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Placebo Response

Understanding primary endpoints and minimising experimental error.

What is placebo response?
The "placebo response" occurs when a person who is ill perceives an improvement, or actually experiences an improvement, in symptoms or overall health from the psychological effect of receiving treatment rather than from the treatment itself.
 
In clinical trials this happens when patients/healthy subjects in the “placebo” arm of the study show significant improvements in their condition/response to an experimental model. MAC conducts placebo response training with all front-end staff, to ensure they understand what it is and what the implications are for data. 

Implications

  • Larger placebo response is associated with lower likelihood of a statistically positive study (Katz, Finnerup, Dworkin: Neurology 2008).

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  • Placebo response may mask genuine treatment effects.

    • Potentially effective treatments may be discontinued.

 

  • Scientific and financial implications.

    • Failed Studies.

 
 
Why does it occur?
 The placebo response may be due to a number of different factors:

 

  • A person's profound desire to get better.

    • “The power of positive thinking”.

 

  • Increased medical attention as result of being in an experimental study of a new treatment.

    • Patients being well looked after feel cared for and reassured which may lead to overall upturn in mood making them “feel” better (medical staff become a form of placebo).

    • Can lead to false positivity.

 

  • An unconscious wish by the person to please the physician by getting better.

 

  • Some scientists believe that certain psychological factors actually cause the body to produce hormones called endorphins, which act as the body's own pain killers, resulting in reduced levels of pain or discomfort.

 

 
How to minimise it

  • Appropriate Patient Selection.

    • Clearly have the disease of interest.

    • Likely to be responsive.

      • Newly diagnosed may be best.

  • Unresponsive to all other therapies may not be responsive.

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  • Appropriate personality and affect.

    • Not overly optimistic/pessimistic.

    • Include some form of psychological screening.

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  • Ability to accurately report change

    • Consider including some sort of screening of reporting ability.

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  • Population homogeneous for the propensity to respond to a drug.

    • Randomized withdrawal studies in those who respond.

    • Prediction of response from baseline characteristics.

 

  • Patient Education

 

  • Managing Expectations.

    • Provide realistic expectation of outcome/benefit.

    • Understanding of likelihood of receiving placebo or that drug may not work.

    • Remove idea that patients will be letting the staff down if drug doesn’t work.  Often patients say they are getting better to be nice to study team as they think that is what they want to hear (placebo is Latin for “I will please”).

    • Stress importance of accurate reporting at all times.

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  • Thorough Endpoint Training

    • Introduce the patient to any rating scales and provide thorough training in how to consistently complete them.

    • Even if it seems like a simple scale, patients who are unfamiliar with it may not understand how to complete them correctly.

    • Define what is meant by different levels of e.g. pain (mild, moderate, severe) and where they would lie on the scale. 

 

 

  • Removing Influences

    • Effect of upturn in mood to be distinguished from actual symptom – focus on actual disorder rather than general well-being.

    • Reasons for improved mood to be controlled (social interactions, empathy, understanding etc.).

    • Discourage discussions about potential treatments or current condition between patients.

 
 

  • Appropriate Staff-Patient Interactions.

    • Neutral behaviour towards patients.

      • Limit sympathy/empathy whilst maintaining professional standard of care.

      • Limit personal interactions, don’t become over-familiar/too friendly with patients.

      • Avoid staff behaviour becoming a form of placebo.

    • Controlled Environment.

      • Environment should be professional and comfortable without being too “over-caring”.

      • Need to maintain a controlled, structured environment in order to limit variability.

 

Optimal Study Design
 

  • Standardize information conveyed to subjects to regularize expectation.

 

  • Appropriate logistics (number of groups/group size) and timing (pharmacodynamics).

 

  • Appropriate measures (mix of objective and subjective endpoints) and baseline inclusion criteria.

 

  • Reduce overall group variability as much as possible.

 

  • Use only highly trained testers for subject ratings, try to stick to same tester per patient.

 

  • Limit principal rater access to patient information, AEs etc.  Limit contact to test sessions (blinded raters).

 
 
Placebo Response Training at MAC Clinical Research
 

  • All patient-facing staff receive instructor-led training in the implications of placebo response and how to minimise it in clinical studies.

 

  • Standard instructions/training for patients implemented for all placebo controlled studies.

 

  • Strict controls out in place in order to standardise study conditions and reduce variability.

 

  • Education of  staff concerning the potential influence of their actions/behaviour on subject response and overall study outcome.

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