Nonclinical Toxicology Testing Strategies and Applicable International Regulatory Guidelines for Using Nonhuman Primates in the Development of Biotherapeutics

Abstract This chapter describes the strategic and regulatory considerations when using nonhuman primates (NHPs) in nonclinical development of biotherapeutics (i.e., biologics). The foundation of the nonclinical development program is the selection of pharmacologically-relevant species, which is based on a weight-of-evidence approach using in silico, in vitro, and in vivo data. The NHP, in particular the cynomolgus monkey, is frequently selected as the relevant species for biotherapeutics programs because of the species specificity of these molecules (in contrast to small molecules, which usually have a broader range of relevant species). There are several international guidelines available to help guide nonclinical biotherapeutics development, the most notable being ICH S6(R1). These guidelines, combined with an understanding of the pharmacology of the target and the mechanism of action of the drug candidate, guide the development of the nonclinical strategy. This chapter focuses on important aspects of nonclinical toxicity programs using NHPs in the assessment of biotherapeutics, such as species selection, study design, and consideration of specialized end points/studies such as safety pharmacology, developmental and reproductive toxicity, and carcinogenicity. In addition, topics relevant to nonclinical biotherapeutics development, such as immunogenicity and hypersensitivity, are described.