September 26, 2024
Docket No. FDA- 2021-D-0789
The National Center for Health Research (NCHR) appreciates the opportunity to express our views on the new FDA Draft Guidance regarding FDA Diversity Action Plans to Improve Enrollment of Participations from Underrepresented Populations in Clinical Studies.
NCHR is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.
Since our Center’s founding in 1999, we have been at the forefront of the public debate on the importance of demographic diversity in clinical trials. We have been concerned that the FDA is the one U.S. public health agency that does not require diversity in clinical trials, and we have focused on the impact of the lack of diversity in terms of sex, race, ethnicity and age in clinical studies that are the basis of FDA decisions. The citations are too numerous to list them all in this comment, but we have provided several examples here. In addition to a chapter in a bioethics textbook on the topic in 2009,[1] we have expressed our concerns about lack of diversity at numerous FDA Advisory Committee meetings reviewing specific medical products,[2] [3] [4] [5] [6] [7] have evaluated the lack of diversity in published articles based on FDA data,[8] [9] and suggested improvements at FDA meetings and requests for public comments regarding diversity from the FDA and other agencies.[10] [11] [12] [13] [14] [15] We have also worked with Members of Congress and note that Congress has repeatedly passed legislation aimed at improving diversity in clinical studies at FDA and other HHS agencies.
We are pleased that the 2024 FDA draft guidance offers more detailed recommendations for setting enrollment goals and that it provides specific information about the statutory requirements. It also creates a waiver system while specifying that no more than five waivers will be granted each year, which we are optimistic will make it clear that Diversity Plans are required of sponsors in all but a few rare instances, even though the guidance itself is not enforceable.
Incentives
Although FDA guidance is not enforceable, we strongly encourage the FDA to provide specific incentives designed to substantially improve compliance. For example:
- The indication that is approved or cleared should be based on meaningful outcomes for the specific types of patients that were studied in terms of sex, race, and age. These groups must be adequately represented in the studies because there is clear evidence that some treatments have greater risks or greater benefits for men compared to women; Whites compared to people of color; children of specific ages compared to other children or to adults; or elderly or frail elderly adults compared to younger adults. For example, if very few people over 65 are included in the study, the indication should specify approval only for people in those age groups that were found to have benefits that outweigh the risks. The indication should be clearly described on the label and should also provide specific information about the ethnicity of the patients studied and any outcomes that appeared relevant to specific ethnic groups. This would provide a strong incentive for sponsors to recruit and study sufficient numbers of patients from underrepresented groups, so that their medical products could potentially be approved for all patients, rather than a subgroup of patients.
- Labeling should clearly report outcomes by sex, race, and age groups. Unfortunately, labeling rarely provides that information, even when there are statistically significant differences in risks or benefits for subgroups that have clear implications for patient health.,[8][16] This is especially important for older age groups, since the risks are often higher and the benefits less meaningful for older patients, especially those over 70 and those with co-morbidities. This would provide important information for patients and their physicians, as well as essential information for CMS as it considers coverage determinations.
- Waivers should only be provided when specific types of diversity are not possible. The lack of information about racial diversity should not be considered sufficient justification for a waiver, because that would create an incentive for companies to not seek information about diversity.
Specific Guidelines and Transparency
- The FDA states that “Enrollment goals should be informed by the estimated prevalence or incidence of the disease or condition in the U.S. intended use population for which the medical product is being studied.” That makes logical sense but is not sufficient to provide useful information for underrepresented groups. Enrollment goals should be based on the goal of providing clinically meaningful outcome data for a reasonable number of patients from each key demographic group, rather than just being proportional to the percentage of patients in that demographic group. For example, if only 2% of patients diagnosed with a common disease are non-white, and a study has 300 patients, 6 non-white patients would be 2% of the study sample but is too small a sample to provide meaningful information regarding the value of the treatment. Demographic groups that are small minorities of those diagnosed with a particular disease or condition (whether age, race, ethnicity, or sex) should be oversampled to provide meaningful information about risks and benefits. While that may not be feasible for studies of treatments for extremely rare diseases, it should be possible for treatments for most rare diseases and patients deserve that information. It is very important for all studies, but especially if certain groups (such as children or elderly) could be at greater risk of death.
- The FDA should be specific regarding progress in achieving diversity plan goals that should be included in the sponsors’ IND annual The word ‘progress’ is vague and the FDA should be more specific about how sponsors should measure and report the progress that they have or have not achieved.
- The FDA should describe in detail what measures the agency will take at any point if the study is not on track to meet the sponsor’s enrollment goals. This should not be left to the sponsors to detail in their application.
- All information about waivers that are granted regarding Diversity Action Plans should be made public in the annual report to Congress, including justification by the sponsor and by the FDA.