The application of ICH S6 to the preclinical safety evaluation of plasma derivative therapeutic products.

The ICH S6 guidance was developed to describe a rational science-based flexible approach to the preclinical evaluation for biotechnology-derived pharmaceutical products. It also suggested that some of the principles described may be suitable for plasma-derived therapeutics. Some of the specific concerns unique to protein-based therapeutics include complexity in structure and potential immunogenicity. S6 has been interpreted by some industry and regulatory authorities, often due to lack of experience with these types of products, as encouraging a broader or more conventional toxicology program similar to that normally conducted for small molecules. The guidance does encourage important and necessary preclinical evaluations but also recognizes the limitations of studies in non-relevant animal species because they are without pharmacological interaction with the biologic. In addition, studies of human proteins are often limited in useful chronic, reproductive and carcinogenic toxicity evaluations by the immunological response in animals. Thus the safety evaluation of biopharmaceuticals and plasma derivatives in animals has limitations that cannot be adequately addressed by the use of testing paradigms used for small molecule pharmaceuticals. S6 focuses evaluations on well-designed studies in relevant species for reasonable time periods to make the best use of available resources and enable clinical trials.