October
2002
Vol. 38, No. 10
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News
& trends
New
Cox-2 pain relievers are marketing marvel, not miracle drugs
Pharmacia Corp.
(recently acquired by Pfizer, Inc.) makes what was the 10th most frequently
prescribed drug in the United States last year. It touts Celebrex
as "a major advance in the treatment of the debilitating diseases
osteoarthritis and rheumatoid arthritis, because of its efficacy and
excellent gastrointestinal safety profile."
When
Celebrex (celecoxib) and Vioxx (rofecoxib)—a new kind of pain
medication known as Cox-2 inhibitors—were introduced in 1999,
manufacturers and medicos alike hailed them as a kind of "super-aspirin"
that lacked the stomach-shredding side effects of the older non steroidal
anti-inflammatory drugs (NSAIDs). But many champions are leaving the
arena as questions arise about the efficacy and safety of Cox-2 drugs.
Vioxx,
manufactured by Merck & Co., "has a demonstrated risk that is
underappreciated by its sponsor and benefits that are oversold to
the public and physicians through an aggressive marketing campaign,
while risks are purposefully hidden," said David Miceli of Montgomery,
Alabama, who cochairs ATLA's Cox-2 Litigation Group. Merck "has profited
tremendously from its bad acts."
Attorneys
across the country are screening Vioxx and Celebrex cases—some
seeking damages for plaintiffs' injuries or potential injuries, others
hoping to hold the manufacturers accountable for overpromoting drugs
that are far more expensive than older versions, but no better at
relieving pain.
The
drugs, approved to treat arthritis, menstrual pain, and "acute" pain
in adults, have been heavily marketed to both doctors and consumers:
Vioxx, which runs ads featuring former Olympic figure skater Dorothy
Hamill, spent over $160 million on consumer advertising in 2000; Celebrex
spent almost $80 million, according to AdWatch, the health policy
arm of the Henry Kaiser Family Foundation. The campaigns are working:
In 2001, Celebrex racked up $3.1 billion in sales worldwide, and Vioxx,
the 13th most-prescribed drug in the United States, had worldwide
sales of $2.6 billion.
Older
NSAIDs—such as ibuprofen, naproxen, and diclofenac—work
by inhibiting the two types of cyclooxygenase enzyme, one of which
causes inflammation and thus pain. The Cox-1 enzyme, however, helps
maintain the muscle surface of the gastrointestinal (GI) tract, so
suppressing the enzyme can increase perforations, ulcers, and bleeding.
Vioxx, Celebrex, and Bextra (valdecoxib, introduced by G.D. Searle
& Co. in 2001) suppress only the second enzyme, leaving the first
alone to protect the GI tract.
While
Vioxx and Celebrex have been marketed as safer than traditional NSAIDs
because of their stomach-protecting propensity, reports of serious
side effects have begun to emerge. In June 2002, a research team led
by A. Whelton noted in a presentation to the European United League
Against Rheumatism an increase in hypertension and heart attacks among
those taking Vioxx. The medical journal the Lancet published
a study associating Vioxx with kidney failure, and other studies have
associated both Vioxx and Celebrex with heart problems, kidney damage,
aseptic meningitis, and slow healing of bone fractures.
Drug
company studies
A
metastudy by the Cleveland Clinic published in the Journal of the
American Medical Association analyzed data from two major studies
funded by the drug companies and two smaller ones—all for cardiovascular
risks. (Debabrata Mukherjee et al., Risk of Cardiovascular Events
Associated with Selective Cox-2 Inhibitors, 286 JAMA 954 (2001).)
It found that neither Pharmacia/Pfizer nor Merck had identified and
studied cardiovascular risks for their products. The annualized heart
attack rates for patients taking Vioxx or Celebrex, the researchers
found, were "significantly higher" than those in a group taking placebos.
"The available data raise a cautionary flag about the risk of cardiovascular
events with Cox-2 inhib itors," they concluded.
The
Pharmacia-sponsored Celebrex Long-Acting Safety Study (CLASS), involving
about 8,000 arthritis sufferers, compared that drug to the older NSAIDs
ibuprofen and diclofenac to determine whether it was less harmful
to the stomach. In a JAMA article in 2000, the researchers
published data accumulated over six months and concluded that Celebrex
caused fewer ulcers than the older drugs. (Fred E. Silverstein et
al., Gastrointestinal Toxicity with Celecoxib vs. Nonsteroidal
Anti-inflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis:
The CLASS Study: A Randomized Controlled Trial, 284 JAMA 1247
(2000).) However, researchers at that point had 12 months of data
that, when analyzed as a whole, showed no significant difference.
The
FDA said the CLASS study "did not show a safety advantage in upper
gastrointestinal events for Celebrex compared to either ibuprofen
or diclofenac." Because some of the study participants were also taking
aspirin, which does affect the stomach, some analysts say the results
may have been skewed. The company maintained that among those not
taking aspirin, the rate of ulcers was lower in Celebrex takers.
Pharmacia
squawked, believing that "the conclusions drawn by the analysis in
the JAMA article were flawed and unsound. It contains no new
clinical information, and is based on an inappropriate re-analysis
of several older clinical studies containing data that were not suitable
for combination and comparison."
In
a June 2002 editorial, the British Medical Journal said the
Celebrex study misled consumers with "overoptimistic" data. It said
the study was "seriously biased" because the complete results "clearly
contradict[ed] the published conclusions" and showed a similar number
of stomach complications in all patients, whether they took Celebrex
or the older pain relievers.
Merck's
Vioxx Gastrointestinal Outcomes Research Study (VIGOR) also involved
about 8,000 participants and assessed only the drug's effects on the
stomach; the company ordered no end-point analyses for effects on
the cardiovascular system.
The
study concluded that Vioxx takers had a lower rate of GI distress
than those taking naproxen. The researchers noted, "the incidence
of myocardial infarction was lower among patients in the naproxen
group than among those in the rofecoxib group," but found "the overall
mortality rate and the rate of death from cardiovascular causes were
similar in the two groups." They drew conclusions only about clinical
upper gastrointestinal events, bleeding, and ulcers.
After
the VIGOR results were released, the FDA said Merck had minimized
the fourfold to fivefold increase in heart attacks among study participants
taking Vioxx compared with those taking naproxen. It found the company's
explanation—that Vioxx did not increase the risk of heart attacks,
but instead, naproxen protected those taking it from heart attacks
because the drug can thin the blood, like aspirin—unacceptable.
In a September 2001 warning letter to Merck, the FDA wrote, "You fail
to disclose that your explanation is hypothetical, has not been demonstrated
by substantial evidence, and that there is another reasonable explanation:
that Vioxx may have pro-thrombotic properties."
FDA
actions
The
FDA, which lists Vioxx and Celebrex information on the "Hot Topics"
section of its Web site, required both drugs to carry the same stomach-upset
and bleeding warnings ibuprofen and naproxen had when the agency approved
them in 1999.
After
the CLASS results, the FDA found that Celebrex is just as likely to
cause ulcers as older NSAIDs and is no better at reducing pain or
inflammation than ibuprofen. In June 2002, it mandated a new label
for the drug, one without any claim that it is safer for the stomach
than other NSAIDs.
The
agency did allow Merck to change its Vioxx label to claim it has a
lower risk than older NSAIDs of causing ulcers, gastrointestinal bleeding,
and other digestive-tract complications.
As
early as November 1999, an FDA memo stated that the board monitoring
the VIGOR study was concerned about "excess deaths and cardiovascular
events experienced in Group A [Vioxx group] compared to Group B [naproxen]."
In March 2002, the FDA reported that five people taking Vioxx had
aseptic meningitis, an inflammation of membranes on the brain and
spine. In April 2002, after the agency warned Merck that it had misrepresented
the drug's safety and minimized potentially serious cardiovascular
complications found in VIGOR, it required the company to include a
warning of cardiovascular risks on the Vioxx label.
Litigation
The
companies continue their full-court-press marketing, but burgeoning
litigation may put the brakes on. Almost two years ago, consumers
began filing suits, and the number of potential actions is now in
the thousands, said Shelly Sanford, a Houston attorney who cochairs
ATLA's Cox-2 Litigation Group with Miceli.
Potential
litigation includes personal injury suits in Texas and Louisiana,
consumer class actions in Illinois and New York (alleging consumer
fraud, RICO violations, negligence, and breach of warranty), a third-party
payer class action in New Jersey, and a payer class action against
Merck in New Jersey (involving breach of warranty, unjust enrichment,
and violations of the state Consumer Fraud Act). Cases are also on
file in California, Mississippi, and other states.
"The
pressure put on doctors by the marketing was huge for Celebrex, which
is not proven to be better for pain and not proven to be better for
gastrointestinal risks compared to other NSAIDs," said Sanford. In
addition, Vioxx "may increase the risk for cardiovascular events,
and both Vioxx and Celebrex increase hypertension and edema."
Third
parties and consumers paid significantly more for Vioxx and Celebrex
than they would have for older NSAIDs, when the Cox-2 drugs were meant
to be prescribed in limited cases involving patients with serious
gastrointestinal risks. The drugs were prescribed for millions of
people and cost at least seven times more than the older NSAIDs but
were of no greater value for pain relief and caused cardiovascular
risks, Sanford said.
John
Xydakis, a plaintiff attorney in Clarendon Hills, Illinois, has filed
a class action in Cook County, alleging Merck misrepresented claims
on its Vioxx labeling and covered up adverse results of the VIGOR
research. The plaintiff, who has not sustained any actual physical
injuries, is suing for the "increased risk" of serious problems that
may be caused by Vioxx. This theory is based on juries' assessment
of increased risk in other types of cases.
While
this may not be an acceptable cause of action in every state, Xydakis
is convinced that Vioxx cases will result in federal multidistrict
litigation because so many cases are pending in the district courts.
Merck is currently trying to remove his class action to federal court,
arguing that the plaintiff's recovery for the costs of medical monitoring
is sure to exceed the jurisdiction's damages limit of $75,000. The
company has stated in other court pleadings and documents that plaintiffs
under these circumstances cannot claim nearly that amount in damages.
Managed
care companies, pharmacy benefits managers, some doctors, and consumer
groups support the plaintiffs' views.
"A
seemingly magic bullet appears to have self-destructed," said Sidney
Wolfe, director of the Public Citizen Health Research Group, in testimony
before the FDA Arthritis Drugs Advisory Committee. He noted that the
benefit of reducing GI distress "appear[s] to have been grossly exaggerated
and oversold" and recommended keeping gastrointestinal warnings on
both Vioxx and Celebrex. He said evidence that is "rapidly accumulating
about the heart damage caused by these drugs" warrants a separate,
boxed warning on labels.
Express
Scripts, Inc., which manages pharmacy benefits for about 50 million
insured Americans, has said that Vioxx, Celebrex, and Bextra are overpriced
and overprescribed. It wants managed care entities to recommend that
doctors prescribe traditional, cheaper NSAIDs first.
—Rebecca
Porter
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