FDA Advisors: Reject Secondary-Prevention Ezetimibe Indication

Deborah Brauser

December 14, 2015

SILVER SPRING, MD ( UPDATED ) — The Endocrinologic and Metabolic Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted 10 to 5 against recommending the expanded use of ezetimibe (Zetia, Merck) by adding it to statin therapy for reduction of cardiovascular events in patients with coronary heart disease.

The committee met to discuss the secondary-prevention IMPROVE-IT trial, which has been reported by heartwire from Medscape throughout its journey, including presentation at last year's American Heart Association annual meeting and its publication in the New England Journal of Medicine this past summer.

Most of the panel members who voted "no" said that the results were just not clinically substantial. "There was a weak and not particularly robust effect," noted Dr Susan R Heckbert (University of Washington, Seattle).

Interestingly, the panel asked for a definition of "substantial evidence" right before voting and were told that "the drug will have the effect it purports to have." And if evaluated in a single trial, it needs to have an "excellent design and be highly reliable."

Panel chair Dr Robert J Smith (Brown University, Providence, RI) said that this was a difficult vote for him but that he needed to vote "no" after hearing the narrow definition. "I do think this is a positive, albeit modest, trial. I don't think it communicates that this drug is not effective in lowering risk; I suspect that it is effective. However, we just don't know that yet," Smith said.

Dr Milton Packer (Baylor University Medical Center at Dallas, TX) also voted against recommendation. "If we gave the investigators the task of doing this trial again, would they find the same things? I don't know. It's a coin toss and that gives me pause."

Several of the panel members also noted concerns with risk for hemorrhagic stroke, about how estimates were handled for "missing" primary end-point data for 11% of the patients, and that the application overreached in wanting to extend ezetimibe for addition to all statins for all patients with CHD.

Perfect: The Enemy of Good?

IMPROVE-IT included more than 18,000 patients with post–acute coronary syndrome and showed that those randomized to ezetimibe/simvastatin (Vytorin, Merck) had a 6.4% relative-risk reduction and a 1.8% absolute-risk reduction of the composite end point of major CV events (CV death, nonfatal MI or stroke, revascularization, or hospitalization) compared with those who received simvastatin alone.

Discussions and debates went on throughout the day about analyses and subanalyses from the trial, on the patient population and subgroups, and about LDL-cholesterol management itself.

Dr Brendan M Everett (Brigham and Women's Hospital, Boston, MA) was among the five "yes" votes. "Perfect is the enemy of the very good. It's just not possible to do a perfect trial to get the perfect answer to the clinical question," he said. "From my standpoint, this does represent substantial evidence that supports approval."

"I think there is a modest, unmet need for add-on LDL-lowering therapy in patients with coronary syndromes," added Dr Michael J Blaha (Johns Hopkins Hospital, Baltimore, MD). "And it's not uncommon for clinicians to deal with an effect size that's small."

Dr William R Hiatt (University of Colorado School of Medicine, Aurora) attended the meeting via phone and also voted for recommending approval. "I was a little surprised by the majority voting 'no' because the IMPROVE-IT trial was positive," he said.

"The discussion of statistical significance vs clinical relevance has come up a number of times. And it seems that the history has been that the FDA's role is to decide if a study is positive or not; and other bodies, such as payers or guideline committees, decide what's clinically significant or applicable," said Hiatt.

At the end of the day, Packer suggested a possible addition to the medication's labeling. "There are not enough data right now for the claim. But I think 18,000 patients followed for 7 years deserves a description in the clinical-trials section, with appropriate caveats and a mention of the concerns expressed today," he said.

"Substitute this for the current language that says 'the effect of this drug on cardiovascular events is unknown.' Otherwise, keeping the current line in the package label is to say this trial didn't teach us anything. And that's not fair."

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