Diversity Action Plans for Clinical Studies: FDA Draft Guidance

The FDA’s draft guidance on Diversity Action Plans is open to comments at this stage (comments due by 09/26/2024). Once the final guidance is issued, it will be in effect after 180 days and sponsors will be required to submit Diversity Action Plans with certain clinical trials. Both developers of drugs (including biologics) and devices will be affected.  Unless there is an unforeseen delay, these requirements will become applicable for trials enrolling subjects by the end of 2025.

Overall, the guidance is significantly aligned for Diversity Action Plans for drugs and device products but there are differences in process and content. The main focus of Diversity Action Plans is across race, ethnicity, sex, and age, however, the guidance also encourages sponsors to consider other factors such as geographic location, gender identity, sexual orientation, socio-economic status (SES) disabilities, pregnancy and lactation status, and co-morbidity.  At this stage, there are no details on actions if enrolment goals are not met. Read on for a summary of the key points from the Guidance for Industry and an explanation of the expected content and process.

Scope – When is a Diversity Action Plan Needed?

Broadly, a Diversity Action Plan is required for studies which will be the primary basis for the FDA review of benefit–risk. More specifically:

• For Drugs (including biologics) – required for Phase 3 or other pivotal study (other than a bioavailability or bioequivalence study).
• For Devices – required for studies included in an (Investigational Device Exemption (IDE) application or when an IDE is not required, with any clinical study of the device. FDA recognises there can be many types of trials with devices and so FDA expects sponsors to develop a Diversity Action Plan for a study that is intended to serve as the primary basis for the FDA’s evaluation of safety and effectiveness and benefit-risk determination.

Progress updates are expected as part of the Investigational New Drug (IND), or IDE, annual report.

Content/format – What Should the Diversity Action Plan Cover?

Per the Federal Food, Drug, and Cosmetic Act (FD&C Act), it must include 3 sections, each section is discussed below;

1. Enrolment goals
2. Rationale for goals
3. Measures to meet goals

FDA also recommends sponsors share their Diversity Action Plan goals with the public, via the sponsor’s website in consumer-friendly language.

1. Enrolment Goals

The Diversity Action Plan must include the sponsor’s goals for enrolment in the clinical study, disaggregated by race, ethnicity, sex, and age group of clinically relevant study populations. Goals should be informed by the estimated prevalence or incidence of the condition in the US and recognised sources and methodology should be included to explain the estimates.

The FDA guidance recognises that sponsors make use of multi-regional trials for global development of FDA-regulated products. The FDA recommends that Diversity Action Plans of such programs should describe enrolment goals for the entire study and not only the US-enrolled patients. Furthermore, such programs should be designed to account for the need to enrol a population representative of the US.

Exceptions – some circumstances may require a different approach and the FDA outlines some examples such as;

• If there are multiple trials planned within a program each trial may not enrol proportionately with the wider population, but the sponsor should plan to collect data across trials that represent the condition.
• When a single pivotal trial is expected (such as in a rare disease setting) small numbers may not allow detection of safety and efficacy differences across groups despite a representative enrolment.
• If the condition is a sub-set of a broader condition and there is limited data to estimate prevalence or incidence in the sub-set then enrolment in line with the broader condition may be reasonable.
• For conditions for which there is no or very limited data regarding prevalence or incidence in the US or the product is intended for general use then the goals may be set by the general US population demographics.

2. Rationale for Goals

To meet the requirement for providing rationale sponsors must include:

• Background information such as how the product is being investigated and the natural history of the condition.
• Rationale for enrolment goals across studies if several trials will support a single marketing submission.

AND

• For Drugs – data describing potential differences across relevant populations such as in PK or PD outcomes.
• For Devices – data and information about the potential differential safety and effectiveness of the device across the intended population.

3. Measures to Meet Goals

The guidance clarifies that the Diversity Action Plan should be focussed on how this particular study will address enrolment and retention strategies to meet diversity goals. The sponsor is encouraged to consult patients and healthcare providers about this.

Examples of strategies include:

• Implementing sustained community engagement.
• Providing training to investigators on cultural competency and proficiency.
• Improving awareness for participant knowledge through language assistance.
• Reducing participant burden.
• Improving access to the study by limiting exclusion criteria and via site selection.
• Using de-centralised study approaches where possible.

This should also be accompanied by the sponsor’s plan to monitor enrolment goals during recruitment and conduct.

Timelines & Process – When Should a Sponsor Submit a Diversity Action Plan and How?

The Diversity Action Plan is expected to be succinct and to limit cross-referencing to previously submitted documents, overall not exceeding 10 pages.

For Drugs:

• Submit Diversity Action Plan to relevant IND in Module 2.5 as soon as practicable but NO later than the date of submission of Phase 3 protocol (or as appropriate, other pivotal study).
• Most effective if submission occurs in the context of design questions – FDA advises submitting as part of EOP2 meetings.
• Modifications can be made and should be accompanied by a summary of changes and justification.
• Updates on sponsor’s progress toward meeting the Diversity Action Plan goals should be included in annual reporting to FDA.
• At the marketing application stage the sponsor should provide an overview and assessment of the Diversity Action Plan as part of Module 2.5.

For Devices:

• If an IDE is required Diversity Action Plan must be included in the IDE application. For Significant Risk (SR) devices with clinical studies the Diversity Action Plan must be part of the IDE application.
• If no IDE is required – the Diversity Action Plan is submitted as part of pre-market notification. Feedback can be sought on the Diversity Action Plan pre-submission. For devices not requiring an IDE application (i.e. Non-SR) the Diversity Action Plan should be part of the 510K, PMA, or device classification request.
• Modifications can be made and should be accompanied by a summary of changes and justification.
• Updates on the sponsor’s progress toward meeting the Diversity Action Plan goals should be included in annual reporting to FDA.
• At the marketing application stage the sponsor should provide an overview and assessment of the Diversity Action Plan.

Waiver Process and Criteria – Is It Possible Not to Submit a Diversity Action Plan?

In rare instances, a sponsor may request the FDA to conduct a case-specific determination regarding the waiving of the requirement to submit a Diversity Action Plan. A full or partial waiver may be granted if defined criteria are met. Such a request can be based on the prevalence or incidence of the condition, conducting the study with a Diversity Action Plan would be impracticable, or a waiver is required to protect public health during a public health emergency. FDA is required to respond within 60 days granting or refusing the waiver request. For drugs, waiver requests should be submitted to the relevant IND in eCTD Module 1.12.5 and for Devices, a stand-alone submission is required.

Experience So Far and How Will the FDA Monitor Diversity Action Plans?

Diversity Action Plans that were submitted voluntarily to CDER  from April 2022 – April 2023 were analysed. As part of Project Equity, the Oncology Division’s analysis of the 91 DAPs submitted found that the majority of plans focussed their efforts on patient-directed measures and community engagement, followed by clinical research workforce-directed measures. This was much more common than changes to eligibility criteria or decentralised trials (Figure 1). Furthermore, of the 41% of Diversity Action Plans for which FDA feedback was sought, 90% of FDA comments were around enrolment goals.

Figure 1 – Diversity Plan Content: Planned Measures to Achieve Enrolment Goals

Project Equity – Diversity Plans – Oncology (fda.gov)

Once Diversity Action Plans are a requirement, the FDA will release a report that summarises the Diversity Action Plans received and whether the clinical studies conducted met the demographic enrolment goals. No details are provided on FDA response to Diversity Action Plans that do not meet intended goals.

Summary

With this guidance, FDA is setting the expectation for sponsors to engage in cross-program considered planning for enrolling a representative population in clinical studies. Knowledge of the condition and intended target population will drive how goals and measures are shaped. An iterative process is accommodated and should allow Diversity Action Plans to be adapted as product development progresses and a better understanding of the data is acquired. Embedding a new submission into development plans can be a challenge, the FDA advises that feedback on the Diversity Action Plan is most effective if asked alongside questions on design and endpoints. Sponsors of relevant clinical trials planning a future US filing should ensure they are prepared to meet these new requirements and be ready to engage with the FDA. DLRC Inc. have extensive experience interacting with the FDA and can assist with Diversity Action Plans and agency feedback.