Design and analysis of biomarker-integrated clinical trials with adaptive threshold detection and flexible patient enrichment

ABSTRACT

We propose a new adaptive threshold detection and enrichment design in which the biomarker threshold is adaptively estimated and updated by optimizing a trade-off between the size of the biomarker positive population and the magnitude of the treatment effect in that population. Enrichment is based on an enrollment criterion that accounts for the uncertainty in estimation of the threshold. Early termination for futility is allowed based on predictive success probability. Valid testing and estimation techniques for the treatment effect overall and inpatient subgroups are studied. Simulations and an example demonstrate advantages of the proposed design over existing designs.

Key words:

• biomarker-integrated clinical trials
• adaptive threshold estimation
• continuous biomarker
• multi-stage design
• patient enrichment
• predictive probability of success
• testing and estimation of treatment effects

Acknowledgments

The research work was partly supported by National Cancer Institute grant P01CA142538 (Ting Wang, Xiaofei Wang and Haibo Zhou), National Institute of Environmental Health Sciences grant P30ES010126 (Ting Wang and Haibo Zhou), and National Institute on Aging grant R01AG066883 (Xiaofei Wang).

Disclosure statement

The authors declare no potential conflict of interests.

Additional information

Funding

This work was supported by the National Cancer Institute [P01CA142538]; National Institute on Aging [R01AG066883]; National Institute of Environmental Health Sciences [P30ES010126] and [P42ES031007].