Administrating and Training on the Placebo-Control Reminder Script: A Deeper Dive Into the Tool’s Psychometric Properties

Apr 21, 2023 | Blog, News, Posters

CenExel is proud to highlight the poster we’re presenting at the Annual Meeting of the American Society of Clinical Psychopharmacology (ASCP), May 2023, Miami, FL.


Introduction: Placebo and nocebo responses continue to hinder potential treatment effects (Haflioadottiret al., 2021). The Placebo-Control Reminder Script (PCRS; Cohen et al., 2020) is the only empirically-validated tool found to significantly mitigate these phenomenon by reviewing factors causing placebo responses (Evans et al., 2021). The PCRS is read by the site rater to each participant throughout the study and assesses participants’ comprehension. The PCRS has been sponsor licensed in over 25 clinical trials. Assessing this tool’s face and content validity is essential for further substantiating its instrument properties (American Educational Research Association, 2014). PCRS raters were surveyed about their training and the effectiveness of the PCRS’s content, structure, phrasing, length, and administration process to mitigate placebo and nocebo responses. This gold standard method for obtaining these validities (Beck & Robert, 2001; Parrott, 1991) also addresses sponsors’ questions regarding the tool’s operational integration into trials. Methods: The PCRS User Survey assessed face and content validity, with four placebo/nocebo content experts confirming this goal. The survey contained four demographic questions, ten 5-point Likert items regarding raters’ views about training and face/content validity principles, and three open ended questions. Sponsors who licensed the PCRS since 2017 agreed to (a) send us the email addresses of the PCRS raters to be emailed a link to the SurveyMonkey questionnaire, or (b) send the survey link by the sponsor. Raters were informed of why they were receiving the survey, how their email addresses were obtained, the voluntariness and anonymity of survey completion, and the 5-minute duration of completion Results: The survey was completed by 169 raters (39% male and 61% female), with a majority (68%) working in the industry for at least 6 years and thus having ample experience to comment on the PCRS. A majority (56%) administered the tool for at least 2 years, and most used the PCRS in depression (78%) and schizophrenia (45%) trials. Rater response rate could not be specifically calculated because three sponsors sent the survey directly to raters without providing us their email addresses, but we estimate the total survey response to be 70%. Using a chi-square test, significantly more raters reported the PCRS has appropriate wording, phrasing, content, and length aimed to reduce the placebo effect, successfully assesses participants’ PCRS understanding, is a better strategy than others used in the industry to reduce the placebo and nocebo effect, and would not revise anything in the PCRS (all factors yielded p<.001). A Pearson coefficient indicated a significant positive relationship between years administering the PCRS and its ease of use (r=.27; p=.001), phrasing/wording (r=.17; p=.03), and length (r=.20; p=.008) which all complemented the tool’s intent. Significantly more raters confirmed the PCRS training was sufficient to administer the tool and that the PCRS integrated well into study procedures (all were p<.001). Discussion: A survey of experienced trial raters provided significant evidence for the PCRS’s face and content validity, noting that the instrument’s language is suitable to address its aim and the content effectively represents what it purports to mitigate. Raters who administered the PCRS longer had greater understanding of the tool’s principles than those with less years using it. Sponsors can be assured the scale does not hinder study processes.


  • The placebo response across various psychological and physiological clinical trial indications continue to permeate within our industry, leading to significant decreases in potential signal detection and thus increasing trial costs (Haflioadottir et al., 2021; Mallinckrodt et al., 2011).
    • A meta-analysis of 96 Major Depressive Disorder studies conducted between 1980 – 2005 representing 9,566 depressed participants found a significant positive correlation between placebo response and publication year (p<.001) (Rief et al., 2009). Jones et al. (2021) also found this significant correlation in 50 treatment-resistant depression trials (of 3228 participants).
    • Schizophrenia trials also experienced significant placebo response increases (Gopalakrishnan et al., 2020; Rutherford et al., 2014).
    • Among 23 antihypertensive clinical trial programs, placebo response increased significantly over time (1990-2016) without a clear explanation as to why after analyzing several physiological and non-physiological potential confounding variables (Khan et al., 2018a). Khan et al. (2018b) found similar results in 19 oral antihyperglycemic agents (23,438 participants and 50 trials).
  • Therefore, strategies to reduce placebo and nocebo effects cannot be overemphasized.
  • The Placebo-Control Reminder Script (PCRS) has been scientifically verified as a tool which significantly reduces these phenomenon in depression and psychosis indication studies (Cohen et al., 2020).
    • The PCRS is a paragraph respective of the study visit which is read by a site staff member (typically the rater) immediately before administering the primary efficacy scale and which thoroughly reviews factors established in the industry as causing placebo and nocebo responses, including expectation bias (Evans et al., 2021; Haflioadottir et al., 2021).
    • At the end of its reading, the rater assesses the participant’s comprehension of the PCRS content.
    • The PCRS has been licensed since its inception in 2017 in over 25 clinical trials across psychiatric and physiological indications (see Table 1).
  • The primary objective of the current study was to advance data on the PCRS’s psychometric property via surveying PCRS raters’ perceptions on training and administration to explore its face and content validity. Evaluating raters’ views to evaluate such validity data is a gold standard method for any ongoing full-scope instrument validation (American Educational Research Association, 2014; Parrott, 1991; Tsang et al., 2017)
  • Sponsors licensing the PCRS frequently ask about the scale’s implementation considering other study procedures. Therefore, the secondary goal of the current study was to query site raters about the operational aspects using PCRS in trials.



  • The PCRS User Survey was developed specifically for the purposes of this study with four demographic questions (e.g., gender and years working in clinical trials), ten 5-point Likert items assessing users’ views on various training and administration standards (e.g., “Agree/Disagree” regarding whether PCRS phrasing was clear and easy to understood given its intention), and three open-ended questions
  • Four placebo/nocebo response experts reviewed the PCRS User Survey to ensure questions were straightforward, unbiasedly phrased, and able to complete the objective of this investigation to assess content and face validity of the tool, as well as address sponsor questions regarding the scale’s implementation respective of other study procedures
  • To send the survey, all sponsors who have licensed the PCRS were contacted to obtain addresses of the respective study’s PCRS certified (trained) administrators/raters
  • Sponsors agreed to either send us the email addresses of the PCRS rater directly to complete the questionnaire via an outside survey company (SurveyMonkey), or directly send the survey link to the raters. Given that three sponsors chose the latter and did not share the raters’ email address with these authors, the survey response rate could not specifically be calculated but we estimate it at 70% given the number of survey responders and number of PCRS study licenses.
  • Regardless of distribution method, all PCRS raters were informed of why they were receiving the survey, how their email addresses were obtained, the voluntariness and anonymity of survey completion, to complete the survey only once (thus, duplicate surveys are unlikely), and the 5 minutes expected duration of completion
  • Three separate reminders requesting completion were sent to all PCRS raters, including when sponsors directly sent the survey and content validity.







A Pearson correlation coefficient indicated a significant positive relationship between years administering the PCRS and its ease of use (r=.27; p=.001), phrasing/wording (r=.17; p=.03), and length (r=.2; p=.008) which all complemented the tool’s intent.


  • Confidence in using the PCRS has been further established in this investigation, as a significant majority of this tool’s raters reported:
    • The PCRS was easy to administer, is user-friendly, accurately used verbiage (i.e., had appropriate content) to help reduce the placebo response in the respective clinical trial, and was appropriate in length given its crucial intent.
      • The more the rater has used the PCRS, the more likely they were to report the above. It thus seems raters who have more PCRS administration sees its value in reducing the placebo and nocebo responses.
    • The questions posed to the participants at the end of reading each script per study visit does help determine if the participant truly understands the PCRS’s content and purpose (i.e., what a placebo is, to have no expectations of improvement, to be honest when reporting symptoms, and that the site will be treating them neutrally rather than therapeutically).
    • No changes are needed in the PCRS (although of course we will continue to evaluate its validity and operational impact to ensure proper streamlined implementation in clinical trials).
    • The tool is better than other strategies which have been implemented in the industry to control the placebo response.
    • The PCRS does not interfere in the conduct of the trial.


Elan A. Cohen,1 Howard A. Hassman,1 David P. Walling,2 Vera M. Grindell,2 Katarzyna Wyka,3 Brett A. English,1,2 Cassie L. Blanchard,1 Jaclyn M. Lobb,1 Djouher Hough,1 Stephanie M. Iglesias,1 and Larry Ereshefsky1,2,4

1CenExel Hassman Research Institute 2CenExel Collaborative Neuroscience Network 3The City University of New York, Graduate School of Public Health and Health Policy 4Retired Professor, The University of Texas

References provided on reverse side of poster handout at conference or upon request to

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