Three years after FDA requested an independent re-adjudication of GlaxoSmithKline PLC’s Avandia (rosiglitazone) RECORD study, the data will be presented to two FDA advisory panels.

The Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee will jointly discuss the “re-adjudication” of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial at a June 5-6 meeting.

The two advisory committees last reviewed the RECORD study and Avandia’s cardiovascular safety risks at a meeting in July 2010. At that time, 12 of 33 members voted for withdrawal of the drug Also see "Avandia Advisory Committee Re-Review Reflects Well On FDA" - Pink Sheet, 19 July, 2010..

In October 2010, FDA Center for Drug Evaluation and Research Director Janet Woodcock called for an independent panel to re-adjudicate cardiovascular endpoints in the 4,400-patient, open-label study in light of evidence of potential cardiovascular risk. Woodcock said the evidence of Avandia’s CV risk was neither robust nor consistent but that there was no reliable evidence refuting multiple signals of concern Also see "Anatomy Of The Avandia Decision: FDA’s Woodcock Splits The Difference Between OND, OSE Views" - Pink Sheet, 4 October, 2010..

At the time there was a division within the agency as to whether the diabetes drug should remain on the market. The Office of Surveillance and Epidemiology favored its withdrawal while the Office of New Drugs advocated that the labeling be revised, the RECORD trial be re-adjudicated, and the post-marketing TIDE study be continued.

The randomized RECORD study compared rosiglitazone-containing combination therapy for type 2 diabetes with the most commonly used dual oral combination of metformin and a sulfonylurea. The study, conducted between 2001 and 2008, was published in The Lancet in 2009. The primary endpoint was cardiovascular hospitalization or cardiovascular death. The study concluded that the addition of rosiglitazone to glucose-lowering therapy increased the risk of heart failure. “Although the data are inconclusive about any possible effect on myocardial infarction, rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs,” the study authors concluded.

Re-Adjudication Outcomes Are Similar To Original RECORD Results

GSK commissioned the Duke Clinical Research Institute to re-adjudicate the RECORD trial. The DCRI study was conducted from January 2011 through March 2012 and GSK submitted the results to FDA last year. The key objectives were to identify all deaths, all suspected myocardial infarction events, and all suspected stroke events among study subjects.

A summary of the results posted on GSK’s clinical trial register states that “there was no evidence of treatment effect on all-cause mortality or cardiovascular plus unknown mortality.”

“The results of the primary analyses and extensive sensitivity analyses using the re-adjudicated outcomes were consistent with the original RECORD results and did not show statistically significant differences between the rosiglitazone and the metformin/sulfonylurea groups for the primary composite of CV death (+unknown), MI or stroke and the individual components,” the summary states.

Approved in 1999, Avandia’s safety was thrown into question after Cleveland Clinic’s Steven Nissen published a meta-analysis in 2007 suggesting the drug was associated with cardiovascular events. FDA subsequently required the addition of a black-box warning and in 2011 it approved a Risk Evaluation and Mitigation Strategy (REMS) restricting Avandia’s distribution Also see "Avandia REMS Limits Access To Mail Order Pharmacies Beginning In November" - Pink Sheet, 18 May, 2011..

In 2012 GSK pled guilty to hiding Avandia safety data from FDA as part of a $3 billion settlement that also involved off-label promotion of Avandia and other drugs, and allegations of kickbacks Also see "GSK’s DoJ Settlement Links Executive Bonus To Continued Compliance" - Pink Sheet, 9 July, 2012..

Avandia RECORD Study Re-Analysis To Get FDA Committee Scrutiny

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