A New Overall-Subgroup Simultaneous Test for Optimal Inference in Biomarker-Targeted Confirmatory Trials

  • Ilana Belitskaya-Lévy
  • Hui Wang
  • Mei-Chiung Shih
  • Lu Tian
  • Gheorghe Doros
  • Robert A. Lew
  • Ying Lu
Article

Abstract

We propose a joint hypothesis test for simultaneous confirmatory inference in the overall population and a pre-defined marker-positive subgroup under the assumption that the treatment effect in the marker-positive subgroup is larger than that in the overall population. The proposed confirmatory overall-subgroup simultaneous test (COSST) is based on partitioning the sample space of the test statistics in the marker-positive and marker-negative subgroups. We define two rejection regions in the joint sample space of the two test statistics: (1) efficacy in the marker-positive subgroup only; (2) efficacy in the overall population. COSST achieves higher statistical power to detect the overall and subgroup efficacy than most sequential procedures while controlling the family-wise type I error rate. COSST also takes into account the potentially harmful effect in the subgroups in the decision. The optimal rejection regions depend on the specific alternative hypothesis and the sample size. COSST can be useful for Phase III clinical trials with tailoring objectives.

Keywords

Subgroup test Confirmatory clinical trial Biomarker 

Supplementary material

12561_2016_9174_MOESM1_ESM.pdf (2 mb)
Supplementary material 1 (pdf 2053 KB)
12561_2016_9174_MOESM2_ESM.pdf (304 kb)
Supplementary material 2 (pdf 304 KB)
12561_2016_9174_MOESM3_ESM.docx (367 kb)
Supplementary material 3 (docx 367 KB)

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Copyright information

© Springer Science+Business Media New York (outside the US) 2016

Authors and Affiliations

  • Ilana Belitskaya-Lévy
    • 1
  • Hui Wang
    • 1
  • Mei-Chiung Shih
    • 1
  • Lu Tian
    • 2
  • Gheorghe Doros
    • 3
  • Robert A. Lew
    • 3
    • 4
  • Ying Lu
    • 1
    • 2
  1. 1.Department of Veterans AffairsCooperative Studies Program Palo Alto Coordinating CenterMountain ViewUSA
  2. 2.Department of Health Research and Policy, Stanford University School of MedicineStanford UniversityStanfordUSA
  3. 3.Department of BiostatisticsBoston University School of Public HealthBostonUSA
  4. 4.Department of Veterans AffairsCooperative Studies Program Boston Coordinating CenterJamaica PlainUSA

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