Re: Merck, Schering-Plough Defend Efforts for Vytorin, Zetia

Vytorin's Missing Fail-Safes
Matthew Herper, 01.25.08, 6:00 AM ET

For Merck and Schering-Plough, the pile-on over the cholesterol drug
Vytorin shows no signs of letting up. The latest: Plaintiffs' lawyers
are licking their chops, and Charles Grassley, the powerful Iowa
senator, has begun his own inquiry into the companies' handling of a
failed clinical trial.

Meanwhile, Michigan Democrats Bart Stupak and John Dingell are asking
about everything from the companies' television advertising to insider
stock sales to mishandling of data. They're also asking Merck and
Schering-Plough some arcane questions about how the failed clinical
trial, called ENHANCE, was constructed.

The answers matter to investors, top researchers say. ENHANCE lacked
expert committees that might have helped the companies avoid delays in
releasing the data. Those committees may also have given them a
legitimate way to handle any problems that came up, averting the
public relations disaster that has caused share price declines of 15%
for Merck and 25% for Schering as investors worry about the future of
the companies' $5 billion cholesterol franchise.

A Jan. 22 letter from the Committee on Energy and Commerce to the
chief executives of Merck and Schering-Plough asks essentially the
same question, eight different ways: Were there standing committees
held to monitor the safety of the trial, or to deal with problems that
came up in its progress?

Schering chief medical officer Robert Spiegel provided the answer in
an interview with Forbes.com more than a week ago. This study had
neither a steering committee, as a group of experts who regularly
convened to discuss the trial and its data, nor a data safety
monitoring board (DSMB), which carefully watches study information to
make sure patients are not harmed.

"You would have thought they would have been more sophisticated in
doing trials and would have had all the right checks and balances,"
says Eric Topol, chief academic officer at the Scripps Health in
California. "Every real trial should have both. You need to have the
weight of a committee. You can't just have one individual to stand up
to the sponsors."

Spiegel said that although steering committees are helpful, that is
simply not the structure chosen for this trial. And a safety board
wasn't necessary, because all patients were clearly getting "adequate
cholesterol therapy."

The 700 patients in the ENHANCE trial, who all had a genetic disease
causing their levels of bad cholesterol to spike without treatment,
were all on the top dose of the cholesterol-lowering drug Zocor. Half
of them also got Zetia, a second cholesterol drug, but there was no
additional benefit on artery plaque. Vytorin is a combo pill of Zetia
and Zocor. There was no sign Zetia was unsafe.

The lack of a data safety monitoring board is "sub-optimal," says
Steven Joffe, a bioethicist and researcher at the Dana Farber Cancer
Center. "It's hard to see who is helping to shape these decisions who
has a strong level of independence from the company. Who has seen the
data who can take public accountability?"

A DSMB might not take direct accountability, he notes, but it provides
a mechanism that can reassure the public when problems happen.

Not everyone agrees. "I do not think a DSMB for ENHANCE was
necessary," says Steven Nissen, head of cardiology at the Cleveland
Clinic. He does, however, think the lack of a steering committee was
"irregular."

Here's the rub: Schering-Plough wound up calling an ad hoc group on
Nov. 16, 2007, to try to decide how to deal with what the company says
were data problems. (See: "Merck and Schering's Secret Panel.")
Schering and Merck have blamed the long delay in releasing details of
the ENHANCE study on problems the companies saw with the imaging data
in the study.

"We did think it was appropriate, as the study was still blinded, to
try and get some outside opinions to just validate that the
assumptions we made when the study started," said Spiegel.

If that decision had been made by a standing group of experts instead
of an ad hoc group, it would have drawn less scrutiny. The same goes
for the long delay in the study--if outside experts had been named
ahead of time to make decisions about the data, there would be no
debate over whether Merck and Schering did the right thing with regard
to this trial.

Instead, they must now face a debate in which many top cardiologists
argue that their drugs should only be used as second-choice options--
and a congressional committee that is questioning every step they
took--with the benefit of 20/20 hindsight.


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