August 10th, 2011
Rethinking Trilipix — And the Process for Approving Lipid-Modifying Drugs
Editor’s Note: In an article published in the New England Journal of Medicine, three members of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (Allison Goldfine, Sanjay Kaul, and William Hiatt) offer their perspective on the May 19 committee meeting to review the controversial ACCORD-Lipid Study. Here, one of those authors, Sanjay Kaul, provides his own account of the session for CardioExchange members.
After reviewing data from the ACCORD Lipid Study, the 13-person Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the FDA has voted unanimously to request that Abbott conduct a new trial of its lipid-modifying drug Trilipix (fenofibric acid). Specifically, EMDAC advises that the trial identify whether men and women who are at high risk for coronary heart disease (CHD) and who have already reached their LDL-cholesterol goals on a statin — but who have persistently high triglycerides and low HDL levels — benefit from Trilipix as add-on therapy.
The original, NHLBI-sponsored ACCORD Lipid Study involved 5518 high-risk patients with type 2 diabetes and LDL levels of 60 to 180 mg/dL (mean, 101 mg/dL). Combination therapy with daily Trilipix (160 mg) plus simvastatin showed no advantage over placebo plus simvastatin in preventing adverse cardiovascular events during a mean follow-up of 4.7 years (annual rate, 2.2% vs. 2.4%). Among women treated with Trilipix, there was a suggestion of harm from the drug; among the subgroup of patients with baseline triglyceride levels ≥204 mg/dL plus HDL levels ≤34 mg/dL (the so-called “dyslipidemic profile”), there was a suggestion of benefit.
Penetrating the nuances of the new EMDAC recommendation requires some background beyond these facts.
A Brief History of Fibrates
After statins, fibrates are the most widely used lipid-modifying agents. Annual sales in the U.S. for the three fibrates currently approved by the FDA to treat hyperlipidemia — gemfibrozil, fenofibrate, and fenofibric acid (Trilipix) — are in the billions of dollars. Trilipix is the only fibrate approved as combination therapy with a statin to reduce triglycerides and increase HDL levels in patients who have mixed dyslipidemia and CHD or a CHD risk equivalent (and who are on optimal statin therapy to achieve LDL goals). The Trilipix/statin combination-therapy approval was based on three 12-week studies of the drug’s impact on lipid biomarkers. No clinical-outcome data currently support this indication.
Indeed, unlike statins, fibrates have had mixed results in placebo-controlled trials when it comes to reducing CHD risk and actually saving lives. Studies of gemfibrozil (conducted before the statin era) have shown primary- and secondary-prevention benefits, whereas trials of fenofibrates have not (see this recap of major fibrate trials). And as summarized above, the recent ACCORD Lipid Study did not show a benefit of fenofibric acid as an add-on to simvastatin in high-risk patients with type 2 diabetes and mixed dyslipidemia.
Nevertheless, fibrate use in the U.S. doubled from 2002 to 2009. Furthermore, the two agents with no clear demonstrated benefit — fenofibrate and fenofibric acid — are gradually displacing gemfibrozil in terms of market share: Fenofibrates and fenofibric acid now command about three-quarters of the fibrate market, compared with about one-quarter for gemfibrozil. Fenofibric acid specifically is used (as add-on to a statin) primarily in dyslipidemic patients, in line with the indication on the prescribing label.
The FDA Committee’s Discussion and Vote
From its review of the ACCORD Lipid Study, EMDAC determined that the trial was not specifically designed to assess the clinical benefit of treating patients with residual low HDL and high triglyceride levels who were on a full-dose statin. Thus, the trial could not adequately evaluate the benefits of Trilipix as add-on therapy.
With regard to the two prespecified subgroup analyses (gender and “dyslipidemic profile”), the committee expressed general caution against acting on the basis of these data. They cited, among other concerns, that the trial as a whole was negative, that the analyses were limited by relatively small numbers of patients and events, and that other relevant adjustments were not performed.
The unanimous vote to call for a new trial came despite the fact that the trial’s aim would be to prove whether the indications already listed on the current medication label are supported by evidence of clinical benefit. With regard to how to handle that conundrum, the committee’s vote was split: 3 in favor of maintaining the current label, 6 in favor of revising the label, and 4 in favor of withdrawing the approved indication.
The committee also discussed the regulatory standard for approving lipid-modifying agents (currently based on proof of improvements in surrogate lipid biomarkers). Some members said that the FDA should instead consider requiring a preapproval cardiovascular-outcomes trial. Others felt that the current surrogate-biomarker–based approval process allows potentially beneficial therapeutic options to become available before results from a definitive outcome study can be obtained.
The Regulatory Fallout
In my opinion, the EMDAC decision has major regulatory implications. Taken together, the data from the ACCORD Lipid Study, ILLUMINATE, and AIM-HIGH strengthen the argument for changing the standard for approving lipid-modifying therapies: from an emphasis on surrogate lipid biomarkers to one on clinical benefits and cardiovascular outcomes. Although such outcome trials are likely to be time- and resource-intensive, if the duration of drug patents were extended, financial risk to the manufacturers would be mitigated. Pharmaceutical companies could fulfill the preapproval outcome-trial requirement yet still have sufficient time to market the drug and earn a return on their investments.
Specifically with regard to Trilipix, if the FDA were to ask the sponsor to conduct the clinical trial recommended by EMDAC, the following conditions would need to be considered:
- Start the trial ASAP, preferably within 6 to 9 months of the FDA’s decision.
- Enroll high-risk cohorts of interest (at least 30% to 40% women and minority groups; at least 50% patients with a “dyslipidemic profile” of elevated triglycerides plus low HDL).
- Ensure proper trial design and conduct, and minimize rates of crossover and dropout.
- Enroll subjects quickly and complete the study within 3 to 5 years.
- Allow the FDA to withdraw the indication if the sponsor does not complete the trial in a timely and efficient manner. Only then would the FDA be able to discourage the sponsor from taking an approach like Merck’s with ezetimibe or GlaxoSmithKline’s in RECORD.
What are your thoughts on the EMDAC recommendations with respect to Trilipix? Does this development affect how you view the general process for approving lipid-modifying drugs?