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Healthy Skepticism Library item: 12361

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Publication type: news

Berenson A.
Drugmakers withheld studies of cholesterol medication, FDA reports
International Herald Tribune 2007 Dec 21

Full text:

New evidence shows that the drugmakers Merck and Schering-Plough have conducted several studies of their popular cholesterol medicine, Zetia, that raise questions about its risks to the liver, but the companies have never published those results.

Partial results of the studies, alluded to in documents on the U.S. Food and Drug Administration’s Web site, raise questions about whether Zetia can cause liver damage when used long term with other cholesterol drugs called statins.

Most of the millions of people who use Zetia take it along with a statin like Lipitor, Crestor or Zocor. Or they take it in a single pill, Vytorin, that combines Zetia with Zocor.

The discovery of the unpublished research comes as Merck and Schering are already under criticism for not yet releasing data from an important Zetia study, called Enhance, that they completed early last year.

The Enhance data may also contain important information about Zetia’s liver risks. At least some patients were dropped from the Enhance study after testing revealed that they had elevated liver enzymes, a Schering-Plough spokesman confirmed this week.

But a full report on that trial, including the number of patients who had liver problems, will not be available until March.

Doctors say that by failing to disclose promptly all their research, Merck and Schering-Plough may be leaving the public with a misleadingly favorable view of Zetia’s safety and benefits.

“You don’t want to have data missing,” said Dr. Bruce Psaty, a professor of medicine and epidemiology at the University of Washington. “When there have been adverse effects, when the benefits don’t look impressive, those are the trials that historically don’t make it to press.”

A Schering executive, when asked by a reporter about the unpublished studies, confirmed their existence. But the executive, Dr. Robert Spiegel, said the companies had not considered the studies scientifically important enough to publish their findings. Some may eventually be published, he said.

“We’re pretty comfortable that people don’t have trouble tolerating Zetia,” said Spiegel, the chief medical officer of the Schering-Plough Research Institute in Kenilworth, New Jersey.

Schering also said that the FDA had reviewed the data from the unpublished studies and had approved Zetia for use alongside statins.

But experts on drug safety say that the agency has been slow to issue warnings about many widely used drugs that have turned out to carry serious risks, including the painkiller Vioxx, the diabetes medicine Avandia and the anti-psychotic drug Zyprexa.

Even doctors critical of Zetia generally say it is safe for most patients. But before the drug was approved in 2002, one FDA reviewer said it should not be cleared for use with statins because the combination had caused liver damage in animals. And in the last two years, scattered case reports of severe liver damage in patients taking Zetia in combination with statins have appeared in medical journals.

In the United States, the product label for Zetia contains only mild warnings about the drug’s potential for liver damage.

But in Australia and Canada, regulators have been more cautious.

Since 2005, they have issued a series of warnings about Zetia’s potential to cause hepatitis, pancreatitis and depression – warnings that have largely gone unnoticed in the United States.

The unpublished studies, conducted from 2000 to 2003, according to the FDA documents, were not listed on the industry Web sites where companies are supposed to register the results of all drug trials that were ongoing after October 2002. The New York Times discovered references to the studies in briefing papers on the FDA Web site.

“We keep telling people we want to practice evidence-based medicine, and what we keep finding out is that much of the evidence is obscured,” said Dr. Harlan Krumholz, a cardiologist at Yale, when told about the previously undisclosed studies. “There is important evidence, but it’s not in public view. It’s hidden from investigators.”

Schering and Merck – which are on track to earn $5 billion this year from sales of Zetia – had already been criticized for not promptly releasing results of the Enhance trial, which was completed in April 2006. Under pressure from Congress and prominent cardiologists, the companies said recently that they would release the full results of the Enhance trial by March.

In response to questions from The Times, the Schering spokesman, Lee Davies, disclosed this week that some patients in the Enhance trial had been dropped from it after tests showed that they had elevated liver enzymes – a potential sign of organ damage. But Davies said he could not disclose how many, and said the companies did not even know if the patients who had been dropped were taking Zetia and a statin, or just a statin. The delay in releasing the Enhance trial data is unrelated to the patients who were discontinued, Davies said.

The Enhance data are expected to provide the clearest picture yet of Zetia’s long-term affects. But the FDA documents show that Merck and Schering conducted several other long-term trials of Zetia without releasing their findings.


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