Decades of experience with non-clinical safety studies using monoclonal antibodies (mAbs) has shown that the safety profile of these molecules is largely driven by their primary pharmacology or by immune responses. Pharmacological effects can largely be anticipated, and it is commonly accepted that immune responses in animals are poorly translatable to humans. Safety studies with mAbs are usually conducted in NHP because it is often the only pharmacologically responsive species that cross-react with the mAb. To evaluate chronic toxicity, ICH S6(R1) recommends both a subchronic repeat dose toxicity study and a chronic study up to 6 months in a pharmacologically responsive species. The use of NHP is ethically challenged but, more importantly, it can be debated whether it is scientifically justified to conduct studies in this species only to confirm anticipated findings. Recent research has suggested that studies with mAbs in NHP beyond 3 months offer limited additional information relevant for the clinic. In addition, a weight of evidence approach could already identify products where risk could be adequately described. In this presentation, the applicability of this Weight of Evidence approach is demonstrated using retrospective case studies and opportunities for regulatory implementation of this approach are discussed from the perspective of European regulatory procedures.
