Lessons From The Vioxx Fiasco

What drugmakers, the FDA, doctors, and patients need to do

What a mess. Weeks after Merck & Co. (MRK ) yanked its blockbuster painkiller Vioxx off the market, the furor is still raging. How could a drug get to $2.5 billion in annual sales despite evidence that it caused heart problems? The company faces personal-injury lawsuits that could cost it billions. The Food & Drug Administration has been widely criticized for its role in assessing Vioxx, and the agency is scrambling to improve its system for catching problems with drugs after they're approved. And Congress is holding hearings to try to figure out who's to blame.

Yet despite the finger-pointing, the fact remains that all drugs have risks, and even the most dangerous can have benefits for some patients. Indeed, some Vioxx users are threatening to sue to get it back on the market. It's a complex story with no black-and-white answers. Here are some of the key questions:

How did this happen?

Even before Vioxx was approved by the FDA in 1999, scientists wondered if it could cause heart problems or stroke. The trials used to win approval didn't raise red flags, but a subsequent study did: Merck found in 2000 that more than twice as many patients had heart attacks when taking Vioxx than when given an older painkiller, naproxen. But it made the questionable argument that the difference was due to protective effects of naproxen, not to a problem with Vioxx. The FDA did add a mild warning to the label, but that didn't stop the drug from being widely used.

When Merck then compared Vioxx to a placebo in a long-term study of patients at risk for colon cancer, the rise in heart attacks was clear. Vioxx was pulled on Sept. 30.

So who is responsible?

There's plenty of blame to go around. Vioxx' big benefit compared with older painkillers such as ibuprofen is that it causes fewer cases of stomach bleeding. But that's a problem for only a small percentage of patients. And thanks to an advertising blitz by Merck, its new drug became a best-seller, used by hundreds of thousands of people who didn't really benefit from its one advantage.

Meanwhile, Merck downplayed evidence of heart problems, including worrisome findings from an unpublished study. And the FDA didn't take initial warning signs seriously enough. "It would have been appropriate to put a black-box warning [on Vioxx' label] or stop the direct-to-consumer advertising until this was sorted out," says Dr. Eric J. Topol, chief of cardiovascular medicine at the Cleveland Clinic.

Are these issues unique to Vioxx?

Sadly, no. Even though the FDA is often criticized for requiring so much safety and efficacy data that drug development is long and costly, the truth is that the approval process never picks up all the side effects -- or benefits -- of a drug. Five years after the approval of any drug, "we don't know all of the harm," says Dr. James M. Wright, a professor of pharmacology at the University of British Columbia. "And there is always harm -- especially with potent drugs that have real benefits." Some doctors even suggest steering clear of most new drugs for seven years.

Drugmakers, of course, want to make as much money as quickly as possible. They spend $3 billion a year advertising their newer drugs directly to consumers. That can be good since it often prods people to go to their doctors. But the ads lead to unrealistic expectations about the benefits of drugs while minimizing risks. Often obscured in the advertising frenzy is the simple truth that many health problems are better solved by a change of diet or lifestyle than treatment with drugs. The result is that medicines are often overused. From 1993 to 2003, the number of prescriptions purchased rose from 2 billion to 3.4 billion, a 70% leap, according to the Henry J. Kaiser Family Foundation. That has led many health-care experts to worry that the U.S. has become an overmedicated society.

Drugmakers don't put the same muscle behind highly beneficial older and cheaper drugs, such as diuretics for high blood pressure. So those drugs are underutilized. Plus, companies tend to bury data from trials that show safety problems, says Dr. Joseph Lau, a professor of medicine at Tufts University. "The problem is that doctors often don't have the right information," he says.

Doctors aren't doing the best job, either. Studies show that many simply don't heed even the sternest warnings issued by the FDA. When patients taking the diabetes drug Rezulin from the former Warner-Lambert Co. (now Pfizer (PFE )) started dying from liver failure in the late 1990s, the FDA repeatedly warned doctors to carefully test patients' liver enzyme levels to spot early signs of trouble. Yet fewer than 5% of patients got the tests, and more people died.

Are there solutions?

Yes. For starters, we need better data about benefits and risks. As a condition of approval for many drugs, the FDA should require that companies collect data on patients receiving treatment or do additional clinical trials. Drugmakers are willing, especially if it means getting their product to market. Finding out more about newly approved drugs "is something we should enter into almost as a contract," says AstraZeneca PLC (AZN ) CEO Sir Tom McKillop. The FDA also must require clearer information about risks and benefits on drug labels. And someone -- probably the government -- must pay for large trials that compare new drugs to older ones.

Beyond that, society needs to understand that drugs are a double-edged sword. Doctors should do a better job of keeping up with pharmaceutical findings. And patients should know that all medicines are potentially dangerous and should be used cautiously. In the past, "people accepted that there was no such thing as a totally safe drug," says McKillop. "Today we have become much more risk-averse." Adds Dr. Mary H. Parks, a top FDA drug-approval official: "Even in the best case, with full due diligence, we will never know everything about a drug." That's why it will always be a struggle to hit just the right balance between help and harm.

By John Carey in Washington and Amy Barrett in Philadelphia, with Carol Marie Cropper in Atlanta

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