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.
Buöen
Camilla
C
Department of Pharmacology, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Holm
Sture
S
Thomsen
Mikael S
MS
D000465:Algorithms; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004358:Drug Therapy; D006801:Humans; D008099:Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012107:Research Design; D018401:Sample Size
D004364:Pharmaceutical Preparations; D006899:Mixed Function Oxygenases