The 2019 FDA immunogenicity guidance for protein therapeutics indicates that appropriate PK/PD assays in lieu of a standalone neutralizing antibody assay can inform neutralizing activity of anti-drug antibodies. In addition, emerging draft FDA guidance is seeking to capture the impact of clinically relevant immunogenicity information on product labeling. As such, the bioanalytical community has the opportunity to develop and incorporate integrated data strategies to support characterization of clinically relevant immunogenicity including the development of appropriately designed PK, PD and immunogenicity assays. Here, we present cases studies to illustrate various strategic approaches to implement integrated immunogenicity, bioanalytical, and biomarker analyses to assess the clinical impact of immunogenicity at various phases of clinical development. Applying such integrated strategies early in clinical development can significantly influence the trajectory of clinical development as well as support efficient utilization of scientific resources. Case study 1 describes a first-in-human clinical trial experience where integration of data from PK, biomarker, ADA and Nab assays reveal the unexpected impact of immunogenicity, specifically that pre-existing ADA result in sustaining exposure beyond the expected half-life, while having no neutralizing impact on drug activity. In case study 2, we describe implementing a stage-gated approach to the development of a NAb assay based on the therapeutic mode of action and associated preclinical immunogenicity experience to assess the risk of clinical immunogenicity. In case study 3, we present a successfully implemented integrated PK/PD/ADA strategy that allowed for marketing authorization without a NAb assay requirement.
Learning Objectives:
Participants will be able to define how integration of PK, PD, and ADA data can inform clinical interpretation of the impact of immunogenicity.
Participants will be able to provide specific examples to their own internal stakeholders of phase-appropriate variations in immunogenicity strategies, including approaches that do not require a neutralizing antibody assay.
Participants will be able to incorporate these concepts into their immunogenicity risk assessments and implement their own bioanalytical strategies to inform the specific risks and development milestones for clinical development.