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The Future of Drug Safety: Promoting and Protecting the Health of the Public THE FUTURE OF DRUG SAFETY PROMOTING AND PROTECTING THE HEALTH OF THE PUBLIC Committee on the Assessment of the US Drug Safety System Board on Population Health and Public Health Practice Alina Baciu, Kathleen Stratton, Sheila P. Burke, Editors INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu
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The Future of Drug Safety: Promoting and Protecting the Health of the Public THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. 223-01-2460, Task Order No. 23; HHSP23320042509XI, Task Order No. 3; and HHSM-500-2005-00026C between the National Academy of Sciences and the Department of Health and Human Services (the Food and Drug Administration, the Agency for Healthcare Research and Quality, the Centers for Medicaid and Medicare Services, the National Institutes of Health), and the United States Department of Veterans Affairs. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. Library of Congress Cataloging-in-Publication Data Institute of Medicine (U.S.). Committee on the Assessment of the US Drug Safety System. The future of drug safety : promoting and protecting the health of the public / Committee on the Assessment of the US Drug Safety System, Board on Population Health and Public Health Practice ; Alina Baciu, Kathleen Stratton, Sheila P. Burke, editors. p. ; cm. Includes bibliographical references. ISBN 978-0-309-10304-6 (pbk.) 1. Pharmaceutical policy—United States. 2. United States. Food and Drug Administration. 3. Drugs—Safety measures—United States. I. Baciu, Alina. II. Stratton, Kathleen R. III. Burke, Sheila P. IV. Title. [DNLM: 1. United States. Food and Drug Administration. 2. Drug Approval—United States. 3. United States Government Agencies—United States. QV 771 I5852f 2007] RA401.A3.I568 2007 362.17′82—dc22 2006039224 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2007 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.
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The Future of Drug Safety: Promoting and Protecting the Health of the Public “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Advising the Nation. Improving Health.
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The Future of Drug Safety: Promoting and Protecting the Health of the Public THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Wm. A. Wulf is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org
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The Future of Drug Safety: Promoting and Protecting the Health of the Public COMMITTEE ON THE ASSESSMENT OF THE US DRUG SAFETY SYSTEM SHEILA P. BURKE, M.P.A., R.N. (Chair), Deputy Secretary and Chief Operating Officer, Smithsonian Institution, Washington, DC DAVID BLUMENTHAL, M.D., M.P.P., Samuel O. Thier Professor of Medicine and Health Policy, Harvard Medical School; Director, Institute for Health Policy, Massachusetts General Hospital/Partners Health Care System, Boston SIR ALASDAIR BRECKENRIDGE, C.B.E., Chairman, Medicines and Healthcare Product Regulatory Agency, London, UK R. ALTA CHARO, J.D., Warren P. Knowles Professor of Law & Bioethics, University of Wisconsin-Madison, WI; Visiting Professor of Law, University of California, Berkeley (2006) SUSAN EDGMAN-LEVITAN, P.A., Executive Director, John D. Stoeckle Center for Primary Care Innovation, Massachusetts General Hospital, Boston SUSAN S. ELLENBERG, Ph.D., Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia ROBERT D. GIBBONS, Ph.D., Director, Center for Health Statistics, University of Illinois at Chicago GEORGE HRIPCSAK, M.D., M.S., Professor of Biomedical Informatics, Vice Chair, Department of Biomedical Informatics, Columbia University, New York DAVID KORN, M.D., Senior Vice President, Division of Biomedical and Health Sciences Research, Association of American Medical Colleges, Washington, DC DAVID MELTZER, M.D., Ph.D., Section of General Internal Medicine, University of Chicago, IL WOODROW A. MYERS, Jr., M.D., M.B.A., Former Executive Vice President and Chief Medical Officer, Wellpoint Inc, CA MARY K. OLSON, Ph.D., Associate Professor of Economics and Political Economy, Tulane University, New Orleans, LA BRUCE M. PSATY, M.D., Ph.D., Professor, Medicine and Epidemiology, Co-director, Cardiovascular Health Research Unit, University of Washington, Seattle CHRISTOPHER H. SCHROEDER, J.D., Charles S. Murphy Professor of Law, Public Policy Studies Director, Program in Public Law, Duke Law School, Durham, NC ANDY STERGACHIS, Ph.D., R.Ph., Professor of Epidemiology and Adjunct Professor of Pharmacy, Interim Chair, Pathobiology, Northwest Center for Public Health Practice, School of Public Health and Community Medicine, University of Washington, Seattle
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The Future of Drug Safety: Promoting and Protecting the Health of the Public Board on Population Health and Public Health Practice Board Liaison GEORGE ISHAM, M.D., M.S., Medical Director and Chief Health Officer, HealthPartners, Minneapolis, MN Study Staff KATHLEEN STRATTON, Ph.D., Study Director ALINA BACIU, M.P.H., Program Officer ANDREA PERNACK ANASON, M.P.H., Program Officer (through September 2005) AMY GROSSMAN, M.P.H., Senior Health Policy Associate RUTH KANTHULA, M.P.H., Senior Project Assistant (through June 2006) NORMAN GROSSBLATT, ELS (D), Senior Editor RENIE SCHAPIRO, M.P.H., Consultant ROSE MARIE MARTINEZ, Sc.D., Director, Board on Population Health and Public Health Practice
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The Future of Drug Safety: Promoting and Protecting the Health of the Public Reviewers This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the NRC’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: J. Lyle Bootman, College of Pharmacy–Pulido Center, The University of Arizona John E. Calfee, American Enterprise Institute, Washington, DC Dan Carpenter, Center for Government and International Studies, Harvard University Ralph Edwards, The Uppsala Monitoring Centre, World Health Organization David W. Feigal, NDA Partners, LLP and Arizona Biodesign Center Garrett Fitzgerald, University of Pennsylvania School of Medicine Henry G. Grabowski, Department of Economics, Program in Pharmaceuticals and Health Economics, Duke University Sean Hennessy, University of Pennsylvania School of Medicine Peter Barton Hutt, Covington & Burling
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The Future of Drug Safety: Promoting and Protecting the Health of the Public Anne Khademian, Center for Public Administration and Policy, Virginia Tech Debra R. Lappin, B&D Sagamore, Washington, DC Arthur Aaron Levin, Center for Medical Consumers, New York Steven M. Paul, Lilly Research Laboratories, Eli Lilly and Company Richard Platt, Department of Ambulatory Care and Prevention, Harvard Medical School Wayne A. Ray, Department of Preventive Medicine, Vanderbilt University School of Medicine Joshua M. Sharfstein, Health Department, City of Baltimore Panos Tsintis, Unit for the Post-Authorisation Evaluation of Medicines for Human Use, European Medicines Agency, London Eleanor M. Vogt, School of Pharmacy, University of California, San Francisco Alastair J.J. Wood, Vanderbilt University Medical School Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Neal A. Vanselow, Tulane University, Professor Emeritus and Joseph P. Newhouse, Harvard University. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
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The Future of Drug Safety: Promoting and Protecting the Health of the Public Preface The year 2006 marks the 100th anniversary of the signing of the Pure Food and Drug Act. During that century, drug regulation at the Food and Drug Administration (FDA) has evolved enormously, both in terms of statutory reforms (with major legislation in 1938, 1962, 1992, 1997, and 2002) and due to internal restructuring and growth in staff. Past changes have frequently been responses to problems in the functioning of the drug regulatory process. Although the agency has gained great respect and importance as one of the world’s premier regulatory bodies, recent drug safety events have called into question FDA’s regulatory decision-making and oversight processes, and caused the public to question its ability to accomplish a balanced evaluation of the safety and efficacy of the drugs it reviews and after their approval, of their performance under real-life conditions. In light of these developments, the Institute of Medicine (IOM) was asked by FDA to examine in detail the system of drug safety in this country. Our committee has, in the course of the last 15 months, undertaken this assessment. The result of our review is a series of recommendations that we believe will improve the drug safety system by strengthening clinical and epidemiological research, and the scientific basis of regulatory action. Although mindful of recent actions by FDA to improve its postmarketing decision-making process, the committee believes a more comprehensive response is required that acknowledges the need for vigilance throughout the lifecycle of a drug. Underlying our 25 recommendations is the fundamental view that the interests of the public are best served when safety and efficacy are considered together. However, factors including, but not limited to, the current organizational culture of the Center for Drug Evaluation and
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The Future of Drug Safety: Promoting and Protecting the Health of the Public Research (CDER), combined with severe resource constraints and a problematic funding mechanism have impeded the development of a system that optimally integrates the safety and efficacy assessments along a drug’s lifecycle, particularly with regard to safety issues arising postmarketing. Further complicating this problem is the lack of a clearly established and consistently applied systematic process of making risk-benefit assessments, and an adequate base of human and technological resources required to meet the center’s critical responsibilities. The committee believes that CDER staff are a dedicated and talented group of public servants who currently lack the organization and resources to address all of the challenges before them and perform the crucial role of advancing and protecting public health in an increasingly complex environment. We believe that Congress needs to ensure that CDER is given the authority and assets (human, financial, technological) it requires. The center’s leaders have to be prepared to address the underlying cultural problems that divide and impair the optimal functioning of center staff, and to effectively use existing and new authorities and resources to achieve the center’s public health and regulatory mission. The committee’s recommendations pertaining to these issues must be viewed as a coherent package of solutions or strategies rather than a menu of choices. I would like to thank my colleagues on the committee for their extraordinary efforts. They have committed countless hours over the last 15 months in meetings, weekly conference calls, and a continuous stream of emails. They have passionately argued their positions, but also accommodated their colleagues and sought responsible consensus. I thank them for all they have done. I would also like to acknowledge the contributions of the IOM staff team—Kathleen Stratton, Alina Baciu, Amy Grossman, Ruth Kanthula, Andrea Pernack Anason, and consultant Renie Schapiro. Their dedication, guidance, and experience were of inestimable value to us in examining the highly complex process of drug evaluation and regulation. We could not have produced this report without them. The committee is grateful to everyone who spoke at our public meetings and who sent material for consideration. I also wish to thank the current and former staff at FDA and particularly CDER who spoke frankly with the committee and provided much needed insight into the workings of this agency. Sheila P. Burke, Chair
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The Future of Drug Safety: Promoting and Protecting the Health of the Public Contents SUMMARY 1 1 INTRODUCTION 15 Changes in the Broad Context of Drug Regulation, 19 Defining and Meeting the Charge, 21 2 NATURAL HISTORY OF A DRUG 31 Economic Impact of Drugs, 32 The Investigational New Drug, 33 Investigational New Drug Submission and Review, 33 New Drug Application, 39 Postmarket Period, 51 3 A CULTURE OF SAFETY 65 Organizational Challenges, 65 The External Environment, 68 Structural Factors, Policies, and Procedures, 75 Proposed Solutions to CDER’s Organizational Dysfunction, 90 4 THE SCIENCE OF SAFETY 105 Generating the Science, 106 Understanding Risk and Benefit for Approval Decisions, 106 Reducing Uncertainty About Risk and Benefit After Approval, 107 Risk Minimization Action Plans, 119 Risk-Benefit Analyses Throughout the Lifecycle, 121
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The Future of Drug Safety: Promoting and Protecting the Health of the Public Credibility of the Science, 126 Expertise in the Center for Drug Evaluaiton and Research, 127 Advisory Committees, 131 Transparency, 142 5 REGULATORY AUTHORITIES FOR DRUG SAFETY 151 History of FDA Drug Regulation, 152 An Aging and Inadequate Statutory Framework, 153 FDA Authority Preapproval, 154 FDA Authority After Approval, 155 Rationale for Strengthening Drug Regulation, 164 Strengthening FDA’s Regulatory Authorities, 167 6 COMMUNICATING ABOUT SAFETY 177 Roles and Needs of Providers and Patients, 178 How Industry Communicates to the Public and Patients, 184 FDA’s Challenges in Communicating to the Public and Patients, 184 7 RESOURCES FOR THE DRUG SAFETY SYSTEM 193 APPENDIXES A Moving Target: Changes at FDA During the Course of the Study 205 B Acronyms 217 C PDUFA Performance Goals—All Years 221 D Committee on the Assessment of the US Drug Safety System Meeting Agendas 255 E Summary, Preventing Medication Errors: Quality Chasm Series, Institute of Medicine 267 F Committee Biographies 309 INDEX 319
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The Future of Drug Safety: Promoting and Protecting the Health of the Public THE FUTURE OF DRUG SAFETY
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