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CC BY-NC-ND 4.0 · Methods Inf Med 2021; 60(01/02): 001-008
DOI: 10.1055/s-0040-1721727
Original Article

Smoothing Corrections for Improving Sample Size Recalculation Rules in Adaptive Group Sequential Study Designs

Carolin Herrmann
1   Charité—Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany
,
Geraldine Rauch
1   Charité—Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Biometry and Clinical Epidemiology, Berlin, Germany
› Author Affiliations Funding This work was supported by the German Research Foundation (grant RA 2347/4-1).
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Abstract

Background An adequate sample size calculation is essential for designing a successful clinical trial. One way to tackle planning difficulties regarding parameter assumptions required for sample size calculation is to adapt the sample size during the ongoing trial.

This can be attained by adaptive group sequential study designs. At a predefined timepoint, the interim effect is tested for significance. Based on the interim test result, the trial is either stopped or continued with the possibility of a sample size recalculation.

Objectives Sample size recalculation rules have different limitations in application like a high variability of the recalculated sample size. Hence, the goal is to provide a tool to counteract this performance limitation.

Methods Sample size recalculation rules can be interpreted as functions of the observed interim effect. Often, a “jump” from the first stage's sample size to the maximal sample size at a rather arbitrarily chosen interim effect size is implemented and the curve decreases monotonically afterwards. This jump is one reason for a high variability of the sample size. In this work, we investigate how the shape of the recalculation function can be improved by implementing a smoother increase of the sample size. The design options are evaluated by means of Monte Carlo simulations. Evaluation criteria are univariate performance measures such as the conditional power and sample size as well as a conditional performance score which combines these components.

Results We demonstrate that smoothing corrections can reduce variability in conditional power and sample size as well as they increase the performance with respect to a recently published conditional performance score for medium and large standardized effect sizes.

Conclusion Based on the simulation study, we present a tool that is easily implemented to improve sample size recalculation rules. The approach can be combined with existing sample size recalculation rules described in the literature.

Keywords

clinical trial - adaptive study design - sample size - performance evaluation

Ethical Approval

This research is exclusively based on simulations and does not involve any human subject data.


Supplementary Material



Publication History

Received: 14 August 2020

Accepted: 23 October 2020

Article published online:
01 March 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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