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It's unlikely that the FDA's decision to loosen some of the restrictions on the controversial type 2 diabetes drug rosiglitazone (Avandia) will have any impact on prescribing in the U.S., according to several experts contacted by MedPage Today.
Since the drug was approved in 1999, several newer classes of medications have come to market that clinicians are more likely to use instead, and the thiazolidinedione (TZD) class has been plagued by other side effects -- including bone fractures, heart failure, and bladder cancer -- that have pushed clinicians toward alternatives.
"The TZDs remain problematic and the recent 'clearing' of the sullied reputation of rosiglitazone with regard to CVD events is very unlikely to change our view of these drugs in general or rosiglitazone in particular," David Nathan, MD, director of the Diabetes Center at Massachusetts General Hospital, said in an email to MedPage Today.
"We used all of the TZDs sparingly, at most, owing to their known adverse effects on bone mass and fluid retention/CHF," he said. "When we (rarely) used TZDs, we would usually use pioglitazone (Actos) since it had a less atherogenic effect on lipid values. Of course, the concern regarding rosiglitazone eliminated almost all of its (limited) use."
But one area where the change may have an impact is with the outcome of several outstanding Avandia lawsuits, some experts said.
GlaxoSmithKline has already paid out hundreds of millions of dollars to settle Avandia lawsuits -- most notably, $460 million in 2010 and $229 million this past July -- and several are still outstanding, according to a company spokesperson, although she did not have an exact figure.
Significance of the RECORD Trial
At the center of the decision is a single randomized controlled trial, the RECORD trial, which the FDA relied heavily upon to make its decisions regarding the risks of rosiglitazone.
When it decided to place heavy restrictions on the drug in 2010, the agency also called for a readjudication of the results of RECORD, which was completed by Duke Clinical Research Institute and financially backed by GlaxoSmithKline.
Critics railed against the trial's open-label design and the fact that it was unblinded. They were also concerned that some of the adverse events had been incorrectly interpreted, with a bias in favor of rosiglitazone.
But the Duke analysis turned up similar results to the initial findings, and an FDA advisory committee voted this past June to recommend toning down some of the restrictions, given the validated reassessment.
That, however, wasn't to the satisfaction of many other parties with deep knowledge of the issue, including , of the Cleveland Clinic, whose 2007 meta-analysis was the spark that ignited the firestorm over the drug and ultimately led to its demise.
"The study does not meet regulatory standards," Nissen said in an email to MedPage Today. "You can't fix a fundamentally flawed trial through transparency."
, of Yale University, agreed: "Given no new information has emerged since the REMS except that Duke weighed in that RECORD was not rigged -- why make the change?" he said in an email. "RECORD is still a flawed study. And no new study has been introduced."
Krumholz added that the Avandia data "are still out of the public domain, so no independent analyses can be conducted."
On Twitter, he called for GlaxoSmithKline to release all patient-level data on rosiglitazone "and fund independent reviews; otherwise will we ever know the truth?"
Avandia was 'Murdered'
But some of Nissen's detractors say his 2007 meta-analysis that found an increased risk of heart attack with the drug effectively and unnecessarily 'murdered' it.
"The initial decision to add restrictions and a black box to Avandia was based upon inaccurate interpretation of incomplete data," , of Indiana University, said in an email to MedPage Today. "It essentially destroyed the market for the drug. No change in wording by the FDA will change that. ... It will not result in a reincarnation of a drug that was essentially murdered."
, of the University of California San Diego, said Nissen was driven in part by a political agenda and said a meta-analysis was "not a very scientific way to study an important research question and especially should not be the definitive answer to safety issues."
He said all of the attention played heavily into the FDA's decision to require cardiovascular safety outcomes studies for any new diabetes drugs -- which can run up costs into the $200 to $300 million range.
Indeed, the issue caught the attention of the which launched an investigation that found GlaxoSmithKline was aware of the possible cardiac risks associated with Avandia years before that evidence became public. It also revealed that a now-prominent -- but little-known at the time -- diabetes physician, , of the University of North Carolina at Chapel Hill, when he spoke out about the drug's risks.
The New Avandia Label
FDA spokesperson Morgan Liscinsky said rosiglitazone's risk evaluation and mitigation strategy (REMS) was loosened, not lifted completely. It will still include elements such as prescriber training and a "Dear Healthcare Provider" and a "Dear Professional Society" letter.
While it will no longer carry a boxed warning on risk of myocardial infarction, rosiglitazone will still carry its original boxed warning on heart failure, which it shares with the only other TZD available, pioglitazone.
Liscinsky noted that it's not uncommon for drugs to be fully or partially released from REMS, and .
Rosiglitazone is still off the market in Europe, and only about 3,000 patients in the U.S. continue to take the drug.