Can the placebo effect really be controlled in clinical trials?

The placebo effect is a psychological phenomenon where patients experience improvements in their condition simply by believing they are receiving treatment rather than from the treatment itself. It’s an issue that has long fascinated and challenged researchers, and it poses a significant hurdle when trying to accurately evaluate the efficacy of a new treatment against a placebo.

The impact on study results

Since the 1950s, placebo-controlled trials have formed the basis for the majority of Phase 1 clinical trials. They have played a crucial role in clinical trials, helping researchers understand the safety and efficacy of new medical treatments.

However, the placebo effect can significantly impact study results by influencing patient-reported outcomes, such as pain levels, mood, and overall feelings of well-being. In some cases, patients receiving a placebo may even report similar improvements to those receiving active treatment, leading to inappropriate estimates of treatment efficacy. This can then obscure the true benefits of the tested treatment, hinder the development of effective therapies, and lead to the premature discontinuation of potentially efficacious treatments.

The placebo effect is also not limited to subjective measures but can also influence objective indicators like biomarker levels or physiological parameters. Studies have shown that the mere act of administering a placebo, even just by verbal suggestion, can trigger neurobiological mechanisms, such as the release of endorphins or activation of specific brain regions associated with pain modulation, and lead to real physiological changes in the body (1).

The scale of the issue

The magnitude of the placebo response varies depending on factors such as the condition being studied, patient expectations, study design, and the intensity of the placebo intervention. Meta-analyses across different therapeutic areas have demonstrated that placebo effects can be substantial, with some studies reporting improvements of up to 28% in placebo-treated groups (2).

The placebo response also appears to be increasing over time in clinical trials, a phenomenon often referred to as the "placebo drift." Some antidepressant clinical trials have reported a “placebo drift” in that the placebo response rate is higher than in trials conducted 30 years ago, with a slight lowering of the response to antidepressants and a substantial narrowing of the drug-placebo difference (3).

This trend has been attributed to several factors, including increasing patient expectations, enhanced study procedures, and cultural influences surrounding medical treatments.

MAC’s Chief Scientific Officer, Dr. John Connell, voices his concerns:

Ethical considerations

The use of placebos in clinical trials raises ethical concerns regarding patient welfare and informed consent. While placebos are essential for rigorously evaluating new treatments, their administration to patients with serious or life-threatening conditions can raise ethical dilemmas.

Informed consent is a cornerstone of ethical research, requiring participants to be fully aware of the potential risks and benefits of participating in a study. However, disclosing the use of placebos to participants may compromise the blinding of the study, influence the placebo response, and confuse the results.

Withholding potentially effective treatments from participants assigned to the placebo group raises questions about the ethicality of exposing individuals to unnecessary suffering or denying them access to potentially life-saving interventions.

However, some researchers argue that the placebo effect can be an effective treatment, that its use does not always entail deception, and that, in select cases, the use of a placebo may even be morally imperative (4).

Controlling the placebo effect

Controlling the placebo effect in clinical trials should begin with implementing rigorous study designs, such as randomisation, blinding, and placebo controls. Additionally, clear communication with participants about the possibility of receiving a placebo and incorporating objective endpoints can help mitigate the influence of patient expectations on study outcomes.

Dr. Connell leads MAC’s Scientific Solutions, which offers services such as psychological assessments, human models of disease, and placebo training for employees and participants. At MAC, we use a three-pronged approach. First, we train investigator site employees to be aware of the dangers of an increased placebo response and the steps that can be taken to minimise the effect. Secondly, we make sure participants know how to report key study endpoints consistently and reliably. And finally, we train study participants on the importance of accurate reporting of their condition at all times.

This strategy helps our study teams avoid speculation on trial effects and helps manage participant and team expectations of the study treatment. Using this approach, MAC has successfully managed the placebo response in many studies across multiple countries and sites.

Supporting reliable and accurate outcomes

Moving forward, researchers will continue to explore innovative strategies for minimising the placebo effect while upholding ethical standards in clinical research. This must include transparent communication with participants, a rigorous study design, and the incorporation of objective endpoints to complement patient-reported outcomes.

By addressing these challenges, the scientific community can improve the reliability and validity of clinical trial results, ultimately advancing the development of safe and effective treatments for patients worldwide.

You can read more about the training services we offer on how to manage the placebo effect here.

If you would like to speak to us about our experience in this area or if you would like more information on how we can support your study, contact us here.

(1) The National Library of Medicine, 2019.

(2) The National Library of Medicine, 2010.

(3) The National Library of Medicine, 2002.

(4) The ethics of the placebo in clinical practice, BMJ Journals, 2004.