Status Update on the Review of DMFs Presented by Dave Skanchy, Ph.D. Director DMF Review Staff GPhA/FDA CMC Workshop June 4, 2013 1
Outline Changes to the DMF Review Staff: Update on GDUFA hiring and the expansion of the DMF Staff Implementation of GDUFA: How we are meeting the requirements in the Commitment Letter. DMF Complete Response Letters DMF No Further Comment Letters 10-day Teleconferences Completeness Assessments Available for Reference List Communication Enhancements 2
Purpose of The DMF Review Staff Mission: Perform review of drug substance information in support of ANDA submissions Increase consistency of DMF reviews Drug substances reviewed in one place DMFs assigned to reviewers (ownership) through the entire process Concentrate subject matter experts in organic chemistry, drug substance process engineering, and analytical chemistry on drug substance review Focal point for all Drug Substance quality issues in OGD Facilitates consistency and better communication with industry Facilitate implementation of GDUFA and other initiatives to improve drug substance review 3
Growth of The DMF Review Staff Started as a pilot in Fall of 2010 with 3 chemists supporting 2 ANDA review teams. Grew to 12 staff (11 chemists and a PM) by October 1, 2012 when GDUFA was implemented At that time supporting review activity in 10 of the 16 ANDA Teams for original ANDAs only 4
Future of the DMF Staff under GDUFA Expansion of Staff DMF Staff has hired 14 new reviewers as a result of GDUFA resources since October 2012. 7 are already on board with the rest expected by September 2013. DMF Staff is now divided into multiple teams and is roughly the same size as an ANDA review division. Currently 19 chemists and a PM Expansion of Scope of Work to include nearly all drug substance review by the end of CY 2013 Support for all 16 ANDA Teams Support for DMFs referenced in supplements Support for drug substance information included in the ANDA Increase resources for Completeness Assessments and other GDUFA related activities 5
DMF Requirements in GDUFA Completeness Assessments (CA) Perform an initial Completeness Assessment on all Type II DMFs referenced for the API Publish the criteria used for the CA (Draft Guidance) Publish a list of all DMFs that are Available for Reference (fee paid and passed the CA) 6
DMF Requirements in the Commitment Letter (Efficiency Enhancements) Enhanced Deficiency Communications (DMF CR) Include all relevant disciplines (including consults) Full division-level (tertiary) review Include information on facilities inspections Communicate Easily Correctable Deficiencies promptly using telephone deficiency/information requests. 10-day teleconferences upon DMF holder request No Further Comment Letters 7
Enhanced Deficiency Letter Created a new letter template and process called the DMF Complete Response In use for all Type II DMFs for APIs since mid-october 2012. Modeled after the ANDA Complete Response Chemistry Deficiencies (if applicable) Microbiology Deficiencies (if applicable) Facilities information Letters reflect the compliance status of facilities at the time the letter issues Deficiencies from any related consults are included under the discipline that requested the consult Issued 122 DMF CR Letters through April 2013. 8
10 day Teleconferences 30 minute t-con for first cycle deficiency letters limited to the contents of the letter To qualify, a written request must be received by FDA within 10 days of receiving the deficiency letter Contact information for requesting these teleconferences is included at the end of the DMF Complete Response letter Meeting timeframe is at the discretion of OGD and availability of involved parties There are limits of one teleconference per DMF holder per month Four requests through April 2013 9
DMF No Further Comments Letter The Commitment letter states: FDA will issue the DMF holder a letter to indicate that the DMF does not have any further open matters as part of the review associated with the referencing ANDA. Issued at the time of approval of the ANDA, not when the DMF is first deemed adequate Not to be construed as an indication of any future status of the DMF (i.e. not equivalent to an approval letter) Goal to issue within 30 days of the ANDA action letter Through April 2013, 318 NFC letters have been issued. 10
Completeness Assessments by the Numbers Fully Implemented on October 1, 2012 Projected number was 700 for the entire FY2013 Current status of the CAs: As of April 2012 OGD received 1087 requests for CA 646 DMFs reviewed and found complete (59.4%) 825 DMFs have completed at least one CA review cycle (76%) An additional 100 CAs are assigned and currently under review (925 or 85% either reviewed or under review) 162 DMFs (15%) in queue for assignment ( backlog ) 11
Completeness Assessments by the Numbers Of those pending assignment, only 9 are associated with a current ANDA submission (i.e. at risk of causing a filing issue) Timelines Average time from payment to completion for an administrative CA (n = 565): 21 days Average time from payment to completion for a full checklist CA (first cycle, n = 291): 83 days 12
Factors Impacting Timelines Large overall number of DMF Payments (3x projected number) Large bolus of payments initially (almost 600 in the first two months) Limited review resources 13
Completeness Assessment Timelines Will improve substantially going forward Decreasing trend in workload Clearing of the initial bolus Additional review resources Experience with the process Current estimates are: Type of CA Priority CA Review Completion (first cycle) Administrative Any Priority Two to Four weeks from the time of fee payment. Full Expedite DLPS Two to Four weeks from the time DLPS notifies DMF Staff of the priority. Full Expedite ANDA Eight to Ten weeks from the time priority is granted. Full Normal Twelve weeks plus 14
Completeness Assessment Priorities Guiding principle Reduce the risk to ANDA sponsors for being RTR due to the DMF not being Available for Reference Tiered risk based prioritization scheme High Low Priority (#) Sorted by. Used for. Expedite DLPS (67) ANDA Submission Date (earliest first) DMFs associated with ANDAs in queue for OGD filing review that DLPS/RSB has identified as expedited. Expedite ANDA/PAS (392) Normal (628) ANDA Submission Date (earliest first) DMF Fee paid date (earliest first) DMFs associated with a submitted ANDA in queue for an OGD filing review. DMFs which have paid the fee but not yet referenced by a GDUFA submission. 15
Future Prioritization Current priority scheme will remain in place until December 31, 2013. After that date DMF holders and ANDA sponsors will take on more responsibility for planning a viable submission strategy. High Low Priority Sorted by. Used for. Expedite DLPS ANDA Submission Date (earliest first) DMFs associated with ANDAs in queue for filing review that DLPS/RSB has identified as expedited. Normal DMF Fee paid date (earliest first) DMFs which have paid the fee but not yet referenced by a GDUFA submission. 16
How is the Generic Industry doing with CAs? Overall Industry is adapting very well. Some metrics: DMFs for Full CA complete on the first cycle: 17% DMFs for Full CA complete by the second cycle: 88% Number of DMFs requiring a third cycle CA: 8 Average response time (first cycle): 30 days Electronic submissions greatly facilitate the process efficiency 17
The Available for Reference List Comprehensive list of all Type II DMFs for APIs that have paid the DMF fee and passed a Completeness Assessment Updated list has been posted on the FDA website on a weekly basis since12/19/2012 Once the DMF is on the list you remain on the list unless fee payment is withdrawn or the DMF has a status other than active All questions regarding the contents of the list should be sent to: DMFOGD@fda.hhs.gov 18
Keys to a Smooth CA Process Submit a complete DMF (use the checklist) Update older DMFs that might not meet the standard (amend or provided a complete update) Respond to Incomplete letters as soon as possible Maintain good communication between ANDA sponsor and the DMF holder Pay the DMF fee as early as possible! 3 months ahead of ANDA submission for nonexpedited ANDAs 6 months for expedited ANDAs Follow instructions on the cover sheet to send email notification of a response to the chemist 19
Acknowledgements and Questions Entire DMF Review Staff Kun Shen (PM) Wei Song Evelyn Hong (OM) Tina Gilliam (OCOMM) 20