Review Points to Nocebo Effect as a Cause of Higher Discontinuation Rates for Biosimilars


In observational studies of patients who have switched treatment from a reference biologic to a biosimilar, some higher rates of discontinuation have been observed when these studies are compared with blinded switching studies.

In observational studies of patients who have switched treatment from a reference biologic to a biosimilar, some higher rates of discontinuation have been observed when these studies are compared with blinded switching studies. A newly published systematic review sought to investigate the reasons for elevated discontinuation and to study the role of potential nocebo responses.

The investigators searched for studies involving at least 1 switch from a reference monoclonal antibody to a biosimilar, with a follow-up of at least 6 months. They arrived at 14 studies, all switches from reference infliximab to CT-P13. The investigators compared mean and median percentage discontinuation rates reported in the included studies with those reported in studies of long-term use of reference products as well as interventional and blinded clinical trials involving a switch.

The threshold for higher-than-expected discontinuation was determined to be greater than 10% (based on data derived from large registry studies and the NOR-SWITCH study).

In the included studies, discontinuation rates for biosimilars ranged from 2.8% to 28.2%. In 8 of the studies, the postswitch follow-up was approximately 1 year, and in these studies, discontinuation rates ranged from 9.7% to 28.2%, with 7 of the studies reporting discontinuation rates higher than 10%. In total, 11 of the 14 studies reported higher-than-expected discontinuation, and the phenomenon was observed across all inflammatory disease states studied.

No clear relationship between discontinuation and duration of treatment with the reference product prior to the switch was observed.

Among the 13 studies that included information on reasons for discontinuation, lack of efficacy and adverse events (AEs) were the most commonly reported, and they accounted for discontinuation in 1.4% to 28.1% of total patient populations.

A subset of studies reported whether loss of efficacy or AEs that led to discontinuation were subjective or objective, and, say the study’s authors, “a considerable proportion of health symptoms could be categorized as subjective, which may be indicative of potential nocebo effects.”

While AEs were reported in 11 of the studies, 7 of the studies included AEs that the authors say may be subjective, including headache and general malaise. Infusion reactions and the development of antidrug antibodies, which may be considered to be more objective, were infrequently reported.

Only 5 of the 14 studies provided information about patient education. In 3 studies, patients were provided with a letter about the switch. In another study, patients were given homogenous, orally delivered information by the attending physician. In the last study, patients were switched on the basis of shared decision-making and voluntary informed consent. In all of these studies, at least some proportion of discontinuation was attributed to subjective effects, “suggesting the possibility for residual deficiencies in communication strategies that could lead to potential nocebo effects.”

The authors concluded that, based on the data in the included studies, evidence supports the observation of higher-than-expected discontinuation rates of biosimilars in the real-world setting. Because these rates could be attributed, at least in part, to subjective factors, this observation could indicate a role of the nocebo effect. Further data collected from well-designed studies that aim to assess nocebo responses will be useful in determining whether patient empowerment and shared decision-making could be effective tools to reduce treatment discontinuation after a switch, wrote the authors.


Bakalos G, Zintzaras E. Drug discontinuation in studies including a switch from an originator to a biosimilar monoclonal antibody: a systematic literature review. Clin Ther. 2019;41(1): 155-173.e.13. doi: 10.1016/j.clinthera.2018.11.002.

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