Impact of Evaluation and Reporting of Age, Race, and Ethnicity on Medical Device Clinical Trials

The FDA has issued final guidance on the evaluation and reporting of age, race, and ethnicity data in medical device clinical studies. This guidance has important implications for trial design, data analysis, and Premarket Approval (PMA) preparation as well a sponsor’s preparation for FDA Advisory Committee (ADCOM) meetings.

Although it is standard practice to perform subgroup analyses for key demographic factors such as age, sex, race, and ethnicity, device clinical trials are notorious for under-enrolling certain patients (e.g., women, ethnic minorities). As a result, sponsors are often unable to draw meaningful conclusions about whether the trial findings are generalizable to the broader patient population. While sponsors typically fall back on the claim that the enrolled study population represents the US population as a whole, the FDA recognizes the challenges in achieving the appropriate enrollment of diverse populations. The guidance document provides recommendations to overcome barriers to enrollment with the least burdensome principles.

Importantly, the FDA’s final guidance points out that “If results of your analysis suggest that there is insufficient data to assess whether age, race, or ethnicity is associated with clinically meaningful differences in outcome, FDA may determine that clinical data from additional subjects in one or several of demographic subgroups may be needed pre- or post-market to address potential age-, race-, or ethnicity-specific questions related to safety or effectiveness (or probable benefit for [humanitarian device exemptions]) in any or all of those subgroups.” Translation? If sponsors don’t have an adequate sample size to look at these important subgroups, the FDA may require enrolling additional subjects, which will translate into delays in product approval.

A Look at the FDA’s Guidance

The final FDA guidance has three objectives. First, it focuses on the pre-investigational device exemption (IDE) phase and encourages sponsors to consider methods to promote subgroup enrollment when designing their clinical trials. Specifically, the guidance states that sponsors should set minimum enrollment targets for age, race, and ethnicity subgroups and highlights the importance of meeting these targets in the study protocols and investigator materials. This includes considering barriers to enrollment such as obstacles to participation; elimination of inclusion or exclusion criteria that could unduly affect a particular group; and pressure on investigators to enroll regardless of demographic profile. The guidance also details ways to help sponsors reduce unbalanced loss to follow-up in these subgroup populations.

The second objective is to outline analysis recommendations. This includes a decision tree illustrating how differences by subgroup impact the interpretation of overall study results. The guidance recommends detailing prespecified subgroup analyses in the statistical analysis plan (SAP), which includes descriptive and multivariate analyses of pre-market data. The guidance is clear: if there are clinically meaningful and statistically significant differences by subgroup, the FDA may consider the data NOT poolable across subgroups, and this may have significant implications on a trial’s ability to meet safety and effectiveness endpoints.

The last objective of the guidance is to specify the FDA’s expectations for reporting subgroup information in summaries and labeling. In addition to reporting subgroup results to the FDA, the guidance calls for public reporting of enrollment proportions and results. The guidance directs sponsors to include demographic data in IDE annual reports, summaries of safety and effectiveness, and all mandated post-market reporting. In this reporting, the FDA is looking for any differences in outcomes by subgroup, including differences that are clinically meaningful and/or statistically significant and analyses conducted to determine subgroup conclusions.

Implications for Sponsors

Given the ongoing questions that sponsors have received both from FDA PMA deficiency letters and from FDA ADCOM members, it appears that device sponsors will need to follow practices already established in many pharmaceutical trials of predefining stratified enrollment to ensure adequate representation of subgroups.

For sponsors in the pre-IDE phase, we recommend careful review of the final guidance and incorporation of a strategy for enrollment and retention of patients in these subgroups. The potential impact of lack of poolability due to differences by subgroup and its impact on overall safety and effectiveness of hypothesis testing should also be considered.

We also recommend seeking feedback from external experts on your study design and approach to enrolling subgroups before IDE submission. These experts can objectively review your strategy and offer specific recommendations as part of an advisory board. Ideally, the advisory board will be comprised of both individuals previously employed by the FDA and those who have been participants in FDA ADCOMs.

For sponsors whose clinical trial has already started, the FDA is clear that pre-market submissions should contain both subgroup analyses and discussion of any observed clinically meaningful differences with respect to the benefit-risk profiles by subgroup. If substantial differences by subgroup are observed, it will be critical to justify your position regarding the need for additional premarket data collection. A deficiency letter from the FDA requiring additional data collection clearly would delay the time to market. Prior to PMA submission, we also recommend that the primary endpoints, subgroup analyses, and benefit-risk profiles be reviewed by an external advisory board.

This final guidance provides additional insights into how the FDA’s Center for Devices and Radiological Health will review future regulatory submissions. Sponsors need to get serious about conducting clinical trials that include a diverse population that reflects the intended use population. Failure to do so may result in consequences that will significantly delay product approvability.