Background: Biosimilars are designed to closely resemble their reference biologics in terms of quality, safety, and efficacy, with only minor variations in clinically inactive components and manufacturing methods. Evaluating the safety of switching between these products is critical for healthcare providers and patients. Concerns may arise when transitioning patients from a reference biologic to a biosimilar or between different biosimilars. Objective: This systematic review and meta-analysis aims to evaluate the frequency of adverse events associated with switching from a reference biologic to its biosimilar, using data derived from randomized controlled trials (RCTs). Methods: A comprehensive search was conducted in MEDLINE and Cochrane Central databases from their inception to December 2024. Studies included RCTs that reported adverse reactions related to switching between reference-to-reference biologics and reference-to-biosimilar biologics. Record screening, data extraction, and risk of bias assessment were performed independently by two reviewers. Random effects models were applied to pool crude outcome data. Results: The search identified 668 abstracts, with an additional 14 studies found through hand-searching review articles. Of these, 12 trials involving 1326 participants in the reference–reference group and 1176 participants in the reference–biosimilar group met the inclusion criteria. The frequency of adverse events, serious adverse events, and treatment-related adverse events did not differ significantly between the reference–reference and reference–biosimilar groups: relative risk (RR) = 0.96 (95% confidence interval [CI], 0.85–1.08), RR = 1.06 (95% CI, 0.68–1.65), and RR = 1.03 (95% CI, 0.66–1.59), respectively. Heterogeneity was generally low to moderate across outcomes, and subgroup analyses based on disease type and reference product showed no differences. Conclusions: Switching between reference biologics and biosimilars demonstrates a comparable safety profile, suggesting that both options are viable. However, the findings are limited by the small number of trials and the scope of patient populations and products studied. PROSPERO registration number: CRD42021267205.
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