On February 21, FDA published a final rule amending its regulations on the acceptance of data from clinical investigations for medical devices (83 Fed. Reg. 7366). These amendments are designed to ensure the quality and integrity of clinical data and the protection of human subjects. FDA simultaneously released a draft guidance listing frequently asked questions about the new final rule. The final rule is effective for all studies in which enrollment begins on or after February 21, 2019.
Overall, the new rule seeks to provide a consistent approach to acceptance of clinical data, regardless of whether the data were collected inside or outside the United States (OUS). To this end, however, the amendments mostly affect the requirements for clinical investigations conducted OUS. As noted in FDA’s draft guidance, these amendments appear to be, in part, the result of sponsors’ increased reliance on data from clinical investigations conducted OUS.
For Investigational Device Exemption (IDE) applications or premarket submissions supported by clinical data from investigations conducted OUS, the final rule adds a new provision to the IDE regulations (21 C.F.R. § 812.28) to ensure that the investigations comply with good clinical practices (GCP). This new provision states that FDA will accept data from a clinical investigation conducted OUS if the investigation is “well-designed and well-conducted” and the following information is provided:
- A statement that the investigation was conducted in accordance with GCP;
- 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;
- A detailed summary of the protocol and results;
- Either a statement that the device used in the investigation is identical to the device that is the subject of the submission, or a detailed description of the device used in the investigation and a comparison to the device that is the subject of the submission;
- If the investigation is designed to support the safety and effectiveness of a device, a discussion demonstrating that the data constitute valid scientific evidence within the meaning of 21 C.F.R. § 860.7;
- The name and address of the Independent Ethics Committee (IEC) that reviewed the investigation;
- A summary of the IEC’s decision to approve or modify and approve the investigation;
- A description of how informed consent was obtained;
- A description of any incentives provided to the subjects to participate;
- A description of how the sponsor monitored the investigation; and
- A description of how investigators were trained to comply with GCP and to conduct the investigation in accordance with the protocol.
For the purposes of this provision, 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 well-being of subjects are protected.” 83 Fed. Reg. 7366, 7386 (new § 812.28(a)(1)).
As noted in items 8 and 9 above, GCP includes review and approval by an IEC. An IEC is defined as an “independent review panel that is responsible for ensuring the protection of the rights, safety, and well-being of subjects involved in a clinical investigation and is adequately constituted to ensure that protection.” 83 Fed. Reg. 7366, 7385 (new § 812.3(t)). The regulation notes that an Institutional Review Board (IRB) is one type of IEC.
For significant risk devices, all of the items in the list above are required. For devices other than significant risk devices, the sponsor only needs to provide items 1, 2, 5, 6, 8‑10, and 12 from the above list in the submission.
If a sponsor is not able to comply with all of the GCP requirements listed above (e.g., because a requirement conflicts with a requirement in the country where the study is conducted), the sponsor may request a waiver from FDA.
The final rule also made conforming revisions to the premarket approval (PMA) application regulations in Part 814. The PMA regulations will now provide that if any clinical investigation in support of a PMA application was not conducted in compliance with Part 50, Part 56, or GCP, FDA may deny or withdraw approval of the PMA.
Now all IDE applications and medical device premarket submissions with OUS data must confirm compliance with GCP, as defined in the new provision described above. Submissions with data collected inside the United States must include a statement that each investigation was conducted in compliance with the applicable requirements in the protection of human subjects regulations (21 C.F.R. Part 50), IRB regulations (21 C.F.R. Part 56), and the IDE regulations (21 C.F.R. Part 812). If any of these regulations do not apply (e.g., for IDE-exempt, non-significant risk studies), or the investigation was not conducted in compliance with these regulations, an explanation must be included in the submission.
In practice, it might be a good idea to for anyone submitting a 510(k) to add a new section that would include the statement of compliance, along with whatever additional information is required under the new rule. One can imagine that FDA will eventually add this statement as another item on the 510(k) “Refuse to Accept” checklist, so a separate section will provide greater clarity that the information is there.
These new provisions and FDA’s draft guidance will hopefully provide greater clarity to sponsors about how to demonstrate that clinical data collected from clinical investigations conducted OUS are adequate under FDA’s standards. However, now that the requirements are explicitly listed in FDA’s regulations, FDA will have less flexibility or discretion to accept OUS clinical data if compliance is not shown. The new regulations will also increase the burden on sponsors, who must now affirmatively produce and/or describe in their IDE applications or premarket medical device submissions the items listed above.
* Law Clerk