CHALLENGES FOR THE FDA

THE FUTURE OF DRUG SAFETY

Workshop Summary

Leslie Pray and Sally Robinson, Rapporteurs

Forum on Drug Discovery, Development, and Translation

Board on Health Sciences Policy

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.
www.nap.edu



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Challenges for the FDA: The Future of Drug Safety - Workshop Summary CHALLENGES FOR THE FDA THE FUTURE OF DRUG SAFETY Workshop Summary Leslie Pray and Sally Robinson, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary 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. Support for this project was provided by the Department of Health and Human Services (Contract Nos. N01-OD-$-2139 and 223-01-2460), American Diabetes Association, American Society for Microbiology, Amgen, Inc., Association of American Medical Colleges, AstraZeneca Pharmaceuticals, Blue Cross Blue Shield Association, Burroughs-Wellcome Fund, Doris Duke Charitable Foundation, Eli Lilly & Co., Entelos, Inc., GlaxoSmithKline, March of Dimes Foundation, Merck & Co., Pfizer Inc., and UnitedHealth Group. 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. International Standard Book Number-13 978-0-309-10986-4 International Standard Book Number-10 0-309-10986-8 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. Suggested citation: Institute of Medicine (IOM). 2007. Challenges for the FDA: The future of drug safety. Workshop summary. Washington, DC: The National Academies Press. 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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Challenges for the FDA: The Future of Drug Safety - Workshop Summary “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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Challenges for the FDA: The Future of Drug Safety - Workshop Summary 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. Charles M. Vest 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. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary PLANNING COMMITTEE FOR THE SYMPOSIUM ON CHALLENGES FOR FDA: THE FUTURE OF DRUG SAFETY Naomi Aronson, Blue Cross and Blue Shield Association, Illinois Catherine Bonuccelli, AstraZeneca Pharmaceuticals, Delaware Robert M. Califf, Duke University Medical Center, North Carolina Susan Ellenberg, University of Pennsylvania School of Medicine Elaine K. Gallin, The Doris Duke Charitable Foundation, New York Jane E. Henney, University of Cincinnati, Ohio IOM Staff Robert B. Giffin, Director Adrienne Stith Butler, Senior Program Officer Sally Robinson, Program Officer Andrea Knutsen, Senior Program Assistant

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 Gail H. Cassell (Co-Chair), Eli Lilly and Company, Indiana Edward W. Holmes (Co-Chair), National University of Singapore Naomi Aronson, Blue Cross and Blue Shield Association, Illinois Leslie Z. Benet, University of California–San Francisco Catherine Bonuccelli, AstraZeneca Pharmaceuticals, Delaware Linda Brady, National Institute of Mental Health, Maryland Robert M. Califf, Duke University Medical Center, North Carolina Scott Campbell, American Diabetes Association, Virginia C. Thomas Caskey, University of Texas–Houston Health Science Center Francis D. Chesley, Jr., Agency for Healthcare Research and Quality, Maryland Peter B. Corr, Pfizer Inc. (retired), New York Jeffrey M. Drazen, New England Journal of Medicine, Massachusetts Joseph M. Feczko, Pfizer Inc., New York Garret A. FitzGerald, University of Pennsylvania School of Medicine Elaine K. Gallin, The Doris Duke Charitable Foundation, New York Steven K. Galson, U.S. Food and Drug Administration, Maryland Alan M. Garber, Stanford University, California Mikhail Gishizky, Entelos, Inc., California Stephen Groft, National Institutes of Health, Maryland Michael Katz, March of Dimes Foundation, New York William F. Keane, Merck and Company, Pennsylvania Ronald L. Krall, GlaxoSmithKline, Pennsylvania Jeffrey M. Leiden, Clarus Ventures, Massachusetts John M. Leonard, Abbott Laboratories, Illinois Garry A. Neil, Johnson and Johnson, New Jersey John R. Marler, National Institute of Neurological Disorders and Stroke, Maryland Musa Mayer, AdvancedBC.org, New York Joshua J. Ofman, Amgen, Inc., California Suzanne Pattee, Cystic Fibrosis Foundation, Maryland Joanne L. Rhoads, National Institute of Allergy and Infectious Diseases (retired), Maryland B. A. Schwetz, U.S. Department of Health and Human Services, Maryland Janet Shoemaker, American Society for Microbiology, Washington, D.C. Lana Skirboll, National Institutes of Health, Maryland 1 Membership as of March 12, 2007.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Nancy S. Sung, Burroughs Wellcome Fund, North Carolina Reed V. Tuckson, UnitedHealth Group, Minnesota Janet Woodcock, U.S. Food and Drug Administration, Maryland

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary 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 National Research Council’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: Catherine Bonuccelli, AstraZeneca Pharmaceuticals Robert Califf, Duke University Medical Center Richard A. Justman, UnitedHealthCare Brian L. Strom, University of Pennsylvania School of Medicine Alastair J. Wood, Symphony Capital LLC Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen by Hellen Gelband, Scholar-in-Residence, Institute of Medicine. Appointed by the National Research Council and Institute of Medicine, she was responsible

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary 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 authors and the institution.

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Preface Americans rely on the drug safety system to ensure that the medications they take are safe and effective. In carrying out its central role within this system, the U.S. Food and Drug Administration (FDA) faces a daunting task: it must balance the public’s desire for rapid introduction of new drugs against the availability of limited safety and efficacy data, as well as monitor drugs after they are on the market. As a result of increases in the number of drugs used by Americans, coupled with greater potential for drug interactions, improved patient access to information, and recent advances in drug development technologies, the public’s expectations of the drug safety system are higher than ever. But recent events—including highly publicized safety concerns and recalls of approved drugs—have shaken the public’s confidence in the ability of the system to meet those expectations. While the public would like the drug safety system to perform flaw-lessly, few understand the enormous constraints faced by the FDA in carrying out its critical functions. The number and complexity of drugs that the FDA must track are continually increasing even as drugs are spending less time in review. And while the world of drug discovery and development has undergone revolutionary change, shifting from cellular to molecular and gene-based approaches, the FDA’s evaluation methods have remained largely unchanged over the last 50 years. Funding for the FDA has not kept pace with the evolution of the underlying science of drug development and the expanding scope of the agency’s mission. Furthermore, the FDA’s limited resources must be allocated to safety

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary assurance not only for drugs, but also for biologics, medical devices, food products, and cosmetics. Indeed, it has been estimated that the FDA regulates products representing nearly a quarter of consumer spending in the United States. CONCERNS THAT LED TO THE INSTITUTE OF MEDICINE’S STUDY ON DRUG SAFETY In 2005 the FDA commissioned the Institute of Medicine (IOM) to perform an independent assessment of the current U.S. drug safety system. In September 2006, the committee impaneled by the IOM to conduct this study released its report—The Future of Drug Safety: Promoting and Protecting the Health of the Public—which included 25 recommendations for improving the system for drug safety review. Since the report was issued, the FDA has taken a number of steps toward implementing those recommendations. Yet the FDA is financially strained by its existing responsibilities as a result of its many unfunded mandates and minimal annual increases in its congressional appropriations. Fully implementing the improvements to the drug safety system recommended in the IOM report will therefore require significant new financial commitments. The IOM report addressed some of the costs associated with its recommendations, but left many unanswered questions about the resources required to fully achieve the envisioned improvements. Absent substantial increases in agency funding, making the recommended improvements in the agency’s ability to identify safety problems with new drugs, monitor routinely submitted safety data, and relay the resulting information to the public would require the diversion of funds from other mission-critical areas. THE ROLE OF THE FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION The Forum on Drug Discovery, Development, and Translation was created in 2005 by the IOM’s Board on Health Sciences Policy to provide an opportunity for leaders from government, academia, industry, patient advocacy, and other stakeholders to meet and discuss issues of mutual interest in a neutral setting. While the Forum was not involved in the IOM’s drug safety study, it closely followed the committee’s work. In October 2006, shortly after the release of the report, members of the committee and IOM staff presented the study findings to the Forum. Among the topics discussed at this meeting was the FDA’s ability to implement the changes called for in the report given the resources likely to be required for the purpose. Attempting to understand these resource requirements is a difficult

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary undertaking. Limited data are available to support such an exercise, and predicting the nature and level of effort associated with the new programs recommended in the drug safety report is even more difficult. In the report, the budget implications of enhancing certain aspects of drug safety science at the FDA are outlined, and a general increase in FDA funding is called for. But the funding required to implement the majority of the report’s recommendations is not enumerated, nor does the report suggest the total investment required to achieve its broad, agency-wide objectives. In the context of current congressional deliberations on reauthorization of the Prescription Drug User Fee Act (a substantial source of FDA funding) and growing pressure for improved drug and food safety processes, concern arose within the Forum that a lack of realistic budget estimates could lead to new legislative demands being placed on the FDA without funds commensurate with those demands being appropriated. This concern led to the Forum’s decision to convene a national symposium aimed at achieving a better understanding of the types and magnitude of resources required to achieve the goals articulated in the IOM report. Participants in the symposium included an impressive range of experts from industry and academia, government officials, policy makers, and patient advocates. Speakers included a former Secretary of Health and Human Services, two former FDA commissioners, many current and former FDA officials, and numerous other experts and stakeholders. Topics discussed included strengthening the scientific base of the agency, integrating pre- and postmarket review, enhancing postmarket safety monitoring, conducting confirmatory drug safety and efficacy studies, enhancing the value of clinical trial registration, and enhancing the FDA’s postmarket regulatory and enforcement authority. The symposium saw spirited, informed, and constructive discussion of the merits of the current drug safety system, the need for more FDA resources, and the ways in which new resources should be deployed. The discussion did not address every recommendation from the IOM report, but focused on selected recommendations with substantial resource implications. Recommendations for organizational and cultural changes at the FDA, for example, were not addressed. Moreover, while the symposium generated numerous insights into the types and magnitude of resources required to enhance the drug safety system, it did not result in detailed budget estimates. Important discussions took place that were tangential to the goal of enumerating costs. One such discussion involved possible formation of a public–private partnership that would consolidate data from multiple stakeholders—such as the Centers for Medicare and Medicaid Services,

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary private health plans, and large provider systems—to support postmarket assessments of drug safety. While many technical challenges would be involved, several speakers suggested that not only is the capacity to accomplish this consolidation is within reach, but also that the costs could be substantially lower than those of using traditional clinical trial methods to achieve the same objectives. Another key discussion involved the human resources needed to meet the challenges of ensuring drug safety and effect the recommended transformation of the FDA. The problem of how to train an adequate workforce of epidemiologists and translational scientists led to discussion of a key concept—the development of a Jet Propulsion Laboratory–style initiative that would generate a cooperative and aggressive training program designed to equip translational scientists with the necessary skills. The symposium provided a valuable opportunity for the broad community of stakeholders who think hard and care passionately about drug safety to further delineate the recommendations of the IOM report and explore ideas for enhancing the drug safety system that is so important to all Americans. I would like to thank all of the individuals who contributed to and participated in the symposium—the panelists, the members of the planning committee, and the members of the Forum who gave so much of their valuable time and generously shared their expertise and guidance. I would also like to thank the Forum staff for their dedication and commitment to making the symposium a success. Gail Cassell, Symposium Chair Co-Chair, Forum on Drug Discovery, Development, and Translation

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Contents     SUMMARY   1 1   INTRODUCTION   9 2   ADDRESSING THE FDA’S RESOURCE CHALLENGES   13      Historical Overview,   13      Current FDA Funding,   15      Industry User Fees,   17      Resource Needs,   17 3   STRENGTHENING THE SCIENTIFIC BASE OF THE AGENCY   19      Research Needed to Improve Drug Safety: Current FDA Initiatives to Expand Research Capacities,   20      Building the FDA’s Capacity for Science-Based Premarket Review,   22 4   INTEGRATING PRE- AND POSTMARKET REVIEW   26      Operational Challenges to Initiating a Life-Cycle Approach to Drug Review,   27      Current Initiatives for Integrating Pre- and Postmarket Review,   28

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary            5   ENHANCING POSTMARKET SAFETY MONITORING   32      FDA Initiatives for Improving Drug Safety Monitoring,   33      Public–Private Partnership for Developing a National Active Surveillance System,   35 6   CONDUCTING CONFIRMATORY DRUG SAFETY AND EFFICACY STUDIES   49 7   ENHANCING THE VALUE OF CLINICAL TRIAL REGISTRATION   54 8   ENHANCING POSTMARKET REGULATION AND ENFORCEMENT   58      The FDA’s Regulatory Authority,   60      The FDA’s Statutory Authority,   61      Phase IV Commitments,   62      Resources for Enhanced Enforcement,   64      The FDA’s Regulatory Authority over Drug Labeling,   67      Patient Safety and Access,   68      Industry Perspective,   68 9   LOOKING TO THE FUTURE   70      Prerequisites for Revitalizing the U.S. Drug Safety System,   70      The Future of Drug Safety Regulation,   73     REFERENCES   78     APPENDIXES     A   Workshop Agenda   81 B   Speaker Biographies   93

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Challenges for the FDA: The Future of Drug Safety - Workshop Summary Tables, Figures, and Boxes TABLE 8-1   Summary of Postmarket Study Commitments (Numbers as of September 30, 2006),   66 FIGURES 2-1   Comparison of NIH, CDC, and FDA budgets between 1986, 1996, and 2006,   16 3-1   Number of new drugs approved in the last 10 years (1996–2006),   23 5-1   Monthly incidence of acute myocardial infarction (AMI) for Vioxx users,   37 5-2   Proposed composition of an enhanced claims database,   39 5-3   NIH’s Clinical and Translational Science Awards: A home for clinical and translational science,   47 6-1   2005 time-adjusted comparative preapproval capitalized cost estimate per approved new molecule,   52 7-1   Monthly registration of trials on ClinicalTrials.gov,   55 7-2   New trials received by ClinicalTrials.gov in 2006,   57 BOX 1-1   Highlights of the FDA’s Response to the IOM Report,   10

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