Alexander Breton, Pharmageddon

David Healy

Pharmageddon

302pp – £19.95

ISBN 978-0520275768

Berkeley: University of California Press, 2012

 

The tale of the big bad pharmaceutical industry misselling its drugs has practically become passé. This may make you ask: why bother with yet another book on the subject? Yet this is a story that has dimensions beyond the issue of patient safety. In fact, the nature of the modern pharmaceutical industry is the elephant in the room when it comes to debates about the cost of healthcare, both in Europe and the US. Big Pharma may well preclude the idea of universal healthcare completely.

Readers interested in this issue may well have read Ben Goldacre’s Bad Pharma. Healy and Goldacre, prominent British psychiatrists, have been indefatigable in their fight against the abuses of the pharmaceutical industry. It was Healy who first identified that SSRIs (selective serotonin reuptake inhibitors – first-line antidepressant drugs) like Prozac and Paxil can lead to suicide. More specifically, a very small minority of patients taking these drugs will become very agitated, with their thoughts and behaviour becoming violent and suicidal. Young people seem to be more likely to have this response. Conveniently for the industry, suicidal thoughts and behaviour are not an uncommon feature of depression, leaving experts with the question of how one can prove that the drug is causing this effect. When the first high-profile news stories broke, involving patients prescribed SSRIs who shot multiple people before killing themselves, Lilly (the company that makes Prozac, the first SSRI) stuck to its line: these people killed themselves because they were depressed. According to Lilly, Prozac had nothing to do with it, and that anyone withholding antidepressants from the depressed on the basis of these reports was actively harming patients by blocking access to effective treatment. It was only when Healy gave Prozac to twelve healthy volunteers and two of them became agitated that the suspicion was firmly placed on the drugs. Healthy people do not simply become agitated without cause. After extensive review, American pharmaceuticals regulator the Food and Drug Administration (FDA), declared that all antidepressants must carry a black-box warning about the risk of agitation and suicidality when given to under-25s.

How did a scandal like this happen? This is the first question that Healy sets out to answer. The root of the current status quo lies in the 1962 Kefauver amendment to the US Food, Drugs and Cosmetics act, which made almost all medications available by prescription only. Given that pharmaceutical companies are granted patents on their molecules, there is an inherently monopolistic character to the market for pharmaceuticals. Moreover, as Senator Kefauver put it “he who orders does not buy; and he who buys does not order”. Doctors were to be the sole arbiter of who received medication, with their experience and knowledge a bulwark against the inevitable befuddlement strategies exercised by marketing departments through their trademarks and promotional materials. The doctor was free to choose the latest aggressively-marketed new molecule or the older, cheap, off-patent alternative, but the patient could only comply. A further requirement of the 1962 Kefauver Amendment was that all drugs had to demonstrate both efficacy and safety in controlled trials before receiving approval from the newly established FDA. These trials were invariably funded by the industry. In this way, a situation was created in which the industry was responsible for generating the evidence required to put a drug on the market, a conflict of interest which completely undermines  the scientific process.

The 1962 Kefauver Amendment was a piece of legislation aimed at safeguarding patients by requiring rigorous proof of efficacy and safety. Unfortunately, this was used to the industry’s advantage. The trials submitted to the FDA are randomised, double-blind controlled trials (RCTs): a group of patients with a disease are recruited and divided randomly into two groups. One gets the new drug, the other gets a sugar pill. The severity of their disease is assessed on a rating scale, essentially a questionnaire that rates signs and symptoms and their severity in order to come up with an overall disease score. Side effects are recorded in both groups. When the new drug consistently causes a bigger drop in disease scores than the placebo, it ‘works’.  Herein lies the first problem: a drop on a disease rating scale is not the same as a patient getting better. Side effects have to be considered. Indeed, there is very little data on what antidepressants do to quality of life as opposed to depression rating scales, and the data that is available is inconclusive. This problem goes beyond psychiatry. For example, bisphosphonates can certainly be shown to ‘work’ in that they successfully raise bone density, but whether this reduces fracture rates in all but the most severe osteoporosis or even benefits the patients as a whole is far less clear.

Whilst a lot of drugs ‘work’ in the narrow, context-free world of rating scales, there is plenty of evidence that drug companies obscure the picture on side effects. The evidence that doctors and regulators see is in the form of research reports, detailing the incidence of various side effects in the study group: headache, nausea, high blood pressure and so on. However, other side effects are less clear. Many antidepressant trials showed patients suffering from ”agitation”, but only when one moves beyond the evidence and into the data (i.e. the accounts of what happens to each and every patient) can one find the truth:  patients coded as having “agitation” were suicidal. A severe drug side effect was thus concealed from regulators by a  sleight of hand.

The industry’s record of abuses goes further. When faced with a system that relied on RCTs for drug approval, drug companies applied Fordian capitalist principles to research. Writing up trials was outsourced to “medical communications companies” which applied the right mixture of coding, obfuscation and spin to play up minor differences between drug and placebo (or competing drugs), and to play down side effects. The papers were then published in major medical journals with leading academics listed as authors, even though they did not write the articles in question. In this way, pharmaceutical companies can churn out research papers that all sing the same company-approved tune. It is no wonder that the small number of publicly-funded trials tend to result in much less favourable conclusions about particular drugs. (The most up-to-date research on this topic comes from a review by Lundh et al (2010).[1])

Today, clinicians must base prescription decisions on the best available trial evidence and guidelines, not marketing from drug companies. However, the Big Pharma marketing machine operates subtly, not by merely bombarding doctors with branded merchandise and visits from slick sales reps. In fact, drug companies have hijacked the entire scientific process, creating a medical-academic-industrial complex that drives much of current consensus-forming in clinical medicine. A case in point occurred in 1992 when Healy was offered the post of Professor of Psychiatry at the University of Toronto’s brand new Centre for Addiction and Mental Health, funded by Lilly. At his inaugural lecture, he told the story of how Lilly hid the data on Prozac and suicide. He was unceremoniously sacked. An unfair dismissal lawsuit was settled out of court, with Healy receiving an undisclosed sum of money and a visiting professorship.

In Pharmageddon, Healy outlines how drug companies hold conference and consensus panels on major clinical issues, such as treatments for bipolar disorder, or whether pharmaceuticals should be given to children with ADHD (attention-deficit hyperactivity disorder, commonly treated with mild stimulants such as Ritalin). These conferences heavily influence the formation of clinical guidelines, to which doctors are increasingly bound; the conferences are attended by the same respected academics and high-flying clinicians who write the guidelines. The outcomes are typically recommendations for newer, more expensive drug treatments in greater quantities.

The huge cost of clinical research is often used by the industry to justify the extraordinary costs of on-patent medication. A month’s supply of aripiprazole, an antipsychotic whose patent is held by Pfizer, costs around £200. Generic antipsychotics cost around a twentieth of that sum. With margins like these, it should come as no surprise that in 2012, only Big Oil and Big Tobacco were able to generate greater net income than Big Pharma.

To date, one of the most widely promoted arguments for liberal capitalism is the huge progress in healthcare brought about by the medical wonders of the three decades following the postwar period. Medicine progressed in leaps and bounds, driven by the commitment to science of research-intensive pharmaceutical companies. Healy discusses the emergence and significance of ‘blockbuster’ drugs: these are drugs aimed at managing chronic diseases for which there is no real cure, or for lowering the risk of morbidity for entire populations. They are dispensed mainly in primary care to millions of patients across the world; their annual sales run into the billions of dollars. Prozac, Lipitor (a cholesterol-lowering drug), various antihypertensives and bisphosphonates for osteoporosis have all been blockbusters. These drugs’ potential revenue for a single company is so gigantic that they are effectively rendered too big to fail: n the case of Prozac, no issue as trivial as side effects or lack of efficacy could be allowed to stand in the way of such profits. If Prozac had failed, Lilly and its stock price would have suffered significantly. Entire companies, dividends and revenue streams are at stake; it therefore makes good commercial sense to ensure that the drug hits the market and is prescribed to as many patients as possible, sidelining issues of patient safety and scientific integrity. Healy describes a surreal moment when the Royal College of Psychiatrists held a consensus meeting, behind closed doors, on the uses of SSRIs in children. Many psychiatrists would contest the idea that children can become truly depressed in the way adults do; in any case, GlaxoSmithKline’s SSRI, Paxil, had demonstrated essentially no efficacy in children, while causing a whole range of serious side effects. The Glaxo representative simply stated very clearly that approximately one third of British pension funds held shares in GlaxoSmithKline, and if the esteemed psychiatrists chose not to sanction Paxil’s use in children, there would be real and serious consequences for the nation’s retirement savings.

So, why is ‘Pharmageddon’ happening now and not earlier? Have these companies not been profit-seeking for decades? Have they not been misrepresenting their medicines’ effectiveness undetected since the 1960s?  These are all questions that Healy deals with convincingly. The first point is that today’s multinational pharmaceutical giants are very different to the pharmaceutical companies of yesteryear, whose management was drawn directly from the pools of doctors, chemists and biochemists that worked in the labs. They were highly research-oriented, carrying out a lot of basic science in order to explore multiple avenues in human physiology and pathology that could eventually lead to a profitable drug. With the advent of managerialism in the 1980s and the flotation of Pharma giants on major stock exchanges, the profit motive became far more pronounced. Stock analysts would scrutinise each company’s drug ‘pipeline’, and any failures to produce marketable treatments would adversely impact the stock price. Executives were drawn from business schools rather than chemical or medical backgrounds, and consultancies were hired to increase profits. As the commitment to basic science was eroded, the reliance on the blockbuster increased, with companies becoming increasingly dependent on a narrow range of big-selling lifestyle drugs; after all, they were far more profitable than any other category.

Of course, the second consequence of this marketisation of the pharmaceutical industry is that drugs do not make it to the market if they reduce disease; they make it to the market if they will make money, and these two goals do not always converge, with potentially dramatic consequences. This is of particular relevance to the developing world, whose nations do not have the resources to afford the drugs made in the West that are indispensable for treating infectious diseases. Healy does not discuss the issue of drugs for Africa, preferring instead to focus on the very Western ills of highly developed and expensive healthcare. Yet there are many cases in which the pharmaceutical business model developed in wealthier countries impacts upon poorer nations: Eflornithine, a highly effective treatment for African trypanosomiasis, is a case in point. Like malaria, trypanosomiasis is a parasitic disease transmitted by the tsetse fly, initially causing a severe fever before attacking the central nervous system. Death is inevitable if patients do not receive treatment, following a whole range of atrocious symptoms including dementia, Parkinsonian tremors, memory loss and personality changes. Eflornithine came very close to being removed from the market altogether; the only use for it was African trypanosomiasis, but due to limited demand, it was not profitable to produce it at a price economical to sub-Saharan Africa. A serendipitous discovery that it strongly inhibited facial hair growth was all it took to relaunch production on a huge scale as a treatment for hirsutism in females. The profits from hormonally perturbed European and American women could, in effect, subsidise the production of Eflornithine  for catastrophic epidemics of a lethal infectious disease in Africa.

Whilst the problem of guaranteeing cheap and effective treatment for African trypanosomiasis is solved, there is a public health problem on the horizon, caused by the way the pharmaceutical industry addresses unmet clinical need. The main issue is antibiotic resistance, recently declared by the World Health Organisation (WHO) to be a global emergency with the magnitude of the 1980s AIDS crisis.[2] It is entirely possible that we will soon be facing a post-antibiotic era in which doctors are powerless to help patients with  infectious diseases such as tuberculosis and gonorrhoea in their antibiotic-resistant forms. Although it is difficult to estimate how many deaths are caused by resistant micro-organisms, guidelines from the National Institute for Health and Clinical Excellence claim that 9000 deaths were caused by MRSA and C.diff in 2007 alone, with 300 000 patients acquiring an infection from the hospital during their care, costing the NHS £1bn every year.[3] Despite this obvious clinical need, the percentage of research funds channelled into antibiotic development is astonishingly low, and this reflects the fact that the market for antibiotics is itself very small, dominated by “pile them high, sell them cheap” generic manufacturers. Furthermore, pharmaceutical companies would earn very little profit from any new antibiotics they develop, given that current policy would be to stockpile them and use already available antibiotics where possible. Finally, antibiotics tend to be taken for a matter of weeks, unlike lifestyle drugs, which can be taken every day for decades. For these reasons, several blue-chip pharmaceutical companies, such as Eli Lilly and Wyeth, do not have divisions researching antibiotics at all, and an analysis of the drug pipeline of the major drug companies worldwide revealed that only three antibiotics are currently undergoing advanced clinical trials. For particular types of resistant bacteria, there are no agents in development. Interested readers may wish to read the joint European Centres for Disease Control – European Medicines Agency report on the challenges of developing new antibiotics.[4]

This grotesque example highlights what is wrong with the industry. It is not, as many argue, simply a case of poor management, inadequate regulation, or isolated greed among a few top executives. Rather, the entire paradigm of drugs as saleable commodities cannot be reconciled with the benevolent scientific humanitarianism that the industry claims to embody. Whilst Healy falls just short of this conclusion, he unequivocally succeeds in highlighting the conflict at the heart of the industry, the fatal flaw in the capitalist logic that underlies it; when the issue of profit collides with the goal of improving health, profit wins.

Where do we go from here? For Healy, the answer lies in stronger safeguards against industry abuses, such as a website he has founded (Rxlist.org) where doctors and patients can post reports of drug-induced side effects in order to build up a database rivalling the undisclosed company trials. This is undoubtedly a move that will bolster efforts to hold pharmaceutical companies fully accountable for the adverse effects of their products, it is no revolution. Similarly, Ben Goldacre’s Bad Pharma has resulted in a national registry of clinical trials so that the industry can no longer hide evidence, but the real data remains company property. This means that the same coding tricks can be used to hide side effects, and ghostwritten, carefully spun papers will continue to be the norm. These solutions, although helpful, are half-measures, inadequate in the face of a system in urgent need of reform. One method of rectifying the imbalances created by the current market system would be to impose a special tax on pharmaceutical company profits, with its proceeds being placed into a fund that would direct money to the sectors most in need of new research. There are existing public research bodies and charities that are well-equipped to do this.  Yet creative accountants working for the pharmaceutical companies would inevitably find ways of avoiding such a tax, even in the unlikely scenario of its adoption across Europe and the United States.

A more radical solution is to dismember the industry entirely and separate drug research and production, in effect turning pharmaceuticals into chemical industries and handing the development and trialling to public and charitable bodies; university departments, charities and the Medical Research Council are all institutions possessing the necessary human resources and facilities to undertake this task. The savings this would generate for public healthcare would be more than adequate to fund the research previously funded by pharmaceutical companies. This option in effect involves institutional change, eliminating the profit motive both from the conduct of clinical trials and the distribution of research funds. As Pharmageddon so convincingly shows, the profit motive in the conduct of clinical trials has had chilling consequences for patient safety; the current situation with antibiotic development demonstrates that the profit-driven model leaves populations across the world vulnerable to a new wave of resistant micro-organisms which doctors are unable to fight for lack of sufficiently profitable drugs. Pharmageddon is a damning and comprehensively researched indictment of Big Pharma, but it falls short in its relatively half-hearted attempts to grasp the political implications of the current status quo and the way forward for policy. Only when managerialism and the pursuit of profit are removed from the development of new drugs will we be able to avoid Pharmageddon.

 

Alexander Breton is a second-year medical student at Trinity College, Oxford.

 

Footnotes:

[1] Lundh et al, ‘Industry sponsorship and research outcome’, The Cochrane Library, available at http://onlinelibrary.wiley.com/doi/10.1002/14651858.MR000033.pub2/abstract, last accessed 25th May 2014.

[2] World Health Organisation, ‘Antimicrobial resistance: global report on surveillance 2014’,  World Health Organisation, available at http://www.who.int/drugresistance/documents/surveillancereport/en/, last accessed 14th May 2014.

[3] National Institute for Health and Care Excellence, E, ‘Infection: Prevention and control of healthcare-associated infections in primary and community care’, Infection Introduction CG139, available at http://publications.nice.org.uk/infection-cg139, last accessed 14th May 2014.

[4] European Centre for Disease Prevention and Control, ‘The bacterial challenge: time to react’, available at http://www.ecdc.europa.eu/en/publications/_layouts/forms/Publication_DispForm.aspx?ID=199&List=4f55ad51-4aed-4d32-b960-af70113dbb90.  last accessed 14th May 2014.

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