National Institute on Aging efforts toward ensuring representation of diverse older adults in clinical studies

Supporting healthy aging and treating health concerns among adults aged 65 and older requires the development of new interventions validated through clinical trials and translated effectively to the clinic. To achieve this goal, clinical studies and clinical trials must be designed using robust methods that maximize the inclusion of older adults. Unfortunately, clinical trials in the United States have often excluded many older adults,1, 2 particularly those with significant comorbidities and individuals aged 80 and older (the so-called "oldest old"). Also often underrepresented in clinical research are members of the National Institute on Aging (NIA) Health Disparities Research Framework3 priority populations, which are consistent with the recently updated NIH-designated disparity populations (rural, socioeconomically disadvantaged, sex and gender minority, disability, American Indian/Native American, Asian American, Black/African American, Latino/Hispanic, Native Hawaiian, and Other Pacific Islanders). Thus, the outcomes of many clinical studies and trials—including those supported by NIH4—are not generalizable to individuals who would potentially benefit from the interventions being tested.5 In addition to compromising the generalizability of results, a lack of appropriate representation in clinical studies compounds health disparities, hinders innovation, and may result in increased healthcare costs.6 Funding research that is not adequately inclusive both perpetuates the paucity of accurate clinical data available to inform treatment decisions for many older adults and contradicts the mission of the NIA. Exclusion of older adults in clinical studies occurs even though they are often the population at highest risk for the disease or condition under study and might most benefit from the intervention (see Table 1).4 To facilitate interpretation of study findings and reduce potential risks to participants, trials often exclude persons with comorbidities or taking certain medications—criteria that can disproportionately affect older adults. Many trials also limit trial inclusion to those adults younger than 75 years of age.4 Even in studies for which inclusion criteria are less stringent, primary care physicians may be reluctant to recommend participation in a clinical trial, regardless of patient eligibility.13 Recruitment of older participants to interventional trials addressing Alzheimer's disease and related forms of dementia (AD/ADRD) may be particularly challenging given the cognitive challenges and increased need for a study partner.14 Reaching and retaining populations that have been traditionally excluded from and underrepresented in research requires proactive planning and implementation of tailored, culturally-appropriate strategies,15 including, in many cases, explicit efforts to gain the trust of the community identified for recruitment.16 Furthermore, specific barriers to participation may differ among ethnic and racial groups.9, 17 In 2015, NIA developed its Health Disparities Research Framework, which identifies nine priority populations and guides researchers to consider four key domains and various levels of analysis in aging research using a life course perspective.3 Subsequently, in 2016, Congress passed the 21st Century Cures Act, which—among other things—required the NIH to examine and address gaps in policies around inclusion and reporting of clinical trial results by age.18 Both the Framework and the Cures Act informed NIA's critical role in the development of two seminal workshops on Inclusion Across the Lifespan (June 2017, September 2020).19, 20 Building upon these activities, in 2019 NIH adopted a new policy requiring clinical trials to include a plan for enrolling individuals across the lifespan and justify any exclusions. Specifically, the requirements include submission of a planned enrollment table outlining sex, race, and ethnicity of participants, and a written scientific justification for any age or sex/gender exclusions.21 NIA also supports a range of programs and initiatives to facilitate and encourage representative participation in interventional trials—for example, through prioritization of funding requests with proposed enrollment that represents the affected population and appropriately includes recruitment of disparity populations as defined within the NIA Health Disparities Research Framework. In addition, NIA requires applicants for grants greater than $500,000 in direct costs in any fiscal year to submit planned enrollment tables as part of their Awaiting Receipt of Application (ARA) package, which must be reviewed and approved prior to submission of the full application for peer review. NIA's Office of Clinical Research (OCR) facilitates efficiency, coordination of clinical research, and operations that promote scientific rigor within NIA's extramural research programs. A new informatics platform, the Clinical Research Operations Management System (CROMS), facilitates real-time tracking and monitoring of clinical trial enrollment data. CROMS provides NIA with the necessary data to work with investigators to monitor progress toward each trial's enrollment goals and to intervene early when challenges arise. Of note, CROMS has the capability to collect participant-specific data for all NIH-designated disparity populations except disability (which is slated to be added to CROMS in 2024). Currently, the CROMS policy only mandates the reporting of participant data for race, ethnicity, age at enrollment, and sex and gender. NIA recognizes the importance of collecting data for all designated populations and intends to convene discussions in 2024 regarding the expansion of the required participant data reported. To support recruitment to AD/ADRD clinical trials, NIA also offers OutreachPro, a free online platform designed to help efficiently create effective, customized materials in five languages (English, Spanish, Chinese, Tagalog, and Hindi). Both CROMS and OutreachPro support the goals of the National Strategy for Recruitment and Participation in Alzheimer's and Related Dementias Clinical Research, which NIA released in 2018.22 The National Strategy was developed in collaboration with government, academic, private, nonprofit, and industry stakeholders as well as patients, caregivers, and study participants, and maintains a particular focus on participation of traditionally underrepresented groups. The NIA Alzheimer's and Dementia Outreach, Recruitment, and Engagement (ADORE)23 platform further supports the goals of the National Strategy by providing resources on clinical research recruitment and retention developed by the NIA, NIA-supported Alzheimer's Disease Research Centers, and other grantees. Designing studies and trials with appropriate levels of analysis and research expertise is essential. The NIA Health Disparities Research Framework encourages researchers conducting research including, but not limited to, clinical and behavioral studies to consider the environmental, sociocultural, behavioral, and biological determinants of health disparities and to assemble a scientific team of researchers most culturally and experientially suitable to lead core components of a study. While it remains a limitation that not all groups experiencing health disparities are captured in the NIH required inclusion and enrollment tables, NIA aims to expand the inclusion and monitoring of these populations in clinical studies. Recent examples include an NIA R24 funding opportunity entitled Examining Diversity, Recruitment, and Retention in Aging Research, and NIA's participation in the trans-NIH R01 funding opportunity Health and Health Care Disparities Among Persons Living with Disabilities. In addition, several NIA-supported longitudinal studies and data resources facilitate identification of locales where socioeconomic disadvantage and health concerns intersect, enabling hypothesis generation and suggesting populations and subpopulations in which intervention development might be appropriate. "While it remains a limitation that not all groups experiencing health disparities are captured in the NIH required inclusion and enrollment tables, NIA aims to expand the inclusion and monitoring of these populations in clinical studies." Finally, funding investigators who share similar social and cultural lived experiences with the proposed study participants may improve recruitment and retention. Such investigators and research partners can provide substantive input on resource needs for appropriate study sites, recruitment plans, and outreach strategies during the study design phase. This in turn may facilitate the successful completion of clinical trials that appropriately represent the U.S. population and those affected by the condition being examined. To build a robust workforce of experts in geriatric clinical studies, consistent with the NIH UNITE program's principles,24 NIA supports initiatives targeting multiple career points to diversify the research workforce. NIA's Resource Centers for Minority Aging Research (RCMAR) program aims to increase the diversity of the social, behavioral, and economic research workforce in aging, as well as creating the infrastructure to support these areas in aging research among all levels of research. Other examples include NIA MSTEM (R25): Advancing Diversity in Aging Research through Undergraduate Education; Dissertation Awards to Increase Diversity (R36); and longstanding participation in the NIH Diversity Supplement Program, which provides principal investigators with additional funds to bring investigators from diverse backgrounds at all levels of experience onto an existing project and into the aging research field. In addition, NIA convenes meetings to raise awareness about research and career development resources available in aging research. For example, the annual NIA Director's Regional Meeting is hosted in collaboration with regional institutions, including resource-limited institutions that engage underrepresented students and faculty; federally recognized Tribal nations; and others depending on the location.25 NIA demonstrates its longstanding commitment to advancing inclusion in clinical studies through an array of programs and initiatives targeted at patients, physicians, and research institutions (Table 2). Working with these important partners, we strive toward consistently developing clinical studies that are appropriately representative of and generalizable to the full population of older adults. Together we will take these important steps toward equity in the health of older adults. All authors contributed to the writing of this article and approved the final version before submission. The authors wish to acknowledge Rebecca Ehrenkranz, M.D., M.P.H. for her assistance in compiling Table 1. The authors have no conflicts of interest to declare. The authors are employed by the National Institute on Aging and this work was completed as part of their professional duties.