After two days of sometimes heated discussion between FDA advisers, GlaxoSmithKline (GSK) representatives and other experts, 20 of the FDA advisory members agreed that GSK’s diabetes drug rosiglitazone (Avandia) can stay on the market—most with further restrictions and warning—while 12 members voted the drug be pulled from the shelves. One member abstained.
The meetings July 14-15 with the FDA’s Encocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee are the second of their kind dealing with rosiglitazone after a meta-analysis featured in the June 2007 edition of the New England Journal of Medicine questioned the safety of the drug and whether it was a risk for cardiovascular (CV) events, including death, in patients who were administered it.
RECORD trial creates concern
To bolster its case, representatives of GSK presented results of the RECORD trial, which actively compared rosiglitazone to other drugs used to treat diabetes including metformin and sulfonylurea.
Results of the open-label trial found that patients administered rosiglitazone saw no increase in CV or all-cause mortality or stroke, reported Philip D. Home, DM, DPhil, a professor of diabetes medicine at the Newcastle University in the U.K., at the meeting. Home was part of the trial.
The “RECORD [trial] did not show an increased risk in major adverse cardiac events (MACE) or CV death or hospitalization versus standards of care,” said Murray Stewart, GSK's vice president of clinical development of biopharm research and development. "When used appropriately," said Stewart, rosiglitazone “has a positive effect … and should remain a treatment option for patients with type 2 diabetes.”
However, while Home concluded that the study did not increase the risk of recurrent events for those who were having MI and that rosiglitazone better managed glucose control for diabetics, he said that the drug does increase the risk of heart failure and distal fractures.
During Tuesday and Wednesday’s meetings, the RECORD trial results were a hotly contested item as FDA advisory members questioned whether or not its evidence was fruitful and unbiased.
Steve Nissen, MD, of the Cleveland Clinic, questioned the validity of the RECORD trial during his presentation and charged that GSK may have had access to treatment codes and knowledge of study data from the start. Additionally, Nissen charged that GSK removed and excluded silent MIs from the endpoint of the study, which could have changed the interpretation of the study and created bias. Nissen was not a member of the FDA advisers.
However, in a statement from GSK, Stewart called this a “misconception” and said that GSK never removed silent MIs from data as they were not an endpoint to begin with.
While Karen M. Mahoney, MD, of the FDA, said that the RECORD trial is the only new randomized controlled CV data since the 2007 committee meeting, “I think most scientists involved in the review of RECORD would agree that it cannot answer every single question one might have about the CV safety of rosiglitazone.”
Adding to the critiques of the RECORD trial, Thomas A. Marciniak, MD, medical team leader division of cardiovascular and renal products at the FDA, called RECORD “a very complex and confusing study,” and said that the trial cannot be depended upon for safety.
Marciniak reviewed 549 case report forms at 56 sites participating in the RECORD trial and found that one in four had a major problem in reporting (13 percent), and by a ratio of 4:1, these “problems” favored rosiglitazone, which included missing endpoints, missing information and adjudication disagreement.
Marciniak blamed the potential biases on the open label design of the RECORD trial and said, “If consulted in advance, I would have rejected this study design as completely inappropriate and biased.”
Ellis F. Unger, MD, deputy director of the Center for Drug Evaluation and Research (CDER) at the FDA, in response to Marciniak’s findings said, “We take these concerns very seriously. Whether or not particular adverse events were forwarded for adjudication, whether there was bias, uncertainty regarding dates, these are all important issues and the issue here is really truth.” However, Unger called Marciniak’s evidence regarding the adjudication bias “exploratory” at best.
According to GSK, 1,600 events during the RECORD trial were sent to adjudication and were peer reviewed.