Index

A

AAMC. See Association of American Medical Colleges

Abbreviated NDAs, 32

“Academic detailing,” 183

Academic research enterprise, 2, 5, 28, 146.

See also Professional societies

Accelerated approval, 165

Accountability, by the FDA, need for greater, 4

Accutane, 120

ACE inhibitors, 38

Adverse drug reactions

monitoring, 98

Adverse event (AE) reporting, 54, 167

background incidence of, 114

electronic submission of, 109

prevalence of, 113

recommendations concerning, 7, 114115

substantial under-reporting, 55, 109

Adverse Event Reporting System (AERS), 5356, 98, 157, 184

Advertising. See Direct-to-consumer advertising;

Pharmaceutical advertising

Advisory committees, 4446, 179, 211

on communication with the public, 188

and the credibility of safety science, 131142

recommendations concerning, 910, 12, 133134, 188189

timeline for planning meetings of, 45

Advocacy movements, 177

for AIDS treatment, 22, 75

AE. See Adverse event reporting

AERS. See Adverse Event Reporting System

The agency. See Food and Drug Administration

Agency for Healthcare Research and Quality (AHRQ), 21, 25, 113, 180, 183, 212

AIDS treatment advocacy movement, 22, 75

ALLHAT. See Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Alosetron (Lotronex), 59

Amlodipine, 115

Antidepressants, warnings added to labels on, 17, 50

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 115

Appropriations

as source of FDA funding, 13, 19, 23, 118, 193, 196, 198

Approval process, 27

accelerated, 165

confirmatory studies, 115119

safety signal generation, 108110



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The Future of Drug Safety: Promoting and Protecting the Health of the Public Index A AAMC. See Association of American Medical Colleges Abbreviated NDAs, 32 “Academic detailing,” 183 Academic research enterprise, 2, 5, 28, 146. See also Professional societies Accelerated approval, 165 Accountability, by the FDA, need for greater, 4 Accutane, 120 ACE inhibitors, 38 Adverse drug reactions monitoring, 98 Adverse event (AE) reporting, 54, 167 background incidence of, 114 electronic submission of, 109 prevalence of, 113 recommendations concerning, 7, 114–115 substantial under-reporting, 55, 109 Adverse Event Reporting System (AERS), 53–56, 98, 157, 184 Advertising. See Direct-to-consumer advertising; Pharmaceutical advertising Advisory committees, 44–46, 179, 211 on communication with the public, 188 and the credibility of safety science, 131–142 recommendations concerning, 9–10, 12, 133–134, 188–189 timeline for planning meetings of, 45 Advocacy movements, 177 for AIDS treatment, 22, 75 AE. See Adverse event reporting AERS. See Adverse Event Reporting System The agency. See Food and Drug Administration Agency for Healthcare Research and Quality (AHRQ), 21, 25, 113, 180, 183, 212 AIDS treatment advocacy movement, 22, 75 ALLHAT. See Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Alosetron (Lotronex), 59 Amlodipine, 115 Antidepressants, warnings added to labels on, 17, 50 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 115 Appropriations as source of FDA funding, 13, 19, 23, 118, 193, 196, 198 Approval process, 27 accelerated, 165 confirmatory studies, 115–119 safety signal generation, 108–110

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The Future of Drug Safety: Promoting and Protecting the Health of the Public safety signal strengthening and testing, 110–115 shortening, 107–119 speed of, 16 APPROVe trials, 55 Association of American Medical Colleges (AAMC), 142, 211 Automated healthcare databases, 7, 114–115 Azidothymidine (AZT), 37 B Bain report, 32 Bayesian analysis, 109–110 Best Pharmaceuticals for Children Act, 57, 152, 165 “Best practices,” disseminating, 87–88 Bias, intellectual, 141 Biologics license application (BLA) submissions, 42 numbers of new approvals, 42 Biotechnology Industry Organization (BIO), 88 Bioterrorism and Preparedness and Response Act, 23 BLA. See Biologics license application submissions Black box warnings, 50, 58–59 Black triangle, 170–171 Booz Allen Hamilton, 211 Boston Consulting Group, 123 British National Formulary, 170 Bromfenac, 38 Bureau of Labor Statistics, 92 Bush, President George W., 88, 207 C C-Path Institute, 213 Calcium-channel blockers, 115 Cardiovascular risks, 112, 116 CBER. See Center for Biologics Evaluation and Research CDC. See Centers for Disease Control and Prevention CDER. See Center for Drug Evaluation and Research CDRH. See Center for Devices and Radiological Health Celecoxib, 17 Center for Biologics Evaluation and Research (CBER), 49, 129, 188 Center for Devices and Radiological Health (CDRH), 188 Center for Drug Evaluation and Research (CDER), ix–x, 15, 21, 31, 46–47, 49, 65, 105, 179, 193–202, 205. See also Organizational dysfunction in the CDER culture; Solutions proposed for CDER’s organizational dysfunction credibility of, 85 history of funding, 194 IT needs within, 202 organizational culture in, 4, 66 press coverage of internal problems in, 2 recommendations concerning review teams, 10, 146–147 relevant changes at, 210 shepherding products through trials, 154 staffing, 195, 199–200 Center for Outcomes and Evidence, 212 Centers for Disease Control and Prevention (CDC), 81, 112, 128 Centers for Education and Research on Therapeutics (CERTs), 109 Centers for Medicare and Medicaid Services (CMS), 21, 25, 115, 180–181, 201 Central Hudson Gas & Electric Corp. v. Public Service Commission, 159–160 Cerivastatin, 17, 109 CERTs. See Centers for Education and Research on Therapeutics CFR. See Code of Federal Regulations Changes at the FDA during course of study, 205–215 Critical Path Initiative and partnerships, 212–213 Drug Safety Initiatives, 205 Drug Safety Oversight Board, 205–206 Drug Watch Web page, 206 labeling, 210 leadership changes in the FDA, 207–208 other relevant changes at the FDA and CDER, 210 program reviews or evaluations, 211–212

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The Future of Drug Safety: Promoting and Protecting the Health of the Public recent materials from the FDA, 208–209 structural changes and leadership changes in the CDER, 206–207 Changes in the broad context of drug regulation, 19–21 The charge (to the committee), 21–24 defining and meeting, 21–28 disclaimers, 24–25 the shifting landscape of drug safety, 26 study process, 25–26 toward a new vision of drug safety, 26–28 Chlorthalidone, 115 Cisapride, 50, 109, 168 Citizens’ Advisory Committee, 130 Clinical development, PDUFA goal for, 42 Clinical holds, 154 Clinical investigation (phase 2) studies, 35 Clinical pharmacology (phase 1) studies, 35 Clinical review templates, in postmarketing, 79–80 Clinical trials, 76, 153 early, and related studies, 34–35 formal (phase 3), 35 in IND submission and review, and their limitations, 37–39 premarket, 38 recommendations regarding, 10, 144–145 clinicaltrials.gov, 143, 145 Clozapine, 168 CMS. See Centers for Medicare and Medicaid Services Code of Federal Regulations (CFR), 153, 159 COI. See Conflict of interest considerations Commissioner of the FDA, 5–6, 9, 92–93, 131. See also individual commissioners instability in the office of, 5, 88–89 Committee on Identifying and Preventing Medication Errors, 24 Committee on Patient Education, 187 Committee on the Assessment of the US Drug Safety System, 2, 17, 65, 105, 178 charge to, 21–24 Communication about safety, 27, 177–192 FDA’s challenges in, 4, 184–190 how industry communicates to the public and patients, 184, 188 improving, 187–190 between providers and the drug safety system, 181–184 between the public and the drug safety system, 178–179 recommendations concerning, 12–13, 188–189 roles and needs of providers and patients, 178–184 structure needed to support an effective drug safety system, 4 Confirmatory studies, 143n reducing uncertainty about risk and benefit after approval, 115–119, 122 Conflict of interest (COI) considerations, 45, 86, 93, 134–142 appearance of, 73 “cover memos” regarding, 135–139 recommendations concerning, 141–142 zero-tolerance policy regarding, 140–141 Congress, 2, 4, 8, 48, 66, 69, 95, 97, 117–119, 153 ensuring that CDER receives needed authority and assets, x, 18 periodic reports to, 23, 71, 197, 202 recommendations to, 6–8, 11–13, 98–100, 117–119, 169–172, 197–203 “Consults,” 78–79, 82 Consumer Bill of Rights, 177 Consumer medication information, 185–187 criteria for useful, 187 Consumer Price Index, 23 Consumer Product Safety Commission, 114 Consumers. See also AIDS treatment advocacy movement; The public empowering, 20 organizations of, 4, 66 representatives of, 179 Council of Public Representatives (COPR), 190 “Cover memos” regarding COI considerations, 135–139 CPI. See Critical Path Initiative Crawford, Acting FDA Commissioner Lester M., 207 Credibility of safety science, 126–147 advisory committees, 131–142 expertise in the CDER, 127–131 transparency, 142–147

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Critical Path Initiative (CPI), 33, 70n, 105, 201, 207, 211–213 report on, 20 Critical Path Opportunities Report, 212–213 Culture of safety in CDER, 27, 65–104 difficulties changing, 90 the external environment, 68–75 organizational challenges, 65–100 solutions proposed for CDER’s organizational dysfunction, 90–100 structural factors, policies, and procedures, 75–90 D “DailyMed” health information clearinghouse, 210 Data management, 39–40 Databases automated, 56 mining, 57, 157 DCLG. See Director’s Consumer Liaison Group DDMAC. See Division of Drug Marketing and Communication DDRE. See Division of Drug Risk Evaluation “Dear Health Practitioner” letters, 58, 158 DEcIDE. See Developing Evidence to Inform Decisions about Effectiveness Network Decision-making concerning postmarket safety of a drug, ix, 47 political considerations in, 90 regulatory, by the FDA, ix science-based, 66, 129 Department of Defense (DoD), 118 Department of Health and Human Services (DHHS), 2, 18, 41, 71, 74n, 93n, 113, 153, 180, 205. See also Secretary of Health and Human Services Department of Health, Education, and Welfare (DHEW), 74n Department of Veterans Affairs (VA), 21, 92, 112–113, 201 “Detailing,” 18, 158, 183–184 academic, 183 Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network, 113, 180 Development cost, of drugs, 32 DHEW. See Department of Health, Education, and Welfare DHHS. See Department of Health and Human Services Dietary supplements, 153 Differing professional opinion (DPO) procedure, 47n Direct-to-consumer (DTC) advertising, 21, 52–53, 158–164, 167, 171–172 court challenges to restricting, 159 deterrence of excessive, 198 need for more robust standards of assessment, 189 recommendations concerning, 11–12, 169–172 Director’s Consumer Liaison Group (DCLG), 190 Disagreement in the face of uncertainty, 127 nurturing a culture that values, 94 scientific, 85–87 Discipline reviews, 79 different perspectives of, 86 Disclaimers, 24–25 Disclosure requirements, 141 Dispute resolution, 84 in NDAs, 47–48 Division of Drug Marketing and Communication (DDMAC), 52, 78, 159, 163, 179 “DDMAC Watch,” 162 Division of Drug Risk Evaluation (DDRE), 32, 36, 51, 56 Division of Neurology Products (DNP), 36 DoD. See Department of Defense DPO. See Differing professional opinion procedure Drug approval process limitations on, 59 pressure to speed up, 22, 40 Drug Development Science Obstacles and Opportunities for Collaborations, 211 Drug industry. See Pharmaceutical industry Drug Price Competition and Patent Term Extension Act, 152 Drug Regulation Reform Act, 156 Drug safety communication about, 27, 177–192 culture of safety in CDER, 27 experts in, 66

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The Future of Drug Safety: Promoting and Protecting the Health of the Public regulatory process and agency able to protect the public health, 27 rigorous science of, 27 the shifting landscape of, 26 toward a new vision of, 26–28 warning the public about risks, 1 Drug safety activities, actionable performance goals for, 97 Drug Safety and Risk Management (DSaRM) Advisory Committee, 46, 87, 112, 133–134, 187 Drug Safety Initiative, 205 Drug Safety Management Board, 144 Drug Safety Oversight Board (DSB), 47, 82, 86–87, 99, 185, 187–188, 205–206 Drug safety system, 3–4, 17 committee convened to assess, 2 communicating with providers, 181–184 communicating with the public, 178–179 communication structure needed to support effectively, 4 financial resources required to enable CDER to support the FDA mission, 4 impairment in, 4 organizational culture of CDER, 4 regulatory authority necessary to provide for drug safety, 4 regulatory science and processes necessary to enhance drug safety, 4 resources for, 4–5, 13–14, 166, 193–204 Drug Watch Web site, 57, 99, 179, 185, 187, 205–206 Drugs. See also New drugs; Prescription drugs; Sponsors of drugs; individual drugs cited conditions linked to, 54 cost of, 178 development costs, 32 effectiveness of, 107 generics, 159 life-saving for specific patients, 1 “lifestyle,” 21 mechanisms of action, 2 milestones in lifecycle of, 167 over-the-counter, 90 pediatric, 165 potential benefit of, 34 promotion and information, postmarket, 52–53 promotion to patients greatly increased, 21 DSaRM. See Drug Safety and Risk Management Advisory Committee DSB. See Drug Safety Oversight Board DTC advertising. See Direct-to-consumer advertising E Economic impact of drugs, 32 Electronic medical records, 117 Electronic submission, of adverse event reports, 109 “End of phase 2 meeting,” in IND submission and review, 35–36 Enforcement tools, 163, 166–167 decisions about, 58 Enhancing Drug Safety and Innovation Act, 201n Environmental Protection Agency, 197n Epidemic Intelligence Service program, 128 Epidemiologic studies, 76, 86, 115, 201 Epidemiologists, safety teams of, 88 European Medicines Agency, 54, 158, 173, 211 Evaluation of FDA’s First Cycle Review Performance—Retrospective Analysis, 209 Exceptions, in FDA’s regulatory authority, 165 Expectations of multiple constituencies, conflicting, 69 Expertise in the CDER, and the credibility of safety science, 127–131 in preapproval evaluation for the PDUFA IV, 98 External environment in CDER’s organizational dysfunction, 68–75, 97–100 the FDA-industry interface, 70–75 F Fast track studies, 39 FDA. See Food and Drug Administration FDA Science Board, 129

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The Future of Drug Safety: Promoting and Protecting the Health of the Public FDAMA. See Food and Drug Administration Modernization Act FD&C. See Food, Drug, and Cosmetic Act Federal Advisory Committee Act, 116, 146, 190 Federal advisory committees, on consumer issues, examples of, 190 Federal Aviation Administration, organizational problems at, 67, 91 Federal Communications Commission, 92, 197n Federal Register, 45, 156, 161, 186 Federal Trade Commission (FTC), 160 Financial resources. See Resources for the drug safety system First Amendment protections, of truthful commercial speech, 159, 161–162, 171, 183 Food and Drug Administration (FDA), ix–x, 1–12, 15, 23–25, 65, 105, 177, 180–181, 205. See also Commissioner of the FDA; Recent FDA materials approval but not a lifetime guarantee, 2 challenges in communicating to the public and patients, 184–190 consumer medication information from, 185–187 credibility of, 4–5, 70, 85, 88, 132 filing and review of submitted marketing applications, PDUFA goal for, 43 history of drug regulation by, 152–153 history of DTC advertising regulation by, 160–161 improving communication with the public, 187–190 increasingly dependent on industry funding, 71 interface with industry, 70–75 need for greater accountability and transparency by, 4 need for increased resources, 151, 193 oversight and review of clinical trial protocols during development, PDUFA goal for, ix, 42 public confidence in eroded, 15 “regulatory capture” of, 73–74, 155, 196–197 regulatory decision-making by, ix relevant changes at, 210 reports from, 20, 209 response to public meeting input, 185 Science Board, 129 Food and Drug Administration (FDA) authority, 51, 151. See also Direct-to-consumer (DTC) advertising; Strengthening FDA’s regulatory authority after approval, 155–164 to compel completion of postmarketing commitments, 155–157 exceptions in, 165 guidance documents, 41, 208–209 oversight of sponsor promotional activities, 158–164 preapproval, 37, 154–155 recommendations concerning, 11, 170 to unilaterally impose risk-reducing remedies, such as label changes and distribution restrictions, 157–158 Food and Drug Administration Modernization Act (FDAMA), 143, 152, 156 Food, Drug, and Cosmetic (FD&C) Act, 16, 22–23, 48, 51, 69, 90, 152, 156, 159, 184 Drug Amendments to, 16, 152 Food Research Laboratory, 129 FTC. See Federal Trade Commission Funding. See Resources for the drug safety system; User-fee funding system G Galson, CDER Director Steven, 207 GAO. See Government Accountability Office Gates Foundation, 212 “General applicability” matters, 134n General Practice Research Database (GPRD), 112, 200 Generic drugs, 159 Goals. See Performance goals Government Accountability Office (GAO), 36, 57, 66, 71–72, 92, 158, 163 Government agencies compared with private-sector counterparts, 68–69 roles of, 180–181 GPRD. See General Practice Research Database

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The Future of Drug Safety: Promoting and Protecting the Health of the Public GRMP. See Guidance for Review Staff and Industry: Good Review Management Principles and Practices for PDUFA Products Guidance documents, 208–209 compared to MAPPs, 77n writing, 41 Guidance for Industry: Consumer-Directed Broadcast Advertisements, 161 Guidance for Industry: Development and Use of Risk Minimization Action Plans, 119, 208 Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment, 208 Guidance for Industry: Investigators, and Reviewers Exploratory IND Studies, 208 Guidance for Industry: Premarketing Risk Assessment, 208 Guidance for Review Staff and Industry: Good Review Management Principles and Practices for PDUFA Products (GRMP), 78 Guidance on Conflict of Interest for Advisory Committee Members, Consultants and Experts, 134 H Health, commodification of, 184n Health care delivery system, 2, 5, 28, 69, 177 Health care entities, 4–5 Healthcare databases, automated, 7, 114–115 Henney, FDA Commissioner Jane, 16, 89 Hinchey Amendment, 45 History of the Food and Drug Administration (FDA) CDER funding, 194 CDER staffing, 195 drug regulation by, 152–153 DTC advertising regulation, 160–161 milestones in, 22–23 HIV/AIDS crisis, 22. See also AIDS treatment advocacy movement HMO Research Network, 111–112 Human subjects, protecting, 33–34 Hypothesis-testing studies, 143 I ICH. See International Conference on Harmonisation IND. See Investigational New Drug submission and review process Indications, re-examination for new, 167 The industry. See Pharmaceutical industry Infliximab, 109 Information technology (IT). See also Databases; Medication information; Reference information needs within the CDER, 202 Ingenix Inc., 111–112 Initial filing review, 40–41 in NDAs, 40–41 Innovation or Stagnation?—Challenge and Opportunity on the Critical Path to New Medical Products, 212 Instability at the top, and CDER’s organizational dysfunction, 88–90 Institute of Medicine (IOM), ix–x, 2–3, 21, 24, 50, 66–67, 178, 182 Committee on Identifying and Preventing Medication Errors, 24 workshops, 143 Institutional review boards (IRBs), 33 Integrated Promotional Services, 56 Intellectual bias, 141 Interdisciplinary tension, 76 International Conference on Harmonisation (ICH), 54, 145, 208 International Society of Pharmacoepidemiology (ISPE), 112, 128 Interoffice polarization, and CDER’s organizational dysfunction, 83–85 Investigational New Drug (IND) submission and review process, 25–26, 33–39 completion of clinical trials and their limitations, 37–39 early clinical trials and related studies, 34–35 “end of phase 2 meeting” and phase 3 trials, 35–36 pre-new drug application submission meeting, 33, 39 roles of the OND and the ODS/OSE premarket, 36–37 IOM. See Institute of Medicine iPLEDGE, 121, 167–168 IRBs. See Institutional review boards

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Isotretinoin, 50, 120, 167–168 ISPE. See International Society of Pharmacoepidemiology IT. See Information technology K Kaiser Foundation Research Institute, 111–112 L Labeling, 49–51, 167–168. See also Off-label use; Symbol needed to denote limited knowledge about new drugs changes, 167 FDA authority to unilaterally impose changes, 157–158 negotiations, 50 recommendations concerning, 11–12, 169–172 relevant changes at the FDA and CDER, 210 Leadership changes at the CDER, 206–207 changes at the FDA, 207–208 in solving CDER’s organizational dysfunction, 91–94 Letters “Dear Health Practitioner,” 58, 158 sent to drug sponsors in NDAs, 51 Lifecycle approach to drug safety, conditions and restrictions on distribution throughout, 96, 167–170 to drugs, 26, 126 to risk and benefit, 28, 96 “Lifestyle” drugs, 21 Lotronex, 59 M Management Advisory Board, appointing an external, 6, 93–94 Management issues in CDER’s organizational dysfunction, 79–90 performance goals for the PDUFA IV, 100 solving, 90–91 Management studies, 68, 89–90, 95 Manual of Administrative Policies and Procedures (MAPPs), 47n, 77, 95 Mechanisms of action. See also New molecular entities of drugs, 2 MedDRA. See Medical Dictionary for Regulatory Activities MedGuides, 50, 157, 186 Medical Dictionary for Regulatory Activities (MedDRA), 54, 57 Medical Officer Retention Subcommittee, 82 Medical records, move toward electronic, 117 Medicare Modernization Act, 113 Medicare Part D, 19, 113 Medication guide, 157. See also MedGuides Medication information, private-sector developers of, 186 Medicine Plus program, 181 Medicines and Health products Regulatory Agency (MHRA), 170 MedWatch reporting system, 53–54, 109–110, 184 MHRA. See Medicines and Health products Regulatory Agency Murglitazar, 107 N NAS. See National Academy of Sciences Natalizumab, 168 National Academies Public Access Records Office, 26n National Academy of Sciences (NAS), 92 National Aeronautics and Space Administration, organizational problems at, 67, 82 National Cancer Institute (NCI), 190 National Disease and Therapeutic Index, 56 National Electronic Injury Surveillance System–Cooperative Drug Adverse Event Surveillance System (NEISS–CADES), 114 National Health Service, 171 National Institute for Health and Clinical Excellence (UK), 125 National Institute of General Medical Sciences, 128 National Institutes of Health (NIH), 20–21, 55, 81, 92, 116, 118, 180, 190

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The Future of Drug Safety: Promoting and Protecting the Health of the Public National Library of Medicine (NLM), 143, 145, 180–181, 183 National Prescription Audit, 56 National Science Foundation (NSF), 92 Natural history of a drug, 31–64 economic impact of drugs, 32 IND submission and review, 33–39 new drug applications, 39–51 postmarket period, 51–59 NCI. See National Cancer Institute NDAs. See New Drug Applications Needs, of providers and patients, 178–184 Negotiations, about label wording, 50 NEISS–CADES. See National Electronic Injury Surveillance System–Cooperative Drug Adverse Event Surveillance System New Drug Applications (NDAs), 22–23, 32, 39–51, 106. See also Abbreviated NDAs; Supplemental NDAs advisory committees, 44–46 assembly of review team and beginning of review, 41, 43–44, 77, 96 composition of review teams, 78, 83 dispute resolution, 47–48 initial filing review, 40–41 key review meetings, 48 letters sent to sponsors, 51, 79 PDUFA timetables and performance goals triggered, 40 postapproval requirements and labeling, 49–51 review teams, 6, 41, 43–44, 77, 96 RiskMAPs, 48–49 safety tracking, 46–47 site inspections, 51 New drugs, 2, 38, 107–119, 165 New molecular entities (NMEs), 41–44, 98, 106, 166 numbers of priority and standard approvals, 42 priority reviews of, 41, 133 recommendations concerning, 9, 12, 133–134, 173 New vision of drug safety, 26–28 NIH. See National Institutes of Health NLM. See National Library of Medicine NMEs. See New molecular entities NSF. See National Science Foundation O ODS/OSE. See Office of Drug Safety/Office of Surveillance and Epidemiology Off-label use, 122 Office of Drug Safety/Office of Surveillance and Epidemiology (ODS/OSE), 32, 48–57, 67, 75–78, 83–86, 129, 146, 207 role in IND submission and review, 36–39 staffing, 107 Office of Drug Safety Policy and Communication. See Office of Safety Policy and Communication Office of Generic Drugs, 32 Office of the Inspector General (OIG), 71, 156 Office of Management and Budget, 18, 95 Office of New Drug Chemistry, 78 Office of New Drugs (OND), 32–36, 51, 56–57, 67, 75–79, 82–86, 105, 146, 194–195, 206–207 role in IND submission and review, 36–37 Office of Safety Policy and Communication, 13, 185, 187, 189, 207 OIG. See Office of the Inspector General OND. See Office of New Drugs Opinion differences and CDER’s organizational dysfunction, 85–87 Organizational dysfunction in the CDER culture, 4, 65–100. See also Solutions proposed for CDER’s organizational dysfunction inconsistency, 87–88 instability and politicization, 88–90 internal disagreements about handling of safety issues, 47 interoffice polarization, 83–85 management issues, 79–81 mass media coverage of, 66, 84 policies, and procedures in solving, 77–90 recommendations concerning, 5–7 scientific disagreement and differences of opinion, 85–87 structural factors, 75–77 suboptimal work environment, 81–83 Orphan Drug Act, 152 Over-the-counter (OTC) drugs, 90, 153

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The Future of Drug Safety: Promoting and Protecting the Health of the Public P Package inserts, for patients, 185 Patient Health Advisories, 206 Patient package inserts, 185 Patients, 2, 5 access to drugs, 16 advocacy movements for, 177 more engaged and knowledgeable, 21 need to reassure, 147 roles and needs of, 178–184 PDUFA. See Prescription Drug User Fee Act Pediatric drugs, 165 Peer-review, 118 recommendations concerning, 12, 173 Performance goals (suggested for) PDUFA IV, 98–100 in performance report to Congress, 98–100 safety-related, 98–100 Pharmaceutical advertising. See also Direct-to-consumer advertising tax deductibility of, 199 Pharmaceutical drugs. See Drugs Pharmaceutical industry, 2, 146, 177. See also Sponsors of drugs; User-fee funding system communications with the public and patients, 158, 184, 186 credibility of, 4–5, 70 social responsibility of, 119 Pharmaceutical Research and Manufacturers of America (PhRMA), 89, 123, 143, 162–163, 196 guiding principles on DTC advertising, 164 Pharmacoepidemiology need for career-development awards in, 128 recommendations concerning, 9, 134–141 Pharmacogenomics, 34 Pharmacovigilance, 208 Phases of clinical trials and medicine development, 35 phase 1–clinical pharmacology studies, 34–35, 37 phase 2–clinical investigation studies, 34–35, 37 phase 3–formal clinical trials, 35–36, 124 phase 4–postmarketing surveillance, including further formal therapeutic trials, 35, 55, 106, 111, 117, 133, 157, 211 Plan B (emergency contraceptive), 89–91 Planning advisory committee meetings, timeline for, 45 Polarization, interoffice, 66, 68, 80–85 Policies and procedures, and CDER’s organizational dysfunction, 77–79 Political considerations, in decision-making, 90–91 Politicization, and CDER’s organizational dysfunction, 88–90 Postmarketing safety of a drug, 51–59, 95–97 decision-making concerning, ix, 47 drug promotion and information, 52–53 identifying and evaluating spontaneous safety signals, 56–58 need to monitor, 59, 74, 156 postmarket data, 55–56 recommendations concerning, 8, 127–131 regulatory actions, 58–59 requirements and labeling, in NDAs, 25, 49–51 risk communication activities and risk management for the PDUFA IV, 99 spontaneous adverse event reporting system, 53–55 Postmarketing study commitments, 155, 172–173, 211 for the PDUFA IV, 99 Postmarketing surveillance, including further formal therapeutic trials (phase 4), 35 PPP. See Pregnancy Prevention Program; Public-private partnership Pre-new drug application submission meeting, 39 Preapproval period, 37, 123, 154–155 safety conferences during, 48 Predictive Safety Testing Consortium, 213 Pregnancy Prevention Program (PPP), 120 Premarket clinical trials, 38 Prescribers’ understanding, 5 Prescription Drug User Fee Act (PDUFA), 15, 66, 70–74, 116, 154–155, 193. See also User-fee funding system clinical development of, 42 deadlines in, 49

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The Future of Drug Safety: Promoting and Protecting the Health of the Public FDA filing and review of submitted marketing applications, 43 FDA oversight and review of clinical trial protocols during development, 42 goals of, 42–43 in NDAs, 40 PDUFA I, 16, 23, 72 PDUFA II, 16, 23, 35–36, 40, 72–73 PDUFA III, 35–36, 40, 48–49, 73, 121 PDUFA IV, 98–100 Reauthorization Performance Goals and Procedures, 23 short history of, 72–73 sponsor-requested meetings with FDA during clinical development, 42–43 sunset of approaching, 19 timetables and performance goals triggered, 40 Prescription Drug User Fee Act (PDUFA): Adding Resources and Improving Performance in FDA Review of New Drug Applications, 209 Prescription drugs off-label use, 122 providers’ knowledge about, 179 safety of, 1–2 taking multiple, 153 Prescriptions, taxing, 198 Preventing Medication Errors, 50, 178, 182 recommendations from, 180–183 Princeton Survey Research Associates, 162 Priority reviews, 133 of new molecular entities, 41 Product seizures, 58 Product submissions, reductions in, 133 Professional opinions. See Differing professional opinion procedure Professional societies, 4–5 Program reviews or evaluations, 211–212 advisory committees, 211 partnerships, 211–212 postmarketing study commitments, 211 Project managers, 34 Promotion of drugs to patients. See also Direct-to-consumer advertising; Pharmaceutical advertising increases in, 21 Propulsid, 17 Protection of human subjects, 33 Providers, roles and needs of, 178–184 The public, 2, 5, 28 improving communication with, 187–190 perspectives on DTC advertising, 162 Public Employees for Environmental Responsibility, 86n Public Health Advisories, 206 Public-private partnership (PPP), 8, 117–119, 201 Pure Food and Drug Act, ix, 19n, 22, 152, 184 Q Quality-adjusted life years (QALYs), 125 R Randomized controlled trials, 86 Rationale for strengthening drug regulation, 164–166 realistic regulatory action on safety needed, without the “last call” of approvals, 166 Reauthorization Performance Goals and Procedures (PDUFA), 23, 196–199 Recent FDA materials, 208–209 guidance documents, 41, 208–209 reports, 209 Recommendations, 5–14 adverse event reporting, 7, 114–115 advisory committees, 9–10, 12, 133–142, 188–189 AERS, 7, 110 amending the FD&C Act, 5–6, 92–93 automated healthcare databases, 7, 114–115 better science and expertise, 7–10 CDER review teams, 10, 146–147 clinical trials, 10, 144–145 for the Commissioner of the FDA, 5–6, 9, 92–93, 131 communication about safety, 12–13, 188–189 conflicts of interest, 10, 141–142 for Congress, 6–8, 11–13, 98–100, 117–119, 169–172, 197–203 for consumers, 180–181 direct-to-consumer advertising, 11–12, 169–172

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The Future of Drug Safety: Promoting and Protecting the Health of the Public external Management Advisory Board, 6, 93–94 FDA authority, 11, 170 labeling, 11, 169–170 NDA, 10, 144–146 NDA review teams, 6, 96 new molecular entities, 9, 12, 133–134, 173 Office of Drug Safety Policy and Communication, 13, 189 organizational culture, 5–7 peer-review, 12, 173 pharmacoepidemiology, 9, 134–141 postmarketing safety of a drug, 8, 127–131 from Preventing Medication Errors, 180–183 for providers and patients, 182–183 public-private partnership, 8, 117–119 regulation, 10–12 resources, 13–14, 197–203 risk-benefit analyses, 8, 125–126 risk management, 11, 169–170 RiskMAPs, 8, 121 safety-related performance goals for the PDUFA IV, 6–7, 98–100 for the Secretary of DHHS, 6, 8, 93–94, 117–119 Reference information, access to comprehensive, 182 Regulatory activities for safety, 4, 31. See also Enforcement tools in the postmarket period, 58–59 realistic needed, without the “last call” of approvals, 166 recommendations concerning, 10–12 Regulatory authority necessary to provide for drug safety, 4, 27, 151–176. See also Food and Drug Administration authority an aging and inadequate statutory framework, 153–166 history of FDA drug regulation, 152–153 strengthening FDA’s regulatory authority, 167–173 “Regulatory briefings,” 46 “Regulatory capture” of the FDA, 73–74, 155, 196–197 Regulatory “tool kit,” 168, 213 Research. See Academic research enterprise Resources for the drug safety system, 5, 166, 193–204 levels required to enable CDER to support the FDA mission, 4 recommendations concerning, 13–14, 197–203 Review elements for new drug approval beginning in NDAs, 41, 43–44 current, 52 data on NMEs, 172–173 meetings key in NDAs, 48 Review Panel on New Drug Regulation, 74, 155–156, 172 Review teams, 34 composition of, 78, 83 in NDAs, assembling, 41, 43–44 Risk-benefit analyses for approval decisions, 106–107, 166 evolving throughout the drug’s lifecycle, 2, 4, 96, 121–126 recommendations concerning, 8, 125–126 Risk communication activities, 27 postmarket, 97 Risk management postmarket, 97 recommendations concerning, 11, 169–170 Risk Minimization Action Plans (RiskMAPs), 119–121, 146, 167 developing and assessing, 57, 158 in NDAs, 48–49 Rofecoxib, 17, 55, 168 Roles, of providers and patients (in drug safety system), 5, 178–184 Rolling reviews, 39–40 S Safety data, gaps in, 37 Safety officers, 37 Safety-related performance goals for the PDUFA IV, 98–100 expertise in preapproval evaluation, 98 monitoring of adverse drug reactions and the AERS, 98 performance management, 100 postmarketing risk communication activities and risk management, 99 postmarketing study commitments, 99

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The Future of Drug Safety: Promoting and Protecting the Health of the Public Safety signals, 27, 84. See also Spontaneous safety signals in the postmarket period in generation, 108–110 reducing uncertainty about and benefit after approval, 108–115 in strengthening and testing, 110–115 Safety teams, of epidemiologists, 88 Safety “tool kits,” 213 Safety tracking, 46–47 in NDAs, 46–47 Science-based decision-making, 66, 129 Science of safety, 27, 105–150 benefits after approval, 107–119, 122 credibility of, 126–147 generating, 106–126 and recommendations concerning expertise, 7–10 reducing uncertainty about, 107–119, 122 rigor in, 27 risk-benefit analyses throughout the drug’s lifecycle, 121–126 risk minimization action plans, 119–121 understanding risk and benefit for approval decisions, 66, 106–107 Scientific advances, 28. See also Academic research enterprise increasing the numbers of targeted drugs, 20 Scientific disagreement, and CDER’s organizational dysfunction, 85–87 Scientific reviewers, 34 Secretary of Health and Human Services, 6, 45, 93–94, 97 Sector maps, 110 Signals. See Safety signals Site inspections, 51 in NDAs, 51 SMART (System to Manage Accutane Related Teratogenicity), 120–121 Social Security Administration, 92 Solutions proposed for CDER’s organizational dysfunction, 90–100 agency leadership, 91–94 external environment, 97–100 management, 90–91 structural factors, 94–97 “Special Government Employees,” 131, 211 Special symbol needed to denote limited knowledge about new drugs, 170–172. See also Black triangle Sponsors of drugs letters sent to, 51 materials generated by, 52 meeting with FDA during clinical development, PDUFA goal for, 42–43 non-compliance by, 18 obligations of, 34 Spontaneous safety signals in the postmarket period AERS, 53–55 identifying and evaluating, 56–58 Stakeholders, 2, 4, 177. See also individual stakeholders Statement of task. See The charge (to the committee) Statutory framework (for drug regulation) aging of, 153–166 FDA authority after approval, 155–164 FDA authority preapproval, 154–155 inadequacy of, 153–166 rationale for strengthening, 164–166 Steering Committee for the Collaborative Development of a Long-Range Action Plan for the Provision of Useful Prescription Medicine Information, 186 Strengthening FDA’s regulatory authority, 167–173 conditions and restrictions on distribution throughout the drug lifecycle, 167–170 greater regulatory flexibility post approval, 166 periodic review of data on NMEs, 172–173 special symbol needed to denote limited knowledge about new drugs, 170–172 Structural changes in the CDER, 206–207 Structural factors in CDER’s organizational dysfunction, 75–77 solving, 94–97 Study process, 25–26 Supplemental NDAs, 31 Supplements, dietary, 153 Surrogate endpoints, 107 Suspension of approval, 173

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The Future of Drug Safety: Promoting and Protecting the Health of the Public T Taxing prescriptions, 198 “Team approach,” 76. See also Review teams; Safety teams Terfenadine, 109 Terminology coding, 54 Thompson v. Western States Medical Center, 160 Throckmorton, CDER Deputy Director Douglas, 207 Timeline, for planning advisory committee meetings, 45 Toxicologic studies, 44 Transparency and the credibility of safety science, 142–147 need for greater, 4–5, 124, 127 Troglitazone, 17, 50, 109 Tufts Center for the Study of Drug Development, 71 U Uncertainty, disagreement in the face of, 127 Under-reporting of adverse events, substantial, 55, 109 Union of Concerned Scientists, 86n University of Arizona, 213 US drug safety system. See also Committee on the Assessment of the US Drug Safety System impaired by, 4 an improved, 13–14 a transformed, 4 Useful consumer medication information, criteria for, 187 User-fee funding system, 16, 23, 40, 70, 83, 196–197 V VA. See Department of Veterans Affairs Vaccine Safety Datalink (VSD), 112 Valdecoxib, 17 Vanderbilt University, 111 Veterans Health Administration, 92 Vioxx, 65 Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, Inc., 159 Vision. See New vision of drug safety von Eschenbach, FDA Acting Commissioner Andrew, 86n VSD. See Vaccine Safety Datalink W Wall Street Journal, 162 Warning the public about drug safety risks, 1. See also Black box warnings; Labeling Washington Legal Foundation, 162 Web sites, 25, 140, 142–143, 159, 172, 179, 181, 187, 190, 210 WHI. See Women’s Health Initiative WHO. See World Health Organization Withdrawals, 1–2, 16, 165, 173 Women’s Health Initiative (WHI), 55, 115, 123–124, 181 World Health Organization (WHO), 143, 145, 212 Z Zero-tolerance policy, regarding COI considerations, 140–141