'Nocebo' Effect May Influence Outcomes After Switching to a Biosimilar


Research shows that some unsuccessful switches from reference products to biosimilars may be attributed to patient perceptions of reduced efficacy and safety.

A recent study found that switching patients with rheumatoid arthritis (RA) from adalimumab (Humira; AbbVie) to a biosimilar for non-medical reasons may cause untoward outcomes, potentially because of the nocebo effect. The study, published by Rheumatology and Therapy, sought to compare real-world outcomes of patients with (RA) administered adalimumab bio-originator (non-switchers) vs patients who had switched to an adalimumab biosimilar (switchers) to evaluate whether their outcomes would differ.

Adalimumab, a tumor necrosis factor (TNF) inhibitor, became the first fully human monoclonal antibody approved to treat RA. Following the expiration of the product patent for adalimumab in 2016, there have been 7 biosimilars approved for use in RA.

“Since biosimilar manufacturers with varying manufacturing processes will not attain identical drug substance and drug product attributes to the bio-originator, biosimilars are not considered identical to their bio-originator,” the study authors wrote. “As such, concerns about switching between a bio-originator and its biosimilar remain.”

The study noted that the significant economic burden of RA and the availability of biosimilars resulted in approximately 35% of European patients being switched to an adalimumab biosimilar by the end of 2019. Non-medical switching is defined as patients receiving well-tolerated and effective therapy from the bio-originator changing to the use of a biosimilar for economic reasons.

“Switching trials have shown that switching from the [adalimumab] bio-originator to a currently approved biosimilar does not significantly impact safety, immunogenicity, or efficacy,” the study authors wrote. “Subtle differences were considered to be due to methodological differences rather than the biosimilar properties. However, some unsuccessful switches have been attributed to patients’ perceptions (the ‘nocebo’ effect), and reduced efficacy and safety.”

They added that the manner and content of communications to patients regarding the reasons for non-medical switching may have a significant impact on their outcome. Further, lower biosimilar retention rates in open-label switch studies compared with double-blind switch studies suggests that the nocebo effect may impact biosimilar retention rates, according to the investigators.

The study authors collected data from the Adelphi RA Disease Specific Programme, which was a point-in-time survey of physicians and patients in France, Germany, Italy, Spain, and the UK conducted in 2020. Physicians completed a questionnaire on their next 10 adult patients with RA, followed by 4 patients who switched from adalimumab to a biosimilar. Physician- and patient-reported outcomes for switchers and non-switchers were evaluated by propensity score matching.

The study evaluated data from 303 rheumatologists for 160 non-switchers and 225 switchers, as well as data provided by 140 patients, of whom 51 were non-switchers and 89 were switchers. Physician-reported disease activity showed that non-switchers were more likely to improve on their current treatment than switchers (68%, n = 108 vs 26%, n = 59 p < 0.001) and less likely to have their condition worsen (1%, n = 2 vs 9%, n = 20; p < 0.01).

The results also showed that physician-reported patient adherence significantly declined among switchers compared with non-switchers (0.66 vs. 0.78, respectively; p = 0.04) and more non-switchers were found to be consistent in taking their RA medication than switchers (p < 0.001).

PRO measures showed that quality of life (QoL) was worse (EQ-5D Visual Analogue Scale: 62.9 vs. 71.9; p < 0.001) and activity impairment was greater (Work Productivity Activity Index: 31.0 vs. 24.4; p = 0.02) for switchers than non-switchers, with trends for poorer health status and greater pain.

“In conclusion, this analysis of the Adelphi RA DSP demonstrated that the switching of patients with RA from [adalimumab] bio-originator to an [adalimumab] biosimilar, may have some unforeseen outcomes that should be considered by health decision makers, such as effects on patients’ disease severity, treatment adherence, and QoL,” the study authors wrote. “Disease severity worsened for a few but remained stable for the majority of switchers throughout the duration of their biosimilar treatment, resulting in relatively poorer outcomes than in the case of non-switchers.”

The authors said that although most studies show positive results after switching to biosimilar therapies, switching patients for non-medical reasons in real-world practice may cause untoward outcomes, with the nocebo effect possibly playing a significant role. They added that the reasons for, and downstream implications of, all possible outcomes in patients switched to biosimilars for non-medical reasons should be explored in future studies.


Taylor, P.C., Gonzalez, Y.S., Clark, R. et al. Outcomes Following Adalimumab Bio-originator to Biosimilar Switch—A Comparison Using Real-world Patient- and Physician-Reported Data in European Countries. Rheumatol Ther (2023). https://doi.org/10.1007/s40744-022-00526-w

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