The Food and Drug Omnibus Reform Act of 2022 (“FDORA” or the “Act”), signed into law on December 29, 2022,[1] required, in part, drug and device manufacturers to submit Diversity Action Plans to the U.S. Food and Drug Administration (FDA) for certain clinical studies involving drugs, biological products, and devices, unless otherwise waived or excepted.[2]

Such Diversity Action Plans needed to clearly outline the clinical study sponsor’s goals, rationale, and approach for enrolling participants who are members of historically underrepresented populations to help improve the strength and generalizability of the evidence for the intended use population. The Act also required FDA to issue or update guidance on the content of the Diversity Action Plans within one year.

On June 26, 2024—nearly a year and a half after FDORA was enacted—FDA issued the long-anticipated draft guidance, titled “Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies Guidance for Industry” (the “Draft Guidance”), to comply with the Act’s requirements and assist sponsors in submitting their Diversity Action Plans. The Draft Guidance, once finalized, will replace FDA’s April 2022 guidance on diversity plans for clinical studies. 

The Draft Guidance is one of FDA’s many ongoing efforts to address the participation of underrepresented populations in clinical trials. According to the press release that accompanied the Draft Guidance, “Enhancing diversity within clinical studies not only facilitates broader applicability of results across a broad spectrum of patient populations, but also enhances understanding of the disease or medical product under study, thus providing valuable insights to inform the safe and effective use of the medical product among patients.”

FDA clarifies in the Draft Guidance which clinical studies require Diversity Action Plans, what should go into a Diversity Action Plan, and how and when Diversity Action Plans should be submitted to FDA. Additionally, FDA includes a helpful appendix that summarizes the elements of a Diversity Action Plan for sponsors.

Notably, the agency did not comment on the consequences if a sponsor fails to meet its enrollment goals, including whether noncompliance could slow the drug or device approval process. FDA instead simply stated, “If such goals are not on track for being met at the conclusion of the study, the status report should include a description of the reason(s) the sponsor is not currently meeting or does not expect to meet enrollment goals and the sponsor’s plan to mitigate such an outcome.”

Like other FDA guidance, the Draft Guidance includes largely non-binding recommendations from the agency (with the exception of certain portions of Section VII). However, once it is finalized, the Draft Guidance is expected to strongly influence sponsors’ approach to clinical study recruitment, enrollment, and diversity. As FDA made clear in its press release, “Generating data for a broader and more representative population early in the clinical development program is among the FDA’s priorities to bring innovative medical products to the public.”

This Insight summarizes the contents of the Draft Guidance as well as additional implications for the industry.

Summary of the Draft Guidance

Clinical Studies Requiring Diversity Action Plans

Drugs:

• A Diversity Action Plan is required for a clinical investigation of a new drug that is a phase 3 study or, as appropriate, another pivotal clinical study of a drug (other than a bioavailability or bioequivalence study).

Devices:

• A Diversity Action Plan must be included in the Investigational Device Exception (IDE) application for clinical studies of a device requiring an IDE.
• A Diversity Action Plan is required for clinical investigations of medical devices that do not require an IDE application, except for studies that are exempt from the requirements of the IDE regulations under 21 CFR 812.2(c). Such Diversity Action Plans must be submitted to FDA in any premarket notification, request for classification, or application for premarket approval (PMA).

  Although medical device postmarketing clinical studies are outside the scope of the Draft Guidance, FDA emphasizes that it considers diversity and representative patient enrollment to be important in postmarketing clinical studies of devices. In fact, the Draft Guidance specifically references FDA’s authority to require certain enrollment expectations for post-approval and postmarket surveillance studies, signaling that FDA may expect these Diversity Action Plans for postmarket device studies in the future.       

Importantly, while FDORA stated that the requirement for submitting a Diversity Action Plan applies to clinical studies for which enrollment commences after 180 days from the publication of the final guidance, FDA recognizes in the Draft Guidance that “sponsors engage in study planning and implementing study activities prior to when enrollment commences” and carves out certain exceptions to this submission timeframe.

What Goes Into a Diversity Action Plan?

A Diversity Action Plan must include:

• the sponsor’s goals for enrollment in the clinical study disaggregated by race, ethnicity, sex, and age group of clinically relevant study populations;
• the sponsor’s rationale for such goals; and
• the sponsor’s explanation of how the sponsor intends to meet such goals.

Addressing Age, Ethnicity, Sex, and Race:

A Diversity Action Plan must include the sponsor’s rationale and patient enrollment goals based on age, ethnicity, sex, and race. FDA directs sponsors to “consider whether certain demographic groups (e.g., older patients, pediatric patients, females, a particular race or ethnic group, or combinations thereof) may have a different response to the medical product—either differential effectiveness or safety . . . .” FDA notes that it may be necessary in some instances to increase the proportional enrollment of certain populations in the clinical study to effectively evaluate outcomes of interest or other clinically relevant factors in that group.

Enrollment Goals:

• While the Draft Guidance recognizes that Diversity Action Plans, consistent with Section 3602(a) of FDORA, are primarily focused on the enrollment and retention of a clinically relevant study population, to help ensure adequate representativeness of study participants that reflect different age groups, sexes, and racial and ethnic demographic characteristics, FDA encouraged sponsors to also consider other factors that impact health disparities (e.g., geographic location, gender identity, sexual orientation, socioeconomic status, physical and mental disabilities, pregnancy status, lactation status, and co-morbidity) when developing enrollment goals.
• Enrollment goals should be informed by the estimated prevalence or incidence of the disease or condition in the U.S. intended use population for which the medical product is being studied. Any deviation from this estimated prevalence must be rationalized in the Diversity Action Plan.
• Sponsors conducting several clinical studies to support a single marketing authorization must prepare a Diversity Action Plan for each study, and such plans should reflect a strategy that leads to an overall proportionate representation, even though individual clinical studies may not have proportionate representation.
• Sponsors are encouraged to use appropriate available sources, both public (e.g., registries, epidemiological surveys, published literature, etc.) and non-public, with appropriate rationale and citation, to obtain information about the estimated prevalence or incidence of the disease or condition across the affected population.
• Where there is limited or no data available to characterize the incidence and/or prevalence of the disease or condition, or the demographic characteristics of the intended population, sponsors should consider:
  • broader disease population and incidence/prevalence information, and
  • general U.S. population demographics.
• Globally conducted clinical development programs should be designed with appropriate consideration given differences in disease characteristics, medical practice, and available therapies when selecting foreign clinical sites and defining geographic regions.

Rationale for Enrollment Goals:

A Diversity Action Plan must include a description of the general approach and rationale for achieving the Diversity Action Plan’s aims, which should include the methodology used to derive target enrollment goals. Sponsors should include citations for the sources of all data and information upon which rationales for enrollment goals are based. Such rationales should include, among other things:

• Background information necessary to understand the disease or condition for which the drug or device is being investigated, including an overview of the natural history of the disease or condition and risk factors, as well as prevalence and incidence estimates, if available.
• Any other background information that justifies the enrollment goals.
• If a sponsor plans to conduct several clinical studies to support a single marketing submission, the sponsor may opt to specify enrollment goals across the planned clinical studies. A sponsor’s rationale for having different enrollment goals across planned studies must be included in the Diversity Action Plan; the rationale provided should indicate how individual clinical studies are intended to contribute to the overall enrollment goals for the clinical development program for the medical product . . . .

Measures to Meet Enrollment Goals:

A Diversity Action Plan should also include a description of the enrollment and retention strategies for the study population. This section of the Diversity Action Plan should focus on specific measures that address the enrollment and retention of participants in the particular clinical study for which the Diversity Action Plan is developed. FDA encourages sponsors to consult patients and health care providers as part of the Diversity Action Plan development process. The Diversity Action Plan should also include a description of the sponsor’s plan to monitor enrollment goals during the conduct of the clinical study to help ensure that goals are met.

Examples of clinical study enrollment and retention strategies provided by FDA include:

• implementing sustained community engagement;
• providing cultural competency and proficiency training for clinical investigators and research staff;
• improving study participant awareness and knowledge of the clinical study (e.g., providing language assistance for persons with limited English proficiency);
• reducing participant burden;
• improving access to the clinical study by limiting clinical study exclusion criteria, selecting clinical study site locations that would facilitate enrollment of a representative study population, and considering the accessibility needs of persons with disabilities; and
• employing clinical study decentralization when appropriate.

Timelines and Procedures for Submitting Diversity Action Plans

The Draft Guidance requires sponsors to incorporate Diversity Action Plans into their clinical study protocols within specified timelines as dictated by FDORA’s, and by extension, the Food, Drug, and Cosmetics Act’s, statutory requirements and provides procedures for submitting the plans to FDA.

Drugs: 

• Sponsors must submit the Diversity Action Plan for a relevant Investigational New Drug (IND) application “as soon as practicable” and, at minimum, upon submission of phase 3 study protocol or other pivotal study protocol.
• FDA notes that FDA will exercise discretion on whether to provide feedback on a Diversity Action Plan, but sponsors may request such feedback or discuss specific questions in meetings with FDA.
• The Draft Guidance contemplates that modifications and status reports regarding the Diversity Action Plan will occur throughout the course of a study. Sponsors are expected to provide progress updates about the Diversity Action Plan in annual IND reports and are permitted to submit modifications to a Diversity Action Plan with an explanation of the changes.

Devices:

• For device studies requiring an IDE application submission, the Diversity Action Plan must be submitted with the IDE application. For all other device studies requiring a Diversity Action Plan, the Diversity Action Plan should be submitted as part of the device’s premarket notification (510(k)), PMA application, or De Novo classification request.
• FDA states that it will consider the Diversity Action Plan for a clinical study “a constituent part of the overall process for generating clinical evidence for the subject device.”
• For device studies that require development of a Diversity Action Plan but do not require an IDE, the Draft Guidance states that FDA anticipates the Diversity Action Plan will often be developed without FDA’s input, although pre-submission of the Diversity Action Plan may be appropriate where the sponsor has specific questions that will guide the development of the device and/or the related submission materials.
• In the case of device studies requiring an IDE application, modifications to the Diversity Action Plan following approval of the IDE application will be considered to be similar to other types of changes made to the approved study.

For both drugs and devices, the Draft Guidance outlines the relevant information that should be included with the submission of the Diversity Action Plan (e.g., the drug or device name and relevant submission numbers), along with processes for submitting a cover letter to alert FDA of the submission. FDA generally encourages sponsors to engage in proactive communication with the agency through meetings or submissions to seek feedback on Diversity Action Plan development and ensure alignment with FDA expectations.

Requesting Waivers

The Draft Guidance states that, in most cases, FDA expects that submission of a Diversity Action Plan will be possible in accordance with the Draft Guidance, indicating FDA’s firm stance on increasing enrollment diversity. However, FDA acknowledges that there are certain “rare instances” in which FDA may waive the Diversity Action Plan requirement if certain statutory criteria are met, including:

• necessity based on the prevalence or incidence of the disease or condition in the United States, including the patient population that may use the drug or device under development;
• impracticality of conducting the clinical study in accordance with a Diversity Action Plan; or
• necessity based on protecting public health during a public health emergency.

Public Posting

In an effort to further promote transparency, FDA strongly encourages sponsors to consider sharing strategies for meeting their Diversity Action Plan enrollment goals with the public—namely, their 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.

Implications for Industry

With the exception of certain portions of Section VII of the Draft Guidance (which specify the form and manner for submission of Diversity Action Plans and will be legally binding once the Draft Guidance is finalized), the Draft Guidance clarifies, as with all FDA guidance, that it does not establish legally enforceable responsibilities, but rather describes FDA’s current thinking on Diversity Action Plans and should be viewed only as recommendations.

Notwithstanding the above, sponsors would be well advised to note this Draft Guidance and the suggestions outlined therein. Because FDORA imposes a statutory requirement on sponsors to submit Diversity Action Plans to FDA, the failure to submit such plans in accordance with FDA’s expectations could result in the agency’s rejection of a sponsor’s plan. As noted above, while FDA has not commented on these potential outcomes, it is plausible that such rejection could consequently lead to delays in clinical study and drug or device approval timelines.

Furthermore, while the U.S. Supreme Court’s recent decision in Loper Bright Enterprises v. Raimondo overruling the Chevron doctrine is not the focus of this Insight, its impact on the deference that was afforded to federal agency interpretations warrants acknowledgment in the context of this Draft Guidance. Although the broader implications of the ruling (i.e., how much deference courts will apply to the agency’s standards, processes, and enforcement in the context of such challenges) remain to be seen, the Loper decision leaves the door open for more frequent, and potentially successful, challenges to FDA’s interpretations of statutory ambiguities.

Comments to the Draft Guidance can be submitted electronically at https://www.regulations.gov/document/FDA-2021-D-0789-0111. The last day to submit comments is September 26, 2024.

ENDNOTES

[1] A copy of the Act (H.R. 2617) is available at 1349, https://www.congress.gov/117/bills/hr2617/BILLS-117hr2617enr.pdf.

[2] This provision of FDORA was later incorporated into the Food, Drug, and Cosmetics Act (FDCA). See Section 505(z) of the FDCA for drugs and Section 520(g)(9)(B) of the FDCA for devices.

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