FDA regulations require clinical trial sponsors to present information from premarket studies on the safety and effectiveness of drugs and biologics in terms of gender, age, and racial subgroups. However, if certain patient populations are not adequately represented in premarket clinical trials, FDA may also require or request collection of such data in the postmarketing setting.

Under 21 CFR 312.85, FDA and the sponsor may also enter into a written postmarketing commitment (PMC) to collect additional data in the postmarketing setting after the drug’s approval. In instances where the safety of the drug is insufficiently understood, under section 505(o)(3) of the Food, Drug, and Cosmetic Act, FDA has authority to impose postmarketing requirements (PMR) to require sponsors to conduct post-approval studies or clinical trials to collect additional important scientific data, or to assess known serious risks, signals of a serious risk, or to identify an unexpected serious risk when data indicate the potential for a serious risk related to the use of a drug.  FDA’s new draft guidance suggests that FDA will use its authorities under section 505(o)(3) and 21 CFR 312.85 to ensure that relevant subpopulation data is collected, if certain patient populations are not adequately represented in premarket clinical trials for drugs and biologics.

As applied in a setting where a sponsor failed to enroll an adequately diverse patient population in a clinical trial, FDA may require the sponsor to conduct postmarketing studies if, for example, there is data to suggest a signal of a serious risk related to reduced effectiveness in an underrepresented population or a subgroup of patients with a particular genetic mutation associated with a specific subpopulation.

Conversely, FDA may enter into a written agreement with the sponsor to conduct postmarketing studies to further characterize clinical benefit of the drug in certain populations for which data is lacking.

In addition, if a drug is to be granted accelerated approval, FDA requires confirmation of clinical benefit in a confirmatory trial, which the guidance recommends should represent the diversity of patients expected to use the drug in the U.S.

In order to assist sponsors in obtaining safety and effectiveness data post-approval, new FDA draft guidance describes design and statistical considerations for various postmarketing approaches to provide additional information regarding traditionally underrepresented populations. These recommendations include considerations for:

• Single-arm trials. The draft guidance advises that single arm trials can be designed with a large enough sample size to rule out a historical rate of safety or efficacy to provide assurance (upon analysis by subpopulations) that the product is safe and effective in a particular subgroup. These studies can include data on patients from pre-approval studies (referred to as “borrowing” patients) in order to meet the required sample size, and they can enroll and analyze the main study’s underrepresented subpopulation in a separate cohort as a parallel arm.

• Randomized trials. FDA notes that clinical trial plans may be revised to enrich the trial for the subpopulation(s) of interest to obtain postmarketing data; however, “it is important to consider and discuss with [FDA] the rationale for the potential changes and any impact on statistical analyses.” The draft guidance urges sponsors to stratify based on the subpopulation(s) of interest if there are potential prognostic implications associated with that subpopulation.

• Real-World Data (RWD) sources. The guidance cautions that there are many “complex issues when considering the use of RWD to obtain postmarketing information on traditionally underrepresented populations,” and thus sponsors should discuss the proposed use of RWD with FDA early on in product development.

• Pooled studies. FDA proposes in the draft guidance that pooling data across sources “may allow for a meaningful evaluation of the drug in patients from different clinically relevant subpopulations,” so long as the clinical studies include an adequate number of patients and sufficient data from each subpopulation.

The draft guidance concludes by noting that when a marketing application is comprised of patients enrolled predominantly outside of the U.S., data and rationale should be submitted to support applicability to the U.S. population and medical practice. In addition, the guidance emphasizes that “FDA may request or require studies or trials to further characterize the efficacy or safety of the product in subpopulations relevant to the U.S. population” when applications rely on data for patients predominantly outside of the U.S.

Increasing focus on diversity in clinical trials

The Congressional spending legislation that was enacted in December 2022 (FDORA) requires sponsors to submit a “Diversity Action Plan” before initiating pivotal trials.  However, this new law stopped short of articulating what, if any, impact a sponsor’s failure to submit a Diversity Action Plan could have on the marketing application itself. The draft guidance clarifies that FDA views postmarketing studies as an avenue for sponsors to collect and evaluate clinically relevant, subpopulation data if the sponsors were unable to do so during the clinical development program, either as a requirement to confirm the safety of the drug in all patients for which the drug is indicated, or to generate additional clinical benefit data. 

The draft guidance further underscores FDA’s willingness to collaborate with sponsors on recruiting a diverse clinical trial population, and aligns with the agency’s recent actions to promote clinical trial diversity, including:

• FDA’s May 2023 draft guidance that encouraged the use of “Decentralized Clinical Trials” and local health care providers as mechanisms for increasing diversity and inclusion in trials, recognizing that bringing trial-related activities to participants’ homes and other locations other than traditional clinical trial sites – including through the use of digital health technologies – may reduce the need for travel and improve engagement, recruitment, enrollment, and retention of a meaningfully diverse clinical population.

• The agency’s April 2022 draft guidance promoting the submission of a “Race and Ethnicity Diversity Plan” before beginning clinical trials, which highlighted how consideration of demographic factors like race and ethnicity are critical to the generalizability of study results. FDA’s draft guidance on postmarketing approaches references these diversity plans, and urges sponsors to collaborate with FDA early in the trial process to determine appropriate benchmarks for an inclusive and representative data package.

• The November 2020 final guidance on “Enhancing the Diversity of Clinical Trial Populations,” which provides recommendations on how to: broaden study subject eligibility criteria by using RWD; include more racial and ethnic minorities; advance community engagement; and make recruitment events more accessible.

• The CDRH/CBER “Breakthrough Devices Program” draft guidance, updated in October 2022, that may favor program eligibility for a medical device that includes user features that are adaptable or more easily used by diverse populations or allow for use in more diverse settings such that a patient subpopulation with limited or no available options may have improved adherence to a prescribed medical regimen.

Speaking at the “Advancing Representative Enrollment in Clinical Trials” Duke-Margolis Center for Health Policy meeting last month, Oncology Center of Excellence Associate Director Lola Fashoyin-Aje said FDA will be providing a public analysis of the “Diversity Plans” submitted thus far, and that the agency will soon be publishing guidance on “Diversity Action Plans,” as separately required by FDORA. Fashoyin-Aje explained that FDORA’s “Diversity Action Plans” include “goals for clinical study enrollment, disaggregated by age group, sex, and racial and ethnic demographic characteristics of clinically relevant study populations, and may include characteristics such as geographic location and socioeconomic status.”

Next steps

FDA will hold a two-day virtual public workshop on enhancing clinical trial diversity on November 29-30. In the next episode of our upcoming “Talking the Cure” podcast, we will explore the latest Congressional and FDA efforts to promote clinical trial diversity; make sure to subscribe to our podcast (on Apple, Google, Spotify or Deezer) to be notified of new episodes, and you can learn more by visiting our podcast website.

The agency is accepting comments on the draft guidance through October 10. If you wish to submit feedback to FDA, or have any questions about this guidance or clinical trial regulations more generally, please feel free to contact any of the authors listed below or the Hogan Lovells attorney with whom you regularly work.