European regulatory body recommends suspension of rosiglitazoneBMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c5291 (Published 24 September 2010) Cite this as: BMJ 2010;341:c5291
The European Medicines Agency (EMA) has recommended the suspension of diabetes drug rosiglitazone (Avandia) made by GlaxoSmithKline (GSK) from the market in Europe.
A statement by the European Medicines Agency says they now believe the “benefits of rosiglitazone no longer outweigh its risks,” pointing to new studies that support an increased cardiovascular risk.
The suspension is pending adoption by the European Commission, but it is expected the drug—and other products containing it—will stop being available in the next few months.
By contrast, the US Food and Drug Administration (FDA) has recommended a package of measures to try to determine the safety of the drug and further restrict its use (BMJ 2010:341: c5287 doi=10.1136/bmj.c5287).
The Medicines and Healthcare Products Regulatory Agency is advising doctors to review all patients currently on rosiglitazone and take appropriate action, according to the individual clinical situation, to change to another suitable treatment.
Unlike in the US, rosiglitazone was only approved as a second line treatment when existing treatments, such as metformin or sulphonylurea, do not work. It subsequently had more restrictions and warnings placed on it after approval, and, according to Hans-Georg Eichler, senior medical officer at the EMA, suspension is the “next step in the chain.”
Suspension, however, allows scope for GSK to provide convincing data to identify a group of patients in whom the benefits of the medicines outweigh their risks. According to Professor Eichler, it’s a legal tool not available to the FDA, which only has the options of withdrawal—a more definitive measure—or restrictions.
A spokesperson for GSK told the BMJ that they continue to believe that rosiglitazone is an important treatment for patients with type 2 diabetes—although they “respect the EMA’s decision” and “will now implement the necessary actions.”
“We will now work with the agency to fully understand what actions GSK could take for the regulator to reconsider the suspension of the marketing authorisation in Europe,” she added.
Donald Singer, professor of clinical pharmacology and therapeutics, at British Pharmacological Society, remains cautious about the drug. “High quality evidence is needed to convince the EMA about justification of a future limited clinical licence for sub-groups of type 2 diabetics in whom the benefits of rosiglitazone may outweigh its potential cardiovascular risks,” he said.
The announcement comes after years of controversy about the side effects of the drug, and the whole process of drug regulation—from licensing to monitoring the drug once it’s on the market and the role of trial design and data collection.
A BMJ investigation published earlier this month (BMJ 2010;341:c4848, doi: 10.1136/bmj.c4848) showed that even upon approval by the EMA in 2000 there were concerns about the effects on cardiovascular safety and the lipid profile. Experts advising the regulator suggested “the long term risk/benefit of rosiglitazone is still unknown and that there are several safety concerns.” Another expert said that there had not been a long term study with hard primary endpoints so it was not clear whether rosiglitazone would have any beneficial impact on cardiovascular disease.
Steve Nissen, a cardiologist from Cleveland Clinic, whose 2007 meta-analysis in the New England Journal of Medicine first drew public attention to an increased risk of myocardial infarction, says it’s essential to fully investigate what went wrong with the regulatory process.
“Although I appreciate that FDA and EMA finally took appropriate actions, this is not an outcome to celebrate. The decision comes more than 5 years after the maker of Avandia, GSK, initially informed the FDA that the drug increased the risk of heart attack and related complications and three and a half years after our analysis, published in the New England Journal of Medicine, first brought this problem to the attention of the medical community and public,” he said.
The EMA also announced that it was currently reviewing the safety profile of a rival drug, pioglitazone (Actos), made by Takeda after concerns it was associated with an increased risk of bladder cancer.
Cite this as: BMJ 2010;341:c5291