The 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. Darshan Kulkarni of Kulkarni Law Firm, writing in December 2023’s DIA Global Forum magazine reviews the relevant legal and regulatory history to document this growing awareness and point 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.
