[Note for evaluation of anticancer agents in man]

The working group (Giens 1996) discussed the (CPMP) note providing guidance for the clinical investigation of anticancer agents and in particular of cytotoxic agents. In Phase I trials, the methodology used relies on the assumption that active and toxic dosages will be closed (i.e. low therapeutic index) studies in normal volunteers are not required. the primary objective is the determination of the maximum tolerated dose (MTD) taking into account any corrective measure and/or prior cytotoxic chemotherapy. Characterization of frequent side-effects and of their dose relationship has to be assessed as well as the qualitative (target organ) and quantitative (predictability, extent, ...) toxicity of the drug. A recommended dose for Phase II trials has to be proposed. Phase II trials are characterized by the investigation of antitumour activity in patients with specific tumour types. Patient population (risk factors) should be clearly defined and the number of patients sufficient to meet the study objectives. Evaluation of toxicity and responses have to be documented according to international standards. Phase III trials are disease-oriented and are comparative in nature, and should allow for the full evaluation (including establishment of a treatment regimen) of the active agent selected at the end of the Phase II study. The primary endpoints are disease-free survival, overall survival and response rate. Several problem areas in the design of clinical trials have been reviewed.