We have seen several changes from FDA with the roll-out of GDUFA III.  Some have been a little frustrating (Controlled Correspondence blog coming soon!), but some have been pretty great!  On February 17, 2023 FDA issued a new GFI, “Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA” (here). This GFI seems to point to the second category- fingers crossed!

Product-Specific Guidances (PSGs) have been around for a while now, though many of us remember the days when they were not.  They have been one of those great communication tools that have been added by FDA, as they outline for industry what the expectations are to demonstrate bioequivalence to the RLD.  Prior to GDUFA III, if you needed to get feedback on a PSG – because you wanted to take a different approach, or you had already run your BE study when it was issued- your only means of communication was through a pre-development meeting (if you had a complex generic product), Controlled Correspondence (CC), or submitting your ANDA with a strong scientific justification and hoping for the best.

This new GFI gives another route for communication on PSGs.  This is a fairly long guidance, so this blog is just to give you some highlights of what it provides.  First of all, this GFI states that the meetings can be held by prospective applicants or applicants that have already submitted ANDAs. The GFI follows that the meetings can be (Section III of the GFI):

  • PSG teleconferences (TCs) (which include pre-submission and post-submission TCs) which are used to get feedback from the Agency on the potential impact of a new or revised PSG on your development program, if this change happens after your studies have already commenced or been completed (this means that the study protocol was signed by the study sponsor and/or the contract research organization before the PSG publication date, or the study is in progress or completed); or
  • Pre-submission or Post-submission1 PSG meetings to discuss scientific rationale for an approach taken other than that recommended in the PSG, to ensure that it complies with relevant statutes and regulations and is acceptable to OGD.

1As noted in GFI footnote 9, there is a risk of conducting the PSG meeting post-submission and prior to ANDA acceptance for filing, as not following the PSG may be considered a refuse to receive violation if adequate justification is not included for not following the approach in a published guidance.

However, you must have a pre-submission PSG TC before you request a pre-submission PSG meeting; likewise, you must have a post-submission PSG TC before you can request a post-submission PSG meeting and the post-submission PSG TC and/or meeting should occur before responding to a possible BE deficiency (either from a DRL or CRL).  If you do respond to the BE deficiency before requesting the meeting, the GFI states they intend to DENY the meeting request (MR) and recommend the sponsor submits a CC (see GFI footnote 14).  Also, if you have a pre-submission PSG TC, then submit your ANDA and request a post-submission PSG meeting, FDA intends to DENY that MR and recommend a CC (see GFI footnote 12); however, the GFI also states you could get feedback through another meeting type, as appropriate (see GFI footnote 16) (refer to GFI Section III).

FDA does provide some specific situations in which a teleconference may not be needed in section III. A. Also, firms should be aware that during a PSG TC, FDA will provide feedback on the potential impact of the recommendations in the PSG, but FDA will not discuss the applicant’s questions regarding an approach other than the approach recommended in the PSG. They may provide a recommendation for future communications with the Agency, whether that be a PSG meeting (pre or post), CC, or another meeting type.

Below is some overall information on each of the meeting types (broken down by pre-submission and post-submission):

Pre-Submission PSG meetings:

  • For a PSG TC: the MR should be submitted within 60 days of the publication of the new/revised PSG (considered as the day it appears on the PSG web page, not the Federal Register publication, per GFI footnote 19).
    • For this MR, applicants can request a teleconference more than 60 days after publication of the new/revised PSG, however the 30-day time frame for conducting PSG teleconferences is only applicable for complete packages submitted within 60 days after publication of the PSG.
  • After the Pre-submission TC- the prospective ANDA applicant has multiple options – if your ANDA is not submitted- you can request a PSG pre-submission meeting, submit a CC, or request another meeting type, as appropriate, to seek input from FDA regarding an alternate BE approach to that in the PSG.
  • The purpose of a pre-submission PSG meeting is to discuss the scientific rationale for an approach other than the recommended approach in the PSG, and to ensure that your approach complies with the relevant statues and regulations and is found acceptable by OGD.
    • Questions unrelated to the alternate BE approach will not be discussed in the meeting.
    • This meeting should be requested in a timely manner after the pre-submission PSG TC.
    • This meeting can be requested even in you have not had a product development meeting.

 

Post-Submission PSG meetings:

  • Post-submission PSG TC can be requested for multiple reasons per this GFI, two of which (#2 & 3) were not described in the GDUFA III commitment letter!
    1. FDA publishes a new/revised PSG that introduces/revises a recommendation related to an in vivo BE study, the ANDA has been submitted, and the applicant has already commenced or completed an in vivo study.
    2. At FDA’s discretion, FDA may grant a meeting when they publish a new PSG which recommends conducting an in vivo BE study and the ANDA applicant did not conduct an in vivo BE study.
    3. FDA publishes a revised PSG which includes a new requirement for an in vivo study when the previous PSG did not include a requirement for an in vivo study, and
      • the ANDA applicant commenced or completed the in vitro BE study or studies that were recommended by FDA in the previous PSG (see footnote 27 for caveat) or
      • studies the ANDA applicant decided to pursue after a prior product development meeting.
  • After the post-submission TC, the ANDA applicant can submit a CC or request another meeting type, or submit a request for a post-submission PSG meeting. A post-submission PSG meeting can be requested regardless of whether they’ve had a product development or post-CRL scientific meeting (GFI footnote 32).
  • Similar to the pre-submission PSG meeting- the purpose is to discuss the scientific rationale for an approach other than the recommendations in the current PSG. They will not discussion questions unrelated to the proposed alternative BE approach to the PSG.
  • Section III. C. discusses timing of a request for a post-submission PSG meeting to have the least impact on review of your ANDA, alternately a post-CRL scientific meeting, if appropriate, could also be used to seek feedback.

Timing commitments (GDUFA III Performance Goals- Section IV)-

  • PSG TCs and meeting requests could have started as of Oct. 1, 2022
  • PSG TCs are to be held within 30 days after receipt of the MR, if the meeting is granted. However, this only applies if the PSG TC MR is submitted within 60 days after the new/revised PSG publication date.
  • For pre-submission PSG meetings, FDA will grant/deny meetings within 14 days, and meetings will be held within 120 days if granted.
  • For post-submission PSG meetings, FDA will grant/deny meetings with 14 days, and meetings will be held within 90 days if granted.

Assorted Last Bits- See referenced sections of the GFI

  • FDA provides very specific instructions in this GFI for what they want in the Request for the Meeting. Go to the guidance and follow their instructions! (See Section V, A, B, & C)
    • For Meeting Package Content, see Section VIII and follow their instructions!
  • FDA gives some reasons why they may deny a MR, one being that they believe this could be answered appropriately through a CC. However, they also do state that you can request a meeting post-CC if there are unresolved issues from the CC. (See Section VI, A)
  • If FDA grants the meeting, they will schedule the meeting as usual. They may also choose to grant in part (only include part of the questions and deny others) and may decide to provide written response only. (See Section VI, B)

Remember, FDA just posted the last batch of new and revised PSGs on February 16th, so your 60 day clock is ticking.

If you’ve made it this far- I hope this unscrambled a bit of this GFI’s confusing parts and if nothing else- I hope you learned that you should always read the footnotes in a GFI!

If you have any questions regarding this GFI or GDUFA III, please reach out to Lachman Consultant’s Regulatory Group – I can be reached at r.welton@lachmanconsultants.com.