On April 22, 2015, the U.S. Food and Drug Administration (FDA) posted draft guidance that articulates the agency’s policy for the acceptance of clinical data from trials conducted outside the United States (OUS) in support of premarket submissions for medical devices [e.g., premarket approval applications (PMA), premarket notifications (510(k)), de novo petitions, investigational device exemptions (IDE), and humanitarian device exemptions (HDE)]. The draft guidance addresses special considerations applicable to OUS data and study design issues. It also provides recommendations to assist sponsors in developing data that are adequate to meet the applicable FDA standards.

The draft guidance is intended to describe the agency’s existing approach to the consideration of OUS data—not to announce new policy. Nevertheless, the draft guidance provides key takeaways for entities that are considering relying on OUS data to support a premarket submission for a medical device:

• Differences between countries in clinical conditions, study populations, and/or regulatory requirements may impact FDA’s willingness to rely on OUS data. The draft guidance identifies the following as “special considerations” when relying on OUS data:

  • Differences in clinical conditions. Foreign countries may have different standards of care than the United States, which can affect the analysis of the benefits and risks of the studied device compared to standard practice. Differences in clinical facilities, and/or levels of clinical skill, can also affect the generalizability of OUS study data to U.S. clinical practice.

  • Differences in study populations. If a device has disparate safety effects or benefits in different demographic groups, differences in the race, ethnicity, age, gender and sex of a foreign population can affect the applicability of the data to the intended U.S. population.  The OUS population may also differ from the intended US population regarding the prevalence of confounding clinical factors that can affect risks of an intervention as well as clinical response.  Cultural and educational differences may also affect the interpretation and applicability of study results, as well as the ability to pool OUS and U.S. data.  

  • Differences in regulatory requirements. An OUS study designed to satisfy the requirements of a foreign country will not necessarily generate the data required to satisfy the FDA’s requirements.  For example, if an OUS study is designed to show that a device meets an endpoint related to performance, the data may not be adequate to show that the probable benefits outweigh the probable risks.

• The FDA recommends that sponsors that intend to rely on OUS data seek input from the agency at the earliest stage possible using the pre-submission process. Because the standards for marketing authorization vary country-to-country, a clinical study that fulfills the standards in one country may not meet the FDA’s requirements. Early collaboration with the agency can facilitate efficient clinical trial design and reduce the possibility that additional clinical studies may be needed to support marketing authorization in the United States. 

The draft guidance gives several examples of issues that may arise when relying on OUS data, and describes how the FDA and sponsors may seek to resolve such issues and the likely FDA review outcomes.  In the examples, the agency indicates that it will—under certain circumstances—take a more flexible approach than it historically has with respect to the acceptance of data that initially raises agency concerns (e.g., the FDA expressed a willingness to rely on (i) post hoc supplementary analyses to address concerns regarding study bias rather than requiring prospective analyses, and (ii) the re-analysis of data for a new endpoint combined with the performance of a small confirmatory study when the original endpoint is not based on current U.S. practices rather than requiring a new, large, prospective trial).

The agency encourages interested entities to submit comments on the draft guidance by July 20, 2015.    

Implications

The draft guidance largely reiterates well-established agency policies with respect to the acceptance of OUS data. That being said, new and experienced medical device sponsors alike may find it useful to review this document. The document provides a high-level overview of the agency’s analytic process for deciding whether to accept foreign clinical data, as well as several examples that illustrate the agency’s position.

Sponsors that are considering whether to rely on OUS data in support of a premarket submission for a medical device should strongly consider heeding the FDA’s advice and meeting with the agency prior to beginning an OUS trial. The draft guidance is the latest statement in which the agency has encouraged sponsors to take advantage of the medical device pre-submission meeting process. This process is intended to give sponsors notice of, and an opportunity to address, the agency’s concerns when such concerns can be more easily addressed (e.g., prior to the finalization of a study design).