Study designs for dose-ranging.

Premarketing dose-ranging studies of a drug are done to establish a reasonable initial dose. According to the current procedure sanctioned by the 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.