US: For Widely Used Drug, Question of Usefulness Is Still Lingering

When the Food and Drug Administration approved a new type of cholesterol-lowering
medicine in 2002, it did so on the basis of a handful of clinical
trials covering a total of 3,900 patients. None of the patients took
the medicine for more than 12 weeks, and the trials offered no evidence
that it had reduced heart attacks or cardiovascular disease, the goal
of any cholesterol drug.

The
lack of evidence has not stopped doctors from heavily prescribing that
drug, whether in a stand-alone form sold as Zetia or as a combination
medicine called Vytorin. Aided by extensive consumer advertising, sales
of the medicines reached $5.2 billion last year, making them among the
best-selling drugs in the world. More than three million people
worldwide take either drug every day.

But there is still no proof
that the drugs help patients live longer or avoid heart attacks. This
year Vytorin has failed two clinical trials meant to show its benefits.
Worse, scientists are debating whether there is a link between the
drugs and cancer.

Researchers
reported last month that patients in three clinical trials had a 40
percent higher chance of dying from cancer if they took Vytorin instead
of a sugar pill or another medicine, although the leader of that study
says the finding might be due to chance.

Now some prominent
cardiologists say that the evidence has swung so decisively against the
drugs that they should not be sold. "The only place people should be
taking it is in a clinical trial," Dr. Allen J. Taylor of the Walter Reed Army Medical Center
said of Zetia. (Vytorin is a single pill that combines Zetia with a
statin, an older form of cholesterol-lowering medicine whose
effectiveness and safety are not in question.)

On Tuesday, in a sign of the high level of interest among doctors that Vytorin and Zetia have generated, the New England Journal of Medicine will publish online two articles and an editorial about the trials that raised the potential cancer concerns.

Merck and Schering-Plough,
which jointly make Vytorin and Zetia, strongly defend their medicines.
The companies say that ezetimibe, the generic name for Zetia, showed no
cancer risk in animal trials and argue that the cancer finding is
probably a result of chance. Some independent scientists agree with the
companies, saying that they are dubious of a link to cancer and that
ezetimibe is a valuable treatment no matter which brand it is sold
under.

About the only point on which both sides agree is that no
one can judge ezetimibe's safety and benefits for certain without more
data, ideally from a clinical trial covering more than 10,000 patients
and lasting several years, long enough to show that the drug actually
helps patients live longer or avoid heart attacks.

But patients
and doctors will have to wait years more for those results. Merck and
Schering did not begin such a trial until October 2005, three years
after ezetimibe was approved. And the completion date for the trial has
been repeatedly postponed. Now the companies estimate that it will not
be finished until at least 2012. By then tens of millions of people
will have taken ezetimibe.

"I don't think the answer on Zetia is
in," said Dr. Robert J. Temple, director for the office of medical
policy at the Center for Drug Evaluation and Research, which is part of
the F.D.A.

The lack of data about ezetimibe highlights an aspect
of the drug approval system that even sophisticated patients may not
understand. Many medicines are approved on the basis of what scientists
call surrogate endpoints, like proof that they lower cholesterol,
rather than because they have been shown to reduce the risk of death or
disease.

For example, a cancer drug might be approved because it causes tumors to shrink, not because its manufacturer can prove that patients live longer after taking it.

Using
these measures makes sense in certain circumstances, researchers say.
If no treatments exist for a disease, the F.D.A. may approve a drug
based on its promise in short-term trials and hope that the medicine
succeeds later in larger trials where its potential to reduce death and
disease will be examined directly.

But several drugs approved
this way have recently proved ineffective or even dangerous. In 1999,
for example, the F.D.A. approved the diabetes drug Avandia
on the basis that it reduced blood sugar. Sales of Avandia and two
related medicines reached $3 billion in 2006. But in 2007, an analysis
of 44 clinical trials of Avandia showed that it could increase heart
attacks. Since then, prescriptions for Avandia have plunged, although the drug remains on the market.

Ezetimibe
is in a similar situation. The medicine has been proved to lower
patients' LDL, or bad, cholesterol by 15 to 20 percent. Decades of
research links lower cholesterol to a reduced risk of heart attacks.
And cholesterol-lowering drugs called statins, including Lipitor and Crestor,
have been proved to reduce heart attacks. But statins work very
differently than ezetimibe, and no one has proved that ezetimibe offers
the same benefits as statins.

"The F.D.A. set the bar too low on
the initial approval," said Dr. Steven Nissen, chairman of cardiology
at the Cleveland Clinic. "It would have been a lot better if the agency
had said, 'Show us that you do more than lower LDL a little bit, show
us evidence of effectiveness.' "

Further, when the F.D.A.
approved Zetia, several statins were already on the market, giving
patients other options to lower their cholesterol. So the agency's
decision to approve Zetia without requiring larger trials is especially
puzzling, Dr. Nissen said.

Dr. Temple said the link between LDL
cholesterol and heart disease was so strong that the agency was
comfortable approving drugs on the basis that they lowered cholesterol
alone. "We accept LDL cholesterol as a valid surrogate," he said.

But the failure nearly two years ago of torcetrapib, an experimental drug from Pfizer, spotlighted the risks of using drugs without long-term data. Torcetrapib raised HDL cholesterol - the so-called "good" cholesterol, which is known to reduce the risk of heart problems.

But
the F.D.A. chose not to approve torcetrapib on the basis of its effects
on HDL. Instead, the agency required that Pfizer first conduct a large
trial. In December 2006, the trial revealed that torcetrapib raised
patients' risk of death by 60 percent, forcing Pfizer to discontinue
development of the drug.

Dr. Curt D. Furberg, an epidemiologist and drug safety expert at Wake Forest University,
said that before approving drugs the F.D.A. should require that drug
companies conduct large trials on whether they reduce death and
disease, except in rare cases where no alternatives exist. If the
agency approves drugs without such data, that fact should be noted
prominently on a drug's label, Dr. Furberg said.

Pharmaceutical
companies argue against changing the current approval system.
Determining whether a drug reduces death or disease can require a trial
that enrolls 10,000 or more patients and lasts four years or more.
Requiring longer and costlier trials might discourage the development
of new medicines, said Ken Johnson, senior vice president of the
Pharmaceutical Research and Manufacturers of America.

He said the current system enabled patients "to access life-saving and life-enhancing remedies more quickly."

The
F.D.A. does seem to be taking a harder line on new diabetes and heart
medicines. In April, the agency turned down an HDL-cholesterol-raising
drug from Merck that did not have long-term trial data. And in July, an
F.D.A. advisory panel recommended 14-2 that companies conduct long-term
trials on new diabetes medicines.

But for drugs already on the
market, no such requirement exists. So ezetimibe remains heavily
prescribed despite questions about both its effectiveness and whether
it is linked to cancer.

In January, Merck and Schering announced
that Vytorin - the combination of ezetimibe and a generic statin called
simvastatin - had failed a clinical trial meant to show that it could
slow the growth of arterial plaque that could cause heart attacks.

Then,
in July, Norwegian researchers reported that another trial showed that
patients taking Vytorin died from cancer more often than those taking a
placebo, or sugar pill. In two other clinical trials still going on,
patients taking Vytorin have also been more likely to die from cancer
than those not taking it. In all, 136 of about 11,000 people taking
Vytorin in the three trials have died of various kinds of cancer,
compared with 95 out of 11,000 who took placebo or simvastatin alone.

With
little long-term data about ezetimibe's risks, scientists are
scrambling to find an explanation for the seeming cancer link. Some
oncologists agree with Merck and Schering that the cancer findings are
probably due to chance.

But other scientists say they have a
plausible explanation for why ezetimibe may cause cancer. Ezetimibe
works by blocking the intestine from absorbing cholesterol. But it also
blocks the absorption of closely related compounds called plant
sterols, which are found in nuts and vegetables. Some studies have
shown that people who eat large amounts of plant sterols have lower
cancer rates than those who do not.

Dr. Peter G. Bradford, a
pharmacologist at the University of Buffalo who has extensively studied
plant sterols, said that in laboratory tests, sterols promote cell
death in a way that could make them valuable anti-cancer agents as
weapons against tumors. By blocking sterol absorption, ezetimibe could
be promoting cancer , he said.

"One might envision that link," he said. "This is a very large question."

Merck
and Schering noted that the drug showed no carcinogenic effects in
mice. In addition, the link between sterols and cancer remains
hypothetical and has never been proved in a clinical trial. Further,
cancer typically takes many years to develop in humans, so the theory
that ezetimibe could cause cancer in a year or two is not plausible,
they say.

Some leading cancer researchers agree. Dr. Tyler Jacks, director of the Koch Institute at the Massachusetts Institute of Technology,
said Merck had asked him to examine the results of the Norwegian trial
and he concluded it was probably a false signal. If ezetimibe causes
cancer, its effects should have become more pronounced as the trial
went on, Dr. Jacks said. Instead, the gap between patients who took
Vytorin and those who took a placebo did not widen over the length of
the trial, he said.

Dr. Terje Pedersen, the Norwegian
cardiologist who conducted the trial, said he also doubted that Vytorin
caused the excess of cancers seen in the study. Even very dangerous
carcinogens - like cigarettes
and radiation - typically require several years, even decades, to cause
cancer. Given that fact, ezetimibe would have to be extraordinarily and
implausibly carcinogenic to have noticeable effects in a three-year
trial, he said.

"The duration of the trial is not long enough to believe that the treatment would cause cancer," Dr. Pedersen said.

Still,
the concerns about ezetimibe's potential risks and lack of
effectiveness have discouraged some patients from using the medicine.
In the United States, prescriptions for Vytorin and Zetia have fallen
40 percent this year.

Dr. Jacks said Merck and Schering could not
easily resolve the questions about ezetimibe's potential risks. "The
answer is to get more data," he said.

• 182 Health
• 208 Regulation