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FDA places greater restrictions on access to rosiglitazone

BMJ 2010; 341 doi: (Published 24 September 2010) Cite this as: BMJ 2010;341:c5287

The US Food and Drug Administration (FDA) has recommended that an independent review is conducted of key data on the cardiovascular effects of the diabetes drug rosiglitazone to try to determine the drug’s safety along with a package of measures to further restrict its use.

Margaret Hamburg, FDA commissioner, said the agency was “significantly restricting” products containing rosiglitazone because of concerns about cardiovascular safety.

It has asked rosiglitazone manufacturer GSK to submit a “risk evaluation and mitigation strategy”—a step that allows access to the drug under restricted conditions.

Unlike the European Medicines Agency, which announced the suspension of rosiglitazone on 23 September (BMJ 2010;341:c5291, doi:10.1136/bmj.c5291), the US drugs regulator does not have the legal means to suspend a drug, although it did not rule out removing the drug from the market at a later date.

Among the conditions placed on the use of products containing rosiglitazone in the US was a requirement to make doctors and patients aware of the potential risks associated with their use and to create a registry of all patients taking the drug.

GlaxoSmithKline has been asked to commission an independent review to re-evaluate key data from the RECORD (rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes) study, which aimed to resolve the uncertainties about the cardiovascular effects of rosiglitazone raised by meta-analyses. The FDA also told the company to suspend the TIDE (thiazolidinedione intervention with vitamin D evaluation) study comparing rosiglitazone with pioglitazone, a step it initially took in July.

Patients already taking rosiglitazone will be allowed to continue taking rosiglitazone “if they appear to be benefiting from it and they acknowledge that they understand these risks,” said Dr Hamburg. Once the risk evaluation and mitigation strategy is in place new patients will only be prescribed rosiglitazone “if they are unable to achieve gylcaemic control on other medications and in consultation with their health care professional, [and] decide not to take pioglitazone for medical reasons,” she said.

Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, said evidence on the side effects of rosiglitazone is mixed, with meta-analysis of efficacy trials “showing an increase in myocardial ischaemia and trends in increased cardiovascular death” but observational studies failing to consistently reach similar conclusions.

She said there is “uncertainty” about the value that should be given to efficacy and observational studies—both within the FDA and among its advisory committee of outside experts. Given those uncertainties, the agency was acting in a manner “most prudent” to restrict access to the drug.

Dr Hamburg said the FDA has been in contact with the European Medicines Agency and that “there is substantial alignment” on the science. “The FDA conducts analyses on the raw data, and the EMEA [European Medicines Agency] does not,” she pointed out. Where the agencies differ is in the administrative tools they have to address the situation.

“We heard very clearly from doctors and patients . . . that this drug was effective for them. We believe that this limited use approach” will allow for informed decisions, she said.

Commenting on the US and European decisions Thomas Marciniak, medical team leader of the FDA’s cardiovascular and renal products division, said that both seemed “reasonable.”

But he added, “I would have preferred that the FDA decision was the same as the EMEA’s because the protection of patients under the FDA decision depends upon the accuracy of the informed consent disclosures and the effectiveness of the REMS.  

“The one part of the FDA announcement I do not like is the required ‘independent’ review of RECORD to be arranged for by GSK. ‘Independent’ and ‘by GSK’ (or any other sponsor on its own study) are mutually exclusive.”

Joshua Sharfstein, second in command at the FDA, said it would take several months to go through all of the administrative steps necessary to implement the risk evaluation and mitigation programme.


Cite this as: BMJ 2010;341:c5287