A second look at GlaxoSmithKline Plc’s once-best-selling diabetes pill found it doesn’t increase overall cardiac death risk, U.S. regulators said.
Findings by London-based Glaxo that Avandia doesn’t raise the overall risk of death, heart attack or stroke appear to be supported in a reanalysis by independent researchers, some Food and Drug Administration staff said today in a report. FDA advisers will reconsider restrictions imposed on Avandia in 2010 at a meeting June 5-6, according to the report.
“It is important to note that FDA has not reached any final updated conclusions” on the cardiovascular safety of Avandia based on the reassessment, said Mary H. Parks, director of the FDA’s division of metabolism and endocrinology products.
The former $3 billion drug generated $9.5 million in sales last year amid strict FDA limits on prescribing and Glaxo’s decision to stop promoting the Type 2 diabetes treatment. The drug came under fire after a New England Journal of Medicine article in 2007 found a 43 percent increased risk of heart attack in a combination of results from smaller studies. Glaxo followed with a study of its own in 2009 that didn’t show an overall higher heart risk.
The FDA sought an independent assessment. The findings of that review, discussed in today’s report, “were consistent with the original trial’s report,” according to one FDA staff review that matched similar comments from other reviewers. The FDA included multiple staff reviews in the report.
Cardiovascular deaths occurred in 34 Avandia patients, or 1.5 percent, and 42, or 1.9 percent, of those who took the drug combination metformin and sulfonylurea, FDA staff said.
Glaxo originally conducted the study, which found Avandia more than doubled the risk of heart failure, at the request of European regulators. The medicine carries a black box warning that alerts patients of the potential for heart failure.
Based on the FDA’s request for an independent assessment, Glaxo asked Duke University School of Medicine’s Duke Clinical Research Institute in Durham, North Carolina, to examine the results of the cardiovascular outcomes study. Known as the Record trial, the study compared Avandia with a drug combination typically tried first among Type 2 diabetes patients.
Some FDA staff questioned whether Duke’s reanalysis can address flaws in the design of Glaxo’s original trial.
Avandia, approved in 1999, was taken up by two FDA advisory panels in 2007 and 2010 that voted to place warning labels on the box and limit some patient access to the drug instead of pulling it from the market. Advisers in 2010 were concerned that the Record trial was conducted in a way that didn’t involve blinding, a method used to minimize bias by not letting trial participants know who is on what drug.
“The Record trial re-adjudication does not provide reassurances regarding the cardiovascular safety of rosiglitazone but reinforces the flaws in Record,” Thomas Marciniak, medical team leader in FDA’s Division of Cardiovascular and Renal Products, said in the report.
Marciniak criticized the reanalysis because it isn’t blinded and Glaxo controlled the information sent to Duke. He also alleged trial misconduct. Other FDA reviewers mostly disagreed with the contentions except for the charge that the study should have been blinded.
“Some aspects of his input (such as those on trial design limitations) are useful and objective, but his allegations of trial misconduct, and in this case, readjudication misconduct, appear unsubstantiated and do not appear to have been reached through a balanced and objective review process, Parks wrote.
Unblinding the trial was necessary because Avandia couldn’t be used with insulin, Murray Stewart, senior vice president of Glaxo’s metabolic pathways and cardiovascular unit, said in an interview. Duke researchers were given blinded data, he said.
The advisory panel will discuss whether more study is needed to fully understand the cardiovascular safety of Avandia.
The FDA restricted access to Avandia in 2010 to only certain doctors, pharmacies and patients. About 117,000 patients took the drug in May 2010, a number that has fallen to 3,000, Glaxo said.
Glaxo agreed to a $3 billion settlement with the U.S. Justice Department almost a year ago involving a failure to report certain safety data about Avandia between 2001 and 2007 and promotion of two other popular drugs for uses that the FDA hadn’t approved. The company also agreed to pay $90 million to settle claims by 37 U.S. states and Washington, D.C., that the company illegally promoted Avandia.