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With industry’s uneven track record in patient representation, sponsors now mandated to submit Diversity Action Plans (DAPs) to FDA for Phase III and pivotal studies.
Policymakers and biopharma companies acknowledge the importance of assessing drugs and medical products on a wide range of ethnic and racial populations to fully understand medical effects on patients. This has bolstered support for studies to enroll patients in proportion to the prevalence and burden of the disease in relevant subgroups, but achieving such equitable patient representation in clinical trials has been difficult to achieve and has been uneven at best.
After years of FDA issuing guidances and launching programs to encourage sponsors to seek broader representation in clinical trials, policymakers have added a “stick” to the process:research sponsors now will be required to tackle this issue by submitting Diversity Action Plans (DAPs) to the agency when proposing and seeking approval of Phase III and pivotal studies. This provision was included in the Food & Drug Omnibus Reform Act (FDORA)1, approved by Congress in December 2022 as part of the massive Consolidated Appropriations Act that authorized federal spending for 2023.2
Among a host of FDORA provisions, including those designed to modernize FDA’s accelerated approval program, bolster FDA inspections and expand oversight of cosmetics, the legislation also requires DAPs that set specific enrollment goals for clinical trials of most drugs and certain medical devices under development. FDA has a year to issue guidance on the program, and there may be some waivers and exceptions, as for bioequivalence studies. But diversity plans will be required for most clinical development programs. FDA will hold a public workshop on the program, issue additional guidances on specific topics, and submit annual reports to Congress once the program gets going.
The need to mandate DAPs is supported by recent studies and analyses showing inadequate patient representation in many clinical trials. A recent retrospective review by GSK of demographic representation in 17 years of clinical trials (2002-2019), for example, paints an uneven picture of trial enrollment of various minority and ethnic groups and how that has varied among different drugs and treatment areas.3
The results are mixed in this review of clinical trial demographic data from 495 clinical trials involving US-based participants.4 There was a greater proportion of Black/African American patients enrolled in trials for asthma drugs than that group’s share of patients for that condition. But a smaller percentage of Black/African American patients participated in studies for HIV drugs compared to the group’s high prevalence in that disease population. Very few Asian patients were included in studies for coronary heart disease, and only slightly more Hispanic patients. And all minority groups were underrepresented in vaccine trials.
Similarly, an analysis by the Government Accountability Office (GAO), issued in December 2022, found that certain population groups remain underrepresented in clinical trials despite years of efforts to improve research diversity.5 This analysis focused on cancer clinical trials and noted consistently low numbers for a range of patients, including those in certain racial and ethnic groups, adolescents and young adults, older adults, women, low-income individuals, and people from rural communities.
The report also described practices developed at certain cancer centers that helped advance diverse enrollment in research. These include assigning community ambassadors to increase awareness of clinical trials in a local area, better training and increased workforce diversity at centers to better explain clinical trial opportunities, and financial and logistical support to overcome barriers to patient participation in research programs.
FDA issued draft guidance in April 2022 on developing Race and Ethnicity Diversity Plans to further research enrollment of appropriate numbers of participants from underrepresented racial and ethnic populations, and that advisory may provide a basis for moving forward with final specifics on the now-required program.6 The guidance emphasizes the value of submitting diversity plans as part of initial investigational plans and later in market applications, noting successes and challenges.
In discussions on this and earlier FDA proposals on this topic, sponsors have queried the agency on specifics for applying diversity goals to global development programs and for assessing “adequate enrollment” of underrepresented populations. Another issue is whether diversity goals should apply to each individual study or to an overall development program. And sponsors particularly want to know more about how FDA will deal with research programs that fail to meet set goals for patient enrollment.
Many of these issues are addressed in a report issued by the National Academies of Sciences, Engineering and Medicine in May 2022 that assesses how the failure to include diverse populations in clinical studies leads to poor health and greater disabilities for populations not included in medical research.7 The expert panel proposed that FDA provide added incentives for sponsors to meet diversity goals in the form of tax credits, fast-track eligibility, reduced fees, and extended market exclusivity, similar to incentives provided firms developing orphan drugs. In addition, researchers could gain more leeway to reimburse minority study participants and to cover expenses for transportation, dependent care, and lost wages. Conversely, FDA might gain authority to refuse to file an application that fails to include appropriate patient representation.