Investigation: Victims of drug that took a hidden toll

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Investigation: Victims of drug that took a hidden toll.

Mon, 22 Aug 2005 00:12:01 +0100

 

 

The Sunday Times - Britain

 

August 21, 2005

 

Investigation: Victims of drug that took a hidden toll.

 

 

Brian Deer on the emerging tragedy of the painkiller Vioxx

WHEN Kenneth Wood died of a heart attack two years ago on the day he

was supposed to go on holiday to America, his wife Margaret blamed

herself.

 

Should she have given him an aspirin, she wondered, to thin his blood

as he lay complaining of chest pains? The ambulance crew had done that

straight away. Could she have done more to galvanise the hospital? The

doctors, she felt, had looked confused.

 

" The shock was that he was so active, " said Margaret, 64. " He used to

go bowling six nights a week, right up until the day before he died. "

 

Last September she got another shock when Vioxx, a painkilling " wonder

drug " , was taken off the market after a clinical trial in America had

shown a link to heart attacks.

 

Wood, 71, a retired laboratory technician from Madeley, Shropshire,

had been taking part in British trials of Vioxx when he died. The

research was designed to establish whether the drug could be extended

from its main purpose, relieving arthritis, to the prevention of colon

cancer.

 

In doing so, Wood became one of numerous victims of a medical

cataclysm highlighted this weekend by a court case in Texas, which saw

the drug's manufacturer, Merck Inc of New Jersey, ordered to pay

£141.1m in damages to the widow of another Vioxx patient.

 

Dozens of British lawyers are now soliciting clients, while some

experts calculate the global toll linked to Vioxx at up to 60,000 deaths.

 

" This, " Dr David Graham, a senior US Food and Drug Administration

(FDA) official, told a stunned Senate committee last November, " would

be the rough equivalent of 500 to 900 aircraft dropping from the sky. "

 

He described it as " what may be the single greatest drug safety

catastrophe " .

 

Although Margaret Wood has no plans to sue anyone, some lawyers

believe she could have grounds. A Sunday Times investigation into the

British connection to the Vioxx project has established that her

husband was never told of all the possible risks when he was recruited

for the trial.

 

This is the essence of what emerged from the court near Houston — that

Merck did not disclose to patients all it knew about problems with the

drug.

 

Margaret did not know, for example, that a doctor working on the trial

had reported to Merck that the drug trial was " probably " to blame for

Wood's heart attack.

 

" I'm very, very angry, " said Margaret when I showed her confidential

documents last month. " I wasn't aware that there were any risks at all. "

 

Her husband died in November 2003, 18 months after volunteering for

the research. The trial, called project " Victor " , was financed by

Merck. Nor did Margaret know that evidence of Vioxx's potential

dangers had first been noted four years earlier. Even after this, the

drug was backed by much of the medical establishment in America and

Britain.

 

Just six months before Wood's death, Britain's leading authority on

painkillers had dismissed rising fears over heart attack deaths

connected to Vioxx as " speculation " .

 

The Wood case is part of a far bigger scandal now threatening to

engulf Merck. When Vioxx was withdrawn, 20m people around the world,

including 400,000 in Britain, were using the drug. Doctors have

formally reported the deaths of 103 people in Britain, but the real

figure may be as high as 2,000 according to some experts.

 

Why was such a potentially dangerous drug allowed to be prescribed so

widely in Britain? Why was it backed so enthusiastically by experts

such as Professor Michael Langman, one of the leaders of the Victor

trial and an expert on painkillers? The answers are both complex and

distressing. They begin with a paradox that Langman had been

struggling with for more than 20 years.

 

LANGMAN, a former dean of Birmingham University's medical school,

became a figure of great influence in 1987 as one of the 36 members of

the government's drugs watchdog, the Committee on Safety of Medicines

(CSM).

 

Painkillers have long been Langman's specialist interest, particularly

aspirin and similar drugs such as naproxen and ibuprofen, known

collectively as " non-steroidal anti-inflammatories " or NSAIDs.

Although they are effective, particularly in osteoarthritis, they can

also cause fatal stomach ulcers and perforations.

 

When Merck announced in 1999 that it had developed a similar drug

without these side effects, Langman was understandably impressed.

 

The new drug was based on Nobel prizewinning research by Sir John

Vane, a British pharmacologist who had found that aspirin blocked two

chemical messengers. One triggered the heat and pain of inflammation,

while the other protected the stomach from ulcers. By blocking one but

not the other, it ought to be possible to give relief without the

usual risks.

 

Few new medicines are truly " miracle drugs " but this was how Merck

sold Vioxx. To advance this image it recruited an army of consultants,

Langman being among the most distinguished.

 

In April 1999 he sat with the Merck delegation when FDA advisers

assembled at the Gaithersburg Holiday Inn in Maryland to consider the

company's application for a marketing licence.

 

" In my country there are hundreds of deaths a year — in all there are

thousands — from NSAIDs complications, " he told the meeting. " It is

the critical issue and if we have information that bears upon it I

have a feeling, as somebody with an interest in public health, it's

our duty to make it known. "

 

Nine days later the CSM approved the drug for marketing in Britain. A

leaflet aimed at British doctors stated: " In eight pooled studies of

up to one year, Vioxx (average dose 25mg) reduced the risk of

developing upper GI (gastro-intestinal) perforations, ulcers and

bleeds by more than half compared to NSAIDs. "

 

Although FDA staff registered " serious concerns " about the analysis,

Langman became the new drug's champion. In one journal he declared

that Vioxx-type drugs " are almost certainly associated with lower

risks of ulcer and its complications, and probably no risk at all " . In

another he later denounced rising fears over heart attacks as " a

flurry of unjustifiable speculation and controversy " .

 

In 2001, at the peak of the Vioxx hype, Merck reportedly spent $160m

advertising the drug. In Britain, where direct advertising is banned,

the promotion was almost wholly through doctors. " The world of relief

is about to change, " screamed promotions issued for Vioxx's British

launch (including a coupon offering doctors a free clock). " True

once-daily dosing for osteoarthritis patients . . . Selective, strong,

simple. "

 

Merck also sought ways of broadening the market for the drug by

demonstrating that, like aspirin, Vioxx was effective for more than

just arthritis. Doctors prescribed it to reduce the inflammation

caused by sports injuries, and in particular it seemed to have

potential for inhibiting tumours, for example in colon cancer.

 

So while an American Merck trial code-named " Vigor " compared Vioxx —

known generically as rofecoxib — with the painkiller naproxen for the

treatment of rheumatoid arthritis, another trial — " Approve " — tested

whether colon cancer could be stayed.

 

In November 1999 the safety committee monitoring Vigor met to discuss

increased blood pressure, " excess deaths and cardiovascular

experiences " . 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, © 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