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US: Merck Admits a Data Error on Vioxx

by Alex BerensonNew York Times
May 31st, 2006

In an admission that could undermine one of its core defenses in Vioxx-related lawsuits, Merck said yesterday that it had erred when it reported in early 2005 that a crucial statistical test showed that Vioxx caused heart problems only after 18 months of continuous use.

That statistical analysis test does not support Merck's 18-month theory about Vioxx, the company acknowledged yesterday.

But Dr. Peter S. Kim, Merck's chief scientist, said the company stood by the overall findings it reported in 2005 — including the conclusion that the drug's heart risks were not apparent if patients took it less than 18 months.

But outside scientists said yesterday that Merck's admission, when considered along with other clinical trials of the drug and studies tracking real-world Vioxx use, supports critics' longstanding claims that Vioxx caused heart problems quickly.

"There never was any evidence for the 18-month story," said Dr. Alastair J. J. Wood, a drug safety expert at Vanderbilt University.

The 18-month issue is crucial both for the 20 million Americans who took Vioxx, an arthritis drug and painkiller, and for Merck's future. Merck faces at least 11,500 lawsuits, covering 23,000 people, from patients who say that Vioxx caused their heart attacks and strokes. Merck cited the 18-month theory when it withdrew Vioxx, a painkiller, from the market in September 2004, based on preliminary findings from a clinical trial called Approve.

In defending the lawsuits, Merck has consistently taken the position that Vioxx can cause heart problems only if it is used continuously for more than 18 months. But in the five Vioxx court cases in which juries have reached decisions so far, Merck has lost three times — twice in cases in which the heart attack victim had taken the drug for fewer than 18 months.

Merck has based the 18-month theory largely on data from the Approve study, in which the company tracked 2,600 patients in a test to see whether Vioxx could prevent colon polyps.

In the Approve study, twice as many patients taking Vioxx suffered heart attacks or strokes as those taking a placebo, or sugar pill. But most of the difference appeared to occur after patients had taken Vioxx for 18 months in a row, Merck has said.

When it reported the Approve results in The New England Journal of Medicine early last year, Merck said that it had performed a statistical test to examine whether Vioxx's risk changed over time. That test found with almost total certainty that the drug had significantly higher risk than placebo only after the 18-month benchmark — but no extra risk before that time.

Yesterday, Merck said it had made a mistake in reporting that result last year.

In reality, the test that the company said it had used to check the results shows that there is a 7 percent chance that Vioxx has an equally high risk of causing heart attacks both before and after the 18-month benchmark is reached.

That 7 percent figure may seem like a relatively small chance of error, but scientists say it is high enough to mean that Merck has not proved its theory.

Critics had recently raised new questions about the Approve trial's results, after the company submitted new data to the Food and Drug Administration as part of a one-year follow-up study of patients in the trial.

Some outside scientists said that the new data indicated that Vioxx's dangers became evident after only about four months of use. Merck disputed that interpretation and said yesterday that its newly discovered mistake was unrelated to that new data.

Dr. Kim said yesterday that Merck found its mistake only last week and immediately told the F.D.A. and the non-Merck researchers who had taken part in the Approve study, which was published in the March 17, 2005, issue of The New England Journal of Medicine.

"We came forth quickly to let the study authors know about the error, let the regulatory agencies know about the error," Dr. Kim said.

But Dr. Steven E. Nissen, the interim chairman of cardiovascular medicine at the Cleveland Clinic, and a frequent critic of Merck, said the mistake the company disclosed yesterday was yet another example of Merck's mishandling data to make Vioxx seem safer.

"They're acknowledging that they misrepresented the Approve data, when they reported that there was a statistically significant difference between the first and the second 18 months," Dr. Nissen said. "There is no biologically plausible reason to expect an 18-month delay. I never thought it made any sense."

Dr. John Baron, a professor at the Dartmouth medical school and one of the authors of the original journal article about Approve, said Merck's mistake was relatively minor. In general, trying to calculate whether risks change over time is very difficult, Dr. Baron said.

"The assessment of this constancy is something of an art. It's not a 'cut and dry, it's there or it's not' business," he said.

"The evidence that the Vioxx effect begins immediately or quickly, or however you want to describe it, is far from conclusive. The evidence that it doesn't begin until 18 months is also not something that has been proven."





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