Pre-“Complete Response” Deficiency Communication Possible For ANDA Sponsors

FDA and GPhA nearing agreement that would let generic drug sponsors receive a list of major application deficiencies before the agency issues its “complete response” letter.

FDA and industry appear close to creating a system allowing ANDA sponsors to receive deficiency information mid-review.

The agency wants examples of what should be included in such a system, but it seems sponsors could get a subset of major application deficiencies found during the review before the “complete response” letter arrives, according to minutes of a recent FDA-Generic Pharmaceutical Association quarterly board of directors meeting. The change, if implemented, could cut a sponsor’s wait time for word on their submission’s status, as well as provide a head-start in making the necessary fixes.

As sponsors absorbed the impact of all the changes spurred by the new generic drug user fee program, a number of problems have emerged, many related to communications. The agency formalized communications when GDUFA launched, requiring all information to go through the regulatory project manager, ending the sponsor practice of consulting review staff for status updates. FDA also stopped sending sponsors deficiencies as each discipline completed its review, in favor of issuing one “complete response” letter after the review was completed.

Sponsors found it difficult to gain information about their submissions under the new review process, which made launch planning difficult (Also see "GDUFA: Industry Says New Information Flow Lacking" - Pink Sheet, 11 Nov, 2013.).

FDA and GPhA proposed a number of solutions, including having the agency send sponsors a list of major application problems before the “complete response” letter was finished. Minutes of a Nov. 19, 2013 meeting between FDA and GPhA officials, released Jan. 9, indicate an agreement may be on the horizon.

Keith Flanagan, Office of Generic Drugs regulatory counsel, was designated the contact point to “produce an agreement or paper” by the end of December, according to the minutes.

GPhA had not provided a list of examples of major deficiencies that could be sent before the “complete response” letter as of the meeting time, but was expected to do so within 10 days. The trade group said Jan. 9 that it still was working on the idea, but it was not quite ready yet.

The agency said at previous meetings with GPhA that sponsors would not be allowed to respond to any deficiencies until they received the CR letter. In addition, the idea, if implemented, would not become a permanent addition to the ANDA review model.

Both sides also continue discussing potential changes to the “easily correctable” application deficiencies policy. Information in the minutes indicates sponsors may want more time to respond to them than is allowed in new draft guidance.

GPhA has formed a working group that is gathering data on easily correctable deficiencies, including those that cannot be responded to within 10 business days and the reasons why. FDA also will begin collecting data on industry’s reasons for not responding to the deficiencies within 10 days, according to the minutes.

The recently-released draft ANDA refuse-to-receive guidance allows sponsors time to correct submissions with fewer than 10 minor deficiencies, but only allows five business days to correct them in order for the application to be considered received on the original submission date (Also see "FDA Will Allow ANDA Corrections … Until 10 Minor Deficiencies Found" - Pink Sheet, 1 Oct, 2013.).

FDA also has indicated that it is considering creating an early notification process for ANDA sponsors to receive advanced notice that an application decision is coming (Also see "ANDA Sponsors May Receive Early Notification Of Upcoming Actions, Woodcock Says" - Pink Sheet, 15 Nov, 2013.).

GPhA Asked To Help Improve Submission Quality

The Office of Generic Drugs also plans to release additional policies related to review prioritization, application quality and multiple review cycles, amendments, dispute resolution, supplement guidance, and controlled correspondence soon.

The minutes indicate the agency hopes to finalize them prior to the start of fiscal year 2015, which is when formal review goals begin. Sixty percent of applications arriving that year must be reviewed within 15 months. OGD reviewers already are preparing for the GDUFA milestone (Also see "Generic Drugs 2014: OGD Creates Internal Review Goals, May Make OND-Inspired Changes" - Pink Sheet, 6 Jan, 2014.).

FDA also remains concerned about overall generic drug submission quality. Agency officials told GPhA during the meeting that many ANDA deficiencies are “submitted and resubmitted time and again,” despite agency efforts to help industry understand what is required, according to the minutes.

GPhA continues to work on a white paper looking at ways to improve submission quality and wants to begin a dialogue on the subject. FDA said it would be opening a docket on application quality and multiple review cycle issues, according to the minutes.

OGD data show refuse-to-receive actions increased dramatically in the fourth quarter of 2013, compared to the same period in 2012, along with submissions (see chart below).

Acting OGD Director Kathleen Uhl told industry officials last fall that the burden of a successful GDUFA implementation falls on industry as well as FDA. Improving application quality and reducing multiple review cycles were among her requested improvements for industry (Also see "GDUFA Success Depends On Industry Changes As Much As Review Improvements, FDA Says" - Pink Sheet, 4 Nov, 2013.).

Compliance Reorganization Planned

CDER’s evolution to deal with the growth of OGD and its generic drug enterprise also continues.

The agency said the Office of Compliance is planning a minor reorganization of the domestic and international manufacturing compliance divisions “to remove the distinction between the two, in recognition of the blending of the two in today’s increasingly global supply chain,” according to the minutes.

The Office of Compliance also will have a new leader following Howard Sklamberg’s appointment as deputy commissioner for global regulatory operations and policy (Also see "FDA Again Taps Compliance Director For Globalization Post" - Pink Sheet, 8 Jan, 2014.).

The change is expected to accompany the establishment of the Office of Pharmaceutical Quality, according to the minutes. Chemistry divisions currently housed in OGD would move to OPQ along with Good Manufacturing Practice and other personnel within CDER to form a new super office. Plans have not been finalized yet, but the move is expected to allow OGD to become more clinically-oriented (Also see "Pharmaceutical Quality And Generic Drugs: Janet Woodcock Explains Her Vision" - Pink Sheet, 25 Mar, 2013.).

FDA expects to add staff that will create “compliance policies for manufacturing quality,” according to the minutes. The agency already is considering collecting specific quality metrics to help inform inspection decisions (Also see "FDA Could Release GMP Data To Prod Manufacturing Improvements" - Pink Sheet, 15 Jul, 2013.).

The agency is in the midst of hiring more than 900 additional personnel to handle its GDUFA responsibilities. It met FY 2013 hiring goals and must add more than 400 employees in FY 2014 (Also see "GDUFA Hiring Ahead Of Pace But Still Faces A Long Road" - Pink Sheet, 30 Sep, 2013.).

Office of Generic Drugs Activity Report-2012 And 2013 Fourth Quarters
Activity	Oct. 2012	Nov. 2012	Dec. 2012	2012 Total	Oct. 2013	Nov. 2013	Dec. 2013	2013 Total
Refuse to Receive	9	10	4	23	30	10	16	56
Withdrawals	3	11	10	24	19	7	5	31
Approvals	35	34	39	108	20	40	30	90
Tentative Approvals	11	10	4	25	4	10	12	26
Complete Responses	126	130	125	381	113	126	111	350
DMF Completeness Assessments	18	127	76	221	181	150	98	429
ANDA Submissions	75	56	163	294	41	58	225	324
Original Amendments	183	147	132	462	176	156	143	475
Source: FDA