With a crucial personal-injury trial over Vioxx set to begin in New Jersey next week, the debate heated up again yesterday about whether Merck understated the drug's risks in a journal article in November 2000.
In an letter published online by The New England Journal of Medicine, 11 scientists who were co-authors of the article said they stood by its original conclusions, despite heavy criticism from the editors of the journal.
The scientists whose letter was published yesterday are not employed by Merck. The company financed the study and their initial work on the paper, and two Merck scientists were also co-authors. In a separate letter also published by the journal yesterday, those Merck scientists said they, too, stood behind their work.
But in an "expression of concern" also published on the Web site yesterday, the journal's editors reaffirmed their earlier complaint, saying the article "did not accurately reflect the potential for serious cardiovascular toxicity with Vioxx."
Merck sold Vioxx from 1999 to 2004. The company withdrew the drug from the market after a clinical trial showed that Vioxx increased the risks of heart attacks and strokes. Merck now faces about 10,000 lawsuits from people who say they or their family members suffered heart damage as a result of using Vioxx, a painkiller that was taken by about 20 million Americans.
Merck has won two of the three lawsuits that have been decided so far, although plaintiffs' lawyers play down the company's victories since they involved cases in which Vioxx was taken for only a few weeks. Jury selection in the next trial, which includes two plaintiffs who suffered heart attacks after taking Vioxx for at least 18 months, will begin Feb. 27 in state court in Atlantic City.
The letters come two months after the editors of The New England Journal of Medicine published their first "expression of concern" about the November 2000 article, sharply criticizing Merck — and, implicitly, the outside scientists who were co-authors — for failing to present a complete picture of Vioxx's heart risks.
In their letter yesterday, the outside scientists strongly disagreed. They said that the journal's concerns were misguided and that the article in 2000 had adequately disclosed Vioxx's risks. "Our original article followed appropriate clinical trial principles and does not require a correction," the scientists wrote.
Dr. Claire Bombardier, a Toronto rheumatologist, was the lead outside author on the study. The article reported on the results of an 8,000-person trial of arthritis patients taking Vioxx or naproxen, an older painkiller sold under the trade name Aleve. Merck conducted the trial in the hope of proving that Vioxx was less likely to cause gastrointestinal bleeding than naproxen.
The trial confirmed that Vioxx seemed to be safer on the stomach, but it also showed that more patients taking Vioxx than naproxen died and that many more suffered heart attacks. As published, the article reported that 17 patients taking Vioxx and 4 taking naproxen had heart attacks during the trial.
In fact, 20 patients on Vioxx suffered heart attacks, but the final three heart attacks were reported after Feb. 10, 2000, a cut-off date specified by Merck for reporting cardiovascular problems.
In their letter, the outside authors said that they could not report the final three heart attacks in the article because the attacks were reported after the study's results had been unblinded — after the scientists knew which drug had caused which problems. A core principle of scientific research is that data should not be added or removed from a clinical trial once the trial has been unblinded, because the bias of the authors may influence the decision to add or remove the information.
In addition, the outside authors said that the additional three heart attacks would not have materially changed the conclusions of the study, because the difference in heart attack risk between Vioxx and naproxen was too large to be attributed to chance, even without counting the additional heart attacks.
But in their response yesterday, the New England Journal editors said that Merck had made an arbitrary decision to set Feb. 10 as a cut-off date for reporting cardiovascular problems, in contrast to the cut-off date a month later for reporting gastrointestinal problems. Because Vioxx reduced gastrointestinal problems but increased cardiovascular problems, the editors said, setting the earlier deadline for reporting cardiovascular problems had the effect of making Vioxx seem safer than it was.
The journal editors also again criticized Merck and the study's outside co-authors for failing to report the total number of serious thromboembolic events — including heart attacks, strokes and blood clots — among patients taking Vioxx in the trial. An internal Merck memo revealed that 47 patients on Vioxx suffered those problems, compared with 20 taking naproxen, according to the editors.
