CF Foundation Provides Feedback to FDA on Clinical Trial Diversity Action Plans

CF Foundation Provides Feedback to FDA on Clinical Trial Diversity Action Plans

In its comments, the Cystic Fibrosis  Foundation commended the U.S. Food and Drug Administration on its ongoing commitment to address the lack of adequate representation with regard to race, ethnicity, sex, and age group in clinical research, and provided a number of recommendations to improve enrollment from underrepresented populations in rare disease clinical trials.

Sept. 26, 2024 | 9 min read

Dear Commissioner Califf:

On behalf of the Cystic Fibrosis Foundation, we write to provide comments in response to the Food and Drug Administration’s draft guidance on Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies. We commend the FDA’s ongoing commitment to rectifying the widespread lack of adequate representation with regard to race, ethnicity, sex, and age group in clinical research. This guidance is a critical step in these efforts, and we appreciate the opportunity to provide feedback on the FDA’s proposed recommendations.

Background on Cystic Fibrosis and Diversity in Cystic Fibrosis Clinical Trials
Cystic fibrosis (CF) is a rare genetic disease that affects nearly 40,000 adults and children of every racial and ethnic group in the United States. In people with CF, mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene result in a buildup of thick mucus in multiple organ systems, leading to lung damage, life-threatening infections, and other complications. To facilitate the development of CF therapeutics, the CF Foundation is engaged in virtually every element of the research and development process, from preclinical discovery and identification of new therapeutics to conducting clinical trials and post-marketing surveillance. Historically, CF clinical development programs have struggled with the inclusion of many underrepresented populations — particularly individuals who are black, indigenous, and people of color, due in part to the misconception that CF only affects white individuals and failure to adequately communicate with and engage these populations. However, enrolling clinical trials that represent the full diversity of the CF community is critical to achieving our mission of a cure for all people with CF. For that reason, the CF Foundation is investing significant time, resources, and attention towards improving the diversity of participants in clinical trials for CF therapeutics. With the experience gained from these efforts in mind, the CF Foundation offers the following considerations for the FDA as the agency refines its recommendations.

Timelines for Submitting Diversity Action Plans
The FDA suggests that sponsors submit a Diversity Action Plan “as soon as practicable but no later than the date on which the sponsor submits the protocol to FDA for the phase 3 study or, as appropriate, other pivotal study,” which is often at the End of Phase 2 (EOP2) meeting. However, we recommend that the FDA request submission of Diversity Action Plans with sponsors’ IND applications. We are concerned that the FDA’s recommendation fails to reflect the value of taking inclusion into account over the entire life cycle of a drug product. The FDA acknowledges that certain demographic groups may have different responses to drug products based on factors such as differential pharmacokinetics (PK), pharmacodynamics (PD), or possible differences in susceptibility to specific adverse events, which may drive meaningful differences in safety or effectiveness. Because clinical pharmacology data are collected as early as phase 1 trials, important differences related to race, ethnicity, sex, or age group could be missed if sponsors do not implement Diversity Action Plans until later in the drug development process. Setting the submission deadline for Diversity Action Plans at the EOP2 meeting therefore fails to capitalize on the opportunity to gather and analyze data from early studies that might identify these critical differences. Furthermore, even if Diversity Action Plans are specifically designed for and implemented during pivotal studies, enrollment and retention of diverse participants in clinical trials requires significant time, resources, and planning; earlier submission will help sponsors lay the groundwork for the efforts described in the Diversity Action Plans prior to initiating a phase 3 or other pivotal study.

Diversity Action Plans and Waivers in the Context of Rare Diseases
The CF Foundation greatly appreciates the FDA’s ongoing efforts to facilitate rare disease drug development. In the context of this guidance, the FDA recognizes that certain development programs, such as those for rare diseases, may rely on a single, small pivotal study that lacks the number of participants required to either discern or robustly analyze differences in safety and effectiveness across a study population. However, there is little additional discussion of rare diseases and the challenges that such limited populations present for the development and execution of Diversity Action Plans. Given some of the inherent challenges with these plans for rare disease products, we request that the FDA elaborate on their expectations for Diversity Action Plans for rare disease programs, including whether and how they may diverge from Diversity Action Plans for programs for diseases with larger populations.

This includes the use of waivers in the context of rare disease programs. According to this document, the FDA may waive either the requirement to submit a Diversity Action Plan (full waiver) or specific elements of a Diversity Action Plan (partial waiver) if “a waiver is necessary based on what is known or can be determined about the prevalence or incidence of the disease or condition in the US” and/or “conducting a clinical investigation in accordance with a DAP would be impracticable.” The FDA has stated that it only expects five waiver requests across CDER and CBER per year and intends to grant waivers only in extremely rare cases. We caution that many rare disease programs could meet one or both waiver criteria; we therefore anticipate significantly more waiver applications than the agency anticipates.

With that said, because Diversity Action Plans are crucial for gathering information regarding demographic-specific differences in the safety and effectiveness of drug products, we believe that it would be reasonable for the FDA to attach conditions to the receipt of a Diversity Action Plan waiver. One potential measure is to require sponsors granted a Diversity Action Plan waiver to collect and utilize certain post-marketing, real-world data from patients who receive the drug product commercially. Though it would be extremely advantageous to have such data prior to commercialization, these mechanisms may allow sponsors to ultimately achieve the goals of the Diversity Action Plan while simultaneously allowing a drug product to reach the market in a timely manner, which may otherwise not be possible.

Diversity Action Plans and Regulatory Decision-Making
The Diversity Action Plan requirement is a critical element of the FDA’s broader efforts to increase clinical trial diversity. This guidance document focuses on the preparation and submission of Diversity Action Plans, without elaborating on subsequent actions that the FDA may engage in, such as the initial review and continuing evaluation of Diversity Action Plan content and implementation later in clinical development. Though beyond the scope of this guidance document as currently written, the FDA’s ability to utilize Diversity Action Plans to their fullest potential is dependent on the extent to which the agency is able to ensure sponsors adhere to and meet the goals set out by their Diversity Action Plans. We therefore request that the FDA develop guidelines or metrics to assess sponsor progress towards their Diversity Action Plan goals, and articulate whether and how a sponsor’s success in achieving the goals of their Diversity Action Plan will contribute to the FDA’s regulatory decision-making, including drug product approval, labeling, and post-marketing commitments.

Additional Recommendations for Enrollment Strategies
The CF Foundation appreciates and agrees with the comprehensive recommendations that the FDA provides for measures to meet enrollment goals. Since our founding, we have focused on ways to incorporate the patient voice into our programming and all aspects of CF care and research. We offer several suggestions for further recruitment and enrollment strategies, which are informed by the knowledge gleaned from our listening and outreach efforts aimed at better understanding the perspective of the CF community on clinical research and therapeutic development.

In addition to the measures in the current draft guidance, the CF Foundation suggests that the FDA recommend the following actions for sponsors: encourage soliciting community and participant involvement in clinical study design, rather than just the drafting of the Diversity Action Plan; recruit a diverse team of clinical investigators and research staff, with ties to the community when possible and appropriate; and perform regular internal and external assessments to determine whether sufficient progress is being made to achieve the goals of the Diversity Action Plan and, if not, which aspects of either the Plan or actions on the part of the sponsor must be modified to better do so.

Importantly, as noted previously, these and other strategies suggested by the FDA are significant endeavors that require extensive time, resources, and planning. We believe that many of the measures — including but not limited to sustained community engagement — cannot be executed to their fullest potential without being initiated much earlier in the drug development process. With this in mind, we reiterate our earlier recommendation that Diversity Action Plans be required at the time of IND submission, even if sponsors do not intend to put them into practice until the initiation of their phase 3 or other pivotal studies.

Once again, the CF Foundation commends the FDA’s commitment to increasing the inclusion of underrepresented populations in clinical research and ensuring that medical products are studied and developed for use across the entirety of the population living with the disease for which those products are intended. We appreciate the opportunity to offer feedback on these recommendations and look forward to continuing to work with the agency to further consider how to increase diversity in rare disease clinical trials.

Download to Read More
Share this article
Topics
Public Policy

The Foundation regularly submits statements, letters, and comments to legislators for consideration.

View all activity
You might also be interested in...
Stay up to date with The Foundation

Sign up for our newsletter to get all of the latest news from The Foundation right in your inbox.

Subscribe