Safety testing preclinical

The last step of the drug discovery process involves the testing of lead compounds to address issues such as efficacy, bioavailability, and safety. Testing may include in vitro assays but ultimately would require a suitable disease model and studies in animals. Many compounds may need to be designed and synthesized to identify the one compound with all the desired properties. Such a compound can be advanced to preclinical studies and eventually to the clinic. 

By the time Phase III testing is completed, some additional preclinical safety tests must also generally be in hand. These include the three separate reproductive and developmental toxicity studies (Segments I and III in the rat, and Segment II in the rat and rabbit) and carcinogenicity studies in both rats and mice (unless the period of therapeutic usage is intended to be very short). Some assessment of genetic toxicity will also be expected. 

Oral contraceptives are subject to special testing requirements. These have recently been modified so that in addition to those preclinical safety tests generally required, the following are also required (Berliner, 1974) ... 

CPMP (1989). Guidelines on the preclinical biological safety testing of medicinal products derived from biotechnology. TIBTECH 7 613-617. 

The appropriate animal model is also important when performing follow-up testing or additional mechanistic tests to further investigate findings observed as part of the routine preclinical safety tests. When possible, these studies should employ the same animals or animal model in which the change was initially observed for several reasons, as outlined by Bloom et al. (1987), including ... 

As a tool to make mutual acceptance of risk assessments possible, OECD has developed the concept of Good Laboratory Practice (GLP). The OECD Principles of GLP are an integral part of the 1981 OECD council decision on the Mutual Assessment of Data (MAD) in the Assessment of Chemicals (revised 1997, Section 2.2.2). MAD also harmonizes procedures of GLP compliance monitoring, ensuring that preclinical safety studies are carried out according to the principles of GLP and that countries can have conftdence in the quahty and rigor of safety tests. 

Chapman K et al (2007) Preclinical safety testing of monoclonal antibodies the significance of species relevance. Nat Rev Drug Discov 6 120-126... 

Brennan FR, Shaw L, Wing MG, Robinson C. Preclinical safety testing of biotechnology-derived pharmaceuticals. Mol Biotechnol 2004 27 59-74. 

Clarke J, Leach W, Pippig S, et al. Evaluation of a surrogate antibody for preclinical safety testing of an anti-CDlla monoclonal antibody. Reg Toxicol Pharmacol 2004 40 219-26. 

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