Challenging the Norm: A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics.

The transition from intravenous (IV) to subcutaneous (SC) administration of biologics is a critical strategy in drug development aimed at improving patient convenience, compliance, and therapeutic outcomes. Focusing on the increasing role of model-informed drug development (MIDD) in the acceleration of this transition, an in-depth overview of the essential clinical pharmacology and regulatory considerations for successful IV to SC bridging for biologics after the IV formulation has been approved are presented. Considerations encompass multiple aspects beginning with adequate pharmacokinetic (PK) and pharmacodynamic (i.e., exposure-response) evaluations which play a vital role in establishing comparability between the IV and SC routes of administrations. Selected key recommendations and points to consider include: 1) PK characterization of the SC formulation, supported by the increasing preclinical understanding of the SC absorption, and robust PK study design and analyses in human; 2) A thorough characterization of the exposure-response profiles including important metrics of exposure for both efficacy and safety; 3) Comparability studies designed to meet regulatory considerations and support approval of the SC formulation, including non-inferiority studies with PK and/or efficacy and safety as primary endpoints; 4) Comprehensive safety package addressing assessments of immunogenicity and patients' safety profile with the new route of administration. Recommendations for successful bridging strategies are evolving and MIDD approaches have been used successfully to accelerate the transition to SC dosing, ultimately leading to improved patient experiences, adherence, and clinical outcomes.