A US Food and Drug Administration (FDA) advisory panel voted today that distribution of Avandia, a once-popular diabetes drug recently linked to heart attack and death in some studies, should be restricted.
Twelve members of the 33-member panel voted to remove the drug from the market altogether. Another ten said the drug should remain on the market but with added warnings and special restrictions on how the drug is sold. Only three decided the drug should continue to be marketed unchanged.
The vote could be a blow to the drug’s maker, GlaxoSmithKline: although such advisory committees do not have the power to pull drugs from the market, the FDA often follows their recommendations.
The committee also voted 20-10 that the TIDE clinical trial, which pits Avandia (also known as rosiglitazone) against a competing drug in the same class, should continue. Some have argued that the trial is unethical, given Avandia’s risks.
This afternoon’s vote brought to an end a two-day, forest-plot filled discussion of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.
The drama started just as the meeting began, when news broke that a decade ago, Avandia’s maker, then called SmithKline Beecham, buried the results of a clinical trial that pitted Avandia against its competitor Actos (pioglitazone), which is manufactured by Takeda. According to documents released by the Senate Finance Committee, that trial yielded early clues about Avandia’s cardiovascular troubles.
Those troubles did not become public until 2007, when the New England Journal of Medicine published a controversial meta-analysis by Steve Nissen at the Cleveland Clinic in Ohio. In the interim, the drug had become a blockbuster: in 2006, sales of Avandia brought in $3.4 billion.
After that meta-analysis, the FDA advisory committee met in 2007 and determined that although there were safety concerns, there was not enough data to show that the drug should be pulled from the market. Instead, the FDA placed a black box warning about possible heart attack risk (to accompany warnings already present on both Avandia and Actos about increased risk of heart failure).
Since then, additional studies have been completed, including RECORD, a randomized, controlled clinical trial of Avandia’s impact on cardiovascular health in 4,447 patients. That trial, performed at the behest of European regulators, found no increase in cardiovascular hospitalizations or deaths among those taking the drug. But another study, an observational trawl through the Medicare records of over 200,000 patients, found an increase in mortality in Avandia users.
Over the past two days, the advisory panel wrestled with the relative significance of those two studies, among others. RECORD had the advantage of being a controlled clinical trial, but the study was open-label, meaning that both patients and doctors knew who was receiving Avandia. The study’s designers argue that this strategy was necessary—because of the trial’s structure, to do otherwise would have required some patients to take sham insulin injections many times a day. Furthermore, they argued, patients would have an easy time figuring out whether or not they were receiving the drug, given that Avandia is known to cause fluid retention. Nevertheless, this design could lend itself to ascertainment bias, skewing results.
And discrepancies in RECORD patient reports found by FDA staffer Thomas Marciniak strongly suggested that the results were biased in favor of Avandia. Marciniak further argued that GSK’s hand was evident in the bias. “It’s not a supposition that GlaxoSmithKline intervened,” he told the panel today. “It’s documented.” Critics had previously noted that although the data was blinded during the statistical analysis, GSK and the contract research organization it had hired to conduct the trials had access to unblinded data, an unusual situation even for open-label trials.
Some panel members were clearly disturbed by the findings—statistician Michael Proschan said the evidence of RECORD’s bias “scares the hell out of me”—but others argued that RECORD was the best of the new data available for the committee. Several noted that observational studies, such as the Medicare records analysis performed by the FDA Office of Surveillance and Epidemiology’s David Graham – are not reliable when dealing with risk increases below two-fold. (By comparison, the Medicare study found that Avandia increased the risk of mortality by a statistically significant but nevertheless diminutive 1.15-fold.)
The panel was also divided on whether Avandia held any real benefit for patients. Several panelists argued that Actos also lowers blood sugar but does not appear to pose the same risk as Avandia, meaning there is no known patient need for Avandia to stay on the market. But patient advocate Rebecca Killion, argued that patients need to have as many treatment options as possible. “I think that this drug is not for everybody,” she said. “But that may not mean that it’s not for anybody.” Killion later voted to restrict Avandia’s sale, but not to take it off the market.
Does this spell the end of Avandia? It’s hard to say how the FDA—which has been famously split over how to handle the drug—will incorporate the panel’s decision. Immediately prior to the vote, Robert Temple, director of the FDA’s Office of Medical Policy, noted that most drugs withdrawn from the market were pulled because of rare but serious side effects. He also noted that approved drugs should be held to the same standards applied when new therapies are under consideration for approval. Several panelists had observed that if the recent data on Avandia’s safety had been available when the drug was first evaluated for approval, Avandia would never have made it to the market.
But Temple was then countered by John Jenkins, of the FDA’s Center for Drug Evaluation and Research, who said that when drugs are withdrawn for cardiovascular concerns, increased risk of cardiovascular events are three or five fold higher when taking the drugs—much higher than the roughly 1.3 fold increase in heart attack seen in those taking Avandia.
The split at the FDA doesn’t mean that the agency is broken, commented panelist and cardiologist Marvin Konstam, but “I think some of the people within FDA might work on getting along better,” he added.
Update: The Indian government has placed a hold on the TIDE trial in that country, due to safety concerns.