House to Hold Vytorin Hearings

When Vytorin was approved by the Food and Drug Administration in 2004, the drug--which combines Zetia (which decreases cholesterol absorption) and Zocor (a lipid-lowering agent now available in generic versions)--was touted as an attractive alternative to statins like Pfizer's Lipitor, the country's top-selling drug. Because of its unique combination, Vytorin was designed to both inhibit the body's own production of cholesterol and block the body's absorption of cholesterol from food. Sure enough, the drug hit $1.9 billion in sales for 2006, becoming a big hit for the companies behind them, Merck and Schering-Plough.

But there's little doubt sales would have been substantially lower had the companies immediately released unfavorable results from a clinical trial of Vytorin that ended in the spring of 2006. The so-called ENHANCE trial, made public this week, found that Vytorin was no more effective than using the generic version of Zocor (simvastin) alone. The delay in releasing the results has attracted the attention not only of patients but politicians. The House Committee on Energy and Commerce plans to hold hearings in the next several weeks. NEWSWEEK's Jennifer Barrett spoke with Rep. Bart Stupak, a Democrat from Michigan, who chairs the Subcommittee on Oversight and Investigations. Excerpts:

NEWSWEEK: You actually began investigating the delay in releasing results from the ENHANCE study last fall. What brought the Vytorin clinical trial to your attention before the public was informed?
Bart Stupak:
We have medical people assigned to the staff who had been hearing rumblings in the medical community. Cardiologists, for example, who might have had a patient or two enrolled in the study had sent the information in a long time ago and never heard back about the results. They were wondering: what happened?

The trial ended in April 2006, but the results weren't released until this month. How have Merck and Schering-Plough explained the delay?
They're used a couple different explanations. They've said they used ultrasound machines to get pictures of the participants' plaque levels [the build-up of cholesterol and other substances that, when found in the arteries, can result in heart disease]. They said the ultrasound images were of poor quality and they were trying to get better quality ultrasound. And they've said they didn't have all the information available and that it was biologically implausible. [Skip Irvine, spokesperson for Merck/Schering-Plough Pharmaceuticals, a joint venture of the two companies, responds: "The rigorous study design and analytical process … was time consuming and took longer than we originally anticipated."]

How could the data be "biologically implausible?"
That comment, to us, was the red flag that their study tanked and they were trying to hide that.

When did the companies register the clinical trial on clinicaltrials.gov?
They may have done the basic outline in October [2007] but they didn't put out a release until Jan. 14. They registered the study but not the results.

That's an important distinction.
Even that [October] is almost 18 months after the study ended.

It appears that Merck and Schering-Plough not only postponed the release of the data but considered changing the study's endpoints, which could effectively change the study's results. What changes did they make?
We don't know that and that's why we're still asking for more information. When the results weren't what they thought they would be, they asked an internal advisory panel--these so-called "independent" people--to look at it. And they said, here are the results. How do we put lipstick on this pig? [Irvine says the end points did not change and, even if they had, the end results would not have differed.]

Do we have more information on who was on that panel? I understand some of the members were doctors who were on the companies' payroll.
We know the names and our preliminary understanding is that three of five had some sort of financial interest with these companies. Dr. [John J.P.] Kastelein [of the University of the Netherlands], the principal investigator, was not included in the independent panel. If he is their expert, don't you think the person who designed the trial should be involved in any decision to change the endpoints of the trial? … We're still trying to understand what the communications were between the doctor and Merck and Schering-Plough and the doctors on this panel. [Irvine says that Kastelein "chose to decline to participate in that meeting so that his attendance would not bias the results."]

If it's determined that the companies intentionally withheld the unfavorable study results from the public for nearly two years, could that be punishable under current law?
At the time that this particular study was completed in April of 2006, there was no requirement and there would be no punishment for not putting it online. [A law passed last year now requires the registration and publication of such trial results online.] There is a problem with the delay, though, and it can be punished administratively and maybe elsewhere in the FDA rules and regulations.

What role could the FDA have in this?
Well, we don't know if they contacted the FDA. It's not clear what role the FDA had, or if they were even aware of [the trial data].

Do you think that Schering-Plough and Merck intentionally sought to delay the release of this data?
Do I think they knew about it and attempted to put lipstick on the pig, so to speak? Yes. They knew about it. This was their blockbuster drug. Take away $5 billion or more from these companies, and man … These allegations are very serious though. We've been on this since October, and we have enough information to go for a hearing now. But we've asked for more information. [The company has denied intentionally delaying the release because of the unfavorable results. "Obviously a positive result would have been more favorable," says Irvine. "(But) this was a very challenging study, given the high hurdle set by the study."]

It appears that at least one top executive at Schering-Plough, executive vice president Carrie Cox, sold millions of dollars worth of company stock after the trial ended but before the results were made public. How concerned are you about the timing of such stock sales?
Before it's made public, if you have insider information, it's definitely illegal. That bothers us quite a bit. They kept it for so long [without releasing the results] then tried to rehabilitate the study and then that fails. Do they then start dumping the stock? We really want to get into this a little more. [Stephen Galpin, a spokesperson for Schering-Plough, responds: "The company has a rigorous process that executives follow before initiating any transaction in company securities including pre-clearance with a securities lawyer. Carrie Cox followed these processes as well as filing required SEC disclosures about the transactions on time. To date the company has received no inquiry from a regulatory body relating to her trades. These trades go back to the spring of 2007 and the data for this trial were only unblinded about two weeks ago."]

According to estimates, the companies have spent more than $250 million in the last couple of years to advertise Vytorin.
In April 2006, when the trial ended, I probably didn't know what Vytorin was. But with the heavy advertising in the last year or so, we all know what it is now. Those ads, which show the food and the relatives [two sources of cholesterol], target a certain patient. The assumption is that lower cholesterol means reduced plaque means reduced risk of heart attack and stroke. But in some patients in this study, the amount of plaque increased … What we're wondering now is, was there an uptick in advertising after they knew the trial results? [Irvine declines to answer that question directly but says the company has "supported Vytorin competitively in all aspects of marketing, sales and managed care since it launch in 2004, including direct to consumer advertising ... in a manner that is consistent with what would be expected of a top-tier product in a highly competitive therapeutic category."]

Doctors wrote about 18 million prescriptions for Vytorin and about 14 million for Zetia in 2006, making them among the most commonly prescribed cholesterol-lowering drugs, and their popularity has continued to grow. Is there concern here that some of those patients might have been better served by other cholesterol-lowering drugs--or, at least, could have saved money by using a generic version of Zocor?
From what I understand, it's just under $4 per pill for Vytorin and about $2 for Zocor [or generic versions].

That could be an issue for patients who are on a tight budget and are paying out of pocket.
It's also an issue for the government, and for taxpayers, because of Medicare and Medicaid--we pay for all that. So we want to see how much Medicaid and Medicare has spent on Vytorin since April 2006 to the present day.

Did the FDA approve these drugs prematurely?
Drug studies go through four phases, really--the fourth is always the American people. You had very limited studies, and the theory behind it is, you had a key group of people you are trying to treat. The protocol of the study--the FDA approved that--and therefore the companies could use it. I have a problem, though, with: Where is the FDA? Whey aren't they bringing all this out? To get them to do anything after they approve a drug, it's hard.

So what happens now?
More letters are going out [from Stupak's committee to the companies] zeroing in on specific issues. We're asking specifically about the cashing in on stock options. There will be hearings ... The night before the hearings, they'll probably drop off all the documents and then we'll probably find the nuggets we're looking for.