FDA has proposed a new application review model that would allow it to call a time-out, which could be used to resolve mid-cycle issues and, the agency argues, potentially bring more predictability to the process.

The idea, if implemented, also could assuage agency concerns that the six- and 10-month times prescribed for priority and standard applications, respectively, are no longer sufficient to actually complete a review.

Minutes of the Sept. 27 industry and FDA Prescription Drug User Fee Act reauthorization negotiation revealed the agency proposed the time-out solution in an effort to create more application review time, while still providing more feedback to sponsors.

The proposal also could be used to address industry requests for a formal mid-cycle meeting to gain agency feedback on an application’s direction, but whether industry will accept it is undetermined.

Ian Spatz, a senior advisor at health care advisory firm Manatt Health Solutions, said the time-out idea could actually create more uncertainty in the process.

“Industry needs to be open to ideas that will improve the review, not just shorten it,” Spatz, a veteran of previous user fee negotiations from his time as Merck's vice president for global health policy, said in an e-mail.

“If a ‘time-out’ is something that FDA can always ask for and always get, this could lead to reduced certainty and make the review deadlines meaningless," he said. "FDA and industry need to work to explore how to address this idea without this happening.”

Industry representatives called for a mid-cycle review in a previous PDUFA negotiating session, but FDA said comprehensive feedback likely was not possible at the midpoint of an application review because its process is not complete.

The time-out idea would create an opportunity for a mid-cycle meeting, but not take away from FDA’s review time. After a comprehensive first review of an application, the agency could issue discipline review letters to the sponsor, if warranted.

DR letters typically are sent to identify scientific and other questions review team members have during an application cycle and are not considered action letters by the agency. Under the new model, the letters would come after a mid-cycle review meeting, but before the final action date. At that point the agency would call its time-out.

More Talks Possible During Time-Out

The length of the review clock stoppage would be fixed, but was not specified in the minutes. FDA said sponsors could use this time to respond to issues raised in the discipline review letters. The agency also still would maintain enough time to schedule and hold advisory committee meetings, determine Risk Evaluation and Mitigation Strategies and complete its review.

FDA argued the time-out plan would offer more predictability to the application review process. The agency also said it is more open to a formal meeting to talk about issues raised in the discipline review letters during the review stoppage time, as well as advisory committee planning and REMS issues, according to the minutes.

An agency willingness to add more meetings to the process is a change from previous discussions with industry, where the agency argued allowing for more meetings could lead to more sponsor questions and create more work for reviewers.

With the time-out proposal, however, the agency's position remains unchanged – even if its negotiating tactics have shifted. The agency argues it cannot provide additional application support with the resources it has, and so its offer to meet when industry wants means the review time must be extended. Now it's explaining the conditions under which it will meet, not just saying it can't meet.

Industry representatives gave no response, indicating they had not sufficiently talked with their members about the idea, but said they would give an opinion at the next PDUFA negotiating session. Representatives also will come prepared to discuss alternative methods of improving review efficiency, according to the minutes.

For example, industry said that new electronic data submission standards, once implemented, also should lessen the burden of some portions of the review process, according to the minutes.

Analysts at Concept Capital took the time-out idea to mean FDA should be expected to increase its review times when the new PDUFA legislation is approved.

“That reinforces our view that it is wise to build in a three-month delay for even a seemingly ‘slam-dunk’ application,” the group said in an Oct. 15 note.

FDA also submitted 12 proposals to use user fee revenue to improve its scientific and regulatory capacity. Many of the ideas are part of Commissioner Margaret Hamburg’s plan to upgrade regulatory science at the agency (Also see "User Fee Discussions Include Funding Parts Of FDA Regulatory Science Plan" - Pink Sheet, 25 October, 2010.).

Existing Review Staples Could Be Improved

Review performance, or lack thereof, has been a prime negotiating point in the PDUFA reauthorization. The program is set to expire in 2012.

From the start of the formal reauthorization process, industry has complained about delayed and inconsistent review times. During an August negotiating session, it offered an analysis indicating a considerable number of applications were not reviewed by their user fee goal between December 2007 and May 2010.

FDA would not accept all the blame, saying its analysis indicated application quality and complexity have affected performance (“PDUFA Negotiations Focus On Review Delays; Firms, FDA See Different Causes,” “The Pink Sheet,” Sept. 9, 2010).

FDA has been willing to make adjustments to improve performance, although they have generally involved extending the review time period so its record of first-cycle reviews can improve.

During a Sept. 13 negotiating session, the agency proposed requiring an automatic review deadline extension if an application requires an advisory committee meeting, foreign facility inspection or certain types of REMS (Also see "PDUFA Update: FDA Wants To Automatically Extend Complex Application Reviews" - Pink Sheet, 4 October, 2010.). It also said any major amendment to an application should trigger a three-month deadline extension, no matter when it is submitted. FDA said it would not extend review dates if it was clear the usual deadlines could be met.

During the most recent meeting, the agency said it is willing to look at new ways to make the 74-day letter more informative as well as create a “mid-cycle communication” to address issues that have come up by that point in the review process.

In addition, the agency said it is open to conducting more meetings to discuss manufacturing issues as part of a push for industry adoption of the Quality by Design program, an effort to implement production processes that ensure quality throughout a product life cycle.

Industry wasn’t ready to agree to review extensions when it first heard the idea, and other stakeholder groups also were concerned about adding time to the review process, according to minutes of a Sept. 29 FDA meeting with patient and consumer advocates and trade associations.

FDA told stakeholder group representatives the NME first-cycle approval rate is about 30 percent throughout PDUFA’s history and the clock extension would help the agency complete more first-cycle approvals and get drugs to patients faster rather than going through an entire extra review cycle.

By Derrick Gingery

PDUFA Negotiations: FDA Wants To Be Able To Call "Time-Out" During Reviews

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