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Evaluation of the Cohort Size in Phase I Dose Escalation Trials Based on Laboratory Data

From the Department of Pharmacology, Royal Danish School of Pharmacy, Copenhagen, Denmark (Ms. Buöen); Chalmers University of Technology, Gothenburg, Sweden (Dr. Holm); and Novo Nordisk A/S, Copenhagen, Denmark (Dr. Thomsen).

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.

Key Words: Phase I study design • dose escalation • cohort size • safety evaluation

Address for reprints: Camilla Buöen, Novo Nordisk A/S, Krogshoejvej 53 A, DK-2880 Bagsvaerd, Denmark.

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				C. Buoen, O. J. Bjerrum, and M. S. Thomsen 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 J. Clin. Pharmacol., October 1, 2005; 45(10): 1123 - 1136. [Abstract] [Full Text] [PDF]