Phase I clinical trials: what is the minimum preclinical package necessary for initiating single-dose studies in man? — a toxicologist’s opinion

Abstract

1. To achieve harmonisation of the requirements for toxicity testing to support the initiation of single-dose studies in man between Europe, the USA and Japan, more emphasis should be placed on the scientific rationale as presented in the safety assessment document (SAD). The SAD contains a summary of the preclinical findings, with a discussion of their clinical relevance, including a quantitative and qualitative assessment. 2. The normal set of toxicity studies for a single-dose Phase I study in humans consists of: single-dose toxicity studies in two animal species using one or two routes of administration; repeated dose toxicity studies in two species using the clinical route of administration and lasting two to four weeks; and two mutagenicity studies, usually an in vitro Ames test and an in vivo micronucleus test. 3. Harmonisation should focus on a flexible, safety-based approach. In addition to optimal compliance with the scientific, regulatory and legal aspects for initiating the first clinical trials in man, ethical considerations are important for both human exposure and laboratory animal use.