The U.S. Food and Drug Administration (FDA) recently issued a final rule describing the criteria for using clinical research data from clinical investigations conducted outside of the U.S. in support of various medical device approval applications. 83 Fed. Reg. 7367 (February 21, 2018). The final rule is effective February 21, 2019 and will apply to all clinical investigations that enroll the first subject on or after the effective date. Given the global reach of many device manufacturers, adherence to this final rule will be critically important to obtaining approval to market devices in the U.S.

Per the FDA, the final rule promotes uniformity about the scientific validity of data and assurances of its ethical collection regardless of the location of the clinical investigation or the type of medical device approval application. These new requirements apply to all clinical investigations, even those that use only de-identified leftover human specimens. The requirements are primarily found in new 21 C.F.R. 812.28. The highlights of the requirements are:

  • The applicant must provide a statement that the investigation was conducted in accordance with Good Clinical Practice (GCP). Previously the standard was compliance with the Declaration of Helsinki or the laws of the country where the investigation was conducted, whichever provides more protection for human subjects. GCP is defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical investigations in a way that provides assurance that the data and results are credible and accurate and that the rights, safety, and wellbeing of subjects are protected. GCP includes review and approval (or provision of a favorable opinion) by an Independent Ethics Committee (IEC) before initiating an investigation, continuing review of an ongoing investigation by an IEC, and obtaining and documenting the freely given informed consent of the subject. Importantly, the FDA is not mandating use of a particular published standard for GCP; instead it is providing a general definition that permits manufacturers to select from several published standards. The information submitted in support of adherence to GCP must include a description of the actions the sponsor or applicant took to ensure that the research conformed to GCP, including:
    • The names of the investigators and the names and addresses of the research facilities and sites where records relating to the investigation are maintained;
    • The investigator’s qualifications;
    • A description of the research facility(ies);
    • A detailed summary of the protocol and results of the investigation and, should FDA request, case records maintained by the investigator or additional background data such as hospital or other institutional records;
    • Either a statement that the device used in the investigation conducted outside the United States is identical to the device that is the subject of the submission or application, or a detailed description of the device and each important component (including all materials and specifications), ingredient, property, and principle of operation of the device used in the investigation conducted outside the United States and a comparison to the device that is the subject of the submission or application that indicates how the device used in the investigation is similar to and/or different from the device that is the subject of the submission or application;
    • If the investigation is intended to support the safety and effectiveness of a device, a discussion demonstrating that the data and information constitute valid scientific evidence;
    • The name, address, and the qualifications of the IEC that reviewed the investigation;
    • A summary of the IEC’s decision to approve or modify and approve the investigation, or to provide a favorable opinion;
    • A description of how informed consent was obtained;
    • A description of what incentives, if any, were provided to subjects to participate in the investigation;

    • A description of how the sponsor(s) monitored the investigation and ensured that the investigation was carried out consistently with the protocol; and
    • A description of how investigators were trained to comply with GCP and to conduct the investigation in accordance with the protocol, and a statement on whether written commitments by investigators to comply with GCP and the protocol were obtained.
  • An applicant may request a waiver of any requirement, which the FDA may grant if doing so is in the public interest.
  • FDA may accept information from a clinical investigation that does not satisfy the requirements if FDA believes that the data and results are credible and accurate and that the rights, safety, and wellbeing of subjects have been adequately protected.

Device manufacturers will want to review their policies and procedures for non-U.S. clinical investigations in light of these new FDA requirements. Coordination of the new FDA requirements with the clinical research laws and privacy requirements of the country where the research is conducted may be challenging and require analysis and training.