VIRUSMYTH HOMEPAGE

THE MONEY SPINNERS

By Brian Deer

The Sunday Times (London) 6 March 1994

When Gertrude Elion joined the laboratories of the New York-based Burroughs Wellcome Company in 1944, its executives only reluctantly accepted her, as a favour to their chief biochemist. "Okay, there's a war on," they conceded, perusing the 26-year-old's details; but she had recently been flitting from job to job and had not got a doctorate. In addition, the more forthright declared, she was female and would therefore quit to get married and drop science for a family.

Fifty years later, generations of the drug firm's management have swept in and later cleared their desks, and the United States operation has moved south to Durham County in North Carolina. But Elion is still on the payroll and shows no sign of quitting yet. Scattered about her office in the British-owned company's headquarters, she has 18 (honorary) doctorates, a Nobel prize and square metres of other awards. She has also confounded her long-gone critics by only ever being married to her job.

But she did help start a celebrated family, though not of the usual kind. With the man who hired her, Dr George Hitchings, her labours in the laboratory spawned a string of related medicines, without which the drugs empire started by the late Sir Henry Wellcome might have gone bust decades ago.

There was 6-mercaptopurine, the first treatment for leukaemia; azathioprine (or Imuran) for use in organ transplants; allopurinol (Zyloric or Zyloprim) for gout; and pyrimethamine (or Daraprim), an anti-malarial. There was trimethoprim (part of Septrin, Septra or Septran), an antibacterial; and acyclovir (Zovirax), the most effective treatment for herpes. These drugs then paved the road to Wellcome's AZT (zidovudine, or Retrovir) for people suffering from AIDS. The scale of this achievement exceeds any easily grasped unit of measure. Both Elion and Hitchings who together shared the 1988 Nobel prize for medicine with Britain's Sir James Black often find it best to put it over with simple anecdotes. Recently, Elion ("Trudy" to her friends) got a letter from a mother whose child's life was saved by a course of acyclovir. Hitchings, who is 89 years old and thinks he met Henry Wellcome in the 1930s, looks back to the decade that followed, when mercaptopurine gave remission to a woman with leukaemia who had a child before she relapsed.

You won't get much help from the pair in ranking the drugs' importance. "It's like being asked to discriminate amongst your children," Elion says. "It's very difficult to say that mercaptopurine was more important than Imuran, was more important than allopurinol. Or that acyclovir was more important than all of them. Because they came at different times. They were for different uses. And each one in its own time was kind of a revolutionary drug."

Viewed by the accountants and sales people at the company's parent in London, however, some of these products look a good deal better than others. Together, a quartet of billion-dollar-revenue drugs allopurinol, Septrin, AZT and acyclovir have turned Wellcome from what was essentially a small-time marketing outfit at the time Elion joined it, into one of the key players in pharmaceuticals today. Producing more than half of the company's £ 2 billion sales last year, those items have transformed it into one of the few world-name corporations still controlled from the United Kingdom.

Moreover, besides filling the coffers of Burroughs Wellcome's parent which trades, confusingly, as the Wellcome Foundation the same four products have also been part of the kitty for the even mightier Wellcome Trust. This body, a registered charity set up under the founder's will, has a controlling interest in the company with 40% of its shares and is today the richest medical research fund anywhere in the world. With assets of more than £ 6 billion, it funds work by thousands of doctors and medical scientists, like a profit-sharing scheme through which these professions receive proceeds from Elion's drugs.

Total spending is more than £ 400m a year, with the biggest awards in 1993 to specialists working in neurosciences, molecular and cell biology, physiology, pharmacology, infectious diseases and immunity. The trust's American equivalent, the Burroughs Wellcome Fund, also makes major grants, mainly to support pharmacology research and as foreign travel expenses.

During the 1970s and 1980s (when the charity held all of the company's shares) it was mostly profits derived from allopurinol and Septrin which flowed through the trust and the fund. Then, in record-breaking stock market flotations in 1986 and 1992, it was AZT and acyclovir that became the source of windfall finance, making the organisation left by Henry Wellcome's death in 1936 more economically influential than even the British government's Medical Research Council. Never before, and nowhere else, has a string of pharmaceutical products produced such a medical money-go-round.

Confronted by Elion's world-weary eyes and no-nonsense charm, it is certainly ill-mannered and perhaps even cruel to say anything ill of her offspring. In stories of her childhood in Brooklyn, she talks about how a favourite grandfather died from cancer, propelling her into a lifelong quest to do something to combat disease. It is a similar story with Hitchings, who grew up on the Pacific coast of Washington state and was just 12 when his father died. For some 45 years this dedicated pair shared the cluttered benches of a lab together, sometimes seven days of the week.

But, as was revealed last week in the first part of our investigation, research suggests that three of Wellcome's big four drugs the antibacterial, Septrin, the AIDS drug, AZT and the herpes treatment, acyclovir have been promoted beyond the best medical opinion. Much of their yield has come from use by patients for whom they may be of trivial benefit, inappropriate, or sometimes even a danger.

It can take years for independent investigators to get the measure of a prescription drug; so it is the older product, Septrin (also marketed as Bactrim and sometimes known as co-trimoxazole), that has prompted the most forceful concerns. In this, a relatively safe and effective compound called trimethoprim (invented by Hitchings) was mixed with a more dangerous and largely redundant sulphur chemical (sulphamethoxazole) in a controversial marketing deal. Since its launch in the late 1960s, research suggests that this combination drug may have been associated worldwide with what could be thousands of deaths and injuries, the bulk of which have gone unreported.

During the past week, people who have been prescribed Septrin telephoned and wrote to The Sunday Times to tell of their experiences. One mother said that her four-year-old son had been rushed to hospital haemorrhaging and close to death after taking the drug for a chest complaint. Another reader recounted how her life had been "ruined" from a chronic syndrome that set in immediately after use of the product. Solicitors acting for Wellcome plc, however, said that our report had "appalled" their clients and that they were considering their legal position.

Wellcome's fourth big earner, the gout drug, allopurinol, was not examined in last week's report. It, too, has been of value to a relatively defined group of people and then greatly extended in its use. Like the other products, it too reveals a system in which some patients can be prescribed medicines which may have few health benefits for them but carry the risk of side-effects.

Gout is one of the many diseases for which there is still no cure. It is caused by an excess of uric acid in the blood (or "hyperuricaemia"), and shows itself, mostly in older people, when it super-saturates the body's tissues, sometimes causing swellings and excruciating pain. In its chronic form, the acid can condense into crystals, particularly in the kidneys and joints, often producing physical deformities and a condition quite like arthritis.

Elion and Hitchings conceived Wellcome's drug almost by accident. Their main interest was in the elusive search for cancer treatments and at first they thought the compound would be useful in leukaemia. But in 1956, it became clear that it lowered uric acid levels and was therefore likely to be effective for the treatment of gout. It was the kind of mix'n'match discovery that was common at the New York laboratory then; and which makes Hitchings smile even now.

"We said: 'Now we've got the drugs,"' he chortles, during an interview in his office, along a wide, carpeted corridor from his lifelong collaborator. "'All we've got to do is find the diseases that go with them."'

Although allopurinol acts in a highly specific way, its benefits and risks need to be carefully balanced by doctors and patients. In some people it may precipitate rather than relieve gout symptoms and there can be side-effects ranging from mild skin rashes to rare fatal blood disorders and hypersensitivity syndromes. With these, among other things, the skin can slough away.

Despite its intended use for a different disease, when the drug was first marketed in 1963 it seemed an unqualified success. Many thousands of people who suffered from chronic gout attacks (Elion included) found that the sharp drop it could bring to uric acid levels meant that the disease became manageable. Although it may have been a distraction from much-needed dietary and lifestyle changes, it at least relieved the symptoms for many of those who took it.

But all drugs, even the most common, have a downside and in 1970 the first death related to allopurinol was reported in The New England Journal of Medicine. It was the case of a 72-year-old man who had been diagnosed with gouty arthritis in 1944, but whose condition seemed to be stable until he took the Wellcome drug. Despite emergency admission to hospital, nothing could be done to arrest the hypersensitivity syndrome's fatal effect.

By January 1986, 22 deaths associated with the drug had been published in the medical press and were reviewed in the journal Arthritis and Rheumatism. This noted "significant morbidity and mortality associated with the allopurinol hypersensitivity syndrome" and warned doctors about their prescribing.

These deaths were certainly out of the ordinary and in that period an estimated 240m doses (or 71 tonnes) of allopurinal a year were prescribed around the world. But fatalities that get written-up in journals are bound to be only a proportion of the true number that occur.

In the meantime, Wellcome had promoted the drug heavily with advertising in medical journals and sales representatives visiting doctors. They were advocating its use not just for people who were suffering from gout, but also for those who were unusual only in that their uric acid level was high. In the same way that the company would later argue that AZT should be used to prevent AIDS developing in HIV-positive people (rather than just for treating the sick) allopurinol was advocated for the much greater numbers who were simply predisposed to gout. "Remember Zyloprim the original (allopurinol)," was one popular advertising campaign for doctors which kept further information to mandatory small-print. Another, which ran at the front of the Journal of Rheumatology between 1974 and 1986, sometimes declared bluntly: "In hyperuricaemia or chronic gouty arthritis Zyloprim".

Yet a further promotion, across three pages of the New England Journal in 1980, featured famous men, such as William Pitt, who reputedly had the complaint. "Today we know what Pitt's physicians didn't," said the message. "That hyperuricaemia causes gout and that the same hyperuricaemia can lead to kidney stones."

Although such advertisements may have been free of technical error, they created a climate for increased use; as sales of allopurinol took off, the numbers suffering its side effects inevitably increased too. While most patients tolerated the drug well, studies showed that about 2% of those for whom it was prescribed experienced adverse events; one survey of hospital patients found that of every 260 treated, one had a life-threatening reaction.

Even more worrying was that clinical surveys showed that most people taking Elion's drug (one said the figure was 80%) were not suitable to do so; researchers publishing in Arthritis and Rheumatism were caustic about the result. "The vast majority of patients both in our series (7 of 8) and reported in the literature (51 of 59) who developed allopurinol hypersensitivity did not have proper indications (ie symptoms) for receiving the drug," they reported. "Serious and often fatal allopurinol hypersensitivity is a high price to pay for inappropriate therapy."

Wellcome points out that it is the medical profession which is responsible for prescribing to patients; but the company is a powerful force in making doctors aware of products and maximising consumption. Advertising in the medical press and sales people who call on doctors have no other plausible purpose. Just as the most authoritative evidence shows that Septrin, acyclovir and AZT found a market among people who may not need them, so allopurinol's use was overextended, along with the risks accompanying it.

Critics may say that this is Wellcome's way; it is what happens when commerce and pharmaceuticals vie with each other. Of course no blame attaches to Elion. "That aspect of the marketing, I have nothing to do with," she says with a Nobel laureate's confidence, when asked about the competing pressures that may exist between good medicine and profitable commerce. "Once the thing is established, sometimes they do things that are commercially feasible and commercially important and perhaps not medically important. And that's a decision that I don't have to make."

Ask Wellcome in London about this state of affairs and it emphasises the value of allopurinol, points to the supervision of licensing bodies and refuses to accept that the public could raise doubts about its strategy. "This is the type of debate which must take place between those able to understand the literature and interpret it," Dr Trevor Jones, its research, development and medical director, told The Sunday Times. "And that is the community of clinical scientists in this area of speciality and the regulatory authorities." At the Wellcome Trust, Dr Bridget Ogilvie, its director, was no more forthcoming. She said that she was not aware of any concern over allopurinol or, indeed, over any of the company's drugs. When asked whether or not the trust had a duty to know about the activities of the giant corporation, she said that this was a not a matter for her, but to be taken up with "regulatory authorities".

That the company and charity speak in much the same terms may come as no surprise; that is what its founder had always wanted to happen. In his will documents, Henry Wellcome made clear his belief that there should be close collaboration between the profitable and philanthropic arms of his empire and that through this route there would be "vast fields opened for productive enterprise for centuries to come".

But the Wellcome Trust sponsors some of the most prestigious medical departments in the world. It has an advisory system of more than 3,500 doctors and scientists. It owns one of the finest medical libraries and on-line data retrieval systems in Britain. It has a multi-million pound research institute inside its headquarters building. Its seven-person governing board includes a doctor and four professors. If it does not know about such widely-used medicines, it is difficult to imagine who would.

In a structure devised to distribute the profits of pharmaceuticals to the research work of doctors and scientists, moreover, there may also be anxieties about Wellcome's wider impact and whether it creates potential conflicts of interest among those who can judge the drugs. When asked whether experts may feel inhibited from criticising the big four products because of the organisation's enormous reach, Ogilvie did not refute the suggestion. She declined to make any comment.

This issue is a sensitive one, steering close to the ethical wind. Increases in research costs and tight controls on public spending for science mean that the trust is being bombarded with requests for grants and sponsorship, two thirds of which are refused. Last year, even on the British government's crucial Committee on the Safety of Medicines, 19 of the 21 members either worked in institutions which received funds from Wellcome, or they were granted a share of the drug revenues in their own professional right.

The potential this creates for a menage a trois between company, charity and experts is perhaps the most worrying feature about Wellcome and not only because of the potential for affecting judgment but because the trust should not use its tax-exempt status to further the company's goals. Yet this idea was central to Wellcome's origins and has been at the heart of the organisation's rise to influence. In his will documents, the founder noted that some people getting research money from his empire would produce "much of purely technical interest". Nevertheless, he went on, some of their work "should also contribute to the discovery of remedies and curative agents and new methods of treatment which may be of practical interest and importance to the industrial organisations of the foundations".

In the United States, the Burroughs Wellcome Fund (of which Elion and Hitchings were for many years directors) has kept particularly close to these aspirations. One of its biggest grants is a $350,000 award for "innovative methods in drug design and discovery", which in 1992 went to a scientist in Oregon, Dr Susan Amara. Her work relates to brain chemicals which, according to the fund "may help physicians combat cocaine addiction". At the same time, Wellcome has a new drug, bupropion, which it says is "undergoing clinical trials in the USA for the treatment of cocaine addiction".

In the clubby atmosphere of British medicine, the cross-fertilisation between company and trust has reached the highest levels. One of the most distinguished figures whose career has risen with Wellcome is Sir Roy Calne of Cambridge University, one of the most accomplished transplant surgeons. As a young man, he helped Elion and Hitchings to develop azathioprine and, in the years that followed, was extensively endowed by the charity with grants, sponsored research assistants and expenses.

Another example of how working with the company can be followed by trust support involves two professors: John Stenlake of Strathclyde University and James Payne of the Royal College of Surgeons. Both were key figures in developing atracurium, a top-selling Wellcome muscle-relaxant drug, with sales of £ 100m a year. Stenlake received trust grants for his work between the late 1960s, when atracurium's development began, and the mid-1970s. Payne got assistance in the early 1970s and the late 1980s.

Among the most recent instances is the case of Herman Waldmann, professor of therapeutic immunology at Cambridge and a fellow of the Royal Society. With financial support from the trust, he advanced a revolutionary Wellcome product called Campath, the world's most developed monoclonal antibody, of potentially enormous commercial value. After assigning the drug to the company, he became an adviser to the charity and sought to obtain further sponsorship. This, however, was blocked last year he believes on the advice of lawyers.

Nobody suggests anything improper by any of these respected figures (who are bound to look for funding from such sources that are available) and the trust would flatly deny that there is any quid pro quo when it offers financial support. But it is clear that at least some applicants for funds believe that they will be rewarded by the trust after helping the company.

The money they receive, of course, does not go into their private accounts. The trust's profit-sharing is a philanthropic enterprise, which supports professional work. But it is rarely cash in the bank that wins the hearts of people of the highest standing in science. They are more often motivated by a desire to further medical progress and to win peer-recognition; it is these, along with essential overseas travel, that rely on financial help. Even those who, like Elion, are payrolled by the company rarely consider the opportunities in terms of their wallets.

"They think that we get some personal monetary reward out of it and that really isn't what we want," she says of the many people who misunderstand this point and assume that she must be rich. "What we want is a chance to do research. A chance to, you know, get some additional people in our departments and so on."

While it is the trust which has handed out most of the money from the big four Wellcome drugs, the kind of opportunities to which Elion is referring can also come more directly. Both the Wellcome Foundation and the Burroughs Wellcome Company make major contributions of their own to swell the medical money-go-round. Unrestrained by charitable rules and regulations, this can quickly be channelled to where it counts: to where it brings the greatest reward.

During the last five years, Wellcome has courted particular controversy over its monetary interventions in AIDS, which some have argued taints vital debates and the development of other treatments. People suffering from this condition will often not only use AZT, but may also take acyclovir and Septrin as well, generating millions of pounds and dollars to support the most influential individuals and bodies. These have ranged from the US department of health, which took $5m, to countless small self-help groups which may receive a few thousand pounds each year.

Much of the money has been given in the form of support for trials of Wellcome products. In an American coast-to-coast test which got AZT its licence in 1987, for instance, one hospital, Massachusetts General, received $140,000 to supply data on just 19 of its patients. Other participating institutions were also paid; far from such payments guaranteeing high quality work, Food and Drug Administration inspectors discovered flaws in methods employed, particularly in Massachusetts.

Another example of company sponsorship in the United States concerns one of the most powerful figures in medicine. Dr Samuel Broder, director of the government's National Cancer Institute and the person most associated with AZT's approval, was himself supported by Burroughs Wellcome at a crucial time for the drug. Although the money went to his laboratory, he accepted a cheque for $55,000 at the time the company's product was under federal review.

AIDS "activists" have also been a target for direct financial initiatives, the most striking among which has been the militant group, Act-Up. In the epidemic's early years, this organisation had broken into company offices among its many protests against Wellcome. But in July 1992, only weeks before the trust floated a huge block of shares in the company, Act-Up leaders appeared at a New York press conference to shake hands and accept a "community work" donation of $1m. Travel deals have also been concluded, with the British company spending £ 60,000 last year to fly Act-Up supporters to a popular conference in Berlin.

Even journalists and politicians are not overlooked by Wellcome's treasury. Writers are often helped to attend meetings and briefings in foreign locations, while the European Community held a parliamentarians' conference in London last year that was sponsored by the Wellcome Foundation. The company's director of European operations gave a key-note address.

Such techniques, which are common to the pharmaceutical business, provoke wry mirth from close observers. Sir James Black, Elion's fellow Nobel prizewinner, smiles at mentions of Wellcome, for which he once used to work. "The industry as I've seen it, I think, takes the view that marketing drugs is the same as marketing anything," he says. "The promotional methods used by the pharmaceutical industry are no different from the promotional methods used in any other branch of the chemical industry."

With that idea Black addresses an issue which the public may overlook: that the drive of a company that manufactures drugs is to sell them what it makes. Wellcome's board is mostly made up of the same kind of people who might run, say, a merchant bank or an oil corporation. There is nothing surprising if they do their job in much the same sort of way. That they are screened from their customers by the judgments of doctors is the only thing that is unique to this particular enterprise.

With the Wellcome Trust too, there have been no doubts about the integrity of the people who are running it. Roger Gibbs, the chairman, has had wide business interests, including the London Clinic and Arsenal football club. Another board member, Sir Peter Cazalet, is a former oil man and a prominent industrialist. But at the end of the day, in the legacy and structures set up by Henry Wellcome, the profit-sharing scheme that continues to grow has acquired a life of its own.

Trying to override this life has proved an endlessly difficult task. At least until 1984 (when such information ceased to be available), the trust, for instance, ploughed money into the British American Tobacco Corporation, as well as the breweries Bass Charrington, Courage, Whitbread and Watney Mann. Possibly good investments but not free of controversy.

More important than such little embarrassments, however, is how the trust and the company may be preparing for the years to come. Both are becoming deeply involved in biotechnology and genetic engineering, areas where a scientific mistake or too much marketing could lead to a catastrophe. As the Wellcome empire continues to grow, through its tax-exempt charitable arm and the company's drug development, the medical money-go-round may one day put humanity into a spin.

Some doctors and scientists may look forward with hope, but there are others who glance back with nostalgia to the kind of free scientific co-operation that is now a thing of the past. "When we first had people working on 6-mercaptopurine, allopurinol, Imuran, we didn't pay one cent for those studies," Elion remembers. "We didn't influence them in any way."

No doubt if her children had been young people instead of drugs, she would have warned them even in those safer times about the risks of taking candy from strangers. *

VIRUSMYTH HOMEPAGE