MONDAY, Feb. 22 (HealthDay News) -- The U.S. Food and Drug Administration on Monday said it was still reviewing documents that examine whether the blockbuster type 2 diabetes drug Avandia raises users' odds for heart attack and heart failure and should be removed from the market.
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In an an agency statement, health officials said they are looking at data from a large, long-term clinical study known as RECORD to see if there are possible heart risks with rosiglitazone (Avandia), although they are also reviewing the results of several observational studies on the cardiovascular safety of Avandia.
"These reviews are ongoing, and no new conclusions or recommendations about the use of rosiglitazone in the treatment of type 2 diabetes have been made at this time," the FDA statement said. "Once [the] FDA completes its review of the data from the RECORD study, the agency will present the totality of new and existing cardiovascular safety data on rosiglitazone at a public meeting in July 2010."
In the meantime, the agency said patients should still take Avandia unless their health-care professional tells them to stop.
On Saturday, The New York Times reported on documents from the U.S. Food and Drug Administration that found that if people now taking Avandia switched to a similar medication, Actos, about 500 heart attacks and 300 cases of heart failure would be eliminated each month. And in a report from the Institute for Safe Medication Practice, Avandia was linked to 304 deaths in the third quarter of 2009 alone, the highest for any prescribed drug in that time period, the Times reported.
In one of the FDA documents, dated October 2008, Drs. David Graham and Kate Gelperin -- drug safety officials at the agency -- agreed that "rosiglitazone should be removed from the market."
The reports, obtained early by the Times, are yet another chapter in Avandia's checkered history. The drug was once taken by millions worldwide, but that changed after a study released in early May of 2007 by the Cleveland Clinic suggested that Avandia carried cardiovascular risks. That study, which included more than 28,000 people, found that Avandia increased a user's odds of heart attack by 43% compared to those not taking the medicine.
At the time, Dr. Bruce M. Psaty of the University of Washington -- who also co-wrote an accompanying editorial in the New England Journal of Medicine -- urged the FDA to restrict access to Avandia and cited both the agency and the drug's maker, GlaxoSmithKline, for poor oversight.
"The primary problem here is that studies that were needed early on about the health benefits of this drug were never done," Psaty told HealthDay. "As a result of the failure of the sponsor to do long-term clinical trials to show health benefits, as a result of the failure of the FDA to insist on it, we have data that are weak."
Following on the Cleveland Clinic study, the FDA demanded "black box" warnings on labeling for both Avandia and Actos, warning of a potentially heightened risk for heart failure. However, other studies found no raised level of heart risk, and at the time the agency said it had not reached a definitive conclusion on the data.
In November of the same year, the FDA updated Avandia's labeling to include a caution regarding heart attack risk. At the time, Dr. Janet Woodcock, acting director of the FDA's Center for Drug Evaluation and Research, said that, "we are keeping Avandia on the market because we have concluded there isn't enough evidence to indicate that the risk of heart attack is higher for Avandia than other type 2 diabetes treatments."
The story got more complicated in 2008, as a number of studies emerged tying the use of Avandia to increased bone fracture risk.
Throughout 2009, more studies reiterating the drug's heart risks also came to light, including one published in the BMJ suggesting that Avandia's risk for heart failure seemed to outstrip those of its related rival, Actos.
By that point, "most clinicians [had] stopped using Avandia -- some will use Actos instead or go to another class completely," Dr. Carl J. Lavie, medical director of cardiac rehabilitation at the Ochsner Heart and Vascular Institute in New Orleans, told HealthDay at the time.
The emergence of the leaked documents on Saturday comes at a time when officials within the FDA seem to be at loggerheads over whether to ban Avandia or not, the Times reported. The newspaper said that some officials believe that safer alternatives exist, while others say the evidence on Avandia's safety is conflicted and the drug should remain available as a treatment option.
Trying to sort things out, in December of 2009 Woodcock asked officials at the FDA to convene another advisory committee to determine whether Avandia should remain on the market, with a decision expected this summer.
In the meantime, a bipartisan Senate investigation -- overseen by Sen. Max Baucus (D-Mont.) and Sen. Charles E. Grassley(R-Iowa) -- has pored over 250,00 internal documents from GlaxoSmithKline. The investigation has placed much of the blame for the Avandia debacle on the company, contending that it neglected to warn patients for years of the drug's dangers.
"G.S.K. executives attempted to intimidate independent physicians, focused on strategies to minimize or misrepresent findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that a competing drug might reduce cardiovascular risk," according to the Senate investigation report, which was slated for release Monday.
Speaking to the newspaper Friday night, agency commissioner Dr. Margaret Hamburg said that, "I await the recommendations of the advisory committee. Meanwhile, I am reviewing the inquiry made by Senators Baucus and Grassley and I am reaching out to ensure that I have a complete understanding and awareness of all of the data and issues involved."
In a statement released Saturday, GlaxoSmithKline said it "rejects the conclusions about the safety of Avandia (rosiglitazone)" as reported in that day's Times story.
"Contrary to the assertions in the story, and consistent with the FDA-approved labeling, the scientific evidence simply does not establish that Avandia increases ischemic cardiovascular risk or causes myocardial ischemic events," the company said. "In 2007, the FDA considered all the available scientific evidence on Avandia, including Dr. Graham's assertions of elevated heart attack risk and demands that the product be withdrawn. Based on the scientific evidence and a recommendation by an independent advisory committee of experts convened by the FDA, the agency has ruled that Avandia remain available to patients for the treatment of Type 2 diabetes."
In the wake of the controversy, GlaxoSmithKline had been directed by the FDA to conduct a trial comparing rates of heart attacks, strokes and heart-linked deaths among users of Avandia, Actos or a placebo. But according to internal documents accessed by the Times, Graham and Gelperin characterized the study, called TIDE, as "unethical and exploitive," with patients being given Avandia despite the fact that it appears to come with greater risks and no added benefit over Actos.
One of the Graham/Gelperin reports -- dated October 2008 -- concludes that, "Although the proposed TIDE trial is motivated by a desire for definitive answers regarding the cardiovascular safety of the drug rosiglitazone, the safety of the study itself cannot be assured and is not acceptable."
However, other FDA officials overruled those concerns and TIDE is still enrolling patients, with preliminary results expected by 2014. Responding to the criticism, GlaxoSmithKline noted Saturday that, "TIDE has been approved by an independent review board and appropriate safety boards that are responsible for assessing the safety of conducting the trial."
The ongoing controversy has dampened patients' and physicians' enthusiasm for Avandia. According to the Times, while sales of the drug topped $3.2 billion in 2006, those numbers plummeted soon after the first studies suggesting risk emerged a year later.
Still, "hundreds of thousands" of people still take Avandia, the Times noted. GlaxoSmithKline's patent on the drug expires in 2012.
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SOURCES; Feb. 22, 2010, statement, U.S. Food and Drug Administration; Carl J. Lavie, M.D., medical director, cardiac rehabilitation, and prevention director, Stress Testing Laboratory, Ochsner Heart and Vascular Institute, New Orleans; Bruce M. Psaty, M.D. Ph.D., University of Washington, Seattle; Feb. 20, 2010, news release, GlaxoSmithKline; Feb 20, 2010, The New York Times