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

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Abstract
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 (↗). Despite the use of non‐linear mixed effect models, the potential influence of confounding factors on ↗ 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)EVsimilar to a regression to the mean gave rise to biases for ↗ designs; (ii) the introduction of a pharmacodynamic carry‐over generates important biases and imprecision for ↗ designs, even when the carry‐over is adjusted for; (iv) the introduction of non‐responders resulted in bias and imprecision for bothEmaxandED50in all three designs.