Safety evaluation to support First-In-Man investigations II: toxicology studies.

Toxicology (single dose, range-finding, repeat dose and genotoxicity) data available in 34 Investigator's Brochures used to support First-In-Man clinical trials over a 10 year period have been evaluated to give an insight into the types of study designs used and how these have changed over the period analysed (1997-2006). Study packages had single dose toxicity studies in the rodent (although there has been a recent trend to reduce the number of these studies), range-finding toxicity studies in the rodent and non-rodent (with only small numbers of the latter used) and key 2- 4 week repeat dose toxicity studies in rodent (usually rat) and non-rodent (both dog and monkey). The majority of the latter studies established No Observed Adverse Effect Levels, showed the rodent to be generally less sensitive to target organ toxicity than the non-rodent and showed the liver and then the kidney to be the most common target organs. Genotoxicity assessment included 2 in vitro assays (a reverse mutation bacteria and either a chromosome aberration or mouse lymphoma assay) and commonly, an in vivo rodent bone marrow micronucleus test. Considerations for general toxicology and genotoxicity study designs are discussed along with the use of appropriate information to help set the clinical starting dose.