2018 has been notable for many reasons, not the least of which has been the flood of guidance documents FDA has issued related to medical devices. This KKB Alert highlights some of the most notable device guidances issued between January 1 and August 30, 2018, as they relate to (1) the implementation of legislative directives in the 21st Century Cures Act (“21CCA”) and the Food and Drug Administration Reauthorization Act of 2017 (“FDARA”), (2) the strategic priorities of the Center for Devices and Radiological Health (“CDRH”), (3) premarket submissions, and (4) postmarket responsibilities and activities. For ease of review, we will post our summary in four parts across four consecutive days to correspond with each of these topics.
III. Guidances Related to Premarket Submissions
In January 2018, FDA updated its PMA filing guidance and checklist. Although much of the guidance is the same, there are a few noteworthy changes. First, although the “preliminary questions” for the initial screening of an application are unchanged, the updated guidance divides the “filing review” questions into two separate categories: (1) “acceptance decision questions,” which address whether the file is administratively complete and (2) “filing decision questions,” which address “whether the data are consistent with the protocol, final device design, and proposed indications.” Second, submission of the manufacturing section is now required for an application to be considered administratively complete. Third, FDA will require sponsors to submit a valid e-Copy before FDA will process a PMA or PMA supplement and begin an acceptance review. Finally, since 21CCA requires submissions for device-led device-drug combination products to include a patent certification statement and provide notice, the updated guidance now contains questions regarding drug patent certifications.
Refuse to Accept Policy for 510(k)s (Jan. 30, 2018) (Final Guidance)
In January, FDA updated in January its “Guidance for Industry: Refuse to Accept Policy for 510(k)s.” This guidance document explains the criteria that FDA uses to assess whether a 510(k) submission is administratively complete and should be accepted for substantive review. FDA staff conducts an acceptance review of all traditional, special, or abbreviated 510(k)s based on criteria listed in the Acceptance Checklist completed by the submitter. All elements identified as RTA (Refuse to Accept) items should be present or the submitter should provide a rationale for why those elements are not applicable. The revised checklist contains new questions that reflect changes that 21CCA made to requirements for combination products.
How to Prepare a Pre-Request for Designation (Pre-RFD) (Feb. 2018) (Final Guidance)
In February, FDA issued a guidance on the pre-RFD process related to combination products. Because the RFD process is formal and binding, sponsors often seek informal advice from the Office of Combination Products (“OCP”) before submitting a formal RFD. FDA issued this guidance to improve the transparency and consistency of the pre-RFD process. According to the guidance, a pre-RFD should be a concise, written submission to OCP with no length limitations (unlike for RFDs, which are limited to 15 pages). Sponsors are required to submit (1) a description of the product, (2) the proposed use or indications for use, and (3) a description of how the product achieves its intended therapeutic/diagnostic effects. The sponsor also has the option of submitting an analysis of the product’s classification, a primary mode of action analysis, a recommendation for an Agency Center assignment, and supportive data/studies.
In 2012, FDASIA amended the FDCA to require FDA to accept data from clinical investigations conducted outside of the United States (“OUS”) if an applicant can demonstrate that the data are adequate under FDA’s standards. In February 2018, FDA issued amended regulations under 21 CFR Parts 807 and 812, clarifying when such data are considered adequate: clinical investigations conducted OUS must comply with good clinical practice (“GCP”) requirements if they will be used to support an investigational device exemption (“IDE”) or marketing application or submission. Some exceptions apply and there is the possibility for seeking a waiver in certain circumstances. FDA issued this final guidance concurrently with the new regulations, which provide further information regarding FDA’s criteria for acceptance of data from OUS clinical investigations. The final rule will be effective one year after publication (February 2019). Investigations conducted OUS that enrolled their first subjects prior to the rule’s effective date may comply with the requirements in 21 CFR 814.45 prior to the rule’s effective date.
Under the existing Abbreviated 510(k) program, FDA permits submitters to use conformity to FDA guidance, FDA-recognized consensus standards, and/or special controls to demonstrate certain performance characteristics necessary to support a substantial equivalence finding. While useful in concept, the Abbreviated 510(k) program has not been widely used and reviews have often taken longer than those under the traditional 510(k) program. Under the proposed Expanded Abbreviated 510(k) program described in this draft guidance, a submitter can compare its device with a legally marketed device by establishing that the device conforms to objective performance criteria established by FDA guidance, FDA-recognized consensus standards and/or special controls to demonstrate that the device meets all the performance characteristics needed to support a substantial equivalence finding. FDA has yet to describe which types of devices may be appropriate for the Expanded Abbreviated 510(k) program. Once developed, FDA will keep an updated list of these devices on its website along with guidance documents identifying the performance criteria for each device type and recommended testing methods.
In May 2018, FDA issued a draft guidance with recommendations regarding the content and format of non-clinical bench performance testing submitted in premarket submissions. The draft guidance outlines the information that sponsors should provide in complete test reports and recommends that all premarket submissions containing complete test reports for non-clinical bench performance test reporting also include a summary report. Specifically, the guidance recommends that the summary briefly describe the test performed, the objective of the test, the test methods/procedures, pre-defined pass/fail criteria (including the clinical/scientific justification for the chosen criteria), the results summary, a discussion of the conclusions, and the location in the submission for each test report. Complete test reports should clearly state the test performed, explain the objective of the test, provide a description of test methods and procedures, report pre-defined pass/fail criteria, list test results (including data points, data analysis, and a description of protocol deviations), and describe the conclusions drawn from tests results as well as the clinical significance of the conclusions.
Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program (June 7, 2018) (Draft Guidance)
Pursuant to MDUFA IV negotiations, FDA agreed to alter the Q-submission program to reflect changes regarding scheduling of Pre-Submission (“Pre-Sub”) meetings and performance goals for FDA feedback on Pre-Subs. The result is an updated guidance pertaining to the Q-submission program, which, when finalized, is intended to supersede the FDA’s final guidance “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff.” The Q-submission draft guidance provides an overview of the methods by which medical device manufacturers can obtain feedback or request meetings with FDA regarding certain premarket submissions such as potential or planned IDE applications, PMAs, HDE applications, de novo requests, 510(k) submissions, and Accessory Classification Requests. The Q-submission program addresses four types of interactions manufacturers may have with FDA prior to submission of an application: (1) Pre-Subs; (2) Submission Issue Requests (“SIRs”); (3) Study Risk Determinations; and (4) Informational Meetings. The guidance provides general parameters for format and information that should be included in a Q-submission as well as specific processes for each submission type. Of particular note, the draft guidance states that FDA will complete acceptance review of valid Pre-Subs within 15 days of receipt.
Use of Electronic Health Record Data in Clinical Investigations (July 2018) (Final Guidance)
In July 2018, FDA finalized its 2016 draft guidance regarding use of electronic health record (“EHR”) data in FDA-regulated clinical investigations. The final guidance makes recommendations on whether and how EHRs should be used as source data for clinical investigations, the interoperability of EHR and electronic data capture systems (“EDC”), how to ensure the quality and integrity of EHR data, and the collection and storage of such data in a manner that follows FDA’s inspection, recordkeeping, and record retention requirements. As part of best practices for using EHRs, the document explains that data management plans should include a list of EHR systems used by each clinical investigation site, and should document the name of the manufacturer, model number, version number, and certification by the Office of the National Coordinator for Health Information Technology (“ONC”). For those systems not certified by ONC, such as EHR systems at foreign clinical sites, FDA recommends that sponsors consider whether such systems integrate certain controls on privacy and security. Additionally, the document explains that although FDA does not intend to assess EHR systems for compliance with 21 CFR Part 11 (Electronic records; Electronic Signatures), it does intend to assess the sponsor’s EDC systems for compliance with Part 11.
 The authors gratefully acknowledge the contributions to this Alert by Dan Logan, KKB associate, and Celeste Wheeler, former KKB associate.