Vytorin Makers Try to Explain Timeline

By RON WINSLOW and ANNA WILDE MATHEWS
January 26, 2008; Page A3

Merck & Co. and Schering-Plough Corp. offered a detailed accounting of
why trial results for their cholesterol drug Vytorin were delayed more
than a year, but in the process fueled more doubts about how the data
were handled and how the study was managed.

The companies, responding to intensifying scrutiny of the trial,
issued a chronology describing a two-year effort they say was aimed at
ensuring the accuracy of imaging data collected in the study.

DELAY AND DOUBTS

But critics said that despite the recounting, they didn't fully
understand why the companies spent so long working on the data. They
said the affair shows the problems that can arise when corporate
sponsors, rather than independent academic investigators, control how
a study is run.

The study, called Enhance, cast doubt about whether Vytorin is better
than a cheaper generic drug in halting the progression of
cardiovascular disease, even though Vytorin was more effective in
reducing LDL, the so-called bad cholesterol, which is a major risk
factor for heart attacks.

The trial was completed in April 2006, but the companies didn't
disclose the disappointing results until Jan. 14 of this year. During
that time, combined annual sales of Vytorin and a sister drug, Zetia,
grew to more than $5 billion.

In November, a firestorm erupted after the companies said they were
changing the trial's primary measure of effectiveness to "expedite"
analysis of data -- a move generally considered a violation of
scientific protocol. That triggered complaints from cardiologists and
a congressional inquiry. The companies have since said they went back
to the primary endpoint.

The study collected images designed to measure the drugs' effect on
the thickness of the wall of the carotid, or neck, arteries.

The companies' chronology indicates that questions about image quality
surfaced in late 2005 during "routine data quality reviews." In
subsequent months, the companies settled on a plan to reanalyze the
images, ran a pilot study of this new approach, hired consultants to
help evaluate quality control and convened at least two outside expert
panels on the problem.

In January 2007, the chronology says, one consultant reported that the
quality issues were similar to those experienced in other trials using
the same imaging technique, but the companies continued their effort
anyway. Throughout the process, the companies say the results of the
study remained "blinded," meaning neither company officials nor people
examining the images knew which patients got Vytorin and which got the
generic.

"The timeline shows what an immense effort the companies went to work
on the data," said Allen Taylor, chief of cardiology service at Walter
Reed Army Medical Center in Washington. "The question is, why were you
doing all that? People don't spend 18 months jumping through hoops for
nothing."

Dr. Taylor said he wonders whether the companies knew all along that
the study failed to show a benefit for the more-expensive Vytorin.
Added Harlan Krumholz, a cardiologist at Yale University: "It's in
their great interest to delay this study if there is any possibility
that it doesn't come out positive."

A Schering-Plough spokesman said the companies didn't know whether the
results were positive or negative until they first looked at them Dec.
31.

"While the Enhance trial was time consuming and took longer than
originally anticipated to complete, our companies acted with integrity
and good faith in connection with the trial," Merck and Schering-
Plough said in a statement. Among other things, they said the delay
resulted from their efforts to find missing or obscure data and re-
examine measurements that seemed implausible.

The decisions to reanalyze the data were made by an internal group
called the Cholesterol Development Committee, and were a significant
departure from the original analysis plan as published in an article
in the American Heart Journal in 2005. A steering committee
independent of the corporate sponsor is commonly named before a study
begins to oversee the scientific aspects.

In Enhance, no steering committee was named and the companies have
controlled the data and the analysis. As a result, Dr. Krumholz said,
"There is no way to determine that the decision [to re-analyze data]
is being driven by science or the best interest of the company."

Schering-Plough said independent oversight boards were not named for
Enhance because the study involved approved drugs at approved doses
and unusual events weren't expected.

The Food and Drug Administration on Friday said it planned to review
the study after the agency gets final results from the companies and
will also look at whether it needs to make changes to its "current
approach to drugs that lower LDL cholesterol."

The FDA expects it will need about six months to evaluate the Enhance
findings. Depending on its analysis, it might require changes to the
Vytorin label reflecting the findings.

FDA officials defended the agency's process for approving Vytorin and
Zetia. They relied on the drugs' impact on LDL rather than insisting
on evidence that the drugs prevented heart attacks or reversed the
progression of cardiovascular disease.

Write to Ron Winslow at ron.winslow@wsj.com and Anna Wilde Mathews at
anna.mathews@wsj.com