Friday, June 08, 2007

FDA Seeks Strictest Warning for Diabetes Drugs

(HealthDay News) -- The U.S. Food and Drug Administration has asked that two controversial type 2 diabetes drugs carry a "black box" warning on the potentially heightened risk of congestive heart failure in some patients.

In prepared testimony before a Congressional committee that was convened Wednesday following a published report on the cardiac dangers of Avandia, FDA Commissioner Dr. Andrew von Eschenbach said the agency had asked that Avandia, made by GlaxoSmithKline, and Actos, made by Takeda Pharmaceuticals, carry the more prominent warning because "despite existing warnings, these drugs were being prescribed to patients with significant heart failure."

According to von Eschenbach's testimony, the request for the warning -- the strictest one possible -- was issued to both companies May 23, two days after publication of a study in the New England Journal of Medicine that found Avandia (rosiglitazone) increased the risk of heart attack by as much as 43 percent.

But the decision to request the heightened warning wasn't made public until von Eschenbach's appearance before the House Committee on Oversight and Government Reform, which is reviewing the FDA's role in the Avandia controversy.

The May 21 Avandia study was led by Dr. Steven Nissen, a Cleveland Clinic cardiologist who was among the first to warn about the heart risks posed by the now-banned arthritis drug Vioxx.

Following the release of the NEJM study on Avandia, the FDA issued a safety alert, but stopped short of asking for a stronger warning label, saying more analysis was needed.

"The Food and Drug Administration is aware of a potential safety issue related to rosiglitazone," Dr. Robert J. Meyer, director of FDA's Office of Drug Evaluation II, said during a May 21 teleconference. But, he added, "At this point, we have not reached a definitive conclusion on the data. We don't feel there is consistent enough data to make a decision from a regulatory standpoint. We are not ready to make an action."

On Tuesday, results of a British study, funded by GlaxoSmithKline, were released and showed no significant increased risk for heart attack or death from heart disease associated with Avandia.

The study, which was released early by the New England Journal of Medicine to coincide with the House hearing, also found no increased risk for cardiac events among diabetics taking Avandia and those not taking it.

"Overall, there was no significant difference between those on rosiglitazone and those not on rosiglitazone," study co-author Stuart J. Pocock, of the London School of Hygiene & Tropical Medicine, said Tuesday. "The concern about cardiovascular death, I think, we have clearly deflated. The concern on heart attack -- our data are modifying that concern, but it's still inconclusive."

But one expert pointed out Tuesday that the original goal of the new study was to show a benefit of rosiglitazone in preventing heart disease.

"When you get a finding that is against the hypothesis, it makes me sit up and take note," said Dr. David M. Nathan, of Massachusetts General Hospital, and author of an accompanying editorial in the journal. "None of the data is reassuring. You don't give the drug the benefit of the doubt -- you give safety the benefit of the doubt."

And another expert, Dr. Bruce M. Psaty, who wrote a second editorial in the journal, said Wednesday of the Avandia findings, "I combined the results from this study with the study by Nissen, and there was still a 33 percent increase in risk of a heart attack."

Psaty, of the University of Washington in Seattle, also testified at Wednesday's House hearing.

Afterwards, he said that the FDA needs to have a "black box" warning about heart attack risk, not just heart failure risk, which he said has been known for a long time.

"It sounds like the FDA has had this data on heart attack risk since 2005," he said. "In Europe, the label was revised back in September."

Psaty added that the FDA needs to mandate post-marketing studies to uncover safety problems.

"You need a drug safety system that is complementary to the rapid approval system that we have in place," Psaty said. "What we are seeing with Avandia and Vioxx is the fallout of the system where you sped up approval and did not do anything to test safety."

Meanwhile, the FDA announced Wednesday that an advisory panel will meet on July 30 to weigh the cardiovascular risks of the class of diabetes drugs that includes Avandia.

In response to that announcement, the Cleveland Clinic's Nissen said in a prepared statement: "We published our meta-analysis on the cardiovascular safety of Avandia because we felt it was our obligation to alert the medical and patient community to a potentially serious drug safety problem and urged comprehensive evaluations to clarify the risks."

He added, "We encourage a lively scientific debate about these issues and look forward to the results of the FDA advisory board hearings in July. During today's congressional hearings, we learned that meta-analyses conducted by the FDA and GlaxoSmithKline showed similar results to our findings. We would like to see those analyses published in peer-reviewed journals so that the totality of information on the cardiovascular safety of Avandia is available to doctors and patients."

Also Wednesday, Takeda Pharmaceuticals announced that it would add the boxed warning requested by the FDA to prescription labels for Actos (pioglitazone).

Dr. Robert Spanheimer, the company's senior medical director for diabetes and metabolism, said in a prepared statement, "Takeda remains confident in the safety and efficacy of Actos when used according to its label, and with this revision, we can heighten patient and physician awareness of an already known, but serious side effect."

On Tuesday, GlaxoSmithKline had issued a prepared statement saying that the British study should reassure type 2 diabetes patients that Avandia was safe.

"They [the findings] add to the weight of evidence, from both previously published long-term clinical trials and other studies, that the overall ischemic cardiovascular safety profile of Avandia is comparable to the traditional anti-diabetes treatments. Patients and physicians should find these data reassuring," said Moncef Slaoui, the company's chairman for research and development.

In response to the growing controversy over Avandia's safety profile, the American Diabetes Association on Wednesday issued an advisory statement.

"As a result of all of this information, the American Diabetes Association strongly encourages patients taking this medication to consult with their physician as to its benefits and risks," the statement read. "The Association also reminds patients, however, that they should not stop taking any prescribed medications without first discussing the issue with their health-care provider."

More information
There's much more on type 2 diabetes at the American Diabetes Association.

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