Pull Controversial Drug from Market, Say Some FDA Staff

Agency reviewers say GlaxoSmithKline mishandled data.

ByEMILY WALKER and CRYSTAL PHEND<br/><a href="http://www.medpagetoday.com/" target="external">MedPage Today</a> Writers
July 09, 2010, 12:34 PM

July 9, 2010 -- Avandia should be pulled from the market because of the "serious" cardiovascular risk the diabetes drug poses, which exceeds that of competitor Actos, according to some FDA staff reviewers.

Avandia is no more effective at improving glycemic control in type 2 diabetes compared with Actos, and provides no known unique health benefits. While both drugs increase the risk of congestive heart failure, Avandia's effect on CHF is "substantially greater," FDA reviewers wrote in a massive briefing document released Friday.

"Our review of the literature finds no evidence of a unique or meaningful health benefit from rosiglitazone [Avandia] that is not also provided by pioglitazone [Actos] and there is substantial evidence that rosiglitazone increases cardiovascular risk compared with pioglitazone," the reviewers said.

A joint panel of outside medical experts will meet July 13 and 14 to recommend, among other things, whether Avandia should be pulled from the market.

The FDA does not have to follow the advice of its advisory committees, but it usually does.

This will be the second time an advisory panel was tasked with guiding the FDA on what to do about Avandia.

In 2007, a panel voted 20-3 that Avandia increased cardiovascular risk, but then 22-1 that the benefits of Avandia outweigh the risks.

The FDA reviewers blasted the logic in the 2007 decision and said the panel failed to prove what, exactly, the benefits of Avandia were. Since then, the benefits of the drug remain unclarified.

"In the three years since that advisory committee meeting, the Office of New Drugs has not answered the question of what are the unique health benefits of rosiglitazone [Avandia] that have justified its continued marketing," the reviewers wrote. "In our opinion, this approach is inconsistent with public health policy that places patient safety first."


The briefing document included an analysis of the controversial RECORD trial, which GlaxoSmithKline has leaned on as one of its main defenses on the cardiovascular safety of Avandia.

The FDA reviewers accuse GlaxoSmithKline of manipulating data, and there's even a section of the report called "Extreme mishandling of events."

"Our review of RECORD leads us to conclude that its design and execution were biased in a manner that consistently favored not finding a cardiovascular effect if it was present," they wrote in the document. "In our view, it provides no credible evidence of rosiglitazone's cardiovascular safety."

FDA Staff Blast Post-Marketing Study

Following the 2007 FDA advisory committee meeting, the FDA required GlaxoSmithKline to conduct a head-to-head outcomes trial comparing Avandia to Actos. That trial -- called TIDE -- has been hampered by sluggish enrollment of patients, possibly because of safety concerns.

The FDA reviewers called TIDE "unethical and exploitative," arguing that GlaxoSmithKline never proved Avandia is equivalent to Actos.

"In our view, the TIDE trial is unethical because it subjects human beings to unnecessary risks without any possibility of a meaningful, unique health benefit from rosiglitazone."

The reviewers added the informed consent document for TIDE was misleading.

"Given the weight of evidence regarding cardiovascular risks with rosiglitazone, we believe that TIDE is an unethical study and that it was unethical before it was started," the reviewers wrote.

At next week's meeting, the Endocrinologic and Metabolic Drugs and the Drug Safety and Risk Management Advisory Committees might vote to halt the TIDE study, or else modify it in some way.

In the company's briefing documents, GlaxoSmithKline said it remains committed to finishing the TIDE trial.

The FDA hopes to avoid some of the sticky ethical questions washed up by the TIDE trial. It asked the Institute of Medicine (IOM) to come up with a framework for obtaining informed consent when comparing two drugs, one of which is believed to carry an increased risk.

On Friday, the IOM published a number of recommendations for the FDA when planning a postmarketing, randomized safety trial, including that the agency only order such trials when the a responsible policy decision cannot be made without the new evidence, and that the informed consent process continues throughout the trial to include relevant findings that might influence a "participant's willingness to accept the risks associated with the trial."

Panelists at next week's meeting likely will heavily weigh an analysis based on data from the Centers for Medicare and Medicaid Services that was published online two weeks ago.

That observational retrospective cohort study of 227,571 Medicare patients age 65 and older from July 2006 to June 2009 found rosiglitazone was associated with a significantly elevated risk of all other endpoints including stroke, heart failure, death and a composite of all four endpoints.

A spokeswoman for GlaxoSmithKline said the company stands behind the safety and efficacy of rosiglitazone.

"Avandia has a positive benefit-risk profile. When you look at the science and the totality of the data -- especially the most rigorous scientific studies -- Avandia has been shown to be a safe and effective diabetes medicine when used appropriately according to its labeling," said Mary Anne Rhyne, director of U.S. media relations for GlaxoSmithKline. "Avandia is an important medicine for the treatment of type 2 diabetes [patients], who often need two or three medicines to hep maintain their blood sugar levels."

Following the United State's lead, Europe's version of the FDA also will launch a review into rosiglitazone. The European Medicines Agency announced Friday its Committee for Medicinal Products for Human will review the safety of rosiglitazone when it meets July 19 to July 22. The committee may decide to suspend marketing for rosiglitazone or remove it from the market.

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