Statistical methods for time-to-event endpoints with non-proportional hazards in clinical trials pivotal for benefit risk decision making

Study identification

• PURI:
  https://redirect.ema.europa.eu/resource/49976
• EU PAS number:
  EUPAS46420
• Study ID:
  49976
• Official title and acronym:
  Statistical methods for time-to-event endpoints with non-proportional hazards in clinical trials pivotal for benefit risk decision making
• DARWIN EU® study:
  No
• Study countries:
  Austria

  Germany

  Sweden
• Study description:
  While well-established methods for time-to-event data are available when the proportional hazards assumption holds, there is no consensus on the best approach under non-proportional hazards. However, a wide range of parametric and non-parametric methods for testing and estimation in this scenario have been proposed. The main objective of this work is to provide recommendations on the statistical analysis and reporting of clinical trials where non proportional hazards are expected, e.g. when treatments have a delayed onset of the treatment effect, if efficacy of the treatment wanes over time, or if the treatment effect is not homogeneous in the population. To this end, we will first perform a literature review on the available methods, review the availability of statistical software that implement these methods, and review scientific advice and marketing authorization procedures to identify relevant scenarios where non-proportional hazards occur. Based on this review, a set of methods will be selected for further assessment. Furthermore, their theoretical properties will be reviewed and operating characteristics will be investigated in an extensive simulation study under a wide range of scenarios considering different trial designs, recruitment and censoring patterns as well as different shapes of the hazard functions.
• Study status:
  Finalised

Research institution and networks

Institutions

Medical University of Vienna

Austria

Universitätsmedizin Göttingen Robert-Koch-Str. 40, 37075 Göttingen, Germany, Uppsala Universitet Von Kraemers Allé 4, 751 05 Uppsala, Sweden, Österreichische Agentur für Gesundheit und Ernährungssicherheit GmbH Spargelfeldstraße 191, 1220 Wien, Austria

Study timelines

Date when funding contract was signed

Planned: 10/12/2021

Actual: 10/12/2021

Study start date

Planned: 24/03/2022

Actual: 24/03/2022

Date of final study report

Planned: 31/01/2023

Actual: 26/06/2023

Sources of funding

EMA

Study protocol

Initial protocol

2022-10-14 CONFIRMS Simulation Study Protocol rev2

Regulatory

• Was the study required by a regulatory body?:
  Yes
• Is the study required by a Risk Management Plan (RMP)?:
  Not applicable