Nonclinical Aspects of Biopharmaceutical Development: Discussion of Case Studies at a PhRMA-FDA Workshop

Abstract

Robust assessments of the nonclinical safety profile of biopharmaceuticals are best developed on a scientifically justified, case-by-case basis, with consideration of the therapeutic molecule, molecular target, and differences/similarities between nonclinical species and humans (ICH S6). Significant experience has been gained in the 10 years ensuing since publication of the ICH S6 guidance. In a PhRMA-FDA-sponsored workshop, "Nonclinical Aspects of Biopharmaceutical Development," industry and US regulatory representatives engaged in exploration of current scientific and regulatory issues relating to the nonclinical development of biopharmaceuticals in order to share scientific learning and experience and to work towards establishing consistency in application of general principles and approaches. The proceedings and discussions of this workshop confirm general alignment of strategy and tactics in development of biopharmaceuticals with regard to such areas as species selection, selection of high doses in toxicology studies, selection of clinical doses, the conduct of developmental and reproductive toxicity (DART) studies, and assessment of carcinogenic potential. However, several important aspects, including, for example, appropriate use of homologues, nonhuman primates, and/or in vitro models in the assessment of risk for potential developmental and carcinogenic effects, were identified as requiring further scientific exploration and discussion.

Developmental and reproductive toxicology studies in nonhuman primates

“…C. Standard design (e.g., small molecule) is control group and 3 dose groups (test article treated). Biologics will frequently employ a control group and 2 dose groups (Chapman et al, 2009), usually multiples of the clinical dose if no toxicity is expected (Buckley et al, 2008). The use of a control group and a single treatment group has also been suggested to reduce NHP use (Stewart, 2009;ICH S6(R1), 2009).…”

Factors Affecting the Pharmacology of Antibody–Drug Conjugates

“…Cross-species differences in the FcRn–IgG interaction have been evaluated to determine the relevance in the use of preclinical models, especially mice. Because of a stronger affinity of human IgG antibodies for murine FcRn (~15-fold greater than human FcRn), human mAbs exhibit slower clearance and longer half-lives in mice, making them poor predictors for allometric correlation to human clearance rates [144,146,147,148]. This leads to a reliance on genetically engineered mouse models (GEMMs), such as transgenic FcRn murine models, over WT strains in preclinical PK studies, though in vitro or ex vivo analysis would be more efficient for high-throughput comparisons [149,150].…”

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…The importance of translational challenges encountered during antibody development is highlighted by the severe adverse events experienced in the first-in-human (FIH) clinical trial in healthy subjects receiving the starting dose of TGN1412 (7). As established by the TGN1412 example, effective translation of information across species will require comparative investigations of the target antigen properties, speciesdependent pharmacology, and antibody design criteria in the pharmacologically relevant species (4)(5)(6)8). Assessment of the factors that regulate antibody exposure-response relationships in the relevant animal models is critical for the design of successful translational strategies from discovery to the clinic (4)(5)(6).…”