On Tuesday, in a sign of the high level of interest among doctors that Vytorin and Zetia have generated, the New England Journal of Medicine will publish online two articles and an editorial about the trials that raised the potential cancer concerns.
Merck and Schering-Plough , which jointly make Vytorin and Zetia, strongly defend their medicines. The companies say that ezetimibe, the generic name for Zetia, showed no cancer risk in animal trials and argue that the cancer finding is probably a result of chance. Some independent scientists agree with the companies, saying that they are dubious of a link to cancer and that ezetimibe is a valuable treatment no matter which brand it is sold under.
About the only point on which both sides agree is that no one can judge ezetimibe’s safety and benefits for certain without more data, ideally from a clinical trial covering more than 10,000 patients and lasting several years, long enough to show that the drug actually helps patients live longer or avoid heart attacks.
But patients and doctors will have to wait years more for those results. Merck and Schering did not begin such a trial until October 2005, three years after ezetimibe was approved. And the completion date for the trial has been repeatedly postponed. Now the companies estimate that it will not be finished until at least 2012. By then tens of millions of people will have taken ezetimibe.
“I don’t think the answer on Zetia is in,” said Dr. Robert J. Temple, director for the office of medical policy at the Center for Drug Evaluation and Research, which is part of the F.D.A.
The lack of data about ezetimibe highlights an aspect of the drug approval system that even sophisticated patients may not understand. Many medicines are approved on the basis of what scientists call surrogate endpoints, like proof that they lower cholesterol, rather than because they have been shown to reduce the risk of death or disease.
For example, a cancer drug might be approved because it causes tumors to shrink, not because its manufacturer can prove that patients live longer after taking it.
Using these measures makes sense in certain circumstances, researchers say. If no treatments exist for a disease, the F.D.A. may approve a drug based on its promise in short-term trials and hope that the medicine succeeds later in larger trials where its potential to reduce death and disease will be examined directly.
But several drugs approved this way have recently proved ineffective or even dangerous. In 1999, for example, the F.D.A. approved the diabetes drug Avandia on the basis that it reduced blood sugar. Sales of Avandia and two related medicines reached $3 billion in 2006. But in 2007, an analysis of 44 clinical trials of Avandia showed that it could increase heart attacks. Since then, prescriptions for Avandia have plunged, although the drug remains on the market.
Ezetimibe is in a similar situation. The medicine has been proved to lower patients’ LDL, or bad, cholesterol by 15 to 20 percent. Decades of research links lower cholesterol to a reduced risk of heart attacks. And cholesterol-lowering drugs called statins, including Lipitor and Crestor, have been proved to reduce heart attacks. But statins work very differently than ezetimibe, and no one has proved that ezetimibe offers the same benefits as statins.
“The F.D.A. set the bar too low on the initial approval,” said Dr. Steven Nissen, chairman of cardiology at the Cleveland Clinic. “It would have been a lot better if the agency had said, ‘Show us that you do more than lower LDL a little bit, show us evidence of effectiveness.’ ”
Further, when the F.D.A. approved Zetia, several statins were already on the market, giving patients other options to lower their cholesterol. So the agency’s decision to approve Zetia without requiring larger trials is especially puzzling, Dr. Nissen said.