Celebrex's Toughest Trial

It'

s been a painful 15 months both for people with arthritis and for the companies that make their painkilling drugs. The once high-flying anti-inflammatories known as cox-2 inhibitors nearly crashed and burned in September 2004, when Merck's popular Vioxx was pulled from the market after a study revealed it could raise the risk of heart attack and stroke. A competitor made by Pfizer, Bextra, was yanked some months later, leaving only Pfizer's Celebrex behind—and a new, required safety warning hasn't exactly done wonders for that drug's appeal. Celebrex sales are off more than 40% for the first nine months of this year, and Pfizer is also watching as Merck parries patient lawsuits, the first batch of what could be many for all of the cox-2 makers.

So it was that Pfizer announced this week that it is going to try to settle the cox-2 safety question once and for all. Working with cardiologist Steven Nissen of the Cleveland Clinic, Pfizer has initiated a massive $100 million, four-year trial that will test the drug on 20,000 arthritis patients who are already at high risk for heart attack or stroke to determine what risk, if any, Celebrex actually poses.

Pfizer's move is a dramatic one, but it's also an important one—and not just for Big Pharma's balance sheets. In the wake of the Vioxx withdrawal, many arthritis sufferers have turned to drugs in the ibuprofen and naproxen families, such as Advil and Aleve. But earlier this year the Food and Drug Administration (FDA) announced that those drugs may also carry cardiovascular risks; in any event, for some people they just don't pack the same pain-relieving punch. Others patients are relying on oxycontin and morphine-based medications, which may not endanger the cardiovascular system in the same way, but carry perils of their own, addiction in particular.

The 20,000 people in the new study, who will be drawn from the U.S., Canada, Eastern Europe, Australia and South America, will be randomly assigned a regimen of either Celebrex, ibuprofen or naproxen. They will also take aspirin, cholesterol-lowering drugs and other medications appropriate for heart patients, as well as a drug to prevent stomach bleeding, which all three of the painkillers may cause. The four-year study should be sufficient time to reveal what risk, if any, the cox-2s pose, but it could end sooner if one of the medications reveals itself as just too dangerous.

The major question raised by such a comparatively high-stakes trial is, Why use such high-risk patients? The last thing people who are already in precarious cardiovascular health need—or so it would seem—is to begin taking a drug that could endanger them even further. Pfizer - not to mention the patients themselves—is apparently banking on the belief that Celebrex simply isn’t that risky, and that any slight dangers are outweighed by the benefits. “Pfizer is fulfilling the commitment it made over a year ago to study Celebrex in this patient population," says Pfizer spokesman Bryant Haskins. When it comes to getting the most reliable data, it's that population—people who are part of the real group the cox-2s are thought to endanger—that produces the best results.

"The idea here is if you know what happens in the highest risk individuals, you will know how to use the drugs in people at lower risk," said Nissen, who served on an FDA panel which last February recommended just such a study. "We will have 10 times the statistical power of any study ever done of these drugs." The results may thus indeed finally answer any lingering questions about how safe Celebrex is, something Pfizer no doubt hopes—but also fears.