BOSTON, Massachusetts—The same day the US Food and Drug Administration (FDA) arthritis advisory committee refused, on safety grounds, to countenance approval of Merck's Arcoxia^R (etoricoxib), the New England Journal of Medicine weighed in on the FDA's drug safety problems with early release of three commentaries critical of the agency's proposal for renewal of the "user fee" program that provides 40% of the budget for the FDA division that reviews new drug applications.

The New England Journal commentaries by Jerry Avorn, MD, by former FDA commissioner Mark McClellan, MD, PhD, and by Sean Hennessy, Pharm D, PhD, and Brian L. Strom, MD, MPH, differ in their analyses of and prescriptions for improving drug safety. Nonetheless, they are unanimous in warning that without systematic reform this important opportunity is likely to be wasted. The PDUFA renewal raised three major issues: how to improve drug safety, how to pay for the regulatory oversight that is needed, and how to accomplish these without impeding access to new and better drugs.

Drug safety requires more money, staff, and timely information

Dr. Avorn, professor of medicine at Harvard Medical School, and chief of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women's Hospital, both in Boston, thinks that funding drug regulation through drug makers' user fees is a mistake. Dr. Avorn warns that PDUFA should be renewed for 6 to 12 months at most "to give the country time to have the debate we deserve over the best way to ensure the efficacy and safety of our medications."¹

Dr. McClellan, visiting senior fellow at the AEI-Brookings Joint Center for Regulatory Studies, in Washington, DC, and currently on leave as associate professor of economics and medicine at Stanford University, in California, is most concerned that "the United States has no active drug-surveillance system."² He points to the widespread electronic processing of prescriptions and the availability of detailed data on healthcare utilization and outcomes as potential building blocks for a "routine, systematic approach to active population-based drug surveillance that could identify potential safety problems much more effectively and relatively inexpensively." The current passive system relies on adverse-events reports from physicians.

All of the authors agree with the IOM's analysis that the FDA is severely underfunded.

Who pays?

Dr. Avorn doubts that any system in which "companies would pay the salaries of agency employees who reviewed the companies' submissions" is a good idea. He points out that drug safety has suffered from the extreme restrictions on how much of this money can be used for evaluating drug side effects after approval. He notes that the current FDA proposal for PDUFA reauthorization "proposes that a trivial less than 7% of the user fees be used to strengthen its capacity for adverse-effects surveillance."

"Colleagues at the FDA have told me of a worrisome side effect of PDUFA: the growing sense that the organization is accountable to the industry it regulates," Dr. Avorn says.

Dr. Avorn also cites the time constraints created by PDUFA's strict guidelines for approval decisions and points to research suggesting that "drugs approved just before the PDUFA deadlines are far more likely than those approved at other points in the review cycle to cause safety problems after they are in widespread use."

The question of drug safety funding is also handled in various ways by the commentators. Current projections are that user fees will generate close to $438 million in revenues for the FDA in 2008, and PDUFA supporters argue that finding that money in the public purse would be impossible. "We spend more than $2 billion on the Iraq war in about a week. A nation as wealthy as ours can afford what it chooses to afford," Dr. Avorn argues.

The pending renewal of PDUFA would devote only $29.3 million (6.7% of the anticipated user-fee revenue for 2008) to improving the drug-safety system. Drs. Hennessy and Strom write, "It is useful to place this $29.3 milliion in perspective by considering the $188.5 billion that was spent on prescription drugs in the United States in 2004 and the $11.9 billion spent on pharmaceutical advertising in the same year."³ Dr. Hennessy is assistant professor of pharmacology and Dr. Strom is professor at the center for clinical epidemiology and biostatistics; both teach at the University of Pennsylvania School of Medicine, in Philadelphia.

Unlike Dr. Avorn, Drs. Hennessy and Strom do not want to abolish PDUFA. "[I]t is unclear whether eliminating or reducing user fees, especially at a time of federal budget deficits, would ultimately benefit the US population, and we are therefore reluctant to recommend doing so. In fact, we believe that relying on the pharmaceutical industry to perform all drug-safety studies creates a more severe conflict of interest—a conflict that could be most logically solved by giving FDA sufficient resources to fund its own safety studies," they write. They also point out helpfully that Congress is not bound by FDA's parsimonious recommendations and could "provide a robust level of funding for postapproval drug safety so as to make full use of the current, transient, ‘golden moment of opportunity.'"

How to keep the NDA pipeline flowing

The PDUFA arose in part as a response to "sit-ins" at FDA by AIDS activists protesting the glacial pace of drug approval in the late 1980s. The user fee strategy was adopted in 1992 as a program under which the pharmaceutical/biotechnology industry provides the FDA with more funding for new drug review without increasing federal spending, and to make new drugs available more quickly.

In that role, PDUFA has been successful. Dr. McClellan cites data suggesting that the resulting reduction in drug review time has saved 180,000 to 310,000 lives. He also suggests a subtle but important point in the current situation. "[S]pecific proposals to reduce dependence on user fees only authorize additional spending—Congress has no plans to actually appropriate the funds for the FDA."

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References

1. Avorn J. Paying for drug approvals—who's using whom? N Engl J Med. 2007;356:1697-1700.
2. McClellan M. Drug safety reform at the FDA—pendulum swing or systematic improvement? N Engl J Med. 2007;356:1700-1702.
3. Hennessy S, Strom BL. PDUFA reauthorization—drug safety's golden moment of opportunity? N Engl J Med. 2007;356:1703-1704.