Study designs for dose-ranging

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Abstract
Premarketing dose-ranging studies of a drug are done to establish a reasonable initial dose. According to the current procedure sactioned by Food and Drug Administration, each patient is given one of several possible doses, including placebo, after an initial placebo run-in period. Data analysis is based on a model in which the mean response at each dose is independent of the magnitude of the dose. The initial dose is the lowest dose tested that has a response that is statistically significantly greater than the response after placebo administration. We suggest that the present conceptual approach to, and standard study design and analysis for, dose-ranging studies be changed. We believe one must begin with a parametric model for patient-specific dose-response curves. Knowledge of the distribution of these curves in a population provides a basis for choice of an initial dose (e.g., the dose that achieves a given response in a given fraction of patients) and, after observation of response to an initial dose, for choice of an incremental dose for a specific patient (by use of Bayes rule). The current parallel-dose design can provide only poor information about the distribution of dose-response curves, biased estimates of the typical curve, and little information on interpatient variability. Crossover studies provide better information. In studies in which a parametric patient-specific dose-response model is used, a dose-escalation design provides no less information than a crossover design, and it has ethical advantages that allow a more representative patient group and clinical setting to be studied.

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