Guidance Breakdown: Diversity Action Plans to Improve Enrollment from Participants from Underrepresented Populations in Clinical Studies
We break down the much-anticipated and heavily overhauled draft guidance on Diversity Action Plans, which was entirely rewritten after the FDA obtained new authority from Congress in 2022.
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In June, the FDA published a much-anticipated draft guidance that recommends more diverse patient cohorts in clinical trials and is meant to improve the data the agency receives in support of premarket applications.
It broadly describes what sponsors should include in their Diversity Action Plans as mandated by Congress.
The guidance details what should go into a sponsor’s Diversity Action Plan, which products require such plans, and how they should be submitted to the FDA. The guidance also discusses how FDA reviewers may decide whether a sponsor can waive the Diversity Action Plan requirement. When finalized, it will replace the agency’s 2022 guidance on diversity plans for clinical trials.
A Little Background and Context
The 2022 Food and Drug Omnibus Reform Act (FDORA) mandated that the FDA require certain late-stage clinical trials and other pivotal studies to include Diversity Action Plans when developing medical products, including drugs, biologics and medical devices.
“Diversity Action Plans are intended to increase enrollment of participants who are members of historically underrepresented populations in clinical studies to help improve the strength and generalizability of the evidence for the intended use population,” the new guidance states. “Such plans must specify ‘the sponsor’s goals for enrollment in [a] clinical study,’ ‘the sponsor’s rationale for such goals,’ and include ‘an explanation of how the sponsor intends to meet those goals.’”
The guidance applies to sponsors conducting clinical investigations under INDs and IDEs, as well as those submitting premarket notifications, PMA applications, and De Novo classification requests. It aims to increase the inclusion of historically underrepresented populations in clinical research, thereby enhancing the generalizability and reliability of study results.
More specifically, the Diversity Action Plan must include the sponsor’s rationale and patient enrollment goals based on age, ethnicity, sex, and race. It also urges sponsors to look beyond those factors to other demographic differences and consider how they may affect the product’s performance.
“In general, clinical study diversity helps ensure that clinical studies appropriately test the product in a representative sample of the product’s intended use population.”
”Factors to consider when setting enrollment goals include demographic characteristics (e.g., race, ethnicity, sex, age group), clinical characteristics (e.g., presence of comorbidities, disease etiology), and other characteristics (e.g., access to standard preventive and diagnostic care, access to standard treatments of the clinically relevant population).”
The FDA emphasizes the importance of integrating Diversity Action Plans early in the clinical study design process and maintaining them as living documents throughout the study lifecycle.
The FDA noted that the draft guidance was developed by the Oncology Center of Excellence Project Equity in collaboration with the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), the Office of Women’s Health (OWH), and the Office of Minority Health and Health Equity (OMHHE).
Who should pay attention to this guidance
The FDA's guidance impacts a wide range of stakeholders involved in the development and approval of medical products. Entities that should pay close attention to this guidance include:
Pharmaceutical Companies: Engaged in the development and clinical testing of new drugs, particularly those conducting Phase 3 or other pivotal studies.
Biotechnology Firms: Developing biologics and combination products that require comprehensive clinical studies for regulatory approval.
Medical Device Manufacturers: Conducting clinical investigations for significant risk and non-significant-risk devices.
CROs: Assisting sponsors in planning, executing, and monitoring clinical studies, including Diversity Action PLan development and implementation.
Regulatory Affairs Professionals: Responsible for preparing and submitting INDs, IDEs, premarket notifications (510(k)), PMA applications, and De Novo classification requests.
Clinical Investigators and Research Staff: Engaged in the design, conduct, and management of clinical trials, ensuring diverse and representative participant enrollment.
Patient Advocacy Groups and Community Health Organizations: Collaborating with sponsors to facilitate community engagement and improve study participation among underrepresented populations.
Healthcare Providers: Involved in clinical research and interested in promoting inclusive and representative clinical trials.
Public Health Officials: Overseeing clinical research initiatives and ensuring that studies reflect the demographics of the populations served.
Legal and Compliance Teams: Ensuring that clinical studies adhere to FDA regulations and guidelines regarding diversity in participant enrollment.
Clinical Studies Requiring Diversity Action Plans
The FDA breaks down Diversity Action Plans for both drugs and devices.
Drugs
A Diversity Action Plan is required for any clinical investigation of a new drug that is classified as a Phase 3 study, as defined in 21 CFR 312.21 or other pivotal studies critical for drug approval. These include trials designed to demonstrate the drug's safety and efficacy to support a marketing application. Bioavailability or bioequivalence studies do not require Diversity Action Plans.
There are a few requirements:
Enrollment Goals: Must specify the target enrollment numbers disaggregated by race, ethnicity, sex, and age.
Rationale: Provide a clear justification for these goals, considering disease prevalence and incidence in the intended population.
Measures to Meet Goals: Outline strategies to achieve the specified enrollment targets, such as community engagement and reducing participant burden.
Devices
A Diversity Action Plan must be included in the IDE application for clinical studies involving significant risk devices, as defined in 21 CFR 812.3(m). (SR devices are those that pose a potential for serious risk to the health, safety, or welfare of a subject.)
Critically, non-significant risk (NSR) device studies that do not require an IDE application are still required to develop and implement a Diversity Action Plan for premarket submissions.
The requirements are similar to those for drug sponsors:
Enrollment Goals: Like drug studies, goals must be set and justified based on the demographic characteristics of the intended use population.
Rationale: Explain how these goals were determined, considering disease or condition prevalence among different demographic groups.
Measures to Meet Goals: Include strategies such as choosing study sites that serve diverse populations and providing cultural competency training for investigators.
The guidance also covers the various submission types:
IDE Application: Required for significant risk devices.
510(k): Required for devices that do not necessitate an IDE but need FDA clearance.
PMA Application: Required for devices needing FDA approval.
De Novo Classification Requests: For devices that are novel and do not have a predicate device, requiring a classification request.
It also lays out the process for “non-IDE” studies: Sponsors must develop a Diversity Action Plan for any clinical study involving a device, even if it does not require an IDE application. They should then submit the plan as part of the device’s premarket notification, PMA application, or De Novo classification request. For device studies not requiring an IDE, it’s crucial to submit the Diversity Action Plan in any applicable premarket submission to ensure compliance with FDA requirements.
Addressing Race, Ethnicity, Sex, and Age Group in Diversity Action Plans
Effective Diversity Action Plans require careful consideration of various demographic factors to ensure that clinical study populations accurately reflect the intended use populations.
Sponsors must disaggregate their enrollment goals to reflect the demographic characteristics of the study population.
This includes providing separate targets for:
Race: Categories should align with FDA guidance on reporting race, typically including groups such as Asian, Black or African American, White, Native Hawaiian or Other Pacific Islander, and other persons of color.
Ethnicity: Categories should align with FDA guidance on reporting ethnicity, typically including Hispanic or Latino but Not Hispanic or Latino.
Sex: Categories should follow FDA guidance on reporting sex, generally categorized as male and female, with consideration for variations.
Age Group: Goals should be set for clinically relevant age groups, which may include pediatric, adolescent, adult, and older adult populations.
The FDA encourages sponsors to use appropriate data sources such as demographic registries, epidemiological surveys, and published literature to inform their disaggregation of enrollment goals. Sponsors should clearly document and justify the methodology used to set disaggregated enrollment goals, ensuring alignment with the prevalence and incidence of the disease or condition in the intended use population.
The FDA urges sponsors to consider whether certain demographic groups may have different responses to the medical products (which can include differences in effectiveness and safety profiles) and adjust their enrollment goals accordingly.
For example:
Consider potential pharmacokinetic and pharmacodynamic variations in drug metabolism and response due to genetic differences prevalent in specific racial or ethnic groups.
Assess if certain populations are more susceptible to adverse events, requiring tailored safety monitoring and reporting.
When adjusting enrollment goals, the FDA makes three specific recommendations:
If data suggests potential differences in response, sponsors should increase enrollment targets for those groups to ensure sufficient representation and robust analysis.
Take into account the varying presentations of diseases or conditions across different demographic groups, which may require adjusted enrollment targets.
Consider geographic location, socioeconomic status (SES), and other factors that may affect access to and participation in clinical studies. Strategies should be developed to mitigate barriers related to these factors.
The guidance also lays out some practical steps sponsors can take to optimize this:
Engage with the FDA early in the study design process to discuss demographic considerations and appropriate enrollment goals.
Design the study to allow for adjustments in enrollment strategies based on ongoing data and feedback.
Involve community leaders and patient advocacy groups to ensure culturally appropriate and effective recruitment strategies.
The agency even lays out some example strategies, like establishing partnerships with local health organizations to reach underrepresented populations, providing training for clinical trial staff to improve engagement and communication with diverse populations, and making sure study sites are accessible to the target populations, potentially offering transportation or childcare to reduce participation barriers.
Content of the Diversity Action Plan
This section of the guidance outlines the necessary elements of a Diversity Action Plan, including the specification of enrollment goals, the rationale for these goals, and the measures to meet them.
Enrollment Goals
The enrollment goals must be clearly specified and disaggregated by race, ethnicity, sex, and age group of the clinically relevant study population. They should reflect the intended use population and are typically informed by the estimated prevalence or incidence of the disease or condition in the U.S. population. Goals should be broken down into subsets such as Asian, Black/African American for race; Hispanic or Latino for ethnicity; male and female for sex; and appropriate age groups relevant to the study.
Rationale for Enrollment Goals
A comprehensive rationale for the enrollment goals is required to meet statutory obligations. This rationale should provide sufficient background information and analysis to explain how the goals were determined.
For drug studies:
Include data on potential differential safety and effectiveness across the clinically relevant population.
Consider genetic differences that might impact drug metabolism or susceptibility to adverse reactions.
Take into account population-level or individual characteristics such as socioeconomic status, geographic location, and comorbidities that might affect clinical outcomes.
For device studies:
Describe potential differential safety and effectiveness, relevant genetic differences, and other factors such as phenotypic, anatomical, technological, or biological factors that could impact device performance.
Provide citations for the sources of data and information used to establish these goals, ensuring transparency and robustness in the approach.
Measures to Meet Enrollment Goals
To achieve the specified enrollment goals, the Diversity Action Plan must detail specific strategies for enrollment and retention of study participants. Effective strategies include:
Community Engagement: Engage with community advisory boards, navigators, community health workers, patient advocacy groups, and local healthcare providers to build trust and facilitate participation.
Cultural Competency Training: Provide training for clinical investigators and research staff to reduce biased communication and avoid cultural generalizations.
Participant Awareness: Improve study participant awareness and knowledge about the clinical study, including providing language assistance for those with limited English proficiency.
Reducing Participant Burden: Minimize unnecessary study-related procedures and offer transportation assistance, dependent care, flexible hours for study visits, and reimbursement for costs incurred.
Improving Access: Through four means:
Limit exclusion criteria.
Select study site locations that serve diverse populations.
Consider the accessibility needs of persons with disabilities.
Employ clinical study decentralization when appropriate.
The plan should also include a detailed description of the sponsor’s plan to monitor enrollment goals during the clinical study. This ensures that goals are on track and allows for prompt intervention to address any barriers. It should specify the manner and frequency of monitoring and outline measures that will be taken if the study is not meeting its enrollment targets.
Timelines for Submitting Diversity Action Plans
While we covered some of this already, the FDA mandates specific timelines for submitting Diversity Action Plans to ensure they are integrated early in the clinical study process. This section outlines the required timelines for both drug and device clinical studies.
For drug studies, sponsors must submit the required Diversity Action Plan to the relevant IND application as soon as practicable. This submission must occur no later than the date on which the sponsor submits the protocol for the phase 3 study or other pivotal study to the FDA. Early submission is encouraged, typically during the End-of-Phase 2 meeting, to allow for timely FDA review and feedback in the context of discussions regarding trial design, study population selection, and other critical aspects of the clinical study.
For device studies, the requirements vary depending on whether the study involves significant risk or non-significant-risk devices.
Significant Risk Devices: Sponsors must include the Diversity Action Plan in the IDE application. This inclusion ensures that the plan is reviewed as part of the overall clinical study application process.
Non-Significant Risk Devices: Although NSR studies do not require an IDE application, sponsors must still develop a Diversity Action Plan. This plan must be submitted as part of the device’s premarket notification (510(k)), PMA application, or De Novo classification request.
The FDA recommends that sponsors seek feedback on their Diversity Action Plans early in the planning stages of the clinical study or development program. For devices, if specific FDA feedback is necessary before submitting the plan in an IDE or marketing submission, sponsors should use the Q-submission process so sponsors can address any critical questions related to study design and conduct before formal submission.
Procedures for Submitting the Diversity Action Plan and Receiving Feedback
The FDA has outlined specific procedures for submitting Diversity Action Plans and receiving feedback.
Submission
Sponsors are required to submit their plans to the relevant IND or IDE. The submission must be clearly labeled to indicate that it includes a Diversity Action Plan.
For drugs, the plan must be submitted to the IND under which the applicable clinical study will be conducted. The cover letter accompanying the submission should alert the FDA that the submission includes a Diversity Action Plan and denote whether the plan is new or revised. Sponsors should use the labels "DIVERSITY ACTION PLAN-Initial" or "DIVERSITY ACTION PLAN-Revised" in large, bolded type to ensure clear identification. If a partial waiver has been granted for the clinical study, this should also be indicated in the cover letter.
For devices, again, the plan must be included in the IDE application for significant risk devices. For non-significant risk devices, which do not require an IDE application, the Diversity Action Plan must be submitted as part of the device's premarket notification (510(k)), PMA application, or De Novo classification request. The cover letter should similarly indicate the inclusion of a Diversity Action Plan and whether it is new or revised.
FDA Feedback
FDA feedback on the Diversity Action Plan can be provided either at the FDA’s initiative or upon the sponsor’s request.
Proactive Feedback: The FDA may provide feedback during the review process of the clinical study application. This feedback is intended to guide sponsors in aligning their study designs with the FDA’s expectations for diverse and representative enrollment.
Requested Feedback: Sponsors can request specific feedback on their Diversity Action Plans. This request can be included as part of meetings with the FDA or through the Q-submission process for devices, which allows sponsors to obtain guidance on particular aspects of their clinical study design, including diversity considerations.
Modifications
Sponsors have the flexibility to submit modifications to their Diversity Action Plans based on feedback from the FDA or on their own initiative.
When submitting modifications, sponsors must include a copy of the Diversity Action Plan with tracked changes as well as a clean version. Additionally, a "Summary of Modifications and Justification" section must be included, outlining the changes made and the rationale behind them.
For significant risk device studies, modifications to the Diversity Action Plan included in an approved IDE should follow the processes outlined in the FDA’s guidance on changes to approved clinical investigations. For studies not requiring an IDE, modifications can be submitted through a pre-submission if FDA feedback is necessary.
Requesting Diversity Action Plan Waivers
The FDA acknowledges that there may be situations where submitting a Diversity Action Plan, or parts thereof, may not be feasible or appropriate. In such cases, sponsors can request waivers for certain requirements. This section outlines the process for requesting and obtaining waivers.
FDA may waive the requirement to submit a Diversity Action Plan, or any part of it, if any of the following statutory criteria are satisfied:
Prevalence or Incidence: A waiver is necessary based on what is known or can be determined about the prevalence or incidence of the disease or condition in the U.S. patient population that may use the drug or device.
Impracticability: Conducting a clinical investigation in accordance with a Diversity Action Plan would be impracticable.
Public Health Emergency: A waiver is necessary to protect public health during a public health emergency.
The FDA also lays out how sponsors should request waivers:
Drug sponsors should submit waiver requests electronically to the IND under which the clinical study subject to the Diversity Action Plan requirement will be conducted. The submission should include the IND number, applicable clinical study name or identification number, and a justification for the waiver request, including relevant data and information. The cover letter should clearly state “DIVERSITY ACTION PLAN- Waiver Request” in large, bolded type.
Waiver requests from device sponsors should be submitted as standalone submissions with an accompanying cover letter that includes “DIVERSITY ACTION PLAN- Waiver Request” in large, bolded type. The request should contain the submission number(s) if available, information about the device, including a description and proposed intended use, the applicable clinical study, the type of marketing submission that the clinical study is intended to support, and a justification for the waiver request, including relevant data and information.
The FDA is required to issue a written response granting or denying the waiver request within 60 days of receiving the request. Sponsors are encouraged to discuss plans to request a waiver early in the clinical study or development program planning stages to allow sufficient time for preparation and submission of the Diversity Action Plan should the FDA deny the waiver request.
Sponsor Public Posting of Key Information from Diversity Action Plans
To promote transparency and public trust, the FDA strongly encourages sponsors to publicly share key information from their Diversity Action Plans. This includes posting clinical study enrollment goals disaggregated by race, ethnicity, sex, and age group, as well as a brief description of the measures taken to achieve these goals.
The agency lays out a few specific recommendations for public posting:
Location of Posting: Sponsors should post key information on their website, preferably in the same location as other clinical trial-related content, such as a “pipeline” page for unapproved, unlicensed, or uncleared products.
Links and Accessibility: Consider linking the public posting to a recruitment website for the trial or a commonly used repository for clinical trial information, such as ClinicalTrials.gov. Similarly, sponsors can link from recruitment websites or clinical trial databases to their public postings.
Consumer-Friendly Language: Use accessible and consumer-friendly language when sharing information to ensure it is understandable to a broad audience.
Elements of a Diversity Action Plan (Summary)
The Diversity Action Plan should contain a clear and concise description of the required elements, with limited cross-referencing to previously submitted documents to facilitate review. In most cases, the Diversity Action Plan should be succinct, generally not exceeding 10 pages, excluding references.
Title Page:
Medical product name.
IND/IDE number (if applicable), and/or other relevant submission information.
Proposed indication(s) for use statement and intended use.
Clinical study identification information (e.g., NCT number, title, study ID).
Diversity Action Plan version number and date.
Enrollment Goals:
Goals must be disaggregated by race, ethnicity, sex, and age group, aligned with FDA guidance for reporting these demographics.
Rationale for Enrollment Goals:
The rationale must include sufficient information and analysis to explain how the enrollment goals were determined, including data on disease prevalence, genetic differences, and relevant population characteristics.
Measures to Meet Enrollment Goals:
A detailed description of strategies to achieve the enrollment goals, including community engagement, cultural competency training, reducing participant burden, improving access, and decentralizing clinical studies when appropriate.
Our Recommendations
To operationalize this guidance on Diversity Action Plans, we suggest sponsors consider and adapt the following strategy.
Establish your enrollment goals. Set specific enrollment goals disaggregated by race, ethnicity, sex, and age group of the clinically relevant study population.
Develop your rationale for those goals. Provide comprehensive data on the disease or condition, including prevalence and incidence estimates. Then, explain the rationale for the chosen enrollment goals, considering factors such as differential safety and effectiveness, genetic differences, and relevant population characteristics (e.g., socioeconomic status, geographic location, comorbidities). Cite sources for all data and information used to establish the goals (e.g., epidemiological databases, registries, published literature).
Determine measures to meet those goals. Refer to the breakdown above for the specific measures.
For drug sponsors, document a plan to submit the Diversity Action Plan to the IND as soon as practicable but no later than the submission of the protocol for the phase 3 study. Ideally, discuss the plan during the End-Of-Phase 2 meeting. Device sponsors with significant risk devices should document a plan to submit with the IDE application; for non-significant risk devices, submit the plan as part of the device’s premarket notification (510(k)), PMA application, or De Novo classification request.
Develop a procedure to ensure a cover letter is included stating "DIVERSITY ACTION PLAN-Initial" or "DIVERSITY ACTION PLAN-Revised" in large, bolded type. If a partial waiver has been granted, indicate this in the cover letter.
Be ready to submit modifications to the Diversity Action Plan based on feedback or on your own initiative. Include a copy with tracked changes and a clean version, along with a "Summary of Modifications and Justification" section.
Also, keep in mind that a waiver may be requested based on the prevalence or incidence of the disease, impracticability, or public health emergency. Drug sponsors should submit waiver requests electronically to the IND, including the IND number, clinical study name, and justification for the waiver. Device sponsors should submit as standalone submissions with an accompanying cover letter and relevant justification data.
Lastly, per the guidance’s recommendation, plan to post key Diversity Action Plan information on your website, ideally in the same location as other clinical trial-related content. Link public postings to recruitment websites or clinical trial information repositories using accessible and consumer-friendly language.
Once the guidance is finalized, sponsors will have 180 days before they must comply with it as they begin new clinical trials. Stakeholders can comment on the draft guidance until September 25th on regulations.gov under docket number FDA-2021-D-0789.
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