September 17, 2021

How much of the measured treatment response in clinical trials is due to the placebo response?

Clinical trials measure efficacy of experimental therapies by comparing outcomes in patients receiving therapeutic interventions (treatment response) with patients receiving placebo (placebo response). In doing so, it immediately becomes clear that the treatment response is comprised, in part, by placebo response – and that the only way to determine the true treatment effect is to understand the contribution of the placebo response. 

The placebo response, however, is itself complex phenomenon that is defined by clinical improvement resulting from the combination of several components. Patients in the control group that receive no intervention or treatment but placebo, demonstrate the combined contributions of natural history and evolution of the disease, regression to the mean and the patient’s response to participating in a clinical study – or study effect. The study effect can include the Hawthorne effect (change in the patient’s symptoms or outcomes as a result of being observed, e.g. the “white coat” effect on blood pressure) and improvement in the patient’s condition resulting from the increased medical care that is generally provided in clinical studies.  Patients that receive placebo experience all these effects observed in the no treatment group coupled by the placebo effect – or the true psycho-social-biological phenomenon that is intrinsic to the patients and influenced by the patient’s individual personality, expectations, etc.  The overall improvements observed the placebo group are generally referred to as the placebo response.  Patients receiving a treatment or intervention experience all these effects observed in the placebo group along with their individual response to treatment

While the placebo response clearly comprises some proportion of the measured treatment response in patients receiving experimental therapies, it is difficult to quantify this precisely. A recent paper by Haflioadottir, et al.1 attempted to address this question by retrospective meta-analysis, in the paper “Placebo response and effect in randomized clinical trials: meta-research with focus on contextual effects”. This study evaluated results from a total of 186 clinical trials that contained no treatment, placebo treatment and a therapeutic intervention. All trials evaluated patients with either somatic or psychiatric diseases or symptoms and included interventions that were either pharmacologic, physical (e.g. surgical) or psychological. In these studies, the placebo response contributed, on average, 54% of the measured treatment response regardless of indication, outcome, study design or year of publication. In trials with pharmacologic interventions only, the relative importance of the placebo response increased to 61% of the measured treatment response. The variation in placebo response between studies could be partially explained by the following factors: concealment of allocation (e.g. concealment of randomization to prevent selection bias), blinding of the outcome assessor, lower mean age of participants and higher proportion of females. In other words, trials in which patient randomization into groups is concealed and outcome assessors are properly blinded tend to result in higher placebo response. 

Several other interesting trends were noted in the study data: 

  • Placebo response was higher in trials where patients were not informed that the study contained a placebo arm 
  • Placebo response was noted in outcomes that are laboratory measured (i.e. objective outcomes), and comprised approximately 30% of the measured treatment response 
  • Trials for chronic conditions yielded lower placebo response than those for non-chronic conditions.  

The results presented in this paper are, not surprisingly, comparable but lower than similar analyses that focused on specific indications. In fibromyalgia, an average of 60% of the treatment response can be attributed to placebo response across endpoints, but these results varied by endpoint (pain, fatigue, Fibromyalgia Inventory Questionnaire (FIQ))2. In osteoarthritis, an average of 75% of the treatment response for pain endpoints can be attributed to the placebo response, which varied by route of administration and treatment type3. In depression, 68% of the measured treatment response was attributable to the placebo response, which was highest for the primary outcome (depression) but also substantial for anxiety, general psychopathy and quality of life4

While the placebo response has long been recognized as a significant issue in clinical trials – and a major cause of clinical trial failure5– this study provides quantitative evidence of its significance across indications. With these data, the significance of the placebo response in clinical trial success or failure cannot be ignored.  Several historical approaches have attempted to reduce the magnitude of the placebo response – for example, by training patients to report symptoms more accurately – but these focus on single component of the entire placebo response and thus are limited in impact. So far placebo effect, which is an important contributor to placebo response and is an inherent patient characteristic, has never been considered. A more effective approach would be to account of the placebo response and placebo effect, when analyzing data. Tools4Patient’s Placebell©™ solution is a method that uses machine learning along with psychological profiling using our proprietary Multi-Dimensional Psychological Questionnaire (MPsQ).  Because Placebell©™ models are trained using data from actual randomized, placebo-controlled clinical trials, they account for several components comprising the placebo response, ranging from regression to the mean to the patient-specific placebo effect.  Contact us today to learn how Placebell©™ can improve clinical trial success. 

Reference:

​1. Hafliðadóttir SH, Juhl CB, Nielsen SM, et al. Placebo response and effect in randomized clinical trials: meta-research with focus on contextual effects. Trials 2021 22:1. 2021;22(1):1-15. doi:10.1186/S13063-021-05454-8 

2. Whiteside N, Sarmanova A, Chen X, et al. Proportion of contextual effects in the treatment of fibromyalgia—a meta-analysis of randomised controlled trials. Clinical Rheumatology. 2018;37(5):1375. doi:10.1007/S10067-017-3948-3 

3.  Zou K, Wong J, Abdullah N, et al. Examination of overall treatment effect and the proportion attributable to contextual effect in osteoarthritis: meta-analysis of randomised controlled trials. Annals of the rheumatic diseases. 2016;75(11):1964-1970. doi:10.1136/ANNRHEUMDIS-2015-208387 

4.  Rief W, Nestoriuc Y, Weiss S, Welzel E, Barsky AJ, Hofmann SG. Meta-analysis of the placebo response in antidepressant trials. Journal of Affective Disorders. 2009;118(1-3):1-8. doi:10.1016/j.jad.2009.01.029 

5.  Dumitrescu TP, McCune J, Schmith V. Is Placebo Response Responsible for Many Phase III Failures? Clinical Pharmacology and Therapeutics. 2019;106(6):1151-1154. doi:10.1002/cpt.1632 

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