NEJM: FDA outlines strategy for restricted access to Avandia

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Despite mounting concerns surrounding the diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) and its potential to spawn certain cardiovascular (CV) events such as MI and possible death, the U.S. has decided to keep the drug on the market.

However, in a perspective published Oct.14 in the New England Journal of Medicine, Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER) at the FDA, and colleagues wrote that the FDA will require GlaxoSmithKline to submit a Risk Evaluation and Mitigation Strategy (REMS) to the agency, which will restrict access to the drug.

The REMS will impose certain restrictions on the drug so that the benefits of the diabetes drug will continue to outweigh its risks. Even with the REMS issued, patients who are unable to achieve glycemic control with other similar medications such as pioglitazone (Actos, Takeda Pharmaceuticals) will have the option to be administered rosiglitazone, but only after a nod from a physician.

Additionally, patients already administered the drug and who are benefiting from it may continue to use the medication, but must acknowledge that they understand the possible risks. FDA speculates that the initiation of the REMS will significantly limit the use of rosiglitazone.

In a July 15 vote, 20 out of 32 voting members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee became concerned with the drug’s potential to increase the risk of CV events compared with other non-thiazolidinedione antidiabetic agents and voted that more stringent actions be taken.

“The rosiglitazone controversy is remarkable because there are strongly held differing positions on how the agency should respond to emerging safety data, both inside the FDA and in the biomedical community,” Woodcock and colleagues wrote.

Because the committees were split on their vote, Woodcock said that “the FDA anticipates questions on whether the agency has gone too far, or not far enough.

“Some may note the limitations of available data and argue that the FDA should provide more information to clinicians but not impose additional restrictions,” they wrote. “The FDA’s response is that a label change alone does not provide adequate assurance that use of rosiglitazone will be limited to appropriate patients. New label warnings are not always read. The significant questions about the drug’s cardiovascular safety justify stronger measures to support good clinical decision making and protect patients.”

In response to the argument that the drug should be pulled from the shelves due to the fact that there is no predefined patient population where the drug is most beneficial, FDA said that the drug “does have benefits in glycemic control,” including the reduction of short-term complications of hyperglycemia.

“Against these benefits, we must assess the evidence of rosiglitazone’s cardiovascular risks. This evidence is concerning, but it is not definitive,” they wrote.

While some state that pioglitazone may be a good alternative to rosiglitazone and have less of a risk, FDA said that it is currently investigating evidence that may link the use of pioglitazaone to bladder cancer.

“When there are just two drugs in a class, and many outstanding uncertainties, maintaining some flexibility may have value for patient care,” the authors noted.

During the ongoing review of rosiglitazone, FDA has requested that the TIDE (Thiazolidinedione Intervention with vitamin D Evaluation) trial be halted and that the endpoints of the RECORD trial be readjudicated to further assess outcomes with rosiglitazone.

Draft guidance issues by FDA in 2008 outlined boundaries for the risk of major adverse cardiovascular event rates in meta-analyses or non-inferiority studies that compare drugs with standard therapy. Additionally, the FDA recommended that longer clinical trials—over two years—take place.

“The case of rosiglitazone underscores the need for a robust evidence base to demonstrate the safety of medicines administered long-term,” the authors concluded.