Broer, S. D. Lana;
White, Ian R;
Morris, Tim P;
Weir, Isabelle R;
Fiocco, Marta;
Quartagno, Matteo;
(2025)
Summary measures in non-inferiority clinical trials with a time-to-event outcome: an empirical comparison of power.
Summary measures in non-inferiority clinical trials with a time-to-event outcome: an empirical comparison of power
, 25
, Article 139. 10.1186/s12874-025-02576-4.
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Abstract
BACKGROUND: Time-to-event data is commonly used in non-inferiority clinical trials. While the hazard ratio is a popular summary measure in this context, the difference in restricted mean survival time has been theoretically shown to increase power and interpretability. This study aimed to empirically compare the power of the hazard ratio, difference in survival and difference in restricted mean survival time for non-inferiority clinical trials with a time-to-event outcome recently published in key clinical journals. METHODS: Sixty-five non-inferiority trials with a time-to-event outcome were included from two literature searches. Individual patient data were reconstructed and reanalysed. The hazard ratio, difference in survival and difference in restricted mean survival time were estimated under proportional hazards, using a Cox model for the hazard ratio and a flexible parametric survival model for the latter two summary measures. The latter measures were additionally estimated non-parametrically. Margin conversion was done using observed data in the control arm. Empirical power was defined as the proportion of trials that rejected the null hypothesis. RESULTS: Difference in restricted mean survival time gave a potential power advantage over the hazard ratio with an empirical power increase of percentage points, and consistently outperformed difference in survival. Difference in survival was more powerful than the hazard ratio, but while difference in restricted mean survival time showed an empirical power advantage even when estimated non-parametrically, this was not generally true for difference in survival. Sub-group analyses consistently showed similar results. Results were more variable when converting margins under an exponential distribution, highlighting the importance of correct margin conversion. CONCLUSION: Our results empirically corroborate the theoretical advantage of difference in restricted mean survival time over the hazard ratio and difference in survival in non-inferiority clinical trials. This advantage is most apparent when estimation is done under proportional hazards. Choosing a relevant time point at which to evaluate the survival-based summary measures is an important aspect that should be carefully considered. We recommend incorporation of the difference in restricted mean survival time in the design and analysis of non-inferiority clinical trials when clinically justifiable. If appropriate, estimation under proportional hazards is preferable.
| Type: | Article |
|---|---|
| Title: | Summary measures in non-inferiority clinical trials with a time-to-event outcome: an empirical comparison of power |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s12874-025-02576-4 |
| Publisher version: | https://doi.org/10.1186/s12874-025-02576-4 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. |
| Keywords: | Power, Non-inferiority, Time-to-event data, Proportional hazards, Hazard ratio, Diference in survival, Restricted mean survival time |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10209029 |
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