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FDA Advisory Panel Rejects Advice To Pull Avandia

July 31, 2007

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Despite the recommendation of an Food and Drug Administration safety scientist and Public Citizen experts, an FDA advisory panel says the diabetes drug Avandia should remain on the market.

The FDA's David Graham told FDA advisors Monday the drug appears to increase risks of a heart attack. The advice was contained in a slide, which was part of a presentation made to the advisory group but released in advance of the meeting.

Dr. Sidney Wolfe, director of the Health Research Group at Public Citizen, detailed pre-approval and post-approval evidence of cardiac toxicity, liver toxicity and anemia. Wolfe also discussed post-approval evidence of increased bone fractures in women and damage to patients' vision associated with the drug.

"Does the overall risk-benefit profile of Avandia support its continued marketing in the United States?" said Wolfe. "The answer is clearly no."

Adverse Reactions

According to Wolfe's testimony, in FDA adverse reaction reports filed since marketing began for the drug in 1999 through the end of last year, there was a 15.2 times higher adjusted rate of heart failure reported with Avandia than for the older diabetes drug Glucotrol. The adjusted rate of liver toxicity with Avandia was 9.5 times higher, and 14.8 times higher for liver failure.

In addition, the adjusted rate of post-approval adverse reaction reports for anemia in patients was 13.3 times higher for Avandia than with Glucotrol. In patients already damaged by heart failure or other cardiac risks associated with the drug, the addition of anemia could significantly worsen their clinical condition, Wolfe warned.

Wolfe also cited in his testimony a recently completed study finding statistically significant increases in bone fractures in women using Avandia compared to those using another diabetes drug.

After listening to Graham’s presentation, the advisory panel agreed there may be heart risks associated with the drug, but voted to reject his advice. Several members did call for a stronger warning label.

43% Higher Risk

Graham cited research to make his argument that there is no evidence of major health benefits from taking the drug, and that leaving it on the market may “cost thousands of lives.” The study in the New England Journal of Medicine linked Avandia with a 43 percent higher risk of heart attacks.

Earlier, government safety scientists advised the FDA that Avandia shouldn't be used in combination with insulin or by patients with heart disease.

The American Association of Clinical Endocrinologists issued a statement in support of the advisory panel recommendation, saying it agreed Avandia should stay on the market, for now.

“Physicians can continue to treat persons with diabetes who are well-controlled with Avandia, knowing that it has been shown useful and effective in controlling glucose, a crucial step to preventing diabetes complications,” the group said in a statement.

“AACE will continue to support the development of approaches to manage the issues of weight gain, of fluid retention, and of reduced bone mass in diabetic patients receiving both Avandia and Takeda’s pioglitazone (Actos), to optimize clinical decision-making in the appropriate use of these important glucose-lowering medicines.”

Vision Impairment

Wolfe said that vision impairment, a major complication of diabetes, is also made worse by Avandia. A mechanism related to heart failure and fluid accumulation has produced macular edema - a swelling in the retina - in many patients, causing usually reversible damage to vision. The adjusted reporting rate for macular edema was 35.3 times higher for Avandia than for Glucotrol.

"There is no evidence of any uniquely beneficial clinical outcome for Avandia and growing evidence of unique risks in multiple organ systems," concluded Wolfe. "If Avandia were up for approval today, based on what is now known, it would be summarily rejected. There should not be a double standard for removing it from the market."

Because of the dangers associated with the drug that are not present in older, safer diabetes medications, Public Citizen is preparing a petition to the FDA to remove Avandia from the market.

Approved in 1999

Avandia was approved in 1999 for treatment of type 2 diabetes, a serious and life-threatening disease that affects about 18 to 20 million Americans. Diabetes is a leading cause of coronary heart disease, blindness, kidney failure and limb amputation.

Since the drug was approved, FDA said it has been monitoring several heart-related adverse events based on signals seen in previous controlled clinical trials of Avandia alone and in combination with other drugs, and from postmarketing reports.

The agency updated the product's labeling on several occasions to reflect these new data, most recently in 2006.

The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia. This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure.

David Graham, a safety scientist with the Food and Drug Administration, told FDA advisors Monday the drug appears to increase risks of a heart attack.

The advice was contained in a slide, which was part of a presentation made to the advisory group but released in advance of the meeting.

Graham cited research to make his argument that there is no evidence of major health benefits from taking the drug, and that leaving it on the market may “cost thousands of lives.” The study in the New England Journal of Medicine linked Avandia with a 43 percent higher risk of heart attacks.

Earlier, government safety scientists advised the FDA that Avandia shouldn't be used in combination with insulin or by patients with heart disease.

GlaxoSmithKlein, the maker of Avandia, disputed Graham’s findings. The company said many studies have already been conducted, involving thousands of subjects, and that “there is no consistent or systematic evidence that Avandia increases the risk of heart attacks or death from cardiovascular disease compared to other drugs.

Avandia was approved in 1999 for treatment of type 2 diabetes, a serious and life threatening disease that affects about 18 to 20 million Americans. Diabetes is a leading cause of coronary heart disease, blindness, kidney failure and limb amputation.

Since the drug was approved, FDA said it has been monitoring several heart-related adverse events based on signals seen in previous controlled clinical trials of Avandia alone and in combination with other drugs, and from postmarketing reports.

The agency updated the product's labeling on several occasions to reflect these new data, most recently in 2006.

The most recent labeling change for Avandia also included a new warning about a potential increase in heart attacks and heart-related chest pain in some individuals using Avandia. This new warning was based on the result of a controlled clinical trial in patients with existing congestive heart failure.

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