Background: Electronic submissions for medical devices
- Under section 745A(b) of the Federal Food, Drug and Cosmetic Act, as amended by the FDA Safety and Innovation Act (FDASIA), the FDA has the statutory authority to require medical device submissions – including amendments or supplements – to be submitted under specific electronic design formats. In 2017, section 207 of the FDA Reauthorization Act (FDARA) further amended the agency’s device authority (FD&C section 745A(b)) to state that once the FDA had issued final guidance on an electronic format for a certain submission, it would be required that the submission (or pre-submission) “be submitted solely in such electronic format.” Under the process laid out in statute, the FDA is tasked with recognizing standards for submissions and then issuing guidance on their use. In its commitment letter to industry under the current medical device user fee program, MDUFA IV, the FDA agreed to develop templates and issue guidance on the use of electronic templates for device submissions.
- So far, CDRH has issued a few guidance documents under section 745A(b). These include guidance on the processes by which it would recognize standard formatting for electronic submissions for medical devices (“745A(b) Parent Guidance”). Following the processes outlined in that guidance, it finalized yet another guidance on eCopy submissions in 2019. An eCopy is an electronic version of the medical device submission that is “created and submitted on a compact disc (CD), digital video disc (DVD), or a flash drive.” Under this guidance, sponsors have been required to submit most submission types solely in electronic format under the eCopy program since 2020. However, sponsors must still physically send the submission on digital media to the CDRH Document Center (e.g., mail the flash drive), accompanied by a signed physical copy of the cover letter.
- CDRH has worked to optimize strategies for digital submissions over the past few years. Rather than seeking to rely on digital versions of hard copies, like the eCopy, CDRH has looked to advance fully digital options. In 2018, the agency launched a Quality in 510(k) Review Program Pilot, which leveraged the eSubmitter software for guided submission compilation. That program ended in 2021, replaced by the electronic Submission Template and Resource (eSTAR) pilot, which had begun in February 2020. Unlike the eSubmitter system, eSTAR is intended as a template for fully digital submissions and designed as an XML-formatted system that is organized and structured in a similar format to the FDA’s internal 510(k) Smart template. According to the FDA announcement on the discontinuation of eSubmitter, “[t]he pilot was a success in producing well-organized submissions. However, with the creation of eSTAR, the FDA identified additional benefits associated with submission preparation using eSTAR rather than eSubmitter.”
- In September 2021, the FDA issued draft guidance to transition all 510(k) submissions to the eSTAR system. This guidance is intended to follow on to the final 745A(b) Parent Guidance, which outlined the process by which FDA will develop templates for submissions. The 2021 draft guidance was intended to provide specific information on timelines, process, requirements and formatting of electronic 510(k) submissions. While parts of the guidance document are legally binding under section 745A(b) of the FD&C Act, which grants “explicit statutory authorization to FDA to specify in guidance the electronic submissions requirement,” the draft noted that “provisions not identified as binding… do not have the force and effect of law.”
The FDA has now issued a final electronic submissions guidance for 510(k) pre-market notification applications
- The guidance document includes both binding and nonbinding provisions. As noted above, FDA is statutorily authorized under the FD&C Act to require submissions be submitted in certain formats, including specific electronic design formats. While most FDA guidance relies on non-binding recommendations, this final guidance does include some policies that are statutorily binding: “insofar as this guidance provides ‘standards,’ ‘timetable,’ or ‘criteria for waivers’ and ‘exemptions’ pursuant to 745A(b) of the FD&C Act, it has binding effect.” The non-binding recommendations in the guidance are intended to “provide clarity” about the legal requirements.
- Timeline and transition: Per the final guidance, “FDA is identifying October 1, 2023 as the date on which the 510(k) electronic submission requirements will take effect” (emphasis added). At that time, all relevant 510(k) submissions will need to be submitted in the electronic template format.
- The guidance document outlines the process for submitting an electronic 510(k). As AgencyIQ has previously noted, this particular guidance is intended to outline the process for electronic submission templates – though this does not necessarily just mean eSTAR, currently, “eSTAR is the only electronic submission template currently available to enable 510(k) electronic submissions.” While the guidance “is not intended to specify the user-interface and detailed content of the eSTAR,” the guidance is intended to outline how the electronic format and standards requirements for 510(k)s will meet the section 745A(b) requirements.
- The guidance finalized the FDA’s definitions of key terms. The guidance outlines specific definitions of relevant terms. This includes the term “electronic submissions” (eSubmissions), or “the submission package produced by an electronic submission that contains the data of a ‘complete’ submission,” and submission template as a “guided submission preparation tool for industry” – of which the specific eSTAR template is one (currently available) type.
- The most significant change between the draft and final versions of this guidance relate to exemptions. Under section 745A(b), the FDA can require that applications be submitted in certain formats, including electronic formatting, but also to set specific exemptions or allow waivers from the electronic submission requirements. In the draft guidance, this section was kept short, with the FDA asserting that it had “not identified any circumstances appropriate for a waiver of or exemption from the 510(k) electronic submission requirements.” However, industry raised some issues with this statement – per AdvaMed’s comments, “based on experience with the eSTAR to-date, improvements to the eSTAR template will need to be made to accommodate large submissions, complex medical devices and systems, and/or bundled 510(k) medical device submissions.” In effect, the eSTAR template, which is currently the only available option, is not technically fit for purpose for larger or more complex submissions “that are limited by the small dialogue boxes in the template and would need to be included as additional separate embedded attachments.”
- The final guidance now includes information on limited exemptions from the electronic submission requirement. Specifically, the agency will not require the following information or 510(k) submissions to be submitted in the electronic template format: interactive review responses or specific amendments (i.e., “appeals/requests for supervisory review; substantive summary requests; change in correspondent amendments; and amendments after final decision (i.e., add-to-files)).” However, the agency still maintains that it “has not identified any particular circumstances appropriate for a waiver of the 510(k) electronic submission requirements and does not intend to grant requests for waiver.”
- The final version of the guidance also provides more clarity for industry about the operational process for electronic submissions. As AgencyIQ has previously discussed, FDA has touted submissions using the template system as a way to increase efficiencies because electronic submissions from a guided template will not be required to undergo a Refuse to accept (RTA) process. However, as trade association AdvaMed noted in its comments on the draft guidance, this raised some questions for industry about a new “technical” screening process and its anticipated 15-day timeline. The final version of the guidance adds new information about the technical screening process, now stating that “the technical screening review time does not impact the review clock for files that pass the technical screening. For a submission that passes the technical screening, the review clock starts on the day the submission was received by FDA.” If the FDA identifies that the eSTAR is not complete, “FDA will notify the submitter via email” and then the submission will remain on hold. Interestingly, the new final guidance also adds several footnotes related to the operation of the eSTAR software – for example, when the “eSTAR Complete” status message can be expected and prompts for different documents.
- Structure of the current eSTAR template: The agency outlines the structure of the current eSTAR electronic submission template in Table 1 (page 10) of the guidance. Compared to the draft guidance, the final version now incorporates references to performance testing for IVDs – as AgencyIQ noted in our analysis of the draft, it was not yet clear the extent to which eSTAR had been pressure-tested for its use with IVDs, and AdvaMed has previously raised concerns with the eSubmitter system about the different data elements needed for IVDs and other medical devices. AdvaMed had requested the addition of IVD in the performance testing portion of this table in their comments on the draft guidance as well. In addition, the table now clarifies hat Administrative Documentation should be in the eSTAR, “including but not limited to a general summary of submission/executive summary (recommended), a Truthful and Accuracy Statement, and a 510(k) Summary or statement,” and further includes a field for Additional Information (AI) responses.
- For Additional Information responses: The agency added a new point of clarification about AI responses (footnote 52): “while the responses to FDA additional information requests are included in this [AI] section [of the template], submitters should include the actual changes to the information to be reviewed by FDA in the respective section of eSTAR (e.g., updated draft labeling should be included in the Labeling section).” As noted above, reviews using interactive review are one of the exemptions from the eSTAR requirement, and the agency goes on to explain (footnote 54) that “if the reviewer used interactive review via phone or email, the submitter should reply to the reviewer via email with he requested attachments and additional information.” However, all other response to requests for additional information “must be submitted in eSTAR.”
What’s next? A transition period and potential changes to eSTAR
- The effective date for the new electronic submission requirement is October 2023. The final guidance document refers to the period between the time when the requirement will take effect and the guidance document’s publication as a “transition period,” during which time, “up to the point when 510(k) electronic submissions will be required… anyone can voluntarily use eSTAR for 510(k) submissions.” Firms can continue to use the current system (saving their 510(k) submission to electronic storage media and mailing it to FDA) during this period, but only “if they are received by FDA before October 1, 2023.”
- New versions of eSTAR. Throughout the guidance, the agency acknowledges that eSTAR as a template continues to evolve, and that the “FDA intends to implement new versions of eSTAR as relevant policies change.” However, whether updates to the template will be able to account for the issues raised by AdvaMed about the more technical and operational shortfalls for more complex submissions remains to be seen – and may become more pressing as the deadline looms.
- The agency is still taking feedback on the eSTAR program, and is working to build it out for other product types – including De Novo requests and certain applications under CBER’s authority. Altogether, it’s likely that the eSTAR template will gain functionality over time, but firms will need to carefully assess their own technological and operational readiness.