A review by U.S. health scientists reinforces potential ties between the diabetes pill Avandia and heart attack and death. The result opens the door for government action, including a possible withdrawal of the once blockbuster drug.
The U.S. Food and Drug Administration posted an exhaustive 700-page review of the British-based GlaxoSmithKline drug online Friday ahead of a meeting next week to review the safety of Avandia, which is used by hundreds of thousands of diabetics in the United States.
FDA scientists reviewed dozens of studies of Avandia, including one that Glaxo has pointed to as proof of the drug's safety. An FDA reviewer said the study was plagued by "serious flaws" and actually supports the case against Avandia.
The FDA holds a special two-day meeting starting Tuesday to help decide what course to take. A panel of outside expert physicians will vote on a range of recommendations including:
• Adding additional warning labels to the drug
• Allowing only certain doctors to prescribe the drug
• Pulling the drug from the market
The FDA is not required to follow the advice of its outside panels, although it normally does.
Part of the reason the FDA is seeking outside advice is because of disagreements among its own scientists.
"There's not complete unanimity within the FDA about interpretation of these data, and that's one of the reasons we're going to the advisory committee," said Dr. Janet Woodcock, head of the FDA's drug center.
Avandia was Glaxo's third best-selling drug in 2006 with U.S. revenue of $2.2 billion, according to health care statistics firm IMS Health. But safety concerns swirling around the drug have pummeled sales since 2007, with sales falling 75 percent to $520 million last year.
In Europe, the agency that evaluates medicine said Friday it will review the safety of the Avandia in consideration of the research that suggests links to a higher risk of heart problems, strokes and deaths in older adults.
The European Medicines Agency said the review will be conducted by its Committee for Medicinal Products for Human Use when it meets from July 19 to July 22. Depending on the outcome, marketing authorization for the drug in Europe could be revoked or changed.
In 2007 an analysis of dozens of studies first linked the drug to heart attacks. The U.S. agency responded by adding a warning label to the drug.
New data on Avandia's risks and pressure from Capitol Hill have prompted the agency to re-examine the drug's safety.
Despite the drop off, Avandia still is used by hundreds of thousands of Americans with type 2 diabetes to control blood sugar levels. The drug works by increasing the body's sensitivity to insulin, a key protein needed for digestion that diabetics lack.
That sort of treatment has long been presumed to lessen the heart risks already associated with the disease.
But critics of Avandia, including a high-profile FDA scientist, argue there are safer alternatives to GlaxoSmithKline's drug.
Last month a leading medical journal published an analysis suggesting Avandia is more likely to cause strokes and heart-related death than a rival drug, Actos, which is made by Japan-based Takeda Pharmaceuticals and has gobbled up 70 percent of the market for diabetes drugs in Avandia's class.
The paper's author, Dr. David Graham, the FDA scientist who wants the pill banned, estimated as many as 100,000 heart-related adverse events may have been caused by Avandia during its time on the market.
Graham and several colleagues analyzed medical records of more than 225,000 elderly patients in the government's Medicare health program for the elderly who were taking Actos or Avandia.
A key question at next week's meeting will be how much weight to give analyses like Graham's, which pool information from massive datasets.
London-based Glaxo has argued for years that Avandia's safety should be assessed based only on clinical trials, which are considered the gold standard of medical research. The studies enroll similar groups of patients who are given one of two pills and followed over time to see how patients fare.
"Our position is that if you look at the randomized clinical trials, all of them do not show evidence of cardiovascular harm," said Dr. Jai Patel, vice president of cardiovascular development at GlaxoSmithKline.
For more than a year the company has pointed to a study called RECORD which showed no heart problems in patients taking Avandia.
According to the FDA's review, however, "RECORD was inadequately designed and conducted to provide any reassurance" about the heart safety of Avandia.
Questions about what Glaxo knew about its drug and when it was known will hang over next week's deliberations. In February a Senate investigation concluded the company knew about safety risks with the drug in 2005, two years before they were publicized. Senate investigators also faulted the FDA for not making the issue public sooner.
Lawmakers on Capitol Hill already have painted Avandia as a test of the agency's enforcement stance, similar to Vioxx. Vioxx was a blockbuster painkiller from Merck which was withdrawn in 2004 after studies showed links to heart attack and stroke. Critics said lives could have been saved had the FDA acted more swiftly.
Some experts reject the comparison between the two drugs.
Parsing Avandia's risks is more challenging than with Vioxx because diabetics already are at increased risk for heart problems, according to UBS analyst Gbola Amusa.
He points out that many top lawyers, including some who sued Merck successfully over Vioxx, already have settled with GlaxoSmithKline, suggesting they did not have enough evidence to take Glaxo to court.
"To show that Avandia was the proximate cause of these heart attacks would be exceptionally difficult," said Amusa, who is trained as a physician.