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Avandia Gets a Positive Vote, but It Might Be too Late to Help

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By Mari Serebrov
Washington Editor

A replay of the data from the RECORD trial seemed to reassure many members of two FDA advisory committees about the use of GlaxoSmithKline plc's diabetes drug Avandia, but they admitted that it's probably too late to rehabilitate the drug's reputation.

After a two-day meeting that looked at independently readjudicated results from the open-label RECORD trial, seven members of the Endocrinologic and Metabolic Drugs and the Drug Safety and Risk Management Advisory Committees voted that restrictions on the prescribing of Avandia (rosiglitazone) should be removed, and 13 members recommended modifying the restrictions of the drug's current Risk Evaluation Mitigation Strategy (REMS). Several who voted for modifications said they were torn between softening the REMS and removing it altogether.

In voting to remove the REMS, patient representative Rebecca Killion noted that she had voted for a REMS in 2010, but she didn't expect it to be as restrictive as what was implemented. "Our charge here is to be safe but to be sane," she said, adding that she didn't want to limit patient choice.

After hearing the readjudicated data, William Hiatt, a cardiology professor at the University of Colorado School of Medicine, said Avandia doesn't look any different from other diabetes drugs.

However, five of his colleagues thought the status quo should be continued, and one member – Ida Spruill, an assistant professor at the Medical University of South Carolina College of Nursing – voted to remove the drug from the market. The last time Avandia came before the joint adcom, 12 members wanted it yanked from the market. (See BioWorld Today, July 15, 2010.)

A diabetic who has personally taken Avandia until recently, Spruill said the data are still inconclusive and "it's been too long, too much too late" for a drug that has been made the "bad boy on the market."

This week's meeting was the third time the drug has been brought before the joint adcom after concerns were first raised in 2007 when an observational study sounded alarms about an increased cardiovascular risk with what had been a blockbuster diabetes drug. Since then, the drug has been tainted by the process, Charles Stanley, a pediatrics professor at the University of Pennsylvania's Perelman School of Medicine, said as he voted to remove the REMS.

Following a second adcom meeting in 2010, the FDA allowed Avandia to remain on the market under a tightly restricted access program. As a result, the number of patients being prescribed the drug dropped from 2.5 million in 2008 to 4,600 in 2012 after the full REMS program was implemented. (See BioWorld Today, Sept. 24, 2010.)

Citing ethical considerations at the time, the agency also halted GSK's large, blinded TIDE trial, which was intended to compare Avandia to placebo as well as Actos (pioglitazone HCI, Takeda Pharmaceuticals Ltd.) – despite a 19-11 adcom vote favoring the continuation of the trial. When it was halted, TIDE had enrolled about 1,100 of the 16,000 subjects that the design called for.

Throughout the discussion Thursday, several panel members and expert witnesses bemoaned the missed opportunities of the TIDE study. "We would clearly have a lot more information and data had the study been allowed to proceed," Hertzel Gerstein, director of endocrinology and metabolism at McMaster University's Population Health Research Institute, told the panel during a presentation on the feasibility of an outcomes trial. Given its size, TIDE would have provided more data than any other study of a diabetes drug to date, he added.

In the future, "large outcomes trials should be done before strong opinions based on unreliable data become entrenched in people's psyche," Gerstein said. Given Avandia's worldwide infamy, he wasn't sure if it would be feasible to do the trial today.

When asked if they would be willing to sponsor such a trial for Avandia, which came off patent last year, GSK officials hedged, saying it would depend on the outcome of Thursday's meeting. If the adcom members believed the readjudicated RECORD results, there'd be no reason to do the outcomes trial, a company official said.

Panelist Maria Suarez-Almazor, a professor at the University of Texas M.D. Anderson Cancer Center, said it wouldn't be feasible or ethical to do the TIDE study now because of the availability of newer diabetes drugs. And it wouldn't be fair to ask patients to enroll in a trial designed only to ensure there are no problems with a drug, she said, if that drug didn't offer the possibility of an improvement.

Given the backtracking on Avandia, Sanjay Kaul, director of the fellowship training program in cardiovascular diseases at Cedars-Sinai Heart Institute, noted that the concerns about the drug had resulted in guidance calling for large cardiovascular outcome trials for all new diabetes drugs. Referring to the guidance as the elephant in the room, he asked the FDA if it would revisit the subject.

He was told that the guidance wasn't the topic of this week's meeting.