© Oxford University Press 2006.
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Drug Safety System Needs Overhaul, Experts Say
The system for establishing and monitoring the safety of new drugs is starting to show its age and will need substantial retooling if it is to better weed out problems before or soon after drugs hit the market, stakeholders told an Institute of Medicine panel.
At the request of the U.S. Food and Drug Administration, IOM formed an ad hoc committee to assess the current system for evaluating and ensuring drug safety after approval and make recommendations to improve risk assessment, surveillance, and the safe use of drugs. In January, the committee held the fourth of a year-long series of meetings, which will culminate in a report scheduled to be released in July.
The FDA request came in response to recent public concerns raised by the high-profile case of COX-2 inhibitor Vioxx (rofecoxib), which was voluntarily removed from the market by its maker Merck & Co., in Whitehouse Station, N.J. A postmarketing cancer prevention study found that use of the drug was associated with cardiovascular problems, but by the time it was pulled from the shelves, 84 million prescriptions for the painkiller had already been written.
Such cases have highlighted gaps in the system of postmarketing surveillance of drug safety, such as its reliance on voluntary reporting, which by the most optimistic estimate occurs only about 10% of the time. "Spontaneous reporting is still the main mechanism for hypothesis generation. It's a 1950s system. We need to do this better," said Brian Strom, M.D., chair and professor of the Department of Biostatics and Epidemiology at the University of Pennsylvania in Philadelphia.
Technologies such as those used for electronic medical records are opening new avenues for collecting and collating data within the postmarketing setting. However, these approaches have so far been hampered by the lack of consistency and comprehensiveness in reporting.
Federal oversight will always be only as good as the available data, said James Nickas, Pharm.D., senior director of development at Genentech Inc., in South San Francisco. He agreed that better adverse event reporting is needed.
The public perception may be that there have been more drug safety problems recently, but withdrawals have remained relatively steady at around 2.5% over the past 30 years, said Geoffrey Levitt, vice president and chief counsel for Wyeth Pharmaceuticals, in Madison, N.J.
"A system that gets it right 97.5% of the time and brings benefits to the public is not fundamentally broken," he said. However, he acknowledged that companies in the pharmaceutical industry will have to make changes to the way they conduct themselves to assuage public concerns.
"We wouldn't be talking here today if a lot of trust had not already been eroded," he said.
Some of that mistrust may be well placed, according to experts who said there are substantial gaps and conflicts of interest built into the current system. And while designing better systems of postmarketing surveillance is important, there is also much room for improvement in assessing the safety of drugs before they are approved.
Steve Nissen, M.D., medical director of the Cardiovascular Coordinating Center at Cleveland Clinic, described the case of muraglitazar, a drug designed to simultaneously treat hyperlipidemia and insulin resistance. "What at one time looked like the next billion-dollar blockbuster now looks dead in the water," he said.
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Bristol-Myers Squibb in Princeton, N.J., began developing the drug, which promised to be the first in a new class of dual peroxisome proliferator–activated receptor agonists. However, what the company's scientists didn't know was that four similar agents had already failed in clinical trials.
"I cannot tell you how fed up I am with negative reporting bias," Nissen said referring to the fact that data on these other agents were never published or otherwise disseminated.
Once the studies were complete, Nissen, an outside observer, saw that there was a clear pattern of excess death and major cardiovascular events. Despite that outcome, the company sought FDA approval to market the drug.
"I assumed that the advisory panel would not approve this agent in the presence of such a strong adverse safety signal," he said. However, the panel did recommend approval. Although not binding, a panel's recommendations are usually followed by FDA.
The company had effectively minimized the safety signal by presenting the trials individually rather than together and dropping the maximum dosage after phase I studies. Moreover, the panel missed the opportunity to ask more probing questions about the heart effects when its sole cardiologist recused himself because of a conflict of interest.
Stunned by the panel's recommendation, Nissen and colleagues quickly wrote up their analysis of the publicly available data and published their findings on the web site of the Journal of the American Medical Association 5 weeks later. That report helped FDA officials raise their own questions, which in turn prompted the drug company to withdraw the new-drug application for muraglitazar.
This is not an isolated case, said Wayne Ray, Ph.D., director of pharmacoepidemiology at Vanderbilt University, in Nashville, Tenn. Most data are open to different interpretations. With millions of dollars on the line, it's not surprising that the company would present their data in the best possible light, he said.
"The question is, how do we get rid of the conflict of interest in these studies," said Ray.
Although some have suggested that an outside and independent review is necessary, it isn't clear how that would be achieved. First of all, outside and independent review is what the FDA advisory panels are supposed to offer. But too often those experts, while well meaning, are overwhelmed by the immense amount of information thrown at them, said Nissen. Drug companies often spend years collecting data, months analyzing it, and weeks preparing to present it. But among panel members, there is a joke that the one with longest plane ride is always the best prepared, he said.
In the end, drugs will always have side effects—that is inescapable, said Penn's Strom. The question is whether FDA can be given the resources needed to properly balance the benefits of a drug against its potential to cause serious side effects or even death.
FDA officials are acutely aware of that balance, said Judith A. Racoosin, M.D., safety team leader at FDA's Center for Drug Evaluation and Research. "Nobody is interested in the safety of a drug if it doesn't work," she said. On the other hand, patients with life-threatening diseases such as cancer may be willing to tolerate a greater risk of serious side effects if a drug holds real promise to extend their lives, she said.
This is not an easy balance to achieve, said Strom. FDA needs to take unsafe drugs off the market without delay, but there is little benefit in acting too quickly and removing an effective medication based on bad data, he said.
And once problems are identified, the issue becomes how to communicate that information to the public. Part of the answer may be better labeling, according to the FDA, which recently released guidelines for a new format designed to give physicians and patients more ready access to the most pertinent information. The labels will feature a highlights section and a table of contents.
These labels may make for better reading, but they aren't likely to change physician or patient behavior, said Strom. They also don't address the differences in how drugs are administered in trials and how they are used in the field.
"The real problem there is not these rare adverse events, but more common dose-related reactions," he said.
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