Improved two-stage group sequential procedures for testing a secondary endpoint after the primary endpoint achieves significance

Huiling Li, Jianming Wang, Xiaolong Luo, Janis Grechko, Christopher Jennison

Research output: Contribution to journalArticlepeer-review

2 Citations (SciVal)


In two-stage group sequential trials with a primary and a secondary endpoint, the overall type I error rate for the primary endpoint is often controlled by an α-level boundary, such as an O'Brien-Fleming or Pocock boundary. Following a hierarchical testing sequence, the secondary endpoint is tested only if the primary endpoint achieves statistical significance either at an interim analysis or at the final analysis. To control the type I error rate for the secondary endpoint, this is tested using a Bonferroni procedure or any α-level group sequential method. In comparison with marginal testing, there is an overall power loss for the test of the secondary endpoint since a claim of a positive result depends on the significance of the primary endpoint in the hierarchical testing sequence. We propose two group sequential testing procedures with improved secondary power: the improved Bonferroni procedure and the improved Pocock procedure. The proposed procedures use the correlation between the interim and final statistics for the secondary endpoint while applying graphical approaches to transfer the significance level from the primary endpoint to the secondary endpoint. The procedures control the familywise error rate (FWER) strongly by construction and this is confirmed via simulation. We also compare the proposed procedures with other commonly used group sequential procedures in terms of control of the FWER and the power of rejecting the secondary hypothesis. An example is provided to illustrate the procedures.

Original languageEnglish
Pages (from-to)893-902
Number of pages10
JournalBiometrical Journal
Issue number5
Early online date7 Jun 2018
Publication statusPublished - 1 Sept 2018


  • closed testing
  • graphical approach
  • group sequential
  • hierarchical testing
  • multiple endpoints

ASJC Scopus subject areas

  • Statistics and Probability
  • Statistics, Probability and Uncertainty


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