From Our 2008 Archives

Drugs Approved Under Deadline More Likely to Run Into Trouble Later

By Amanda Gardner
HealthDay Reporter

WEDNESDAY, March 26 (HealthDay News) — New research shows that drugs that are approved quickly to meet mandated deadlines are more likely to run into trouble down the line, after they are in millions of Americans' medicine cabinets, than drugs that receive more deliberation before approval.

"It's not necessarily the case that these drugs should not have been approved, but it may have helped to have a black box warning in the first place rather than adding one three years later," said study author Daniel Carpenter, a professor of government at Harvard University. "It's not just the fact of approval. It's approval or regulatory processes assisting clinicians and patients with optimal use down the road. That's a big part of the approval process. It's not just saying yes and no, but saying with conditions and information that help us use drugs well."

The Prescription Drug User Fee Act (PDUFA), enacted in 1992, mandated that the U.S. Food and Drug Administration must act on 90 percent of all drug applications within 12 months of submission of the application or face funding cuts. That deadline was narrowed to 10 months in 1997.

"This study actually puts quantitative information around the question of whether the PDUFA user fee laws have resulted in a rush to approve things or to make decisions too quickly and many people, myself included, have worried about this," said Dr. Steven Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic Foundation.

Many critics have also pointed out that the tighter deadlines were not accompanied by necessary increases in funding. "Every group that has looked at the FDA says it is underfunded," said Nissen, who has advocated for repealing PDUFA. "The right answer was to provide more resources so the FDA could evaluate applications more accurately but to do so in a way that doesn't put the FDA in the bind of making decisions too quickly and without adequate consideration of the implications."

Carpenter and his colleagues used a mathematical model to look at the association between PDUFA deadlines, the timing of FDA drug approval and the likelihood of post-marketing safety problems in drugs approved since 1950. The study is published in the March 27 issue of the New England Journal of Medicine.

After PDUFA was initiated, approval decisions tended to be concentrated in the two months preceding the deadlines.

Drugs approved before the looming deadline were more than five times more likely to be withdrawn from the market for safety reasons; more than four times more likely to have to add a black-box warning; and more than three times more likely to have one or more dosage forms voluntarily discontinued by the manufacturer.

Some examples provided by Carpenter:

  • Baycol, a statin approved exactly one day to the year after the application was submitted, and withdrawn four years later due to reports of death from rhabdomyolysis, a breakdown of muscle fibers.
  • The diabetic drug Rezulin was given priority status, approved before the six-month deadline, then given a black-box warning, withdrawn from the market, and eventually reintroduced.
  • The infamous arthritis drug Vioxx was also a priority drug, approved within six months and later withdrawn because of cardiac side effects, to much hoopla.

"In doing a lot of interviews at the FDA, they'll tell you that the culture of CDER [Center for Drug Evaluation and Review] is fairly dominated by these review deadlines," said Carpenter, who is writing a book on the FDA.

But this doesn't necessarily mean the FDA should do away with deadlines altogether, Carpenter said.

"It strikes me we should think about deadlines less and on resources more for accelerating and maintaining FDA drug approval," he said. "Nobody wants to go back to the years where it was taking three to four years to get drugs through the FDA. Right now, 90 percent of these drugs have to be decided on in a certain time. What if we pushed that back to 60, 70, 80 percent and doubled the number of people reviewing drugs?"

Nissen said: "I also think we need to distinguish between routine approval and approvals of drugs that are really breakthrough drugs. I would argue compelling reason to move drugs that have major new benefits through the process more quickly... But 'me-too' drugs — that's another drug in the same class where there are already drugs available — that may not fit the bill. What you really want to do is accelerate the novel drugs. PDUFA doesn't distinguish, but I think it's a problem."

The FDA said it was performing its own analysis.

Another study, this one published in the March 26 issue of the Journal of the American Medical Association, looked at differences in the approval process for two lipid-altering drugs.

The first, ezetimibe, was approved in October 2002 on the basis of its ability to reduce LDL ("bad") cholesterol levels but without evidence of its effects on atherosclerosis or clinical events. A large trial to evaluate the drug more closely for major cardiovascular events began in January 2006 but is not expected to end until January 2011. Nevertheless, the drug was approved and marketed aggressively (sales reached $5 billion in 2007).

On the other hand, torcetrapib, a drug developed to raise HDL ("good") cholesterol levels never made it to market because a large, well-designed trial found an increased incidence of major cardiovascular events and death. The trial was halted early and the drug was never approved.

"Of the two approaches, torcetrapib was clearly the more successful," wrote the study's author, Dr. Bruce Psaty of the University of Washington, in Seattle. "For drugs used to treat cardiovascular risk factors, the FDA needs to work with the sponsor, as it wisely did for the approval of torcetrapib, so that large, long-term trials evaluating new drugs that will be used by millions of U.S. individuals start early, evaluate the reduction in cardiovascular disease incidence, and are completed soon after drug approval."

SOURCES: Daniel Carpenter, Ph.D., professor of government, Harvard University, Cambridge, Mass.; Steven Nissen, M.D., chairman, Department of Cardiovascular Medicine, Cleveland Clinic Foundation; March 27, 2008, New England Journal of Medicine; March 26, 2008, Journal of the American Medical Association

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