A Changing Paradigm For Non-Rodent Species In Nonclinical Safety Studies

Drug development is a highly regulated field, with guidance documents available to assist in determining the appropriate species for nonclinical safety studies. The most commonly referenced guidelines are ICH S6 (R1) for biologics and ICH M3 (R2) for small molecules. For small molecules, nonclinical safety studies require two mammalian species: a rodent and a non-rodent, with species selection primarily based on metabolism. Traditionally, the dog has been the non-rodent species of choice for most programs. For biologics, safety studies should only be conducted in ‘pharmacologically relevant’ species, and in some cases, a single species may suffice.

Nonclinical safety studies in non-relevant species are strongly discouraged. The non-human primate (NHP) is the most commonly used non-rodent species in large molecule programs. When there is no clear distinction based on metabolism or pharmacology, other factors are considered in species selection, such as metabolic and pharmacokinetic profiles, plasma protein binding, and potential tolerability concerns like histamine release or emesis. Additional considerations include the availability of historical data for various species and strains, as well as practical aspects like the route of administration and the ease of performing certain procedures in specific species.

Initially used for medical research in Europe, miniature swine were introduced to the U.S. in the 1980s. Their use is now extending to many therapeutic areas due to an increasing body of knowledge supporting their appropriateness for nonclinical safety studies.