Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page R1
Committee on Ethical and Scientific Issues in
Studying the Safety of Approved Drugs
Board on Population Health and Public Health Practice
OCR for page R2
THE NATIONAL ACADEMIES PRESS 500 Fifth Street NW 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. HHSF223200810020I between the National
Academy of Sciences and the Food and Drug Administration. 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 sup -
port for this project.
International Standard Book Number-13: 978-0-309-21813-9
International Standard Book Number-10: 0-309-21813-6
Library of Congress Control Number: 2012944110
Additional copies of this report are available from the National Academies Press, 500
Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313;
http://www.nap.edu.
For more information about the Institute of Medicine, visit the IOM home page at: www.
iom.edu.
Copyright 2012 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 Museum in Berlin.
Suggested Citation: IOM (Institute of Medicine). 2012. Ethical and Scientific Issues in
Studying the Safety of Approved Drugs. Washington, DC: The National Academies Press.
OCR for page R3
“Knowing is not enough; we must apply.
Willing is not enough; we must do.”
— Goethe
Advising the Nation. Improving Health.
OCR for page R4
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 examina -
tion 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
iv
OCR for page R5
COMMITTEE ON ETHICAL AND SCIENTIFIC ISSUES IN
STUDYING THE SAFETY OF APPROVED DRUGS
RUTH R. FADEN (Co-Chair), Philip Franklin Wagley Professor of Biomedical
Ethics and Executive Director, Berman Institute of Bioethics, Johns
Hopkins University, Baltimore, MD
STEVEN N. GOODMAN (Co-Chair), Professor of Medicine and Health
Research and Policy, Associate Dean for Clinical and Translational
Research, Stanford University School of Medicine, CA
ALASDAIR BRECKENRIDGE, Chairman, Medicines and Healthcare
Product Regulatory Agency, London, UK
LISA EGBUONU-DAVIS, Executive Advisor, Booz Allen Hamilton,
Washington, DC
MIGUEL A. HERNÁN, Professor of Epidemiology, Harvard School of Public
Health, Boston, MA
GRACE M. LEE, Associate Professor of Population Medicine & Pediatrics,
Harvard Pilgrim Health Care Institute, Harvard Medical School &
Children’s Hospital Boston, MA
MICHELLE MELLO, Professor of Law and Public Health, Harvard
University, Cambridge, MA
ERIC M. MESLIN, Director, Indiana University Center for Bioethics,
Associate Dean for Bioethics, Indiana University School of Medicine,
Indianapolis
LARRY I. PALMER, (Retired), Professor, Department of Health
Administration, Virginia Commonwealth University and Professor of Law,
College of William & Mary Law School, Richmond, VA
BRUCE M. PSATY, Professor, Medicine, Epidemiology, and Health Services;
Co-Director, Cardiovascular Health Research Unit, University of
Washington; Investigator, Group Health Research Institute, Seattle
THOMAS R. TEN HAVE, Professor of Biostatistics, Perelman School of
Medicine, University of Pennsylvania, Philadelphia
WILLIAM K. VAUGHAN, (Retired), Health Policy Analyst, Consumers
Union, Washington, DC
Consultants
THOMAS J. BOLLYKY, Senior Fellow, Council of Foreign Relations,
Washington, DC
RICHARD A. MERRILL, Professor of Law Emeritus, University of Virginia,
Charlottsville
EMILY L. EVANS, Ph.D. Candidate, Georgetown University, Washington, DC
v
OCR for page R6
IOM Staff
MICHELLE C. CATLIN, Study Director
ALEJANDRA MARTÍN, Research Assistant
ALLISON L. BERGER, Senior Project Assistant (June 2010–August 2011)
THOR YOUNG, Senior Project Assistant (August 2011–November 2011)
NORMAN GROSSBLATT, Senior Editor
ROSE MARIE MARTINEZ, Director, Board on Population Health and
Public Health Practice
CAROL MASON SPICER, Associate Program Officer
vi
OCR for page R7
Reviewers
This report has been reviewed in draft form by persons 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, evi -
dence, 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:
Jesse Berlin, Janssen Research & Development
Dan Carpenter, Harvard University
Perry D. Cohen, Project Director for the Parkinson Pipeline Project
Susan Ellenberg, University of Pennsylvania School of Medicine
Barbara Evans, University of Houston
Thomas R. Fleming, University of Washington
Sean Hennessy, University of Pennsylvania
Peter Honig, AstraZeneca
Karen Jenni, Insight Decisions, LLC
Cato T. Laurencin, University of Connecticut
Bernard Lo, University of California, San Francisco
Jon Merz, University of Pennsylvania
Richard Platt, Harvard Medical School
Joseph Rodricks, ENVIRON
Paul D. Stolley, University of Maryland School of Medicine
vii
OCR for page R8
viii REVIEWERS
Although the reviewers listed above have provided many constructive com-
ments and suggestions, they were not asked to endorse the conclusions or recom -
mendations, nor did they see the final draft of the report before its release. The
review of this report was overseen by Ron Brookmeyer, University of California,
Los Angeles, and Brian L. Strom, University of Pennsylvania School of Medi-
cine. Appointed by the National Research Council and the 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.
OCR for page R9
Preface
This report comes, not coincidentally, at an extraordinary time for both
the US Food and Drug Administration (FDA) and this country. With half of all
Americans taking at least one prescription drug daily and many older Americans
using five or more, and with an increasing array of drugs available to treat more
illnesses and more people, the public health consequences of drug exposure—
both negative and positive—could not be higher.
At the same time, the costs of health care consume a steadily increasing
proportion of our nation’s budget, with drug expenditures representing a sizable
fraction of total health care dollars. Finally, there is the role of US academic and
industry pharmaceutical research as an engine of innovation, bringing enormous
economic, scientific, and medical benefits to our populace.
In the middle of this stands FDA, whose goal is to balance those pressures
appropriately and to ensure that the drugs it approves do not have risks that
outweigh their benefits, while not acting in ways that stifle biomedical innova-
tion. The passage of the FDA Amendments Act of 2007 has afforded FDA broad
new powers to monitor the safety of drugs after they reach the marketplace and
to take corrective action if drugs’ risks are judged to be unacceptable in light of
their benefits.
Over the last few decades, there has been a series of high-profile episodes in
which drugs in wide use after approval were found to cause harms that justified
their withdrawal or restricted use. The highest-profile of these involved Vioxx ®
(rofecoxib), selective serotonin reuptake inhibitors (SSRIs) in children, Fen-Phen
(fenfluramine and phentermine), and most recently, Avandia® (rosiglitazone). It is
no secret that the present report was born amid the challenges that FDA was fac-
ing in its consideration of the cardiovascular risks associated with the antidiabetic
ix
OCR for page R10
x PREFACE
drug Avandia. FDA first requested a letter report from this committee to aid in its
deliberation about the scientific and ethical issues surrounding the continuation
of the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial,
which had been required of the Avandia manufacturer by FDA. The letter report
was presented during the Avandia hearings and is included as an appendix.
But both the letter report and this longer, final report are about much more
than the Avandia case. The final report was prepared in response to a series of
questions about the kinds of studies and protections for research participants that
could or should be mounted by FDA in response to drug safety concerns in the
postmarketing period. The committee quickly recognized that the questions posed
were not readily answerable when framed from the vantage of a postmarketing
crisis where there are few, if any, good options. To provide useful guidance, the
committee found itself inexorably drawn to how FDA could have avoided these
moments of crisis when the costs in human suffering and dollars to get the evi-
dence it needed were seen by many as unacceptable. The committee hopes that
its recommendations, if adopted, will go much further toward resolution of the
questions that were posed to it than would have been the case if it had taken a
more narrow approach.
This journey took longer than we expected it to, but it produced a report
that should stand the test of time. The committee’s most important recommenda -
tion is that FDA, in its role as a public health agency, be active in shaping its
postmarketing drug safety monitoring role, taking it as seriously as it does its
responsibility to approve safe and efficacious drugs. The committee calls this,
as did an Institute of Medicine (IOM) committee that preceded it, “the lifecycle
approach”. Obtaining new information about a drug’s benefits and risks in the
postmarketing context is expected in the lifecycle approach. If acquired and
responded to in a timely way, new information need not and should not result in
controversies of the Avandia or Vioxx type. The committee hopes that if FDA
adopts its findings and recommendations, these kinds of controversies will be
minimized in the future and the public will have renewed faith in the agency as
protecting of its health while allowing access to the marketplace for drugs that
have great potential to cure disease and relieve suffering.
The committee thanks colleagues, organizations, and agencies that were
willing to share their expertise, time, and information during the committee’s
information-gathering meetings (see Appendix C for the names of speakers).
Their contributions informed the committee deliberations and enhanced the
quality of this report. The committee learned a great deal about drug safety in
the context of regulatory science, pharmacovigilance, science and ethics, and
the perspectives of both public and patient interest groups. The study sponsor,
FDA, gladly provided information and responded to questions. The committee
is particularly grateful to Joshua Sharfstein and Janet Woodcock, who provided
valuable information and feedback during the committee’s deliberation process;
to Joshua Sharfstein and Margaret Hamburg for commissioning this study; and to
OCR for page R11
xi
PREFACE
Carolyn Clancy and Francis Collins for their interest and their agencies’ financial
support of the study.
We are honored to have worked with wise, creative, and indefatigable com-
mittee members, whose names are listed in this volume. The IOM staff, including
board director Rose Marie Martinez, study director Michelle Catlin, and research
assistant Alejandra Martin, as well as Allison Berger, Thor Young, Carol Mason
Spicer, Joel Wu, Erin Rusch, and Hope Hare, were critical in shepherding the
report through all its stages and incarnations. The committee was also assisted in
its work by study consultants Emily Evans, Thomas Bollyky and Richard Merrill,
and by senior editor Norman Grossblatt.
Finally, with deepest gratitude and great sorrow, we dedicate this report to
a member of our committee, Thomas Ten Have, who succumbed to a chronic
illness during the creation of the report and did not survive to see his contribu -
tion take flight. We hope that the report serves as an appropriate capstone to his
brilliant and productive career in biostatistics and public health.
Ruth R. Faden and Steven N. Goodman, Co-Chairs
Committee on Ethical and Scientific Issues in Studying
the Safety of Approved Drugs
OCR for page R12
OCR for page R13
In Memoriam
This report is dedicated to
Dr. Thomas Ten Have,
a leader in biostatistical analysis of health outcomes,
a humanitarian,
a valued member of the committee,
and an irreplaceable colleague and friend.
xiii
OCR for page R14
OCR for page R15
Contents
ABSTRACT 1
SUMMARY 3
Charge to the Committee, 4
Committee’s Approach to Its Charge, 4
Benefit–Risk Assessment and Management Throughout a
Drug’s Lifecycle, 4
Evidence and Decision-Making, 7
Selection and Oversight of Required Postmarketing Studies, 8
Responses to the Charge Questions, 11
Findings and Recommendations, 14
1 INTRODUCTION 29
The Evolution of the Food and Drug Administration’s Responsibilities in
the Postmarketing Setting, 30
The Context of This Report, 46
Charge to the Committee, 47
The Committee’s Approach to Its Charge, 50
Overview of the Report, 56
References, 57
2 INCORPORATING BENEFIT AND RISK ASSESSMENT AND
BENEFIT–RISK MANAGEMENT INTO FOOD AND DRUG
ADMINISTRATION DECISION-MAKING 61
Evaluating Benefit and Risk Over a Drug’s Lifecycle, 61
xv
OCR for page R16
xvi CONTENTS
Three-Stage Framework for Regulatory Decision-Making, 63
Benefit and Risk Assessment and Management Plan Document, 94
Special Considerations in the Decision of Whether to Require a
Postmarketing Study, 98
Summary, 109
Findings and Recommendations, 109
References, 113
3 EVIDENCE AND DECISION-MAKING 121
Statistical Inference and Decision-Making, 122
Why Scientists Disagree, 128
Implications for Regulatory Decisions: The Importance of
Understanding the Sources of Disagreements, 156
Reproducible Research, Data Sharing, and Transparency, 157
Findings and Recommendations, 158
References, 162
4 SELECTION AND OVERSIGHT OF REQUIRED
POSTMARKETING STUDIES 169
The Postmarketing Context, 170
Requiring Observational Studies and Randomized Controlled Trials, 173
Design, Analytic, and Ethical Considerations in Selecting Specific
Observational and RCT Designs to Require, 181
The Food and Drug Administration’s Ethical Obligations Regarding the
Conduct and Oversight of Required Postmarketing Studies, 187
Summary, 201
Findings and Recommendations, 202
References, 207
5 SYNTHESIS 213
Responses to the Charge Questions, 214
References, 226
APPENDIXES
A Other Elements of the Food and Drug Administration
Amendments Act 227
B Committee’s Letter Report 231
C Open Session Agendas 251
D Decision Conferencing and Multicriteria Decision Analysis 255
E Benefit and Risk Assessment and Management Plan Document
Template 261
F Committee Biosketches 269
