The 3R concept and DART evaluation in nonhuman primates – an appraisal

抄録

Nonhuman primate (NHP) models play an important role in the development and safety assessment of (bio)pharmaceuticals depending on the particular properties of the drug candidate. In many instances, the experimental use of NHPs is subject to special regulations and animal welfare considerations among which the 3R principles are of pivotal importance. Since NHP models will unlikely be replaced by alternatives in the near future, 3R efforts should focus on reduction and refinement. For reduction, some guideline changes related to biologics –ICH M3(R2) and ICH S6(R1) – can provide an option for using lesser NHPs. ICH S6(R1) makes specific recommendations on how many live infants are required per group for a NHP pre- and postnatal development study. This recommendation in conjunction with the use of reference data and normogram data can be used to reduce the number of NHPs needed for developmental toxicity testing. Also, under certain circumstances, the conduct of dedicated reproductive toxicity evaluation as per ICH S5(R2) can be incorporated in chronic toxicity studies thus further lowering the demand for NHPs. Importantly, refinement should be a key focus of any 3R efforts in order to optimize the use of NHP models. Recent work has provided statistical power estimates for some fertility parameters relative to group size that will aid developing appropriate study designs. Also, the potential of combining pre- and postnatal testing with juvenile toxicity testing has been raised. In summary, various options are available to optimize NHP DART testing in the spirit of 3R.