Around the Globe: US
The Evolution of US FDA Diversity Requirements in Clinical Research
Darshan Kulkarni
Kulkarni Law Firm

he US Food and Drug Administration has increasingly recognized the importance of diversity and representation in clinical trials over the past few decades. This evolution reflects growing awareness across medicine that differences in age, gender, race, and ethnicity can impact disease risk, treatment response, and health outcomes. A review of the relevant legal and regulatory history helps document this growing awareness and points the way to further necessary advances to make clinical research truly available to all and representative of all.

Throughout the 1980s, women and minority groups were often underrepresented in clinical research. Trials frequently focused on white men, raising concerns that results did not apply to the whole population. The 1988 Guideline for the Format and Content of the Clinical and Statistical Sections of New Drug Applications emphasized the importance of including analyses of demographic data in NDA applications.

The 1993 Guideline for the Study and Evaluation of Gender Differences in Clinical Evaluation of Drugs made it clear that women should be included in all phases of clinical drug development. This was promulgated specifically to reverse a long-standing regulatory barrier to women with childbearing potential participating in clinical trials. Unlike women with childbearing potential, there has never been a regulatory barrier to the inclusion of minorities in clinical trials and there does not exist any guidance that addresses only minority enrollment in clinical trials. The portion of the 1993 Gender Guideline cited above clearly articulates the expectation of FDA that all appropriate demographic subgroups should be included in product development, but the fact that this statement is found in the Gender Guideline might conceivably diminish its impact on minority recruitment.

The NIH Revitalization Act of 1993 continued this process and mandated inclusion of women and minorities in clinical studies funded by the US National Institutes of Health (NIH).

FDA also took other early steps, such as issuing guidelines in the 1990s on evaluating gender differences in drugs and including demographic data in applications. A major milestone was accomplished when the FDA, as part of the Food and Drug Administration Modernization Act of 1997 (FDAMA), required that “the Secretary shall, in consultation with the Director of the National Institutes of Health and with representatives of the drug manufacturing industry, review and develop guidance, as appropriate, on the inclusion of women and minorities in clinical trials.” The FDA responded by publishing its Demographic Rule, requiring summary data on age, gender, and race in New Drug Applications and aimed to enable analysis of safety and efficacy across subgroups. This is consistent with the 1998 Federal Register Notice on INDs and NDAs. FDA doubled down in its 1998 proposed clinical hold rule Investigational New Drug Applications; Proposed Amendment to Clinical Hold Regulations for Products Intended for Life-Threatening Diseases, which proposed allowing FDA to place an IND, or specific protocols under an IND, on clinical hold if a sponsor proposes to exclude from study women or men with reproductive potential because of a risk, or a potential risk, of reproductive or developmental toxicity from use of an investigational drug product.

In the 2000s, the FDA expanded requirements for demographic reporting and pediatric studies. Guidance also recommended collecting ethnicity data using Office of Management and Budget (OMB) categories for race and ethnicity. The National Institutes of Health’s 2001 policy on the inclusion of women and minorities in clinical research defined the minimum standards for maintaining, collecting, and presenting data on race and ethnicity for all federal reporting. As a result of this policy, NIH was required to use these definitions to allow comparisons to other federal databases, especially the census and national health databases. Additionally, the policy clarified the language governing NIH-defined phase 3 clinical trials to be consistent with the mandate for the inclusion of women and minorities as clinical research subjects.

The need to close demographic data gaps was highlighted in a 2013 FDA report to Congress, which catalyzed the agency’s current diversity action plan under the FDA Safety and Innovation Act (FDASIA 907 Action Plan). Released in 2014, this plan provided recommendations to improve demographic representation, data quality, and public availability; it also called for standardizing data collection and integrating diversity considerations throughout the product lifecycle.

This plan is consistent with the 2016 FDA guidance Collection of Race and Ethnicity Data in Clinical Trials. In this guidance, the FDA provides updated instructions for sponsors to collect high-quality, consistent demographic data to enable assessment of safety and efficacy across diverse subgroups. FDA further recommends methodology for collecting race and ethnicity data in clinical trials and suggests using standardized OMB categories to do so. This guidance outlines expectations to enroll representative populations and integrate diversity considerations throughout product development.

In November 2020, the FDA released the guidance Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs, which reflects the FDA’s efforts to modernize clinical research practices and recommends:

  • Broadening eligibility criteria to include more diverse populations (e.g., sex, race, ethnicity, age, etc.)
  • Using study designs and mechanisms that reduce the burden of participation (e.g., decentralized trials, adaptive designs, etc.)
  • Expanding enrollment and retention of subjects for rare diseases studies (e.g., using natural history studies, patient registries, etc.)

FDA’s latest guidance on collecting race and ethnicity data, Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials published in 2022, represents the current state of policy:

  1. The guidance provides recommendations to sponsors developing medical products on how to create a Race and Ethnicity Diversity Plan (the Plan) to enroll more participants from underrepresented racial and ethnic groups in the US into clinical trials.
  2. The guidance explains the benefits of the Plan, such as enhancing the generalizability and applicability of trial results, addressing health disparities, and increasing trust and engagement of diverse communities.
  3. The guidance outlines the elements of the Plan, such as identifying barriers to enrollment, developing strategies to overcome them, implementing and monitoring the Plan, and reporting the results.

Most recently, passage of the Consolidated Appropriations Act, 2023 (Public Law 117–328) included the Food and Drug Omnibus Reform Act of 2022 (“FDORA”), which includes several provisions intended to promote diversity in clinical trial enrollment. The law requires that clinical trial sponsors submit “diversity action plans” for certain late-stage drug trials, including all phase 3 trials, as well as most device studies. FDORA further directs the Secretary to convene public workshops in consultation with appropriate stakeholders to get input regarding enhancing enrollment in clinical studies of historically underrepresented populations. For investigators, clinical trial sites, and institutional review boards (IRBs), FDORA’s requirements will likely build on long-standing ethical and IRB considerations pertaining to equitable subject selection.

The Consolidated Appropriations Act, 2023 also created the NIH Office of Autoimmune Disease Research within ORWH (OADR-ORWH). As part of the creation of this office, the NIH has created new funding opportunities to support autoimmune disease research including for understanding chronic conditions understudied among women.

Looking ahead, diversity and inclusion will remain central pillars of FDA’s mission of protecting and promoting public health. Demographic data guide efforts to ensure the safety and effectiveness of medical products for all populations. However, there are already calls to include and consider diversity of weight, gender identity, disability status, and more. Companies making diversity efforts should exceed simply meeting regulatory standards and instead work to consider all types of diversity. Ongoing dedication to these principles will advance health equity and enable the delivery of quality, equitable care for all.