IMPROVING AND ACCELERATING
THERAPEUTIC DEVELOPMENT FOR
NERVOUS SYSTEM DISORDERS

WORKSHOP SUMMARY

Forum on Neuroscience and
Nervous System Disorders

Board on Health Sciences Policy

Sheena M. Posey Norris, Diana E. Pankevich, Miriam Davis,
and Bruce M. Altevogt, Rapporteurs

INSTITUTE OF MEDICINE
              OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

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Forum on Neuroscience and Nervous System Disorders Board on Health Sciences Policy Sheena M. Posey Norris, Diana E. Pankevich, Miriam Davis, and Bruce M. Altevogt, Rapporteurs

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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 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 project was supported by contracts between the National Academy of Sciences and the Alzheimer’s Association; CeNeRx Biopharma; the Department of Health and Human Services’ National Institutes of Health (NIH, Contract No. HHSN26300026 [Under Master Base # DHHS-10001018]) through the 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 (101-D27015); Eli Lilly and Company; Fast Forward, LLC; Foundation for the National Institutes of Health; GE Healthcare, Inc. (2580261187); GlaxoSmithKline, Inc.; Johnson & Johnson Pharmaceutical Research and Development, LLC; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkinson’s Research; the National Science Foundation (Contract No. OIA-0753701); One Mind for Research; Pfizer Inc.; the Society for Neuroscience; and Wellcome Trust. The views presented in this publication are those of the editors and attributing authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-29246-7 International Standard Book Number-10: 0-309-29246-8 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 2014 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. Cover image courtesy of Dr. Lawrence Goldstein, University of California, San Diego. Suggested citation: IOM (Institute of Medicine). 2014. Improving and accelerating therapeutic development for nervous system disorders: Workshop summary. Washington, DC: The National Academies Press.

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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 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 engineers. 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 engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr., 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 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. www.national-academies.org

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PLANNING COMMITTEE ON ACCELERATING THERAPEUTIC DEVELOPMENT FOR NERVOUS SYSTEM DISORDERS TOWARD FIRST-IN-HUMAN TRIALS1 JOHN DUNLOP (Co-Chair), AstraZeneca FRED GAGE (Co-Chair), Salk Institute NEIL BUCKHOLTZ, National Institute on Aging DANIEL BURCH, Pharmaceutical Product Development, LLC (PPDi) ROBERT CONLEY, Eli Lilly and Company DANIEL GESCHWIND, University of California, Los Angeles MAGALI HAAS, Orion Bionetworks STEVEN HYMAN, The Broad Institute of the Massachusetts Institute of Technology and Harvard University NI KHIN, U.S. Food and Drug Administration DAVID MICHELSON, Merck Research Laboratories ALEXANDER PLOSS, Rockefeller University WILLIAM POTTER, National Institute of Mental Health RAJESH RANGANATHAN, National Institute of Neurological Disorders and Stroke VICKI SEYFERT-MARGOLIS, Precision for Medicine, Inc. STEVIN ZORN, Lundbeck Research USA IOM Staff BRUCE M. ALTEVOGT, Project Director DIANA E. PANKEVICH, Program Officer SHEENA M. POSEY NORRIS, Research Associate RACHEL J. KIRKLAND, Senior Program Assistant ___________________________ 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. v

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FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS1 STEVEN HYMAN (Chair), The Broad Institute SUSAN AMARA, Society for Neuroscience MARC BARLOW, GE Healthcare, Inc. MARK BEAR, Massachusetts Institute of Technology KATJA BROSE, Neuron DANIEL BURCH, Pharmaceutical Product Development, LLC (PPDi) MARIA CARRILLO, Alzheimer’s Association C. THOMAS CASKEY, Baylor College of Medicine TIMOTHY COETZEE, Fast Forward, LLC EMMELINE EDWARDS, National Center for Complementary and Alternative Medicine MARTHA FARAH, University of Pennsylvania RICHARD FRANK, GE Healthcare, Inc. DANIEL GESCHWIND, University of California, Los Angeles HANK GREELY, Stanford University MYRON GUTMANN, National Science Foundation MAGALI HAAS, Orion Bionetworks STUART HOFFMAN, U.S. Department of Veterans Affairs RICHARD HODES, National Institute on Aging THOMAS INSEL, National Institute of Mental Health PHILLIP IREDALE, Pfizer Global Research and Development DANIEL JAVITT, Nathan S. Kline Institute for Psychiatric Research FRANCES JENSEN, University of Pennsylvania School of Medicine STORY LANDIS, National Institute of Neurological Disorders and Stroke ALAN LESHNER, American Association for the Advancement of Science HUSSEINI MANJI, Johnson & Johnson Pharmaceutical Research and Development, LLC DAVID MICHELSON, Merck Research Laboratories RICHARD MOHS, Lilly Research Laboratories JONATHAN MORENO, University of Pennsylvania ATUL PANDE, GlaxoSmithKline, Inc. 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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STEVEN PAUL, Weill Cornell Medical College TODD SHERER, The Michael J. Fox Foundation for Parkinson’s Research PAUL SIEVING, National Eye Institute MARC TESSIER-LEVIGNE, Rockefeller University WILLIAM THIES, Alzheimer’s Association JOANNE TORNOW, National Science Foundation NORA VOLKOW, National Institute on Drug Abuse KENNETH WARREN, National Institute on Alcohol Abuse and Alcoholism DAVID WHOLLEY, Foundation for the National Institutes of Health JOHN WILLIAMS, Wellcome Trust STEVIN ZORN, Lundbeck Research USA CHARLES ZORUMSKI, Washington University School of Medicine IOM Staff BRUCE M. ALTEVOGT, Forum Director DIANA E. PANKEVICH, Program Officer SHEENA M. POSEY NORRIS, Research Associate RACHEL J. KIRKLAND, Senior Program Assistant ANDREW M. POPE, Director, Board on Health Sciences Policy viii

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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: Bruce Baron, Sanofi Bill Deakin, University of Manchester Martien Kas, University Medical Center Utrecht Bruce Psaty, University of Washington School of Medicine Scott Small, Columbia University Although the reviewers listed above have provided many construc- tive 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 Eric B. Larson, Group Health Research Insti- tute. Appointed by the Institute of Medicine, he was responsible for mak- ing 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. ix

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Contents 1 INTRODUCTION AND OVERVIEW 1 2 DRUG DEVELOPMENT CHALLENGES 9 3 TARGET IDENTIFICATION 25 4 TARGET VALIDATION 41 5 OPPORTUNITIES TO IMPROVE AND ACCELERATE THE DRUG DEVELOPMENT PIPELINE 51 6 PERSPECTIVES ON NEXT STEPS 73 APPENDIXES A References 79 B Workshop Agenda 87 C Registered Attendees 101 xi

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