Kristin Karlsson, Mats O. Karlsson, Anders Grahnén and E. Niclas Jonsson
Uppsala University, Sweden
Background: Historically the most used clinical trial design to describe the effectiveness of a drug is the randomized dose-controlled clinical trial (RDCT). About a decade ago an alternative to the RDCT was introduced; the randomized concentration-controlled trial (RCCT) design [1]. Contrary to the RDCT, the RCCT consider the pharmacokinetic variability and is suggested to be used to characterize exposure-response relations to achieve a theoretical gain in statistical power. However, it has been shown that the gain in statistical power with the RCCT design is model dependent [2].
Aim: To investigate, from a power point of view, the hypothesis that the most beneficial trial design and analysis strategy is to randomize as far as possible from, and use an independent variable as close as possible to the clinical endpoint in the mechanistic pathway of drug response.
Methods: The hypothesis is tested using simulations where the basic setup consists of a one compartment pharmacokinetic model at steady state conditions and a sigmoidal Emax pharmacodynamic model. The studies are simulated with randomization schemes on dose (RDCT) and concentration (RCCT), and the analysis of the data is performed with dose and concentration as independent variables, respectively. The significance criterion used for the statistical power of the studies is the log-likelihood ratio test. All the simulations and the analyses were made in the NONMEM software.
Results: The RDCT with concentration as the independent variable in the analysis yield the greatest power followed by the RCCT with concentration as the independent variable in the analysis.
Discussion: Our hypothesis seems to hold under the simulation conditions used. Real-life factors that may influence this result are: correlation between pharmacokinetic and pharmacodynamic parameters, patient drop-outs and model misspecification or complexity. Another real-life factor that may influence the randomization scheme, from a side-effect perspective, is safety, i.e. it may be necessary to have close control of the drug concentration levels that patients are exposed to and this may necessitate an RCCT design despite its expected lower statistical power.
References:
[1] Sanathanan LP, Peck CC. The randomized concentration-controlled clinical trial: an evaluation of its sample size efficiency. Control Clin Trials 1991;12:780-94.
[2] Endrenyi L, Zha J. Comparative efficiencies of randomized concentration- and dose-controlled clinical trials. Clin Pharmacol Ther 1994;56:331-8.
Reference: PAGE 12 (2003) Abstr 428 [www.page-meeting.org/?abstract=428]
Poster: poster