Pharmageddon (10 page)

Faced with the competing pressures on doctors, Pinel stressed that physicians needed to combine their roles as givers of care and as scientists. It was only through the application of science, he said, that doctors would be able to distinguish among the conditions they were treating and establish the natural history of each. This would give them the best chance to discover the anatomical basis of these conditions and might lead to new therapies for both individual patients and the wider community.

Pinel's approach both to science and its public dimension was vindicated in the 1880s, when laboratory science began to demonstrate links between diseases and microbes. Once it was clear infections were transmissible, medicine had to have a public dimension. In our day this dimension is global. Drug-resistant tuberculosis in Russia and AIDS in Africa pose threats to all of us.
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If in principle the mission of medicine has been to treat the diseased and dying wherever they are, that of the pharmaceutical industry has increasingly been to protect its patents and its profits. The clash of these values came to a dramatic head in the late 1990s with the struggles to make antiretroviral drugs available in sub-Saharan Africa for the treatment of HIV-AIDS, just as Glaxo Wellcome and SmithKline Beecham were in merger talks. The first of the antiretroviral drugs, zidovudine, also called AZT, was developed in university laboratories with public funding—the first of which, for marketing and distribution purposes, was offered to Burroughs Wellcome (prior to the merger with Glaxo) to patent, which it did and then marketed as Retrovir.
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The fear of AIDS in the 1990s ensured that Glaxo Wellcome and other companies marketing these drugs had a rich return on these products.

In the early 1980s AIDS appeared to be confined to the United States or the Western Hemisphere, but by the 1990s it was clear that there were far higher rates of infection in Africa and a risk of the disorder spreading to Asia and elsewhere. The rates were so high that many African countries faced being crippled by the disease. Supported by all other companies, GlaxoSmithKline (GSK) refused to either permit other companies to offer the drug in generic form at much lower prices or to lower the price on AZT themselves to a level that would make it possible for the hundreds of thousands suffering in Africa to benefit from it and thereby stem the tide of an enormous tragedy. To do so, GSK argued, would breach patent law in a manner that would compromise future drug discoveries. It was as though the companies who produced diphtheria antitoxin a century earlier had refused to make it available. The outrage of almost the entire world forced GSK to back down.

Glaxo and other pharmaceutical companies have been willing to treat the West and, more recently, the wealthy parts of China, India, and Brazil, as gated communities, within which one form of healthcare will be available and outside of which no questions will be asked. Some of those inside the gates may regret this policy, but provided their children and families are not the ones dying from diphtheria or AIDS these regrets are unlikely to lead to action. But this is short-sighted in the extreme. The same patent and marketing factors that have led companies to lose interest in developing drugs for Third World diseases if these do not afford a sufficient return on investment by today's blockbuster standards, mean that the drug companies are no longer likely to play the kind of role they once did in eliminating disorders like diphtheria or bacterial endocarditis. Indeed, they didn't develop AZT or the other retrovirals for AIDS; these applications were developed elsewhere with public funds. They are not likely to develop better anticonvulsants for epilepsy or bring treatments for multiple sclerosis on the market, since even within the gated communities of the developed world the incidence of these conditions is such that it is not worth their while to make the investment. Return on investment rather than elimination of disease is, after all, what drives a pharmaceutical company.

This philosophy is as diametrically opposed to that of Philippe Pinel, Alfred Worcester, and Richard Cabot as it is possible to get. For over a century patients have assumed that the knowledge a doctor like Cabot brings to helping them stems primarily from what is known about the condition being treated or that what a doctor like Worcester brings stems from a judicious appraisal of the limits of current knowledge and treatments. But in the past two decades what is “known” has come increasingly to be dominated by the self-interested constructions of the pharmaceutical companies, through the activities they sponsor, the kind of research they promote, and the information they choose to reveal—or conceal. Under siege, doctors like Dr. N have turned to the appearances of science and spend their time filling standardized forms in medication clinics rather than talking to or looking at their patients. In this process they have become the faithful if unwitting collaborators of the pharmaceutical companies, almost as though the debates between Cabot and Worcester about the purpose of medicine had not taken place a century ago—or worse, almost as though Clark Stanley marketing snake oil or Thomas Beecham marketing his pills had not faded away in the face of developments in medical science or a growing commitment to medical care of the type Pinel and Worcester advocated but had instead taken over the health service business.

In 1909 Beecham's Pills ran into trouble when their claims to be a cure-all for lifestyle problems included suggestions that this combination of aloes, ginger, and soap, whose retail price was 500 percent of its costs of production, might be useful for “maladies of indiscretion.”
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This claim was read as offering a “morning after” service. In 2009, GSK, whose fortunes at the time of the patent disputes over AZT rested on the SSRI Paxil, a drug a former CEO had derided as a lifestyle drug but which Glaxo had inherited when taking over SmithKline Beecham, lost a legal verdict to Michelle David, who claimed Paxil had caused congenital heart defects in her son Lyam Kilker.
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The evidence in this, and Gina Fromm's subsequent case, made it clear that in addition to doubling rates of congenital malformations it doubles the rate of miscarriages and increases voluntary terminations of pregnancy.

Yet extraordinarily in the face of this evidence not only doctors but even ethicists line up to say antidepressants are being underused in pregnancy.
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There is a suspension of common sense here that has been brought about by company marketing of controlled trials and evidence based medicine. Ironically a requirement for controlled trials was built into Senator Kefauver's 1962 amendments as this seemed a method to limit rather than promote treatments, but these trials have in fact become the primary marketing tool of pharmaceutical companies. The marketers have selected the trials that suit, had them polished by ghostwriters just as much as a political speech might be, before smuggling them past the peer review systems of academic journals and meetings. But none of this would have the power to influence doctors had the very meaning of clinical trials not been turned inside out.

3

Follow the Evidence

When a journalist jumps out from behind a hedge on the eleventh hole of a Caribbean golf course to ambush a professor of medicine from one distinguished university and a professor of psychiatry from another after both gave brief lectures that morning, and he asks the men whether their company-sponsored trip would influence their judgment, the response will be “Of course not!” If asked what does influence them, these academics will confidently point to the published evidence. They follow the evidence, not the money. Even if a doctor is pocketing the lecture fee rather than putting it into a research fund, the answer will still be the same.

There is a rich literature on how even minor gifts can hugely influence the recipient,
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and an equally rich literature on how doctors, when asked, readily agree that their colleagues are swayed by favors while still denying that they themselves can be influenced.
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That gifts can corrupt seems so obvious to everyone except doctors that in 2009 a Sunshine Act was introduced in the US Senate to mandate disclosure by pharmaceutical companies of money or other gifts given to doctors or medical academics.
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The response from the medical community to moves like the Senate's bill that seem to impugn medical professionalism is bewilderment. While traditionally doctors have put great store in professionalism, at least as important in their response to this issue is their belief that scientific research is immune to gifts, biases, or conflicts of interest. It's taken for granted that data don't lie, and this leaves medical personnel and their academic colleagues sanguine about gifts, from pens to all-expenses- paid conferences in the Caribbean. If anyone in the media can point to a mismatch between what doctors on the golf course prescribe in their practice and the published evidence, that would be another matter—but until Birnam Wood comes to Dunsinane there is no reason for concern.

These days, almost as though Macbeth's witches had invested in the fixedness of Birnam Wood, pharmaceutical companies also take their stand on the published evidence. From senior executives mingling with medical academics to drug reps visiting medical trainees, company personnel tout the virtues of controlled trials and exhort doctors to practice evidence-based medicine at every turn.

In its first manifestations, controlled trials and evidence-based medicine were known for demonstrating that fashionable treatments did not work. If now pharmaceutical companies invoke what they call evidence- based medicine to justify the status quo, that should at least raise some suspicion about what might be going on. In
chapter 4
and 5 we will look at how companies cherry-pick the trial data that suits them, leaving inconvenient data unpublished and making a mockery of science. But in this chapter the focus is on how they have managed to turn controlled trials inside out, neutering their potential to show that some currently fashionable drugs don't work and transforming them into a means to sell worthless remedies.

THE TURN TO NUMBERS

Insofar as the Hippocratic dictum of “first do no harm” appears a good idea, we should adopt the view that we know very little. But faced with real diseases from Alzheimer's dementia to malignant cancers to rheumatoid arthritis, when both those affected and their doctors become desperate and vulnerable, remaining calm and skeptical is easier said than done. This is precisely why we need to pin down how much we do know about medical treatments, and for this purpose controlled trials can be a godsend.

There are many situations where it is not difficult to know when a drug or a medical procedure works. In the case of alcohol, for instance, we comfortably base our judgments on the fact that we can see certain effects occur reliably soon after intake of the drug, with some relationship between how much we imbibe and the effects we experience. We know about the analgesic effect of opium and the sedative effects of the barbiturates in the same way as we know about alcohol and about the benefits of having a dislocated shoulder popped back into place or a kidney stone removed, from the immediate relief.

Not all treatments have effects that are this clear-cut, though, nor are all the effects even of alcohol or sedatives self-evident. While a sedative may be usefully sedating and in this sense work, it still may not be all that useful in the long run for nervous conditions. Even bigger problems arise when the beneficial effects of a treatment are less immediate than those of alcohol or opiates, or when there are substantial differences in the effect of a treatment from one person to the next, or when the natural history of a condition is such that some people would have recovered anyway. In these cases, treatments may appear to be linked to cures and doctors or patients, who understandably want to see a treatment working, may jump to the conclusion that the treatment has worked when in fact it hasn't. This is a gap that quacks and charlatans exploit. In a world where nothing much worked, the charlatan engendered many false hopes. In today's world, where getting the wrong prescription may mean you needlessly suffer harmful side effects or miss out on a treatment that really would have helped, the consequences may be more serious.

In these more ambiguous cases—of which there are many in medicine—how do you know whether or not a treatment is likely to have any benefits and what hazards it may entail? For several centuries at least some physicians appreciated that before a proposed new remedy could be accepted, its effects would need to be observed under controlled conditions. There would need to be some way to demonstrate that any improvement in patients was due to the remedy, and not to some other factor, or even to chance. Some group of patients living under similar conditions that could be divided into comparable groups, only some of which were given the remedy, would be needed. But short of imprisonment or quarantine, this is not easily done.

In 1747, James Lind, the Scottish physician who served as ship's doctor on the South Seas-bound
Salisbury
, was given the perfect opportunity. Some of the sailors developed scurvy, a fearsome disease that caused tissue breakdown—wounds failed to heal, teeth fell out, and victims began to bleed into their skin or from their bowels. In some long-distance sea voyages up to half a ship's crew might die from it. Faced with twelve sailors whose “cases were as similar as I could have them” and who were all on the same diet, Lind was able to give two of the men cider, two vitriol, two vinegar, two sea-water, two oranges and lemons, and two a mix of nutmeg, garlic, mustard seed, and balsam of Peru. Those given the oranges and lemons improved rapidly, the others languished.
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Even though there was limited scope for any other explanation of these recoveries, many attributed the improvement to ventilation (although that was the same for all twelve patients), while even Lind himself was slow to credit the citrus fruits for the favorable response. It took the British navy another fifty years to include lime juice in the provisions for a voyage, after which British sailors were widely termed limeys. In this case, when faced with a choice between their expectations and the evidence, observers at first clung to their expectations—a pattern we shall see again and again.

On a much grander scale, but in a less controlled fashion, in 1802 in the midst of the revolutionary ferment in France, Philippe Pinel, the general physician now commonly seen as the father of modern psychiatry, working at the Salpêtrière asylum, became the first to commit medicine to an evidence-based approach. At the time typical treatments for mental illness included bloodletting, brutality, forced immersion in cold baths, being hosed down with water jets or subjected to a variety of purgatives, emetics, diuretics, and other drugs. Although there were elegant rationales for some of these treatments, and in some cases the treatments stemmed back to antiquity and had been advocated by history's most distinguished medical names, Pinel was skeptical. Patients often seemed to get better when the doctor waited to intervene, he had observed. Learning the typical course of a disorder, he reasoned, would make it possible to predict when patients might turn a corner for the better on their own. This appreciation underpinned his dictum that the greater art in medicine lay in knowing when to refrain from treatment.
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Between April 1802 and December 1805, 1,002 patients were admitted to the Salpêtrière, and Pinel was able to follow these individuals during their stay to see who recovered and who didn't, whether patients in particular diagnostic groups fared better than others—and hence whether diagnoses in use at the time were worthwhile or not. This was a first example of what later came to be called a statistical approach to illness. Why do it? Pinel laid out his reasons.

In medicine it is difficult to come to any agreement if a precise meaning is not given to the word
experiment
, since everyone vaunts their own results, and only more or less cites the facts in favor of their point of view. However, to be genuine and conclusive, and serve as a solid basis for any method of treatment, an experiment must be carried out on a large number of patients following the same rules and a set order. It must also be based on a consistent series of observations recorded very carefully and repeated over a certain number of years in a regular manner. Finally it must equally report both events, which are favorable and those which are not, quoting their respective numbers, and it must attach as much importance to one set of data as to the other. In a nutshell it must be based on the theory of probabilities, which is already so effectively applied to several questions in civil life and on which from now on methods of treating illnesses must also rely if one wishes to establish these on sound grounds. This was the goal I set myself in 1802 in relation to mental alienation when the treatment of deranged patients was entrusted to my care and transferred to the Salpêtrière.
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There had never been anything like this in medicine before. Overall, 47 percent of the patients recovered, Pinel found, but of those who had been admitted for the first time, who had never been treated elsewhere, who had a disorder of acute onset, and who were treated only using Pinel's methods, up to 85 percent responded. When left to recover naturally, many more of the first-timers did so than did those among the patients who had been treated previously by other methods. Not only that, within a short time of admission Pinel could tell who was likely to recover and who was not based on their clinical features. In other words there seemed to be different disorders, and people suffering from some types would recover if left alone while inmates with some other types would not regardless of what treatments they were given. Finally, following the patients after discharge brought a whole new group of periodic disorders into view for the first time, laying the basis for the later discovery of manic-depressive illness and other recurrent mental disorders.

Aware of the pioneering nature of his research, Pinel presented his data, on February 9, 1807, to the mathematical and physical sciences faculty at the National Institute of France rather than to the country's Academy of Medicine. This was hard science and the first time in medicine that results were presented as ratios across a number of patients studied, rather than as accounts of individual cases.

In reporting these findings, Pinel showed that he was well aware that his personal bias could have colored the results. But, as he noted, while an individual patient in London could not properly be compared to one in Paris or Munich, the results of complete groups of patients could be, and the registers of Salpêtrière patients were publicly available. So he confidently challenged others to contest his findings based on their outcomes.

The scientists were impressed. The physicians weren't. It took thirty years before another French physician picked up the baton and further unsettled the medical establishment with numbers. In 1836, Pierre Louis outlined a new numerical method that controlled for variations by using large numbers of patients: “in any epidemic, let us suppose five hundred of the sick, taken indiscriminately, to be subjected to one kind of treatment, and five hundred others, taken in the same manner, to be treated in a different mode; if the mortality is greater among the first than among the second, must we not conclude that the treatment was less appropriate, or less efficacious in the first class than in the second?”
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The treatment Louis assessed was bleeding—which in fact works well in disorders such as heart failure. But when he compared bleeding to doing nothing in a sufficiently large number of patients during the course of an epidemic, he sparked a crisis in therapeutics. Doctors expected bleeding to work better than doing nothing, but “the results of my experiments on the effects of bleeding in inflammatory conditions are so little in accord with common opinion [those who were bled were more likely to die, he found] that it is only with hesitation that I have decided to publish them. The first time I analyzed the relevant facts, I believed I was mistaken, and I repeated my work but the result of this new analysis remains the same.”
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These results led to howls of outrage from physicians who claimed that it was not possible to practice medicine by numbers, that the duty of physicians was always to the patient in front of them rather than to the population at large, and that every doctor had to be guided by what he found at the bedside.

Ironically, it was Louis and Pinel who were calling on physicians to be guided by what was actually happening to their patients, not by what the medical authorities traditionally had to say. As the marketers from GlaxoSmithKline and other companies might have told Louis and Pinel, though, for many physicians to be convinced there has to be a theory, a concept about the illness and its treatment, to guide the doctor. “The practice of medicine according to this [Louis's] view,” went one dismissal, “is entirely empirical, it is shorn of all rational induction, and takes a position among the lower grades of experimental observations and fragmentary facts.”
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