The last blog that we drafted on this topic, The Curious Case of the Late Cycle Amendment under GDUFA III, was posted last summer (here). As a quick refresher on what we covered, the GDUFA III Commitment Letter (here) included several new enhancements to the Generic Drug User Fee Program, one of which was the inclusion of a mechanism for response to an Information Request (IR) or a Discipline Response Letter (DRL) sent to an applicant within three months of the goal date that could lead to an approval or tentative approval (TA) in the current assessment cycle and that would extend the goal date by ninety days from the date of the applicant’s response – known as the late-cycle amendment (LCA). Since the introduction of the LCA in October 2023, the use of LCAs and their effect on Abbreviated New Drug Application (ANDA) goal dates has been inconsistent, at best, and, at worst, a frustrating process of attempting to guess the approval date.

In the first year of GDUFA III, many of our clients expressed frustration with the goal date creep that was an inevitable effect of this new provision. Clients expressed frustration with receiving more than one IR from the same discipline and receiving several IRs that moved the goal date more than once, making it impossible to plan for the launch of their product. Last year’s blog was an evaluation of first impressions and experiences communicated from our clients. This time, as Alice says in Adventures in Wonderland, “I think I should understand that better if I had it written down,” so we have compiled submission data into a spreadsheet to include the data across applications and applicants to see whether the impact was real or imagined and whether there were only a few “curious cases” of goal date creep or if this is more of a growing trend. The application correspondence for several different ANDAs were tracked using the original goal dates, IR dates, and reassigned LCA goal dates in order to determine how many LCAs each application received, which disciplines sent IRs, whether the final action in the review cycle was a Complete Response Letter (CRL), and which disciplines included deficiencies in the CRL. The results were mixed with examples of the expected use of LCAs, in which one or two LCAs were used to move the goal date before a final action was provided that was an approval or tentative approval, but also cases where the final action was a CRL. Even more surprising, there were cases where the CRL contained comments from the same disciplines that issued late-cycle IRs, and some even included the same or similar comments from the IRs but also new comments that were not provided in earlier IRs or DRLs.

Several other oddities emerged from the data:

      1. In one example, the goal date was moved twice due to LCAs (one quality and one labeling), then another labeling IR was issued, but no acknowledgement letter was received with a new goal date. Another labeling IR and response prompted an email to the FDA Project Manager (PM), who noted that the FDA intended to rely on imminent action. A fifth IR followed and, again, the FDA did not move the date for the last amendment as it had already been missed, and the PM confirmed that the Agency would continue to work under “imminent action.” With these last two labeling IRs issued and amendments provided within the month before and after the goal date, imminent action was a reasonable response, but the application remained pending for several months. It was finally approved nearly four months after submission of the last LCA response, far beyond the sixty days mentioned in the GDUFA III Commitment Letter as the time frame for imminent action, which made it impossible for the application holder to know when action would be taken and to be able to plan for launch.

     

      1. In another example, an application received a labeling IR that ended up not being a true IR. When the applicant asked a clarifying question, they were told to disregard the comments and match the model labeling, which was the labeling previously submitted for review. The response referenced the already submitted labels, and there was no impact on the goal date. Subsequently, this application received a quality IR asking that a test be added to an excipient specification. After reviewing the USP monograph, it was revealed that specific test was not applicable to the hydration state of the excipient used in that drug product. The response returned to the FDA for the IR was a narrative discussion on the lack of applicability, supported by correspondence from the USP that did not change any information provided in Module 3. However, this amendment received an acknowledgement that moved the goal date by three months. While neither of these IR responses changed the information provided in the application, they were treated differently when received by the FDA such that one team left the goal date as it was, and one team moved the goal date per the LCA provision in GDUFA III. One can only conclude that the OPQ (Office of Pharmaceutical Quality) treats the “may extend the goal date” as a “will extend the goal date.” After responding to these labeling and quality discussions late in the review, and with the prodding of many communications to the PMs and escalated communications on behalf of this client, the FDA did not use the extension it had assigned and was able to provide an approval by the original goal date.

     

      1. There are two separate examples of applications that missed the originally assigned goal dates, and the dates remain missed. The Agency is still sending IRs and DRLs so it appears to be continuing the review of both applications, but it is not using the LCA process to change to goal dates. One has received three IRs (quality and labeling), and the other has received four (also quality and labeling). Both remain pending with no final action yet received and no explanation as to why the LCA process is not being used with these applications.

     

    1. The final example is an ANDA that received five separate reassignments of its goal date due to LCAs. Unlike the example above that was subject to imminent action, each of these LCAs moved the goal date later down the calendar. The early IRs included several quality IRs and one BE IR, but one of the quality amendment acknowledgements was due to a Drug Master File (DMF) amendment received during the review period that also moved the goal date for the ANDA. After the DMF LCA, another quality IR was received, and the goal date was moved for the fifth time. It was not until the ANDA received a tentative approval letter that the multiple IRs and goal date moves made sense. In the case of this ANDA, the FDA may have been trying to wrap up the review and avoid a complete response as the legal approval date was within a few months of the TA date.

As in the last example, only time will tell whether the collection of data in the assembled spreadsheet will remain a nonsensical string of events, like the story in Alice’s Adventures in Wonderland, or whether a pattern and meaning can be divined through retrospection. The lack of pattern to date may be due to the relatively small sample size compared to the overall body of applications that have been pending and processed so far during this GDUFA cycle, but we are only in year two so there is plenty of time left to continue to gather data. We will continue to update the spreadsheet with the goal of finding whether we are all mad here or if there is some order to be found (as it would be so nice if something made sense for a change). Of course, we are not in Wonderland so a far easier solution would be more transparency and predictability from the relevant review Offices in the spirit of the GDUFA III commitments.