I think it is important that the language used in patient information leaflets reflects the fact that, in clinical trials, it is usually not known whether the drug will work any better than a placebo or not.
Dr Felicity Bishop
While placebos have been thought of as medically ineffectual, taking the form of inert drugs or sham procedures, the physical and psychological benefits that are often conferred by placebos on participants in clinical trials are well-known and well-documented.
An analysis conducted by researchers at the University of Southampton in collaboration with others at Harvard Medical School and Northern Arizona University has found that the potential health changes caused by placebos are often bypassed or altogether ignored in the literature received by participants before a trial begins.
This information bias in favour of the drug or treatment being tested – the target treatment – may have a number of implications for the outcomes of trials wherein a placebo is used, but the researchers are also concerned that the issue constitutes a major breach of the proper ethical codes which all clinical trials must subscribe to.
I spoke to Dr Felicity Bishop, lecturer in health psychology at the University of Southampton and lead author of the study, who began by explaining the potential effects of placebos.
"Placebos can have all sorts of effects depending on the trial conditions, the context, the symptoms, the setting and all kinds of other factors," Dr Bishop stated. "We know that placebos can reduce the effect of psychological symptoms like depression, and we know they can influence pain too. Placebo analgesia is a particularly well-known phenomenon, and neuroscientists have been mapping the brain pathways through which placebos can reduce the experience of pain."
Placebos do affect people’s health, and this is why they are used in clinical trials, Dr Bishop explained. The idea is to try to identify the specific effect that the target drug or treatment has over and above
any additional non-specific or placebo effects that it might also have.
"The effect of any drug or treatment is made up of a specific pharmacological effect produced by the active ingredient, and the other non-specific or contextual effects. These can come from, for example, the act of receiving treatment, the feeling of being cared for by the doctor, having someone give you attention, or from expecting or hoping to get better.
"All these factors which we term placebo effects have an impact not only if you give someone a placebo, but if you give them the ‘real’ drug as well. That’s why we have placebo groups in trials; so that it is possible to subtract those effects away in order to determine what the specific effect of the ‘real’ treatment is."
At the moment the information given in leaflets for patients in clinical trials largely ignores the effects of placebos, according to the analysis carried out by Dr Bishop and her colleagues. They examined the wording of 45 participant information leaflets approved for use in trials involving placebos as controls that were listed on the UK Clinical Research Network Database. I asked why it is so important that patients are made aware of the possible health effects of placebos.
"In a typical clinical trial where a placebo is used, patients have a 50 per cent chance of getting the placebo as a control treatment and a 50 per cent chance of getting the drug or treatment being trialled," Dr Bishop replied. "At the moment, information leaflets give participants a lot of information about the new drug that is being trialled. They understand why that drug might work, they understand the effects it might have on them – and this is a new drug so we don’t know for sure that it will have these effects – and they understand the possible mechanisms at work and the possible side-effects it could have.
"However, we found that patients are told very little about the placebo. This means that they don’t know in advance that if they get the placebo during the trial they might still experience health benefits or even side-effects. In essence, patients are consenting to the chance of getting the ‘real’ drug, but are not really giving informed consent to the chance of getting the placebo. Hence we feel that there is an ethical issue here.
"There is also a scientific issue in that this might be having an impact on the outcome of trials. This is a complicated problem and largely hypothetical, but we think that, where it is the case that patients have these strong expectations and beliefs about the real treatment, it might lead to patients guessing which treatment they are on – known as unblinding – which would introduce bias into the results of the trial."
The study observed the use of words such as ‘genuine’ and ‘real’ to describe the target in patient literature, whereas the placebo – if it was referred to directly at all – was often characterised as ‘fake’ or a ‘dummy’ treatment. It was also found that the desirability of receiving the target treatment over the placebo was emphasised.
"I think it is important that the language used in patient information leaflets reflects the fact that, in clinical trials, it is usually not known whether the drug will work any better than a placebo or not," Dr Bishop stated. "I think if you place too much emphasis on describing the drug and don’t give any background or rationale about the placebo being used, you are not fully representing the uncertainty that exists about the possible effects of the drug in relation to the known effects that placebos can have."
I asked Dr Bishop whether, from a researcher’s perspective, it is more desirable for the patient to believe that a placebo will or will not have an effect, given the impact that this belief might have on trial outcomes.
"I think you could see it both ways. Some researchers might want to minimise people’s beliefs about the placebo in an attempt to maximise the difference between the two groups, but that’s very hypothetical and we don’t know whether researchers are doing this or what effect it would have on the trial outcomes."
The research team argue that the informed consent of participants is jeopardised if they do not receive a full and fair description of the effects a placebo may have. More research into alternatives for participant literature will be needed, Dr Bishop told me.
"We are about to start a small project to develop test different forms of wording on people because we would like to be able to provide some evidence-based suggestions on how to make patient information leaflets better.
"I think it will also be very important to engage the research ethics committees in this area, because it is part of their role to give approval to the documents that are used in clinical trials. They really need to be involved as well."