Glaxo's Avandia Faces Potential Recall in U.S. Advisers' Vote

GlaxoSmithKline Plc’s Avandia may face tougher scrutiny from a U.S. advisory panel reviewing whether the diabetes pill should be pulled from the market than a similar analysis in 2007, doctors said.

Avandia was linked to heart attacks and other cardiovascular complications in two new studies published yesterday that the authors say should prompt U.S. regulators to block its sale. Outside advisers to the U.S. Food and Drug Administration will meet for two days beginning July 13 and are likely to consider whether the pill should remain on the market, deputy commissioner Joshua Sharfstein said.

Glaxo’s treatment, approved in 1999, generated $1.1 billion in revenue last year. The new research and the FDA’s increased focus on patient safety will make for a “politically charged’ panel meeting, said Harlan Krumholz, a cardiologist and professor of medicine at Yale University.

“The growing clamor about drug safety and increasing concerns about the transparency of data and the balancing of risks and benefits are putting the FDA in the position where they’re probably a little more on the defensive” than in 2007, Krumholz said.

Almost 50,000 elderly Americans died, suffered strokes or developed heart failure after taking Avandia instead of a rival medicine since the Glaxo treatment was approved, according to a drug safety reviewer at the FDA who conducted one of the new studies. A second study, from the scientists who first raised the alarm about Avandia, found one of every 52 patients taking the drug was harmed.

Earlier Vote

An FDA advisory panel reviewed the drug in 2007 and “the vote was 22-1 in favor of keeping Avandia available for patients,” Glaxo spokeswoman Mary Anne Rhyne said yesterday in an e-mail. “FDA has not issued its list of questions for this meeting yet so we can’t really comment further.”

The results of the two studies, which include information gathered since Avandia was first linked to heart complications in 2007, may provide the impulse the agency needs to take action, said Steven Nissen, head of cardiology at the Cleveland Clinic in Ohio and the second study’s lead author.

“You have not one, but two studies that come at the problem using completely different methods and populations, and they both fundamentally show a hazard,” Nissen said in a telephone interview. “I think we’ve got more than enough evidence to say this drug should not be used.”

Advocate Effort

The research, published in the Journal of the American Medical Association and the Archives of Internal Medicine, is part of a push by safety advocates to get Avandia taken off the market. A rival medicine, Takeda Pharmaceutical Co.’s Actos, lowers diabetics’ blood sugar levels as well as Avandia and doesn’t raise heart attack risks, according to Nissen.

While the new studies aren’t definitive, they “reinforce the message that there is a cloud hanging over this drug,” Krumholz said.

“The serious issues delineated in these two new, independent reports put additional onus on advisory committee members when they meet in July,” U.S. Senator Charles Grassley, an Iowa Republican, said in a statement.

Grassley and Senator Max Baucus, a Montana Democrat, in February released a report that said Glaxo knew Avandia may cause heart damage several years before Nissen’s study documented the risk.

Glaxo Analysis

Results from six trials made available since questions about Avandia were first raised show the drug doesn’t increase the overall risk of heart attack, stroke or death, said Glaxo’s Rhyne. The company’s review combining 52 studies shows no increase in myocardial ischemia, or reduced blood flow to the heart, she said in an e-mail. Several new observational studies suggest patients taking Avandia and Actos have about the same risk of heart attack, she said.

Glaxo fell 1.5 pence, or 0.1 percent, to close at 1,143.5 pence in London trading. The shares have fallen 13 percent this year.

Nissen and Kathy Wolski, a statistician, updated the original 2007 analysis that publicized Avandia’s risk. They combined data from every study on the drug, published on London- based Glaxo’s website, to determine if it raised heart attacks or deaths from heart disease. Patients on Avandia had a 28 percent to 39 percent elevated risk of heart attack, though deaths from heart disease weren’t significantly higher.

Heart Attack

“Any potential benefit from lowering blood sugar modestly can’t possibly compensate for increasing an event as serious as a heart attack,” Nissen said.

The original analysis found a 43 percent increased risk of heart attack with Avandia. Sales plummeted after the report was published, falling from a peak of $3 billion in 2006, when it was the top-selling diabetes drug in the world.

FDA advisers reviewing the data in the summer of 2007 concluded that the evidence suggested a heart risk in diabetics. Still they said the drug’s benefit outweighed its dangers. Avandia remained on the market, with an added warning about potential heart attacks. The outcome of the panel hearing may be different this time, Nissen said.

“A tincture of time has an effect on the way people think,” he said. What’s more “if we are right and Avandia increases heart attacks and deaths, and we wait a decade to find that out, we will kill or harm a huge number of people. If we are wrong, and you take this drug off the market, there is another drug that is just as effective.”

Second Study

In the other study published yesterday, David Graham, an official in the FDA’s Office of Surveillance and Epidemiology, and his colleagues analyzed data on 227,571 Medicare patients who took Avandia or Takeda’s Actos from July 2006 to June 2009.

Avandia patients were 27 percent more likely to have a stroke, 25 percent more likely to develop heart failure and 14 percent more likely to die. There was an 18 percent increased risk for all three, plus heart attacks, they found.

“We show with a fairly high degree of certainty that Avandia increases serious risks of cardiovascular disease and death compared to Actos in older Americans,” Graham said in an interview. “There is no doubt about it. The real question is why would anyone, a physician or a patient, choose to be on the losing end of this equation.”

Graham estimated that almost 50,000 elderly Americans died, suffered strokes or developed heart failure after taking Avandia, he said in the interview.

Not Real

“These numbers do not reflect reality,” Rhyne, the Glaxo spokeswoman, said in an e-mailed statement. “If these numbers about Avandia were true, we would have seen them clearly in the long-term studies we have already done. None of these sources are showing adverse events even remotely comparable to these numbers.”

More than 4,000 lawsuits have been filed against Glaxo alleging Avandia causes heart attacks and strokes in some users. Glaxo in May agreed to pay $60 million in the first settlements of the litigation, people familiar with the accords said then.

Contrary to the Graham analysis, Nissen’s study didn’t find a significantly increased number of deaths in people taking Avandia. The difference stems from the age of the patients involved, according to Nissen. The Medicare analysis looked at older patients who are more likely to die if they have a heart attack. More than half of Avandia use is in younger patients, who have a greater chance of surviving a heart attack, he said.

“It’s two sides of the same coin,” Nissen said. “It’s really about how you die and when you die. If you followed the people in our study long enough, the fact that they had heart attacks means they are more likely to die sooner.”

To contact the reporters on this story: Molly Peterson in Washington at mpeterson9@bloomberg.net; Michelle Fay Cortez in London at mcortez@bloomberg.net

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