Draft Guidance on Evaluation and Reporting of Age, Race and Ethnicity May Have Significant Impact on Medical Device Clinical Trials


On June 1, FDA issued a draft guidance, Evaluation and Reporting of Age, Race and Ethnicity Data in Medical Device Clinical Studies, which provides recommendations for the evaluation and reporting of age, race, and ethnicity data in medical device clinical studies.  This draft guidance has important implications for trial design, data analysis, and PMA preparation as well Sponsor’s preparation for FDA advisory committee meetings.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 fallen back on the claim that the enrolled study population represents the U.S. population as a whole, it is clear that this will not be adequate once this guidance is formalized.

Importantly, FDA’s new draft guidance points out that “If results of your analysis suggest that there is insufficient data to assess whether age, race or ethnicity is associated with clinically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 outcomes, 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 ethnic-specific questions related to safety or effectiveness in any or all of those sub-groups.” Translation?  If Sponsors don’t have adequate sample size to look at these important subgroups, FDA may require enrolling additional subjects, which will translate into delays in product approval.

Guidance Summary

The new FDA draft guidance has three objectives.  First, it focuses on the pre-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 highlight 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 impacts the interpretation of overall study results.  The guidance recommends detailing pre-specified subgroup analyses in the Statistical Analysis Plan (SAP) which include descriptive and multivariate analyses of pre-market data.  The guidance is clear that if there are clinically meaningful and statistically differences by subgroup, the FDA may consider the data are 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 FDA’s expectations for reporting subgroup information in summaries and labeling.  In addition to reporting subgroup results to FDA, the guidance calls for pubic reporting of enrollment proportions and results.  The guidance directs for inclusion of demographic data in IDE annual reports, Summary of Safety and Effectiveness, and all mandated post-market reporting.  In this reporting, FDA is looking for any differences in outcomes by subgroup. This includes differences that are clinically meaningful and/or statistically significant and analyses conducted to determine subgroup conclusions.

Implications for Sponsors

Based on the FDA’s intent to expand the policy set in the 2014 Guidance Evaluation of Sex-Specific Data in Medical Device Clinical Studies to age, race and ethnicity, it is unlikely that this will remain a draft guidance for long.  Given the ongoing questions that Sponsors have received both from FDA PMA deficiency letters and from FDA Advisory Committee 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 draft 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 to overall safety and effectiveness hypothesis testing should also be considered.

We also recommend seeking feedback with 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, this Advisory Board would be comprised of both individuals previously employed by the FDA and those who have been participants on an FDA Advisory Panel.

For Sponsors whose clinical trial has already started, 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 FDA requiring additional data collection clearly would delay time to market.  Prior to PMA submission, we also recommend that the primary endpoints, subgroup analyses, and benefit-risk profile be reviewed by an external Advisory Board.

This new draft guidance provides additional insight into how CDRH will review future regulatory submissions.  It is clear that Sponsors will need to get serious about conducting clinical trials that include a diverse population that reflect the intended use population.  Failure to do so may result in consequences that will significantly delay product approvability.


headshot-susan-resnickSusan Resnick, PhD, has 20 years of experience in clinical research, medical device technology and regulatory strategy. As a scientific executive at 3D Communications, she guides clients through critical meetings with FDA, including Advisory Committee meetings. She has published more than 35 articles in peer-reviewed medical journals. Connect with her on LinkedIn