by Crystal Phend and Emily Walker
Despite hints that the FDA may be leaning toward pulling rosiglitazone (Avandia) from the market, it’s going to be a tough decision for the advisory committee slated to begin meeting on Tuesday, and things could still go either way, leading endocrinologists predict.
“I think the FDA advisory committee is going to struggle with this because none of the data is conclusive,” endocrinology expert David Nathan, MD, of Massachusetts General Hospital in Boston said in an interview with MedPage Today.
However, “damning” conclusions reached in the briefing documents “may provide more support to the advisory committee to [recommend pulling] the drug,” Nathan suggested.
The FDA posted a 765-page briefing document on Friday, in advance of this week’s hearing. In the document, FDA staff reviewers came down hard on rosiglitazone, saying it should be pulled from the market because of serious cardiovascular risks.
The document included an analysis of the controversial RECORD trial, which GlaxoSmithKline has leaned on for proof of the cardiovascular safety of rosiglitazone. FDA staff reviewers, led by Thomas Marciniak, MD, strongly criticized the trial’s design, conduct, and results.
Despite the scathing review, GlaxoSmithKline will defend RECORD at the advisory committee meeting, arguing that it was a well-designed trial that showed no increased overall cardiovascular morbidity or mortality associated with use of rosiglitazone.
“We are not going to downplay RECORD,” Alex Cobitz, MD, director of the Cardiovascular and Metabolism Medical Development Center at GlaxoSmithKline, told MedPage Today in an interview that was monitored by a GSK press officer.
“GlaxoSmithKline feels RECORD was conducted properly and is essentially a well-powered study to meet its endpoints,” Cobitz said.
Cobitz strongly disagreed with Marciniak‘s assessment of the RECORD trial, and said others at the FDA do as well. He predicted the advisory committee hearing will showcase differing views within the agency regarding rosiglitazone.
The FDA staff review also criticized GlaxoSmithKline’s ongoing trial comparing rosiglitazone to pioglitazone (Actos), calling that study “unethical and exploitative,” and adding that the informed consent document for the postmarketing trial was misleading.
Endocrinologist John Buse, MD, PhD, of the University of North Carolina in Chapel Hill, called the FDA staffers’ conclusions scathing.
“I do not think it is unfair,” he said in an e-mail, “but it’s a level of scrutiny that few trials have faced.”
GlaxoSmithKline will also defend that follow-up trial — called TIDE — on Tuesday and Wednesday and refute accusations that it is anything but ethical, Cobitz said.
The Endocrinologic and Metabolic Drugs and the Drug Safety and Risk Management Advisory Committees will meet Tuesday and Wednesday to review rosiglitazone data, discuss the risks and benefits of the drug, and ultimately vote on whether it should be removed from the market.
The meeting will be the second in three years to review rosiglitazone’s risks.
The FDA does not have to follow the advice of its advisory committees but it usually does.
However, it’s still not clear what level of evidence the FDA would require to actually act against the drug, Mass General’s Nathan said.
Most of the data on rosiglitazone’s cardiovascular safety have come from observational data and meta-analyses.
Now that the FDA’s own review of the data from RECORD has uncovered deeper issues, including a substantial number of misclassifications of cardiovascular events for the primary outcome of the trial, that already-controversial trial has become even less reliable, Nathan said.
“It puts the whole study into question,” Nathan told MedPage Today. “I don’t think the RECORD trial could ever be used to exonerate the drug from the charges that it increases cardiovascular risk.”
Buse called the lack of evidence unfortunate because it distracts the diabetes community from moving forward.
“I do not think that a truly scientific analysis supports the requirement that rosiglitazone be pulled,” he wrote in an e-mail. “There is no role for rosiglitazone that is not equally or arguably better met by pioglitazone in the U.S. But I do not think that is justification for regulatory action.”
At issue is science versus the practice of medicine, agreed Robert H. Eckel, MD, an endocrinologist at the University of Colorado in Denver and a past president of the American Heart Association.
“The science is not there, and the positions being taken are quite biased,” he said in an e-mail. “Yet, when prescribing, it would appear at this time that pioglitazone might be a better choice than rosiglitazone. Whether the FDA will allow ‘public sentiment and passion’ to rule remains to be determined.”
Regardless of the advisory panel’s vote — and the FDA’s ultimate decision — the Centers for Medicare and Medicaid Services (CMS) will likely not take a stance on the drug. CMS does not generally convene a Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) to review evidence on drugs that are paid for under Part D, a CMS spokesman said.
Crystal Phend is a MedPage Today Senior Staff Writer and Emily Walker is a MedPage Today Washington Correspondent.