Re-thinking the current paradigm for clinical immunogenicity assessment: an update from the discussion in the European Bioanalysis Forum.

Immunogenicity regulatory guidance and industry recommendations have evolved over the last two decades since unexpected immune reactions were first reported with erythropoietin. Since then, the guidelines and practices for immunogenicity have stemmed from a reaction to a high-risk molecule causing significant clinical impact. Similar thinking is often applied to all biotherapeutic drugs, even when a well-defined risk assessment suggests otherwise. In recent years, the current testing paradigm for immunogenicity has been challenged with more informative approaches being proposed. In a Focus Workshop held by the European Bioanalysis Forum in September 2023, the current immunogenicity testing paradigm was challenged based on the experience and learning of 20+ years of immunogenicity strategies. The workshop recommendations proposed a new paradigm, challenging the value of multiple tiers depending on the immunogenicity risk assessment based on context of use and moving toward treating immunogenicity as a pharmacodynamic biomarker for the drug. Such rethinking ultimately results in the appropriate and efficient focusing of resources on immunogenicity testing strategies that benefit patients most, moving to a new paradigm where implementation of appropriate and truly informative immunogenicity testing strategies, depending on the context-of-use, become the norm .