Using a dose-finding benchmark to quantify the loss incurred by dichotomization in Phase II dose-ranging studies

Pavel Mozgunov (1) , Thomas F. Jaki (1) , Xavier Paoletti (2, 3)

1 Lancaster University
2 CESP - Centre de recherche en épidémiologie et santé des populations
3 Institut Curie

While there is recognition that more informative clinical endpoints can support better decision-making in clinical trials, it remains a common practice to categorize endpoints originally measured on a continuous scale. The primary motivation for this categorization (and most commonly dichotomization) is the simplicity of the analysis. There is, however, a long argument that this simplicity can come at a high cost. Specifically, larger sample sizes are needed to achieve the same level of accuracy when using a dichotomized outcome instead of the original continuous endpoint. The degree of “loss of information” has been studied in the contexts of parallel-group designs and two-stage Phase II trials. Limited attention, however, has been given to the quantification of the associated losses in dose-ranging trials. In this work, we propose an approach to estimate the associated losses in Phase II dose-ranging trials that is free of the actual dose-ranging design used and depends on the clinical setting only. The approach uses the notion of a nonparametric optimal benchmark for dose-finding trials, an evaluation tool that facilitates the assessment of a dose-finding design by providing an upper bound on its performance under a given scenario in terms of the probability of the target dose selection. After demonstrating how the benchmark can be applied to Phase II dose-ranging trials, we use it to quantify the dichotomization losses. Using parameters from real clinical trials in various therapeutic areas, it is found that the ratio of sample sizes needed to obtain the same precision using continuous and binary (dichotomized) endpoints varies between 70% and 75% under the majority of scenarios but can drop to 50% in some cases.

Mots clés: continuous endpoint; dichotomization; dose-ranging trials; nonparametric optimal benchmark; phase II

Domaines: Sciences du Vivant [q-bio]

Pavel Mozgunov, Thomas F. Jaki, Xavier Paoletti. Using a dose-finding benchmark to quantify the loss incurred by dichotomization in Phase II dose-ranging studies. Biometrical Journal, 2020, 62 (7), pp.1717-1729. ⟨10.1002/bimj.201900332⟩. ⟨hal-03032293⟩