In February 2019, the FDA will require that data from medical device studies conducted outside the U.S. be gathered in accordance with good clinical practices, including review and approval from an independent ethics committee and well-documented informed consent.
While many sponsors may already conduct international clinical investigations in accordance with GCPs, the agency said these practices will now be mandatory. However, the FDA will allow for flexibility when the requirements cannot be met, and grant waivers on a case-by-case basis.
The agency’s final rule applies to data intended to support IDE applications, 510(k) submissions, and de novo classification requests, as well as applications for premarket approval, product development protocols and humanitarian device exemptions. It also applies to bench and in vitro diagnostic studies of de-identified specimens.
The new mandates would replace the current pre-market approval regulations that require clinical studies to conform to the Declaration of Helsinki or the law of the country where the research is conducted, whichever carries greater protection for human subjects, the FDA said. The rule does not apply to all clinical investigations performed overseas, but only sets criteria for FDA acceptance of data used to support device marketing applications or submissions.
Included in 21 CFR 812.28, the updated regulations do not specify a particular GCP standard for sponsors to follow, but instead include a more flexible definition of principles that it describes as well-recognized and generally accepted. The rule defines GCP as standards for the “design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical investigations” that assure results are accurate and the rights and safety of subjects were protected. This includes initial and continuing ethics committee approval, and obtaining freely given informed consent.
This definition allows sponsors of clinical trials conducted outside the U.S. to determine their own appropriate standard, the FDA said.
As an example of an applicable standard, the agency pointed to the ISO’s GCPs for medical device clinical investigations, ISO 14155:2011, which was recognized by the FDA in 2012 and was developed with the participation of several countries and device companies. The ISO standard is also recognized by most of the members of the International Medical Device Regulators Forum, the agency said. “Such standards help provide assurance not only that the research results are credible and accurate, but that the rights, safety and well-being of patients participating in these studies are protected,” Scott Gottlieb, commissioner of the FDA said, describing how the new regulations can also make product development more efficient, by helping device companies determine earlier in the process whether their global clinical trials can support an FDA marketing authorization.
The final rule requires sponsors to provide statements of compliance, the names of the investigators and their qualifications; a description of the research facilities and their addresses; the location of sites used for maintaining study records; and a detailed summary of the protocol and results of the investigation. Descriptions of the informed consent process, participation incentives, monitoring procedures, and GCP training should be provided as well.
Sponsors must also summarize the ethics committee’s decision to modify or approve the investigation, and records describing the qualifications of committee members must be available for agency review upon request.
The final rule includes several changes to the version first proposed by the FDA in February 2013 — including different requirements for supporting information based on whether the device carries significant risk. Sponsors of non-significant risk devices need to submit their rationale for the categorization, and do not need to submit demonstrations that their data constitutes valid scientific evidence.
The FDA also published a frequently asked questions guidance on how to meet the agency’s requirements, request waivers and provide the required information to support clinical data submissions.
Outside of official waiver requests, sponsors can include statements in premarket submissions and applications explaining why the investigation was not conducted under GCPs, while describing the steps taken to ensure accurate results and patient well-being.
The agency does not expect many waivers to be requested, but allows that certain circumstances may require it. For example, the FDA requests investigator case records, hospital records or additional background data that cannot be provided as required because disclosure is prohibited by local laws. For the FDA to rely on the affected data, the guidance said, the sponsor and the agency would have to agree on an alternate validation procedure. Waiver requests should include the sponsor’s rationale and an alternative course of action, and should be submitted as part of a pre-submission, submission or application amendment.
Waivers may also be requested before initiating a clinical study.
The full final rule is available here: https://s3.amazonaws.com/public-inspection.federalregister.gov/2018-03244.pdf.
The full FDA guidance is available here: https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM597273.pdf.