On the Efficiency of Interim Analyses Applied to Nonclinical Studies

Abstract

Interim analyses, commonly applied in clinical trials, are rarely used in the nonclinical field, although they are potentially useful for ethical and practical reasons. The purpose of our work was to evaluate the benefits of such analyses in the discovery area, with the aim of reducing sample size. Following a literature review, we focused on the Bauer and KOhne method (Biometrics 1994) because it allows early stopping in favor of HO and H1 in either one- or two-sided situations. Moreover, as the methodology is based on Fisher combination of P values, it can be applied to any selected statistical test. Early stopping requires the selection of two interdependent parameters: α 0 and α 1 (thresholds for early stop in favor of HO and H1, respectively) while controlling the type I error rate. The efficiency of the several-stage design compared to the single-analysis design was investigated using simulations based on realistic characteristics of the preclinical area: small sample sizes, low expected proportions of active compounds in screening process, and large effect sizes. The assessment criteria were (1) the sample size gain compared to the single-analysis design at fixed power and (2) the proportions of early stops in favor of HO and/or HI. In addition, the simulations allowed the determination of optimal values for α 0 and α 1 . Results obtained in one- and two-sided situations in the case of a two-group comparison using a two-stage design are presented and illustrated in an application. Our first results led, within a relatively simple framework, to the conclusion that although appealing, interim analyses have a smaller application potential in terms of sample size reduction in the nonclinical field than initially expected.