On September 30, 2013, before the federal government shut down hit, FDA published a new guidance, “ANDA Submissions-Refuse-to-Receive Standards“. FDA’s guidance explains many of the principles that have been articulated in FDA’s “ANDA [Abbreviated New Drug Application] Checklist for Completeness and Acceptability of an Application” (“ANDA Checklist”), which is reviewed quarterly basis (calendar year) and updated on an “as needed” basis. The Guidance reported that refusal-to-receive decisions (“RTRs”) “underscore the need for improvement in the quality of original ANDAs.” Between 2009 and 2012, FDA’s Office of Generic Drugs (“OGD”) refused to receive 497 ANDAs, the Guidance explains. RTRs occurred with regard to original submissions, in 2009 – 12%; 2010 – 18%; 2011 – 15.5%, and 2012-9.4% (estimated). The most common reasons for RTRs included serious bioequivalence deficiencies and serious chemistry deficiencies, with other lead causes being format or organizational flaws, clinical deficiencies, and inadequate microbiology. As a result, FDA believes that it would help to clarify its RTR criteria to help improve ANDA quality.
First, FDA noted that as part of its threshold determination for filing, FDA reviews ANDAs following the ANDA Checklist, which is formatted to mirror the organization of the Electronic Common Technical Document (“eCTD”). As a matter of general policy, FDA will notify an applicant if it will issue a RTR and provide the applicant with the opportunity to withdraw its ANDA, amend to correct the deficiencies, or take no action. FDA intends to work with applicants if there are fewer than ten minor deficiencies, with such notification by phone, e-mail, or facsimile. If the applicant can correct the deficiencies within five business days and FDA so finds, then FDA will still receive the application from its original receipt date; if not so corrected, FDA will RTR the application. FDA will issue an RTR, however, if the application contains more than ten minor deficiencies or one or more major deficiencies.
The Guidance goes on to explain what FDA considers major deficiencies: failure to submit a completed FDA Form 356h, organizational/format failures, non-payment of Generic Drug User Fee Act payment obligations, lack of a U.S. agent for a foreign applicant, failure to provide an environmental assessment (or claim of categorical exclusion), failure to ensure the proposed labeling is consistent with the filed patent statement (i.e., the proposed method of use, with one exception where a patent is listed but the referenced listed drug (“RLD”) does not include the claimed use (Here, OGD will advise if this approach was correct or if the labeling or patent statement need revision.), citing an incorrect or unfounded basis of submission, other labeling deficiencies (not electronic or not the same as the RLD with not appropriate explanation for certain allowed differences such as change of manufacturer name), drug master file deficiencies, chemistry deficiencies, and bioequivalence and clinical deficiencies. Where an applicant has questions, FDA encourages Control Correspondence for guidance, with the exception that applicants are to consult product-specific bioequivalence recommendations rather than sending FDA Control Correspondence except for further guidance to explain the public guidance. FDA will consider alternative bioequivalence or other criteria in some instances with adequate justification, the Guidance further explains.
As more GDUFA measures are implemented over time, as with this one, it will be interesting to see if FDA will report improved ANDA quality or if the problems persist.