Drug Research and Development for Adults Across the Older Age Span: Proceedings of a Workshop (2021)

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Drug Research and Development for Adults Across the Older Age Span PROCEEDINGS OF A WORKSHOP Erin Hammers Forstag and Carolyn Shore, Rapporteurs Forum on Aging, Disability, and Independence Forum on Drug Discovery, Development, and Translation National Cancer Policy Forum Board on Health Care Services 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 Administration for Community Living; American Association for Cancer Research; American Association for Retired Persons; American Cancer Society (Contract No. 66383); American College of Radiology; American Geriatrics Society; American Society of Clinical Oncology; Amgen Inc. (Contract No. GHCCOPS-CSARF-175837); Association of American Cancer Institutes; Association of American Medical Colleges; Association of Community Cancer Centers; AstraZeneca; Biogen; Biomedical Advanced Research and Development Authority; Bristol-Myers Squibb (Contract No. 57015377); Burroughs Wellcome Fund (Contract No. 1020264); Cancer Support Community; Centers for Disease Control and Prevention (Contract No. 200-2011-38807; Task Order No. 75D30119F00080); CEO Roundtable on Cancer; Consumer Technology Association Foundation; Critical Path Institute; Eli Lilly and Company (Contract No. 4900709231); FasterCures, Milken Institute; Flatiron Health; Foundation for the National Institutes of Health; Friends of Cancer Research; The Gerontological Society of America; GlaxoSmithKline (Contract No. OTH-PPL-32245); The John A. Hartford Foundation; Johnson & Johnson; LeadingAge; Merck & Co., Inc. (Contract Nos. MRLCPO-19-9858 and MRLCPO-19- 106723); National Comprehensive Cancer Network; National Institute on Disability, Independent Living, and Rehabilitation Research (Contract No. HHSP233201400020B); National Institutes of Health (Contract No. HHSN263201800029I; Task Order No. HHSN26300007): National Cancer Institute, National Center for Advancing Translational Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Office of Extramural Research, Office of Science Policy; National Institutes of Health (Contract No. HHSN263201800029I; Task Order No. HHSN26300008 and Contract No. HHSN263291800029I; Task Order No. 75N98019F00848): National Institute on Aging; National Patient Advocate Foundation; New England Journal of Medicine; Novartis Oncology (Contract No. NGC38403); Oncology Nursing Society; Paraprofessional Healthcare Institute; Pfizer Inc.; Sanofi (Contract No. 57505685); Society for Immunotherapy of Cancer; Takeda Pharmaceuticals (Contract No. 53108); and U.S. Food and Drug Administration (Grant No. 5R13FD005496-05). 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-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/25998 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 2021 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. 2021. Drug research and development for adults across the older age span: Proceedings of a workshop. Washington, DC: The National Academies Press. https://doi.org/10.17226/25998. 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. John L. Anderson 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 study’s 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 committee’s 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 

DRUG RESEARCH AND DEVELOPMENT FOR ADULTS ACROSS THE OLDER AGE SPAN1 JAMES APPLEBY (Chair), The Gerontological Society of America MARIE A. BERNARD, National Institute on Aging, National Institutes of Health BARRY S. COLLER, The Rockefeller University DEBORAH COLLYAR, Patient Advocates in Research DONALD HARVEY, Emory University School of Medicine ALEX JOHN LONDON, Carnegie Mellon University DAVID REUBEN, University of California, Los Angeles MARK ROGGE, Takeda Pharmaceuticals JANICE B. SCHWARTZ, University of California, San Francisco MIRIAM MOBLEY SMITH, Northeastern University Bouvé College of Health Sciences School of Pharmacy ROBERT TEMPLE, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, JONATHAN WATANABE, University of California, Irvine, School of Pharmacy and Pharmaceutical Sciences BARBARA ZAROWITZ, University of Maryland School of Pharmacy Health and Medicine Division Staff CAROLYN SHORE, Director, Forum on Drug Discovery, Development, and Translation LORI BRENIG, Research Associate (from May 2020) AMANDA WAGNER GEE, Program Officer JENNIFER HINNERS, Program Officer (through October 2020) EESHAN KHANDEKAR, Associate Program Officer (through October 2020) MELVIN JOPPY, Senior Program Assistant ANDREW M. POPE, Senior Director, Board on Health Sciences Policy Consultant ERIN HAMMERS FORSTAG, Science Writer 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. PREPUBLICATION COPY: UNCORRECTED PROOFS vii 

FORUM ON AGING, DISABILITY, AND INDEPENDENCE2 STEPHEN EWELL (Co-Chair), Consumer Technology Association Foundation REBECCA JACKSON STOECKLE (Co-Chair), Education Development Center JOHN AUERBACH, Trust for America’s Health MARIE A. BERNARD, National Institute on Aging JULIE BYNUM, University of Michigan Medical School MARGARET L. CAMPBELL, Campbell & Associates Consulting BRUCE CHERNOF, The SCAN Foundation TAMALA DAVID, State University of New York College at Brockport THOMAS E. EDES, U.S. Department of Veterans Affairs ROBERT ESPINOZA, Paraprofessional Healthcare Institute DONNA FICK, The Pennsylvania State University College of Nursing TERRY T. FULMER, The John A. Hartford Foundation KATHY GREENLEE, Greenlee Global LLC ROBERT JARRIN, The Omega Concern LLC SUSAN JENKINS, Administration for Community Living JANNI LEHRER-STEIN, Disability Policy Consultant and Advocate SARAH RUIZ, National Institute on Disability, Independent Living, and Rehabilitation Research KATIE SMITH SLOAN, LeadingAge ERWIN TAN, AARP FERNANDO TORRES-GIL, University of California, Los Angeles Forum Staff TRACY A. LUSTIG, Forum Director SIOBHAN ADDIE, Program Officer RUKSHANA GUPTA, Senior Program Assistant SHARYL NASS, Senior Director, Board on Health Care Services 2 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables 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. PREPUBLICATION COPY: UNCORRECTED PROOFS viii 

FORUM ON DRUG DISCOVERY, DEVELOPMENT, AND TRANSLATION3 ROBERT M. CALIFF (Co-Chair), Duke University and Verily Life Sciences GREGORY SIMON (Co-Chair), Kaiser Permanente Washington Health Research Institute and University of Washington AMY ABERNETHY, Office of the Commissioner, U.S. Food and Drug Administration CHRISTOPHER P. AUSTIN, National Center for Advancing Translational Sciences LINDA BRADY, National Institute of Mental Health, National Institutes of Health BARRY S. COLLER, The Rockefeller University THOMAS CURRAN, Children’s Mercy, Kansas City RICHARD DAVEY, National Institute of Allergy and Infectious Diseases, National Institutes of Health KATHERINE DAWSON, Biogen JAMES H. DOROSHOW, National Cancer Institute, National Institutes of Health JEFFREY M. DRAZEN, New England Journal of Medicine STEVEN K. GALSON, Amgen Inc. CARLOS O. GARNER, Eli Lilly and Company JULIE L. GERBERDING, Merck & Co., Inc. ANNE HEATHERTON, Takeda Pharmaceuticals DEBORAH HUNG, Harvard Medical School ESTHER KROFAH, FasterCures, Milken Institute LISA M. LAVANGE, University of North Carolina ROSS MCKINNEY, JR., Association of American Medical Colleges JOSEPH P. MENETSKI, Foundation for the National Institutes of Health ARTI RAI, Duke University School of Law KELLY ROSE, Burroughs Wellcome Fund SUSAN SCHAEFFER, Patients’ Academy for Research Advocacy JOSEPH SCHEEREN, Critical Path Institute ANANTHA SHEKHAR, University of Pittsburgh JAY SIEGEL, Retired ELLEN V. SIGAL, Friends of Cancer Research LANA R. SKIRBOLL, Sanofi AMIR TAMIZ, National Institute of Neurological Disorders and Stroke, National Institutes of Health ANN TAYLOR, AstraZeneca PAMELA TENAERTS, Clinical Trials Transformation Initiative, Duke University JOANNE WALDSTREICHER, Johnson & Johnson ROBERT WALKER, Biomedical Advanced Research and Development Authority JONATHAN WATANABE, University of California, Irvine, School of Pharmacy and Pharmaceutical Sciences CARRIE WOLINETZ, Office of Science Policy, National Institutes of Health ALASTAIR WOOD, Vanderbilt University JANET WOODCOCK, Center for Drug Evaluation and Research, U.S. Food and Drug Administration Forum Staff CAROLYN K. SHORE, Forum Director JENNIFER HINNERS, Program Officer (through October 2020) AMANDA WAGNER GEE, Program Officer 3 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables 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. PREPUBLICATION COPY: UNCORRECTED PROOFS ix 

EESHAN KHANDEKAR, Associate Program Officer (through October 2020) MELVIN JOPPY, Senior Program Assistant ANDREW M. POPE, Senior Director, Board on Health Sciences Policy PREPUBLICATION COPY: UNCORRECTED PROOFS x 

NATIONAL CANCER POLICY FORUM4 EDWARD J. BENZ, JR. (Chair), Dana-Farber Cancer Institute and Harvard Medical School PETER C. ADAMSON, Sanofi GARNET L. ANDERSON, Fred Hutchinson Cancer Research Center and the University of Washington KAREN BASEN-ENGQUIST, University of Texas MD Anderson Cancer Center SMITA BHATIA, University of Alabama at Birmingham LINDA BOHANNON, Cancer Support Community CHRIS BOSHOFF, Pfizer Inc. CATHY J. BRADLEY, Colorado School of Public Health and the University of Colorado Cancer Center OTIS W. BRAWLEY, Johns Hopkins University CYNTHIA BROGDON, Bristol-Myers Squibb Company WILLIAM G. CANCE, American Cancer Society ROBERT W. CARLSON, National Comprehensive Cancer Network GWEN DARIEN, National Patient Advocate Foundation NANCY E. DAVIDSON, Seattle Cancer Care Alliance; Fred Hutchinson Cancer Research Center; and University of Washington GEORGE D. DEMETRI, Harvard Medical School; Dana-Farber Cancer Institute; and Dana- Farber/Harvard Cancer Center JAMES H. DOROSHOW, National Cancer Institute NICOLE F. DOWLING, Centers for Disease Control and Prevention SCOT W. EBBINGHAUS, Merck Research Laboratories KOJO S. J. ELENITOBA-JOHNSON, Perelman School of Medicine, University of Pennsylvania STANTON L. GERSON, Case Western Reserve University and University Hospitals Seidman Cancer Center HEDVIG HRICAK, Memorial Sloan Kettering Cancer Center MIMI HUIZINGA, Novartis Oncology ROY A. JENSEN, Association of American Cancer Institutes; The University of Kansas Cancer Center; and Kansas Masonic Cancer Research Institute RANDY A. JONES, University of Virginia School of Nursing BETH Y. KARLAN, University of California, Los Angeles LISA KENNEDY SHELDON, Oncology Nursing Society SAMIR N. KHLEIF, Georgetown University Medical Center/Society for Immunotherapy of Cancer KAREN E. KNUDSEN, Sidney Kimmel Cancer Center MIA LEVY, Rush University Cancer Center and the Rush System for Health NEAL J. MEROPOL, Flatiron Health MARTIN J. MURPHY, CEO Roundtable on Cancer RANDALL A. OYER, Penn Medicine Lancaster General Health CLEO A. SAMUEL-RYALS, University of North Carolina at Chapel Hill RICHARD L. SCHILSKY, American Society of Clinical Oncology JULIE SCHNEIDER, U.S. Food and Drug Administration LAWRENCE N. SHULMAN, University of Pennsylvania LARA STRAWBRIDGE, Centers for Medicare & Medicaid Services GEORGE J. WEINER, The University of Iowa ROBERT A. WINN, Virginia Commonwealth University Massey Cancer Center 4 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables 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. PREPUBLICATION COPY: UNCORRECTED PROOFS xi 

Forum Staff ERIN BALOGH, Senior Program Officer LORI BRENIG, Research Associate (from May 2020) ANNALEE GONZALES, Administrative Assistant SHARYL NASS, Director, National Cancer Policy Forum, and Senior Director, Board on Health Care Services PREPUBLICATION COPY: UNCORRECTED PROOFS xii 

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: CONSTANCE CITRO, The National Academies of Sciences, Engineering, and Medicine PATRICIA JONES, National Institute on Aging, National Institutes of Health JONATHAN WATANABE, University of California, Irvine 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 LESLIE BENET, University of California, San Francisco. 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. PREPUBLICATION COPY: UNCORRECTED PROOFS xiii 

Acknowledgments Support from the sponsors of the National Academies’ Forum on Aging, Disability, and Independence; Forum on Drug Discovery, Development, and Translation; and National Cancer Policy Forum is crucial to support this and other work of the National Academies. The National Academies staff wish to express their gratitude to the speakers whose presentations helped inform workshop discussions on the state of drug research and development for adults across the older age span; the members of the planning committee for their work in developing the workshop agenda and shaping the discussions; Harpreet Singh for her valuable contributions; and National Academies staff without whom this workshop and the accounting thereof would not have been possible: Christie Bell, Robert Day, Sadaf Faraz, Andrew Grafton, Devona Overton, Bettina Seliber, Lauren Shern, Victor Stewart, and Taryn Young. PREPUBLICATION COPY: UNCORRECTED PROOFS xiv 

Contents BOXES, FIGURES, AND TABLES ....................................................................................... xvii ACRONYMS AND ABBREVIATIONS ................................................................................. xix 1 INTRODUCTION................................................................................................................... 1-1 2 INCLUSION OF OLDER ADULTS IN CLINICAL TRIALS: AN EVOLVING LANDSCAPE ............................................................................................................................ 2-1 Knowledge Gaps and Issues Unique to Older Adults, 2-1 Age-Related Changes That Impact Drug Metabolism, 2-3 Barriers to Conducting Clinical Trials That Include Older Adults, 2-5 Discussion, 2-9 3 OVERCOMING KEY BARRIERS ...................................................................................... 3-1 Inclusion/Exclusion Criteria and Trial Design, 3-2 Organ Function Criteria Expansion, 3-5 Regulatory Considerations, 3-6 Ethical Considerations, 3-8 Discussion, 3-11 4 ALTERNATIVE STUDY APPROACHES .......................................................................... 4-1 Adaptive Trial Design, 4-1 Home-Based Clinical Trials, 4-3 Real-World Clinical Trials, 4-5 Quantitative Systems Pharmacology Models, 4-6 Clinical Trial Simulation, 4-8 Discussion, 4-9 5 STRATEGIES FOR ENGAGING OLDER ADULTS IN CLINICAL RESEARCH ...... 5-1 Outreach and Networking Strategies for Engaging Older Adults, 5-2 Los Angeles Barbershop Blood Pressure Study, 5-4 A Patient Perspective, 5-7 A Caregiver Perspective, 5-8 A Community Provider Perspective, 5-9 Discussion, 5-10 6 CLINICAL TRIALS IN THE ERA OF COVID-19 AND BEYOND ................................ 6-1 A Regulatory Perspective, 6-2 PREPUBLICATION COPY: UNCORRECTED PROOFS xv 

A Clinician Perspective, 6-3 Telehealth Applications, 6-5 Digitization of Medicine, 6-8 A Patient Perspective, 6-8 Discussion, 6-9 7 REFLECTIONS AND KEY TAKEAWAYS ....................................................................... 7-1 Transparency and Engagement, 7-1 Practical Application of Science and Policy, 7-2 Enabling Innovation, 7-3 Discussion, 7-4 Reflections, 7-7 APPENDIXES A References ............................................................................................................................... A-1 B Workshop Agenda ....................................................................................................................B-1 C Speaker Biosketches ................................................................................................................C-1 PREPUBLICATION COPY: UNCORRECTED PROOFS 

Boxes, Figures, and Tables BOXES 1-1 Statement of Task, 1-2 5-1 Personal Stories from the Los Angeles Barbershop Blood Pressure Study, 5-6 FIGURES 2-1 Systems-based approaches to drug metabolism, 2-4 3-1 Common chronic conditions for adults 65 years and over, 3-2 3-2 Mean age in technology assessment study populations compared with Medicare beneficiary populations, 3-3 3-3 Utility of clinical trial attributes, 3-10 4-1 Number of women who passed each step in the REMOTE protocol, 4-4 4-2 Impact of quantitative systems pharmacology modeling: Clarifying mechanisms reduces risk, 4-7 6-1 COVID-19-associated hospitalizations by age, 6-3 6-2 Medicare fee-for-service beneficiaries receiving telehealth services per week, 6-5 6-3 Internet and home broadband access for adults 65 years and older, 6-6 TABLES 2-1 Mean Age of Trial Participants for Select Types of Studies, 2-6 2-2 Percentage of Clinical Trials That Exclude Participants Based on Specific Exclusion Criteria, 2-6 2-3 Top Perceived Benefits and Risks to Clinical Research Participation, 2-8 PREPUBLICATION COPY: UNCORRECTED PROOFS xvii 

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Acronyms and Abbreviations ASPREE Aspirin in Reducing Events in the Elderly BiTE Bispecific T-Cell Engager CDER Center for Drug Evaluation and Research CDN Clinical Directors Network COPD chronic obstructive pulmonary disease FDA U.S. Food and Drug Administration FQHC Federally Qualified Health Center GFR glomerular filtration rate GI gastrointestinal IAL Inclusion Across the Lifespan IRB Institutional Review Board LABBPS Los Angeles Barbershop Blood Pressure Study MRI magnetic resonance imaging NIA National Institute on Aging NIH National Institutes of Health PACE Programs for All-inclusive Care for the Elderly PBRN Practice Based Research Network PCORI Patient-Centered Outcomes Research Institute PD pharmacodynamics PK pharmacokinetics PRO patient-reported outcome PTZ Piperacillin/Tazobactam QSP Quantitative Systems Pharmacology R&D research and development RCT randomized controlled trial REMAP Randomized, Embedded, Multifactorial Adaptive Platform TAVR transcatheter aortic valve replacement PREPUBLICATION COPY: UNCORRECTED PROOFS xix