Healthy Skepticism Library item: 11048

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Publication type: news

Harris G.
F.D.A. Panel Votes to Keep Diabetes Drug on Market
New York Times 2007 Jul 30
http://www.nytimes.com/2007/07/30/health/30cnd-avandia.html?pagewanted=1&_r=1

Full text:

GAITHERSBURG, Md., July 30 – A federal drug advisory committee voted 20 to 3 late this afternoon that Avandia, a controversial diabetes drug made by GlaxoSmithKline, raises the risks of heart attacks, but it then voted 22 to 1 that the drug should nonetheless remain on the market.

The divided vote came after committee members said that studies concerning Avandia were too murky to merit drastic regulatory action and that other diabetes medicines might have similar risks.

“My feeling here is that we’re being asked to take a very draconian action based on studies that are very inadequate for us to make that kind of decision,” said Rebecca Killion, a patient representative and committee member from Bowie, Md.

Dr. Clifford J. Rosen, chairman of the committee who is from St. Joseph Hospital in Bangor, Me., said after the meeting that “there was enough concern on the advisory committee that virtually everybody felt there was risk” of heart attacks from taking Avandia.

Patients who have congestive heart failure or a history of cardiovascular disease, or those taking insulin or nitrates should not be given Avandia, Dr. Rosen said.

“There are going to be changes in the way this is promoted and certainly in how physicians use this drug,” Dr. Rosen predicted.

GlaxoSmithKline told the committee that it did not believe that Avandia increases the risks of heart attacks “and we still don’t,” said Christopher A. Viehbacher, president of the company’s American drug business, after the meeting ended.

He said that if the F.D.A. ordered a strong warning placed on Avandia’s label, some patients would take other medicines that might be more dangerous. “I don’t think it’s a slam dunk yet as to what the F.D.A. is going to do with this,” he said.

The votes came after an extraordinary meeting in which officials from the Food and Drug Administration, which brought the committee together, openly disagreed with one another about the right course to take.

Dr. David Graham, a drug safety officer at the F.D.A., called for the drug’s withdrawal and estimated that its toxic effects on the heart had caused as many as 205,000 heart attacks, strokes and death from 1999 to 2006. For every month that Avandia is sold, he said, another 1,600 to 2,200 patients are likely to suffer from heart attacks and strokes, some of them fatal.

Dr. Robert Meyer, director of the office within the F.D.A. that approved Avandia’s initial application, immediately disagreed with Dr. Graham.

“I think it’s important that the committee understand there’s a fundamental disagreement” within the agency, he said. Other diabetes drugs also have risks, Dr. Meyer said, and doctors and patients need a variety of treatment options.

Dr. Douglas C. Throckmorton, a deputy director of the F.D.A.’s center for drugs, explained at a news conference after the meeting that the split within the agency resulted from the “complexity” of the issue.

The F.D.A. usually follows the advice of its advisory committees, especially when the votes are so lopsided. Agency officials said they did not know when they would come to a decision and refused to characterize the form that any new Avandia warning might take.

The open disagreement within the F.D.A. reflects a fierce debate that has occurred among diabetes experts across the country since The New England Journal of Medicine published a study in May suggesting that Avandia increases the risks of heart attacks.

In the revelations since then, F.D.A. officials have said that GlaxoSmithKline told the agency about these risks nearly two years ago, but that because of fierce internal disagreements, the agency never warned patients about them. In Europe, regulators required that the drug’s label reflect some concerns about these risks.

The agency’s lack of action helped persuade some lawmakers to support legislation that has since passed both the House and Senate that provides the agency with more money and power to police drug safety issues. That legislation is expected to be sent to President Bush within days.

About a million patients in the United States took Avandia last year, and a nearly identical number took Actos, a similar pill made by Takeda that may be safer. Avandia’s global sales last year totaled $3.4 billion, but its sales have plunged since May.

The Avandia controversy largely revolves around whether several highly complex statistical analyses of dozens of studies show that Avandia increases the risks of heart attacks. Separate from this argument, there is considerable evidence that both Avandia and Actos worsen the condition of heart failure.

Dr. Murray Stewart, a GlaxoSmithKline vice president, said that in recent months the company has examined data from several large managed care companies in the United States that included 1.35 million patients with diabetes. The company’s analyses, he said, showed that patients who took Avandia suffered no greater risk of heart attack or death from heart problems.

The committee disagreed, with most members saying that while GlaxoSmithKline should continue to market Avandia, the F.D.A. should place strict warnings on its label.

“I also think there needs to be a stiffening of the warnings,” said Dr. Peter J. Savage, a committee member from the National Institutes of Health, echoing the comments of others.

Dr. Steven Nissen, a Cleveland Clinic cardiologist who authored the study in The New England Journal of Medicine in May, said in an interview after the hearing that he would have voted to remove Avandia from the market. But he said he was encouraged that the committee “affirmed the finding that there was an increased cardiovascular risk from the drug.”

He predicted that Avandia’s sales would plunge with the new warning.

The disagreements within the F.D.A. affected almost every aspect of the hearing. In their presentations, Dr. Graham and his boss, Dr. Gerald Dal Pan, both referred to studies that suggested that Actos is safer to the heart than Avandia. But the Actos studies have not been thoroughly reviewed by the F.D.A., and the underlying data from them were not given to committee members.

When asked why, Dr. Graham said that “we were promised that that would be done for this meeting.” Officials eventually explained that the agency did not enough resources to get the analysis done for the meeting, he said.

“So then I’m faced with a dilemma,” Dr. Graham said. “Do I keep silent about that and not breathe a word of it, or do I present it?”

Dr. John R. Teerlink, a committee member from the University of California in San Francisco, said that the agency should “either have the political will to either schedule the meeting when we had the data or not to present data that we couldn’t look at.”

The public debate about Avandia has brought about a remarkable number of independent examinations of the drug’s safety, and several researchers shared their findings with the committee during the hearing’s open public comment period.

Executives with both Tricare, a managed care company that serves active and retired military personnel, and WellPoint, a huge health insurer, said they had found no evidence in their records that patients given Avandia had suffered more heart attacks.

Dr. Sidney Wolfe of the drug safety advocacy group Public Citizen, said F.D.A. records show that Avandia has a lot more problems associated with it than just heart risks.

“If Avandia were up for approval today, based on what we know now, it would be rejected,” he said.

Multiple speakers reminded the committee that few diseases have a greater public health impact than diabetes. Each day in the United States, there are 4,100 new diabetes cases and 810 deaths from the disease, said Dr. Robert E. Ratner of the MedStar Research Institute in Washington. Also every day, about 230 diabetes patients suffer amputations, 120 suffer kidney failure and 55 go blind.

He said that while controlling blood sugar levels has proven health benefits in the short term, no study has proven that diabetes drugs extend lives.

“We’re not keeping people alive with our drug therapy because our drug therapy isn’t adequate,” he said. And he said that no diabetes medicine has conclusively proven that it helps protect the heart. He also noted that diabetes patients often fail to take their medicines properly, and that doctors often fail to treat the disease aggressively enough.

“Why do we need new therapies for type-two diabetes?” Dr. Ratner asked. “We have an epidemic of diabetes and its complication that will soon swamp our medical delivery system.”

Most diabetics die from heart disease, since the disease has severe effects on the heart. If Avandia actually increases the risks of heart attacks, that “denotes a serious limitation” of the drug’s usefulness, an F.D.A. reviewer concluded in a report before the meeting.