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. 2019 Dec 20;38(29):5445-5469.
doi: 10.1002/sim.8370. Epub 2019 Oct 17.

Two-stage enrichment clinical trial design with adjustment for misclassification in predictive biomarkers

Yong Lin  1   2 , Weichung J Shih  1   2 , Shou-En Lu  1   2
Affiliations

Two-stage enrichment clinical trial design with adjustment for misclassification in predictive biomarkers

Yong Lin et al. Stat Med. .

Abstract

A two-stage enrichment design is a type of adaptive design, which extends a stratified design with a futility analysis on the marker negative cohort at the first stage, and the second stage can be either a targeted design with only the marker positive stratum, or still the stratified design with both marker strata, depending on the result of the interim futility analysis. In this paper, we consider the situation where the marker assay and the classification rule are possibly subject to error. We derive the sequential tests for the global hypothesis as well as the component tests for the overall cohort and the marker-positive cohort. We discuss the power analysis with the control of the type I error rate and show the adverse impact of the misclassification on the powers. We also show the enhanced power of the two-stage enrichment over the one-stage design and illustrate with examples of the recent successful development of immunotherapy in non-small-cell lung cancer.

Keywords: composite hypothesis; enrichment design; predictive biomarker; sensitivity and specificity.

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Figures

FIGURE 1
FIGURE 1
Contour of global power surface for α = 0.025
FIGURE 2
FIGURE 2
Contour of power surface for overall cohort effect when α = 0.025
FIGURE 3
FIGURE 3
Contour of power surface for marker-positive cohort effect when α = 0.025
FIGURE 4
FIGURE 4
Power and sample size comparison between two-stage and single stage design
See this image and copyright information in PMC

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References

    1. Renfro LA, Mallick H, An MW, Sargent DJ, Mandrekar SJ. Clinical trial designs incorporating predictive biomarkers. Cancer Treatment Reviews. 2016;43:74–82. - PMC - PubMed
    1. Shih WJ, Lin Y. On study designs and hypotheses for clinical trials with predictive biomarkers. Contemporary Clinical Trials. 2017;:235–394. - PubMed
    1. Shih WJ, Lin Y. Relative efficiency of precision medicine designs for clinical trials with predictive biomarkers. Statistics in Medicine. 2018;54(3):411–424. - PMC - PubMed
    1. Wang SJ, O’Neill RT, Hung HMJ. Approaches to evaluation of treatment effect in randomized clinical trials with genomic subset. Pharmaceutical Statistics. 2007;6(3):227–244. - PubMed
    1. Wang SJ, Hung HMJ, O’Neill RT. Adaptive patient enrichment designs in therapeutic trials. Biometrical Journal. 2009;51:358–374. - PubMed

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