But Merck wrote back (its letter was published in February), standing by the results of the study. Shortly thereafter, in the March 16, 2006 issue, NEJM ran another piece, reaffirming its expression of concern. But it also included a letter from the non-Merck investigators, which was equally vehement in affirming the validity of the study. From the looks of it, the back-and-forth is not over yet.
One of the authors of that letter, and a VIGOR investigator, was Thomas Schnitzer, MD, a professor of rheumatology and assistant dean for clinical research at Northwestern University Feinberg School of Medicine. Schnitzer has conducted clinical trials on all the major COX-2 drugs, and is currently the lead clinical trials investigator for the French biopharmaceutical company NicOx, which recently netted a technology deal with Merck. Here, Schnitzer reflects on this discourse with NEJM, and the problems with developing pain medications.Pharm Exec: In their Expression of Concern, NEJM editors noted the omission of three myocardial infarctions in the published VIGOR study. Why were these events omitted?
Schnitzer: During the course of the study, there was an independent data safety and monitoring board (DSMB) that determined it needed to look at cardiovascular events. The DSMB determined a specific cut-off date for collection of this data. It also determined not to tell the investigators that, because investigators are supposed to be isolated from what the DSMB does—unless they want to stop the study.
What was unfortunate was the date for cutting off collection of gastrointestinal events was different than [the date for] cardiovascular events. The date picked was different by two weeks or so. As a result, what was reported was all the GI events up to the cut-off date for the GI events. And all the cardiovascular events were reported up to the date for the cardiovascular endpoint that was prespecified. But because the two dates were different, there were cardiovascular events that happened between the end of the GI and the end of the cardiovascular studies.
Did the investigators know about the additional adverse events?
The investigators, other than the people at Merck, didn't know about this for six months after the study was published. But one could argue that we didn't have to know about it because it's not a part of the predefined study.
The reality of the situation is that when you do clinical trials, you decide when you're going to stop them before you start working on things. You don't change the rules later. It's a cardinal rule of doing clinical research.
In your mind, do the additional cardiovascular events change the conclusion of your study?
It turns out that if you put those three events in, do the analyses all over again, the hazard ratio—the risk associated with rofecoxib—goes from four to five. The people who do this for a living will tell you that if you have four times the risk or five times the risk, it's essentially the same risk.
Why is this communiqué happening now?
The reality is that these extra events that occurred were in the public domain since early February 2001. The journal knew about them since that time. And if the journal had a concern for the last five years about these events and the implications they had, it had five years to do something about it.
The question is, why would they have an interest in doing something about it at the time that at least one high-profile trial is ongoing? But what probably started the ball rolling is when the editor at the New England Journal was subpoenaed by the plaintiffs.