Neuroscience Trials of the Future: Proceedings of a Workshop (2016)

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Sheena M. Posey Norris, Lisa Bain, and Clare Stroud, Rapporteurs Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy Health and Medicine Division 

THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, NW • Washington, DC 20001 This project was supported by contracts between the National Academy of Sci- ences and the Alzheimer’s Association; Brain Canada Foundation; Cohen Vet- erans Bioscience; the Department of Health and Human Services’ Food and Drug Administration and National Institutes of Health (NIH) (HHSN26300089 [Under Master Base # DHHS-10002880]) through the National Center for Com- plementary and Integrative Health, National Eye Institute, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Nation- al Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, Na- tional 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; Janssen Research & Development, LLC; Lundbeck Research USA; Merck Re- search Laboratories; The Michael J. Fox Foundation for Parkinson’s Research; National Multiple Sclerosis Society; National Science Foundation (BCS- 1064270); One Mind for Research; Pfizer Inc.; Pharmaceutical Product Devel- opment, LLC; Sanofi; Society for Neuroscience; Takeda Pharmaceutical Com- pany Limited; 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: 978-0-309-44255-8 International Standard Book Number-10: 0-309-44255-9 Digital Object Identifier: 10.17226/23502 Additional copies of this publication 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. Copyright 2016 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. 2016. Neuroscience trials of the future: Proceedings of a workshop. Washington, DC: The National Academies Press. doi: 10.17226/23502. 

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PLANNING COMMITTEE ON NEUROSCIENCE TRIALS OF THE FUTURE1 RICHARD KEEFE (Co-Chair), Duke University Medical Center ATUL PANDE (Co-Chair), Tal Medical BRUCE BEBO, National Multiple Sclerosis Society STEPHEN BRANNAN, FORUM Pharmaceuticals, Inc. DANIEL BURCH, Pharmaceutical Product Development, LLC TIMOTHY DENISON, Medtronic, Inc. HANK GREELY, Stanford University FRANCES JENSEN, University of Pennsylvania Perelman School of Medicine AMIR KALALI, Quintiles, Inc. PETRA KAUFMANN, National Center for Advancing Translational Sciences THOMAS LAUGHREN, Laughren Psychopharm Consulting, LLC HMD Staff CLARE STROUD, Forum Director SHEENA M. POSEY NORRIS, Program Officer JOANNA ROBERTS, Senior Program Assistant (from January 2016) ANNALYN WELP, Senior Program Assistant (until December 2015) ANDREW M. POPE, Director, Board on Health Sciences Policy 1 The National Academies of Sciences, Engineering, and Medicine’s 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 



FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS1 STEVEN HYMAN (Chair), The 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, Inc. KATJA BROSE, Cell Press EMERY BROWN, Harvard Medical School and Massachusetts Institute of Technology DANIEL BURCH, Pharmaceutical Product Development, LLC SARAH CADDICK, Gatsby Charitable Foundation ROSA CANET-AVILES, Foundation for the National Institutes of Health MARIA CARRILLO, Alzheimer’s Association KAREN CHANDROSS, Sanofi, Inc. (until June 2016) E. ANTONIO CHIOCCA, Harvard Medical School TIMOTHY COETZEE, National Multiple Sclerosis Society JONATHAN COHEN, Princeton University FAY LOMAX COOK, National Science Foundation BRUCE CUTHBERT, National Institute of Mental Health BILLY DUNN, Food and Drug Administration EMMELINE EDWARDS, National Center for Complementary and Integrative 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, U.S. 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 1 The National Academies of Sciences, Engineering, and Medicine’s 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. vii 

WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke ALAN LESHNER, American Association for the Advancement of Science (Emeritus) HUSSEINI MANJI, Janssen Research & Development, LLC DAVID MICHELSON, Merck Research Laboratories PATRICIO O’DONNELL, Pfizer Inc. JAMES OLDS, National Science Foundation ATUL PANDE, Tal Medical STEVEN PAUL, Voyager Therapeutics, Inc. EMILIANGELO RATTI, Takeda Pharmaceuticals International TODD SHERER, The Michael J. Fox Foundation for Parkinson’s Research DAVID SHURTLEFF, National Center for Complementary and Integrative Health PAUL SIEVING, National Eye Institute NORA VOLKOW, National Institute on Drug Abuse STEVIN ZORN, MindImmune Therapeutics, Inc. HMD Staff CLARE STROUD, Forum Director SHEENA M. POSEY NORRIS, Program Officer NOAM I. KEREN, Associate Program Officer (from June 2016) JOANNA ROBERTS, Senior Program Assistant (until April 2016) DANIEL FLYNN, Senior Program Assistant (from September 2016) JIM BANIHASHEMI, Financial Officer HILARY BRAGG, Program Coordinator ANDREW M. POPE, Director, Board on Health Sciences Policy viii 

Reviewers This Proceedings of a Workshop has been 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 institution in making its published Proceedings of a Workshop as sound as possible and to ensure that the Proceedings of a Workshop 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 Proceedings of a Workshop: RAY DORSEY, University of Rochester Medical Center DONALD JONES, Scripps Translational Science Institute SALLY OKUN, PatientsLikeMe WILLIAM POTTER, National Institute of Mental Health STEVEN ROMANO, Mallinckrodt Pharmaceuticals Although the reviewers listed above have provided many construc- tive comments and suggestions, they did not see the final draft of the Proceedings of a Workshop before its release. The review of this Pro- ceedings of a Workshop was overseen by JOSEPH T. COYLE, Harvard Medical School. He was responsible for making certain that an inde- pendent examination of this Proceedings of a Workshop was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this Proceedings of a Workshop rests entirely with the rapporteurs and the institution. ix 



Contents 1 Introduction 1 Workshop Objectives, 3 Organization of Proceedings, 3 2 Neuroscience Clinical Trials: An Overview of Challenges and Potential Opportunities 5 Challenges and Barriers to Neuroscience Clinical Trials, 6 Opportunities to Improve Neuroscience Clinical Trials, 8 3 Clinical Trial Design 15 Alternatives to the DSM, 16 Better Disease Models, 20 Biomarkers, 22 Clinically Meaningful Outcomes, 27 Novel Clinical Trial Designs, 28 Lessons Learned from Other Therapeutic Areas, 32 Developing More Effective Therapeutics Through Precision Medicine: Implications for Clinical Trials, 34 4 Transforming Clinical Trials with Technology 37 Patient Recruitment and Retention in Clinical Trials, 38 Novel Assessment Tools, 40 xi 

xii CONTENTS 5 The Regulatory Landscape: International Opportunities and Challenges 43 Regulatory Perspectives from the United States, 44 Regulatory Perspectives from Italy, 46 Potential Regulatory Implications for Clinical Research Innovations, 48 6 Ethical Considerations 53 Data Protection, 54 Human Subjects Protection, 56 7 Improving the Evidence Base for Real-World Use 59 Perspectives from Payers, 60 Perspectives from the Pharmaceutical Industry, 61 Methodology for Observational Studies, 62 Methodology for Pragmatic Trials, 62 Data Sources for Real-World Trials, 64 Final Remarks, 66 APPENDIXES A References 69 B Workshop Agenda 79 C Registered Attendees 91