The Automatic Substitution of Biosimilars: Definitions of Interchangeability are not Interchangeable

Abstract

In the USA, an interchangeability designation provides biosimilar sponsors with a pathway for achieving what is standard for small-molecule generics: pharmacy-level auto-substitution for an innovator. No other major health authority links interchangeability to automatic substitution, as all require the involvement of the prescriber or patient in a medication change. This editorial considers the clinical impact and practicality of auto-substitution. First, interchangeability is linked to non-medical switching (NMS), the practice of switching treatment in patients with stable disease for non-clinical reasons. NMS may generate negative sentiment in those unwilling or reluctant to switch, which can adversely impact treatment outcomes (i.e., nocebo effect). Indeed, in real-world studies of tumor necrosis factor inhibitors, discontinuation rates have been shown to be higher in patients switched to biosimilars for non-medical reasons than in historical cohorts maintained on innovators. Second, interchangeability may impede pharmacovigilance and traceability, as not all jurisdictions require innovators and biosimilars to have distinct biologic names. Third, an interchangeability designation from the US Food and Drug Administration only permits a biosimilar to be automatically substituted for its innovator, not other biosimilars (if available). Pharmacist education would be needed to avoid off-label, automatic substitution among biosimilars of a single innovator. Last, once granted, an interchangeability designation exists in perpetuity under current US federal law. However, the supply chains of innovators and biosimilars are maintained independently, with no requirement for reconfirmation of biosimilarity or interchangeability. We feel that additional guidance is needed for the auto-substitution of biosimilars and innovators to become a reality.

An Introduction to Biosimilars for the Treatment of Retinal Diseases: A Narrative Review

“…Indeed, systematic literature reviews conclude that the current body of evidence suggests no clinically relevant impact of initiating or switching to biosimilars across a number of therapeutic areas [ 74 , 83 , 84 ]. However, interchangeability may impede pharmacovigilance and traceability as not all jurisdictions require innovators and biosimilars to have distinct biological names [ 85 ].…”

Patient-Reported Outcomes in Rheumatoid Arthritis: A Key Consideration for Evaluating Biosimilar Uptake?

“…The available data indicate that some RA patients may be more susceptible to nocebo effects, especially in patients with non-medical switching, suggesting that knowledge of a switch to a biosimilar product may have affected treatment efficacy. 31 , 76 , 80 Switching between a reference biologic and a biosimilar for non-medical reasons may generate negative sentiment in those unwilling or reluctant to change.…”

“…Although it is uncertain to what degree biosimilars will lower costs, discounts vary by market and product, early entrants have validated the estimates of a price 15–60% lower than the originator biologic. 27 , 30 , 31 …”

Is There Any Research Evidence Beyond Surveys and Opinion Polls on Automatic Substitution of Biological Medicines? A Systematic Review

“…Our findings reflect the fact that automatic substitution practices are largely not allowed or implemented across Europe and other regions of the world. Further, the concept of automatic substitution varies between different jurisdictions [67]. While the EU remits the decision on interchangeability and its practical execution to each Member State, in the US, automatic substitution is only possible for interchangeable biosimilars.…”