules are narrow and necked, with some tilted and overlapping.\n\nMiddle image: Blue-toned blister packaging with several oval tablets or capsules pressed into the foil pockets. The pills are shown close up with a shallow depth of field.\n\nRight image: Laboratory glassware on a light surface, including a graduated cylinder filled with blue liquid, several Erlenmeyer flasks containing green and teal liquids, and a yellow liquid in a flask. A glass funnel sits above the cylinder.\n\nWebsite text at bottom left: www.fda.gov", "n_tokens": 177, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-8-1", "doc_id": "AAMkeynoteChoe2021", "page": 8, "text": "FDA's Pre-ANDA Program\n\nThe slide contains a diagram of five blue rectangular boxes with white text, arranged in two rows: three boxes in the top row and two boxes in the bottom row centered beneath them. Reading left to right, top row: \"Reduce time from development to market\"; \"Address complex scientific issues\"; \"Communicate with prospective applicants.\" Bottom row: \"Help applicants develop more complete submissions\"; \"Clarify regulatory expectations.\"\n\nThe footer shows the website \"www.fda.gov.\"", "n_tokens": 107, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-9-1", "doc_id": "AAMkeynoteChoe2021", "page": 9, "text": "The Center for Research on Complex Generics\n\nA faded light blue-gray graphic appears in the upper left corner. Its content is hard to make out.\n\nDiagram: Five dark blue rounded rectangles sit side by side, each shading from darker at the top to lighter at the bottom. Each rectangle has an empty white circle near its top and a white label below it. From left to right, the labels are:\n1. research and training\n2. webinars\n3. workshops\n4. laboratory projects\n5. Scholars program\n\nA light blue-gray double-headed arrow runs horizontally beneath all five rectangles, spanning from the left edge of the first to the right edge of the last. No numbers, axes, or legend appear on the slide.\n\nFooter text in blue at bottom left reads: www.fda.gov", "n_tokens": 167, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-11-1", "doc_id": "AAMkeynoteChoe2021", "page": 11, "text": "Global Engagement\n\nThis slide contains a diagram: a left-to-right flow of four overlapping circles connected by large dark blue arrows. The circles, in order, read:\n\n1. Parallel Scientific Advice with European Medicines Agency\n2. ICH Generic Drug Discussion Group and ICH M13 Expert Working Group\n3. Generic Drug Global Cluster\n4. International Pharmaceutical Regulators Programme Working Groups\n\nThe background is a faded image of the Earth viewed from space. The footer shows the website www.fda.gov.", "n_tokens": 96, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-12-1", "doc_id": "AAMkeynoteChoe2021", "page": 12, "text": "Upcoming Events\n\nLeft side: a blue underlined hyperlink reading \"GDUFA III Public Meeting.\" Below it is a screenshot of a webpage titled \"Generic Drug User Fee Amendments.\" Above the text is a row of share buttons labeled \"Share,\" \"Tweet,\" \"LinkedIn,\" \"Email,\" and \"Print.\" The visible text reads: \"On August 18, 2017, the President signed into law the Food and Drug Administration Reauthorization Act (FDARA), which includes the reauthorization of the Generic Drug User Fee Amendments (GDUFA) through September 2022. Congress first enacted GDUFA in 2012, following negotiations between the FDA and industry and with input from public stakeholders. Congress enacted GDUFA to ensure patients have access to safe, high-quality, and affordable generic drugs. GDUFA enables FDA to assess industry user fees to bring greater predictability and timeliness to the review of generic drug applications.\" The next line reads: \"This page features news and information for industry and stakeholders about GDUFA, its\" and is cut off.\n\nRight side: a promotional graphic for a workshop. A photo on the right shows a syringe needle inserted into a medicine vial, with a blue-toned background. The text on the left of the graphic reads: \"Establishing the Suitability of Model-Integrated Evidence to Demonstrate Bioequivalence for Long-Acting Injectable and Implantable Drug Products Workshop.\" Below that, in red capital letters: \"NOVEMBER 30, 2021.\" At the bottom are two logos: \"Center for Research on Complex Generics\" and \"U.S. Food & Drug Administration.\"\n\nFooter: \"www.fda.gov\"", "n_tokens": 359, "kind": "vision"}
{"chunk_id": "AAMkeynoteChoe2021-14-1", "doc_id": "AAMkeynoteChoe2021", "page": 14, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or images other than the FDA logo, which is omitted as requested. No numbers, axis labels, or legend entries appear.", "n_tokens": 41, "kind": "vision"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-0-1", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 0, "text": "Biosimilar Regulatory Policy: Understanding the Landscape and Relevance to Medical Practice\n\nPresenter credit (white band at bottom left): Sue Lim, M.D., Director of the Scientific Staff, Therapeutic Biologics and Biosimilars Staff/CDER/FDA\n\nImages: The background is a blue-to-yellow gradient, running from dark navy at the lower left through medium blue to golden yellow at the right. Along the right side and across the top and bottom edges are many small, stylized line drawings of antibody molecules, each shaped like a Y with two square-like antigen-binding arms and a stem. The drawings are outlined in white or pale tones and vary in size and orientation. They are decorative and contain no numbers, labels, axes, or legends.", "n_tokens": 156, "kind": "vision"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-1-1", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 1, "text": "Disclosure Information\n\n- I have no financial relationships to disclose.\n- I will not discuss off label use and/or investigational use in my presentation.", "n_tokens": 29, "kind": "vision"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-2-1", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 2, "text": "Overview of Presentation\n\nBulleted outline with the following items and sub-items:\n\nBiosimilars\n- Data supporting approval\n- Clinical studies and extrapolation\n\nInterchangeable Products\n- Data supporting approval\n- Switching study design\n\nKey Points and Practical aspects\n- \"Substitution\" vs \"Switch\" vs. \"Switches\"\n\nSummary\n\nThe slide contains no charts, tables, diagrams, or images other than the FDA logo, which is omitted.", "n_tokens": 82, "kind": "vision"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-3-1", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 3, "text": "Biosimilars: Data to Support Approval\n\nThis slide has no charts, tables, diagrams, or images beyond the title text. The slide title is \"Biosimilars: Data to Support Approval,\" set in blue bold type on a white background.", "n_tokens": 52, "kind": "vision"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-10-1", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 10, "text": "Extrapolation Considerations: \"Stand-alone\" Drug Development\n\nThe diagram shows four indications for a drug, each drawn as a column of green boxes. A red rectangle outlines the top row of boxes across all four columns.\n\nIndication 1 (leftmost column) is a stack of four green boxes. From top to bottom they read: \"Clinical Safety & Efficacy\" (also inside the red outline), \"Clinical Pharmacology\", \"Animal\", and \"Analytical\". Below the stack is the label \"Indication 1\".\n\nIndication 2, Indication 3, and Indication 4 each have a single green box reading \"Clinical Safety & Efficacy\", which sits inside the red outline. Below each box is its label: \"Indication 2\", \"Indication 3\", and \"Indication 4\" respectively.\n\nNo axes, units, legend entries, or numerical values appear on the slide.", "n_tokens": 179, "kind": "vision"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-12-1", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 12, "text": "Interchangeable Products: Data to Support Approval\n\nThis slide has no charts, tables, diagrams, or other images. It contains only the title text, centered in blue bold type on a white background.", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice-26-1", "doc_id": "Biosimilar_Regulatory_Policy_Understanding_the_Landscape_and_Relevance_to_Medical_Practice", "page": 26, "text": "Slide title: None visible. The slide contains only closing text.\n\nText on the slide, centered on a white background:\n\"Thank you for your attention.\"\n\"For more information, go to www.fda.gov/biosimilars\"\n\nThe web address is underlined and appears as a hyperlink.", "n_tokens": 63, "kind": "vision"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-0-1", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 0, "text": "Biosimilar and Interchangeable Products: The U.S. FDA Perspective\n\nThe slide has a blue-to-yellow gradient background with a decorative pattern of stylized antibody-like Y-shaped illustrations in outline form, mostly along the right side and in the lower right corner. These are decorative only and contain no data, labels, or numbers.\n\nPresenter credit, bottom left: Joe Franklin, J.D., Ph.D., Director of the Policy Staff, TBBS/OND/CDER/FDA.\n\nNo charts, tables, or diagrams appear on this slide.", "n_tokens": 118, "kind": "vision"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-1-1", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 1, "text": "Disclosure Information\n\nAACR 2018\nJoe Franklin\n\nBody text: \"I have no financial relationships to disclose.\"\nCentered connector: \"- and -\"\nBody text: \"I will not discuss off label use and/or investigational use in my presentation.\"\n\nThe slide has no charts, tables, diagrams, or images.", "n_tokens": 63, "kind": "vision"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-2-1", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 2, "text": "Overview of Presentation\n\nBulleted outline with the following content:\n\nBackground and key concepts\n- BPCI Act\n- Terminology\n- 351(k) Biologics License Application\n- Interchangeability\n- Biological product naming\n\nBiosimilars program at FDA\n\nThere are no charts, tables, diagrams, or images on this slide.", "n_tokens": 60, "kind": "vision"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-3-1", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 3, "text": "BACKGROUND AND KEY CONCEPTS\n\nThis slide is a section divider with no charts, tables, diagrams, or images beyond the title text. The title \"BACKGROUND AND KEY CONCEPTS\" appears in bold black capital letters, positioned in the lower-left portion of an otherwise blank white slide.", "n_tokens": 55, "kind": "vision"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-14-1", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 14, "text": "BIOSIMILARS PROGRAM AT FDA\n\nThis slide is a title slide with no charts, tables, diagrams, or other images. The only text is the title, shown in bold black capital letters across the lower-middle portion of an otherwise white background.", "n_tokens": 50, "kind": "vision"}
{"chunk_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective-20-1", "doc_id": "Biosimilar_and_Interchangeable_Products_The_US_FDA_Perspective", "page": 20, "text": "Thank you for your attention.\n\nThis slide has no separate title. The text in the center reads: \"Thank you for your attention.\" Below it: \"For more information, go to www.fda.gov/biosimilars\" (the web address is underlined and appears as a hyperlink).\n\nThe slide contains no charts, tables, diagrams, or other images.", "n_tokens": 78, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-0-1", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 0, "text": "CDER New Drugs Program: 2017 Update\n\nPresenter and event details: Patrick Frey, Chief of Staff, Office of New Drugs, CDER/FDA. FDA/CMS Summit, December 5th, 2017.\n\nThis slide has no charts, tables, diagrams, or images other than the FDA logo, which is skipped.", "n_tokens": 63, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-10-1", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 10, "text": "USA Share of New Active Substances Launched on World Market Remains High\n\nNew Drug Activity in 2017 (header text at top left of slide)\n\nChart: Line chart showing the share of new active substances launched on the world market by regulatory authority, by year. Y-axis: percent share, labeled 0% to 100% in 10% increments. X-axis: years 2001 through 2016, one label per year. Legend (labels placed at the end of each line): US (dark navy), EU (blue), Other Authorities (light green), Japan (teal). Values below are approximate, read from the chart.\n\nUS (approximate values by year): 2001 39%, 2002 55%, 2003 58%, 2004 39%, 2005 52%, 2006 61%, 2007 56%, 2008 47%, 2009 52%, 2010 43%, 2011 64%, 2012 58%, 2013 61%, 2014 59%, 2015 65%, 2016 62%.\n\nEU (approximate values by year): 2001 33%, 2002 21%, 2003 13%, 2004 30%, 2005 10%, 2006 23%, 2007 12%, 2008 28%, 2009 31%, 2010 34%, 2011 12%, 2012 17%, 2013 11%, 2014 14%, 2015 12%, 2016 15%.\n\nOther Authorities (approximate values by year): 2001 11%, 2002 3%, 2003 19%, 2004 17%, 2005 23%, 2006 6%, 2007 24%, 2008 13%, 2009 7%, 2010 9%, 2011 15%, 2012 14%, 2013 19%, 2014 11%, 2015 7%, 2016 15%.\n\nJapan (approximate values by year): 2001 17%, 2002 21%, 2003 10%, 2004 12%, 2005 16%, 2006 10%, 2007 8%, 2008 13%, 2009 10%, 2010 14%, 2011 9%, 2012 11%, 2013 8%, 2014 16%, 2015 16%, 2016 9%.\n\nFootnote text: \"Data as of 11/30/2017\"\n\nSource text: \"Source: Scrip Magazine (1982 - 2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007 - 2016)\"", "n_tokens": 470, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2017_Update-24-1", "doc_id": "CDER_New_Drugs_Program_2017_Update", "page": 24, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images apart from the logo, which is omitted as instructed. There is no other text or numerical content.", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-0-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 0, "text": "CDER New Drugs Program: 2019 Update\n\nThis is a title slide. It contains no charts, tables, diagrams, or images beyond the FDA logo, which is omitted here.\n\nText on the slide, from top to bottom:\n\nKhushboo Sharma, MBA, RAC\nDeputy Director for Operations\nOffice of New Drugs, CDER/FDA\n\nFDA/CMS Summit\nDecember 3rd, 2019", "n_tokens": 78, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-3-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 3, "text": "CDER New Molecular Entity Approval Rates by PDUFA Cohort\n\nThis is a line chart showing the percentage of New Molecular Entities (NMEs) receiving approval over elapsed time in months, for four PDUFA cohorts.\n\nThe vertical axis is labeled \"% NMEs Receiving Approval,\" with tick labels from 0% to 100% in 10% increments. The horizontal axis is labeled \"Elapsed Time (months),\" with tick labels AP, 6, 12, 18, 24, 30, 36, 42, 48, and 54. A vertical light blue reference line is drawn at the 12-month mark.\n\nThe legend is labeled directly on the lines:\n- PDUFA V (purple line). A purple dashed line labeled \"Estimated\" continues it beyond the solid line.\n- PDUFA IV (green line).\n- PDUFA I-III (blue line).\n- Pre-PDUFA (orange-labeled line, drawn in brownish red).\n\nApproximate values read from the chart at the 12-month line: PDUFA V about 75%, PDUFA IV about 56%, PDUFA I-III about 42%, and Pre-PDUFA about 17%. The PDUFA V dashed estimate ends near 89% at about 35 months. All four curves converge near 80% by about 48 to 58 months.\n\nFootnote text: \"Projection estimates account for actions to date and elapsed time to date for non-approvals\"\n\nSource note: \"Data as of 9/30/19\"", "n_tokens": 322, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-8-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 8, "text": "NME FILINGS BY FISCAL YEAR AND THERAPEUTIC AREA\n\nThis is a stacked vertical bar chart. Each therapeutic area has three bars, one for each fiscal year period. Each bar is divided into an Orphan segment (dark navy, at the bottom) and a Not Orphan segment (medium blue, on top). The total for each bar is printed above it. The chart has no y-axis scale or axis title, so the segment sizes are not labeled numerically. The x-axis labels are the fiscal year periods (FY 2005 - 2009, FY 2010 - 2014, FY 2015 - 2019) for each bar, and the therapeutic areas below them.\n\nLegend: Orphan (dark navy); Not Orphan (blue).\n\nTotals shown above each bar, by therapeutic area and period:\nOncology: FY 2005 - 2009 = 28; FY 2010 - 2014 = 44; FY 2015 - 2019 = 63.\nInfectious Disease: FY 2005 - 2009 = 22; FY 2010 - 2014 = 24; FY 2015 - 2019 = 35.\nNeurology: FY 2005 - 2009 = 11; FY 2010 - 2014 = 9; FY 2015 - 2019 = 32.\nMetabolism and Endocrinology: FY 2005 - 2009 = 20; FY 2010 - 2014 = 21; FY 2015 - 2019 = 18.\nHematology: FY 2005 - 2009 = 8; FY 2010 - 2014 = 7; FY 2015 - 2019 = 15.\nAll Others: FY 2005 - 2009 = 81; FY 2010 - 2014 = 69; FY 2015 - 2019 = 87.\n\nFootnote at bottom left: \"Data as of 9/30/2019.\"", "n_tokens": 343, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-10-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 10, "text": "CDER Orphan Drug Approvals by FY\n\nFootnote: \"* Data as of 9/30/2019\"\n\nChart: Stacked bar chart titled \"CDER Orphan Drug Approvals by FY.\" The vertical axis has no label or units shown, and its tick values are 0, 20, 40, 60, and 80. The horizontal axis is labeled \"Fiscal Year\" and shows the years 2005 through 2019, one bar per year. The legend has three entries: \"New Molecular Entity\" (dark navy), \"Secondary Indication\" (red), and \"New Formulation or Route of Administration\" (blue). The chart has no data labels, so the values below are approximate readings from bar heights, listed as New Molecular Entity / Secondary Indication / New Formulation or Route of Administration, with the approximate bar total in parentheses:\n\n2005: about 4 / 3 / 5 (about 12)\n2006: about 10 / 7 / 1 (about 18)\n2007: about 5 / 13 / 1 (about 19)\n2008: about 7 / 4 / 1 (about 12)\n2009: about 7 / 7 / 4 (about 18)\n2010: about 10 / 5 / 1 (about 16)\n2011: about 8 / 11 / 3 (about 22)\n2012: about 9 / 7 / 1 (about 17)\n2013: about 14 / 10 / 4 (about 28)\n2014: about 18 / 16 / 2 (about 36)\n2015: about 15 / 21 / 4 (about 40)\n2016: about 18 / 25 / 4 (about 47)\n2017: about 17 / 33 / 11 (about 61)\n2018: about 29 / 39 / 10 (about 78)\n2019: about 24 / 46 / 6 (about 76)", "n_tokens": 348, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-11-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 11, "text": "USA Share of New Active Substances Launched on World Market Remains High\n\nThis slide has one line chart. It shows the percentage share of new active substances launched on the world market, by year, for four groups.\n\n Axes and legend: The vertical y-axis is labeled in percent, from 0% to 80% in 10% steps. The horizontal x-axis shows years from 2001 to 2018, one labeled tick per year. The legend is printed as direct labels at the right end of the lines: \"US\" (purple line), \"EU\" (dark red line), \"Japan\" (orange line), and \"Other Authorities\" (light blue line).\n\n The chart has no printed data values. The approximate values below are visual readings from the lines.\n\n US (purple), approximate: 2001 about 39%; 2002 about 55%; 2003 about 58%; 2004 about 39%; 2005 about 52%; 2006 about 61%; 2007 about 56%; 2008 about 47%; 2009 about 52%; 2010 about 43%; 2011 about 63.5%; 2012 about 58%; 2013 about 61%; 2014 about 59%; 2015 about 65%; 2016 about 62%; 2017 about 67%; 2018 about 65%.\n\n EU (dark red), approximate: 2001 about 33%; 2002 about 21%; 2003 about 13%; 2004 about 30%; 2005 about 16%; 2006 about 22.5%; 2007 about 12%; 2008 about 28%; 2009 about 31%; 2010 about 34%; 2011 about 12%; 2012 about 17%; 2013 about 11%; 2014 about 13.5%; 2015 about 11.5%; 2016 about 14.5%; 2017 about 12%; 2018 about 11%.\n\nJapan (orange), approximate: 2001 about 17%; 2002 about 20.5%; 2003 about 9.5%; 2004 about 13%; 2005 about 9.5%; 2006 about 9.5%; 2007 about 8%; 2008 about 12.5%; 2009 about 10%; 2010 about 14%; 2011 about 9%; 2012 about 11%; 2013 about 8%; 2014 about 16.5%; 2015 about 16%; 2016 about 9%; 2017 about 9%; 2018 about 13%.\n\n", "n_tokens": 468, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-11-2", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 11, "text": "Other Authorities (light blue), approximate: 2001 about 11%; 2002 about 3.5%; 2003 about 19%; 2004 about 17.5%; 2005 about 22.5%; 2006 about 6.5%; 2007 about 24%; 2008 about 12.5%; 2009 about 7%; 2010 about 8.5%; 2011 about 15%; 2012 about 14%; 2013 about 19.5%; 2014 about 11%; 2015 about 7%; 2016 about 14.5%; 2017 about 11%; 2018 about 7%.\n\n Footnotes at the bottom left read: \"Data as of 9/30/2019\" and \"Source: Scrip Magazine (1982 - 2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007 - 2018)\".", "n_tokens": 170, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-14-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 14, "text": "In FY 2019, CDER Continued To Ensure The Efficiency Of First Cycle Review\n\nBullet points:\n- All of the (100%) NMEs/BLAs approved in FY 2019 met their PDUFA goal dates.\n- All but three (93%) of the drugs approved in FY 2019 were approved in the first review cycle.\n\nChart 1: Donut chart titled \"Met PDUFA Goal Date.\" The entire ring is green, with no other segments visible. The center label reads \"100%.\"\n\nChart 2: Donut chart titled \"Approved on First Cycle.\" The large majority of the ring is red and a smaller segment is gray. The center label reads \"93%.\" No legend is visible; the red segment corresponds to the 93% approved on first cycle, and the gray segment to the remainder (three drugs, per the bullet text).", "n_tokens": 179, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-18-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 18, "text": "Development Phase Work Continued to Grow in 2019\n\nThis slide has one chart: a stacked vertical bar chart showing values for each year from 2004 to 2019. The horizontal axis shows the years 2004 through 2019. The chart has no visible vertical axis title or tick labels, and the units are not stated. The legend has two entries: \"Drug INDs\" (dark blue) and \"Biologic INDs\" (red). Each bar has a dark blue segment labeled with the Drug INDs value and a red segment labeled with the Biologic INDs value.\n\nYear: Drug INDs, Biologic INDs\n2004: 3773, 588\n2005: 4023, 586\n2006: 4281, 695\n2007: 4516, 672\n2008: 4808, 713\n2009: 5002, 726\n2010: 5026, 732\n2011: 5067, 808\n2012: 5278, 824\n2013: 5258, 879\n2014: 5186, 1218\n2015: 5412, 1367\n2016: 5261, 1480\n2017: 5358, 1662\n2018: 5397, 1804\n2019: 5429, 1903\n\nFootnote text: \"Data are from the PDUFA Workload Adjuster and represent an Academic Year (12 month period of July 1st - June 30th).\"\n\nSlide number: omitted.", "n_tokens": 275, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-19-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 19, "text": "CDER Breakthrough Therapy Requests by Division\n\nSubtitle: Oncology, Hematology, and Neurology account for over 50% of Breakthrough Requests. The words \"Oncology\" (dark navy), \"Hematology\" (red), and \"Neurology\" (green) are colored to match the pie chart slices.\n\nChart: Pie chart of CDER Breakthrough Therapy Requests by division. It has no axes. The chart's legend is given by the colored subtitle words. Labeled slices:\n- Dark navy slice: 26% (Oncology)\n- Red slice: 16% (Hematology)\n- Green slice: 9% (Neurology)\n- All remaining slices are gray and unlabeled.\n\nChart caption: 793 Requests since BT Program Inception in July 2012\n\nRight panel heading: Some notable conditions for FY 19 include\n- Ebola Virus Disease\n- Fragile X Syndrome (Cannabidiol)\n- Chronic Hepatitis D\n\nFooter: Data as of 9/30/2019", "n_tokens": 206, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-20-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 20, "text": "CDER Breakthrough Therapy Grants by Division\n\nLeft chart: The header reads \"Of 793 BT Requests CDER issues a BT Grant about 38% of the time,\" with \"38%\" displayed in large type above the chart. Below it is a vertical bar chart showing the outcomes of BT requests. The x-axis categories are Granted, Denied, Withdrawn, and Pending. The y-axis has no visible label or units. Values:\n- Granted: 38% (dark blue bar)\n- Denied: 46% (gray bar)\n- Withdrawn: 13% (gray bar)\n- Pending: 3% (gray bar)\n\nRight chart: The header reads \"Oncology, Hematology, and Antiviral account for the majority of Breakthrough Grants,\" with \"Oncology\" in dark navy, \"Hematology\" in red, and \"Antiviral\" in light blue. Below it is a donut chart with the center label \"304 Granted.\" The legend lists three entries: Oncology (dark navy), Hematology (red), and Antiviral (light blue). Labeled segments:\n- Oncology: 32%\n- Hematology: 21%\n- Antiviral: 10%\n\nThe remaining segments are unlabeled gray slices with no visible percentages or names.\n\nFootnote: \"Data as of 9/30/2019\" appears in the lower left corner.", "n_tokens": 285, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-21-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 21, "text": "CDER Breakthrough Therapy Approvals by FY\n\nThis slide contains one chart: a stacked bar chart titled \"CDER Breakthrough Therapy Approvals by FY.\"\n\n- Horizontal axis: labeled \"Fiscal Year,\" with categories 2014, 2015, 2016, 2017, 2018, and 2019.\n- Vertical axis: no axis label, units, or tick values are shown.\n- Each bar is divided into colored segments. The legend lists three categories:\n  - NME (dark navy)\n  - Non-NME (red)\n  - New or Expanded Indication (light blue)\n- The segments are not labeled with individual values.\n- Total values shown above each bar:\n  - 2014: 10\n  - 2015: 17\n  - 2016: 25\n  - 2017: 32\n  - 2018: 36\n  - 2019: 27\n\nFootnote at bottom left: \"* Data as of 9/30/2019\"", "n_tokens": 169, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-22-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 22, "text": "CDER Active Breakthrough Development Programs\n\nThis slide contains one chart, a stacked area chart showing the number of CDER active breakthrough development programs over time. The vertical axis runs from 0 to 160, with tick labels at intervals of 20 (0, 20, 40, 60, 80, 100, 120, 140, 160). The vertical axis has no printed axis title. The horizontal axis shows dates at roughly two-year intervals, labeled 30-Sep-12, 30-Sep-13, 30-Sep-14, 30-Sep-15, 30-Sep-16, 30-Sep-17, 30-Sep-18, and 30-Sep-19. The horizontal axis has no printed axis title.\n\nThe legend below the chart has two entries: \"IND Phase,\" shown as a dark navy square, and \"Review Phase,\" shown as a light blue area with a red outline. The chart also has in-chart labels reading \"Review Phase\" (in the light blue band, near the 30-Sep-16 date) and \"IND Phase\" (in the dark navy area, near the 30-Sep-16 date).\n\nThe dark navy IND Phase area starts near 0 at 30-Sep-12 and rises to about 122 at the right edge (30-Sep-19). The light blue Review Phase band sits on top of the IND Phase area, with its top boundary, marked by a red line, reaching about 143 at 30-Sep-19. The top boundary is near 83 around 30-Sep-16 and near 20 at about 30-Sep-12 to early 2013. Both areas trend upward across the period.\n\nFootnote text at the bottom left reads: \"* Data as of 9/30/19 .Figures includes total # of granted breakthrough designations for drug/indications under active IND development but have not yet received marketing approval or rescission decision.\"", "n_tokens": 386, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-23-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 23, "text": "CDER PDUFA Formal Meeting Requests by FY\n\nThis is a vertical bar chart with navy bars on a white background. The horizontal x-axis is labeled \"Fiscal Year\" and shows the years 2003 through 2019*. The chart has no visible y-axis label, no y-axis tick marks, and no units are shown. There is no legend. Each bar has its value printed inside it. The values, read from left to right, are:\n\n2003: 1464\n2004: 2015\n2005: 2236\n2006: 2256\n2007: 2209\n2008: 2027\n2009: 1969\n2010: 2008\n2011: 2010\n2012: 2073\n2013: 2221\n2014: 2360\n2015: 2732\n2016: 2885\n2017: 3053\n2018: 3179\n2019*: 3450\n\nNotes printed in the lower left corner:\n\"Data as of 9/30/2019\"\n\"BLAs were transferred to CDER in FY2004\"\n\"*2019 Data is preliminary\"", "n_tokens": 197, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-24-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 24, "text": "CDER Denied Meeting Requests By FY\n\nThis slide contains one line chart.\n\nChart: Line chart showing the percentage of CDER denied meeting requests by fiscal year. The y-axis is labeled in percent, from 0.0% to 25.0% in 5% increments. The x-axis is labeled with fiscal years, FY 08 through FY 18. The chart has no legend. Above the plot area, three period labels appear: PDUFA IV (above roughly FY 08 to FY 11), PDUFA V (beginning at FY 13), and PDUFA VI (at FY 18). A vertical divider line marks the boundary between PDUFA IV and PDUFA V, and vertical gridlines mark FY 08, FY 13, and FY 18.\n\nData labels, as read from the chart:\nFY 08: 21.8%\nFY 09: 15.2%\nFY 10: 10.5%\nFY 11: 7.1%\nFY 12: 5.9%\nFY 13: 4.5%\nFY 14: 4.2%\nFY 15: 4.0%\nFY 16: 4.0%\nFY 17: 3.2%\nFY 18: 3.1%\n\nFootnote: \"Data as of 9/30/2019.\"\n\nSlide number: 25", "n_tokens": 284, "kind": "vision"}
{"chunk_id": "CDER_New_Drugs_Program_2019_Update-32-1", "doc_id": "CDER_New_Drugs_Program_2019_Update", "page": 32, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images, and no other text. The only element is the logo, which is omitted as instructed.", "n_tokens": 38, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-0-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 0, "text": "CDER Office of Surveillance and Epidemiology: 2017 Update\n\nGerald J. Dal Pan, MD, MHS\nDirector\nOffice of Surveillance and Epidemiology\nCenter for Drug Evaluation and Research\n\nFDA/CMS Summit\nDecember 5, 2017", "n_tokens": 47, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-1-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 1, "text": "Adverse Event Data\n\nThis slide has no charts, tables, diagrams, or images beyond the text title. The title \"Adverse Event Data\" is centered in large blue text on a white background. The slide is otherwise blank.", "n_tokens": 44, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-2-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 2, "text": "FDA Adverse Event Reporting System (FAERS)\n\nChart: A three-dimensional stacked bar chart titled \"Number of Adverse Event Reports.\" Each bar is one year, and each bar is divided into three color-coded segments.\n\nY-axis label: \"Number of Reports.\" Tick labels, from bottom to top: 0, 200,000, 400,000, 600,000, 800,000, 1,000,000, 1,200,000, 1,400,000, 1,600,000, 1,800,000.\n\nX-axis labels, from left to right: 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016.\n\nLegend (top left of plot area), from top to bottom:\nNon-Expedited (purple segment, top of each bar)\n15-Day (red segment, middle of each bar)\nDirect (green segment, bottom of each bar)\n\nThe bars have no printed data labels. Approximate total bar heights read against the y-axis: 2004 about 280,000; 2005 about 325,000; 2006 about 340,000; 2007 about 375,000; 2008 about 450,000; 2009 about 500,000; 2010 about 685,000; 2011 about 795,000; 2012 about 945,000; 2013 about 1,085,000; 2014 about 1,215,000; 2015 about 1,735,000; 2016 about 1,700,000.\n\nThe Direct (green) segments are small in every year, appearing as thin bands at the base of each bar. The 15-Day (red) segments are the largest in most years. The Non-Expedited (purple) segments sit on top and are largest in the later years.", "n_tokens": 367, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-3-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 3, "text": "Best Practices for Pharmacovigilance\n\nText annotation at upper left: \"FDAAA 2007 establishes requirement for 18-month/10,000 patient safety review.\"\n\nA boxed statutory quotation reads: \"(D) preparing, by 18 months after approval of a drug or after use of the drug by 10,000 individuals, whichever is later, a summary analysis of the adverse drug reaction reports received for the drug, including identification of any new risks not previously identified, potential new risks, or known risks reported in unusual number;\"\n\nA downward arrow leads from this quotation to a journal article image. The image shows a header labeled \"ARTICLES\" above a blue rule. The article title reads: \"Assessment of the Impact of Scheduled Postmarketing Safety Summary Analyses on Regulatory Actions.\" The authors are listed as: \"S Sekine 1,2, EE Pinnow 1, E Wu 1, R Kurtzig 1, M Hall 1 and GJ Dal Pan 1,\" with numeric superscripts.\n\nA downward arrow leads from the article image to the text annotation: \"Impact analysis show that these reviews have little value.\"\n\nA second arrow runs from below that annotation to the right and points to a third boxed text, which reads: \"(b) FAERS REVISION.—Section 505(r)(2)(D) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(r)(2)(D)) is amended by striking \", by 18 months\" and all that follows through the semicolon at the end of the sub-paragraph and inserting \"and making publicly available on the Internet website established under paragraph (1) best practices for drug safety surveillance activities for drugs approved under this section or section 351 of the Public Health Service Act;\".\"\n\nThe text annotation next to that arrow reads: \"21st Century Cures Act 2016 removes this requirement.\"", "n_tokens": 403, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-11-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 11, "text": "Methods Development\n\nThe slide contains no charts, tables, or diagrams. It shows three screenshots of journal article pages.\n\nTop screenshot: Journal article header with the title \"Pharmacovigilance from social media: mining adverse drug reaction mentions using sequence labeling with word embedding cluster features.\" Authors listed: Azadeh Nikfarjam, Abeed Sarker, Karen O'Connor, Rachel Ginn, Graciela Gonzalez. Date box reads: RECEIVED 29 July 2014; REVISED 2 December 2014; ACCEPTED 4 December 2014; PUBLISHED ONLINE FIRST 9 March 2015. Logos shown: AMIA and OXFORD UNIVERSITY PRESS.\n\nMiddle screenshot: Article page titled \"Evaluation of Facebook and Twitter Monitoring to Detect Safety Signals for Medical Products: An Analysis of Recent FDA Safety Alerts.\" Authors listed: Carrie E. Pierce, Khaled Bouri, Carol Pamer, Scott Proestel, Harold W. Rodriguez, Hoa Van Le, Clark C. Freifeld, John S. Brownstein, Mark Walderhaug, I. Ralph Edwards, Nabarun Dasgupta. A small green icon appears after the last author's name.\n\nBottom screenshot: BMJ Open article with the logo \"BMJ Open\" and the title \"Utility of social media and crowd-sourced data for pharmacovigilance: a scoping review protocol.\" Authors listed: Andrea C Tricco, Wasifa Zarin, Erin Lillie, Ba Pham, Sharon E Straus.\n\nSource line at bottom left, in italics: \"Source: Nikfarjam et al. J Am Med Inform Assoc c 2015;22:671–681; Tricco et al. BMJ Open l (http://dx.doi.org/10.1136/bmjopen-2016- 013474); Pierce et al. Drug Saf 2017;40:317–331\"", "n_tokens": 400, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-12-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 12, "text": "Sentinel\n\nThis slide has no charts, tables, diagrams, or images beyond the title text. The slide shows the single word \"Sentinel\" in large blue text, centered in the middle of a plain white background.", "n_tokens": 42, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-13-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 13, "text": "FDA Sentinel System\n\nBullet points on the slide:\n- National medical product monitoring system.\n- 17 data partners with 178 million members with pharmacy and medical coverage.\n- Distributed system where data partners retain physical control of data to protect privacy and security.\n\nWeb link on the left side: www.sentinelinitiative.org/\n\nImage: A screenshot of the Sentinel website homepage. The header shows the \"Sentinel\" logo in blue script. A blue navigation bar lists these tabs: \"Sentinel\" (highlighted, with a red underline), \"Drugs,\" \"Vaccines, Blood & Biologics,\" \"Communications,\" and \"FDA-Catalyst.\" The main banner has a blue background with a faint network-line graphic and the white text \"Sentinel is a National Medical Product Monitoring System.\" Below that is a red button labeled \"LEARN MORE.\"", "n_tokens": 175, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-14-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 14, "text": "Timeline\n\nThis slide shows a horizontal timeline with six color-coded milestones from 2007 to 2016, each with a year, a description, and an icon in a circle. The milestones are connected to the timeline by dotted lines. Reading from left to right:\n\n2007 (teal, Capitol building icon, above the timeline): Congress passes Food and Drug Administration Amendments Act (FDAAA).\n\n2008 (red, checkbox icon, below the timeline): FDA launches Sentinel Initiative.\n\n2009 (purple, network hierarchy icon, above the timeline): FDA launches Mini-Sentinel Pilot.\n\n2011 (light blue, bar chart with upward arrow icon, below the timeline): Mini-Sentinel distributed dataset reaches 100 million lives mark mandated by FDAAA.\n\n2012 (orange, wrench icon, above the timeline): Mini-Sentinel has suite of reusable programming tools for routine queries.\n\n2016 (dark blue, gears icon, below the timeline): FDA launches Sentinel System.\n\nThe slide includes the source URL at the bottom left: https://www.sentinelinitiative.org/background", "n_tokens": 223, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-17-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 17, "text": "Sentinel ARIA Analyses (N=233)\n\nThis is a stacked bar chart showing the number of Sentinel ARIA analyses by quarter, for 2016 and 2017. The y-axis runs from 0 to 70 in increments of 10, with no unit label visible. The x-axis shows quarters QTR1 through QTR4, grouped under the years 2016 and 2017. The legend has four entries: ST (blue), L1 (red), L2 (green), and L3 (purple). A footnote reads \"From all FDA Centers, by date of distribution to Data Partners.\"\n\nValues labeled within the bars, by quarter:\n2016 QTR1: ST 16, L1 5, L2 1. A black label \"1\" sits above the bar.\n2016 QTR2: ST 15, L1 15, L2 3.\n2016 QTR3: ST 16, L1 14. An unlabeled thin green (L2) segment sits on top. A black label \"1\" sits above the bar.\n2016 QTR4: ST 10, L1 12, L2 2.\n2017 QTR1: ST 16, L1 4, L2 3. An unlabeled thin purple (L3) segment sits on top. A black label \"1\" sits above the bar.\n2017 QTR2: ST 16, L1 12, L2 2.\n2017 QTR3: ST 56, L1 6. An unlabeled thin green (L2) segment sits on top. A black label \"1\" sits above the bar.\n2017 QTR4: L1 5 only.", "n_tokens": 337, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-18-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 18, "text": "10th Annual Public Workshop\n\nThis slide contains a screenshot of a webpage from the Duke Margolis Center for Health Policy, with the Duke and Margolis Center logos at the top. The navigation menu reads Home, About, Our Work, People, News, Events (highlighted), and Support Our Work. A search box appears at the top right. The breadcrumb reads \"Home > Events > 2018 Sentinel Initiative Annual Public Workshop.\"\n\nPage heading: \"2018 Sentinel Initiative Annual Public Workshop\"\n\nDate and time: February 7, 2018 - 9:00 am\n\nVenue: Hyatt Regency Bethesda, 1 Bethesda Metro Center, Bethesda, MD 20814\n\nA button labeled \"Register now\" appears beside the date and venue.\n\nDescription heading: \"Description\"\n\nDescription text (partly cut off at the bottom of the screenshot): \"This annual workshop serves as a forum to bring together leading experts and interested stakeholders to discuss the ongoing development of the Sentinel Initiative. The Food and\" The rest of the text is not legible.\n\nSpeakers box heading: \"Speakers\"\n\nSpeaker listed: \"Dr. Gerald Dal Pan, Director of the Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research\" (the text is partly cut off after \"Epidemiology, Center for Drug Evaluation and Research\").\n\nURL printed below the screenshot: https://healthpolicy.duke.edu/events/2018-sentinel-initiative-annual-public-workshop", "n_tokens": 307, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-20-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 20, "text": "New Base Contract for Sentinel Coordinating Center\n\nThis slide contains a screenshot of a FedBizOpps.gov (Federal Business Opportunities) notice page. It is not a chart, table, or diagram.\n\nHeader: \"FEDBIZOPPS.GOV Federal Business Opportunities\" and \"E-GOV USA.gov\". Navigation tabs: Home, Getting Started, General Info, Opportunities (highlighted), Agencies, Privacy. Top-right links: \"Buyers: Login | Register\", \"Vendors: Login | Register\", \"Accessibility\".\n\nNotice title: \"Sentinel Initiative Request for Information\"\nSolicitation Number: FDA-RFI-18-0001\nAgency: Department of Health and Human Services\nOffice: Food and Drug Administration\nLocation: Office of Acquisitions and Grants Services - Rockville\n\nTabs: \"Notice Details\" (selected), \"Packages\", \"Interested Vendors List\". Icons: \"Print\", \"Link\".\n\nLeft column: \"Original Synopsis\", \"Dec 01, 2017\", \"12:46 pm\".\nButtons: \"Return To Opportunities List\", \"Watch This Opportunity\", \"Add Me To Interested Vendors\".\nSolicitation Number: FDA-RFI-18-0001. Notice Type: Special Notice.\nSynopsis heading, followed by \"Added: Dec 01, 2017 12:46 pm\".\nNote: \"Please consult the list of document viewers if you cannot open a file.\"\nAttached file: \"Sentinel Initiative Request for Information FY19\".\n\nRight column, \"ALL FILES\": \"Sentinel Initiative Request for Information FY19\", \"Dec 01, 2017\", and \"Sentinel Initiative ...\".\n\"GENERAL INFORMATION\": Notice Type: Special Notice. Posted Date: December 1, 2017. Response Date: Mar 01, 2018 11:59 pm Eastern.\n\nFooter URL: https://www.fbo.gov/index?s=opportunity&mode=form&id=ec59b8dbb36970e2912801aa2cfdd87d&tab=core&_cview=0", "n_tokens": 437, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-23-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 23, "text": "Risk Evaluation and Mitigation Strategies\n\nThis slide contains only a title and the FDA logo (skipped). It has no charts, tables, diagrams, or other images. The slide title is \"Risk Evaluation and Mitigation Strategies,\" displayed in large blue text centered on a white background, with the remainder of the slide blank.", "n_tokens": 67, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-24-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 24, "text": "Format and Content of REMS Document\n\nBullet points:\nFormat and Content of a REMS Document\nRevised draft guidance\nIncludes a section for each participant\nWho\nWhat\nWhen\nWith what\n\nImage: a thumbnail of the cover page of a document. The text reads:\n\nFormat and Content of a REMS Document\nGuidance for Industry\nDRAFT GUIDANCE\nThis guidance document is being distributed for comment purposes only.\nComments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.\nFor questions regarding this draft document, contact (CDER) Gita Toyserkani at 301-796-1783, or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.\nU.S. Department of Health and Human Services\nFood and Drug Administration\nCenter for Drug Evaluation and Research (CDER)\nCenter for Biologics Evaluation and Research (CBER)\nOctober 2017\nDrug Safety\nRevision 1", "n_tokens": 275, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-25-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 25, "text": "Use of a Drug Master File for Shared System REMS Submissions\n\nText bullets on the left side of the slide:\nDraft guidance issued November 2017\nIntended to improve efficiency\n\nImage on the right: a cover page of an FDA guidance document. The readable text on the cover reads:\n\"Use of a Drug Master File for Shared System REMS Submissions\"\n\"Guidance for Industry\"\n\"DRAFT GUIDANCE\"\n\"This guidance document is being distributed for comment purposes only.\"\n\"Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to https://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.\"\n\"For questions regarding this draft document, contact (CDER) Gita Toyserkani 301-796-1783 or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.\"\nFooter: \"U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), November 2017, Procedural.\"", "n_tokens": 302, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-26-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 26, "text": "REMS Document and Structured Product Labeling\n\nSlide text: REMS into SPL format. Draft guidance. Make REMS information available within existing healthcare systems and workflows. Easier sharing of information and incorporation in health information technology.\n\nImage: A thumbnail of the cover of an FDA draft guidance document. It is a white page with a black border and no graphics other than text and a horizontal rule above and below the title block.\n\nTitle on cover: \"Providing Regulatory Submissions in Electronic Format — Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling\"\n\nCover text: \"DRAFT GUIDANCE\"\n\n\"This guidance document is being distributed for comment purposes only.\"\n\n\"Comments and suggestions regarding this draft document should be submitted within 180 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.\"\n\n\"For questions regarding this draft document, contact (CDER) Adam Kroetsch, 301-796-3842; Aaron Sherman, 240-402-9469; or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.\"\n\nAgency footer: \"U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER)\"\n\nDate and label: \"September 2017, Electronic Submissions\"", "n_tokens": 365, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-30-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 30, "text": "Framework for Benefit-Risk Counseling to Patients About Drug with a REMS\n\nBullet points:\nPart of REMS Integration Initiative\nFour Es:\nEvaluate\nEducate\nEngage\nEnsure\n\nImage: A photograph of a clinician's hands holding a stethoscope against a patient's bare upper arm, with a person's face partly visible at the top. Overlaid on the photo is a blue box with white text reading \"A Framework for Benefit-Risk Counseling to Patients About Drugs with a REMS.\" Small text in the top corner of the image reads \"U.S. FOOD & DRUG ADMINISTRATION,\" and small text in the bottom corner reads \"www.fda.gov.\" This image is a cover of the document shown on the slide.", "n_tokens": 149, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-31-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 31, "text": "Prescription Opioid Abuse\n\nThis slide has no charts, tables, diagrams, or images beyond the title text. The slide shows the title \"Prescription Opioid Abuse\" in large blue bold text, centered near the upper middle of a white background. The rest of the slide is blank.", "n_tokens": 58, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update-35-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2017_Update", "page": 35, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images apart from the logo, which is omitted as instructed. It has no other text.", "n_tokens": 36, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-0-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 0, "text": "CDER Office of Surveillance and Epidemiology: 2018 Update\n\nPresenter and event details: Gerald J. Dal Pan, MD, MHS, Director, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research. FDA/CMS Summit, December 11, 2018.\n\nThis slide contains no charts, tables, diagrams, or images other than the FDA logo, which is omitted.", "n_tokens": 80, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-1-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 1, "text": "Label Changes Study\n\nThis slide shows a template mockup of a drug label's Highlights of Prescribing Information page, with a set of sections outlined in red. It contains no charts, graphs, or data plots. The page is laid out in two columns, with placeholder text in square brackets.\n\nLeft column:\n\nHIGHLIGHTS OF PRESCRIBING INFORMATION\nThese highlights do not include all the information needed to use [DRUG NAME] safely and effectively. See full prescribing information for [DRUG NAME].\n[DRUG NAME (nonproprietary name) dosage form, route of administration, controlled substance symbol]\nInitial U.S. Approval: [year]\n\nBoxed warning (outlined in red): WARNING: [SUBJECT OF WARNING]. See full prescribing information for complete boxed warning. Two placeholder bullets: [text], [text].\n\nRECENT MAJOR CHANGES\n[section (X.X)] [m/year]\n[section (X.X)] [m/year]\n\nINDICATIONS AND USAGE\n[DRUG NAME] is a [name of pharmacologic class] indicated for: two placeholder bullets: [text], [text].\n\nDOSAGE AND ADMINISTRATION\nTwo placeholder bullets: [text], [text].\n\nDOSAGE FORMS AND STRENGTHS\nOne placeholder bullet: [text].\n\nRight column:\n\nCONTRAINDICATIONS (outlined in red): two placeholder bullets: [text], [text].\n\nWARNINGS AND PRECAUTIONS (outlined in red): two placeholder bullets: [text], [text].\n\nADVERSE REACTIONS (outlined in red): Most common adverse reactions (incidence > x%) are [text].\nTo report SUSPECTED ADVERSE REACTIONS, contact [name of manufacturer] at [phone #] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.\n\nDRUG INTERACTIONS (outlined in red): two placeholder bullets: [text], [text].\n\nUSE IN SPECIFIC POPULATIONS\nTwo placeholder bullets: [text], [text].\n\nSee 17 for PATIENT COUNSELING INFORMATION [and FDA-approved patient labeling OR and Medication Guide].\nRevised: [m/year]\n\nSource line at bottom: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]", "n_tokens": 485, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-3-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 3, "text": "Results\n\n278 NMEs approved between October 1, 2002 and December 31, 2014.\n1 safety withdrawal\n195 (70.1%) with ≥ 1 safety outcome\n83 (29.9%) no safety related label change or withdrawal\n\nSource: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]\n\nImage: A stylized graphic of a magnifying glass lying over the word \"RESULTS,\" which is written in large dark blue and light blue letters. The magnifying glass lens highlights the letters \"SUL\" and has a black handle extending to the lower right. There are no charts, tables, or diagrams.", "n_tokens": 146, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-4-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 4, "text": "Results\n\nTotal: 278 Drugs\n\nThis slide is a graphic with three columns, labeled Drugs, Label Updates, and Safety Issues. Each column is split into six horizontal color bands, with row labels on the left. The row labels, from top to bottom, are: Total (Any of the 5 sections of the label), Boxed Warnings, Warnings & Precautions, Contraindications, Adverse Reactions, and Drug Interactions. The drawn shapes differ by column: Drugs is a pill-shaped outline, Label Updates is a rectangular container outline, and Safety Issues is a shield outline. The chart has no axes or units. Each number is a count.\n\nDrugs column (pill shape):\n- Total: 278\n- Boxed Warnings: 25\n- Warnings & Precautions: 165\n- Contraindications: 71\n- Adverse Reactions: 160\n- Drug Interactions: 47\n\nLabel Updates column (rectangular container):\n- Total: 703\n- Boxed Warnings: 28\n- Warnings & Precautions: 388\n- Contraindications: 92\n- Adverse Reactions: 441\n- Drug Interactions: 78\n\nSafety Issues column (shield shape):\n- Total: 2505\n- Boxed Warnings: 51\n- Warnings & Precautions: 842\n- Contraindications: 123\n- Adverse Reactions: 1635\n- Drug Interactions: 108\n\nSource line at the bottom: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi: 10.1002/cpt.994 [Epub ahead of print]", "n_tokens": 292, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-7-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 7, "text": "Average number of issues per year of follow-up\n\nThis slide contains one chart: a box-and-whisker plot with mean and median markers, showing the number of issues per year across follow-up periods.\n\n Y-axis: \"Number of issues per year.\" The lower section is labeled 0, 1, 2, 3, and the upper section (separated by a break) is labeled 10, 20, 30, 40, 50, 60.\nX-axis: \"Follow-up period (in years),\" labeled 1 through 13.\n\n Legend entries: Mean (red diamond); Median (blue triangle); Upper IQR (box outline); Lower IQR (box outline); Range (Low-High) (vertical line).\n\n Table beneath the x-axis with two rows, \"Range\" and \"n,\" for each follow-up period:\nYear 1: range 0-2, n 278\nYear 2: range 0-4, n 248\nYear 3: range 0-3, n 221\nYear 4: range 0-3, n 190\nYear 5: range 0-4, n 166\nYear 6: range 0-3, n 147\nYear 7: range 0-2, n 131\nYear 8: range 0-4, n 109\nYear 9: range 0-3, n 93\nYear 10: range 0-2, n 76\nYear 11: range 0-2, n 57\nYear 12: range 0-2, n 27\nYear 13: range 0-1, n 6\n\nApproximate values read from the chart:\n Median is 0 in every follow-up period.\n Mean (approximate): Year 1 about 0.33; Year 2 about 1.65; Year 3 about 2.0; Year 4 about 2.5; Year 5 about 2.0; Year 6 about 1.47; Year 7 about 1.75; Year 8 about 1.0; Year 9 about 0.9; Year 10 about 0.63; Year 11 about 0.78; Year 12 about 0.5; Year 13 about 0.75.\n Upper edge of the IQR box (approximate): Years 2, 3, 5 and 7 about 2.1; Year 4 about 3.1; Years 6, 8, 10 and 13 about 1.1. Years 1, 9, 11 and 12 show no visible box above 0.\n", "n_tokens": 482, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-7-2", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 7, "text": "Top of the range line (approximate): Year 1 about 14; Year 2 about 26; Year 3 about 35; Year 4 about 39; Year 5 about 26; Year 6 about 14; Year 7 about 61; Year 8 about 16; Year 9 about 11; Year 10 about 9; Year 11 about 11; Year 12 about 3; Year 13 about 3.\n\n Source: Pinnow et al. Clin Pharmacol Ther 2017 Dec 20 doi:10.1002/cpt.994 [Epub ahead of print].", "n_tokens": 112, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-8-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 8, "text": "Adverse Event Data\n\nThis slide contains no charts, tables, diagrams, or other images beyond the title text. The title \"Adverse Event Data\" is centered in blue bold type on a white background.", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-9-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 9, "text": "FDA Adverse Event Reporting System (FAERS)\n\nChart: Stacked bar chart titled \"Reports received by Report Type.\" The y-axis is labeled \"Report Count\" and runs from 0 to 2,000,000, with tick marks at 500,000, 1,000,000, 1,500,000, and 2,000,000. The x-axis shows years from 2009 to 2018, with an asterisk after the 2018 label. Each bar is divided into three segments. The legend, in the upper left of the plot area, lists: Direct (dark blue), Expedited (red), and Non-Expedited (green).\n\nTotal labels above each bar, from left to right:\n2009: 490,043\n2010: 672,494\n2011: 782,098\n2012: 933,110\n2013: 1,074,593\n2014: 1,203,989\n2015: 1,727,478\n2016: 1,691,823\n2017: 1,815,716\n2018: 1,971,272\n\nFootnote at bottom left: \"*2018 data through 20 November 2018\"", "n_tokens": 241, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-10-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 10, "text": "Sentinel\n\nThe slide has a white background with the word \"Sentinel\" centered in large blue text. There are no charts, tables, diagrams, or other images on the slide.", "n_tokens": 35, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-11-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 11, "text": "FDA Sentinel System\n\nBullet points on the slide:\n- National medical product monitoring system.\n- 17 data partners with 178 million members with pharmacy and medical coverage.\n- Distributed system where data partners retain physical control of data to protect privacy and security.\n\nText on the slide: www.sentinelinitiative.org/ (shown as a blue underlined hyperlink).\n\nImage: A screenshot of the Sentinel website homepage. The site header shows the \"Sentinel\" logo at top left and a blue navigation bar with the menu items \"Sentinel\" (highlighted), \"Drugs,\" \"Vaccines, Blood & Biologics,\" \"Communications,\" and \"FDA-Catalyst.\" The main banner has a blue, geometric network-pattern background with the text \"Sentinel is a National Medical Product Monitoring System\" and a red button labeled \"LEARN MORE.\"", "n_tokens": 172, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-13-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 13, "text": "ARIA is Comprised of Modular Programs\n\nThe slide shows a diagram of three rounded rectangular boxes of increasing height, arranged left to right like ascending steps. Each box is labeled with a level and a description:\n\nLeft box (green gradient): \"Level 1\" followed by \"Descriptive Analyses, Unadjusted Rates\"\n\nMiddle box (blue gradient): \"Level 2\" followed by \"Adjusted Analyses with Sophisticated Confounding Control\"\n\nRight box (purple gradient): \"Level 3\" followed by \"Sequential Adjusted Analyses with Sophisticated Confounding Control.\" The word \"Sequential\" is underlined.\n\nThe diagram has no axes, units, legend, or numerical values.", "n_tokens": 135, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-14-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 14, "text": "The FDA Sentinel Initiative — An Evolving National Resource\n\nThis slide is a screenshot of the first page of a New England Journal of Medicine Perspective article. The label \"Perspective\" appears at the upper right of the journal header. The small red circular emblem at the upper left is the journal's seal. Beneath the header is the article title, followed by the author line: Richard Platt, M.D., Jeffrey S. Brown, Ph.D., Melissa Robb, M.S., Mark McClellan, M.D., Ph.D., Robert Ball, M.D., M.P.H., Michael D. Nguyen, M.D., and Rachel E. Sherman, M.D., M.P.H.\n\nThe visible body text, set in three columns and cut off at the bottom, reads in part: \"The Food and Drug Administration (FDA) Sentinel Initiative, which was launched in 2008, has matured from a pilot program designed to assess potential drug-safety signals in insurance claims into a core component of the agency's evolving safety surveillance system. Sentinel is a flexible and robust program that provides evidence on the effects of medical products while protecting...\" The second column continues: \"secure querying system, created a very large rigorously curated and updated distributed health information data set, and developed tools permitting rapid, customized analysis. Distributed data systems, in which data partners maintain physical and operational control over their data, provide a high level of protection for the privacy and security of patients' health...\" The third column continues: \"viding guidance on the best use of their data. Although data partners have chosen to respond to nearly all questions sent to them, their ability to opt out of specific queries remains an important contributor to their willingness to participate in the program. Administrative claims data are the foundation of the Sentinel infrastructure because they are the most reliable and readily avail-...\"\n\nBelow the article image is the URL: https://www.nejm.org/doi/full/10.1056/NEJMp1809643\n\nThe slide contains no charts, tables, or diagrams.", "n_tokens": 445, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-19-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 19, "text": "FDA's MyStudies Application (App)\n\nThis slide contains a screenshot of a U.S. Food and Drug Administration web page titled \"FDA's MyStudies Application (App).\" It is not a chart, table, or diagram.\n\n Page header and navigation, as readable: \"U.S. Department of Health and Human Services\" (top bar); \"U.S. FOOD & DRUG ADMINISTRATION\"; links \"A to Z Index\", \"Follow FDA\", \"En Español\"; search box \"Search FDA\". Main tabs: \"Home\", \"Food\", \"Drugs\" (selected), \"Medical Devices\", \"Radiation-Emitting Products\", \"Vaccines, Blood & Biologics\", \"Animal & Veterinary\", \"Cosmetics\", \"Tobacco Products\". Section heading: \"Drugs\". Breadcrumb: \"Home > Drugs > Science & Research (Drugs)\".\n\n Left-side menu, as readable: \"Science & Research (Drugs)\" (highlighted), \"Regulatory Science at CDER\", \"Research Tools and Resources\", \"Scientific Public Private Partnerships and Consortia\", \"CDER Scientists\", \"Regulatory Science in Action\", \"Videos and Podcasts on Regulatory Science at CDER\", \"Work With Us\", \"Science & Research (Drugs) Content Map\".\n\n Share buttons, as readable: \"SHARE\", \"TWEET\", \"LINKEDIN\", \"PIN IT\", \"EMAIL\", \"PRINT\".\n\n Body text, as readable: \"The U.S. Food and Drug Administration (FDA) is posting computer code and a technical roadmap that will allow researchers and developers to customize and use the FDA's newly created MyStudies app. The FDA MyStudies App is designed to facilitate the input of real world data directly by patients which can be linked to electronic health data supporting traditional clinical trials, pragmatic trials, observational studies and registries. It was developed by the FDA and private sector partners, but open source code and technical documentation are being released to the public, so the app and patient data storage system can be reconfigured by organizations conducting clinical research. The app bore the FDA brand while its functionality was tested in a pilot study, but it can now be rebranded by researchers and developers who would like to customize and rebrand the app.\"\n\n", "n_tokens": 507, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-19-2", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 19, "text": "\"The FDA MyStudies App has several important features, including:\"\n\nBullet 1: \"The data storage environment is secure and supports auditing necessary for compliance with 21 CFR Part 11 and the Federal Information Security Management Act, so it can be used for trials under Investigational New Drug oversight. \"\n\nBullet 2: \"The app is configurable for different therapeutic areas, and health outcomes, which reduces software development hurdles for non-FDA users. \"\n\nSource links printed below the screenshot:\nhttps://www.fda.gov/NewsEvents/Newsroom/FDAInBrief/ucm625228.htm\nhttps://www.fda.gov/Drugs/ScienceResearch/ucm624785.htm\nhttps://github.com/PopMedNet-Team/FDA-My-Studies-Mobile-Application-System", "n_tokens": 186, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-21-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 21, "text": "Signal Detection Approaches Available in Sentinel\n\nThe slide is a diagram with four rows, each showing a colored map-pin icon, a heading, a gray subtitle, and, for the first three rows, a matching check mark at the right.\n\nRow 1, dark slate pin: \"Pre-Specified Panel of Select Outcomes.\" Subtitle: \"Prospective sequential surveillance tool (Level 3).\" Dark slate check mark at right.\n\nRow 2, orange pin: \"One Product, All Outcomes.\" Subtitle: \"TreeScan.\" Orange check mark at right.\n\nRow 3, green pin: \"One Outcome, All Products.\" Subtitle: \"DrugScan.\" Green check mark at right.\n\nRow 4, light blue pin: \"All Products, All Outcomes.\" Subtitle: \"No existing tool in Sentinel.\" No check mark.", "n_tokens": 177, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-27-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 27, "text": "Risk Evaluation and Mitigation Strategies\n\nThis slide has a title only. It contains no charts, tables, diagrams, or other images beyond the FDA logo, which is omitted as requested. The slide body is blank.", "n_tokens": 43, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-31-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 31, "text": "FDA REMS Resources Portal\n\nLaunched in 2018 in response to stakeholder requests for easier access and to improve their understanding of REMS.\n\nThe slide contains a screenshot of an FDA web announcement. It has a dark navy banner reading \"U.S. FOOD & DRUG ADMINISTRATION\" with the FDA logo and \"ADMINISTRATION\" beneath it. The heading below reads \"New REMS Webpages Launched.\" The text in the screenshot reads:\n\nToday the U.S. Food and Drug Administration (FDA) is launching a new set of web pages that aims to provide a one-stop source for general information about Risk Evaluation and Mitigation Strategy (REMS) programs. These webpages organize general REMS information according to audience (i.e., patients, health care professionals and industry) and most pages are presented in a short question and answer format.\n\nIn 2007, the Food, Drug Administration Amendments Act gave FDA the authority to require a REMS when FDA determines it is necessary to ensure the benefits of the drug outweigh the risks. Over the past decade, REMS have enabled FDA to approve drugs that otherwise might not have been approvable. However, REMS can also place a burden on the healthcare delivery system.\n\nOne piece of value feedback FDA has received regarding REMS is that information on drug-specific REMS, and on REMS more generally, can be difficult to locate on the web. REMS information will now be easier to find, relevant and ultimately more useful because organization of the new web content is based on the role a person might have in a REMS program. Also, other newly created pages guide visitors to current information about REMS programs, FDA guidances, public meetings, and educational resources.\n\nOur goal is to enable easier compliance with these programs so that patient access to drugs with REMS can be maintained, while still preserving their safe use.\n\nAs always, FDA welcomes feedback. Please use the Contact REMS Form to send us any comments you have on the newly created REMS webpages.\n\nThe phrases \"new set of web pages\" and \"Contact REMS Form\" appear as underlined hyperlinks in the screenshot.", "n_tokens": 441, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-32-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 32, "text": "Navigating Within the Portal\n\nThis slide shows two linked screenshots of the FDA website, labeled \"Landing page\" (left) and \"Navigation Bar\" (right), with a red arrow pointing from the landing page to the navigation bar.\n\n Landing page screenshot: The top menu tabs read Home, Food, Drugs, Medical Devices, Radiation-Emitting Products, Vaccines, Blood & Biologics, Animal & Veterinary, Cosmetics, and Tobacco Products. The page heading is \"Drugs.\" The breadcrumb reads \"Home > Drugs > Drug Safety and Availability > Risk Evaluation and Mitigation Strategies (REMS).\" The left-side menu lists \"Risk Evaluation and Mitigation Strategies (REMS)\" (highlighted in blue), \"What's in a REMS?\", \"Frequently Asked Questions (FAQs) about REMS\", \"Roles of Different Participants in REMS\", \"FDA's Role in Managing Medication Risks\", and \"REMS News, Education, Meetings and Improvement Efforts.\" Below it is a \"Resources for You\" section with the link \"Current REMS.\" The main page text includes the heading \"Risk Evaluation and Mitigation Strategies (REMS),\" a partly obscured paragraph beginning \"A Risk Evaluation and Mitigation Strategy (REMS) is a drug safety program that the U.S. Food and Drug Administration (FDA) can require...,\" a highlighted box beginning \"REMS are designed to help reduce the occurrence and/or severity of certain serious risks...,\" a paragraph beginning \"REMS are not designed to mitigate all the adverse events of a medication...,\" and a section titled \"REMS in Action: An Example\" describing \"Zyprexa Relprevv REMS.\" A red dashed circle surrounds the left-side menu.\n\n Navigation bar screenshot: The dark blue header reads \"Risk Evaluation and Mitigation Strategies (REMS).\" The items listed beneath are \"What's in a REMS?\", \"Frequently Asked Questions (FAQs) about REMS\", \"Roles of Different Participants in REMS\", \"FDA's Role in Managing Medication Risks\", and \"REMS News, Education, Meetings, and Improvement Efforts.\" Below this is a grey \"Resources for You\" section containing \"Current REMS.\" A red dashed circle surrounds the five menu items.\n\n", "n_tokens": 506, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-32-2", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 32, "text": "Annotations: Gold star symbols mark selected items. One star is next to \"What's in a REMS?\", two stars are next to \"Roles of Different Participants in REMS,\" one star is next to \"REMS News, Education, Meetings, and Improvement Efforts,\" and two stars are next to \"Current REMS.\" A handwritten-style label in gold text reads \"'Key HCP Pages'\" and sits beside the red dashed circle. A red double-headed arrow appears to the right of \"Current REMS.\"", "n_tokens": 116, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-33-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 33, "text": "Medication Error Prevention Program\n\nThis slide has no charts, tables, diagrams, or images beyond the title text. The slide shows only the title \"Medication Error Prevention Program\" in large blue bold type, centered in the upper-middle area of a white background. The remaining slide area is blank.", "n_tokens": 58, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-36-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 36, "text": "Prescription Opioid Abuse\n\nThis slide has no charts, tables, diagrams, or images beyond the title text. The slide shows only the title \"Prescription Opioid Abuse\" in large blue text, centered on a white background.", "n_tokens": 46, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-37-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 37, "text": "Trends in Drug Overdose Deaths\n\nHeader text: Annual Surveillance Report of Drug-Related Risks and Outcomes | United States. CDC National Center for Injury Prevention and Control | 2018.\n\nFigure 2A caption: Age-adjusted rates (superscript a) of drug overdose deaths (superscript b) and drug overdose deaths involving any opioid (superscript c) for all intents and for unintentional intent by year, United States, 1999–2016.\n\nChart: A line chart with four lines showing rates from 1999 to 2016. Both lines and values rise over the period.\n\nY-axis label: \"Rate per 100,000 population.\" Tick labels: 0.0, 5.0, 10.0, 15.0, 20.0, 25.0.\n\nX-axis label: \"Year.\" Tick labels: every year from 1999 to 2016.\n\nLegend entries:\n1. Solid dark purple line: \"Drug overdose deaths (of all intents)\"\n2. Green dashed line: \"Unintentional drug overdose deaths\"\n3. Blue dotted line: \"Drug overdose deaths involving any opioid (of all Intents)\"\n4. Solid orange line: \"Unintentional drug overdose deaths involving any opioid\"\n\nApproximate values read from the chart (no data labels are printed on the lines):\nDrug overdose deaths (of all intents): about 6.0 in 1999, about 11.5 in 2006, about 13.2 in 2011, about 19.8 in 2016.\nUnintentional drug overdose deaths: about 4.0 in 1999, about 8.8 in 2006, about 10.6 in 2011, about 17.2 in 2016.\nDrug overdose deaths involving any opioid (of all intents): about 2.6 in 1999, about 5.8 in 2006, about 7.3 in 2011, about 13.2 in 2016.\nUnintentional drug overdose deaths involving any opioid: about 2.1 in 1999, about 4.7 in 2006, about 6.3 in 2011, about 11.9 in 2016.\n\nSource line: https://www.cdc.gov/drugoverdose/pdf/pubs/2018-cdc-drug-surveillance-report.pdf", "n_tokens": 461, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-38-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 38, "text": "Opioids\nAnother busy year!\nSeven of nine Drug Safety and Risk Management Advisory Committee meetings 2018 concerned opioids\nIncreasing public health focus", "n_tokens": 27, "kind": "vision"}
{"chunk_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update-40-1", "doc_id": "CDER_Office_of_Surveillance_and_Epidemiology_2018_Update", "page": 40, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images. The only element is the logo, which is omitted as requested.", "n_tokens": 33, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-0-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 0, "text": "CDISC-SEND Common Issues and CDER Policy Updates\n\nHeader banner on the left: \"CDER Small Business and Industry Assistance (SBIA) WEBINAR SERIES.\"\n\nPresenters listed in two columns:\nJesse Anderson, MPH, Program Manager, OCS\nJennifer Feldmann, Contractor, OCS\nStephanie Leuenroth-Quinn, PhD, Pharmacologist, OND\nPatricia Brundage, PhD, Pharmacologist, OND\n\nDate: June 15, 2020\n\nThere are no charts, tables, diagrams, or other images on this slide apart from the webinar series banner and the FDA logo.", "n_tokens": 125, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-2-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 2, "text": "Today's Topics\n\nThis slide is a diagram listing three topics in a vertical sequence, each shown as a blue bar with a circular icon on its left, connected by a thin line.\n\n1. Icon: a dark blue circle with a document-and-arrow graphic (a document with a green up arrow and a blue down arrow). Label: \"SEND at the FDA\"\n2. Icon: an orange-ringed white circle containing the text \"KickStart.\" Label: \"Common SEND Data Fitness Issues\"\n3. Icon: a dark blue circle with a megaphone graphic. Label: \"FDA Communication on SEND\"", "n_tokens": 127, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-4-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 4, "text": "Nonclinical Regulatory Review\n\nThe slide contains one flow diagram with a blue border and the tagline \"Better Data | Better Tools | Better Decisions\" at the bottom left. The footer shows \"www.fda.gov.\"\n\nThe diagram reads from left to right and top to bottom, connected by blue arrows:\n\n1. At the upper left is a pile of multicolored building blocks (red, yellow, green, blue, and orange).\n2. An arrow points right to a computer monitor icon labeled \"eCTD Submission.\" On the screen are folder icons and a circular arrow.\n3. An arrow points right to a green circle with a white checkmark, labeled \"eCTD Validation Rules.\"\n4. An arrow points down to a funnel. Inside the funnel are three overlapping circles: \"SDTM\" (red), \"SEND\" (red), and \"ADaM\" (faded red).\n5. An arrow points down from the funnel to a second green circle with a white checkmark, labeled \"Study Data Validation Rules.\"\n6. An arrow points right from this checkmark to a graphic labeled \"KickStart Services.\" The graphic shows a green upward arrow and a small running figure.\n7. An arrow points right from KickStart Services to a dark blue silhouette of a human head containing white gears.\n\nTwo items stand apart from this sequence and are not connected by arrows:\n- Above the Analytical Tools icon, a cylinder-shaped icon labeled \"Janus\" contains three interlocking circular arrow segments in dark gray, blue, and yellow.\n- Below Janus, a grid of nine circular icons in blue, teal, purple, gray, and green is labeled \"Analytical Tools.\"", "n_tokens": 353, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-7-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 7, "text": "SEND Studies in Janus Nonclinical\n\nThis slide has an area chart and a summary table of counts.\n\nArea chart: The chart shows studies loaded in Janus Nonclinical over time. The vertical axis is labeled \"Studies Loaded in Janus Nonclinical,\" with tick labels from 0 to 225 in steps of 25. The horizontal axis shows monthly time labels from Nov, 2017 to Nov, 2019, labeled at intervals of two months: Nov, 2017; Jan, 2018; Mar, 2018; May, 2018; Jul, 2018; Sep, 2018; Nov, 2018; Jan, 2019; Mar, 2019; May, 2019; Jul, 2019; Sep, 2019; Nov, 2019. The chart has no legend. The series starts near 0 in Nov, 2017, rises to small values in early 2018, dips to 0 around Mar, 2018 (between Jan and Mar 2018), and then generally increases with several peaks. The highest visible peak is just above 200 in about Jul, 2019. The series ends near 180 in late 2019. The chart values are not individually labeled; the values above are approximate readings from the axis.\n\nSummary table: The table has columns labeled 2017, 2018, 2019, and \"Total in Janus.\" It has two rows, each marked with an upload-arrow icon.\n\nRow 1, \"Studies Loaded\": 2017 = 33; 2018 = 354; 2019 = 1359; Total in Janus = 1740+. The cells are joined by \"+\" signs and an \"=\" sign before the total.\n\nRow 2, \"Applications Loaded\": 2017 = 25; 2018 = 173; 2019 = 539; Total in Janus = 735+. The cells are joined by \"+\" signs and an \"=\" sign before the total.", "n_tokens": 367, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-17-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 17, "text": "Example SEND Package\n\nThe slide has a Windows File Explorer screenshot on the left and a text box on the right.\n\nFile Explorer screenshot: The address bar shows the breadcrumb path \"[application] > [sequence] > m4 > datasets > [study-id] > tabulations > send\". The left navigation tree shows the folders m4, datasets, [study-id], tabulations, and send, with send highlighted and selected. The right pane has a column header \"Name\" and lists these files in this order: bw.xpt, cl.xpt, define.xml, define2-0-0.xsl, dm.xpt, ds.xpt, ex.xpt, fw.xpt, lb.xpt, ma.xpt, mi.xpt, nsdrg.pdf, om.xpt, pc.xpt, pp.xpt, relrec.xpt, se.xpt, suppma.xpt, suppmi.xpt, supppc.xpt, ta.xpt, te.xpt, ts.xpt, tx.xpt. Each .xpt file has a green spreadsheet-style icon. define.xml has a plain document icon, define2-0-0.xsl has a browser-style icon, and nsdrg.pdf has a red PDF icon.\n\nText box: The heading reads \"Example SEND Package\". Bullet 1: \"define.xml and referenced stylesheet\". Bullet 2: \"SEND dataset files follow naming convention in SENDIG\". Bullet 3: \"nsdrg.pdf\". Below the bullets, the text reads \"All files in the same folder\".", "n_tokens": 376, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-21-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 21, "text": "Common Issues with Standardization of Timing Variables\n\nThis slide has no charts, tables, diagrams, or images. It lists three bullet points:\n\n- Planned/nominal day does not align data with the study report summary.\n- Incorrect reporting of timing for tests or observations scheduled relative to dose.\n- Incorrect reporting of result from unscheduled tests or observations.\n\nFooter text: www.fda.gov", "n_tokens": 78, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-23-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 23, "text": "VISITDY/--NOMDY and –ELTM Use for Analysis\n\nText box at top: \"Example: Sponsor reported sample collection day in VISITDY when samples collected at times relative to dose. Tabular data is therefore mislabeled; graphs of results relative to dose do not include data for timepoints > 24 hrs post dose\"\n\nTable header strip (blue tabs, seven columns): \"0 Hrs - Day 1\", \"0.5 Hrs - Day 1\", \"1 Hrs - Day 1\", \"2 Hrs - Day 1\", \"6 Hrs - Day 1\", \"12 Hrs - Day 1\", \"24 Hrs - Day 2\". The last tab, \"24 Hrs - Day 2\", is outlined in red.\n\nCallout box: \"Day 1 24hr\", in a red box with a red line pointing to the outlined \"24 Hrs - Day 2\" tab.\n\nLine chart with markers: Y-axis label \"Concentration (ng/mL)\", tick labels 0, 20k, 40k, 60k. X-axis label \"Time (hr)\", tick labels 0, 2, 4, 6, 8, 10, 12. No legend is visible. Three series are plotted with different markers and colors, and a single blue dot sits at about 0 on the axis. Approximate readings from the graph:\n- Red line with plus markers: about 1.5k at 0 hr; about 70k at 0.5 hr; about 51k at 1 hr; about 50k at 2 hr; about 23k at 4 hr; about 9k at 8 hr; about 28k at 12 hr.\n- Green line with diamond markers: about 1k at 0 hr; about 26k at 0.5 hr; about 29k at 1 hr; about 21.5k at 2 hr; about 8k at 4 hr; about 3.5k at 8 hr; about 12.5k at 12 hr.\n- Orange line with square markers: about 0 at 0 hr; about 5k at 0.5 hr; about 8k at 1 hr; about 3k at 2 hr; about 1.2k at 4 hr; about 0.2k at 8 hr; about 0.9k at 12 hr.", "n_tokens": 477, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-28-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 28, "text": "Example Incidence Counts for LB in Janus\n\nThis is a screenshot of a data table from the Janus software interface, showing the \"GROUPED SUMMARY : NON-NUMERIC\" view. Above the table are four tabs: \"GROUPED SUMMARY : NUMERIC,\" \"GROUPED SUMMARY : NON-NUMERIC\" (currently selected), \"DAILY BY ANIMAL,\" and \"ANIMAL DETAILS.\" Below the tabs is a search box labeled \"Filter table data by term...\" and a row of icon buttons.\n\nThe table has four left-hand columns: Category, Test, Day, and Value. A header band above the data columns reads \"Female.\" Four data columns sit under that band, labeled \"Control [Terminal,Recove...],\" \"Low [Terminal,Recove...],\" \"Mid [Terminal,Recove...],\" and \"High [Terminal,Recove...].\" The column labels are cut off in the image.\n\nAll rows show Category \"URINALYSIS\" and Test \"Protein.\" Values are listed as Day, Value, then Control, Low, Mid, High counts (blank cells are empty in the image):\n\nDay 29, Value \"N\": 19, 19, 19, 20\nDay 29, Value \"0.3 (g/L)\": 7, 4, 4, blank\nDay 29, Value \"1 (g/L)\": blank, 1, blank, blank\nDay 29, Value \"Negative\": 4, 2, 4, 14\nDay 29, Value \"Trace\": 8, 12, 11, 6\nDay 43, Value \"N\": 10, 10, 9, 10\nDay 43, Value \"0.3 (g/L)\": blank, 2, 3, 2\nDay 43, Value \"1 (g/L)\": blank, blank, blank, blank\nDay 43, Value \"Negative\": 3, 1, 4, 2\nDay 43, Value \"Trace\": 7, 7, 2, 6\n\nA grey caption box below the table reads: \"Tests with no LBSTRESN reported with summary incidence counts in Janus Nonclinical.\"\n\nFooter text: www.fda.gov", "n_tokens": 463, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-29-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 29, "text": "Example of Incorrect Standardization\n\nScreenshot of a data table interface, with a second window overlaid on the lower right.\n\nUpper table: A grid with the columns Day, Category, Test, Unit of the Standardized Result, an unlabeled column, and, under the heading \"Male,\" four dose-group columns: \"Group 1,0mg/kg/d... [Terminal,R...],\" \"Group 4,600-400mg/kg/... [Terminal,R...],\" \"Group 2,60mg/kg/... - Terminal,\" and \"Group 3,200mg/k... - Terminal.\" The first row is a collapsed group labeled Day -8. Two data rows follow:\n- Category URINALYSIS, Test Protein, Unit g/L, statistic Mean. Values: 0.000 (Text) for Group 1,0mg/kg/d; 0.000 (Text) for Group 4,600-400mg/kg/; 0.000 for Group 2,60mg/kg/; 0.000 (Text) for Group 3,200mg/k.\n- Category URINALYSIS, Test Protein, Unit g/L, statistic Std Dev. Values: ±0.000 (Text) for Group 1; ±0.000 (Text) for Group 4; ±0.000 for Group 2; ±0.000 (Text) for Group 3.\n\nLower window: A table with the columns Animal ID, Day, Result, and Result in Character. The Result in Character column appears empty. Rows:\n- Animal ID 1001, Day -8, Result 0.0\n- Animal ID 1002, Day -8, Result 0.0\n- Animal ID 1003, Day -8, Result 0.0\n- Animal ID 1004, Day -8, Result 0.3-0.7\n- Animal ID 005 (as displayed), Day -8, Result 0.0\n- Animal ID 1006, Day -8, Result 0.1-0.2\n\nButtons at the bottom of the window read CLOSE, DAILY BY ANIMAL, and ANIMAL DETAILS.\n\nCaption text: \"Semi-quantitative urine protein test are in SEND with the result range in LBSTRESC and with values incorrectly in LBSTRESN. This causes Janus Nonclinical to report means and standard deviations on those numeric results rather than incidence counts.\"", "n_tokens": 508, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-31-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 31, "text": "Example: LBCALCN Not Supplied\n\nThe slide shows a data table from a study-results tool, a pop-up window over it, a text excerpt from a study report, and a callout box.\n\n Main table: Columns are Day, Specimen Material Type, Sub Category, Test, Unit of the Standard Result, an unlabeled column with values Mean, Std Dev, and N, and then two groups. The Male group has columns 0 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg. The Female group has columns 0 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg. The Male 0 mg/kg column is the only one fully visible; the rest is covered by the pop-up.\n\n Day 29 rows: Specimen PLASMA, Sub Category Clinical Chemistry, Test Sorbitol Dehy..., Unit U/L.\n- Mean: 1.500 (Text), in Male 0 mg/kg (the cell is outlined)\n- Std Dev: ±0.577 (Text)\n- N: 12 (Text)\n\nDay 58 rows: Specimen PLASMA, Sub Category Clinical Chemistry, Test Sorbitol Dehy..., Unit U/L.\n- Mean: 2.200 (Text)\n- Std Dev: ±0.837 (Text)\n- N: 6 (Text)\n\n Pop-up window: Title area is blank. The table has columns Animal ID, Day, Result, and Result in Character. Rows (all Day 29):\n- 10001: Result 2, Result in Character 2\n- 10002: Result <1.0\n- 10003: Result 1, Result in Character 1\n- 10004: Result <1.0\n- 10005: Result 1, Result in Character 1\n- 10006: Result <1.0\n- 10007: Result <1.0\n- 10008: Result 2, Result in Character 2\n- 10009: Result <1.0\n- 10010: Result <1.0\n- 10011: Result <1.0\n\nA scrollbar is on the right, indicating more rows. Buttons at the bottom read CLOSE, DAILY BY ANIMAL, and ANIMAL DETAILS.\n\n", "n_tokens": 457, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-31-2", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 31, "text": "Study report excerpt (lower left, on white background): Column header U/L. Values listed in order: 2.0, 0.5 }, 1.0, 0.5 }, 1.0, 0.5 }, 0.5 }, 2.0, 0.5 }, 0.5 }, 0.5 }, 0.5 }. Summary rows: n 12, Mean 0.83, S.D. 0.58. A yellow-highlighted footnote reads: \"} : Below the LLOQ, represented as a half value of LLOQ\".\n\n Callout box text: \"Study Report indicates that half of LLOQ is used for results <1.0. LBCALCN not supplied so results <1.0 eliminated from mean in FDA Tools\"", "n_tokens": 169, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-33-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 33, "text": "Examples of Undefined Code/Abbreviations\n\nThe slide has four tables. Red boxes highlight specific cells in each.\n\nTable 1 has the columns Test, Sign, Location of a Finding, and Comments. Its one row reads: Clinical Observation | scaly skin | dose site | D. The Comments cell \"D\" is outlined in red.\n\nTable 2 has the columns Organ/Tissue, Test, Exclusion Flag, and Reason for Exclusion. Its one row reads: GLAND, THYROID/GLAND, PARATHYROID | Weight | Y | E. The Reason for Exclusion cell \"E\" is outlined in red.\n\nTable 3 has the columns Category, Test Code, Test, and Standardized Result in Character Format. Its one row reads: URINALYSIS/URINE CHEMISTRY | COLOR | Color | CO. The result cell \"CO\" is outlined in red.\n\nTable 4 has the columns Category, Test Code, Test, Standardized Result in Character Format, and Unit of the Standardized Result. Its two rows read:\nURINALYSIS | CREATVOL | Creatinine Volume | 115.4 | umol/cp\nURINALYSIS | GLUCVOL | Glucose Volume | 9.5 | umol/cp\nThe Unit of the Standardized Result cells for both rows are outlined in red.\n\nFooter text: www.fda.gov", "n_tokens": 266, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-34-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 34, "text": "SEND Data Quality Assessment\n\nChart 1: The chart is titled \"Relative Number of Issues in SEND Datasets Per Study, Normalized, All Kickstart Studies.\" It is a vertical bar chart with blue bars, one bar for each period, and an orange dotted trend line running across the bars from upper left to lower right. The x-axis has three labels: \"Feb 2018\" at the far left, \"Jan 2019\" near the middle, and \"Dec 2019\" at the far right. The y-axis has no label, units, or numeric tick values. No legend is visible. A red rectangle outlines the bars from about Jan 2019 through Dec 2019, and a red arrow runs from the bottom of that rectangle down to Chart 2.\n\nChart 2: The chart is titled \"Relative Number of Issues in SEND Datasets Per Study, Calendar 2019 Only.\" It is a vertical bar chart with blue bars and an orange dotted trend line running from upper left to lower right. It has no visible x-axis labels, no y-axis label or units, no numeric values, and no legend. It shows the same kind of data as the highlighted section of Chart 1, limited to calendar year 2019.", "n_tokens": 250, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-37-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 37, "text": "OND Responses to Common SEND Questions\n\nPresenters named on the slide:\nPatricia Brundage, PhD, Pharmacologist\nStephanie Leuenroth-Quinn, PhD, Pharmacologist\n\nAffiliation text:\nU.S. Food and Drug Administration\nCenter for Drug Evaluation and Research\nOffice of New Drugs\n\nEvent line at bottom in italics: SBIA Webinar/ June 15, 2020\n\nThe slide contains no charts, tables, diagrams, or other images beyond the logo, which is omitted as requested.", "n_tokens": 99, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-39-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 39, "text": "Outline\nCommonly asked Questions about SEND\nSEND Requirements versus the Technical Rejection Criteria (including the simplified ts.xpt)\nwww.fda.gov", "n_tokens": 27, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-40-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 40, "text": "COMMONLY ASKED QUESTIONS ABOUT SEND\n\nThe slide has no charts, tables, diagrams, or images beyond the FDA logo, which is omitted. The slide contains the title above and the email address edata@fda.hhs.gov, shown as a blue underlined hyperlink in the lower left area.", "n_tokens": 60, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-41-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 41, "text": "Q: Draft Versus Final Study Reports?\n\nA: SEND datasets are required when submitting a draft or final study report for study types modeled in an FDA supported SEND Implementation Guide (SENDIG) version.\n\nDiagram: A flow diagram with three stages, read left to right.\n\nLeft: Two red-outlined document icons stacked vertically. The upper one is labeled \"DRAFT REPORT\" and the lower one is labeled \"FINAL REPORT.\" Each has four blue horizontal lines representing text.\n\nCenter: A large blue circle with a red outline containing a black silhouette of a person seated behind a laptop. The laptop screen is labeled \"REVIEW.\"\n\nRight: A red-outlined rounded box labeled \"Regulatory Decisions for Clinical Development,\" containing three blue horizontal lines.\n\nArrows: A red curved arrow runs from the Draft Report to the Review circle. A second red curved arrow runs from the Final Report to the Review circle. A straight red arrow runs from the Review circle to the Regulatory Decisions box.", "n_tokens": 196, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-45-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 45, "text": "Q: SEND for Animal Rule Studies?\n\nBody text: \"A: The Federal Register Notice was published announcing FDA support of the CDISC SDTM v1.8 & CDISC SENDIG-AR v1.0 on March 15, 2020. These new standards will be required in submissions to FDA effective March 15, 2022.\"\n\nImage: A screenshot of a Federal Register notice header. The header shows the National Archives logo, the words \"FEDERAL REGISTER\" with the subtitle \"The Daily Journal of the United States Government,\" and a government seal. Below is a blue bar with a circled \"N\" and the label \"Notice.\" The notice title reads: \"Electronic Study Data Submission; Data Standards; Support and Requirement Begin for Study Data Tabulation Model Version 1.8 With Standard for Exchange of Nonclinical Data Implementation Guide-Animal Rule Version 1.0.\" The footer line reads: \"A Notice by the Food and Drug Administration on 03/11/2020.\"\n\nNumbers and labels in the slide: March 15, 2020 (date FDA support was announced in the Federal Register notice); March 15, 2022 (date the standards are required in submissions to FDA); SDTM v1.8 and CDISC SENDIG-AR v1.0 (the standards named in the body text and notice title); 03/11/2020 (date of the notice by the Food and Drug Administration).", "n_tokens": 297, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-49-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 49, "text": "SEND REQUIREMENTS VERSUS THE TECHNICAL REJECTION CRITERIA\n\nThis slide contains only the title text above. It has no charts, tables, diagrams, or other images. The slide background is white, and the title is in bold blue capital letters, set across two lines.", "n_tokens": 50, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-56-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 56, "text": "USING THE SIMPLIFIED TS.XPT\n\nThis slide has only a title. It contains no charts, tables, diagrams, or other images, and no additional text or bullet points are visible.", "n_tokens": 37, "kind": "vision"}
{"chunk_id": "CDER_SEND_Webinar_June_2020-63-1", "doc_id": "CDER_SEND_Webinar_June_2020", "page": 63, "text": "The slide has no separate title. Its only text is a centered statement reading: \"That concludes the SBIA presentations. We are going to take a quick break to review the submitted questions and will begin answering them in a few minutes.\" The slide contains no charts, tables, diagrams, or images.", "n_tokens": 61, "kind": "vision"}
{"chunk_id": "CDER_Update_Presentation-0-1", "doc_id": "CDER_Update_Presentation", "page": 0, "text": "CDER Update\nJanet Woodcock MD\nDirector, CDER, FDA\nDecember 5, 2017", "n_tokens": 17, "kind": "vision"}
{"chunk_id": "CDER_Update_Presentation-1-1", "doc_id": "CDER_Update_Presentation", "page": 1, "text": "2017: Busy Year\n\nThe slide is a text-only bulleted list with no charts, tables, diagrams, or images. The bullets read:\n\n- High levels of applications and approvals in many premarket programs\n- Implementation of cures and reauthorized UFs\n- Ongoing opioid crisis\n- Increased emphasis on competition\n- Drug shortage exacerbation by hurricane activity\n- Continuing implementation of DQSA", "n_tokens": 82, "kind": "vision"}
{"chunk_id": "CDER_Update_Presentation-4-1", "doc_id": "CDER_Update_Presentation", "page": 4, "text": "21st Century Cures Implementation\n\nThe slide is a text-only bulleted list with no charts, tables, diagrams, or images. The bullet items, in order, are:\n\n- Real world evidence policy development\n- Patient-focused drug development\n- Drug development tools program\n- New hiring authorities\n- Antimicrobial drugs breakpoint information\n- Novel trial designs\n- Model-based drug development", "n_tokens": 75, "kind": "vision"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-0-1", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 0, "text": "State of CDER\n\nFDLI Annual Conference\nOctober 8, 2020\n\nPatrizia Cavazzoni, MD\nActing Center Director\nCenter for Drug Evaluation and Research\nU.S. Food and Drug Administration\n\nwww.fda.gov", "n_tokens": 44, "kind": "vision"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-3-1", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 3, "text": "CTAP Treatment Acceleration Program\n\nLeft panel: A graphic showing a blurred streak of light racing through a dark tunnel, with blue and white light trails curving toward the viewer. Overlaid text reads \"Coronavirus Treatment Acceleration Program (CTAP)\" followed by the paragraph: \"CTAP will use every available method to move new treatments to patients as quickly as possible, balancing patient needs for medicine while supporting trials to gather evidence and weighing the risks and benefits.\"\n\nCenter text, under the heading \"As of August 31:\" three bullet points:\n- \"Over 590 drug development programs in planning stages*\"\n- \"Over 310 trials reviewed by FDA**\"\n- \"5 treatments authorized for Emergency Use\"\n\nFootnotes to the right of the bullets:\n- \"*Active Pre-INDs excluding vaccines\"\n- \"**Safe to proceed IND excluding vaccines\"\n\nTop-right photo: A hospital setting showing a patient in a bed with a clinician in full protective gear (face shield, mask, gown) leaning over them. Medical monitoring equipment with screens and IV lines is visible in the foreground, blurred.\n\nBottom-center photo: A close-up of blue-toned pharmaceutical content, showing a stack or spill of blue and white capsules and tablets in the right portion, with laboratory glassware and a dropper or pipette tip in the left portion.", "n_tokens": 273, "kind": "vision"}
{"chunk_id": "Cavazzoni_Presentation_FDLI2020-10-1", "doc_id": "Cavazzoni_Presentation_FDLI2020", "page": 10, "text": "QUESTIONS?\n\nThis slide has no charts, tables, diagrams, or images. It contains only the centered title text \"QUESTIONS?\" on a white background, with a light blue header bar across the top.", "n_tokens": 41, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-2-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 2, "text": "DMEPA's Premarket and Postmarket Activities in Preventing Medication Errors\n\nThe slide has a light blue title banner with the title in dark blue text. Below the banner on the left is a headshot photo of a smiling woman with dark hair, wearing a dark top, in front of an American flag. To the right of the photo is the presenter text: \"Mishale Mistry, PharmD, MPH\" in bold, followed by \"Associate Director, FDA, CDER, OSE, OMEPRM, Division of Medication Error Prevention and Analysis (DMEPA).\"\n\nThe slide contains no charts, tables, diagrams, or other data graphics.", "n_tokens": 136, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-7-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 7, "text": "Medication Errors and Product Life Cycle\n\nThis slide contains one diagram, a product life cycle flow.\n\nThe diagram shows a large light-blue arrow pointing to the right, with six teal rounded boxes placed in sequence along it, from left to right:\n1. Discovery & development\n2. Preclinical research\n3. Clinical research\n4. FDA review\n5. Market approval\n6. Postmarket safety monitoring\n\nA vertical dashed blue line separates the fifth box, Market approval, from the sixth box, Postmarket safety monitoring. The dashed line sits at the boundary between these two stages.\n\nBelow the arrow, two labeled rectangles are connected by curved blue arrows that loop back and forth between them:\n- A wide rectangle on the left labeled \"Premarket (pre-approval)\", positioned under the stages before the dashed line.\n- A narrower rectangle on the right labeled \"Postmarket (post-approval)\", positioned under the stage at and after the dashed line.\n\nTwo curved arrows link the rectangles: an upper arrow curves from the premarket box to the postmarket box, and a lower arrow curves from the postmarket box back to the premarket box.\n\nNo numbers, axes, units, or legend entries appear on this slide.", "n_tokens": 254, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-23-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 23, "text": "Product Strength and Net Quantity Statements\n\nThe slide's left panel reads: \"Safety Considerations for Container Labels and Carton Labeling to Minimize Medication Errors.\" Below that it reads: \"Draft Guidance for Industry, April 2013.\"\n\nThe slide has two Remeron carton images and one Temodar bottle image, plus a Temodar carton image to the right of an arrow. Red boxes highlight the strength and net quantity statements on each.\n\nImage 1: Remeron carton, 15 mg. A green carton labeled \"REMERON (mirtazapine) Tablets,\" with NDC code 0052-0165-30 (partly legible). A red box highlights \"15 mg\" on the left side of the front panel. A second red box highlights \"30 Tablets\" on the lower front. The carton states \"Rx only\" and \"Manufactured for Organon Inc., West Orange, NJ 07052 USA, By N.V. Organon Oss, The Netherlands.\"\n\nImage 2: Remeron carton, 30 mg. Matching layout to Image 1. A red box highlights \"30 mg\" on the left side of the front panel. A red box highlights \"30 Tablets\" on the lower front.\n\nCallout beside Images 1 and 2: \"Note the placement of strength and net quantity.\"\n\nImage 3: Temodar bottle. A brown bottle labeled \"Temodar (temozolomide) Capsules,\" with \"20 CAPSULES\" on the label. A red box highlights \"100 mg\" on the label. The label also reads \"For Oral Administration.\"\n\nCallout beside Image 3: \"Note prominence of strength.\"\n\nArrow: a blue arrow pointing from the Temodar bottle image to the Temodar carton image.\n\nImage 4: Temodar carton. NDC 0085-1366-01. A red box highlights \"100 mg per capsule.\" The carton reads \"Temodar (temozolomide) Capsules,\" \"For Oral Administration Rx only,\" and \"THIS PACKAGE CONTAINS 14 CAPSULES.\"", "n_tokens": 438, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-35-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 35, "text": "Human Factors Considerations\n\nLeft panel text: \"Safety Considerations for Product Design to Minimize Medication Errors.\" Below it: \"Guidance for Industry, April 2016.\"\n\nDiagram: A flow diagram with two column headings, \"HF Considerations\" on the left and \"Outcome\" on the right, separated by a vertical dashed line. On the left, three colored arrows point into a central black box labeled \"Device Use.\" From top to bottom, the arrows are labeled \"Users\" (crimson red), \"Use Environment\" (orange), and \"Device / Interface\" (light blue). On the right, two colored arrows lead out of the black box. The upper arrow, in green, is labeled \"Safe & Effective.\" The lower arrow, in red, is labeled \"Unsafe, Ineffective.\" No numbers, axes, or units appear in the diagram.", "n_tokens": 176, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-37-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 37, "text": "Postmarket Surveillance of Medication Errors\n\nThis slide is a section title slide with no charts, tables, diagrams, or images beyond the title text. The title \"Postmarket Surveillance of Medication Errors\" is set in white text on a teal horizontal banner with an arrow-shaped right end. The FDA logo and slide number are omitted here.", "n_tokens": 67, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-45-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 45, "text": "A Lot Happens When You Report A Medication Error or Hazard to FDA and ISMP\n\nThe slide has a light blue title band across the top with the title in black text. Below it is a photo of a smiling older man with gray hair and glasses, wearing a navy sweater over a collared shirt, seated in front of a window with horizontal blinds. To the right of the photo is the text \"Michael R. Cohen RPh, MS, ScD (hon), DPS (hon)\" in bold black, followed by \"President, Institute of Safe Medication Practices (ISMP)\" and \"(www.ismp.org)\" in regular black text. The bottom left corner shows the ISMP logo, a blue wordmark with a green checkmark and a curved line, with the text \"An ECRI Affiliate\" beneath it. The bottom right corner shows the footer \"www.ismp.org\".", "n_tokens": 189, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-51-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 51, "text": "Where does ISMP get its information? Where does it go?\n\nThis is a flow diagram with inputs on the left, ISMP in the center, and outputs on the right. Arrows show the direction of information flow.\n\nLeft side, inputs with arrows pointing to ISMP:\n- \"ISMP MERP and VERP\"\n- \"Providers, Consumers\"\n- \"FDA MedWatch\"\n- \"News media, other sources\"\n\nFar left: a logo image reading \"MEDICATION ERRORS REPORTING PROGRAM,\" with a circular symbol containing a magnifying-glass-like icon.\n\nCenter: the ISMP logo with the text \"An ECRI Affiliate.\" Below it, a list reading \"ISMP Canada,\" \"ISMP Spain,\" \"ISMP Brazil,\" and \"IMSN.\"\n\nRight side, outputs with arrows pointing away from ISMP:\n- \"Healthcare providers\"\n- \"Healthcare organizations\"\n- \"Consumers\"\n- \"Regulatory\"\n- \"Industry\"\n\nFar right: a thumbnail of an ISMP newsletter page. Readable text includes \"ISMP\" in the header, \"Acute Care,\" \"ISMP Medication Safety Alert!\", and the article headline \"Errors associated with oxytocin use: A multi-organization analysis by ISMP and ISMP Canada.\" A sidebar reads \"SAFETY brief,\" and a caption reads \"Figure 1.\" The remaining body text is too small to read.\n\nBottom left: the ISMP logo with the text \"An ECRI Affiliate.\"\nBottom right: the footer text \"www.ismp.org.\"", "n_tokens": 324, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-53-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 53, "text": "Slide title: Report received and entered into ISMP database\n\nBody text, two bullets:\n- Report entered into one of our databases and initially reviewed by ISMP nurse or pharmacy technician analyst\n- ISMP sends an email to reporter to confirm receipt of the report and thank him or her for reporting\n\nDiagram: A blue-ringed circle with a white center containing a computer monitor icon. A dotted line runs from the circle down to a small open circle containing a blue dot. The label below the diagram reads \"REPORT.\"\n\nLogo, bottom left: \"ISMP\" in blue, with a teal arc and checkmark above it, and the text \"An ECRI Affiliate\" beneath.\n\nFooter, bottom right: \"www.ismp.org\"", "n_tokens": 151, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-61-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 61, "text": "Aggregate data from error databases analyzed and published periodically\n\n The slide has a title bar and three visual elements, left to right.\n\n Left: A circular icon with a white stop-hand symbol inside a hexagon, surrounded by an orange ring. A dotted line runs down from the icon to an orange dot. The word \"PREVENT\" appears beneath it.\n\n Center: The cover of \"The ISMP National Vaccine Errors Reporting Program (VERP).\" A photo shows a young girl looking down while a gloved healthcare worker gives her an injection in the upper arm. A purple banner reads \"2017-2018 BIANNUAL REPORT.\" The cover text reads \"The ISMP National Vaccine Errors Reporting Program (VERP)\" and \"www.ismp.org.\" Below the cover is the caption URL: https://www.ismp.org/resources/2017-2018-vaccine-bi-annual-report\n\nRight: A screenshot of an \"ISMP Medication Safety Alert!\" newsletter for Acute Care, dated February 13, 2020, Volume 25, Issue 3. The lead article is titled \"Errors associated with oxytocin use: A multi-organization analysis by ISMP and ISMP Canada.\" Its text includes these numbers: 144 incidents reported to ISMP Canada and NSIR between 2000 and 2019; 12% of oxytocin reports to ISMP Canada and 29% of oxytocin reports to NSIR involved maternal, fetal, or neonatal harm; 52 voluntary reports to ISMP's National Medication Errors Reporting Program (ISMP MERP) between 1999 and 2019; about 10% of reports described more than one oxytocin error; about 84% of events originated during dispensing; 23% during administration; 13% during prescribing; about 8% were hazards that did not result in errors; 25% of all events resulted in maternal, fetal, or neonatal harm. The analysis identifies 3 main themes in the 144 incidents and five themes across both data sets. Theme 1 is \"PRESCRIBING ERRORS.\" Drug names in the text include OXYTOCIN, PITOCIN, PITRESSIN, OXYCONTIN, and OXYCODONE. A sidebar reads \"Now Available from ISMP: Expanded Smart Pump Guidelines.\"", "n_tokens": 474, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-61-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 61, "text": "A \"SAFETY briefs\" section titled \"Problems with containers with dual linear barcodes\" includes a photo of B. Braun Duplex containers, labeled Figure 1: \"Nurses are confusing the two linear barcodes on B. Braun Duplex containers.\" The caption URL is https://www.ismp.org/node/14240. The page footer reads www.ismp.org.\n\n The slide displays ISMP and ISMP Canada logos, and the bottom-left logo reads \"ISMP An ECRI Affiliate.\"", "n_tokens": 111, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-65-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 65, "text": "ISMP Publications\n\nThe slide has a title, a bulleted list, and one diagram. The diagram is a circular icon with a red-to-orange gradient ring around a white center. The center shows a small document icon with a pie chart and bar-like lines. A dotted line runs down from the circle to a small red dot, and the label beneath it reads \"INFORM.\" No axes, units, or numeric values appear.\n\nThe main text is a dash-led heading, \"Regular Journal and Newsletter Features:\", followed by seven bulleted items in italic type:\nPharmacy Practice News\nNursing 2020\nHospital Pharmacy\nPharmacy Times\nPharmacy Today\nUS Pharmacist\nJournal of Emergency Nursing\nHome Healthcare Now\n\nThe bottom left corner shows the ISMP logo with the text \"An ECRI Institute Affiliate.\" The bottom right footer reads \"©2020 ISMP | www.ismp.org.\"", "n_tokens": 184, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-66-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 66, "text": "Error reporting outcomes\n\nThe slide has a large gray title, \"Error reporting outcomes,\" with a blue horizontal line beneath it. The body of the slide is blank. There are no charts, tables, diagrams, or other images. In the lower left is the ISMP logo, a blue wordmark with a teal arc and check mark, and the text \"An ECRI Affiliate\" below it. In the lower right is the footer \"www.ismp.org.\" No FDA logo appears on this slide.", "n_tokens": 106, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-68-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 68, "text": "Hazard/Error Story & Recommendations Shared\n\nThe slide shows two scanned newsletter pages side by side, with the ISMP logo at lower left (\"An ECRI Affiliate\") and the footer \"www.ismp.org\" at lower right. The branding is ISMP (Institute for Safe Medication Practices), not FDA.\n\n Left page: ISMP Medication Safety Alert! newsletter, dated February 25, 2009, Volume 14, Issue 4. Its visible headings and text include \"SafetyNotes (continued from page 2),\" which discusses vaccine abbreviations and mentions the CDC, ACIP, the American Academy of Pediatrics Red Book, DT, Td, Tdap, and \"Special Announcement,\" which promotes an ISMP teleconference. The page also contains \"Inattentional blindness\" and \"Unusual explanation for hyperglycemia in patients on insulin,\" which describes the NOVOLOG (insulin aspart) FlexPen and the NovoFine Autocover. A footer reads \"Please encourage your patients and staff to visit www.consumermedsafety.org often. It may save a life!\" The page's small print includes \"ISSN 1530-4132\" and \"ISMP Medication Safety Alert! Acute Care. \"\n\n The page has two figures. Figure 1 is labeled \"NovoFine Autocover\" and shows a needle with a shield that automatically recovers and locks over the needle when the injection is completed. Its labels are \"Outer Cover\" and \"Needle Shield.\" Figure 2 is labeled \"BD Ultra-Fine II pen needle\" and shows the outer cover and inner needle cover, with the labels \"Outer Cover,\" \"Needle Shield,\" and \"Inner cover must be removed prior to injection.\" A sticker-style graphic reads \"ISMP Medication Safety Alert!\"\n\n Right page: National Alert Network (NAN) alert, dated October 12, 2017, with the vertical banner \"NAN ALERT\" and a red box containing the number \"1.\" The headline reads \"Severe hyperglycemia in patients incorrectly using insulin pens at home.\" The page text includes \"The Institute for Safe Medication Practices (ISMP) National Medication Errors Reporting Program (MERP)\" and says the alert is based on information from that program. It describes the NovoFine Autocover, which has an outer cover and a needle shield, and mentions the NOVOFINE AUTOCOVER (Novo Nordisk) and BD AUTOSHIELD DUO.", "n_tokens": 505, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-68-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 68, "text": "It also refers to diabetic ketoacidosis and continuation on page 2.\n\n The right page has two figures. Figure 1 is labeled \"NovoFine Autocover,\" an example of a safety pen needle, with the labels \"Outer Cover,\" \"Needle Shield,\" and \"Safety Pen Needle.\" Figure 2 is labeled \"Standard Pen Needle,\" an example of a standard pen needle, with the labels \"Outer Cover,\" \"Needle Cover,\" and \"Standard Pen Needle.\" The footer states that the National Alert Network (NAN) is a coalition of members of the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP), and that the alert is distributed to healthcare providers.", "n_tokens": 148, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-69-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 69, "text": "Your Reports at Work\n\nThe slide has two parts: a scanned FDA letter on the left and a text panel on the right, with a caption below the panel.\n\n Left: FDA letter, \"LABELING CHANGE REQUEST,\" dated September 26, 2018, with the FDA U.S. Food & Drug Administration logo at top. It is addressed \"Dear Manufacturer\" and comes from the FDA Center for Devices and Radiological Health (CDRH). Key items it lists:\n- Postmarket safety issue with pen needles used with pen injectors.\n- Regulation: 21 CFR 880.5570, product code FMI (Hypodermic Single Lumen Needle).\n- Standard pen needles have an outer cover and a removable inner needle cover, both removed before injection.\n - Other pen needles have an outer cover that is removed and a fixed inner needle shield (sharps injury prevention feature) that is not removed before injection.\n- Reported harms: hyperglycemia and diabetic ketoacidosis, including one death, associated with failure to remove the inner needle cover.\n- Sources named: Institute for Safe Medication Practices (ISMP), National Alert Network (NAN), Medical Device Reports (MDRs), FDA Adverse Event Reporting System (FAERS), and a published literature reference.\n - FDA review of instructions for use (IFU) found some manufacturers do not provide directions on removing both covers, some provide only written instructions, and some graphics are limited.\n- FDA requests manufacturers review IFU and training materials and consider adding a warning similar to the one quoted.\n- Footnotes list: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=880.5570; https://www.ismp.org/alerts/severe-hyperglycemia-patients-incorrectly-using-insulin-pens-here; https://www.nccmm.org/sites/default/files/nan-2017012.pdf (partly legible); and", "n_tokens": 433, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-69-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 69, "text": "Truong, T. H., Nguyen, T. T., Armor, B. L., & Farley, J. P. (2017), Diabetes Therapy, 8(2), 221-226, doi:10.1007/s13300-017-0242-y.\n\nRight: a text panel headed \"Your Reports at Work\" with a blue icon of a United States map, a circular arrow, and a speech bubble with three dots. The panel's headline reads \"FDA tells pen injector needle manufacturers to improve patient instructions.\" Its text says that, thanks to reporting about patients who failed to remove the inner pen needle cover before injecting insulin, the US Food and Drug Administration (FDA) asked needle manufacturers to update labeling and improve patient instructions. It explains that standard pen needles have outer and inner covers that must both be removed, while some hospital safety needles have an outer cover to remove and an inner shield that retracts during injection. It cites an ISMP and American Society of Health-System Pharmacists (ASHP) National Alert Network (NAN) Alert from October 2017 at www.ismp.org/node/44. It states that FDA asked manufacturers to review labeling and educational materials and add a warning: \"Remove both the outer cover and the inner needle cover before an injection. If both the outer cover and the inner needle cover are not removed before use, the medication or dose may not be injected, which may result in serious injury or death.\" The panel gives the FDA labeling request link as www.ismp.org/ext/155.\n\nCaption below the panel: \"ISMP Medication Safety Alert! January 31, 2019.\"", "n_tokens": 355, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-70-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 70, "text": "Working with industry to improve products\n\nLeft side: A photograph of two medication boxes side by side. The upper box is a green and white Prolia carton. Its visible text includes the AMGEN logo, \"prolia (denosumab)\", \"60 mg/mL\", \"Injection - For Subcutaneous Use Only\", \"Single Use Prefilled Syringe. Discard unused portion.\", \"Sterile Solution - No Preservative\", \"Refrigerate at 2° to 8°C (36° to 46°F). Do not freeze. Avoid excessive shaking. Protect from direct light and heat. \", \"This Product Contains Dry Natural Rubber. \", \"Rx Only\", \"Manufactured by Amgen Inc., Thousand Oaks, CA 91320-1799\", \"Product of Singapore\", \"NDC 55513-710-01\", and \"1 x 60 mg Single Use Prefilled Syringe.\" A green circle reads \"60 mg/mL.\" Part of the Prolia box is partly covered by the lower box. The lower box is a white and green Udenyca carton. Its visible text includes the Coherus logo, \"NDC 70114-101-01\", \"UDENYCA\", \"pegfilgrastim-cbqv\", \"Injection\", \"6 mg/0.6 mL\" (also in a green circle), \"6 mg in 0.6 mL Single-Dose Prefilled Syringe\", \"For Subcutaneous Use\", \"Sterile Solution - No Preservative\", \"Pegylated Recombinant Methionyl Human Granulocyte Colony-Stimulating Factor (PEG-rmetHuG-CSF) derived from E. coli\", \"One 6 mg/0.6 mL single-dose Prefilled Syringe\", and \"Rx Only. \"\n\nRight side: A table of medication safety reports titled with the column headers \"#\", \"Report Date\", \"Description\", and \"Product.\" All rows list the product as PROLIA. The rows, from top to bottom, are:\n\n74092, 10/22/2019: Udencya and Prolia have very similar packaging. A patient was dispensed Udencya instead of Prolia.", "n_tokens": 498, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-70-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 70, "text": "Luckily the error was caught by the RN before it reached the patient, but I feel like a change of the packaging is necessary to prevent this from happening in the future.\n\n 73744, 7/19/2019: This error is in regards to the medications Prolia and Udenyca. The packages for both medications, from different manufacturers are very similar. Because of this, the medications were placed in the same bin in the refrigerator at XXXXXXX XX XXXXXXX Medical Center in XXXXX XXXXX, XXXXXXXXXXXX. This could have potentially led to the wrong medication being given to a patient within the hospital.\n\n73708, 07/11/2019: Look alike packaging for Udenyca (biosimilar for Neulasta) made by Coherus and Prolia (Denosumab) made by Amgen. Udenyca is a newer biosimilar that has come to market. The box containing the product is, ironically, very similar looking to an AMGEN product, Prolia. Neulasta is also made by AMGEN. Both carry similar font and coloring including a green dot for the dosage/concentration. Udenyca is 6 mg and Prolia is 60 mg. If you contact me with an email address, I can attach a photo I took with them next to each other. Significant chance of staff grabbing 2 different medications with very different outcomes.\n\n73678, 6/28/2019: We encountered a look-alike packaging in our ambulatory clinics. Please see the attached photos of very similar packing of Prolia (denosumab) and Udenyca (pegfilgrastim-cbqv). These are both used in the same areas within in our clinics.\n\n 73674, 6/28/2019: Our practice recently started purchasing pegfilgrastim-cbqv (Udenyca), a biosimilar product. When we received it, we noted that the packages are very similar to denosumab (Prolia). The packages are of similar size, have similar coloring and other features. We are concerned that this is a potential safety issue and may lead to medication errors if the drug is incorrectly dispensed due to lookalike packaging.\n\n 73596, 06/06/2019:", "n_tokens": 487, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-70-3", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 70, "text": "I know ISMP often includes alerts in your newsletter regarding products with similar packaging, just found one that I haven't seen reported yet. Product packaging very similar on Prolia and Udenyca. Similarly sized box, same color scheme etc.\n\n73550, 5/22/2019: Medication safety issue with look-alike packaging between Udenyca and Prolia. Both are routinely use medications at an outpatient cancer center. See attached images.\n\n73516, 5/15/2019: While trying to obtain a Prolia injection from their unit's Omnicell they noticed that the wrong medication had be stock in the cabinet. Udenyca had been stocked in the wrong location. Upon review by the pharmacy staff it was noted that the packaging was VERY similar despite having different manufactures. Both medications have green and white packaging with the concentration of the medication listed in a green circle in the same location.\n\n73490, 5/6/2019: Prolia syringes were found stocked in place of Udenyca syringes at an infusion site at my institution. No patient harm occurred. Contributed to this medication error is likely that their boxes are very similar in appearance in color and word placement, as well as their supply as a single-dose pre-filled syringe for subcutaneous administration (see image of both products side-by-side). It was thought that both items may have also been delivered in the same bag from our supplier in our order since they both require refrigeration, and that may have also contributed to the error. The very similar labeling and supply of these two commonly utilized medications at outpatient infusion centers may contribute to medication errors with these agents.\n\n Footer: ISMP logo with \"An ECRI Affiliate\" and \"www.ismp.org\".", "n_tokens": 375, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-71-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 71, "text": "Working with industry to improve products\n\nThe slide shows a scanned letter titled \"IMPORTANT DRUG WARNING,\" with a Coherus BioSciences logo at top right. The letter is dated October 2019. A boxed subject line reads: \"Subject: Potential of carton confusion between UDENYCA® and Prolia® packaging associated with the risk of administration or dispensing error and adverse events. \"\n\nThe letter begins \"Dear Health Care Provider,\" and states: \"The purpose of this letter is to make you aware of the potential of carton confusion between the UDENYCA® (pegfilgrastim-cbqv) and Prolia® (denosumab) packaging which could lead to a risk of product administration or dispensing error and adverse events. \"\n\nUnder the bold heading \"Potential of carton confusion between UDENYCA® and Prolia®,\" the letter says: \"UDENYCA® and Prolia® have a similar carton appearance (Figure 1) which has led to product administration or dispensing errors and adverse events.\" It then lists:\n\n1. Carton Appearance: Both cartons look similar with a green/white color scheme and green horizontal bands across the top (Figure 1).\n 2. Presentation and Strength: Both cartons hold one single-dose prefilled syringe, and both medications are intended for subcutaneous administration. The UDENYCA® syringe contains 6 mg and the Prolia® syringe contains 60 mg.\na. The needle guard of UDENYCA® syringe is colorless while the Prolia® syringe is translucent green (Figure 2).\n 3. Storage: Both are refrigerated items and have the potential to be stored next to each other.\n\n Figure 1: UDENYCA® (left) and Prolia® (right) Cartons. Two carton images are shown side by side. The UDENYCA carton has a white background with green accents and the text \"UDENYCA\" and \"pegfilgrastim-cbqv,\" plus a Coherus logo. The Prolia carton has a green background with a white panel, a \"60\" badge, and the text \"Prolia\" and \"denosumab.\" Smaller text on both cartons is not legible at this resolution.\n\n", "n_tokens": 496, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-71-2", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 71, "text": "Figure 2: UDENYCA® (left) and Prolia® (right) Syringes. Two prefilled syringe photographs are shown side by side. The left syringe has a colorless needle guard and a green-and-white label. The right syringe has a translucent green needle guard and a green label. Other small text is not legible.\n\n The letter footer reads: \"Coherus BioSciences, Inc. 333 Twin Dolphin Drive, Suite 600 Redwood City, CA 94065. \"\n\nSlide footer: ISMP logo with \"An ECRI Affiliate,\" and the website \"www.ismp.org.\"", "n_tokens": 140, "kind": "vision"}
{"chunk_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL-78-1", "doc_id": "DDI_Medication_Errors_CE_March_2020_DMEPA_and_ISMP_combined_slides_FINAL", "page": 78, "text": "FDA Advise-ERR in ISMP Medication Safety Alert! publications and FDA website\n\nThe slide shows a bordered box titled \"ISMP FDA Advise-ERR Articles.\" It contains seven hyperlinked article titles, each followed by an external-link icon:\n\n1. FDA Advise-ERR: Taking Crysvita with active vitamin D analogs is contraindicated\n2. FDA Advise-ERR: Covers still being applied without the cloNIDine patch\n3. FDA Advise-ERR: Lumoxiti has unique preparation instructions!\n4. FDA Advise-ERR: Vyxeos: Verify Drug Name and Dose to Avoid Errors!\n5. FDA Advise-ERR: Concomitant use of Entresto and ACE inhibitors can lead to serious outcomes\n6. FDA Advise-ERR: Veterinary Drug and Human Drug â A Drug Name Mix-up\n7. FDA Advise-ERR: Avoid using the error-prone abbreviation, TPA\n8. FDA Advise-ERR: MefloquineâNot the same as Malarone!\n\nBottom left: ISMP logo with the text \"An ECRI Affiliate.\" Bottom right: footer text \"www.ismp.org.\"", "n_tokens": 245, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-2-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 2, "text": "Pharmaceutical Supply Chain\n\nDiagram: A left-to-right supply chain shown inside a large chevron-shaped outline with arrows between stages. Each stage has a small illustration and a label:\n1. Drums/barrels, labeled \"Medical Product Components Supplier or Manufacturer\"\n2. Stacked boxes on a pallet, labeled \"Component Distributor\"\n3. Factory building, labeled \"Finished Product Manufacturer\"\n4. Stacked boxes on a pallet, labeled \"Finished Product Distributor (Primary and Secondary)\"\n5. Hospital and pharmacy buildings, labeled \"Dispensers (Hospitals and Pharmacies)\"\n6. Group of people with a pill or capsule, labeled \"Patients\"\n\nText below the diagram:\n\"Maintaining integrity from manufacturer to patient(s)\"\n• Who touches the product?\n• Where are the vulnerabilities?\n• What are the threats?\n\nBottom line: \"Protect the product\" followed by a blue arrow pointing to \"Protect the patient\"\n\nFooter: www.fda.gov", "n_tokens": 198, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-4-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 4, "text": "Recent Counterfeits\n\nTop left: News excerpt headline reading \"Gilead Warns of Counterfeit HIV Medication Being Distributed in the United States,\" with dateline \"Foster City, Calif., August 5, 2021 – Gilead Sciences has become,\" cut off at the end.\n\nBelow it, caption \"Biktarvy tablets (Image from Gilead).\" Two reddish-brown oval tablets are shown. The left tablet is imprinted \"GSI\" and the right tablet is imprinted \"9883.\"\n\nBelow that, caption \"Descovy tablets (Image from Gilead).\" Two light blue oval tablets are shown. The left tablet is imprinted \"GSI\" and the right tablet is imprinted \"225.\"\n\nTop right: caption \"Symtuza tablets (Image from Janssen/Johnson & Johnson).\" A photo shows two orange-yellow oval tablets stacked vertically. The top tablet is imprinted \"JG\" and the bottom tablet is imprinted \"8121.\"\n\nBeside the photo: excerpt of a Janssen media statement with the Janssen logo and \"Pharmaceutical Companies of Johnson & Johnson.\" Heading \"Media Statement,\" dated \"December 24, 2020.\" Text reads \"Janssen Alerts Counterfeit SYMTUZA® (darunavir/ cobicistat/ emtricitabine/ tenofovir alafenamide) is Being Distributed in the United States.\"\n\nBottom banner in bold text: \"Protecting the supply chain ultimately protects patients!\"\n\nFooter: \"www.fda.gov\"", "n_tokens": 325, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-8-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 8, "text": "DSCSA Key Requirements\n\nThe slide has four blue rectangular boxes arranged in a two-by-two grid under the title. Each box contains one label:\n\nTop left: Product Tracing\nTop right: Verification\nBottom left: Product Identifier\nBottom right: Authorized Trading Partner\n\nThe slide contains no charts, tables, numbers, or axis labels. The website www.fda.gov appears in small blue text at the bottom left.", "n_tokens": 84, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-9-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 9, "text": "Trading Partners under DSCSA\n\nThis slide is a diagram showing five trading partner categories under the Drug Supply Chain Security Act (DSCSA), listed top to bottom in a vertical flow connected by a line. Each entry has a circular icon and a blue label bar:\n\n1. Manufacturers (icon of a factory building)\n2. Repackagers (icon of a box or package)\n3. Wholesale Distributors (WDDs) (icon of a warehouse or distribution building)\n4. Dispensers (primarily Pharmacies) (icon of a storefront)\n5. Third-party logistics providers (3PLs) (icon of a globe with network and transport symbols)\n\nThe slide has no charts, tables, numbers, or axis labels. The website www.fda.gov appears in the bottom left corner.", "n_tokens": 166, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-16-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 16, "text": "Challenge Question #1\n\nKey supply chain security requirements under DSCSA include which of the following?\nA. Product Tracing\nB. Verification\nC. Product Identifier\nD. Authorized Trading Partner\nE. All of the above\n\nThe slide has no charts, tables, diagrams, or images apart from the FDA logo and the website footer www.fda.gov.", "n_tokens": 71, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-17-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 17, "text": "DSCSA Key Requirements\n\nThe slide has four blue rectangular boxes arranged in a two-by-two grid under the title. Each box contains one label:\n- Top left: Product Tracing\n- Top right: Verification\n- Bottom left: Product Identifier\n- Bottom right: Authorized Trading Partner\n\nThe footer reads www.fda.gov.", "n_tokens": 67, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-36-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 36, "text": "Challenge Question #3\n\nIs the following statement true or false?\n\nEnhanced drug distribution security requirements that go into effect in 2023 include the exchange of transaction information and transaction statements in a secure, interoperable, electronic manner.\n\nA. True\nB. False\n\nFooter text: www.fda.gov", "n_tokens": 59, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-38-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 38, "text": "Enhanced Drug Distribution Security\n\nThis slide is a stacked diagram with four labeled boxes arranged in a pyramid shape. At the top is a light blue box reading \"Effective November 27, 2023.\" Below it is a larger gray box reading \"Enhanced Drug Distribution Security.\" Beneath that are two smaller boxes side by side, the left reading \"Electronic\" and the right reading \"Interoperable.\" At the base is a wide box reading \"System across the pharmaceutical distribution supply chain.\" The lower boxes support the gray box above them. The footer text reads \"www.fda.gov.\" There are no charts, tables, legends, axes, or numerical data on the slide.", "n_tokens": 138, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-39-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 39, "text": "How DSCSA Protects Patients\n\nThis slide has a diagram of three stacked horizontal bars, each with a circular icon on its left edge, connected by a thin vertical line running along the left side.\n\nTop bar, with a shield icon: \"Prevent harmful drugs from entering the supply chain.\" The word \"Prevent\" is in bold.\n\nMiddle bar, with a concentric circles (target-like) icon: \"Detect harmful drugs if they enter the supply chain.\" The word \"Detect\" is in bold.\n\nBottom bar, with a circular arrows (refresh-like) icon: \"Respond rapidly when harmful drugs are found.\" The word \"Respond\" is in bold.\n\nThe bars shade from darker blue at the top to lighter blue at the bottom. The slide also includes the website address www.fda.gov in the lower left corner.", "n_tokens": 171, "kind": "vision"}
{"chunk_id": "DSCSA_Webinar_October_2021-41-1", "doc_id": "DSCSA_Webinar_October_2021", "page": 41, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images apart from the logo, which is omitted as requested. No numbers or labels appear.", "n_tokens": 36, "kind": "vision"}
{"chunk_id": "DrThrockmorton1-0-1", "doc_id": "DrThrockmorton1", "page": 0, "text": "FDA Role in Regulation of Cannabis Products\n\nNIDA\nFebruary 2019\n\nSharon Lindan Mayl, J.D.\nSenior Advisor for Policy\nOffice of Foods and Veterinary Medicine\nFood and Drug Administration\n\nDouglas C. Throckmorton, M.D.\nDeputy Director for Regulatory Programs\nCDER, FDA", "n_tokens": 56, "kind": "vision"}
{"chunk_id": "DrThrockmorton1-3-1", "doc_id": "DrThrockmorton1", "page": 3, "text": "Regulatory Landscape\n\nBullet text: Federal/state coordination is necessary:\n- States\n- DEA\n- FDA\n- USDA\n- Others: SAMHSA, NIDA, ONDCP\n\nThe slide contains no charts, tables, diagrams, or images other than the FDA logo and slide number, which are omitted.", "n_tokens": 59, "kind": "vision"}
{"chunk_id": "DrThrockmorton1-4-1", "doc_id": "DrThrockmorton1", "page": 4, "text": "Intra-Agency Team\n\nFDA has a cross-Agency team that works on cannabis issues:\nAll product divisions represented as well as field inspectorate\nPolicy\nEnforcement\nOutreach\nInteragency coordination\nFederal, state, international", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "DrThrockmorton1-6-1", "doc_id": "DrThrockmorton1", "page": 6, "text": "The Farm Bill - FDA\n\nFDA's authorities under the FD&C Act and section 351 of the PHS Act were specifically preserved by the Farm Bill.\n\nCannabis and cannabis-derived products are subject to the same authorities and requirements as FDA-regulated products containing any other substance.", "n_tokens": 56, "kind": "vision"}
{"chunk_id": "DrThrockmorton1-12-1", "doc_id": "DrThrockmorton1", "page": 12, "text": "Other Applicable Regulatory Requirements for Foods\n\nAll foods are subject to a number of other regulatory requirements related to topics such as:\n- Safety of ingredients\n- Production controls\n- Labeling", "n_tokens": 32, "kind": "vision"}
{"chunk_id": "DrThrockmorton1-19-1", "doc_id": "DrThrockmorton1", "page": 19, "text": "FDA Website\n\nThis is a screenshot of a page on the FDA website, with the URL shown below it: https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm421168.htm\n\nThe page header reads \"U.S. FOOD & DRUG ADMINISTRATION.\" Top-right links read \"A to Z Index,\" \"Follow FDA,\" and \"En Español.\" A search box reads \"Search FDA.\"\n\nThe navigation tabs, from left to right, read: Home, Food, Drugs, Medical Devices, Radiation-Emitting Products, Vaccines, Blood & Biologics, Animal & Veterinary, Cosmetics, Tobacco Products.\n\nThe section heading reads \"News & Events.\" The breadcrumb trail reads \"Home > News & Events > Public Health Focus.\"\n\nThe left sidebar has a blue header reading \"Public Health Focus\" and one item reading \"Expanded Access (Compassionate Use).\"\n\nThe main page title reads \"FDA and Marijuana: Questions and Answers.\" Share buttons read \"SHARE,\" \"TWEET,\" \"LINKEDIN,\" \"PIN IT,\" \"EMAIL,\" and \"PRINT.\"\n\nThe page lists ten questions, numbered 1 to 10:\n1. How is marijuana therapy being used by some members of the medical community?\n2. Why hasn't the FDA approved marijuana for medical uses?\n3. Is marijuana safe for medical use?\n4. How does FDA's role differ from the role of other federal agencies when it comes to the investigation of marijuana for medical use?\n5. Does the FDA object to the clinical investigation of marijuana for medical use?\n6. What kind of research is the FDA reviewing when it comes to the efficacy of marijuana?\n7. How can patients get into expanded access program for marijuana for medical use?\n8. Does the FDA have concerns about administering a cannabis product to children?\n9. Does the FDA have concerns about administering a cannabis product to pregnant and lactating women?\n10. What is FDA's reaction to states that are allowing marijuana to be sold for medical uses without the FDA's approval?", "n_tokens": 438, "kind": "vision"}
{"chunk_id": "DrThrockmorton1-21-1", "doc_id": "DrThrockmorton1", "page": 21, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images apart from the logo, which is omitted as instructed. No other text is visible.", "n_tokens": 36, "kind": "vision"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-0-1", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 0, "text": "Federal Efforts to Prevent Drug Shortages\nAn FDA Perspective\n\nDouglas C. Throckmorton, MD\nDeputy Director for Regulatory Programs\nCenter for Drug Evaluation and Research\nFDA\n\nDuke Margolis Center for Health Policy\n\nNovember 27, 2018\n\nThis slide contains no charts, tables, diagrams, or images other than the FDA logo, which is omitted as requested.", "n_tokens": 66, "kind": "vision"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-2-1", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 2, "text": "Trends in New Drug Shortages 2010-2017\n\nThis slide has one bar chart. The chart has no printed data labels, so the values below are estimated from the gridlines.\n\nChart: Stacked bar chart showing the number of new drug shortages by calendar year.\nY-axis label: \"Number of New Shortages.\" Tick marks at 0, 50, 100, 150, 200, 250, and 300.\nX-axis label: \"Calendar Year.\" Categories are 2010, 2011, 2012, 2013, 2014, 2015, 2016, and 2017.\nLegend: \"CDER\" (blue) and \"CBER\" (red).\n\nApproximate bar values:\n2010: about 180, all CDER (blue).\n2011: about 250, all CDER (blue).\n2012: about 116, all CDER (blue).\n2013: about 44, all CDER (blue).\n2014: about 44, all CDER (blue).\n2015: about 33, all CDER (blue).\n2016: about 34 in total. CDER is about 29 (blue) and CBER is about 5 (red, on top).\n2017: about 40 in total. CDER is about 35 (blue) and CBER is about 5 (red, on top).\n\nSource note printed below the chart: \"From FDA Drug Shortage Report to Congress, 2017\" followed by the URL https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM610662.pdf", "n_tokens": 312, "kind": "vision"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-4-1", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 4, "text": "Sources of Shortages: Natural Disasters\n\nThe slide contains a satellite photograph of two large storm systems over dark blue ocean water, with some land visible at the edges. The storm on the left is larger and shows a well-defined spiral of white cloud around a central eye. The storm on the right is smaller and also shows a spiral pattern. The image has no axis labels, units, legend, or readable numbers.\n\nSlide text: Hurricane Maria affected multiple manufacturers in Puerto Rico. Sub-point: IV fluid shortages, which began in 2014, were worsened due to Baxter facility impact in PR.", "n_tokens": 118, "kind": "vision"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-6-1", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 6, "text": "What FDA Cannot Do to Address Drug Shortages\n\nFDA cannot require:\n- A company to disclose details of why a shortage occurs\n- A company to make a drug\n- A company to make more of a drug\n- How much and to whom the drug is distributed", "n_tokens": 49, "kind": "vision"}
{"chunk_id": "Drug_Shortage_Presentation_Throckmorton_24-10-1", "doc_id": "Drug_Shortage_Presentation_Throckmorton_24", "page": 10, "text": "Thank You\n\nThe slide contains one photograph. It shows a large brick building with a light stone central section that has tall vertical windows and columns. A glass-roofed entrance canopy sits at the base of the central section. In front of the building, a curved green lawn is bordered by a low wall faced with pink-gray stone, with small recessed lights set into it. A light paved walkway curves along the wall and meets a dark road on the right. A black SUV is parked near the entrance area. Several leafy green trees stand along the building and on the right side. The sky is clear and blue. The photo has no charts, tables, diagrams, or readable text labels.", "n_tokens": 140, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-0-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 0, "text": "FDA Office of Generic Drugs (OGD) Keynote Address\nGDUFA: Past, Present and Future\n\nPresenter and event details, shown below the title:\nKathleen Uhl, MD\nDirector, Office of Generic Drug\nCDER/FDA\nGPhA Annual Meeting\nFebruary 14, 2017\n\nThis slide contains no charts, tables, diagrams, or images other than the FDA logo, which is skipped as requested.", "n_tokens": 77, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-3-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 3, "text": "GDUFA Overview\n\nThe slide has a title, \"GDUFA Overview,\" and a numbered list of four items:\n1. Past\n2. Present\n3. Future\n4. Closing Thoughts\n\nThere are no charts, tables, diagrams, or images apart from the logo and slide number, which are omitted.", "n_tokens": 61, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-4-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 4, "text": "GDUFA Overview\n\nThe slide has an agenda list with four numbered items. Item 1, \"Past,\" is in bold black text and is the current section. Items 2 through 4 are in lighter gray text and are not highlighted:\n1. Past (highlighted)\n2. Present\n3. Future\n4. Closing Thoughts\n\nThere are no charts, tables, diagrams, or images other than the FDA logo, which is omitted here.", "n_tokens": 85, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-6-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 6, "text": "GDUFA Overview\n\nThis slide has an agenda list with four numbered items. Item 2, \"Present,\" is in bold black text and is the current section. The other items, \"Past,\" \"Future,\" and \"Closing Thoughts,\" are in light gray text.\n\n1. Past\n2. Present\n3. Future\n4. Closing Thoughts\n\nNo charts, tables, diagrams, or other images appear on this slide.", "n_tokens": 85, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-7-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 7, "text": "GDUFA: Present\n\nThe slide contains no charts, tables, diagrams, or images apart from the FDA logo, which is omitted as requested. The text reads:\n\nFDA is meeting or exceeding the GDUFA goals\nNumerous other significant accomplishments\nMain outstanding challenge is multiple review cycles\nLeads to a huge amount of re-work for FDA and applicants alike", "n_tokens": 68, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-8-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 8, "text": "GDUFA Goal: Original ANDAs\n\nThe slide contains no charts, tables, diagrams, or images, only text bullets.\n\nBullet points:\n- GDUFA goal: Review and act on 60% of FY2015 Original ANDAs within 15 months of submission. The \"60%\" is underlined.\n- FDA acted on 97% of FY2015 Original ANDAs within 15 months of submission. The \"97%\" is bolded, red, and underlined.\n- FY2016 original submissions are just now starting to hit their GDUFA goal dates.", "n_tokens": 118, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-16-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 16, "text": "Other Accomplishments: PAS Actions\n\nThis is a table titled \"PAS Actions.\" It has a blank top-left header cell and five column headers: FY2013, FY2014, FY2015, FY2016, and FY2017 (as of Jan 30, 2017). It has three row labels, and each row lists one number per fiscal year.\n\nReceived: 482 (FY2013), 436 (FY2014), 563 (FY2015), 567 (FY2016), 160 (FY2017 as of Jan 30, 2017)\n\nApproved: 532 (FY2013), 654 (FY2014), 616 (FY2015), 542 (FY2016), 145 (FY2017 as of Jan 30, 2017)\n\nCR Letter: 8 (FY2013), 18 (FY2014), 185 (FY2015), 242 (FY2016), 75 (FY2017 as of Jan 30, 2017)", "n_tokens": 230, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-17-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 17, "text": "Other Accomplishments: Filing\n\nThe slide contains two bullet points of text and no charts, tables, diagrams, or images other than the FDA logo, which is omitted.\n\n- More than 900 original ANDAs, resubmissions, and PASs underwent filing review in FY2016.\n- Also, OGD has eliminated large filing backlog.", "n_tokens": 68, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-19-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 19, "text": "Other Accomplishments: Product-Specific Guidances\n\nThis slide contains one stacked bar chart.\n\nChart: Stacked bar chart showing the number of product-specific guidances by fiscal year. The y-axis is labeled \"Number of Guidances\" and runs from 0 to 250 in increments of 50. The x-axis shows fiscal years: FY 13, FY 14, FY 15, FY 16, and FY 17*. The legend has two entries: \"New Guidance\" (light blue) and \"Revised Guidance\" (dark navy). Each bar's total is printed above it.\n\nValues for each fiscal year (Revised Guidance in the dark segment, New Guidance in the light segment, total above the bar):\n- FY 13: Revised Guidance 41; New Guidance 61; total 102\n- FY 14: Revised Guidance 56; New Guidance 78; total 134\n- FY 15: Revised Guidance 69; New Guidance 154; total 223\n- FY 16: Revised Guidance 41; New Guidance 94; total 135\n- FY 17*: Revised Guidance 50; New Guidance 65; total 115\n\nThe asterisk after FY 17 is printed on the slide without a footnote visible on this slide.", "n_tokens": 247, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-25-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 25, "text": "Outstanding Challenge: Multiple Review Cycles\n\nThe slide contains one chart. Above the chart title is a faint, partially cut-off line of text that is not legible.\n\nChart 15. Review Cycles for ANDAs, 2009 through July 2014. This is a vertical bar chart with a red trendline. The y-axis is labeled \"Number of Approvals,\" with gridlines from 0 to 600 in increments of 100. The x-axis is labeled \"Cycle Number,\" with categories 1 through 11. The legend shows one entry: \"Moving Average Trendline,\" a red line.\n\nBar values by cycle number (number of approvals):\nCycle 1: 27\nCycle 2: 343\nCycle 3: 561\nCycle 4: 476\nCycle 5: 308\nCycle 6: 127\nCycle 7: 55\nCycle 8: 26\nCycle 9: 15\nCycle 10: 3\nCycle 11: 1\n\nThe red moving average trendline rises from about 180 at cycle 2, peaks at about 510 near cycle 4, and then declines toward near 0 at cycle 11.", "n_tokens": 210, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-26-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 26, "text": "Outstanding Challenge: Multiple Review Cycles\n\nThis slide contains one bar chart and one callout box.\n\nBar chart: The chart title is partly obscured by the slide title but appears to read \"Chart 10: First Cycle Approval Rate Under PDUFA.\" The subtitle reads \"CDER NME NDAs/BLAs First Action Approval Rate,\" and the legend entry reads \"First Action Approval Rate.\" The chart shows a single series of dark blue vertical bars, each labeled with its percentage.\n- Y-axis label: \"First Cycle Approvals.\" Units are percent, scaled 0% to 100% in 10% increments.\n- X-axis label: \"Fiscal Year of Receipt.\" Categories run from 1993 to 2015, with the final category marked \"2015*\" (the asterisk is not explained on the slide).\n\nValues read from the bars, by fiscal year of receipt:\n1993: 36%\n1994: 23%\n1995: 30%\n1996: 50%\n1997: 35%\n1998: 25%\n1999: 54%\n2000: 31%\n2001: 25%\n2002: 50%\n2003: 48%\n2004: 42%\n2005: 45%\n2006: 52%\n2007: 52%\n2008: 46%\n2009: 43%\n2010: 56%\n2011: 70%\n2012: 72%\n2013: 78%\n2014: 89%\n2015*: 95%\n\nCallout box: A red-outlined box in the upper left of the chart area contains the text \"Lesson Learned from PDUFA: If submission is 'right the first time,' FDA can approve in the first cycle.\"\n\nSlide number: omitted.", "n_tokens": 328, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-28-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 28, "text": "Outstanding Challenge: Multiple Review Cycles\n\nThis slide contains one line chart, titled \"ANDAs Under FDA Review.\" A blue line with arrowheads connects three data points, moving from left to right across the chart.\n\nY-axis: labeled \"ANDAs,\" with tick marks from 0 to 3,500 in increments of 500.\nX-axis: three date categories, labeled \"Oct. 1, 2012,\" \"Jan. 1, 2016,\" and \"Jan. 1, 2017.\"\nLegend: none.\n\nData labels:\n- \"2,866\" at Oct. 1, 2012\n- \"~2,950\" at Jan. 1, 2016\n- \"~2,350\" at Jan. 1, 2017\n\nFootnote at bottom left: \"*Approximate Values, January 2017\"", "n_tokens": 162, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-29-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 29, "text": "Outstanding Challenge: Multiple Review Cycles\n\nThis slide has one chart, titled \"Complete Response Letters (CRs) & TAs.\" It is a line chart with a thick blue arrow that rises from the lower left to the upper right, with arrowheads at the two later data points, showing growth over time.\n\nThe y-axis is labeled \"ANDAs\" and runs from 0 to 2000 in increments of 200. The x-axis shows three dates: Oct. 1, 2012; Jan. 1, 2016; and Jan. 1, 2017.\n\nData labels:\n- Oct. 1, 2012: 100\n- Jan. 1, 2016: ~1,150\n- Jan. 1, 2017: ~1,850\n\nNo legend is shown.\n\nFootnote at bottom left: \"Approximate Values, January 2017\"", "n_tokens": 163, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-30-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 30, "text": "Outstanding Challenge: Multiple Review Cycles\n\nThe most common deficiencies are:\n- Inadequate CMC\n  - Stability\n  - Dissolution\n  - Inactive ingredients\n- Inadequate facilities", "n_tokens": 27, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-32-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 32, "text": "GDUFA Overview\n\nThe slide has an agenda list of four items, numbered 1 to 4. Item 3, \"Future,\" is in bold black text and is the current section. Items 1, 2, and 4 are in gray text:\n1. Past\n2. Present\n3. Future\n4. Closing Thoughts\n\nThere are no charts, tables, diagrams, or other images on the slide.", "n_tokens": 78, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-33-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 33, "text": "GDUFA II\n\nProposed agreement between FDA and industry stakeholders\n– Generic Pharmaceutical Association (GPhA)\n– Bulk Pharmaceutical Task Force (BPTF)\n– Pharma and Biopharma Outsourcing Association (PBOA)\n– European Fine Chemical Group (EFCG)", "n_tokens": 55, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-34-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 34, "text": "GDUFA II\n\nWhile there is a proposed agreement between FDA and industry stakeholders, Congress needs to reauthorize by October 1, 2017 -- otherwise, GDUFA expires\n\n\"Goals\" or \"Commitment\" letter:\nhttp://www.fda.gov/downloads/forindustry/userfees/genericdruguserfees/ucm525234.pdf", "n_tokens": 82, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-37-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 37, "text": "GDUFA II Highlights\n\n\"No submission left behind\"\n\nGDUFA Goals for all ANDAs and amendments\n\nGDUFA I \"Bridging\" – E.g., any pre-FY2015 ANDAs with missed/never assigned TADs as of Oct. 1, 2017 will get a GDUFA II goal date NLT July 31, 2018", "n_tokens": 74, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-38-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 38, "text": "GDUFA II Highlights\n\nPre-ANDA Program\n\nClarify regulatory expectations early in product development, so ANDA can be \"right the first time\"\n\nIncrease odds of first cycle approval\n\nReduce number of cycles to approval\n\nMore efficient and effective review process", "n_tokens": 47, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-40-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 40, "text": "GDUFA II Highlights\n\nDMF Review Program Enhancements\n\nDMF program enhancements were developed in collaboration with API manufacturers.\n\nNew efficiencies and better coordination with ANDA review will benefit ANDA sponsors.", "n_tokens": 44, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-46-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 46, "text": "GDUFA Overview\n\nThis slide has an agenda list with four numbered items: 1. Past, 2. Present, 3. Future, 4. Closing Thoughts. Items 1 through 3 appear in light gray, and item 4, \"Closing Thoughts,\" appears in bold black, which marks it as the current section.\n\nThe slide contains no charts, tables, diagrams, or other images.", "n_tokens": 77, "kind": "vision"}
{"chunk_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future-48-1", "doc_id": "FDA_Office_of_Generic_Drugs_OGD_Keynote_Address_GDUFA_Past_Present_and_Future", "page": 48, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images. Its only element is the agency logo, which is omitted as requested.", "n_tokens": 34, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-0-1", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 0, "text": "FDA Role in Marijuana Regulation\n\nDouglas C. Throckmorton, M.D.\nFood and Drug Administration (FDA)\nFDLI\nJuly 19, 2017\n\nImages along the bottom of the slide, left to right:\n1. Laboratory glassware: several clear glass vials and flasks containing yellow-green liquid, with one vial labeled with a small handwritten-style tag.\n2. A close-up pile of pharmaceutical pills and capsules in white, yellow, orange, and black colors.\n3. The FDA logo over a faded background image of a red-toned microscopic or tissue-like pattern.\n4. Clear multi-well cell culture plates with pink-tinted liquid, with a pipette or dropper tool visible above one well.\n5. Clear plastic containers or bowls filled with assorted colorful tablets and capsules in red, orange, green, blue, and white.", "n_tokens": 179, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-1-1", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 1, "text": "Disclosure Statement\n\nI have no financial relationships with proprietary entities that produce health care goods and services\n\nThe opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-4-1", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 4, "text": "Status of Marijuana Laws in the US\n\nThis slide is a color-coded map of the United States showing state marijuana laws, with each state labeled by its two-letter postal abbreviation. Source note at lower right: \"Source: Marijuana Policy Project.\" The map has four colored categories and a fifth uncolored (white) group with no legend entry.\n\nLegend entries (top to bottom):\n- Light gray: \"States with medical marijuana laws\"\n- Dark gray: \"States that have removed jail time for possessing small amounts of marijuana\"\n- Black: \"States that have both a medical marijuana law and have removed jail time for possessing small amounts of marijuana\"\n- Blue: \"Marijuana is legal for adults and is taxed and regulated similarly to alcohol; state also has a medical marijuana law\"\n\nStates labeled in blue: WA, OR, CA, NV, CO, AK, ME, MA.\n\nStates labeled in black: MN, IL, OH, NY, VT, RI, CT, DE, MD, DC.\n\nStates labeled in dark gray: NE, MO, MS, NC.\n\nStates labeled in light gray: MT, ND, MI, PA, NJ, NH, AZ, NM, AR, FL, HI.\n\nStates labeled in white (no legend category shown): ID, UT, WY, SD, IA, KS, OK, TX, WI, IN, KY, TN, AL, GA, SC, LA, VA, WV.\n\nNote: The map includes the District of Columbia (DC) and Hawaii (HI) as an inset-style label. Alaska (AK) is shown in its own inset area at lower left, and Hawaii's islands appear beneath the southwestern coast.", "n_tokens": 350, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-8-1", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 8, "text": "FDA Support for Drug Development from MJ\n\nBody text: Three products approved:\nMarinol (dronabinol) (1985): nausea from cancer chemotherapy\nCesamet (nabilone) (1985 (2006)): nausea & neuropathic pain\nSyndros (dronabinol) (2017)\n\nImages: Two product photographs are shown.\n\nThe first photo, placed at upper right, shows a Marinol carton and a white pharmacy-style bottle. Visible text on the carton includes \"MARINOL,\" \"5 mg,\" \"Capsules,\" and a partially visible NDC number beginning \"NDC 0...\". The bottle label is partly legible and reads \"MARINOL\" and \"C-II,\" with a red and white cap.\n\nThe second photo, placed at lower center, shows a Cesamet carton and a white bottle with loose capsules in front. The carton reads \"Cesamet C-II,\" \"(Nabilone Capsules),\" \"1 mg,\" \"NDC 0037-1221-50,\" \"50 Capsules,\" and \"MEDA Pharmaceuticals.\" The bottle label reads \"Cesamet C-II,\" \"(Nabilone Capsules),\" \"1 mg,\" \"NDC 0037-1221-50,\" and \"MEDA.\"\n\nFooter: www.fda.gov", "n_tokens": 295, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-12-1", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 12, "text": "FDA Enforcement Role in Regulating MJ\n\nCannabidiol Edibles (red text in the center of the slide)\n\nThe slide shows four product photos.\n\nTop left: A purple-and-white package labeled \"Canna-Pet.\" Text on the package reads \"Administer one capsule every twelve (12) hours,\" \"30 Capsules,\" \"360 mg,\" \"Large,\" and \"45-95 pounds.\" A dog illustration appears on the label. Vertical side text reads \"Cannabidiol\" and \"Terpenes.\" A barcode is printed below, with partially legible number \"8 56562 00515 7.\"\n\nTop right: A clear package of a cookie labeled \"COMPASSION,\" with a green-and-pink label. Legible text includes \"SNICKERDOODLE,\" \"classic cookie,\" \"REGULAR STRENGTH,\" and \"WARNING CONTAINS CANNABIS\" in a yellow box. Small print is not fully legible. A \"MedicalJane\" watermark appears in the lower right corner. A cookie is shown beside the package.\n\nBottom left: A display of blue boxes of \"Cheeba Chews\" in front of a stacked display. Legible text includes \"Cheeba Chews,\" \"CBD Chew,\" \"Medicated Taffy,\" \"Cannabidiol / THC mix for pain relief | 35 Calories,\" and \"Good Dose CBD Chews\" repeated on the boxes.\n\nBottom right: Three bottled drinks side by side with labels and colored caps. From left to right: a pink cap with a label reading \"STRAWBERRY\" and \"LEMONADE\"; a purple cap with a label reading \"GRAPE CANNABIS QUENCHER\"; and a yellow cap with a label reading \"LEMONADE.\" Some smaller label text is not fully legible.", "n_tokens": 377, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Marijuana_Regulation-15-1", "doc_id": "FDA_Role_in_Marijuana_Regulation", "page": 15, "text": "Results of Analytic Testing\n\nFDA has tested these products, and many were found to not contain the levels of CBD they claimed to contain. Consumers should beware purchasing and using any such products.\n\nReference link: http://www.fda.gov/newsevents/publichealthfocus/ucm484109.htm", "n_tokens": 70, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-0-1", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 0, "text": "FDA Role in Regulation of Cannabis Products\n\nPresenter: Douglas C. Throckmorton, MD, Deputy Director for Regulatory Programs, CDER, FDA\n\nEvent: New Jersey Association of County and City Health Officials (NJACCHO) Meeting\n\nDate: September 16, 2021\n\nThis slide has no charts, tables, diagrams, or images other than the FDA logo, which is skipped.", "n_tokens": 74, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-19-1", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 19, "text": "Other FDA Activities: Real-World Data\n\nHyperlink text at top: \"FDA Voices Blog: Better Data for a Better Understanding of the Use and Safety Profile of Cannabidiol (CBD) Products\"\n\nImage: A black tablet displays a web article. There are no charts, tables, or diagrams.\n\nArticle headline on the tablet: \"A Practical Framework for Robust, Collaborative CBD Data Projects to Inform Public Health Decisions\"\n\nArticle text on the tablet (partly cut off at the bottom):\n\nParagraph 1: \"Here, we describe a framework for the FDA's work in the development of research projects that lay the methodological groundwork for high quality RWD science on the safety and use of CBD products. These research projects would be aimed at building upon currently existing independent state and national quality and safety monitoring efforts, observational study data models, and novel data sources to develop more robust capabilities and methods for CBD data collection and analysis.\"\n\nParagraph 2: \"We know from experience that collaborative projects with researchers across government, academia, and the private sector can stimulate rapid progress in the development of rigorous methods for collecting and analyzing RWD. Most recently, in the context of COVID-19, collaborative research projects between the FDA and outside data experts have focused on using RWD to improve analytical methods and inform the public health response to the pandemic.\"\n\nParagraph 3: \"It is important to note that there are research questions for which RWD research projects are unlikely to substitute for certain types of traditional studies. We do not expect that analyses of observational data will substitute for other types of studies in certain contexts. For example, appropriately designed animal studies can address toxicological issues that are difficult to study in humans, such as chronic, developmental, and reproductive toxicity.\"\n\nParagraph 4: \"However, we strongly believe that RWD, when collected and analyzed using rigorous methods, can be important for moving the science forward, including by aiding hypothesis generation and by refining the design of follow-up studies. For example, RWD may identify new potential adverse events or subpopulations of CBD users that should be\" (text cut off)\n\nPhoto on the article page: A smiling woman with shoulder-length blonde hair, wearing a blue top and a necklace, in front of an American flag. Caption beneath the photo: \"Amy Abernethy, M.D., Ph.D.\"", "n_tokens": 487, "kind": "vision"}
{"chunk_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL-22-1", "doc_id": "FDA_Role_in_Regulation_of_Cannabis_Products_NJACCHOmeeting16SEP21_FINAL", "page": 22, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images apart from the logo, which is omitted as requested. No numbers or text other than the logo are present.", "n_tokens": 41, "kind": "vision"}
{"chunk_id": "FDA_Update_2018_May_21_2018-0-1", "doc_id": "FDA_Update_2018_May_21_2018", "page": 0, "text": "FDA Update: 2018\n\nTitle slide text, top to bottom:\n\nDouglas C. Throckmorton MD\nDeputy Director for Regulatory Programs\nCDER, FDA\n\nAmerican College of Surgeons\nMay 21, 2018\n\nFooter: www.fda.gov\n\nThere are no charts, tables, diagrams, or other images on this slide.", "n_tokens": 61, "kind": "vision"}
{"chunk_id": "FDA_Update_2018_May_21_2018-1-1", "doc_id": "FDA_Update_2018_May_21_2018", "page": 1, "text": "No slide title is visible.\n\nThe slide contains one block of centered text, a disclaimer: \"The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA.\"\n\nThe slide has no charts, tables, diagrams, or images.", "n_tokens": 58, "kind": "vision"}
{"chunk_id": "FDA_Update_2018_May_21_2018-2-1", "doc_id": "FDA_Update_2018_May_21_2018", "page": 2, "text": "Drug Overdose Deaths\n\nChart: \"Drugs Involved in U.S. Overdose Deaths, 2000 to 2016.\" This is a multi-line chart. The vertical y-axis runs from 0 to 25,000 in steps of 5,000 (tick labels: 0, 5,000, 10,000, 15,000, 20,000, 25,000). No y-axis title or unit label is visible. The horizontal x-axis shows years from 1999 through 2016, with a tick for each year (1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016).\n\nLegend entries are labeled at the right end of each line, with 2016 values:\n- Synthetic Opioids other than Methadone: 20,145 (light blue line)\n- Heroin: 15,446 (dark gray line)\n- Natural and semi-synthetic opioids: 14,427 (gray line)\n- Cocaine: 10,619 (light gray line)\n- Methamphetamine: 7,663 (lighter gray line)\n- Methadone: 3,314 (pale gray line)\n\nVisible trends: the Synthetic Opioids other than Methadone line stays low, around 1,000 to 3,000, from 1999 to about 2012, then rises steeply to about 20,145 by 2016. The Heroin line rises from about 2,000 in 1999 to about 15,446 in 2016, with its steepest climb after about 2010. The Natural and semi-synthetic opioids line rises from about 4,000 in 1999 to about 14,427 in 2016. The other lines are labeled with their 2016 values only.\n\nCaption below the chart: \"Drugs Involved in U.S. Overdose Deaths* - Among the more than 64,000 drug overdose deaths estimated in 2016, the sharpest increase occurred among deaths related to fentanyl and fentanyl analogs (synthetic opioids) with over 20,000 overdose deaths. Source: CDC WONDER\"\n\nFooter URL: https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates", "n_tokens": 457, "kind": "vision"}
{"chunk_id": "FDA_Update_2018_May_21_2018-3-1", "doc_id": "FDA_Update_2018_May_21_2018", "page": 3, "text": "What does 53,000 people look like?\n\nThe slide has one photograph, a wide-angle view of a packed football stadium. Stands in every section are filled with spectators, many wearing orange. A player in an orange jersey with the number 9 is visible in the lower right foreground, and a second person in orange with the number 9 is at the lower left edge. The field is green with white yard lines. The end zone has \"BENGALS\" painted in large orange letters with black outlining. The stadium has a curved roof canopy at the top edge, and a city skyline with tall buildings sits behind the stadium on the upper left. A video board or signage is visible at the upper left of the stands. There are no charts, tables, or diagrams.\n\nSource caption below the photo: http://www.espn.com/nfl/team/stadium/_/name/cin/cincinnati-bengals", "n_tokens": 187, "kind": "vision"}
{"chunk_id": "FDA_Update_2018_May_21_2018-4-1", "doc_id": "FDA_Update_2018_May_21_2018", "page": 4, "text": "Overdose Death Rates\n\nThis slide has two county-level choropleth maps of the United States, labeled 1999 (left) and 2014 (right). Each map shows the continental United States, with Alaska and Hawaii as separate insets below. Each county is shaded by its estimated age-adjusted death rate from overdose. Small \"Year\" labels appear inside each map, reading \"1999\" and \"2014.\"\n\nLegend for both maps, titled \"Estimated Age-adjusted Death Rate per 100,000\":\n\n1999 map legend entries: 0-2; 2.1-4; 4.1-6; 6.1-8; 8.1-10; 10.1-12; 12.1-14; 14.1-16; 16.1-18; 18.1-20; >20.\n\n2014 map legend entries: 0.0-2.0; 2.1-4.0; 4.1-6.0; 6.1-8.0; 8.1-10.0; 10.1-12.0; 12.1-14.0; 14.1-16.0; 16.1-18.0; 18.1-20.0; >20. The 2014 legend text is small and partly hard to read, so these values are approximate.\n\nVisible numbers and labels on the maps are limited to the legend values and the years. No other numeric values or county names are legible.\n\nSource and credit text at the bottom left: \"Designed by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System.\"\n\nPartially cut-off text at the bottom right: \"Science = Solutions.\"", "n_tokens": 358, "kind": "vision"}
{"chunk_id": "FDA_Update_2018_May_21_2018-7-1", "doc_id": "FDA_Update_2018_May_21_2018", "page": 7, "text": "Responding to Challenges: Opioids\n\nThis slide is a title slide. It contains only the title text in blue bold type, centered between two thin gray horizontal rules. There are no charts, tables, diagrams, or images on the slide.", "n_tokens": 48, "kind": "vision"}
{"chunk_id": "FDA_Update_2018_May_21_2018-11-1", "doc_id": "FDA_Update_2018_May_21_2018", "page": 11, "text": "Thank You\n\nPhotograph: A large brick building with light stone trim and a central entrance section with tall vertical windows. A glass-roofed canopy extends over the entrance at ground level. A curved, pale stone-faced retaining wall and a paved curved walkway sit in front of a green lawn. Several leafy trees stand on the left and right, and a black SUV is parked on the road at the right. The sky is clear blue with a faint contrail across the upper left. No readable text, labels, numbers, charts, or tables appear in the photograph.", "n_tokens": 114, "kind": "vision"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-0-1", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 0, "text": "Some of CDER's Top Issues, Priorities, and Goals\n\nPatrizia Cavazzoni, M.D., Director, Center for Drug Evaluation and Research, Food and Drug Administration, U.S. Department of Health and Human Services\n\nPresented at Food and Drug Law Institute Annual Conference, May 18, 2023\n\nA circular U.S. Department of Health and Human Services seal appears at the upper right, showing an eagle with the text \"DEPARTMENT OF HEALTH & HUMAN SERVICES · U.S.A.\" around its edge.", "n_tokens": 109, "kind": "vision"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-1-1", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 1, "text": "Areas We Will Cover Today\n\nThe slide has a title, \"Areas We Will Cover Today,\" in dark blue text, with a horizontal red line beneath it. The top right corner shows the Department of Health and Human Services seal and an FDA logo. There are no charts, tables, diagrams, or images beyond these logos.\n\nBulleted list:\n- Availability of medicines\n- Safety:\n  - Substance use and misuse\n  - Supply chain integrity\n- Process enhancement and modernization", "n_tokens": 91, "kind": "vision"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-2-1", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 2, "text": "Availability of Medicines: What CDER Can Do\n\nThe slide has a white background with the title centered in large dark blue bold text on two lines: \"Availability of Medicines:\" and \"What CDER Can Do.\" A thin horizontal dark red line sits below the title. Near the top right are the seal of the U.S. Department of Health and Human Services and the FDA logo, which are omitted from this description. The rest of the slide is blank. There are no charts, tables, diagrams, or other images.", "n_tokens": 107, "kind": "vision"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-14-1", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 14, "text": "Safety: Substance Use and Misuse Supply Chain Integrity\n\nThe slide has a title block in the upper-middle area, with a horizontal red line beneath it. The lower portion of the slide is blank. The slide contains no charts, tables, diagrams, or other images apart from the logos in the top right corner, which are the Department of Health and Human Services seal and the FDA logo (the FDA logo is skipped per instructions).", "n_tokens": 87, "kind": "vision"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-16-1", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 16, "text": "CDER's \"Opioid Policy Refresh\" in Action\n\nThis slide is a timeline diagram. A horizontal arrow runs across the middle, with circular pin markers and dashed lines that link each event to its date. Events above the arrow are listed first, then events below it. The diagram has no axes, units, or legend. The events, in the order they appear from left to right, are:\n\nSeptember 23, 2022: \"FDA Issues New Guidance to Help Facilitate Availability of Naloxone to Prevent Opioid Overdoses and Reduce Death\" (above the arrow).\n\nMarch 29, 2023: \"FDA Approves First Over-the-Counter Naloxone Nasal Spray.\" Subtitle: \"Agency Continues to Take Critical Steps to Reduce Drug Overdose Deaths Being Driven Primarily by Illicit Opioids\" (below the arrow).\n\nApril 3, 2023: \"FDA Moves Forward with Mail-back Envelopes for Opioid Analgesics Dispensed in Outpatient Settings.\" Subtitle: \"Agency Continues to Take Steps to Reduce New Cases of Opioid Use Disorder\" (above the arrow).\n\nApril 13, 2023: \"FDA announces new safety label changes for opioid pain medicines\" (below the arrow).\n\nJune 26-27, 2023: \"Defining and Evaluating In-Home Drug Disposal Systems for Opioid Analgesics.\" A National Academies of Sciences, Engineering, Medicine logo appears in this box (above the arrow).", "n_tokens": 308, "kind": "vision"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-20-1", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 20, "text": "Xylazine Activities\n\nThis slide shows a timeline with two dated entries, each linked to an FDA web article. The timeline is a horizontal light-blue line with an arrow at the right end. Each entry has a teardrop-shaped marker on the line and a dashed connector.\n\nEntry 1, marker on the left: the date \"November 8, 2022\" appears above a boxed headline reading \"FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs.\" Beneath the headline is a row of social sharing buttons labeled \"Share,\" \"Tweet,\" \"LinkedIn,\" \"Email,\" and \"Print.\"\n\nEntry 2, marker in the middle-right: the date \"February 28, 2023\" appears below a boxed headline reading \"FDA Takes Action to Restrict Unlawful Import of Xylazine.\" Below the headline is an italic subtitle reading \"Agency Aims to Maintain Availability for Legitimate Use in Animals while Preventing Importation for Illicit Purposes.\" Beneath that is a row of sharing buttons labeled \"Share,\" \"Tweet,\" \"LinkedIn,\" \"Email,\" and \"Print.\"", "n_tokens": 238, "kind": "vision"}
{"chunk_id": "FDLI_FDA_CDER_PCavazzoni-28-1", "doc_id": "FDLI_FDA_CDER_PCavazzoni", "page": 28, "text": "Process Enhancement and Modernization\n\nThe slide has a title in large dark blue text, centered on the white background, reading \"Process Enhancement and Modernization.\" A thin dark red horizontal line sits beneath the title. The slide contains no charts, tables, diagrams, or other images beyond the header logos, which are omitted here as requested. The rest of the slide is blank.", "n_tokens": 73, "kind": "vision"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-0-1", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 0, "text": "2023 PDA/FDA JOINT REGULATORY CONFERENCE\n\nSubtitle: CGMP: Quality Through Science and Innovation\n\nDate and location: 18-20 SEPTEMBER | WASHINGTON, DC\n\nHashtag: #PDAFDA\n\nWebsite in upper right: pda.org/2023PDAFDA\n\nBottom left: a teal box with the text \"CONNECTING PEOPLE SCIENCE AND REGULATION\" and a registered trademark symbol.\n\nBottom right: the PDA logo, which reads \"PDA Parenteral Drug Association\" with a globe graphic.\n\nThe slide has no charts, tables, or diagrams. The main image is a stylized, geometric illustration of Washington, DC landmarks. It shows the blue dome and facade of the U.S. Capitol building at center, a red obelisk on the right that represents the Washington Monument, a columned building with a triangular pediment on the left, a teal columned structure behind the Capitol, and an American flag on a pole at left. A large translucent gray diamond shape sits behind the landmarks, with a faint gray outline of the District of Columbia map below them. The background is a gradient from red at the left to dark navy at the right, with a horizontal teal bar near the top.", "n_tokens": 245, "kind": "vision"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-2-1", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 2, "text": "Areas We Will Cover Today\n\nThe slide has four bulleted items:\nManufacturing Issues Leading to Drug Shortages\nInspections\nAchieving Sustainable Compliance\nCall to Action\n\nThe slide also shows the U.S. Department of Health and Human Services seal at the top right. The footer reads \"2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER,\" with PDA and FDA logos at the bottom left. There are no charts, tables, diagrams, or other images.", "n_tokens": 92, "kind": "vision"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-7-1", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 7, "text": "Current US Shortage of Critical Oncology Drugs\n\nThe slide has two main parts: a magazine article image on the left and two New York Times headlines on the right.\n\n Left: Article image. A black-background article page with a red \"CLINICAL\" tag. Headline: \"Cisplatin, carboplatin shortage prompts rationing of lifesaving drugs—patients will die.\" Byline: \"By Paul Goldberg.\" Subhead: \"Thousands of cancer patients across the U.S. are getting bewildering news from their oncologists:\" Body text, small and partly legible: \"Proven curative regimens containing platinum-based drugs—cisplatin and carboplatin—have become largely unavailable because of a nationwide drug shortage. The institutions that have some supplies of cisplatin and carboplatin are setting up algorithms for rationing their dwindling stocks, which usually means giving top priority to patients treated with curative intent and denying standard-of-care treatment to patients who cannot be cured but who can still benefit from these drugs.\" A second paragraph reads in part: \"Cisplatin and carboplatin are old, generic drugs. Cisplatin was first described in medical literature in 1844 (The Cancer Letter April 25, 2014). Both cisplatin and carboplatin have been widely used since the 1970s. Since platinum drugs are thoroughly studied and are a staple in oncology, this means they are often present in regimens on both the experimental and control arms of clinical trials. \"\n\nLeft: Graphic. A fuel-gauge style diagram with a needle pointing toward the low end. The scale is labeled \"H\" at the top and \"L\" at the bottom. There are no numeric values, axis labels, units, or legend entries. A red vial icon appears beside the top of the gauge, and a small red bar marks the low end.\n\n Right: Two New York Times article headlines, each with the masthead \"The New York Times. \"\nHeadline 1: \"Rising Rate of Drug Shortages Is Framed as a National Security Threat.\" Subhead: \"A Senate homeland security committee examined growing health care shortages amid reports of rationing within hospitals.\"\n Headline 2: \"Drug Shortages Near an All-Time High, Leading to Rationing.\" Subhead: \"A worrisome scarcity of cancer drugs has heightened concerns about the troubled generic drug industry.", "n_tokens": 496, "kind": "vision"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-7-2", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 7, "text": "Congress and the White House are seeking ways to address widespread supply problems.\"\n\n Footer: Partly visible date text reads \"20 SEPTEMBER,\" with the rest cut off.", "n_tokens": 34, "kind": "vision"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-10-1", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 10, "text": "Compliance and Inspections\n\nThis slide has no charts, tables, diagrams, or content images beyond logos. Visible elements:\n\nTop: a horizontal gradient bar running from red on the left to dark navy on the right.\n\nUpper right: the U.S. Department of Health & Human Services seal (eagle emblem with circular text reading \"DEPARTMENT OF HEALTH & HUMAN SERVICES · USA\") and an FDA logo.\n\nCenter: a horizontal red line beneath the title.\n\nBottom: a teal gradient bar with the FDA and PDA logos at the lower left, and the text \"2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER\" at the lower right.", "n_tokens": 132, "kind": "vision"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-12-1", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 12, "text": "Enforcement and Advisory Tools\n\nThis slide contains one chart: a stacked bar chart titled \"Shift in Source of Information for Drug Adulteration Advisory Actions Warning Letters FY18-23**\".\n\nThe x-axis shows fiscal years 2018, 2019, 2020, 2021, 2022, and 2023. The y-axis has no visible label or unit scale. Each bar shows counts, with percentages in parentheses.\n\nLegend, titled \"Basis for Action\":\n- 704(a)(4) Request-Related (red)\n- Failure to Respond to 704(a)(4) Request (light pink)\n- Sample-Related (orange)\n- FDA Inspection-Related (blue)\n\nValues labeled on the chart:\n- 2018: 94 (100.0%), FDA Inspection-Related (blue segment only).\n- 2019: 99 (100.0%), FDA Inspection-Related (blue segment only).\n- 2020: 79 (97.5%), FDA Inspection-Related (blue); 2 (2.5%), Sample-Related (orange, top segment).\n- 2021: 21 (25.6%), FDA Inspection-Related (blue, bottom segment); 49 (59.8%), Sample-Related (orange); 2 (2.4%), label in the segment above the orange segment; 10 (12.2%), top segment (red, 704(a)(4) Request-Related).\n- 2022: 50 (69.4%), FDA Inspection-Related (blue); 19 (26.4%), Sample-Related (orange); 3 (4.2%), top segment (red, 704(a)(4) Request-Related).\n- 2023: 54 (81.8%), FDA Inspection-Related (blue); 4 (6.1%), Sample-Related (orange); 2 (3.0%), light pink segment (Failure to Respond to 704(a)(4) Request); 6 (9.1%), top segment (red, 704(a)(4) Request-Related).\n\nFootnotes:\n\"** Warning Letters through July 31, 2023\"\n\"Excludes compounding-related actions\"\n\nFooter text: \"2023 PDA/FDA JOINT REGULATORY CONFERENCE | 18-20 SEPTEMBER\"", "n_tokens": 498, "kind": "vision"}
{"chunk_id": "FINALCLEAN_2023PDAFDA_PCavazzoni-21-1", "doc_id": "FINALCLEAN_2023PDAFDA_PCavazzoni", "page": 21, "text": "No slide title is visible.\n\nThe slide has a red-to-dark-navy diagonal gradient background with a thin teal horizontal bar across the upper area. The left side is empty.\n\nThe right side has a stylized, faceted illustration of Washington, D.C. landmarks in red, teal, blue, and gray. It shows the U.S. Capitol building with a blue dome, a red obelisk to the right of the dome (resembling the Washington Monument), a gray classical columned building on the left, and a teal columned building behind the dome. An American flag on a tall flagpole stands at the left of the Capitol. A large, semi-transparent gray diamond sits behind the landmarks, with a faint gray silhouette of the District of Columbia outline below them.\n\nBottom left: a teal rectangular box with the tagline \"CONNECTING PEOPLE SCIENCE AND REGULATION\" in white text, with \"SCIENCE AND\" and \"REGULATION\" in bold.\n\nBottom right: the PDA logo, which reads \"PDA\" with \"Parenteral Drug Association\" below it and a globe graphic.\n\nThere are no charts, tables, diagrams, axes, legends, or numbers on this slide.", "n_tokens": 245, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-0-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 0, "text": "CDER New Drugs Program: 2018 Update\n\nKhushboo Sharma, MBA, RAC\nChief of Staff\nOffice of New Drugs, CDER/FDA\n\nFDA/CMS Summit\nDecember 11th, 2018", "n_tokens": 40, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-3-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 3, "text": "CDER New Molecular Entity Approval Rates by PDUFA Cohort\n\nThis is a line chart. The y-axis is labeled \"% NMEs Receiving Approval,\" with tick labels from 0% to 100% in 10% steps. The x-axis is labeled \"Elapsed Time (months),\" with tick labels at 6, 12, 18, 24, 30, 36, 42, 48, and 54. A thin vertical blue line is drawn at the 12-month mark.\n\nThe chart has four labeled series, identified by direct labels on the lines:\nPDUFA V (purple line)\nPDUFA IV (green line)\nPDUFA I-III (blue line)\nPre-PDUFA (orange line)\n\nThe purple PDUFA V line rises steeply, reaching roughly 75% near 11 months, and ends near 86% at about 22 months. The final segment is dashed.\nThe green PDUFA IV line is at roughly 57% at 12 months and levels off near 79% by about 48 months.\nThe blue PDUFA I-III line is at roughly 43% at 12 months and reaches about 77% near 42 months, then continues close to 79%.\nThe orange Pre-PDUFA line is at roughly 18% at 12 months and reaches about 80% near 52 months, then stays near 80% through about 58 months.\n\nFootnote text below the chart reads: \"Projection estimates account for actions to date and elapsed time to date for non-approvals.\"\nFooter text reads: \"Data as of 11/30/18.\"", "n_tokens": 325, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-9-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 9, "text": "CDER Approved Orphan Indications for all NDAs and BLAs† by CY\n\nHeader text at top left: New Drug Activity in 2018\n\nChart: Vertical bar chart with single-color navy bars. No legend. The y-axis has no visible label, units, or tick values. The x-axis is labeled \"Calendar Year\" and shows one bar per year from 1983 to 2018*. Each bar's value is printed inside or at the top of the bar, as listed below. The 1983 bar has no visible number label.\n\nValues by calendar year:\n1983: no label visible\n1984: 3\n1985: 5\n1986: 6\n1987: 6\n1988: 9\n1989: 10\n1990: 9\n1991: 12\n1992: 13\n1993: 11\n1994: 10\n1995: 10\n1996: 23\n1997: 18\n1998: 19\n1999: 18\n2000: 12\n2001: 6\n2002: 14\n2003: 11\n2004: 14\n2005: 15\n2006: 22\n2007: 13\n2008: 15\n2009: 16\n2010: 15\n2011: 23\n2012: 24\n2013: 24\n2014: 46\n2015: 43\n2016: 39\n2017: 74\n2018*: 75\n\nFootnotes at bottom left:\n† Includes Efficacy Supplements\n* Data as of 11/30/2018", "n_tokens": 242, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-10-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 10, "text": "USA Share of New Active Substances Launched on World Market Remains High\n\nThis slide has one line chart. It shows the share of new active substances launched on the world market, by market authority, from 2001 to 2017. The y-axis is labeled in percent, from 0% to 80% in 10% steps. The x-axis shows years, 2001 through 2017. The chart has no axis titles. Four lines are labeled at their right ends: US (dark blue), EU (red), Other Authorities (light blue), and Japan (yellow). The values below are approximate readings from the chart, not printed data labels.\n\n US (dark blue): 2001 about 39%; 2002 about 55%; 2003 about 58%; 2004 about 39%; 2005 about 52%; 2006 about 61%; 2007 about 56%; 2008 about 47%; 2009 about 52%; 2010 about 43%; 2011 about 63%; 2012 about 58%; 2013 about 61%; 2014 about 59%; 2015 about 65%; 2016 about 61%; 2017 about 67%.\n\n EU (red): 2001 about 33%; 2002 about 21%; 2003 about 13%; 2004 about 30%; 2005 about 16%; 2006 about 22%; 2007 about 12%; 2008 about 28%; 2009 about 31%; 2010 about 34%; 2011 about 12%; 2012 about 16%; 2013 about 11%; 2014 about 13%; 2015 about 11%; 2016 about 14%; 2017 about 12%.\n\n Other Authorities (light blue): 2001 about 11%; 2002 about 3%; 2003 about 19%; 2004 about 17%; 2005 about 22%; 2006 about 6%; 2007 about 24%; 2008 about 12%; 2009 about 7%; 2010 about 8%; 2011 about 15%; 2012 about 14%; 2013 about 19%; 2014 about 11%; 2015 about 7%; 2016 about 15%; 2017 about 12%.\n\nJapan (yellow): 2001 about 16%; 2002 about 21%; 2003 about 10%; 2004 about 13%; 2005 about 10%; 2006 about 10%; 2007 about 8%; 2008 about 12%; 2009 about 10%; 2010 about 14%; 2011 about 9%; 2012 about 11%; 2013 about 8%; 2014 about 16%; 2015 about 16%; 2016 about 9%; 2017 about 9%.\n\n", "n_tokens": 491, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-10-2", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 10, "text": "Footnotes below the chart read: \"Data as of 11/30/2018\" and \"Source: Scrip Magazine (1982 - 2006), Pharmaprojects/Citeline Pharma R&D Annual Review (2007 - 2017).\"", "n_tokens": 54, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-13-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 13, "text": "In CY 2018, CDER Continued To Ensure The Efficiency Of First Cycle Review\n\nBullet points on the slide:\n- All of the (100%) NMEs/BLAs approved to date in 2018 met their PDUFA goal dates.\n- All but three (95%) of the drugs approved to date in 2018 were approved in the first review cycle.\n\nChart 1: A donut chart titled \"Met PDUFA Goal Date.\" It is a single fully green ring with no segments other than the green fill. The center label reads \"100%.\"\n\nChart 2: A donut chart titled \"Approved on First Cycle.\" It is mostly red, with a small gray segment at the top, approximately one-twentieth of the ring. The center label reads \"95%.\" No axis labels, units, or legend entries are shown beyond the chart title.", "n_tokens": 175, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-16-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 16, "text": "Development Phase Work Continued to Grow in 2018\n\nThis is a stacked bar chart showing development phase work from 2004 to 2018. Each bar has two segments: a dark blue segment labeled Drug INDs at the bottom and a red segment labeled Biologic INDs on top. The x-axis shows years, 2004 through 2018. The chart has no visible y-axis label, scale, or units. Values are shown as white numbers inside each segment.\n\nDrug INDs (dark blue, bottom segment), by year:\n2004: 3773\n2005: 4023\n2006: 4281\n2007: 4516\n2008: 4808\n2009: 5002\n2010: 5026\n2011: 5067\n2012: 5278\n2013: 5258\n2014: 5186\n2015: 5412\n2016: 5261\n2017: 5358\n2018: 5397\n\nBiologic INDs (red, top segment), by year:\n2004: 588\n2005: 586\n2006: 695\n2007: 672\n2008: 713\n2009: 726\n2010: 732\n2011: 808\n2012: 824\n2013: 879\n2014: 1218\n2015: 1367\n2016: 1480\n2017: 1662\n2018: 1804\n\nFootnote text: \"Data are from the PDUFA Workload Adjuster and represent a 12 month period of July 1st - June 30th\"", "n_tokens": 269, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-17-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 17, "text": "CDER Breakthrough Therapy Requests by Division\n\nSubtitle: Oncology, Hematology, and Neurology account for over 50% of Breakthrough Requests.\n\nThe slide contains a pie chart and a text list.\n\nPie chart: The chart shows the division breakdown of CDER Breakthrough Therapy requests. The legend lists three entries: Oncology (dark blue), Hematology (red), and Neurology (green). The labeled segments are Oncology at 26%, Hematology at 15%, and Neurology at 10%. The remaining segments are grey and unlabeled. Caption below the chart: 663 Requests since BT program inception in July 2012.\n\nText on the right: The heading reads \"Some notable conditions include:\" followed by three conditions: Pheochromocytoma and Paraganglioma; Hemophagocytic Lymphohistiocytosis (HLH); and Lambert Eaton Myasthenic Syndrome (LEMS).\n\nFooter: Data as of 11/30/2018.", "n_tokens": 217, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-18-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 18, "text": "CDER Breakthrough Therapy Grants by Division\n\nLeft side: Text reads \"Of 663 BT Requests CDER issues a BT Grant about 38% of the time.\"\n\nLeft bar chart: Titled as the outcome distribution of 663 BT requests. Categories on the horizontal axis: Granted, Denied, Withdrawn, Pending. No vertical axis labels or units are shown. Bar labels: Granted 38%, Denied 46%, Withdrawn 13%, Pending 3%. The Granted bar is dark blue; the other three bars are light gray.\n\nRight side: Heading text reads \"Oncology, Hematology, and Antiviral account for the majority of Breakthrough Grants.\" The words Oncology, Hematology, and Antiviral are colored navy, red, and light blue respectively.\n\nRight donut chart: Center label reads \"251 Granted.\" It shows the division breakdown of granted breakthrough therapy grants. Legend entries: Oncology (navy), Hematology (red), Antiviral (light blue). Other segments are gray and unlabeled. Labeled percentages: Oncology 32%, Hematology 20%, Antiviral 10%.\n\nFooter: \"Data as of 11/30/2018.\"", "n_tokens": 248, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-19-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 19, "text": "CDER PDUFA Formal Meeting Requests by FY\n\nThis is a vertical bar chart with dark navy bars. The horizontal x-axis is labeled \"Fiscal Year\" and lists fiscal years 2003 through 2018*. The chart has no y-axis label or legend. Each bar's value is printed in white text inside or at the top of the bar. The values are:\n\n2003: 1464\n2004: 2015\n2005: 2236\n2006: 2256\n2007: 2209\n2008: 2027\n2009: 1969\n2010: 2008\n2011: 2010\n2012: 2073\n2013: 2221\n2014: 2360\n2015: 2732\n2016: 2885\n2017: 3053\n2018*: 3179\n\nFootnotes at the bottom left read: \"Data as of 9/30/2018\", \"BLAs were transferred to CDER in FY2004\", and \"*2018 Data is preliminary\".", "n_tokens": 180, "kind": "vision"}
{"chunk_id": "FinalFDACMSSummit1_10_18KSCorrected-21-1", "doc_id": "FinalFDACMSSummit1_10_18KSCorrected", "page": 21, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images. Its only element is the logo, which is omitted as requested.", "n_tokens": 33, "kind": "vision"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-0-1", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 0, "text": "Future of Drug Development\n\nJanet Woodcock\nDirector, CDER, FDA\n\nThe slide is a title slide with no charts, tables, diagrams, or other images. The title \"Future of Drug Development\" appears in large black text near the vertical middle of the slide. Below it, in smaller gray text, are the presenter's name, \"Janet Woodcock,\" and her title, \"Director, CDER, FDA.\"", "n_tokens": 86, "kind": "vision"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-1-1", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 1, "text": "THESIS\n\nThis slide has the title \"THESIS\" centered in bold black text on a plain white background. It contains no charts, tables, diagrams, images, or other body text. The only other element is the FDA logo in the upper right corner, which is omitted from this description.", "n_tokens": 57, "kind": "vision"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-2-1", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 2, "text": "Multiple Forces Are Driving the Shape of the Future\n\nThe slide is text only, with no charts, tables, diagrams, or images beyond the FDA logo, which is omitted here. It contains a bulleted list of six items:\n- International regulatory convergence\n- Advanced manufacturing\n- Rise of biosimilars\n- New science and technology\n- Digital revolution\n- Drug costs\n\nBelow the list, in capital letters, is a closing statement: THE GENERIC INDUSTRY AND ITS REGULATORS NEED TO BE AHEAD OF THESE TRENDS", "n_tokens": 96, "kind": "vision"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-8-1", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 8, "text": "New Science and Technology\n\nThe slide contains no charts, tables, diagrams, or images other than text bullets.\n\nText content:\n\n- Some rapid uptake by generics—e.g., abuse deterrent opioid formulations\n- Combination products\n  - Advanced delivery systems\n    - Inhalers\n    - Auto-injectors\n    - Future—into CNS, other spaces\n  - Other drug-device combos", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-11-1", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 11, "text": "Drug Costs\n\nThe slide contains bulleted text only, with no charts, tables, diagrams, or images. The bullet points read:\n\nWill be an ongoing theme\nGeneric industry (most) seen as good guys, but issues with single source products\nClearly will be a continued focus in US and elsewhere\nVarious types of pressures on regulators\nWe will continue to be asked ways to mitigate drug cost issues", "n_tokens": 76, "kind": "vision"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-12-1", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 12, "text": "GENERIC INDUSTRY AND ITS REGULATORS NEED TO BE AHEAD OF THESE TRENDS\n\nThis slide contains only the title text above. It has no charts, tables, diagrams, or other images. The FDA logo in the upper right corner is omitted per instructions. The remainder of the slide is blank white space.", "n_tokens": 57, "kind": "vision"}
{"chunk_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA-16-1", "doc_id": "Future_of_Drug_Development_with_Janet_Woodcock_Director_CDER_FDA", "page": 16, "text": "Summary\n\nThis slide has no charts, tables, diagrams, or images other than the FDA logo, which is skipped. It contains five bullet points of text:\n\nBold future for the affordable pharmaceuticals industry!\nPace of change will be rapid\nNeed to work with regulators to enable\nGDUFA 2 (and BSUFA 2) are next steps\nIndustry undoubtedly will expand its role as major source of pharmaceutical care for the world's population", "n_tokens": 84, "kind": "vision"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-0-1", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 0, "text": "Advancing Efficient and Inclusive Clinical Trials\n\nMeeting of the Directors of the NCI-designated Cancer Centers\n\nOctober 4, 2021\n\nDr. Patrizia Cavazzoni\nDirector, Center for Drug Evaluation and Research, FDA\n\nWebsite shown at bottom left: www.fda.gov\n\nThis slide contains no charts, tables, diagrams, or images other than the FDA logo, which is omitted.", "n_tokens": 74, "kind": "vision"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-1-1", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 1, "text": "FDA Multipronged Approach to Facilitate Innovative, Efficient, and Inclusive Clinical Trials\n\nThe slide contains a bulleted list of six items, with no charts, tables, diagrams, or images:\n- FDA Real-World Evidence Program\n- Efficient Safety Reporting\n- Increasing Diversity in Clinical Trials\n- Decentralized Clinical Trials\n- Digital Health Tools\n- Lessons from the Pandemic\n\nThe website www.fda.gov appears in the footer.", "n_tokens": 84, "kind": "vision"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-2-1", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 2, "text": "FDA Real-World Evidence Program\n\nThis slide has a blue gradient background with the title at the top. The slide contains three images, one centered text statement, and two year labels. It has no charts, tables, or diagrams.\n\n Left image: A blue panel reading \"FRAMEWORK FOR FDA\" above large white text \"REAL-WORLD EVIDENCE PROGRAM.\" The right part of the panel is partly covered by the web page screenshot.\n\n Center image: A screenshot of an FDA web page. The breadcrumb reads \"Home / Drugs / Drug Safety and Availability / FDA Approves New Use of Transplant Drug Based on Real-World Evidence.\" The headline reads \"FDA Approves New Use of Transplant Drug Based on Real-World Evidence.\" The body text reads: \"Today, the U.S. Food and Drug Administration approved a new use for Prograf (tacrolimus) based on a non-interventional (observational) study providing real-world evidence (RWE) of effectiveness. FDA approved Prograf for use in combination with other immunosuppressant drugs to prevent organ rejection in adult and pediatric patients receiving lung transplantation.\" The right side shows \"Content current as of: 07/16/2021\" and \"Regulated Product(s): Drugs.\" The left sidebar lists \"Drug Safety and Availability\" and \"Information about Nitrosamine Impurities in Medications.\"\n\nRight image: A document cover page titled \"Real-World Data: Assessing Electronic Health Records and Medical Claims Data To Support Regulatory Decision-Making for Drug and Biological Products.\" Below it are the labels \"Guidance for Industry\" and \"DRAFT GUIDANCE,\" followed by small print: \"This guidance document is being distributed for comment purposes only.\" The cover also lists \"U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Oncology Center of Excellence (OCE),\" and \"September 2021, Real World Data/Real World Evidence (RWD/RWE).\" The fine print includes the contact email CDERMedicalPolicy-RealWorldEvidence@fda.hhs.gov.\n\n Centered text in blue: \"We want to provide the clarity needed to realize the full potential of Real-World Data. \"\n\nYear labels: \"2018\" appears at the lower left, below the left image.", "n_tokens": 505, "kind": "vision"}
{"chunk_id": "MeetingofNCICancerCenterDirectors_10042021-2-2", "doc_id": "MeetingofNCICancerCenterDirectors_10042021", "page": 2, "text": "\"2021\" appears at the lower right, below the document cover.\n\n Footer: A URL reads \"https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/RealWorldEvidence/UCM627769.pdf.\"", "n_tokens": 60, "kind": "vision"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-0-1", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 0, "text": "The Food and Drug Administration's Emergency Use Authorization: Lessons Learned from the Past to Guide the Future\n\nAffiliation line at top: National Academies of Sciences, Engineering, and Medicine\n\nPresenter block: Center for Drug Evaluation and Research. Patrizia Cavazzoni, MD. October 5, 2021\n\nThis slide has no charts, tables, diagrams, or images other than the FDA logo, which is omitted as requested.", "n_tokens": 82, "kind": "vision"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-1-1", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 1, "text": "Panel 1: Use of the Emergency Use Authorization During the COVID Pandemic\n\nOpening Remarks", "n_tokens": 18, "kind": "vision"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-9-1", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 9, "text": "Slide title: None visible. The slide's main text reads: \"While our work to respond to the pandemic isn't over, we are taking stock of our experience and capturing lessons learned\"\n\nThe slide contains no charts, tables, diagrams, or images. The only other element is the FDA (U.S. Food & Drug Administration) logo, which is omitted here.", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-11-1", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 11, "text": "Lessons Learned – Evidence Generation\nThe value of master protocols:\n\nLeft panel: a flowchart titled \"RECOVERY trial design.\"\nEligible patients box lists: 1. Admitted to hospital. 2. Proven or suspected SARS-CoV-2 infection.\nAn arrow leads to a green-outlined circle labeled \"R.\"\nTwo green boxes sit beside the flow: \"Convalescent plasma\" and \"Control.\"\nFive treatment arms follow from R:\n- \"No additional treatment\"\n- \"Lopinavir-ritonavir 400/100 mg bd PO for 10 days\"\n- \"Dexamethasone 6 mg od PO/IV for 10 days\"\n- \"Hydroxychloroquine. See protocol for dosing\"\n- \"Azithromycin 500 mg od PO/IV for 10 days\"\nAn arrow leads to an Outcomes box.\nPrimary outcome: \"28-day mortality.\"\nSecondary outcomes: \"Duration of hospitalisation\"; \"Mechanical ventilation or death.\"\n\nRight panel: five stacked blue banners, each with a photo of clinical care settings and a label:\n- \"ACTIV-1: Immune Modulators.\" Caption below: \"The ACTIV-1 master protocol will test promising immune modulator compounds, a class of drugs that help minimize the\" (text cut off).\n- \"ACTIV-2: Outpatient Monoclonal Antibodies and Other Therapies.\"\n- \"ACTIV-3: Inpatient Monoclonal Antibodies and Other Therapies.\" Caption below: \"ACTIV-3 protocols are Phase 3 randomized, placebo-controlled trials testing multiple therapies, beginning with monoclonal\" (text cut off).\n- \"ACTIV-4: Antithrombotics.\"\n- \"ACTIV-5: Big Effect Trial.\"", "n_tokens": 377, "kind": "vision"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-14-1", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 14, "text": "FDA's Strength Is Its People\n\nThis slide has a row of three arrow graphics inside a blue-bordered box. It has no axes or legend.\n\n- Left: a red arrow pointing up, labeled 43%. Caption: \"New INDs received.\"\n- Middle: a red arrow pointing up, labeled 26%. Caption: \"Formal meeting requests.\"\n- Right: a green arrow pointing down, labeled 50%. Caption: \"Avg time between request and meeting.\"\n\nBelow the box is a sentence: \"To be ready to respond to pandemics, FDA needs to be able to build enduring surge capacity in the core scientific disciplines and supporting operations.\"", "n_tokens": 139, "kind": "vision"}
{"chunk_id": "NASEUAworkshop21_PCavazzoni_forposting-15-1", "doc_id": "NASEUAworkshop21_PCavazzoni_forposting", "page": 15, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images. Its only visual element is the agency logo, which is omitted as instructed. No other text or numbers appear.", "n_tokens": 42, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-0-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 0, "text": "Ongoing FDA Work Related to Opioid Overdose Prevention\n\nDouglas C. Throckmorton, MD\nDeputy Director for Regulatory Programs\nCenter for Drug Evaluation and Research\nFDA\n\nOffice of the Assistant Secretary for Health (OASH)\nJanuary, 2019", "n_tokens": 45, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-6-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 6, "text": "Next Steps\n\nFDA meeting internally on AC recommendations\n- Plan response to Citizen Petition\n- Discuss ideas raised by Committee membersReview AC Docket comments (>220 comments received so far)\n- Engage external stakeholders\n- Propose next steps to leadership", "n_tokens": 45, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-7-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 7, "text": "II. Over-The-Counter Naloxone: Why OTC Naloxone?\n\nThe slide contains only bulleted text, with no charts, tables, diagrams, or images.\n\nBullet points:\n- Existing expanded access programs (such as pharmacy standing order programs) are a significant tool, but more is needed – not everyone can/wants to obtain the product through a healthcare professional\n- Surgeon General's 2018 Advisory", "n_tokens": 85, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-10-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 10, "text": "Translate the Approved RX Product Label….\n\nThe slide shows a dense collage of about a dozen pages from a prescription drug label, laid out in a grid with overlapping edges. The text is too small to read reliably, but the first page appears to be headed \"Ibuprofen Tablets, USP.\" Legible section headings across the pages include DESCRIPTION, CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, ADVERSE REACTIONS, OVERDOSAGE, DOSAGE AND ADMINISTRATION, and HOW SUPPLIED. Some pages contain small tables, including one in the ADVERSE REACTIONS area with multiple columns, but their entries cannot be read. The slide has no charts, graphs, or diagrams, and no axes, units, or legends.", "n_tokens": 156, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-11-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 11, "text": "To a Label for OTC Products.....\n\nDrug Facts Label\n\nThis image shows a Drug Facts label for an over-the-counter tablet, shown in two boxed panels. It has no charts or diagrams. The first panel is the main label, and the second is a continuation panel at the bottom.\n\nMain panel:\n\nDrug Facts\n\nActive ingredient (in each tablet): Chlorpheniramine maleate 2 mg. Purpose: Antihistamine\n\nUses: temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: sneezing, runny nose, itchy watery eyes, itchy throat\n\nWarnings\n\nAsk a doctor before use if you have: glaucoma; a breathing problem such as emphysema or chronic bronchitis; trouble urinating due to an enlarged prostate gland\n\nAsk a doctor or pharmacist before use if you are taking tranquilizers or sedatives\n\nWhen using this product: drowsiness may occur; avoid alcoholic drinks; alcohol, sedatives, and tranquilizers may increase drowsiness; be careful when driving a motor vehicle or operating machinery; excitability may occur, especially in children\n\nIf pregnant or breast-feeding, ask a health professional before use.\n\nKeep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.\n\nDirections (table with two columns, Who and Dose):\nAdults and children 12 years and over: take 2 tablets every 4 to 6 hours; not more than 12 tablets in 24 hours\nChildren 6 years to under 12 years: take 1 tablet every 4 to 6 hours; not more than 6 tablets in 24 hours\nChildren under 6 years: ask a doctor\n\nContinuation panel:\n\nDrug Facts (continued)\n\nOther information: store at 20-25°C (68-77°F); protect from excessive moisture\n\nInactive ingredients: D&C yellow no. 10, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch", "n_tokens": 415, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-12-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 12, "text": "OTC Consumer Studies\n\nThis slide is a diagram of four stacked boxes. Each box has a colored header bar with the study name and a bullet line beneath it describing that study.\n\nLabel Comprehension Study (dark blue header): Understanding the key label messages\n\nSelf-Selection Study (green header): Choosing the right product for \"me\"\n\nActual Use Study (red header): Using according to labeled directions\n\nHuman Factors Study (brown header): Interacting with the product", "n_tokens": 91, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-17-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 17, "text": "III. Systems Model of Opioids Crisis Including Role of Naloxone\n\nThe slide contains bullet text only, with no charts, tables, diagrams, or images other than the FDA logo, which is omitted.\n\nBullets:\n- Deliverable for the BHCC\n- Successful model will help identify high-impact actions and anticipate consequences of policy changes\n- Experts from across HHS providing input", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-19-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 19, "text": "Elements of Opioid Use/Misuse/Abuse Model (Simplified)\n\nThis is a simplified diagram of overlapping colored ellipses connected by black arrows. It has no axes, legend, or numbers. The only text is the labels below.\n\nLabels and shapes:\n- \"General population\": a small green circle on the upper left.\n- \"Rx policies\": an orange circle below the green circle, partly overlapping the large yellow ellipse.\n- \"Misuse & use disorder\": a large yellow ellipse in the center. The orange and red shapes overlap its edges.\n- \"Overdose\": a horizontal red ellipse at the upper right, overlapping the upper right edge of the yellow ellipse.\n- \"Treatment and relapse\": a large blue ellipse at the lower right, overlapping the lower right of the yellow ellipse.\n\nArrows:\n- A thick black arrow points right from the General population circle into the yellow ellipse.\n- A thick black arrow points up from the Rx policies circle toward the horizontal arrow from General population.\n- A pair of thick black diagonal arrows runs between the yellow ellipse and the blue ellipse, pointing in opposite directions.\n- A thick black arrow points up from the blue ellipse toward the red Overdose ellipse.\n\nFooter navigation text, in small type near the bottom center: \"AGENDA | PROJECT CONTEXT | SYSTEMS MODEL | PROJECT TIMELINE | DISCUSSION\". The words \"SYSTEMS MODEL\" are in black and the other section names are in colored text.", "n_tokens": 316, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-21-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 21, "text": "Thank You\n\nThe slide shows a photograph of a large multi-story brick building with a central stone-faced section containing tall vertical windows. A glass-roofed canopy extends over the entrance at the center of the building. A curved green lawn sits in front of the building, bordered by a curved low wall of pinkish-gray stone with small inset lights. A paved walkway curves along the wall, and a paved road runs along the right side. A black SUV is driving on the road near the building's entrance. Mature trees stand on both sides of the building, and the sky is clear blue with a thin white contrail across it.", "n_tokens": 130, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-22-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 22, "text": "Backup Slides\n\nThis slide has no charts, tables, diagrams, or images beyond the text title. The slide is otherwise blank white space.", "n_tokens": 27, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-28-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 28, "text": "MODEL BACKBONE\n\nThis slide shows a flow diagram titled \"Model Backbone\" with blue rectangular and hexagonal boxes connected by arrows. The diagram has no axes, units, or legend. Reading left to right, the boxes and connections are:\n\n- \"General Population\" (rectangle) is on the far left. An arrow runs from it to \"Opioid Use as directed\" and another arrow runs from it to \"Opioid misuse.\"\n- \"Opioid Use as directed\" (rectangle) has an arrow to \"OUD (unmanaged).\" A line runs from its top edge up, left, and down into \"General Population,\" with an arrowhead at General Population.\n- \"Opioid misuse\" (rectangle) sits below \"Opioid Use as directed,\" with an arrow from the upper box down to it. It has an arrow to \"OUD (unmanaged).\"\n- \"OUD (unmanaged)\" (rectangle) has a connector to \"Well managed OUD\" (rectangle) above it, with arrowheads at both ends of the connector. It also has an arrow to \"Overdose.\"\n- \"Well managed OUD\" (rectangle) sits above and to the right of \"OUD (unmanaged).\" It has an arrow down to \"Overdose.\"\n- \"Overdose\" (hexagon) receives arrows from \"OUD (unmanaged)\" and \"Well managed OUD.\" A line from the bottom of \"Opioid misuse\" runs right beneath the diagram and enters \"Overdose\" from below with an arrowhead. It has an arrow to \"Overdose Death.\"\n- \"Overdose Death\" (hexagon) is on the far right and is the final box in the diagram.\n\nNo numbers appear within the diagram. The footer navigation text reads: \"AGENDA | PROJECT CONTEXT | SYSTEMS MODEL | PROJECT TIMELINE | DISCUSSION,\" with \"SYSTEMS MODEL\" highlighted in black text, while the other items are in green or blue.", "n_tokens": 425, "kind": "vision"}
{"chunk_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention-29-1", "doc_id": "OngoingFDAWorkRelatedtoOpioidOverdosePrevention", "page": 29, "text": "Illustrative pathway (simplified)\n\nThe slide is a simplified diagram made of overlapping colored ellipses connected by black arrows. It has no axes, legend, or numeric values.\n\nEllipses, from left to right and top to bottom:\n- A small green ellipse labeled \"General population,\" at the upper left.\n- An orange ellipse labeled \"Rx policies,\" below and partly overlapping the lower right of the green ellipse.\n- A large yellow ellipse in the center labeled \"Misuse & use disorder.\" The orange ellipse overlaps its lower left edge.\n- A wide red ellipse at the upper right labeled \"Overdose.\" It overlaps the upper right edge of the yellow ellipse.\n- A large blue ellipse at the lower right labeled \"Treatment and relapse.\" It overlaps the lower right edge of the yellow ellipse.\n\nArrows:\n- A thick black arrow points right from the green \"General population\" ellipse toward the yellow \"Misuse & use disorder\" ellipse.\n- A thick black arrow points up from the orange \"Rx policies\" ellipse toward the same arrow and the yellow ellipse.\n- A pair of thick black parallel diagonal arrows connects the yellow \"Misuse & use disorder\" ellipse and the blue \"Treatment and relapse\" ellipse, with one arrowhead pointing toward each ellipse.\n- A thick black arrow points up from the blue \"Treatment and relapse\" ellipse to the red \"Overdose\" ellipse.\n\nFooter navigation text reads: \"AGENDA | PROJECT CONTEXT | SYSTEMS MODEL | PROJECT TIMELINE | DISCUSSION.\" The item \"SYSTEMS MODEL\" is in black text and the other items are in colored text.", "n_tokens": 369, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-0-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 0, "text": "FDA Update on Drug Compounding\n\nPresenter text on the slide:\nJulie Dohm, J.D., Ph.D.\nSenior Science Advisor for Compounding, CDER\nAgency Lead on Compounding, FDA\n\nVisual elements: A blue vertical bar runs along the left edge, with a small orange speech-bubble icon at the top left corner. In the lower right corner is the logo for the International Seminar, consisting of a blue and gold molecular-network graphic beside the stacked words \"INTERNATIONAL SEMINAR\" in blue capitals. The slide has no charts, tables, or diagrams beyond this logo.", "n_tokens": 117, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-1-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 1, "text": "Outline\n\nThe slide has a white-to-light-gray background with a vertical blue bar along the left edge. The text is black.\n\nBullet list:\n- Regulatory Framework\n- Compounding Program\n  - Compounding Policy\n  - Inspections and Enforcement\n  - Stakeholder Engagement\n\nBottom right: an \"International Seminar\" logo, with a blue and gold network-style graphic of connected dots next to the words \"INTERNATIONAL SEMINAR.\"", "n_tokens": 81, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-5-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 5, "text": "Policy, Oversight, and Stakeholder Engagement\n\nDiagram: Organizational hierarchy chart with one top-level box connected by lines to three boxes below it.\n- Top box: \"Compounding Program\"\n- Second-level boxes, left to right:\n  - \"Compounding Policy\" (outlined with a thick yellow border, the only highlighted box)\n  - \"Inspections and Enforcement\"\n  - \"Stakeholder Engagement\"\n- No numbers, axes, units, or legend appear on the slide.\n\nOther visible element: \"International Seminar\" logo at the bottom right, with a blue vertical bar along the left edge.", "n_tokens": 117, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-21-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 21, "text": "Examples of Policies Applicable to Outsourcing Facilities under Section 503B\n\nThe slide has three bullet points:\n- CGMP interim draft guidance for outsourcing facilities\n- Compounding using bulk drug substances under section 503B\n- Compounded drug products that are essentially copies of approved drug products under section 503B\n\nImage in the lower right corner: the International Seminar logo. It has a blue and gold network-style icon of connected circles and dots, with the text \"INTERNATIONAL SEMINAR\" beside it.", "n_tokens": 101, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-28-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 28, "text": "Examples of Policies Applicable to Compounders under Sections 503A and 503B\n\nThe slide has three bulleted items:\nRepackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities\nMixing, diluting, or repackaging biological products outside the scope of an approved biologics license application\nInsanitary Conditions\n\nThe slide has a blue vertical bar along its left edge. In the bottom right corner is an International Seminar logo, which shows a cluster of blue and gold connected circles and nodes beside the words \"INTERNATIONAL SEMINAR.\" The slide contains no charts, tables, or diagrams other than this logo.", "n_tokens": 125, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-32-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 32, "text": "Inspections and Enforcement\n\nThis slide contains a diagram, a hierarchy chart with one top box and three boxes beneath it, connected by lines.\n\nTop box: \"Compounding Program\"\n\nThree boxes below, left to right:\n- \"Compounding Policy\"\n- \"Inspections and Enforcement\" (this box is outlined in a yellow highlight)\n- \"Stakeholder Engagement\"\n\nLower right corner: \"International Seminar\" logo with a small network-style graphic. The slide has no numbers, axes, units, or legend.", "n_tokens": 100, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-36-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 36, "text": "Insanitary Condition Example\n\nPhotograph of a ceiling tile lying on a black plastic bag on a gray floor with scattered spots. The tile is off-white to tan with faint printed text and stripes that are too blurred to read. Its lower-center area has large dark brown to black blotches with a mottled, spotty pattern, and a yellowish-tan discolored area runs beside them. The floor shows scattered darker spots.\n\nCaption text to the right of the photo: \"Visible microbial contamination on a ceiling tile in a clean room\"\n\nBottom-right logo: \"INTERNATIONAL SEMINAR\" with a blue and yellow molecular-network graphic. No FDA logo appears on this slide.", "n_tokens": 140, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-37-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 37, "text": "Insanitary Condition Example\n\nThe slide has two photographs with a red arrow and a text caption.\n\nLeft photograph: A ceiling panel corner is visible at the top, with dark insulation or lining exposed at its edge. Below it is a doorway with glass-panel framing and a white partition. Beyond the doorway, a room with ceiling lights and equipment is partly visible.\n\nRed arrows: One arrow runs from the corner of the left photograph to the right photograph's upper area. A second arrow runs from the same corner down to the bottom edge of the right photograph.\n\nCaption (right of the left photograph): \"Ceiling above the doorway to cleanroom with exposed insulation.\" A line above this caption is cut off and unreadable.\n\nRight photograph: A ceiling cavity with rust-stained metal framing and joists. White fiberglass insulation with a blue printed label is visible. Silver foil-wrapped ducting runs along the left side. Electrical wires and cables hang through the cavity. A white fixture or frame with a partly visible letter \"P\" appears at the bottom edge.\n\nLogo: \"International Seminar\" logo at the bottom right.", "n_tokens": 230, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-38-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 38, "text": "Insanitary Condition Example\n\nThe slide has a photograph on the left and a text caption on the right.\n\nThe photograph shows the interior edge of an ISO 5 hood, looking at a white pre-filter frame. Above the frame is a dark, fibrous filter surface with two or three white paper or tissue pieces stuck to it. Along the white frame lies a scattered mix of debris: small yellow, red, blue, and white plastic fragments, several round gray and yellow items that appear to be medical supply components, small metallic pieces, a white paper or wrapper piece with printed text that is not legible, and fine dust. A dark strip runs along the lower part of the frame. A gray rectangular box with a small label reading \"(b) (4)\" sits in the lower right corner of the photo, obscuring part of the image.\n\nCaption text on the right reads: \"Filth under the hood including multiple pieces of medical supply waste and dust build up in the pre-filter for the ISO 5 hood.\"\n\nAn International Seminar logo appears in the lower right corner of the slide.", "n_tokens": 227, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-39-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 39, "text": "Insanitary Condition Example\n\nThis is a photograph of laboratory equipment, with the caption \"Equipment, located in cleanroom, used to produce injectable drugs visibly dirty.\" The equipment is a magnetic hotplate stirrer with a yellow base and a white ceramic top plate. A glass beaker containing a pale yellow liquid sits on the plate. Brown staining is visible on the top plate near the beaker, and dark spots and residue are visible on the control panel.\n\nThe control panel shows a red LED digital display reading \"100\" with \"°C\" printed beside it. The left dial is labeled \"HEAT,\" with \"OFF\" marked at the bottom of its scale. The right dial is labeled \"STIR,\" with scale numbers 2, 6, 10 and 12 and \"OFF\" marked at the bottom. The brand name \"CIMAREC\" is printed on the panel. Partially legible text on a device at the upper left of the photo appears to read \"LabLine\" and \"Orbit.\" The beaker has graduated markings, but they are not legible. A white paper towel is visible at the right edge.\n\nThe slide's bottom-right corner shows the logo and text \"INTERNATIONAL SEMINAR.\"", "n_tokens": 249, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-40-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 40, "text": "Insanitary Condition Example\n\nPhotograph of a cleanroom. A person in a light blue disposable gown and hood stands in the center, facing away from the camera. Their face is covered by a gray rectangle with small text reading \"(b)(6)\". Between the bottom of the gown and blue shoe covers, the person's bare legs are visible. The legs are the focus of the caption.\n\nOther visible items: a white folding chair at left; a workbench at left with a small instrument and cables; a glass-fronted cabinet or hood with a window; a glass door in the background; a stainless steel work surface at right holding a white analytical balance with a digital display and a glass draft shield; and a beige tiled floor.\n\nText on the slide, right of the photo: \"Gowned employee working in the cleanroom, exposing legs\"", "n_tokens": 180, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-41-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 41, "text": "Insanitary Condition Example\n\nThe slide contains one photograph on the left. It shows a person in a light blue disposable gown and a light blue bouffant hair cover, bent forward over a stainless steel work surface. The gown is over a patterned top, and the person wears light gloves. Above the work surface is a stainless steel hood with a gooseneck lamp. A color-coded control panel with several labeled segments sits on the left side of the surface. A white spray bottle is at the lower left edge. On the right is a wire shelving unit holding blue bins and white packaged items. Cables run along the floor below the bench.\n\nText on the right side of the slide reads: \"Poor personnel practices – leaning into ISO-5\"\n\n\"Average normal human sheds about 37 million CFU/hour\"\n\nThe bottom right corner shows the International Seminar logo. The slide has no charts, tables, or diagrams, and no axis labels, legend entries, or other numbers beyond the 37 million CFU/hour figure and the ISO-5 reference in the text above.", "n_tokens": 220, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-42-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 42, "text": "Insanitary Condition Example\n\nA black-and-white, high-contrast photograph shows a countertop-style toaster oven on a light-colored shelf or cart. The oven has a dark front panel with two round dials on the right side and a small rectangular slot or display area on its front. A thin wire or probe extends upward from the top of the oven. To the left is a dark vertical post or door frame, and a door handle is partly visible at the left edge. Behind the oven, on a higher shelf or wall-mounted surface, is a grey electronic device with a vent grille on top and a cord running down toward the oven. A partial label on the device is not legible. On the right side of the shelf is a dark rectangular object with a small label, and beyond it is a black device with a label that is not legible. Below the shelf are tangled black cables and a dark box with a keypad-like panel. No numbers or readable chart labels appear in the photograph.\n\nText to the right of the photograph reads: \"Toaster oven used to dry heat sterilize and depyrogenate glassware; oven was not capable of reaching high enough temperature to be effective.\"\n\nIn the bottom right corner is the International Seminar logo, with the words \"INTERNATIONAL SEMINAR\" beside a stylized blue and gold molecular graphic.", "n_tokens": 278, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-43-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 43, "text": "Insanitary Condition Example\n\nThis slide has a text block and two photographs.\n\nText block, upper right: \"Observed conditions: Stain due to product which had exploded due to excessive pressure applied when forcing product through a sterilizing filter. The device used to force through filter was a non-sterilized caulking gun.\"\n\nLeft photograph: A laboratory bench scene. A red oval outlines a caulking gun mounted on a black stand, with its barrel pointing upward and a cylindrical tube visible. Behind it are light blue plastic bins holding small items, each with a white label. To the left are electronic instruments and a white box. On the right is a sterilizer or oven-type unit with a control panel showing a blue display and a small glass door. A date stamp in the lower right of the photo reads \"03/05/2013.\"\n\nRight photograph, lower right: A close-up of a light-colored mesh or perforated panel with a brownish stain near its center. A partial date stamp in the lower right corner reads \"03/\" and is cut off.\n\nBottom right corner: International Seminar logo.", "n_tokens": 232, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-44-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 44, "text": "Insanitary Condition Example\n\nThe slide has one photograph and one text block. The photograph shows a hand holding a yellow plastic bag of coffee filters against a light background with a wire shelf and dark items at the left edge. The bag's top brand word is partly obscured by the hand. The visible brand text is \"& Simple\" in black, with the ampersand on a red background. A red banner across the bag reads \"#4 COFFEE FILTERS.\" Below that is a black \"DG\" logo and a red box reading \"40 FILTERS.\" Small print on the bag reads \"cone-style for 0-12 cup coffeemakers\" and \"100% biodegradable.\" The bag also shows \"2.06 IN (5.24 cm) BASE.\"\n\nText block to the right of the photo: \"Coffee filters used to filter particulates in suspensions prior to filling and autoclaving.\"\n\nBottom right corner: International Seminar logo with the text \"INTERNATIONAL SEMINAR.\"", "n_tokens": 206, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-45-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 45, "text": "Insanitary Condition Example\n\nPhotograph of the interior of a compartment with a white wall on the left and a light gray textured surface in the center. A small brown insect lies on the gray surface, with thin legs or antennae visible around it, and a few small dark specks are nearby. On the right is a teal-green plastic piece with two visible screw holes. A white rod or tube runs diagonally across the lower part of the photo. No numbers, chart axes, or legends appear.\n\nText on right side of slide: \"Insects (vermin) dead or alive\"\n\nLogo at bottom right: \"INTERNATIONAL SEMINAR\"", "n_tokens": 128, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-49-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 49, "text": "Outsourcing Facility Registration\n\nThis slide contains one bar chart with no visible y-axis title or x-axis title. The vertical axis runs from 0 to 90 in increments of 10. The horizontal axis lists the categories FY 2015, FY 2016, FY 2017, and FY 2018. The legend shows a blue bar for \"Total Outsourcing Facilities Registered\" and a red bar for \"Outsourcing Facilities Registered at End of FY.\"\n\nData labels, by fiscal year (blue bar, then red bar):\nFY 2015: Total Outsourcing Facilities Registered = 64; Outsourcing Facilities Registered at End of FY = 55\nFY 2016: Total Outsourcing Facilities Registered = 68; Outsourcing Facilities Registered at End of FY = 64\nFY 2017: Total Outsourcing Facilities Registered = 77; Outsourcing Facilities Registered at End of FY = 71\nFY 2018: Total Outsourcing Facilities Registered = 76; Outsourcing Facilities Registered at End of FY = 74\n\nImage: a logo in the lower right corner with the text \"INTERNATIONAL SEMINAR.\"", "n_tokens": 227, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-50-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 50, "text": "Stakeholder Engagement\n\nDiagram: Organizational chart. A top box reads \"Compounding Program.\" Three connecting lines run from it to three boxes arranged side by side beneath it, from left to right:\n1. \"Compounding Policy\"\n2. \"Inspections and Enforcement\"\n3. \"Stakeholder Engagement.\" This box is outlined in yellow and is the only box highlighted.\n\nLogo at bottom right: \"International Seminar,\" with a small network-style graphic in blue and gold.", "n_tokens": 96, "kind": "vision"}
{"chunk_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update-56-1", "doc_id": "PCCA_InternationalSeminarOn102518_JAD_100418_stats_update", "page": 56, "text": "Slide title: THANK YOU / ANY QUESTIONS?\n\nThe slide has a light gray background with a vertical blue bar and thin parallel lines along the left edge. It contains two centered lines of black uppercase text: \"THANK YOU\" near the top, and \"ANY QUESTIONS?\" lower down, with a blank space between them.\n\nIn the bottom-right corner is a logo. A stylized icon of connected nodes in blue and yellow sits to the left of the text \"INTERNATIONAL SEMINAR,\" with \"INTERNATIONAL\" in blue above \"SEMINAR\" in dark blue.\n\nThe slide contains no charts, tables, diagrams, or other images. The logo reads \"International Seminar,\" not FDA.", "n_tokens": 136, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-0-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 0, "text": "2021 PDA/FDA JOINT REGULATORY CONFERENCE\n\nThe slide has a bright blue gradient background. The text \"pda.org/2021pdafda\" appears in the upper right. The left side shows the PDA logo (Parenteral Drug Association, a globe emblem) and the title in white text. A blue box at the lower left reads \"CONNECTING PEOPLE SCIENCE AND REGULATION.\"\n\nThe right side has a flat illustration of Washington, D.C. landmarks in blue and red. It includes the U.S. Capitol dome in blue on the left, a red obelisk on the right that resembles the Washington Monument, a red domed building with columns in the center that resembles the Jefferson Memorial, a blue colonnaded building in the background, and a red classical building with columns at the upper right. A small figure stands in the entrance of the red central building.\n\nLower right text: \"27-29 SEPTEMBER | LIVE. INTERACTIVE. ONLINE.\" Below it: \"EXHIBITION: 27-29 SEPTEMBER\" and \"#PDAFDA.\"\n\nThe slide contains no charts, tables, or diagrams with axes, legends, or data values.", "n_tokens": 231, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-1-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 1, "text": "Patrizia Cavazzoni, MD\n\nDirector\nCenter for Drug Evaluation and Research\nU.S. Food and Drug Administration\n\nThe slide has a red bar across the top and a blue gradient bar across the bottom. The bottom bar reads \"2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER.\" The slide contains no charts, tables, diagrams, or images other than the logos.", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-2-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 2, "text": "Pandemic Response Highlights\n\nThis slide has no charts, tables, diagrams, or images beyond text. The slide contains a red bar across the top, a white main area with the title centered, and a blue footer band. The footer reads \"2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER.\" The PDA logo appears in the footer.", "n_tokens": 76, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-6-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 6, "text": "Shortage Mitigation\n\nChart: Total Prevented US Drug Shortages Per Year. This is a stacked vertical bar chart showing the number of prevented US drug shortages for each calendar year from 2010 to 2020. Bars are stacked by center: CDER (blue, bottom segment) and CBER (red, top segment).\nY-axis label: \"Number of Prevented Shortages\" (no units given), scale 0 to 300 in increments of 50.\nX-axis label: \"Calendar Year,\" with years 2010 through 2020.\nLegend: blue square = CDER; red square = CBER.\nNo data labels are printed on the bars. Values below are approximate, read from bar heights:\n- 2010: about 39 total (all CDER; no visible CBER segment)\n- 2011: about 195 total (all CDER)\n- 2012: about 281 total (all CDER)\n- 2013: about 170 total (all CDER)\n- 2014: about 100 total (all CDER)\n- 2015: about 143 total (all CDER)\n- 2016: about 126 total (CDER about 114; CBER about 12)\n- 2017: about 136 total (CDER about 118; CBER about 18)\n- 2018: about 166 total (CDER about 147; CBER about 19)\n- 2019: about 159 total (CDER about 141; CBER about 18)\n- 2020: about 199 total (CDER about 178; CBER about 21)\n\nCaption below chart: \"Communications with manufacturers and others helps prevent drug shortages\"\n\nFooter text: \"2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER\"", "n_tokens": 331, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-7-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 7, "text": "Understanding Shortages\n\nPercentage of Drugs Newly in Shortage by Reason, 2013-2017\n\nThis is a horizontal bar chart. It shows the share of drugs newly in shortage, by reason. The chart has no visible axis titles or legend. Each bar is labeled with its category name on the left and its percentage on the right. The bars are in different colors.\n- Quality Issues: 62%\n- Unknown: 18%\n- Increase in Demand: 12%\n- Natural Disaster: 5%\n- Production Discontinuation: 3%\n\nCaption below the chart: \"Most drugs in shortage were experiencing supply disruptions, with a majority caused by quality issues.\"\n\nFooter text: \"2021 PDA/FDA Joint Regulatory Conference | 27-29 September\"", "n_tokens": 147, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-9-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 9, "text": "Manufacturing Quality\n\nThis slide has a plain white background with a red band across the top and a blue gradient band across the bottom. The title \"Manufacturing Quality\" is centered in large black text. The bottom band reads \"2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER,\" with the PDA logo at the lower left. The slide contains no charts, tables, diagrams, or other images.", "n_tokens": 82, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-10-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 10, "text": "Challenges of the COVID-19 Pandemic for Drug Manufacturing\n\nBold heading text: Long-existing quality issues are now magnified\n\nBullet points:\nInformation about current state of drug manufacturing and distribution\nSupply chain vulnerabilities\nShortages due to manufacturing and distribution issues\n\nImage: A large circular illustration of a coronavirus particle on a dark gray background. The particle has a gray, textured spherical body covered with many red, crown-like spike projections. Some small orange and yellow dots are visible on the surface. The image is cut off at its left edge by a red band.\n\nFooter text: 2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER", "n_tokens": 132, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-11-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 11, "text": "Supply Constraints\n\nThe slide has a centered statement in dark gray text: \"The supply chain supporting the manufacture of FDA-regulated products has become constrained at multiple levels during the COVID19 public health emergency.\" The words \"multiple levels\" are underlined.\n\nThe slide contains a diagram of five icons connected by arrows that point left to right. From left to right, the icons show: a hexagonal molecular-style structure, a rack of test tubes, a factory with a tall cylinder and pill-shaped icon beside it, a closed cardboard box, and a hospital bed with a heart-rate monitor on the wall above it.\n\nBelow the chain is a rectangular box containing four labeled icons: \"personnel\" (a group of people with a lightning-bolt symbol above them), \"materials\" (an ore-filled mine cart), \"services\" (a wrench), and \"equipment\" (a front-loading washing machine). Four blue arrows rise from a single point at the bottom center of this box and point to the first, second, third, and fourth supply-chain icons (the molecule, test tubes, factory, and box).\n\nNo chart axes, units, or numerical values appear on the slide.\n\nFooter text in the bottom bar reads: \"2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER.\"", "n_tokens": 274, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-19-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 19, "text": "Guidance for Non-sterile Manufacturers\n\nThis slide has a white background with a red bar across the top and a blue gradient bar along the bottom. The title is centered in large black text. The bottom bar shows the logos of the FDA and PDA, along with the event text \"2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER.\" The slide contains no charts, tables, diagrams, or other images.", "n_tokens": 85, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-20-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 20, "text": "Microbiological Hazards in Non-Sterile, Water-Based Products\n\nThis slide shows a screenshot of an FDA web page. It contains no charts, tables, diagrams, or graphs.\n\n Page headline: \"FDA advises drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, water-based drug products\"\n\nShare buttons: Share, Tweet, LinkedIn, Email, Print\n\nLeft sidebar, \"Drug Safety and Availability\" menu: Information about Nitrosamine Impurities in Medications (partly blurred); Drug Alerts and Statements; Medication Guides; Drug Safety Communications; Drug Shortages; FDA Drug Safety Podcasts; Information by Drug Class; Medication Errors Related to CDER-Regulated Drug Products; Postmarket Drug Safety Information for Patients and Providers\n\nRight margin: \"Content current as of: 07/07/2021\"\n\nBody text:\n\n\"(7/7/2021) The FDA advises drug manufacturers of non-sterile, water-based drug products that Burkholderia cepacia complex (BCC or B. cepacia) continues to pose a risk of contamination. BCC is a group of gram-negative bacteria comprising more than 20 species that has been linked to multiple instances of opportunistic infections. For example, Paroex® Chlorhexidine was recalled in 2020 due to objectionable microbial contamination including the BCC species B. lata. Inadequate design, control, or maintenance of pharmaceutical water systems have led to contamination with BCC and other water-borne opportunistic pathogens. \"\n\n\"Patients exposed to BCC contamination may be at an increased risk for illness or infection, especially patients with compromised immune systems or who are otherwise susceptible to infection. In 2016, severe BCC infections occurred when contaminated docusate oral solution was used in intubated children and other compromised patients. Repeated recalls of nonsterile antiseptics, such as povidone iodine, benzalkonium chloride, and chlorhexidine gluconate, have occurred in the U.S. and overseas. These drugs may be used in hospitals when caring for patients who are often particularly vulnerable due to their medical conditions.\"\n\n\"It is essential that manufacturing facilities, equipment, and processes are designed to prevent contamination and strict sanitary standards are continually followed. There is a long history of product recalls due to BCC contamination traced back to deviations from current good manufacturing practice (CGMP) requirements.", "n_tokens": 503, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-20-2", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 20, "text": "\"\n\n\"In light of these BCC contamination incidents, the FDA is reminding drug manufacturers to:\" (text ends here on the slide)\n\n Hyperlinked words: \"recalled\" and \"current good manufacturing practice (CGMP) requirements\"\n\nFooter banner: \"2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER\"", "n_tokens": 68, "kind": "vision"}
{"chunk_id": "PDA_FDA_Slides2021_Cavazzoni-22-1", "doc_id": "PDA_FDA_Slides2021_Cavazzoni", "page": 22, "text": "Warning Letter Trends\n\nThis slide has a plain white background with a red bar across the top and a blue gradient bar across the bottom. The only text is the title, centered in large black type. There are no charts, tables, diagrams, or images.\n\nThe bottom bar reads \"2021 PDA/FDA JOINT REGULATORY CONFERENCE | 27-29 SEPTEMBER.\"", "n_tokens": 71, "kind": "vision"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-0-1", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 0, "text": "Bridging Justifications: Supporting the Safety of Excipients in Generic Drug Products\n\nPresenter details: Robert T. Dorsam, Ph.D., Office of Generic Drugs (OGD), Division of Clinical Review (DCR), Pharmacology/Toxicology Team Leader.\n\nThis slide contains no charts, tables, diagrams, or images other than the FDA logo, which is skipped.", "n_tokens": 83, "kind": "vision"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-1-1", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 1, "text": "Disclaimer\n\nThe slide contains a single block of italic text, centered on the slide, reading: \"The opinions expressed in this presentation are those of the speaker and may not reflect the position of the U. S. Food and Drug Administration.\"\n\nThere are no charts, tables, diagrams, or images on this slide.", "n_tokens": 66, "kind": "vision"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-2-1", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 2, "text": "Outline\n\nExcipient safety review in generic drug applications\n\nBridging justifications for excipients in generic drugs\n– What is their utility?\n– What are important factors to consider?\n\nCase Studies\n– Excipient grade, dose, duration, route of administration, patient population", "n_tokens": 57, "kind": "vision"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-14-1", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 14, "text": "Case Studies\n\nCases are a composite of past experience\n- Highlight important elements in bridging justifications\n\nCase 1: Bridging excipient grade and amount\nCase 2: When context differs (duration, route)\nCase 3: Grade and patient population\nCase 4: Bridging a route of administration", "n_tokens": 60, "kind": "vision"}
{"chunk_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products-26-1", "doc_id": "Presentation_Bridging_Justifications_Supporting_the_Safety_of_Excipients_in_Generic_Drug_Products", "page": 26, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images, and no text beyond the logo, which is omitted as instructed.", "n_tokens": 33, "kind": "vision"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-0-1", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 0, "text": "CDER 2016 Update for Rare Diseases\n\nRichard Moscicki, M.D.\nDeputy Center Director for Science Operations\nCDER, FDA\n\nThe slide has no charts, tables, diagrams, or other images beyond the text above.", "n_tokens": 45, "kind": "vision"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-2-1", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 2, "text": "Predicting the Future of Rare Disease Drug Development: Orphan Designation Applications\n\nThis slide contains a line chart, a table, and two arrows.\n\nLine chart: The chart plots counts by year. The y-axis is labeled with numbers from 0 to 700 in increments of 100, with no unit label. The x-axis is labeled \"Year\" and shows years from 1983 to 2016, one label per year. The legend has two entries: \"No. Received,\" a blue line with diamond markers, and \"No. Designated,\" a red line with square markers. Both lines start near zero in the early years and rise over time. Parts of the lines after about 2013 are dashed. The chart has these labels:\n- \"582\" at the right end of the blue line, which is the No. Received value for 2016.\n- \"333\" at the right end of the red line, which is the No. Designated value for 2016.\n\nTwo blue arrows point down at the chart. One is near 2002 and the other is near 2008. They sit above the lines and have no text labels.\n\nTable: The table is inside the chart area in the upper left. It has three columns: a time period, \"Average # Received,\" and \"Average # Designated.\" Its rows are:\n- 1983-2001: Average # Received 82; Average # Designated 59\n- 2002-2008: Average # Received 173; Average # Designated 119\n- 2009-2016: Average # Received 374; Average # Designated 248\n\nFooter text at the bottom right reads: \"Office of Orphan Products Development.\"", "n_tokens": 323, "kind": "vision"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-3-1", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 3, "text": "The slide has no visible title.\n\nThe slide contains one bullet point: \"Orphan Drug Approvals now greater than 40% of approvals for new molecular entities in 2015 and 2016.\"\n\nThe slide has no charts, tables, diagrams, or images. The footer reads \"www.fda.gov.\"", "n_tokens": 62, "kind": "vision"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-4-1", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 4, "text": "CDER Novel Orphan Drug Approvals CY 2014-2016*\n\nFootnote: \"* as of 31 December 2016\"\n\nChart: Vertical bar chart of CDER novel drug approvals by year. The y-axis runs from 0 to 50 in increments of 10, with no axis title visible. The x-axis shows the years 2014, 2015, and 2016. The legend, in the upper right, has three entries: TOTAL (solid blue bar), Orphan (solid red bar), and Orphan Licensed First in US (red hatched bar).\n\nValues labeled on the bars:\n- 2014: TOTAL 41; Orphan 17; Orphan Licensed First in US 11\n- 2015: TOTAL 45; Orphan 21; Orphan Licensed First in US 14\n- 2016: TOTAL 22; Orphan 9; Orphan Licensed First in US 8", "n_tokens": 164, "kind": "vision"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-5-1", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 5, "text": "Expediting Rare Diseases Drug Development\n\nSlide body text: \"Programs have been developed to target serious diseases with unmet medical needs when a new treatment could provide meaningful clinical benefit\"\n\nFooter citation: \"Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics, May 2014\"\n\nThe slide contains no charts, tables, diagrams, or other images beyond the FDA logo, which is omitted here.", "n_tokens": 83, "kind": "vision"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-12-1", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 12, "text": "Flexible Clinical Development Programs\n\nSubtitle: CDER NME approvals 2008-2016\n\nTable with the column headings \"NOVEL ENDPOINTS\", \"Yes N=38\", and \"No N=270\". Each row gives the percentage in the Yes and No columns for the listed group.\n\nRow: RARE, n=113. Yes 22%. No 78%.\nRow: Oncology (under RARE). Yes 2%. No 98%.\nRow: Non-Oncology (under RARE). Yes 44%. No 56%.\nBlank separator row.\nRow: NON-RARE, N=195. Yes 7%. No 93%.\nRow: Oncology (under NON-RARE). Yes 0%. No 100%.\nRow: Non-Oncology (under NON-RARE). Yes 7%. No 93%.", "n_tokens": 175, "kind": "vision"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-18-1", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 18, "text": "Targeted APs Trending Up Over Time\n\nThis slide contains one table titled \"CDER Targeted Therapy NME/BLA Approvals.\" The table's column group header reads \"Targeted Therapies, % of Total,\" with three sub-columns: All, Rare, and Common. The first column is labeled \"Year.\" The table shows the percentage of targeted therapies among total approvals for each period:\n\n1990-1992: All ~8%; Rare ~30%; Common ~2%\n2000-2002: All ~10%; Rare ~45%; Common ~5%\n2010-2014: All ~25%; Rare ~45%; Common ~12%", "n_tokens": 140, "kind": "vision"}
{"chunk_id": "Presentation_CDER_2016_Update_for_Rare_Diseases-23-1", "doc_id": "Presentation_CDER_2016_Update_for_Rare_Diseases", "page": 23, "text": "RPD Requests and Determinations\n\nThis slide contains one line chart titled \"RPD Requests and Determinations.\" The chart has no axis titles or units printed on it. The vertical axis is numeric, running from 0 to 35 in steps of 5. The horizontal axis shows the years 2012, 2013, 2014, 2015, and 2016.\n\nThe legend has two entries. \"RPD Requests\" is a blue line with diamond markers. \"RPD Designations\" is a red line with square markers. Beside the legend is the note \"(Includes Designations and Consults).\"\n\nValues read from the chart:\nRPD Requests: 2012 about 0; 2013 about 5; 2014 about 19; 2015 about 33; 2016 about 30.\nRPD Designations: 2012 about 0; 2013 about 2; 2014 about 8; 2015 about 22; 2016 about 9.\n\nFooter text in the lower right reads \"Data as of September 15, 2016.\" The lower center shows the web address \"www.fda.gov.\"", "n_tokens": 203, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-0-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 0, "text": "FDA's Role in Confronting the Opioid Epidemic\n\nDouglas C. Throckmorton, MD\nDeputy Director for Regulatory Programs\nCDER, FDA\n\nAlliance for Balanced Pain Management\n\nNovember 14, 2017\n\nThis slide has no charts, tables, diagrams, or images beyond text.", "n_tokens": 53, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-1-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 1, "text": "Slide title: None. The slide has no separate title.\n\nMain text: \"The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA\"\n\nThere are no charts, tables, diagrams, or other images on this slide.", "n_tokens": 55, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-4-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 4, "text": "Overdose Death Rates\n\nThis slide has two choropleth maps of the United States, side by side, with the year labeled above each map. Each map shows counties colored by estimated age-adjusted death rate per 100,000. Each map includes inset maps of Alaska (lower left) and Hawaii (lower center).\n\nLeft map: Year 1999. Legend title: \"Estimated Age-adjusted Death Rate per 100,000\". Legend entries, with colors from purple to maroon: 0-2; 2.1-4; 4.1-6; 6.1-8; 8.1-10; 10.1-12; 12.1-14; 14.1-16; 16.1-18; 18.1-20; >20.\n\nRight map: Year 2014. Legend title: \"Estimated Age-adjusted Death Rate per 100,000\". Legend entries, with colors from purple to maroon: 0.0-2.0; 2.1-4.0; 4.1-6.0; 6.1-8.0; 8.1-10.0; 10.1-12.0; 12.1-14.0; 14-16.0; 16.1-18.0; 18.1-20.0; >20.\n\nFooter credit text: \"Designed by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System\"\n\nFooter tagline at lower right: \"Science = Solutions\"", "n_tokens": 318, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-5-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 5, "text": "Opioid Epidemic in Maryland\n\nThe slide has three bullet points:\n- In 2015, 1259 overdose deaths state wide.\n- In first 9 months of 2016, 1468 overdose deaths.\n- Comparing the first 9 months of 2016 to 2015, overdose deaths increased 62%.\n\nBelow the bullets is a map outline of the state of Maryland, filled with the Maryland state flag design. The western and southern portions show the black and gold (yellow) diagonal pattern. The northeastern portion shows the red cross and white field of the flag's upper section. The map has no axis labels, units, or legend.", "n_tokens": 121, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-6-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 6, "text": "Impact of Crisis: Increasing Prenatal Exposure\n\nThis slide contains one line chart with x markers at each data point. The chart has no legend. Its label reads \"Admissions for Newborn Withdrawal Syndromes (Number per 1000 Admissions).\" The x-axis shows years from 2004 to 2013. The y-axis runs from 0 to 35, with tick labels at 0, 5, 10, 15, 20, 25, 30, and 35. The y-axis unit is number per 1000 admissions, as stated in the chart label.\n\nApproximate values read from the line, with no exact labels printed on the chart: 2004 about 7; 2005 about 7.5; 2006 about 7; 2007 about 8; 2008 about 9.7; 2009 about 12.7; 2010 about 17; 2011 about 21.7; 2012 about 25.7; 2013 about 28.\n\nThe source citation at the bottom right reads: Tolia VN, Patrick SW, et al. NEJM 2015;372:2118-2126.", "n_tokens": 206, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-7-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 7, "text": "Impact of Crisis: Infectious Disease Transmission\n\nHIV and Hepatitis C Outbreak Linked to Oxymorphone Injection Use in Indiana, 2015\n\nThe slide has a blue CDC MMWR logo reading \"Centers for Disease Control and Prevention,\" \"MMWR,\" \"Early Release / Vol. 64,\" \"Morbidity and Mortality Weekly Report,\" and \"April 24, 2015.\"\n\nCitation text at lower right: \"Peters et al.,\" \"The New England Journal of Medicine,\" \"2016;375:229-239.\"\n\nThe slide contains no charts, tables, diagrams, or other images.", "n_tokens": 121, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-13-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 13, "text": "The Opioid Crisis: An FDA Priority\n\nBanner text: Take immediate steps to reduce the scope of the epidemic of opioid addiction\n\nBullet points:\n- May 2017: Established an FDA Opioid Policy Steering Committee (OPSC)\n- September 2017: Soliciting public input on how FDA authorities can or should be used to address the crisis", "n_tokens": 69, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-16-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 16, "text": "The Opioid Crisis: FDA's Priorities\n\nThe slide has four blue rounded boxes stacked vertically, each containing one numbered priority in white text:\n\n1. Decreasing Exposure & Preventing New Addiction\n2. Supporting the Treatment of Those With Opioid Use Disorder\n3. Fostering the Development of Novel Pain Treatment Therapies\n4. Improving Enforcement & Assessing Benefit-Risk\n\nThere are no charts, tables, diagrams, or other images beyond the text boxes and the FDA logo, which is omitted here.", "n_tokens": 98, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-29-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 29, "text": "Thank You\n\nThe slide shows a photograph of a large multi-story brick building with white stone trim. At the center is a tall, pale stone entrance with vertical columns and a flat glass-roofed canopy over the doorway. Rows of rectangular windows extend across both wings. A curved lawn sits in front of the entrance, bordered by a low, curved wall of pinkish-gray granite with small recessed lights along its base. A light-colored paved walkway curves around the lawn to a road at the right, where a black SUV is parked. Mature green trees stand near the building and along the right edge, and a thin white contrail crosses a clear blue sky. The slide contains no charts, tables, diagrams, or numerical data.", "n_tokens": 148, "kind": "vision"}
{"chunk_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic-30-1", "doc_id": "Presentation_Douglas_Throckmorton_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 30, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images. The only element is a logo, which is omitted as requested.", "n_tokens": 33, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-0-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 0, "text": "FDA Perspective on Abuse-Deterrent Opioid Development\n\nPresenter: Douglas C. Throckmorton, MD, Deputy Director for Regulatory Programs, CDER, FDA\n\nEvent: CBI Abuse Deterrent Formulations Summit\n\nDate: March 7-8, 2017\n\nThis slide has no charts, tables, diagrams, or other images.", "n_tokens": 65, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-1-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 1, "text": "No separate slide title appears. The slide's main text reads: \"The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA\"\n\nThis slide contains no charts, tables, diagrams, or images other than the FDA logo, which is omitted as requested.", "n_tokens": 62, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-2-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 2, "text": "Outline\n\nThe slide is a text outline with no charts, tables, diagrams, or images beyond the FDA logo, which is skipped here. It lists four main bullet points:\n\nBackground on Epidemic\n\nFederal Context for FDA Efforts to Address Prescription Opioid Abuse\n  – Other Federal Efforts\n\nFDA Action Plan\n\nFDA Focus on Abuse-Deterrent Formulations of Opioids", "n_tokens": 69, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-6-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 6, "text": "Overdose Death Rates\n\nThis slide has two choropleth maps of the United States, side by side, showing death rates by county. Each map has an inset of Alaska and Hawaii in the lower left.\n\nLeft map, labeled \"1999\" (large blue text above it). Year label in the map key: \"Year 1999\".\nRight map, labeled \"2014\" (large blue text above it). Year label in the map key: \"Year 2014\".\n\nMap key for both maps, titled \"Estimated Age-adjusted Death Rate per 100,000\". Color swatches with entries, from lowest to highest:\n- 1999 key: 0-2, 2.1-4, 4.1-6, 6.1-8, 8.1-10, 10.1-12, 12.1-14, 14.1-16, 16.1-18, 18.1-20, >20\n- 2014 key: 0.0-2.0, 2.1-4.0, 4.1-6.0, 6.1-8.0, 8.1-10.0, 10.1-12.0, 12.1-14.0, 14-16.0, 16.1-18.0, 18.1-20.0, >20\n\nColor order in the key runs from purple (0-2) through blue, teal, light green, yellow-green, pale yellow, orange, and red, to dark maroon (>20). Each county is shaded by its rate range. The maps show no numeric values for individual counties.\n\nSource note at bottom left: \"Designed by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System.\"\n\nBottom right text: \"Science = Solutions\"", "n_tokens": 382, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-9-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 9, "text": "Increasing Neonatal Abstinence Syndrome\n\nThis slide contains one line chart with a single data series, shown as a black line with x-shaped markers at each year. It has no legend. The chart's inside label reads \"NICU Admissions for NAS (Number per 1000 Admissions).\"\n\nThe vertical y-axis has no separate axis title, but the inside label gives the unit as number per 1000 admissions. Its tick labels run from 0 to 35 in steps of 5.\n\nThe horizontal x-axis shows years labeled 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, and 2013.\n\nApproximate values read from the chart, as points on the line: 2004 about 7; 2005 about 7.5; 2006 about 7; 2007 about 8; 2008 about 9.7; 2009 about 12.6; 2010 about 17; 2011 about 21.7; 2012 about 25.8; 2013 about 28.2.\n\nSource text below the chart reads: \"Source: Tolia VN, Patrick SW, et al. NEJM 2015;372:2118-2126.\"\n\nBottom right branding text reads: \"Science = Solutions.\"", "n_tokens": 237, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-10-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 10, "text": "FDA is a Part of a Larger Governmental Response to Opioids Abuse\n\nThe slide has no charts, tables, diagrams, or images other than the FDA logo, which is omitted as requested.\n\nOffice of the National Drug Control Policy (ONDCP) Plan\n\nHealth and Human Services (HHS) Secretary's Plan", "n_tokens": 63, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-11-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 11, "text": "ONDCP National Drug Abuse Prevention Plan\n\nBulleted text reads: Issued April 2011. Four major areas of focus to reduce prescription drug abuse and other harm from drugs: Education; Monitoring; Proper medication disposal; Enforcement.\n\nOn the right is an image of a document cover. The cover has a small gold emblem at the top, and the title \"EPIDEMIC: RESPONDING TO AMERICA'S PRESCRIPTION DRUG ABUSE CRISIS\" appears in blue capital letters in the center. Below the title is the year \"2011\" in small gray text. At the bottom is a circular government seal with an eagle, and its outer ring text is too small to read clearly.", "n_tokens": 128, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-14-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 14, "text": "FDA Response to Opioids Abuse\n\nThis slide has no charts, tables, diagrams, or images beyond the title text and the logo. The title is centered in large bold black text on a plain white background. The U.S. Food & Drug Administration logo appears in the upper right corner.", "n_tokens": 59, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-17-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 17, "text": "FDA and Abuse-Deterrent Formulations of Opioids\n\nSubtitle: Part of Larger FDA/HHS Efforts to Improve Tools for Pain Management\n\nThis slide has no charts, tables, diagrams, or images beyond the title text and subtitle.", "n_tokens": 51, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-27-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 27, "text": "Thank you\n\nPhotograph of a large brick building with multiple rows of windows and a central limestone-framed entrance with a glass canopy over the doors. In front is a green lawn and a curved light-colored paved walkway bordered by a low pinkish-gray stone wall with small recessed lights. A black SUV is parked on a road to the right, and several leafy green trees stand along the building and roadway. The sky is clear blue with a faint white contrail.\n\nFooter text: www.fda.gov", "n_tokens": 104, "kind": "vision"}
{"chunk_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development-28-1", "doc_id": "Presentation_FDA_Perspective_on_Abuse_Deterrent_Opioid_Development", "page": 28, "text": "No slide title is visible. This slide contains no charts, tables, diagrams, or other images, and no other text or numbers. The only element is the FDA logo, which was omitted as instructed.", "n_tokens": 41, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-0-1", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 0, "text": "FDA's Actions to Address the Opioid Epidemic\n\nPresenter: Douglas C. Throckmorton, MD, Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research, FDA\n\nEvent: CBI Abuse-Deterrent Formulation Summit\n\nDate: March 14, 2018\n\nThis slide is a title slide with no charts, tables, diagrams, or images other than the FDA logo, which is omitted.", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-1-1", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 1, "text": "The slide has no visible title. The only text is a centered disclaimer: \"The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA.\" The slide contains no charts, tables, diagrams, or other images.", "n_tokens": 56, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-4-1", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 4, "text": "Overdose Death Rates\n\nThis slide shows two county-level choropleth maps of the United States, side by side, each with insets for Alaska and Hawaii. The left map is labeled \"1999\" and the right map is labeled \"2014.\" Each county is shaded by its estimated age-adjusted death rate.\n\nLeft map (1999): The legend title reads \"Estimated Age-adjusted Death Rate per 100,000,\" and a small label reads \"Year 1999.\" Legend entries, from lowest to highest: 0-2, 2.1-4, 4.1-6, 6.1-8, 8.1-10, 10.1-12, 12.1-14, 14.1-16, 16.1-18, 18.1-20, >20. Each entry is a color swatch (purple, blue, teal, green, pale yellow, yellow, light orange, orange, red-orange, pink-red, and dark magenta for >20).\n\nRight map (2014): The legend title reads \"Estimated Age-adjusted Death Rate per 100,000,\" and a small label reads \"Year 2014.\" Legend entries, from lowest to highest: 0.0-2.0, 2.1-4.0, 4.1-6.0, 6.1-8.0, 8.1-10.0, 10.1-12.0, 12.1-14.0, 14-16.0, 16.1-18.0, 18.1-20.0, >20. The color scale matches the 1999 legend.\n\nFooter text reads: \"Designed by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System.\"", "n_tokens": 375, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-5-1", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 5, "text": "Impact of Crisis: Increasing Prenatal Exposure\n\nThis slide contains one line chart with markers at each data point. It has no legend.\n\nThe chart's y-axis ranges from 0 to 35, with tick labels at 0, 5, 10, 15, 20, 25, 30, and 35. The text inside the chart reads \"Admissions for Newborn Withdrawal Syndromes (Number per 1000 Admissions).\" The x-axis shows years labeled 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, and 2013.\n\nApproximate values read from the line, which are estimates because no values are printed on the chart: 2004 about 7; 2005 about 7.5; 2006 about 7; 2007 about 8; 2008 about 9.7; 2009 about 12.7; 2010 about 17; 2011 about 21.7; 2012 about 25.7; 2013 about 28.\n\nSource citation printed at the lower right: \"Tolia VN, Patrick SW, et al. NEJM 2015;372:2118-2126.\"", "n_tokens": 213, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-6-1", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 6, "text": "Impact of Crisis: Infectious Disease Transmission\n\nHIV and Hepatitis C Outbreak Linked to Oxymorphone Injection Use in Indiana, 2015. \"HIV\" and \"Hepatitis C\" are highlighted in blue.\n\nThe slide includes the logo of the Centers for Disease Control and Prevention, with \"MMWR\" in large blue letters. Below it are the labels \"Early Release / Vol. 64,\" \"Morbidity and Mortality Weekly Report,\" and \"April 24, 2015.\"\n\nThe citation at lower right reads: Peters et al., The New England Journal of Medicine, 2016;375:229-239.\n\nThe slide contains no charts, tables, diagrams, or other images.", "n_tokens": 135, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-14-1", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 14, "text": "The Opioid Crisis: FDA's Priorities\n\nThe slide contains no charts, tables, diagrams, or photographs. It presents four numbered priorities, each in a dark blue rounded bar with white text:\n\n1. Decreasing Exposure & Prevent New Addiction\n2. Supporting the Treatment of Those With Opioid Use Disorder\n3. Fostering the Development of Novel Pain Treatment Therapies\n4. Improving Enforcement & Assessing Benefit-Risk", "n_tokens": 83, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic-25-1", "doc_id": "Presentation_FDAs_Actions_to_Address_the_Opioid_Epidemic", "page": 25, "text": "Thank You\n\nThis slide has a title, \"Thank You,\" and one photograph. It shows a large multi-story building with red brick facades and light-colored stone trim. A central entrance has a tall, recessed section with vertical windows and a flat glass canopy over the doors. Rows of rectangular windows extend to both sides. Several mature green trees stand in front of and beside the building. In the foreground, a curved paved walkway with light gray pavers wraps around a circular grassy lawn. A low wall of pinkish-gray stone runs along the edge of the lawn, with small rectangular lights set into it. On the right, a dark SUV is parked on a paved road, and a few small trees and light poles are visible. The sky is clear and blue. The slide has no charts, tables, diagrams, or numbers other than the slide number, which is omitted here.", "n_tokens": 181, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-0-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 0, "text": "FDA's Role in Confronting the Opioid Epidemic\n\nDouglas C. Throckmorton, MD\nDeputy Director for Regulatory Programs\nCDER, FDA\n\nCEPOP\nSeptember 18, 2017", "n_tokens": 35, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-1-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 1, "text": "The slide has no separate title. Its main text is a disclaimer: \"The opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA.\"\n\nThe slide contains no charts, tables, diagrams, or other images. The only other element is the FDA logo, which is omitted as requested.", "n_tokens": 70, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-2-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 2, "text": "Overall Message\n\nThe slide contains one bullet point: \"The FDA response to the opioids crisis and the larger Federal efforts reflect the critical nature of the crisis and the human toll it is having.\"\n\nThe slide has no charts, tables, diagrams, or images other than the text.", "n_tokens": 57, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-4-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 4, "text": "Overdose Death Rates\n\nThis slide has two county-level choropleth maps of the contiguous United States, with Alaska and Hawaii shown as separate inset maps. Each map is labeled with a year. Counties are shaded by estimated age-adjusted death rate per 100,000 population.\n\n Left map, labeled \"1999\" (large blue heading above the map; small \"Year 1999\" label in the legend area). Legend title: \"Estimated Age-adjusted Death Rate per 100,000\". Legend entries, from lowest to highest: 0-2, 2.1-4, 4.1-6, 6.1-8, 8.1-10, 10.1-12, 12.1-14, 14.1-16, 16.1-18, 18.1-20, >20. Each entry has its own color swatch, running from purple (lowest) through blue, teal, green, yellow, and orange to red and dark magenta (highest). Visually, most counties in the central and eastern United States are shaded purple and blue, with scattered green, yellow, and orange counties, especially in parts of the West and Southeast.\n\n Right map, labeled \"2014\" (large blue heading above the map; small \"Year 2014\" label in the legend area). Legend title: \"Estimated Age-adjusted Death Rate per 100,000\". Legend entries, from lowest to highest: 0.6-2.0, 2.1-4.0, 4.1-6.0, 6.1-8.0, 8.1-10.0, 10.1-12.0, 12.1-14.0, 14-16.0, 16.1-18.0, 18.1-20.0, >20. The color scale is the same as the 1999 map. Visually, many counties in the western United States and parts of the Appalachian and Southeastern regions are shaded dark red/magenta (>20), while many counties in the Plains and parts of the Northeast are shaded blue, teal, green, and yellow. Alaska's inset shows mixed orange, red, green, and blue counties. Hawaii's inset shows mostly yellow.\n\n Slide title: \"Overdose Death Rates\"\n\nFooter text: \"Designed by L. Rossen, B. Bastian & Y. Chong.", "n_tokens": 491, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-4-2", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 4, "text": "SOURCE: CDC/NCHS, National Vital Statistics System\"\n\nFooter banner text: \"Science = Solutions\"", "n_tokens": 22, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-5-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 5, "text": "HHS Response to Opioid Epidemic\n\nThis slide has no charts, tables, diagrams, or images beyond the title text. The only other visible element is the U.S. Food & Drug Administration logo in the upper right corner, which is omitted per instructions.", "n_tokens": 53, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-6-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 6, "text": "HHS Opioid Strategy\n\nThis slide contains a cycle diagram with five blue rounded boxes arranged in a circle, connected by thin lines. Reading clockwise from the top, the boxes say:\n\n1. Strengthening public health surveillance\n2. Advancing the practice of pain management\n3. Improving access to treatment and recovery services\n4. Targeting availability and distribution of overdose-reversing drugs\n5. Supporting cutting-edge research\n\nThe diagram has no axes, units, legend, or numerical values.", "n_tokens": 94, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-11-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 11, "text": "FDA Response to Opioid Epidemic\n\nThis slide is a title slide. It contains no charts, tables, diagrams, or other images beyond the U.S. Food & Drug Administration logo, which is omitted as requested. The only text on the slide is the title above.", "n_tokens": 55, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-13-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 13, "text": "FDA Opioids Action Plan\n\nText on slide: \"To reverse the epidemic while still providing patients with access to effective relief\"\n\nDiagram: A vertical stack of seven colored rounded rectangles, each with white centered text, listed top to bottom:\n1. Advisory Committees (red)\n2. IR Labeling (green)\n3. Post-market (purple)\n4. REMS (teal)\n5. Abuse Deterrent (orange)\n6. Supporting Treatment (red)\n7. Risk-Benefit (green)", "n_tokens": 102, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-21-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 21, "text": "Thank You\n\nThe slide contains one photograph, with no charts, tables, or diagrams. It shows a multi-story brick building with stone-trimmed vertical window bays and a light stone central section. A covered entrance with a glass-and-metal canopy sits at the center of the facade. In the foreground, a curved paved walkway wraps around a green lawn, bordered by a low pink-gray granite retaining wall with small recessed lights along its face. A dark SUV is parked on the road at the right edge, and several trees stand around the building. The sky is clear blue with a faint white contrail crossing it.", "n_tokens": 127, "kind": "vision"}
{"chunk_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic-22-1", "doc_id": "Presentation_FDAs_Role_in_Confronting_the_Opioid_Epidemic", "page": 22, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images. Its only content is the FDA logo, which was skipped as requested.", "n_tokens": 34, "kind": "vision"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-0-1", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 0, "text": "Center Updates: CDER\n\nDouglas C. Throckmorton MD\nDeputy for Regulatory Programs, CDER FDA\n\nSeptember 12, 2017\n\nFooter: PDA and FDA logos, and the text \"2017 PDA/FDA Joint Regulatory Conference | September 11-13, 2017 | Renaissance Washington, DC Downtown Hotel | Washington, DC\"\n\nThe slide contains no charts, tables, diagrams, or other images.", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-1-1", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 1, "text": "Central Messages\n\nBullet points:\n- Three innovative and ongoing activities chosen\n- Focus on illustrating CDER support for product quality and innovation through\n  - Process improvement\n  - Targeted new resources\n\nFooter text: \"2017 PDA/FDA Joint Regulatory Conference | September 11-13, 2017 | Renaissance Washington, DC Downtown Hotel | Washington, DC\"", "n_tokens": 64, "kind": "vision"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-5-1", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 5, "text": "Conclusions\n\nSupporting innovative manufacturing and controls systems is a priority for FDA\n\nFooter text: 2017 PDA/FDA Joint Regulatory Conference | September 11-13, 2017 | Renaissance Washington, DC Downtown Hotel | Washington, DC\n\nThe slide contains no charts, tables, diagrams, or other images beyond the logos.", "n_tokens": 59, "kind": "vision"}
{"chunk_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017-6-1", "doc_id": "Presentation_The_Collaborative_for_Effective_Prescription_Opioids_quarterly_meeting_on_September_18_2017", "page": 6, "text": "Thank You\n\nThis slide is a photograph of a large multi-story brick building under a clear blue sky. The building has rows of rectangular windows, and its central section is set forward and faced with light stone, with tall vertical window panels and a flat top edge. A dark canopy extends over the entrance at ground level, with columns and a few visible doorways beneath it. Several trees stand in front of and beside the building, and a wide, flat green lawn lies in the foreground. A curved, light-colored paved walkway runs across the lower part of the image, bordered by a low curved wall of pinkish-gray stone with a few small rectangular markers set into its face. On the right, a dark SUV is parked on a paved road that curves past the wall. Thin light streaks of cloud appear in the upper left sky. The slide has no charts, tables, diagrams, or readable numbers or labels other than the title.", "n_tokens": 191, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-0-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 0, "text": "Keynote: Generic Drug Program Update\n\nSally Choe, PhD\nDirector, Office of Generic Drugs\nCenter for Drug Evaluation and Research\nU.S. Food and Drug Administration", "n_tokens": 31, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-1-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 1, "text": "Outline\n\nThe slide is a text-only agenda with no charts, tables, diagrams, or other images. It lists five numbered items:\n\n1. Introduction\n2. Generic Drug Program Overview\n3. Generic Drug User Fee Amendments (GDUFA)\n4. Drug Competition Action Plan (DCAP)\n5. Conclusion", "n_tokens": 61, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-2-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 2, "text": "Introduction\n\nThe slide lists the following affiliations, one per line:\n\nFDA Office of Generic Drugs, CDER\nFDA Office of Study Integrity and Surveillance, Office of Translational Sciences (OTS), CDER\nPAREXEL Consulting\nFDA Office of Clinical Pharmacology, OTS, CDER\nPfizer, Ann Arbor, MI\nBMS, Princeton, NJ\nUniversity of Michigan, Ann Arbor, MI\n\nThere are no charts, tables, diagrams, or images on this slide.", "n_tokens": 96, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-3-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 3, "text": "Generic Drug Program Overview\n\nThis slide has no charts, tables, diagrams, or other images beyond the title text. The title is centered near the top of the slide in large black text on a white background.", "n_tokens": 41, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-6-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 6, "text": "Generic Drug Program\n\nThis slide is a circular collage of seven photographs arranged around the title text \"Generic Drug Program.\" The footer at bottom left reads \"www.fda.gov.\" There are no charts, tables, or diagrams.\n\nTop left: Close-up of pharmaceutical manufacturing equipment with metal machinery and tubing, with orange tablets visible in a clear container.\n\nTop right: A smiling health care worker in teal scrubs, wearing a stethoscope, examines an older woman with short gray hair who is smiling back.\n\nMiddle right: A hand holding an open pill bottle over a blue pill organizer tray, with several pills and capsules, and other amber prescription bottles visible in the background.\n\nBottom right: Two lab workers in white coats and face masks working inside an enclosed laboratory cabinet, handling vials and sample tubes.\n\nBottom center: A close-up of a health insurance form with the printed headings \"MEDICAL INSURANCE\" and \"HEALTH INSURANCE,\" with a stethoscope resting on it.\n\nBottom left: The U.S. Capitol building under a partly cloudy blue sky, with trees and a lawn in front.\n\nMiddle left: The exterior of a brick FDA building with a sign reading \"U.S. Department of Health and Human Services, Food and Drug Administration,\" with trees and a walkway in front.", "n_tokens": 271, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-7-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 7, "text": "Generic Drug User Fee Amendments (GDUFA)\n\nThis slide has no charts, tables, diagrams, or images beyond the title text. The only other element is the FDA U.S. Food & Drug Administration logo, which is omitted as requested.", "n_tokens": 50, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-8-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 8, "text": "GDUFA\n\nReflects negotiated agreements with industry\nGoals based on assessment of program activities\nGDUFA I (2012)\nGDUFA II (2017)\nGDUFA II Commitment Letter (hyperlink)\nwww.fda.gov/GDUFA (hyperlink)", "n_tokens": 52, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-9-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 9, "text": "GDUFA II Features\n\nThe slide is a text list with no charts, tables, diagrams, or images other than the FDA logo in the top right corner, which is omitted here. The list reads:\n\nI. Submission Review Performance Goals\nII. Original ANDA Review Program Enhancements\nIII. Pre-ANDA Program and Subsequent Mid-Review-Cycle Meetings for Complex Products\nIV. DMF Review Program Enhancements\nV. Facilities\nVI. Enhanced Accountability and Reporting (this item is formatted as a hyperlink)", "n_tokens": 103, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-10-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 10, "text": "GDUFA Program Performance\n\nThis slide is a title slide with the heading \"GDUFA Program Performance\" centered in black text on a white background. The U.S. Food & Drug Administration logo appears in the upper right corner. The slide contains no charts, tables, diagrams, or other images.", "n_tokens": 61, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-11-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 11, "text": "ANDA Receipts (Originals)\n\nThis is a vertical bar chart showing ANDA receipts (originals) by fiscal year. The y-axis runs from 0 to 1600 in increments of 200, with no axis title or units visible. The x-axis lists fiscal years FY10, FY11, FY12, FY13, FY14, FY15, FY16, FY17, and FY18. There is no legend. All bars are the same blue color.\n\nPeriod labels appear in red above the chart: \"Pre-GDUFA\" is over FY10 to FY12, \"GDUFA I\" is over FY13 to FY17, and \"GDUFA II\" is over FY18. Two red vertical lines separate these periods, one between FY12 and FY13 and one between FY17 and FY18.\n\nValues printed on the bars, by fiscal year:\nFY10: 813\nFY11: 893\nFY12: 1103\nFY13: 968\nFY14: 1473\nFY15: 539\nFY16: 853\nFY17: 1306\nFY18: 1044", "n_tokens": 251, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-14-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 14, "text": "Regulatory Actions\n\nUnder GDUFA, FDA has committed to take regulatory actions by the goal date:\n1. Approval (AP)\n2. Tentative Approval (TA)\n3. Complete Response Letter (CR or CRL)", "n_tokens": 43, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-15-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 15, "text": "Filing - Refuse to Receive (RTR) (based on cohort year of submission)\n\nThis is a bar chart showing the percentage of submissions refused to receive (RTR), grouped by cohort year of submission. The vertical axis runs from 0 to 30 in increments of 5, with no axis title visible. The horizontal axis shows the fiscal year categories. The legend reads \"% RTR\" and corresponds to the blue bars. A red downward arrow points to the FY 18 bar.\n\nValues shown on the bars:\n- FY 15: 19\n- FY 16: 25\n- FY 17: 13\n- FY 18: 8.3\n\nThe red arrow above the FY 18 bar highlights that bar's value of 8.3.", "n_tokens": 153, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-16-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 16, "text": "Approval and Tentative Approval Totals\n\nThis slide contains one chart, a stacked bar chart. The vertical axis runs from 0 to 1200 in increments of 200, with no unit label visible. The horizontal axis lists fiscal years FY 10, FY 11, FY 12, FY 13, FY 14, FY 15, FY 16, FY 17, and FY 18. The legend shows AP as a blue square and TA as a red square. Each bar shows the AP value in blue at the bottom and the TA value in red on top.\n\nValues by fiscal year (AP, TA):\nFY 10: AP 426, TA 139\nFY 11: AP 458, TA 139\nFY 12: AP 517, TA 102\nFY 13: AP 440, TA 95\nFY 14: AP 409, TA 91\nFY 15: AP 492, TA 120\nFY 16: AP 651, TA 184\nFY 17: AP 763, TA 174\nFY 18: AP 781, TA 190\n\nTwo red vertical lines divide the chart. The first sits between FY 12 and FY 13, and a red label \"GDUFA I\" appears above the bars between the two lines. The second sits between FY 17 and FY 18, and a red label \"GDUFA II\" appears above the FY 18 area, to the right of the second line.", "n_tokens": 291, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-17-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 17, "text": "GUDFA Performance – Originals (new applications)\n\nThis is a bar chart showing GUDFA performance for original new applications across four fiscal years. A black step line labeled \"GDUFA Goal\" is drawn over the bars.\n\nThe vertical axis runs from 0 to 100, with gridlines and labels at 0, 20, 40, 60, 80, and 100. No axis title or units are shown. The horizontal axis labels are FY 15, FY 16, FY 17, and FY 18. No legend is shown.\n\nBar values, shown above each bar:\n- FY 15: 93\n- FY 16: 98\n- FY 17: 96\n- FY 18: 96\n\nText inside each bar:\n- FY 15: \"15 months\"\n- FY 16: \"15 months\"\n- FY 17: \"10 months\"\n- FY 18: \"8-10 months\"\n\nGDUFA Goal line (black step line, labeled \"GDUFA Goal\"): approximately 60 across FY 15, approximately 76 across FY 16, and approximately 91 across FY 17 and FY 18, as read from the y-axis positions.", "n_tokens": 238, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-19-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 19, "text": "Product-Specific Guidance\n\nThis slide contains one bar chart.\n\nChart title: Posted Product Specific Guidance by Fiscal Year\n\nType: stacked bar chart with two segments per bar, plus a total label above each bar.\n\nY-axis label: Number of Guidances Posted. Scale runs from 0 to 300 in increments of 50.\n\nX-axis labels: FY 13, FY 14, FY 15, FY 16, FY 17, FY 18.\n\nLegend entries:\n- Revised Draft Guidance (light blue, upper segment)\n- New Draft Guidance (dark navy, lower segment)\n\nData labels, by fiscal year (New Draft Guidance segment / Revised Draft Guidance segment / total):\n- FY 13: New Draft Guidance 61; Revised Draft Guidance 41; total 102\n- FY 14: New Draft Guidance 78; Revised Draft Guidance 56; total 134\n- FY 15: New Draft Guidance 154; Revised Draft Guidance 69; total 223\n- FY 16: New Draft Guidance 94; Revised Draft Guidance 41; total 135\n- FY 17: New Draft Guidance 108; Revised Draft Guidance 86; total 194\n- FY 18: New Draft Guidance 136; Revised Draft Guidance 72; total 208\n\nPage number visible in the lower right corner: 20", "n_tokens": 250, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-20-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 20, "text": "Pre-ANDA Meetings for Complex Generics\n\nThe slide has no charts, tables, diagrams, or images other than the FDA logo, which is omitted here.\n\nText content:\n- Pre-ANDA meetings have new GDUFA II commitments and timelines\n- Provide opportunities to discuss new or alternative bioequivalence approaches for complex products\n  - Focus on content not covered by PSGs", "n_tokens": 77, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-21-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 21, "text": "Pre-ANDA Meeting Requests\n\nThis is a bar chart titled \"Pre-ANDA Meeting Requests.\" The vertical y-axis is labeled \"Number of Requests Received,\" with tick marks from 0 to 90 in increments of 10. The horizontal x-axis is labeled \"Fiscal Year\" and shows the categories FY13, FY14, FY15, FY16, FY17, and FY18. The chart has no legend. Each bar is printed with its value above it.\n\nValues shown for each fiscal year:\n- FY13: 21\n- FY14: 14\n- FY15: 30\n- FY16: 32\n- FY17: 27\n- FY18: 83", "n_tokens": 148, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-22-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 22, "text": "Pre-ANDA Meeting Requests – Fiscal Year 2018\n\nThis slide contains one table with three columns: Task, Target, and Actual.\n\nRow 1: Task \"Grant or Deny Meeting within 30 Days\"; Target 90%; Actual 99%.\n\nRow 2: Task \"Hold Meeting or Written Response within 120 Days\"; Target 60%; Actual 100%.\n\nRow 3: Task \"Send Meeting Minutes within 30 Days\"; Target N/A; Actual 100%.", "n_tokens": 93, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-25-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 25, "text": "Additional Fiscal Year 2018 Program Highlights\n\nThe slide contains a bulleted list of three items, each shown as a blue underlined hyperlink:\n\n- Timely and successful update of Orange Book to reflect marketing status updates as required by FDARA\n- Competitive generic therapy (CGT) designation and exclusivity requests\n- Drug Competition Action Plan (DCAP)\n\nThe slide has no charts, tables, diagrams, or other images.", "n_tokens": 83, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-26-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 26, "text": "Drug Competition Action Plan (DCAP)\n\nThe slide has no charts, tables, diagrams, or images beyond the title text. It contains only the title \"Drug Competition Action Plan (DCAP)\" centered on a white background, with the FDA logo in the upper right corner (omitted per instructions).", "n_tokens": 61, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-28-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 28, "text": "Improving the Efficiency of Generic Drug Development, Review, and Approval\n\nThe slide contains three bulleted hyperlinked items:\n\nGood ANDA Submission Practices, followed by the text \"Draft Guidance\"\n\nGood ANDA Assessment Practices, followed by the text \"MAPP\"\n\nANDA Submissions--Amendments to Abbreviated New Drug Applications Under GDUFA, followed by the text \"Final Guidance\"\n\nThere are no charts, tables, diagrams, or other images on this slide.", "n_tokens": 91, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-31-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 31, "text": "Slide title: Encouraging Development of Generic Drugs in Markets with Limited Competition\n\nThis slide contains no charts, tables, diagrams, or images. It has two bulleted items, each with underlined blue hyperlinked text:\n\n1. \"List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic\" (hyperlinked), followed by the text \"(Published in June 2017; updated biannually)\".\n2. \"Addition of patent submission dates\" (hyperlinked), followed by the text \"to the Orange Book where available (Nov. 2017)\".", "n_tokens": 121, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-34-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 34, "text": "Generic Drug Program\n\nThis slide is a circular diagram with six photographs arranged around the central title \"Generic Drug Program.\" Each photo sits in a blue-bordered frame on a light purple circular band. The footer shows the website www.fda.gov.\n\nGoing clockwise from the top left:\n\nTop left: A close-up of pharmaceutical manufacturing equipment. Orange tablets or pills move along a metal conveyor or chute in a machine with valves and pipes.\n\nTop right: A smiling health care provider in teal scrubs uses a stethoscope to listen to the chest of a smiling older woman with short gray hair, who wears a white top.\n\nMiddle right: A close view of a person's hands in a white lab coat sorting medications. Pill bottles, loose pills, and a blue divided tray with colored capsules and tablets are visible, along with a yellow-and-white package.\n\nBottom right: Two people in white lab coats and face masks work inside an enclosed laboratory hood. One person is handling vials or test tubes, and the other stands beside them.\n\nBottom center: A medical insurance form with the printed words \"MEDICAL INSURANCE\" and \"HEALTH INSURANCE,\" with a stethoscope resting on it and a pen lying across the form.\n\nBottom left: The U.S. Capitol building in Washington, D.C., with its dome, columns, and front steps, set under a blue sky with clouds and trees.\n\nMiddle left: The exterior of a brick and glass government building with a sign reading \"U.S. Department of Health and Human Services, Food and Drug Administration.\" A lawn, trees, and a paved walkway are in front of it.", "n_tokens": 342, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-35-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 35, "text": "Office of Generic Drugs Mission and Vision\n\nOur Mission\nOGD makes high quality, affordable medicines available to the public.\n\nOur Vision\nOGD is the world leader in the science and regulation of generic medicines.\n\nThe lower right of the slide has a circular diagram of six photographs connected by arrow segments around a central label reading \"Generic Drug Program.\" Going clockwise from the top left, the photos show: laboratory equipment with orange vials or containers; a smiling health care worker in teal scrubs with a patient; orange pill bottles and tablets with a hand; a person in a lab coat working at a computer or instrument; a stethoscope resting on papers; and the U.S. Capitol building under a blue sky. A sixth photo on the left shows a brick building with an FDA sign.", "n_tokens": 160, "kind": "vision"}
{"chunk_id": "SallyCKeynote20192019_04_01SCfinal_1-36-1", "doc_id": "SallyCKeynote20192019_04_01SCfinal_1", "page": 36, "text": "No slide title is visible. The slide contains only the agency logo, which is omitted here. There are no charts, tables, diagrams, or other images.", "n_tokens": 32, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-0-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 0, "text": "Search for Balance: FDA's Approach to the Opioids Crisis\n\nDouglas C. Throckmorton, MD\nDeputy Director for Regulatory Programs\nCenter for Drug Evaluation and Research\nFDA\n\nVirginia Pain Society\nMarch 9, 2019\n\nThis slide has no charts, tables, diagrams, or images other than the FDA logo, which is omitted here.", "n_tokens": 65, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-1-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 1, "text": "Topics for Today\n\nBulleted list of slide topics:\nScope and sources of opioid crisis of abuse and overdose\nNeed for adequate pain treatment\n - Pain in America\n - Shortages of injectable opioids\nFDA response\nSelected FDA activities\n\nThe slide contains no charts, tables, diagrams, or other images.", "n_tokens": 59, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-3-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 3, "text": "The Opioid Challenges:\nOpioid Abuse and Misuse\nPain in America\nInjectable Opioid Shortages\n\nThis slide has no charts, tables, diagrams, or images other than the FDA logo, which is skipped. The title is in large black bold text. The first subtitle, \"Opioid Abuse and Misuse,\" is in dark navy bold text and is the highlighted topic. The second and third subtitles, \"Pain in America\" and \"Injectable Opioid Shortages,\" are in lighter gray text. The background is white.", "n_tokens": 116, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-5-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 5, "text": "Consequences: Prescription Opioids and Overdose Death in the US\n\nThis slide has one line chart titled \"Drugs Involved in U.S. Overdose Deaths, 1999 to 2017.\" The horizontal axis shows years labeled 1999, 2000, 2001, 2002, 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, 2016, and 2017. The vertical axis shows numeric ticks at 0, 5,000, 10,000, 15,000, 20,000, 25,000, and 30,000. No axis title or unit label is visible.\n\nThe chart has six series, identified by direct labels at the right edge of the plot:\n- Synthetic Opioids other than Methadone, 29,406 (light blue line, the highest endpoint, rising steeply after about 2013)\n- Heroin, 15,958 (dark olive green line)\n- Natural and semi-synthetic opioids, with no value visible (green line)\n- Cocaine, labeled \"14,958\" (light green line; the label text appears partly garbled, reading \"1¹14,9586\")\n- Methamphetamine, 10,721 (pale green line)\n- Methadone, 3,295 (pale grey-green line, the lowest endpoint, staying relatively flat near 3,000 to 5,000 in later years)\n\nA red arrow with no text points downward at the Natural and semi-synthetic opioids line at approximately 2009, at about the 9,500 level on the vertical axis.\n\nBelow the chart are the footer lines: \"Figure Source: National Institute on Drug Abuse Data Source: CDC Wonder\" and \"Available from: https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates\". The footer also shows the website \"www.fda.gov.\"", "n_tokens": 396, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-9-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 9, "text": "The Opioid Challenges:\n\nThis slide has no charts, tables, diagrams, or images. It lists three topics under the title, in this order: \"Opioid Abuse and Misuse,\" \"Pain in America\" (shown in dark blue, the only topic in that color), and \"Injectable Opioid Shortages.\" The footer reads \"www.fda.gov.\"", "n_tokens": 83, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-12-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 12, "text": "The Opioid Crisis: FDA's Priorities\n\nThe slide has no charts, tables, diagrams, or images. It lists four priorities in dark blue rounded boxes, numbered 1 to 4:\n\n1. Decreasing Exposure & Prevent New Addiction\n2. Supporting the Treatment of Those With Opioid Use Disorder\n3. Fostering the Development of Novel Pain Treatment Therapies\n4. Improving Enforcement & Assessing Benefit-Risk\n\nFooter text at the bottom left reads: www.fda.gov", "n_tokens": 95, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-18-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 18, "text": "Issue: Opioid Analgesics in the Home Can Feed Other Problems if Misused\n\nDiagram: A flow diagram showing how opioid analgesics in the home can lead to other problems. It contains four circles connected by arrows from left to right, plus an input box and two added factors.\n\nLabels and elements:\n- Callout box (top left, with a black arrow pointing to the first circle): \"Excess Supply after Treatment of Acute Pain\"\n- Circle 1 (brown, left): \"Available Supply\"\n- Circle 2 (orange): \"Third Party Access\"\n- Circle 3 (olive green): \"Misuse and Related Outcomes\"\n- Circle 4 (purple): \"Accidental Exposure\"\n- Arrows: An orange arrow runs from \"Available Supply\" to \"Third Party Access.\" A green arrow runs from \"Available Supply\" to \"Misuse and Related Outcomes.\" A purple arrow runs from \"Available Supply\" to \"Accidental Exposure.\"\n- Below \"Available Supply\" is a black plus sign, followed by a bulleted list of two factors: \"Non-Secure Storage\" and \"Lack of Disposal.\"\n\nText at bottom left: www.fda.gov", "n_tokens": 241, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-23-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 23, "text": "SAFE OPIOID DISPOSAL AND STORAGE\n\nThis slide contains only the title text above. It has no charts, tables, diagrams, or other images.", "n_tokens": 29, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-26-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 26, "text": "Drug Disposal (cont)\n\nThis slide is an FDA infographic titled \"Drug Disposal Options,\" with the subtitle \"Do you have medicine you want to get rid of?\" The small text \"www.fda.gov\" appears in the lower right corner of the graphic.\n\nOn the left, a man holding a pill bottle says in a speech bubble, \"I need to get rid of this medication.\"\n\nA central brown box asks, \"Do you have a drug take-back option readily available?\" Below it reads: \"Check the DEA website as well as your local drugstore and police station for possible options.\" \"DEA website\" is hyperlinked.\n\nThe box branches into two paths:\n\nNO (red label): Below it, the question \"Is it on the FDA flush list?\" is shown, with two sub-branches.\n- NO (red label): \"Follow the FDA instructions for disposing of medicine in the household trash.\" The illustration shows a bag of trash being dropped into a trash can.\n- YES (green label): \"Immediately flush your medicine in the toilet. Scratch out all personal info on the bottle and recycle/throw it away.\" The illustration shows a toilet with a pill bottle label.\n\nYES (green label): \"Take your medicine to a drug take-back location. Do this promptly for FDA flush list drugs!\" The illustration shows a woman walking with a bag.\n\nThe background shows a living room on the left and a city street on the right.\n\nBelow the graphic, outside the image, the hyperlink \"www.fda.gov/drugdisposal\" appears.", "n_tokens": 338, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-27-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 27, "text": "Opioids and Drug Disposal: Drug Takeback Day\n\nBullet text: \"Nationwide effort to get unneeded drugs out of homes.\" \"April 2018-- 348 pounds of drugs returned at FDA main campus.\"\n\nImage: A photo of a folding table with a brown cardboard box on it labeled \"TAKE BACK DAY.\" The table holds several clear plastic bags filled with loose pills and capsules of many colors, along with plastic bottles and orange prescription vials, some with white caps. A clear zip-top bag holds bottles with red and white caps. At the right edge, a pink cloth and a few more bottles are partly visible. Behind the table are a white railing and windows with blinds. A wooden chair sits at the left.\n\nFooter: www.fda.gov", "n_tokens": 159, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-28-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 28, "text": "Remove the RISK\n\nThe title is a stylized logo reading \"Remove\" in blue serif type, with \"the\" in smaller script above \"RISK\" in large dark blue letters. A white pill graphic replaces the letter \"o\" in \"Remove.\"\n\nBody text: This opioid disposal education and outreach campaign, with digital toolkits available in English and Spanish, can be used when talking with others about safe opioid disposal.\n\nThe slide shows eight icon-and-label pairs arranged in two columns. Each icon is a square with a simple white symbol.\n\nLeft column, from top to bottom:\n1. Video Public Service Announcements (PSAs): video camera icon with a play button.\n2. Radio PSAs: radio icon.\n3. Print PSAs: document with picture icon.\n4. Social Media Graphics: image icon with a \"GIF\" label.\n\nRight column, from top to bottom:\n1. Social Media Posts: icon of a group of people with wireless signal waves.\n2. Fact Sheets: document icon.\n3. Drop-in Content: window icon with a cursor arrow.\n4. Website Badges: laptop icon with a browser window.", "n_tokens": 239, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-30-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 30, "text": "Video PSAs\n\nKeep Your Family Safe From Unused Opioid Pain Medicines (0:30)\nVideo thumbnail: A woman in a blue top stands in front of an open medicine cabinet with glass shelves holding many pill bottles, containers and other products. A play button is centered on the image.\n\nMedicamentos opioides no utilizados: Mantenga a su familia segura (0:30)\nVideo thumbnail: A woman with shoulder-length dark hair in a teal top opens a white medicine cabinet on a blue-walled bathroom wall, with a mirror reflecting her face to the right and a sink and outlet visible below. A play button is centered on the image.\n\nFooter website: www.fda.gov", "n_tokens": 153, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-31-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 31, "text": "EXPANDED NALOXONE AVAILABILITY AND USE\n\nThis slide contains no charts, tables, diagrams, or images beyond the title text. The footer shows the website www.fda.gov.", "n_tokens": 37, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-33-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 33, "text": "Recent and Ongoing Activities Related to Naloxone\n\nThe slide contains no charts, tables, diagrams, or images other than the FDA logo, which is omitted here. The text on the slide reads:\n\nCo-prescribing of Naloxone with RX Opioids\n- Results of recent public FDA Advisory Committee\n\nOver-the-Counter (OTC) Naloxone\n- Research to support labeling for OTC naloxone products to support product development\n\nThe footer shows the website www.fda.gov.", "n_tokens": 107, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-37-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 37, "text": "II. Over-The-Counter Naloxone\n\n- Existing expanded access programs (such as pharmacy standing order programs) are a significant tool, but more is needed: not everyone can or wants to obtain the product through a healthcare professional.\n- Surgeon General's 2018 Advisory\n\nFooter text: www.fda.gov", "n_tokens": 64, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-40-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 40, "text": "Translate the Approved RX Product Label.\n\nThe slide shows a collage of many pages from a prescription drug label, laid out in overlapping columns and rows, with small printed text that is too small to read reliably. The pages are a label document, not a chart, table, or diagram of data. The readable section headings are: \"Ibuprofen Tablets, USP\" (title block on the left), \"DESCRIPTION,\" \"CLINICAL PHARMACOLOGY,\" \"INDICATIONS AND USAGE,\" \"CONTRAINDICATIONS,\" \"WARNINGS,\" \"PRECAUTIONS,\" \"ADVERSE REACTIONS,\" \"OVERDOSAGE,\" \"DOSAGE AND ADMINISTRATION,\" and \"HOW SUPPLIED.\" The DESCRIPTION section includes a small chemical structure drawing with a caption beneath it, but the caption text is not legible. The \"HOW SUPPLIED\" section contains a list of product entries, with package and strength details that are not legible. No other numbers, axis labels, or legends can be read.", "n_tokens": 209, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-41-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 41, "text": "To a Label for OTC Products.....\n\nDrug Facts Label\n\nThe image shows a sample over-the-counter drug facts label in two boxed panels, with no charts, graphs, or legends.\n\nTop panel:\n\nDrug Facts\nActive ingredient (in each tablet): Chlorpheniramine maleate 2 mg. Purpose: Antihistamine.\nUses: temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: sneezing; runny nose; itchy, watery eyes; itchy throat.\nWarnings:\nAsk a doctor before use if you have: glaucoma; a breathing problem such as emphysema or chronic bronchitis; trouble urinating due to an enlarged prostate gland.\nAsk a doctor or pharmacist before use if you are taking tranquilizers or sedatives.\nWhen using this product: drowsiness may occur; avoid alcoholic drinks; alcohol, sedatives, and tranquilizers may increase drowsiness; be careful when driving a motor vehicle or operating machinery; excitability may occur, especially in children.\nIf pregnant or breast-feeding, ask a health professional before use.\nKeep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.\nDirections:\nAdults and children 12 years and over: take 2 tablets every 4 to 6 hours; not more than 12 tablets in 24 hours.\nChildren 6 years to under 12 years: take 1 tablet every 4 to 6 hours; not more than 6 tablets in 24 hours.\nChildren under 6 years: ask a doctor.\n\nBottom panel:\n\nDrug Facts (continued)\nOther information: store at 20-25°C (68-77°F); protect from excessive moisture.\nInactive ingredients: D&C yellow no. 10, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch.", "n_tokens": 396, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-45-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 45, "text": "The Opioid Challenges:\n\nThe slide's subtitle lines are Opioid Abuse and Misuse, Pain in America, and Injectable Opioid Shortages. The first two are in gray text, and the last, Injectable Opioid Shortages, is in dark text. The slide contains no charts, tables, diagrams, or other images.", "n_tokens": 75, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-49-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 49, "text": "FDA Response to IV Opioids Shortage (cont)\n\nThe slide contains no charts, tables, diagrams, or images. It consists of text only.\n\nBullet points:\n- Coordinating with DEA on quota issues\n  - FDA shares information with DEA through a Memorandum of Understanding\n  - Providing a market assessment to DEA to assist them in their decision about whether to grant the quota\n\nFooter: www.fda.gov", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-50-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 50, "text": "Trends in New Drug Shortages 2010-2017\n\nThis is a stacked bar chart showing the number of new drug shortages per calendar year from 2010 to 2017. The y-axis is labeled \"Number of New Shortages\" and runs from 0 to 300, with gridlines at intervals of 50. The x-axis is labeled \"Calendar Year\" and lists the years 2010, 2011, 2012, 2013, 2014, 2015, 2016, and 2017. The legend has two entries: CDER (blue) and CBER (red). No numeric data labels appear on the bars, so the values below are approximate readings from bar heights.\n\nApproximate totals by year: 2010 about 180; 2011 about 250; 2012 about 116; 2013 about 43; 2014 about 43; 2015 about 33; 2016 about 34; 2017 about 39.\n\nBars for 2016 and 2017 show a red CBER segment on top of the blue CDER segment. For 2016 the CBER segment is about 5 and the CDER segment about 29. For 2017 the CBER segment is about 5 and the CDER segment about 34. Bars for 2010 through 2015 are entirely blue (CDER).\n\nSource note below the chart reads: \"From FDA Drug Shortage Report to Congress, 2017\" followed by the URL https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM610662.pdf.\n\nFooter text reads: www.fda.gov", "n_tokens": 294, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-52-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 52, "text": "What FDA Cannot Do to Address Drug Shortages\n\nFDA cannot require:\n- A company to disclose details of why a shortage occurs\n- A company to make a drug\n- A company to make more of a drug\n- How much and to whom the drug is distributed\n\nFooter: www.fda.gov", "n_tokens": 57, "kind": "vision"}
{"chunk_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79-58-1", "doc_id": "SearchforBalanceFDAsApproachtotheOpioidsCrisis_79", "page": 58, "text": "Thank You\n\nThe slide shows a photograph of a multi-story brick building with a central entrance featuring tall vertical windows set between pale stone columns and a flat stone cornice. A glass-roofed canopy extends over the entrance area. Rows of rectangular windows run along both wings of the building. Several green trees stand in front of and beside the building. In the foreground, a curved paved walkway with light-colored pavers wraps around a circular lawn. A low wall of pinkish-gray granite borders the walkway and has small rectangular lights set into its face. To the right, a black SUV is parked on a paved road that curves past the building. The sky is clear blue with a thin white contrail stretching diagonally across the upper left.", "n_tokens": 149, "kind": "vision"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-0-1", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 0, "text": "State of CDER\n\nPatrizia Cavazzoni, MD\nDirector\nCenter for Drug Evaluation and Research\nU.S. Food and Drug Administration\nFDLI Annual Conference\nMay 20, 2021\n\nWebsite shown at bottom left: www.fda.gov", "n_tokens": 48, "kind": "vision"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-1-1", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 1, "text": "Pandemic Response Highlights\n\nThis slide has a title, \"Pandemic Response Highlights,\" in bold blue text, centered on the right side of the slide. On the left is a large decorative panel with a blue-to-purple gradient, curved on its right edge. The slide contains no charts, tables, diagrams, or other data visuals, and no other text is visible.", "n_tokens": 78, "kind": "vision"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-8-1", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 8, "text": "Programmatic Updates\n\nThe slide has a title in bold blue text reading \"Programmatic Updates.\" On the left is a decorative vertical panel with a blue-to-purple gradient and a curved right edge. There are no charts, tables, diagrams, or other images containing data.", "n_tokens": 56, "kind": "vision"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-15-1", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 15, "text": "Complex Generic Programs\n\nThe title is partly covered by a light blue icon of a handshake over a magnifying glass, which overlaps the first letter of the title.\n\nThe slide has two side-by-side text blocks and no charts, tables, or diagrams.\n\nLeft block: \"Pre-ANDA Program.\" Beneath it: \"Collaborate early for long-term success.\"\n\nRight block: \"Center for Research on Complex Generics.\" Beneath it: \"Enhance research collaborations with industry.\"", "n_tokens": 103, "kind": "vision"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-18-1", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 18, "text": "Bolstering Our Efforts to Fight the Opioid Epidemic\n\nThis slide is a vertical diagram of four horizontal bars, stacked from top to bottom. Each bar has an empty circle at its left end, and the circles are joined by a thin connecting line. The bars shade from blue at the top to dark green at the bottom. The circles contain no numbers or symbols. The four bars read:\n\n1. Decrease exposure and Prevent New Addiction\n2. Support the Treatment of those with Opioid Use Disorder\n3. Foster the Development of Novel Pain Treatment Therapies\n4. Improve Enforcement and Assess Benefit-Risk", "n_tokens": 121, "kind": "vision"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-20-1", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 20, "text": "Bringing Therapies to Underserved Populations with Unmet Medical Needs\n\nAreas of focus include:\nRare diseases and Neurodegenerative diseases\nInfectious/Emerging/Neglected Diseases\nBiosimilar insulin", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-21-1", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 21, "text": "Rare Diseases\n\nText on the slide:\n58% of all new drug approvals in CDER for 2020.\n31 Approved NMEs with Orphan Designation in 2020.\n29 of the 31 (94%) novel orphan approved used one or more expedited program.\nA record-breaking 284 pediatric rare-disease designation requests.\n\nChart: Combined bar and line chart titled by its axis labels, showing NME approvals by calendar year from 2010 to 2020.\nLeft y-axis: \"Number of NME Approvals,\" scale 0 to 60 in steps of 10.\nRight y-axis: \"% of Approvals that are Orphan,\" scale 0% to 60% in steps of 10%.\nX-axis: \"Calendar Year,\" labeled 2010 through 2020.\nLegend: \"Orphan NME\" (green bar segment), \"non-Orphan NME\" (blue bar segment), \"Orphan Drug % of All Approvals\" (purple line with gray markers).\n\nValues read from the chart, by year (Orphan NME green segment, non-Orphan NME blue segment, Orphan Drug % of All Approvals line label):\n2010: Orphan NME 6, non-Orphan NME 15, line 29%\n2011: Orphan NME 11, non-Orphan NME 19, line 37%\n2012: Orphan NME 13, non-Orphan NME 26, line 33%\n2013: Orphan NME 9, non-Orphan NME 18, line 33%\n2014: Orphan NME 17, non-Orphan NME 24, line 41%\n2015: Orphan NME 21, non-Orphan NME 24, line 47%\n2016: Orphan NME 9, non-Orphan NME 13, line 41%\n2017: Orphan NME 18, non-Orphan NME 28, line 39%\n2018: Orphan NME 34, non-Orphan NME 25, line 58%\n2019: Orphan NME 21, non-Orphan NME 27, line 44%\n2020: Orphan NME 31, non-Orphan NME 22, line 58%", "n_tokens": 389, "kind": "vision"}
{"chunk_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515-25-1", "doc_id": "State_of_CDER_FDLI2021_PCavazzoni_20210515", "page": 25, "text": "Thank You To The CDER Team!\n\nThe image is an illustration of six silhouetted figures posed like a team of superheroes against a blue sunburst background with a curved orange and red border on the right side and a gray ground at the bottom. Two dark gray figures stand in the back: a muscular male figure on the left and a female figure on the right, both with hands on hips. In front are three brightly colored figures. On the left, a blue figure wears a suit and tie. In the center, a magenta figure wears a suit and holds a folder or clipboard. On the right, an orange figure with hands on hips wears a suit or dress. The image contains no charts, tables, diagrams, numbers, or other text.", "n_tokens": 154, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-0-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 0, "text": "STATE OF OGD: Pivoting to GDUFA II\n\nKathleen Uhl, MD\nDirector, Office of Generic Drug\nCDER/FDA\n\nAAM Fall Technical Conference\nNovember 6, 2017", "n_tokens": 37, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-2-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 2, "text": "Overview\n\nThe slide is a text-only agenda with no charts, tables, diagrams, or images beyond the FDA logo, which is omitted here as requested.\n\nNumbered list:\n1. Update on GDUFA I\n   - Receipts\n   - Actions towards Goals\n   - Other accomplishments\n2. Brief comments on GDUFA II\n3. Closing Comments", "n_tokens": 64, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-4-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 4, "text": "GDUFA I workload\n\nThe slide is a text-only bulleted list with no charts, tables, diagrams, or images. The points read:\n\nNumber of original applications exceeded estimates.\nNumber of applications continues to rise.\nNumber of amendments continues to rise.\nNumber of controls continues to rise.\nSub-point under controls: More complex controls.\nNumber of companies increasing.\nNumber of facilities increasing.", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-6-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 6, "text": "ANDA Receipts (Originals + CR Responses/Amendments)\n\nThis slide contains one bar chart with an overlaid trend line.\n\nChart: Bar chart titled \"ANDA Receipts.\" The subtitle in parentheses reads \"Originals + CR Responses/Amendments.\"\nY-axis: labeled \"ANDA Receipts.\" Scale runs from 0 to 3,000 in increments of 500 (0, 500, 1,000, 1,500, 2,000, 2,500, 3,000). No units are stated.\nX-axis: categories labeled \"FY 15,\" \"FY 16,\" and \"FY 17.\"\nLegend: none shown.\n\nData labels on bars:\n- FY 15: 1,547\n- FY 16: 1,848\n- FY 17: 2,849\n\nThe bars are blue. A thin black straight trend line runs upward from the FY 15 bar area to the FY 17 bar area. It has no label.\n\nFootnote at bottom left: \"* Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\"", "n_tokens": 236, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-10-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 10, "text": "To date, FDA has met or exceeded EVERY formal negotiated GDUFA goal\n\nThis slide contains only text. The word \"EVERY\" is underlined. There are no charts, tables, diagrams, or other images.", "n_tokens": 43, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-19-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 19, "text": "Prior Approval Supplements (PASs)\n\nThis slide contains no charts, tables, diagrams, or images beyond the title text.", "n_tokens": 23, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-21-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 21, "text": "PAS Actions\n\nThis slide contains a table with the title \"PAS Actions\" that shows counts of PAS actions by fiscal year. The column headers are FY2013, FY2014, FY2015, FY2016, and FY2017. The row labels are Received, Approved, and CR Letter.\n\nReceived: FY2013 482; FY2014 436; FY2015 480; FY2016 478; FY2017 415.\n\nApproved: FY2013 535; FY2014 659; FY2015 624; FY2016 481; FY2017 431.\n\nCR Letter: FY2013 8; FY2014 18; FY2015 185; FY2016 228; FY2017 223.\n\nFootnote text at the bottom reads: \"*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\"", "n_tokens": 208, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-22-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 22, "text": "Controlled Correspondence \"Controls\"\n\nThis slide has no charts, tables, diagrams, or images beyond the FDA logo, which is omitted as requested. The slide contains only the title text above, centered on a white background.", "n_tokens": 43, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-25-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 25, "text": "OGD FILING REVIEW\n\nThe slide has one bulleted statement: \"> 1,100 original ANDAs, resubmissions, and PASs underwent filing review in FY2017.\" The figure \"> 1,100\" is underlined and bolded.\n\nThe slide contains no charts, tables, diagrams, or other images.", "n_tokens": 67, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-28-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 28, "text": "RTR is a CRITICAL \"Vital Sign\"\n\nIf ANDA received RTR....\nLess 1st cycle AP or TA\nMore deficiencies in CRL\nWorse (\"major\") deficiencies\nIf RTR resubmitted quickly to FDA, even lower likelihood for AP or TA\n\nImage: A cartoon red heart character with blue eyes and a smile stands on white sneakers. It wears white gloves and holds a blue-gray blood pressure cuff with a dial gauge (orange needle) around its left arm. Its right hand points forward. There are no charts, tables, or diagrams.", "n_tokens": 117, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-35-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 35, "text": "FDA Commissioner Scott Gottlieb, MD\n\nThe slide has four bullet points on the left:\nHuge interest and focus on Generic Drugs\nNumerous internal briefings provided regarding the generic drug program, GDUFA, Hatch-Waxman, and other activities\nAttendance at OGD All Hands\nDrug Competition Action Plan\n\nOn the right is a photograph of a man in a dark suit, light shirt, and dark tie, standing at a wooden podium beside a microphone on a stand. Next to him is a woman with short light-brown hair, wearing a light cream knit top, who is looking down at papers she holds at the podium. Both are looking downward. The background is a plain, light-colored wall and ceiling. The photo has no chart, table, diagram, or readable text.", "n_tokens": 157, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-38-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 38, "text": "FDA's Generic Review Pipeline\nBy Submission Cohort as of September 30, 2017\n\nThis is a diagram showing the flow of generic drug applications through FDA review, with arrows indicating ANDAs moving into review, through the pipeline, and out as approvals, plus exchanges with industry.\n\nLeft arrow (light blue): labeled \"ANDAs & ANDA Re-submissions.\" It enters the pipeline.\n\nCentral pipeline (horizontal cylinder divided into stacked horizontal bars, one per submission cohort): The bars are labeled from top to bottom:\n- PRE GDUFA SUBMISSIONS\n- FY2013\n- FY2014\n- FY2015\n- FY2016\n- FY2017\n\nEach bar is orange, representing \"Under FDA Review (includes many re-submissions).\" Hatched yellow sections at the left of each bar represent \"First FDA review pending.\" The hatched portion is short for the pre-GDUFA, FY2013, FY2014, FY2015, and FY2016 bars, and the FY2017 bar has a hatched section extending to roughly two-thirds of its length, with the remaining third solid orange.\n\nLegend (above the pipeline):\n- Hatched yellow: \"First FDA review pending\"\n- Solid orange: \"Under FDA Review (includes many re-submissions)\"\n\nBracket below the pipeline: labeled \"Approximately 2,500 Total ANDAs.\"\n\nRight arrow (green): labeled \"3,435 Approvals & Tentative Approvals GDUFA I.\"\n\nLower section (pink arrows and box):\n- Downward pink arrow labeled \"To Industry\"\n- Upward pink arrow labeled \"From Industry\"\n- Pink box below the arrows: \"Approx. 1,750 ANDAs w/ industry (1,400 pending response & 350 TAs)\"", "n_tokens": 369, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-39-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 39, "text": "Getting to \"Stable Footing\"\n\nANDA Inventory\n\nThis is a line chart titled \"ANDA Inventory.\" The y-axis is labeled \"ANDAs\" and runs from 0 to 4,000 in increments of 500. The x-axis shows monthly dates from Oct, 2014 to Aug-17, with labels every two months (Oct, 2014; Dec, 2014; Feb, 2015; Apr, 2015; Jun, 2015; Aug, 2015; Oct, 2015; Dec, 2015; Feb, 2016; Apr, 2016; Jun-16; Aug-16; Oct-16; Dec-16; Feb-17; Apr-17; Jun-17; Aug-17). The chart has two legend entries: \"With FDA\" (blue line) and \"With Industry\" (red line).\n\nThe chart has no printed data labels. Approximate values read from the axis:\n- With FDA (blue): begins near 3,575 in Oct, 2014; declines to about 2,030 by Oct-16; reaches a low near 1,970 around Nov-16; rises to about 2,120 in early 2017; and ends near 2,180 in Aug-17.\n- With Industry (red): begins near 700 in Oct, 2014; rises to about 1,000 around Dec, 2015; reaches about 1,680 by Oct-16; peaks near 1,760 around Dec-16; dips to about 1,670 around Jun-17; and ends near 1,750 in Aug-17.\n\nFootnote at bottom left: \"*Updated 10/1/2017. Numbers are based on preliminary data that will be reviewed and validated for official reporting purposes.\"", "n_tokens": 348, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-40-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 40, "text": "ANDAs in CR status with industry\n\nThe slide contains no charts, tables, diagrams, or images apart from the FDA logo, which is omitted here.\n\nFDA needs a better understanding of this\n– Predictors of when amendment will be submitted to FDA\n– Workload predictions and forecasting, capacity analytics, etc.\n\nFDA asked industry for data/analysis during QTR GDUFA II FDA-industry meeting", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-41-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 41, "text": "Application \"approvability\"\n\nThe slide has a single text block enclosed in a red-bordered box, reading: \"FDA will Approve or TA an ANDA WHEN it meets the Agency's standards for approval.\" The word \"WHEN\" is underlined. There are no charts, tables, diagrams, or other images.", "n_tokens": 66, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-43-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 43, "text": "Overview\n\nThe slide lists the following agenda items:\n\n1. Update on GDUFA I\n   - Receipts\n   - Actions towards Goals\n   - Other accomplishments\n2. Brief comments on GDUFA II (this item is in bold, unlike the others)\n3. Closing Comments\n\nThe slide contains no charts, tables, diagrams, or images.", "n_tokens": 63, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-45-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 45, "text": "GDUFA II\n\n\"Goals\" or \"Commitment\" letter:\nhttp://www.fda.gov/downloads/forindustry/userfees/genericdruguserfees/ucm525234.pdf\n\nPLEASE READ!\n\nThe slide has one image: a blue poster with a white crown at the top and the words \"KEEP CALM AND READ ON\" in white capital letters. It is a parody of the \"Keep Calm and Carry On\" poster style.", "n_tokens": 98, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-46-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 46, "text": "GDUFA II Pre-ANDA Program\n\nThe slide has a bulleted list with one main bullet, \"Session:\", and one sub-bullet beneath it: \"Tuesday November 7, 2017, 9:00am-10:00am\". There are no charts, tables, diagrams, or images on the slide.", "n_tokens": 67, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-47-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 47, "text": "GDUFA II Review Program Enhancements\n\nSessions:\n- Tuesday November 7, 2017, 10:30am-12:30pm\n- Tuesday November 7, 2017, 1:30pm-3:30pm", "n_tokens": 42, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-48-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 48, "text": "Lessons learned from PDUFA I-V & GDUFA I\n\nThe slide has no charts, tables, diagrams, or images beyond the FDA logo and slide number, which are omitted here. The body text reads:\n\nCritical/Pivotal role of RPM\nComplete Application is critical\nHigh quality NDA & ANDA applications result in:\nLow Refuse To File (RTF)/Refuse to Receive (RTR) rates\nFirst cycle approvals\nShorter time to approval", "n_tokens": 90, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-54-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 54, "text": "The slide has no visible title.\n\nThe image is a word cloud of \"thank you\" in many languages. The English \"thank you\" is the largest and most central word, in red. Other words are in varying sizes, colors, and fonts. Readable words include: danke, 謝謝, спасибо, gracias, bedankt, obrigado, dziękuje, sukriya, merci, grazie, arigato, tak, takk, dakujem, tapadh leat, teşekkür ederim, ngiyabonga, go raibh maith agat, mochchakkeram, terima kasih, kop khun krap, dank je, спасибо, рахмат, баярлалаа, ευχαριστώ, 감사합니다, ありがとうございます, and мерси.\n\nBelow the word cloud are four bullet points:\n\n- For your feedback and endurance during the tremendous processes changes under GDUFA\n- Your engagement and input were critical to its success\n- It was a team effort with FDA and industry\n- There is still plenty of work to go around with GDUFA II", "n_tokens": 289, "kind": "vision"}
{"chunk_id": "State_of_OGD_Pivoting_to_GDUFA_II-55-1", "doc_id": "State_of_OGD_Pivoting_to_GDUFA_II", "page": 55, "text": "No slide title is visible. The slide has no other text, charts, tables, diagrams, or images.", "n_tokens": 22, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-0-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 0, "text": "The Public Health Role of Drug Regulation in the US\n\nPresenter: Douglas C. Throckmorton, M.D., Deputy Director for Regulatory Programs, CDER, FDA\n\nDate: March 20, 2017\n\nThis slide is a title slide with no charts, tables, diagrams, or other images beyond the FDA logo, which is omitted as requested.", "n_tokens": 69, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-1-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 1, "text": "Disclosure Statement\n\nI have no financial relationships with proprietary entities that produce health care goods and services\n\nThe opinions and information in this presentation are my own and do not necessarily reflect the views and policies of the FDA", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-2-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 2, "text": "FDA's Regulatory Scope: 20 cents of every GDP dollar\n\nThis slide has no chart, table, or diagram. It contains a collage of about 13 photographs and illustrations with no axis labels, legend, or units. The only readable text is the title and the numbers on the blood pressure monitor.\n\nTop left: a pink lipstick tube with its applicator partly extended, beside a compact mirror.\n\nNext to it: a mixed pile of fresh produce, including carrots, green grapes, red and yellow peppers, a banana, apples, strawberries, and an orange.\n\nCenter top: an illustration of a lit cigarette with wavy smoke rising from the burning tip.\n\nTop right: a man in a white coat with glasses and a stethoscope examining a small white-and-brown dog on a metal table.\n\nFar right top: two brown-and-white cows grazing on a green mountain pasture under a blue sky with clouds.\n\nMiddle left: an X-ray image of two hands, showing the bones of the fingers and wrists.\n\nCenter: an assortment of pills and capsules in orange, white, and green, with orange prescription-style bottles in the background.\n\nRight middle: a tabby kitten sitting beside a food bowl and a golden puppy standing beside it.\n\nLower right of center: a teal, virus-like particle cluster beside an illustration of a DNA double helix.\n\nBottom left: a set of surgical instruments, including forceps and scissors, and a blood collection tube with a purple cap.\n\nBottom center: a digital blood pressure monitor with a cuff. The display reads \"120\" over \"80.\"\n\nCenter bottom: a microscope-style image of red blood cells.\n\nBottom right: gloved hands inserting a needle or catheter into a person's arm.", "n_tokens": 362, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-3-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 3, "text": "FDA Mission\n\nThe slide body text reads: \"FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation.\" The phrases \"protecting the public health by\" and \"assuring the safety, efficacy, and security\" are underlined. A small orange speech-bubble icon appears in the top-left corner. The slide contains no charts, tables, diagrams, or images.", "n_tokens": 109, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-5-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 5, "text": "FDA Mission\n\nFinally, FDA plays a significant role in the Nation's counterterrorism capability. FDA fulfills this responsibility by ensuring the security of the food supply and by fostering development of medical products to respond to deliberate and naturally emerging public health threats.\n\nThe slide has no charts, tables, diagrams, or images. The phrases \"significant role in the Nation's counterterrorism capability\" are underlined.", "n_tokens": 85, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-7-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 7, "text": "A Horse Named Jim\n\nLeft photo: A black-and-white photograph of a horse held in a harness and halter, with a white cloth draped over its body. Two men in white coats and caps stand beside it. One works near the horse's side, and a tube runs from the horse to glass containers on a table. Two bottles are dark and one is clear. A metal pole rises beside them, and white basins sit in the lower left corner.\n\nRight photo: A color photograph of a small glass bottle with a flared neck and a stopper. Dark brownish material is visible inside the neck. The bottle has a paper label with this partly visible text:\n- Handwritten in red ink at top: a partial date ending in \"189\" and a dotted line.\n- Printed title, cut off at the left edge: \"...phtheria-Antitoxin\"\n- \"10 Cubic Centimeters\"\n- \"Immunizing strength 1 to\" followed by a partly cut-off number\n- \"...ared at the Hygienic Labo...\" (cut off)\n- \"U.S. Marine-Hospital Ser...\" (cut off)", "n_tokens": 244, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-9-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 9, "text": "Pre-1938\n\nFDA could only respond to problems when identified.\nNo requirements for testing or approval.\nNo data of any kind had to be submitted before marketing.\nGovernment could seek to remove dangerous or misbranded products.\n\nNot surprisingly, there were some disasters:\n\nImage: A vintage color poster advertising \"Buffalo Bill's Wild West.\" The large red-and-yellow title reads \"BUFFALO BILL'S WILD WEST.\" Smaller text beneath the title is only partly legible. The lower text is also partly legible and includes the words \"WILD WEST COWBOYS.\" The painting shows a dense, chaotic scene of mounted riders in fringed and feathered clothing, with rearing and galloping horses, raised weapons, and smoke or dust. At the right edge, a standing figure in a wide-brimmed hat and long coat is beside a horse. The poster has no numbers, axes, or legend.", "n_tokens": 184, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-11-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 11, "text": "The Food, Drug and Cosmetic Act of 1938 (FD&C) – Age of Safety\n\nTwo Requirements:\n1. Pre-market notification\n2. Demonstration of safety", "n_tokens": 33, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-18-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 18, "text": "Critical Part of FDA Work: Sustaining Medical Product Innovation\n\nThe slide contains no charts, tables, diagrams, or images apart from the FDA logo, which is omitted as instructed. The body text is a bulleted list of four points:\n\nOur high failure rates for drug development.\nRising R & D costs.\nA limited pipeline of potential drugs.\nA lack of basic information about the causes of the disease and the pathways for slowing its progress.", "n_tokens": 86, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-20-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 20, "text": "Improving Evidence Generation Essential\n\nThis slide contains a diagram showing three inputs converging on a central point labeled EBP.\n\n- Top box, dark blue outline with arrow pointing down toward EBP: \"Clinical Expertise\"\n- Left box, teal/green outline with arrow pointing right toward EBP: \"Best Research Evidence\"\n- Right box, red outline with arrow pointing left toward EBP: \"Patient Values & Preferences\"\n- Center label: \"EBP\"\n\nNo numbers, axes, units, or legend appear on the slide.", "n_tokens": 111, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-23-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 23, "text": "Many Stakeholders in Clinical Trials Enterprise\n\nThis slide is a diagram of puzzle-piece hexagons fitted together around a central gray hexagon. The title sits above a horizontal blue rule.\n\nCenter: a gray hexagon labeled \"Drug Development.\"\n\nSurrounding pieces, going clockwise from the top:\n- Top: a light tan/beige piece with no visible text.\n- Upper right: a dark navy piece labeled \"Regulatory Agencies.\" The label is partly cut off at the edges and reads as \"egulator y Agencies\" in the image.\n- Lower right: a gold/yellow piece labeled \"Consortia,\" shown split as \"Conso rtia.\"\n- Bottom: a light blue piece labeled \"Patient Groups, Foundations, and Professional Societies,\" which spills below the piece.\n- Lower left: a gray piece labeled \"Federal Partners.\"\n- Upper left: a medium blue piece labeled \"Academia.\"\n\nThe slide contains no numbers, charts, tables, axes, units, or legend.", "n_tokens": 205, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-26-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 26, "text": "Old Shenzhen (1982)\n\nThis slide contains one black-and-white photograph of a wide, unpaved dirt road with gravel and loose dirt at the lower left. Three dark, horned animals, likely buffalo or cattle, walk across the road. A person in a white short-sleeved shirt and dark trousers walks among them, seen from behind. Near the center, a dark truck or bus with a canvas or open rear has people visible in its back, and a white van or small truck is parked or moving to its left. A person on a bicycle wearing a white hat rides at the right, and another cyclist in a dark top appears at the far right edge. Several other people, some on foot and some cycling, are scattered along the road in the middle distance. In the background are low, flat-roofed buildings, a taller multi-story white building, utility poles with wires, a tree at the far left, and a flat, open area with construction or excavation. The slide has no charts, tables, diagrams, legends, axis labels, or other readable text beyond the title.", "n_tokens": 223, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-27-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 27, "text": "New Shenzhen (2013)\n\nThis slide has one image and no charts, tables, or diagrams. The image is an aerial photograph of a city at dusk. A pale moon is visible in the upper left of the sky. Mountains form a dark ridge across the background. A dense skyline of high-rise residential and office towers fills the middle ground, with many windows lit. A tall, slender glass skyscraper stands near the center-right of the skyline. In the foreground, a large oval stadium with a blue-gray roof is brightly lit, and a crowd is visible in the stands around the field. Smaller buildings, roadways, a parking area, trees, and a green sports field appear near the stadium. A faint reflection of the image appears along the bottom edge of the slide.", "n_tokens": 158, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-31-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 31, "text": "Overdose Death Rates\n\nThis slide shows two side-by-side choropleth maps of the United States, labeled 1999 (left) and 2014 (right). Each map shows counties shaded by estimated age-adjusted death rate from overdose, with separate insets for Alaska (lower left) and Hawaii (lower center). Counties are colored by range.\n\nLeft map, labeled \"Year 1999\" in the lower right of the map. Legend title: \"Estimated Age-adjusted Death Rate per 100,000.\" Legend entries: 0-2, 2.1-4, 4.1-6, 6.1-8, 8.1-10, 10.1-12, 12.1-14, 14.1-16, 16.1-18, 18.1-20, >20.\n\nRight map, labeled \"Year 2014\" in the lower right of the map. Legend title: \"Estimated Age-adjusted Death Rate per 100,000.\" Legend entries: 0.6-2.0, 2.1-4.0, 4.1-6.0, 6.1-8.0, 8.1-10.0, 10.1-12.0, 12.1-14.0, 14.1-16.0, 16.1-18.0, 18.1-20.0, >20.\n\nSlide header text above the maps: \"1999\" (left) and \"2014\" (right).\n\nSource credit at bottom left: \"Designed by L. Rossen, B. Bastian & Y. Chong. SOURCE: CDC/NCHS, National Vital Statistics System.\"\n\nBottom right text: \"Science = Solutions.\"\n\nThe bottom edge has a decorative bar in blue, green, brown, and gray segments.", "n_tokens": 370, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-32-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 32, "text": "Important: FDA One of Many Stakeholders\n\nThe slide has three rows, each with a text label on the left and a box with a diagram on the right.\n\nRow 1: Text reads \"FDA evaluates benefits/risks for the population.\" The box shows a balance scale. The left pan holds a crowd of silhouetted people and is labeled \"Benefits.\" The right pan holds a smaller group of silhouetted people and is labeled \"Risks.\" The left pan sits lower than the right pan.\n\nRow 2: Text reads \"Provider evaluates benefits/risks for a patient.\" The box shows a balance scale with a doctor in a white coat and a patient figure at the fulcrum. The left pan holds several stacked letters \"B\" and is labeled \"Benefits.\" The right pan holds three letters \"R\" and is labeled \"Risks.\" The left pan sits lower than the right pan.\n\nRow 3: Text reads \"Patient evaluates benefits/risks in terms of personal values.\" The box shows a silhouette of a standing person with both arms outstretched. The word \"Benefits\" appears over the left hand and the word \"Risks\" appears over the right hand. The two words are shown at different sizes.", "n_tokens": 247, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-37-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 37, "text": "What is the Role of the Regulator in Responding to Public Health Challenges and Supporting Innovation?\n\nThis slide contains no charts, tables, diagrams, or images. It consists only of the title text above, centered on a white background.", "n_tokens": 45, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-43-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 43, "text": "No separate slide title is visible. The most prominent text is \"WARNING\" at the top of the slide.\n\nThe slide shows a yellow road-style warning sign with a thin black border. The top line reads \"WARNING.\" Below it is a black-outlined diamond containing a black symbol: an upward-pointing arrow at the top, with a shaft that bends into an S-shaped curve below it. The bottom line reads \"CHALLENGES AHEAD.\"\n\nThere are no charts, tables, axes, units, legends, or numbers on the slide.", "n_tokens": 110, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-45-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 45, "text": "The slide has no visible title. The only content is a single bulleted quotation in black text on a white background: \"The art of progress is to preserve order amid change and to preserve change amid order.\" The attribution below it reads \"---Alfred North Whitehead.\" The slide contains no charts, tables, diagrams, or other images.", "n_tokens": 74, "kind": "vision"}
{"chunk_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US-46-1", "doc_id": "The_Public_Health_Role_of_Drug_Regulation_in_the_US", "page": 46, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images, and the only element is the FDA logo, which is omitted as instructed. No numbers or labels are visible.", "n_tokens": 42, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-2-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 2, "text": "Organizational Structure\n\nThis slide contains only a title. It has no charts, tables, diagrams, or other images beyond the FDA logo in the top right corner and the footer website text \"www.fda.gov\" in the bottom left corner.", "n_tokens": 49, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-3-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 3, "text": "No slide title is visible.\n\nImage: A dark blue space scene with a curved, sunlit ring system in the upper left corner, appearing as pale tan and beige bands with a bright edge. A faint, diagonal bluish haze band crosses the middle, and scattered small stars are visible. Near the center-left is a tiny bright bluish dot, marked by a red line that leads to the red capitalized label \"EARTH.\" No axis labels, units, legend, or other numbers appear.\n\nFooter text: www.fda.gov", "n_tokens": 110, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-7-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 7, "text": "OPDP Research Team\n\nThe slide lists four members of the team as bulleted text. There are no charts, tables, diagrams, or other images.\n\n- Kathryn Aikin, Ph.D. (Team Lead)\n- Kevin Betts, Ph.D.\n- Amie O'Donoghue, Ph.D.\n- Helen Sullivan, Ph.D., M.P.H.\n\nThe footer shows the website www.fda.gov.", "n_tokens": 92, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-10-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 10, "text": "Role of Research Team (cont.)\nHow we do it\n\nApply social science and communication principles to OPDP's:\n- Advice to industry, academia or internal FDA stakeholders\n- Guidance and policy development\n- Research\n- Surveillance and compliance activities\n\nFooter: www.fda.gov", "n_tokens": 55, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-11-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 11, "text": "OPDP's Research Agenda\n\nThe slide contains only bulleted text with no charts, tables, diagrams, or images.\n\nProvide science-based evidence and perspective\n\nStudies are proposed and selected to fulfill a number of purposes such as:\n– Congressional mandate\n– Help inform guidance and policy development\n– Enhance scientific literature base\n\nThe footer shows the website www.fda.gov.", "n_tokens": 72, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-12-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 12, "text": "Application of Social Science Principles to Research\n\nThe slide has a bulleted list with no charts, tables, diagrams, or images.\n\nAdvertising Features\n- Content\n- Format\n\nTarget Population(s)\n\nResearch Quality\n\nFooter text reads www.fda.gov.", "n_tokens": 48, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-14-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 14, "text": "Focus of OPDP's Research Studies (cont.)\n\nThe slide is text only, with no charts, tables, diagrams, or images to describe. Its content is as follows.\n\nTarget Population\n- How does understanding of prescription drug product risks and benefits vary as a function of audience?\n- Variables include:\n  - Literacy\n  - Education\n  - Age\n\nFooter text: www.fda.gov", "n_tokens": 77, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-15-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 15, "text": "Focus of OPDP's Research Studies (cont.)\n\nBody text:\nResearch Quality\n– How can the quality of the research data be maximized to ensure the best possible return on investment for FDA?\n– Variables include:\n• Analytical methodology development\n• Sampling and response issues\n\nFooter: www.fda.gov\n\nThis slide contains no charts, tables, diagrams, or images other than the FDA logo, which is omitted as requested.", "n_tokens": 86, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-18-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 18, "text": "Public Comment Periods for OPDP Social Science Research\n\nThe slide has three bullet points. The first reads \"Two statutory comment periods.\" The second reads \"60-day Federal Register Notice,\" with a sub-point reading \"Comments to FDA.\" The third reads \"30-day Federal Register Notice,\" with a sub-point reading \"Comments to OMB.\"\n\nBelow the bullets is a process diagram: a horizontal gray arrow running left to right through five rounded rectangular boxes. The boxes, in order, read:\n\n1. \"Agency Develops Information Collection Request\"\n2. \"60-day Federal Register Notice\"\n3. \"Agency Considers Public Comments\"\n4. \"30-day Federal Register Notice & Submit to OMB for Review\"\n5. \"OMB Review\"\n\nThe footer at the bottom left reads \"www.fda.gov.\"", "n_tokens": 172, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-19-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 19, "text": "Sneak Peek at Upcoming Research\n\nThe slide has three bulleted items:\nFocus groups\nSurveys\nExperimental studies\n\nThe footer shows the website www.fda.gov.", "n_tokens": 30, "kind": "vision"}
{"chunk_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies-27-1", "doc_id": "The_Role_of_Social_Science_in_Prescription_Drug_Promotion_at_FDA_and_Preview_of_Upcoming_Studies", "page": 27, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images, and no text other than the logo, which is omitted as instructed.", "n_tokens": 34, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-0-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 0, "text": "Addressing Opioids: The FDA Response to Challenges in Public Health\n\nPresenter: Douglas C. Throckmorton, MD, Deputy Director for Regulatory Programs, Center for Drug Evaluation and Research, FDA\n\nEvent: FDA-CMS Summit\n\nDate: December 12, 2018\n\nThis slide contains no charts, tables, diagrams, or other images.", "n_tokens": 66, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-1-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 1, "text": "Central Message\n\nFDA is responding to the public health challenges of opioids using all of our available tools to:\n- Address the ongoing crisis of opioid abuse and misuse\n- Address the ongoing shortages of injectable prescription opioids", "n_tokens": 48, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-2-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 2, "text": "The Opioid Challenges:\nOpioid Abuse and Misuse\nInjectable Opioid Shortages\n\nThe slide has no charts, tables, diagrams, or other images. The only other text is a URL at the bottom: https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates", "n_tokens": 71, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-5-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 5, "text": "Consequences: Prescription Opioids and Overdose Death in the US\n\nThis slide contains one line chart titled \"Drugs Involved in U.S. Overdose Deaths, 1999 to 2017.\" The chart has no printed axis titles. The vertical axis runs from 0 to 30,000 in steps of 5,000, and the horizontal axis lists each year from 1999 to 2017. The lines are labeled directly at their right-hand ends rather than in a separate legend. The labels and values shown are:\n\nSynthetic Opioids other than Methadone, 29,406 (the steepest line, rising sharply from about 2013 to the top of the chart in 2017)\nHeroin, 15,958\nNatural and semi-synthetic opioids (no value shown in the label)\nCocaine, 1 14,9586 (as printed; the value appears to read 14,958 or 14,986, and the label is partly unclear)\nMethamphetamine, 10,721\nMethadone, 3,295 (the flattest line near the bottom of the chart)\n\nA red arrow points downward to the Natural and semi-synthetic opioids line at about 2009, with no text attached to it.\n\nBelow the chart is the source line: \"Figure Source: National Institute on Drug Abuse. Data Source: CDC Wonder. Available from: https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates\"\n\nThe footer reads www.fda.gov.", "n_tokens": 304, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-7-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 7, "text": "The Opioid Crisis: FDA's Priorities\n\nThe slide contains no charts, tables, or images. It shows four stacked, rounded blue boxes with white text, listed from top to bottom:\n\n1. Decreasing Exposure & Prevent New Addiction\n2. Supporting the Treatment of Those With Opioid Use Disorder\n3. Fostering the Development of Novel Pain Treatment Therapies\n4. Improving Enforcement & Assessing Benefit-Risk", "n_tokens": 82, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-14-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 14, "text": "Issue: Opioid Analgesic in the Home Can Feed Other Problems if Misused\n\nDiagram: A flow diagram of four circles connected by curved arrows, with a callout box and bullet points.\n\nCallout box (top left, black outline, with a black arrow pointing to the first circle): \"Excess Supply after Treatment of Acute Pain\"\n\nCircles, left to right:\n1. Brown circle: \"Available Supply\"\n2. Orange circle: \"Third Party Access\"\n3. Dark green circle: \"Misuse and Related Outcomes\"\n4. Purple circle: \"Accidental Exposure\"\n\nArrows: All arrows start at the Available Supply circle. An orange arrow points to Third Party Access, a green arrow points to Misuse and Related Outcomes, and a purple arrow points to Accidental Exposure. The purple arrow is the longest and arcs over the other two.\n\nBelow the first circle, a black plus sign (+) links to two bullet points:\n- Non-Secure Storage\n- Lack of Disposal\n\nNo numbers, axis labels, units, or legend appear on this slide.", "n_tokens": 212, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-16-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 16, "text": "The Opioid Challenges:\n\nOpioid Abuse and Misuse\nInjectable Opioid Shortages\n\nThis slide has no charts, tables, diagrams, or images other than the FDA logo, which is omitted here.", "n_tokens": 43, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-20-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 20, "text": "FDA Response to IV Opioids Shortage (cont)\n\nThe slide contains no charts, tables, diagrams, or images. It consists of text only:\n\nCoordinating with DEA on quota issues\n- FDA shares information with DEA through a Memorandum of Understanding\n- Providing a market assessment to DEA to assist them in their decision about whether to grant the quota", "n_tokens": 67, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-21-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 21, "text": "Trends in New Drug Shortages 2010-2017\n\nThis slide contains one vertical stacked bar chart. The y-axis is labeled \"Number of New Shortages,\" with tick marks from 0 to 300 in increments of 50. The x-axis is labeled \"Calendar Year\" and shows the years 2010 through 2017. The legend has two entries: CDER, shown in blue, and CBER, shown in red. The bars have no printed data labels, so the values below are estimates read from the bar heights.\n\n2010: about 180 new shortages, all CDER (blue).\n2011: about 250 new shortages, all CDER (blue).\n2012: about 115 new shortages, all CDER (blue).\n2013: about 43 new shortages, all CDER (blue).\n2014: about 43 new shortages, all CDER (blue).\n2015: about 33 new shortages, all CDER (blue).\n2016: about 34 new shortages in total, with about 29 CDER (blue) and about 5 CBER (red).\n2017: about 39 new shortages in total, with about 34 CDER (blue) and about 5 CBER (red).\n\nSource note below the chart: \"From FDA Drug Shortage Report to Congress, 2017\" followed by the URL https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM610662.pdf.", "n_tokens": 292, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-23-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 23, "text": "What FDA Cannot Do to Address Drug Shortages\n\nFDA cannot require:\n- A company to disclose details of why a shortage occurs\n- A company to make a drug\n- A company to make more of a drug\n- How much and to whom the drug is distributed", "n_tokens": 49, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-24-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 24, "text": "Trends in Preventing Drug Shortages 2010-2017 (FDA)\n\nThis slide contains one vertical bar chart.\n\nChart: Number of prevented drug shortages by calendar year, 2010 to 2017. Each bar is stacked by agency, with CDER in blue and CBER in red. The chart has no printed data labels, so the values below are approximate readings from the bar heights.\n\nY-axis label: \"Number of Prevented Shortages.\" Scale runs from 0 to 300, with gridlines at 0, 50, 100, 150, 200, 250, and 300. The unit is number of prevented shortages.\n\nX-axis label: \"Calendar Year.\" Categories are 2010, 2011, 2012, 2013, 2014, 2015, 2016, and 2017.\n\nLegend: \"CDER\" (blue) and \"CBER\" (red).\n\nApproximate values, read from the chart:\n2010: about 39 total, all CDER.\n2011: about 195 total, all CDER.\n2012: about 280 total, all CDER. This is the highest bar.\n2013: about 171 total, all CDER.\n2014: about 100 total, all CDER.\n2015: about 143 total, all CDER.\n2016: about 126 total, with about 113 CDER and about 13 CBER.\n2017: about 136 total, with about 117 CDER and about 19 CBER.\n\nSource note in the lower right: \"From FDA Drug Shortage Report to Congress, 2017\" with the URL https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM610662.pdf", "n_tokens": 325, "kind": "vision"}
{"chunk_id": "TmortonFDA_CMS1218update_50-28-1", "doc_id": "TmortonFDA_CMS1218update_50", "page": 28, "text": "Thank You\n\nThe slide contains one photograph, with no charts, tables, or diagrams. It shows a large brick building with a central stone facade of tall vertical columns and a flat roofline, and rows of rectangular windows on both wings. A glass-roofed canopy extends over the entrance at the base of the central section. In front is a green lawn bordered by a curved low wall of pinkish-gray stone, with a light paved walkway curving along it. Small lights are set into the top of the wall. A black SUV is driving on a road to the right of the entrance. Several leafy green trees stand near the building, and a clear blue sky with a faint contrail is visible above.", "n_tokens": 142, "kind": "vision"}
{"chunk_id": "Tmorton_NASEM_SOW_4-0-1", "doc_id": "Tmorton_NASEM_SOW_4", "page": 0, "text": "Charge to the Committee\n\nNational Academies of Science, Engineering, and Medicine\nNovember 13, 2018\n\nDouglas C. Throckmorton, MD\nDeputy Director for Regulatory Programs,\nCenter for Drug Evaluation and Research, FDA", "n_tokens": 40, "kind": "vision"}
{"chunk_id": "Tmorton_NASEM_SOW_4-3-1", "doc_id": "Tmorton_NASEM_SOW_4", "page": 3, "text": "The Opioid Crisis: FDA's Priorities\n\nThis slide is a diagram consisting of four stacked blue rounded rectangles, each containing a numbered priority. The text reads:\n\n1. Decreasing Exposure & Prevent New Addiction\n2. Supporting the Treatment of Those With Opioid Use Disorder\n3. Fostering the Development of Novel Pain Treatment Therapies\n4. Improving Enforcement & Assessing Benefit-Risk\n\nNo charts, tables, or numerical data appear on the slide.", "n_tokens": 91, "kind": "vision"}
{"chunk_id": "Tmorton_NASEM_SOW_4-5-1", "doc_id": "Tmorton_NASEM_SOW_4", "page": 5, "text": "Treatment Guidelines\n\nBullet points:\n- Provide best available evidence for prescribers\n- Support more appropriate prescribing of opioids while ensuring that patients with pain are adequately treated\n- Develop new evidence where needed\n\nThere are no charts, tables, diagrams, or images on this slide.", "n_tokens": 56, "kind": "vision"}
{"chunk_id": "Tmorton_NASEM_SOW_4-10-1", "doc_id": "Tmorton_NASEM_SOW_4", "page": 10, "text": "Thank You\n\nPhotograph of a large multi-story brick building with a light-colored stone central entrance section featuring tall vertical windows or columns. A curved, low pinkish-gray stone retaining wall with small recessed lights runs along a green lawn in the foreground, next to a curved light-colored paved walkway. A black SUV is parked on a road at the right edge of the building. Several green trees stand around the building, and the sky is clear blue with a faint white contrail. No readable text, numbers, charts, or labels appear in the photo.", "n_tokens": 116, "kind": "vision"}
{"chunk_id": "Tmorton_NASEM_SOW_4-11-1", "doc_id": "Tmorton_NASEM_SOW_4", "page": 11, "text": "No slide title is visible. The slide shows only the logo on a plain white background. It contains no charts, tables, diagrams, or other images.", "n_tokens": 31, "kind": "vision"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-0-1", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 0, "text": "Update: Biosimilar Program in the U.S.\n\nPresenter and event text on the slide: Leah Christl, Ph.D., Associate Director for Therapeutic Biologics and Director of Therapeutic Biologics and Biosimilars Staff, CDER/FDA. Medicines for Europe Biosimilar Medicines Conference, April 27, 2018.\n\nImage: On the right side of the slide is a photograph of three or more small glass vials with gray metal caps, arranged in a diagonal row receding into the background. The vials are clear and partially filled with a clear liquid. The background is white to light gray, fading toward the bottom.", "n_tokens": 133, "kind": "vision"}
{"chunk_id": "Update_Biosimilar_Program_in_the_US-7-1", "doc_id": "Update_Biosimilar_Program_in_the_US", "page": 7, "text": "For more information, go to www.fda.gov/biosimilars\n\nThe slide has no separate title. The main text is a centered call to action, \"For more information, go to,\" followed by the web address \"www.fda.gov/biosimilars,\" which is formatted as a blue, underlined hyperlink. The slide contains no charts, tables, diagrams, or other images.", "n_tokens": 87, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-0-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 0, "text": "Use of Bayesian Hierarchical Models in the Presentation of Subgroup Analyses*\n\nMark Rothmann\nU.S. Food and Drug Administration\nDIA Bayesian Scientific Working Group Webinar Series\nNovember 19, 2021\n\nThis slide contains no charts, tables, diagrams, or other images beyond the title text.", "n_tokens": 56, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-1-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 1, "text": "Disclaimer\n\nThe slide has a title, \"Disclaimer,\" and one line of body text: \"* The views expressed in this talk are those of the speaker and not necessarily those of the FDA\"\n\nThere are no charts, tables, diagrams, or other images on this slide.", "n_tokens": 59, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-2-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 2, "text": "Outline\n\nThe slide is a bulleted list with no charts, tables, diagrams, or images. The items, in order, are:\n\nDrug Trials Snapshots (DTS)\nHeterogeneous Treatment Effects\nDifferent Perspectives\nStory\nShrinkage Estimation\nBayesian Hierarchical Models\nExamples\nConcluding Remarks", "n_tokens": 55, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-3-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 3, "text": "Drug Trials Snapshots (DTS)\n\nThis slide has a blue background with a white curved panel on the left side. The slide contains no charts, tables, diagrams, or data. The only other graphic is a black icon in the upper left corner showing a person holding a megaphone. The footer reads \"www.fda.gov\".", "n_tokens": 71, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-5-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 5, "text": "Message from Margaret A. Hamburg, M.D., Commissioner of Food and Drugs\n\nThe slide has a photo on the left and text on the right. The photo shows a smiling woman with shoulder-length dark hair, wearing a dark pinstriped jacket and a pearl necklace. Behind her are a flag with red and white stripes on the left and a blue flag with a yellow emblem on the right. The slide does not contain any charts, tables, or diagrams.\n\nText on the slide:\n\nOne of the core tenets of rigorous biomedical research, as well as a guiding principle of the FDA's goal to meet the health needs of patients across the demographic spectrum, is the importance of encouraging diversity in clinical trials.\n\nWhen a more diverse population participates in clinical trials, we increase the potential to know more about the extent to which different subgroups (males and females, young and old, people of various racial and ethnic backgrounds, and patients with differing comorbid diseases and conditions) might respond to a medical product. And when subgroup data are analyzed, we have available more information about the product that can be communicated to the public. The result is greater assurance in the safety and effectiveness of the medical products used by a diverse population.\n\nFooter: www.fda.gov", "n_tokens": 255, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-9-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 9, "text": "Another difference between snapshots and package inserts\n\nLeft column header: Drug Trials Snapshots\nLeft column text: Subgroup analyses, interpretations and conclusions are those of FDA\n\nRight column header: Package Inserts\nRight column text: Negotiated between FDA and sponsor\n\nThere are no charts, tables, diagrams, or other images on this slide.", "n_tokens": 65, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-10-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 10, "text": "Audience\n\nThis slide contains no charts, tables, diagrams, or images. It has only bulleted text:\n\nShould consider audience when constructing a DTS\n  – What is the effect someone like me can expect?\nIncrease usage of subgroup analysis in Safety\n  – treatment-related adverse events can be more frequent as age increases", "n_tokens": 60, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-11-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 11, "text": "Heterogeneous Treatment Effects (HTE)\n\nThis slide is a section divider with a blue background and a white curved panel on the left side. A black icon of a person holding a megaphone appears in the upper left corner. The website www.fda.gov appears at the bottom center. The slide contains no charts, tables, diagrams, or other images with data.", "n_tokens": 77, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-12-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 12, "text": "Treatment effects vary across subgroups of a factor\n\nBullet points:\n- Factor an effect modifier or\n- Factor associated/correlated with one or more effect modifiers\n\nThe slide contains no charts, tables, diagrams, or images.", "n_tokens": 44, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-19-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 19, "text": "Different Perspectives/Frameworks\n\nThe slide has a blue background with a white curved panel on the left side. The left panel is blank, with no text, charts, tables, diagrams, or images. A black silhouette icon of a person holding a megaphone appears in the upper-left corner. The slide's title text is centered on the right side, and a small \"www.fda.gov\" web address appears at the bottom center.", "n_tokens": 90, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-20-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 20, "text": "Different subgroup analyses perspectives/frameworks\n\nThe slide contains no charts, tables, diagrams, or images. It has two bulleted text items:\n\n- L1: Actual (signed) differences in treatment effects vs\n- L2: Variability in treatment effects", "n_tokens": 49, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-22-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 22, "text": "Estimating treatment effects across subgroups\n\nThe slide has one bullet point: \"No difference in effects is at an extreme location (i.e., τ² = 0).\" The word \"extreme\" is underlined.\n\nThe slide has one diagram, a horizontal line with an arrowhead at the right end. A short vertical tick mark sits at the left end, labeled \"0\" below it. Beneath the 0, the text reads \"τ² = 0\" and then \"100% borrowing,\" positioned at the far left. A large blue right-pointing block arrow sits in the middle of the line, below it, labeled \"Less Borrowing.\" The diagram has no axis units or legend.", "n_tokens": 143, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-23-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 23, "text": "Story\n\nThe slide has a blue background with a white curved shape on the left side and a thin light-blue curved border along its edge. The title \"Story\" appears in white on the right side. In the top-left corner is a black silhouette icon of a person holding a megaphone. Near the bottom center is the small white text \"www.fda.gov\". The slide contains no charts, tables, diagrams, or other images beyond this icon.", "n_tokens": 94, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-25-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 25, "text": "Treatment Decisions\n\nPhysicians make treatment decisions on past experience with patients", "n_tokens": 11, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-27-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 27, "text": "As Previous Experience Grows\n\nObserve the outcomes from more and more males and females\nThe relevancy of the results from males in what the next female can expect. Depends on\n– How similar the results from males are to the results from females\n– How much data on females", "n_tokens": 52, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-30-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 30, "text": "Shrinkage Estimation\n\nThis is a title slide with a blue background and a large white curved panel on the left. It contains no charts, tables, diagrams, or other images beyond a black icon in the top-left corner showing a figure holding a megaphone. The slide text reads \"Shrinkage Estimation\" in white, and the footer shows the website \"www.fda.gov.\"", "n_tokens": 79, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-31-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 31, "text": "What is Shrinkage Estimation?\n\nA shrinkage estimate of a parameter for a subgroup\n– a weighted average of sample estimate and overall estimate (stratified by subgroup).\n• Could be a posterior mean in a Bayesian setting\n– Sample estimate is \"shrunk\" towards the overall estimate", "n_tokens": 58, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-32-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 32, "text": "Amount of Borrowing\n\nThis slide contains a diagram: a horizontal double-headed arrow (a blue line with arrowheads at both ends) with three tick marks along it. Beneath each tick mark is a green box with red text and a black upward arrow pointing to a label in bold black text. Read left to right:\n\n- Left tick mark: green box labeled \"Sample estimate.\" Arrow points to the label \"No borrowing.\"\n- Middle tick mark: green box labeled \"Shrinkage estimate.\" Arrow points to the label \"Some borrowing.\"\n- Right tick mark: green box labeled \"Overall estimate.\" Arrow points to the label \"100% borrowing.\"\n\nThe diagram has no numbers, axis units, or legend entries. The slide number 33 appears in the bottom right corner and at the top left corner.", "n_tokens": 164, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-33-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 33, "text": "Two components of variability in sample estimates across subgroups\n\nThe total variability in the sample estimates is sum of\n- the within subgroup variability of the sample estimator and\n- the across subgroups variability in the underlying/true parameter values\n\nThis slide contains no charts, tables, diagrams, or images.", "n_tokens": 58, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-36-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 36, "text": "Model for Shrinkage Estimation\n\nBullet point: Do Shrinkage Estimation through Bayesian Hierarchical Models\n\nThe slide contains no charts, tables, diagrams, or other images.", "n_tokens": 31, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-37-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 37, "text": "Bayesian Hierarchical Models\n\nThis is a title slide with a blue background and a white curved panel on the left side. A black icon of a presenter holding a megaphone appears in the top-left corner. The title text is centered on the right side in white. The footer shows the website www.fda.gov. The slide contains no charts, tables, diagrams, or other images beyond the presenter icon.", "n_tokens": 83, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-38-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 38, "text": "Hierarchical Models\n\nBullet text: \"Statistical model written in multiple levels (hierarchical form).\"\n\nDiagram: Two side-by-side tree-style layouts. Each has a top-level red rounded rectangle, a row of three orange ovals below it, and a row of green rectangles below the ovals.\n\nLeft group: Red box labeled \"Study 1\". Three orange ovals labeled \"Sub 1\", \"Sub 2\", and \"Sub 3\". Below them are seven green rectangles. The first green rectangle, at the far left, is labeled \"P1\" in small text. Three rectangles sit under Sub 1 (including P1), two under Sub 2, and two under Sub 3.\n\nRight group: Red box labeled \"Study 2\". Three orange ovals labeled \"Sub 1\", \"Sub 2\", and \"Sub 3\". Below them are seven green rectangles with no labels. Three rectangles sit under Sub 1, two under Sub 2, and two under Sub 3.\n\nNo axes, units, legend, or other numbers appear on the slide.", "n_tokens": 232, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-39-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 39, "text": "Linking\n\nBullet text: Treatment effects (e.g., across studies, subgroups, products in the same class) are linked. This linking of the parameters makes their estimation linked.", "n_tokens": 37, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-41-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 41, "text": "Common choice for a model\n\nTreatment effects drawn randomly from the same distribution implies that treatment effects are exchangeable", "n_tokens": 20, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-44-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 44, "text": "Example\n\nThe slide has a blue background with a white curved panel on the left. The title \"Example\" appears in white on the right side. In the top-left corner is a black silhouette icon of a person holding a megaphone. The white panel contains no visible text, charts, tables, or diagrams. The footer reads \"www.fda.gov.\"", "n_tokens": 75, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-45-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 45, "text": "LEADER trial\n\nCardiovascular outcome trial\nLiraglutide vs. placebo\nTime to first major adverse cardiac event\nRule out a hazard ratio greater than 1.3\n\nOverall Result: HR = 0.87, 95% CI (0.78, 0.97)", "n_tokens": 52, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-46-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 46, "text": "Subgroup Analyses\n\nThis is a table with two columns. The first column is headed \"Region.\" The second column is headed \"Results,\" with a sub-header \"HR (95% CI).\"\n\nRows:\n- Asia: 0.62 (0.37, 1.04)\n- Europe: 0.82 (0.68, 0.98)\n- North America: 1.01 (0.83, 1.22)\n- The Rest of The World: 0.83 (0.68, 1.03)", "n_tokens": 109, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-52-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 52, "text": "Example - ACR20 response\n\nThe slide has a blue background with a white curved panel on the left side. The panel is empty. A black icon of a person holding a megaphone appears in the upper left corner. The footer reads \"www.fda.gov\". The slide contains no charts, tables, diagrams, or other images with data.", "n_tokens": 72, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-55-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 55, "text": "Concluding Remarks\n\nThis slide has a blue background with a white curved panel on the left side. A black silhouette icon of a person holding a megaphone appears in the upper-left corner. The slide contains no charts, tables, diagrams, or other images beyond that icon. The footer reads \"www.fda.gov.\"", "n_tokens": 66, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-57-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 57, "text": "Let's Do Things Better\n\nThe slide has no charts, tables, diagrams, or images. It contains only bulleted text:\n\nGreater precision\n– narrower 95% CIs\n\nAddresses random highs and random lows\n– 95% CIs have 95% coverage after the data are known\n\nWhen exchangeability assumptions do not hold, can possibly do even better", "n_tokens": 66, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-58-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 58, "text": "Chapter from a new book\n\nThe slide contains a single block of text citing a reference. There are no charts, tables, diagrams, or images.\n\nCitation text: Pennello G., Rothmann M., Bayesian Subgroup Analysis with Hierarchical Models, in Biopharmaceutical Applied Statistics Symposium Volume 2: Biostatistical Analysis of Clinical Trials, Eds. Karl E. Peace, Ding-Geng Chen, Sandeep Menon, Springer", "n_tokens": 91, "kind": "vision"}
{"chunk_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses-59-1", "doc_id": "UseofBayesianHierarchicalModelsinthePresentationofSubgroupAnalyses", "page": 59, "text": "Thank You! Questions!\n\nThis slide has no charts, tables, diagrams, or images. It contains only the two lines of text above, in large black type on a white background.", "n_tokens": 37, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-3-1", "doc_id": "final_ce_dental_caries", "page": 3, "text": "OPIOID CRISIS AND OPIOID USE DISORDER (OUD)\n\nThis slide is a title slide with a white background. The main title is centered in black text: \"OPIOID CRISIS\" in large bold capitals, followed by \"AND\" in smaller bold capitals, followed by \"OPIOID USE DISORDER (OUD)\" in large bold capitals. The website \"www.fda.gov\" appears in blue text in the bottom left corner. The slide contains no charts, tables, diagrams, or other images.", "n_tokens": 106, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-4-1", "doc_id": "final_ce_dental_caries", "page": 4, "text": "Opioid Crisis\n\nOpioid crisis declared a Public Health Emergency on October 26, 2017.\n\n\"Crisis\" is a broad term covering many aspects of the public health issue:\n- Misuse and Abuse\n- Addiction (Opioid Use Disorder (OUD))\n- Overdose\n- Death\n\nFooter: www.fda.gov", "n_tokens": 65, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-10-1", "doc_id": "final_ce_dental_caries", "page": 10, "text": "SAFETY SIGNAL\n\nThis slide contains only a title, centered in bold black capital letters on a white background. It has no charts, tables, diagrams, or other images. The footer shows the website www.fda.gov in blue text at the lower left.", "n_tokens": 52, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-16-1", "doc_id": "final_ce_dental_caries", "page": 16, "text": "REVIEW OF SAFETY SIGNAL\n\nThis slide contains only a title, centered in bold black uppercase text on a white background. There are no charts, tables, diagrams, or other images. The footer shows the website www.fda.gov in blue text at the bottom left.", "n_tokens": 55, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-23-1", "doc_id": "final_ce_dental_caries", "page": 23, "text": "REGULATORY FRAMEWORK\n\nThis slide has a plain white background with the title \"REGULATORY FRAMEWORK\" centered in bold black capital letters. It contains no charts, tables, diagrams, or other images. The footer shows the website www.fda.gov in blue text at the bottom left.", "n_tokens": 55, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-26-1", "doc_id": "final_ce_dental_caries", "page": 26, "text": "What Can be Changed?\n\n This slide is a mockup of the Highlights of Prescribing Information section of a prescribing information document. Three areas are outlined in red boxes: the boxed warning on the left, a group of sections on the right, and the \"Medication Guide\" reference at the bottom right. The slide has no charts, graphs, or diagrams.\n\n Left column:\n\nHIGHLIGHTS OF PRESCRIBING INFORMATION\n These highlights do not include all the information needed to use PROPRIETARY NAME safely and effectively. See full prescribing information for PROPRIETARY NAME.\n PROPRIETARY NAME (nonproprietary name) dosage form, route of administration, controlled substance symbol\nInitial U.S. Approval: YYYY\n\nRed-boxed warning:\nWARNING: TITLE OF WARNING\nSee full prescribing information for complete boxed warning.\n • Text (4)\n• Text (5.x)\n\nRECENT MAJOR CHANGES\nSection Title, Subsection Title ( x.x) M/YYYY\nSection Title, Subsection Title (x.x) M/YYYY\n\nINDICATIONS AND USAGE\nPROPRIETARY NAME is a {[insert FDA established pharmacologic class text phrase]} indicated for ... (1)\nLimitations of Use\nText (1)\n\nDOSAGE AND ADMINISTRATION\n• Text (2.x)\n • Text (2.x)\n\nRight column:\n\nDOSAGE FORMS AND STRENGTHS\nDosage form(s): strength(s) (3)\n\nRed-boxed section:\nCONTRAINDICATIONS\n• Text (4)\n• Text (4)\n\nWARNINGS AND PRECAUTIONS\n• Text (5.x)\n• Text (5.x)\n\nADVERSE REACTIONS\nMost common adverse reactions (incidence > x%) are text (6.x)\n To report SUSPECTED ADVERSE REACTIONS, contact name of manufacturer at toll-free phone # or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.\n\nDRUG INTERACTIONS\n• Text (7.x)\n• Text (7.x)\nEnd of red-boxed section.\n\n USE IN SPECIFIC POPULATIONS\n• Text (8.x)\n• Text (8.x)\n\nSee 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling OR and Medication Guide\n(\"OR\" and \"Medication Guide\" are underlined; \"Medication Guide\" is inside a red box.)\n", "n_tokens": 466, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-26-2", "doc_id": "final_ce_dental_caries", "page": 26, "text": "Revised: M/YYYY\n\nFooter link: https://www.fda.gov/drugs/fdas-labeling-resources-human-prescription-drugs/prescribing-information-resources", "n_tokens": 45, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-33-1", "doc_id": "final_ce_dental_caries", "page": 33, "text": "REGULATORY ACTION\n\nThis slide contains only a title. It has no charts, tables, diagrams, or images. The slide title is centered in bold black capital letters on a white background. The website www.fda.gov appears in blue text at the bottom left.", "n_tokens": 52, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-40-1", "doc_id": "final_ce_dental_caries", "page": 40, "text": "COMMUNICATIONS PLAN AND PUBLIC RECEPTION\n\nThis slide has a plain white background with centered black text reading \"COMMUNICATIONS PLAN\" in large bold capitals, \"AND\" in smaller bold capitals beneath it, and \"PUBLIC RECEPTION\" in large bold capitals below that. There are no charts, tables, diagrams, or other images on the slide. At the bottom left is the website address \"www.fda.gov\" in blue text.", "n_tokens": 83, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-43-1", "doc_id": "final_ce_dental_caries", "page": 43, "text": "Social Media Reaction\n\nThis slide has no charts, tables, diagrams, or graphs. It shows seven boxed social media posts, one highlighted box, and a web address. Some words in the posts are blacked out. The posts appear in this order:\n\n1. \"Omg I F[redacted]ng knew it! I'm glad they acknowledge it finally!\"\n\n2. \"So that's why some of my teeth are rotting... my teeth were f[redacted] fine at the beginning of the year, and they just nose dived over the last 6 months, with me starting subs in April...\"\n\n3. \"I f[redacted] in knew my teeth issues were from this s[redacted]. Never had any problems before n now teeth r breaking, cavities in all my teeth n have no insurance so what do I have to do? Pull the teeth as they get too bad. It makes me just cry inside as I was so proud of my teeth n constantly brush n floss them. It's so depressing...I rarely smile anymore. \"\n\n4. \"I had strong beautiful teeth when I started [redacted] in 2008. Had to have every single tooth yanked in 2017 for dentures. I couldn't even get implants if they were affordable due to my gums couldn't support them. The above being said. I am still thankful for [redacted] for all of the reasons we take it. I just hate that many of us weren't aware of the dental ramifications. Oh well, at least I DID get healthier once all of those terrible teeth came out of my head!\"\n\n5. \"My teeth my have not been great but when i started using bupe my teeth literally started to break apart after like 6-8 months\"\n\n6. \"This is honestly the biggest thing I did not plan out when I became a junkie. It got exponentially worse in 6 months on subs vs 10 years on heroin. \"\n\n7. \"Yes, I brush and floss regularly. I've had cavities in the past but this is RAPID. like 10 years worth of decay in one year.\"\n\n8. In a green-outlined box at the bottom: \"It good to know they are finally taking notice to long-term side effects of buprenorphine\"\n\n9.", "n_tokens": 498, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-43-2", "doc_id": "final_ce_dental_caries", "page": 43, "text": "Source web address at the bottom: https://www.reddit.com/r/suboxone/comments/s2nifc/warning_to_suboxonesubutex_users_just_got_an_fda/", "n_tokens": 52, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-46-1", "doc_id": "final_ce_dental_caries", "page": 46, "text": "Q & A PANEL\n\nThis slide has no charts, tables, diagrams, or images. It contains only the centered title text \"Q & A\" with \"PANEL\" beneath it, on a plain white background. The footer shows the website www.fda.gov.", "n_tokens": 54, "kind": "vision"}
{"chunk_id": "final_ce_dental_caries-51-1", "doc_id": "final_ce_dental_caries", "page": 51, "text": "No slide title is visible. The slide contains only the FDA logo, which is omitted as requested. It has no charts, tables, diagrams, photographs, legends, numbers, or other text.", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "global_pharmaceutical_quality_summit-0-1", "doc_id": "global_pharmaceutical_quality_summit", "page": 0, "text": "The State of Pharmaceutical Quality\n\nPresenter details: Patrizia Cavazzoni, M.D., Director, Center for Drug Evaluation and Research, Food and Drug Administration, U.S. Department of Health and Human Services.\n\nEvent: Presented at IPA 8th Global Pharmaceutical Quality Summit.\n\nDate: June 22, 2023.\n\nImage: A circular U.S. Department of Health and Human Services seal, in black and white, with the text \"HEALTH & HUMAN SERVICES · U.S.A.\" and \"DEPARTMENT OF\" around the rim, and an eagle-like emblem in the center.", "n_tokens": 121, "kind": "vision"}
{"chunk_id": "global_pharmaceutical_quality_summit-14-1", "doc_id": "global_pharmaceutical_quality_summit", "page": 14, "text": "No slide title is visible. The slide contains no charts, tables, diagrams, or other images beyond the logo, which is omitted as requested. The rest of the slide is blank white space.", "n_tokens": 39, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-1-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 1, "text": "Pharmaceutical Quality\n\nSlide text: \"A quality product of any kind consistently meets the expectations of the user.\"\n\nImages: Three black silhouette icons appear side by side below the text. From left to right, they show a desktop computer monitor with a keyboard base, a car shown in side view, and a mobile phone with a keypad. No labels, numbers, axes, or legend entries appear on the icons.\n\nFooter: www.fda.gov", "n_tokens": 90, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-2-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 2, "text": "Pharmaceutical Quality\n\nThe slide has the text \"A quality product of any kind consistently meets the expectations of the user.\" Below it are four black icons in a row: a desktop computer monitor, a car, a mobile phone, and a capsule pill with one half filled in black. Beneath the icons is the text \"Drugs are no different.\"\n\nFooter text: www.fda.gov", "n_tokens": 78, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-3-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 3, "text": "Patients expect safe and effective medicine with every dose they take.\n\nThe slide has no chart, table, or diagram. The image shows a close-up of a hand holding an orange plastic prescription pill bottle with its cap off, tilted toward the palm. Two white oblong tablets rest in the open palm. The bottle has a white label with a yellow-green stripe, but its printed text is too small and blurred to read. The background is out of focus, with a grayish-blue sleeve visible at the upper right. The text \"www.fda.gov\" appears in small blue type at the bottom left.", "n_tokens": 125, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-4-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 4, "text": "Pharmaceutical quality is\n\nPharmaceutical quality is assuring every dose is safe and effective, free of contamination and defects.\n\nThis slide has a photo of a person's hand holding an orange prescription pill bottle with the cap off and tipped toward the palm. Two white oblong tablets rest in the open palm. The bottle label is blurred and unreadable. The text is overlaid on the photo. The footer reads www.fda.gov. There are no charts, tables, or diagrams.", "n_tokens": 98, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-5-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 5, "text": "It is what gives patients confidence in their next dose of medicine.\n\nThis is a photograph of a person's hand holding an orange plastic prescription pill bottle, tilted with its cap off, over an open palm. Two white oval tablets sit in the palm, and a third white tablet is partly visible behind them. The bottle has a white label with a small yellow-green rectangle on it. The printed text on the label is rotated and blurred, and it is not legible. The background is out of focus, with a grey-blue sleeve at the top right. The slide's large white text overlays the lower-middle part of the image, with \"next\" in italics. The footer in the lower left reads \"www.fda.gov\".", "n_tokens": 157, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-6-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 6, "text": "Communication Expectations and Best Practices\n\nThe slide has a centered image on a pale beige background. It shows overlapping speech bubbles and rounded rectangles in teal, pink, orange, purple, red, yellow, dark blue, magenta, and green. Each bubble contains a white icon: a gear, an envelope, a house, a globe, a thumbs-up, a download arrow, a group of people, a Wi-Fi or signal symbol, an upload arrow, a circular refresh arrow, and chat bubbles. Decorative elements include a dotted arc, dots, lines, small triangles, orange and green chevrons, and a small horizontal scale-like bar. Below the bubbles, the word \"COMMUNICATION\" appears in large letters, each letter in a different color. The slide contains no charts, tables, axis labels, legends, or readable numbers. The footer text reads \"www.fda.gov\".", "n_tokens": 188, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-10-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 10, "text": "SUPPLEMENT COVER LETTER\n\nBullet text: \"Clearly identify the overall proposed change classification as either CBE-0, CBE-30, or PAS. For multiple changes, a summary table listing each changes and the classification with justification for each\"\n\nTable with three columns: \"Change Description,\" \"Filing Category,\" and \"Basis for Classification.\" The column headers \"Change Description,\" \"Filing Category,\" and \"Basis for Classification\" are highlighted in yellow.\n\nRow 1:\nChange Description: \"Removal of excipient Identification Test C testing to align with USP\"\nFiling Category: \"CBE-30\"\nBasis for Classification: \"Guidance for Industry, Changes to an Approved NDA or ANDA, April 2004, Section VIII.C.1.e, classifies \"Relaxing an acceptance criterion or deleting a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements\" as a CBE-30 supplement. As such, the change to delete the excipient Identification Test C testing to align with the USP monograph aligns with the CBE-30 filing category.\"\n\nRow 2:\nChange Description: \"Removal of excipient heavy metal specification to align with USP\"\nFiling Category: \"Annual Report\"\nBasis for Classification: \"FDA Guidance for Industry, Changes to an Approved NDA or ANDA, 2004, Section VIII.C.1.e, classifies \"Relaxing an acceptance criterion or deleting a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements as a CBE-30 supplement. However, per Guidance for Industry: Elemental Impurities in Drug Products, Guidance for Industry, June 2016, Section III.E: changes made to comply with General Chapters <232> and <233> which follow the recommendations of ICH Q3D are considered to have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product may be reported in an annual report. The excipient supplier performed a Risk Assessment in alignment with ICH Q3D guidance. The assessment concluded that the elemental impurity levels are consistently below 30% of the control threshold so additional controls are not required.\"", "n_tokens": 453, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-12-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 12, "text": "MODULE 3\n\nThis slide contains a pyramid diagram of the Common Technical Document (CTD) structure. The pyramid is divided into three horizontal tiers and several sections, with brackets on the sides labeling groups of modules.\n\nTop tier (red triangle tip):\n- \"Regional administrative information,\" labeled \"Module 1.\"\n- A bracket to the right of this tip is labeled \"Not part of the CTD.\"\n\nMiddle tier (purple/lavender band), divided into three columns:\n- Left column: \"Quality overall summary.\"\n- Center column, upper row: \"Non-clinical overview.\"\n- Center column, lower row: \"Non-clinical summary.\"\n- Right column, upper row: \"Clinical overview.\"\n- Right column, lower row: \"Clinical summary.\"\n- A bracket on the left side of the pyramid, spanning the middle tier and bottom-left section, is labeled \"Module 2.\"\n- A bracket on the right side, spanning the middle and bottom tiers, is labeled \"The CTD\" (in green text).\n\nBottom tier (base), divided into three colored sections:\n- Left section (blue): \"Quality,\" labeled \"Module 3.\"\n- Center section (green): \"Non-clinical study reports,\" labeled \"Module 4.\"\n- Right section (dark blue/purple): \"Clinical study reports,\" labeled \"Module 5.\"\n\nLabels and legend: The slide has no separate legend or numerical data. The only text is the labels listed above, including the module numbers 1 through 5 and the bracket labels \"Not part of the CTD,\" \"Module 2,\" and \"The CTD.\"", "n_tokens": 343, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-15-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 15, "text": "DRUG SUBSTANCE MANUFACTURING PROCESS CHANGES\n\nSlide body text:\n- Submissions should include Certificate of Analysis (CoA) for both the Drug Substance and Drug Product Manufacturer\n- If either is missing an Information Request will be issued and this may potentially delay filing classification\n\nThe slide contains no charts, tables, diagrams, or images other than the FDA logo and slide number, which are omitted.", "n_tokens": 71, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-25-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 25, "text": "POST-MARKETING INQUIRIES\n\nTwo bullet points are listed on the slide:\n\nLabeling Supplements: genericdrugs@fda.hhs.gov\n\nANDA Transfer of Ownership, Withdrawal and Consolidation are managed by the Office of Generic Drugs: genericdrugs@fda.hhs.gov\n\nThere are no charts, tables, diagrams, or other images on this slide.", "n_tokens": 72, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-26-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 26, "text": "Thank you!\n\nThe slide has no charts, tables, diagrams, or images. The only text is the large blue cursive words \"Thank you!\" centered on a white background, and the footer web address \"www.fda.gov\" at the bottom left.", "n_tokens": 56, "kind": "vision"}
{"chunk_id": "olugbengaokubadejoAAM2021-27-1", "doc_id": "olugbengaokubadejoAAM2021", "page": 27, "text": "No slide title is visible.\n\nThe slide contains no charts, tables, diagrams, or other images, and no readable text beyond the logo, which is omitted as requested. The rest of the slide is blank white space.", "n_tokens": 45, "kind": "vision"}