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

Abstract

BACKGROUND: Several authors have hypothesized that adverse drug events (ADEs) upon switching from reference biologics to biosimilar products are related to the nocebo effect. However, a thorough and current review of the existing literature has not been conducted. OBJECTIVE: 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 ADEs likely to be susceptible to the nocebo effect.METHODS: Studies reporting efficacy and safety outcomes of a switch from a reference product to a biosimilar product were reviewed. Biologics with FDA-approved biosimilars in the United States were considered for review, including adalimumab, bevacizumab, etanercept, and infliximab. Studies were identified by searching controlled vocabulary (e.g., MeSH terms) and keywords within MEDLINE (via PubMed) and Embase. Descriptive statistics were used to quantify subjective and objective complications in doubleblinded and single-blinded or open-label studies.RESULTS: Thirty-one trials including 3,271 patients were reviewed in the full analysis. 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-blinded studies. Discontinuation rates for ADEs were 5.6% (range = 0.0-24.2) in open-label studies versus 3.1% (range = 2.0-5.2) in double-blinded studies, suggesting the nocebo effect does affect biosimilar adoption. Subgroup analyses of antidrug antibody (ADA) development and infusion reactions were similar between infliximab open-label and doubleblinded studies. Discontinuation rates for any reason, for ADEs, and for lack of efficacy were generally higher in infliximab open-label trials compared with double-blinded trials. Etanercept biosimilar discontinuation rates for any reason were similar between study designs; however, incidences of injection site reactions and discontinuation rates for ADEs were higher in double-blinded compared with open-label study designs.CONCLUSIONS: Current evidence is insufficient to confirm a biosimilar nocebo effect, although higher discontinuation rates in infliximab biosimilar open-label studies support this theory. Further studies are needed to evaluate the existence of a biosimilar nocebo effect.

Treatment retention of infliximab and etanercept originators versus their corresponding biosimilars: Nordic collaborative observational study of 2334 biologics naïve patients with spondyloarthritis

“…The outcome in these observational studies has differed, generally (but not exclusively15) slightly disfavouring the biosimilar product. This has largely been attributed to a nocebo effect, although the evidence for such an effect has been disputed 16. Furthermore, the observed differences could potentially be due to the drugs performing differently in a clinical setting as opposed to the highly selected patients included in RCTs 17…”

Does a mandatory non-medical switch from originator to biosimilar etanercept lead to increase in healthcare use and costs? A Danish register-based study of patients with inflammatory arthritis

“…However, patient related factors and non-specific drug effects seemed to affect retention to biosimilar—as previously demonstrated in other switch cohorts 15 31. The existence of a nocebo effect that is, poor performance of a treatment due to negative expectations has been widely discussed when it comes to the biosimilar biological treatments 7 26 28 32. Thus, it has been demonstrated that patients and physicians may be reluctant to use the biosimilars 6.…”

“…This would potentially allow more patients to be treated 4. The economic benefit from switching may potentially be partly outweighed by extra costs if the number of outpatient visits and contacts to healthcare providers rises due to for example, patient education or closer monitoring 5–8. However, existing pharmaco-economic and health-economic studies have focused mainly on drug prices and the direct cost of treatment,9 whereas overall utilisation of healthcare and associated costs have not been addressed.…”

Enhancing treatment success in inflammatory bowel disease: Optimising the use of anti-TNF agents and utilising their biosimilars in clinical practice

“…The 'nocebo effect' does not currently have a single consensus definition but may be broadly defined as the development of adverse events or disease worsening in response to treatment, which cannot be attributed to the specific therapy used. In other words, it involves negative consequences resulting from negative expectations [43] -the opposite of the placebo effect.…”