INFLUENCE OF CONFOUNDING FACTORS ON DESIGNS FOR DOSE-EFFECT RELATIONSHIP ESTIMATES

Three types of designs can be used to estimate the drug dose-effect relationship during phase II clinical trials: parallel-dose designs (//); cross-over designs (X), and dose-escalation designs (NE arrow). Despite the use of non-linear mixed effect models, the potential influence of confounding factors on NE arrow designs has not been previously fully elucidated; we undertook simulations to investigate this for all three experimental designs. We found that: (i) monotonic spontaneous evolution of the effect (EV) did not affect the maximum effect estimation (E(max)) and the dose giving 50 per cent of this (ED(50)); (ii) EV similar to a regression to the mean gave rise to biases for NE arrow designs; (ii) the introduction of a pharmacodynamic carry-over generates important biases and imprecision for NE arrow designs, even when the carry-over is adjusted for; (iv) the introduction of non-responders resulted in bias and imprecision for both E(max) and ED(50) in all three designs.