COMPARATIVE EFFICIENCIES OF RANDOMIZED CONCENTRATION-CONTROLLED AND DOSE-CONTROLLED CLINICAL-TRIALS

Objective: To compare efficiencies of randomized dose- and concentration-controlled trials (RDCT and RCCT) for estimating the parameters of concentration-effect relationships. Rationale: In 1991 Sanathanan and Peck (Controlled Clin Trials 1991;12:780-94) suggested that estimation by RDCT is biased and much less efficient than analysis by RCCT. Their conclusion was based on a pharmacodynamic model that characterizes the effect of theophylline in subjects with asthma, in which the response was related linearly to a limited range of concentrations and independent of concentration otherwise. Therefore it was intended to explore whether the conclusion of Sanathanan and Peck applied to other pharmacodynamic models. Results: The results of Sanathanan and Peck were confirmed for the restricted linear, baseline-plateau model: with large pharmacokinetic and no pharmacodynamic variability, RCCT was 3.1 times more efficient than RDCT. However, under the same conditions, the efficiency of RCCT exceeded that of RDCT only 1.5 and 1.2 times when response was related, without restrictions, to concentration and log concentration, respectively. Moreover, in the presence of even moderate pharmacodynamic variability, the ratio of RCCT/RDCT efficiencies did not exceed 1.30 and 1.08, respectively. The parameters estimated by RDCT with these two models were not biased. Finally, in the presence of interindividual variability of the median effective concentration (EC(50)), pharmacokinetic variability did not affect the observed variation of the parameters in the log-linear pharmacodynamic relationship. Conclusions: RCCT generally estimates pharmacodynamic parameters with an efficiency that is not much higher than, or even similar to, those yielded by RDCT. Therefore statistical benefits often do not call for the application of RCCT. However, sometimes its use should be seriously considered, particularly for drugs having small therapeutic indexes or when the baseline and plateau of the response occur near the therapeutic region of concentrations.