The numbers are the numbers: Avandia, heart attacks, and leaked messages

A recently released report from the US Senate Finance Committee led by Senator Charles Grassley (who has also queried several medical journals, and medical schools, regarding their policies on ghostwriting) concludes that drug manufacturer GlaxoSmithKline probably knew of the increased cardiovascular risk associated with its diabetes drug Avandia (rosiglitazone), many years before publication of a critical meta-analysis by Nissen and Wolski  demonstrating the risk. The Senate report describes how a peer-reviewer of the Nissen paper leaked the critical meta-analysis to the company while it was still under consideration at the New England Journal of Medicine, enabling GSK to attempt to mitigate effects of publication of the meta-analysis. Senator Grassley’s report states:  “…GSK’s statistical experts were examining the study for potential flaws. In addition, GSK officials were drafting ‘‘key messages’’ to undermine the main conclusion of the Nissen study”. Part of that strategy of mitigation included initiating publication of an interim analysis of another GSK trial, RECORD — although that interim analysis was underpowered, and the findings compatible with those of the Nissen meta-analysis.

Previous research has found that published drug trials carried out by pharmaceutical companies are more likely to generate conclusions favouring the company than trials done by other sponsors. A recent analysis of 202 studies on the risk of heart attack associated with rosiglitazone use finds much the same thing, as summarised in a recent posting on theheart.org. The analysis looks at 107 (53% of 202) studies which provide conflict of interest statements; of the studies concluding rosiglitazone does not increase the risk of heart attack, “86% had relationships with rosiglitazone’s manufacturer” [GSK], whilst of the articles concluding there was an unfavourable risk, “18% had relationships with rosiglitazone’s manufacturer that were disclosed in the papers”.

The proposal has been raised many, many times before – particularly by journal editors – but isn’t it time for key, clinically directive trials to be carried out by researchers with no stake in the outcome of the study, and with full freedom to publish their findings independently of the interventions’ manufacturers?

Note: for a fuller history of the development and assessment of Avandia, see a recent editorial by Nissen:

Nissen SE. The rise and fall of rosiglitazone. European Heart Journal 2010. doi 10.1093/eurheartj/ehq016

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