PDUFA Pilots: Risk/Benefit Plan Takes Off As “Continuous” Applications Stop

FDA's proposals for renewal of the Prescription Drug User Fee Act will continue the program's function as an incubator of new regulatory approaches by the agency.

While some of the changes proposed are technical accounting modifications that adjust how the agency collects fees, other initiatives could profoundly alter how sponsors bring applications to review by the agency.

Under the new cycle, FDA will spend user fee money to support agency "participation in workshops and other public meetings to explore new approaches to a structured model for benefit/risk assessment," ¹ FDA's proposal states.

"The results of these interactions would be used to assess whether pilot(s) of such new approaches can be conducted during PDUFA IV. These efforts may lead to the development of guidance documents."

Creation of quantitative risk/benefit analysis measures for the approval process has been one step industry has urged in order to help the agency improve its public image (² (Also see "FDA Needs Quantitative Risk/Benefit Analysis To Quell Industry Approval Fears" - Pink Sheet, 5 Jun, 2006.), p. 18).

FDA itself has suggested that it may be able to refine its risk/benefit analysis by considering the tradeoffs that companies weigh when they trim products from their pipelines (³ (Also see "Can FDA Learn From Industry’s Risk/Benefit Decisions?" - Pink Sheet, 10 Apr, 2006.), p. 22).

Creating structured review criteria for risk/benefit evaluation could give sponsors considerable clarity about the potential fate of their applications, allowing them to plan clinical development in much the same way that PDUFA's review timetables have allowed firms to plan launches based on submission dates.

A possible downside for industry, though, is that once a concrete formula for evaluating risk and benefit is established, adding prerequisites for comparative- (or even cost-) effectiveness to the equation would be easier. While obviously unenthusiastic about such requirements, firms are already undertaking many studies addressing those issues in response to market pressures (⁴ (Also see "Payers Having More Impact On R&D, Pfizer Says; Asenapine Is Early Casualty" - Pink Sheet, 18 Dec, 2006.), p. 10).

The agency's efforts in the postmarketing arena will also focus PDUFA money on fundamental issues of how products are reviewed and used (⁵ , p. 3).

As part of the post-market work, FDA is planning research contracts to "answer such central questions as the number and types of safety concerns that are discovered by various types of adverse event collection, the age of the medical products at the time such safety concerns are detected, and the types of actions that are subsequently taken and their ultimate effect on patient safety."

While the impact of the risk/benefit pilots is uncertain, some of the new user fee goals proposed for PDUFA IV seem likely to be warmly embraced by industry, such as FDA's establishment of review times for DTC advertising and drug names. Those programs will routinize activities that FDA and sponsors already undertake and give clarity to promotional planning (⁶ (Also see "User Fee Deal For Ad Review Funds Stems From PhRMA DTC Principles" - Pink Sheet, 4 Dec, 2006.), p. 4).

The drug name review is accompanied by a pilot program under which industry would test the safety of proprietary names and FDA would review the data (⁷ (Also see "Drug Names Will Be Reviewed By FDA Within 90 Days Under PDUFA Timetable" - Pink Sheet, 22 Jan, 2007.), p. 7).

Several new approaches adopted as part of the last user fee program renewal in 2002 have become valued parts of the agency's review operations.

The "74-day letters" - correspondence in which FDA alerts sponsors to potential deficiencies in their applications after an initial evaluation - will take on additional weight in the new user fee cycle as the agency uses them to set the timetable for many aspects of the review (⁸ (Also see "User Fee Hike Will Give Sponsors Clarity On Label, Postmarketing Discussions" - Pink Sheet, 15 Jan, 2007.), p. 4).

However, other initiatives which were launched as part of PDUFA III have failed to demonstrate their benefit and are being swept to the regulatory dustbin.

Two pilot programs to test novel interaction techniques between FDA and industry during application review have not succeed. "Continuous Marketing Application" Pilot 1 allowed sponsors to submit "reviewable units" in advance of the complete submission; Pilot 2 created a schedule of meetings to allow for more interaction than FDA and the sponsor usually have.

"FDA and industry representatives have agreed that although the pilots demonstrated value in some areas, the overall added benefits of the programs did not justify their costs to FDA," the agency said.

"Industry strongly valued the subtle differences that Pilot 1 offered over the fast track/rolling review program where FDA remained neutral," a ⁹ report on the application pilots by Booz Allen Hamilton concluded. The report emphasized the need for additional resources if the program were to continue.

Independent consultations on trials for biotech products is another PDUFA III program that did not make it into round IV. Under the program, sponsors of biologic products could request the participation of an independent consultant, selected by FDA, in the agency's review of the protocols for a product's pivotal studies (¹⁰ (Also see "FDA Biotech Consultants Should Be Vetted By Companies, BIO Says" - Pink Sheet, 18 Aug, 2003.), p. 26).

The agency has received "no requests under this initiative ... and, after discussions with industry representatives, FDA is proposing not to include this initiative in the recommended PDUFA IV program."

The absence of requests for independent consultants suggests industry comfort with the special protocol assessment process. Use of SPAs has jumped in recently years, and the agency cites the growth in related workload as one of the reasons for the proposed user fee hike (¹¹ , p. 20).

- M. Nielsen Hobbs