FDA's PDUFA III implementation program includes three working groups focusing on changes to the review process under the new user fee program.

FDA has begun work on guidances for three new programs under PDUFA III: good review management principles, pre- and peri-NDA/BLA risk management plan activities, and continuous marketing application pilot programs. The guidances are slated to be issued by fiscal 2004.

FDA's new PDUFA initiatives are described in the ¹ PDUFA III performance goals letter, released in March (² Also see "PDUFA III “Good Review Management Principles” To Stress Early Action" - Pink Sheet, 18 March, 2002., pp. 3-6).

In addition to the working groups focusing on operational details of the new law, the agency is also putting together a PDUFA III implementation team that will track user fee initiatives across all affected FDA centers.

The Prescription Drug User Fee Act reauthorization was signed by President Bush during a Rose Garden ceremony June 12. Acting Commissioner Lester Crawford, PhD, was among the government officials in attendance.

One of the PDUFA initiatives already underway is development of an FDA guidance on good review management principles that will be primarily for internal agency use.

The guidance working group will look at big-picture issues involved in product review, such as how best to integrate disciplines and how to move the application through the review process most efficiently. The group will also examine best practices from FDA review divisions.

"This will be a guidance document primarily for our own staff, to explain to them the principles that result in a good review, in an efficient review, that embodies appropriate and timely communication with the industry, so that there aren't any ugly little surprises at the end of the review period," Center for Biologics Evaluation & Research Associate Director for Review Management Robert Yetter, PhD, said during the Biotechnology Industry Organization annual meeting in Toronto June 12.

The development of good review management principles "will also incorporate training of our staff in good review management principles and in appropriate communication with industry," Yetter said.

The issue of appropriate communication between FDA and industry was spotlighted during the June 13 Energy & Commerce/Oversight Subcommittee hearing on ImClone's Erbitux (see ³ Also see "Erbitux Hearing Puts Focus On Pre-Approval Promotion, FDA Communication" - Pink Sheet, 17 June, 2002. ).

FDA will continue to develop a Good Review Practices guidance separately from the PDUFA III "principles." The GRP effort, which has been under way for several years, is intended to be more specific, focusing on particular scientific issues and how to do each kind of discipline review.

The second PDUFA III guidance will focus on risk management plans during the pre- and peri-approval period (⁴ Also see "PDUFA III Includes Risk Management Fees For “Peri-Approval” Phase" - Pink Sheet, 11 March, 2002., p. 3). The guidance will address good risk assessment, risk management and pharmacovigilance practices.

"The idea is that during the pre-marketing application time period, you'll enter into discussions with the agency to determine what sort of a plan you should have to deal with possible adverse events or other occurrences that might pose a risk," Yetter said.

"In many cases it may be nothing more than adequate labeling," he continued. "In other cases there may need to be other things such as patient registries, specific postmarketing studies in particular patient populations and so on."

FDA began work on a risk management "white paper" and guidance last year, and was expected to issue them this spring (⁵ Also see "FDA Sees Risk Management Role For Sales Forces; Drug Safety Cmte. Coming" - Pink Sheet, 12 November, 2001., p. 16).

HHS Secretary Tommy Thompson highlighted an increased focus on risk management at FDA during a speech at the BIO meeting June 10.

Acting Commissioner Crawford "and I share a bold new vision for the FDA where risk management is the rule, not the exception," Thompson declared. "We're putting together extensive risk management programs, the most far reaching in the history of the FDA....You will not recognize FDA a year from now."

The third FDA working group is developing guidances on two pilot programs implementing the continuous marketing application mechanism created under PDUFA III.

In the first pilot, sponsors can submit "reviewable units" of an application on a rolling basis and receive a discipline review letter within six months. The second pilot, which will be limited to one application per review division, will involve a formal program of frequent scientific feedback and communication between the sponsor and FDA.

The pilot programs are open only to fast track applications. FDA's fast track program already allows for rolling NDAs, but the continuous marketing application adds the requirement for FDA to respond to each section as it comes in. "It is an extension of what we think is a good program in its initial conception," Yetter explained.

Another FDA focus under PDUFA III will be on improving first-cycle review performance.

Yetter acknowledged that "first-cycle approvals have decreased. It's the case for CDER. It's even more the case for CBER....We do the best we can, but there may be ways that we can improve it."

One way PDUFA attempts to improve first-cycle review performance is by committing FDA to report to sponsors within 14 days deficiencies in an application that are identified during FDA's initial filing review.

"It is not uncommon that during that review, even though it's fairly high-level, we will identify an issue or concern or deficiency in the application that while it does not rise to the level of preventing us from filing that application, is something that we know is going to be a concern that will prevent approval of the application," Yetter said.

"Normally, we try to communicate these. What we are doing here is committing to informing you of those....So, if you are filed but we identify problems, we'll let you know what the problems are, so that you can start dealing with them."

An evaluation of first-cycle review performance will also be one of the first initiatives funded by a $7 mil. "performance fund" created by PDUFA III.

BIO Director-Regulatory Affairs & Bioethics Wendy Taylor highlighted the PDUFA III program that allows biotech sponsors to ask FDA to bring in a consultant to give advice on the protocols. "Overall, the original agreement that was contained in the joint recommendations was left intact," Taylor said. "There were a few things that we had to fight for in the end, including our independent consultant provision, but that did remain in there."

FDA is expected to accept a sponsor's request for an independent consultant "except in the most unusual circumstances (for example, it is clearly premature)," the FDA PDUFA III goals state.

Yetter elaborated on potential denials of independent consultant requests. "Normally, we would only deny this if we believe it would not serve a useful purpose," Yetter said. "You only get one shot at this during your development. If...for some reason we think that you are going to be wasting your opportunity at this time, we will deny the request. We will tell you why we deny the request if we do."

Yetter noted that FDA is planning a guidance on the independent consultant program. Under the program, the agency will choose from a list of consultants submitted by companies. Yetter noted that consultants will have to pass conflict of interest clearance, and will receive government-level pay (funded by the sponsor).

"Now let me make one thing clear: you may always bring any expert or consultant that you wish to any meeting with the FDA," Yetter said. "This however allows you to request us to engage our own consultant. Evidently there was some feeling that we might look on your consultants with shall we say a jaundiced eye, because they were after all your consultants. These will be our consultants."

BIO's Taylor also mentioned several provisions the association was able to keep out of PDUFA III.

Sen. Edward Kennedy (D-Mass.) "sought increased assurances that FDA would increase their spending on postmarket surveillance activities, also enforcement of prescription drug advertising, and review of generic drugs. In fact, he tried to create triggers so that FDA would have to spend a certain amount in all of these areas, or they wouldn't be able to collect user fees at all," Taylor said.

"Needless to say, FDA opposed this very strongly and, in fact...there was talk about potentially vetoing the bioterrorism bill altogether over that. So those items were compromised out." Instead, the conference bill recommends more appropriations for postmarketing surveillance, advertising oversight and review of generic drugs (⁶ Also see "PDUFA III Authorizes FDA To Alert MDs To Failed Phase IV Commitments" - Pink Sheet, 27 May, 2002., p. 3).

PDUFA III Implementation Begins: FDA Working Groups Under Way

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