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The Pink Sheet – PDUFA V: FDA Relaxes Pre-Submission Meeting Requirement

The Pink Sheet – PDUFA V: FDA Relaxes Pre-Submission Meeting Requirement


Sponsors may have negotiated a four-month reprieve for the required pre-submission meeting in the proposed new application review system expected to be implemented with PDUFA V.

FDA has agreed the pre-submission meeting does not have to be a minimum of six months before the application is filed. At industry’s prodding, the agency said it would allow pre-submission meetings as little as two months before the expected filing date.

The move is a significant win for industry, which with the pre-submission meeting faced another FDA attempt to further stretch its review timeline. Industry still does not appear entirely happy with the proposal, but seems more willing to accept it, according to minutes of a Jan. 24 Prescription Drug User Fee Act reauthorization negotiation.

FDA asked for the meeting in advance of the anticipated filing date to increase communication with the sponsor and allow enough time to deal with pre-submission issues before the package reaches the agency.

The meeting also could be used to determine what would be needed for the agency to consider the submission complete, as well as what data could arrive later.

And in addition to helping ensure the application is more complete, the mandatory pre-submission meeting could also make FDA’s review process more predictable by forcing applicants to determine a submission target date so the agency can be better prepared to start the review.

New molecular entities and novel biologics license applications would be subject to the pre-submission meeting under the new review model set to launch in pilot form as part of PDUFA V (“FDA May Require NDA Pre-Filing Meeting Under PDUFA V Review Model; Pilot Launching Soon,” “The Pink Sheet,” Feb. 28, 2011).

FDA had offered to reduce the pre-submission requirement to three months before submission. But industry still opposed that timetable because it would force sponsors to meet with FDA potentially before Phase III trials were complete. While industry felt the meeting would be more productive if conducted simply after the trials were finished, it agreed to the two-month timeframe.

FDA agreed, noting that was the minimum time that it felt might be needed to make any pre-submission changes.

It appears the agency wants to create a “waiting period” after the meeting where the application could not be filed, forcing sponsors to fix any problems the agency identified.

Agency officials have been telling industry repeatedly over the last few months the applications should be complete when they are filed to ensure reviews are finished on time (“PDUFA V: FDA Application Completeness Crackdown Continues,” “The Pink Sheet,” Feb. 7, 2011).

Current policy does not require companies to give a firm date for when they plan to file an IND or NDA, the agency said.

Unsolicited Amendments Remain An Issue

Both sides continue to battle over whether unsolicited amendments will be allowed in the pilot program, although some progress appears to have been made.

Industry again requested agency flexibility in allowing unsolicited amendments to address issues FDA identified during mid- or late-cycle meetings. While the agency did not waiver from its original position that additions to an application would raise completeness problems, it also said it still would handle them according to current Good Review Management Principles and Practices.

The GRMPP guidance issued in April 2005 indicates FDA will review all amendments it asks a sponsor to provide. It states the agency will attempt to review unsolicited amendments during the first review cycle, but may not be able or choose not to if, for instance, the data do not address an application problem.

Both sides agreed FDA would be bound by GRMPP in the pilot program, ensuring the agency would not be able to reject unsolicited amendments outright.

Industry also asked for the ability to cancel the pilot program if assessments show it is not improving review efficiency. FDA said that likely would be difficult because the agreement would be included in the Congressional record, but said after an interim assessment is completed, it would decide whether to continue the program through the rest of PDUFA V, according to the minutes.

The review model has been the largest and most debated change since PDUFA talks began last year. It has evolved through several versions to include the pre-submission meeting as well as a mandatory two-month filing period before the review clock begins (“FDA Floats 15-month Review Timeline For PDUFA V; Firms Mull Tradeoff On Speed Vs. Certainty,” “The Pink Sheet,” Dec. 13, 2010).

FDA is also hoping to extend the time it has to review some manufacturing changes, due in part to the difficulty of foreign travel (see related story, “FDA Wants To Lengthen Review Time For Some Prior Approval Supplements”).

Industry Mulling Added FDA Staff Costs

The agency also is figuring the cost of hiring more staff to handle the additional meetings and clerical work that would come with added sponsor meetings and communications.

In addition, more people would be needed to “fully integrate that staff in the review of all applications in the pilot program,” the agency said in the minutes. The hiring also would ensure the new staff was fully active in the review process earlier, an industry concern.

Adding staff to support regulatory science upgrades, like dedicated teams for meta-analysis and biomarkers research, also remain on the table. FDA said all the regulatory science staffing must be taken as a group. Industry will respond after it determines how much more it would be able to pay, based on the expected improvements, according to the minutes.

Small Business Waiver Stalemate

Neither side is backing down from its stance on making what FDA is calling a technical change to the small business user fee waiver requirements.

Businesses that have never submitted an application and have fewer than 500 employees, including affiliates, can have the PDUFA application fee waived.

The agency wants to tighten the rules governing eligibility to ensure it can consider current and former company affiliates in making a waiver decision. A recent court judgment could force FDA to only include current affiliates when making the decision (“User Fee Waivers For Small Businesses Might Get Smaller Under PDUFA V,” “The Pink Sheet,” March 14, 2011).

Allowing only current affiliates could let companies receive waivers that previously were not eligible, the agency argued in minutes of a Jan. 27 Financial Sub-Group meeting. Industry has said only present affiliates should be considered when determining whether the company meets the first-time applicant requirement and the rules should not change.

FDA asked whether industry would accept including an expiration date on waivers for affiliates divesting from a firm, but industry maintained its position.

FDA acknowledged in the minutes both sides were at an impasse. This proposal almost certainly would not sink the entire user fee negotiation, but it indicates industry and FDA likely will not compromise on all issues.

There was no indication in the minutes whether the full negotiating teams from both sides would consider the proposal.

Agree And Disagree On Meeting Policy

Disagreements also continue to pervade talks about creating more opportunities for inexperienced companies to ask FDA clarifying questions.

The agency has agreed to allow companies that do not have an FDA approved product to ask questions, as long as they pertain to a previous meeting with FDA and meet other requirements.

The idea is expected to increase reviewer workloads, but industry said it is willing to pay extra money for the service (“FDA Could Answer ‘Clarifying’ Questions, But Only For Firms Without Approved Product,” “The Pink Sheet,” Feb. 28, 2011).

When FDA presented a workload analysis related to the clarifying questions proposal during the Jan. 24 meeting, industry disputed the findings, according to the minutes. Industry also said an expected 45 day-response time is too long to be helpful.

Industry said it would submit another counter-proposal that would address agency concerns.

Both sides did agree a written-only response to sponsor questions could be used for pre-IND meetings. FDA said the concept, known as a Type C2 meeting, more accurately reflects current practice, according to the minutes.