Placebo Response in Psychiatric Clinical Trials: What is it and what can we do about it?

High placebo responses have been steadily increasing in the CNS space since 1960. 80-85% of CNS clinical trials fail and 30-50% of those are due to increased placebo response.

What are the contributors to this high placebo response?

Here are some below:

  • Participant expectations – the expectation to improve with experimental medicine.
  • Inaccurate participant report – either conscious or unconsciously wanting to please provider, sponsor/CRO/site incentives to stay in the trial, or hearing other participants’ reports in the waiting room.
  • Site staff/investigator influence – if interactions with the site staff are overly warm or personal, they can have a therapeutic effect. In addition, overly enthusiastic staff may inadvertently give participants too much hope about their receiving the active treatment or the likelihood of response.
  • Inconsistent measurement reliability – switching raters during the trial can cause variations in the reported outcome measure, even when there is no significant clinical change

We cannot eliminate placebo response completely, but we can mitigate it. Placebo is an active intervention with a proven history of leading to response. How can we mitigate?

Site Actions:

  • Regular and rigorous placebo response training for all staff. Remember that managing the participants expectations begins at the very first contact.
  • Use the same rater at each visit. Have uniform and consistent rater training.
  • Limit interaction with efficacy raters to only during rating. Raters should stay neutral and limit empathy. Raters should not use participant’s first name and should limit eye contact.
  • Keep staff interactions with participants neutral and less personal. This should apply to all staff, including recruiter or scheduler. Staff should not discuss their own personal life with the participants.
  • Reduce any form of physical contact that is not necessary
  • Use a placebo response script. Include the following:
  • Include in this script an explanation as to why the interactions at a clinical site may be different than those at a regular doctor’s office. Participants may not understand why we are not asking about their drive to the office or how their day is going. Explaining upfront that those type of interactions can influence the data we are gathering will make the less personal interactions more comfortable for everyone.
  • Make clear that neither the staff nor the participant will know if they are on the active drug or the placebo, so it is important to report all symptoms, good or bad, as accurately and honestly as possible.
  • Assure the participant that there are no wrong answers, and it is okay if they do not get better, that information is just as important as if they do get better
  • Remind the participant of the possibility that they are on placebo at every visit.

Sponsor/CRO Actions:

  • Include equal numbers in each treatment group. Placebo response can be increased if participants think they are more than 50% likely to get active drug.
  • Remove incentives to under/over reporting such as:
  • milestone payments/rewards;
  • free medication post study if participant reaches a certain milestone;
  • allow participants who have to discontinue the investigational product due to lack of efficacy or AEs to complete remaining visits.
  • Use lead-in or crossover study designs.
  • Require clear and unambiguous rater training.
  • Include a placebo response script or video before every efficacy assessment.

Placebo response is to be expected, but we can all have a role in keeping it low.

Citations are available upon request.