Summing Up The FDA's Long-Anticipated Draft Guidance On Diversity Action Plans
By Marylana Saadeh Helou, health care and life sciences partner, Epstein Becker & Green, P.C.
Nearly a year and a half after the Food and Drug Omnibus Reform Act of 2022 (FDORA, or the Act) was enacted, the FDA issued on June 24 its long-anticipated draft guidance, “Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies Guidance for Industry.” The draft guidance, one of the FDA’s many ongoing efforts to address the participation of underrepresented populations in clinical trials, once finalized, will replace FDA’s April 2022 guidance on diversity plans for clinical studies.
FDORA, which was signed into law on Dec. 29, 2022, required, in part, that drug and device manufacturers submit Diversity Action Plans (DAPs) to the FDA for certain clinical studies involving drugs, biological products, and devices, unless otherwise waived or excepted. (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.) Such DAPs 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 the FDA to issue or update guidance on the content of the DAPs within one year.
The draft guidance clarifies which clinical studies require DAPs, what should go into a DAP, and how and when DAPs should be submitted to the FDA. Additionally, the FDA includes a helpful appendix that summarizes the elements of a DAP. Notably, however, 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Like other FDA guidance, this draft guidance includes largely nonbinding recommendations from the agency (except certain portions of Section VII). That said, once it is finalized, the draft guidance is expected to strongly influence sponsors’ approach to clinical study recruitment, enrollment, and diversity. As the 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.”
Comments on the draft guidance can be submitted electronically until Sept. 26, 2024. Sponsors are encouraged to read the draft guidance critically and to submit comments to the FDA to request clarification on certain of the FDA’s recommendations.
Below is a summary of the contents of the draft guidance as well as additional implications for the industry.
Clinical Studies Requiring DAPs
Drugs:
- A DAP is required for a clinical investigation of a new drug that is a Phase 3 study or is a pivotal clinical study of a drug.
Devices:
- A DAP must be included in the Investigational Device Exception (IDE) application for clinical studies of a device requiring an IDE.
- A DAP 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 DAPs must be submitted to the FDA in any premarket notification, request for classification, or application for premarket approval (PMA).
Importantly, while FDORA stated that the requirement for submitting a DAP applies to clinical studies for which enrollment commences after 180 days from the publication of the final guidance, the FDA recognizes in the draft guidance that “sponsors engage in study planning and implementing study activities before when enrollment commences” and carves out certain exceptions to this submission time frame.
What Goes Into A DAP?
A DAP 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 DAP 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, [...], or due to differential presentation of the disease or condition.” 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 DAPs 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, the FDA encourages 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 comorbidity) 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 DAP.
- Sponsors conducting several clinical studies to support a single marketing authorization must prepare a DAP 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 DAP must include a description of the general approach and rationale for achieving the DAP’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 DAP; 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 DAP should also include a description of the enrollment and retention strategies for the study population. This section of the DAP should focus on specific measures that address the enrollment and retention of participants in the particular clinical study for which the DAP is developed. FDA encourages sponsors to consult patients and healthcare providers as part of the DAP development process. The DAP 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.
Timelines And Procedures For Submitting DAPs
The draft guidance requires sponsors to incorporate DAPs 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 DAP for a relevant IND application “as soon as practicable” and, at minimum, upon submission of Phase 3 study protocol or other pivotal study protocol.
- FDA notes that the FDA will exercise discretion on whether to provide feedback on a DAP, but sponsors may request such feedback or discuss specific questions in meetings with the FDA.
- The draft guidance contemplates that modifications and status reports regarding the DAP will occur throughout a study. Sponsors are expected to provide progress updates about the DAP in annual IND reports and are permitted to submit modifications to a DAP with an explanation of the changes.
Devices:
- For device studies requiring an IDE application submission, the DAP must be submitted with the IDE application. For all other device studies requiring a DAP, the DAP 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 DAP for a clinical study “a constituent part of the overall process for generating clinical evidence for the subject device.”
- For device studies that require the development of a DAP but do not require an IDE, the draft guidance states that the FDA anticipates the DAP will often be developed without the FDA’s input, although pre-submission of the DAP 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 DAP 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 DAP (e.g., the drug or device name and relevant submission numbers), along with processes for submitting a cover letter to alert the FDA of the submission. FDA generally encourages sponsors to engage in proactive communication with the agency through meetings or submissions to seek feedback on DAP development and ensure alignment with FDA expectations.
Waivers
Although FDA expects that submission of a DAP will be possible in accordance with the draft guidance in most instances, it acknowledges that there are certain “rare instances” in which it may waive the DAP requirement, including (i) necessity based on the prevalence or incidence of the disease or condition in the U.S., including the patient population that may use the drug or device under development; (ii) impracticality of conducting the clinical study in accordance with a DAP; or (iii) necessity based on protecting public health during a public health emergency.
Implications For Industry
Except certain portions of Section VII of the draft guidance (which specify the form and manner for submission of DAPs 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 DAPs 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 DAPs 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 the 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.
Epstein Becker Green attorneys Kate Gallin Heffernan, Olivia K. Plinio, Laura J. DePonio, and Brooke A. Mangiarelli also contributed to the preparation of this article.
About The Author:
Marylana Saadeh Helou, JD is a health care and life sciences partner at the law firm Epstein Becker & Green, P.C. She advises academic medical centers, pharmaceutical and medical device companies, digital health companies, and other health care technology companies on a comprehensive range of issues affecting biomedical research. Attorney Helou’s experience includes counseling on the structure of research agreements for multi-site global industry-sponsored clinical trials and strategic research collaborations, and assisting clients in the drafting and negotiation of such agreements and related informed consent forms and authorizations. She advises clients on complex and evolving regulatory issues and considerations related to structuring decentralized clinical trials, mobile app/device research, and repositories for health data, genomic, and biospecimen research, including navigating secondary uses of stored materials, and psychedelic research. She also regularly advises clients on FDA requirements for clinical investigations, treatment with investigational products under the FDA’s Expanded Access Program and Right to Try laws.