When will the pain stop? The Vioxx saga continues and the more I hear, the sicker I feel. Like most rheumatologists, I too fell for the line that the increased number of cardiac events in the Vioxx arm of the Vigor trial was not a Vioxx problem but rather a naproxen cardioprotective effect. It made sense at the time. I was always taught, up to that time, that naproxen had an anti-platelet effect. I even remember in the old days discussing whether aspirin was necessary for patients on naproxen or other NSAIDs. And I didn't swallow it without a fight. I was concerned enough that I cancelled a half day clinic to go to a mid-afternoon conference on this exact topic, given by a cardiologist. Yes, it was a speaker brought in by Merck, but he was a significant name in the field. When I specifically pressed him about the anti-prostacyclin effect of Vioxx, he insisted that prostacyclin was such a minor component of the coagulation process he could not see it being of any consequence. After he mentioned that the number of cardiac events would have been lower had all patients at risk been removed at onset, I asked him if this might mean that cardiac patients were at greater risk. He again blew me off with little or no explanation. So what's a clinical rheumatologist to do, after all, it was a terrific anti-inflammatory. So I, along with everybody else, was considerably disturbed when the drug was removed from the market because of cardiac concerns. ( I got the news from my mom, calling me at the office) I was disturbed, but really not upset. After all, these things happen. Honest misinterpretation of the initial studies, and unfortunate post-marketing results.
Then in 2007 I read an interesting but frightening article by Sergio Sismondo in PLOS Medicine, about ghost writing and ghost management of pharmaceutical research. The article demostrated how many companies do their own research and then hire out communication companies to guide the studies through to publication. One facet of this process is the hiring of influential researchers to add their name as authors, even though they had nothing to do with the study itself and may not have even seen the raw data. And what example did Sismondo use to highlight these unseemly techniques: Vioxx and the ADVANTAGE trial
.For example, as reported in The New York Times [4], an Annals of Internal Medicine article on Merck's “Advantage” trial of Vioxx omitted some trial participants' deaths. Distancing himself from the Annals article, first author Jeffrey Lisse said in an interview that “Merck designed the trial, paid for the trial, ran the trial…Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck, and then it was sent to me for editing” [4].
Yikes! Okay, so now I'm thinking that not only were there some honest misinterpretations, there may have been some grossly biased presentation.Then along comes this week's JAMA blockbuster. Having access to the many private communications of Merck, because of their ongoing litigation, the authors Psaty and Kronmal expand upon Sismondo's previous revelations and add to it a suggestion that the company purposely deceived the FDA, and therefore you and me, about the cardiac risks of Vioxx. Long before we heard about the confirmed increased risk of cardiac morbidity, Merck was apparently well aware. As written in that article:
In contrast, in April 2001, the company's internal intention-to-treat analyses of pooled data from these 2 trials identified a significant increase in total mortality (hazard ratio [HR], 4.43; 95% CI, 1.26-15.53 for protocol 091, and HR, 2.55; 95% CI, 1.17-5.56 for protocol 078), with overall mortality of 34 deaths among 1069 rofecoxib patients and 12 deaths among 1078 placebo patients (HR, 2.99; 95% CI, 1.55-5.77). These mortality analyses were neither provided to the FDA nor made public in a timely fashion. The data submitted by the sponsor to the FDA in a Safety Update Report in July 2001 used on-treatment analysis methods and reported 29 deaths (2.7%) among 1067 rofecoxib patients and 17 deaths (1.6%) among 1075 placebo patients. This on-treatment approach to reporting minimized the appearance of any mortality risk. In December 2001, when the FDA raised safety questions about the submitted safety data, the sponsor did not bring these issues to an institutional review board for review and revealed that there was no data and safety monitoring board for the protocol 078 study. The findings from this case study suggest that additional protections for human research participants, including new approaches for the conduct, oversight, and reporting of industry-sponsored trials, are necessary.
So now, if this article is to be believed, we've gone from honest mistake, to biased reporting, to sleaze in fairly short order. Can it get worse? Wouldn't bet against it. But even if there is no more blood-letting, a lot of damage has already been done; to the reputations of the pharmaceutical industry, the researchers who were complicit in the scams, and the regulators who dropped the ball. Unfortunately, individual clinicians who prescribed the stuff didn't fair so well either. Patient-doctor trust took a hit. Not as big a hit as the Vioxx victims themselves, but maybe as significant in the long run.
