Concentration-Controlled Trials: Basic Concepts, Design, and Implementation

Abstract

A Concentration-Controlled Trial (CCT) is one where subjects are assigned to predetermined levels of average plasma drug concentration. These target concentrations are achieved (within reasonable ranges) by an individualized pharmacokinetically (PK) controlled dosing scheme. In a recent paper (Sanathanan and Peck, 1991), we have investigated the sample size efficiency of the Randomized CCT (RCCT) design in comparison to the traditional Randomized Dose-Controlled Trial (RDCT). We have pointed out that in addition to safety concerns which strongly suggest the use of CCTs for drugs with narrow therapeutic windows, sample size considerations favor the choice of CCTs in many situations. In particular, substantially smaller sample sizes are possible with CCTs which are designed to minimize the interindividual PK variability within comparison groups and consequently decrease the variability in clinical response within these groups. In a subsequent paper (Sanathanan and co-workers, 1991), we proposed a Phase II randomized concentration-controlled titration design with the objective of streamlining the drug development process. In this chapter we present a brief overview of the basic concepts underlying the design and implementation of CCTs.

This work was performed while the author was employed by the Food and Drug Administration. Dr. Sanathanan is presently affiliated with IBRD (Institute for Biological Research and Development, Inc.) Blue Bell, PA.