U.S. Congress embraces FDA’s approach to clinical trial diversity in new Omnibus legislation

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In the waning days of 2022, Congress passed the omnibus spending legislation to provide funding for the federal government through September 2023. The legislation contains numerous reforms focused on FDA bundled under Title III, the Food and Drug Omnibus Reform Act of 2022, or FDORA. Among the many provisions is chapter 1 of subtitle F, Clinical Trial Diversity and Modernization, which amends the Federal Food, Drug, and Cosmetic Act to require drug and device sponsors to submit diversity action plans articulating goals for increasing enrollment of subjects from historically underrepresented populations. These provisions reflect the principles outlined in FDA’s April 2022 draft guidance, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials,” (“2022 Guidance on Diversity Plans for Underrepresented Racial and Ethnic Populations”) and previous agency guidance documents focused on clinical trial diversity, and expand the scope of characteristics required to be considered in a diversity plan.

Several clinical trial diversity bills have circulated Congress in recent years as patients, caregivers, and health care professionals have emphasized the need to evaluate treatments in a clinical trial population representative of the demographics of the disease or broader US population. FDA’s 2022 Guidance on Diversity Plans for Underrepresented Racial and Ethnic Populations articulated an ambitious framework to encourage sponsors to address diversity enrollment gaps in clinical trials. With the passing of FDORA, Congress has endorsed and fortified FDA’s ability to require that sponsors diversify their clinical trials by recruiting, enrolling, and retaining participants from previously underrepresented racial and ethnic groups, as well as other underrepresented demographic groups.

The legislation requires drug sponsors to submit a diversity action plan to FDA no later than the date upon which sponsors submit protocols for the phase 3 or other pivotal trial. Sponsors of devices for which an Investigational Device Exemption (IDE) submission to FDA is required must submit the diversity action plan in the IDE application. In addition, sponsors of device trials that do not require an IDE submission must also develop a diversity action plan, which will be submitted to FDA in the future marketing application (i.e., a 510(k) premarket notification, a premarket approval application, a De Novo classification request, or an Humanitarian Device Exemption application) will also be required to submit a diversity action plan to the agency. Notably, the scope of device clinical trials subject to the diversity action plan requirement is broader than for drug trials (i.e., device first-in-human, early feasibility and pilot studies are not exempt). It is not yet known whether FDA intends to address this discrepancy through rulemaking or in the form of guidance, or if the agency will let the distinction stand.

Consistent with FDA’s 2022 Guidance on Diversity Plans for Underrepresented Racial and Ethnic Populations, FDORA requires diversity action plans to include the (1) sponsor’s enrollment goals, (2) rationale for the goals, and (3) an explanation of how the sponsor intends to meet the goals. Newly created by FDORA is a waiver provision, which permits FDA to waive the diversity action plan requirement at its own discretion or upon sponsor request. The waiver may be granted depending on what is known, or can be determined, about the prevalence or incidence of the disease or condition for which the product is under investigation; if conducting the investigation in accordance with a diversity action plan would be impracticable; or if the waiver is necessary to protect public health during an emergency. FDA will have 60 days to render a decision on a waiver application, which is notably longer than the IND and IDE review period. This means that sponsors will likely need to seek such waivers in advance of their IND or IDE application.

FDA is required to update existing guidance or issue new guidance on diversity action plans related to the sponsor’s goals for enrollment by age group, sex, and racial and ethnic demographic characteristics of clinically relevant study populations, including the rationale for enrollment and explanation of how the diversity goals will be attained. Future guidance should list considerations for the public posting by a sponsor of key information from the diversity action plan that would be useful to patients and providers on the sponsor’s website, and criteria that the FDA will consider in assessing whether to grant a diversity action plan waiver. In addition to issuing guidance, FDA is also directed to hold public workshops with stakeholders to solicit input on: increasing the enrollment of historically underrepresented populations in clinical studies, including by the establishment of specific inclusion and exclusion criteria for certain subgroups; considerations regarding informed consent with respect to individuals with intellectual or development disabilities or mental illness, including ethical and scientific considerations for those individuals; and use of decentralized clinical trial or digital health tools.

FDORA’s clinical trial diversity provisions are a clear step forward towards promoting the agency’s long articulated goal of ensuring that clinical trials are conducted to evaluate the safety and efficacy of treatments in all relevant patient populations, regardless of race, sex, or ethnicity. However, it remains to be seen what action, if any, FDA may take against sponsors who fail to achieve their enrollment goals and how falling short will impact the marketing application.

The 2022 Guidance on Diversity Plans for Underrepresented Racial and Ethnic Populations recommended sponsors develop a plan and justification for collecting data in the post-marketing setting if the diversity enrollment goal was not met during the clinical trial program. The FDORA legislation is notably silent on this topic. It requires future FDA guidance to address how sponsors may update the agency on the sponsor’s progress towards meeting or not meeting the goals described in the diversity action plan but makes no mention of post-approval requirements.

Similarly, there is the question of what FDA will require of sponsors in terms of their statistical analysis plans. If FDORA mandates FDA to review enrollment of historically underrepresented groups so that clinical outcomes within these groups can be better understood, it is foreseeable that the agency may require that trials be designed in ways to improve the scientific validity of the conclusions drawn for these groups. FDORA requires FDA to hold public workshops on approaches to support the inclusion of underrepresented populations, including considerations related to inclusion and exclusion criteria for certain subgroups, clinical endpoints, and biomarker selection, which will likely inform FDA’s future expectations for statistical analysis plans.

Although questions remain about how FDA will implement these provisions in FDORA, it is possible that sponsors of marketing applications across product areas could face certain regulatory risks if they fail to comply with the new diversity requirements. For example, FDA could potentially determine that an application is not approvable (or at least greatly limit the intended use population) if it fails to contain sufficient information about certain racial and ethnic groups who will be treated with the product after approval, as described in the diversity plan. Likewise, if data is collected in a way that undermines the validity or generalizability of the results for a subgroup, a similar unfavorable decision by the agency is possible. For instance, FDA has raised concerns with marketing applications solely dependent on data from a single forewing country with demographics distinguishable from that of the US population. Such marketing applications are likely to come under greater scrutiny post-FDORA. With these considerations in mind, sponsors should promptly address how these new requirements may impact ongoing and future clinical development programs.

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