FDA remains firm in its push for application completeness in PDUFA V, despite its willingness to add two new review cycle meetings with sponsors.

Industry asked for some leniency in sending additional submissions while the application is undergoing filing activities under the proposed new review model. The agency offered a little slack, but indicated it is not likely.

FDA appears to be sticking to one of its credos in this Prescription Drug User Fee Act reauthorization negotiation: Applications should have everything required when they are submitted in order to increase the number of reviews completed on time.

Industry asked the agency to accept a filing during the filing period, when the review clock’s start would be held for 60 days, if it had been discussed during a pre-submission meeting. But FDA implied in the minutes there should be no reason for sending additional submissions at that time.

“The pre-submission meeting should partially serve to document what items will constitute a complete application,” the agency said in minutes of a Dec. 13 PDUFA Pre-Market Sub Group meeting.

Agency officials would not ban all additional submissions once the application is filed. They said in limited circumstances additional submissions for some priority applications may be accepted, according to the minutes.

Office of New Drugs Director John Jenkins already said the agency will not back away from its submission expectations.

Meanwhile, industry has been asking for clarification of what constitutes a complete application. Sponsors also want to know the FDA’s data threshold to make an approval decision, arguing it now appears to be a moving target (Also see "What’s A "Complete" Application? Clarity From FDA Could Speed Review Times" - Pink Sheet, 17 January, 2011.).

Under the new review model proposal, applications would be expected to be submitted with complete lists of manufacturing facilities and possibly clinical investigation sites along with other required documentation.

Sponsors Would Get More Timely Information

The longest and most extensive debates throughout the PDUFA reauthorization discussions have focused on changing the application review process. Industry has been looking for more communication with reviewers and faster decisions, while FDA wants to improve its record of first-cycle approvals.

The proposal on the table would indirectly extend the review cycle two months for NME new drug applications and novel BLA applications, with the potential for extending it another three months. But it also would create a mid- and late-cycle meeting between sponsors and FDA officials to talk about application issues.

The review clock on NME NDAs and novel BLAs would not begin for 60 days after submission to allow FDA to ensure the application is filed, pushing the goal date to one year for standard applications. Major amendments, no matter when they were submitted, would warrant an automatic three-month extension, which could push the goal to 15 months.

In return for the wait, sponsors would get a mid-cycle meeting with project managers during the 30-day period following an FDA internal mid-cycle meeting, according to the latest PDUFA negotiation minutes. In addition to updating the sponsor on application progress, reviewers also could talk about “high-level deficiencies.”

After the agency finishes its primary and secondary reviews, a late-cycle meeting would be scheduled with higher-level FDA authorities. The agency also agreed to give the sponsor the advisory committee briefing package prior to that meeting (Also see "FDA Floats 15-Month Review Timeline For PDUFA V; Firms Mull Tradeoff On Speed Vs. Certainty" - Pink Sheet, 13 December, 2010.).

Under the new review model, FDA also would write and issue Discipline Review Letters once its secondary review is finished, which would give sponsors a clear indication of the deficiencies found.

Industry officials said those problems may not be included in the advisory committee background package and sponsors can better use the information if it is received prior to the late cycle meeting, according to the minutes.

FDA also seemed to be establishing ground rules for the late cycle meetings to control the flow of extra submissions, which can slow reviewers’ progress.

The agency said discussions about deficiencies in late-cycle meetings would not necessarily be considered a solicitation for another sponsor submission. FDA said in the minutes the review division could accept the filing, but would be under no obligation to conduct a late review of it.

And if the submission was large enough, it could be considered a major amendment and garner a three-month goal extension.

Defining “Major Amendment”

Industry and FDA also discussed what constitutes a major amendment, but the minutes did not provide any more detail of the definition.

Questions also remain about when major amendments will constitute a review clock extension.

FDA said modifying a REMS proposal submitted with the application could count as a major amendment and be subject to the automatic extension. The additional time would be needed because REMS can only be reviewed after labeling and other issues are completed, according to the minutes.

The agency already is trying to deal with the squeeze on review resources stemming from increased application complexity by adjusting user fee calculation formulas, which help determine personnel levels (Also see "User Fee Inflation Calculations May Need To Change Due To Slow Economic Recovery" - Pink Sheet, 17 January, 2011.).

Review cycle discussions were expected to continue at additional meetings scheduled for early this year.

By Derrick Gingery

PDUFA V: FDA Application Completeness Crackdown Continues

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