By Allyson B. Mullen –
On April 22, 2015, FDA released a draft guidance regarding use of clinical data generated outside of the U.S. (OUS) in medical device premarket submissions. A copy of the draft guidance can be found here.
FDA states in the guidance that it has a longstanding policy of accepting OUS clinical data in device submissions. However, as many of our readers know, FDA can be very picky when it comes to clinical study data that were not conducted in the U.S. under an Investigational Device Exemption. In 2012, FDASIA attempted to allow greater use of OUS clinical data with the addition of Section 569B of the Federal Food, Drug, and Cosmetic Act. Section 569B requires that FDA accept OUS clinical data if the sponsor has demonstrated that “such data are adequate under applicable standards to support approval, licensure, or clearance of the . . . device in the United States.” 21 U.S.C. § 360bbb-8b(a). If FDA finds that the data are inadequate, FDA must provide written notice to the sponsor with FDA’s rationale for its conclusion. Id. § 360bbb-8b(b).
The draft guidance provides some clarification as to why CDRH and CBER may find that OUS clinical data are inadequate. Specifically, the draft guidance highlights that premarket submission reviewers carefully consider the following when evaluating OUS clinical data:
- Differences in Clinical Conditions. The standard of care for clinical conditions may be different around the world. FDA will likely want to understand how the clinical practice in the region(s) where the study was performed compare to the U.S. as differences in clinical practice can affect the risk benefit profile of the device.
- Differences in Study Population. The patient populations can vary greatly depending on the country in which the study is performed. This differences can affect the applicability of the data to the proposed U.S. population. For example, there may be significant demographic differences (race, ethnicity), rates of certain diseases, or prevalence of other factors (obesity, smoking). FDA will likely want to understand how the study population is representative of the proposed U.S. patient population and that any differences are adequately explained.
- Differences in Regulatory Requirements. The draft guidance notes that the standards for regulatory approval vary depending on the region (e.g., safety and effectiveness versus safety and performance). This difference could also affect a company’s selection of endpoints or control device, if one is used. Thus, the draft explains that the outcome of the study must show that the probable benefits outweigh the probable risks, or although not stated, that the device meets the applicable premarket standard (e.g., substantial equivalence).
None of these considerations come as a surprise and they are routine comments that come up during premarket submission reviews for submissions including OUS data. The draft guidance does provide a number of helpful examples for companies who are unfamiliar with these issues.
The draft guidance recommends that sponsors who intend to utilize OUS data in their submissions contact FDA through the pre-submission process as early as possible so that FDA can provide input. This guidance, however, applies not to just prospective OUS studies, but also to those that have already been performed. There may be little value in seeking FDA input through a pre-submission on a study that is already completed, when this same information can be obtained through the premarket submission review process. This guidance could likely serve as a reminder checklist for sponsors utilizing OUS to data to confirm that they have addressed these considerations in their premarket submissions before submitting to FDA, regardless of whether a pre-submission meeting is held.