FDA officials clarify how diversity action plans intersect with multiregional clinical trials
US Food and Drug Administration (FDA) officials recently clarified how sponsors can achieve agency diversity action plan (DAP) goals within multiregional clinical trials (MRCTs) in a perspective published in the New England Journal of Medicine.One of the requests stakeholders made of FDA when responding to the agency’s recent draft guidance on MRCTs was for the DAP and MRCT draft guidances to complement one another. Among other points, stakeholders asked FDA to clarify how the two are aligned and whether flexibility exists in gathering postmarketing supplementary data for diversity enrollment goals. (RELATED: Stakeholders seek changes to FDA’s oncology multiregional trial guideline, Regulatory Focus 20 November 2024; FDA issues diversity action plan draft guidance, Regulatory Focus 26 June 2024)
Gautam Mehta, of the Oncology Center of Excellence at FDA, and colleagues, said that although MRCTs typically contain around 20% of participants based in the US, DAP and MRCT goals complement one another because the need for greater diversity in clinical trials exists at a national level, aren’t mutually exclusive, and “can be supported by means of an international commitment to promoting trial diversity and evaluation of intrinsic factors characteristic of the U.S. population in representative patients outside the United States.”
“Given the diversity of the United States, U.S. patients are positioned to benefit from multiregional enrollment,” they said.
FDA officials said that assessment of extrinsic and intrinsic factors may require increasing the number of US participants enrolled in MRCTs, but analysis of intrinsic characteristics in an MRCT can be augmented with data from participants from other regions with similar intrinsic characteristics.
Concerning site selection, Mehta and colleagues said regulatory agencies may be useful in suggesting DAP-related geographic distribution and target enrollment for MRCTs even if they have not traditionally been consulted in this way. Sponsors should also discuss accrual goals to avoid bridging trials. “Ideally, MRCTs should enroll substantial numbers of participants from all relevant geographic areas and should avoid enrolling participants predominantly from a single region,” they said.
In general, and in situations where the MRCT may end up being the pivotal clinical trial, sponsors should communicate early with FDA about DAPs, the authors said. “Even when early-phase trials suggest associations between intrinsic and extrinsic factors and outcomes, a DAP is still important, since MRCTs provide the most comprehensive data on safety, efficacy, and consistency of effects among subgroups,” they explained.
FDA encourages selection of underutilized trial sites in the US for pivotal trials, developing a trial support staff from local communities, and engagement with the community through patient navigators, community advisory boards, and local organizations. Sponsors should also consider site development in other areas of the world where US patients have ancestral origins. “Although information regarding extrinsic factors from these sites may have limited generalizability to the U.S. population, insights may be gained into intrinsic factors,” Mehta and colleagues said.
Any new sites developed in the US or elsewhere need to meet regulatory requirements, may improve data quality, and increase confidence of regulatory submissions in the future, they noted.
“Greater use of pragmatic elements and decentralized designs in MRCTs may support the participation of new study sites and augment accrual at established sites,” the authors said. Such pragmatic trials would eliminate exclusion criteria, data collection, and procedures for testing that are unnecessary, with primary endpoints that can be tested in clinical practice and have clinical benefits with a minimum of subjectivity and bias.
“The simplicity of these trials may enable patients to provide truly meaningful informed consent,” Mehta and colleagues said. “Trial personnel who are engaged in clinical care may also see them as more relevant than traditional trials. Decentralized trials may permit research participation in underserved areas or by patients who are unable to travel.”
The authors acknowledged that DAPs will not fix every clinical trial and health care inequality issue in the US, but addressing issues associated with site activation delays, high costs, slow enrollment, and contract negotiations can improve representation in trials.
“Drug development has become increasingly international, and global demand for representation and diversity will result in larger later-phase and postmarketing trials that provide more comprehensive evidence regarding the appropriate use of drugs in practice,” Mehta and colleagues said
New Eng J Med Mehta et al.
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