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.
Girard
P
P
Service de Pharmacologie Clinique, Lyon, France.
Laporte-Simitsidis
S
S
Mismetti
P
P
Decousus
H
H
Boissel
J P
JP
D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D015982:Bias; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation; D015986:Confounding Factors, Epidemiologic; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D015987:Effect Modifier, Epidemiologic; D006801:Humans; D015233:Models, Statistical; D015990:Placebo Effect; D011897:Random Allocation; D012044:Regression Analysis; D012107:Research Design
D000959:Antihypertensive Agents