GlaxoSmithKline Plc’s study of its once best-selling diabetes pill Avandia doesn’t prove the drug is safe, according to U.S. regulators considering whether to recall it amid doctors’ concerns it causes heart complications.
The study, called Record, “was inadequately designed and conducted to provide any reassurance about the cardiovascular safety” of the drug, said Thomas A. Marciniak, a medical team leader at the Food and Drug Administration, in an agency review of Avandia released today. “The results do confirm and extend the recognized concerns regarding increased heart failure and heart failure deaths.”
Avandia generated $1.1 billion last year for London-based Glaxo, about one-third of the revenue it had before data emerged in 2007 linking the medicine to a 43 percent increased risk in heart attacks. An FDA panel agreed that year that the drug carried risks though it should remain available. Almost a dozen more clinical trials and studies have been completed in the past three years, prompting the agency to re-examine the issue.
“We cannot rely upon Record to provide reassurances regarding the effects of rosiglitazone upon cardiovascular risk,” said Marciniak, using the chemical name for Avandia.
Glaxo shares were unchanged at 1,142 pence at the close of trading in London. The stock has declined 13 percent so far this year, compared with a 0.5 percent gain in the 17-member Bloomberg Europe Pharmaceutical Index.
Outside advisers to the FDA will meet July 13-14 to evaluate Avandia and vote on whether it should remain on the market, be restricted to certain patients, or withdrawn. While the agency usually follows the recommendations of its advisers, it isn’t required to do so.
“The panel is going to presented with conflicting views and conflicting data yet again, and all we can do is look at what happened last time -- and that’s when they left Avandia on the market,” said Jeff Holford, a Jefferies International analyst who has a buy rating on Glaxo shares, in a telephone interview today. “Just discrediting Record is not enough to take Avandia off the market.”
Glaxo conducted the Record trial at the behest of European regulators to look at Avandia’s cardiovascular risks. The study generated substantial controversy, and the U.S. agency conducted multiple reviews and audits of the trial, said Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research. The European Medicines Agency said today that it’s conducting a safety review similar to that of the FDA.
Doubled the Risk
Avandia more than doubled the risk of heart failure without increasing the rate of hospitalization or death from cardiovascular causes in the 4,447-person study, called Record, which compared the drug with older diabetes medicines. The data, presented in June 2009, are limited because more people in the group receiving Avandia were taking cholesterol medications and patients and doctors knew which diabetes drug was prescribed.
“There is no evidence of harm here, and this fact seems incontrovertible,” said Ellis Unger, deputy director of the FDA’s Office of Drug Evaluation, in the agency’s report today. “I deem the results of Record to be reassuring.”
David Graham, from the FDA’s Office of Surveillance and Epidemiology, and Steven Nissen, head of cardiology at the Cleveland Clinic in Ohio, will present the FDA panel next week with findings from their recent research into Avandia linking the drug to heart attacks and cardiovascular complications. The studies were published last month by the Journal of the American Medical Association and the Archives of Internal Medicine.
Glaxo will focus its presentation to the FDA panel on the Record study, which ran for more than five years, said Jai Patel, the company’s vice president in metabolic clinical research.
“Avandia may not be right for every single patient, but it certainly is an important medicine that should be available to patients,” Patel said yesterday in a telephone interview. “When your disease progresses and other agents don’t work, the long-term durable effect will potentially be useful in that patient population.”
Measures used by the FDA to alert doctors and patients of potential risks, or to control access to potentially dangerous drugs, won’t work with Avandia, said Harlan Krumholz, cardiologist and professor of medicine at Yale University, in a telephone interview. The standard approach of a warning on a drug’s prescribing information doesn’t go far enough, he said.
“You assume if you can go to a pharmacy and buy it, it must be safe,” he said. “It’s hard to leave it on the market and send a strong enough message about the concerns.”