On June 26, 2024, the U.S. Food and Drug Administration (“FDA”) released its much-anticipated draft guidance for industry entitled “Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies” (the “Draft Guidance”), which delineates FDA’s expectations regarding the types of clinical studies for which a Diversity Action Plan (“DAP”) is required as well as the format, content, and process for submitting DAPs to FDA. In late 2022, Congress granted FDA new authority to require DAPs for certain clinical studies through enactment of the Food and Drug Omnibus Reform Act (“FDORA”). The Draft Guidance fulfills a legal obligation set forth in FDORA that FDA update or issue guidance on the “format and content” of DAPs. While the Draft Guidance officially replaces FDA’s April 2022 draft guidance entitled “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials,” it is far more substantive than the earlier guidance, which was drafted prior to the enactment of FDORA.
Unlike most FDA guidance documents, which do not have binding effect, the Draft Guidance when finalized will create certain legally binding obligations on study sponsors. This is due to FDORA’s requirement that FDA specify the “form and manner” for submission of DAPs in guidance. The DAP requirements will apply to certain clinical studies for which enrollment commences 180 days after publication of the final guidance, which is due on June 26, 2025 (i.e., nine months after closure of the Draft Guidance comment period on September 26, 2024). If this timeline holds, this would likely make the DAP requirement effective for trials that begin enrollment in the final days of 2025. Clinical study sponsors should therefore expect DAP requirements to take effect in the near future and begin preparing accordingly.
This Alert summarizes key principles from the Draft Guidance and describes implications and considerations for industry.
What Is a Diversity Action Plan?
FDORA added Sections 505(z) and 520(g)(9) to the Federal Food, Drug and Cosmetic Act (“FDCA”), requiring sponsors of certain clinical studies of drugs and medical devices to submit a DAP to FDA that specifies the study’s enrollment goals, the rationale for such goals, and plans for monitoring and achieving such goals. The aim of this requirement is to increase clinical trial enrollment of populations that have historically been underrepresented in clinical studies, which has been a longtime policy goal for FDA.
The Draft Guidance, consistent with FDORA, focuses primarily on ensuring adequate representation along four aspects of diversity, namely age, sex, racial and ethnic demographic characteristics. FDA also encourages sponsors, however, to consider other facets of diversity when developing DAPs, such as geographic location, gender identity, sexual orientation, socioeconomic status, physical and mental disabilities, pregnancy status, lactation status, and co-morbidity status, to the extent such factors are relevant to the population who may use a medical product.
Which Clinical Studies Must Have a Diversity Action Plan?
Under Sections 505(z) and 520(g)(9) of the FDCA, submission of a DAP is required for a Phase 3 study of a new drug or any other pivotal clinical study of a drug. A device sponsor must submit a DAP for any clinical study of an investigational device, unless the study qualifies for an investigational device exemption (“IDE”) exemption (e.g., many in vitro diagnostic device studies). FDA does not intend to receive or review DAPs for studies not designed to collect definitive evidence of the safety and effectiveness of a device for a specified intended use. While the Draft Guidance reiterates that not all studies require DAPs (as described above), FDA strongly recommends that sponsors adopt a comprehensive diversity strategy across their entire clinical development program, including in early trials.
Content of a Diversity Action Plan
The FDCA, as amended by FDORA, specifies three required parts of a DAP, which are further discussed below:
- The sponsor’s enrollment goals, disaggregated by age group, sex, race, and ethnicity of clinically relevant study populations;
- The sponsor’s rationale for its enrollment goals; and
- An explanation of the sponsor’s plans for meeting its enrollment goals.
Enrollment Goals
According to the Draft Guidance, enrollment goals should primarily be informed by the estimated prevalence or incidence of the relevant disease or condition in the U.S. intended use population for which the drug or device is being developed. FDA recommends that sponsors use publicly available resources, such as registries that are reasonably expected to be demographically representative, published literature, and epidemiological surveys, to find information regarding the estimated prevalence and incidence of the relevant disease or condition across the affected population by age, sex, race, and ethnicity. Sponsors may also use non-publicly available resources such as electronic health records to find this information, but their plans should explain the rationale for using such resources and citations to the data.
The Draft Guidance provides recommendations for circumstances in which enrollment goals may be more difficult to determine or achieve, some of which are outlined below.
- Multiple Studies Supporting Marketing Authorization. While each clinical study supporting a marketing submission may not individually have proportionate representation, all of the clinical studies together should provide for overall proportionate representation across the development program.
- Rare Diseases. FDA acknowledges that pivotal studies of drugs and devices for rare diseases may be too small to draw meaningful comparisons among subpopulations; however, according to the Draft Guidance, representative enrollment is still necessary and important because it may over time inform hypothesis generation and further studies.
- Global Studies. For a study being conducted in multiple countries, the sponsor should describe enrollment goals for the overall study rather than being limited to the U.S.-enrolled population. The sponsor should consider the need to enroll a study population that is representative of the U.S. intended use population as part of the overall development program.
Rationale for Enrollment Goals
The Draft Guidance specifies that the rationale portion of a sponsor’s DAP should include background information on the disease or condition for which the drug or device is being investigated, including the natural history, risk factors, prevalence and incidence estimates, and any other information that may justify the sponsor’s enrollment goals. When a sponsor plans to conduct multiple studies to support marketing authorization, the rationale should explain why studies have different enrollment goals (if this is the case) and how the studies together will meet the overall enrollment goals. For both drug and device studies, sponsors should discuss any data or information that suggests a potential for differential safety and effectiveness of either the investigational drug or device among the clinically relevant population.
Plans for Meeting Enrollment Goals
The final portion of a DAP should contain a description of the sponsor’s plans for meeting its enrollment goals, including enrollment and retention strategies. The Draft Guidance provides examples of strategies for sponsors to consider, including community engagement, cultural competency and proficiency training for clinical investigators and research staff, language assistance, reducing participant burden through transportation assistance and flexible hours, limiting study exclusion criteria, selecting study sites that serve demographically diverse and relevant populations, and when appropriate, using decentralized study design. A sponsor should also describe in its DAP how it intends to monitor and track progress on the enrollment goals.
Timeline and Procedure for Submitting DAPs
Drugs. As required by Section 505(z)(3) of the FDCA, drug sponsors must submit DAPs to FDA no later than the date on which the sponsor submits the protocol for the Phase 3 study (or other appropriate pivotal study) to FDA. However, FDA encourages sponsors to submit the DAP earlier, such as at the End-of-Phase 2 meeting when discussions regarding trial design and other aspects of the clinical trial are ripe and underway. DAPs must be submitted to the investigational new drug application (“IND”) under which the applicable clinical study will be conducted. After an initial DAP submission, modifications may be submitted based on FDA feedback or at a sponsor’s own initiative. Any changes must, among other things, provide a rationale for why the adjustments are being made. As part of the IND annual report, sponsors should provide an update on their progress towards meeting DAP enrollment goals.
Devices. For device clinical studies requiring an IDE application, the DAP must be included in the application. Sponsors of studies for which an IDE application is not required must submit the DAP as part of the device’s premarket notification (510(k)), PMA application, or De Novo classification request, as applicable. If FDA’s input is needed as part of the product or submission development process, sponsors are advised to follow the Q-submission process for obtaining feedback or requesting a meeting with FDA. The approach for DAP modifications varies based on whether an IDE application was necessary for the device study to be conducted. As for drugs, device sponsors should include an update to FDA on progress toward meeting DAP enrollment goals as part of periodic reporting requirements under applicable FDA regulations.
For both drugs and devices, FDA expects DAPs to be succinct, generally not exceeding 10 pages, excluding references.
Waivers
The Draft Guidance clarifies that submission of a DAP will be possible in most cases and that a full or partial waiver of the DAP submission requirement may occur in “rare instances.” The Agency notes that it generally does not intend to waive DAP requirements even if the disease or condition under study is relatively homogenous with respect to race, ethnicity, sex, or age group. The Draft Guidance reiterates the statutory criteria for appropriateness of a waiver, which FDA will assess when considering a possible waiver:
- Prevalence/Incidence: A waiver is necessary based on what is known or what can be determined about the prevalence or incidence in the U.S. of the disease or condition for which the new drug or device is under development;
- Impracticability: The conduct of a clinical trial in accordance with a DAP would otherwise be impracticable; or
- Public Health Emergency: A waiver is necessary to protect public health during a public health emergency.
The Draft Guidance explains that, because FDA is required to issue a written response granting or denying a waiver request within 60 days of receipt, such requests should be submitted no later than 60 days before the DAP is required.
Public Posting
According to the Draft Guidance, sponsors are “strongly encourage[d]” to share with the public their strategies for meeting DAP enrollment goals. In the interest of transparency, this can include key information from the DAPs themselves, such as clinical study enrollment goals disaggregated by race, ethnicity, sex, and age group, and a brief description of the measures taken to achieve the stated goals. FDA recommends that such detail be provided in consumer-friendly language and advises that while such information may be posted at any time, if a study is still open for recruitment, it may be advisable to link to such information from a trial recruitment website or clinical trial databases such as ClinicalTrials.gov.
Implementation and Exemptions
As discussed above, the DAP requirements will attach to certain clinical studies for which enrollment begins 180 days after the publication of the final guidance. The Draft Guidance does, however, list three categories of studies for which FDA does not expect sponsors to submit a DAP:
- Clinical studies of drugs with protocols submitted within 180 days following publication of the final guidance and for which enrollment is scheduled to begin within 180 days after the final guidance;
- Clinical studies of devices received by FDA in IDE applications within 180 days after publication of the final guidance; and
- Clinical studies of devices that do not require an IDE that are approved by an institutional review board or independent ethics committee within 180 days after the date of publication of the final guidance.
Implications for Sponsors
With the new requirements expected to take effect in the coming months, clinical study sponsors should ensure that they are prepared to meet FDA’s expectations for any clinical studies that will be required to have a DAP and engage with the FDA as necessary in a timely fashion.
While neither the enabling statute nor the guidance itself provides any details on enforcement penalties should sponsors fail to meet DAP requirements, it is possible that the public posting “encouragement” could serve as a public policing mechanism. Competitors or public interest groups might call each other out in the court of public opinion for failure to share such details. It remains to be seen whether FDA will refuse to file an IND or IDE for failure to submit a DAP. Additionally, it is not yet clear how failure to meet enrollment goals specified in a DAP may impact the timeline for submission or FDA action on marketing applications.
In the Draft Guidance, FDA also encourages sponsors to consider aspects of diversity beyond those required by FDORA, such as geographic location, socioeconomic status, gender identity and pregnancy status, lactation status, and comorbidity status. Questions remain about how FDA will seek to guarantee inclusion of these additional factors in DAPs.
As sponsors seek to collect additional categories of information to satisfy their DAP requirements, such as data on study subject or prospective subject race and ethnicity, sponsors will need to be mindful of complying with requirements in U.S. state as well as ex-U.S. data privacy laws. These laws frequently treat such categories of information as sensitive information deserving of heightened protection and in some cases impose additional notice, consent and opt-out requirements with respect to the collection of such information.
The docket for the Draft Guidance is currently open for comment through September 26, 2024. Ropes & Gray will continue to monitor developments in this area. If you have any questions regarding this Alert, please contact any member of Ropes & Gray’s FDA Regulatory or Health Care practice or your usual Ropes & Gray advisor.
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