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A third of drugs got extra safety warnings after they were already on the market

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Nearly a third of drugs cleared for sale in the U.S. between 2001 and 2010 posed safety risks that were identified only after their approval, according to a study published Tuesday.

The results underscore a continuing need to monitor medications for safety problems even years after FDA approval, according to the report in the Journal of the American Medical Association. It can be found at j.mp/safetydrugs.

Three of 222 drugs reviewed during that period were taken off the market for safety reasons; 61 received new warnings on the box, and the Food and Drug Administration issued 59 safety advisories. The boxed warnings are issued for major, potentially fatal risks; the advisories for less serious problems.

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Cardiovascular concerns caused the withdrawal of valdecoxib (Bextra), an anti-inflammatory used for arthritis; and tegaserod (Zelnorm), for irritable bowel syndrome. Risk of a dangerous brain infection called progressive multifocal leukoencephalopathy caused withdrawal of efalizumab (Raptiva), an immunosuppressive drug.

Post-approval safety problems occurred more frequently in biotech drugs such as monoclonal antibodies, psychiatric medications, those getting accelerated approval and those approved near the regulatory deadline for action, the study found.

“We seem to have decided as a society that we want drugs reviewed faster,” said lead author Dr. Joseph Ross, an associate professor of medicine and public health at Yale University. That makes it critically important “that we have a strong system in place to continually evaluate drugs and to communicate new safety concerns quickly and effectively,” he said.

Cherry-picking

To win FDA approval, medications must be shown to be safe and effective. But many pivotal clinical trials used for approval involve fewer than 1,000 patients with follow-up of six months or less, according to the study. Safety problems often crop up years later after therapies have been used by much larger numbers of patients.

“No drug is completely safe, and during premarket evaluation, we are not going to pick up all the safety signals,” said Ross.

An agency spokeswoman said that “FDA performs post-market monitoring to identify new safety information that may impact product labeling. In general, the FDA does not comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

The FDA requires drug makers to report adverse events they learn of to the agency. The agency also relies on voluntary reports from patients, doctors and the public to its MedWatch program.

Additionally, the agency sometimes requires what are called Phase 4 trials, conducted after the three-phase approval process is completed as a condition of marketing approval. These are meant to find more information about the drug’s long-term risks, benefits, the best ways to use it, or to test in different groups of patients.

The results weren’t surprising, said Dr. Eric Topol, a Scripps Health cardiologist-geneticist and founder and director of the Scripps Translational Science Institute in La Jolla.

Topol, who was not involved in the research, added, “the fact that it is one out of three of FDA-approved drugs is troubling.”

Part of the problem, he said, is that clinical trials often cherry-pick patients likely to produce the best results.

“Usually those clinical trials are relatively small, and they are not representative of the real world of patients, with multiple medical conditions and variable age, and all other things that you don’t capture in a clinical trial,” Topol said. “Clinical trials have inclusion and exclusion criteria — it’s a contrived setting. And then, when the drug is put out in the real world, with mass quantities of exposure, all of a sudden you find things that you never saw before.”

Topol suggested that the FDA consider granting new drugs conditional approval, then collect safety data from every patient to see, early on, whether a problem emerges. Only after that probationary period has been passed would drug companies be allowed to do mass advertising.

“We don’t have those systems, and it’s amazing, because we’re in a digital world, and they’d be very straightforward to implement,” he said.

Early detection

With such a precautionary system in place, health authorities could get an early handle on potential problems before large numbers of people are harmed, he said.

Topol has long warned of the dangers of insufficient monitoring of drug safety problems. In a 2004 article in the New England Journal of Medicine, Topol commented on the debacle of the anti-inflammatory rofecoxib, sold as the arthritis drug Vioxx.

He said that both the FDA and Merck, the maker of Vioxx, had failed their duty to safeguard public health by not examining Vioxx for potential cardiovascular problems, which forced the drug’s withdrawal in 2004.

“Even though the drug was approved in 1999 on the basis of data submitted to the FDA, the data were not submitted to a peer-reviewed journal until the following year and did not appear in print until November 23, 2000, one and a half years after commercial approval had been granted,” Topol wrote.

“The cardiovascular data reported in that article were incomplete, in part because of incomplete ascertainment: the design and execution of the trial had not anticipated that untoward cardiovascular events might occur.”

The criticism by Topol, then at the Cleveland Clinic, created a storm of controversy. His relationship with clinic chief Toby Cosgrove deteriorated. In 2006, he moved to San Diego for his job with Scripps Health.

The Washington Post contributed to this article.

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bradley.fikes@sduniontribune.com

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UPDATES:

1:20 p.m.: This article was updated with additional details.

This article was originally published at 11:50 p.m.