Monday, December 14, 2015

FDA Committee Is Meeting Right Now -- To Discuss Label Expansion For Merck's Vytorin®/Zetia®: Cardio Protective?

FINAL UPDATE: Advisory Committee votes 10 to 5 AGAINST new indication. Pretty surprising -- and of course, the full FDA need not follow the panel's recommendation -- so Merck could still pull one out of its hat -- but those will be long odds, now. Thanks again go to Larry for liveblogging it all! More in a later post, tonight.

Sometime in early 2016, if all goes well today, Kenilworth will be able to add a claim to the labels for the above two drugs, indicating that -- at least for diabetics over the age of 75 -- taking the pills may reduce one's clinical risk of heart attack, stroke and/or MI. That is a full nine years after then Schering-Plough CEO Hassan proclaimed that the drug would take the world by storm -- and propel Scheing-Plough back to the top of the multi-national pharmaceuticals heap.

[So much has happened since then -- most of it not very helpful to the fortunes of these drugs. Just search Vytorin in the box above, to see some 300 posts on the topics, generally.] I'll link only this one of my backgrounders, though -- which as my graphic at right indicates -- may well mean that the label change is more an academic victory than a meaningful real world clinical outcomes acheivement. That is, not likely to be one that drives a wide change in prescribing patterns, in the US.

Updated: Dr. Larry Husten is live blogging the committee sessions, here -- do go listen in. . . . We will let you know how today's meeting turns out, end of day, here. And here is a bit of the FDA's material data-set -- on the topic -- for the Advisory Committee's discussion this day:

. . . .The committee will discuss the results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). IMPROVE-IT was a clinical trial that studied the effect of ezetimibe/simvastatin compared with simvastatin on the occurrence of cardiovascular events in patients with recent acute coronary syndrome. The results from this trial have been submitted to support supplemental new drug applications 21445/S-038 and 21687/S-054, ZETIA (ezetimibe) and VYTORIN (ezetimibe/simvastatin) tablets, respectively, by MSD International GmbH. The proposed indication for ZETIA (in combination with a statin) and VYTORIN is to reduce the risk of cardiovascular events in patients with coronary heart disease. . . .

To be clear, I do expect the committee will recommend a narrow label expansion to the full commission, and in mid January 2016, Merck will have spent perhaps $700 million on IMPROVE-IT -- to preserve a small tail for these now fading franchises. So it goes. John McCain was wrong about many things in 2008, but he was right insofar as he chose a generic statin, over Vytorin, in my opinion. Onward -- on a warm but rainy Monday!

UPDATED: 12.14.2015 @ 2:48 EST: Larry Husten's live blogging has been invaluable -- here is just a bit -- but the conclusion among the whole committee seems to be that the effect seen, though positive (in a generally very well-designed and well-run study of over 18,000 people), was very, very small.

. . . .12/14/2015 13:53 -- [Committee member] Blaha: one has to be very careful-- but both diabetic and old age subset are at higher risk-- especially when effect size is small then it will be easier to see the benefit. But warns against over-interpreting the subgroup. . . .

. . . .12/14/2015 13:27 -- Committee Chairman's summary: everyone agrees it was a remarkable trial. Universally committee agrees that the effect on the primary endpoint is relatively small. Perhaps some difference of opinion about how to manage the statistical significance and a number of panel members express some questions about whether it really convincingly demonstrates signficance. . . and some questions about whether it met anticipated goals.

A general view of uncertainty about the clinical signficance of the magnitude of effect. That has given us pause. . . .

Many members were concerned about the missing data. . . .

12/14/2015 13:06 -- [Committee member] Fleming is spectacularly unimpressed by this trial: 88,000 person years, 5,000 primary endpoint events -- 16 fewer deaths, 16 fewer STEMIs, and overall 60 endpoint events. We know the truth. Fleming says the problem isn't that the trial is underpowered but that it is overpowered for its primary endpoint-- "There's no difference at all, especially when I look at things that matter. . . ."

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