New Trial of Fenofibrates Needed, Says FDA Panel

Fenofibrate pan urges new trial to examine questions in ACCORD

Reed Miller

May 20, 2011

May 19, 2011 (Silver Spring, MD) – An FDA advisory panel agreed unanimously that a new trial is needed to understand which diabetic patients on statins benefit from the addition of fenofibrate (Trilipix, Abbott), but most of the panel voted in favor of keeping the current indication for coadministration with a statin in fenofibrate's approved labeling.

The panel voted 13 to 0 to recommend that Abbott launch a new trial of fenofibrate in diabetic patients who have met their LDL-cholesterol goal on a statin but still have high triglycerides and low HDL cholesterol. Patients in the trial should be randomized to fenofibrate plus a statin or placebo plus a statin, and the trial's primary end point should be based on clinical outcomes and not just changes in triglycerides or HDL-cholesterol levels, the panel agreed.

Statistician Dr Erica Brittain (National Institutes of Health, Bethesda, MD) said a trial specifically targeted at this population is needed because "there is certainly uncertainty about where this drug works and what values of baseline triglyceride and HDL it would work for."

Epidemiologist Dr Susan Heckbert (University of Washington, Seattle) agreed. "Based on the totality of the evidence reviewed today as well as the lack of evidence regarding the performance of triglycerides and HDL as surrogate end points, I believe that the FDA should change the standard required for developing an indication for adding lipid-lowering drugs to statin therapy--change it from a reliance on surrogate end points to one relying on outcomes trials."

No firm conclusions can be drawn from subset analysis

Fenofibrate was approved in 2008 to be used with a statin to reduce triglycerides and increase HDL cholesterol in diabetic patients with mixed dyslipidemia and coronary disease or at risk of coronary disease who are already on optimal statin therapy to achieve their LDL-cholesterol goal.

As reported by heartwire , the FDA's Endocrinologic and Metabolic Drugs Advisory panel met May 19 to decide the fate of the coadministration indication after the lipid substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed fenofibrate plus statins did not reduce cardiovascular events more than statins alone.

Over nearly five years of follow-up in ACCORD, the composite of fatal cardiovascular events, nonfatal MI, and nonfatal stroke was around 11% in both patients randomized to simvastatin plus fenofibrate and patients randomized to simvastatin plus placebo. Also, in women, major adverse events were less frequent in the simvastatin/placebo group than the simvastatin/fenofibrate group (6.6% vs 9.1%, interaction p=0.01 vs men).

However, in the subgroup of patients with baseline levels of triglycerides >204 mg/dL and HDL cholesterol <34 mg/dL, the incidence of adverse events was 17.3% in the placebo group compared with 12.4% fenofibrate group (interaction p=0.06 vs all others).

Abbott representatives at the meeting maintained that this finding supports coadministration of fenofibrate with statins in patients with high triglyceride levels and low HDL-cholesterol levels, but the panel was unwilling to draw any firm conclusions based on subset analysis.

Basing FDA decisions on subset analysis is appropriate only if "the evidence is statistically convincing and clinically sensible, and I have not seen any statistically persuasive data to suggest that the ACCORD data are distinguishable for any subgroup," panelist Dr Sanjay Kaul (Cedar Sinai Medical Center, Los Angeles, CA) argued. "There are some important pieces of information [in the ACCORD data], but I don't think that information is actionable."

Despite the uncertainty, most, but not all, of the panel voted to advise the FDA to keep the statin-coadministration indication on fenofibrate's label.

Panel split on whether to modify existing label

Six panelists voted to leave the indication intact but to add information about the ACCORD results to help physicians and patients make decisions about the risks and benefits of adding fenofibrate to a statin. One of them, Dr David Oakes (University of Rochester, NY), said, "I didn't feel there was really sufficient negative information to remove the indication. That would send a signal that this group feels that this medication, as used, was unsafe or inappropriate. We don't have the data to say that. It would be a different question if we were starting with a blank slate, but we're starting from the present indication."

Dr Edward Gregg (Centers for Disease Control and Prevention, Atlanta, GA) agreed that the indication should stay but more information should be added to the label. "This is a drug and an indication approved on one set of information, and now we're presented with a trial that was not really catered to address this question and required us to go to secondary data that . . . actually provided more support of [benefit] than harm," he said. "But because the overall science is not great here, there should be much stronger labeling and perhaps a more specific indication to prevent overmarketing of this drug to people who are not going to benefit from it."

Three panelists voted to leave the label as is pending further clinical data. Dr Eric Felner (Emory University, Atlanta, GA) explained that he voted for the status quo because "there really wasn't enough information to warrant eliminating or withdrawing the indication, especially since . . . 90% of the [use of fenofibrate] is in patients with very high triglycerides and low HDL, and I was fearful that if we [removed it] you would lose the benefit where most patients get treated." Felner added that he did not believe that adding information about the ACCORD results would be helpful, since subset analysis cannot be relied on, and "everybody agreed that we're going to do a new clinical trial, so we're going to get the proper information in the appropriate way," he said.

Four panelists voted to remove this indication and allow Abbott to market the drug only as monotherapy to reduce triglyceride levels in patients with severe hypertriglyceridemia or to reduce elevated LDL cholesterol, total cholesterol, triglycerides and apolipoprotein B and to increase HDL cholesterol in patients with primary hyperlipidemia or mixed dyslipidemia.

Heckbert voted to withdraw the coadministration indication, because the "FDA ought to be moving toward requiring trial evidence based on relevant clinical cardiovascular outcomes for therapy that's added onto a statin where the goal is to reduce triglycerides or increase HDL." Ophthalmologist Dr Terry Smith (University of Michigan, Ann Arbor) also voted to withdraw the coadministration indication. "I just don't see how we can allow this to be an indication for cotherapy if we're acknowledging a lack of a good evidence base for it."