Keeping Your Hands Clean  
3/31/2008 6:08:32 PM

Keeping Your Hands Clean

Let's start with a summary of the events so far: After a nearly two-year delay, Merck and Schering-Plough finally release results of the now-notorious ENHANCE study. The study looked at 720 patients with a genetic predisposition leading to very high cholesterol levels. Researchers compared the effects of Vytorin (a combination of the generic statin Zocor and the branded drug Zetia) versus Zocor alone. They looked at the formation of arterial plaques as well as the incidence of various cardiovascular events.

The surprising result: Vytorin is seemingly no better than Zocor and actually trended worse in plaque formation. And now the fallout: Reps. John Dingell (D-Mich.) and Bart Stupak (D-Mich.) are investigating the delay in releasing the results, as well as the fact that the companies hired a not-so independent panel to look at changing the study endpoints after the fact.

Then renowned cardioligist Steven Nissen of the Cleveland Clinic went on NBC to say that Vytorin and Zetia should be prescribed only as drugs of "last resort." (Nissen is known, among other things, for his role in highlighting potential risks associated with GlaxoSmithKline's diabetes drug Avandia). Then the American College of Cardiologists (ACC) came out with a statement saying that reaction to the ENHANCE study has been overblown, that there is no reason to take patients off the meds, and that we should wait for further studies, expected over the next couple years, to shed further light on the situation. This echoed several Wall Street analysts, one of whom rather bizarrely called the study results a "non-event."

Still with me? Okay. ACC is right to say that there's no need to panic. Vytorin did do a good job lowering LDL cholesterol, and had a nearly identical rate of cardiovascular complications. The trend toward plaque formation was not statistically significant, and may even have something to do with lousy study design and poor data--the ultrasound images of arterial plaques were reportedly hard to read and sometimes yielded results that weren't biologically possible, leading one to question the quality of the results. It may even be that further studies will ultimately highlight advantages of the expensive branded drugs, though right now things seem to be cutting the other way.

But there's no mystery that the billions of dollars in sales brought in by Zetia and Vytorin since the conclusion of ENHANCE in April 2006 posed a pretty strong incentive to delay any bad news. No matter what the reasons were, it sure looks bad.

Is there a solution to problems like this? Yes. Put the clinical databases in the hands of the study researchers, not the company. That should be a no-brainer, and it's increasingly done in clinical trials...but it wasn't for ENHANCE. Merck and Schering-Plough claim an almost two year delay was caused by the difficulty in going through massive piles of data, but they'd be a lot more credible if the data scrubbing were out of their hands. As it stands, it's hard not to give some credence to the conspiracy theorists.

The icing on the cake? Pharmalot reports that the unsigned ACC statement urging calm was drafted in part by Roger Blumenthal, director of the Ciccarone Cardiology Center at Johns Hopkins, who is also on the speaker's bureau for Merck and Schering-Plough and has received research grants from Merck. I don't think there's anything to that--Blumenthal has been on record himself questioning the delay of the ENHANCE study results as an ominous sign. But industry and ACC need to take a reminder from this: Appearances matter. Disclosure is easy, and it takes firepower away from your enemies.