Clinical Research Representation: Pass it On

Thirty two years ago today, on June 10, 1993, Congress passed the landmark National Institutes of Health (NIH) Revitalization Act to remedy historical exclusion of women and minorities from research participation.  The law directed the NIH Director to ensure the inclusion of women and minorities as research subjects in NIH conducted or supported research unless doing so was “inappropriate” with respect to their health.  The law also required such research to be designed to enable a “valid analysis of whether the variables being studied in the trial affect women or members of minority groups, as the case may be, differently than other subjects in the trial.”

Contemporaneous with the NIH Revitalization Act, the Food and Drug Administration (FDA) reversed longstanding guidance categorically excluding non-pregnant women of childbearing potential from phase I and early phase II clinical trials in favor of encouraging women’s participation, requiring gender-based safety and efficacy analyses, and instituting contraception or abstinence stipulations for women of childbearing potential in early trials.

These events marked a turning point in expanding representation in clinical studies and opening the door to more personalized medical care.  Today it is widely accepted that both sex and race may be meaningfully correlated with physiological and pathological functions and that increasing trial representativeness may produce new biologic insights, improve the generalizability of research findings, and yield targeted therapeutic strategies with improved safety and effectiveness. Advancing the frontier of scientific knowledge has been an important rationale for diversifying trials.

Since 1993, Congress has continued to direct the federal government, and in particular FDA, to take steps to close the gap in clinical research representation.  For example:

• The Food and Drug Modernization Act of 1997 (FDAMA) directed FDA to develop guidance on the inclusion of women and minorities in research.
• The Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law in 2012, directed FDA to investigate how well demographic subgroups (sex, age, race and ethnicity) were included in clinical trials to support approval of applications for medical products and whether subgroup-specific safety and effectiveness data were available.
• The FDA Reauthorization Act of 2017 (FDARA) directed FDA to develop guidance to enhance diversity in clinical trials.
• The Food and Drug Omnibus Reform Act of 2022 (FDORA) required sponsors of certain clinical trials for drugs, biologics and devices to submit Diversity Action Plans (DAPs) to improve enrollment of underrepresented populations and to ensure that participants in pivotal clinical trials reflect the demographic diversity of the population that will ultimately use the medical product, if approved. FDORA further directed FDA to issue guidance on the format and content of DAPs.

These legislative mandates in turn resulted in new initiatives by FDA to expand diversity and inclusivity in clinical trials.  In 2016—dubbed the “Year of Clinical Trials Diversity”  by FDA—the agency published two guidance documents in furtherance of FDASIA related to the standardized collection and reporting of race and ethnicity data in submissions of drug and device clinical trials (see our previous blog post on the device guidance here). In 2020, as required by FDARA,  FDA published guidance to enhance diversity in clinical trials that makes recommendations regarding (1) broadening eligibility criteria and avoiding unnecessary exclusions for clinical trials; (2) developing eligibility criteria and improving trial recruitment so the enrolled population better reflects the population most likely to use the drug, if approved; and (3) applying the recommendations for broadening eligibility criteria to clinical trials of drugs intended to treat rare diseases or conditions.

In 2024, FDA issued its long overdue draft guidance on DAPs as required by FDORA (which we blogged about here). Under this guidance, sponsors must submit a DAP to the FDA for a Phase 3 or other pivotal study that describes the sponsor’s enrollment goals for the study disaggregated or tabulated by race, ethnicity, sex, and age group of the clinically relevant population, the sponsor’s rationale for its goals, and an explanation of how the sponsor intends to meet those goals. The draft guidance also encourages sponsors to consider additional factors that may affect clinical outcomes when developing DAP goals (e.g., demographic, socioeconomic, presence of co-morbidities).

FDORA directed FDA to finalize the draft DAP guidance no later than 9 months after closing the comment period, which will be June 26, 2025.

Recent developments give reason for concern about whether FDA will meet this deadline and, more broadly, about whether FDA will continue to implement Congress’ mandates for clinical trial diversity and inclusion.  In January 2025, FDA removed three draft and final guidance documents from its website: the 2024 draft guidance on DAPs; a 2025 draft guidance on sex- and gender-based differences in device development; and a 2020 final guidance on enhancing diversity in clinical trials.  FDA gave no public notice and offered no explanation for its actions.  Following a February 11, 2025 temporary restraining order issued by the U.S. District Court for the District of Columbia the documents were restored with a disclaimer stating: “Any information on this page promoting gender ideology is extremely inaccurate and disconnected from the immutable biological reality that there are two sexes, male and female,” (see 2/15/25 archive of FDA’s draft DAP guidance). As of the date of this blog, the 2024 draft guidance on DAPs and 2020 final guidance on enhancing clinical trial diversity appear to have been removed again (see here and here, respectively).

Ensuring diversity and inclusion in clinical trials is a scientific and public health imperative.  Lack of representation has serious and wide-ranging adverse consequences that include comprising generalizability of clinical research findings, hindering medical innovation, increasing healthcare costs, exacerbating disparities in healthcare, and undermining trust in the research enterprise.

Consistent with its mission to protect and promote public health, FDA has for decades been at the forefront of efforts to expand clinical trial diversity and inclusion.  Although political priorities may shift, continued commitment to its mission—as well as to implementation of Congress’ directives– requires FDA to continue the forward momentum toward greater representation in clinical research.  We hope FDA will issue the final DAP guidance by June 26, as required by Congress, and thereby signal its continued commitment to advancing this goal.