Vioxx, the FDA and the Lancet

On November 2, the FDA published the text of a study looking at the cardiovascular risk of Vioxx compared to Celebrex and other NSAIDS. It found a 3.7-fold increase in cardiovascular risk when high dose Vioxx (>25 mg/day) was compared to Celebrex, and a 1.5-fold increase when the standard dose of Vioxx was compared with Celebrex.

Some more information came out of this report, such as the lack of protective effective of conventional NSAIDS, but this was a large, retrospective, case-control study, subject to all of the limitations of non-randomized trials and thus not to be taken too seriously. In this case, the problems of confounding and bias which plague non-randomized studies are mitigated by the fact that two different COX-2 inhibitors are being compared. The choice of a specific COX-2 inhibitor is less likely to be related to cardiac risk than, say, the choice of a COX-2 inhibitor vs. a standard NSAID or no drug at all. Nevertheless, this sort of data should not be taken as conclusive proof of the safety of other COX-2’s.

Interestingly, the posting of this report by the FDA seems to have seriously ruffled feathers at the Lancet, which was reviewing it for publication. In an editorial, Richard Horton takes the FDA mightily to task for poor regulatory oversight, and then states:

“On Nov 2, 2004, the FDA tried to shore up its tarnished reputation by posting on its website an early version of a recently completed observational study into the safety of Vioxx. The report comes with a warning that it has “not been fully evaluated by the FDA and may not reflect the official views of the agency”. The FDA investigators estimate that over 27 000 excess cases of acute myocardial infarction and sudden cardiac death occurred in the USA between 1999 and 2003. “These cases”, they write, “would have been avoided had celecoxib been used instead of rofecoxib”. This study is presently under review at The Lancet. It is unclear why the FDA could not have waited for the fully evaluated report to have been scrutinised, revised, and published according to the norms of scientific peer review. Bypassing independent peer review smacks of panic in the FDA, which is under intense reputational pressure. And yet its decision to try to undermine the integrity of this work again shows that the agency’s senior management is more concerned with external appearance than rigorous science.”

Just when the Lancet is about to publish this timely report, the FDA goes and posts it on its website. Shades of Ingelfinger (prior publication elsewhere)! The Lancet is not amused.