“Thou Shalt Not”: FDA Issues Two Guidances on ANDA Refuse-to-Receive Issues on the Eve of GDUFA Public Meeting

By Kurt R. Karst –      

There are mortal sins and there are venial sins.  In the latest guidance documents FDA announced (here and here) earlier this week – a final guidance on ANDA Refuse-to-Receive (“RTR”) standards and a draft guidance on ANDA RTR for lack of proper justification of impurity limits – FDA focuses on the mortal sins of ANDA submission that will generally result in the Office of Generic Drugs (“OGD”) refusing to accept an ANDA for review.  Indeed, the phrase “FDA will refuse-to-receive an ANDA” (followed by or preceded by some example) appears not less than 24 times in FDA’s final ANDA RTR standards guidance. 

Both ANDA RTR guidances were issued on the eve of a September 17th public meeting on implementation of the Generic Drug User Fee Amendments of 2012 (“GDUFA”).  FDA requested comment at the meeting on the ANDA RTR impurity limits draft guidance and other recent guidances on GDUFA implementation (see our previous posts here, here, and here).  FDA also solicited comment on “GDUFA Implementation Related to Generic Drug Exclusivity” and “GDUFA Implementation and Potential First Generics.”  Although very few comments (see here) were submitted to FDA in response to the Agency’s solitation, we understand that the public meeting was well attended and included statements from an array of generic drug industry stakeholders, including the Generic Pharmaceutical Association (see here and here).  The September 17th public meeting follows a solitication from FDA earlier this year seeking input and suggestions on ways to improve the quality of ANDAs and on how to best communicate those suggestions to the generic drug industry (see our previous post here).  About a dozen comments have been submitted to the docket FDA established for that solicitation.

FDA’s ANDA RTR standards guidance finalizes a draft version of the guidance released in October 2013.  In addition to providing greater clarity around major deficiencies (i.e., mortal sins) that will generally result in an RTR decision and minor deficiencies (i.e., venial sins) that can be easily corrected, the guidance makes several important changes to the draft version.  Bob Pollock from Lachman Consultants covers those changes in his recent post. 

In the ANDA RTR impurity limits draft guidance – a guidance FDA presumably issued in draft form and separate from the ANDA RTR standards guidance because the issue was not addressed in the draft ANDA RTR standards guidance – FDA lays out serious deficiencies in impurity information that could cause FDA to RTR an ANDA. The deficiencies described in the draft guidance include: “(1) Failing to justify proposed limits for specified identified impurities in drug substances and drug products that are above qualification thresholds; (2) failing to justify proposed limits for specified unidentified impurities that are above identification thresholds; and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) above identification thresholds.” 

As Bob Pollock notes, the position FDA takes in the draft guidance “is consistent with past Guidance issued by OGD on the requirements for justification of impurity limits, but, in the past, OGD has not stated that if such justification is lacking, they will issue an RTR letter rather than handling the issue as a review issue.”  This is an important observation, because it shows that OGD is making an effort to clarify the sometimes fuzzy line between what constitutes a deficiency for ANDA RTR purposes, and what is properly an ANDA review issue (and not an RTR issue).  Indeed, we’re likely to see more follow-on, issue-specific guidances like the ANDA RTR impurity limits draft guidance as the new ANDA filing and review groups within OGD hash things out and establish brighter lines between ANDA filing and review issues.  FDA says as much in the notice announcing the ANDA RTR impurity limits draft guidance: “FDA intends to develop additional guidance documents further clarifying the enhanced refusal to receive standards.”