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FDA U-turn on Avandia

Published on 26/11/13 at 09:51am
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The FDA has delivered a shock verdict that the stringent restrictions on GlaxoSmithKline’s diabetes medicine Avandia should be lifted, despite saying in 2010 that it was too dangerous for most patients.

The US regulator released a statement yesterday saying that its review of data for Avandia (rosiglitazone) and its generics versions “do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines metformin and sulfonylurea”. 

The agency said that as a result “we are requiring removal of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010”. 

It added: “This decision is based on our review of data from a large, long-term clinical trial and is supported by a comprehensive, outside, expert re-evaluation of the data conducted by the Duke Clinical Research Institute.” 

Troubled past

Avandia was suspended by European regulator the EMA in September 2010 because of perceived high levels of heart attack, heart failure and stroke in patients, but its US counterpart the FDA allowed it remain on the market, albeit with further restrictions on its use.

Both the FDA and EMA decisions came after a long period of doubt over Avandia's side effects. These concerns had been growing since a meta-analysis was published in the New England Journal of Medicine in May 2007.

Conducted by independent cardiologist Dr Steve Nissen, the available data showed a link between Avandia and both heart attacks and an increased risk of fatal cardiovascular events.

But GSK maintains there is a discrepancy between Nissen’s data and the firm's own RECORD trial data. And this they argue meant the meta-analysis was ‘not a true representation’ of the facts.

But despite GSK's assurances that the drug was safe, in 2012 the firm produced its own U-turn and pled guilty to criminal misconduct - related in part to concealing the hazards of Avandia - and it paid a $3 billion fine, one of the largest in US history.


It appeared as if this was an open and shut case, but in June this year an FDA Advisory Committee re-assessed the data, which has led to today’s shock reversal.

Although some scientific uncertainty about the cardiovascular safety of rosiglitazone-containing medicines still remains, in light of the new re-evaluation of the RECORD trial, the FDA says that its concern is ‘substantially reduced’

It will now go about easing the restrictions on the drug. Currently only 3,000 patients take what was once the best-selling oral diabetes treatment in the world.

GSK said it “welcomes the decision of the FDA” and “appreciates the Agency’s robust review of the science with regard to Avandia”. The London-based firm said however that it still maintains its view that Avandia is a ‘safe and effective treatment’ for type 2 diabetes.

The company added that it will work with the FDA to update labelling and to implement the Agency’s decisions regarding easing restrictions on the medicine.  

Hidden agenda

Whilst GSK may be celebrating, Nissen - who is now chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic - has been raising concerns all year about the FDA’s review.

Writing for Forbes earlier this year he expressed concerns that the most likely explanation for this U-turn is that the leadership of the division of the FDA responsible for drug regulation - the Center for Drug Evaluation and Research (CDER) - is “seeking to avoid accountability for its role in the Avandia tragedy”.

He said this is because in May 2007 when he published an independent analysis of Avandia in the NEJM showing a statistically significant 43% increase in heart attack, CDER officials acknowledged that FDA statisticians had confirmed the findings.

“The leadership of CDER was intensely embarrassed by these revelations and furious with us for publicly challenging the safety of Avandia (and indirectly the competence and integrity of CDER),” he says, and believes that the review is an attempt at saving face.

Nissen ended with the warning: “If CDER is allowed to re-write the history of Avandia, this vital FDA centre will continue to function as an unsupervised, self-regulating bureaucracy, accountable to no one. That’s just unacceptable when the public health is at stake.”

Ben Adams 

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