Healthy Skepticism Library item: 4962

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Publication type: news

Herper M.
The Vioxx Maelstrom
Forbes.com 2006 May 22
http://www.forbes.com/2006/05/22/merck-vioxx-approve-cx_mh_0522mrk_print.html

Full text:

New York –
With all the sturm und drang surrounding the release of new data from
the
study that caused Vioxx to be pulled from the market, you’d think that
there
would be some answers about the drug’s real public health risks.

But clear answers aren’t coming. For one thing, any scientific debate
is
colored by the more than 11,000 lawsuits mounting against the drug’s
maker,
Merck. For another, the APPROVe, the 2,600-patient study that led Merck
to
pull Vioxx in September 2004, was not designed to provide clear answers
to
questions about the drug’s potential to cause heart attack and stroke.
So
now, even as new data emerge from the study, clear answers seem to be
slipping further away.

Instead, the Vioxx mess is signaling big changes for how clinical
trials
will be conducted. More information about studies will likely be
published
before they are started, so that scientists can debate the way they are
designed before they are signed up. Moreover, drug firms are
increasingly
pushing to eventually make more results publicly available on Web
sites. But
those changes are coming too late for Merck, and now the company and
its
critics are left in a public battle over exactly what the results of
the
study mean.

“A lot of people are talking off the cuff here,” says Robert Bresalier,
APPROVe’s first author and a cancer prevention expert at M.D. Anderson
Cancer Center. “I’ve never seen anything that’s generated so much
emotion
and speculation and comments from people I normally think of as fairly
reputable that I think are to some extent not based on hard data.”

APPROVe was designed to test whether Vioxx reduced the risk of colon
polyps,
but instead it showed that patients who took the drug for at least 18
months
had double the risk of heart attack and stroke as those who took
placebo.
Bresalier says the authors had to rush to get the paper published in
the New
England Journal of Medicine ahead of a February 2005 meeting by U.S.
Food
and Drug Administration experts.

By showing that it took 18 months for Vioxx to cause problems, APPROVe
gave
Merck a built-in legal defense. But critics say a 108-page data package
Merck sent to the FDA two weeks ago put the 18-month defense on shaky
ground. The existence of this data package was first reported by NPR,
and a
copy was provided by Merck.

One of the shortcomings of the New England Journal of Medicine paper
from
last March was that it only followed patients for two weeks after they
had
stopped taking Vioxx. But Merck had collected data for longer than two
weeks—and analyses with these data seem to cut the key 18-month period
down
to as little as three months.

Cleveland Clinic cardiologist Steven Nissen, a longtime Vioxx critic,
says
that every analysis shows an earlier risk except the one that was used
in
the New England Journal. He worries that Merck may have chosen to
present
the data in a way that would be best for its legal defense. “It makes
you
very uncomfortable,” he says. However, says, the studies don’t clearly
show
exactly when the risk from Vioxx begins. “I think that we don’t know,”
he
says.

Merck argues that using the graphs provided in its data package to
pinpoint
exactly when risk emerges is not scientifically valid. Bresalier says
he
does not see the risk emerging earlier but said he and his co-authors
will
be looking at the new data package in detail over the next week. He
says
that he only got it recently. However, he also says that too much may
have
been made of the 18-month cut-off. “Nothing fell out of the air
magically on
that date,” says Bresalier.

The New England Journal, which has published editorials expressing
concern
over another key Vioxx study, says it is examining APPROVe but that it
will
take considerable time to look over all this data. “This underwent
extensive
review,” says Bresalier. “They didn’t have to publish it if they didn’t
think it was reasonable.” He also says that the authors, Bresalier and
John
Baron of Dartmouth Medical School, not Merck, wrote the paper.

This controversy that has besieged the major studies of Vioxx—and that
has
also affected the New England Journal of Medicine—is likely to
increase the
pressure for airing more decisions about designing clinical trials in
the
open. It would be much more difficult for critics to cry foul if the
APPROVe
authors had disclosed ahead of time that they would be tracking heart
attacks and strokes for only two weeks after patients stopped using
Vioxx.

Already, the pressure is on for more disclosure. On Friday, the World
Health
Organization called for all clinical trials to be registered in a
public
database as soon as they begin. Such a move could even eventually save
drug
firms money by revealing why certain medicines fail. For instance, a
half-dozen medicines designed to treat diabetes and high cholesterol at
the
same time have been torpedoed by side effects, and more access to data
might
help companies prevent history from repeating itself.

But issues relating to Vioxx have moved out of the realm of science.
The
18-month defense hasn’t helped Merck; it has so far lost one of two
long-term use cases, and two of four short-term cases. At the same
time, the
Vioxx legal battle may scuttle any hope of getting better data from
already
conducted studies. Bresalier says that a legal injunction prevents the
APPROVe authors from doing new analyses on their data.

And just because scientists are arguing does not mean jurors will care.