title: First exposure in man: toxicological considerations.
abstract: The safety of a volunteer/patient who participate in the very first human trial relies on data from animal experimentation and on the design of the trial. Recommendations on the type and extent of preclinical safety studies that should be conducted prior to first dose in man have been developed by the International Conference on Harmonisation, and the European Committee for Proprietary Medicinal Products. These recommendations include studies designed to characterise local tolerance and general toxicity of the drug candidate as well as its genotoxic potential and ability to interfere with reproduction. For trials which can be categorised as low dose PK screening trials and trials with products where rodent and non-rodent (primarily dog) models do not show any biological response (e.g. some biotechnology-derived hormones and cytokines) other testing paradigms should be used. The present recommendations for preclinical testing have had an important impact on the documented impressive safety record of phase I clinical trials. In this spirit we extend our warmest and sincerest thanks to Professor Jens S. Schou for his long and deep engagement in European and International harmonisation of preclinical test recommendations. His efforts have had a substantial impact on the present testing recommendations, which are of obvious benefit to the safety of the patient.
authors.affiliation: Danish Medicines Agency, Bronshøj. pesp@novo-dk
authors.forename: P
authors.initials: P
authors.lastname: Spindler
authors.forename: P
authors.initials: P
authors.lastname: Sjöberg
authors.forename: L E
authors.initials: LE
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods*; D004285:Dogs; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005260:Female; D017408:Guidelines as Topic; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D009152:Mutagenicity Tests; D012377:Rodentia