This is not the first time that the Office of Generic Drugs (OGD) has issued a guidance document that requires firms to assure that they have essential information in their original abbreviated new drug applications to permit a substantive scientific review. Remember prior to the 1992 Hatch-Waxman final rule when an ANDA could be submitted with just a bioequivalence protocol and the actual biostudy could be submitted as an amendment? Or even prior to that when ANDAs were accepted with one month stability data and the remainder of the data could be submitted as it became available? The Center for Drug Evaluation and Research sent several letters telling firms to improve their submissions. One such letter was dated November 1, 1990 (here).
Over the years, OGD has issued Completeness and Acceptability checklists in an effort to make ANDA applicants aware of the latest requirements for submission. In addition, OGD often holds joint meeting with GPhA to provide industry with the most recent information necessary to file complete applications. All of these efforts have been undertaken to improve the efficiency of the ANDA review and approval process. The goal is to have the most complete application submitted, and thus, making the review of the application, hopefully, a one or two cycle process. You send OGD the application, they tell you what is wrong with it, and then fix it. Thse meeting and exchanges are essential for successful submissions.
Unfortunately, history really does repeat itself. The first series of letters and advice to industry relative to the need to submit a complete application was to level the playing field and assure that every firm was doing the necessary work to submit a complete application, as many firms were just trying to get something into the Agency to get the clock started or to try to capture the first-to-file place in line.
Well now we are right back to where we were in the late 80s when firms tried get the clock started by submitting an ANDA that might not quite be what they really want in terms of potential conditions of marketing. For instance, a firm may submit an application with one source of API, but really want to use another. They may not really want to commercialize a product from the filed manufacturing site or they may want to use a different contract packager for commercial operations. GUDFA takes care of that to a certain extent by adding review time penalties for major and multiple minor amendments to the application. But the question of what gets you in the door first still matters.
On September 30, 2013, OGD issued a draft guidance for industry entitled, ANDA Submissions – Refuse-to-Receive (RTR) Standards, that outlines how your application will be evaluated for receipt purposes. The Guidance divides deficiencies into major (for which a RTR will automatically be triggered) and minor (for which you may have 5 days to correct) categories for the completeness and acceptability review process. Have 1 major or 10 or more minor deficiencies and your application will not be received. Penalty for such a determination is a loss of 25% of the ANDA user fee.
The guidance document (here) discusses the RTR history over the last four year where OGD has RTRed some 497 ANDAs with the % of RTRs actually falling from 18% in 2010, to 15.5% in 2011, and 9.4% in 2012 (however, the 2012 figures are based on incomplete data, given many of the ANDA submitted in 2012 have not yet completed their completeness and acceptability review). Most of the 100 RTR letters in 2012 fell into one of three categories, serious bioequivalence issues accounting for 40%, 36% for serious chemistry issues, and 13% for format or organizational flaws.
The 9/30/13 guidance will likely result in an initial increase in the rate of RTR letters for 2013 submissions. This will likely be compounded by the upcoming increase in stability requirements to take effect in June of 2013; however, at least firms are now on notice about current expectations. In addition, OGD updates its ANDA checklist quarterly to capture new areas of concern and focus. The most recent ANDA checklist for Quarter 2 of 2013 can be found here.