June 5th, 2013

FDA Gives Avandia Another Look

FDA Gives Avandia Another Look
MedPage Today
Published: June 03, 2013

This is another "I TOLD YOU SO" as I have always said chemically it is probably the best oral antidiabetic drugs made for the older patient and did not have the risks wrongly placed on the drug.

A reassessment of the results of the RECORD trial by independent reviewers has turned up similar results to the initial report, possibly signaling new life for the embattled diabetes drug rosiglitazone (Avandia), according to FDA documents.

In briefing documents released ahead of a 2-day hearing on the re-adjudication of the results -- sanctioned by the FDA in 2010 -- reviewers from Duke University found similar results for overall mortality and cardiovascular mortality.

"Overall, the re-adjudication supports the previous observation that, in this trial, rosiglitazone was not associated with increased all-cause mortality or increased cardiovascular mortality," the FDA wrote in the review documents.

But critics -- namely Steve Nissen, MD, of the Cleveland Clinic, who sparked concerns about rosiglitazone in a 2007 New England Journal of Medicine meta-analysis that showed an increased risk of MI among patients on the drug -- have charged that the FDA is merely trying to wash its hands of culpability for its role in ongoing issues with the drug.

In an article in Forbes, Nissen charges that the FDA and drugmaker GlaxoSmithKline knew about the cardiovascular risks associated with the drug at least a year before his study was published.

"Since 2006, the [FDA's Center for Drug Evaluation and Research] CDER has expended considerable taxpayer dollars trying to absolve itself of responsibility for this inexplicable error in judgment that cost many lives," Nissen wrote.

The re-adjudication of RECORD results was commissioned by CDER director Janet Woodcock, MD, in September 2010 when the agency acknowledged "multiple and conflicting signals" of cardiovascular risk associated with rosiglitazone. The agency allowed the drug to stay on the market, but with severe restrictions including a risk evaluation and mitigation strategy (REMS).

European regulators, on the other hand, suspended the drug's marketing authorization in Europe at that time.

Woodcock asked GSK to hire an external organization to re-adjudicate the RECORD trial results, since it was the only large, randomized, long-term trial comparing the cardiovascular safety of rosiglitazone with other diabetes medications.

Interim results of the trial, reported just weeks after the Nissen meta-analysis, found a nonsignificant increase in the risk of MI with rosiglitazone, and numerically more deaths from heart failure, but it also found a nonsignificant reduction in risk of stroke and all-cause death with the drug.

Final results also showed no overall increased risk of cardiovascular morbidity or mortality, though the trial did show a twofold higher risk of heart failure, and an increased risk of fracture in women.

However, concerns arose about trial design, particularly its open-label nature and the choice of cardiovascular hospitalization as a primary endpoint -- casting doubt on the reliability of the results.

In its reassessment, the Duke Clinical Research Institute found highly similar results for overall mortality and cardiovascular mortality compared with the original RECORD results. There were also numerically more heart failure deaths for rosiglitazone patients, and no increased risk of death from MI -- as was seen in the initial trial.

In documents that it prepared for the hearing, GSK highlights the fact that the mortality and major adverse cardiovascular events (MACE) data are similar to those of the original trial.

"In the accepted hierarchy of evidence generation, the results of a randomized controlled trial is usually considered to take precedence over other forms of evidence, such as meta-analysis and observational studies," the company wrote. "Despite some limitations of trial design, including the open-label nature of the study, RECORD remains the only randomized trial of cardiovascular outcomes for rosiglitazone at this time."

"The confirmation of the RECORD results by the independent re-adjudication support a positive benefit-to-risk profile for rosiglitazone for the treatment of type 2 diabetes in appropriate patients," the company concluded.

At the upcoming hearing, FDA advisory committee members will be asked to vote on one of four outcomes for rosiglitazone: remove its REMS, continue its REMS without changes, modify the REMS, or withdraw the drug from the market.

Diabetes experts contacted by MedPage Today generally had a favorable view of the meeting.

"With a disease as widespread as diabetes and in an environment where we increasingly find treatment options limited, we rely on the FDA to monitor the use of medications and their unintended adverse effects," David Lam, MD, an endocrinologist at the Icahn School of Medicine at Mount Sinai, in New York City, said in an email to MedPage Today. "This allows us to treat patients in the safest manner possible, all in an unbiased manner."

Ronald Kahn, MD, chief academic officer of the Joslin Diabetes Center in Boston, called the move a "smart decision by FDA."

"I think the evidence which was used to create the current guidelines is not that strong and the thiazolidinediones are very useful drugs for type 2 diabetes that still are widely used elsewhere in the world," Kahn told MedPage Today. "It seems to me that they have gone further than necessary and some reconsideration is appropriate."