Big Pharma: a paper tiger?

• The Constant Gardener, John Le Carre, Hodder, 2001
• The Truth About the Drug Companies, Marcia Angell, Random House 2004
• Selling Sickness: How Drug Companies Are Turning Us All Into Patients, Ray Moynihan, Alan Cassells, Allen & Unwin, 2005
• Inventing Disease and Pushing Pills: Pharmaceutical Companies and the Medicalisation of Normal Life, Jorg Blech, Routledge 2006

In The Constant Gardener, John Le Carre’s 2001 novel that has since become a major motion picture and box office hit starring Ralph Fiennes and Rachel Weisz, John Le Carre put the drug companies in the position that the evil empire of the Soviet Union occupied in his Cold War novels.

Perfidious big pharma is revealed to be testing dangerous drugs on impoverished Africans, suppressing information about their lethal side-effects, and murdering whistleblowers. Le Carre tells a convoluted tale of violent intrigue on three continents which the cover blurb describes as ‘a magnificent exploration of the dark side of unbridled capitalism’.

It is remarkable that this preposterous depiction of the pharmaceutical industry, one of the most successful sectors of the world economy, and the British economy, in recent decades, should strike such a popular chord. Yet, while drug companies claim that they have made a major contribution to health and welfare with a range of new medications, they are widely believed to put profits before safety. Even if few will go all the way with Le Carre’s paranoid fantasy, many accept the depiction of big pharma as a ruthless and corrupt form of capitalist enterprise.

This indictment of pharmaceuticals is not confined to fiction. Last week, Consumers International, the world federation of consumer organisations, issued a damning exposure of the scale of illicit practices by drug companies across Europe. The report concluded that ‘irresponsible marketing practices form a serious, persistent and widespread problem among the entire pharmaceutical industry’ (Guardian, 26 June 2006). Senior executives at six major British drug companies are currently under investigation concerning allegations of running a cartel, costing the NHS more than £100million, fixing the prices of generic drugs and sharing the profits (The Times (London), 12 September 2005).

A series of high-profile scandals has brought the pharmaceutical industry into disrepute – and a stream of books documents the case for the prosecution. For Marcia Angell, former editor of the New England Journal of Medicine and author of The Truth About the Drug Companies, the industry is ‘now primarily a marketing machine to sell drugs of dubious benefit’, which ‘uses its wealth and power to corrupt every institution that might stand in its way, including the US Congress, the Food and Drug Administration, academic medical centres and the medical profession itself’.

For journalists Ray Moynihan and Alan Cassells, in their book Selling Sickness: How Drug Companies Are Turning Us All Into Patients, the industry is ‘fundamentally distorting medical science, corrupting the way medicine is practised and corroding the public’s trust in their doctors’. Jorg Blech, whose German best-seller Inventing Disease and Pushing Pills: Pharmaceutical Companies and the Medicalisation of Normal Life has just been published in English, also accuses the drug companies of ‘turning people into patients’ by inventing a variety of diseases which are deemed to require drug treatment.

At a time when the British government is looking to the spirit of private enterprise to revive public services, including health, this comprehensively negative judgement on one of the country’s leading spheres of private enterprise – and one with close links to the world of health – raises serious questions.

The current backlash against big pharma is to some extent a result of the way that a small number of drugs have been over-promoted and over-used. In recent years, the drug companies have developed a number of useful drugs – including stomach acid blockers and anti-cancer drugs. But in the quest for increased sales, drug companies have sought to expand the market for some of their products by encouraging people to consider themselves ill and doctors to treat them with new (and expensive) medications. As more and more people take medications for which their need is less and less clear, the balance of benefits to risks shifts towards the latter, a trend reinforced by the wider climate of risk aversion. This ultimately provokes a tendency to over-react, as patients blame drugs for the problems they experience and critics of big pharma find a popular resonance for their accusations.

In her substantial critique of the pharmaceutical industry, American author Marcia Angell challenges the industry’s self-presentation as innovative and dynamic. Though she acknowledges some important new drugs, such as anti-retroviral and anti-cancer drugs, she insists that most of the research for these was carried out in publicly-funded universities and research institutions. By contrast, the major drug companies have concentrated on ‘me-too’ imitations and on a range of protectionist strategies for ‘stretching out monopolies’ on existing products (leading to a damning 2002 Federal Trade Commission report on the industry’s ‘anti-competitive practices’). Though the industry proclaims a commitment to ‘research and development’, and uses its R&D investment to justify the exorbitant costs of new drugs (like Herceptin for breast cancer), Angell shows that much of this expenditure is in fact devoted to marketing. There is little dispute that, as big pharma’s profits have soared over the past two decades, the flow of useful new drugs on to the market has slowed to a trickle.

For all its claims to entrepreneurial flair, big pharma turns out to be highly dependent on state patronage. Angell cites the extraordinary 2003 Medicare reform package through which the US federal government agreed to fund prescription charges for the over-65s by guaranteeing a payment of $400billion to the drug companies. Not only did this ‘bonanza for big pharma’ provide a guaranteed market, by prohibiting the government from bargaining it allowed the industry to set its own prices. In common with many critics, Angell argues that the network of links between the industry, the political process and the Food and Drugs Administration, has rendered the regulatory process ineffectual.

In Selling Sickness, Moynihan and Cassells describe how ‘awareness-raising’ campaigns seek to transform the ‘worried well’ into the ‘worried sick’. They show how techniques such as ‘astro-turfing’, the formation by drug company PR professionals of fake grassroots advocacy groups, often featuring celebrities, have helped to popularise new disorders and increase demand for treatments. Yet their narrow focus on the drug companies neglects the wider forces that have encouraged the medicalisation of the lives of individuals and society.

Whereas 20 or 30 years ago, the medical profession was the main target of critics of medicalisation, today doctors appear more the victim of pressures from above and below, from government and from the public – and the drug companies have become the new demons. The drug companies have undoubtedly skilfully exploited these trends and have benefited handsomely from them, but they did not create them.

To explore these processes in more detail, let’s take three areas of recent controversy – the SSRI anti-depressants, the cholesterol-lowering statins and the anti-inflammatory pain-killers known as CoxII inhibitors.

The SSRIs

When I first went into General Practice in the early 1980s, the leading drugs in the treatment of depression were Amitriptyline and Imipramine, known, after their molecular structure, as ‘tricyclic’ anti-depressants. When these drugs first came into widespread use, less than two decades earlier, they were regarded as a major breakthrough. Before the tricyclics there was little in the way of drug treatment for depression, and severe cases often ended up in catatonic states in mental hospitals where some underwent ECT. For many patients tricyclics were effective in enabling them to overcome their paralysing symptoms and allowing them to live a normal life. The problem with the tricyclics was their side-effects. At least a third of patients taking them experienced intolerable drowsiness, dryness of the mouth, blurred vision and constipation. They were also dangerous if taken in overdose – which some patients with depression inevitably did.

The adverse effects of the tricyclics encouraged the quest for an alternative anti-depressant that did not cause sedation and other side-effects. This quest culminated in the discovery of fluoxetine (marketed as Prozac in 1987), which was said to work by increasing the level of the neurotransmitter serotonin in the brain (by selectively inhibiting its reuptake at nerve junctions – hence SSRI). Though fluoxetine was no more powerful than the tricyclics in relieving depression (some psychiatrists believe it is less effective), the key to its success was that it caused a much lower rate of side-effects (it was also relatively safe in overdose). Prozac was one of the first of the ‘blockbuster drugs’. In addition to being heavily promoted among doctors, it rapidly acquired celebrity status, featuring in popular magazines, TV talk shows and novels. Within five years of its launch, eight million people had taken Prozac, four million in the USA alone.

The success of Prozac had a number of consequences. Recognising the commercial potential of the SSRIs, rival drug companies launched a range of ‘me-too’ products, seeking to win a share of the fluoxetine market with drugs with a similar mode of action. Before long a dozen different SSRIs were available, though it was doubtful whether any offered significant advantages over fluoxetine, in terms of either efficacy or safety. More importantly, in the drive to expand the market for these medications, pharmaceutical companies teamed up with academic and professional institutions in psychiatry to promote greater public awareness of diagnoses of depression, anxiety and a range of newly minted conditions, such as social phobia and post-traumatic stress disorder, all of which could be treated with SSRIs.

Whereas in the 1950s, depression was recognised in around 0.5 per cent of the population, by the 1990s the Defeat Depression Campaign in the UK (sponsored by the Department of Health, the Royal Colleges of Psychiatry and General Practice, and generously supported by drug companies) estimated a lifetime prevalence of depression of ‘one in four’ and an annual prevalence of around 10 per cent. When people responded to these initiatives by reinterpreting experiences of loss, personal disappointment or unhappiness in terms of depression, many went to see their GPs. Given the limited availability of psychotherapeutic ‘talking cures’, many were prescribed SSRIs – and a number of other brand names joined Prozac as major earners for big pharma.

Before long, some negative consequences of the SSRI boom became apparent. Though SSRIs cause less adverse reactions than earlier drugs, by the time several million people were taking them, the numbers experiencing significant side-effects were substantial. One problem was that some patients experienced withdrawal symptoms on stopping treatment. The high level of popular anxiety about the dangers of dependence on medication – in part the legacy of the benzodiazepine tranquillisers popularised in the 1960s – has fostered an acute public sensitivity to this problem. Withdrawal symptoms were said to be more severe with certain SSRIs – notably paroxetine – and there have been allegations that drug companies suppressed data from early studies that revealed the scale of this problem.

Another problem was suicide. It has long been recognised that people sometimes kill themselves when they are depressed and, further, that this is more likely to occur when they seem to be emerging from a depressive episode than when they are in the depths of paralysing despair. Hence it is not surprising that there is a higher incidence of suicide among people who are taking anti-depressants, particularly when most people who are depressed are taking anti-depressants. Given the trend for virtually anybody with a mental health problem to be prescribed an SSRI, particularly in the USA, it was also inevitable that some would commit serious crimes, even murder, while taking such medications. Whether SSRIs cause dependency, suicide or homicide is very difficult – if not impossible – to establish.

But in the wider culture of risk aversion that gathered momentum through the 1990s, many people now blame the SSRIs and their manufacturers for these problems and are seeking redress through the courts.

The statins

First and second places in the world Top 10 drugs of 2003 were taken by statins – atorvastatin (earning $10billion for Pfizer) and simvastatin ($6billion for Merck). These products – by far the biggest selling drugs in the history of pharmaceuticals – are at the centre of the global ascendancy of big pharma over the past decade. By inhibiting an enzyme (HMGCoA) involved in the synthesis of cholesterol in the liver, the statins reduce the level of circulating cholesterol in the blood stream and hence reduce the development of coronary heart disease, the major killer in advanced industrial societies.

The rise of the statins has been dramatic. When I started running a diabetic clinic in general practice about 20 years ago, I was reluctant to measure patients’ cholesterol levels. Even if we found they were high enough to cause an increased risk of heart attack or stroke, there was not much that we could do to reduce this risk. Contrary to an assiduously promoted myth, it is difficult to influence cholesterol levels by diet – and the drugs that were then available to reduce cholesterol were not very effective and caused such a high rate of unpleasant side-effects that few patients could tolerate them for long.

Then came the statins. There can be little doubt that these are remarkable drugs: in most patients they reduce the cholesterol level sharply and consistently and, though they are known to cause muscle pains and abnormalities of liver function (and, rarely, more serious side-effects) these are uncommon. There is also good evidence that, at least in patients with established heart disease or high risk factors (diabetes, high blood pressure), statins reduce the incidence of further cardiac events (though the fact that they achieve this, to some degree, independently of their effect on circulating cholesterol levels raises some uncertainty about their mode of action). Given this clinical record, it is not surprising that the number of patients taking statins in the UK is now approaching two million.

Just as Prozac begot numerous ‘me-too’ SSRIs, so there are now several different statins – none with any particular merit over another – competing for market share. Again, in common with the SSRI story, the drug companies have sought to boost sales by expanding the market for the statins. One method for achieving this was by increasing the population deemed eligible for treatment. When I first started measuring patients’ cholesterol levels, the upper limit of normal was 6.5; now, following the deliberations of an elite medical-political body, it has been reduced to 5.2 – at a stroke boosting the market for statins by several million people. Critics of big pharma allege that several members of such bodies promulgating treatment guidelines are, in one way or another, beneficiaries of drug company largesse.

By promoting public awareness of the cholesterol-heart disease link – and more recently by popularising cholesterol testing (in GP surgeries, pharmacies, even with home-testing kits) – the manufacturers of statins have sought to extend their use among lower risk populations. As a result, more and more people of all ages are testing their cholesterol levels. They soon discover that so-called healthy diets – and intensively marketed ‘cholesterol-lowering’ food products – have only marginal effects on cholesterol levels. Some inevitably present themselves at their GPs demanding treatment with statins. One statin is now available ‘over the counter’ in pharmacies.

However, though the benefits of statins for people with heart disease or high risk factors are well-established, the benefits for those of lower risk are questionable. A major study conducted among healthy people in Scotland found that if 10,000 people took statins for five years, 9,755 would receive no benefit (while carrying the burden of believing themselves to be in need of long-term medical treatment). Furthermore, as more and more people take statins, just as with the SSRIs, even though the incidence of side-effects is relatively low, the numbers experiencing these problems will become substantial. One statin has already been withdrawn because of a particularly high rate of muscle inflammation and more problems in this area – with the familiar allegations of conspiracy and cover-up – are inevitable.

The Cox2 Inhibitors

Vioxx (rofecoxib) was a pharma meteor. After one of the most spectacular launches in pharmaceutical history in 1994 it rapidly became one of the blockbusters of the 1990s: a decade later it was earning $2.5billion from 100million prescriptions in the USA alone. Then in 2004, amid allegations of an increased incidence of heart attacks and other cardiac events and a flurry of law suits, it (and a number of ‘me-too’ competitors) were hurriedly withdrawn from the market.

Named after their mode of action as selective inhibitors of the enzyme cyclo-oxygenase 2, the Cox2 inhibitors were the latest development in the category of ‘non-steroidal anti-inflammatory drugs’ (NSAIDs). As their name suggests, these drugs emerged as alternatives to cortisone, prednisolone and other ‘steroid’ drugs which were first used in suppressing joint inflammation in conditions such as rheumatoid arthritis in the late 1940s. Though they were dramatically effective, they were soon found to cause a wide range of serious side-effects which greatly restricted their use. The most promising alternatives were drugs such as ibuprofen, naproxen and diclofenac which are still in widespread use. These drugs, however, all cause high rates of stomach irritation, even to the extent of provoking ulcers (which may bleed or perforate, with occasionally fatal consequences, particularly in old people).

Pain, in an infinite variety of forms, is a common complaint in general practice and there is a high level of demand for effective ‘pain-killers’. When simple analgesics, such as paracetamol, fail to satisfy, GPs often resort to treatment with anti-inflammatory medications. For the simple reason that much pain is not caused by inflammation, but is an expression of existential distress, anti-inflammatory drugs often fail to relieve symptoms. Even when there is abundant evidence of joint inflammation – as in elderly patients with osteoarthritis or younger patients with confirmed inflammatory joint disease – NSAIDs are often not very effective.

Hence there is a ready demand for a new anti-inflammatory analgesic and the Cox2 inhibitors were skilfully marketed to meet this need. However, there is considerable doubt whether they were any more effective than established NSAIDS, or indeed whether they were much more successful in avoiding gastrointestinal adverse effects – the major claim of their manufacturers (who have been accused of exaggerating the dangers of the old drugs to boost demand for the new ones). The major problem that emerged was that patients taking Cox2s appeared to suffer an increased incidence of heart attacks and other cardiac events. This is controversial because it emerged in comparison with established NSAIDs which have some protective effect in relation to heart problems. However, after high-profile allegations from academics over trial results, and conflicts among regulators over safety procedures in the USA, matters are now proceeding through the courts.

Conclusion

While Marcia Angell offers a well-informed account of developments in the USA, Moynihan and Cassells provide a more international perspective, focusing on the manipulation of consumer demand. Jorg Blech gives further illustrations of the role of pharmaceutical companies in ‘disease mongering’ and a witty and engaging discussion of such areas of medicalisation as the femininity syndrome and the male menopause. Jacky Law brings together much of the material in Angell’s book with that of Moynihan and Cassells, with some useful detail on the SSRI and Cox2 controversies. Unfortunately, her book is marred by excessive use of American brand names and by a woefully ill-informed account of the MMR-autism controversy.

On closer inspection big pharma is neither a great Satan poisoning and corrupting the world, nor a model of thrusting capitalist enterprise and altruistic commitment to public health. It turns out to be something of a paper tiger, a cautious and conservative industry relying on a small number of ‘blockbuster’ drugs and clinging to its restrictive practices and state subsidies. While it has benefited handsomely from the increasing medicalisation of society, it has also become a victim of the blame and compensation culture that has advanced in parallel with it.

Dr Michael Fitzpatrick is author of The Tyranny of Health: Doctors and the Regulation of Lifestyle, Routledge, 2000 (buy this book from Amazon UK or Amazon USA).