Placebo and Nocebo Response Mitigation

Empirical Strategies to Mitigate Placebo and Nocebo Effects

Apex is committed to enhancing our understanding of the causes and implications of the placebo and nocebo effects within central nervous system and internal medicine clinical trials and developing solutions to mitigate them. Under the leadership of Elan Cohen, Ph.D., Principal Investigator at HRI and a thought leader in clinical rater assessment services, Apex researchers meet regularly to discuss and develop systemic strategies to help overcome the primary causes of the placebo and nocebo responses or Placebo Response Factors (PRFs), namely subjects’ naivety of the placebo, expectation bias, misconception of expected interactions with research site staff, and uncertainty of their role in the trial.

A significant development toward this purpose is the copyrighted Placebo-Control Reminder Script (PCRS). The PCRS is a methodical instrument which carefully reviews the PRFs with trial participants; it is diligently read to each study subject starting at the SCR Visit and at all study visits thereafter before any efficacy scales are administered.

Apex has engaged in thoroughly empirically exploring the efficacy of the PCRS to manage placebo and nocebo responses among trial participants with major depressive disorder (MDD) and schizophrenia/schizoaffective disorder as well as among migraine sufferers:


The current PCRS results have prompted the FDA to review this tool and its associated research, commenting: “It’s amazing how a simple intervention like the PCRS can be so effective in reducing placebo response!” (J. Toure, FDA Sr. Policy Advisor of Division of Psychiatry Products, email communication dated March 27, 2019) and “We [FDA] found the approach interesting and that a simple intervention like education can be quite impactful.” (J. Toure, FDA Sr. Policy Advisor of Division of Psychiatry Products, email communication dated April 12, 2019).

Following the publishing of our empirical findings and the FDA’s appraisal of the PCRS, sponsors and CROs have expressed great interest in applying the script to their respective clinical trials, and as such, Apex licenses the PCRS for such purposes. The license includes actual PCRS source specifically tailored for the respective clinical trial design and methodology to be read by the site staff member (typically the psychometric rater administering the primary efficacy scale in the study) as well as a PowerPoint slide deck training the site staff member on using the PCRS. The PCRS has also been incorporated into a computerized tablet system where the script interaction between the rater reading the script to the subject and the participant summarizing the primary concepts of the PCRS (to exhibit a meta-understanding of the script, a key efficacy aspect to this instrument) is recorded for quality checks and sponsor review at any time.

For more information on Apex’s research in this crucial area within our industry and licensing the PCRS, please contact us.

In conjunction with our PCRS and our concerted determination to stay current on recent literature regarding theories of what promulgates placebo and nocebo responses, Apex has implemented our own proprietary Placebo-Control Daily Reminder Campaign (PCDC) for subjects participating in our Single- or Double-Blind Placebo-Control clinical trials. The PCDC involves providing such subjects with a small, convenient magnet participants take home after their Baseline Visit to place on their refrigerator (or any other convenient place where they will see the magnet daily and be reminded of its message). The campaign also involves reminding subjects of the intended message (see below) during their actual visits at our site, and as such, a banner was also created and hung in all our common areas (inpatient and outpatient facilities).

The magnet and banner indicate: “Speak Your Truth. No Expectations.*” with the smaller font at the bottom: “*Ask your Coordinator or Rater.” Why these words? Research continues to strongly show that unchecked and any level of expectations from subjects about their own improvement in a study and what they perceive from study staff as wanting them to improve or not improve during their participation has the strong potential of generating a placebo effect. An expectation is also derived from subjects forgetting they may be on a placebo and thinking that they are receiving true medicine to help them with their respective indication. While there is arguably minimal empirical evidence that shows implementing actual interventions to control and educate subjects about such expectations subsequently reduces a placebo effect (apart from our multi-site study investigating the efficacy of the PCRS to reduce the placebo effect; see posters which present our findings), it makes rational sense to incorporate such continued education in our work at Apex.

While our PCRS is read to all subjects at all our Placebo-Control study visits, this script is only provided once a week / per study visit. In contrast, the PCDC is a continual reminder to our Placebo-Control investigation subjects that we have no expectations, that they should have no expectations, and that they should simply come to the site per their study visits reporting “the truth” of their symptoms. If a subject asks any of our staff what the message means, they ardently refer to the verbiage from our PCRS, i.e., to tell the subject none of us at the site have expectations of how you should or should not be feeling because none of us here at the site know if you are randomly assigned to receive the active medication or the placebo (remind subject what a placebo is) and that their role in the study is to simply come to each visit and be truthful in describing how they are doing in regard to their symptoms.


Essential Perspectives from the End User

PCRS User Survey Obtains Raters’ Perspectives on the Tool

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The Placebo-Control Reminder Script in Depression and Psychosis Trials

An Antidote for the Placebo and Nocebo Response

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Managing the Placebo and Nocebo Perils

Applying the Placebo-Control Reminder Script in Psychosis Trials

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Broadening the Empirical Exploration of the Placebo-Control Reminder Script to Reduce Placebo and Nocebo Effects

A Preliminary Data Analysis of Subjects with Schizophrenia and Schizoaffective Disorders

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A Subject-Targeted Placebo-Control Reminder Script

An In-Depth Empirical Exploration of How Subject Characteristics Moderate Placebo Response

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Enhancing Subjects’ Awareness of Key Placebo Response Factors

The Importance of Implementing a Brief Educational Placebo Response Video

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Taming the Placebo Effect in Depression Clinical Trials

The Methodological Implementation of a Placebo-Control Reminder Script

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A First-Time Investigation of a Subject Intervention to Reduce the Placebo and Nocebo Effects

A Multicenter, Randomized, Single-Blind, All Placebo Study of a Placebo-Control Reminder Script for Subjects with Major Depression

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Can subjects with major depression learn about key placebo response factors?

The effect of an educational placebo response video

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The Power of an Educational Placebo Response Video

Strengthening Subject Placebo Response Awareness Across Demographic Variables and Diagnoses

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