Issues with introducing new immunotoxicology methods into the safety assessment of pharmaceuticals.

Unfortunately, the principal routine toxicology methods employed for the safety assessment of new products are over 40 years old and rely primarily on histopathological evaluation. It is difficult to introduce newer immunotoxicology or molecular toxicology methods into toxicity assessment without extensive and time consuming validation requiring several years due to concern for standardization of methods, inter-laboratory replication of these methods and resistance to acceptance of new methods by both regulatory agencies and industry. During the past 15 years, significant progress has occurred in the fields of molecular biology and basic/clinical immunology which promoted the establishment of newer more sensitive methods to assess cell injury or immune system effects in humans and laboratory animals. This brings us to the challenges associated with trying to introduce new immunotoxicology or molecular toxicology methods into the safety assessment of new products. Our experience at Sanofi Research with immunotoxicity methods development or validation and approaches for molecular toxicology and their application to the preclinical development of new chemical drug entities (NCE) will be discussed. Laboratories to investigate immunotoxicity and molecular toxicology were established during the past 10 years among several industrial research groups for the evaluation of new chemicals and drug candidates. Immunotoxicology methods have been selected and optimized for rodent testing leading to four inter-laboratory collaborative studies to demonstrate the reproducibility and value of these methods for predicting toxicity. Our experience at Sanofi has led us to believe that these newer methods can represent an important part of drug development, should be applied on an as needed basis, and should be driven by data suggestive of an immune or molecular toxicology effect or by the class of the chemical being evaluated. Ex vivo and in vitro assays are selected from a menu of validated methods for application on a case-by-case basis. Results in this area with inter-laboratory validation of these methods will be discussed. Newer molecular toxicology and immunotoxicity methods are beginning to play a more important role in the safety evaluation and risk assessment process.