Potential Major Changes in Updated Draft Pre-Sub Guidance

By far one of CDRH’s greatest recent successes has been the Pre-Submission program. In our experience, more companies have been engaging early and often with the Agency to discuss product-related regulatory issues and questions. Under the Food and Drug Administration Reauthorization Act and the MDUFA IV Commitment Letter, certain changes were made to the Pre-Submission program. Most of these were minor timing changes, which were implemented in FDA’s revision to the Pre-Submission guidance issued in September 2017 (see our earlier post here).

The MDUFA IV Commitment Letter indicated that CDRH would issue a revised draft of the Pre-Submission guidance before October 1, 2018. Well ahead of schedule, FDA released a revised Pre-Submission draft guidance on June 7, 2018 (see draft here). We were a bit surprised about by the fact that the new draft guidance was a complete rewrite of its current version because the changes directed in the MDUFA IV Commitment Letter were relatively minor appeared to have been addressed in the September 2017 version of the guidance. In addition, the MDUFA IV Commitment Letter stated, “FDA will continue the Pre-Submission program as described in the Guidance on ‘Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with FDA Staff’ with process improvements and performance goals as noted in this section.”

Despite this obligation to continue the Pre-Submission program as described in the guidance, the draft guidance includes several changes that potentially limit the scope and utility of certain pre-submission types. As discussed further below, FDA proposes limiting pre-submissions to only 3 to 4 substantive questions. The Agency also proposes changing the Submission Issue Meeting Request program to only give certain requests the 21 day review priority, and all others will receive the standard review.

In prior versions of the Pre-Submission guidance, FDA has not limited the scope of a Pre-Submission. In the current draft, however, FDA states that the Agency “has found it difficult to address more than 3-4 substantial questions in a single Pre-Sub.” This isn’t explicitly saying that sponsors need to limit their Pre-Submissions to only this small number of questions, but it certainly shows FDA’s preferences for shorter, more targeted pre-submissions. In a normal Pre-Submission, three-to-four questions could relate to a clinical study plan alone without addressing other important questions such as regulatory strategy. The guidance does not state what, if anything, it will do if a manufacturer submits a Pre-Submission with more questions. Perhaps companies will respond by collapsing multiple questions into a single, broader question rather than multiple, more targeted queries.

Second, and potentially more significant, the draft guidance proposes changes to the Submission Issue Meeting (SIM) Request process. Of all the Pre-Submission types, I must admit that this process is my personal favorite. It gives manufacturers a tremendous opportunity to interact with a submission’s review team as it is preparing a response to a request for additional information (e.g., for a 510(k) or a De Novo). We have found this process to be very productive, including allowing manufacturers the ability to push back on and discuss alternative strategies for responding to FDA’s additional information requests. For those who have not utilized the program, as with all Pre-Submissions, it takes sponsors time to prepare a SIM Request package in order to gain meaningful feedback. For example, it often takes significant time to research and prepare draft protocol outlines or alternative approaches to address FDA’s requests. Currently, the Pre-Submission guidance indicates that FDA will hold SIMs within 21 days of receiving such a request. The draft guidance, on the other hand, proposes only meeting the 21-day timeframe for SIM Requests submitted within 30 days of a request for additional information being issued. SIM Requests submitted after 30 days will receive feedback within the standard 70-day timeframe for a normal Pre-Submission.

FDA’s stated rationale for prioritizing SIM requests submitted within 30 days is that it allows the Agency to “leverage the familiarity with a recent review without the need to re-review the issues. This also incentivizes prompt resolution of issues by both FDA and Industry in order to achieve the MDUFA Shared Outcome goals for Total Time to Decision.” While we appreciate that it takes time for FDA to refresh its memory on a particular AI request, this rationale, in our view, is a stretch. Let’s take a typical example: FDA issues a request for additional information for a 510(k) around FDA day 60. The Sponsor then has 180 days in which to respond to the request. In our experience, most companies take more than 30 days to respond to FDA’s request; in fact many take close to or all 180 days. When the Sponsor does respond, FDA has approximately 30 days left in which to make its decision under its MDUFA goal. Once the substantive response is received, regardless of how long it took the Sponsor to prepare it, FDA does not appear to have an issue refreshing its memory on the file or the questions that were asked in order to make a final, substantive decision in 30 days. Thus, it seems implausible that an SIM Request, which usually covers only a subset of a larger AI Request, submitted more than 30 days after issuance of an AI request would require such significant effort on the part of the Agency to “refresh” its memory that it could not provide feedback to a Sponsor in 30 days.

This change could have significant, practical consequences for submission sponsors and CDRH. Thirty days is a very short timeframe to prepare and submit a meaningful SIM Request, particularly for a substantial additional information request. For example, if a company receives an additional information request with 30 or more individual requests, it may take 45 – 60 days to prepare a SIM Request covering the various issues/questions that the sponsor may have within those 30 days. If a Sponsor submits an SIM under FDA’s new proposal on day 60 of the Sponsor’s 180-day response clock, FDA will not provide its feedback until day 130 (70 days after the date the request was submitted). This would leave Sponsors with very little time in which to address FDA’s feedback and meet the 180-day response deadline. Diminishing the value of SIMs doesn’t benefit either FDA or Sponsors. Moreover, an unintended consequence could be companies racing to submit their SIM, which could result in submissions that just aren’t as good as they could have been with more time. We strongly recommend that manufacturers who anticipate continuing the use of the SIM process – or who may use it in the future – to comment on this significant limitation posed in the new draft guidance.

Finally, the guidance includes a revised acceptance checklist, which is much shorter than the current checklist, likely meaning that fewer Pre-Submissions will be rejected as administratively incomplete. The draft also includes sample meeting questions and sample meeting minutes.