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This activity was supported by contracts between the National Academy of Sciences and Acadia Pharmaceuticals; Alzheimer’s Association; American Brain Coalition; American Neurological Association; Boehringer Ingelheim; California Institute for Regenerative Medicine; Cerevel Therapeutics; Cohen Veterans Bioscience; Department of Health and Human Services’ Food and Drug Administration (R13FD005362) and National Institutes of Health (NIH) (75N98019F00769 [Under Master Base HHSN263201800029I]) through the National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Environmental Health Sciences, 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, NIH Blueprint for Neuroscience Research, and NIH BRAIN Initiative; Department of Veterans Affairs (36C24E20C0009); Eisai Inc.; Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Harmony Biosciences, Janssen Research & Development, LLC; Karuna Therapeutics; Lundbeck Research USA; Merck Research Laboratories; The Michael J. Fox Foundation for Parkinson’s Research; National Multiple Sclerosis Society; National Science Foundation (DBI-1839674); One Mind; The Paul G. Allen Frontiers Group; Sanofi; Simons Foundation Autism Research Initiative; Takeda; 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 the project.

International Standard Book Number-13: 978-0-309-70847-0
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Digital Object Identifier: https://doi.org/10.17226/27208

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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2023. Multimodal biomarkers for central nervous system disorders: Development, validation, and clinical integration: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/27208.

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MULTIMODAL BIOMARKERS FOR CENTRAL NERVOUS SYSTEM DISORDERS PLANNING COMMITTEE

LINDA BRADY (Co-Chair), National Institute of Mental Health

VIKAS SHARMA (Co-Chair), Boehringer Ingelheim

ALAN ANTICEVIC, Yale University

ADRIANA DI MARTINO, Child Mind Institute

STUART HOFFMAN, Department of Veterans Affairs

SAMANTHA HUTTEN, The Michael J. Fox Foundation for Parkinson’s Research

HARTMUTH KOLB, The Janssen Pharmaceutical Companies of Johnson & Johnson

VALENTINA MANTUA, Food and Drug Administration

ALESSANDRA ROVESCALLI, National Institute of Aging

CAROL TAYLOR-BURDS, National Institute of Neurological Disorders and Stroke

ALESSIO TRAVAGLIA, Foundation for the National Institutes of Health

CHARISSE WINSTON, University of California, San Diego

Health and Medicine Division Staff

SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders

EVA CHILDERS, Associate Program Officer

MAYA THIRKILL, Associate Program Officer (starting May 2023)

EDEN NELEMAN, Senior Program Assistant (until August 2023)

CHRISTIE BELL, Senior Finance Business Partner

CLARE STROUD, Senior Director, Board on Health Sciences Policy

National Academy of Medicine Fellow in Osteopathic Medicine

JULIEANNE P. SEES, Thomas Jefferson University School of Medicine

Consultant

SARAH CARTER, Science Writer

FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS¹

FRANCES JENSEN (Co-Chair), University of Pennsylvania

JOHN KRYSTAL (Co-Chair), Yale University

RITA BALICE-GORDON, Muna Therapeutics

DEANNA BARCH, Washington University in St. Louis (starting August 2023)

KATJA BROSE, The Chan Zuckerberg Initiative

EMERY BROWN, Massachusetts General Hospital (until July 2023)

TERESA BURACCHIO, Food and Drug Administration (starting June 2023)

JOSEPH BUXBAUM, Icahn School of Medicine at Mount Sinai (until July 2023)

SARAH CADDICK, The Gatsby Charitable Foundation

ROSA CANET-AVILÉS, California Institute for Regenerative Medicine

MARIA CARRILO, Alzheimer’s Association

MICHAEL CHIANG, National Eye Institute

TIMOTHY COETZEE, National Multiple Sclerosis Society

JONATHAN COHEN, Princeton University (until July 2023)

BEVERLY DAVIDSON, University of Pennsylvania

BILLY DUNN, Food and Drug Administration (until March 2023)

MICHAEL EGAN, Merck Research Laboratories (until December 2022)

MICHELLE ELEKONICH, National Science Foundation

NITA FARAHANY, Duke University

EVA FELDMAN, University of Michigan

BRIAN FISKE, The Michael J. Fox Foundation for Parkinson’s Research

JOSHUA GORDON, National Institute of Mental Health

MORTEN GRUNNET, Lundbeck (starting March 2023)

MAGALI HAAS, Cohen Veterans Bioscience

RICHARD HODES, National Institute of Aging

STUART HOFFMAN, Department of Veterans Affairs

YASMIN HURD, Icahn School of Medicine at Mount Sinai

STEVEN HYMAN, The Broad Institute of MIT and Harvard

MICHAEL IRIZARRY, Eisai Inc.

PUSHKAR JOSHI, One Mind

GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism

WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke

GEORGINA MACKENZIE, Wellcome Trust

HUSSEINI MANJI, Oxford University; Duke University; UK Government Mental Health Mission (starting June 2023)

BILL MARTIN, The Janssen Pharmaceutical Companies of Johnson & Johnson

HUGH MARSTON, Boehringer Ingelheim (starting June 2023)

JOHN NGAI, BRAIN Initiative

GENTRY PATRICK, University of California, San Diego (starting August 2023)

STEVE MARC PAUL, Karuna Therapeutics, Inc

KATHRYN RICHMOND, Allen Institute (starting June 2023)

M. ELIZABETH ROSS, American Neurological Association (starting June 2023)

MARSIE ROSS, Harmony Biosciences

KATIE SALE, American Brain Coalition (starting June 2023)

RAYMOND SANCHEZ, Cerevel Therapeutics

TERRENCE SEJNOWSKI, Salk Institute for Biological Studies (starting August 2023)

SARAH SHEIKH, Takeda Pharmaceutical

DAVID SHURTLEFF, National Center for Complementary and Integrative Health

JOHN SIMS, Eli Lilly and Company (until December 2022)

JOHN SPIRO, Simons Foundation

ALESSIO TRAVAGLIA, Foundation for the National Institutes of Health

NORA VOLKOW, National Institute on Drug Abuse

DOUG WILLIAMSON, Acadia Pharmaceuticals

RICHARD WOYCHIK, National Institute of Environmental Health Sciences

STEVIN ZORN, MindImmune Therapeutics, Inc.

Health and Medicine Division Staff

SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders

EVA CHILDERS, Associate Program Officer

MAYA THIRKILL, Associate Program Officer (starting May 2023)

EDEN NELEMAN, Senior Program Assistant (until August 2023)

CHRISTIE BELL, Senior Finance Business Partner

CLARE STROUD, Senior Director, Board on Health Sciences Policy

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:

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 ELI Y. ADASHI, Brown University. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with 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

ACRONYMS AND ABBREVIATIONS

1 INTRODUCTION AND BACKGROUND

Workshop Objectives

Organization of Proceedings

2 MULTIMODAL BIOMARKERS FOR CENTRAL NERVOUS SYSTEM DISORDERS

Highlights

Understanding the Importance of Multimodal Biomarkers to Patients

Understanding How Multimodal Biomarkers Fit into FDA’s Regulatory Oversight

3 EXPLORING THE STATE OF THE SCIENCE OF MULTIMODAL BIOMARKERS FOR CENTRAL NERVOUS SYSTEM DISORDERS

Highlights

Alzheimer’s Disease

Parkinson’s Disease

Huntington’s Disease

Lessons Learned for Developing Multimodal Biomarkers

4 OPPORTUNITIES FOR PRECISION MEDICINE

Highlights

Meaningful Measures: A Patient Perspective

Precision Psychiatry

Pediatric Neuroradiology

Neurodevelopmental Disorders

Digital Behavioral Biomarkers

Moving Toward Precision Medicine in CNS Disorders

5 STANDARDIZATION AND METHODOLOGY FOR MULTIMODAL BIOMARKERS

Highlights

Using Biomarkers for Patient Selection in New Drug Development

Methods for Validation and Standardization

Rethinking Clinical Trials and Clinical Use

6 REGULATORY DECISION MAKING

Highlights

Building Consortia for the Development of Multimodal Biomarkers

Decision Making Among Regulators and Payors

Transdiagnostic Multimodal Biomarkers: A New Conceptualization of Disease

Multimodal Biomarkers and Explanability

7 EXPLORING OPPORTUNITIES TO MOVE FORWARD

Highlights

Value of Multimodal Biomarkers

Importance of Data and Collaboration

Clinical Integration of Multimodal Biomarkers

Accessibility and Cost

Concluding Remarks

APPENDIXES

A References

B Agenda

Acronyms and Abbreviations