The FDA often stresses the importance of enrolling diverse patient populations in clinical trials conducted to support product applications — both in industry guidance documents and during interactions with product sponsors. In Evaluation and Reporting of Age-, Race-, and Ethnicity-Specific Data in Medical Device Clinical Studies, guidance released in September 2017, the FDA makes multiple recommendations for submissions, from advising sponsors to “recruit diverse populations that ideally reflect the intended population,” to suggesting they “discuss how clinically meaningful differences across subgroups may contribute to differences in benefit-risk profile in certain subpopulations.”1 When applicable, sponsors should also “submit and publicly report study demographics, including proportion by subgroup and comorbidities.”
But the words “Contains Nonbinding Recommendations” appear at the top of each of the document’s 36 pages — just as they do on most pages of recent FDA industry guidance. In bolded italics, the words suggest that sponsors have some leeway when it comes to heeding FDA guidance. And, to a large degree, they do: Industry guidance is not legally enforceable.
“It’s not that, if you don’t follow [FDA guidance], you have violated a law,” explained attorney Alan Minsk, a partner at Arnall Golden Gregory, in an interview. “You don’t have to take it, but if you don’t take it, at least think about it.” FDA guidance documents often outline specific methodologies and approaches to product development that, if followed, should yield data to support a product’s safety and efficacy, the underlying standards on which the FDA approves or denies applications. Industry guidance “is kind of a word to the wise,” Minsk said. The agency cannot formally deny an application just because a sponsor took another route. Sponsors are free to develop alternative ways of meeting those underlying standards, but it’s up to the FDA to judge whether an alternative satisfies relevant statutes and regulations, generates results demonstrating safety and efficacy and merits approval.
Researchers from Yale University and the University of California-San Francisco recently concluded that sponsors evaluating the safety and efficacy of proposed devices rarely account for the potential influence of a patient’s sex, age or race and/or ethnicity, despite FDA recommendations. A research team examined labels and Summaries of Safety and Effectiveness Data (SSEDs) for each of the 42 original premarket approval (PMA) devices approved in 2015 by the FDA. In all, sponsors performed 82 studies to support the 42 approved PMA applications.
The researchers collected data on the number of patients enrolled according to age, sex and race and/or ethnicity, and also determined whether sponsors had analyzed study results by age, sex and race and/or ethnicity. If they had, the researchers looked to see whether the sponsor had identified a difference in device safety or efficacy.
Their findings appear in the September 2017 issue of JAMA Internal Medicine.2 Overall, sponsors analyzed study results according to age, sex and race and/or ethnicity for fewer than 20% of studies performed to support original PMA devices approved in 2015. Other findings include:
- Age was reported in the SSED for 65% of the 82 studies; for 50%, age was reported in the device label. Sponsors analyzed study data by age in just seven of the 82 studies (9%); one found the device to be less effective in younger patients, while two found the device less effective in older patients. In device labels, six studies (7%) reported results by age.
- Race and/or ethnicity was reported in the SSED for 51% of the 82 studies; for 33%, it was reported in the label. Sponsors analyzed study data by race in three of the 82 studies (4%); of the three, one found the device to be less effective in non-white subjects. In device labels, one study (1%) reported results by race and/or ethnicity.
- Of the 82 studies, 77 included both men and women. Sex composition was reported in the SSED for 66% of them; for 49%, it appeared in the device label. Sponsors analyzed study data by sex in 13 of 77 studies (17%). Of the 13, one found the device to be less safe in men; one found it less safe in women; and one found the device to be less effective in women. In device labels, 12 studies (16%) reported results by sex.
- Dhruva SS, Mazure CM, Ross JS, et al. Inclusion of Demographic-Specific Information in Studies Supporting US Food & Drug Administration Approval of High-Risk Medical Devices. JAMA Intern Med. 2017 Sep 1;177(9):1390-1391. doi: 10.1001/jamainternmed.2017.3148.
Editor’s Note: A longer version of this article was originally published in the Journal for Clinical Studies.