In the first two years of GDUFA, the Office of Generic Drugs (OGD) DMF review team has been hard at work clearing up the backlog of DMF reviews and trying to figure out how to stay ahead of the game once the GDUFA metrics kick in in 2015.  OGD did not want to penalize GDUFA submissions based on DMF submissions too severely because the DMF review process was so dramatically impacted and adjusted once GDUFA went into effect.  So  for years 1 and 2 of GDUFA, OGD exercised some regulatory flexibility in establishing a workable system.  Now OGD has some advice for ANDA applicants that must be incorporated into your development and submission plans before your application is submitted.    

The big change is that, beginning in FY 2015 (October 1, 2014), any Type II DMF referenced in the ANDA must be on the “available for reference” list at the time of ANDA submission. The list will be checked at the beginning of the ANDA filing review. This differs from current practice of waiting until the end of filing review to confirm that the DMF is available for reference – which gave about a 4 month window for the DMF to undergo a completeness assessment.

Other nuggets outlined by a representative of the DMF Review Team during the presentation were:

  • Submitting DMFs in paper format can cost the firm an extra 7-10 days of review time because the DMFs are stored off site-all the more important to submit the DMF in electronic format.  Also, submitting the DMF in eCTD format improves efficiency and avoids errors – improving the chances of a first-cycle complete assessment
  • DMFs that received a full scientific review after 2007 undergo an administrative complete assessment that takes approximately 20 days.  If unsure whether your older DMF qualifies for an administrative complete assessment contact OGD – dmfogd@fda.hhs.gov
  • Submit the DMF and pay the fee six months in advance of the ANDA submission to allow enough time for the DMF to undergo a complete assessment
  • Average time to respond to an incomplete action by OGD’s DMF team is currently 45 days – OGD is encouraging industry to reduce response time to 30 days

The complete assessment process was outlined by OGD in the following diagram:

 

Note that only 18% of DMFs receive a complete assessment (CA) upon the first cycle of review. Approximately 88% of the DMFs receive a CA on the second cycle. ECTD DMFs have a higher rate of first-cycle CAs.

FDA outlined some common clarifications for DMFs:

  • API is a substance or a mixture when the substance is unstable or cannot be transported on its own.
  • DMF for a mixture (e.g. API plus an excipient) can qualify as the API under GDUFA. We ask that a justification be submitted to the DMF when this claim is made. Note that these situations also have important facility fee implications.
  • The CA requires that a DMF be for a single API produced by a single manufacturing process.
  • Stability studies must have started when the DMF is submitted and must contain one time point past initial results.

The current DMF review staff stands at just under 39, with 14 hired in FY 2013 and a 25 hired (so far) in FY 2014. The goal is to have a DMF staff of 61 by the end of 2014.

Pay attention to the advice of OGD and get out to a conference to hear the latest.  The screws will be tightening on filing reviews relative to having DMFs in and on the acceptable for reference list shortly.  Failure to do so may result in a refuse-to-receive,  a result you should try hard to avoid as it will cost you 25% of the ANDA application fee and may put a first-to-file opportunity at risk. Please contact Terri Nataline at t.nataline@LachmanConsultants.com or one of our other regulatory experts at Lachman for any questions you may have regarding this process.