The randomized concentration-controlled trial: an evaluation of its sample size efficiency

A randomized concentration-controlled trial (RCCT) is one in which subjects are randomly assigned to predetermined levels of average plasma drug concentration. These target concentrations can be achieved (within reasonable ranges) by an individualized pharmacokinetically controlled dosing scheme. The RCCT is designed to minimize the interindividual pharmacokinetic (PK) variability within comparison groups and consequently decrease the variability in clinical response within these groups. In this paper, we investigate the extent of improvement in sample size efficiency that can be gained from the RCCT design in comparison to the traditional randomized dose-controlled trial (RDCT) design. Our investigations involve both theoretical arguments and simulation studies, illustrated with data on PK and pharmacodynamic (PD) characteristics of the antiasthma drug theophylline. Aside from safety concerns that strongly suggest the use of RCCT for drugs with narrow therapeutic windows, sample size considerations favor the choice of RCCT in many situations, as shown in this paper.