FDA panel advises clinical trial, revised labeling of fenofibric acid

Issue: June 2011

The FDA Endocrinologic and Metabolic Drugs Advisory Committee unanimously recommended a clinical trial to assess the cardiovascular benefits of adding fenofibric acid to statin treatment in high-risk men and women with high triglycerides and low HDL.

The panel also narrowly advised for revision of the fenofibric acid (Trilipix, Abbott) drug labeling regarding co-administration to include recent data from the Action to Control Cardiovascular Risk Diabetes (ACCORD) Lipid Trial.

Discussion of data

Results of two subgroup analyses conducted during the ACCORD-Lipid trial were at the center of the panel discussion. One analysis revealed a higher rate of CV events, especially myocardial infarction, in women taking fenofibrate plus statin vs. men taking the same combination (HR=1.38 vs. HR=0.82). Henry Ginsberg, MD, lead research for the ACCORD-Lipid trial and director of the Irving Institute for Clinical and Translational Research at Columbia University, noted no difference in baseline lipids or lipid response after 48 months between men and women. He said this issue warrants further investigation.

A second subgroup analysis of patients with dyslipidemia revealed a lower rate of major adverse cardiac events among participants with triglycerides in the highest tertile and HDL in the lowest tertile compared with the entire study cohort.

Careful consideration

Despite the results of the ACCORD-lipid analyses, as a whole, the panel was hesitant to make recommendations for subgroups because ACCORD-Lipid was a negative trial overall. Consequently, the panel unanimously voted for a clinical trial to be conducted using major adverse cardiac events as an endpoint to test the benefit of adding fenofibrate to statin therapy in high-risk patients with high triglycerides and low HDL.

"In reviewing the data for fibrates, it's not clear to me if these drugs are beneficial or not," William R. Hiatt, MD, professor of medicine at the University of Colorado Denver, said at the meeting.

The committee was divided regarding fenofibric acid's labeling indication for co-administration with a statin. Three members voted to continue marketing and maintain the current indication; four voted to withdraw that particular indication; and six voted to revise the indication for co-administration to incorporate the principal findings from ACCORD.

Edward W. Gregg, PhD, from the division of diabetes translation at the CDC, voted to revise the indication. he said the available evidence indicates potential negative effects, but the data are not strong enough to warrant complete removal. Nevertheless, he said, "I think there should be a more specific indication to prevent overmarketing to people who may not benefit."

In response to the committee's decision, Eugene Sun, MD, vice president of Global Pharmaceutical Clinical Development of Abbott, said in a press release: "We also appreciate the request for more clinical data and look forward to further discussions with the FDA."

ACCORD-Lipid is a randomized, double blind, placebo-controlled, add-on trial that evaluated the efficacy and safety of adding fenofibrate to simvastatin (Zocor, Merck) therapy in more than 5,500 patients with type 2 diabetes. During an average 4.7 years, researchers found no significant difference in the proportion of patients treated with simvastatin plus placebo (11.3%) vs. simvastatin plus fenofibrate (10.5%) who experienced a major adverse cardiac event (HR=0.92; 95% CI, 0.79-1.08).

Fenofibric acid is the active ingredient of fenofibrate. Fenofibrate is a peroxisome proliferator-activated receptor-alpha agonist (PPAR-alpha) that was approved for the treatment of hypertriglyceridemia in 1993. In 2009, the FDA approved the new drug application for fenofibric acid in combination with a statin.

While the FDA is not required to follow the recommendations of the advisory committee, it usually does. - by Melissa Foster

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