Improving Representation in
Clinical Trials and Research
BUILDING RESEARCH EQUITY FOR
WOMEN AND UNDERREPRESENTED GROUPS
Kirsten Bibbins-Domingo and Alex Helman, Editors
Committee on Improving the Representation of Women and Underrep-
resented Minorities in Clinical Trials and Research
Committee on Women in Science, Engineering, and Medicine
Policy and Global Affairs
A Consensus Study Report of
THE NATIONAL ACADEMIES PRESS
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2022. Improving Representation in Clinical Trials and Research: Building Research Equity for Women and Underrepresented Groups. Washington, DC: The National Academies Press. https://doi.org/10.17226/26479.
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COMMITTEE ON IMPROVING THE REPRESENTATION OF WOMEN AND UNDERREPRESENTED MINORITIES IN CLINICAL TRIALS AND RESEARCH
KIRSTEN BIBBINS-DOMINGO, M.D., Ph.D., M.A.S. (Chair) (NAM),1 Professor and Chair of the Department of Epidemiology and Biostatistics and Lee Goldman, MD Endowed Chair and Professor of Medicine, University of California, San Francisco; Inaugural Vice Dean for Population Health and Health Equity, UCSF School of Medicine
MARCELLA ALSAN, M.D., Ph.D., M.P.H., Professor of Public Policy, Harvard Kennedy School; Co-Director of the Health Care Delivery Initiative Abdul Latif Jameel Poverty Action Lab, Massachusetts Institute of Technology
ARLEEN BROWN, M.D., Ph.D., Professor of Medicine, University of California, Los Angeles; Chief of General Internal Medicine and Health Services Research, Olive View-UCLA Medical Center
GLORIA CORONADO, Ph.D., Epidemiologist and Mitch Greenlick Endowed Distinguished Investigator in Health Disparities Research, Kaiser Permanente Center for Health Research
CARLOS DEL RIO, M.D. (NAM), Distinguished Professor of Medicine, Emory University School of Medicine; Professor of Epidemiology and Global Health, Rollins School of Public Health, Emory University; Executive Associate Dean for Emory University School of Medicine, Grady Health System
XINQI DONG, M.D., M.P.H., Director of the Institute for Health, Health Care Policy, and Aging Research (IFH) and Inaugural Henry Rutgers Professor of Population Health Sciences, Rutgers University
DANA GOLDMAN, Ph.D. (NAM), Dean of the Sol Price School of Public Policy, C. Erwin and Ione L. Piper Chair, and Leonard D. Schaeffer Director’s Chair, Schaeffer Center for Health Policy & Economics, University of Southern California
SHARON K. INOUYE, M.D., M.P.H. (NAM), Professor of Medicine, Harvard Medical School; Milton and Shirley F. Levy Family Chair, and Director, Aging Brain Center, Marcus Institute for Aging Research, Hebrew SeniorLife
JONATHAN JACKSON, Ph.D.,2 Executive Director of Community Access, Recruitment, and Engagement (CARE) Research Center, Massachusetts General Hospital and Harvard Medical School
___________________
1 Designates membership in the National Academy of Sciences (NAS), National Academy of Engineering (NAE), or National Academy of Medicine (NAM).
2 Dr. Jonathan Jackson resigned from the Committee on Improving Representation of Women and Underrepresented Minorities in Clinical Trials and Research, effective June 2, 2021.
AMELIA KNOPF, Ph.D., M.P.H., Assistant Professor of Nursing, Indiana University
EDITH A. PEREZ, M.D., Chief Medical Officer of Bolt Therapeutics, Inc.; Professor of Medicine, Mayo Clinic; Director of the Mayo Clinic Breast Cancer Translational Genomics Program
PHYLLIS PETTIT NASSI, B.S., M.S.W., Associate Director for Research and Science, Special Populations, American Indian Program, Huntsman Cancer Institute, University of Utah
JASON RESENDEZ, B.A., President and CEO, National Alliance for Caregiving
SUSAN SCHAEFFER, B.F.A., Founder, President, and CEO of The Patients’ Academy for Research Advocacy
Study Staff
ALEX HELMAN, Ph.D., Study Director and Program Officer, Committee on Women in Science, Engineering, and Medicine
ASHLEY BEAR, Ph.D., Director, Committee on Women in Science, Engineering, and Medicine
LAURA AIUPPA, M.S., Senior Program Officer, Board on Health Care Services
AUSTEN APPLEGATE, Research Associate, Committee on Women in Science, Engineering, and Medicine
JOHN VERAS, Senior Program Assistant, Committee on Women in Science, Engineering, and Medicine (August 2020 to February 2022)
ABIGAIL HARLESS, Senior Program Assistant, Committee on Women in Science, Engineering, and Medicine (from February 2022)
MOLLIE MARR, Ph.D., Mirzayan Fellow, Committee on Women in Science, Engineering, and Medicine
ANNE MARIE HOUPPERT, MSLS, Senior Librarian
Consultants
FRANCHESCA ARIAS, Ph.D., Instructor in Neurology and Assistant Scientist, Harvard Medical School
ADAM BRESS, PharmD., M.S., National Academy of Medicine Fellow in Pharmacy
BRANDON BROWN, Ph.D., M.P.H., Associate Professor, University of California, Riverside
FARAH ACHER KAIKSOW, M.D., M.P.P., Assistant Professor of Medicine, Harvard Medical School
AISHWARYA BHATTACHARYA, M.P.H., Student Research Assistant, Yale School of Public Health
LAURA BOTHWELL, Ph.D., M.Phil., M.A., Associate Research Scientist, Yale School of Public Health
JOCELYN CARTER, M.D., M.P.H., Professor of Medicine, Harvard Medical School
AMBER DATTA, M.P.H., Student Research Assistant, Yale School of Public Health
JAKUB HLÁVKA, Ph.D., Fellow, USC Schaeffer Center for Health Policy & Economics; Research Assistant Professor, Health Policy and Management, USC Price School of Public Policy; Research Fellow, USC Center for Risk and Economic Analysis of Terrorism Events (CREATE)
AARON KESSELHEIM, M.D., J.D., M.P.H., Professor of Medicine, Harvard Medical School
AMY J. H. KIND, M.D., Ph.D., Professor of Medicine, University of Wisconsin School of Medicine and Public Health
NIROOP RAJASHEKAR, B.S., Student Research Assistant, Yale School of Medicine
NICOLE ROGUS-PULIA, Ph.D., M.A., Assistant Professor of Medicine and Surgery, University of Wisconsin School of Medicine and Public Health
BRYAN TYSINGER, Ph.D., Director of Health Policy Microsimulation, USC Schaeffer Center for Health Policy & Economics; Fellow, USC Schaeffer Center; Research Assistant Professor, USC Price School of Public Policy
LESLIE WANG, M.S., Student Research Assistant, Yale School of Medicine
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Acknowledgments
This Consensus Study Report 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 report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process.
We thank the following individuals for their review of this report:
Margarita Alegria, Harvard University; Susan Ellenberg, University of Pennsylvania; Ayana Elliott, Gilead Sciences, Inc.; Celia Fisher, Fordham University; Sara Goldkind, Independent Consultant; Gina Green-Harris, University of Wisconsin; Jose Pagán, New York University; Eric Rubin, New England Journal of Medicine; William Schpero, Cornell University; Joshua Sharfstein, Johns Hopkins University; Jonathan Skinner, Dartmouth College; Stephanie Studenski, University of Pittsburgh; and Consuelo Wilkins, Vanderbilt University.
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by Thomas LaVeist, Tulane University, and Eve Higginbotham, University of Pennsylvania. They were responsible for
making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies.
Preface
The year the issues in this report, Improving Representation in Clinical Trials and Research, became urgent for me was 2017. I was then chair of the U.S. Preventive Services Task Force (USPSTF)—an independent body charged with reviewing the scientific literature to generate evidence-based guidelines on the use of clinical preventive services. USPSTF guidelines are widely disseminated, and their audience includes patients, clinicians, and policy makers alike. During my tenure, we had issued recommendations on preventing diabetes and common cancers such as breast, colorectal, lung, and prostate that are responsible for considerable morbidity and mortality in the United States, as well as being important contributors to health disparities. Reaching patients and frontline clinicians directly was particularly compelling given the exceptionally strong evidence that clinical interventions work in preventing these diseases and because the Affordable Care Act had ensured that interventions for which evidence was clear would be covered by commercial insurers.
In my formal talks and informal discussions with lay and professional stakeholders, I inevitably encountered a similar pattern of questions:
How confident are you that these recommendations and the evidence on which they are based apply to me and to patients like me?
You are recommending screening for diabetes in those who are overweight or obese, but my Asian patients seem to develop diabetes at lower BMI, what about them?
What about my Latino patients who are developing diabetes at younger ages or my Black patients who are developing colorectal cancer at younger ages—shouldn’t we start screening earlier?
Black women get breast cancer at the same rate as others, but are more likely to die—should we screen differently?
My recurring response was, “Unfortunately, we just don’t have the studies in these populations that allow us to say with certainty whether or how to adapt our prevention guidelines.” While it is true, this answer rang hollow. As a physician caring for patients in an urban safety-net setting and wanting to provide the best evidence-based preventive care, these were my questions as well. Inevitably in these sessions, I would spend as much time on the science as I devoted to reinforcing with patients why they should still trust these guidelines and the process, despite the unrepresentative populations in the evidence base. With clinicians, we discussed how we might adapt the guidelines to the needs of our patient populations, what kind of evidence would be necessary, and how we might advocate together to ensure that coverage was preserved.
The year these issues became personal for me was also 2017. This was the year my father lost his battle with prostate cancer and another very close family member received a new diagnosis of this same disease. Prostate cancer is the most common cancer in men in the United States; its incidence in Black men (like the two in my family) is at least 75 percent higher than men of other races and ethnicities. My father was fortunate to have received care from outstanding physicians and to have had access to clinical trials as his disease advanced. He was a career Army officer, a veteran, and a strong supporter of science and medicine. He had even served as a lay reviewer for federal funding of prostate cancer research. As my father’s journey with prostate cancer ended and another family member’s began coincident with my work on the USPSTF, the stark absence of representation of Black men in prostate cancer research became acutely distressing. Black men constitute 13.4 percent of the U.S. population, have a higher prostate cancer incidence, and die at double the rate of other men in the United States. Yet the screening trials from which the USPSTF derived evidence for prevention included less than 5 percent Black men, and the number in late-stage treatment trials was recently reported at 2.4 percent.
I am grateful to have worked with the excellent members of this consensus committee. All generously volunteered their time and expertise over the past 18 months to develop an approach to this report and to crafting recommendations on improving representation in clinical trials and clinical research. I am grateful to the many experts who shared their knowledge of the complex clinical research landscape in our public meetings and to the outstanding teams that created our four commissioned papers. And I am particularly grateful to the National Academies of Sciences, Engineering, and Medicine staff, led by Dr. Alex Helman, who adroitly guided this complex work during a global pandemic over Zoom, by phone, and via email. Most of all, I am grateful that across the different perspectives and points of view on the nuances of these issues, all who were involved
shared an understanding of their importance and producing a report with findings and actionable recommendations that would improve outcomes.
I hope that you will read this report in its entirety, through to the epilogue, where the committee envisions a better world for clinical research. I hope you will read with the intention to work to implement our findings and recommendations in whatever part of the clinical research ecosystem you influence. Whether you are motivated by the goal of producing the highest quality science, by pursuit of fairness and equity in how science might translate into better health for our patients, or by the enormous economic toll of health disparities in the United States, I hope you embrace the urgency of improving representation and inclusion in clinical research.
Kirsten Bibbins-Domingo, Chair
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Contents
Lack of Representation in Clinical Research Threatens the Overarching Goals of Clinical Research
Clinical Trials Production Process
Current Status of Clinical Trial and Clinical Research Participation: Little Change Over Time
3 POLICIES TO IMPROVE CLINICAL TRIAL AND RESEARCH DIVERSITY: HISTORY AND FUTURE DIRECTIONS
4 BARRIERS TO REPRESENTATION OF UNDERREPRESENTED AND EXCLUDED POPULATIONS IN CLINICAL RESEARCH
Individual and Community Factors
5 FACILITATORS OF SUCCESSFUL INCLUSION IN CLINICAL RESEARCH
Insights into Effective Facilitators and Strategies for Inclusion
6 RECOMMENDATIONS FOR IMPROVING REPRESENTATION IN CLINICAL TRIALS AND CLINICAL RESEARCH
EPILOGUE: ENVISIONING A NEW FUTURE
A Quantifying the Potential Health and Economic Impacts of Increased Trial Diversity
Boxes, Figures, and Tables
BOXES
2-1 Example: Adjustment of Dosing for Warfarin
2-2 Economic Cost of Lack of Representation in Clinical Trials and Research
2-4 Task Force on Research Specific to Pregnant Women and Lactating Women Report Recommendations
4-1 Community Health Applied Research Network
5-1 Federal Support of Early-Career Researchers Can Affect Access to Opportunities
5-2 Promising Practices for Supporting a More Diverse and Equitable Medical Workforce
5-3 Patient-Centered Outcomes Research Institute: Supporting Engagement
5-4 Case Study: The Wisconsin Alzheimer’s Institute, Regional Milwaukee Office Community Engagement
FIGURES
2-1 Overview of the clinical trial ecosystem
2-2 Average percent of women in trials by year of FDA approval and therapeutic area (n = 287)
5-1 Improving diversity in enrollment
B-1 Average % of females in trials by year of FDA approval and therapeutic area (n = 287)
B-2 Mean % of females by year of FDA approval (non-gender-specific trials only, n = 255)
B-3 Average % of white patients in trials by year of FDA approval and therapeutic area (n = 287)
B-4 Average % of patients over 65 in trials by year of FDA approval and therapeutic area (n = 287)
B-10a Availability of results among all trials, by primary completion year
B-10b Availability of results among Phase 3 trials, by primary completion year
C-1 Flow chart illustrating process for identification of trials
TABLES
2-1 Adjusted Relative Risks for Key Parameters of Interest with 95% Confidence Intervals
5-1 Strategies to Achieve Representation in Clinical Research by Theme
A-1 1998–2018 Health and Retirement Study Sample Characteristics
A-2 Adjusted Relative Risks for Key Parameters of Interest
A-3 Baseline Characteristics at Simulation Start
A-4 Life Years, Disability-free Life Years, and Remaining Work Years for Diabetes Scenario
A-5 Life Years, Disability-free Life Years, and Remaining Work Years for Heart Disease Scenario
A-6 Life Years, Disability-free Life Years, and Remaining Work Years for Hypertension Scenario
A-7 Aggregate Value of Diabetes Scenario
A-8 Aggregate Value of Heart Disease Scenario
A-9 Aggregate Value of Hypertension Scenario
A-10 Population Value for Scenarios through 2050
B-1 Demographics of Participants in Trials Supported by NIH Centers and Institutes
C-1 Number of Trials in Each Disease Category by U.S. Census Geographic Regions and Divisions
C-2a Starting with Intention and Agency to Achieve Representativeness
C-2b Establishing a Foundation of Trust with Participants and Community
C-2c Anticipating and Removing Barriers to Study Participation
C-2d Adopting a Flexible Approach to Recruitment and Data Collection
C-2e Building a Robust Network by Identifying All Relevant Stakeholders
C-2f Navigating Scientific, Professional Peer, and Social Expectations
C-2g Optimizing Study Team to Ensure Alignment with Research Goals
C-2h Attaining Resources and Support to Accomplish a Representativeness
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