The U.S. Food and Drug Administration (FDA) released a new draft guidance in June 2024 to enhance the diversity of clinical trial participants. The guidance details the format and content of the Diversity Action Plan required from sponsors. This plan must include three key elements:
- The sponsor's enrollment goals for the clinical study, informed by the prevalence of the disease in the U.S. intended use population.
- The rationale behind these goals, including an analysis of how the sponsor determined its enrollment targets.
- An explanation of how the sponsor intends to achieve these goals, including a description of the strategies for enrollment and retention of the study population. [1]
The Diversity Action Plan for drugs is required for Phase 3 studies or any pivotal clinical study other than a bioavailability (BA) or bioequivalence (BE) study. The FDA expects sponsors to submit their Diversity Action Plan no later than the date on which they submit the clinical trial protocol for the Phase 3 or other pivotal study [1].
Why Diversity Matters
New medications are usually brought to market after a series of successful clinical trials where the drug is tested on an increasing number of volunteers to assess its safety and effectiveness. Ideally, sponsors designing clinical trials should ensure that the participants represent the population who will be using the drug. Unfortunately, many racial and ethnic groups, as well as women, have historically been underrepresented in clinical trials. This lack of diversity can lead to serious life-threatening reactions in these groups of people [2].
According to the guidance: “Diversity Action Plans are intended to increase enrollment of participants who are members of historically underrepresented populations in clinical studies to help improve the strength and generalizability of the evidence for the intended use population.” [1]
The Tegretol (carbamazepine) Case
Tegretol (carbamazepine) is a drug developed to prevent and treat epileptic seizures (anticonvulsant). While it was observed that all patients treated with the drug are at risk for serious skin reactions such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), patients in Asian countries or of Asian ancestry were 10 times more likely to develop them. Further research revealed that the severe skin reactions are associated with the HLA-B*1502 allele, which is more prevalent in certain Asian populations. This case is a prime example of pharmacogenomics and showcases how different groups of people might react to a drug, further highlighting the necessity for diverse representation in clinical trials [3].
Factors Contributing to Underrepresentation in Clinical Testing
Systemic barriers in healthcare exist and lead to different levels of participation among various groups. A meta-analysis of 72 published studies identified the main barriers [4] :
- Language and communication: The ability to speak English, particularly among recent immigrants.
- Lack of trust: Many potential participants don’t trust the healthcare system in general and the drug industry in particular.
- Lack of access to trials: Participants don’t have sufficient information about eligible trials or are not invited to participate.
- Eligibility criteria (inclusion/exclusion): Pregnant women, older adults, overweight individuals, and people with chronic conditions are often excluded from studies.
- Attitudes and beliefs (unwilling to participate): Religious beliefs, “guinea pig” perceptions, privacy concerns, and negative attitudes towards clinical trials.
- Lack of knowledge about clinical trials: Among ethnic minorities, there is often a lack of knowledge about the clinical trials process and data collection.
- Logistical and practical issues: Lack of transportation, time, additional costs, and family and work responsibilities.
Enrollment and Retention Strategies
To overcome these barriers, sponsors must include in their Diversity Action Plan an explanation of how they plan to enroll and retain a diverse group of participants needed for their clinical trials. In the guidance, the FDA provides six strategies that sponsors can use to meet their enrollment and retention goals [1]:
- Engage communities continuously through advisory boards, navigators, community health workers, patient advocacy groups, local healthcare providers, and organizations.
- Train clinical investigators and research staff in cultural competency to build trust, reduce bias, and avoid stereotypes when interacting with participants.
- Increase participant awareness by providing language assistance for those with limited English proficiency.
- Minimize participant burden by avoiding unnecessary procedures, using convenient sites, offering transportation and dependent care, allowing flexible study hours, and reimbursing costs.
- Improve study access by limiting exclusion criteria, choosing sites that serve diverse populations, considering accessibility for those with disabilities, and starting studies in experienced locations.
- Use decentralized study methods when appropriate.
The guidance was issued to satisfy section 3602 of the Food and Drug Omnibus Reform Act (FDORA) of 2022 and when finalized, will replace the previous guidance on diversity plans for clinical trials.
Author: Edouard AL Chami
References
[1]- FDA (June 2024) . FDA. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-action-plans-improve-enrollment-participants-underrepresented-populations-clinical-studies.
[2]-Schwartz, A. L., Alsan, M., Morris, A. A., & Halpern, S. D. (2023). Why Diverse Clinical Trial Participation Matters. The New England journal of medicine, 388(14), 1252–1254. https://doi.org/10.1056/NEJMp2215609.
[3]-Chen, P., Lin, J. J., Lu, C. S., Ong, C. T., Hsieh, P. F., Yang, C. C., Tai, C. T., Wu, S. L., Lu, C. H., Hsu, Y. C., Yu, H. Y., Ro, L. S., Lu, C. T., Chu, C. C., Tsai, J. J., Su, Y. H., Lan, S. H., Sung, S. F., Lin, S. Y., Chuang, H. P., … Taiwan SJS Consortium (2011). Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. The New England journal of medicine, 364(12), 1126–1133. https://doi.org/10.1056/NEJMoa1009717.
[4]-Bodicoat, D. H., Routen, A. C., Willis, A., Ekezie, W., Gillies, C., Lawson, C., Yates, T., Zaccardi, F., Davies, M. J., & Khunti, K. (2021). Promoting inclusion in clinical trials-a rapid review of the literature and recommendations for action. Trials, 22(1), 880. https://doi.org/10.1186/s13063-021-05849-7.