FDA clinical trial diversity workshop reveals agency’s expectations for sponsors

FDA’s latest two-day workshop was aimed at promoting diversity in clinical trial enrollment and patient participation to reflect the demographic subgroups represented in the disease/condition being studied. Academics, industry stakeholders, and the Directors of the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH) offered suggestions for enhancing clinical trial diversity. The workshop was one of several diversity-related activities required by FDORA, which we previously summarized online here.

In her opening remarks, CDER Director Patrizia Cavazzoni emphasized the importance of FDA and industry collaborating in this effort, noting FDA’s related August 2023 draft guidance on post-marketing approaches to obtaining data on underrepresented populations, which we analyzed online here.

Clinical study diversity: Where are we now?

In the first session of the workshop, CDER Oncology Center for Excellence (OCE) Deputy Division Director Dr. Lola Fashoyin-Aje stressed shifting the conversation from explaining the importance of diversity towards identifying solutions.

FDA issued draft guidance in April 2022 recommending that drug and device sponsors to submit Diversity Plans describing their plans to enroll racially and ethnically representative populations in pivotal clinical trials, as we previously analyzed online here. Fashoyin-Aje announced that OCE’s Project Equity recently summarized diversity plans voluntarily submitted to CDER’s oncology review divisions between April 2022 and April 2023. Notably, FDA’s analysis uncovered that 13% of the diversity plans received were incomplete -- lacking one or more elements that a diversity plan should contain. Further, of comments provided by FDA to sponsors about their diversity plans, 90% of agency feedback addressed diversity enrollment goals. Sponsors should therefore be careful to provide FDA with a comprehensive diversity plan, paying close attention to the enrollment goals section.

The workshop also brought attention to the industry's historical neglect of certain patient populations which has left patients under-educated about clinical research generally and uninterested in study participation. Panelists asserted that a three-pronged strategy — engaging with patient communities, hiring diverse research personnel and leaders, and streamlining the informed consent process — is essential to bringing traditionally excluded patients back into the fold.

Establishing clinical study enrollment goals

Recruiting patients who are representative of the disease population is critical to meeting clinical study enrollment goals. Panelists advocated for recruitment incentives as a tool to increase diversity. Panelists argued that potential concerns about paying clinical trial participants and the associated risks of monetary incentives in studies were based on outdated factors that are largely no longer applicable. They urged FDA to issue new guidance on incentives and remuneration, asserting that Institutional Review Boards’ (IRBs) interpretations of existing agency guidance as limiting or prohibiting study subject payments deter sponsors from using payment as an effective recruitment tool.

To achieve enrollment goals, sponsors should also statistically monitor the baseline characteristics of recruited, screened, and enrolled participants in trials. This demographic data should be compared to available prevalence data in order to determine whether representation targets are being achieved. Reviewing enrollment, identifying demographic trends in the patients who are successfully retained, and making adjustments as needed is key.

Approaches to support the inclusion of underrepresented populations, including pregnant and lactating persons, children and geriatric patients, individuals with mental illness, and individuals with intellectual and development disabilities

Sessions on the inclusion of pregnant persons, individuals with mental illness, and individuals with intellectual and development disabilities made clear that FDA’s notion of diversity encompasses more than race, ethnicity, gender, and sexual orientation. These groups in particular were highlighted as examples of patient populations for whom categorical exclusion from trials is often the norm.

Study design features can help or hinder efforts to diversifying clinical studies. For example, criteria for a heart disease study drug that excludes patients that don’t experience chest pain may inadvertently disqualify women, who may be less likely to experience that particular symptom. Panelists suggested that criteria that would exclude significant subgroups of otherwise eligible patients within the disease population should be scrutinized to ensure that a strong scientific justification for the exclusion exists.

Researchers’ perception of the capacity of specific patient populations as a whole may also affect who is and is not included in research. For example, individuals with mental illness are often considered incapable of providing consent even if such a belief is not adequately justified, panelists argued, which hinders their ability to enroll in trials. Because of this belief, it may not be until the post-marketing setting that researchers learn of any specific risks that a drug may pose to mentally ill patient, specifically. Individual capacity assessments are critical to understand and support the decision-making of clinical trial participants with perceived cognitive challenges.

Appropriate use of DCTs, DHTs, and other trial elements

Panelists discussed approaches to support inclusion of underrepresented populations and to encourage clinical study participation reflecting the population expected to use the investigational drug or device, including the appropriate use of decentralized clinical trials (DCTs) and digital health tools (DHTs), clinical endpoints, biomarker selection, and analysis of study results. We recently analyzed here FDA’s May 2023 draft guidance on the implementation of DCTs to increase diversity in clinical trial recruitment.

FDA also recently published draft guidance on “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations,” which advises that it is the responsibility of the DCT sponsor to ensure that DHTs used are available and suitable for use by all trial participants. FDA urges clinical trial sponsors to ensure that participants who do not have a protocol-specified DHT are not excluded from the DCT for that reason; and in doing so, the guidance targets barriers to diverse representation in clinical trials.

Panelists also discussed that patient referrals by local health care providers influences patients’ decisions to later enroll in trials, and they suggested hiring study investigators who have similar demographics to the patient communities to assist with this effort.

Community engagement

Community engagement was a recurring theme throughout the workshop. Panelists and FDA representatives urged the importance of connecting with patients consistently, even as early as Phase I trials to obtain input on the trial protocol. The emphasis placed on engaging with patient communities early and consistently before, during, and after the trial is part of FDA’s expectation that sponsors’ diversity plans delve into strategies that involve partnering with patient communities.

Examples of community engagement proposals included the dissemination of clinical study demographic data and study results to the public in understandable language. Panelists also suggested giving former participants access to their individual study data after the trial.

The future of clinical trial diversity efforts

Closing out the workshop, the directors of CBER, CDRH, and other FDA officials punctuated key themes and the importance of embedding diversity throughout the clinical trial enterprise.

Summarizing takeaways from the workshop, CDER Office of Medical Policy (OMP) Deputy Director Karen Hicks identified the following takeaway from the panel conversations: researchers must acknowledge the mistrust felt by many patients towards clinical research, establish trust, address patients’ fears, and then invite patients to participate. And patient participation begets more patient participation. CBER Director Peter Marks spotlighted the importance of awareness among potential clinical trial participants that others within similar demographics have already been studied, especially in regard to vaccine studies.

FDA representatives also highlighted tools that may make trial diversity efforts more efficient. For example, CDRH Director Jeff Shuren proposed that leveraging a single, central IRB would increase efficiency and may also reduce the burden on clinical trial subjects.

Echoing comments from Fashoyin-Aje on the opening panel of the workshop, OCE Deputy Director Marc Theoret advocated for conducting trials in regions such as sub-Saharan Africa and Latin America as the data may be generalizable to the U.S. population. Theoret urged sponsors to begin thinking about diversity related issues as early as Phase 1.

Similarly, Peter Stein, director of CDER’s Office of New Drugs, also emphasized the importance of increasing early community engagement with clinical trials, admonishing that consideration of this issue requires upfront planning, tracking progress, and planning before Phase 1.

Next steps

The workshop suggests that FDA expects sponsors to think about diversity in broader strokes than simply race and ethnicity, and to carefully consider how diversity objectives can be incorporated into the entire clinical trial framework, from trial design and recruiting diverse investigators, to post-study follow-up communications to populations of interest.

Notably, FDA representatives largely steered clear of legal and regulatory comments such as the implementation date of the diversity plan requirement. This is an issue that the agency is likely to address soon, as FDORA mandates FDA issue new guidance or update existing guidance on diversity plans before the end of 2023.

Please contact one of the authors of this client alert or your Hogan Lovells attorney for assistance if you have any questions on submitting a Diversity Plan or clinical trial diversity issues more generally, or if you may wish to submit a comment to FDA on the public workshop docket.

Authored by Heidi Gertner, Robert Church, Deborah Cho, Stephanie Agu, and Akosua Tuffuor