Every 5 years, the user fee programs (UFAs) are renegotiated and, for each UFA program, there is a commitment letter that outlines the agreed-upon goal dates and program enhancements that will dictate the five-year reauthorization period when Congress passes the Reauthorization Act (likely in mid to late FY 2022). This is a piece of must-pass legislation that has to be in place prior to the start of FY 2023 (which is true for all of the UFA programs). OGD Posted the GDUFA III commitment letter late on Friday October 29, 2021 (here), just two days before Halloween – so take a good read to see if this is a trick or a treat.  Many of the review goals remain the same, but there are some changes and additions, so be sure to “read the Commitment letter, read the commitment letter and then read the commitment letter”, to quote Kathleen “Cook” Uhl, the previous OGD Director, when speaking about the GDUFA I and II commitment letters.

This 5-year cycle’s commitment letter breaks the bank in terms of length.  GDUFA II’s commitment letter was 22 pages long and the GDUFA III commitment letter is 49 pages.  There are lots of details and it will likely take a bit of time and a few FDA presentations to assure that we all know what the GDUFA III negotiating team and OGD/FDA really means.  As you remember, in past cycles, even though there were commitment letters, there was some disagreement about what was and was not included.  Perhaps the increase in length of the GDUFA III letter by some 27 pages is testament to assuring agreement between industry and the Agency.

The first change noted is the goal date for an ANDA submitted when there is a facility that is not yet ready for inspection.  Under the new provisions, OGD will “[i]f, upon initial submission, a standard or priority original ANDA contains a certification that a site/facility listed on the Form FDA 356h is not ready for inspection (i.e., the box “no” is checked in response to “is the site ready for inspection?” in section 28), FDA will set a goal date that is 15 months from the date of submission.” While OGD will conduct the filing review, they will not begin a substantive assessment until the ANDA is amended to indicate the firm(s) are now ready for inspection and will then adjust goal date accordingly. There are further penalties in terms of setting goal dates for significant delays in submitting the amendment.

The goals of 90% assessment and action in accord with the goal date applies to all applications and amendments, but the goal date obviously changes.

In addition, OGD will “[a]ssess and act on standard Major Amendments within 8 months of the date of amendment submission if preapproval inspection is not required’, and 10 months if an inspection is required.   For priority Major amendments, a 6-month goal is set if no inspection is required and 8 months if it is and a Pre-Submission Facility Correspondence (PFA) is submitted at least 60 days prior to the submission of the amendment; otherwise, the goal date will be 10 months (other restrictions apply so please read the document carefully). All standard and priority amendments have a 3-month action goal date.

Prior approval supplements (PAS) have the following goal dates – standard PAS 6 months, 10 months if inspection needed. For a priority PAS, the goal date will be 4 months if no inspection is required, 10 months if inspection is required, and for those that require inspection and if a PFC is submitted at least 60 days prior to submission, that goal date will be 8 months (again with other restrictions). The goal dates are the same as described above also for major and minor amendments for standard and priority PAS submissions.

Controlled correspondence (CC) stayed the same for standard and complex CCs, at 60 and 120 days respectively; however, the goal date for clarification post receipt of a CC response from the Agency jumped from 14 days to 21 days for GDUFA III.

The section on ANDA Assessment Transparency and Communications Enhancements is long and complex, I suggest a deep, detailed review of this section.  A couple of highlights include:

  • Provisions for consults with an extension of the goal date for the assessment cycle
  • Extension of goal date by 90 days if applicant responds fully to information request (IR) or discipline review letter (DRL) by due date if there is a likelihood that the response will lead to approval or tentative approval. FDA will provide correspondence regarding extension of the goal date.
  • FDA may extend goal dates where labeling issues such as a “carve outs” are requested as a consult may be needed, and “FDA will minimize issuing CRLs that contain only labeling deficiencies by, for example, utilizing later-cycle IRs and the imminent action process.”
  • Imminent actions when approaching goal dates and need to continue review towards approval or tentative approval are further clarified in the commitment letter.
  • If the issuance of a major deficiency is likely, the regulatory project manager (RPM) may notify the applicant. In addition, if OGD will miss a goal date, the RPM will also notify the applicant. In both instances the RPM will provide general information on the contents of the deficiency or why the FDA will miss the goal date and give an estimate of when the Agency will likely complete its assessment.
  • If a major amendment is issued, FDA will indicate the basis for the classification.
  • Assessment Classification changes are described including standard and priority review changes as well as facility-based major amendments along with how the Agency will communicate and explain its decisions.
  • There appears to be some relief for sponsors submitting ANDA suitability petitions which have generally been ignored by OGD for over the last 10 years. The tiered approach for addressing these petitions is a bit complex but describes how and when the Agency will begin to meet and conduct its review assessments of these petitions. Of particular interest, petitions submitted in FY 2024-2027 will receive a completeness assessment within 21 days and a goal date, those submitted prior to that will not. FY 2023, the first year of GDUFA III, FDA will use its resources to assure that current pending petitions are still relevant and of interest to the petitioner.  FDA suggests in the commitment letter that the petitioners for older petitions who want to have a goal date may want to withdrawal and resubmit their petitions. It seems to me that if you want action on a petition, your firm will have a year to prepare a new petition, but to assure action, wait until the start of FY 2024 to submit.
  • FDA also identifies a priority scheme for petition actions. The goal dates to be established for petitions will be 6 months from the date of final assessment of the petition rather than the current 90-day statutory requirement. FDA describes its goals as follows: act on 50% of petitions submitted in FY 2024 for up to 50 petitions, which increases to 70% for up to 70 petitions in FY 2025, 80% for up to 80 petitions in FY 2026, and 90% for up to 90 petitions in FY 2027. (See the appendix on page 49 of the letter to see how the FDA will prioritize suitability petitions from 2024 onward through GDUFA III. As a note, there is no proposed fee for the submission of and assessment of ANDA suitability petitions.)

There is an entire section on product specific guidance (PSG) where FDA indicates how it will prioritize development of PSGs, how to request guidances through a controlled correspondence (CC) even though the correspondence will not be considered a CC but it will put the Agency on notice that sponsors have a desire to see a PSG on a specific drug.  There is also a discussion of the instances where the sponsor has already conducted a bioequivalence study on a product and the Agency subsequently issues a PSG and how the sponsor can arrange a teleconference to discuss the different approach used. This can happen either pre or post submission of the ANDA.

Product development meetings and pre-submission meetings are also addressed in the letter along with associated timelines and goal dates for granting/denying and holding such meetings. In addition, mid-cycle and enhanced mid-cycle (something new, I believe) meetings are described and outlined.

There are several program enhancement issues discussed, some highlights are:

  • For DMF deficiencies (just to name a few) –
    • FDA will ensure that DMF assessment comments submitted to the DMF holder are issued at least in parallel with the issuance of review comments relating to the DMF for the ANDA.
    • FDA will grant and conduct teleconferences when requested to clarify deficiencies in first cycle DMF deficiency letters, with FDA striving to grant meetings within 30 days of receiving the deficiencies.
    • Once a DMF has undergone a full scientific assessment and the ANDA referencing the DMF has been approved or tentatively approved, FDA will issue a “no further comment” letter.
    • New rules for DMF assessment prior to ANDA submission to provide a scheme where reviews are prioritized based on certain factors

There a significant number of program enhancements outlined regarding inspections, facility reinspection, the inspection database, response to warning letters, and the Agency’s aspirational commitment to providing timelines for decision after response from a firm. Thus, GDUFA III will provide additional resources to enhance resolution of inspectional issues which will also include post-warning letter meetings. There are goal dates for reinspection for domestic (4 months) and international inspections (8 months), but these goal dates don’t kick in until FY 2024 and are goal-tiered according to the FY and percentages to meet the goal of 60% for 2024, 70% for 2025, and 80% for 2025 and 2026.

There are also enhancements in the continued user fee management and planning relative to the GDUFA program. The so-called Capacity Planning Adjustment (CPA) as defined in the commitment letter is designed to assure that resources are being efficiently used (hopefully to hold down or minimize further increases in fees) and will be tied to additional transparency in reporting and driven by the inflow of work to the Agency as outlined in the document (e.g., ANDAs, supplements, CCs meeting requests, etc).

The letter indicates that FDA will hire an additional 128 staff in FY 2023 and report on the progress of hiring GDUFA III staff in their 5-year financial plan. In addition, the FDA commits to revising Guidances and MaPPs that reflect the new commitments for GDUFA III.

As noted above, there are a lot of details in this 49 page letter and we have just scratched the surface in this blog, because who want to read a 49 page blog post?  Anyway, I remind you again of the words of Kathleen “Cook” Uhl, “read the letter, read the letter, read the letter”.  Good luck to the industry and FDA in GDUFA III- we will be there with you all.