Tuesday, May 24, 2011

Abbott Trilipix Demonstrates the Sponsor-As-Bystander

FDA is holding more advisory committees than ever and it’s hard for some not to get lost in the mix.

Take the May 19 Endocrinologic & Metabolic Drugs Advisory Committee meeting, for example. The committee was convened to review data from an outcomes trial that was more than a year old, with no overall safety signal, for a class of drugs that have been on the market for years.

Nevertheless, the panel meeting proved to be an important one, not only for the sponsor involved, Abbott Laboratories, but for drug developers in general.

To recall, the advisory committee was convened to review the results of the ACCORD-Lipid trial and how they relate to the approved indication for Abbott Laboratories’ Trilipix (fenofibric acid) for coadministration with a statin.

The results from the National Heart, Lung and Blood Institute-conducted ACCORD study were released in March 2010. The trial was the first major cardiovascular outcome trial to evaluate the combination of fenofibrate (Abbott’s Tricor) with a statin in a diabetic population and compare it to statin monotherapy.

After an average follow-up of 4.7 years, there were 291 (10.5%) major fatal or nonfatal cardiovascular events in the fenofibrate-simvastatin therapy study arm and 310 (11.3%) events in the simvastatin monotherapy study arm; the results were not statistically significant.

Not a great result for Abbott, to be sure, considering the company’s Trilipix/Tricor franchise generates over $1 bil. in US revenue. Panelist William Hiatt (University of Colorado Denver), a former chairman of the Cardio-Renal Advisory Committee, was blunt: “It’s a clearly negative trial.”

Abbott was clear upfront that the company had nothing to do with ACCORD. James Stolzenbach, Dyslipidemia Divisional VP, who handled the MC duties for the company during the sponsor presentation, made clear that Abbott was not seeking a new indication for Trilipix nor did the company conduct or have a role in conducting the ACCORD study; Stolzenbach “apologized in advance” to the committee if Abbott could not answer all the questions asked of them because the firm was not privy to the full dataset.

Stolzenbach’s comments underscored the fact that Abbott was a bystander for a critical regulatory re-review of one of its most important product franchises. In essence, the company was watching while one agency, FDA, was figuring out what to do with the results of a government-run study conducted by another agency, NIH.

The way the advisory committee review was set up and played out, it appeared clear that FDA has wanted Abbott to conduct another trial of a fibrate/statin combo for some time and the way to do it was take the question to panel in the absence of an overt safety signal that would trigger the agency’s authorities under the FDA Amendments Act.

In a memorandum dated April 25 from Division of Metabolism & Endocrinology Products Deputy Director Eric Colman to the committee, a key question—question 6—was originally proposed with five options for the committee to vote on and the committee could recommend more than one action:

a) allow continued marketing of Trilipix’s indication for coadministration with a statin without revision of the labeling;

b) withdraw approval of Trilipix’s indication for coadministration with a statin;

c) allow continued marketing of Trilipix’s indication for coadministration with a statin with revision of the labeling to incorporate the principal findings from ACCORD-Lipid;

d) Require the conduct of a clinical trial designed to test the hypothesis that, in high-risk men and women at LDL-C goal on a statin with residually high TG and low HDL-C, add-on therapy with Trilipix versus placebo significantly lowers the risk for MACE; and/or

e) other.

But in the draft questions to the advisory committee, question 6 was broken up into two parts, A and B. Question 6A asked the committee to vote first (“yes” or “no”) on whether FDA should require a new study as described above in d). Question 6B asked the committee to vote for only one option of the following: no change to the Trilipix indication, withdraw the indication for coadministration with a statin, or allow continued marketing of Trilipix with a revision of the labeling to include the principle findings from ACCORD.

The panel voted unanimously (13-0) that Abbott should conduct another clinical study. Specifically, the trial should study the hypothesis that in high-risk men and women at LDL-C goal on a statin with residually high triglyceride levels and low HDL-C, add-on therapy with Trilipix versus placebo significantly lowers the risk of major adverse cardiovascular events (MACE).

Now, it appears as though Abbott will have to conduct a large clinical study that, if positive, would show an outcome benefit for a more defined patient population than the broader FDA-approved indication the company already has.

We asked Cleveland Clinic cardiologist Steve Nissen, an occasional Cardio-Renal panelist, for his take on the ACCORD study. “These drugs have done amazingly well in the absence of any evidence of a health outcome benefit,” he said. “Trilipix was approved to ‘reduce triglycerides’ based upon the premise that high trigs are associated with pancreatitis. Only one problem – no one has ever demonstrated that lowering trigs with fenofibrate or fenofibric acid actually reduces the incidence of pancreatitis.”

Nevertheless, the Trilipix advisory committee review highlighted the lack of control Abbott had over the review of its product. That outcome could befall other sponsors as they are further removed from postmarket evaluations of their products.

Call it Bystander Syndrome.

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