Drug regulators on the two sides of the Atlantic reached significantly different decisions today on the safety of the controversial diabetes drug Avandia (rosiglitazone) made by GlaxoSmithKline (GSK).
The European Medicines Agency pulled the type 2 diabetes drug from the European market, saying in a press release that “the benefits of rosiglitazone no longer outweigh its risks.” The agency said that, when it considered new data on the cardiovascular risks of the drug, which has been marketed in Europe since 2000, it could not identify additional measures to further reduce its risk in patients with ischemic heart disease, short of pulling it entirely from the market.
Simultaneously today, the US Food and Drug Administration announced that it is significantly restricting access to Avandia in the US, where roughly 600,000 patients are taking the drug – without removing it from the market. Its decision will leave Avandia available to patients currently taking it, and to some new patients, by implementing a “Risk Evaluation and Mitigation Strategy (REMS)”—a tailored plan that requires enrolment by physicians, patients and pharmacists, as well as detailed documentation that patients have fully understood the drug’s risk.
(A comprehensive catalog of FDA documents relating to its decision is available here).
“The agency anticipates that the REMS will limit use of rosiglitazone significantly,” Margaret Hamburg, the FDA commissioner, said in a conference call with reporters on Thursday morning.
Asked why her agency reached a different conclusion than the EMA, Hamburg said that “there was substantial alignment between the agencies” in assessing the drug and its risks to public health, and that the difference in outcomes reflected only a different approach to risk management between the agencies.
Further defending her agency’s decision, she said: “We heard very clearly from both providers and patients that some patients felt that they were unable to tolerate other diabetes medications and that this drug was effective for them.”
While recent metaanalyses have left “a cloud of concern over the drug,” added Janet Woodcock, the director of FDA’s Center for Drug Evaluation and Research, “We are not withdrawing the drug at this time because there is considerable uncertainty about the signal [of cardiovascular risk], whether or not it is valid.”
Patients currently taking Avandia will be able to continue if they enrol, with their physician, in the REMS programme. Those not yet taking the drug will be able to begin doing so only if their blood sugar cannot be controlled with other classes of diabetes drugs, and if they cannot take the one other availble drug in Avandia’s class for medical reasons.
GSK said in a statement that it “continues to believe that Avandia is an important treatment for patients with type 2 diabetes.”
Ellen Strahlman, the company’s Chief Medical Officer, added: “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.”
Agency officials said that roughly 30 drugs are currently marketed under the restrictive REMS requirements in the United States. Those requirements, which will be accompanied by a label change on Avandia, will not be in place for several months, the officials said.
The EMA in its announcement said that Avandia would cease to become available in Europe “within the next few months.”
The FDA also announced that it is requiring GSK to sponsor an independent re-adjudication of a randomized clinical trial known as RECORD. That trial looked at Avandia’s impact on cardiovascular health in 4,447 patients, and found no increase in cardiovascular hospitalizations or deaths among those taking the drug.
The agency also placed on hold a large clinical trial called TIDE which was examining the cardiovascular effects in subjects taking Avandia long term and in those taking its key competitor, Actos (pioglitazone), made by Takeda Pharmaceutical.
“This study does not meet the criteria recommended by an Institute of Medicine Committee for [post-market] safety studies at this time,” Hamburg said.
GSK also issued a gloomy pronouncement about Avandia’s financial status, noting that US sales dropped 23% in the first six months of 2010, and European sales 17 percent. “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,” the company said.
In 2006, the last year before news of Avandia’s cardiovascular issues became public, sales of the drug brought in $3.3 billion [corrected].
For a report on the key meeting of FDA advisors this summer that informed today’s decision, see this Nature blog.
You can find a related Nature magazine story about the possible physiological mechanisms behind Avandia’s cardiovascular effects here.