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Neil Weisfeld, Rebecca A. English, and Anne B. Claiborne, Rapporteurs Forum on Drug Discovery, Development, and Translation Board on Health Sciences Policy
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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 Govern- ing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineer- ing, and the Institute of Medicine. This study was supported by contracts between the National Academy of Sciences and Department of Health and Human Services (Contract Nos. N01-OD-4-2139 TO #158 and HHSF223001003T), American Society for Microbiology, Amgen Inc., Association of American Medical Colleges, Bristol-Myers Squibb, Burroughs Wellcome Fund, Celtic Therapeutics, LLLP, Critical Path Institute, Doris Duke Charitable Foundation, Eli Lilly & Co., FasterCures, Foundation for the NIH, Friends of Cancer Research, GlaxoSmithKline, Janssen Research & Development, LLC, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, and Pfizer Inc. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number-13: 978-0-309-25315-4 International Standard Book Number-10: 0-309-25315-2 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 Museen in Berlin. Suggested citation: IOM (Institute of Medicine). 2012. Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020: 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 Academy has a mandate that requires it to advise the federal govern - ment 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 mem - bers, sharing with the National Academy of Sciences the responsibility for advis - ing 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 fed - eral 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 engineer- ing 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 SERIES ON IMPROVING THE CLINICAL TRIAL PROCESS IN THE UNITED STATES1 JEFFREY M. DRAZEN (Chair), New England Journal of Medicine, Boston, MA BARBARA ALVING,2 National Center for Research Resources, Bethesda, MD ANN BONHAM, Association of American Medical Colleges, Washington, DC LINDA BRADY, National Institute of Mental Health, Bethesda, MD ROBERT CALIFF, Duke University Medical Center, Durham, NC SCOTT CAMPBELL,3 Foundation for the National Institutes of Health, Bethesda, MD GAIL H. CASSELL, Harvard Medical School (visiting), Carmel, IN JAMES H. DOROSHOW, National Cancer Institute, Bethesda, MD PAUL R. EISENBERG, Amgen Inc., Thousand Oaks, CA GARY L. FILERMAN, Atlas Health Foundation, McLean, VA GARRET A. FITZGERALD, University of Pennsylvania School of Medicine, Philadelphia PETRA KAUFMANN, National Institute of Neurological Disorders and Stroke, Bethesda, MD RONALD L. KRALL, University of Pennsylvania Center for Bioethics, Steamboat Springs, CO FREDA LEWIS-HALL, Pfizer Inc., New York, NY ELLEN SIGAL, Friends of Cancer Research, Washington, DC JANET TOBIAS, Ikana Media and Mount Sinai School of Medicine, New York, NY JANET WOODCOCK, Food and Drug Administration, White Oak, MD IOM Staff ANNE B. CLAIBORNE, Forum Director REBECCA A. ENGLISH, Associate Program Officer ELIZABETH F. C. TYSON, Research Associate ANDREW M. POPE, Director, Board on Health Sciences Policy ROBIN GUYSE, Senior Program Assistant 1 Institute of Medicine planning committees are solely responsible for organizing the work- shop, identifying topics, and choosing speakers. The responsibility for the published work- shop summary rests with the workshop rapporteurs and the institution. 2 Barbara Alving was with the National Center for Research Resources until September 30, 2011. 3 Scott Campbell was with Foundation for the National Institutes of Health as of the dates of the workshop. v
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FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 JEFFREY M. DRAZEN (Co-Chair), New England Journal of Medicine, Boston, MA STEVEN K. GALSON (Co-Chair), Amgen Inc., Thousand Oaks, CA MARGARET ANDERSON, FasterCures, Washington, DC HUGH AUCHINCLOSS, National Institute of Allergy and Infectious Diseases, Bethesda, MD LESLIE Z. BENET, University of California-San Francisco ANN BONHAM, Association of American Medical Colleges, Washington, DC LINDA BRADY, National Institute of Mental Health, Bethesda, MD ROBERT CALIFF, Duke University Medical Center, Durham, NC C. THOMAS CASKEY, Baylor College of Medicine, Houston, TX GAIL H. CASSELL, Harvard Medical School (visiting), Carmel, IN PETER B. CORR, Celtic Therapeutics, LLLP, New York, NY ANDREW M. DAHLEM, Eli Lilly & Co., Indianapolis, IN TAMARA DARSOW, American Diabetes Association, Alexandria, VA JAMES H. DOROSHOW, National Cancer Institute, Bethesda, MD GARY L. FILERMAN, Atlas Health Foundation, McLean, VA GARRET A. FITZGERALD, University of Pennsylvania School of Medicine, Philadelphia MARK J. GOLDBERGER, Abbott, Rockville, MD HARRY B. GREENBERG, Stanford University School of Medicine, CA STEPHEN GROFT, National Center for Advancing Translational Sciences, Bethesda, MD LYNN HUDSON, Critical Path Institute, Tuscon, AZ THOMAS INSEL, National Center for Advancing Translational Sciences, Bethesda, MD MICHAEL KATZ, March of Dimes Foundation, White Plains, NY PETRA KAUFMANN, National Institute of Neurological Disorders and Stroke, Bethesda, MD JACK D. KEENE, Duke University Medical Center, Durham, NC RONALD L. KRALL, University of Pennsylvania Center for Bioethics, Steamboat Springs, CO FREDA LEWIS-HALL, Pfizer Inc., New York, NY MARK B. McCLELLAN, The Brookings Institution, Washington, DC CAROL MIMURA, University of California, Berkeley 1Institute of Medicine forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published workshop summary rests with the work - shop rapporteurs and the institution. vi
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ELIZABETH (BETSY) MYERS, Doris Duke Charitable Foundation, New York, NY JOHN ORLOFF, Novartis Pharmaceuticals Corporation, East Hanover, NJ AMY PATTERSON, National Institutes of Health, Bethesda, MD MICHAEL ROSENBLATT, Merck & Co., Inc., Whitehouse Station, NJ JANET SHOEMAKER, American Society for Microbiology, Washington, DC ELLEN SIGAL, Friends of Cancer Research, Washington, DC ELLIOTT SIGAL, Bristol-Myers Squibb, Princeton, NJ ELLEN R. STRAHLMAN, GlaxoSmithKline, Research Triangle Park, NC NANCY SUNG, Burroughs Wellcome Fund, Research Triangle Park, NC JANET TOBIAS, Ikana Media and Mount Sinai School of Medicine, New York, NY JOANNE WALDSTREICHER, Janssen Research & Development, LLC, Raritan, NJ JANET WOODCOCK, Food and Drug Administration, White Oak, MD IOM Staff ANNE B. CLAIBORNE, Forum Director RITA S. GUENTHER, Program Officer REBECCA A. ENGLISH, Associate Program Officer ELIZABETH F. C. TYSON, Research Associate ANDREW M. POPE, Director, Board on Health Sciences Policy ROBIN GUYSE, Senior Program Assistant vii
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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 pub- lished 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: Deborah D. Ascheim, Department of Health Evidence and Policy and the Cardiovascular Institute, Mount Sinai School of Medicine Ralph I. Horwitz, GlaxoSmithKline James R. O’Dell, Rheumatoid Arthritis Investigational Network, University of Nebraska Medical Center Deborah A. Zarin, National Library of Medicine, ClinicalTrials.gov Although the reviewers listed above have provided many construc - tive comments and suggestions, they did not see the final draft of the report before its release. The review of this report was overseen by Daniel R. Masys, University of Washington. Appointed by the Institute ix
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x REVIEWERS of Medicine, he was responsible for making certain that an independent examination of this report was carried out in accordance with institu - tional procedures and that all review comments were carefully consid - ered. Responsibility for the final content of this report rests entirely with the authors and the institution.
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Contents ACRONYMS xv 1 INTRODUCTION 1 Defining the Problem, 4 Linking the Transformation of the Clinical Trials Enterprise and Improving Quality of Care, 5 Purpose and Structure of the Workshop, 7 Organization of the Report, 10 2 INTEGRATING COMMUNITY PRACTICE AND CLINICAL TRIALS 13 A Call for Disruptive Innovation in the Clinical Trials Enterprise, 13 A Framework for the Clinical Trials Enterprise in the Health Care System of 2020, 17 The Learning Health System, 22 3 IMPROVING PUBLIC PARTICIPATION IN CLINICAL TRIALS 27 Developing a Robust Clinical Trials Workforce, 27 Opportunities to Create a Sustainable Workforce for the Clinical Trials Enterprise, 31 Sustaining Institutional Support and Patient Engagement in Clinical Trials, 36 xi
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xii CONTENTS 4 CREATING A NEW BUSINESS MODEL FOR CLINICAL TRIALS 43 Transforming the Economics of Clinical Trials, 43 Identifying Opportunities to Improve Regulatory Frameworks for Clinical Trials, 47 Opportunities for Aligning Cultural and Financial Incentives in Clinical Trials, 48 5 BUILDING AN INFRASTRUCTURE TO SUPPORT CLINICAL TRIALS 53 Gaps and Challenges in the Current Clinical Trials Infrastructure, 54 Establishing an Infrastructure to Support a Transformed Clinical Trials Enterprise, 56 6 SUGGESTING AN AGENDA FOR TRANSFORMING ELEMENTS OF THE CLINICAL TRIALS ENTERPRISE 63 Reflecting on Potential Paths Forward, 66 Building a Framework and Suggesting an Agenda, 73 REFERENCES 81 APPENDIXES A WORKSHOP AGENDA 85 B PARTICIPANT BIOGRAPHIES 97 C REGISTERED WORKSHOP ATTENDEES 123 D DISCUSSION PAPER: The Clinical Trials Enterprise in the 133 United States: A Call for Disruptive Innovation E DISCUSSION PAPER: Developing a Robust Clinical Trials 161 Workforce F DISCUSSION PAPER: Transforming the Economics of Clinical 183 Trials G DISCUSSION PAPER: Developing a Clinical Trials Infrastructure 193 H DISCUSSION PAPER: Canadian Strategy on Patient-Oriented 203 Research I DISCUSSION PAPER: Health Research as a Public Good ˆ J DISCUSSION PAPER: Novel Ways to Get Good Trial Data: 211 The UK Experience K IOM STAFF PAPER: Context and Glossary of Select Terms 225 Associated with the Clinical Trials Enterprise
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Tables, Figures, and Boxes TABLES 2-1 The Four “Laboratories” of a Transformed Clinical Trials Enterprise, 15 2-2 Potential Features of the Clinical Trials Enterprise and Health Care System of 2020, 18 3-1 Education and Training Needs of Groups in the Clinical Trials Workforce, 30 5-1 Some Clinical Trials Infrastructure Challenges and Possible Courses of Action Mentioned at the Workshop, 61 6-1 Illustrative Strategies for Action by Stakeholder Groups Suggested by Individual Workshop Participants, 79 FIGURES 2-1 U.S. costs per clinical trial are noncompetitive, 16 2-2 Example of a sequential clinical trial design that administers and tests three drugs (drug A1, A2 and B1) in a tiered fashion, 25 3-1 Five suggested tiers for the workforce to meet the demands of a transformed clinical trials enterprise, 29 xiii
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xiv TABLES, FIGURES, AND BOXES 3-2 The protocol navigator interface at the National Institute of Allergy and Infectious Diseases (NIAID), 39 5-1 The PACeR (Partnership to Advance Clinical electronic Research) system fills the EMR clinical data gaps and captures uniform data across all clinical data capture sites, which is needed for evidence- based research, 59 BOXES 1-1 Stakeholders in the U.S. Clinical Trials Enterprise, 2 1-2 Selected Challenges Facing the U.S. Clinical Trials Enterprise, 5 1-3 Workshop Task and Objectives, 8 2-1 Some Aspects of the Challenge of Persuading Clinicians to Engage in Research, 21 3-1 NIH Clinical Center Key Services for Researchers and Patients, 37 4-1 Selected Potential Strategies for Avoiding Unnecessary Costs in Clinical Trials, 46 5-1 Elements of the Clinical Trials Infrastructure Discussed at the Workshop, 55 6-1 Key Themes of Clinical Trials Enterprise Transformation Suggested at the Workshop, 64 6-2 CEOs of Integrated Health Systems Could Promote Clinical Research, 67 6-3 Aspects of a High-Performance Clinical Research System, 69 6-4 Possible Ways to Manage the Research Portfolio in the United States, 71 6-5 One NIH Official’s Reflections on Collaborating with Patient Advocates, 71 6-6 Components of the Canadian Strategy for Patient-Oriented Research, 73 6-7 Public Engagement in Clinical Trials, 75 6-8 Individual Workshop Participants’ Suggestions for Simplifying the IRB Process, 77
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Acronyms ACO Accountable Care Organization AHRQ Agency for Healthcare Research and Quality AHSS academic health science system AMI acute myocardial infarction CDC U.S. Centers for Disease Control and Prevention CED Coverage with Evidence Development CER comparative effectiveness research CERN European Organization for Nuclear Research CF cystic fibrosis CMS Centers for Medicare & Medicaid Services CRO contract research organization CTE clinical trials enterprise CTSA Clinical and Translational Science Award CTTI Clinical Trials Transformation Initiative DoD U.S. Department of Defense EDC electronic data capture EHR electronic health record EMA European Medicines Agency FDA U.S. Food and Drug Administration FNIH Foundation for the National Institutes of Health xv
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xvi ACRONYMS GCP Good Clinical Practice GenISIS Genomic Informatics System for Integrative Science GMP Good Manufacturing Practice HCA Hospital Corporation of America HHS Department of Health and Human Services HIPAA Health Insurance Portability and Accountability Act HITECH Health Information Technology for Economic and Clinical Health HMORN HMO (health maintenance organization) Research Network i2b2 Informatics for Integrating Biology and the Bedside IHS integrated health system IND Investigational New Drug INTERMACS Interagency Registry for Mechanically Assisted Circulatory Support IOM Institute of Medicine IRB Institutional Review Board IT information technology MRSA methicillin-resistant Staphylococcus Aureus NCI National Cancer Institute NHLBI National Heart, Lung, and Blood Institute NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NINDS National Institute of Neurological Disorders and Stroke OAT Occluded Artery Trial PACeR Partnership to Advance Clinical electronic Research PCORI Patient-Centered Outcomes Research Institute RCT randomized controlled trial REDUCE-MRSA Randomized Evaluation of Decolonization versus Universal Clearance to Eliminate-MRSA SEMATECH Semiconductor Manufacturing Technology consortium VA U.S. Department of Veterans Affairs VINCI VA Informatics and Computing Infrastructure