Pharmageddon (14 page)

Almost all the drugs trials now conducted are done by their manufacturers to get their compounds on the market or to establish a market niche. Once completed, these trials mark the point at which any science stops—a drug has been shown to “work,” companies say, and the job of doctors is now to prescribe it—whereas entry into the market should mark the point where science begins to establish who benefits from which drug. If only a small number of people respond specifically to a statin for cholesterol levels or a biphosphonate for osteoporosis, we should be identifying who these specific responders are. Until we answer this we remain in the position of congratulating ourselves on the use of plaster casts when in three out of four cases they have been put on the wrong limb—but of course this is the question no company wants answered.

Even without fully understanding why a treatment helps, though, more can be done to improve how it is used. For instance, we have many different kinds of blood pressure medication, but almost no research to discover how they compare or who they suit. The first thiazide antihypertensives in the 1950s were succeeded by James Black's propranolol in the 1960s and 1970s, the ACE inhibitors in the 1980s, sartans in the 1990s, and a string of others, with each new drug marketed as the best. When the first proper head-to-head studies were done fifty years later, they showed that, in fact, the thiazides were the most effective and the safest.
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For fifty years we have used a succession of ever more expensive treatments, while the best and safest and least expensive treatments fell out of favor.

Similarly, the SSRIs in clinical trials got far fewer severely depressed patients well than older antidepressants.
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But to get on the market they did not have to be compared to an older drug; they had only to beat the placebo. As a result of marketing, the more recent drugs have almost completely replaced older antidepressants, even for the most severe depressions, for which there is not a scrap of evidence the newer drugs work.

The story is similar for the analgesics, drugs for osteoporosis, blood- sugar-lowering drugs, the antipsychotics, and almost every other best- selling drug. Best-sellers are not best sellers because they are in fact better than the drugs previously available. Yet in all these areas of treatment, doctors who are supposedly following the evidence make the latest drugs into best sellers.

There is more going on here than simply squandering money in the pursuit of the trivial (though profitable) new drug or giving patients suboptimal medicine. Company trials have radically changed how doctors treat patients. Before 1962 when the FDA stepped in and required companies to provide evidence of trials to bring their drug on the market, doctors for centuries had to learn how to use a drug when it became available. Digitalis offers a good example. This drug works by removing excess fluid from the body in cases of heart failure, but as with all drugs, digitalis came with problems. So doctors, when giving it, would typically start at a low dose, and work upward depending on how the patient responded.

But in company trials, no company is prepared to take a chance that their drug won't beat the placebo, so they err on the side of a higher or more poisonous dose. If these studies get the drug on the market, the trial results are then taken to mean that doctors should use the dose of the statin, analgesic, or antidepressant used in the trial, even though it is likely to be too high for many people. On the basis of early trials, the thiazides were given for hypertension in doses ten times higher than necessary, for example, while the lowest dose of Prozac for depression was four times higher than many people needed.
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Once a drug is launched, companies could run studies to find the right starting dose or determine which drug suits which kinds of patients, but marketing departments have resisted studies of lower doses of a drug—on the grounds that they want to keep things simple for doctors. Their dream is one-size-fits-all treatment, and they refuse to make lower dose formulations of a medicine available. In this way companies are, in essence, removing the craft as well as the art from medicine and encouraging overmedication.

But there are even bigger problems than this. Company trials trap both doctors and patients into treatment with the wrong medication. The antipsychotic group of drugs shows how badly wrong things can go. The first of these was chlorpromazine, a drug discovered in 1952 and widely cited as rivaling penicillin as a key breakthrough in modern medicine. It and succeeding tranquilizers had a magical effect on manic and delirious states and on some acute psychoses, sometimes restoring patients to normal functioning within days, or weeks, sometimes in hours. This was not a matter of small changes on a rating scale; there was no question but that chlorpromazine worked.
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Its French discoverers were sure, however, that it was not a cure for schizophrenia. In some cases it provided a useful tranquilization, but in up to a third of schizophrenic patients it made their condition worse, and in a further third the benefits were minimal. Nevertheless, most company trials to bring the successors of chlorpromazine to the US market were undertaken in schizophrenia. When responders, minimal responders, and those who got worse were combined, the results for these drugs could be shown to be, on average, marginally better than for the placebo—which was all it took to get these drugs on the market. These results, reinforced by rebranding the tranquilizers as antipsychotics, made it seem these drugs “worked” for schizophrenia. For the FDA, and most doctors, the one in three patients who got worse on treatment vanish into a statistical ether—but these patients don't vanish from the hospital and the clinic.

The antipsychotics are drugs to use judiciously. They increase rates of heart attacks, strokes, diabetes, and suicides. Studies that have examined longer term outcomes for patients on these drugs universally show a reduction in life expectancy measured in decades, not just years.
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This is not an argument against their use, but it is definitely an argument for ensuring that they actually are producing benefits that warrant the risks undertaken. Unfortunately, even when faced with a patient who is not responding or responding negatively and for whom therefore the treatment should be stopped, the drug often keeps being given. Nursing staff, hospital administrators, relatives, and other doctors find it inconceivable that a doctor might not give a drug that “works” to a patient who is so clearly ill with the condition that the drug supposedly benefits—to the point that a refusal to prescribe is in many settings getting ever closer to being grounds for dismissal.

In similar fashion, the company trials of statins for lowering cholesterol, biphosphonates for osteoporosis, and for other medicines that suggest these drugs “work” exert pressure on clinicians to prescribe and patients to acquiesce in treatment. This pressure cannot simply be put down to corruption by the pharmaceutical industry. No one, it seems, wants a doctor to wait judiciously to see if a treatment is really warranted. We might like the idea of an Alfred Worcester in books or movies but not in real life.

In addition to these serious consequences for medical care, there is a huge ethical problem with company trials. Randomized controlled trials began in conditions of scarcity after World War II, when those who volunteered to be left untreated or to get a potentially dangerous new treatment did so for the sake of their families, their relatives, or the communities from which they came. They consented, in other words, because they thought they were helping to improve medical care, and in so doing they did in fact lay the basis for our current freedom from infectious diseases, malignant hypertension and other disorders, and our better life expectancies in the face of tumors. The same spirit is now invoked when patients are asked to consent to company-run trials. But they are not told that these studies are designed to secure a business advantage, that they will lead to marketing that often substitutes giving drugs for caring, that far from benefitting their communities the studies may result in treatments that shorten lives, or that data from these studies may be sequestered so that nobody ever finds out about the side effects of treatment. They never get a chance to decide freely whether to consent to this or not.

If the primary ethical as well as scientific purpose of controlled trials was initially to debunk unwarranted therapeutic claims, companies have transformed them into technologies that mandate action. The method originally designed to stop misguided therapeutic bandwagons has in company hands become the main fuel of the latest bandwagons. A method that is of greatest use when it demonstrates drugs either do not work or have minimal effects has become a method to transform snake oil into a must-use life-saving remedy. In the process, evidence-based medicine has become evidence-biased medicine.

EVIDENCE-BIASED MEDICINE

In 1972, two decades after randomized controlled trials came into use, Archie Cochrane, a physician based in Cardiff, Britain, who had worked with Austin Bradford Hill when the first clinical trials were being set up, published an influential book on the role of evidence in medicine. The vast majority of medical services and procedures still had not been tested for their effectiveness, he noted, while many other services and procedures that had been tested and shown to be unsatisfactory, still persisted.
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Cochrane was a randomization extremist; in his view, not only doctors but also judges and teachers should be randomizing what actions they took to see what worked, but all three unfortunately had God complexes—they “knew” what the right thing to do was. As late as the 1980s, Cochrane claimed fewer than 10 percent of the treatments in medicine were evidence based.
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Cochrane made it clear that using controlled trials to evaluate treatments was not a matter of dragging rural hospitals up to the standards of Harvard or Oxford. Rather, mortality often seemed to him greater where there were more medical interventions rather than fewer. After coronary care units (CCUs) came into fashion in the 1960s, for instance, he suggested randomizing patients who were having heart attacks to treatment in a CCU versus home treatment. Cardiff physicians refused to participate on the grounds that CCUs were so obviously right. Cochrane ran the trial in neighboring Bristol instead. When he first presented the results, he transposed them so that the home treatment results, which were actually the better ones, appeared under the CCU column and vice versa. His audience demanded an instant halt to home treatment. But the response was quite different when the “error” was corrected and it was made clear that the data favored home treatment. To this day there is a reluctance to believe that home care might be better than care in a CCU.

Iain Chalmers, a perinatologist and health services researcher from Oxford picked up the baton from Cochrane. He was similarly struck that physicians often seemed slow to implement procedures that had been shown to work and instead stuck with approaches that had not been shown to work or had been shown not to work. His concern lay not just in encouraging trials but in accessing the information from trials that had already been done.
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Everyone knew there had been an explosion in the medical literature since World War II, but efforts to collect reports of clinical trials began to reveal that there were far fewer published trials than many had thought. Some of the trials done had been published multiple times, while others had not been published at all.

Many of the articles that dictated clinical practice, furthermore, were framed as review essays, published under the names of some of the most eminent academics in the field, but on closer inspection, these often lengthy articles with their impressively long reference lists espoused only one point of view of a topic. These academics were not systematically considering all the available research, in other words. These were not scientific reviews—they were rhetorical exercises. Recognition that a scientific review should be systematic led Chalmers to set up the Cochrane Center in 1992 dedicated to amassing all available clinical trial evidence in every branch of medicine, even when the evidence had not been published.

It was David Sackett at Canada's McMaster University, outlining a program for educating medical students to practice according to the evidence, who branded the new dispensation evidence-based medicine.
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When it came to considering the evidence, Sackett drew up a hierarchy in which systematic reviews and randomized controlled trials offered gold standard evidence, while at the bottom of the hierarchy came individual clinical or anecdotal experience. This was a world turned upside down. Just a few years earlier, clinical judgment had been seen as the height of medical wisdom.

The implication was that we should submit every procedure to controlled trial testing. Even if newer treatments were more expensive as a result, in due course the health services would gain because money would be saved as ineffective treatments were abandoned and better treatments reduced the burden of chronic illnesses. This seemed to be a win-win claim for those paying for health services, for physicians and their patients, as well as for scientific journals. It quickly became almost impossible to get anything other than clinical trials published in leading journals.

When Cochrane advocated for randomized controlled trials, Chalmers campaigned for comprehensive collection of their results, and Sackett drew up his hierarchy of evidence placing trial results at the top, no distinction was drawn between independent and company trials. Controlled trials were controlled trials. It seemed so difficult to get doctors to accept the evidence that their pet treatments didn't work, that any indication that doctors were practicing in accordance with clinical trial evidence seemed a step in the right direction.

There are two problems with this approach. The first applies to both independent and company trials—namely, that we appear to have lost a sense that, other than when they demonstrate treatments don't work, what controlled trials do primarily is to throw up associations that still need to be explained. Until we establish what underpins the association, simply practicing on the basis of numbers involves sleepwalking rather than science—equivalent to using plaster casts indiscriminately rather than specifically on the fractured limb.