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.

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THE LEARNING HEALTH SYSTEM SERIES ROUNDTABLE ON VALUE & SCIENCE-DRIVEN HEALTH CARE and FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION LARGE SIMPLE TRIALS AND KNOWLEDGE GENERA TION IN A LEARNING HEALTH SYSTEM Workshop Summary Claudia Grossmann, Julia Sanders, and Rebecca A. English, Rapporteurs Roundtable on Value & Science-Driven Health Care 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 workshop that is the subject of this workshop summary was ap- proved 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 Sci- ences 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, Criti- cal 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, Hos- pital 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 Out- comes 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 Additional copies of this workshop summary are available for sale from the Na- tional 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 2013 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 ad- opted 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). 2013. Large simple trials and knowledge generation in a learning health system: Workshop summary. Washing- ton, 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. C. D. Mote, Jr., 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 Sci- ences 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 Coun- cil 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. www.national-academies.org

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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 work- shop, identifying topics, and choosing speakers. The responsibility for the published workshop summary rests with the workshop rapporteurs and the institution. v

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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 vi

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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. vii

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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) viii

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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 ix

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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. xi

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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 Katz, 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 xii

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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 xiii

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Reviewers This workshop summary has been reviewed in draft form by individu- als chosen for their diverse perspectives and technical expertise, in accor- dance 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 ac- cordance 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. xv

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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 en- gage 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 Medi- cine’s Roundtable on Value & Science-Driven Health Care (the Roundtable) and the Forum on Drug Discovery, Development, and Translation (the Fo- rum) to convene a workshop, Large Simple Trials and Knowledge Genera- tion 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 continu- ously learning health system. The work of the Roundtable is focused on moving toward a continu- ously learning health system, one in which every care encounter is an op- portunity for learning and evidence is applied to ensure and improve best care practices. Since its inception in 2006, the Roundtable has set out to xvii

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xviii PREFACE 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 dia- logue and collaboration among thought leaders and stakeholders in govern- ment, 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 trans- formative 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 practi- cality 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 struc- tural, cultural, and regulatory barriers hindering the development of an enhanced LST capacity; discuss needs and strategies in building public de- mand 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 coun- sel 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 in- creased use of LSTs that rely on larger, more representative populations,

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PREFACE xix and optimize data collection could serve to speed the necessary transforma- tion. 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 1 INTRODUCTION 1 Workshop Scope and Objectives, 4 Organization of the Summary, 6 References, 8 2 Large Simple Trials Now and Looking Forward 11 Introduction, 12 A Vision for Large Simple Trials in the Learning Health System, 12 Opportunities and Challenges for LSTs, 15 References, 17 3 Examples of Large Simple Trials 19 Introduction, 20 VITamin D and OmegA 3 TriaL, 20 Post-Myocardial Infarction Free Rx Event and Economic Evaluation Trial, 22 High Five for Kids Trial and Study of Technology to Accelerate Research, 23 Heart Outcomes Prevention Evaluation Trial, 24 References, 25 4 Medical Product Regulatory Issues 27 Introduction, 28 Trial Complexity, 28 xxi

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xxii CONTENTS Simplifying Clinical Trials, 30 FDA Perspective, 33 References, 34 5 Infrastructure Needs and Opportunities 35 Introduction, 36 Aligning Care and Research to Reduce Burdens and Improve Integration, 37 Point-of-Care Trials Using EHR Platforms, 38 Obtaining Research-Quality Data from EHRs, 39 Building Reusable Research Networks, 41 6 Ethical and Privacy Policy Issues 43 Introduction, 44 Policy Overview, 44 Ethical Issues in Bringing Research and Care Closer Together, 45 Challenges with the Clinical Trial Process, 47 7 Research Partner Perspectives 49 Introduction, 50 Patient Perspective, 50 Health Systems/Clinician Perspective, 51 Payer Perspective, 52 8  Randomized Evaluations of Accepted Choices The in Treatment Trials 55 Introduction, 55 Randomized Evaluations of Accepted Choices in Treatment Trials, 56 Reference, 58 9 Strategies Going Forward 59 Learning-Ready Records, 59 Network for Question Development, 60 Science Stewardship, 61 Facilitative Oversight, 62 Learning Culture, 63 APPENDIXES A Workshop Agenda 65 B Biographical Sketches of Speakers 77