An FDA advisory panel on Monday voted 10-5 against an expanded indication for Merck’s ezetimibe (Vytorin, Zetia). The current label states that the drugs have not been shown to improve cardiovascular morbidity or mortality. The proposed expanded indication was based on findings from the IMPROVE-IT trial.
The panel spent most of the day trying to interpret the trial, which resulted in a small but statistically significant 6% reduction in the risk of cardiovascular events in more than 18,000 patients with a recent acute coronary event followed for 7 years.
A number of speakers expressed agreement with panel member Thomas Fleming (University of Washington), an influential statistician: “the goal of clinical research should not be to achieve statistical significance.” There was widespread agreement with another panel member, Sanjay Kaul, who said he was “not convinced there’s a robust treatment effect.”
Even panel members who voted in favor of the proposed indication, such as Michael Blaha (Johns Hopkins), agreed that the effect seen in the trial was small. Nevertheless he said the trial has “practice implications.”
Robert Shamburek (NHLBI) also voted for the indication. He said IMPROVE-IT was a “clinically important trial in a population with an unmet need.” The results, he said, are consistent with previous analyses of cholesterol lowering drugs.
Milton Packer said that “the limitations of this trial have nothing to do with the investigators or their conduct of the trial. The limitations have to do with the nature of the benefit. The benefit here is small. It is not robust. You blink and you miss it.”
An important issue raised by the FDA reviewers was incomplete data from the IMPROVE-IT trial. For the primary endpoint data was available for only 91% of the randomized patients. But in the end, despite a lot of discussion, the missing data did not appear to be a central factor in the committee’s thinking. The general feeling was that the missing data was only important because the main results were so marginal. The missing data only served to highlight the already weak edifice of the trial results.
The FDA reviewers also expressed concern about the finding that nearly all the benefit from ezetimibe in IMPROVE-IT occurred in diabetics and in patients over the age of 75. In the end this didn’t appear to greatly influence the committee, as they remained cautious. A subgroup analysis should only be used to generate a hypothesis, they agreed.
The committee also struggled with Merck’s request to apply the results of the IMPROVE IT trial in ACS patients to the more general population of CHD patients. The committee generally agreed that there is a continuum between acute patients and chronic heart disease patients but were concerned that the small effect seen in IMPROVE-IT would become even smaller in the chronic population.
There was good and bad news for ezetimibe on the safety front. Everyone agreed that the IMPROVE-IT trial provided no support to strengthen the cancer signal seen in the SEAS trial in 2008. On the other hand, the committee did express concern about a small but troubling increase in hemorrhagic strokes in the ezetimibe group.
Colin Baigent (Oxford University) presented data from theCollaborations showing that a very small increase in the risk of hemorrhagic stroke has been consistently seen with statins. He said that the finding in IMPROVE-IT was “something we would expect” and helps support the idea that the other benefits with ezetimibe were real.
After the vote Milton Packer pointed out that ezetimibe remains available and that “everyone who wants to use this drug for risk reduction in cardiovascular disease can use it right now with the current label… You don’t need the label change.”
Packer said that although the trial did not provide sufficient evidence to support a change in indication, he thought it would be a “useful addition” to the clinical trials section of the label. “It’s not a claim. It’s a piece of information… The sponsor has made an enormous effort to define that. It’s a narrow and unimpressive effect, but… it’s not fair to say that this trial didn’t teach us anything.”