Big Pharma’s little critics

Based in Connecticut, John LaMattina was president of Pfizer’s global effort in research and development (R&D). When he retired in 2007, it was after 30 years’ service, culminating in the management of 13,000 scientists and technicians. In his second book on the pharmaceutical industry, Devalued and Distrusted: Can the Pharmaceutical Industry Restore its Broken Image?, he cuts straight to the chase.

LaMattina describes his experience on an American talk show, The Dr Oz Show, during which the host catalogued, to great audience acclaim, the existence of Four Secrets That Drug Companies Don’t Want You To Know:

1. Drug companies underestimate dangerous side-effects
2. Drug companies control much of the information your doctor gets
3. You’re often prescribed drugs that you don’t need
4. Drugs target the symptoms, not the cause

This is an apt and, in its conciseness, rather rare summary of the low esteem in which ‘Big Pharma’ is held. Does LaMattina mount a successful defence?

Before going any further, we should note that GSK, Lilly, Pfizer, Merck, Astra Zeneca, Roche and others have, between them, plenty of perfidy and patient damage to answer for, and, just as outrageous, are pushing through large and draining cuts in R&D right now. Still, the pharmaceutical sector is better known for being over-reliant both on ‘me-too’ derivatives (close copies of their rivals’ hit products), and, more fundamentally, for being too narrow-minded in its search for ‘blockbuster’ compounds – branded, prescription drugs that generate £1 billion or more in sales. Scams around pharmaceutical prices and patents are also well known. Importantly, drug firms play a part in general disease-mongering. Last, and the three British books reviewed here say much on this, drug companies do suppress data from patient trials that reveal adverse side-effects.

For LaMattina, by contrast, each of Oz’s four ‘secrets’, though ‘rooted in a valid starting point… paralleled many preconceived incorrect notions, which… need to be corrected before the pharmaceutical industry can regain trust as an innovator against disease’. One can quarrel with the author on that, but on one thing he is right: rather than yet another revelation of Dr Oz’s four secrets, it would make a change if more people understood the dynamics of the international pharmaceutical industry’s weakening record in innovation. Pharmaceuticals, arguably the most science-intensive sector in the world, is not only closing down whole sites for R&D, but also, in terms of bringing serious innovations to market, is getting fewer bangs for the buck – what is known in the sector as the ‘productivity of R&D’.

Side effects – and secrecy

Certainly, big drug companies now run large-scale programmes of ‘pharmacovigilance’ to watch out for side-effects. Certainly, if aspirin was first discovered in 2013, its side-effects would prevent it from ever being developed. And, yes, most clinical trials, though funded by drug firms, are run by independent physicians at various academic centres and teaching hospitals around the world. However, I can’t quite share LaMattina’s credulity toward either the rigour of pharmacovigilance programmes, or the good sense and goodwill of pharmaceutical publishing.

For the author, medical journals are right to be selective in what they print: they are ‘simply publishing meaningful data, be it positive or negative’. Now it is true that, as Glasgow GP and medical commentator Margaret McCartney says, we need not more information from drug companies, but better; but in the meantime, full and comprehensive information would be a terrific step forward. Society needs all the trial data it can get hold of – both in and beyond medical science. We need all the data from the world’s clinical trials, all the code used in analyses, and all the world’s medical journals to be open-access: in the era of the web and Big Data, anything less isn’t enough. We need to be able to see both pre-market and post-market (‘outcome’) studies.

Similarly, we need trials to be larger and longer, if simpler. We need these things not because Big Pharma must improve its transparency if it is to win back trust and restore its image, as LaMattina says, but because the fullest and very best data are necessary if the world’s research teams are not unwittingly to repeat each other’s efforts; if compare-and-contrast exercises with the results of studies (‘meta-analyses’) are really to bring insights; if, in short, genuine medical innovation is to advance.

The world is not, as Cardiff university professor of psychiatry David Healy suggests in Pharmageddon, in the manner of the cranky 1970s Swiss priest Ivan (Medical Nemesis) Illich, so awash with medicine’s nasty side-effects that we are left with ‘potentially reduced life expectancies’ (which is untrue – life expectancies are in fact rising year on year). The overwhelmingly safe postwar progress made by pharmaceuticals cannot rationally be negated like this. Yet LaMattina only partly succeeds in dismissing Dr Oz’s Secrets 1 and 2.

The perspectives that Healy and the bestselling science writer and doctor Ben Goldacre have on Oz Secret 2 – pharmaceutical company control over trial data – are also deeply flawed. In familiar style, Goldacre, in his Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients, makes far too much of the corruption and secrecy that certainly surround pharma companies, the results of their trials, and regulatory agencies. Both the front and back cover of his book are adorned by a skull and crossbones; on the inside front cover the blurb opens, in bold type, with the Cameronish proclamation: ‘Medicine is broken’ (it continues that pharma is a $600 billion business ‘riven with corruption and greed’). Goldacre presents everything as a Guardian sleuth, breathlessly self-conscious in letting you in, at length, on the dirt you already knew was coming. He is right to slam the obfuscations of bureaucrats at the European Medical Agency around trial data, but he is so transfixed by wanting to make the world transparent that he has few other proposals for reform of state regulators. He never really asks whether the pharmaceutical industry’s desperate fondness for smoke and mirrors in data reflects the very real crisis of innovation in the sector. As a result, Goldacre inspires among patients a kind of visceral mistrust of drugs, which can only impair today’s growing and commendable, though difficult, efforts to share patient data about them.

Healy is more useful in arguing that corporate tricks with trial data are themselves an outcome of the state intervention that followed the Thalidomide scandal. In 1962, US food and drug legislation was amended to reinforce prescription-only status among drugs and to require drug-makers to demonstrate not just safety but efficacy, through randomised controlled trials (RCTs), in which new drugs do battle with placebos. At the time this was mostly a good thing, but over the years the promise of basing cures purely on science has turned into a neutral-sounding but fairly fraudulent system of ‘evidence-based’ medicine organised, in fact, by the drug companies.

There is something in this; but, at both start and finish, state intervention has tended to have the last word. It is not just that there is a vast literature, as Goldacre rightly observes, on ‘regulatory capture’ – the seizure of the regulators by the rapacious drug combines. Rather, as two of Healy’s many fascinating historical excursions confirm, the template for this rather superficial critique of pharmaceutical ‘sharp practice’ in general and suborning of regulators in particular was shaped, in the US, all the way back in the 1959, with the seminal Kefauver-Harris hearings on pharma cartels, price-rigging, advertising, patents and all the rest of it. Then, the Democratic Party senator for Tennessee, Estes Kefauver, said that the influence wielded with regulators by the drug-makers’ lobby was one which made lobbyists for the giant US steel industry ‘look like popcorn vendors’.

At the height of the Cold War and in that era’s spirit of wide-ranging Democratic Party dissent, Kefauver’s fundamentally conservative, trust-busting critique of the pharmaceutical industry, culminating in what we now know across many industrial sectors as ‘consumer protection’, did not appear conservative. Yet now that half a century has gone by, critiques of pharmaceuticals firms that merely add iffy conduct with patient trials to the charge sheet can all too easily miss the point. The capitalist state cannot, through its regulation, guarantee the safety of nearly enough patients. In drugs, as in other industries, the private sector has its full and usual share of conspiracies and victims; but the state sets the economic, political and personal agenda for pharmaceuticals much more than drug-makers set the agenda for the state.

Around the world, it is the state, more and more, that pays for drugs. The state runs the patent system for drugs, which, as Healy underlines, can produce egregious results (and not just in pharma, either). As LaMattina shows, when it was found that GSK’s Avandia treatment for diabetes lowered blood sugar but not the heart attacks and strokes that can follow diabetes, Time magazine pontificated in August 2010 that the drug-approval process was ‘too easy’ for pharmaceutical companies to ‘game’. Meanwhile, Iowa Republican Senator Chuck Grassley discovered that the links which the US Food and Drug Administration enjoys with the drug industry were ‘too cozy’. Yet as it has transpired, there are compounds given the green light in the 1990s that would not be approved today. The kind of outcome studies favoured by the FDA are on 10,000 to 30,000 patients, run up to five years, and cost $100-$300million per drug. In new drugs for chronic diseases, bringing an idea to approval now typically takes not 15 years, but 10.

Venture capitalists are still ready to finance a new effort to develop a drug for diabetes or obesity, and, if a compound can successfully clear these hurdles, it will be a true blockbuster and will make a real difference. But the fact is that FDA stringency, however proper, does play a part in deterring and slowing innovation. When corporate pharmacoeconomics groups now consider the rising costs even of winning tough regulatory approvals for new, more science-intensive drugs, they also inevitably consider whether – particularly when put up against existing or prospective drugs that are cheap and unbranded (‘generic’) – anyone or any organisation will be prepared to pay reimbursements for those costs.

FDA strictures are rightly more demanding in the domains of safety, efficacy and pre-approval data around diabetes, obesity, cancer, osteoporosis, and heart disease. At the same time however, there’s no need to be a glib free-market critic of regulation to observe that these strictures help mediate the corporate innovation slowdown. Against this important mechanism, corporate cosyness with the state is, relatively speaking, pretty incidental.

False needs – and the treatment of symptoms, not causes

Are we often prescribed unneeded drugs, Dr Oz’s third ‘secret’ withheld by the pharmaceutical companies? While Healy and especially Goldacre perform the usual surgical skewering of Roche over its evasions around the anti-flu drug Tamiflu, the longstanding controversies around statins, the mass drugs deployed to lower cholesterol and thus heart attacks and strokes, are more nuanced. I don’t doubt that McCartney is right that we need to track the side-effects of statins with the help of more long-term studies. On the other hand, the 2001 Heart Protection Study of Oxford University’s Dr Richard Bulbulia and others, which was 11 years in the making, would seem in LaMattina’s account to convince most readers of the efficacy of statins.

Perhaps, in line with Dr Oz’s fourth and final secret, the drug industry targets symptoms such as ‘bad’ cholesterol instead of the causes of disease. Yet, as LaMattina says, it’s fair enough that headache and stomach pills give only symptomatic relief; and, conversely, antibiotics can be said to target causes, as well as diminishing symptoms. What the pharmaceutical industry’s critics’ confusion over symptoms and causes really suggests is, as LaMattina points out, that the industry invents diseases. As Healy argues it, in the 1990s Abbott Laboratories came up with the idea of a ‘mood stabiliser’ to deal with what quickly became known as bipolar disorder – a rebranding of manic depression. In the same way ‘impotence vanished and was replaced by erectile dysfunction, frigidity by female sexual desire disorder, boisterousness in children by ADHD’.

In fact, things are not quite as simple as Healy would have it. LaMattina writes: ‘First of all, a company cannot simply declare a new disease and market a drug to treat it. The disease must be recognised by global regulatory agencies which setup criteria that a drug must meet in order to have even the most remote chance to be approved. Second, payers must believe that the condition is serious enough to warrant reimbursement… Third, physicians must believe the diseases serious enough to be willing to prescribe a drug… Patients must be concerned enough about their pain or discomfort to be willing to seek treatment in the first place. Last, in order for the “world disease mongering conspiracy” to be successful, patients, physicians, players, and regulators must act in concert with the exploitative drug companies. Doesn’t this seem the least bit far-fetched?’

Yes, it is a bit far-fetched, and today’s vogue for finding conspiracies is all too alive and well in popular treatments of the drug industry. But what LaMattina neglects is how the state, though accompanied by others, is the lead player, not so much in mongering diseases, but in spreading health panics. The powerful forces of state intrusion around diet, exercise, obesity, smoking, alcohol, sugary drinks and sexually-transmitted diseases dominate our culture and our media, and the savvy pharma company is able to put the sensibilities whipped up by these forces to good use.

Like producers of consumer goods, drug manufacturers are, as Healy keeps telling us, ruthlessly commercial in outlook and practice. But if the medical field preeminently lends itself to claims that are scientific, the state’s highly dubious but broader-than-medical elevation of ‘the science’ and ‘evidence’ as a means of gaining popular trust is what gives the yarns spun by pharma firms their traction. Quack remedies in bottles have been legion since the late nineteenth century. What is new today is the state’s broadly unacknowledged fondness for quack therapies of a broader, insidious sort – and it is this that legitimates the drug merchants’ bad science.

LaMattina cannot see this. In fact, and in telling style, he completely buys into the state’s deification of diet and exercise, and also into its hysteria about obesity. Without a blink, or even a nod at the notoriously unreliable Body Mass Index, he quotes a 2010 Atlanta Center for Disease Control study suggesting that over 30 per cent of the adult population is obese in no fewer than 12 US states. In laughable style, he presents two charts correlating the geography of type-2 diabetes in US states with that of obesity – obesity, he says, ‘is already resulting into’ [sic] type-2 diabetes, as if that is all there is to the matter.

The context for funny business around trials

Since the early 1970s, the drug investigations preferred by mainstream opinion in society have more been to do more with Watergate journalism and ‘the people have a right to know’ than with fundamental scientific enquiry. The flimsy Democratic Party critique of capitalism as the ripping-off of consumers has ensured that sharp practice and cover-ups, not a deficiency of innovation, are what has caused comment. Of a piece with this, the forces ranged against Big Pharma always represent both doctors and patients as the stupid dupes of pharmaceutical company marketing departments. Healy is aghast, holding that doctors are ‘unaware’ that marketers craftily distinguish high-flyer doctors from the rule-bound sort. Well, maybe. Yet in the age of the internet-browsing patient, it is more surprising still for Goldacre to imagine that ordinary people lack the wit to discriminate in medicine.

He follows current orthodoxies in public health by approving bans on direct pharma ads to patients (LaMattina is equally hostile to Super Bowl and general TV ads). But instead of this not-in-front-of-the-children paternalism, why not let the people decide – and decide, moreover, not just about the medical claims made by the private sector, but also the still more ‘neutral’, influential and scientifically questionable claims made by public health officials, the Royal College of Physicians, the World Health Organisation, and so on? To their credit, both McCartney and Goldacre follow the eminent Michael Baum in exposing what Goldacre terms the ‘startlingly bad behaviour’ of zealots for breast-cancer screening. But as alerts made by doctors go, theirs are exceptions. In medical matters as elsewhere, the strongest shield wielded by the public will not be another unimpeachably independent commission of expert and diligent professionals, but the vigilance of the public. Goldacre should have the courage of his convictions and his relentlessly marshalled exposés, and trust the people to deal with the malfeasance of capital in the pharmaceutical sector.

McCartney is nearest the mark in contrasting state and private campaigns to worry or even harm the ‘well’ around diagnostic screenings with the NHS habit of not bothering enough with the unwell. Here we have a hint of the inner, mediated logic that forms the context for funny business around pharmaceutical trials.

In terms of periodisation, Healy is wrong to suggest that the mid 1970s ‘can be seen as close to the acme of medicine’s ascendancy’. In fact, the classic crisis of capitalist profitability that emerged in the early 1970s also marked the onset of long-run trends: more and more treacle in innovation processes, a trickle of product innovations and, outside of IT, few truly revolutionary breakthroughs. Like other sectors, pharmaceuticals began to find innovation harder. Like others, pharmaceuticals moved into marketing and branding: biological research became more important, but so did branding. What’s more, critiques of medicine took a more popular shape in the early 1970s, from the English translation of Michel Foucault’s 1963 book The Birth of the Clinic, through a Kefauveresque Communist Party pamphlet directed against the pharmaceutical sector (1) and on to a Penguin Special titled There’s Gold in them Thar Pills (2).

As state expenditure rose in the West, it was Margaret Thatcher, a chemist, who pioneered state attempts to use science – for example, over ‘sustainability’ – to authorise capitalist rule. After 1988, LaMattina makes clear, mergers and acquisitions (M&A) eliminated 31 out of 42 members of America’s Pharmaceutical Research and Manufacturing Association, distracting management from innovation, disrupting drug development pipelines (3), and leaving fewer firms to pursue each research task. Also, between the 1990s and the noughties, FDA approvals of new US drugs fell, from 315 over 1991-2000 to 231 over 2001-2010… despite the successes recorded by the Human Genome Project.

By the mid 1990s, anyway, conventional left-right politics had given way to statecraft around personal lifestyles – what we know as Tony Blair’s Third Way. As corporate life made a strong shift from innovation to financialisation and state medical laboratories were scaled back, so state prohibitions about individual behaviour and health drew the public and media gaze away from what had happened. The state led the way not in medical innovations, but in medicalising nations. For example: when the terrorist attacks on 9/11 happened, primetime TV in the US was filled with experts quacking on about its effect on the mental health of TV-watching children. And when, a week later, five people died as letters containing anthrax were mailed around the US, it proved to be the occasion for more than a decade’s worth of massive spending and discussion on ‘biodefence’.

In the feverish, therapeutic framework drawn up by the state as a response to faltering economics and faltering innovation, pharma firms have had a basis for distorting the results of trials and so making highly mendacious statements. The problem is not their venal opacity: like families and doctor-patient relationships, research scientists have a right to intimate, free-wheeling, off-the record discussions. The problem is that pharma firms prefer to step away from the mountainous research problems of biology and loiter, instead, in the foothills not just of marketing but also of regulator management, the legal protection of state patents and intellectual property, and the offshore cheapening of state-procured manufactures – in part, by offshoring R&D.

In some ways, as Healy observes, Indian and Chinese pharma companies may be more innovative in producing ‘novel and needed drugs’ than are Western concerns. What, then, is to be done to improve R&D output in the West? There, pharma companies, LaMattina argues, should beware outsourcing their early-stage research if they care about their profitability or their later checks on trial data; not outsource the majority of their R&D, stop relying on M&A, and stop cost-cutting when it gets too disruptive.

For the author, scale in terms of the number of people in any research team counts, and so, does the calibre of those people. High-throughput Screening (HTS), a longstanding ‘industrialised’ approach in which researchers fish for leads in millions of different compounds set in microarrays, also has much to offer, as do early-stage inter-company collaborations around HTS and other powerful new technologies (nanotechnology, biomarkers, imaging, drug delivery technologies, IT).

According to LaMattina, it is silly to urge pharma firms to stop looking for blockbusters, since they find it very hard to predict for blockbusters in the first place (the blockbuster to beat them all, Lipitor, by Warner-Lambert, had unexpectedly high sales, peaking at a worldwide figure of £13 billion). There are still opportunities to make blockbuster breakthroughs. In a related vein, the author holds it wrong to urge firms to move into specialty medicines, since these, like any others nowadays, will take at least a decade for a company to see through. Anyway, biopharmaceutical companies have used new genetic insights to pioneer blockbusters of a niche variety since as far back as the 1990s.

Last, LaMattina believes that repurposing old or discarded experimental medicines for new uses, though useful, will not be a major source of new products.

All of these insights are more or less sound. However LaMattina isn’t wholly right to recommend the pursuit of multiple promising pharmaceutical solutions to the same medical problem in the cause of maximising the productivity of R&D. That kind of effort is no substitute for what he rather dismissively refers to as ‘interesting science’. His declarations to the contrary, this is a scattershot approach, one which values ‘drug candidate flow’ more than the patient assembly of fundamental insights.

By accessing the specific, biologically targeted, personalised medicines that are only now just starting to reach pharmacies, LaMattina contends, doctors, patients and payers will have confidence in new medicines. He is right. But today’s merely ‘interesting’ basic, scientific research, at just 15 per cent of pharma R&D budgets (the other 85 per cent being the arduous and ever more costly process of development), is tomorrow’s superbly practical theory.

Pharmaceutical innovation cannot move forward unless core biological mechanisms are better understood and, equally, state nostrums about individuals making ‘informed healthcare choices’ are rejected for their authoritarianism and their manipulation of the ‘evidence’. And so long as pharmaceutical innovation stagnates, conduct with and the veracity of pharmaceutical trials will continue to be the object of suspicion.

James Woudhuysen is professor of forecasting and innovation at De Montfort University, Leicester, and editor of Big Potatoes: the London manifesto for innovation.