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Study Test of Rosiglitazone Drug for Diabetes in Jeopardy
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NY Times
By STEPHANIE SAUL
Published: May 26, 2007
A large clinical study meant to test the heart safety of the diabetes treatment Avandia may be in jeopardy as a result of recent reports of the drug's risks, according to an executive at its maker, GlaxoSmithKline.
Dr. Ronald L. Krall, the medical director for GlaxoSmithKline, said in a telephone interview yesterday that some of the 4,450 patients enrolled in the drug trial, called Record, have dropped out this week because of safety concerns about Avandia.
Dr. Krall said he did not yet know how many patients have withdrawn, but said Glaxo was now worried about whether it could complete the drug trial, which has been scheduled to run through next year. The company has been counting on a successful outcome from the study to dispel widespread concerns that Avandia carries a higher risk of heart attacks than other diabetes drugs.
Now, though, the independent research committees overseeing the study "are concerned about the ability of the study to continue" and are "considering what to do to prevent people from dropping out of the trial," Dr. Krall said.
The safety concerns were ignited by an analysis published Monday in The New England Journal of Medicine suggesting that Avandia, used to treat Type 2 diabetes, carries an increased risk of heart attack, estimated at 43 percent, compared with other diabetes drugs or placebos.
In response to the medical journal article, the Food and Drug Administration, issued a safety alert for Avandia and advised patients who take it to consult their doctors.
Avandia, which was approved by the F.D.A. in 1999, has been used by an estimated seven million people, six million of them in the United States.
Yesterday, the F.D.A. said its own recent analysis of more than 40 clinical studies of Avandia seemed to confirm the findings in The New England Journal of Medicine's study, whose lead author was the influential Cleveland Clinic heart specialist Steven E. Nissen.
But an agency spokeswoman yesterday urged caution in interpreting those results.
"Dr. Nissen's meta-analysis and the F.D.A.'s meta-analysis both arrived at a similar figure of 40 percent" the F.D.A. spokeswoman, Julie Zawisa, wrote in an e-mail message. "But this alone, is not conclusive of anything. What it does mean is that we need to try to reconcile the meta-analysis finding with clinical trial data that DO NOT show this increased risk."
People with Type 2 diabetes are already at risk of heart attacks, facing a 20.2 percent chance of such an attack over seven years. One of the main reasons for controlling blood sugar in diabetic patients is to manage that risk.
But if Dr. Nissen's analysis is an accurate reflection of Avandia's increased risk, it appears the drug would do more cardiovascular harm than good. Diabetics taking Avandia would run a 28.9 percent chance of heart attack over the same seven-year period, according to his analysis.
GlaxoSmithKline's own meta-analysis, submitted to the F.D.A. last August, showed a slightly lower 31 percent increased risk of heart attack.
A meta-analysis, which involves comparing the results of disparate clinical trials, is not considered as definitive as a uniform, controlled patient study of the sort GlaxoSmithKline has been counting on with its Record trial. Both GlaxoSmithKline and the F.D.A. have said that the meta-analyses indicating a heart risk with Avandia are contradicted by an interim look at Record, as well as data from an analysis of more than 20,000 patients enrolled in a UnitedHealthcare plan.
But neither GlaxoSmithKline nor the F.D.A. has released results from that interim assessment of Record, which was conducted within the last month.
The F.D.A. has received heavy criticism this week from Capitol Hill, where members of Congress have suggested that Avandia is shaping up as another Vioxx - a painkiller that became a bestseller, despite periodic questions about its safety, before being taken off the market in 2004 when its heart risks became irrefutable.
The F.D.A. plans to ask an advisory panel to review the Avandia data. Such panels, if they find safety risks with a drug, can recommend that the agency require a stronger warning label or ban the drug altogether.
Avandia is Glaxo's second-largest selling drug, with more than $3 billion in sales last year worldwide. The company's American depository receipts fell nearly $5 this week on news of safety concerns about the drug. The shares closed yesterday at $52.43.
GlaxoSmithKline has urged regulators and the public not to rush to judgment based on the New England Journal of Medicine article and has said that the Record trial, which began in 2000, would be a more reliable way to estimate the drug's cardiovascular risks.
In that study, half of the 4,450 patients are being treated with Avandia in combination with another diabetes drug, while the others are being treated with two other drugs.
The trial is designed to determine whether patients taking Avandia are more likely to have a range of cardiovascular problems, including heart attack and stroke.
From Reuters
GlaxoSmithKline spokeswoman Mary Anne Rhyne said Grassley's use of the estimate was ``irresponsible.''
``They are extrapolations of extrapolations, and do not reflect reality. If these numbers were true, we would have seen them clearly'' in long-term studies and databases of real-world use, she said.
Glaxo has said Avandia's cardiovascular safety is similar to other oral diabetic drugs, and the benefits of treatment outweigh the risks.
The FDA is continuing to review data on Avandia and plans to ask an advisory panel of outside experts for input.
The Union of Concerned Scientists and several consumer groups wrote the FDA on Friday urging officials to chose advisers with no financial ties to Glaxo for the past 36 months.
``By staffing the Avandia advisory committee with scientists from diverse specialties who are non-conflicted, you will send a message that the FDA cares about avoiding conflicts of interest and evaluating drugs on the basis of unbiased scientific findings,'' the letter said.
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