We've been covering the Avandia witch hunt story for more than three years now (see e.g. Avandia: Burn Her Anyway? and Avandia: A Fair Cop? ) and would like to take this opportunity to say "We told you so" and point you to this month's New England Journal of Medicine where you can read her posthumous pardon (such as it is) in The Cardiovascular Safety of Diabetes Drugs — Insights from the Rosiglitazone [Avandia] Experience. The story will be a familiar one made all the more appalling by the fact that the FDA again played the role of the fool who was tricked into thinking he was a superhero - just as it had been in the breast implant affair.
In Act I, a meta-analysis of prior epi studies showed an increase in risk of cardiovascular events among those taking Avandia (rosiglitazone). Yet those first epidemiological studies hinting at a problem post-marketing "had substantial methodologic shortcomings, including multiplicity, which meant that a statistically positive finding might be a false positive result". Meanwhile, analyses of pre-marketing data was "relatively insensitive in assessing cardiovascular risk" in large part because nobody suspected that improving glycemic control (an approach taken by a whole class of diabetes drugs) would increase the risk of cardiovascular events. Nevertheless, Avandia was suddenly deemed to be dangerous.
In Act II the RECORD study, one that could actually uncover any increased risk and which in fact had demonstrated none, was denounced as hopelessly flawed "corporate science" based largely (or at least most stridently) on a claim of conflict of interest given that it was done at the behest of the manufacturer.
In Act III The New York Times and other news outlets decided Avandia was a perfect example of a narrative they were advancing; specifically that new drugs were no better than older generic versions, were only designed and marketed in order to gouge health care consumers and were more dangerous too. For months they hyped the story often claiming that tens of thousands of Avandia users had already suffered serious cardiovascular events and often death due to the drug. Eventually The NYTimes would quote the author of the meta-analysis that started it all as as calling the licensing of Avandia "one of the worst drug safety tragedies in our lifetime."
Act IV, meant to be the last, began with an emboldened FDA severely restricting the use of Avandia despite the growing need for effective type 2 diabetes treatments. Then the FDA killed the TIDE trial - "a large cardiovascular-outcome trial designed to evaluate the benefit of rosiglitazone and pioglitazone (a/k/a Actos - Avandia's cheaper rival) as compared with placebo ... and the safety of rosiglitazone as compared with pioglitazone". It was the one study that could have answered the question of whether or not Avandia was better and safer than its generic rival (which btw itself is now the subject of considerable litigation ). So, Avandia having been hauled off to the stake and the evidence that might have acquitted her having been forbidden from being gathered it looked like the story would have a heroic and happy ending. A suddenly cocksure and vastly more powerful FDA, heedless of uncertainty, rushes in and rescues the helpless consumer from the clutches of Big Pharma.
But like all true stories this one didn't end so cleanly. Over the usual objection that anything, including data, ever touched by a corporation is forever corrupted the FDA did what it's actually supposed to do. It was curious and it asked a question. What, it asked, would the RECORD trial data reveal if it was handed off to and reanalyzed by a wholly independent group researchers with impeccable credentials and reputations. The answer came earlier this year and it "provided reassurance that rosiglitazone (Avandia) was not associated with excess cardiovascular risk."
So what had the FDA really done? Because almost nothing was known about the cardiovascular risk posed by other diabetes drugs " the FDA decision may have had unintended consequences. The intense publicity about the ischemic cardiac risk of rosiglitazone may have diverted attention from the better-established risk of heart failure that is common to the drug class. Restricted access led patients to switch from rosiglitazone to other diabetes drugs of unproven cardiovascular safety." In short the FDA had snatched consumers from uncertainty and delivered them into greater uncertainty.
The authors of the perspective conclude their piece hopefully and delicately. "Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for that expenditure." We can only hope.
