CLAUDE BERNARD, An Introduction to the Study of Experimental Medicine (1865)
To the proponents of evidence-based medicine, the tortured history of the clinical trial is an epic of an almost biblical nature. Its eventual acceptance, in the late twentieth century, as the gold standard of medical research is the triumph of rational medicine over quackery, dimly foreseen by such early prophets as Jurin, Semmelweis and Lister who were, during their day, lone voices crying in the wilderness.
The truth is not quite so simple. The rise to dominance of the clinical trial has not been an unambiguous victory for rational medicine. Beecher saw it as a way of overcoming centuries of blind appeal to authority and intuition. Ironically, however, the final acceptance of placebo controls owed more to Beecher’s own authority and intuition than to proper scientific evidence. Beecher was a respected researcher, so nobody paused to question the accuracy of his 1955 paper. Nobody suspected that he had reshaped the data so that they would support his prior intuitions about the power of the placebo effect.
The result is that, fifty years later, many medical researchers accept without question that placebo effects are ubiquitous and powerful. Take this dramatic passage by two experts on alternative medicine, Dr Robert Buckman and Karl Sabbagh, for example:
… placebos are extraordinary drugs. They seem to have some effect on almost every symptom known to mankind, and work in at least a third of patients (usually) and sometimes in up to 60 per cent. They have no serious side-effects and cannot be given in overdose. In short, they hold the prize for the most adaptable, protean, effective, safe and cheap drugs in the world’s pharmacopoeia. Not only that, but they’ve been around for centuries, so even their pedigree is impeccable.13
A respected biologist states that ‘placebo medical procedures have proved to be effective against a wide range of medical problems including chronic pain, high blood pressure, angina, depression, schizophrenia and even cancer’.14 A leading authority on alternative medicine goes even further, claiming that ‘the range of susceptible conditions appears to be limitless’.15
In fact, almost all the supposed ‘demonstrations’ of the placebo effect on which these hyperbolic claims are based turn out to embody the same flaws that bedevil Beecher’s paper. Whenever people in the placebo arm of a clinical trial get better, they assume that this improvement is due entirely to the placebo, without considering any of the other possible causes – spontaneous remission, natural fluctuation of symptoms, other treatments, and so on. If this kind of sloppy thinking was applied to the testing of real drugs, it would be spotted immediately. When it comes to testing placebos, however, rigour goes out of the window. There seems to be a clear double standard in medical research.
To be consistent, we should apply the same rigorous scientific principles to the study of placebos that we apply to the evaluation of real treatments. No scientist would accept claims advanced on behalf of a new drug without evidence that people who are treated with it are at least more likely to get better than those who remain untreated. It should be no different when it comes to the claims made on behalf of placebos. In other words, to calculate the true placebo effect, the rate of spontaneous remission shown by those receiving no treatment at all must be subtracted from the observed placebo effect. Without a no-treatment arm, there is no way to distinguish the effects of the placebo from the natural course of the disease and various other confounding variables, such as other treatments taken outside the context of the trial.
In fact, no-treatment groups are rarely included in clinical trials today. One survey of the medical literature between 1986 and 1994 found that fewer than 4 per cent of clinical trials and meta-analyses published during that period included both placebo and untreated groups.16 The result is that, despite half a century of placebo-controlled clinical trials, we have surprisingly little solid data about the extent of the placebo response. The lack of such data has even led a few sceptics to argue that the placebo response does not really exist. They claim that the improvement shown by patients receiving placebos in clinical trials is due entirely to spontaneous remission and random fluctuations in the course of the disease.17
This is going too far. Solid evidence in favour of the placebo response is hard to find, but it does exist. Some studies do include no-treatment control groups, and some of these show that patients receiving placebos do better than those who receive nothing. But they are few and far between, and they do not always make sure that the only difference between the placebo group and the no-treatment group is the placebo itself. For example, the patients in the placebo group may receive all sorts of extra attention that those in the no-treatment group do not. As a result, we cannot really be sure that any improvement they may show, compared to the no-treatment group, is due to the placebo rather than to the various other things that they received, but which the no-treatment group did not.
THE LIVES TO COME
Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.
WORLD MEDICAL ASSOCIATION, Journal of the American Medical Association (1964)
There are obvious ethical problems with the idea of using a no-treatment control group. To withhold all medical treatment from a group of patients, simply for the sake of scientific research, seems to flout some of the most basic principles of medical ethics. Similar concerns were raised in the late 1940s and early 1950s when Gold, Beecher and others argued for the need to include placebo control groups in clinical trials. How could doctors justify doing nothing for patients who were clearly in need of help, when active treatments were readily available?
As we have already seen, Beecher answered these objections by claiming that giving patients placebos was far from ‘doing nothing’. If placebos were as powerful as he argued, then the patients in the control group would not fare much worse than those in the experimental group. The same cannot be said, of course, for those in a no-treatment group. In that case, doctors do not even give a placebo. This seems much harder to justify.
Actually, there are several considerations that make the inclusion of no-treatment groups in clinical trials less ethically dubious than it may initially appear. First, the term ‘no-treatment group’ is misleading, since patients in such groups need not be deprived of all medical care. In fact, if we are simply interested in measuring the placebo effect, the ideal situation would be for the ‘no-treatment’ group to be treated in exactly the same way as the placebo group, with the sole exception of not receiving the placebo. Only then could researchers be confident that any differences between the recovery rates of the two groups were due to the administration of the placebo and not some other factor. So the no-treatment group should, ideally, be visited by the doctor as frequently as the placebo group, be given the same encouragement and support, and so on. It would be more accurate to call this a ‘no-placebo’ group rather than a ‘no-treatment’ group.
There is also the possibility that the experimental treatment is not, in fact, effective, in which case those who are not receiving it do not suffer by comparison with those who are. This also applies to the placebo treatment. If the placebo effect really is just a myth, as the critics claim, or if placebos simply do not work for the particular medical condition being examined, then giving patients placebos really is not much better than giving them nothing at all. It may make them feel slightly better, but it would have no effect on their disease. In this case, Beecher’s justification for including placebo groups in clinical trials falls apart.
There is another ethical consideration, though, that applies equally to both placebo control groups and no-treatment arms, irrespective of whether the placebo effect is real or not. This is the idea that the needs of current patients should be balanced against those of future generations. Depriving a small group of patients for a short time of all treatment might be defensible