Industry and FDA agreed to a recommendation package for the PDUFA V commitment letter after dividing agency proposals into three tiers and funding two. Industry had considered 11 changes proposed by FDA for inclusion in the reauthorization of the Prescription Drug User Fee Act. Ultimately, three proposals were not funded because industry did not see them as pressing needs. However, firms did agree to FDA’s higher projections for the additional employees and other costs that would be required to fund the other programs. FDA would not confirm an agreement had been reached. The agency expects to publish the proposals, likely in late summer or early fall, after their clearance by the full administration. As of March 31, the agency and industry appeared to have reached an agreement on a package of recommendations for the PDUFA V commitment letter. Minutes of that meeting, released April 28, indicated final reviews and minor clarifying edits were made to the package (“PDUFA V Agreement Appears Set Between FDA And Industry,” “The Pink Sheet” DAILY, April 28, 2011). Trial Design, Inspections Left Unfunded Proposals to expand the Quality-by-Design program, enhance agency capacity to review and develop non-inferiority and adaptive trial designs, and conduct more real-time clinical trial site inspections were not funded. Industry said based on input from its members, “the needs in the areas of non-inferiority and adaptive trial designs and Quality-by-Design are not as great” as some other areas, according to minutes of a Feb. 10 negotiating session. Industry also said clinical trial oversight was a job sponsors take seriously and member companies felt they were currently meeting appropriate standards, according to the minutes. The cut likely was an effort to limit the increase in user fees necessary to handle the additional staff that would be required for the new programs. Industry already had spent part of the negotiations attempting to change inflation and other user fee revenue adjustment formulas so they would more accurately reflect current economic conditions (“PDUFA Formula Could Better Incorporate Present Economic Conditions,” “The Pink Sheet,” April 18, 2011). The move meant eight proposals, in addition to changes to the application review system, were included in the commitment letter that both sides were reviewing for the final time during the March 31 session. Adding patient and advocate views to risk-benefit decision-making, increasing staff for rare disease and biomarker development, creating a dedicated meta-analysis team, and standardizing Risk Evaluation and Mitigation Strategies for better integration into the health care system were among those in the agreement (see chart, "PDUFA Proposal Sheds Tier 3 Funding"). FDA agreed to limit the commitments to the top two tiers of proposals, but would not agree to the 100 additional full-time equivalents industry proposed to staff the programs. That estimate did not include additional personnel required for changes to the application review system. The agency said it required full resourcing of the proposals, including “drug safety staff critical to REMS and other safety-related work.” At a Feb. 15 meeting, FDA said it would need 119 FTEs and an additional $4.17 million per year in “other direct costs,” according to minutes of the session. By March 10, when reviews of the draft commitment letter had begun, industry had agreed to FDA’s request, according to minutes of that session. Industry asked the agency to give annual reports on the progress of the initiatives, including hiring and staff placements. FDA agreed to post annual reports on its website, according to the minutes. New Review Model Alters Submisson Timeline The application review system changes mostly followed the model that had evolved through the PDUFA process, but the sides could not agree on a system for allowing inexperienced drug sponsors to ask FDA clarifying questions related to their applications. Both sides debated adjustments to the review system throughout the negotiation process, which began in July 2010. Industry wanted to include more communication between sponsors and FDA during the review, while FDA wanted to improve its record of first-cycle approvals. The two sides decided on a new system that will be used for new molecular entity new drug applications and novel biologics license applications that would result in a de facto two-month extension of review times, and more formal opportunities for sponsor interaction with the agency. The program had been scheduled to start as a pilot, but both sides decided it would apply throughout the user fee cycle. Pre-submission meetings will be required at least two months before the application is filed, where the agency and sponsor will talk about what components must be submitted and which can be sent within 30 days after the original filing. An applicant that does not have a pre-submission meeting would essentially not be allowed to amend the application after it was submitted, according to the minutes. It is a nod to FDA’s efforts over the past several months to remind sponsors that applications must be as complete as possible at submission so agency staff can better plan the review (“PDUFA V: FDA Relaxes Pre-Submission Meeting Requirement,” “The Pink Sheet,” March 28, 2011). For sponsors that do have a pre-submission meeting, unsolicited amendments will be handled using current guidance. Both sides also agreed to definitions of whether a modification to a REMS submission constitutes a major amendment, including instances where REMS changes would not be considered a major amendment. Major amendments would warrant a three-month timeline extension, although there was no mention in minutes of the Feb. 10 meeting, during which the proposal was agreed to, whether the new system would require the extension no matter when the amendment was received. The review clock will not start until after a 60-day filing period, and sponsors will be able to talk with agency officials at mid- and late-cycle meetings to discuss application problems. Late-cycle Meeting Might Lack Division Letters Industry proposed another change to the system during a March 25 session that would have required FDA to send all primary and secondary discipline review letters to sponsors eight to 12 days prior to the late-cycle meeting to ensure substantive discussions would be possible. The letters are used to communicate application problems found by different review teams looking at an application. FDA refused, but said if discipline review letters were not ready before the late-cycle meeting, the pre-meeting memoranda would include the problems identified. Applications in the program will be tracked to note review team performance. An interim assessment also will be conducted to determine whether the program should continue through fiscal years 2016 and 2017, the final two years of PDUFA V. If it is scrapped, applications received during that time would be governed by rules that apply to all other applications, according to the minutes. Industry has pushed throughout the process for assessments of new programs as well as the ability to change them during the PDUFA cycle if they are not effective (“PDUFA Needs Mid-Cycle Correction System As Part Of Reauthorization, Industry Says,” “The Pink Sheet,” April 18, 2011). By Derrick Gingery | 
