Will new FDA meeting on Avandia prompt withdrawal of drug?

April 15, 2013

Silver Spring, MD - Two US Food and Drug Administration (FDA) panels will meet for a couple of days in early June to discuss the results of an independent readjudication of an important trial with the type 2 diabetes drug rosiglitazone (Avandia, GlaxoSmithKline), according to an announcement published today in the Federal Register[1].

Rosiglitazone is a diabetes drug from the thiazolidinedione class; in September 2010, it was suspended by the European Medicines Agency (EMA) because it deemed that the product's cardiovascular risk outweighed its benefits.

At the same time, the FDA deemed there was "a signal of harm" but decided not to suspend the drug. Instead it requested readjudication of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) study at the individual patient-data level. The agency also required that rosiglitazone-containing medicines be subject to a risk evaluation and mitigation strategy (REMS) program to ensure the safe use of the medicine in patients with no other options.

For the new meeting, on June 5 and 6, 2013, the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee will convene to discuss the reanalysis of RECORD.

One expert, Dr David Juurlink (University of Toronto, ON), said: "This is the closure of the exercise. I suspect the number of [cardiovascular] events will go up [in RECORD]." He added that, in his view, this could even lead to complete withdrawal of rosiglitazone from the worldwide market.

Spokesperson for GlaxoSmithKline, Mary Anne Rhyne, said that the company "expects to be to be asked to present about this reexamination of the RECORD trial [and] to give an update on the safety and risk management program we were asked to implement. We've not requested any changes to the labeling or the distribution [of rosiglitazone]." She added that the reanalysis of the RECORD trial was submitted to the FDA "last year."

How will June meeting affect use of rosiglitazone in US?

The September 2010 decisions by the EMA and FDA on rosiglitazone followed years of debate about the safety of this drug, including whether the data on MI and cardiovascular deaths with rosiglitazone were reliable in the RECORD trial. The latter issue was one of the key points of discussion in a July 2010 two-day FDA panel safety review of this drug prior to the decision to severely restrict its use in the US.

Juurlink said, ''It's almost impossible to envision that any reanalysis of RECORD will lead to resurgence in the use of the drug. There is still a compelling body of evidence that it is less safe a drug than pioglitazone [Actos, Takeda Pharmaceuticals]. I know there are still a handful of people on Avandia and a handful more on pioglitazone, which has its own issues. But if a physician really felt compelled to prescribe a thiazolidinedione, it's virtually impossible to craft an argument whereby rosiglitazone would be the preferred drug. I just can't imagine why a doctor would choose to prescribe it or a patient would chose to take it when that other option is on the table."

And he added: "If it is the case that the original analysis of RECORD systematically biased the results in favor of rosiglitazone," as has been claimed, "it is likely that an independent and more objective reanalysis of RECORD would lead to a less favorable view of the drug. That may well trigger the withdrawal of the drug from the worldwide market, which is, I think, what should happen. It should have happened three years ago."

Juurlink believes the EMA "made the right call" in 2010 with regard to rosiglitazone and the FDA "made the wrong call . . . because the whole premise of REMS is that you can find a subgroup of patients in whom the benefits of the drug outweigh the risks, and it's not really possible to do that reliably [in this case]."

Juurlink has declared no relevant financial relationships.

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