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Analysis: Allegations fuel Avandia fire

By STEVE MITCHELL, UPI Senior Medical Correspondent

WASHINGTON, May 23 (UPI) -- The controversy over whether GlaxoSmithKline's diabetes drug Avandia increases the risk of heart problems heated up Wednesday, with allegations the Food and Drug Administration was concerned about the danger years ago, but never took any action.

Public Citizen released an internal FDA memo from 2002 citing 25 cases of heart failure associated with Avandia, and the Los Angeles Times reported that Sen. Charles Grassley, R-Iowa, said he was aware of information indicating the agency's safety office had once recommended a black-box warning for the drug but was overruled.

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Sidney Wolfe, director of Public Citizen's Health Research Group, likened the FDA's handling of Avandia to the debacles involving Vioxx and Rezulin -- both pulled off the market due to safety reasons -- and said it highlights much larger problems at the agency.

"These people (at the FDA's Center for Drug Evaluation and Research) just are not as willing as they should be or would be if they weren't funded so heavily by the industry to act on evidence-based recommendations," Wolfe told United Press International.

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He called the Avandia situation another example of why the FDA's division for evaluating postmarketing safety of drugs should be removed from under the auspices of the agency's Center for Drug Evaluation and Research and made an independent branch in the agency.

The agency memo released by Public Citizen also cited the heart risk of Takeda's Actos and recommends the reports of heart failure be included on labeling.

In the memo, FDA reviewers analyzed 47 cases of heart failure requiring hospitalization -- 22 occurred in patients taking Actos and 25 in those taking Avandia.

"Data from this case series provides evidence that (thiazolidinediones, the class of drugs that includes Actos and Avandia) may be associated with (congestive heart failure) to an extent not clearly defined in the product labels," the reviewers concluded.

They go on to note that the cases do not show conclusively the drugs caused the heart failure, but they say labeling should mention the condition has occurred in diabetic patients taking the medications.

Although Avandia's labeling mentions the risk of heart failure has been detected in clinical studies, Wolfe said the FDA failed to heed the advice of its reviewers and require the listing of the postmarketing reports -- which now number 415.

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However, the labeling does mention, albeit in vague terms, that heart failure has been observed in patients taking the class of drugs that includes Avandia: "In postmarketing experience in patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported."

The controversy over Avandia erupted earlier this week when the New England Journal of Medicine issued a meta-review of dozens of studies that found a significant increase in heart attack and heart death in patients taking the drug.

The FDA issued a safety alert in response to the study but said it was still analyzing all the available data about Avandia before reaching a decision about the drug's heart risk. The agency also plans to have an advisory committee discuss the issue.

Both Wolfe and Cleveland Clinic cardiologist Steven Nissen, the author of the New England Journal of Medicine article, thought the FDA was dragging its feet and not fully realizing the gravity of the matter.

"Some of the statements made by the FDA were obscene," Wolfe said, referring to the agency's intention to study the issue further. "They've had the Glaxo data almost for a year and the other data are from their own database," he said, referring to a meta-analysis GSK submitted to the FDA that also found an increased risk of heart attack and heart death in patients taking Avandia.

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Nissen said it took him only six days to do his analysis and submit the findings for publication to the New England Journal of Medicine. He noted the FDA has had access to the same data for several months, if not longer.

"I literally realized it was my responsibility to move as fast as I could to get the information into press," Nissen told UPI.

He declined to say how he thought the FDA should address Avandia's potential heart risk but said the agency should act as soon as possible. "What I don't want them to do is defer this to an advisory committee months from now," he said.

GSK has come out swinging at Nissen's findings, faulting the limitations of a meta-review and saying its own trials have not found a significant heart risk from Avandia. But the company's own meta-analysis of the same data arrived at similar conclusions: a 30 percent to 40 percent increase in heart attack and other heart-related adverse events.

Jean-Pierre Garnier, GSK's chief executive officer, also has addressed the issue, assuring shareholders at the annual meeting in London Wednesday that Avandia was a safe drug.

Nissen acknowledged his study had limitations and that the best way to determine the heart risk would be a large trial designed specifically to examine the issue.

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But he added, "The magnitude of the effect we saw is sufficiently disturbing that it seems very unlikely to me that effect is going to go away."

Nissen also said GSK's trials were too small individually to answer the question. "What you're getting here is a lot of spin," he said. "I have no ax to grind here, but I do think there's a very important public health issue."

Takeda spokeswoman Jocelyn Gerst told UPI the heart-failure risk was already known with this class of drugs and that Actos has been shown to decrease the risk of heart attacks.

A study called PROactive "showed Actos on top of standard of care reduced the risk of heart attacks by 28 percent," Gerst said.

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