(M1130-11-65) A Retrospective Study of Mid-review Cycle Meetings (MRCMs) within Generic Drug User Fee Amendments (GDUFA) II

Purpose: As described in the Generic Drug User Fee Amendments Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022 (GDUFA II Goals or Commitment Letter) and the guidance for industry Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA, an Abbreviated New Drug Application (ANDA) applicant of a complex product that was granted a Product Development Meeting or pre-submission meeting has the option of a mid-review cycle meeting (MRCM) with the FDA. The purpose of an MRCM is to provide the applicant with an update on the status of the review of their application and to discuss issues identified during the review. The analysis described herein provides a summary of MRCM discussion topics since the start of the GDUFA II program with the focus on questions pertaining to bioequivalence (BE). The results of this survey will assist in understanding the nature of MRCMs in GDUFA II and identifying common issues in the BE portion of complex product ANDAs which should ultimately reduce the number of review cycles.

Methods: A retrospective survey of ANDAs that were granted an MRCM between October 1, 2017 and February 22, 2022 was conducted, where the meeting status, the dosage form, and questions discussed in each MRCM were documented. We further analyzed BE-related questions based on dosage form and the nature of the questions (e.g., overall BE approach, in vivo/in vitro BE study, formulation, dissolution, physiochemical properties, etc.).

Results: MRCM discussion topics were analyzed for a total of 64 ANDAs with a completed MRCM. Topical (including ophthalmic and vaginal routes) gel/cream/emulsion/transdermal system (27 out of 64 [42.19%]) and injectable solution/suspension/emulsion (23 out of 64 [35.94%]) dosage forms accounted for the majority of the 64 ANDAs. A total of 228 questions were raised in the 64 MRCMs, with most questions pertaining to pharmaceutical quality (118 out of 228 [51.75%]) and BE (88 out of 228 [38.60%]). The 88 BE-related questions were raised for 34 out of the 64 (53.13%) ANDAs (18 topical, 7 injectable, 5 oral, and 4 inhalation), with 46 questions from the applicant and 42 questions from the Agency mostly seeking clarification (82 out of 88 [91.11%]). The majority of BE questions were related to a pivotal in vitro BE study (42 out of 88 [47.73%]), overall BE approach (16 out of 88 [18.18%]), and a pivotal in vivo BE study (11 out of 88 [12.50%]); other BE questions pertained to formulation, dissolution, physiochemical properties, etc. For pivotal in vitro BE studies, the most commonly raised questions were related to pre-study method development and validation, study design, statistical analysis and batch acceptability for the BE study. Out of the 34 ANDAs with BE-related MRCM questions, six were deemed BE adequate and 3 were approved by the end of the first review cycle following the Agency’s review of applicant’s amendment submission after the MRCM.

Conclusion: MRCMs in GDUFA II provide an opportunity for both the applicant of complex drug products and FDA to ask clarifying questions, discuss significant concerns identified during review, as well as identify next steps. The majority of the ANDAs with completed MRCMs were for topical and injectable dosage forms. The most commonly raised topics for BE were in vitro/in vivo BE studies and overall BE approach. The results of this survey will assist in understanding the nature of MRCMs in GDUFA II and identifying common issues in the BE portion of complex product ANDAs which should ultimately reduce the number of review cycles.

Acknowledgements:This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.