Final FDA Guidance Reinforces Increased Focus on Diversity and Inclusion in Clinical Development

On November 9, 2020, the US Food and Drug Administration (FDA or the Agency) released a final guidance, entitled "Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs," finalizing the draft issued last June.¹ The new guidance, which is the latest step in FDA's efforts to modernize clinical research practices, provides recommendations for sponsors to ensure that studies used to support product marketing approvals or clearances are sufficiently reflective of the populations those products are intended to serve. Specifically, the guidance encourages potential study sponsors to:

• Broaden eligibility criteria to increase diversity in trial enrollment, through inclusive trial practices and other means;
• Rethink study design and conduct to improve enrollment generally, such as by making participation less burdensome; and
• Consider rare diseases or conditions when developing eligibility criteria and recruitment activities.²

The guidance is timely as research equity and healthcare accessibility have increasingly become public priorities and an important concern for the FDA.³ The guidance will also be of interest to medical product developers seeking to conduct trials to support intended uses and marketing claims targeted at specific demographics, including specific ethnicities, age groups, or other cohorts.

Background

FDA released the guidance to fulfill its obligations under Section 610(a)(3) of the FDA Reauthorization Act of 2017 (FDARA), which required the Agency to issue guidance on approaches that sponsors of investigational drugs can use to broaden eligibility criteria for clinical trials and expanded access trials, develop eligibility criteria and increase trial recruitment so research subjects more accurately reflect the patients most likely to receive the drug while establishing safe use and substantial evidence of effectiveness, and applying the foregoing to drugs intended for the treatment of rare diseases or conditions.⁴ Even before FDARA, however, FDA engaged in actions to expand diversity in clinical trials. For example, FDA issued its Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, which proposed strategies to encourage greater clinical trial participation and improve clinical trial diversity, as well as the final guidance, entitled "Collection of Race and Ethnicity Data in Clinical Trials."⁵ Similarly, FDA issued guidance documents addressing inclusion of particular populations, such as older adults, pregnant women, and subjects with rare diseases.⁶

While efforts to improve clinical trial diversity ultimately help patients and their physicians, they also provide important data to manufacturers of studied product. In particular, obtaining data from diverse populations in clinical studies may enable a manufacturer to address safety issues unique to such sub-populations, or even to substantiate marketing claims that could provide a potential competitive and business advantage. In the case of prescription drugs and biologics, FDA may permit a manufacturer to use promotional claims regarding the effect of a product on a particular sub-population within the approved patient population even if such information is not contained in the product's FDA-approved labeling.⁷ Similarly, for certain over-the-counter products, data from appropriately designed studies, could help substantiate sub-population-specific claims, which may serve as a differentiator between the studied product and competitor products.

Summary of Guidance

The guidance addresses how sponsors of clinical trials in support of a new drug application or biologics license application may increase enrollment of underrepresented populations in such trials through (i) broadening eligibility criteria; (ii) utilizing study designs and mechanisms that make participation less burdensome; and (iii) expanding enrollment and retention of subjects for studies in rare diseases. These considerations are critical to sponsors who intend to use the data collected in clinical trials to support intended use and marketing claims in particular sub-populations. They also reflect the Agency's aspirations of incentivizing more equitable research practices.

Increase Diversity in Enrollment with Broadened Eligibility Criteria

Inclusive Trial Practices

This guidance builds on FDA's past efforts to broaden eligibility criteria—the characteristics participants must have, or must not have, to enroll in a clinical trial. Broadening eligibility criteria ensures that individuals are not unnecessarily excluded from clinical trials and helps to "create a study population that more accurately reflects the patients likely to take the drug if it is approved."⁸ While the guidance acknowledges that there are several valid reasons for clinical trial exclusions, such as excluding patients vulnerable to certain risks, FDA makes several recommendations concerning exclusions, including:

• Broadening eligibility criteria throughout a study as the safety experience of a product increases since dose adjustments could be made to mitigate risks of including certain demographics, such as comorbidities. FDA also encourages sponsors to increase diversity by using more inclusive trial practices, trial design and methodological approaches, and employing enrichment strategies;
• Evaluating exclusion criteria to determine whether they are necessary and specifically defined to avoid overgeneralized exclusion categories; and
• Removing or modifying exclusion criteria between Phase II studies and Phase III trials or developing specific studies that account for higher risk populations to avoid restrictive limits on the study population, such that by the end of the Phase II meeting, sponsors have a plan to "enroll participants who reflect the characteristics of clinically relevant populations with regard to age, sex, race, and ethnicity."⁹ This approach is intended to help ensure product safety and effectiveness and can be achieved by including children and adolescents in confirmatory trials involving adults when appropriate, adequate numbers of both sexes to allow detection of sex-related differences in drug response, or racial and ethnic minorities to determine population-specific responses and signals.

Trial Design and Methodological Approaches

To enroll broader populations, the guidance also urges sponsors to consider:

• Using trial designs that characterize drug metabolism and clearance groups in early clinical development, which may avoid late population exclusions and provides an opportunity to optimize effectiveness and safety across different populations;
• Allowing changes to broader or more narrow enrollment based on pre-specified interim data points (i.e., adaptive trial designs); and
• Developing pediatric programs early, and include pharmacokinetic sampling to establish dosing for women who become pregnant during trial, which may avoid excluding children and pregnant women, who have been historically underrepresented.

Most notably, FDA's suggestion to employ adaptive trial designs solves for situations where a sponsor may want to start with a more narrow population and then potentially expand to a broader population or where the sponsor wants to start with a broader population and adjust enrollment accordingly based on interim data. FDA issued a final guidance on adaptive trial designs in November 2019, and has previously encouraged their use as flexible and efficient alternatives to non-adaptive designs to, among other things, identify dosage forms or sub-groups where a drug is efficacious while avoiding over-exposing subjects who may be prone to adverse events.¹⁰ Adaptive trial designs may help mitigate potential sponsor concerns with broadening eligibility criteria, especially when using enrichment strategies, while also providing advantages such as statistical efficiency, improved understanding of drug effects, and the ability to fend off allegations that a product has not been shown to be sufficiently effective for certain sub-groups to be promoted as efficacious for all populations or promotional materials targeted at a specific sub-population. 

Broadening Eligibility Criteria in Trials Using Enrichment Strategies

FDA supports the use of enrichment trial design strategies, which include "targeted inclusion of certain populations," but cautions against using strategies that exclude certain demographic groups.¹¹The guidance discusses two types of enrichment: prognostic and predictive.

• Prognostic enrichment enrolls individuals who have a more severe disease or that are more likely to reach the study endpoint.
• Predictive enrichment enrolls individuals who are more likely to respond to an intervention.

While these enrichment strategies can make a trial more likely to detect an effect of a new product, FDA still recommends including broad participant groups, such as marker-negative participants, who do not meet enrichment criteria and participants across differing disease severity to provide efficacy information for the broader population.

Improving Diversity Through Less Burdensome Study Designs and Other Mechanisms

Make Trial Participation Less Burdensome for Participants

The guidance also discusses ways that sponsors may ameliorate practical problems that impede participation in clinical trials. According to FDA, sponsors should make an effort to improve diversity in clinical trials by accounting for logistical challenges that may result from frequent visits, financial costs, and psychological and physical burdens that disincentivize enrollment. These challenges particularly impact older adults, children, disabled and cognitively impaired individuals, participants who live far from research facilities, and those in rural or remote locations that require transportation. Financial costs from travel and missing work are especially problematic for individuals with work, family, and/or community obligations. FDA recommends reducing these burdens by:

• Reducing the frequency of study visits;
• Adding more flexibility to study visit timing;
• Implementing electronic communication and digital health technology tools to replace site visits; and
• Using mobile medical professionals to visit participants at their locations.

While FDA policy on payments to research subjects has been limited to-date, it is important to note that the guidance recognizes the important role that appropriate sponsor financial, travel, and other logistical support can play to ensure that vulnerable or special sub-populations have opportunities to take part in clinical research and be considered in the development of new therapies. For example, to reduce financial barriers, FDA notes that sponsors can offer participants reimbursement for reasonable travel expenses, parking, and lodging without raising issues of undue influence or inducement, especially if the proposed reimbursement has been reviewed by the relevant Institutional Review Board or Ethics Committee.¹²

Adopt Enrollment and Retention Practices That Enhance Inclusiveness

In the guidance, FDA also provides several recommendations to improve inclusion in clinical trial enrollment and retention. The guidance suggests that sponsors should:

• Design studies to enhance recruitment by collaborating with patient advocacy groups and medical associations to employ public outreach and education to inform participants about clinical trial participation;
• Incorporate patient-focused research into trial designs by working with communities to address patient needs and remove elements that discourage participation; and
• Foster and maintain community engagement and provide cultural competency and proficiency training to clinical investigators and research staff to build trust with participants and expand recruitment and retention. This approach, for example, could be well suited for the recruitment of underrepresented racial groups that have historical and deep rooted skepticism and/or fear of clinical investigations because of prior clinical study misconduct.

With respect to racial and ethnic diversity in particular, FDA recognizes that "racial and ethnic minorities currently compose a small percentage of clinical trial participants relative to the prevalence of disease in these populations."¹³ Therefore, FDA recommends that sponsors:

• Choose clinical trial sites in geographic locations with higher concentrations of racial and ethnic minorities and indigenous populations;
• Broaden minority participation by choosing locations where minority populations receive healthcare and selecting diverse healthcare providers and study coordinators; and
• Make recruitment events more accessible to diverse populations by holding them often, during the evening and weekend, and at trusted locations like worship centers, commercial venues, and public events.

FDA also suggests improving recruitment of diverse populations by providing documents in multiple languages, having multilingual staff or interpreters, using real-world data, and using online or social media strategies to identify more study sites and participants. FDA also recommends:

• Utilizing agreements that facilitate the exchanges of medical records between clinical trial sites and using "electronic informed consent" forms that allow participants to sign remotely when appropriate to increase retention; and
• Utilizing more accessible locations for consenting processes because some underrepresented populations need an in-person interaction to better understand risks and benefits.

Expanded Access

FDA acknowledges that, even after broadening inclusion criteria, some patients will still not be eligible to participate in a clinical trial. To potentially provide investigational product to these individuals, the guidance cites the Agency's expanded access regulations as an option. These regulations enable a patient to receive treatment with an investigational drug when they have a serious or immediately life-threatening disease or condition and certain criteria are met, including that there is no comparable or satisfactory alternative therapy.¹⁴ Although the purpose of expanded access is treatment, FDA recognizes that there are some instances in which data from expanded access can inform clinical development (e.g., identifying patient populations).

Expand Enrollment and Retention of Participants with Rare Diseases

Achieving enrollment of subjects in clinical trials of investigational drugs intended to treat rare diseases presents unique challenges because of the limited number of patients. The guidance includes approaches for sponsors to broaden clinical trial eligibility, participation, and retention of participants in clinical trials of investigational drugs for rare diseases. To increase recruitment, FDA recommends engaging early with patient advocacy groups, experts, and patients with the disease to seek their input about design of trials. FDA notes that, while participants that received a therapy in a Phase I trial are usually considered ineligible for Phase III trials, it may be reasonable to re-enroll participants when medically appropriate and scientifically sound, there is no unreasonable anticipate safety issue, and the drug received in Phase I is not expected to change the course of the disease. Re-enrolling participants could provide a better evaluation of safety and efficacy in a broader population although it should be done on a limited basis. However, the guidance cautions that sponsors using this approach should avoid selection bias that re-enrolls participants who experienced more effectiveness in early trials, which could lead to unrepresentative safety findings. After early-phase studies, FDA recommends conducting an open-label extension study with broader inclusion criteria in order to broaden participation and ensure all participants have access to the investigational treatment.

Conclusions

The new guidance is consistent with an increased regulatory and public policy focus on addressing healthcare disparities, in part by encouraging more robust enrollment of clinical trial subjects. Such enrollment is expected to help improve patient care and access to potential treatments as well as the development and dissemination of data that may be useful for physicians, sponsors and academia. The considerations set forth in the guidance also may have an other consequences, such as providing a roadmap for deficiencies citable in challenges by competitors or regulators should a product developer utilize inadequate data to substantiate claims targeting a sub-population or suggesting efficacy in all populations. Ultimately, sponsors seeking to improve diversity and expand enrollment in their studies by following the recommendations in the guidance should engage in careful planning, as many of FDA's recommendations require execution well before pivotal Phase III studies.

© Arnold & Porter Kaye Scholer LLP 2020 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.