Better Late Than Never – Unpacking FDA’s Highly Anticipated (and Long Overdue) Draft Guidance on Diversity Action Plans

The Food and Drug Omnibus Reform Act (“FDORA”), enacted in December 2022, added a requirement that sponsors submit Diversity Action Plans (“DAPs”) for certain clinical studies involving drugs, biological products, or devices (codified at 21 U.S.C. § 355(z)(3) and 21 U.S.C. § 360j(g)(9)(A)).  For drugs, the relevant studies are any Phase 3 study or, as appropriate, another pivotal study of a new drug (other than bioavailability or bioequivalence studies).  For devices, the requirement is a bit more nuanced.  A DAP is required for studies of medical devices for which an Investigational Device Exemption (“IDE”) application is required and also for those for which an IDE is not required unless the study is an “exempted investigation” under the regulations.

The statute specifies that DAPs are to include the sponsor’s goals for enrollment in the relevant study, the sponsor’s rationale for such goals, and an explanation of how the sponsor intends to meet these goals. These new requirements apply only to investigations for which enrollment commences 180 days after publication of final guidance required under this section.

The statute also states that DAPs should be “in the form and manner specified by the Secretary in guidance.”  To encourage the development of such guidance, Congress directed FDA to issue a draft guidance not later than 12 months after the date of FDORA’s enactment and to finalize such guidance not later than 9 months after closing the comment period.

FDA issued its draft guidance titled “Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies,” (the “Draft Guidance”) which replaces the previous pre-FDORA April 2022 draft guidance of the same name.  The deadline for the Draft Guidance was December 29, 2023, so the draft, issued on June 26, 2024, is about 6 months late under FDORA’s mandate.

We’ve blogged about some of FDA’s efforts to increase diversity in clinical trials previously, and the Draft Guidance itself describes a variety of these efforts.  However, this Draft Guidance, in combination with the relevant provisions in FDORA, represents potentially the biggest change to date in how industry must incorporate these efforts into development programs.

The Draft Guidance

FDA states in the Draft Guidance that unlike most guidances (including the draft guidance it replaced), the Draft Guidance, when finalized, will, in part, have the force of law because FDORA specifically dictates that the “form and manner” for the submission of DAPs are specified in guidance; thus, language regarding the form and manner of such plans in the Draft Guidance, when finalized, will have binding legal effect.

DAP Content

In developing DAPs, the Draft Guidance recommends that sponsors consider whether certain demographic groups may have a different response to a medical product regarding either effectiveness or safety.  This could be based on differential pharmacokinetics (“PK”) or pharmacodynamics (“PD”), possible differences in susceptibility to specific adverse events of concern, or due to differential presentation of the disease or condition.

A DAP must include enrollment goals for a covered clinical study, disaggregated by race, ethnicity, sex, and age group of the clinically relevant population.  Although these are the characteristics required to be included by FDORA, the Draft Guidance notes that other factors (e.g., geographic location, gender identity, sexual orientation, socioeconomic status, physical and mental disabilities, pregnancy status, lactation status, and co-morbidity) may impact outcomes.  Although not required by FDORA, FDA encourages sponsors to consider such additional factors, which may support subgroup analyses, when developing DAP goals.

The enrollment goals should be informed by the estimated prevalence or incidence of the disease or condition in the U.S. intended use population.  On occasion, greater than proportional enrollment of certain populations may be needed to elucidate potentially clinically important differences in responses between subsets of the study population.  Where there is insufficient information on incidence, prevalence, or demographics, the Draft Guidance recommends considering alternative approaches:

• Where a subset of a disease is being studied, it may be acceptable to use prevalence and incidence for the broader disease and base enrollment on the demographic characteristics of that population;
• Where the product is intended for a general use population, it may be acceptable to set enrollment goals based on general U.S. population demographics; or
• Where there are limited or no data to characterize demographic characteristics of the intended use population, it may be acceptable to set enrollment goals based on the general U.S. population demographics.

Where sponsors plan to conduct several clinical studies that may be subject to DAP requirements, the plan for each study should reflect a strategy that leads to an overall proportionate representation, even though individual studies may not.  For rare diseases, although patient numbers may be too small to detect meaningful differences in safety or effectiveness, the Draft Guidance states that consistent representative enrollment may still provide opportunities for hypothesis generation and further study.

A DAP for a multi-national clinical study must describe enrollment goals for the entire study, not just U.S.-enrolled participants, and these goals must be based on the U.S. intended use population.  Interestingly, in recent remarks at an industry conference, Commissioner Califf challenged focusing exclusively on the U.S. population in light of the U.S. role in global health.  The Draft Guidance states that FDA recognizes that the distribution of the disease or condition across the clinically relevant population may differ by geographic region based on several factors (including risk factors, screening practices, and available treatments), and recommends engaging early with FDA review divisions to discuss how to address these factors in the DAP.

DAP Goal Rationales

The sponsor must also provide a rationale for the study’s proposed enrollment goals, including information and analysis to explain how these goals were determined.  As such, the sponsor should include background information on the disease or condition, as well as prevalence and incidence estimates, if available, and any other background information justifying the enrollment goals.  Where a sponsor intends to conduct several clinical studies to support a marketing authorization that may be subject to DAP requirements, the DAP for each study should describe how the enrollment goals of the individual study fit into the sponsor’s goal of having an overall proportionate representation across all of the planned clinical studies, the sponsor’s rationale for the different enrollment goals for each study, and how the individual studies are intended to contribute to the overall enrollment goals for the clinical development program.

For drugs, the rationale should describe data and information, if any, that suggest the potential for differential safety and effectiveness across the clinically relevant population, such as possible differences in PK or PD. Sponsors should describe the relevancy of other characteristics that available data suggest have an impact on clinical outcomes (e.g., socio-economic status, geographic location, comorbidities).

For devices, the rationale should describe data and information, if any, about the potential for differential safety and effectiveness of the device across the clinically relevant populations and available data regarding differences expected to impact safety or effectiveness (e.g., by sex, age or by genetic variations).  Similar to the requirement for drugs, sponsors of device clinical trials should describe, as applicable, the relevance of other population-level or individual characteristics that may impact clinical outcomes (e.g., socio-economic status, geographic location, comorbidities).  Data on relevant factors for device performance (e.g., phenotypic, anatomical, technological, or biological factors) should be evaluated to characterize any differential effects across a diverse population by the relevant demographic characteristics.

Measures to Meet Enrollment Goals

Sponsor plans to meet the specified enrollment goals, including a description of enrollment and retention strategies for the study population, should also be included in the DAP, as well as specific measures to accomplish these goals.  FDA encourages sponsors to consult patients and healthcare providers to assist in developing such strategies.  Examples of these strategies include:

• Sustained community engagement;
• Providing cultural competency and proficiency training for investigators and research staff;
• Improving study participant awareness and knowledge of the clinical study (e.g., providing language assistance);
• Reducing participant burden (e.g., avoiding unnecessary procedures, imaging, and laboratory tests; employing sites for procedures and laboratory tests that are convenient to the specific populations in the enrollment goals; providing transportation assistance; providing dependent care; allowing flexible hours for study visits; reimbursement for costs incurred);
• Limiting study exclusion criteria, selecting study site locations that would facilitate enrollment of a representative study population, and considering accessibility needs of persons with disabilities; and,
• Employing clinical study decentralization when appropriate.

A plan to monitor enrollment goals during the study to help ensure goals are met and to facilitate prompt intervention to address barriers to meeting such goals should also be included.

Timelines for Submission

Drug sponsors must submit their plans to the Investigational New Drug (“IND”) no later than the date on which the sponsor submits the protocol to FDA for the relevant study.  In the Draft Guidance, FDA recommends submitting the DAP earlier when the sponsor is seeking feedback regarding the applicable clinical study (typically at the End-of-Phase 2 meeting).  Sponsors may discuss DAPs with FDA sooner.

For device clinical studies, a DAP must be included at the time of an IDE submission, if applicable. Sponsors of certain studies where an IDE submission is not required are should submit a DAP as part of the premarket notification (e.g., 510(k) submission, De Novo classification request, Premarket Approval (“PMA”) application).

Procedures for Submitting the DAP

Sponsors should describe the DAP clearly and concisely, with limited cross-referencing to previously submitted documents.  The Draft Guidance states that the length should generally not exceed 10 pages, excluding references.  For drugs, the relevant CDER/CBER Division may or may not provide feedback; sponsors with specific questions may include them as a topic for discussion in meetings with FDA.

The status of the DAP submission and any interactions with FDA regarding the DAP should be included in the regulatory history for milestone meetings and marketing submissions.  IND annual reports should also include updates on progress toward meeting enrollment goals; this should include any plans to mitigate outcomes where goals are not on track to be met.

In marketing application submissions, sponsors should provide a brief overview of the DAP, an assessment of whether the relevant enrollment goals were met, and, as appropriate, an explanation of what measures may have contributed to the observed outcomes with respect to the enrollment goals.

For device studies, FDA considers the DAP to be a part of the overall process for generating clinical evidence for the subject device.  Therefore, a sponsor may seek FDA feedback through the Q-submission process before submitting a DAP as part of the IDE application for studies of SR devices.  FDA expects that DAPs for studies not requiring IDE applications may be developed without FDA feedback.

DAP Waivers

According to FDORA, some or all the requirements for a DAP may be waived based on the prevalence or incidence of the disease or condition, because such a plan would make the conduct of a clinical trial impracticable, or because a waiver is necessary to protect public health during a public health emergency.

FDA may waive a requirement either on its own initiative or at a sponsor’s request, and the appropriateness of a waiver is a case-specific determination.  However, the Draft Guidance states that full or partial waivers will only be granted in rare instances.  FDA generally does not intend to waive requirements even if the disease or condition is relatively homogenous.  Instead, this information can be included in the rationale supporting enrollment goals in the DAP.  Recent comments by FDA officials have made it clear that FDA expects that waivers will be rare.

FDA is required to issue a written response to a waiver request within 60 days of receipt.  Therefore, requests should be submitted no later than 60 days before the DAP is required for submission.  FDA strongly encourages sponsors to discuss plans for a waiver early in the planning stages of the study or development program.  If FDA determines that a waiver will be issued, it may consider public communications about the decision.

Analysis

The goal of this Draft Guidance, and DAPs more broadly, is laudable, and we applaud efforts by Congress and FDA to expand involvement in medical product development to populations that have been historically excluded or underrepresented.  Moreover, it is extremely important to understand as best as reasonably possible how medical products affect all populations that may use them.  DAPs for clinical trials are not new inventions, as previously mentioned; however, the new mandates under FDORA are designed to shift these plans from “should” to “must.”

Some unanswered questions remain.  Since it is only the submission of the plan that is required by law, how, if at all, will FDA communicate that a plan does not meet the requirements for submission?   A sponsor could conduct a study that is not initially viewed as pivotal but which ends up being so for its marketing application.  What if no DAP was provided or implemented for that study based on its initial objectives?  It seems like it would be prudent for a sponsor who believes a study could even potentially be pivotal to submit a DAP, even if such possibility appears remote.  The potential cost of not submitting a plan as required by law would appear to outweigh the risk of any potential downside; however, sponsors should assess whether this is the case for their development programs.

It is also not clear what happens if the goals in the DAP are not met.  The current requirements are limited to having a DAP – it remains to be seen how FDA will evaluate whether or what actions it might take if goals are not met or if FDA concludes adequate good faith efforts were not employed to implement the DAP.  The statute and Draft Guidance do not provide for penalties or consequences.  Would any such failure to meet DAP goals be reflected in labeling?  Could the FDA require a post-marketing commitment on a sponsor to conduct another clinical trial that enrolls appropriately diverse patient populations under the original or a revised DAP or could a potential risk signal for a certain population trigger a post-marketing requirement?  Or maybe we will see an increased utilization of and reliance on registries and other real-world evidence to gather this information in the post-market setting.

Another question is the impact on rare disease drug development, where broader populations are small and there may be limited knowledge about differential impacts of disease.  Senior FDA leadership recently described an intention to be “sensible” regarding how to approach these concerns for rare diseases to avoid “slow[ing] down development by significant amounts because of this.”  As the Draft Guidance describes that waivers will be rare, what does this mean for flexibility on the enrollment goals for clinical trials for rare diseases subject to DAP requirements?

Requiring DAPs is an important first step in ensuring that the clinical studies supporting marketing authorization include information about the broad array of individuals who may be treated with new medical products. Nevertheless, implementation will not necessarily answer questions about other under-represented populations, such as multiracial individuals, who according to the 2020 US census, account for 10% of the population or under-represented populations that are not defined on race, ethnicity, sex, or age, such as pregnant and lactating persons who have historically been excluded from clinical research. The Draft Guidance encourages sponsors to consider factors beyond racial and ethnic demographic characteristics when developing DAP enrollment goals, but without clear expectations to enroll these populations, they may continue to be excluded from clinical research.

While the Draft Guidance encourages sponsors to consider many dimensions of clinical trial diversity, even those that extend beyond ethnicity, sex, and race, to enroll populations that represent the patients who will be treated if the product is approved, the question remains how far the Draft Guidance will actually move the needle and result in the data necessary for these patients and their physicians to make informed treatment decisions.  We hope the answers to these and other questions are coming.  As with any new program, it is likely that certain kinks will have to be worked out as we go along.

Comments on the Draft Guidance can be submitted to the docket through September 26, 2024.  This means, under Congress’s direction in FDORA, the FDA should be trying to finalize the Draft Guidance around June 2025.  If FDA meets this timeline, the requirement to submit DAPs for relevant clinical studies would begin around the end of 2025.