Safety and Toxicology Studies

Histiopathic examination of the heart is necessarily an integral part of the echocardiographic studies performed to investigate effects on cardiac function in the dog and monkey. Properly formulated patterns of histio-pathologic findings similar to those reports in the safety and toxicology studies, with myocardial necrosis of the papillary muscle, intraventricular septum, and left ventricular wall, are seen. 

No adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine. Therefore preclinical and toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/ vaccine combination [60], Evaluation in preclinical studies is important for identifying the optimum composition and formulation process and also for allowing development of tests for quality control [61]. Data from these studies also helps plan protocols for subsequent clinical trials from which safety and efficacy in humans can be evaluated. 

Safety concerns may arise from the presence of impurities or contaminants. It is preferable to rely on purification processes to remove impurities and contaminants rather than to establish a preclinical testing program for their qualification. In all cases, the product should be sufficiently characterized to allow an appropriate design of preclinical safety studies. In general, the product that is used in the definitive pharmacology and toxicology studies should be comparable to the product proposed for the initial clinical studies. (ICH S6)... 

Although differing in format for each application, an integrated summary that interrelates the pharmacology, pharmacokinetic and toxicology study information, and what significance the data has to human safety, is paramount (Peck et al., 1992). A... 

Current advances in epidemiological and toxicology studies have documented the potential harm that PAHs pose to human health. Therefore, the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) have published exposure standards for individuals working in facilities that use or handle PAHs. For example ... 

Development usually starts with the discovery synthesis, a process designed to produce only small quantities, and often involving chemicals and procedures not amenable to a manufacturing process. Early development converts the discovery route to a synthetic route that does not have chemical, safety, environmental, or operational issues that would prevent it from being commercially viable. This must be done before the drug substance solid form and impurity profile become set by formulation development and toxicological studies. 

Comparison of metabolic pathways across species which can in turn be used to explain pharmacologic or toxicologic differences between species Justification of species for preclinical safety and pharmacokinetics studies Help identify enzyme systems involved in metabolic clearance Support clinical development... 

---