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Catch it! Bin it! Profit from it! Swine Flu and those who did well On 30 September 2009, Professor David Salisbury, the Department of Health's Director of Immunisation, sent a detailed letter to the people who were responsible for our future wellbeing during thoutbreak. The recipients included all "Flu Directors and Co-ordinators" and "Pandemic Influenza Leads" in every health authority and NHS primary care trust in England, a rigorously marshalled and prepared bunch, several hundred in total. The letter concerned the new flu vaccine, which was three weeks from being widely available and couldn't come soon enough. After a lull over the summer, the outbreak was on the rise again: within two weeks of Salisbury's letter, it rose to an estimated 27,000 new cases in a week, double the total of a fortnight before. The greatest rise had been seen in people below 25. The vaccine, which offers protection specifically against the H1N1 virus rather than the seasonal three-strain jab, is manufactured by GlaxoSmithKline under the name Pandemrix. It will be delivered in batches of 500 doses, each batch sent in a container the size of a shoebox, and GPs will receive £5.25 for each jab (the shot will be free to patients). Professor Salisbury hoped 9.5 million people will be vaccinated, the number of people in England judged to be in the clinical risk groups – the elderly, pregnant women, those with immuno-compromised conditions and heart disease, and healthcare workers. Ideally, the vaccine should be delivered in two doses three weeks apart, but it was thought that one dose would also provide adequate protection. Salisbury's letter contained much information about the constitution of the vaccine, which contained trace elements of mercury to maintain stability, and he also noted that although most doses were given without any trouble at all, rare cases could have side-effects; in these circumstances, anyone affected would be covered under the Vaccine Damage Payments Scheme. But how would this information be shared with the population? Salisbury was cautious. "Publicity campaign plans for the swine flu vaccine are in development," he wrote. "This is a complex task, as they need to be considered against the wider picture of other communications that might be required about flu, for example on where to get treatment and on prevention via good hygiene practice." He anticipated that the first phase of the publicity campaign would commence in mid-October, and would focus on "inviting" people in the prioritised groups to present themselves. "It will be important that we give the public a consistent message on the new vaccine to avoid confusion." Salisbury's instructions concluded with a reminder that although much progress had been made – the vaccine had been prepared in just under four months, two months less than it takes each year to make the regular seasonal flu jab – this was only part of the story. The fight against the virus was far from over. "I would like to take this opportunity to thank all of you for what you have done so far," he told his lieutenants, "and what I am sure you will continue to do." This letter, which had the tang of a wartime bulletin, marked a turning point in our ability to cope with this year's big health challenge, and it had a reassuring air. Things are under control. Should things get worse, we are prepared. The NHS has again proven its worth and its expertise. Science has pulled us through, and there is a sense of relief. But there is another side to this. The relief is partly due to the fact that to date in the UK swine flu has not reached the levels we once feared: following the first UK infections at the end of April, epidemiologists suggested there may soon be 100,000 new cases per day. At the peak of the first wave of the epidemic in the summer, the Chief Medical Officer feared a worst-case scenario of 30% of the UK population infected, with 65,000 deaths. (By mid-October, there had been 83 deaths in England, 15 in Scotland, 4 in Wales and 4 in Northern Ireland. There have been an estimated 370,000 cases of swine flu in Britain.) And there is relief that we have managed to survive with a supply of drugs that have shown themselves to be only marginally better than the defences we could offer against the three great pandemics of the past 50 years in which millions died. In the last six months, Tamiflu and Relenza have become famous drugs, brand names that will define a decade in the same way AZT and Prozac defined the 80s and Viagra the 90s. And they may turn out to be more significant than any of these, for the wrong reasons. Despite great initial optimism, a survey of all the available patient research has shown them to be only mildly effective at best. In the vast majority of cases where flu lasts a week, the drugs reduce the symptoms by half or three-quarters of a day. Efficacy will be less – perhaps zero – if the drugs are not taken within the first 48 hours, with the side-effects outweighing any benefits. The manufacturers have made no secret of the efficacy – or otherwise – of their drugs. And yet about 270m treatments of Tamiflu have been purchased by governments worldwide since 2006, about half of this in the past six months, while GlaxoSmithKline increased its capacity to produce 190m courses of Relenza by the end of the year, three times its usual annual output. In England, 644,000 courses of these antivirals have been provided by the National Pandemic Flu Service between its inception on 23 July and 7 October. In the three months before this web and phoneline prescription system was established, the drugs were prescribed through primary care trusts, believed to be an additional several hundred thousand courses. The British government has spent more than £500m on antiviral drugs and vaccines since its flu epidemic planning began in 2005. The Department of Health will not disclose a more detailed breakdown with regards to swine flu, but mass purchasing of Tamiflu (23m courses) and Relenza (10.5m) may account for at least half of this expenditure. Inevitably, these stockpiles have boosted both the earnings and share price of their manufacturers, Roche and These figures prompt a slew of questions. Have our healthcare officials been so keen to provide something to reassure us in a pandemic that they have supplied us with treatments they know to be second-rate? Have we wasted vast amounts of money on products that are little better than a placebo? What is to account for such a vast prescription of these drugs (and such clamouring demand from patients) when, 10 years ago, the National Institute for Health and Clinical Excellence (Nice) reviewed the drugs but refused approval because of insufficient benefits? And why, as recently as September 2009, did the Department of Health provide clear guidelines to GPs and hospital staff that, in normal cases of flu, they should not prescribe either Tamiflu or Relenza? If these drugs are deemed inadequate for the seasonal outbreak, what hope do they have in a pandemic? The answers to these questions lie in desperation. Despite our spectacular medical advances, we are still laid low each year by the genetic make-up of everyday viruses that threaten to mutate out of control, and it is a tough failure to acknowledge. A pandemic can multiply this failure and concern to the point where responsible governments feel compelled to take action, however inadequate they know it to be. But can this ever be a wise policy? And will it worsen our health in the future? Since the Spanish flu outbreak of 1918-19, which killed up to
50m, a cure for influenza has been a holy grail of medical science.
Many pharmaceutical companies have regarded the conquest of
flu as one of their biggest potential money-earners, while aware
that (like cancer) they are not dealing with one foe but an
inestimable number. In an average winter 3,000 to 4,000 people in
the UK will die from its complications, the majority of them elderly,
while 100,000 may perish globally. But when an unfamiliar strain
arises, the impact can be overwhelming. Major outbreaks of Asian
flu (1957), Hong Kong flu (1968) and Russian flu (1977) affected
the functioning of entire cities, and it was thought that another fatal
pandemic was narrowly avoided in 1997 when a lethal type of Hong Kong bird flu was contained by the mass slaughter of hundreds of thousands of infected chicken and ducks, which (with pigs) scientists believe are the original incubators of human influenza. But the "big one" may lie around the corner: the World Health Organisation has consistently warned that, because of the way flu viruses mutate, a devastating outbreak for which humans have no immune response is not only possible but likely. We now know, with gratitude, that the symptoms of swine flu are, in the vast majority of cases, similar to those of seasonal flu: aching limbs, headache, coughing, hot and cold feverish sweats, lack of appetite and nausea. It is easy to forget how hellish this combination can be even for otherwise healthy adults; one would do almost anything to make it end, if only one could get out of bed. So it is hardly surprising that the prospect of even a mediocre drug is seized upon with unbound enthusiasm. But the drugs we have been taking for swine flu were not invented with this particular strain in mind. Rather, they came about by chance, and by a piece of blind faith, in a laboratory in Australia in the early 1980s. The story of their development and subsequent fame provides a sober insight not only into what we understand about the mechanism of flu, but how hard it continues to be to combat it. In Melbourne in 1983 a virologist named Peter Colman was attempting to understand how the influenza virus changes from year to year. It was a fairly lonely endeavour: the virus mutated so often that it was believed no drug could keep up with it, and most scientists and all the leading drug companies had begun to despair of finding a therapy. But Colman was studying the changes in the three-dimensional shape of the virus as it appeared in each new epidemic when he found something that upturned previous wisdom: he saw that one aspect of the virus didn't change at all. The surface of the flu virus is studded with two key proteins. Haemagglutinin binds the virus to receptors on a person's healthy cells, while the enzyme neuraminidase breaks it down to enable new particles to be released and infect other cells (these are the H and the N of H1N1 – there are 16 types of the former, 9 of the latter). For years, scientists had battled to create "neuraminidase inhibitors" that would control the spread of infection, but had been defeated by a lack of knowledge about the structure and action of the protein. "The belief in the early 80s was that neuraminidase had become a bit boring," Dr Colman told me almost two decades after he found otherwise. But he and his team, employed by Australia's Commonwealth Scientific and Industrial Research Organisation (CSIRO), discovered that drugs would finally have a fixed target. "It was clearly a very exciting time," he said. The research was published in the journal Nature, and at first the response was muted. "It wasn't as if every drug company on earth came rushing to our door wanting to work with us," he recalled. More than a year passed before Biota Holdings, a new biotech firm in Melbourne, took any interest. CSIRO agreed to license Colman's work to Biota in return for a royalty on the sale of any drugs that made it to market. After three years of further research, Biota confirmed what Colman had suspected, that a so-called neuraminidase "plug drug" could strangle the spread of the disease. Biota developed thousands of potential suitable compounds, but was too small to conduct large-scale trials. So, in February 1990, it licensed its data to the same British company that had previously been sceptical of Colman's findings, Glaxo. Dr Richard Bethell, a young enzymologist, believed flu would be one of the last things he'd be working on when he joined Glaxo in 1989. Almost all the attention in his virology department was on HIV. "Nothing had been discovered with regard to flu since the 60s," he remembered. The drug amantadine had been partially effective against Type A flu (the most frequently mutating strain, which H1N1 belongs to), but it had several side-effects and the virus has long ago proved resistant to it. "Our own programme was just bouncing along the bottom," Bethell recalled. One of his first jobs was to develop a chemical test by which Glaxo might examine the many compounds arriving from Biota. Hundreds were eventually tested, but none showed more promise than a molecule in the first batch of 15. Codenamed GG167 and soon to be called by its trade name zanamivir, it became one of the first drugs to be fully developed on computer – a process of rational design, rather than the traditional route of laboratory trial and error. There was one big potential problem: neuraminidase exists not only in the flu virus but also in human cells which function normally; any drug had to be sufficiently strong to kill flu, but sufficiently weak to leave human neuraminidase unaffected. Bethell did the safety tests himself and was relieved to discover that he had to vastly increase the doses before he saw any effect on human neuraminidase: "It turned out that zanamivir is about 1m times less active against human neuraminidase than against influenza neuraminidase." This was the breakthrough. "It was really that result which said that there is now a convincing basis for believing that this molecule will be very safe." Animal trials began in 1993, but production of zanamivir was complex. Sialic acid, a chemical which coats the infected cells in the respiratory tract where the virus spreads, was too expensive at $1,000 a gram. Initial supplies came from Japan, where it was extracted from birds' nests. There was a delay until a synthetic substance could be found. The first volunteers were infected in January 1994. Groups of eight college students at the University of Virginia were paid to contract a flu virus through nasal drops and then kept in isolation for several days. Other students were given a placebo. This was thought to be the first time a flu drug had been taken in clinical trials for more than 20 years. When the first results came back, "they were fantastic", Bethell remembered. "Both in prophylaxis [prevention] and in treatment, the drug was incredibly effective. They weren't coughing, they weren't collecting lots of mucus. Those who had been given zanamivir didn't have fever. But the control group were all in pretty bad shape." The next trials involved patients in America, Europe, South Africa and New Zealand who had gone down with flu naturally. Any patient who contacted their doctor within 48 hours of their first symptoms was enrolled in a clinical study and given either zanamivir or a placebo. Again, the results looked impressive. Patients on the drug found that their symptoms cleared up between a day and two-and-a-half days earlier than those who had received nothing. "I don't think any of us thought that you'd just take a couple of doses and then you'd be right again," Bethell recalled. "Once you've got symptoms, the virus really has taken hold. But a 30 to 40% improvement is very significant." Before it was submitted for approval by the European regulatory bodies, the drug had been tested on about 3,000 patients. Glaxo was delighted that the publication of its trial results boosted its share price. Towards the end of 1999, investment analysts estimated that the market for its flu drug might be worth as much as $5bn annually in the US alone. But there was a problem. After experimenting with several methods of administering zanamivir – injection, pill or inhaler – researchers at Glaxo found that it had very poor bioavailability (it didn't break down well into the bloodstream). The only effective method would be through its patented Diskhaler, a plastic device resembling a toy model of the Starship Enterprise. "It's a simple, breath-activated device," Bethell told me not long before its launch, demonstrating in his lab with a sucking motion and using an unfortunate turn of phrase: "It's no more difficult than smoking a cigarette." But the Diskhaler was always going to be a major hurdle to zanamivir's success. Despite the fact that, unlike a pill, an inhaler would pass efficiently to the lungs and precisely target the area where the virus multiplies, the process would always be clumsy and unfamiliar. To combat a normal bout of flu, you need two doses of zanamivir each day for five days. The doses – fine particles of dry powder – are in a blister pack that, once inserted into the device, automatically pierces each time the lid of the Diskhaler is raised. But the race to get the drug to market was gathering pace. Glaxo began discussing its new product with the NHS, and had given zanamivir a catchier name. After months of consultation with global trademark agencies, the drug had become a brand: Relenza (RELief of influENZA). And no sooner had this happened than staff at Glaxo started to learn that they had serious competition. Their biggest fear would soon be realised – a drug that worked in a similar way to Relenza, but in a pill: Tamiflu. Gilead Sciences, a small biotech company near San Francisco,
became interested in neuraminidase inhibitors as soon as it saw
Glaxo's early trial results in Nature in 1994. "We had a flu
programme before," Dr Choung Kim, Gilead's senior director at the
time, told me, "but we were looking at a different target. One
reason we switched was because the Glaxo compound was not
orally bioavailable. I've been in the drug-development business for
25 years, working on many anti-bacterial drugs in both injectable,
inhalant and pill form. In the end, the pill is always the big winner."
The Gilead compound, named GS 4104 and then oseltamivir, would soon attract the attention of the huge Swiss company, Hoffmann- La Roche. A pill required an entirely different drug design to zanamivir, but relied on the same basic crystal structure studied by Peter Colman a decade before. And, again using computerised design models, Gilead made swift progress. By the beginning of 1995, it already had a compound suitable for clinical trials. Initially, it experimented in mice, rats, ferrets and dogs. The ferret bioavailability was disappointing, but success in the dog was almost 100%. Trial results in humans compared well with those of zanamivir, although some patients reported side-effects of nausea and vomiting. Human trials were completed just three years after the drug was planned, remarkably quickly for a process which commonly takes at least 10 years. "Our big motivation was that we had to catch up with Glaxo," said Dr Kim. "Roche absolutely recognised how important it would be to come to market simultaneously or, at the most, a few months after." When I first talked to the makers of these exciting new drugs a decade ago, there was no disguising their sense of achievement. "We're thrilled!" exclaimed Gilead's communications officer, Susan Hubbard. "I think that the whole team is over the moon," said Glaxo's Dr Bethell. "We all believe it is an absolutely fantastic drug – the most effective, and also the most safe." But things have changed. Both Tamiflu and Relenza have been widely available since 2000, but it is only in the past six months that they have been so widely used. In one week at the end of July more than 100,000 courses of the antivirals were issued in England, and such a rapid uptake by patients who have never taken the drugs before has inevitably caused problems. Side-effects have been reported in almost 10% of cases, particularly vomiting, headache and diarrhoea, although it is difficult to distinguish the effects of the drugs from the effects of the illness. There have been concerns about the drugs' safety for the under-12s and in pregnant women, and there have recently been laboratory indications that H1N1 strain has become resistant to Tamiflu. But another detrimental pattern has also emerged: the more Tamiflu and Relenza are tested, the less positive are the results. The early hopes for the drugs have faded, and we are left to question our faith in medical progress and the wisdom of our advisors. Intriguingly, the early warning signs were there at the very beginning. In 1999, the drugs advisory body Nice had just been established to advise on best clinical practice within the NHS, and Relenza was its first subject. Another flu epidemic was building, Nice fast-tracked its examination of trial evidence to only a few months (the norm was about a year) and decided against recommending the drug. A year later, in November 2000, after further trials and lobbying by Glaxo (which by then had become GlaxoWellcome), it delivered another discouraging report. The drug could be useful for adults in the usual at-risk groups – those over 65, people with chronic respiratory or heart disease, or those with type 1 diabetes – provided treatment began within 48 hours. But, it concluded, "the NHS should not use zanamivir to treat flu in people who are otherwise healthy". Those who became unwell were advised not to visit their GP, but to stay at home and take the usual action: paracetamol, warmth, plenty of water. This advice remained unchanged for several years and was extended to cover not only Relenza but also Tamiflu. It did not examine the potential value of the antivirals in a pandemic, but as the results of further trials appeared it became clear neither Tamiflu nor Relenza would offer much in the way of prophylaxis – a preventative role wherein people without symptoms may take the drugs in the hope of protecting themselves from the virus. In 2006, the Lancet published the results of an international survey examining 19 studies of the flu drugs, in which the researchers concluded there was therapeutic value in both Relenza and Tamiflu in specific, identified strains of the virus, but did not recommend them for general use. "We do not see a role for the use of neuraminidase inhibitors in seasonal influenza, since the evidence shows that they are ineffective against influenza-like illness." The same conclusion was reached for prophylactic use. Another study, in the September 2009 issue of Lancet Infectious Diseases, found flu symptoms in healthy adults taking Relenza were reduced by just over half a day (0.57 days), while with Tamiflu it was 0.55. This was quite a contrast with the "30 to 40%" improvement estimated a decade ago by Glaxo. The effects were slightly greater in patients with risks of complications: 0.74 with Tamiflu, and 0.98 with Relenza. These findings, conducted by nine researchers at several British universities, again reached a familiar conclusion: "In view of the advantages and disadvantages of different management strategies for controlling seasonal influenza in healthy adults, recommending the use of antiviral drugs for the treatment of people presenting with symptoms is unlikely to be the most appropriate course of action." The latest guidelines issued by Nice, published in February 2009 and unchanged through the swine flu pandemic, anticipate these findings and recommend the use of neuraminidase inhibitors only for at-risk groups. The advice states specifically that it "does not cover widespread epidemics", and then defines its terms: "A flu outbreak is called an epidemic when more than 400 people in every 100,000 visit their GP with flu symptoms each week." But in the first week of October the Royal College of General Practitioners reported the number of people with flu-like illness to be 26.3 in 100,000. At present we are not even close to an epidemic. So how to account for the poor efficacy of the drugs after such high hopes, and how to explain the conservatively estimated 1m courses of Tamiflu and Relenza prescribed in the past six months? One eminent virologist who has worked on flu treatments for several years told me: "The consensus in the field has been that the neuraminidase inhibitors are showing us the limits of what can be achieved by an antiviral drug that inhibits just viral replication. The available evidence suggests that the peak of viral replication in people with flu is at around the time of the onset of symptoms. Add to that the 48 hours before drug treatment starts, and the virus levels are already starting to fall before drug administration starts." Both Tamiflu and Relenza have some effect on the speed at which the virus declines, but they arrive too late for many of the immunological responses that have already occurred. Once again, there is disillusion among researchers; the hunt for mechanisms that may further accelerate the elimination of the virus appears to have been exhausted. Dissenting voices have, in confidence, cited a number of reasons for the failure to follow Nice guidance and the findings in the leading medical journals. At the top of this list is over-caution, a fear of inaction and unpreparedness by the Department of Health which would lead to cataclysmic disapproval in the media. Then there is our over-zealous desire to be protected from all of life's ills; a feeling that in this age of mass surveillance, we should, at the very least, also expect mass cosseting. "It was felt it'd simply be unacceptable to the UK population to tell them we had a huge stockpile of drugs but they were not going to be made available," Professor Robert Dingwall, a member of the Committee on Ethical Aspects of Pandemic Influenza, told The Observer in August. We may reasonably ask, how else should the Department of Health have reacted? Much of its policy appeared sound: the television adverts, for instance, in which a man sneezed in a lift and thus infected everyone who touched the handrail, and then everyone who touched the people who touched the handrail, gave a simple message, not least when the actor in the lift really did get swine flu. The print advertisement and hand-delivered leaflets advising us to use more tissues and then throw them away had a slightly patronising air and an unfortunate tagline – "Catch it! Bin It! Kill It!" – which half-suggested we were being advised to catch swine flu. And some policies, such as quarantine orders and the closure of schools, seem preposterous with hindsight but vaguely understandable – medical practice guided by fear of the unknown. Unusually, the government has admitted as much. Documents released by the Department of Health and the Cabinet Civil Contingencies Committee show that in the past six months it has had two distinct policies towards the issue of antiviral treatments. Both, in their different ways, accounted for the over-prescription and mass availability of Tamiflu and Relenza for the general population. The government met several times in May and June with the Scientific Advisory Group for Emergencies (Sage) and the Pandemic Influenza Clinical and Operational Group (Pico) in an attempt to formulate its policy on antiviral distribution. The results of these meetings emerged on 2 July, in a letter written by David Nicholson, NHS Chief Executive, to his staff. "As little was known about the new virus when the outbreak started," Nicholson explained, "it was sensible to take all possible measures to slow its spread while we learned more." This included the swabbing of all patients suspected of having swine flu, and the distribution of Tamiflu and Relenza not only to those diagnosed, but also those who may have come into contact with them but were still asymptomatic. This would include not only relatives and friends, but also school classes and offices. This method of containment was abandoned shortly after 11 June, when the World Health Organisation raised its pandemic alert to its highest, level 6. On 16 July, the Cabinet Civil Contingencies Committee issued its latest planning assumptions, which included a worst-case scenario for September of 30% of the population infected, entailing 12% of the workforce. "The proportion of the population infected (the serological attack rate) may, finally, be as high as 60%. This is because, in addition to the 25-30% who develop clinical symptoms, a further 25-30% may be infected but show no or insignificant symptoms." The fatality rate was put as high as 0.35% of cases. It is this doomsday figure that best accounts for the stockpiling of antiviral drugs and the race to develop the vaccine. "We always knew that we could not contain or prevent the spread indefinitely," Nicholson wrote, "and that is why today ministers across the UK have agreed that it is time to move from containment into the treatment phase." This new phase would curtail the issuing of antivirals to those who had not fallen ill, but also "rely on symptoms rather than swabbing to diagnose the virus". This meant the establishment of the National Pandemic Flu Service (NPFS), effectively a system of self-diagnosis. A patient or a "flu friend" would contact the NPFS on the phone or online and, according to how they answered a checklist of symptoms, would be issued with a code enabling them to pick up Tamiflu or Relenza from a local chemist. This was an entirely new model for healthcare in England, and was open to both error and fraud. Before the system came into place in the last week of July, there were many reports of the hotlines being staffed by teenagers with very limited training, while its launch coincided with the peak of swine flu hysteria. Tourism suffered, while those going abroad refused to travel unless they had first packed Tamiflu. An online black market thrived. Couples were reported to have put off having children until the outbreak subsided. The BBC was accused of stockpiling Tamiflu for overseas staff. The Mail on Sunday reported that "doctors want guards on the doors of hospitals… in case the families of swine flu victims become violent if they are refused treatment". The business pages told other stories, notably how Glaxo's profits were soaring. Its share price rose 8% in the week following the first cases in April, while those in Biota Holdings jumped 16%. Sales of Relenza were $99m up to the end of June (before the greatest demand took hold), compared to $5m in the second quarter of 2008. In mid-October, Roche reported that sales of Tamiflu were worth 2bn Swiss francs (£1.2bn) in the first nine months of 2009, an increase of 362% over the same period last year. When I visited GlaxoSmithKline at the beginning of October, it was hard not to be struck by the corporate glare: the lobby of the huge glass and metal edifice just off the M4 in west London presented just the sort of bustling activity one would expect at the world's second largest pharmaceutical company (Glaxo Wellcome merged with SmithKline Beecham in 2000). I was there to meet Dr John Dillon, the Medical Director of GSK's Pandemic Centre of Excellence, and he was keen to point out that Relenza was remarkably robust, with no significant signs of H1N1 developing resistance against it. We then talked about the questionable efficacy of the drug, and he said, "There is no such thing as a touch of flu," stressing that any relief of symptoms should be welcomed. Dr Dillon then showed me a new and simpler way of taking the drug, which substituted the disk and Diskhaler in favour of a Rotahaler, which took capsules. As our conversation continued it became clear that Relenza, and all its delivery systems, was not, for a while at least, the most significant swine flu treatment in the building any more. Final arrangements were being made for the mass worldwide shipping of GSK's H1N1 vaccine Pandemrix. The company had received global orders of 440m doses by the first week of October, an increase of 149m doses from just six weeks before. The old drugs would still be used with limited purpose by those who weren't protected by the jab, but now there was a new way of safeguarding our health in an unpredictable world. Until, perhaps, next time.

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