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Vioxx: the UK connection

The Sunday Times

Victims of drug that
took a hidden toll

The Sunday Times, August 21 2005

Special investigation by Brian Deer

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”.

Vioxx: the UK connection
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This report is copyright, Brian Deer. No portion of this article on the Vioxx (rofecoxib) disaster may be copied, retransmitted, reposted, duplicated or otherwise used without the express permission of the author. Responses, information and other feedback are appreciated