The top editors of the
New England Journal of Medicine
resumed their criticism of a study, sponsored by
, on the arthritis drug Vioxx, repeating that the November 2000 article should be corrected.
Officials from Merck and other authors of the article responded in separate letters to the
Wednesday, saying their manuscript followed proper standards of research and presentation.
"Our original article followed appropriate clinical trial principles and does not require a correction," says the response of the non-Merck researchers, including Dr. Claire Bombardier, of the University Health Network, who was the lead author for the clinical trial, known as VIGOR.
editors reiterated their "expression of concern"
that was issued in December. They said the VIGOR article was based on an "untenable" trial design, "which inevitably skewed the results." They said the article "did not accurately reflect the potential for serious cardiovascular toxicity" with Vioxx.
The latest fight between editors and authors is contained in an online release of letters for an upcoming issue of the
. The editors' criticism that some data was withheld from publication is being used by plaintiffs' lawyers to press their case against Merck. As of Dec. 31, Merck was the defendant in 9,650 U.S. personal- injury suits and 190 class-action suits alleging personal injuries or economic losses. Merck has won two cases, and the company is appealing the one case that it lost.
Merck withdrew Vioxx from the market in September 2004 after being informed by an independent safety monitoring committee that another clinical trial, known as APPROVE, had detected a higher cardiovascular risk among patients taking Vioxx vs. those taking a placebo after 18 months. APPROVE was testing whether Vioxx could treat colon polyps.
The VIGOR trial wasn't looking for heart risks, but was designed to assess if Vioxx caused fewer gastrointestinal side effects than an older pain reliever, naproxen. VIGOR found that both drugs were equally effective and that Vioxx caused fewer gastrointestinal problems, a key issue for people taking pain relievers, especially the elderly.
But VIGOR also discovered a higher rate of cardiovascular problems in Vioxx patients compared with those taking naproxen. At the time the article was published, Merck had hypothesized that this disparity was due to a heart-protecting effect of naproxen rather than a heart-damaging effect of Vioxx.
Critics of Vioxx used VIGOR's results to seek restrictions on the drug. A Food and Drug Administration advisory panel discussed the VIGOR trial in early 2001. In April 2002, Merck revised the Vioxx label to include information about cardiovascular risks identified in the VIGOR trial.
editors on Wednesday repeated their initial assertion that three patients' heart attacks weren't included in the original VIGOR article, even though, they say, the researchers had sufficient time to include the information. "Because these data were not included in the published article, conclusions regarding the safety of
Vioxx were misleading," the editors said.
Merck officials have said these cases weren't included because the clinical trial had a cut-off date. The information, they added, was quickly reported to the FDA and the scientific community.
The letter from the non-Merck authors noted that, excluding the extra three cases, Vioxx patients had a 4.25 times greater risk of a heart attack. Including the extra cases, Vioxx patients risk went up five times. "We do not accept, therefore, that the addition of three
heart attacks leads to qualitatively different conclusions," the authors said.
editorial incorrectly suggests that relevant data was removed from the manuscript, they added. "Thus, we stand by our original article."
Two Merck officials who worked on the VIGOR article, Dr. Alise Reicin and Deborah Shapiro, said the company "consistently made full and appropriate disclosures" of the cardiovascular findings. The extra heart-attack cases were promptly disclosed to the FDA and were "included in subsequent communications," such as scientific publications and press releases.
"Adherence to a prespecified plan is routine and appropriate when reporting scientific data precisely because this practice avoids later allegations that data were manipulated," they said.
Given the editors' comments about wanting post-cutoff data prior to publication, "we regret not providing them with those data," they said. "However, we stand firmly behind the propriety of the scientific analysis and presentation of data in the paper."