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Jun 10, 2013
 |  BioCentury  |  Regulation

Avandia's Real Lesson

Avandia's real lesson: How to use melange of data in real-world risk management

After six years of public debate, an FDA panel put to rest many of the concerns about the cardiovascular safety of Avandia rosiglitazone using a mix of observational studies, meta-analyses and controlled trials. The panel's deliberations could shed light on how to balance and interpret such data as the agency is increasingly faced with a similar melange of real-world and clinical data to evaluate the benefit and risks of drugs in the postmarket.

At a joint meeting of the Endocrinologic and Metabolic Drugs and the Drug Safety and Risk Management advisory committees last week, panel members voted to relax the REMS on diabetes drug Avandia from GlaxoSmithKline plc.

Among the 26-member panel, 13 voted to modify the REMS, 7 to remove it, 5 to maintain it, and 1 to withdraw Avandia from the market. Twelve of the 13 who voted to modify the REMS recommended that it be eased.

The vote is an about-face from a 2010 recommendation to place restrictions on the drug after the panel determined results from the RECORD cardiovascular outcomes trial could not be trusted. While the original RECORD results showed no increased CV risk for Avandia, FDA's Thomas Marciniak, medical team leader in the Division of Cardiovascular and Renal products, picked apart the trial at that meeting and suggested impropriety by GSK in the handling of the data.

At the time, the panel struggled to balance GSK's reported results with Marciniak's critique of RECORD, along with previous meta-analyses and observational studies that suggested an increased risk.

In September 2010, FDA restricted the use of Avandia and requested that GSK have the RECORD data readjudicated by a third party (see BioCentury, July 19, 2010).

The game changer at last week's panel was the independent readjudication of RECORD by Duke Clinical Research Institute. The readjudicated results found no increased cardiovascular risk for Avandia, confirming the original analysis.

"What's different now is that the results of readjudication in RECORD, in my mind, have moved the needle," said temporary voting member Marvin Konstam.

Konstam, chief physician executive of the Cardiovascular Center at Tufts Medical Center, voted to withdraw Avandia in 2010, but last week voted to relax the drug's REMS.

While Marciniak again attempted to discredit RECORD along with the readjudication process, senior FDA officials and staff pushed back, and the committee ultimately devoted little time to Marciniak's latest critique.

Instead, the panel focused on weighing the strength of evidence from observational studies and meta-analyses alongside RECORD.

While most members acknowledged that randomized, controlled trials with robust clinical data collection processes remain the gold standard, they said observational studies and meta-analyses with large effect sizes where the hypothesis is prespecified are valuable and could be used to make clinical decisions.

The panel's deliberations could be relevant to FDA's efforts to assess benefit-risk in the postmarket setting and also could have implications for decisions that payers and clinicians will be making based on real-world data once a drug is approved.

Time warp

The debate over Avandia's CV risk has stretched across six years and three FDA advisory committee meetings.

A firestorm was sparked in 2007, when Steven Nissen and Kathy Wolski of the Cleveland Clinic published a meta-analysis of 42 trials that showed an increased risk of myocardial infarction (MI) and CV mortality for Avandia.

Nissen and Wolski identified a 43% higher risk of MI for Avandia (95% CI: 1.03, 1.98) and an increased risk of 64% for CV mortality (95% CI: 0.98, 2.74). Results were published in the June 14, 2007, New England Journal of Medicine.

In August 2007, FDA held its first panel meeting to discuss the results along with FDA's own meta-analysis and an interim look at the RECORD data. FDA's meta-analysis showed an increased risk of 50% for MI (95% CI: 0.9, 2.5) and 70% for cardiovascular death (95% CI: 0.7, 4.0). RECORD did not.

RECORD was an open-label trial that enrolled 4,447 patients and compared Avandia plus metformin or a sulfonylurea to metformin plus sulfonylurea. The primary endpoint was the composite of CV death and CV hospitalizations.

An interim analysis showed little to no effect for Avandia. The HR for CV mortality was 0.83 (95% CI: 0.51, 1.36; p=0.46), and the HR for MI was 1.16 (95% CI: 0.75, 1.81; p=0.50).

Despite the mixed signals, members of the 2007 panel concluded the benefits of Avandia outweighed the risks and voted 22-1 in favor of keeping the drug on the market (see BioCentury, Aug. 6, 2007).

In July 2010, the panel met to discuss the complete results from RECORD.

The trial met the primary endpoint with an HR of 0.99 (95% CI: 0.85, 1.16). Also, the upper bound of the 95% confidence interval was below the 1.3 threshold required under FDA's 2008 guidance for cardiovascular outcomes trials of diabetes drugs.

However, FDA's Marciniak cast considerable doubt on the results and suggested GSK mishandled...

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