Safety Pharmacology Study Design and Statistics

The International Conference for Harmonisation harmonized tripartite guidelines S7A (2001), S7B (2005), S6 R1 (2011), and S9 (2009) not only defined the term “safety pharmacology” as an applied field of pharmacology but also defined the core battery requirements for all new pharmaceuticals entering human trials. The primary objective of the safety pharmacology core battery studies is to protect clinical trial participants and patients from potential unwanted effects of pharmaceuticals while avoiding unnecessary use of animals. For molecules starting clinical trials in healthy volunteer subjects, in vivo assessments in preclinical species of the cardiovascular, respiratory, and central nervous systems are required as even brief disruption of their function can be life threatening. Although the guidelines provide a basic framework to define the typical studies that would fulfill the requirements, there are multiple options available and factors that must be considered for each potential new molecule. This review highlights several current technologies used to assess respiratory (head-out plethysmography, whole-body plethysmography, jacketed telemetry, implanted telemetry), cardiovascular (implanted telemetry, jacketed telemetry), and neurobehavioral (functional observational battery, Irwin) functions. In addition, factors such as species, model selection, study design, inclusion of safety pharmacology endpoints onto toxicology studies, number of animals, dose selection, and sex are discussed.