LARGE SIMPLE TRIALS AND
KNOWLEDGE GENERATION IN
A LEARNING HEALTH SYSTEM
Workshop Summary
Claudia Grossmann, Julia Sanders, and Rebecca A. English, Rapporteurs
Roundtable on Value and Science-Driven Health Care
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.
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
NOTICE: The workshop that is the subject of this workshop summary 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 activity was supported by contracts between the National Academy of Sciences and the U.S. Department of Health and Human Services (Contract No. N01-OD-4-2139 TO #203 and HHSN26300023 [Under Base No. HHSN263201200074I] and Contract No. N01-OD-4-2139 TO #276; HHSF22301026T [Under Base No. HHSF223200810020I]), AbbVie Inc., Agency for Healthcare Research and Quality, American Diabetes Association, American Society for Microbiology, Amgen Inc., Association of American Medical Colleges, AstraZeneca, Blue Shield of California, Blue Shield of California Foundation, Bristol-Myers Squibb, Burroughs Wellcome Fund, Celtic Therapeutics, LLLP, Centers for Medicare & Medicaid Services, Critical Path Institute, Doris Duke Charitable Foundation, Eli Lilly and Company, Epic Systems, Inc., FasterCures, Friends of Cancer Research, GlaxoSmithKline, Gordon and Betty Moore Foundation, Health Resources and Services Administration, Hospital Corporation of America, Inc., Johnson & Johnson, Kaiser Permanente (East Bay Community Foundation), March of Dimes Foundation, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Partners HealthCare, Patient-Centered Outcomes Research Institute, Pfizer Inc., Premier, Sanofi, United Health Foundation, and WellPoint, Inc. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for the activity.
International Standard Book Number-13: 978-0-309-28911-5
International Standard Book Number-10: 0-309-28911-4
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Suggested citation: IOM (Institute of Medicine). 2013. Large simple trials and knowledge generation in a learning health system: Workshop summary. Washington, DC: The National Academies Press.
“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.
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.
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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. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council.
PLANNING COMMITTEE FOR THE WORKSHOP
ON LARGE SIMPLE TRIALS AND KNOWLEDGE
GENERATION IN A LEARNING SYSTEM1
DAVID L. DEMETS (Co-Chair), Professor, Biostatistics and Medical Informatics, University of Wisconsin School of Public Health
RICHARD E. KUNTZ (Co-Chair), Senior Vice President and Chief Scientific, Clinical, and Regulatory Officer, Medtronic
WILLIAM H. CROWN, President, HEOR and Late Phase Research, OPTUMInsight Life Sciences
JEFFREY M. DRAZEN, Editor-in-Chief, New England Journal of Medicine
RALPH I. HORWITZ, Senior Vice President, Clinical Sciences Evaluation, GlaxoSmithKline
PETRA KAUFMANN, Director, Office of Clinical Research, National Institute of Neurological Disorders and Stroke
JUDITH M. KRAMER, Senior Scientific Advisor, Clinical Trials Transformation Initiative, Duke Translational Medicine Institute
MICHAEL S. LAUER, Director, Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute
JOANN E. MANSON, Professor of Medicine, Harvard Medical School
JOHN J. ORLOFF, Chief Medical Officer and Senior Vice President, Global Development, U.S. Medical and Drug Regulatory Affairs, Novartis Pharmaceuticals Corporation
ERIC D. PETERSON, Professor of Medicine, Division of Cardiology, Duke University Medical School
RICHARD PLATT, Chair, Population Medicine, Harvard Medical School
JOE V. SELBY, Executive Director, Patient-Centered Outcomes Research Institute
RACHEL E. SHERMAN, Director, Office of Medical Policy, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
JOSE M. VEGA, Vice President, Global Safety, Amgen Inc.
________________
1 Institute of Medicine planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution.
IOM Staff
CLAUDIA GROSSMANN, Senior Program Officer
ANNE B. CLAIBORNE, Senior Program Officer
REBECCA A. ENGLISH, Associate Program Officer
ELIZABETH F. C. TYSON, Research Associate
JULIA SANDERS, Senior Program Assistant
ELIZABETH JOHNSTON, Program Assistant
ROUNDTABLE ON VALUE & SCIENCE-DRIVEN HEALTH CARE1
MARK B. MCCLELLAN (Chair), Senior Fellow and Director, Health Care Innovation and Value Initiative, The Brookings Institution
RAYMOND BAXTER, Senior Vice President, Community, Benefit, Research and Health Policy, Kaiser Permanente
DAVID BLUMENTHAL, President, The Commonwealth Fund
BRUCE G. BODAKEN, Former Chairman and Chief Executive Officer, Blue Shield of California
PAUL CHEW, Chief Science Officer and Chief Medical Officer, Sanofi U.S.
FRANCIS COLLINS, Director, National Institutes of Health (Ex Officio) (designee: Kathy Hudson)
HELEN DARLING, President, National Business Group on Health
SUSAN DEVORE, Chief Executive Officer, Premier, Inc.
JUDITH FAULKNER, Founder and Chief Executive Officer, Epic Health Systems
THOMAS R. FRIEDEN, Director, Centers for Disease Control and Prevention (Ex Officio) (designee: James Galloway)
PATRICIA A. GABOW, Former Chief Executive Officer, Denver Health
ATUL GAWANDE, General and Endocrine Surgeon, Brigham and Women’s Hospital
GARY L. GOTTLIEB, President and Chief Executive Officer, Partners HealthCare
JAMES A. GUEST, President and Chief Executive Officer, Consumers Union
GEORGE C. HALVORSON, Chairman and Chief Executive Officer, Kaiser Permanente
MARGARET A. HAMBURG, Commissioner, U.S. Food and Drug Administration (Ex Officio) (designee: Peter Lurie)
JAMES HEYWOOD, Cofounder and Chairman, PatientsLikeMe
RALPH I. HORWITZ, Senior Vice President, Clinical Evaluation Sciences, GlaxoSmithKline
PAUL HUDSON, Executive Vice President, AstraZeneca
BRENT C. JAMES, Chief Quality Officer, Intermountain Healthcare
CRAIG JONES, Director, Vermont Blueprint for Health
GARY KAPLAN, Chairman and Chief Executive Officer, Virginia Mason Health System
________________
1 Institute of Medicine 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.
DARRELL G. KIRCH, President and Chief Executive Officer, Association of American Medical Colleges
RICHARD KRONICK, Director, Agency for Healthcare Research and Quality (Ex Officio)
RICHARD C. LARSON, Mitsui Professor, Massachusetts Institute of Technology
JAMES L. MADARA, Chief Executive Officer, American Medical Association
FARZAD MOSTASHARI, National Coordinator, Office of the National Coordinator for Health IT (Ex Officio)
MARY D. NAYLOR, Director, NewCourtland Center, University of Pennsylvania
WILLIAM D. NOVELLI, Former Chief Executive Officer, AARP; Professor, Georgetown University
SAM R. NUSSBAUM, Chief Medical Officer, WellPoint, Inc.
JONATHAN B. PERLIN, President, Clinical and Physician Services and Chief Medical Officer, Hospital Corporation of America, Inc.
ROBERT A. PETZEL, Under Secretary for Health, U.S. Department of Veterans Affairs (Ex Officio)
RICHARD PLATT, Chair, Population Medicine, Harvard Medical School
MICHAEL ROSENBLATT, Executive Vice President and Chief Medical Officer, Merck & Co., Inc.
JOHN W. ROWE, Former Chairman and Chief Executive Officer, Aetna; Professor, Columbia University
JOE V. SELBY, Executive Director, Patient-Centered Outcomes Research Institute
MARK D. SMITH, President and Chief Executive Officer, California HealthCare Foundation
GLENN D. STEELE, President and Chief Executive Officer, Geisinger Health System
MARILYN TAVENNER, Administrator, Centers for Medicare & Medicaid Services (Ex Officio) (designee: Patrick Conway)
REED V. TUCKSON, Former Executive Vice President, UnitedHealth Group; Managing Director, Tuckson Health
MARY WAKEFIELD, Administrator, Health Resources and Services Administration (Ex Officio)
DEBRA B. WHITMAN, Executive Vice President, Policy and International, AARP
JONATHAN WOODSON, Assistant Secretary for Health Affairs, U.S. Department of Defense (Ex Officio)
IOM Staff
KATHERINE BURNS, Program Assistant
CLAUDIA GROSSMANN, Senior Program Officer
DIEDTRA HENDERSON, Program Officer
ELIZABETH JOHNSTON, Program Assistant
ELIZABETH ROBINSON, Research Associate
VALERIE ROHRBACH, Senior Program Assistant
JULIA SANDERS, Senior Program Assistant (through August 2013)
ROBERT SAUNDERS, Senior Program Officer
BARRET ZIMMERMANN, Program Assistant (through October 2013)
J. MICHAEL MCGINNIS, Senior Scholar, Executive Director, Roundtable on Value & Science-Driven Health Care
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FORUM ON DRUG DISCOVERY,
DEVELOPMENT, AND TRANSLATION1
JEFFREY M. DRAZEN (Co-Chair), Editor-in-Chief, New England Journal of Medicine
STEVEN K. GALSON (Co-Chair), Global Regulatory Vice President, Amgen Inc.
RUSS BIAGIO ALTMAN, The Kenneth Fong Professor of Bioengineering, Genetics, Medicine, and (by courtesy) Computer Science, Stanford University
MARGARET ANDERSON, Executive Director, FasterCures
HUGH AUCHINCLOSS, Deputy Director, National Institute of Allergy and Infectious Diseases
CHRISTOPHER P. AUSTIN, Director, National Center for Advancing Translational Sciences
ANN C. BONHAM, Chief Scientific Officer, Association of American Medical Colleges
LINDA BRADY, Director, Division of Neuroscience and Basic Behavioral Science, National Institute of Mental Health
GAIL H. CASSELL, Visiting Professor, Department of Social Medicine and Global Medicine, Harvard Medical School
PETER B. CORR, Cofounder, Managing General Partner, Auven Therapeutics, LLP
ANDREW M. DAHLEM, Vice President and Chief Operating Officer, Lilly Research Laboratories, Eli Lilly and Company
JAMES H. DOROSHOW, Deputy Director for Clinical and Translational Research, Division of Cancer Treatment and Diagnosis, National Cancer Institute
GARY L. FILERMAN, President, Atlas Health Foundation
MARK J. GOLDBERGER, Divisional Vice President, Regulatory Policy and Intelligence, Pharmaceutical Products Group, Abbott Pharmaceuticals
HARRY B. GREENBERG, Senior Associate Dean for Research and Joseph D. Grant Professor of Medicine, Microbiology, and Immunology, Stanford University School of Medicine
PETER K. HONIG, Global Vice President, Regulatory Affairs, AstraZeneca
KATHY L. HUDSON, Deputy Director for Science, Outreach, and Policy, National Institutes of Health
________________
1 Institute of Medicine 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.
LYNN D. HUDSON, Chief Science Officer, Critical Path Institute
S. CLAIBORNE JOHNSTON, Professor of Neurology and Epidemiology, Associate Vice Chancellor of Research, and Director, Clinical and Translational Science Institute, University of California, San Francisco
MICHAEL KAT Z, Senior Advisor, Transdisciplinary Research, March of Dimes Foundation
PETRA KAUFMANN, Director, Office of Clinical Research, National Institute of Neurological Disorders and Stroke
JACK D. KEENE, James B. Duke Professor of Molecular Genetics and Microbiology, Duke University Medical Center
RUSTY KELLEY, Program Officer, Burroughs Wellcome Fund
RONALD L. KRALL, Associate Fellow, University of Pennsylvania Center for Bioethics
FREDA C. LEWIS-HALL, Executive Vice President and Chief Medical Officer, Pfizer Inc.
CAROL MIMURA, Assistant Vice Chancellor for Intellectual Property & Industry Research Alliances, University of California, Berkeley
BERNARD H. MUNOS, Founder, InnoThink Center for Research in Biomedical Innovation
ELIZABETH (BETSY) MYERS, Program Director for Medical Research, Doris Duke Charitable Foundation
JOHN J. ORLOFF, Chief Medical Officer and Senior Vice President, Global Development, U.S. Medical and Drug Regulatory Affairs, Novartis Pharmaceuticals Corporation
ROBERT E. RATNER, Chief Scientific Medical Officer, American Diabetes Association
MICHAEL ROSENBLATT, Executive Vice President and Chief Medical Officer, Merck & Co., Inc.
JAMES S. SHANNON, Chief Medical Officer, GlaxoSmithKline
JANET SHOEMAKER, Director, Office of Public Affairs, American Society for Microbiology
ELLEN V. SIGAL, Chair and Founder, Friends of Cancer Research
LANA R. SKIRBOLL, Vice President, Academic and Scientific Affairs, Sanofi
BRIAN L. STROM, Executive Vice Dean for Institutional Affairs and Professor, University of Pennsylvania Perelman School of Medicine
JANET TOBIAS, President, Sierra/Tango Productions, Ikana Media
JOANNE WALDSTREICHER, Chief Medical Officer, Johnson & Johnson
JANET WOODCOCK, Director, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
IOM Staff
ANNE B. CLAIBORNE, Forum Director
REBECCA A. ENGLISH, Associate Program Officer
ELIZABETH F. C. TYSON, Research Associate
ROBIN GUYSE, Senior Program Assistant
ANDREW M. POPE, Director, Board on Health Sciences Policy
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Reviewers
This workshop summary 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 workshop summary as sound as possible and to ensure that the workshop summary 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 workshop summary:
STEFAN JAMES, Uppsala University Hospital
Elliott Levy, Bristol-Myers Squibb
Sean Tunis, Center for Medical Technology Policy
Paul J. Wallace, Optum Labs
Although the reviewers listed above have provided many constructive comments and suggestions, they did not see the final draft of the workshop summary before its release. The review of this workshop summary was overseen by Joel Kupersmith, Veterans Health Administration. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this workshop summary was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this workshop summary rests entirely with the rapporteurs and the institution.
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Preface
The current paradigms for effectiveness research and drug development face increasingly acute challenges in cost, timing, and applicability, given their reliance on classic randomized controlled trials. Opportunities to engage these challenges by the use of large simple trial (LST) designs and the integration of research at the point of care prompted the Institute of Medicine’s Roundtable on Value & Science-Driven Health Care (the Roundtable) and the Forum on Drug Discovery, Development, and Translation (the Forum) to convene a workshop, Large Simple Trials and Knowledge Generation in a Learning Health System, which is summarized in this publication.
Experts from a wide range of disciplines—including health information technology, research funding, clinical research methods, statistics, patients, product development, medical product regulation, and clinical outcomes research—met to marshal a better understanding of the issues, options, and approaches to accelerating the use of LSTs. This publication summarizes discussions on the potential of LSTs to improve the speed and practicality of knowledge generation for medical decision making and medical product development, including efficacy and effectiveness assessments, in a continuously learning health system.
The work of the Roundtable is focused on moving toward a continuously learning health system, one in which every care encounter is an opportunity for learning and evidence is applied to ensure and improve best care practices. Since its inception in 2006, the Roundtable has set out to
help realize this vision through the support, involvement, and activities of senior leadership from key stakeholders in the health care system.
Since its creation in 2005, the Forum has provided a platform for dialogue and collaboration among thought leaders and stakeholders in government, academia, industry, foundations, and patient advocacy. Since 2009, the Forum has convened an ongoing initiative dedicated to addressing the challenges facing the U.S. clinical trials enterprise by bringing together the broad range of clinical research stakeholders to surface potentially transformative strategies to improve the efficiency and effectiveness of clinical trials. The Forum’s public meetings focus substantial public attention on critical areas of drug discovery, development, and translation and in doing so serve to educate the policy community about issues where science and policy intersect.
Building on this groundwork, the objectives of this workshop were to explore acceleration of the use of LSTs to improve the speed and practicality of knowledge generation for medical decision making and medical product development; consider the concepts of LST design, examples of successful LSTs, the relative advantages of LSTs, and the infrastructure needed to build LST capacity as a routine function of care; identify structural, cultural, and regulatory barriers hindering the development of an enhanced LST capacity; discuss needs and strategies in building public demand for and participation in LSTs; and consider near-term strategies for accelerating progress in the uptake of LSTs in the United States.
Multiple individuals donated valuable time toward the development of this publication. We acknowledge and offer strong appreciation to the contributors to this publication for their presence at the workshop and their efforts to further develop their presentations into the summaries contained in this publication. We are especially indebted to those who provided counsel by serving on the planning committee for this workshop.
A number of Roundtable and Forum staff played instrumental roles in coordinating the workshop and translating the workshop proceedings into this summary, including Claudia Grossmann, Anne Claiborne, Julia Sanders, Rebecca A. English, Elizabeth Johnston, Elizabeth Tyson, Valerie Rohrbach, Robin Guyse, Barret Zimmermann, Rob Saunders, Diedtra Henderson, and Elizabeth Robinson. Finally, we thank Daniel Bethea, Marton Cavani, Laura Harbold DeStefano, and Chelsea Frakes for helping to coordinate various aspects of review, production, and publication.
A fundamental component of a learning health system is the ability to improve the speed and practicality of knowledge generation. The increased use of LSTs that rely on larger, more representative populations,
and optimize data collection could serve to speed the necessary transformation. We believe that Large Simple Trials and Knowledge Generation in a Learning Health System: Workshop Summary will be a valuable resource in informing this transformation.
David L. DeMets
Planning Committee Co-Chair
Professor
University of Wisconsin School of Public Health
Richard E. Kuntz
Planning Committee Co-Chair
Senior Vice President and
Chief Scientific, Clinical, and Regulatory Officer
Medtronic
J. Michael McGinnis
Senior Scholar
Executive Director
Roundtable on Value & Science-Driven Health Care
Institute of Medicine
Andrew M. Pope
Director
Board on Health Sciences Policy
Institute of Medicine
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Contents
2 LARGE SIMPLE TRIALS NOW AND LOOKING FORWARD
A Vision for Large Simple Trials in the Learning Health System
Opportunities and Challenges for LSTs
3 EXAMPLES OF LARGE SIMPLE TRIALS
Post-Myocardial Infarction Free Rx Event and Economic Evaluation Trial
High Five for Kids Trial and Study of Technology to Accelerate Research
Heart Outcomes Prevention Evaluation Trial
5 INFRASTRUCTURE NEEDS AND OPPORT UNITIES
Aligning Care and Research to Reduce Burdens and Improve Integration
Point-of-Care Trials Using EHR Platforms
Obtaining Research-Quality Data from EHRs
Building Reusable Research Networks
6 ETHICAL AND PRIVACY POLICY ISSUES
Ethical Issues in Bringing Research and Care Closer Together
Challenges with the Clinical Trial Process
7 RESEARCH PARTNER PERSPECTIVES
Health Systems/Clinician Perspective
8 THE RANDOMIZED EVALUATIONS OF ACCEPTED CHOICES IN TREATMENT TRIALS
Randomized Evaluations of Accepted Choices in Treatment Trials