Competence Centre for Methodology and Statistics
I think the placebo gets a bad press with ethicists. Many do not seem to understand that the only purpose of a placebo as a control in a randomised clinical trial is to permit the trial to be run as double-blind. A common error is to assume that the giving of a placebo implies the withholding of a known effective treatment. In fact many placebo controlled trials are ‘add-on’ trials in which all patients get proven (partially) effective treatment. We can refer to such treatment as standard common background therapy. In addition, one group gets an unproven experimental treatment and the other a placebo. Used in this way in a randomised clinical trial, the placebo can be a very useful way to increase the precision of our inferences.
A control group helps eliminate many biases: trend effects affecting the patients, local variations in illness, trend effects in assays and regression to the mean. But such biases could be eliminated by having a group given nothing (apart from the standard common background therapy). Only a placebo, however, can allow patients and physicians to be uncertain whether the experimental treatment is being given or not. And ‘blinding’ or ‘masking’ can play a valuable role in eliminating that bias which is due to either expectation of efficacy or fear of side-effects.
However, there is one use of placebo I consider unethical. In many clinical trials a so-called ‘placebo run-in’ is used. That is to say, there is a period after patients are enrolled in the trial and before they are randomised to one of the treatment groups when all of the patients are given a placebo. The reasons can be to stabilise the patients or to screen out those who are poor compliers before the trial proper begins. Indeed, the FDA encourages this use of placebo and, for example, in a 2008 guideline on developing drugs for Diabetes advises: ‘In addition, placebo run-in periods in phase 3 studies can help screen out noncompliant subjects’.
However, there is a problem: what do you tell the patient? Do you explain that a placebo will be given during a run-in period? This would clearly vitiate the purpose of having the run-in. Do you lie to the patient and seek to make him or her believe that an active treatment is being given? This is a clear violation of the principle of informed consent. Most trialists seem to opt for a third option: they somehow fudge the issue and hope that the patient won’t guess. But suppose the patient says to the physician ‘I understand that in many trials there is a placebo run-in; is that the case here?’ What does the physician reply? Clearly the trial must be carried out in the hope that this question is not put and the fact that the trialist has this hope shows that informed consent is not being practised.
Quite different is the use of placebo in the trial proper. Here the treating physician can explain to the patient that he or she will be randomly allocated either placebo or active treatment and neither patient nor physician will know. This is a strategy of mutually agreed deception rather than covert deceit and does not violate informed consent.
The standard we should observe in running clinical trials is ‘open protocol, hidden allocation’. We should hope that patients understand what is being done rather than fearing that they may find out. Placebo run-ins are in clear violation of informed consent and it is a scandal that they continue to be used and that regulatory authorities continue to recommend them.
Stephen: Thanks so much for this. I take it that you regard it as unethical because the patient is not told that, at this point, (a) she is only being tested for compliance ability, and (b) everyone is getting a placebo. Were she told these things, it might preclude a reliable assessment of compliance. But since (you’ve said elsewhere) the goal is determining what the drug can do (not what it is likely to do) then why not tell them they’re going to first be in a run-in trial?*
I’m no ethicist, but it is interesting to have this matter turn on whether some patients are getting the drug. Perhaps having identified some compliants, the new group could include some to be tested for compliance some to be tested on the drug (with some assignment protocol). How to evaluate the result would be a statistical issue.
Aside: It might be interesting to compare if the compliant ones do better than the less compliant ones on the placebo.
*Is the information of average level of compliance (shown by the run-in stage) taken account of in assessing the drug, since you’re always going to have that?