Contributed by: Ari Gnanasakthy, MBA, MSc
Principal Scientist, Patient-Centered Outcomes Assessment
RTI Health Solutions
Almost 40% of the American population belongs to a racial or ethnic minority. However, clinical trials for new drugs predominantly involve White participants, making up 80% to 90% of the study groups. This demographic disparity raises significant concerns because, ultimately, medications will be used by racial and ethnic minority groups as well.
Conditions like heart disease, cancer, and diabetes, along with their contributing factors, vary among different ethnic groups, just as they do between sexes. Research shows that there are differences in the efficacy, pharmacokinetics, and adverse effects of statins between East Asian and White populations, most likely related to genetic variations, drug transporters, and drug targets. Without including diverse populations in clinical trials, study sponsors struggle to ensure the effectiveness of treatments across all demographics or predict potential side effects specific to certain groups.
Diversity Action Plans
To address this lack of diversity in clinical trials, the Food and Drug Administration (FDA) recently released draft guidance that introduces the use of Diversity Action Plans (DAPs). These plans outline specific diversity requirements sponsors must submit for clinical studies involving drugs, devices, and biological products. Compliance with these guidelines will be mandatory 180 days after the final guidance is published for clinical trials beginning enrollment.
This requirement for DAPs aims to enhance the enrollment of underrepresented populations in clinical studies, thereby improving the generalizability and robustness of clinical data. DAPs will specifically focus on recruiting study participants from demographic groups underrepresented based on race, ethnicity, sex, or age.
Diversity Action Plan Requirements
The FDA’s guidance outlines detailed expectations for DAPs. These plans must include the sponsor’s enrollment goals, the rationale behind these goals, and strategies to achieve them. Enrollment goals should be specified by race, ethnicity, sex, and age groups to ensure participants mirror the intended patient population for the medical product’s use. Additionally, DAPs should include background information on disease understanding, associated risk factors, and demographic prevalence and incidence of the disease or condition.
When establishing enrollment goals, the FDA advises sponsors to consider their broader clinical development strategy. This means that even if a specific clinical study does not achieve proportionate representation, sponsors should aim for an “overall proportionate representation” across multiple studies subject to DAP requirements.
Overcoming Obstacles to Enrollment
Sponsors are encouraged to identify potential obstacles to enrollment, such as geographic disparities and socioeconomic factors, and to develop plans to overcome these challenges. Early engagement with the FDA is crucial for study sponsors to address these issues effectively.
For drug submissions, sponsors must include the DAP with the relevant Investigational New Drug (IND) application as soon as practicable. This submission must occur no later than the date on which the sponsor submits the protocol to the FDA for the phase 3 study or, if applicable, another pivotal study.
Surprisingly, the guidance does not grant exemptions from complying with DAP requirements for rare disease programs that typically involve small, pivotal studies that often consist of patients recruited from specialized study centers across the world.
Diversity Action Plan Submission and Feedback from the FDA
The guidance outlines the process for submitting DAPs to the FDA and describes how sponsors can receive feedback from the agency. Sponsors must include DAPs as part of their clinical study applications and provide updates on their progress toward enrollment goals in annual reports to the FDA. Importantly, the guidance allows sponsors to adjust DAPs based on FDA feedback or new insights, ensuring these plans evolve appropriately throughout the clinical trial phase.
The FDA recognizes that creating a DAP may not always be feasible, such as in studies during public health emergencies. Therefore, under specific circumstances, the FDA may waive the requirement to submit a DAP, either partially or entirely, at the agency's discretion or upon request from the sponsor.
The draft guidance includes an Appendix outlining the essential components of a DAP and provides a suggested format for sponsors to follow when preparing these submissions. Emphasizing brevity, the plan should typically not exceed 10 pages in length, excluding references.
It is noteworthy that the agency did not address the potential consequences if a sponsor fails to meet its enrollment goals, such as whether noncompliance could delay the approval process for the medical product. Instead, the FDA simply stated, "If enrollment goals are not expected to be met by the study's conclusion, the status report should explain the reasons for current or anticipated non-compliance and outline the sponsor's plan to mitigate this issue." The message is clear: Opting out of DAP is not an option.
Clinical Trial Recruitment Requirements
Traditionally, pharmaceutical companies prioritized fast access to the market, often recruiting patients for its clinical trials without sufficient consideration for generalizability. Although the guidance is well-intended and long overdue, it undoubtedly increases the burden on developers of medical products who are continually striving to shorten development timelines.
The FDA guidance requires that clinical study enrollment goals align with the estimated prevalence of the condition in the intended United States (US) population. This poses significant challenges for study sponsors who increasingly rely on patient participation from countries across the world to meet tight deadlines. Health outcomes are influenced by factors beyond age, sex, race, and ethnicity. Patients eligible to participate in clinical trials may decline participation due to reasons such as health literacy challenges, fear of the unknown, lack of trust, inconvenient study logistics, or time constraints. Hard-to-reach communities within the US often experience higher rates of certain illnesses. These communities, including religious minorities, indigenous groups, senior citizens, and people with disabilities, face disparities in living conditions, health perceptions, behaviors, and systemic discrimination.
Collaborative efforts and innovative solutions are essential for pharmaceutical companies to address these challenges effectively. Looking ahead, the effectiveness of any industry-wide collaborative approach among study sponsors will need to be evaluated within the fiercely competitive landscape of pharmaceutical research.
Overall, the FDA guidance on DAPs represents a crucial advancement toward achieving more inclusive clinical trials, with the aim of improving generalizability and robustness of study data. The guidance is clearly ambitious in its intent. While aiming to guarantee the safe and effective use of new medical products, the outlined approach presents challenges. It will be intriguing to observe how the pharmaceutical industry responds to the recommendations put forth in this guidance.