Study designs for dose-ranging

Abstract

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.

Is there a SSRI dose response in treating major depression? The case for re-analysis of current data and for enhancing future study design

“…In drug development across all types of medicine, dose-response studies are recognized to be valuable in addressing a range of questions, including: 1) minimum and maximum ef fective doses, 2) optimal initial dose given the trade-off of ef ficacy vs. side effects, and 3) the appropriate subsequent doses if the initial dose elicits inadequate response [e.g., Emilien et al, 2000;Sheiner et al, 1989Sheiner et al, , 1991Spilker, 1991a,b]. A variety of study designs including titration, parallel group, cross-over, sequential or dose escalation, and factorial designs have been employed and their relative merits including their relative suitability to address one vs. another of the previously noted questions has been discussed [e.g., Emilien et al, 2000;Sheineret al, 1989Sheineret al, , 1991Spilker, 1991a,b].…”

Pharmacokinetic-Pharmacodynamic Modeling of Antibacterial Drugs

“…In 1981, D'Argenio performed simulations for trial design (D'Argenio, 1981), and in 1989, Sheiner and Beal presented the application of stochastic simulations for a dose-ranging study to explore different assumptions and scenarios (Sheiner et al, 1989). The concept of clinical trial simulation was extended in the 1990s to include different aspects of the trial design, the aim being to integrate relevant information before conducting the trial and thereby reduce the risk of a trial to fail because of poor design.…”

Changes in prescribed drug doses after market introduction

“…The identification of optimal dosing regimens has long been a subject of debate in clinical pharmacology, with new elements now being added by developments in pharmacogenetics. [3][4][5] The establishment of recommended dosing regimens has always been a difficult aspect of drug development. Great pressure is placed on arriving at the earliest possible definition of a recommended dose, so that definitive clinical trials can commence.…”