Healthy Skepticism Library item: 934

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Publication type: news

Wilde Mathews A
Vioxx Recall Raises Questions On FDA's Safety Monitoring
The Wall Street Journal 2004 Oct 4

Full text:

Merck & Co.‘s withdrawal last week of its blockbuster arthritis medicine Vioxx lends new urgency to a congressional investigation into how effectively the Food and Drug Administration handles drug-safety concerns.

In June, House and Senate committees asked the Government Accountability Office, the investigative arm of Congress, to examine the relationship between the FDA’s drug-review divisions and the agency office that focuses on drug safety, to determine whether safety researchers’ views are taken seriously enough. The broad inquiry was sparked by the FDA’s response to the potential risks posed by antidepressants, but the Senate Finance Committee has since asked the FDA specifically about Vioxx.

Though FDA officials have said they believe that they took the proper actions with respect to Vioxx, based on the information they had — including warning language added to the drug’s label in 2002 — others are raising questions. “I’m concerned about how the agency has been handling matters of drug safety,” Senate Finance Committee Chairman Charles Grassley, an Iowa Republican, said in a statement. He added that in the wake of Merck’s voluntary recall of Vioxx he was worried that the FDA might have been “foot dragging” in its handling of the drug.

Merck’s decision to withdraw the drug came after new data showed that after patients had been on it for 18 months, there was a correlation between low doses of the drug and an increased rate of heart attacks and strokes. There had been years of studies showing potential problems at a higher dose — including a recent one led by an FDA researcher.

The FDA has said it pressed Merck for a strong safety component in the three-year study that ultimately found the increased risks. “You can’t look backward and say we should have known this at the point we had to make the decision,” said Steven Galson, acting director of the FDA’s drug center. He said that Vioxx held a “special benefit,” because it was supposed to be less likely to cause gastrointestinal problems.

“The signals beforehand were not black and white, were not conclusive,” said Brian Strom, a professor at the University of Pennsylvania and a former member of the FDA’s drug-safety advisory committee. He adds that if there had been more safety studies of Vioxx, the additional evidence might have led the FDA to more aggressive action earlier.

The Vioxx recall also is casting the spotlight on other long-running concerns about how regulators detect and respond to evidence of possible risks once a drug has been approved. Among the issues researchers have
raised: the limited resources devoted to studying the safety of medical products once they’re already approved; weaknesses in the current system for tracking drug reactions; and the difficult question of what the FDA can — or should — do in striking a balance between the risks and benefits of drugs.

Adverse reactions to drugs kill more than 100,000 Americans a year, and injure another 1.5 million people badly enough to require hospitalization, according to a 1998 paper in JAMA, the Journal of the American Medical Association. That estimate was based on the patients hospitalized in 1994.

Last year, a gathering of experts sponsored by federally funded Centers for Education and Research on Therapeutics found that the “current U.S. system for assessing the risks of therapeutics is outdated and inadequate.”

The U.S. “is not doing an adequate job of monitoring the safety of drugs on the market,” said Wayne Ray, a professor at Vanderbilt University whose studies showed potential problems with Vioxx. “Maybe this will…provoke us into doing a better job.”

In the past, some researchers have called for increased funding for detecting potential risks from medical products, including possibly setting up an independent “office of drug safety” that would be in charge of monitoring already approved drugs. Under a law that funds FDA drug reviews with industry user fees and imposes deadlines on the agency for completing them, pressure has grown on the FDA to move quickly — which has raised questions about whether reviewers have time to fully explore potential risks. FDA officials, however, say the rate of drug withdrawals hasn’t increased since the user fees began.

The FDA, for its part, said it has taken a number of recent steps to improve its ability to detect adverse drug reactions or side effects, and has acted against drugs when the evidence warranted. “We are stuck in the middle of a very contentious and fractious debate that has on one side people saying ‘we want more cures, shorter development times’…and we have people on the other side saying we’re too lax,” said Dr. Galson, who is also an assistant surgeon general in the U.S. Public Health Service. He added, “we’re not sitting back and saying everything’s OK and perfect” in the agency’s risk-detection tools.

Consumer groups have raised safety concerns about a number of other drugs that remain on the market. Among them are Crestor, the anti-cholesterol medication from AstraZeneca PLC, which may be tied to serious muscle conditions; Meridia, an obesity drug marketed by Abbott Laboratories that can raise patients’ blood pressure; and Arava, an Aventis SA treatment for rheumatoid arthritis that has been potentially linked to rare instances of severe liver problems. All three drugs already have warnings on their labels, and the FDA has said it is monitoring them carefully.

The process for getting a drug approved in the U.S. is rigorous but it isn’t designed to detect every possible risk. That would require studies so large and long that few new medicines would ever hit the market.

After a drug or device is allowed on the market, the FDA and the drug’s maker are supposed to watch for evidence of new risks among its users. The FDA oversees a database that gets reports of about 280,000 incidents a year of potential adverse drug reactions. About 90% of those reports come from drug makers, who are required to disclose them; doctors and other medical personnel aren’t required to participate. By some estimates, FDA’s database may reflect as few as 10% of such incidents.

The reports are sometimes of limited value, since it is hard to pinpoint for sure that a drug is the cause of a problem. Some researchers have argued that the reporting database needs to be supplemented by more active studies to search for and confirm safety problems of drugs already in broad use. For instance, a 1998 editorial in JAMA called for a new “office of drug safety with the authority, independence, funds and legal mandate” to more actively track problems.

Once a drug is approved, the FDA has limited authority to order a company to do a safety study, but it has indirect leverage because if it has strong enough evidence it can force labeling changes or take a drug off the market.

As part of the approval process, the FDA can also sometimes require that so-called phase four studies be done later, after the drug goes on the market. An FDA report in March said that through Sept. 30, 2003, the agency had 1,338 outstanding post-marketing commitments for drugs, with 65% of the studies not yet initiated. The FDA has said it is monitoring compliance with such commitments.

A few years ago, drug companies pulled a number of medicines off the market or severely restricted their use because of dangerous side effects. Among them were Rezulin, a diabetes drug that could cause liver damage, Baycol, an anti-cholesterol medication that was tied to higher rates of muscle problems than its competitors, and the diet drug Redux. The FDA has defended its decisions, generally saying it relied on the evidence available at the time, and had to balance the benefits against the risks.

The Senate Finance Committee and the House Energy and Commerce Committee made their requests for the GAO study of how the FDA responds to safety concerns after both panels investigated FDA officials’ initial decision not to allow a staffer to publicly present his conclusion that antidepressants could be linked to suicidal tendencies in young people. The FDA said it thought that conclusion was premature when the staffer was supposed to present it in February. The FDA later confirmed the finding through further analysis unveiled in August and plans to put a warning on the drugs’ labels.

An FDA spokeswoman said the agency’s reviewers and its safety analysts agree “the vast majority of the time” and have “a lot of collaborating back and forth.”

Dr. Galson said the agency is moving to improve how it finds and responds to risks from medical products, including trying to do better data-mining of adverse events and using electronic filing to process reports. The agency is examining health-care provider data, he said. It also hopes to stimulate new scientific research to improve the design of clinical trials of drug safety and promote research on pharmacogenetics, which may help to identify which people will react badly to drugs. To limit potential risks, the FDA in the past few years also has been more active in pushing for conditions on use at the time a drug is approved.