On June 28, 2024, the Food and Drug Administration (FDA) released draft guidance for industry, titled Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies(the Draft Guidance), for public review and comment. The Draft Guidance was issued pursuant to a directive from Congress in the Food and Drug Omnibus Reform Act (FDORA), signed into law in December 2022, which required FDA to issue or update guidance on diversity action plans that sponsors submit for certain clinical studies of investigational drugs and medical devices. The Draft Guidance also serves to update guidance that FDA previously issued on the topic in April 2022.

Background

The United States has made significant strides in clinical trial research over the past several decades. However, it is often the case that the populations for whom prescription drugs or devices are intended are frequently underrepresented or not actively recruited to participate in said research. For example, despite Black individuals comprising over 33% of those with kidney failure, only 9% participate in related clinical trials. Similarly, Latinos, who experience a higher incidence of cancer, make up less than 10% of participants in cancer clinical trials and only 11% of all U.S. clinical trial participants. The lack of participant diversity in clinical trials can have negative implications on both individual and public health, as the results from such studies do not represent the broader population or, oftentimes, even those would most benefit from the investigational product. The disconnect renders these treatments less effective and potentially harmful for certain groups. 

There are several reasons for the lack of representation of certain communities in clinical trials; we summarize the most significant of them below but note that others exist as well. These complexities emphasize the breadth and scope of the problem that Congress and FDA are attempting to address with the Draft Guidance. 

• Historical Mistrust
• The United States Public Health Service led a 40-year clinical trial study, known as the Tuskegee Experiment, in which hundreds of Black men with syphilis were experimented on without their informed consent. Although participants were promised medical care they would not otherwise receive, they were deceived, not informed of their syphilis diagnosis, and subjected to experiments decades after a cure was known. By exploiting the participants’ socioeconomic status, the study researchers violated ethical standards, leading to significant mistrust in clinical research within the Black community. The experiment resulted in 128 deaths from syphilis or related complications, infected 40 of the participants’ partners, and caused 19 children to be born with congenital syphilis.
• Another clinical trial, known as the Puerto Rican Pill Trials, involved women from the poorest areas of San Juan, Puerto Rico and neighboring cities who were given birth control pills without being informed they were part of an experiment or a clinical trial. When participants reported side effects, such as nausea, headaches, and depression, researchers often dismissed their claims.
• Lack of Engagement
• Underrepresented groups are not effectively approached or informed of clinical trial opportunities, nor are they provided sufficient or culturally sensitive information to make informed decisions about participation.
• One study found that a major barrier to enrolling racial and ethnic minority patients in clinical trials is that patients are unaware that they are eligible for an existing clinical trial. One of the most important facilitators of participation is social support and recommendations from physicians.
• Another study examining Black Americans’ unwillingness to participate in clinical trials concluded that there was a perception that the trial would benefit white Americans more than underrepresented populations. This disparity issue was cited by survey respondents as a leading reason for their unwillingness to participate in clinical research. 

Other considerations include constraints related to scheduling, transportation access, and language barriers.

Which Drugs and Devices Require Diversity Action Plan Submission?

As described at length in FDA’s Draft Guidance, diversity action plans (DAPs) place the impetus on drug and device developers (also referred to as clinical trial “sponsors”) to consider and combat the above-described factors when developing clinical trials for new drugs and devices. For drugs, a DAP is required for a clinical investigation of a new drug that is a Phase 3 study or other pivotal trial. For medical devices, DAPs will be required to be submitted to FDA in most instances. If the sponsor is applying for an investigational device exemption or IDE, a diversity action plan must be submitted, whereas in instances where an IDE is not required for the clinical study to proceed, the DAP should be included in any premarket notification, request for classification as a de novo device, or premarket approval application. 

The Draft Guidance outlines the actual format and content that FDA expects in a DAP and includes an appendix summarizing required elements. It also describes the timing and process for DAP submission, and criteria that FDA will use in evaluating a sponsor’s request not to submit a DAP (i.e., a waiver request). 

Further, the Draft Guidance specifies three instances in which diversity action plans are not required to be submitted: 

• Clinical studies of drugs with protocols submitted within 180 days after publication of the final guidance, when enrollment is scheduled to begin 180 days after publication;
• Clinical studies of devices received by FDA in IDE applications within 180 days after publication of the final guidance; or
• Clinical studies of devices that do not require submission of an IDE that are approved by an institutional review board or independent ethics committee within 180 days after publication of the final guidance.

Addressing Race, Ethnicity, Sex, and Age (And More) in Diversity Action Plans

Under FDORA, diversity action plans must specify goals for clinical study enrollment, and those goals are required to be disaggregated by the clinically relevant population’s race, ethnicity, sex, and age group. The sponsor’s rationale, plan of action for meeting these enrollment goals, and method for monitoring goal progression must also be detailed in the plan. In other words, enrollment goals must be presented across different subsets of the study’s population. Though the Draft Guidance focuses on a relevant population’s race, ethnicity, sex, and age group, it also recognizes that health disparities and access to health care and clinical studies are influenced by a host of different demographics and other social determinants of health. These include, but are not limited to, geographic location, gender identity, sexual orientation, socioeconomic status, physical and mental disabilities, pregnancy status, lactation status, and co-morbidities. As such, sponsors are encouraged to consider these additional demographics when developing enrollment goals.

In developing their DAPs, sponsors must not only contemplate the clinical impacts of their drug or device trials but also anticipate the potential social impact the study can have as well. Indeed, diversifying the clinical study population will help more comprehensively understand the biological impact that the drug or device can have on the relevant population. But it is Congress’s hope that the benefits of diversifying enrollment go beyond just clinical outcomes. Ideally, cultivating clinical studies that are inclusive of diverse populations – particularly when those experiences are positive – can aid in the building of trusting relationships with participants, promoting increased scientific and clinical knowledge, and advancing health care equity. 

Conclusion

FDA will be accepting comments on the Draft Guidance through Thursday, September 26, 2024, which can be submitted electronically to Docket No. FDA-2021-D-0798 ( paper submissions can also be made to the address listed in the agency notice announcing the Draft Guidance’s availability). Typically, guidance that is issued by a federal agency is not binding. However, because FDA is required by statute to specify the manner and form by which DAPs are submitted for review, those sections of the guidance (when finalized) will have binding effect. 

The Draft Guidance presents a new approach for diverse communities to build trust in our healthcare system and, likewise, for drug and device sponsors to earn that trust. In addition to the new guidance, FDA’s broader push for enrollment and retention strategies that include ongoing community engagement via local organizations, healthcare providers, and patient advocacy groups as well as FDA’s support for the decentralization of clinical trials, will increase opportunities for broader participation and allow for diverse perspectives to be vocalized and heard. Thoughtful and inclusive recruitment may foster stronger relationships between the medical field and underserved communities, increasing the likelihood of their participation in advancing new drugs and medical technologies for treating diseases and illnesses. By enhancing diversity and inclusion in clinical studies, the medical and scientific community will be better positioned to understand and treat disease and illness across all populations.