Genomic Classifier for Patient Enrichment: Misclassification and Type I Error Issues in Pharmacogenomics Noninferiority Trial

Abstract

Unlike the phenotypic characteristics, a genomic diagnostic assay is needed to assess whether a patient truly has the genomic characteristics of interest for therapeutic investigation. However, in reality, the diagnostic assay is not perfect without misclassification error. We consider a targeted or enrichment pharmacogenomics clinical trial with a noninferiority objective. We assume the probability of response of the misclassified subjects is identical in the treated and control groups because the blinding should yield no preferential misclassification. We show that the maximum Type I error rate associated with falsely concluding noninferiority can be substantially liberal if the accuracy of the diagnostic assay is much less than perfect. When the diagnostic assay has moderate to high sensitivity and specificity, a reasonable range of false nondisease prediction rate among test positives can be identified where the maximum Type I error rate inflation is much less. To achieve a prescribed level of positive predictive value, the feasibility of a genomic biomarker for enrichment in a noninferiority study is a function of disease prevalence. Given the evidential standard of much less inflation of Type I error rate can be shown, a genomic biomarker, if qualified, may be useful as an adjunct tool for patient selection.

Keywords: :

• Biomarker qualification
• Disease prevalence
• False positive classification
• Nondifferential misclassification
• Noninferiority
• Positive predictive value
• Type I error probability