espite broad awareness and acknowledgement about the lack of diversity in clinical trials, challenges remain. In their 2020 Drug Trials Snapshots Summary report, FDA provided average percent participation in clinical trials by subpopulation for new molecular entities and therapeutic biologics approved in 2020 and the results were stark, with disproportionately high rates of white participants (75% white) and low percentages in other groups (11% Hispanic, 8% Black or African American, and 6% Asian). These disparities were more apparent compared to the US population composition (61.6% white, 18.7% Hispanic, 12.6% Black or African American, and 6% Asian).

Table 1. Clinical trial participation by subpopulation for new molecular entities and therapeutic biologics approved by the FDA in 2020.

Barriers to resolving the lack of participation from historically underrepresented and marginalized communities include, but are not limited to, medical mistrust, trial availability, access, eligibility, enrollment practices, and lack of awareness. The challenges to ensuring diversity are exacerbated in rare diseases due to inherently small patient populations and difficulties with recruitment unique to rare diseases, such as low number of treatment centers. In fact, the FDA 2021 Drug Trials Snapshots Summary report noted that “representation from some racial and ethnic groups was low,” including in trials for products with orphan disease indications. Unique and strategic approaches are needed to ensure diversity in clinical trials for orphan drugs in particular.

The GOOD news in the US is that the FDA and Congress both recognize the importance of diversity in clinical trials and have taken steps to increase diversity in clinical research. On April 3, 2022, the FDA issued guidance for industry on developing plans to enroll more clinical trial participants from underrepresented racial and ethnic populations in the US. This guidance was issued in addition to final guidance issued in 2020 on Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs and in 2021 on Evaluation and Reporting of Age-, Race-, and Ethnicity-Specific Data in Medical Device Clinical Studies. Additionally, in 2022, Congress passed omnibus spending legislation (i.e., the Food and Drug Omnibus Reform Act [or FDORA] of 2022), which includes provisions aimed at increasing diversity in clinical trials and addressing health disparities. Diversity in clinical trials is now supported and mandated by law in the United States.

Draft Diversity Guidance Considerations

In the April 2022 diversity plan draft guidance, FDA recommends that industry sponsors develop a diversity plan and submit it to the investigational new drug (IND) application prior to, or no later than, when sponsors request agency feedback regarding the applicable pivotal trial(s) for the drug (often during the End of Phase 2 [EOP2] meeting). Specifically, sponsors should define enrollment goals for underrepresented racial and ethnic participants (based in part on the pre-specified protocol objectives) as early as practicable in clinical development for a given indication.

Sponsors should also discuss this plan with the Agency as soon as possible during medical product development but no later than when a sponsor is seeking FDA feedback regarding the proposed pivotal (usually phase 3) trial(s).

Omnibus Reform Act Considerations

To further illustrate what is expected of sponsors to prospectively plan to increase diversity in clinical trials, FDORA outlines many additional requirements to increase accountability of both sponsors and the Agency.

Call to Action

To address the lack of diversity in clinical trials and meet the Diversity Plan requirements outlined in the FDORA provisions, pharmaceutical companies and principal investigators must invest adequate resources in research that includes diverse populations. Suggestions for accomplishing this include:

• Engaging diverse investigators and staff who can help ensure culturally competent interactions with patients and their families, eliminating unconscious/implicit bias
• Recruiting patients in nontraditional locations
• Broadening eligibility criteria and avoiding unnecessary exclusions for clinical trials that will impact specific communities
• Increase transparency, engaging study participants throughout the drug development process to inform trial design, endpoint selection, and communicating results
• Sustain patient community engagement to help foster trust
• Communicate sponsor and investigator commitment to improving healthcare outcomes of patients regardless of their background.

It is important that all stakeholders engaged in clinical research make a valiant effort to reduce disparities and advance health equity across patient populations through thoughtful, innovative, and persistent approaches. With the passage of FDORA, Congress fortified FDA’s authority to require that sponsors diversify their clinical trials by recruiting, enrolling, and retaining participants from previously underrepresented demographic groups. FDORA’s provisions codified the agency’s goal of ensuring that clinical trials are conducted to evaluate the safety and efficacy of treatments in all relevant patient populations regardless of race, sex, or ethnicity and is a solid step forward to achieving truly representative clinical trials. Given this positive development, we eagerly await FDA’s ability and willingness to enforce these provisions until we see progress.