Why rosiglitazone would not have been approved today

Avandia continues to dominate cardiovascular-related news this week. Recently, the AHA and the ACC issued a highly detailed, thoughtful, though perhaps slightly over-diplomatic science advisory on TZDs and CV risk. Taking a completely opposite tack, GSK, in no mood to take prisoners, and apparently about to nominate itself for a Nobel Prize, issued a 30 page White Paper in response to the Senate report published on Saturday.

At the core of the AHA/ACC advisory is a detailed analysis of all the available rosiglitazone data. I’m not aware of a more detailed or objective analysis. After a careful review of the data the authors conclude that “an association between rosiglitazone and IHD outcomes has not yet been firmly established,” but goes on to admit that “sufficient evidence has emerged to raise concerns about a potential adverse effect.” The authors, including first author and chair, Sanjay Kaul, appear to endorse the FDA and European Medicines Agency decisions in 2007 to allow rosiglitazone to remain on market, though with additional warnings. But it’s hardly a strong endorsement. Not surprisingly, they write that “given this clinical equipoise, we call on academic researchers, industry, and government agencies to collaborate on definitive randomized trials to answer these important clinical questions.”

By contrast, the GSK White Paper makes no efforts whatsoever to be balanced. The document seeks to discredit the Senate report, but GSK harms its own case by refusing to consider that there might be any ambiguity in the issue, or to admit that the company might, at any time, have acted in some way that was inappropriate. Is there anyone out there who is impressed, for instance, by “the extensive measures GSK undertook to study Avandia prior to marketing approval”? The one thing that just about everyone except GSK now seems to agree upon is that the cardiovascular safety of the drug was not adequately studied prior to approval.

Similarly, the company’s claims that it has been “proactive in investigating safety data” is just plain laughable, unless of course attempts to intimidate one’s opponents are considered “proactive.” Finally, the document goes to great lengths to discredit the famous Nissen meta-analysis (and many of these points have some validity, as the AHA/ACC advisory makes clear) but fails to address the multiple reports that the company’s own scientists turned up similar results.

GSK doesn’t do itself any favors with its strategy of massive retaliation, but GSK’s opponents aren’t necessarily helping their case with their extreme tactics either. A recent New York Times’ story about Steve Nissen’s secret recording of a meeting with GSK executives is a case in point. As pointed out by Paul Raeburn, the veteran journalist who covers medical reporting for the Knight Science Journalism Tracker blog, the story turns out to be much ado about very little. The only thing “secret” in the recording of the meeting was the recording itself. There was no actual new information contained in the recording or in the Times article. Though it had at first appeared to be an important story, Raeburn concludes: “maybe not such an important story after all. Sometimes a poorly organized story is a reflection of reporting that doesn’t have much to tell.”

One final thought: it’s clear that by 2010 standards rosiglitazone never would have been approved. The question then is, what to do about a drug like rosiglitazone that has already been approved? What type of danger signal (or lack of efficacy, as in the ezetimibe case) would be needed to warrant removing the drug from the market? I don’t think there’s been an explicit discussion of this issue. Once again, as happened in the debate over ARBITER 6, an important major public health issue has taken center stage and there is a paucity of good data.

That’s the real tragedy here.

Larry Husten is a writer and editor of CardioBrief.org.

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