- VICTIMS
OF DRUG THAT TOOK A HIDDEN TOLL Page
2
In
October 2000 Merck supplied the FDA with a string of
death reports involving heart attacks and strokes. In
response, Dr Shari Targum, the FDA analyst, wrote in
a report dated January 2001: “It would be
difficult to imagine inclusion of Vigor results in
the rofecoxib labelling without mentioning
cardiovascular safety results in the study
description, as well as the Warnings section.”
This
advice was dispatched to other regulators around the
world. Yet none of this was notified to patients such
as Wood when a colon cancer trial in Britain was set
up by Langman in partnership with David Kerr, who
headed the Cancer Research Campaign Institute. The
trial was established under the auspices of the main
British ethics, research and regulatory bodies.
Kerr,
now a professor at Oxford, was a rising star in the
new Labour medical firmament — close to Alan
Milburn, who was health secretary, and his expertise
repeatedly acknowledged by Tony Blair.
The
Victor trial was approved by a West Midlands medical
ethics committee in November 2000 and aimed to
recruit 7,000 volunteers at 168 British hospitals,
plus more in Australia and New Zealand. Half would
get Vioxx and the rest a placebo. They had all
received “potentially curative” surgery for
colon cancer.
Victor
was trumpeted throughout the medical profession.
“The idea of maintaining all the beneficial
possibilities of aspirin but without the side effects
was clearly very attractive,” said Desmond
Laurence, emeritus professor of pharmacology at
University College London, who was invited to join
Victor but refused.
Wood
was among the first volunteers for Victor. The
“informed consent sheet” that the Royal
Shrewsbury hospital gave him in May 2002 itemised
only these possible side effects: “tummy pain,
dizziness, fluid retention leading to ankle swelling,
increase in blood pressure, indigestion and
heartburn, mild headache, itching”. There was
nothing about heart attacks or anything too serious.
Informed
consent documents obtained by The Sunday Times show
that even by the time the project was abandoned in
November 2004 the full range of hazards was not
revealed.
Wood’s
death certificate read: “1 (a) Myocardial
rupture, (b) Acute myocardial infarction, (c)
Coronary artery atheroma (furring of the
arteries).” Decoded, Wood died of a heart attack
so massive that it would have resembled a gunshot
wound.
What
the certificate did not say was whether Vioxx was
involved, so it came as a shock to Margaret when I
read her a confidential report from Merck giving the
opinion of a Shrewsbury hospital doctor.
“The
investigator felt that the myocardial infarction was
not related to disease/other illness,” said the
report. “The investigator felt that the
myocardial infarction and myocardial rupture were
probably related to study therapy, and that the
coronary atheroma was possibly related to study
therapy.” In other words, the doctor, reporting
privately to other doctors, said that in his view it
was probably the Vioxx that had killed Wood.
THE
$250m verdict in Texas, after a five-week hearing,
followed claims that Merck had lied about the
drug’s risks, an allegation that it strongly
denied. The company has said that it will appeal. The
dispute could cost Merck $20 billion, according to
Wall Street analysts, one third of its total value.
The
core question is why the firm took so long to act. In
papers disclosed for the litigation, company e-mail
chatter discussing fears of cardiovascular risks
dates back to 1997. In that year researchers from
London’s Royal Brompton hospital warned that
Vioxx-type drugs could trigger heart attacks.
According
to Merck there was no reliable evidence until its
Approve project, testing Vioxx’s use against
colon cancer, spat out preliminary numbers last
September. “New and unexpected data emerged
showing an increased risk,” a spokesman for its
British subsidiary said. “Within one week of
learning those results, Merck acted in what it
believed was the best interest of patients and
voluntarily withdrew Vioxx from the market.”
However,
confidential documents obtained in the investigation
raise questions over whether what the company has
said publicly reflected what it knew about possible
hazards. In Britain the first heart attack deaths
were flagged up at the Medicines and Healthcare
products Regulatory Agency (MHRA) within nine months
of the product’s launch.
No
less disturbing were reports of fatal gut damage, the
problem Vioxx was intended to solve. “There have
been a number of spontaneous reports of GI
perforations, ulcerations and bleeds associated with
rofecoxib,” MHRA staff reported confidentially
to the CSM in July 2000. “While in some
instances these may be related to concomitant
medication, or use in patients with known high risk
of GI complications, the event rate is considered
significant.”
The
CSM considered the matter in December 2001. The
minutes show that Langman was asked to stay in the
room “to answer questions” even though at
the meeting to license Vioxx he had withdrawn due to
a possible conflict of interest, given his links with
Merck and its financial support for his research. He
was deemed to be needed in the room as the authority
on painkillers.
After
Langman left the room, the regulators limply
concluded that “sufficient concern (about heart
attacks) now exists from different data sources that
it would be prudent to advise prescribers and
patients by updating product information”. Yet
five months later Wood joined the Victor trial
without receiving any warning of serious heart risks.
Some documents point to Langman’s apparent
reluctance to accept the evidence against Vioxx.
On
September 30, 2004, Vioxx was withdrawn. After five
years of intense marketing, Merck acknowledged the
implications of research, including its own, which
linked its product to possibly tens of thousands of
deaths.
“We
are taking this action because we believe it serves
the best interests of patients,” the company
announced, pulling what had become the quickest
selling new drug in history. “We concluded that
a voluntary withdrawal is the responsible course to
take.”
LANGMAN,
who had championed the drug for so long, was
effectively left in the lurch. Declining to be
interviewed for this article, he told me: “I
don’t think I’ve done anything other than
express what I regarded as an honest opinion.”
After
contacting the Medical Protection Society, he later
issued a one-page statement saying he had followed
the rules for CSM members and that although the
company had sponsored Victor and other research
projects, he had had no personal financial interest
for seven years.
The
Victor trial, he said, was approved or monitored by
the West Midlands ethics committee, Cancer Research
UK, an independent data safety committee specially
supervising the project, and, at the start, the MHRA.
“I believe strongly in the need for research to
improve the quality of patient care,” Langman
said, “and have dedicated much of my
professional life to this goal while striving to
bring a balanced and objective viewpoint to my
work.”
The
criticism is not that Langman lacked dedication. It
is that he was taken in, like countless others.
Industry figures suggest that a new product such as
Vioxx may consume £500m in investment; and once
giant clinical trials such as Victor are under way,
the corporate imperatives to see the drug profitably
marketed can shoulder aside appropriate caution.
“I’m
sure he believed the data,” said Professor Kim
Rainsford, editor of the journal
Inflammopharmacology. “I hold Mike (Langman) in
very, very high regard and so I was a little
concerned to see him come out so strongly in support
of this drug. But whether he’s done the right or
wrong thing here, I think you’re right. There
was so much hype that everyone had to jump on the
bandwagon.”
Others
believe there are wider implications for the
supervision of medical research. Dr Evan Harris,
Liberal Democrat MP for Oxford West and Abingdon and
the party’s science spokesman, said it was
“unacceptable for patients in a trial to have
withheld from them information about the risks of
serious side effects”.
He added: “Clinical trials are critical to the
development of medicine and science, and that is why
the apparent failure of the research ethics system to
act on emerging concerns about the risks in this case
suggests that reform is needed.”
Nobody
has yet got in touch with Margaret Wood to explain
what role Vioxx may have played in her husband’s
death. Nor has anyone told her about the compensation
scheme in place for the Victor trial.
“They’ve never told us anything,” she
said. “The only contact I’ve had is when I
rang the hospital to ask what to do with his tablets.
They said, ‘Take them to a chemist’. And
that was that.”
* * * * *
The
history
Vioxx
is an anti-inflammatory painkiller made by Merck,
based in New Jersey, America. It was launched in
Britain in 1999 Merck believed Vioxx would
revolutionise pain relief, offering the benefits of
aspirin without the older drug’s risk of stomach
ulcers
Elderly
people suffering from arthritis were the main
patients, but doctors also prescribed it for other
kinds of pain, such as that caused by sports injuries
Concerns
were raised after research linked the drug to heart
attacks and bleeding in the gut At the time of its
withdrawal in 2004, 20m people around the world,
including 400,000 in Britain, used Vioxx
More
than 4,200 claims have been lodged against Merck with
courts in America - including one by Carol Ernst,
left, who was awarded more than $250m this weekend
Copyright,
Brian Deer. All rights reserved. No portion of this
article on Vioxx (rofecoxib) may be copied,
retransmitted, reposted, duplicated or otherwise used
without the express written approval of the author.
Responses, information and other feedback are
appreciated - via the briandeer.com
homepage.
