Hard Sell

By Brian Deer
The Sunday Times (London) 27 Feb. 1994

Were you to travel to London's Euston Road and stand outside the seven-storey building at number 183, you would not think that you were close to anything of note. The structure's white Portland stone facade and Greek-columned central pavilion are reminiscent of nothing more than, say, a United States courthouse or a down-sized Bank of England. It is a self-important but bland creation. To see it once is to forget.

But if you sneaked through its revolving front door and up 12 cold steps to the grand high-ceilinged lobby, you would find yourself in awesome spaces that shout most loudly of money. Number 183 is the creation of the late Sir Henry Wellcome, architect of the modern pharmaceutical industry; and the builders knew that this meant they need not skimp on the job.

On the day it opened in 1932, only four years before Henry died, it was a point of distinction that no wood or cheap metals should be visible anywhere. The floors, walls and staircases were in fine imported marbles. The doors, windows and fittings were exclusively of bronze. It was all to the taste of a president or a king a style to suit the man.

Such hidden grandeur does perfect justice to the building's extraordinary role. Number 183 is the headquarters of the Wellcome Trust the world's biggest private medical research fund, a charity with assets worth more than £ 6 billion. Though little known to the public, here is by far the United Kingdom's richest body with the tax-breaks of charitable status. (It is twice as wealthy, for instance, as the Church of England commissioners.)

From this building the trust controls a commercial drug company, the Wellcome Foundation, one of the top pharmaceutical manufacturers in the world and, through that, Burroughs Wellcome, its giant United States offshoot. Within these operations, in turn, are the coffers that supply the Burroughs Wellcome Fund, one of the 50 leading American foundations. At 183 is also based the Wellcome Institute, a multi-million-pound centre that researches and shapes medicine's history, politics and ideology.

From all of these through grants and sponsorship government agencies, universities and hospitals are influenced everywhere. The trust alone distributes more money to institutions than even the British government's Medical Research Council: some £ 400m annually to doctors and scientists in Britain and around the world.

In offices on this building's first floor, decisions have been reached that have affected lives and health on a scale that compares with minor wars. In the conference room, set high above the street, and the meeting hall in the basement, rulings in biotechnology and genetics are being handed down that will help to shape the future of the human race itself.

If all of this is news to you, then at least some Wellcome products should be more familiar. The Wellcome Foundation (which recently decamped to a tower-block at 160 Euston Road) most notably sells AZT, the controversial AIDS drug, which last year commanded a market of £ 248m. Even more commercially noteworthy is its herpes treatment acyclovir sold under the brand name Zovirax which grossed £ 760m.

There are also over-the-counter cough and cold products, Sudafed and Actifed, which brought in £ 141m; and some 50 other treatments ranging from an antibacterial, marketed as Septrin, Septra or Septran, depending on the country, to a gout remedy, allopurinol, known as Zyloric or Zyloprim. Total sales revenues are more than £ 2billion annually.

Number 183, the citadel of this empire, is even more impressive today than when it was constructed. In its sumptuous, galleried library on the second and third floors, the quality of the furnishings is on a par with a five-star hotel. On the upper ground floor, a high-tech science exhibition is like a cross between Disney World and the toy department at Harrods. On every level there are old master paintings and glossy publications.

The building's special place of honour, however, is below street level, where the trust keeps a nominal shrine to the man who started it all. Here there are examples of merchandise that got the company going; there are some of Henry's personal items, medals and his soft-spined preacher-style Bible; and, by the staircase near the entrance, there is an oil painting of the founder as he was in middle age with a thick handlebar moustache that dominates his face.

On a winter evening among these things you can almost feel his ghostly presence. This man, whose life was as controversial as his legacy, not only built the formidable organisation which centres on this building and through it helped shape the rise of 20^th-century medicine but did so in a way that allows him to brood over human health even from beyond the grave.

Shortly before the building was opened (and not long after he was knighted by George V), Henry knew that he was approaching the end of his life and filed a remarkable will. With it he included a lengthy handwritten memorandum. Together these papers set out a detailed plan of how his empire would continue long after he was gone.

Though you will not find them on display, or listed in the library, these documents are held by the Charity Commission in London and, with Wellcome's inexorable rise, have turned out to be among the most important papers in the history of medicine.

What Henry set out was a blueprint for a philanthropic research body now the Wellcome Trust with all the tax and image advantages that such entities enjoy. The idea was that this charity would be the flagship for profit-making enterprises or, as he called them, "industrial organisations" which today trade under the name of the Wellcome Foundation Ltd.

So audacious and so successful was this scheme that, despite the efforts of some of the most honest among Britain's "great and good" who have taken charge of both enterprises over the years, it has placed the course of health and medicine into Henry's posthumous grip.

Urging that there should be "frequent consultations" between the charitable and the commercial parts of his empire, Henry revealed in the memorandum the scale of his ambitions. "With the enormous possibility of development in chemistry, bacteriology, pharmacy and allied sciences," he predicted, "if my desires and plans are carried out in the way of research co-operation with the several industrial organisations, there are likely to be vast fields opened for productive enterprise for centuries to come."

The key exhibit at no 183 is Henry's personal Bible. For many years the trustees who run his affairs have kept this black volume on display, open at one of the passages he pencilled for special contemplation. "And thou shalt bestow that money for whatsoever thy soul lusteth after," it says in the 26^th verse from the 14^th chapter of the Old Testament's Deuteronomy. "For oxen, or for sheep, or for wine, or for strong drink, or for whatsoever thy soul desireth."

If Henry's soul desirethed anything, it was power and wealth and the markings suggest that he sought biblical authority for the quest on which he embarked. His father, two of his uncles and his brother were all Christian ministers, and a deeply felt religiousness was a constant theme in his life.

Henry Solomon Wellcome had been born in 1853 in the American Midwest and grew up in Minnesota, where his father was a noted lectern-thumper of the Second Adventist Church (then in some turmoil after an end-of-the-world prophecy had expired in 1844). According to his faith, righteous people such as Henry presumed himself to be would rise from the dead and live again when Christ returned to earth.

From his father, Henry acquired not only a tough-minded religious fundamentalism but also, most usefully, an evangelist's facility to persuade. For a while "Hank", as he was then known, worked in a drugstore started by an uncle in the frontier settlement of Garden City. It was there, when the future pharmaceutical millionaire was just 16, that he came up with (an admittedly childish) sales ploy that set the cast for what was to come.

Realising that it was not so much what a drugstore sold that made the money, but the way that it went about selling it, Henry bottled what was probably lemon juice and advertised it for invisible writing. "Wellcome's Magic Ink The Greatest Wonder of the Age", he called this, his first foray into business. His pitch would have shamed many a snake-oil salesman and continued in similar style. "This," it said, "is something entirely New And Novel!"

There is no available record of this venture's success, but life in his uncle's drugstore propelled Henry into pharmacy college, where he learned that the most profitable involvements in health care were more to be found in marketing than they were in medicine.

In 1880, at the age of 26, he moved to Britain and went into partnership with an even better salesman than himself, one Silas Burroughs (who died in 1895); and the pair put together a business which was to shape the pharmaceutical industry as it affects our lives today.

Their most important inspirations lay in promotion and presentation. At the time medicines were mainly prescribed as powders or liquids, so the two men set up a European agency for new-fangled American tablets. With these, Henry prepared attractive-looking chests containing such age-old remedies as ipecacuanha, strychnine and quinine, and called the products "Tabloid" brand an expression registered in 1884 as a catchword for Wellcome drugs (and still, in the fine print of legality, the organisation's property).

The Tabloid chests (some of which are displayed at number 183) were often given away to influential people and became the starting point for the modern industry's much loved "freebies". Beginning as cartloads of complimentary first-aid kits, hauled around London for the king, prime minister and other ruling-class figures, the idea was soon widened to include foreign travel expenses and "tell your friends" financial support for anyone else of use.

In particular, Henry became an ardent backer and no-charge supplier to his close friend Sir Henry Stanley and other African explorers, who generated publicity to bring glamour to his products.

The two partners were especially noted for pioneering door-to-door selling to doctors. They had found that people who became physicians often did so mainly for reasons of family, prestige or money and had little developed interest in the drugs they prescribed. Burroughs was particularly adept at calling at their offices, giving free samples and a smart sales pitch, pointing out the latest advertising and departing with the knowledge that a new crop of patients had been won to the brand.

Henry had comparable business acumen, but he also spent a great deal of time in less commercially minded pursuits. Since he believed that the Bible was literally true and therefore in conflict with evolution theory he spent huge sums hunting throughout Africa for proof that white tribes existed in humanity's prehistory. In Sudan he hired 4,000 people to scrape at the earth for four years in this inevitably futile quest to overturn scientific progress.

During such bizarre ventures, the kind of individual that Henry really was came dramatically to the fore. Donning the white pith helmet of the British imperial explorer, he would distribute peacock feathers to workers who abstained from the local drink (which he was convinced was the root cause of "all-night drunken orgies"). He would also whip men caught asleep on watch at night.

These aspects of Henry's character have given headaches to those concerned ever since with boosting Wellcome's image. Although the organisation pays homage to its founder, information about him has been studiously controlled. Much of his personal archive is claimed to have been destroyed, while a biography commissioned in the 1940s from a staff member (who wrote of Henry's "inflexible spirit of intolerance") was suppressed on its completion.

Nothing has been more problematic than one of the key chapters of Henry's life: his marriage (in 1901) and subsequent divorce. His wife, Syrie Barnardo, daughter of Britain's most celebrated child-care philanthropist, Dr Thomas Barnardo, was 27 years younger than her husband; and though they had a child together, their relationship was not good. According to her friends, Syrie particularly disliked Henry's persistent cruelty most notably that he beat her with a sjambok, a South African cattle whip.

Perhaps in reaction, Syrie used Henry's absences looking for white tribes to court other men in London. George Selfridge, the American-born department store magnate, was one. Then, some time around 1911, she met and later had a sexual relationship with the young Willie Somerset Maugham. He was England's most celebrated playwright at the time and, awkwardly for her, gay.

Although Maugham and Syrie had a child together and later married, he mainly needed her as a dinner-party escort; when Henry petitioned for divorce over the adultery, the writer accepted it cheerfully. But according to the suppressed Wellcome biography (which the trust refuses to make available, but was once briefly seen by someone writing about Syrie) the effect of the affair on Henry "soured his character for the remainder of his life". By the time he drafted the will and memorandum that were to establish the Wellcome organisation as a dominant force in medical science, the book concludes that the old man had lapsed "into a morbid misery only to be soothed by a vicious preoccupation in his own interests".

If Henry's ghost is somewhere among the marble and bronze of 183 Euston Road, he could only be of the conclusion that the God he looked to for comfort in life was consoling him after death. At the time of the divorce, he could hardly bring himself to think of Syrie's acts of alleged betrayal and of the homosexual Maugham's lack of Christian morality. But with the passing of years, it was precisely the conduct that had caused him misery which gave his empire its clout.

For there are no enterprises possibly excepting contraceptive pill manufacturers which have profited as much as Wellcome has from changing attitudes to sex.

Before the 1960s "sexual revolution", which saw the annual number of gonorrhoea cases jump 300% in a decade, the Wellcome company was an obscure pharmaceutical house with a few bright scientists and a modest reputation in cancer. But as the word "adultery" fell out of popular usage and promiscuity lost its stigma, it was Henry's empire that was on the spot with drugs for the accompanying complaints.

In the 1990s, the most high-profile of its products is AZT for AIDS, in the majority of cases a sexually-transmitted disease. When this drug was first marketed in the spring of 1987 it was hailed as a breakthrough, especially among gay men. Though the company initially priced the treatment in America at more than $10,000 a year, doctors and their patients seized on it as giving some brief last-ditch respite.

Such was the commercial success of AZT or zidovudine that a 20% block of shares in the Wellcome Foundation sold by Henry's trust in 1986 at £ 1.20 each had soared to £ 12 each five years later. In the summer of 1992, when the trust cashed in more fully on the drug's incredible publicity and sold another 40%, it grossed £ 2.2billion, while retaining a controlling interest. In London it was the largest private flotation in the history of the Stock Exchange.

Unfortunately, the benefits of AZT have remained mired in controversy. First synthesised in 1964 as a possible cancer treatment, it was abandoned for that purpose because it could kill the patients before it killed their tumours. In people with AIDS, who seemed likely to die anyway, scientists noticed that (possibly as the sufferers' immune systems rallied against the chemical) it gave them a kind of kick-start, often lasting only weeks or months, during which improvement was sometimes apparent.

This small sad benefit, first revealed in a Sunday Times investigation in April 1989, may justify a transitory role for some AIDS patients. But for others the drug's severe side effects can prove disabling and sometimes fatal.

Had an organisation other than Wellcome developed AZT, it is possible (though by no means certain) that it would have concentrated its efforts on targeting the drug on particular kinds of patient. Henry's legacy, however, demanded that, whatever the medical justification, selling was the first priority.

In a move which surprised some doctors, the company promoted the notion that people who were HIV positive but had not quite developed AIDS should take the drug; then those who showed no visible symptoms but whose immune systems were weakened; and finally people who were HIV-positive, but who were otherwise apparently well.

Although The Lancet, perhaps the world's most respected medical journal, warned that "there is no evidence to suggest that clinicians should be encouraged to give zidovudine to most symptom-free patients", Wellcome was drawn towards a market that could be one hundred times bigger than just those diagnosed with AIDS.

To pursue this avenue over which it is now facing a lawsuit in Britain Wellcome mobilised the creative talents in its marketing departments. In a worldwide campaign, medical journals were utilised for advertising and promotional articles; doctors were bombarded with calls from sales representatives and with independent-looking material; and, perhaps most worryingly, patients were targeted with what seemed to be objective advice. The high profit margins on AZT thought to be 70% net of all costs meant that the budgets available to push the product had rarely been seen before.

The trust even installed a permanent exhibit for the drug at 183 Euston Road perhaps thinking that a hard sell was what Henry would have wished. Remembering the success of his Tabloid chest promotions, the founder had instructed his successors in his will memorandum: "I consider it in the best interests of the several industrial organisations and of all concerned that the publicity, advertising and other propaganda shall be steadily increased as the output is increased in volume and in profits."

Despite the hype around AZT, however, Wellcome's drug for herpes simplex acyclovir or Zovirax is contributing three times as much to the company's turnover. Surveys have shown that, while this condition is only rarely life-threatening, the virus linked with it is at least 100 times more prevalent than the one associated with AIDS. In America, an estimated one in five of the sexually active population is infected with genital herpes and, though not all have symptoms, the number of visits to doctors for such infections has jumped 16-fold in 20 years.

At the level of science, acyclovir was something of a landmark. Synthesised in Wellcome's American laboratories in 1974, it was the first significant medicine that could safely block a virus. Although acyclovir does not cure the often recurring herpes it showed that, in principle, the smallest known infectious agents could be pharmaceutically attacked. Since the drug's release in 1982 it has saved the lives of many intensive-care and transplant patients who, due to immune suppression, are at special risk from the disease.

Among people with the common genital condition, however, the picture is a lot less clear. Key research (which took place a decade after the tests which established the product on the market) reveals that, though acyclovir tablets can suppress symptoms, the virus often continues to "shed", even in the presence of the drug. This means that, although the blisters associated with herpes may not be visible, the person may continue to be infectious and can therefore pass it on.

Thus, acyclovir (for which Wellcome charges $2,500 for six months' treatment in the United States) may be lulling users into a false sense of security causing more, not less, transmission.

Medical ethics might suggest that doctors should be loudly alerted to this problem in order to warn their patients. But, instead of prioritising this, Henry's organisation has used the sales techniques he pioneered in a worldwide campaign to boost the product, including forms other than the tablets and for conditions other than herpes simplex. In both situations, evidence suggests, the biggest gainer may be Wellcome's accounts rather than public health.

The most visible aspect of this campaign is a reformulation of acyclovir as a cosmetic lip cream for cold sores, or "herpes labialis". Though the company says its research shows that this non-prescription product now advertised on television can prevent attacks, the most authoritative independent report, published in the British Medical Journal by two hospital teams, found that the plain cream base for the medication may be just as good.

"As we have failed to show any therapeutic efficacy with this preparation and its widespread use may encourage the development of strains of herpes simplex that are resistant to acyclovir," they said, "we are reluctant to advocate its use in herpes labialis."

Also open to question is another Wellcome initiative: to sell acyclovir for chickenpox. This illness, which affects almost every child, which rarely has complications and which may be a normal part of our body's training to fight infections, is caused by another virus of the herpes family.

The biggest-ever published study in the New England Journal of Medicine showed that taking acyclovir meant that children had, on average, 294 spots instead of 347 on a placebo. Acyclovir has no effect on the transmission of the virus, but could net up to $150m a year for the company in the United States alone. The science correspondent of America's NBC News has called the drug's use in these circumstances an example of "irrationality and the quest for profits".

No better phrase, perhaps, could describe the dilemmas in the organisation which hark back to Henry's time. For, while the efforts to push AZT and acyclovir will be disturbing enough for some people, they are only among the more recent examples of the company's general approach.

In response to inquiry, Wellcome presents its affairs in an unequivocal way. Protesting to The Sunday Times about what it calls our "tendentious and frequently alarmist generalisations", it said that the company took great care to comply with all relevant procedures and requirements. "Products marketed by Wellcome over the years have saved many lives and improved the quality of life for many patients," it said.

But key issues remained unaddressed by the company and it is clear that, under the controlling watch of a registered charity, the long-term business advantages of Henry's empire may sometimes have been given a higher place than the health of those consuming its products.

Its top-selling antibacterial, marketed as Septrin, Septra or Septran, is probably the best example of how this can come about. Although, like acyclovir, it was rooted in the brilliance of Wellcome's own researchers, saturation promotion which accompanied it has been followed by associated deaths. Though grave worries have been expressed about this for the best part of 20 years, little has been done.

Septrin is a mixture of a remarkably safe drug called trimethoprim (patented by the company in 1957) and a more dangerous product called sulphamethoxazole, which belonged to the Swiss pharmaceutical super-giant, Hoffman-La Roche. Both are useful in certain diseases, but have been particularly popular in urinary tract complaints which often are related to sexual activity and for some sexually transmitted infections. Many people were prescribed the combination during the 1970s and 1980s for "non-specific urethritis".

That Septrin could injure or even kill emerged soon after it hit the market in 1969. Reports appeared in journals and a survey by Britain's Committee on the Safety of Medicines in the mid-1970s found a startling number of related deaths that were not picked up by doctors.

In 1979, the company organised a conference at which some of these were discussed but broadly dismissed as being either coincidental or outweighed by the drug's benefits. In an interview with The Sunday Times, Dr Trevor Jones, Wellcome's medical director, confirmed its commitment to the product. "Millions of people have benefited significantly," he said. "I am very proud of the contribution to health that Septrin has brought the world."

Nobody knows exactly how many deaths may have been associated with Septrin (also marketed by Roche under the brand name Bactrim), but the compound was the top anti-bacterial of its time (grossing more than $5billion) and so the figure may run into thousands. Most problems have concerned older people suffering from complaints which could mask the drug's side effects. Other reports, however, have involved younger patients, including children. The company insists that, although these followed use of the drug, causality should not be assumed. Although government agencies have allowed the product to be marketed, Wellcome cannot dispute that the sulphamethoxazole content of Septrin had a well-known record of causing serious reactions. Nor that its combination with trimethoprim is hard to justify for the treatment of most patients.

In 1973, a report warned about this in the journal Chemotherapy. In 1974, the Annals of Clinical Research and the Journal of Clinical Pathology both made similar points. In 1978, the advice was repeated in the British Medical Journal. In 1980, a team summed up in The Lancet that, compared with Septrin "single therapy with trimethoprim has the advantage of smaller tablets and fewer side effects, and it is cheaper".

But even though powerful doubts had been raised about the product, Wellcome remained loyal to Henry's ideas and sharpened its marketing. Such was the force of its promotion to doctors, for instance, that from August 1981 the fortnightly journal, World Medicine, carried a full-page colour Septrin advertisement in every issue for a year. Other influential publications were similarly used, with the general marketing slogan: "Today's antibacterial".

Considered alongside the controversy over AZT and acyclovir, the promotion of Septrin may cause some to feel uncomfortable about Wellcome's sales approach. Although Henry could never have dreamed of the sexual disease epidemics and commercial advances that were to come, there is a common thread which starts with him and runs through to the present day. While executives deny that there has been excessive marketing, these stories raise questions about whether its greater commitment is to fighting sickness or to maximising commercial success.

For the Wellcome Trust, which holds the reins and on whose reputation the company trades, it can only prompt further inquiries about the scope of its philanthropic intentions. How is it that a giant, respected organisation that is granted charitable status to relieve human suffering and which is taking a commanding position in medical science can be historically and financially rooted in the sale of drugs which may be of trivial use and may be inappropriate or even dangerous?

The company says responsibility for prescribing and the patients' best protection is firmly with the medical profession. There are also journals and government regulations which have a special influence. The Wellcome Trust, its officers say, has no involvement in the company's products, but promotes independent research. In short, that most of what has been said so far is not true at all.

But as the Wellcome story unfolds, it is not hard to feel that the most worrying thing about Henry's organisation is that in the structures he created and amid the inevitable conflicts between commerce and sound medicine even the best efforts of sincere people can produce perverse results.

It can also make you wonder whether, if the founder's ghost does wander the cold, concealed splendour of number 183 Euston Road, he would be moaning over the memory of his wife and Somerset Maugham. Or whether he would be chuckling at the achievements of his empire and its drugs. *