Financial Incentives to Encourage Development of Therapies That Address Unmet Medical Needs for Nervous System Disorders: Workshop Summary (2015)

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FINANCIAAL INCEN NTIVES TO O ENCOU URAGE OPMENT OF THER DEVELO RAPIES THAT ADDREESS UNMMET MEDICAL NEEEDS FOR NEERVOUS SYSTEM DISORD DERS WORKSH HOP SUMMA ARY A Collaborationn of the Forum on Neuroscience and Nervous System D Disorders and the Forum on Drug Disscovery, Development, and Translatio on Sheena M. Posey y Norris, Eveelyn Strauss,, Christopheer DeFeo, annd Clare Strooud, Rapporrteurs Forum on Neurosciencce and Nervous System Disoorders Forum on n Drug Discoovery, Developmeent, and Trannslation Board B on Heealth Sciencees Policy 

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 AbbVie; the Alzheimer’s Association; American Diabetes Association; American Society of Microbiology; Amgen Inc. (Contract No. GHCCOPS-CSARF-63987); Association of American Medical Colleges; AstraZeneca; Baxter BioScience; Brain Canada Foundation; Burroughs Wellcome Fund (Contract No. 1015149); Critical Path Institute; the Department of Health and Human Services’ Food and Drug Administration (Contract No. 1R13FD005154-01) and National Institutes of Health (NIH, Contract Nos. HHSN26300026 and HHSN263201200074I, Task Order HHSN26300023 [Under Master Base #DHHS-10001292]) through the National Cancer Institute, National Center for Advancing Translational Sciences, National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Allergy and Infectious Disease, 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); Doris Duke Charitable Foundation (Contract No. 2015103); Eli Lilly and Company; FasterCures; Foundation for the National Institutes of Health; Friends of Cancer Research; the Gatsby Charitable Foundation; GlaxoSmithKline, Inc. (Contract No. 005319); Johnson & Johnson Pharmaceutical Research and Development, LLC; Lundbeck Research USA; Merck & Co., Inc. (Contract No. CMO-141224-000649); The Michael J. Fox Foundation for Parkinson’s Research; the National Multiple Sclerosis Society; the National Science Foundation (Contract No. BCS-1064270); New England Journal of Medicine; One Mind for Research; Orion Bionetworks; Pfizer Inc.; Pharmaceutical Product Development, LLC; Sanofi; the Society for Neuroscience; Takeda Pharmaceutical Company Limited (Contract No. 53108); and Wellcome Trust. The views presented in this publication do not necessarily reflect the views of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-37323-4 International Standard Book Number-10: 0-309-37323-9 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 2015 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. Suggested citation: IOM (Institute of Medicine). 2015. Financial incentives to encourage development of therapies that address unmet medical needs for nervous system disorders: Workshop summary. Washington, DC: The National Academies Press. 



The National Acadeemy of Sciencces is a privaate, nonprofit, self-perpetuatiing society of distinguish hed scholars en ngaged in scienntific and engin ineering researcch, dedicatted to the furth herance of scieence and technnology and to their use for tthe generall welfare. Uponn the authority of the charter ggranted to it byy the Congresss in 1863, thhe Academy haas a mandate th hat requires it too advise the fedderal governmeent on scieentific and tecchnical matterss. Dr. Ralph JJ. Cicerone is president of tthe Nationaal Academy off Sciences. The National Acadeemy of Engin neering was eestablished in 1964, under tthe charter of the Natio onal Academy of Sciences, as a parallel organization of outstan nding engineerss. It is autonomoous in its adminnistration and iin the selectionn of its mem mbers, sharing with w the Nation nal Academy oof Sciences the responsibility ffor advisin ng the federal government. The T National Academy of E Engineering allso sponsorrs engineeringg programs aim med at meetinng national neeeds, encouragges educatiion and researcch, and recogn nizes the superrior achievemeents of engineeers. Dr. C. D. D Mote, Jr., is president of th he National Acaademy of Enginneering. The Institute of Med dicine was estaablished in 19770 by the Natioonal Academy of Sciencees to secure th he services of eminent membbers of approppriate professioons in the examination e of policy matterrs pertaining too the health off the public. T The Institutte acts under th he responsibilitty given to the National Acaddemy of Sciencces by its congressional c charter c to be an n adviser to thee federal goverrnment and, uppon its own n initiative, to identify issuees of medical care, researchh, and educatioon. Dr. Vicctor J. Dzau is president of th he Institute of M Medicine. The National Research Council was w organized by the Natioonal Academy of Sciencees in 1916 to asssociate the brooad communityy of science andd technology w with the Accademy’s purp poses of furth hering knowleddge and adviising the fedeeral governm ment. Function ning in accordaance with geneeral policies deetermined by tthe Academ my, the Counccil has becomee the principall operating ageency of both tthe Nationaal Academy of o Sciences an nd the Nationaal Academy off Engineering in providin ng services to the t governmentt, the public, annd the scientificc and engineeriing commu unities. The Co ouncil is admiinistered jointlyy by both Accademies and tthe Institutee of Medicine. Dr. Ralph J. Cicerone C and DDr. C. D. Mote, Jr., are chair aand vice chair, respectivelyy, of the Nation nal Research Coouncil. w www.nationall-academies.o org 

PLANNING COMMITTEE ON FINANCIAL INCENTIVES TO SUPPORT UNMET MEDICAL NEEDS FOR NERVOUS SYSTEM DISORDERS1 DENNIS CHOI (Co-Chair), Stony Brook University TIMOTHY COETZEE (Co-Chair), National Multiple Sclerosis Society MARGARET ANDERSON, FasterCures ROBERT ARMITAGE, Eli Lilly and Company MARC BOUTIN, National Health Council LINDA BRADY, National Institute of Mental Health WILLIAM FISHER, Harvard Law School RICHARD HODES, National Institute on Aging STEVEN HYMAN, The Broad Institute of Massachusetts Institute of Technology and Harvard University JEFF KAHN, Johns Hopkins University WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke GARDINER LAPHAM, Citizens United for Research in Epilepsy HUSSEINI MANJI, Johnson & Johnson Pharmaceutical Research and Development, LLC RICHARD MOHS, Eli Lilly and Company KIRAN REDDY, Biogen Idec BENJAMIN ROIN, Harvard Law School TODD SHERER, The Michael J. Fox Foundation for Parkinson’s Research PHIL SKOLNICK, National Institute on Drug Abuse GEORGE VRADENBURG, USAgainstAlzheimer’s JANET WOODCOCK, Food and Drug Administration STEVIN ZORN, Lundbeck Research USA, Inc. IOM Staff BRUCE M. ALTEVOGT, Project Director (until February 2015) CLARE STROUD, Senior Program Officer (as of October 2014) ANNE B. CLAIBORNE, Senior Program Officer DIANA PANKEVICH, Program Officer (until August 2014) 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 

REBECCA ENGLISH, Program Officer CHRISTOPHER DEFEO, Program Officer SHEENA M. POSEY NORRIS, Associate Program Officer KATHRYN HOWELL, Senior Program Assistant SOPHIE YANG, Senior Program Assistant (from December 2014) ANNALYN WELP, Senior Program Assistant (from November 2014) ANDREW M. POPE, Director, Board on Health Sciences Policy vi 

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), Former Director, National Institute of Neurological Disorders and Stroke SUSAN AMARA, Society for Neuroscience STEPHEN BRANNAN, Takeda Pharmaceuticals International, Inc. KATJA BROSE, Cell Press 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 C. THOMAS CASKEY, Baylor College of Medicine KAREN CHANDROSS, Sanofi US TIMOTHY COETZEE, National Multiple Sclerosis Society FAY LOMAX COOK, National Science Foundation WILLIAM DUNN, Food and Drug Administration EMMELINE EDWARDS, National Center for Complementary and Integrative Medicine MARTHA FARAH, University of Pennsylvania DANIEL GESCHWIND, University of California, Los Angeles HANK GREELY, Stanford University MAGALI HAAS, Orion Bionetworks RAMONA HICKS, One Mind for Research RICHARD HODES, National Institute on Aging STUART HOFFMAN, Department of Veterans Affairs THOMAS INSEL, National Institute of Mental Health PHILLIP IREDALE, Pfizer Global Research and Development JOHN ISAAC, Wellcome Trust INEZ JABALPURWALA, Brain Canada Foundation FRANCES JENSEN, University of Pennsylvania School of Medicine GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke 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 

ALAN LESHNER, American Association for the Advancement of Science (Emeritus) HUSSEINI MANJI, Johnson & Johnson Pharmaceutical Research and Development, LLC DAVID MICHELSON, Merck Research Laboratories RICHARD MOHS, Eli Lilly and Company JAMES OLDS, National Science Foundation ATUL PANDE, Tal Medical STEVEN PAUL, Weill Cornell Medical College, Voyager Therapeutics TODD SHERER, The Michael J. Fox Foundation for Parkinson’s Research DAVID SHURTLEFF, National Center for Complementary and Integrative Medicine PAUL SIEVING, National Eye Institute NORA VOLKOW, National Institute on Drug Abuse STEVIN ZORN, Lundbeck Research USA, Inc. IOM Staff BRUCE M. ALTEVOGT, Forum Co-Director (until May 2015) CLARE STROUD, Forum Co-Director SHEENA M. POSEY NORRIS, Associate Program Officer ANNALYN M. WELP, Senior Program Assistant ANDREW M. POPE, Director, Board on Health Sciences Policy viii 

FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION1 JEFFREY M. DRAZEN (Co-Chair), New England Journal of Medicine STEVEN K. GALSON (Co-Chair), Amgen Inc. RUSS BIAGIO ALTMAN, Stanford University MARGARET ANDERSON, FasterCures HUGH AUCHINCLOSS, National Institute of Allergy and Infectious Diseases CHRISTOPHER P. AUSTIN, National Center for Advancing Translational Sciences ANN C. BONHAM, Association of American Medical Colleges LINDA BRADY, National Institute of Mental Health GAIL H. CASSELL, Harvard Medical School (Visiting) ANDREW M. DAHLEM, Eli Lilly and Company JAMES H. DOROSHOW, National Cancer Institute GARY L. FILERMAN, Atlas Health Foundation HARRY B. GREENBERG, Stanford University School of Medicine KATHY L. HUDSON, National Institutes of Health LYNN D. HUDSON, Critical Path Institute S. CLAIBORNE JOHNSTON, Dell Medical School, University of Texas, Austin MICHAEL KATZ, March of Dimes Foundation JACK D. KEENE, Duke University Medical Center RUSTY KELLEY, Burroughs Wellcome Fund RONALD L. KRALL, University of Pittsburgh FREDA C. LEWIS-HALL, Pfizer Inc. CAROL MIMURA, University of California, Berkeley BRIGGS W. MORRISON, AstraZeneca BERNARD H. MUNOS, InnoThink Center for Research in Biomedical Innovation, FasterCures ELIZABETH (BETSY) MYERS, Doris Duke Charitable Foundation JOHN J. ORLOFF, Baxter BioScience RAJESH RANGANATHAN, National Institute of Neurological Disorders and Stroke ROBERT E. RATNER, American Diabetes Association MICHAEL ROSENBLATT, Merck & Co., 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. ix 

MICHAEL SEVERINO, AbbVie JAMES S. SHANNON, GlaxoSmithKline ELLEN V. SIGAL, Friends of Cancer Research LANA R. SKIRBOLL, Sanofi BRIAN L. STROM, Rutgers, the State University of New Jersey JANET TOBIAS, Ikana Health JOANNE WALDSTREICHER, Johnson & Johnson JANET WOODCOCK, Food and Drug Administration IOM Staff ANNE B. CLAIBORNE, Forum Director REBECCA A. ENGLISH, Program Officer CHRISTOPHER J. DEFEO, Program Officer EMILY BUSTA, Associate Program Officer KATHRYN HOWELL, Senior Program Assistant ANDREW M. POPE, Director, Board on Health Sciences Policy x 

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: SUSAN AXELROD, Citizens United for Research in Epilepsy RAJ LONG, The Bill & Melinda Gates Foundation ARTI RAI, Duke School of Law DAVID RIDLEY, Duke University KATIE SALE, American Brain Coalition ANDREW SPERLING, National Alliance on Mental Illness PAUL SUMMERGRAD, Tufts University School of Medicine LUC TRUYEN, Johnson & Johnson 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 BRADFORD GRAY, Urban Institute. Appointed by the Institute of Medicine, he was responsible for making certain that an independent examination of this workshop summary was xi 

xii REVIEWERS 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. 

Contents 1 Introduction and Overview 1 Workshop Objectives, 2 Organization of the Report, 5 Unmet Medical Needs in Nervous System Disorders, 5 Topics Highlighted During Presentations and Discussions, 10 2 Improving Market Protection 13 How Companies Make Decisions, 14 Business Implications of the Stagnant R&D Climate for CNS Drugs, 18 Overview of the Current Intellectual Property (IP) Environment for the Private Sector, 18 Legislation Establishing Market Protection Periods, 20 Potential New Approaches to Extending Market Protection, 24 Opportunities to Incentivize R&D Through Improved Market Protection, 28 3 Strengthening the Regulatory Pathway 31 Drug Development: A Regulatory Viewpoint, 32 Regulatory Challenges Specific to CNS Disorders, 35 Potential Mechanisms to Address Regulatory Challenges, 38 Clarity of Regulatory Processes and Decisions, 42 Reimbursement: The Decision-Making Process, 46 Opportunities to Incentivize R&D by Strengthening Regulatory Pathways, 48 xiii 

xiv CONTENTS 4 Patient Benefit and Engagement 51 Patient Involvement: Understanding Risks and Benefits, 52 Determining Value to Patients, 54 Creatively Engaging Public−Private Partnerships, Advocacy Groups, and Nonprofit Health Organizations, 58 Opportunities to Encourage Patient Involvement in the Drug Development Process, 59 APPENDIXES A References 61 B Workshop Agenda 65 C Registered Attendees 79 D Participant Biographies 87