FDA 'Mea Culpaâ€ Part of a Cautionary Tale
Published Online: September 25, 2013
Tracey L. Regan
Three years after the once-popular diabetes drug Avandia (rosiglitazone) largely disappeared from medicine cabinets following a dramatic reappraisal of its cardiovascular risk, the drug’s partial vindication on June 6, 2013, by a US Food and Drug Administration (FDA) advisory panel1 has come too late to revive its fortunes, experts say.
But the controversy that engulfed Avandia and its roller coaster ride through the regulatory process continue to have farreaching implications for clinical practice and drug development.
“Now that the water has cleared, we look back and see that it never was a problem. There was no cardiovascular benefit, but no problem either,” said Fernando Ovalle, MD, director of the Multidisciplinary Comprehensive Diabetes Clinic at the University of Alabama-Birmingham. Ovalle was referring to the findings of an independent team of researchers from the Duke Clinical Research Institute commissioned by the FDA to analyze, or readjudicate, data from drug maker GlaxoSmithKline’s RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial.
The Duke team concluded that Avandia did not present a serious cardiovascular risk to diabetes patients, although it pointed out flaws in the trial’s design, noting that its unblinded nature could have affected the outcome. Based on that readjudication, the FDA panel voted in June to ease the tight restrictions on the drug put in place by the agency in 2010 and 2011.2,3
“This has put the FDA in something of a bad spot, because the agency can’t really admit it was wrong, although that is what the advisory panel said,” Ovalle noted. But Ovalle, who stopped prescribing the drug more than 2 years ago, said the findings have come too late to sway public opinion.
“Avandia’s reputation has been irreparably damaged,” he said. The drug’s maker, GlaxoSmithKline, awaits a final ruling from the FDA, but does not plan to relaunch it in the United States. “There is no news yet from the FDA, and so nothing’s changed since the adcom (advisory committee) meeting in June. The committee’s recommendations were not definitive, and the FDA takes them under advisement, and so we’re in a holding pattern,” said company spokeswoman Heidi Siegel, adding, however, “There are no plans to promote it again in the US.”
But the readjudication was not pointless, some FDA observers say. Rather, it provided a forum for the agency to scrutinizei ts own practices, while furthering public debate on wide-ranging issues related to drug review and development.
“The review was done not so much to save or damn the drug, but rather to have a thoughtful look back at what happened, recognizing that the way the saga unfolded had negative effects on the environment in which drugs are developed,”said G. Alexander Fleming, MD, the president and CEO of healthcare consulting firm Kinexum and a former FDA regulator who led the review of metabolic therapies such as Metformin. “And I think the agency’s objective was accomplished: to air the process warts and all, and to demonstrate that the FDA has a responsibility to be data-driven.”
He added, however, “In part, the review and hearing also reflect the FDA saying ‘mea culpa’ for stopping a head-tohead comparison trial of Avandia and Actos. based on the Agency’s safety concerns about Avandia. At the recent hearing, FDA acknowledged that the trial probably was justified and the results would have been valuable.” Actos (pioglitazone), manufactured by Takeda Pharmaceuticals, was Avandia’s leading competitor at the time.
Ovalle still vividly recalls Avandia’s promising debut in 1999 and its subsequent fall from grace a decade later, saying the dramatic turn of events was “hard to believe” at the time.
“The drug took off. It was one of the few agents available to type 2 diabetes (T2DM) patients, and we liked the effect it had on glucose for people who had never had it under control,” he said, adding, “There was some concern early on about possible liver toxicity, given the history of Rezulin—a similar drug—at that time, so we did liver exams every 3 months, but we didn’t find anything and we were very happy about that. In fact, we kind of fell in love with it.”
The drug was an important tool in states with high diabetes rates, such as Alabama, where 11.1% of adults were diagnosed with the disease in 2010, putting the state second only to Mississippi, with a rate of 11.3%, according to data from the Centers for Disease Control and Prevention (CDC).4
In a class of drugs called thiazolidinediones, or TZDs, Avandia works as an insulin sensitizer, reducing the body’s resistance to insulin. Ovalle said clinicians had some new concerns about the drug after a few years, noting that some of their patients gained weight and developed problems with edema. A few ended up in the hospital, although he said that was rare.
“We still defended the drug because there was nothing like it that improved glucose numbers the way it did. In terms of cardiovascular risk, we saw LDL numbers go up a little bit, and so we said we’d watch that closely,” he recalled.
“On the other hand, small studies of Avandia and Actos, another TZD insulin sensitizer, showed signs of improvement as well— cardiovascular benefits in all markers except LDL, from blood pressure, to inflammatory markers, to C-reactive protein— and so it looked like these drugs were going to lower cardiovascular events significantly. But then the studies turned out negative, showing no effect. It was disappointing to learn there were no benefits,but there weren’t clear bad effects either.”
He added that most physicians believed that it would be hard for these drugs to show definitive beneficial effect from a cardiovascular perspective given that statins were of proven benefit and standard of care therapy, and had to be given to patients during clinical trials. Despite some of these uncertainties, however, he said clinicians were stunned in 2007 when Steven Nissen, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic, published in The New England Journal of Medicine the results of a meta-analysis of Avandia trial data that showed a 43% increase in heart attacks for those taking the drug.5
Three years later after Nissen’s report, the FDA announced it would restrict use of Avandia to patients unable to control their diabetes on other medications, ultimately requiring them to enroll in the agency’s Risk Evaluation and Mitigation Strategy program in order to receive it.2,3 “Steve Nissen’s paper came as a complete surprise to many of us who thought the opposite. He said the drug caused heart attacks. And while the medical community was given the impression with his meta-analysis that the drug was dangerous, to be fair, the meta-analysis was incomplete and heavily criticized by statisticians, but that didn’t matter in the ensuing public controversy. Things became politicized, and the debate was no longer based on science,” he recalled.
“The FDA responded by making the ‘safe’ move in sharply restricting Avandia and that killed the drug. The perception was so poor that patients were asking to be taken off it. As a doctor, if you tried to reassure them, you put yourself in a bad position. Lawyers were out there advertising, saying, ‘If you took Avandia, call us.’ I stopped prescribing it.” Fleming described Avandia’s situation as “almost unique along the spectrum of what happens in drug development and regulation.”
Nissen took a look at the publically available Avandia trial data and added up the cardiovascular events associated with Avandia and the control treatment. This approach is called a meta-analysis and is generally regarded as “hypothesisgenerating, never definitive because of some significant limitations,” Fleming said. “There was nothing wrong with Nissen performing the meta-analysis or even the Journal publishing it, though it rarely publishes meta-analyses. The problem was with Nissen’s over-reaching conclusions and the editors allowing the title of the article itself, which implied both definitiveness and that higher death rates were caused by Avandia,” he said.
“Nissen went on to publish conclusions that the closely related and competing drug, pioglitazone (Actos), provided cardiovascular benefits, making Avandia even more untenable.” Multiple FDA advisory panels were called—including one the resulted in the FDA “guidance,” published in record time, that cardiovascular safety trials would have to be completed before any therapy for T2DM could be approved. This requirement suddenly added years and perhaps as much as $500 million to the cost of developing a drug for T2DM, Fleming said.. The controversy around Avandia itself escalated. In the wake of the Nissen paper, at FDA there was a storm of additional reviews and different opinions reached about Avandia.
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