FDA wants industry to agree to a set of reasons that would automatically trigger a longer application review as part of the negotiations on reauthorizing the Prescription Drug User Fee Act.

Most of the agency's proposed criteria have to do with the added time required to deal with a complex application and appear intended to cut down on the number of multiple-review cycles, which would improve FDA's performance metrics.

The agency proposed that applications requiring certain types of Risk Evaluation and Mitigation Strategies, advisory committee meetings and foreign facility inspections should automatically get an extension from the typical six- or 10-month review time.

“FDA expressed concern that the NDA/BLA review times established in 1997 no longer provide sufficient time to conduct a complete review due to post-FDAAA factors,” according to the minutes of a Sept. 13 meeting with industry.

The agency also proposed a three-month deadline extension be automatically granted if a major application amendment is submitted at any time during the process. Today, the agency allows a three-month extension if a major amendment is submitted within the last three months of the review cycle. No other review extensions are available, the agency said.

Representatives from the Biotechnology Industry Organization and the Pharmaceutical Research and Manufacturers of America were concerned about allowing review extensions for divisions that already are meeting review goals, according to the minutes. FDA said it would not extend a user fee date if current deadlines could be met.

Industry highlighted the agency’s lackluster record of meeting user fee goals at an Aug. 9 PDUFA negotiation. PhRMA said a “considerable” proportion of NMEs were not reviewed by their user fee goal during the 2.5-year period between December 2007 and May 2010 compared to previous years. Priority review applications also tended to extend beyond target dates.

FDA submitted an analysis indicating more complex and lower-quality applications affected review performance (“PDUFA Negotiations Focus On Review Delays; Firms, FDA See Different Causes,” “The Pink Sheet,” Sept. 9, 2010).

FDA Wants To Eliminate Some Regulations

The agency also wants to improve its handling of electronic application data, since "the variability in the data format and terminology in current submissions presents a major obstacle to conducting a timely, efficient and predictable review," according to the minutes.

FDA proposed two changes to accomplish this: allowing user fee money to be spent on standard development, and changing that governing statute to allow the agency to modify standards without having to issue a regulation each time.

While the agency called rewriting the statute a "technical change," industry, even as it recognized the value of data standardization, expressed "some concerns about a requirements process that did not require a formal process for receiving feedback on proposed data standards from stakeholders such as the research community and sponsors," according to the minutes.

More Meetings Are Not Better For Agency

Review process management has become one of the major issues for the PDUFA V reauthorization. The Sept. 13 meeting focused solely on improvements both sides want to either improve review times or the likelihood of a first-cycle approval.

Review process improvements also were part of the agenda for the next meeting, along with proposals to increase public confidence and strengthen the program's science base, according to the minutes.

Among the industry proposals explored in more detail during the Sept. 13 meeting was adding a formal mid-cycle meeting between the sponsor and FDA to talk about substantive issues and concerns, based on a comprehensive mid-cycle review.

Industry representatives said the meeting could allow sponsors an opportunity to address agency concerns about an application before it takes action. The meeting also could help sponsors plan for manufacturing capacity and clinical development activities, according to the minutes.

FDA countered that comprehensive feedback would not be possible mid-review because the process is only partially complete at that stage. Agency officials also said a mid-cycle review would lead to more sponsor questions, requests for meetings and application amendments that would increase reviewers’ workloads.

Industry also asked for “Type C” meetings that could be conducted face-to-face or in writing to give sponsors more options to ask questions. FDA said written response options are potentially useful and already in use in some review divisions, but are not less labor-intensive than face-to-face meetings.

FDA Not Excited About Giving “Advice”

Industry also asked FDA to make time to break out of its formal meeting process and give “non-binding” advice to companies with development questions.

Small companies with little experience working with the agency should be allowed opportunities to ask simple or clarifying questions of agency officials during early development stages without triggering formal responses that can cause significant delays, industry argued, according to the minutes.

The issue is of major importance to developers of drugs for neglected tropical diseases, such as malaria or tuberculosis. During a public hearing on development of therapies in that area, several company officials asked FDA to provide non-binding advice to help navigate the approval process.

Peter Hotez, president-elect of the American Society of Tropical Medicine and Hygiene, said non-profit groups developing products for neglected diseases could benefit from FDA acting as a mentor as they prepare for the application process.

Hotez said pre-IND meetings are helpful, but still have a formal tone.

“It would be interesting to explore whether there could be another venue created that allows that exchange in a less formal manner,” he said during the Sept. 23 hearing. “Because they’re under-resourced, often [their] staff has less experience than those with the pharmaceutical companies. We’re kind of searching our way through how to do this the right way.”

Yet FDA’s response at the PDUFA meeting and public hearing was the same: Non-binding advice puts the agency in an uncomfortable position.

“These interactions, I think, have been very helpful and very productive, but there have also been instances where there was misunderstanding,” said Marion Gruber, deputy director of the CBER Office of Vaccines Research and Review, at the hearing on neglected tropical diseases. “The scientific consultation provided by FDA was mistakenly taken for regulatory binding advice on the side of the applicant and it was somewhat rocky.”

Both sides at the PDUFA meeting said more discussion on what constitutes non-binding advice is necessary.

Give Us Information Earlier, Industry Says

Industry also wants advisory committee briefing materials earlier and by a set date, but FDA said that is not feasible.

REMS discussions earlier in the review cycle also are needed, but again, FDA said it may not be possible because risk-benefit calculations that help determine whether a REMS is needed are not complete until near the end of the review cycle.

The agency already is beginning to develop a standardized REMS system that includes support from some health care groups (Also see "REMS Templates Get Nod From FDA, With Nudge From Pharmacists" - Pink Sheet, 28 July, 2010.).

Agency officials said a standardized system also could reduce the subsequent negotiating time, according to the minutes.

By Derrick Gingery

PDUFA Update: FDA Wants To Automatically Extend Complex Application Reviews

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