Dear Commissioner Califf:
On behalf of the Cystic Fibrosis Foundation, we write to provide comments in response to the Food and Drug Administration’s draft guidance on the Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products. We commend the FDA’s ongoing commitment to rectifying the lack of adequate representation of diverse racial and ethnic groups in clinical research. Developing policies for the collection, standardization, and utilization of race and ethnicity data in clinical trials is a critical step in these efforts, and we appreciate the opportunity to provide feedback on the FDA’s proposed recommendations.
Background on Cystic Fibrosis and Diversity in Cystic Fibrosis Clinical Trials
Cystic fibrosis is a rare genetic disease that affects nearly 40,000 adults and children of every racial and ethnic group in the United States. In people with CF, mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene result in a buildup of thick mucus in multiple organ systems, leading to lung damage, life-threatening infections, and other complications.
To facilitate the development of CF therapeutics, the CF Foundation is engaged in virtually every element of the research and development process, from preclinical discovery and identification of new therapeutics to conducting clinical trials and post-marketing surveillance. Historically, CF clinical development programs have struggled with the inclusion of many underrepresented racial and ethnic populations, due in part to the misconception that CF only affects white individuals. However, enrolling clinical trials that represent the full diversity of the CF community is critical to achieving our mission of a cure for all people with CF. For that reason, the CF Foundation is investing significant time, resources, and attention towards improving the diversity of participants in clinical trials for CF therapeutics. With these efforts in mind, the CF Foundation offers the following considerations for the FDA as the agency refines its recommendations.
Collecting Race and Ethnicity Data in Clinical Trials and Clinical Studies
The CF Foundation supports the revisions to Statistical Policy Directive No. 15 (Directive No. 15): Standards for Maintaining, Collecting, and Presenting Federal Data on Race and Ethnicity recently published by the Office of Management and Budget. These revisions include the use of one combined question for race and ethnicity and encouraging respondents to select as many options as apply to their self-identification; the addition of “Middle Eastern or North African” to the set of minimum race and/or ethnicity categories; and requiring the collection of additional detail beyond the minimum required race and ethnicity categories for most situations to ensure further disaggregation in the collection, tabulation, and presentation of data when useful. We strongly encourage the FDA to amend this guidance to reflect these new standards.
Use of More-Detailed Racial and Ethnic Categories for Trials Outside the US
The specific use case for additional granularity in racial and ethnic designations mentioned in this guidance is clinical trials that enroll outside of the United States. Though the FDA acknowledges that “the recommended categories for race and ethnicity were developed in the United States and that these may not adequately describe racial and ethnic groups in other countries,” it subsequently recommends following the 2011 HHS Implementation Guidance on Data Collection Standards for Race, Ethnicity, Sex, Primary Language, and Disability Status and speaking with the appropriate review division. However, both the HHS guidelines and the OMB standards (pre- and post-revision) are still US-centric, and review divisions may not be equipped to reconcile the non-HHS/OMB racial and ethnic designations with US data collection standards. Given the increasing globalization of clinical trials and potential usefulness of more granular racial and ethnic stratification, we encourage the FDA to offer more information about how to proceed when the most useful or appropriate race and ethnicity categories for a given study do not easily align with those outlined by HHS/OMB guidelines.
Presentation of Race and Ethnicity Data in Clinical Trials and Clinical Studies: Product Labeling
We urge the FDA to expand recommended reporting on race and ethnicity data in product labeling to include different responses to the therapeutic product, in addition to demographics of the trial population. Collecting data on race and ethnicity in clinical studies for FDA-regulated medical products is critical for identifying potential differences in response to these products in racially and ethnically distinct populations in the United States. However, the FDA only recommends that the “Clinical Studies” and “Adverse Reactions” sections of the proposed labeling of a drug or biological product include the baseline demographics (including racial and ethnic characteristics) of the studied population. We urge the FDA to recommend that sponsors also provide descriptive analyses of treatment differences by racial and/or ethnic groups. This is important, even in the absence of a formal statistical testing framework, for transparently depicting potential differences in response to medical products and providing details that may be relevant to consumers (e.g., which racial and/or ethnic groups included in the study population exhibited a differing response to the drug product, whether the difference was efficacy- or safety-based, what the clinical manifestations of the differing response were, etc). Often these analyses are avoided due to lack of statistical power; however, relevant information should still be communicated in the form of descriptive comparisons with appropriate error to provide clarity regarding the potential heterogeneity of response across diverse racial and ethnic populations. This is vital, actionable information that may affect how the product is prescribed and used, and sponsors should publicly share this critical data. In a similar vein, we also recommend that the FDA consider whether it would be appropriate for sponsors to include relevant information about the use of race-specific outcome measures within product labeling, if applicable.
Reconciliation of Race and Ethnicity Data from Multiple Data Sources
Given the increasingly frequent use of external control data to support regulatory decision-making, we request that the FDA provide more information about how to reconcile race and ethnicity data from external data sources and clinical trial data when those data were collected using different standards. Use of external control data is critically important to the current CF drug development pipeline, as the emergence and widespread clinical use of CFTR modulator therapies has effectively resulted in a new, ultra-rare population of people with CF who are either modulator-ineligible or modulator-intolerant. This has necessitated a re-imagining of clinical trial design in the CF space, as companies developing critical therapies to meet the unmet needs of this population have found it increasingly difficult to perform right-sized, placebo-controlled RCTs. With this in mind, it has become clear that the utilization of external control data may mitigate the logistical and ethical difficulties of executing CF clinical trials in a post-modulator era.
The CF Foundation has access to a wealth of potential external control data, including real-world data available through the CF Foundation Patient Registry and multiple datasets from previously conducted clinical trials. However, we recognize that there may be discordance between governmental and non-governmental standards for the collection of race and ethnicity data (e.g., patients able to select more than one race for data collection during a clinical trial but only offered the choice of “more than one” or “multiracial” when self-identifying race and ethnicity for an observational registry), especially for external control data sources such as legacy registries. This an especially critical consideration for the use of external controls for the development of CF therapeutics: people of color with CF are overrepresented in the modulator-ineligible CF population, which is the primary target for many therapies currently in development, compared to the overall CF population. For this reason, we request that the FDA provide guidance regarding best practices for reconciling race and ethnicity data used to support regulatory decision-making from multiple sources with differing standards.
Once again, the CF Foundation commends the FDA’s commitment to improving the inclusion and experience of diverse racial and ethnic groups through the collection, standardization, and utilization of race and ethnicity data in clinical trials for FDA-regulated medical products. We appreciate the opportunity to offer feedback on these recommendations and look forward to collaborating with the agency on this topic in the future.