title: A fit-for-purpose strategy for the risk-based immunogenicity testing of biotherapeutics: a European industry perspective.
abstract: There is much debate in the pharmaceutical industry on how to translate the current guidelines on immunogenicity testing for biotherapeutics into a testing strategy that suits the specific requirements of individual drug candidates. In this paper, member companies from the European immunogenicity platform (EIP) present a consensus view on the essential requirements for immunogenicity testing of a biotherapeutic throughout the various phases of drug development, to ensure patient safety and to enable successful market entry. Our aim is to open the debate and provoke discussion on this important topic which is unique to biotherapeutic drug development. The scope of this paper is limited to aspects relevant to biotherapeutic drug development and does not include fundamental academic studies of immunogenicity. Here, we propose two pre-defined testing strategies for the detection and characterization of anti-drug antibody (ADA) responses where the different strategies are based on the phase of development for a biotherapeutic, a. without (category 1) and b. with (category 2) the expected potential to elicit ADA mediated severe clinical consequences. The harm of a potential ADA response determines which of the two testing strategies is adopted. Rather than replacing the overall risk assessment which is known to be challenging and multi-factorial, the testing strategy selection is a starting point for immunogenicity testing which adapts throughout drug development as more information becomes available. The scientific rationale on which the "case-by-case" approach advocated in white papers and guidance documents may be translated for each individual drug development program is provided and, underpins the recommendations made here.
authors.affiliation: Dept of Analytical Development & Validation, The Netherlands.
authors.forename: Cathelijne
authors.initials: C
authors.lastname: Kloks
authors.affiliation: Abbott Products GmbH, Preclinical Development-Nonclinical Safety & DMPK, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Berger
authors.affiliation: Sanofi, Research and Development, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cortez
authors.affiliation: NovImmune SA, NovImmune SA, Switzerland.
authors.forename: Yann
authors.initials: Y
authors.lastname: Dean
authors.affiliation: Roche Diagnostics GmbH, Pharma Research and Early Development, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Heinrich
authors.affiliation: Novo Nordisk A/S, Immunogenicity Assessment, Denmark.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Bjerring Jensen
authors.affiliation: Hexal AG, Sandoz Biopharmaceuticals, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Koppenburg
authors.affiliation: Crucell BV, Clinical Immunology, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kostense
authors.affiliation: Sanofi, Research and Development, Germany. Electronic address: daniel.kramer@sanofi.com.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kramer
authors.affiliation: Novartis Pharma AG, DMPK-Biologics Bioanalytics, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Spindeldreher
authors.affiliation: UCB Celltech, DMPK Biologics, United Kingdom.
authors.forename: Hishani
authors.initials: H
authors.lastname: Kirby
mesh_terms: D057134:Antibodies, Neutralizing / Q000032:analysis*; D001691:Biological Therapy / Q000009:adverse effects*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods* / Q000592:standards; D004345:Drug Industry / Q000639:trends*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000276:immunology*; D005060:Europe; D017408:Guidelines as Topic; D006801:Humans; D007159:Immunologic Tests / Q000592:standards*
chemical_list: D057134:Antibodies, Neutralizing
keywords: Anti-drug antibodies; Biologicals; Biotherapeutic; Immunogenicity; Neutralization; Risk based approach