FDA Issues Final Guidance on the Medical Device Pre-Submission Program

By Allyson B. Mullen –

On February 18, 2014, the FDA issued the Final Guidance “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff” (the “Pre-Sub Guidance”).  FDA, Guidance for Industry and FDA Staff, Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff (February 2014).  Subsequently, on February 26, 2014, FDA held a webinar regarding the Pre-Sub Guidance (the “Webinar”).  During the Webinar, FDA explained the key provisions of the Pre-Sub Guidance, and discussed various types of requests for feedback that are covered by the guidance.  FDA will be posting a transcript, audio recording and slides will be available here. 

As you may remember from our earlier post, a draft of the Pre-Sub Guidance was issued in July 13, 2012.  The draft guidance was issued to document the expansion of the pre-Investigational Device Exemption ("IDE") program to include requests for feedback on other device pre-market submission types such as premarket approval ("PMA") applications, humanitarian device exemption ("HDE") applications, and premarket notification (510(k)) submissions.  The draft guidance also broadened the program to include devices regulated by the Center for Biologics Evaluation and Research ("CBER"). 

Since the issuance of the draft guidance, the Pre-Sub program has been a useful mechanism for applicants and study sponsors to obtain feedback from FDA.  Similarly to the draft guidance, the Pre-Sub Guidance provides direction as to when a Pre-Sub is particularly useful.  For example, a Pre-Sub is recommended (i) before conducting a long-term or material investigation of a new device, particularly, if the device involves novel technology, a “first of a kind” indication for use, or does not have a clear regulatory pathway, and (ii) before conducting a clinical study without an IDE, including clinical studies outside the US, non-significant risk clinical studies and IDE exempt studies.  Pre-Sub Guidance at 9-10.  Although the Pre-Sub process can be useful in many situations, it is not for everything, including general information requests or questions regarding FDA policy or procedures, and requests for clarification regarding technical guidance documents.  Id. at 12. 

The Pre-Sub Guidance has been expanded from its draft form (obvious from its length alone, growing from 35 pages to 53 pages).  The Pre-Sub Guidance encompasses Pre-Subs and also various meetings with FDA, including:

• Formal early collaboration meetings to provide direction regarding development and testing of devices that require a clinical study(ies) to support their pre-market applications (“Determination Meetings” pursuant to Section 513(a)(3)(D) of the Federal Food, Drug, and Cosmetic Act (the “Act”) and “Agreement Meetings” pursuant to Section 520(g)(7) of the Act);
• Meetings required no later than 100 days after receipt of a PMA application (“Day-100 Meetings” pursuant to Section 515(d)(3) of the Act);
• Informal meetings to discuss additional information requests on pending pre-market submissions (“Submission Issue Meetings”);
• Requests for determination regarding whether a proposed clinical study is exempt from or subject to the IDE regulations, and if a study is subject to the IDE regulations, whether a study is significant risk or non-significant risk (“Study Risk Determinations”); and
• Meetings to inform or educate FDA about devices in development and/or planned submissions without requesting feedback (“Informational Meetings).

79 Fed. Reg. 9226, 9227 (Feb. 18, 2014).  All Pre-Subs and meeting requests will be referred to by FDA as “Q-Subs” and will be assigned a Q number (Q followed by two digits for the year and four digits representing the order in which it was received).  Pre-Sub Guidance at 5.  Appendix 1 of the Pre-Sub Guidance contains recommendations for each type of Q-Sub.  Id. at 31.

The major changes in the final Pre-Sub Guidance from the draft guidance include:

• Revisions to broaden the overview of possible mechanisms for FDA feedback prior to a planned submission;
• Reorganization to include a discussion of the various request types first, followed by a section regarding meeting procedures, which applies to all feedback mechanisms that request a meeting or teleconference; 
• Revisions to include an acceptance review process, including an acceptance checklist for all Q-Subs; and 
• Revisions to clarify that if more than one year has passed since the Agency provided feedback on a Q-Sub and the applicant has not submitted an application to the Agency, the applicant can confirm the validity of the prior feedback by calling the lead reviewer or the branch chief.

79 Fed. Reg. at 9928.  Regular readers of our Blog will also be happy to hear that the Pre-Sub Guidance states that applicants must submit an eCopy, thereby correcting the inconsistency that existed between the draft guidance and the eCopy Guidance.  Pre-Sub Guidance at 6.  Applicants should ensure that their Pre-Submissions comply with the requirements of the final guidance document for the eCopy Program for Medical Device Submissions (the “eCopy Guidance,” we previously blogged on the guidance here and here.) 

One other administrative change that FDA emphasized during the Webinar was the change to the process for meeting minutes.  Following the meeting or teleconference, the applicant should draft meeting minutes and submit the draft (including any slides from the meeting) to the Document Control Center (“DCC”) within 15 calendar days of the teleconference or meeting. In the draft guidance, meeting minutes were submitted to the lead reviewer following the meeting.  In the Pre-Sub Guidance, the draft minutes will be logged as a formal amendment to the Q-Submission. The Webinar presenters explained that FDA will review and edit the meeting minutes, if necessary, within 30 days of receipt.  FDA’s edited version, if edits were made, will become the final record of the meeting/teleconference 15 calendar days after the applicant receives FDA’s edits, unless the applicant submits a “meeting minutes disagreement” during that timeframe.  A “meeting minute disagreement” should be filed by the applicant as an amendment to the Q-Sub through the appropriate Document Control Center.  Id. at 29.  These procedures underscore how the process has been greatly formalized compared to the Pre-IDE process.

Although FDA received comments regarding the timeframe for providing responses to Pre-Subs (a goal of 75 to 90 days in the draft guidance), this time frame has not changed for Pre-Subs.  However, the Pre-Sub Guidance does contain a helpful chart with the feedback timeframes for each type of Q-Sub:

Id. at 5.  During the Webinar, FDA explained that the Q-Sub review timeline will not change if the underlying pre-market submission has been granted priority review.

The most interesting of the changes to the Pre-Sub Guidance is certainly the addition of the Q-Sub Acceptance Checklist (Appendix 2), which applies to all Q-Subs except for PMA Day 100 Meeting requests.  Id. at 47.  FDA intends to perform an “Acceptance Review” within 14 calendar days of receiving a Q-Sub that includes a valid eCopy.  Id. at 6.  As explained during the Webinar, the Acceptance Review will be performed by the reviewing branch at the Center.  The Acceptance Review is intended to “(1) determine if the request meets the definition of the identified Q-Sub type and (2) determine if a qualifying request is administratively complete.”  Id.  If the submission does not include sufficient information to allow the Agency to make these determinations then the applicant will receive a notice indicating the reasons that the submission was not accepted.  During the Webinar, FDA explained that it will begin performing the Acceptance Review in the next few weeks. 

In addition, the Webinar presenters stated that the Acceptance Review will be performed in parallel with the timeframes listed in the table, above.  For example, if an applicant submits a Submission Issue Meeting request, the first 14 days of the 21 day timeframe for review will be allocated to the Acceptance Review.  Thus, the total timeframe for Submission Issue Meeting review will be 21 days, not 35 days (14 days for Acceptance Review + 21 days for substantive review).  In fact, FDA noted during the Webinar that it understands the urgency of Submission Issue Meetings, and plans to perform the Acceptance Review for these Q-Subs in less than 14 days, if possible.

The Pre-Sub Guidance attempts to distinguish the Acceptance Review from the 510(k) and PMA Refuse to Accept (RTA) Policies by not including a list of required elements, which need to be in a Q-Sub in order for it to be accepted.  In fact, the Pre-Sub Guidance indicates that, if the Q-Sub includes the basic information necessary for FDA to provide the requested feedback and/or identify the appropriate attendees for scheduling of a meeting or teleconference, then “additional clarifying or explanatory information” can be provided after acceptance upon request of the lead reviewer, if needed. 

We certainly hope that the Pre-Sub Acceptance Review has better success than the 510(k) RTA process (some of the issues with the 510(k) RTA process are discussed in our recent post here).  As of September 2013, approximately 60% of all newly filed 510(k)s were refused under the RTA.  CDRH Meeting FDASIA Goals, Confirms Compliance Re-Org, DEVICES & DIAGNOSTICS LETTER (FDA News, Falls Church, V.A.), Sept. 30, 2013, at 1.  If 60% of new Pre-Subs are refused under the Pre-Sub Guidance’s Acceptance Review, it would unduly delay requests for feedback that are often times meant to take place early in the development and planning process.  Thus, this could cause delays to device approvals/clearances and/or initiation of clinical trials for new devices, which could discourage companies from conducting clinical trials in the United States (note: one of FDA’s strategic priorities for 2014-2015 is to encourage sponsors of clinical trials to conduct those trials in the United States rather than overseas and to do so early in the device development process (see our earlier post here).  Even with this added administrative hurdle for applicants to navigate, we expect that the Pre-Sub Program will continue to be a useful process for applicants to receive feedback from FDA prior to or in connection with nearly any type of device pre-market submission and/or clinical study design.