This morning I read Zach Brennan’s post on RAPS, titled FDA Smashes Record for Most ANDA Complete Responses Letters (CRLs) in One Year (here ).  In his piece, he wrote:

But the gap between this year and years past – 2,515 complete responses have been issued so far in 2018 vs. 1,603 in FY 2017 and 1,725 in FY 2016 – may be attributed to a spike in applications or other reasons.

It was the phrase “may be attributed to a spike in applications or other reasons” that got me thinking.

Application submissions have certainly been higher in previous years, even as OGD heads to another 1000+ ANDA submissions in FY 2018.  For instance, in 2017, OGD received 1306 ANDAs, and in FY 2014, OGD received 1473.  But the year following the FY 2014 surge, OGD issued only 1180 CRLs.  So why the huge difference?

David Gaugh, Senior Vice President of Science and Regulatory Affairs at the Association of Accessible Medicines, told RAPS “Year one of GDUFA II, and the volume of completed responses, are performing consistent with expectations that were set when the new goals and metrics were negotiated.  It’s important to note that as part of the migration to GDUFA II, there was a bridging process that established a goal date of July 31, 2018 for the approximately 800 applications that did not have an official goal date in GDUFA I, which very likely accounts for the perceived surge in overall applications over this time period”, according to Zach’s article cited above.

While I think this may be part of the problem, I also think that David was being somewhat kind to FDA and the industry as a whole.  Certainly, the number of additional staff and the stand up of Office of Pharmaceutical Quality (OPQ) contributed to the increased CRL output but, I believe that “other reasons” may include the following:

  • OGD is very GDUFA goal-conscious and, while they have said that they would miss a goal date if it meant imminent approval could be reached, I am not sure that they have been doing that consistently. As a matter of fact, an article I read yesterday suggested just that, as OGD said they would be more willing to miss a goal date now!
  • Secondly, there has also been a surge in the number of information requests (IRs) and discipline review letters (DRLs) during the review of the ANDA. Many times, the number of IRs and DRLs overwhelm the sponsors and they cannot respond in the allotted time and have to continually prioritize which of these missives they will respond to first, based on the products’ importance to their bottom line.  This delay in response to other IRs and DRLs of lesser importance can cause the OGD to issue a CRL.  Remember that IRs and DRLs apply only to GDUFA II applications, and GDUFA I applications, while they all have GDUFA goal dates now, don’t get the benefit of mid-cycle review comments.  This could drive some of the increase in CRLs.
  • I know that OGD is looking for more first-cycle approvals, but what I don’t understand is that many established firms continue to receive rather lengthy CRLs In her recent presentation at the GRx-Biosims AAM meeting in Baltimore, Dr. Kathleen “Cook” Uhl said that with regards to refuse-to-receive actions (and I am sure it applies to original ANDA submissions as well): “Slow down and QA/QC the entire ANDA before submitting/re-submitting”.  That is a great suggestion, but the same admonition needs to be applied to the ANDA reviewers, perhaps they also need to slow down and QA/QC their reviews, as some of the questions are either not applicable to the product or the information is clearly in the application.  I think there is some blame on both sides.  Maybe when FDA revises the review process to a more data-driven and less narrative-driven application, this will help.

I don’t mean to beat up the FDA, I do know that industry has its problems too.  I wish I knew how to fix the problem, but one would think that, unless the firm is new in the industry, they could (by now) hit the nail on the head and get it right the first time.  The industry continues to complain about the age-old problem of the “moving review target” and with the diversity or the reviewers who often raise quite different questions during a review, continues to make it hard for industry to get it right the first time.  It seems something along the lines of – you can please some of the people some of the time, but you can’t seem to please the reviewers very often.  Maybe GDUFA III will help iron out some of these issues (if industry can afford the freight).