FDA Opens Door to Wider Avandia Prescribing

The FDA has loosened restrictions on the diabetes drug rosiglitazone (Avandia) - under fire since 2007 because of potential cardiovascular risks - and will allow drugmaker GlaxoSmithKline to drop the TIDE trial comparing rosiglitazone to pioglitazone (Actos), the only other thiazolidinedione available.

In a press release issued Monday, the agency cited a re-examination of the RECORD trial as the primary reason for scaling back the prescribing limits on the drug, noting it found no increased risk of a composite of cardiovascular death, MI, or stroke with rosiglitazone.

“Given these new results, our level of concern is considerably reduced; thus, we are requiring the removal of certain prescribing restrictions,” Janet Woodcock, MD, director of the FDA’s center for drug evaluation and research (CDER), said in a statement.

Steve Nissen, MD, of the Cleveland Clinic, whose 2007 meta-analysis found rosiglitazone was associated with a greater risk of heart attack, called the FDA decision inappropriate.

“The reasoning around the lifting of these restrictions is faulty,” Nissen told MedPage Today. “It makes no regulatory sense to reanalyze a previously unblinded clinical trial that was poorly designed in the first place.”

RECORD is the only large randomized outcomes trial of rosiglitazone, but experts questioned its methodology. So when it initiated restrictions on the drug in 2010, the FDA also called for a re-adjudication of RECORD data, which was completed by Duke Clinical Research Institute.

Last June, an FDA advisory committee examined the Duke analysis and concluded that the restrictions could be lifted. But critics maintained that the data were flawed.

“Everybody knew which patients got Avandia and which got the comparator,” Nissen said in an interview with MedPage Today at the time. “Once that happened, the integrity of the trial was destroyed and it can never be resurrected.”

He also noted that one of the FDA’s own internal reviewers found an increased risk of heart attack among patients on the drug.

In a statement, the FDA said the reanalyzed data from the RECORD trial “do not confirm the signal of increased risk of heart attacks that was found in a meta-analysis of clinical trials first reported in 2007.”

The move means the drug will no longer be limited to certain patients, as changes will be made to the drug’s risk evaluation and mitigation (REMS) program. There will also be labeling changes, including a modification to the information about cardiovascular safety, the agency said.

And GlaxoSmithKline will be allowed to drop the TIDE trial, which was already struggling with enrollment issues.

The drug will be indicated as an adjunct to diet and exercise for patients with type 2 diabetes, and will be available through retail and mail-order pharmacies.

It remains to be seen whether clinicians will be inclined to start prescribing the drug again.

“The totality of evidence does not support the safety of this drug,” Nissen told MedPage Today. “I do not think physicians will start using it again.”

Ronald Tamler, MD, director of the Mount Sinai Diabetes Center, said the decision is “irrelevant in clinical practice.”

“Patients have been reading about increased risk of cardiovascular events with rosiglitazone since 2007 and will not abandon their concerns overnight, despite the FDA decision,” Tamler told MedPage Today. “Moreover, a medication with similar properties, pioglitazone, is available as a generic drug at a much lower cost.”

Fernando Ovalle, MD, of the University of Alabama at Birmingham, said that while it might be the right decision at this point, “it may be too late to rescue this class of drugs.”

“Now that other drugs have come to market, physicians have found other ways to control hypoglycemia, and they probably will remain skeptical of the drug just because the question was raised, and once that happens, it’s hard to clear the name,” Ovalle said.

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By Kristina Fiore, Staff Writer, MedPage Today