September 3, 2008
For a Widely Used Drug, a Question of Usefulness
By Alex Berenson
When the U.S. Food and Drug Administration approved a new type of cholesterol-lowering medicine in 2002, it did so on the basis of a handful of clinical trials covering a total of 3,900 patients. None of the patients took the medicine for more than 12 weeks, and the trials offered no evidence that the treatment had reduced heart attacks or cardiovascular disease, the goal of any cholesterol drug.
The lack of evidence has not stopped doctors from heavily prescribing that drug, whether in a stand-alone form sold as Zetia or as a combination medicine called Vytorin. Aided by extensive consumer advertising, sales of the medicines reached $5.2 billion last year, making them among the best-selling drugs in the world. More than three million people worldwide take either drug every day.
But there is still no proof that the drugs help patients live longer or avoid heart attacks. This year Vytorin has failed two clinical trials meant to show its benefits. Worse, scientists are debating whether there is a link between the drugs and cancer.
Researchers reported last month that patients in three clinical trials had a 40 percent higher chance of dying from cancer if they took Vytorin instead of a sugar pill or another medicine, although the leader of that study says the finding might be due to chance.
Now some prominent cardiologists say the evidence has swung so decisively against the drugs that they should not be sold. "The only place people should be taking it is in a clinical trial," Dr. Allen Taylor of the Walter Reed Army Medical Center said of Zetia.
Vytorin is a single pill that combines Zetia with a statin, an older form of cholesterol-lowering medicine whose effectiveness and safety are not in question.
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 published 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, saying that they doubt 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 be certain about ezetimibe's safety and benefits without more data, ideally from a clinical trial with more than 10,000 patients over 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 Temple, director for the office of medical policy at the Center for Drug Evaluation and Research, part of the Food and Drug Administration.
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 Food and Drug Administration 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 FDA 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 it 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 link 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 FDA 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 FDA 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, Nissen said.
Temple said the link between LDL cholesterol and heart disease was so strong that the agency was comfortable approving drugs on the sole basis that they lowered cholesterol. "We accept LDL cholesterol as a valid surrogate," he said.
But the failure nearly two years ago of torcetrapib, an experimental drug from Pfizer, spotlighted the risks of using drugs without long-term data. Torcetrapib raised HDL cholesterol - the so- called good cholesterol, which is known to reduce the risk of heart problems.
But the FDA chose not to approve torcetrapib on the basis of its effects on HDL. Instead, the agency required that Pfizer first conduct a large trial. In December 2006, the trial revealed that torcetrapib raised patients' risk of death by 60 percent, forcing Pfizer to discontinue development of the drug.
Originally published by The New York Times Media Group.
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