The GlaxoSmithKline (GSK)' controversial type 2 diabetes drug Avandia (rosiglitazone) has been banned in Europe by the European Medicines Agency (EMA), while the US Food and Drug Administration (US FDA) has significantly restricted the use of the drug. These decisions come in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia.

“The FDA is taking this action today to protect patients, after a careful effort to weigh benefits and risks,” said FDA Commissioner Margaret A. Hamburg, M.D. “We are seeking to strike the right balance to support clinical care.”

“Allowing Avandia to remain on the market, but under restrictions, is an appropriate response, given the significant safety concerns and the scientific uncertainty still remaining about this drug,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

The FDA will require that GSK develop a restricted access programme for Avandia under a risk evaluation and mitigation strategy, or REMS. Under the REMS, Avandia will be available to new patients only if they are unable to achieve glucose control on other medications and are unable to take Actos (pioglitazone), the only other drug in this class. Current users of Avandia who are benefiting from the drug will be able to continue using the medication if they choose to do so.

Doctors will have to attest to and document their patients' eligibility; patients will have to review statements describing the cardiovascular safety concerns associated with this drug and acknowledge they understand the risks. The agency anticipates that the REMS will limit use of Avandia significantly.
Also today, the FDA ordered GSK to convene an independent group of scientists to review key aspects of the company’s clinical trial known as RECORD, which studied the cardiovascular safety of Avandia compared to standard diabetes drugs. During the course of the FDA’s review of the RECORD study, important questions arose about potential bias in the identification of cardiovascular events. The FDA is requiring this independent review to provide additional clarity about the findings.

In addition, the agency halted the GSK’s clinical trial known as TIDE and rescinded all of the regulatory deadlines for completion of the trial. The TIDE trial compares Avandia to Actos and to standard diabetes drugs.

In the European Union, the EMA has suspended the marketing authorisation for all rosiglitazone-containing medicines (Avandia, Avandamet and Avaglim). As a result, physicians in Europe are being advised that affected patients need to be transitioned to alternative treatment options. The EMA has stated that the suspension will remain in place unless convincing data are provided that identify a group of patients in whom the benefits of the medicine outweigh its risks.

Dr Ellen Strahlman, GSK’s chief medical officer, said: “Our primary concern continues to be patients with type 2 diabetes and we are making every effort to ensure that physicians in Europe and the US have all the information they need to help them understand how these regulatory decisions affect them and their patients.”

The company continues to believe that Avandia is an important treatment for patients with type 2 diabetes and is now working with thea FDA and EMA to implement the required actions. GSK will also work closely with other regulatory agencies to comply with any decisions made by them regarding rosiglitazone-containing medicines. GSK will voluntarily cease promotion of Avandia in all the countries in which it operates and will continue to respond to requests for information and support from healthcare professionals and patients.

According to a GSK press release, the total sales of Avandia products in the first half of 2010 were £321m (-18%); US £164m (-23%); Europe £72m (-17%); Emerging Markets £37m (-5%); RoW £48m (-6%). As a result of the regulatory updates in both the US and EU, GSK now expects global sales of Avandia products to be in a range of approximately £100m - £150m in the second half of 2010 and with minimal annual sales thereafter. These estimates are net of customer returns of product previously sold. Associated one-off costs in 2010 comprising stock write-offs, asset write-offs and other related one-off costs are currently expected to be approximately £100m on a pre-tax basis.