In an unusual notice published today in the Federal Register, the FDA announced that it was getting ahead of one of the commitments it made under the GDUFA III commitment letter by requesting feedback on a specific appendix within a 2018 guidance document explaining how the agency categorizes amendments to generic drug submissions.
- How generic drugs are reviewed by the FDA: Most companies seeking approval for a generic drugs submit an Abbreviated New Drug Application (ANDAs), through which the sponsor provides evidence that their product is “bioequivalent” (BE) to an already-approved drug, known as the “ Reference Listed Drug” (RLD). Bioequivalence refers to the absence of differences between the rate and extent to which an identical drug is absorbed into the body. An ANDA applicant’s product must be the same in all material aspects as the RLD, including, dosage form, strength and labeling. This allows the sponsor to avoid conducting extensive clinical trials to re-confirm the benefit of a product that is already known to be safe and effective in its original form.
- What are amendments to ANDAs? According to 21 CFR 314.96, “an applicant may amend an ANDA that is submitted under 314.94, but not yet approved, to revise existing information or provide additional information.” Amendments to ANDAs were first defined as being either “major” or “minor” in FDA’s 2001 amendments guidance, which has since been withdrawn. According to the FDA, major amendments “contain a substantial amount of new data or new information not previously submitted to or reviewed by FDA, requiring, in FDA’s judgment, a substantial expenditure of FDA’s resources.” In contrast, a minor amendment requires fewer resources to review and typically is in response to an easily correctable deficiency such as the applicant providing clarity to information already submitted, according to the FDA.
- The user fee program for generic drugs expounded on how the FDA would categorize, classify and address amendments to ANDAs. As part of the Generic Drug User Fee Act of 2012 (GDUFA I) commitment letter, the FDA agreed to meet certain performance goals around the review of amendments to ANDAs or prior approval supplements (PAS) received on or before October 1, 2014. In addition, the commitment letter classified the amendments into a tier-based system that considered factors such as whether the amendment was solicited or unsolicited, major or minor, the number of amendments an applicant submitted to a single ANDA or PAS and whether the FDA needed to conduct an inspection to address the amendment. (This commitment letter was updated in 2017 under GDUFA II).
- In July 2014, the FDA released a draft guidance document, “ANDA Submissions – Amendments and Easily Correctable Deficiencies Under GDUFA.” The draft guidance provided more clarity about the tier system for the different type of amendments, explained FDA’s review process, the amendment submission process, how review dates would be calculated, and how applicants could request for reconsideration of FDA classified amendment.
- In July 2018, the FDA released a final guidance document, “ ANDA Submissions — Amendments to Abbreviated New Drug Applications Under GDUFA.” The aim of this guidance was to clarify some of the changes made to the generic drug review program under the GDUFA II legislation and commitment letter. The guidance also superseded two earlier guidance documents we mentioned: The 2014 guidance on easily correctible deficiencies, and the 2001 amendments guidance.
- As with the earlier 2014 guidance, the 2018 guidance contains a series of appendices offering examples of what changes would constitute different types of amendments to complement the guidance’s higher-level explanations of what would constitute both Major or Minor amendments and how those amendments would be submitted and reviewed by the FDA. Amendments could further be broken down into “priority” or “standard” amendments, and those requiring or not requiring a pre-approval inspection. Finally, amendments could be made to both an ANDA submission or a PAS, which are handled according to a conceptually similar framework.
- Appendix A of the guidance contains examples of major deficiencies, including those related to Drug Master Files, the drug product, processes, microbiology, biopharmaceutics and facilities.
The FDA has now issued a notice “to solicit comments on the content of Appendix A in the July 2018 guidance.”
- According to the notice, the FDA is “taking this action to fulfill the Agency’s commitment” outlined in the upcoming GDUFA III commitment letter (section IX.B). According to the letter, the FDA agreed to issue this Federal Register notice on or before April 30, 2023, “, to solicit public comment on the content of Appendix A.”
- The topic of amendments had come up during the negotiation of the GDUFA III commitment letter, including on October 1, 2020 and November 19, 2020.
- Specifically, FDA’s Federal Register notice explains that “FDA is seeking comments on the examples of major deficiencies listed in Appendix A of the ANDA amendments guidance, as well as comment on how any proposed revisions to that list could be beneficial to industry in understanding ANDA amendment classification.”
- Industry comments to guidance document’s docket had raised concerns with the examples of major deficiencies listed in Appendix A, likely explaining industry’s interest in this particular document. While the comments are relatively few in number (only 6 comments total), industry representatives such as Teva Pharmaceuticals, Perrigo and trade associations like the Association for Accessible Medicines all expressed concerns with Appendix A. One of the common themes in the feedback suggested that “some of the examples in Appendix A are [not] appropriately characterized as major amendments.” For example, industry raised concerns with the FDA “classifying all deficiencies associated with facilities as major.”
- There are two notable and unusual aspects to this request. First, the GDUFA III letter is not yet official, as it has not been recognized by Congress as part of the user fee reauthorization legislation. FDA’s publication of this notice indicates that it may be looking to get ahead of its commitments, especially for things that do not take significant effort to accomplish. Second, it is highly unusual for the FDA to request public comments for a specific part of a guidance document, rather than the entire guidance. While this was negotiated as part of the commitment letter, we are still unable to think of another time in which this has happened.
- The federal docket is open for public comment. The public comments must be submitted within 60 days (February 2023) of the release of the notice. While the commitment letter compels the FDA to solicit industry feedback, it does not contain any requirements for the FDA to modify the guidance.
Featuring prior research from former AgencyIQ analyst Lily Rosenfield.
To contact the author of this item, please email Bennie Johnson.
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