The AAM GRx+Biosims meeting recently concluded, and it was great to see so many familiar faces and to meet individuals in person for the first time. This conference always affords attendees opportunities to hear new insights from FDA leadership and catch up with colleagues. I’m sure that attendees all had a favorite session or discussion, and it was great to see AAM recognize Paul Schwartz, Ph.D. with AAM’s Lifetime Achievement Award, a well-deserved honor for Paul, who has left his mark at the FDA and assisted many in industry over his 35-year FDA career.
I was fortunate enough to receive an invite from AAM to participate in a panel discussion titled “Common Deficiencies for ANDAs and Supplements.” The presentations during this session covered both ANDA filing-related issues and review issues with a focus on Quality-related concerns. While not included on the slides themselves, Johnny Young, M.S., Director for the Division of Filing Review, noted that currently about 4% of ANDAs were determined to be incomplete at filing, resulting in the issuance of refuse-to-receive letters. Of these ANDAs, about 21% were refused due to incomplete stability, 19% were refused for non-Q1/Q2 determinations, and 16% were refused for issues related to incomplete or improper 356h forms. The statistic that jumps out to me here is the 16% related to a sponsor’s 356h. The FDA’s regulation at 21 CFR 314.101(d) states:
NDA or ANDA deficiencies. FDA may refuse to file an NDA or may not consider an ANDA to be received if any of the following applies:
(1) The NDA or ANDA does not contain a completed application form.
Thus, the FDA’s regulation clearly states that the Agency may not consider an ANDA to be received, but whether or not the Agency actually refuses to receive an ANDA appears to hinge on the FDA’s interpretation of the word “may.” From the discussion panel, it appears that the FDA interprets “may” in the regulation to be definitive and, thus, instructs that the FDA will refuse to receive an ANDA if the 356h form is incomplete or improper. However, another interpretation of “may” could be taken by the FDA where the FDA has the discretion to take a refuse-to-receive action rather than binding the Agency to issue a refuse-to-receive letter. It’s interesting to juxtapose the language of 21 CFR 314.101(d) with the language in 21 CFR 314.101(e), which states:
Regulatory deficiencies. The Agency will refuse to file an NDA or will consider an ANDA not to have been received if any of the following applies:
What follows the 21 CFR 314.101(e) regulation isn’t relevant to this discussion, but anyone can clearly see that the FDA’s own regulations applicable to ANDAs distinguish between what actions the FDA may take and what actions the FDA will take.
There are several reasons for pointing this out. Probably the most obvious is that no ANDA sponsor wants to receive a refuse-to-receive letter and forfeit 25% of their GDUFA application fee, which amounts to $89,562 based on the FY 2026 ANDA application fee of $358,247. Above and beyond that, a deficiency or issue with a 356h that makes it “improper” is something that can easily be fixed by the ANDA sponsor. The very regulation that the FDA relies on to refuse an ANDA based on a deficient 356h was promulgated in the early 90s, when all applications were submitted on paper and revised versions of documents took days to weeks to be updated and submitted to the FDA. With today’s technology, an OGD filing reviewer can send an e-mail to a sponsor informing them of the specific problem with the 356h, the sponsor can acknowledge this request and correct the deficient 356h either the same day or next day. This results in no loss of time for the FDA to undertake a substantive review of an application after filing. It seems a bit draconian to refuse to receive ANDAs in 2025 when the sole deficiency is an FDA form that can readily be corrected and resubmitted within twenty-four to forty-eight hours.
I will also point out that the conference was opened with a keynote address by the OGD’s Director, Iilun Murphy, M.D. Dr. Murphy’s presentation covered many of the topics related to the generics program: statistics, first generic approvals, refuse-to-receive top issues, past goal date ANDAs, complex generics, and so forth. Dr. Murphy also acknowledged that the refuse-to-receive rate is around 4% and highlighted the same three top reasons for refusal of ANDAs: incomplete stability data, formulation sameness, and incomplete 356h forms. She noted that much progress had been made from years ago when the refuse-to-receive rate was as high as approximately 20%, but also noted that it was one of her goals to further reduce the rate to 1% or less. While there also remains work to be done by industry to reduce refuse-to-receive rates, particularly in relation to incomplete stability data, it would appear that the FDA could reduce the rate almost immediately by simply reinterpreting its policy for refusing ANDAs based on incomplete or deficient 356h forms and the wording of the regulation.
