On April 22, 2015, the US Food and Drug Administration (FDA) released for comment a draft guidance on the Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States (OUS). This document is directed to sponsors using clinical data from OUS studies to support device submissions in the US. Comments regarding the draft need to be submitted by July 20, 2015.
Framework for Acceptance of OUS Data
In July 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) was put into effect requiring further evaluation of OUS clinical data. Specifically, according to the updated section 569B of the Food, Drug, and Cosmetic Act (FD&C Act), FDA recommends that for OUS clinical data to be used, it needs to be “adequate under applicable standards to support approval, licensure, or clearance of the device in the United States.” FDA has identified many challenges in the acceptance of OUS data including differences in the study population, extrapolated endpoints, disease characteristics, and standard of treatment in the US.
FDA has a long history of accepting OUS clinical data and has issued the draft guidance to assist sponsors in developing clinical data that are adequate to support approval or clearance of the device in the US.
Valid Scientific Evidence
To be accepted for US device submissions, OUS data must constitute “scientifically valid” clinical evidence. In the guideline, FDA defines valid scientific evidence to be evidence from well-controlled investigations, partially-controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, or reports of significant human experience with a marketed device, from which it can be fairly and responsibly concluded that there is reasonable assurance of safety and effectiveness under the intended use. FDA advises sponsors to seek approval and feedback on OUS data as early as possible using the Pre-Submission process, preferably before the initiation of the OUS study to ensure the avoidance of duplicate studies with the US. Considerations that could impact the use of OUS data include:
- Differences in clinical conditions
- Inconsistencies in clinical facilities, levels of clinical skill, and standards of care.
- These differences can affect the analysis of the benefits and risk of the studied device relative to US practice and could impact the ability of the data to support safety and/or effectiveness of the device.
- Differences in study populations
- Inconsistencies in demographics, culture, education, language, and confounding clinical factors (i.e. race, ethnicity, gender, sex, smoking, diabetes, obesity).
- These differences can affect the applicability of the data to US population.
- Differences in regulatory expectations
- Inconsistencies in setting the null hypothesis, appropriate endpoints, and implementation of good clinical practice appropriate to FDA standards.
- These differences can affect the overall study design and may not allow for appropriate evaluation of the benefit verses probable risk even if OUS data demonstrates that the device met its assigned endpoint. In many cases, OUS studies are designed to demonstrate safety and performance rather than the US requirements of safety and effectiveness.
In response to what they have previously experienced or can predict, FDA advises that “the sponsor should mitigate the differences or adequately describe why they do not believe those differences would impact the evaluation of the safety and/or effectiveness of the device.”
Due to the variability in the types of issues that may arise when using OUS data, FDA provides example cases along with their considerations for the situation. For more information and detailed examples of potential issues, FDA response, and subsequent outcomes please refer to the FDA draft guidance.
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US Food and Drug Administration. Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States: Draft Guidance for Industry and Food and Drug Administration Staff. April 22, 2015. Available at:http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm443133.pdf.
Submit comments by July 20, 2015 to http://www.regulations.gov or by mail to Division of Dockets Management (HFA-305), Food and Drug Administration, 175630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Identify all comments with the docket number (FDA-2015-D-0975) listed in the notice of availability that publishes in the Federal Register (http://www.gpo.gov/fdsys/pkg/FR-2015-04-21/html/2015-09176.htm).