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Health Care Policy and Law
February 22, 2021

Placebo—the Unknown Variable in a Controlled Trial

Author Affiliations
  • 1Institute for Scientific Freedom, Copenhagen, Denmark
  • 2Nordic Cochrane Centre, Rigshospitalet, Copenhagen, Denmark
JAMA Intern Med. Published online February 22, 2021. doi:10.1001/jamainternmed.2020.8670

The use of a placebo in controlled trials is essential for the reliable assessment of a therapeutic drug. Sometimes trialists use an active placebo that can mimic the possible harms of the experimental drug with no therapeutic effects on the condition being treated. For example, active placebos, such as atropine, may be used in trials of antidepressants, where the drugs under investigation can cause noticeable harms and the risk of bias owing to unblinding may be high.1

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    1 Comment for this article
    Assessment of blinding in clinical trial subjects
    DAVID KELLER, MD, MS | Internal Medicine
    A clinical trial can measure how well the subjects are blinded by routinely asking each subject, at every encounter, to guess whether they believe they are receiving placebo or active treatment, or have no idea. It may be useful to further inquire what makes them believe they have correctly guessed their assignment - which may be due to the efficacy of the treatment, side effects of treatment, taste of the pills, or the noisiness of therapy machines - don't leave them unplugged for the placebo group!

    Purely due to the location of my office, I witnessed some of
    the earliest testing of botulinum toxin injections for the treatment of torticollis. The subjects who received placebo had no change in neck posture, while those who were treated with active botulinum injections demonstrated obvious visible straightening of the neck, which the patients discussed freely among themselves in the waiting room. That sort of loss of blinding - caused by lack of equipoise for a very effective treatment - is usually a very welcome departure from experimental protocol.

    For less obviously effective treatments, the percentage of subjects who correctly guessed their assignment to placebo or active treatment at every encounter should be tracked longitudinally over time, and confidence limits applied to their guesswork. The success with which subjects correctly guess their assignment to placebo or active treatment should ideally resemble coin-flip statistics. The investigator can use the guesswork data to quantify the quality of the placebo as an impostor for the active treatment, and estimate the magnitude of expectation effects on the outcome of the experiment.