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.”
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