Literature Review Inconclusive on “Nocebo” Effect of Biosimilars

Researchers have hypothesized that when patients experience adverse events (AEs) upon switching from a reference biologic to a biosimilar product, a nocebo effect can occur—a detrimental effect on health produced by psychological or psychosomatic factors such as negative expectations of treatment or prognosis. The researchers conducted a literature review to evaluate if patient and/or physician knowledge of a switch from a reference biologic product to a biosimilar product was associated with an increase in AEs that may produce a nocebo effect. The results were published in the Journal of Managed Care & Specialty Pharmacy.

Researchers assessed Medline, PubMed, and Embase to identify studies reporting efficacy and safety outcomes of a switch from a reference product to a biosimilar product, including studies of U.S. Food and Drug Administration-approved biosimilars products: adalimumab, bevacizumab, etanercept, and infliximab. They used descriptive statistics to quantify subjective and objective complications in double-blind, single-blind, or open-label studies.

They analyzed data from 31 double-blind and open-label studies that included 3,271 patients who were switched from originator to biosimilar infliximab (28 studies; 2,956 patients; 2 double-blind studies) or from originator to biosimilar etanercept (3 studies; 315 patients; 2 double-blind studies).

The median discontinuation rates for any reason were 14.3% (range = 0.0-33.3%) in open-label studies compared with 6.95% (range = 5.2-11.0%) in double-blind studies. Discontinuation rates for AEs were 5.6% (range = 0.0-24.2%) in open-label studies versus 3.1% (range = 2.0-5.2%) in double-blind studies, “suggesting [that] the nocebo effect does affect biosimilar adoption,” according to the authors. Discontinuation rates for lack of efficacy were 6.45% (range = 0.0-18.1%) in open-label studies versus 1.2% (range = 1.2-1.2%) in double-blind studies.

Subgroup analyses of antidrug antibody development and infusion reactions were similar between open-label and double-blind studies. Discontinuation rates for any reason, for AEs, and for lack of efficacy were generally higher in open-label trials compared with double-blind trials. Etanercept biosimilar discontinuation rates for any reason were similar between study designs; however, incidences of injection-site reactions and discontinuation due to AEs were higher in double-blind studies compared with open-label studies.

“Current evidence is insufficient to confirm a biosimilar nocebo effect, although higher discontinuation rates in infliximab biosimilar open-label studies support this theory,” the authors concluded, noting the need for additional studies on the subject.