FDA and Manufacturers Map Out PDUFA Reform Priorities

A year-long process reauthorizing the Prescription Drug User Fee Act (PDUFA) was launched July 15, 2015 with a public meeting, setting the stage for monthly discussions with industry beginning this fall and regular meetings for FDA to hear the views of patient, consumer, and health professional representatives. The current program (PDUFA V) sunsets in September 2017, which means an agreement for PDUFA VI should be in place by the middle of next year.  FDA also has held kick-off meetings on new user fees for generic drugs and medical devices, which follow similar renewal timetables.

The schedule is particularly tight this time because the user fee reauthorization process coincides directly with the presidential elections. A new administration and a new Congress will begin in January 2017, and any user fee agreements will have to be ready for review by both outgoing and incoming administration officials before going to Congress.

The importance of the PDUFA program to FDA was apparent in appearances at the meeting by acting commissioner Stephen Ostroff and deputy commissioner Robert Califf, both new to the agency’s negotiating process. Center for Drug Evaluation and Research (CDER) director Janet Woodcock provided summary of the day, highlighting the importance of patient input in drug development and review, interest in expanding FDA’s Sentinel program to strengthen oversight of postmarketing safety, and further efforts to bolster regulatory science. CDER “continues to struggle” with the recruitment and retention of critical staff, Woodcock observed, making numerous comments that FDA’s ability to attract top scientists is key to achieving a more predictable and efficient drug development and approval program.

Theresa Mullin, director of CDER’s Office of Strategic Programs, has the job of keeping the PDUFA negotiations on track. She noted that PDUFA V focused on enhancing the review program for important new drugs, achieving an increase in first-cycle approvals through enhanced communication with sponsors. High-level priorities, she said, are to continue to enhance the drug review process and its predictability, to maintain a fair and efficient fee structure, and to use funds to hire and retain top talent for the agency.

Patient groups and professional organizations proposed a range of initiatives meriting PDUFA support: validation of more biomarkers and patient reported outcomes (PROs), pediatric and neonatal drug development, expanded use of registries, data transparency initiatives, and greater consistency across CDER review divisions on acceptance of expedited review pathways. Several commentators urged further assessment of the 60-day waiting period, established under PDUFA V to ensure that new drug applications are complete before starting the review clock, and whether it has accelerated or slowed application review times.

Fees and outsourcing

Rena Conti, assistant professor at the University of Chicago, raised questions about whether facility user fees provide an incentive for manufacturers to outsource production and limit backup supplies, a possibility that could increase the risk of shortages, especially for generic drugs. Conti proposed that FDA provide information from its database on drug manufacturing sites to support research on dual sourcing and supply forecasting related to the PDUFA fee schedule.

Excipient makers called for a user fee program to support FDA review of the safety of novel inactive ingredients, separate from the new drug review process. Such a program, said David Shonecker, speaking for IPEC-Americas, would enhance the development of innovative therapies and the use of advanced manufacturing processes.

A main theme was expanding the use of real-world evidence to accelerate drug development. Greg Daniel of the Brookings Institution described how PDUFA VI should shift from a focus on streamlining application review, to strategies for tapping clinical evidence and other data to support agency decisions and to document product safety in the postmarket setting. Allan Coukell of the Pew Charitable Trusts similarly emphasized the value of better access to observational data from health-claims databases, in addition to clinical trials. And Marc Boutin of the National Health Council highlighted the need to clarify that sponsors engaging with patients early in the development of new experimental uses of a therapy does not constitute off-label promotion.

A main goal for manufacturers, said Kay Holcombe of the Biotechnology Industry Organization (BIO), is to further integrate patient perspectives into drug development and regulatory decision-making. This involves shifting from an anecdotal to a data-driven, systematic process built on a structured benefit-risk framework and clear FDA guidance. Sponsors also seek improvements in FDA communication and practices across CDER review divisions:  a BIO survey finds that half its members report beneficial and productive interactions with FDA, but half see “room for improvement.”

FDA officials emphasized that the user fee program deals only with agency processes related to drug development and review-and not with policy issues that require legislative or regulatory action. Yet, proposals to expand the use of real-world evidence and other data sources may fall into the “policy” bucket.

And Holcombe raised a clear legislative issue: industry wants Congress to ensure “long-term stability” for PDUFA by clarifying that user fees are not subject to future budget sequestration actions. Under sequestration three years ago, a portion of industry fees became unavailable to FDA, delaying important regulatory science initiatives and enhancements, and, she asserted, “We cannot let that happen again.”