Avandia stays in U.S. market with restrictions; EU seeks to shelve
The European Medicines Agency has forwarded the recommendation to the European Commission for the adoption of a legally binding decision.
In the U.S., however, the FDA published a 12-page memorandum from Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, explaining the rationale for the decision.
"The evidence pointing to a cardiovascular ischemic risk with rosiglitazone is not robust or consistent. Nevertheless, there are multiple signals of concern, from varied sources of data, without reliable evidence that refutes them," according to the memorandum.
Woodcock also noted that there is no cardiovascular risk with pioglitazone (Actos, Takeda), the only other FDA-approved thiazolidinedione (TZD)-class drug.
"Therefore, based on this safety information, it is necessary to restrict access to rosiglitazone until more substantial evidence of its safety becomes available," she said.
According to the memorandum, Avandia can remain on the market if the following actions are taken:
- GlaxoSmithKline (GSK) creates a safety risk program that ensures current and future users of the drug are provided complete risk information and that documentation appears in their medical records that the information has been received and understood;
- GSK must commission an independent re-adjudication of the RECORD study. This could be conducted in a stepwise manner with initial examination of the mortality finding; if the mortality finding is determined to be valid, then the other MACE elements should be re-adjudicated; and
- The TIDE trial is placed on full clinical hold and the regulatory deadlines for its conduct are rescinded. If reliable information on ischemic risk can be obtained from the re-adjudication of RECORD, the benefit-risk information for rosiglitazone should be re-evaluated and the conduct of further safety studies (including studies versus pioglitazone) should be reconsidered.
In July, the FDA placed a partial hold on the TIDE trial, allowing those already enrolled to continue in the study, while disallowing the recruitment of new patients.
The new restrictions for Avandia are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke.
In July, 20 members of an FDA panel voted to keep the drug on the market—most with further restrictions and warning—while 12 members voted the drug be pulled from the shelves.
According to the memorandum, the reasons for restriction rather than market removal include:
- The cardiovascular safety profile of rosiglitazone is still an open question because there are conflicting data on the existence and magnitude of the risk, and a detailed re-adjudication and analysis of data from the RECORD study needs to be conducted;
- There are individuals with Type 2 diabetes who may benefit from therapy with a TZD because they are unable to achieve glycemic control on other medications but who cannot tolerate pioglitazone or for whom it may not be the best medical choice (e.g., individuals with Type 2 diabetes and prior bladder cancer); and
- There are individuals currently taking rosiglitazone who, with full knowledge of the potential risk and in consultation with their healthcare providers, may wish to remain on the drug rather than revise their treatment regimens.