How first-time-in-human studies are being performed: a survey of phase I dose-escalation trials in healthy volunteers published between 1995 and 2004.

First-time-in-human studies are small, time-lagged dose-escalation studies including volunteer subjects evaluating safety and tolerability. There is little consensus in the design of a first-time-in-human study, and it is difficult to get an overview of studies performed. One hundred five studies comprising 3323 healthy volunteers published in the 5 major clinical pharmacology journals since 1995 were analyzed. The average trial was placebo controlled, double blind including 32 subjects at 5 dose levels but with great variation in cohort size and dose-escalation method. The parallel single-dose design was the most common design, with the crossover designs being more frequent in the early publications. Despite discussions on the optimization of phase I trials, little seems to be happening. The development of study designs and evaluation methods for cancer trials is extensive, but formal statistically based methods and more scientific study designs are unusual in phase I dose-escalation trials in healthy volunteers.

Evaluation of the cohort size in phase I dose escalation trials based on laboratory data.

A survey of Phase I dose escalation trials published since 1995 shows that there is great disparity in all aspects of the design of the studies, and the cohort sizes range from 2 to 16 subjects with a great variety in the distribution between active and placebo-treated subjects. This study investigates the impact of the cohort size on Type I error and power in Phase I dose escalation trials based on laboratory data, with the hospitalization-induced increase in hepatic enzyme levels taken into consideration. The power of a Phase I dose escalation trial is very low, and only events with a very high probability of occurrence are detectable with acceptable power. For studies with cohort sizes smaller than 6 active subjects, there is much to gain with the inclusion of 1 extra subject, but for more than 10 subjects, little is gained by increasing the cohort size. With increasing cohort sizes, the probability of spontaneous non-drug-related events also increases, and this background rate needs to be considered when evaluating the trial.