Nonclinical pharmacologic and toxicologic considerations for evaluating biologic products

Prior to a Phase 1 clinical study, products are studied preclinically to establish evidence of pharmacologic activity, gain an understanding of the mechanism of action, evaluate the potential human risk, and establish a clinical study dose range. Although it is possible to follow this generic itinerary for the development of biologic products, it is difficult to develop generic protocols that will suffice for addressing these preclinical concerns for every biological product. Peptide hormones, cytokines, growth factors, vaccines, allergenics, plasma proteins, enzymes, toxins, monoclonal antibodies, and other heterologous antisera are unique in their physiological interactions, and therefore the toxicologic concerns and suggested studies are tailored to the uniqueness of the compound. This paper represents an attempt to share the thought processes that have been used at the Food and Drug Administration (FDA) to address the nonclinical pharmacology and toxicology study concerns. This presentation of considerations is based on an analysis of what has been done in recent years as a basis for initiating Phase 1 studies (first administration of drugs to humans) and progressing to Phase 2/3 studies (evaluation of optimal dose, effectiveness, and safety in humans), while I was Assistant Director (Pharmacology/Toxicology) of the Office of Biologics and since, as Assistant Director (Pharmacology/Toxicology) of the Office of Drug Evaluation II and a consultant to the Center for Biologics Evaluation and Research.