Diversity action plans: Stakeholders seek clarity on demographic data, enrollment, and global trials

The more than 130 comments responding to the US Food and Drug Administration’s (FDA) draft guidance on clinical trial diversity were largely positive, with stakeholders wanting more information on the types of studies that require a Diversity Action Plan (DAP), alignment on data collection categories for demographics, applicability of DAP requirements to global trials, and what happens if sponsors fail to meet the outlined DAP requirements.

FDA’s draft guidance, released in June, served as an update for the agency’s 2022 draft guidance on the same topic and focuses on the types of products that require a DAP, the content of the plans, timelines for submitting DAPs, and how to address factors such as race, ethnicity, sex, and age group in DAPS. The draft guidance also covers the public posting of key information from DAPS by sponsors and how to receive a DAP waiver. (RELATED: FDA issues diversity action plan draft guidance, Regulatory Focus 26 June 2024)

Key issues raised by commenters in response to the draft guidance included requests for clarification on enrollment goals, requests for examples of situations that do and do not require a DAP, alignment of race and ethnicity categories with established definitions, the potential inclusion of other categories and acknowledgement of intersectionality, whether the draft guidance could be successfully applied to global trials and products for rare diseases, and that the draft guidance is unclear about when DAP requirements are not met.

Enrollment goals, aligning definitions, data gaps

The American Medical Association (AMA) said that it wants FDA to align this guidance and others with the Office of Management and Budget’s Statistical Policy Directive No. 15, which “incorporates many of the recommendations we previously provided to the Office of Management and Budget in 2023, including the adoption of a single combined question on race and ethnicity.” Other groups, such as the American Geriatrics Society, encouraged FDA to take this approach. AMA also recommended FDA “encourage the disaggregation of demographic data for historically minoritized and marginalized populations, as outlined in Policy Directive 15.”

The Biotechnology Innovation Organization noted that the agency should offer an example of an enrollment goal with disaggregation by required categories of race, ethnicity, sex, and age. “This would clarify the Agency’s DAP expectations, especially for enrollment goal categories that were previously not commonly utilized by sponsors,” they said.

Women of Color in Pharma also recommended disaggregating the data, rather than providing an annual aggregated report. “This will provide the public with clear information on each Sponsor's progress towards achieving diversity goals within DAPs for pivotal studies,” they said.

The Alliance for Regenerative Medicine requested FDA clarify the need to publish DAP information with the public, recommending that “these efforts not be included as a formal DAP submission but instead discussed with the Agency during sponsor meetings to ensure alignment with FDA’s intent.”

In their comment, the Medical Device Manufacturers Association (MDMA) said the draft guidance does not provide examples of how to address data collection issues and data gaps, pointing out that in some jurisdictions, certain demographic information is not permissible to collect, or may be restricted to certain populations sponsors are able to enroll.

MDMA as well as several other groups such as the Alliance for Regenerative Medicine asked FDA to consider the option of grouping race and ethnicity categories in situations where the global data are not aligned with the US.

“We recognize that the Agency recommends that enrollment goals for a diversity action plan should be informed by the estimated prevalence or incidence of the disease or condition in the U.S. population for which the device is being studied, allowing sponsors to utilize claims data as an available source to obtain information about the estimated prevalence or incidence of a disease or condition. However, a lack of appropriately disaggregated data sources may present challenges for developing diversity action plans under this approach,” MDMA said. “The final guidance should make clear that manufacturers may establish goals using certain combined categories where supported by appropriate rationale (e.g., literature references).”

The Pharmaceutical Research and Manufacturers of America (PhRMA) agreed that race and ethnicity terminology in non-US countries can differ in addition to data collection and data use practices, which can cause issues for developing a DAP. “We recommend that FDA define key terminology in the final guidance and initiate a process to achieve longer-term international harmonization on these terms,” they said.

Commenting on the nature of collecting imperfect data, IQVIA said it is key to set appropriate goals to achieve “lasting success and progress,” and noted that “committing to the enrollment goals in the absence of certainty” is a chief concern among sponsors. “While this is understandable, we believe that data does not have to be perfect to estimate goals – as long as there is flexibility with how goals are set and achievement is calculated,” IQVIA wrote. “Available prevalence data will likely never be perfectly applicable and setting goals will always need to be done in context of each target patient population, which is where thoughtful analysis and critical thinking are important.”

Clarity on DAP requirements

A number of commenters asked FDA to clarify certain requirements around DAPs, such as the definition of a new drug and a pivotal study where FDA requires DAPs, or whether a DAP is required for multiple studies.

“The definitions of these terms are critical to allowing sponsors to evaluate which clinical studies will require a DAP,” PhRMA wrote. “PhRMA recommends that the final guidance acknowledge that a single DAP covering multiple studies evaluating a specific indication or condition may be appropriate or encouraged in some situations; if a single DAP is submitted, PhRMA recommends that the enrollment goals for each pivotal study may be presented individually.”

Writing to FDA, the Advanced Medical Technology Association (AdvaMed) requested more information about specific situations where Investigational Device Exemptions (IDEs) may or may not require DAPs. “[T]here are instances where an IDE is required, but the study is not designed to collect definitive evidence of the safety and effectiveness of the device. Therefore, submitting a DAP for such studies would not provide meaningful value,” they explained. MDMA noted that the final version of the guidance “should provide sponsors the flexibility to design diversity action plans that are relevant to their specific device types and indications, with appropriate rationale.”

The Alliance for Regenerative Medicine and BIO also requested FDA consider supplemental data collection and/or the use of real-world evidence in situations where products are intended for a small patient population, such as in the case of novel cell and gene therapies or rare diseases.

Definitions of gender and sex

In their comment, the Society for Women’s Health Research (SWHR) expressed their support for including sex as a biological variable in the guidance. “SWHR supports studying, analyzing, and reporting on biological sex as standard practice across all research, including clinical trial research. Recognizing the role of Sex as a Biological Variable (SABV) is essential to ensuring that the scientific enterprise is accurately interpreting, validating, and implementing research results, and it is critical for reducing disparities in our understanding of women’s health,” they said.

SWHR encouraged the agency to clarify terminology around biological sex and gender identity. “Clear and standard definitions will help ensure consistency in studies and regulatory processes, allowing for more accurate data collection and analysis,” they said. “Doing so will not only help to ensure social inclusivity but will also help ensure research accuracy and precision.”

BIO also raised concerns that there are ambiguities in how the draft guidance defines gender and sex, sometimes using them interchangeably. “It is important that these terms are used carefully throughout the guidance. It will be helpful for the final guidance to clarify whether the Agency will consider inclusion of gender (and other Sexual Orientation and Gender Identity data) to contribute to diversity enrollment goals,” they said.

Expansion of data collection

Several commenters requested FDA expand the data being collected in DAPs. The American Academy of Pediatrics acknowledged FDA’s consideration of other factors like geographic location and socioeconomic status, but noted that they are currently “optional considerations in already voluntary guidance.” They also asked FDA to consider factors like language, insurance status, disability, and immigration status in addition to requesting clarity on race, ethnicity, sex, and age categories.

The American Geriatrics Society requested FDA include more representation of older adults, particularly for products intended to treat diseases that disproportionately impact older minority populations. They also noted that while FDA highlighted considerations for additional demographic factors in the draft guidance, “there is minimal guidance on how to use this data for the DAP.”

In a joint comment, the National LGBTQI+ Cancer Network and allied partner organizations asked FDA to “consider strengthening the language that encourages sponsors to add additional categories,” encouraging the agency to adopt the definitions stated in Section 1557 of the Affordable Care Act and Title IX definitions of “sex” that include subcategories for pregnancy, sexual orientation, gender identity, and sex characteristics.

SWHR and other groups also recommended FDA acknowledge intersectionality in the draft guidance. “Embedding sex and gender as well as race and ethnicity considerations into clinical research design is critical for closing the health gaps faced by women of intersectional identities,” SWHR said.

Community collaboration

Commenters highlighted community collaboration as a critical issue to identifying and enrolling patients in diverse populations. The organization Latinos in Clinical Research told FDA that Latino populations commonly prefer hybrid or entirely onsite study models because they value face-to-face interactions and communications with site staff. “In-person visits enable site staff to engage more effectively with patients, reducing the potential for errors that may arise when patients are required to use off-site technology, which could affect the quality and accuracy of their responses, ultimately reflecting it on the quality of the study data,” they wrote.

Latinos in Clinical Research also recommended DAPs be implemented from study inception, rather than by phase 3, “as attempting to meet diversity goals only in Phase 3 will likely lead to inconsistencies in data.”

The American Medical Association said FDA should encourage sponsors to consult stakeholders such as community leaders, patient advocacy groups, academic institutions, and local health organizations “early in the trial design process, regularly throughout the study, and through reporting of outcomes.”

Applicability to global trials

Many commenters requested FDA elaborate on how to apply the draft guidance to global trials. Women of Color in Pharma said they recommend the guidance be expanded to “allow enrollment of underrepresented racial/ethnic minorities living outside the US, particularly when the standard of medical care is comparable.”

However, PhRMA noted that basing enrollment goals on US prevalence or incidence data “goes beyond the statutory text of FDORA, which contemplates that goals ‘may’— not ‘must’—be based on U.S. prevalence data, and could complicate enrollment of global clinical trials.”

IQVIA stated the sponsor has typically been the one to justify achievement of enrollment goals based on US prevalence and patient characteristics. “While visibility to the overall study distribution is a valuable add to the DAP, the language seems to imply that the global study population should reflect the racial and ethnic makeup of the U.S. patient population,” they wrote. “A one-size-fits-all expectation would be fraught with challenges and unintended consequences, many counter to the goals of diversity and possibly ethical conduct.”

AdvaMed pointed out that there may be legal and ethical considerations that impede sponsors’ ability to collect demographic data, such as explicit consent provisions in the European General Data Protection Regulation (GDPR).

BIO said an interpretation of the draft guidance that bases global enrollment plans around US prevalence and incidence, “rather than local demographics and immediate patient needs” could be “impractical for sponsors for many reasons, including, as noted by FDA, the lack of uniformity in language for population descriptors across the globe.”

Accountability for not meeting DAP

The American Geriatrics Society pointed out that the DAP does not specify what occurs when a sponsor fails to meet enrollment goals. “We believe accountability would be best ensured through an enrollment analysis at the annual review of a sponsor’s trial and potential consequences of failing to meet ultimate enrollment targets,” they said.

Women of Color in Pharma noted that if there is no requirement to respond to FDA feedback of DAPs, a “public listing of compliance with current policy and/or guidance can serve as a powerful tool to self monitor.”

Regarding the potential for missing enrollment goals, AdvaMed asked FDA for “recommendations and examples for how sponsors should mitigate such an outcome.”

Citing the longstanding challenge of increasing diversity in clinical trials, BIO said sponsors will “inevitably” run into situations where they cannot meet enrollment goals “despite their good faith efforts.”

“We request that the FDA specifically acknowledge in the guidance that, on occasion, the enrollment of study participants in complete alignment with the US prevalence or incidence of a given disease may be unrealistic; despite sponsor efforts, enrollment will continue to be affected by factors outside the control of sponsors, including systemic racism, historical mistrust in clinical research, healthcare inequities, and differences in health literacy,” they wrote. “We assume that the Agency will be flexible in the setting of enrollment goals, including opportunities to revisit enrollment goals where necessary, to help ensure goals reflect what is reasonable and achievable.”

BIO added that it is “difficult to inform precise enrollment goals for each race category recommended in the draft guidance,” and asked the agency for flexibility in prevalence and incident reporting for available data sources, including the ability to use an estimated range for a subgroup rather than a proportion. MDMA expressed concern with the 180-day deadline for implementation and requested FDA use discretion in enforcement to give industry “adequate time to comply with the new requirement.”

Draft guidance

Diversity action plans: Stakeholders seek clarity on demographic data, enrollment, and global trials

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