Saturday, July 09, 2011

The long Avandia endgame : The Lancet

The long Avandia endgame

Asher Mullard
1 year after drug regulators finished re-reviewing Avandia's safety profile, the diabetes community is still left unsettled by the case. Asher Mullard reviews the lessons learned.
On July 13, 2010, 33 US Food and Drud Administration (FDA) panellists gathered to recommend a fate for GlaxoSmithKline's (GSK) Avandia (rosiglitazone) over longstanding concerns that the antidiabetic drug raises cardiovascular risk. 1 year on—after the FDA's decision to restrict access to the drug and the European Medicine Agency's decision to withdraw it—the drug's days are numbered. But even as its seemingly last chapter comes to a close, many in the speciality remain concerned.
Avandia was approved in the USA in 1999 and in the European Union in 2000 for the treatment of type 2 diabetes. In 2007, however, the results of a meta-analysis raised alarm bells over the thiazolidinedione's cardiovascular profile. The FDA has since held two panel meetings and re-reviewed the drug twice, US Congress has published a critical report about GSK and the FDA's handling of the Avandia affair, and hundreds of pages have been written by the medical and scientific community about the drug's pros and cons.
Through all this difference of opinion, says Rury Holman, director of the University of Oxford Diabetes Trials Unit, UK, a clear problem emerges: there are not enough data to make a definitive policy decision about access to the drug, even though it has been on the market for over a decade. “It's just amazing that the right studies were never done to study the long-term benefits or harm of the drug”, he says. Investigators, regulators, and drug firms have a responsibility to collect better datasets in the future, he adds.
Harlan Krumholz, a cardiologist at Yale School of Medicine, CT, USA, adds that this failure to properly study the drug—and the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial in particular—severely threaten to undermine patient trust. When the long-term post-marketing RECORD study reported in 2009 that Avandia was not linked with an increase in cardiovascular morbidity or mortality, GSK pointed to these data as evidence of their drug's safety. Although the design and conduct of the trial have been heavily debated, a potentially more sinister problem emerged at the latest panel meeting; FDA employee Thomas Marciniak challenged RECORD's conclusions after finding that details in the trial's records had been changed or mishandled in a way that favoured Avandia. “This suggests the possibility that there was fraud”, says Krumholz. “I don't understand why this didn't send bigger shockwaves through the community”, he adds.
In view of this finding, and at the behest of the FDA, GSK has now commissioned Duke Clinical Research Institute, NC, USA, to re-adjudicate the RECORD data. A first stage of the review, re-examining mortality events, is due to be completed by September, says the FDA.
Meanwhile, Krumholz asks why the FDA has taken so long to implement restrictions, despite announcing that they were needed in September, 2010. The FDA approved an updated label for the drug in February, 2011, but it did not announce further details of its plan to restrict access until May, 2011. And the complete suite of measures—which include having patients sign off confirmation that they are aware of Avandia's risks—are not due to be fully rolled out until November, 2011. “The agency needs to be held accountable for the speed with which it acts”, says Krumholz.
The FDA maintains that this timeline is in accord with its expectations and that the delay is “reasonable” to allow patients to transition gradually to other products. But Krumholz disagrees. “There's no excuse for them taking so long to implement these restrictions. Either they don't believe in the decision and don't care when it gets implemented, or they care and just aren't addressing it in a timely way.”
Despite the many questions, and even with the RECORD re-adjudication ongoing, Avandia's fate seems sealed. “The drug is gone, it's dead”, says Victor Montori, an endocrinologist at the Mayo Clinic, MN, USA. Global sales of Avandia have decreased by more than ten times since their heyday, from £414 million in the first quarter of 2007 to £36 million in the first quarter of 2011. The restrictions, when they are implemented in the USA, will probably drive use and sales lower still. Takeda's Actos (pioglitazone), the only remaining thiazolidinedione on the market, escaped largely unscathed by the Avandia debacle, but is coming under increased scrutiny over concerns that it raises the risk of bladder cancer.
There are some positive signs of change. Holman says that investigators are keen to do more real-world setting trials that can better elucidate a drug's safety profile, and regulators are now taking a harder line in reviewing experimental antidiabetic drugs.
But Montori remains concerned that the most important lesson has not been learned. “The fact that we can imagine these sorts of problems happening again with other drugs is a major issue. It spells for trouble ahead”, he says.

Posted via email from Jack's posterous

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