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Expression of Concern: Bombardier et al., “Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis”
Gregory Curfman, New England Journal of Medicine, 12-8-05

The New England Journal of Medicine has released a much publicized “note of concern” that important data may have been withheld from a study published on Vioxx four years ago.

The VIGOR study was designed primarily to compare gastrointestinal events in patients with rheumatoid arthritis randomly assigned to treatment with rofecoxib (Vioxx) or naproxen (Naprosyn), but data on cardiovascular events were also monitored. Three myocardial infarctions, all in the rofecoxib group, were not included in the data submitted to the Journal. The editors first became aware of the additional myocardial infarctions in 2001 when updated data were made public by the Food and Drug Administration. Until the end of November 2005, we believed that these were late events that were not known to the authors in time to be included in the article published in the Journal on November 23, 2000. It now appears, however, from a memorandum dated July 5, 2000, that was obtained by subpoena in the Vioxx litigation and made available to the Journal, that at least two of the authors knew about the three additional myocardial infarctions at least two weeks before the authors submitted the first of two revisions and 41∕2 months before publication of the article. Given this memorandum, it appears that there was ample time to include the data on these three additional infarctions in the article. …
Lack of inclusion of the three events resulted in an understatement of the difference in risk of myocardial infarction between the rofecoxib and naproxen groups (presented in the article as a reduction in the risk with naproxen but shown here as an increase in the risk with rofecoxib).

Derek Lowe, author of the blog In the pipeline, speculates on why the NEJM editors suddenly decided to publish their “concerns” four years after they actually knew of the data in question:

Don't get me wrong: I think Merck had every intention of making their VIGOR data look as good as possible when the study was published. Companies do that, and they should be punished when they push things too far. But if these three MI cases that we're disputing really did occur after the cutoff date for the study, then Merck had every right to exclude them from the data. (They had to be reported to the FDA, though, which is exactly what happened when it came time for approval). So why is the journal so worked up? …
Could it be that the plaintiff's attorneys, while questioning Gregory Curfman, mentioned that there could be more targets for litigation than just Merck? You run a prestigious journal there. . .probably influenced a lot of physicians to prescribe Vioxx, eh? Didn't see anything odd in the cardiovascular data, you say? Why, that's nearly a tort right there. . . I don't like to think that this is what happened. But it's not impossible, either. The journal's actions look like those of an organization that fears the legal discovery process. And why would you fear that, unless you fear that you'll be sued?

The article’s authors should be publishing a reply soon, which will hopefully shed some more light on the incident. In the mean time, the timing is certainly unusual.

Project FDA.
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