Many of our blog readers have likely encountered moving goal dates for their ANDAs since October 1, 2022 and the beginning of GDUFA III.  The GDUFA III Commitment Letter, available here, included several new enhancements to the generic drug user fee program as each iteration of the program has continued to do.  The changes made to promote transparency and communication between the FDA and ANDA applicants, as described in Section II, Part B, are meant to reduce the number of review cycles and to shorten the overall review time for ANDAs to facilitate access to generic products in a timelier manner.  While it is too soon to tell whether the overall goal has been met, what has become clear is that the approval date for an ANDA has become much less predictable. 

Under the program enhancements, applicants may see minor or major deficiencies in Discipline Review Letters (DRLs) provided in the first review cycle.  This means that the deficiencies may be significant and, in some cases, cannot be completely addressed by the applicants in the time allotted for the DRL response.  This is to be expected for some applications, but there may be some applications where the applicant has the data on hand and can respond in the time allotted, thereby putting them back on the path to firstcycle approval.  Once the major amendment is received, the FDA will adjust the goal date for review to account for the major amendment review where previously those major comments would have been held and not communicated until a CRL, which meant a new review cycle for the application.  Allowing communication of major deficiencies in a DRL, and allowing the goal date to be adjusted for review of the response, keep the application in the same review cycle.  This is the type of enhancement that we all want to see to the program. 

Also, as part of GDUFA III, the FDA will issue IRs or DRLs after the midpoint of the review cycle if it believes that resolution of the request could lead to approval or tentative approval in the current assessment cycle.  This is where many applicants are seeing unexpected delays and where changing goal dates have caused confusion and frustration. 

In the last few months, some of our clients have received IRs prior to the assigned goal date, to which they respond by the date requested.  The amendment is then confirmed by the FDA with an acknowledgement letter assigning a new goal date, ninety days from the date of the response, which leads to an extension of the previously assigned goal date.  This is explained in the Commitment Letter, Section B.1.c.i., and is another good example of the transparency that GDUFA III was meant to provide.  However, if another IR is sent and another response is provided, a new acknowledgment letter will be issued with a new goal date ninety days from the date of the response amendment.  This can lead to the goal date marching down the calendar with each IR sent, and is the reason that approval dates have become far less predictable.  On the bright side, the application will still be in the current assessment cycle as the FDA has not issued a final action (CRL or approval letter), but with each extension frustration can grow. 

This goal date creep is frustrating applicants as there have been examples of small items requested in an IR that, in the opinion of the applicant, could have been requested sooner, but since it was late in the review cycle, the goal date was extended when they provided their response.  There have also been examples of one discipline sending an IR, to which the applicant responded, then it was followed by another IR from the same discipline, to which the applicant responded.  The two IRs were sent from the same review division and did not appear to be related, yet because each request was identified late in the review cycle, the goal date moved with each response, much to the annoyance of the application holder.  At some point, it makes more sense to send a CRL, even if it will be minor.  At least with a CRL, the applicant will have the Agency’s comments that are, in theory, a comprehensive list, and they shouldn’t be surprised by more comments a few weeks later.  The primary beneficiary of this “enhancement” appears to be the Office of Generic Drugs.  The OGD will potentially be able to show an improvement in firstcycle approvals, but this appears to come at the expense of approval predictability for manufacturers and which may not result in quicker access for patients as applicants scramble to adjust launch plans. 

Time will tell whether this is a “new normal” for ANDA review, but some applicants that manufacture their products outside of the U.S. are finding it very difficult to predict when they will receive approval, which complicates their launch planning.  PLAIRs are rejected if the Quality discipline is still under review and if an applicant doesn’t know when they will receive approval, they can’t plan for product launch.  The advent of the latecycle amendment may shorten the overall time to approval, but it is causing chaos for scheduling and logistics teams trying to finalize product launch plans.  Time will tell whether this enhancement is truly a benefit that enhances generic drug access or not worth the worry and frustration.  In an industry where being first to market can mean everything to a company’s bottom line, this “enhancement” may not be worth the cost to manufacturers in the long run.