FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION

TRANSFORMING CLINICAL RESEARCH IN THE UNITED STATES

CHALLENGES AND OPPORTUNITIES

WORKSHOP SUMMARY

Rebecca A. English, Yeonwoo Lebovitz, and Robert B. Giffin, Rapporteurs

Forum on Drug Discovery, Development, and Translation

Board on Health Sciences Policy

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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FORUM ON DRUG DISCOVER Y, D EVELOPMENT, A ND TRANSLATION TRANSFORMING CLINICAL RESEARCH IN THE UNITED STATES CHALLENGES AND OPPORTUNITIES WORKSHOP SUMMARY Rebecca A. English, Yeonwoo Lebovitz, and Robert B. Giffin, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy

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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. This project was supported by the Department of Health and Human Services (Contract Nos. N01-OD-4-2139 and 223001003T), the American Diabetes Association, the American Society for Microbiology, Amgen Inc., the Association of American Medical Colleges, AstraZeneca Pharmaceuticals, the Burroughs-Wellcome Fund, Celtic Therapeutics, LLLP, the Critical Path Institute, the Doris Duke Charitable Foundation, Eli Lilly & Co., Entelos Inc., Genentech, GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals Corporation, and Pfizer Inc. 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 agen- cies that provided support for this project. International Standard Book Number-13: 978-0-309-15332-4 International Standard Book Number-10: 0-309-15332-8 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 2010 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. Suggested citation: IOM (Institute of Medicine). 2010. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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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 Acad- emy 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 en- gineers. 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 engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent 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 Insti- tute 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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PLANNING COMMITTEE FOR THE WORKSHOP ON TRANSFORMING CLINICAL RESEARCH IN THE UNITED STATES1 BARBARA ALVING, National Center for Research Resources, Maryland LINDA BRADY, National Institute of Mental Health, Maryland ROBERT CALIFF, Duke University Medical Center, North Carolina SCOTT CAMPBELL, American Diabetes Association, Virginia GAIL H. CASSELL, Eli Lilly and Company, Indiana JAMES H. DOROSHOW, National Cancer Institute, Maryland JEFFREY M. DRAZEN, New England Journal of Medicine, Massachusetts GARRET A. FITZGERALD, University of Pennsylvania School of Medicine PETER K. HONIG, Merck Research Laboratories (retired), Pennsylvania RONALD L. KRALL, GlaxoSmithKline (retired), Pennsylvania MUSA MAYER, AdvancedBC.org, New York IRENA TARTAKOVSKY, Association of American Medical Colleges, Washington, DC JORGE A. TAVEL, National Institute of Allergy and Infectious Diseases, Maryland IOM Staff ANNE B. CLAIBORNE, Director (as of April 5, 2010) ROBERT B. GIFFIN, Director (until February 26, 2010) REBECCA A. ENGLISH, Research Associate YEONWOO LEBOVITZ, Program Associate GENEA S. VINCENT, Senior Program Assistant RONA BRIERE, Consulting Editor 1 The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what oc- curred at the workshop. 

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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 Gail H. Cassell (Co-Chair), Eli Lilly and Company, Indiana Jeffrey M. Drazen (Co-Chair), New England Journal of Medicine, Massachusetts Barbara Alving, National Center for Research Resources, Maryland Leslie Z. Benet, University of California–San Francisco Ann Bonham, Association of American Medical Colleges, Washington, DC Linda Brady, National Institute of Mental Health, Maryland Robert M. Califf, Duke University Medical Center, North Carolina Scott Campbell, Foundation for the National Institutes of Health, Maryland Peter B. Corr, Celtic Therapeutics Management Company, LLP, New York James H. Doroshow, National Cancer Institute, Maryland Paul R. Eisenberg, Amgen, Inc., California Gary L. Filerman, ATLAS Research, Washington, DC Garret A. FitzGerald, University of Pennsylvania School of Medicine Elaine K. Gallin, The Doris Duke Charitable Foundation, New York Steven K. Galson, Science Applications International Corporation, Virginia Harry B. Greenberg, Stanford University School of Medicine, California Stephen Groft, National Institutes of Health, Maryland Peter K. Honig, AstraZeneca Pharmaceuticals, Delaware Annalisa Jenkins, Bristol-Myers Squibb, New Jersey Michael Katz, March of Dimes Foundation, New York Jack D. Keene, Duke University Medical Center, North Carolina Ronald L. Krall, GlaxoSmithKline (retired), Pennsylvania Freda Lewis-Hall, Pfizer, Inc., New York William Matthew, National Institute of Neurological Disorders and Stroke, Maryland Mark B. McClellan, Brookings Institution, Washington, DC Carol Mimura, University of California-Berkeley John Orloff, Novartis Pharmaceuticals Corporation, New Jersey Amy Patterson, National Institutes of Health, Maryland Janet Shoemaker, American Society for Microbiology, Washington, DC Nancy S. Sung, Burroughs Wellcome Fund, North Carolina Jorge A. Tavel, National Institute of Allergy and Infectious Diseases, Maryland Janet Tobias, Ikana Media, New York Joanne Waldstreicher, Johnson & Johnson, New Jersey Janet Woodcock, U.S. Food and Drug Administration, Maryland Raymond Woosley, The Critical Path Institute, Arizona 1 IOM forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. i

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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 process. We wish to thank the following individuals for their review of this report: Timothy Coetzee, Fast Forward, LLC, National Multiple Sclerosis Society Marlene E. Haffner, Haffner Associates, LLC Steven E. Kahn, Division of Metabolism, Endocrinology, and Nutrition, Seattle VA Puget Sound Health Care System Michael S. Lauer, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the final draft of the report before its release. The review of this report was overseen by Alastair J.J. Wood, Symphony Capital, LLC. Appointed by the Institute of Medicine, he was 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 authors and the institution. ii

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Preface Clinical trials are the way the medical field tests whether a new thera- peutic product performs as expected and actually makes a difference in treating disease. Hundreds of innovative therapies are generated in labora- tories, but few survive early development to reach the point of human test- ing. Clinical trials in patients suffering from a specific condition represent the crucial link between scientific discovery and medical utility. To plan and execute a clinical trial today can take years and cost hun- dreds of millions of dollars. In the past, the United States was considered the best place to conduct clinical trials because of the right mix of clinical and scientific expertise and an understanding of the research process. How- ever, many believe that the clinical research enterprise in the United States has failed to keep pace with that in the rest of the world because of this time and cost burden. To evaluate the state of clinical research in the United States and identify strategies for enhancing the effectiveness and efficiency of clinical trials, the Institute of Medicine’s Forum on Drug Discovery, De- velopment, and Translation convened a public workshop on October 7−8, 2009, titled Transforming Clinical Research in the United States. Clinical trial experts from academic research centers, pharmaceutical companies, contract research organizations, government, nonprofit research networks, and patient advocacy groups came together to discuss their clinical trial suc- cesses and failures, the challenges they face in conducting clinical research, and strategies for improving the efficiency of clinical trials while maintain- ing the highest standards for the data generated. The intent of the workshop was to engage stakeholders in an honest discussion of the state of clinical trials today and to gain an understanding ix

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x PREFACE of what has and has not worked in planning and executing trials. The work- shop was focused on four disease areas: cardiovascular disease, depres- sion, cancer, and diabetes. Although “clinical research” is a generic term, a clinical trial in breast cancer, with 5-, 10-, or 15-year outcomes, is quite different from a clinical trial in cardiovascular disease, where the outcome of interest may occur in a month or less. The disease being studied also af- fects the kind of patients needed and how they are recruited and retained. Gaining an appreciation of the differences in clinical trials by disease helped generate ideas for improving the clinical research enterprise as a whole. This workshop is part of a broader initiative of the Forum addressing different aspects of clinical research. Future Forum plans include the follow- ing: further examining regulatory, administrative, and structural barriers to the effective conduct of clinical research; developing a vision for a stable, continuously funded clinical research infrastructure in the United States; and considering strategies and collaborative activities to facilitate more robust public engagement in the clinical research enterprise. As the starting point for the Forum’s work in the area of clinical re- search, it is our hope that this workshop summary will serve as a resource for all organizations and individuals seeking a greater understanding of how the clinical research enterprise works and how it can improve. The workshop showcased the best examples from clinical research conducted to date and developed novel ideas for organizing and conducting clinical trials. Ultimately, as the health care system moves forward, we hope our work can serve as a source of information and inspiration to those involved in clinical research as sponsors, investigators, clinicians, patients, and policy makers. Jeffrey M. Drazen, Co-Chair Forum on Drug Discovery, Development, and Translation

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Contents ACRONYMS x 1 INTRODUCTION 1 The Clinical Trials Process, 2 Workshop Scope and Objectives, 4 Organization of the Report, 5 2 THE STATE OF CLINICAL RESEARCH IN THE UNITED STATES: AN OVERVIEW 7 Clinical Research Networks, 8 Tools for Assessing Clinical Research in the United States, 9 Volume and Type of Clinical Trials Conducted, 11 The Clinical Investigator Workforce, 15 Capacity of the Clinical Research Enterprise, 16 3 CHALLENGES IN CLINICAL RESEARCH 19 Prioritizing of Clinical Research Questions, 20 The Divide Between Clinical Research and Clinical Practice, 22 Globalization of Clinical Trials, 24 The Cost of Clinical Trials, 26 Narrow Incentives for Physician Participation in Clinical Research, 27 Shrinking Clinical Research Workforce, 28 Need to Navigate Administrative and Regulatory Requirements, 30 Recruitment and Retention of Patients, 35 xi

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xii CONTENTS 4 CLINICAL TRIALS IN CARDIOVASCULAR DISEASE 37 Clinical Research Models for Coronary Syndromes, 37 The Thrombolysis in Myocardial Infarction Study Group, 39 The Occluded Artery Trial, 45 5 CLINICAL TRIALS IN DEPRESSION 49 Clinical Trials in Depression: A Patient Perspective, 50 The Contract Research Organization Model, 51 Issues in Conducting Clinical Trials in Depression, 53 Developing Informative Clinical Trials for Depression, 56 6 CLINICAL TRIALS IN CANCER 63 Clinical Trials in Cancer: A Patient Perspective, 64 The National Cancer Institute’s Clinical Trials Cooperative Group Program, 66 Industry-Sponsored Cancer Clinical Trials, 67 7 CLINICAL TRIALS IN DIABETES 71 Government-Sponsored Trials in Diabetes, 72 TrialNet: A Network Approach to Type 1 Diabetes Trials, 75 Case Study: Government- vs. Industry-Sponsored Trials in Type 2 Diabetes, 77 Overcoming Regulatory Challenges, 80 8 BUILDING A ROBUST CLINICAL TRIALS INFRASTRUCTURE 87 Current Efforts to Improve Clinical Trials, 88 Large, Simple Clinical Trials, 95 Suggestions from the Breakout Sessions, 96 Transforming Clinical Research, 100 REFERENCES 103 APPENDIXES A Agenda 107 B Participant Biographies 115

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Tables, Figures, and Boxes TABLES 3-1 Global Research Costs: Relative Cost Indexes of Payments to Clinical Trial Sites, 25 3-2 Breakdown of the Costs for a Large, Global Clinical Trial (14,000 patients, 300 sites), 26 7-1 Structure of Study Centers for a Government-Sponsored Randomized Controlled Trial (Diabetes Prevention Program [DPP]) and an Industry- Sponsored Randomized Controlled Trial (A Diabetes Progression Outcomes Trial [ADOPT]), 80 FIGURES 2-1 Timeline reflecting the number of clinical trials registered on clinicaltrials. gov and regulatory changes affecting the database registration from 2001 to 2009, 10 2-2 Percentage of the 10,974 ongoing clinical trials and 2.8 million study subjects being sought by intervention being tested, 13 2-3 Number of the 8,386 clinical trials involving FDA-regulated products and 1.9 million study subjects being sought for these trials by phase of research, 14 2-4 Number of the 10,974 ongoing clinical trials and 2.8 million study subjects being sought by disease being studied, 14 xiii

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xi TAblES, FIgURES, ANd bOxES 2-5 The proportion of clinical investigators from North America has decreased since 1997, while the proportion of investigators from Western Europe and the rest of the world has increased, 16 3-1 While the number of senior NIAID/NIH tenured investigators is relatively stable, the number of NIAID/NIH tenure-track principal investigators is decreasing, 29 4-1 Classification system for the spectrum of acute coronary syndromes that helps practitioners identify a study population more easily, 40 4-2 Timeline for the NIH-sponsored Occluded Artery Trial (OAT), 47 Figure in Box 5-1 STAR*D clinical trial results: remission rates by treatment level (monotherapy or combination treatment), 61 7-1 Study management structure for a government-sponsored randomized controlled trial (Diabetes Prevention Program [DPP]) and an industry- sponsored randomized controlled trial (A Diabetes Progression Out- comes Trial [ADOPT]), 79 7-2 Patient recruitment rates for four type 1 diabetes trials, 82 8-1 CTSAs include 46 institutions in 26 states, 89 8-2 Typical NIH clinical trial network with academic health center sites surrounding the hub of a data coordinating center, 93 8-3 A vision of an integrated clinical research system linking existing networks (patients, physicians, and scientists) to form communities of research and conduct clinical trials more effectively, 93 BOXES 4-1 Case Study: Acute Decompensated Heart Failure and Acute Myocardial Infarction, 40 5-1 Case Study: STAR*D, 60 6-1 Current Initiatives of NCI’s Clinical Trials Working Group to Optimize the Clinical Trials System, 68

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Acronyms ACS acute coronary syndromes ADA American Diabetes Association ADOPT A Diabetes Outcome Progression Trial AHA American Heart Association AHRQ Agency for Healthcare Research and Quality ARO academic research organization ARRA American Recovery and Reinvestment Act of 2009 caBIG Cancer Biomedical Informatics Grid CDER Center for Drug Evaluation and Research CEC clinical events committee CER comparative effectiveness research CMS Centers for Medicare and Medicaid Services CNS central nervous system CRF case report form CRN clinical research network CRO contract research organization CTA clinical trial agreement CTEP Cancer Therapy Evaluation Program CTSA Clinical and Translational Science Awards CTTI Clinical Trials Transformation Initiative DBSA Depression and Bipolar Support Alliance DCRI Duke Clinical Research Institute DMC data monitoring committee x

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xi ACRONyMS DPP diabetes prevention program DSMB data safety monitoring board ECG electrocardiogram ECOG Eastern Cooperative Oncology Group FDA U.S. Food and Drug Administration FDAAA Food and Drug Administration Amendments Act of 2007 FDAMA Food and Drug Administration Modernization Act of 1997 HAM-D Hamilton Depression Rating Scale HHS U.S. Department of Health and Human Services HIPAA Health Information Portability and Accountability Act ICMJE International Committee of Medical Journal Editors IECRN Inventory and Evaluation of Clinical Research Networks IOM Institute of Medicine IRB Institutional Review Board ISIS International Study of Infarct Survival JDRF Juvenile Diabetes Research Foundation MI myocardial infarction MTA material transfer agreement NCI National Cancer Institute NCRR National Center for Research Resources NDA New Drug Application NHLBI National Heart, Lung, and Blood Institute NIA National Institute on Aging NIAID National Institute of Allergy and Infectious Diseases NIDDK National Institute of Diabetes and Digestive and Kidney Diseases NIH National Institutes of Health NIMH National Institute of Mental Health NLM National Library of Medicine OAT occluded artery trial OPEN oncology patient enrollment network PBRN Practice-Based Research Network PCI percutaneous intervention

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xii ACRONyMS PCORI Patient-Centered Outcomes Research Institute PhRMA Pharmaceutical Research and Manufacturers of America PI principal investigator RCT randomized controlled trial RFA Request for Applications SSRI selective serotonin reuptake inhibitor STAR*D Sequenced Treatment Alternatives to Relieve Depression STEMI ST segment elevation myocardial infarction TIMI Thrombolysis in Myocardial Infarction Study Group VA U.S. Department of Veterans Affairs WHO World Health Organization