Dust Yourself Off and Try Again: GAO Report On ANDA Approval Shows that Multiple Review Cycles Are Still Often Necessary

August 9, 2019By Sara W. Koblitz

Over the last few years, FDA has clearly prioritized efficient generic development (see, for example, the Drug Competition Action Plan).  While FDA hosted public meetings, published MAPP revisions, and compiled lists of off-patent/off-exclusivity drugs, Congress reauthorized the Generic Drug User Fee Act in 2017 and included a provision requiring GAO to study issues regarding approval of a generic drug applications in the first review cycle.  Further, as part of GDUFA II, FDA committed make changes in an effort to minimize the number of review cycles necessary for applicants to attain approval.    This month, the GAO released its report commenting on both the first review cycle statistics and FDA’s efforts to minimize review cycles thus far.

The GAO Report looked at generic drug approvals between FY 2015 and 2017 – before implementation of the GDUFA II commitments – as well as documentation from the first review cycle for 35 applications from FY 2017 and 2018.  GAO identified several factors that may impact approval in the first cycle, including the sufficiency of the application, deficiencies in drug quality, the type of drug reviewed, and the application’s priority status.  Ultimately, GAO made two recommendations: FDA should improve consistency in communication between reviewers and sponsors, and FDA should assess the effect of brand-name labeling changes on approval of generic drugs.

Given the timeframe of the approvals reviewed, the Report tells us little about FDA’s success in achieving its GDUFA II commitment with respect to first cycle reviews.  The Report also relies on a small sample size of detailed application review (35) and interviewees (15).  But the Report is nonetheless enlightening.  Notably, of the 2030 generic drug applications reviewed by FDA from FY 2015 through 2017, only 12 percent (or approximately 244) applications were approved in a first review cycle.  That means that 1786 ANDAs went through subsequent review cycles to obtain approval, potentially delaying approval for years.  On average, from 2013 through 2017, it took three review cycles for ANDAs to attain approval.

Some of the GAO’s findings were neither surprising nor attributable to FDA:  some applications, particularly those of unsophisticated sponsors, simply were not sufficient.  Either the application was not complete or the applicants did not fully understand and fulfill application requirements, directly impacting the likelihood of receiving approval during the first review cycle.  Applications that FDA initially Refused to Receive were slightly less likely to be approved in the first review cycle.  All of this makes sense if one assumes that the RTRs and insufficient applications were filed by relatively inexperienced filers.  An inexperienced filer is more likely to get tripped up than a sponsor that has been through the process before.  Additionally, drug complexity factored into likelihood of approval during the review cycle.  Again, this makes sense: route of administration, formulation, combination drugs, complex APIs, and like factors impact the sufficiency and complexity of the data needed for approval.   Drug quality deficiencies, like the drug manufacturing facilities, were also responsible for large share of failure to attain approval during the first review cycle.

Interestingly, the GAO also noted that the type of Priority Review designation a product receives may be correlated with first cycle failures.  According to the GAO analysis, rates of approval in the first cycle were lower for first generics than for applications with no priority designation.  Meanwhile, first-cycle approval rates for other types of priority designations (i.e. drug shortages or public health emergencies) were higher than for applications with no priority designation.  The GAO report hypothesized that rushing to submit applications to get first generic status may result in lower quality applications.

The Report does highlight some of the changes that FDA has adopted since 2013 to enhance communication with applicants and improve reviewer consistency.  FDA has issued 993 new and revised product-specific guidance documents since 2013, in addition to other regulatory guidance to facilitate approval and reduce deficiencies.  378 of the product-specific guidances have been focused on complex drugs.  At the GAO’s suggestion, FDA now publicly announces its plans for issuing new and revised product-specific guidances.  Additionally, FDA now encourages reviewers to communicate with applicants about issues and issue discipline review letters at the mid-point of the review cycle rather than at the end of the cycle to provide applicants with an opportunity to address issues before issuing a Complete Response Letter.  FDA has also taken steps to enhance consistency from FDA reviewers, including review templates and adopting common phrases for communicating deficiencies.

The GAO Report notes that, even with FDA’s enhancements, inconsistency among generic drug application reviewers persists.  These inconsistencies may play a big role in approval during the first review cycle because reviewers may provide substantively different assessments of similar generic applications.  Some reviewers provide suggestions on how to remedy a deficiency while others do not even specify what further information may be required.  This inconsistency could mean the difference between addressing deficiencies in a timely manner during the first review cycle and a Complete Response Letter.  As such, inconsistency in reviewer communication is a major focus of the GAO’s recommendations to FDA.

Further, based on interviews, the Report posits that brand-name drug labeling changes occurring mid-cycle may impact first review cycle approvals.  Because the generic sponsor must change the labeling to match the Reference Listed Drug, such a change midway through the review cycle may require the ANDA sponsor to revise its labeling.  FDA thought that gamesmanship in labeling changes to delay generic competition would be challenging to coordinate but acknowledged that such a scenario was a possibility.  However, because the Office of Generic Drugs does not coordinate on timing of approval of brand-name drug label changes with the Office of New Drugs, the Agency could not speak to this directly.  As such, GAO recommended that FDA assess the extent to which brand-name label changes impact first review cycle approval of generic drugs.

On the whole, the Report was not too critical of FDA considering the statistics.  With a paltry 12 percent of ANDAs approved in the first review cycle, one would think that GAO would have a myriad of recommendations.  But it didn’t, which may indicate that FDA’s changes are helping ANDA review trend in the right direction.  But for now, as FDA further implements these changes to meets its GDUFA II goals, those ANDA sponsors who don’t attain that elusive first review cycle approval must continue to try.  In the words of the late Aaliyah: If at first you don’t succeed (first you don’t succeed), dust yourself off, and try again.