The Vytorin Question

[JohnMack]

Source: Forbes.com

Matthew Herper

Every day millions of people swallow Zetia and Vytorin in the hopes of reducing their risk of heart attacks and strokes, generating $5 billion a year in sales for Merck and Schering-Plough, which produce them.

Do they work?

Despite millions of prescriptions, no study has ever shown that these $3-a-day pills prevent heart attacks, strokes or deaths any better than just taking older drugs like Pfizer's Lipitor or Merck's off-patent Zocor, even though they're proven cholesterol fighters. That's why a two-year delay in a 720-person study aimed at clarifying the issue has cardiologists expressing skepticism and spinning conspiracy theories. If the news were good, the companies would rush it out, the thinking goes. Delay doesn't bode well.

"It starts to raise suspicion," says Allen J. Taylor, head of cardiology at Walter Reed Army Medical Center. "The more time it takes, the more you start to naturally wonder what is wrong."

Roger Blumenthal, a director of the Ciccarone Cardiology Center at Johns Hopkins, says he currently suspects the trial may not show a benefit for Vytorin. "I think anyone would have to think that," he says. He blames the study's design, not problems with the drug itself.

The study, called ENHANCE, began in 2002 to answer the question of whether Zetia increases the effectiveness of Zocor at preventing heart attack by keeping plaque from building up in the arteries. Vytorin is a combo pill of Zetia and Zocor.

Zocor or Vytorin was given to 720 patients with a genetic disorder that causes high cholesterol. Ultrasound pictures were taken of arteries in their thighs and necks. If adding ezetimibe, the crucial ingredient in the drugs, was good for the arteries, the people who took Vytorin would have less heart attack-causing plaque than those who just got Zocor.

All the patients had been treated, and their arteries measured, by April 2006. Cardiologists expected to see results at a medical meeting in November, then at another in March 2007, then at another this month. But none materialized. Schering-Plough and its researchers say the delay springs from technical difficulties reading more than 30,000 artery pictures. Researchers are "reading thousands and thousands of pictures and trying to validate them and make sure the data is right," says Fred Hassan, Schering's chief executive.

"I certainly want it finished," says John J.P. Kastelein of the University of the Netherlands, who led the study. "There are all sorts of conspiracy theories that are not good for my reputation."

Schering and Merck did not list the trial on the government Web site clinicaltrials.gov, which is supposed to have records of all clinical studies, until asked by Forbes.com about its absence. The companies say that it was an oversight resulting from the fact that ENHANCE began before the industry listed every study online.

Another source of suspicion: Top clinical trial experts often now recommend that the outside researchers conducting a study, not the company, have control over the computerized database created to analyze study results. In this case, that database is held by Schering-Plough.

But Kastelein says nothing nefarious is going on with the trial. Explaining the delays, he narrates a long tale of woe, including switching from roomfuls of VHS tapes to new digital imaging technology, training technicians and insuring the security of Internet connections.

The study was the biggest Kastelein had ever attempted. His last project had looked at the arteries of 350 patients at two medical centers. ENHANCE signed up three times as many patients at 26 different medical centers. But everything went smoothly, he says, in terms of recruiting patients and taking artery measurements.

Still, ENHANCE is being delayed again. Schering Plough and Kastelein decided the data needed a rescrubbing through quality control. Kastelein says he thinks that the fact that patients were randomly assigned one treatment or another would solve some of the differences. He says Schering is within its rights to want every "i" dotted and "t" crossed. The delay won't change the way the data is analyzed. Results are now expected at a medical meeting in March.

Skeptics remain. Walter Reed's Taylor worries that if Schering doesn't think the results are positive, its incentive is to delay as long as possible in the hope that better data might emerge from another study. But Paul D. Thompson, director of cardiology at Hartford Hospital in Connecticut, counters that he's not overly concerned about the delay. Kastelein is "a stand-up guy," he says, and the stakes are high. A bad result would cause Pfizer and AstraZeneca sales reps to turn up at every hospital in the country "within milliseconds."

"We'd all agree that having this long a delay after a study's over is a bad thing," says Robert Califf of Duke University, who is one of the leaders of a giant study comparing Vytorin and Zocor on their ability to prevent heart attacks. "I sure hope Zetia works," he says. "I'm taking it myself."

Other doctors argue that even if the data show no difference, it might not mean all that much. Hopkins' Blumenthal notes that only one study has shown that a cholesterol-lowering pill actually reduced artery plaque. "This isn't going to determine the future of Vytorin," he says. For that, doctors will have to wait for studies like the one Califf is conducting.

Prediman K. Shah, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, says that lowering cholesterol is almost always a good thing, and it would not make “an iota of sense” for Zetia not to work. However, Richard Lange of Johns Hopkins University notes that so far there is no evidence patients get extra benefit from adding Zetia. “They're going to have to explain exactly what the delay was,” Lange says. “At that point we'll have enough information to know it passes the sniff test.”

At the very least, the story of the delayed Vytorin trial shows the immense pressure companies are under to prove their medicines really work as advertised--and to show how easy it would be for them to delay negative results. Right now, there's really no way to know what's going on with ENHANCE--at least, not until the data are made public.

Update: After this story’s publication, Merck and Schering-Plough issued a press release (see "Merck/Schering-Plough Pharmaceuticals Provides Update on ENHANCE Trial"; see Reply) saying that they had convened an expert panel on Nov. 16 to offer advice on how to analyze the ENHANCE trial. The panel recommended focusing only on arteries in the neck, not in both the neck and the thigh. John Kastelein, the study's lead investigator, said in a statement that the results should be available at a medical meeting in March.

[JohnMack]

Source: Merck Press Release

Merck/Schering-Plough Pharmaceuticals Provides Update on ENHANCE Trial

WHITEHOUSE STATION, KENILWORTH, N.J., Nov. 19, 2007 - Merck/Schering-Plough Pharmaceuticals today announced that an independent panel of clinical and biostatistics experts was convened on Friday, November 16, 2007 to offer advice about the prospective analysis of the ENHANCE trial. ENHANCE is a multinational, randomized, double-blind, trial that examines the effects of the highest approved dose of VYTORIN/INEGY (10 mg ezetimibe + 80 mg simvastatin) versus the highest approved dose of simvastatin 80 mg alone in patients with Heterozygous Familial Hypercholesterolemia (HeFH). Patients with this uncommon genetic condition usually have very high cholesterol levels. HeFH occurs in approximately 0.2 percent of the population.

The independent panel recommended focusing the primary endpoint to the common carotid artery to expedite the reporting of the study findings. Merck/Schering-Plough now anticipates that these results of the ENHANCE study will be presented at the American College of Cardiology meeting in March 2008.

While the clinical portion of the ENHANCE study is complete, the study remains blinded and the data are now being analyzed. The rigorous study design and analytical process specified in the study protocol require examination of more than 40,000 scans of the arterial intima-media thickness (IMT) of the carotid and femoral arteries collected in eighteen multi-national study sites. This has been time consuming and taken longer than originally anticipated because during the analysis, observations of variability in some of the data were detected as part of the validation/data review procedures. Such potentially confounding observations are not unusual in studies of this kind.

The primary objective of the ENHANCE trial is to measure the change in the intima media thickness at three points of the carotid artery (the internal carotid, carotid bulb and the common carotid), at the beginning of the study and at two years. The ENHANCE trial employs a novel non-invasive methodology to assess the intima-media thickness using digital single-frame ultrasound imagery of the arteries. This technique was pioneered by Professor John Kastelein, the lead investigator of the ENHANCE study.

"It is critically important for researchers to take the appropriate time and rigor to conduct clinical trials, analyze data and report study results. The ENHANCE trial is complex and is being conducted with great care," said John Kastelein, M.D., Ph.D., professor of medicine and chairman, Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands. "We view the experts panel's recommendation to narrow the primary endpoint to the common carotid artery as helpful, and we will continue to expedite the completion of ENHANCE and reporting of its results, while ensuring the integrity of the data." Kastelein added, "We anticipate that results of the ENHANCE study will be presented at the American College of Cardiology meeting in 2008, dependent upon successful completion of the data analysis."

About ENHANCE
The ENHANCE study was initiated in 2002, and involves over 700 HeFH patients. HeFH is characterized by markedly elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol (LDL-C), typically well above the 95th percentile for age and sex.i Images from HeFH patients in this study are analyzed from the right and left carotid arteries at numerous time points (baseline, 6, 12, 18 and 24 months). Images of the femoral arteries are also analyzed at numerous time points in the ENHANCE trial, a surrogate endpoint study.

In addition, Merck/Schering-Plough Pharmaceuticals is conducting a robust clinical outcomes studies program to evaluate the effects of VYTORIN/INEGY, which includes more than 20,000 high-risk patients enrolled in three outcomes studies: SHARP, SEAS and IMPROVE-IT.

More...

[JohnMack]

Source: TheLedger.com


ALEX BERENSON

Prescriptions for the cholesterol-lowering drugs Zetia and Vytorin are written for almost 800,000 Americans every week, at a cost this year of about $4 billion. Yet it still is not clear how well the drugs work.

Nearly two years after the medicines’ makers, Merck and Schering-Plough, completed a clinical trial of the drugs, they still have not released the findings. The delay has led to a growing chorus of complaints from cardiologists. And yesterday, the companies responded by promising to publish a portion of the results next March — but not the entire set of data.

Doctors say that decision is highly unusual and will do little to quell concerns about the trial, as well as broader questions about the effectiveness of the drugs.

Cardiologists have been awaiting the results of the trial, called Enhance, to learn how well Zetia and Vytorin work. If they are not as effective as other cholesterol medicines, patients taking them may be putting themselves at unnecessary risk of heart attacks.

“There’s clearly some rightful interest in what the results are,” said Dr. Allen J. Taylor, chief of cardiology at Walter Reed Army Medical Center. “You’ve got millions of people treated with the drugs.”

Whatever its results, the trial will not answer all questions about Zetia and Vytorin, either positively or negatively. Those answers may have to wait for a bigger study that will not be completed until at least 2010. But with so many patients taking the drugs, cardiologists are looking for whatever information they can get.

The delay in publishing the Enhance results also raises broad questions about whether the drug industry is sticking to its promises to improve the disclosure of clinical trials. After sharp criticism for failing to disclose trials that had negative results, drug makers promised two years ago to publicly register clinical trials in advance and promptly disclose their findings. But in practice they face few penalties for failing to meet those promises.

Of particular concern in this case is that Merck and Schering-Plough said yesterday that they had changed the trial’s “primary endpoint” — the main medical result being measured. The companies now say that they will use only partial results to assess the trial’s success in deterring the formation of plaque that can cause artery blockages and lead to heart attacks.

Merck and Schering-Plough say that the change is appropriate and will enable them to finish their work in time to present the trial’s results in March, at the American College of Cardiology annual conference in Chicago.

But scientists generally assume that for a clinical trial to be valid, its goals must be defined before it begins and never changed afterward. Otherwise, the people conducting the trial could change their goals to conform to the data the trial has actually produced.

“This sounds highly unusual to me,” said Dr. Bruce Psaty, a professor of medicine and epidemiology at the University of Washington. “You need to live with your primary endpoint.”

Another big drug maker, Pfizer, for example, was harshly criticized in 2001 for reporting that its painkiller Celebrex caused fewer ulcers than older drugs after six months of use. Pfizer’s study had originally been designed — but failed — to show that Celebrex caused fewer ulcers after a full year of use.

Yesterday, Merck and Schering said they did not yet know the results of the trial. They said they were changing the endpoint only because they want to be able to analyze the data more quickly.

A panel of outside scientists recommended the change last Friday, said Lee Davies, a spokesman for Schering. Mr. Davies declined to disclose the members of the panel.

Dr. Howard Weintraub, the clinical director of the New York University center for the prevention of cardiovascular disease, said cardiologists were especially concerned about the trial’s results because Zetia works differently from other cholesterol-lowering medicines like Lipitor or Merck’s own Zocor.

Unlike the other medicines, called statins, Zetia has not yet been proven to prevent heart attacks. The Food and Drug Administration approved it in 2002 on the basis of trials that showed it could lower LDL, or so-called bad cholesterol, by 15 to 20 percent.

Zetia is the brand name for a cholesterol-lowering medicine called ezetimibe. It can be taken with any statin. Vytorin is a single pill that combines Zetia with simvastatin, the active ingredient in Merck’s Zocor statin.

Together, Zetia and Vytorin have grabbed nearly 20 percent of the American market for cholesterol-lowering drugs, because of aggressive marketing from Merck and Schering-Plough that highlights Zetia’s uniqueness among cholesterol medicines.

Because Zetia’s cholesterol-lowering effect comes on top of that produced by statins, doctors often prescribe the drug in combination with low-dose statins, as an alternative to increasing the statin dose. Some patients do not like taking high-dose statins because they can cause muscle pain.

Merck’s Zocor is now subject to cheap competition from generic simvastatin that costs pennies a day. But Merck can continue to command name-brand prices through Zetia and Vytorin, which both cost about $3 a day, similar to other branded cholesterol-lowering drugs like Lipitor.

Merck and Schering co-market Zetia and Vytorin and split revenues and profits roughly equally.

Despite the success of the marketing campaign, some cardiologists say they are concerned that reducing cholesterol through Zetia may not protect the cardiovascular system as much as reducing it through a statin.

“Cholesterol lowering with this drug might not provide the same benefits as statins for the same degree of cholesterol reduction,” said Dr. Steven Nissen, the chairman of cardiovascular medicine at the Cleveland Clinic.

The Enhance trial was supposed to end those questions. It was intended to show that Zetia and simvastatin would reduce the growth of plaque in blood vessel walls more than simvastatin alone — an important measure of the effectiveness of cholesterol-lowering medicines.

The companies had said they would measure the thickness of plaque in two arteries — the carotid, which runs through the neck and supplies the brain with blood, and the femoral, which runs through the hips and supplies the legs. The primary endpoint of the trial was supposed to be the amount of plaque at three points in the carotid artery.

But the companies said yesterday that they had changed the primary endpoint to measuring thickness at just one place in the carotid. And they do not expect to release any results at all from the femoral artery.

Dr. John Kastelein, the Dutch cardiologist who oversaw the Enhance trial, said he believed that the trial should still be considered valid. The single carotid endpoint is still an important measure of the drug’s effectiveness, he said.

The Zetia-Vytorin dispute adds to the controversy that has engulfed the field of medical clinical trials. After being criticized for hiding negative trials, the industry promised to improve disclosure by listing most new trials at their outset on a federally financed Web registry. A separate registry, run by an industry lobbying group, is supposed to provide a place for companies to post the results of trials shortly after their completion.

But the still-unreleased data from the Enhance trial indicates the limits of the system, doctors say. Companies do not face meaningful penalties for failing to post results, and they can delay disclosure for years by saying that that they are still analyzing data.

The Enhance trial, which involved 720 patients with very high cholesterol, began in June 2002. In June 2006, a Schering executive told investors that the Enhance data would be ready by year-end, although it might not be publicly presented until 2007. At the latest, doctors had expected the results by the American College of Cardiology conference in March 2007.

In an interview yesterday morning, Dr. Kastelein, the study’s leader, said he had hoped to present the results of the trial at the March 2007 conference. But Schering and Merck controlled the raw data and raised questions about its accuracy, resulting in long delays, he said.

“There was friction and tension,” he said. But he added that he did not believe the companies had manipulated the data.

The delays in the Enhance results stand in sharp contrast to a similar trial conducted by AstraZeneca on its cholesterol-lowering drug Crestor. That trial, called Meteor, compared Crestor to a placebo in patients with moderately high cholesterol and also involved measuring plaque.

It was completed in May 2006, and the results were released 10 months later, showing positive results for Crestor. Dr. John R. Crouse, a Wake Forest University professor who oversaw the AstraZeneca trial, said he knew the Crestor’s trial’s findings by September 2006.

Still, Dr. Crouse said that measuring plaque can be complicated and that Merck and Schering might simply have run into delays in analyzing their data. “It’s easy for things not to go the way you would hope they would go,” he said.

Some other cardiologists are less willing to wait for Merck and Schering to finish their analysis.

“Statins have diverse effects beyond simple LDL cholesterol lowering, such as potent anti-inflammatory actions,” said Dr. Eric J. Topol, a cardiologist and director of the Scripps Translational Science Institute in La Jolla, Calif. Referring to Zetia, he said, “There has yet to be a clinical trial to show that ezetimibe improves clinical outcomes.”