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US restricts, Europe withdraws, Avandia

Due to safety concerns, GSKs diabetes drug Avandia has been restricted in the US and had its marketing authorisation suspended in the EU

GlaxoSmithKline's (GSK) controversial type II diabetes drug Avandia (rosiglitazone) has had its marketing authorisation suspended in Europe and is to be marketed under a restricted access programme in the US. The changes are the result of concerns that the drug raises the risk of cardiovascular disorders, including heart attack and stroke, in patients with diabetes.

The European Medicines Agency's (EMA) Committee on Medicinal Products for Human Use (CHMP) recommended the suspension of the marketing authorisation as 'the benefits no longer outweigh the risks', while the US Food and Drug Administration's (FDA) restriction will limit use of Avandia to patients who have been unable to control their glucose with other medicines and cannot take Takeda's Actos (pioglitazone), the only other marketed drug in the thiazolidinedione (TZD) class.

Withdrawal in Europe
Avandia was indicated in Europe as second line therapy in the treatment of type 2 diabetes in patients for whom metformin is inappropriate, or in combination with either metformin and/or a sulphonylurea in patients with inadequate diabetes control despite existing treatment with these drugs.

Avandia's original licence included a warning about the risks for patients with heart failure, which was expanded to cover further cardiac conditions after more research into its effects was conducted.

The UK Medicines and Healthcare products Regulatory Agency (MHRA) conducted its own assessment of the safety of rosiglitazone and sought the advice of the UK's Commission on Human Medicines (CHM). The CHM advised in July 2010 that the risks of rosiglitazone outweighed its benefits and that it no longer had a place on the UK market. In addition, the CHM considered action should be taken promptly and ideally within the appropriate EU framework, which led to the suspension of the marketing authorisation. According to the BBC website, currently more than 100,000 diabetes patients are treated with Avandia in the UK alone.

Regarding the European decision to withdraw Avandia, chief executive of the MHRA Professor Kent Woods said: "Patient safety is the top priority for the MHRA and we have been constantly monitoring the situation regarding rosiglitazone. [The] suspension means that clinicians should review all patients currently on rosiglitazone and take appropriate action, according to the individual clinical situation, to change to another suitable treatment.”

Following the MHRA determination, the German regulatory agency Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) has also announced that it will withdraw Avandia from the market, effective November 1, 2010.

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. The European Commission will now make a decision on the EMA's recommendation.

The MHRA statement about the suspension of the marketing authorisation for Avandia is available at: http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON094127

Restriction in the US
Conversely in the US, Avandia can still be marketed but is only available as part of a restricted programme.

At the FDA's Endocrinolic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee earlier this year, the advisors voted 20-to-12 to keep Avandia on the market, but most of those who voted in favour of continued marketing also favoured restrictions to increase safety. 

Under the new Risk Evaluation and Mitigation Strategy (REMS), doctors will have to document patients' eligibility, and patients will have to certify that they understand the drug's risks before Avandia may be prescribed. The restrictions apply only to new patients, the FDA noted: people who are already taking the drug and are benefiting from it can continue to receive prescriptions. 

In July 2010, the FDA asked GSK to end enrollment in TIDE, the company's post-marketing clinical study of Avandia. TIDE, designed to compare Avandia and Actos, is the only current company-sponsored trial of Avandia and is now to be brought to a close, at the request of the FDA.

The FDA is also ordering GSK to have an independent review conducted of the company's clinical trial RECORD, which compared Avandia's cardiovascular safety to the safety of other 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 agency said. "The FDA is requiring this independent review to provide additional clarity about the findings." GSK's handling of the data from its Avandia studies has also been under investigation by US Senate Finance Committee, whose leaders have accused the company of suppressing potentially damaging safety information.

GSK said that it will work closely with the FDA to institute the requirements and will voluntarily stop promoting Avandia in all markets, although it will continue to provide information about the drug in response to requests from doctors and patients.

The future for GSK
In a statement released to the London Stock Exchange, Dr Ellen Strahlman, chief medical officer at GSK, commented: "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."

Christine Henry, healthcare analyst at business information provider Datamonitor, commented: "Although Avandia franchise sales have already declined significantly from a high of $3.2bn in 2006 worldwide to $1.2bn in 2009, the suspension of sales in Europe and the limiting of availability in the US still represents a significant loss for GSK, which has continued to defend its trial programme and the safety of Avandia."

"Datamonitor expects that some patients will switch to Takeda's class competitor Actos, although Actos was itself recently announced as the subject of an FDA safety review into a possible bladder cancer link. The chances for Takeda to capitalize on Avandia's further misfortune are limited, as Actos loses patent protection in January 2011. Other antidiabetics that are likely to gain sales following the Avandia restrictions are Merck & Co's blockbuster DPP-4 drug Januvia (sitagliptin) and other DPP-4 inhibitor drugs."

Total global sales of Avandia products in the first half of 2010 were £321m. 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 to have minimal annual sales thereafter.

24th September 2010

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