Equivalence and switching between biosimilars and reference molecules in rheumatoid arthritis: protocol for two systematic reviews and meta-analyses

Abstract

Background Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven to the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. These two systematic reviews aim to investigate the efficacy and safety profile of biosimilars compared to biologics (systematic review 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (systematic review 2).Methods Electronic searches will be performed through MEDLINE (via Pubmed), EMBASE, LILACS, and CENTRAL (from inception to September 2020). Risk of bias assessments will be carried out with the Cochrane risk of bias tool, supplemented with specific domains from equivalence trials. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. Between-trial heterogeneity will be tested and quantified with the Q-test and I2 metric, respectively, whereas assessment of small-study bias will be examined through contour-enhanced funnel plots and Egger and Harbord's tests. Meta-regression models will be fitted when appropriate. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20) and the co-primary outcome will be the Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of evidence will be assessed based on the GRADE system.Discussion The two systematic reviews described here, to the best of our knowledge, are the first ones proposing a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. The results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA. Systematic Review Registration Protocol synopses were previously registered on PROSPERO (CRD42019137152 and CRD42019137155).