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FDA Panel Votes to Change Tight Restrictions on Diabetes Drug Avandia

Controversial decision comes after a second look at major data review focused on heart risks

By Dennis Thompson
HealthDay Reporter

THURSDAY, June 6 (HealthDay News) -- An expert advisory panel to the U.S. Food and Drug Administration voted narrowly Thursday to recommend changing tough safety restrictions on the diabetes drug Avandia, which was all but banned nearly two years ago because of reported links to heart problems.

The panel's decision came after a review of data that suggested the medication might not be as harmful as once thought.

However, because of initial concerns over cardiovascular safety, Avandia had been taken off drugstore shelves and its use restricted to patients who first signed a waiver saying they understood the possible risks. The drug was also dispensed only through specially registered pharmacies.

But the new recommendation might change all that. Thirteen members of the 26-person panel voted to alter the safety restrictions, the Associated Press reported, while seven voted to remove the restrictions altogether. Five panelists voted to keep the restrictions in place, while one panelist voted to withdraw Avandia from the marketplace.

The exact nature of any changes to current restrictions are yet to be decided. The FDA is not obligated to follow its advisory panels' decisions, but it usually does.

The panelists spent the past two days reconsidering evidence from an independent review by Duke University researchers of Avandia's original clinical trial, called RECORD. That review did uncover some previously unreported cases of heart complications and deaths, but the Duke team concluded that those cases did not significantly raise the overall risk of heart disease.

"I'm considerably reassured, in light of the reanalysis, that the magnitude of risk we're talking about here is not very great," Dr. Dale Hammerschmidt, of the University of Minnesota, who voted on Thursday to modify the safety limits, told the AP.

The drug's maker, GlaxoSmithKline, which had funded the Duke review, said it was satisfied with the panel's decision.

"We appreciate the committee's thorough examination of the RECORD results and will continue to work with the FDA as it considers the recommendation of the committee," the company's chief medical officer, Dr. James Shannon, said in a statement. "We continue to believe that Avandia is a safe and effective treatment option for type 2 diabetes when used for the appropriate patient and in accordance with labeling."

Not everyone is likely to be so pleased. The FDA's reconsideration of Avandia's safety has prompted stinging criticism from the drug's detractors, who say the agency is trying to save face following a very public embarrassment over the drug.

"This is a drug that has essentially been off the market in almost the entire world for the last three years. It has been banned in most countries, and is available in the United States under such strict requirements that only 3,000 patients now take it," said Dr. Steven Nissen, the Cleveland Clinic cardiologist who first led the charge against Avandia. "It's really about the FDA wanting to clean up its image, not about whether the drug is actually safe or unsafe."

But the FDA defended its decision to review the Duke re-analysis of the original trial.

"Given the public interest in Avandia, the extensive history of the product and the continued uncertainty of risk, the FDA is holding the advisory committee meeting to have a transparent, public discussion of the results of the RECORD readjudication," FDA spokesperson Morgan Liscinsky said.

Avandia quickly became a blockbuster diabetes drug following its release in 1999, with sales topping $3 billion in 2006.

But in 2007, Nissen published a study showing that Avandia raised the risk of heart attack by more than 40 percent. The outcry that followed led to Senate hearings in which the FDA's drug approval process came under intense scrutiny.

An FDA analysis of more than 50 studies of Avandia found that the drug was linked to an increased risk of heart problems. One study tied Avandia use to more than 47,000 cases of heart attack, stroke or heart failure during a 10-year period, even though the company-funded RECORD trial had not found an increased risk of cardiovascular trouble.

The FDA ended up pulling Avandia from pharmacy shelves in November of 2011, placing severe restrictions on the drug that limited its use to extremely ill diabetics. Patients wanting to take the medication now must enroll in a special program to qualify for its use.

Critics called this week's meetings a waste of taxpayer dollars, arguing that so many concerns have been raised about Avandia's safety that a green light now from the FDA would be meaningless.

"It's not an issue of any importance to the medical community," Nissen said. "It's all about the FDA. If the FDA is allowed to whitewash the Avandia affair, it makes it less likely the right thing will be done when issues like this come up in the future," he added.

"Unfortunately, the public is caught in the crossfire," he continued. "The last thing we want to do is promote the use of an agent that is not helpful and is almost certainly harmful in the majority of the people who take it."

Nissen and other critics noted that the Duke review was funded by GlaxoSmithKline and have questioned the independence of the follow-up research.

A panel of FDA officials had vouched for the Duke report, however, and argue that its findings deserve scrutiny in a public forum.

"The FDA strongly believes that regulatory decisions should be based on strong scientific evidence. If such evidence becomes available to revisit previous regulatory decisions, it is important for the FDA to consider this evidence in a transparent process," Liscinsky said. "The FDA is critically evaluating the RECORD readjudication. Once the advisory committee meeting has been held and review is complete, the FDA will determine if the results of the readjudication in the context of all the pertinent available data affect the agency's assessment of the risk-benefit information for rosiglitazone [Avandia]."

Dr. George King, director of research for the Joslin Diabetes Center and a professor of medicine at Harvard Medical School, said Avandia use needs to be restricted but has no problem with the FDA taking a look at the new evidence.

"A reanalysis is always good," King said. "Why spend all that money to do the study if you're not going to consider the data, right?"

King noted that Avandia and other drugs in its class, called thiazolidinediones, occupy a unique place in diabetes treatment. They decrease insulin resistance in the body by binding to receptors in fat cells and making those cells more responsive to insulin.

"We don't have any other diabetic medications that can actually improve insulin resistance," he said. "The others either promote more insulin production from the pancreas, make you urinate out more glucose or help your liver handle glucose better."

On the other hand, thiazolidinediones also cause problems with fluid retention. "In diabetic patients who are older, almost all of them have some kind of cardiovascular problem," King noted. "If you retain fluid, you are going to have increased risk for cardiovascular problems and mortality."

Both sides in the debate have a point, King concluded.

"From my view of it, it does have a niche for use, but the restrictions have to be there," he said. "The people who think it is absolutely safe are absolutely not right, but others who are focused on finding fault with it are overlooking some benefits."

More information

For more on the latest look at Avandia, go to the U.S. Food and Drug Administration.


SOURCES: Steven Nissen, M.D., cardiologist, Cleveland Clinic, Ohio; Morgan Liscinsky, spokesperson, U.S. Food and Drug Administration; George King, director, research, Joslin Diabetes Center, and professor, medicine, Harvard Medical School; briefing materials, U.S. Food and Drug Administration; June 6, 2013, news release, GlaxoSmithKline

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