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Advancing Therapeutic Development for Pain and Opioid Use Disorders Through PublicâPrivate Partnerships PROCEEDINGS OF A WORKSHOP Lisa Bain, Sheena M. Posey Norris, and Clare Stroud, Rapporteurs Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy Health and Medicine Division PREPUBLICATION COPY: UNCORRECTED PROOFS
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by contracts between the National Academy of Sciences and the Alzheimerâs Association; Brain Canada Foundation; Cohen Veterans Bioscience; Department of Health and Human Servicesâ Food and Drug Administration (5R13FD005362-02) and National Institutes of Health (NIH) (HHSN26300089 [Under Master Base #DHHS-10002880]) through the National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, and NIH Blueprint for Neuroscience Research; Department of Veterans Affairs (VA240-14-C-0057); Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; George and Anne Ryan Institute for Neuroscience at The University of Rhode Island; Janssen Research & Development, LLC; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkinsonâs Research; National Multiple Sclerosis Society; National Science Foundation (BCS-1064270); One Mind; Pfizer Inc.; Pharmaceutical Product Development, LLC; Sanofi; Society for Neuroscience; Takeda Pharmaceuticals International, Inc.; and Wellcome Trust. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for this project. International Standard Book Number-13: International Standard Book Number-10: Digital Object Identifier: https://doi.org/10.17226/25060 Additional copies of this publication are available for sale 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. Copyright 2018 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2018. Advancing therapeutic development for pain and opioid use disorders through publicâprivate partnerships: Proceedings of a workshop. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/25060. PREPUBLICATION COPY: UNCORRECTED PROOFS
The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. C. D. Mote, Jr., is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org. PREPUBLICATION COPY: UNCORRECTED PROOFS
Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the studyâs statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committeeâs deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/ about/whatwedo. PREPUBLICATION COPY: UNCORRECTED PROOFS
PLANNING COMMITTEE ON ADVANCING THERAPEUTIC DEVELOPMENT FOR PAIN AND OPIOID USE DISORDERS THROUGH PUBLICâPRIVATE PARTNERSHIPS 1 WALTER KOROSHETZ (Co-Chair), National Institute of Neurological Disorders and Stroke STORY LANDIS (Co-Chair), Director Emeritus, National Institute of Neurological Disorders and Stroke NORA VOLKOW (Co-Chair), National Institute on Drug Abuse ANDREW AHN, Eli Lilly and Company KATJA BROSE, Chan Zuckerberg Initiative JOHN DUNLOP, Amgen ROBERT DWORKIN, University of Rochester SHARON HERTZ, Food and Drug Administration LINDA PORTER, National Institute of Neurological Disorders and Stroke TARAK SAMAD, Pfizer Inc. FRIEDHELM SANDBRINK, Department of Veterans Affairs ROBERT SHIBUYA, Food and Drug Administration DAVID SHURTLEFF, National Center for Complementary and Integrative Health JACK STEIN, National Institute on Drug Abuse JAMES SULLIVAN, AbbVie Inc. CHRISTIN VEASLEY, Chronic Pain Research Alliance TONY YAKSH, University of California, San Diego Health and Medicine Division Staff CLARE STROUD, Forum Director SHEENA M. POSEY NORRIS, Program Officer NOAM I. KEREN, Associate Program Officer DANIEL FLYNN, Research Assistant ANDREW M. POPE, Director, Board on Health Sciences Policy 1The National Academies of Sciences, Engineering, and Medicineâs planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution. v PREPUBLICATION COPY: UNCORRECTED PROOFS
FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS 1 STEVEN HYMAN (Chair), Broad Institute of Massachusetts Institute of Technology and Harvard University STORY LANDIS (Vice Chair), Director Emeritus, National Institute of Neurological Disorders and Stroke SUSAN AMARA, Society for Neuroscience RITA BALICE-GORDON, Sanofi KATJA BROSE, Chan Zuckerberg Initiative EMERY BROWN, Harvard Medical School and Massachusetts Institute of Technology JOSEPH BUXBAUM, Icahn School of Medicine at Mount Sinai SARAH CADDICK, Gatsby Charitable Foundation ROSA CANET-AVILES, Foundation for the National Institutes of Health MARIA CARRILLO, Alzheimerâs Association E. ANTONIO CHIOCCA, Harvard Medical School TIMOTHY COETZEE, National Multiple Sclerosis Society JONATHAN COHEN, Princeton University FAY LOMAX COOK, National Science Foundation JAMES DESHLER, National Science Foundation BILLY DUNN, Food and Drug Administration MICHAEL EGAN, Merck Research Laboratories JOSHUA GORDON, National Institute of Mental Health HANK GREELY, Stanford University RAQUEL GUR, University of Pennsylvania MAGALI HAAS, Cohen Veterans Bioscience RAMONA HICKS, One Mind RICHARD HODES, National Institute on Aging STUART HOFFMAN, Department of Veterans Affairs MICHAEL IRIZARRY, Eli Lilly and Company INEZ JABALPURWALA, Brain Canada Foundation FRANCES JENSEN, University of Pennsylvania GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism 1The National Academies of Sciences, Engineering, and Medicineâs forums and round- tables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution. vi PREPUBLICATION COPY: UNCORRECTED PROOFS
WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke JOHN KRYSTAL, Yale University ALAN LESHNER, American Association for the Advancement of Science (Emeritus) HUSSEINI MANJI, Janssen Research & Development, LLC DAVID MICHELSON, Merck Research Laboratories (until December 2017) JAMES OLDS, National Science Foundation (until December 2017) ATUL PANDE, Tal Medical STEVEN PAUL, Voyager Therapeutics, Inc. STEPHEN PEROUTKA, Pharmaceutical Product Development, LLC RODERIC PETTIGREW, National Institute of Biomedical Imaging and Bioengineering (until November 2017) EMILIANGELO RATTI, Takeda Pharmaceuticals International TAREK SAMAD, Pfizer Inc. (until December 2017) DOUGLAS SHEELEY, National Institute of Dental and Craniofacial Research TODD SHERER, The Michael J. Fox Foundation for Parkinsonâs Research DAVID SHURTLEFF, National Center for Complementary and Integrative Health PAUL SIEVING, National Eye Institute NORA VOLKOW, National Institute on Drug Abuse ANDREW WELCHMAN, Wellcome Trust DOUG WILLIAMSON, Lundbeck STEVIN ZORN, MindImmune Therapeutics, Inc. Health and Medicine Staff CLARE STROUD, Forum Director SHEENA M. POSEY NORRIS, Program Officer NOAM I. KEREN, Associate Program Officer DANIEL FLYNN, Research Assistant JIM BANIHASHEMI, Financial Officer (until October 2017) BARDIA MASSOUDKHAN, Financial Associate (from October 2017) ANDREW M. POPE, Director, Board on Health Sciences Policy vii PREPUBLICATION COPY: UNCORRECTED PROOFS
Reviewers This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process. We thank the following individuals for their review of this proceedings: CHAD MICHAEL BRUMMETT, University of Michigan KATHERINE DAWSON, Biogen LUDA DIATCHENKO, McGill University MICHAEL OSHINSKY, National Insitute of Neurological Disorders and Stroke HOWARD B. ROSEN, Independent Consultant KENNETH VERBURG, Pfizer Inc. Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by SARA ROSENBAUM, The George Washington University, and BRADFORD H. GRAY, The Urban Institute. They were responsible for making certain that an independent examination of this proceedings was carried out in accordance with ix PREPUBLICATION COPY: UNCORRECTED PROOFS
x REVIEWERS standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.
Contents 1 INTRODUCTION AND BACKGROUND 1 Workshop Objectives, 4 The Public Health Impact of Pain and Opioid Use Disorders, 4 Selected Federal Initiatives to Address the Challenge of Treating Pain and Opioid Use Disorders and Related National Academiesâ Reports, 5 Organization of Proceedings, 9 2 EXPLORING CHALLENGES TO DEVELOPING TREATMENTS FOR PAIN AND OPIOID USE DISORDERS 11 The Complex Experience of Pain, 11 Insufficient Resources to Treat Pain, 12 Insufficient Understanding of Pain Mechanisms, 13 Understanding Challenges in Conducting Clinical Trials, 13 The Pendulum Swing of Care: Understanding Patient Needs, 14 3 EXPLORING THE STATE OF THE SCIENCE AND PRECLINICAL MODELS FOR PAIN THERAPEUTIC DEVELOPMENT 17 Neural Circuits, Cells, and Molecular Mediators of Pain, 18 Preclinical Efforts to Identify Pain Targets and Treat Pain, 20 4 CLINICAL DEVELOPMENT OF NON-ADDICTIVE PAIN MEDICATIONS 29 Biomarkers: A Bridge to Clinical Studies, 31 xi PREPUBLICATION COPY: UNCORRECTED PROOFS
xii CONTENTS A Targeted Approach to Therapy Development in the Clinical Space, 35 Preventing the Acute-to-Chronic Pain Transition, 38 Regulatory Challenges Related to the Approval of Pain Medications, 42 5 THERAPEUTIC DEVELOPMENT FOR OPIOID DISORDERS AND OVERDOSE PREVENTION AND REVERSAL 45 New Treatments in Development for Opioid Use Disorders, 49 Therapeutic Development to Reverse Overdose, 52 6 PRIVATEâPUBLIC PARTNERSHIPS TO ADVANCE PAIN AND OPIOID USE DISORDERS RESEARCH AND DEVELOPMENT 55 PublicâPrivate Partnerships to Accelerate Development of Non- Addictive Pain Medications, 57 Partnerships to Address Opioid Use Disorders and Reverse Overdose, 64 Understanding the Role of Payers in Supporting Therapeutic Development for Pain and Opioid Use Disorders, 66 Final Remarks, 67 APPENDIXES A References 69 B Workshop Agenda 79 C Registered Attendees 89 PREPUBLICATION COPY: UNCORRECTED PROOFS