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 (parallel); cross-over designs (X), and dose-escalation designs ([symbol: see text]). Despite the use of non-linear mixed effect models, the potential influence of confounding factors on [symbol: see text] 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 (Emax) and the dose giving 50 per cent of this (ED50); (ii) EV similar to a regression to the mean gave rise to biases for [symbol: see text] designs; (iii) the introduction of a pharmacodynamic carry-over generates important biases and imprecision for [symbol: see text] designs, even when the carry-over is adjusted for; (iv) the introduction of non-responders resulted in bias and imprecision for both Emax and ED50 in all three designs.