Beyond the first switch: multiple switching, cross-switching, and nocebo-aware implementation of biosimilars in...

In health systems outside the United States (US) with longer biosimilar experience, use has shifted from a question of adoption to one of implementation. Tenders, formularies, and payer policies are progressively driving reference-product-to-biosimilar, biosimilar-to-biosimilar, switchback transitions, and retransitioning in routine care, posing significant clinical, operational, and governance difficulties.

This structured narrative review examines evidence published from 1 January 2015 to 15 March 2026 on repeated switching within a single reference-product family. It focuses on efficacy, safety, immunogenicity, persistence, switchback, clinician-led and non-medical switching, nocebo mechanisms, communication, patient education, device support, pharmacovigilance, and traceability.

While data on repeated and cross-switching are promising yet nascent, particularly outside tumor necrosis factor (TNF) inhibitors and beyond short-term follow-up periods, current evidence unequivocally supports initial switching. Successful outcomes depend upon pharmacovigilance, traceability, structured communication, and device support, in addition to molecular comparability. Injection-site pain during adalimumab transitions may be attributed to citrate content, pH, injection volume, or device variations, and should not be prematurely categorized as a nocebo effect. Explicit governance frameworks for repeated-switch programs and prospective, implementation-sensitive evidence are requisite for future clinical advancements.