Consumer groups are advocating the creation of a "conditional" approval authority for FDA through the reauthorization of the Prescription Drug User Fee Act.

"We need to think about an addition to the current 'all or nothing' approval process," Center for Medical Consumers Director Arthur Levin said at a Nov. 14 public meeting on the reauthorization of PDUFA.

The concept was echoed by National Consumers League Food & Health Policy Assistant Director Alison Rein.

A "provisional status for some drugs" would "allow for limited exposure of the product to appropriate patients, thereby mitigating the likelihood of inappropriate use and overexposure, while additional post-approval safety data collection is ongoing," Rein said.

The expansion of FDA's current system also could yield faster approvals, stakeholders noted.

"We need a series of shorter steps of conditional approvals....That way you could get some early approvals...as well as continued maintenance of some of the bigger safety problems," Perry Cohen, project director of the Parkinson Pipeline Project, said.

Conditional approval has been a topic of mounting interest of late, particularly due to the European Medicines Agency's adoption of a conditional approval mechanism as part of its accelerated approval program (¹ Also see "“Exceptional” Approval Could Replace “Accelerated” For Rare Cancer Drugs" - Pink Sheet, 14 November, 2005., p. 9).

The conditional approval endorsements were made against a chorus of participants advocating that FDA be granted the authority to enforce post-marketing studies.

"Phase IV is unfortunately the agency's Maginot line....Without such a grant in additional authority, post-marketing studies may never become a reliable mechanism of surveillance," Levin said.

Participants expressed differing views as to which specific post-marketing activities could be added or expanded from those allowed under PDUFA III and how these activities would be funded.

Levin suggested that a shift be made from a "passive, reactive system [like FDA's MedWatch], to one which is active and proactive."

"This would involve using large administrative databases where drug use and clinical history of individual patients can be easily linked and real-time monitoring for safety signals is a possibility," he said.

Levin suggested that FDA should vastly expand its contracts to use private-sector databases, criticizing those that were recently signed as not being sufficiently comprehensive (² Also see "FDA Postmarketing Surveillance System Adds Kaiser Retrospective Database" - Pink Sheet, 3 October, 2005., p. 11).

In addition to private-sector registries, such as Kaiser Permanente's California retrospective database, which was included in FDA's cooperative agreement program, Levin suggested monitoring the military's TRICARE populations and future Medicare Part D beneficiaries.

"The agency must be given the resources necessary to update its computers and the human capacity for real-time trolling of large databases for safety signals and have the skilled staff available to drill down on those signals where appropriate," Levin added.

On the other hand, Friends of Cancer Research Chairperson Ellen Sigal advocated enhancing MedWatch to increase "FDA's capacity to process and analyze adverse events."

Consumer groups are not alone in their campaign for strengthened post-marketing activities. During the meeting, both Center for Drug Evaluation & Research Director Steven Galson and Acting Commissioner Andrew von Eschenbach suggested that this area warrants expansion (³ Also see "PDUFA IV: FDA Stresses Burden Of Industry Meetings In User Fee Discussions" - Pink Sheet, 21 November, 2005., p. 3).

Stakeholders also believe PDUFA fees should be used to bolster oversight of direct-to-consumer advertising.

In a ⁴ white paper on PDUFA's reauthorization released before the meeting, FDA agreed that it is inadequately funded to assure timely review of all broadcast DTC ads. The agency reviewed less than one-third of all disseminated broadcast DTC ads in 2004.

The white paper also explains the paradox the agency faces: further submissions of ads would result in greater compliance but also greater workloads, and greater workloads would result in delays that would discourage further submissions.

"Although FDA review of all materials would ensure alignment with the approved labeling and a fair balance of information on benefits and risks, current FDA resourcing for this work would probably result in delayed reviews if all companies were to submit their ads," the white paper states.

"Such delays would likely affect companies' ability to meet their marketing timelines, and discourage them from submitting the materials for prior FDA review."

Consumers Union Senior Policy Analyst Bill Vaughan said that while adequate funding and pre-clearance of all DTC ads would be optimal, an adversarial approach from the agency may be more realistic.

Vaughan suggested that FDA be granted the ability to impose civil monetary penalties for DTC ad violations, especially repeat violations.

"If FDA decides not to proceed with [the pre-clearance] recommendation, it should require corrective ads, and take other enforcement action and seek [civil monetary penalty] authority for any violations of truth and accuracy," Vaughan's written comments state.

Consumers Union and the National Consumers League agreed that a moratorium on DTC ads should be placed on new drugs, though Rein went a step further. The NCL rep advocated that FDA assess fees for pre-clearance of DTC ads and that revenue be used not only to hire more ad review staff, but also to support other drug safety initiatives.

"The revenue derived from the new fees could be used to support a number of currently under-funded agency activities, including, but not limited to, funding of post-market safety studies, as deemed necessary, on a case by case basis."

Along the lines of Levin's recommendation, Rein also said that DTC fees could be used for expanded use of large databases. Furthermore, she suggested that fees should go toward disease awareness, as well as "increased expenditure on public information sharing about emerging safety issues."

During his book tour in May, Pfizer CEO Hank McKinnell hinted that he may not be opposed to DTC-related pre-clearance fees, as long as there was a degree of protection from enforcement actions (⁵ Also see "Pfizer Supports Stronger FDA Oversight Of DTC Promotions" - Pink Sheet, 23 May, 2005., p. 23).

American Pharmaceutical Association VP-Policy & Communications Susan Winckler suggested PDUFA be used to improve FDA's employment of risk management techniques by creating a "means test" for determining when and what type of risk management system should be employed.

"You may have a new drug coming to market where a specific risk is identified and so a formal risk management system is instituted," but the problem is that "there is a drug that is already on the market that has the same risks and is not subject to the same risk management system," Winckler noted.

APhA also suggested that better assessments be done of risk management plans.

Wyeth Exec VP-Regulatory Affairs & Compliance Bruce Burlington, on behalf of the Pharmaceutical Research & Manufacturers of America, stressed that FDA continue work begun in PDUFA III on the usefulness of risk management plans (⁶ Also see "BIO Suggests Re-Evaluation Of Continuous Marketing Application Programs" - Pink Sheet, 21 November, 2005., p. 5).

The Biotechnology Industry Organization supported improving the efficiency of trade name evaluation as a way of ensuring drug safety.

Echoing this position, Institute for Safe Medication Practices Executive Director Allen Vaida pushed for guidance from FDA on proprietary name safety testing. "We also need to have the FDA look at the information that it already has on the look-alike, sound-alike [names and] a lot of the packaging," Vaida said.

Contending that the comparative effectiveness studies mandated by the Medicare Modernization Act have been under-funded, CU's Vaughan suggested that PDUFA fees be used to fill the gap.

"We hope that PDUFA reauthorization will be accompanied by requirements for Phase IV trials that require new drugs be compared for effectiveness against other drugs in their class," Vaughan said.

In response to concerns over the funding level for drug safety activities and the proportion of appropriated funds versus user fee monies, many stakeholders rallied behind the FDA Improvement Act. Introduced by Rep. Maurice Hinchey (D-N.Y.) in May, the bill would prohibit FDA from directly collecting fees paid by companies in an attempt to stem conflict-of-interest.

User fees would instead be deposited in to the general Treasury; FDA would then be funded by the Treasury at mandatory funding levels.

PDUFA Provides Opportunity For Conditional Approvals, Consumer Groups Say

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