The Biosimilar Nocebo Effect? A Systematic Review of Double-Blinded Versus Open-Label Studies

Area of Science:

• Pharmacology
• Clinical Trials
• Patient Safety

Background:

• Hypotheses suggest the nocebo effect contributes to adverse drug events (ADEs) during switches from reference biologics to biosimilars.
• Existing literature requires a comprehensive and current review to validate these hypotheses.

Purpose of the Study:

• To determine if patient or physician awareness of a switch to a biosimilar product correlates with an increased incidence of ADEs susceptible to the nocebo effect.
• Investigate the association between knowledge of biosimilar transitions and the occurrence of nocebo-effect-related adverse events.

Main Methods:

• A systematic review of trials assessing efficacy and safety outcomes after switching from reference biologics to biosimilars.
• Included biologics with FDA-approved biosimilars in the US: adalimumab, bevacizumab, etanercept, and infliximab.
• Searched MEDLINE and Embase databases; analyzed descriptive statistics for subjective and objective complications in blinded vs. open-label studies.

Main Results:

• 31 trials (3,271 patients) reviewed; open-label studies showed higher discontinuation rates (14.3%) versus double-blinded studies (6.95%).
• Discontinuation rates due to ADEs were higher in open-label (5.6%) versus double-blinded studies (3.1%), suggesting a nocebo effect.
• Infliximab open-label trials had higher discontinuation rates for any reason and for ADEs compared to double-blinded trials; etanercept showed higher injection site reactions and ADE-related discontinuations in double-blinded studies.

Conclusions:

• Evidence is currently insufficient to definitively confirm a biosimilar nocebo effect.
• Higher discontinuation rates in infliximab biosimilar open-label studies lend support to the nocebo effect theory.
• Further research is essential to conclusively evaluate the existence and impact of a biosimilar nocebo effect.