Americans should feel reasonably safe taking government-approved prescription drugs-- with a few caveats-- even after a popular arthritis medication was pulled from the market, medical experts say. Vioxx was the first prescription drug since 2001 to be taken off the market for safety reasons. Its maker, Merck & Co., cited an increased risk of heart attack and stroke in people who used the medication.
The withdrawal on Thursday came just weeks after the company defended the safety of the drug, which accounted for $2.5 billion in worldwide sales in 2003, and the Food and Drug Administration approved the use of Vioxx in children as young as 2 years old.
The problems with Vioxx raise questions about the agency's safety review process and the length of time it took Merck to pull the drug, observers say.
"No drug is fully safe," said Crystal Rice, an FDA spokeswoman. "Our job is to appropriately balance our decisions, based on the risk-benefit profile for a drug and the societal need and desire for new drugs," Rice said in an e-mail. "We believe that our actions regarding Vioxx were appropriate and consistent with our public health mission."
The FDA has come under intense pressure from the industry and elsewhere to approve drugs more quickly, despite clinical trials that some say enroll too few patients and for too short a time for worrisome side effects to surface.
Research from Harvard, Vanderbilt University and Merck's own clinical trial long ago uncovered concerns about an increased risk of heart attacks and high blood pressure linked to Vioxx, said Dr. Jerry Avorn, who pointed to the issue in his book, "Powerful Medicines: The Benefits, Risks and Costs of Prescription Drugs."
"Why does it take this long for them to acknowledge the risk?" he asked. "I fear that FDA has gotten a little bit too cowed by industry demands to function as a good regulator," said Avorn, an associate professor of medicine at Harvard Medical School who is affiliated with Brigham and Women's Hospital in Boston.
An agency spokeswoman, Kathleen K. Quinn, said the FDA gets "pressure from all sides-- allegations that we're too fast, too slow. We make decisions on the basis of the science. We weigh the benefits against the risks, ... and we make the tough calls."
Because of inherent limitations in clinical trials, problems can lie hidden until drugs go into wider used.
"More than half of all drugs introduced have a new side effect ... after approval with the current system. I find that disturbing," said Curt Furberg, a public health sciences professor at Wake Forest University School of Medicine. For three decades, Furberg has conducted research on how clinical trials are designed.
Dr. Wayne A. Ray, a Vanderbilt professor of preventive medicine, said the FDA has a reason to make judgment calls on less than perfect clinical trial data.
"The FDA is not going to hold up a medication for a generation to make sure it's safe. And similarly, they're not going to require you to study half a million people," Ray said.
Still, Ray acknowledged that after drugs are approved, data gaps loom larger.
Take a drug such as the widely used antibiotic erythromycin. When the antibiotic is used in concert with newer drugs, the risk of cardiac death is five times higher, according to a study that Ray conducted. The findings were published in early September in the New England Journal of Medicine.
An FDA spokesman said erythromycin labels already note that risk. Still, the agency is reviewing the study to see if additional label changes are warranted.
Ray said the single study points to a larger problem.
"There is no provision for systematically assessing and reviewing the safety of the many, many medications that are out there," Ray said. "And the patients are the ones who are going to suffer."
The vast majority of companies do not follow through on promises to conduct those reviews, the FDA says. The FDA received 2,400 agreements to conduct post-marketing studies on drugs. Only 882 such studies were completed, according to an FDA analysis from Feb. 8, 2002, the most recent data available.
The FDA could take a simple step that would improve clinical trial quality before it approved drugs, observers say. Drug companies with products comparable to Vioxx could be required to conduct longer clinical trials.
"If you're the FDA, you'll say `OK, all bets are off. We're going to make you do studies lasting 18 months,'" said Dr. Sidney Wolfe, director of Public Citizen.
At the time of approval, the FDA had data from clinical trials on Vioxx that lasted for 12 months. The increased risk of heart attack and stroke that prompted Merck to pull Vioxx did not begin to appear until older patients had taken took the drug for 18 months.
In a telephone briefing with reporters, Dr. Steven Galson, the agency's acting director of the Center for Drug Evaluation and Research, said the FDA will move in that direction for comparable drugs on the market and for such drugs that might be approved in the future.
"It's too early for me to say, right now, how we're going to change our requirements," Galson said. "But, obviously, we're going to be more interested in long-term data."
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