“There should be no confusion about who FDA serves … It’s important to get drugs rapidly to market, but rapid does not mean reckless …We’re not focused on where our resources come from — only on what they allow us to do!” These assertions, taken from FDA commissioner Andrew von Eschenbach’s opening remarks at a public meeting to discuss reauthorization of the Prescription Drug User Fee Act (PDUFA 4), betray a clear sensitivity to charges that the integrity of the regulatory process has been compromised by FDA’s increasing reliance on user fees provided by the regulated industry. The public meeting, held 2/16 in Washington, DC, was designed to explain the agency’s position regarding PDUFA reauthorization, and to obtain stakeholders’ reaction to a number of specific changes proposed by the agency to the existing legislation. He indicated that these changes are intended to place the agency’s human drug review program on a sound financial footing; enhance the process for premarket review of human drug applications; and includes proposals for modernizing and transforming the postmarket safety system. In addition, the agency presented a related proposal (however, separate from PDUFA) that would assess fees for advisory reviews of direct-to-consumer (DTC) television advertisements.

FDA chief medical officer Janet Woodcock presented statistics demonstrating the agency’s growing reliance on user fees from October 1992, when PDUFA was first enacted, through Fiscal Year 2006. She emphasized, however, that “User fees are not in any way related to approving products, but are spent overseeing the eligibility of products for market – that is, whether they are safe and effective.” Positive results made possible by PDUFA funding, in terms of augmented review staff and reduction in review and approval times, were cited by CDER director Steven Galson. He pointed out, however, that the agency’s premarket review capability is losing “funding stability” because the actual cost of inflation is greater than adjustment fees authorized by the current legislation (PDUFA 3); he also indicated that the current “workload adjuster” does not adequately account for actual increases in review work. Moreover, Galson said, demands on the postmarket safety system are growing, with significant growth in reports of serious and unexpected adverse events, and he complained of “understaffing” in the areas of postmarket surveillance and analysis.

Details on proposed changes to place the agency on a “sound financial footing” were provided by assistant commissioner for planning Theresa Mullin. She explained that the “inflation adjuster” in current law includes the cost of federal salary increases, but omits other payroll cost increases, such as health and retirement benefits. Mullin said that, while the “workload adjuster” in PDUFA 3 takes into account growth in the number of applications (NDAs, BLAs, INDs), it makes no provision for growth in sponsor-requested meetings, special protocol assessments and other areas of demand for FDA services. To remedy this growing problem, Mullin said FDA is proposing that PDUFA 4 change the method for calculating the inflation adjustment to reflect actual increases in costs of pay and benefits per full time equivalent (FTE) over the most recent five-year period. She said the agency will recommend that the “workload adjuster” for INDs be based on the total number of active commercial INDs in a given year, rather than simply the number of new commercial INDs received each year. She also indicated FDA is proposing a “proportionate” workload adjustment relating to INDs, NDAs and BLAs, to reflect increased numbers of meetings and special protocol adjustments for INDs, and increased meetings, labeling supplements and annual reports for NDAs and BLAs.

Legislative proposals designed to enhance premarket reviews and expedite drug development were discussed by CDER Office of New Drugs director John Jenkins. In particular, Jenkins said increased resources and staffing proposed for PDUFA 4 will allow FDA to commit to developing a review plan for each application that includes target dates for completion of various review activities, and to communicate the intended review timeline to sponsors in the “74-day letter,” thus increasing review transparency. Further, Jenkins said, FDA will commit to publishing a series of new draft guidances to clarify the agency’s current thinking on certain critical trial design issues, including guidances on such issues as clinical hepatotoxicity, non-inferiority trials, adaptive trial designs, multiple endpoints in clinical trials, and enriched trial designs.

Office of Planning staff director Malcolm Bertoni testified to progress made under PDUFA 3 in developing a modern information technology (IT) infrastructure, which will permit a fully automated human drug review process. With funding proposed for PDUFA 4, Bertoni said industry will be able to send in electronic applications with automated cross-links to previously submitted data, eliminating need for multiple submissions of the same information. “FDA reviewers will be able to retrieve all relevant submissions and related data electronically from their work stations, and they will have efficient tools for searching and analyzing data to support reviews,” he said. Bertoni also indicated that FDA will have the capability to handle two-way regulatory correspondence with industry, which will accelerate the movement toward an “all-electronic submission and review environment.”

According to CDER Office of Executive Programs director Deborah Henderson, FDA will propose that PDUFA 4 provide the wherewithal for a new “transformational strategy” to enhance and modernize the agency’s postmarket drug safety program. Elements of the program include: a contract study into ways of maximizing the benefit collecting information on adverse events through a product’s life cycle; developing a guidance document identifying epidemiology “best practices”; expanding access to important population databases for additional epidemiologic research and for targeted safety surveillance; assessing the effectiveness of Risk Minimization Action Plans (RiskMAPS) and other risk management tools; and modernizing the proprietary name review program, to include publication of a guidance document on good naming, labeling and packaging practices and good proprietary name evaluation practices. On this latter initiative, the agency will launch a pilot program for a new proprietary name review “paradigm,” which will allow industry to propose proprietary names according to the to-be-published proprietary name guidance.

CDER associate director for policy Jane Axelrad described a program for reviewing DTC television ads, to be submitted as a legislative proposal, separate from PDUFA 4. She said only firms that voluntarily submit DTC television ads for advisory review will pay the fees, projected to be $6.25 million annually, adjusted for inflation and workload. Axelrad explained there would be a one-time participation fee in the first year of the program, based on anticipated submissions, and annual pre-payment for advisory reviews thereafter. The cost for each submission will be $6.25 million divided by the total number of submissions that are identified by sponsors. Axelrad said the fees will support a staff of 27 FTEs to conduct premarket advisory reviews, with a goal, by the fifth year of the program, of completing reviews in 45 days and reviewing resubmissions in 30 days. A cap of $83,000 per submission will apply in the first year of the program to protect sponsors against the uncertainty of low program participation.

Afternoon sessions of the public meeting were devoted to comments by representatives of patient and consumer groups, healthcare professionals, and industry. Comments ran the gamut from full support for PDUFA reauthorization; to qualified support based on expressed discomfort with the concept of user fees, but coupled with a realization of their practical necessity; to outright opposition to reauthorization of PDUFA, or to any legislation featuring user fees.

Several presenters expressed concern that increased emphasis by FDA on drug safety might have the unintended effect of delaying or denying useful products to patients with severe, debilitating, or life-threatening diseases. Amy Comstock, representing the Parkinson’s Action Network, said “Time is in no way neutral to persons with a debilitating disease, and we are fearful that safety concerns will trump speed in getting drugs to market.” She expressed concern that no mention was made by FDA presenters with respect to authority for “fast track” or expedited reviews. Similar concerns were expressed by Jeff Allen, director of science policy for Friends of Cancer Research. “Fast review of promising new drugs is especially important to cancer patients. Their willingness to accept risk is not the same as for other populations.” He said user fees were “not enough” and urged that Congress increase appropriations for FDA.

Genzyme senior vice president for regulatory affairs Alison Lawton speaking for the Biotechnology Industry Organization (BIO), expressed “full support” for PDUFA 4, but said user fees were always intended to be “additive” to the agency’s core (appropriated) funds, and she also urged greater Congressional funding.

Pharmaceutical Research and Manufacturers of America deputy vice president for regulatory affairs Alan Goldhammer praised the successes of PDUFA to date, but expressed reservations regarding the value of monitoring products for safety late in their life cycles. “Safety monitoring is costly and few problems are likely to be discovered late in the life cycle,” he said. “Resources could be better used in other safety-related areas.”

U.S. Chamber of Commerce executive director of health care policy Anthony Wisniewski applauded PDUFA’s success “improving the drug approval process,” but said such success has “also made PDUFA an attractive vehicle for increasing user fees to fund other programs such as postmarket safety surveillance and DTC advertising.” He urged the agency to apply PDUFA funds in support of Critical Path projects, designed to help accelerate the development of new drugs. And he urged creation of a “generic PDUFA program” for the review and approval of generic drugs.

Coalition for Healthcare Communications executive director John Kamp took a jaundiced view of FDA’s proposal to strengthen its premarket review of TV ads through a new user fee program. “The existing program works; if it’s not broken, don’t fix it,” he said. He called for “clearer guidance” on DTC, and warned that FDA must bear the “burden of proof” in limiting advertising speech, or run a risk of violating First Amendment rights.

Consumers Union patient advocate Bill Vaughan expressed extreme reticence toward PDUFA and the concept of user fees, charging that financial support for FDA from the industry it regulates means that “If it is not bought, then at least it can be pressured (for favorable treatment).” He contrasted the specific PDUFA timelines agreed to by FDA for product reviews with the much “fuzzier” agency goals expressed in the area of postmarket safety. Academy of Managed Care Pharmacy executive director Judith Cahill offered general support for reauthorizing PDUFA, but suggested that FDA be given authority to require Phase 4 (postmarket) safety studies, and similarly, that prior approval be mandatory for all DTC ads.

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