Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in phase I clinical trials

Objective: Laboratory data are key evaluation procedures for Phase I clinic al pharmacology for two reasons. Firstly, laboratory data are used within t he screening process to exclude subjects with asymptomatic diseases, which could result in increased danger to themselves or confuse interpretation of the study results. Secondly, during study implementation, safety evaluatio n and in particular maximum tolerated dose determination have to be done by a case-by-case analysis, sometimes using laboratory adverse events (LAEs). Thus, relevant limits are needed to discriminate between a usual common va riation and a significant abnormality, which is considered to be a LAE. Thi s report presents laboratory data distribution, reference values and ref er ence changes and, based on previously published new methods, suggests inclu sion limits at screening and laboratory adverse event limits for analysis d uring study implementation. Subjects and methods: Nine hundred and twenty-seven young healthy male volu nteers were recruited in one centre (Association de Recherche Therapeutique ). A standard screening process was carried out. Protocols were approved by the local ethics committee. Blood sampling was performed in the same condi tions. Reference values (at screening and at baseline) were determined by a non-parametric procedure selecting 2.5% and 97.5% of the distribution of d ata. Reference changes were also defined as the 2.5-97.5% interval of distr ibution of the variations between the end of treatment and baseline. Inclus ion limit and LAE limit methods of determination used had been specified in previous articles. Results: Detailed results of laboratory data distribution, reference values at screening and at baseline, reference changes, inclusion limits and LAE limits are presented in tables with number of subjects, mean, median, stand ard deviation, minimal and maximal values and the 2.5-97.5% interval for ea ch laboratory parameter. Conclusion: The key aims of this paper are to provide clinical pharmacologi sts with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, thes e data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies.