Journal
JOURNAL OF BIOPHARMACEUTICAL STATISTICS
Volume 24, Issue 5, Pages 1011-1021Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/10543406.2014.931411
Keywords
Ascertainment; Biomarker; Clinical trials; Stratification
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Funding
- Intramural NIH HHS [Z99 CA999999] Funding Source: Medline
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This article examines the role of stratification of treatment assignment with regard to biomarker value in clinical trials that accept biomarker-positive and -negative patients but have a primary objective of evaluating treatment effect separately for the marker-positive subset. It also examines the issue of incomplete ascertainment of biomarker value and how this affects inference about treatment effect for the biomarker-positive subset of patients. I find that stratifying the randomization for the biomarker ensures that all patients will have tissue collected but is not necessary for the validity of inference for the biomarker-positive subset if there is complete ascertainment. If there is not complete ascertainment of biomarker values, it is important to establish that ascertainment is independent of treatment assignment. Having a large proportion of cases with biomarker ascertainment is not necessary for establishing internal validity of the treatment evaluation in biomarker-positive patients; independence of ascertainment and treatment is the important factor. Having a large proportion of cases with biomarker ascertainment makes it more likely that biomarker-positive patients with ascertainment are representative of the biomarker-positive patients in the clinical trial (with and without ascertainment), but since the patients in the clinical trial are a convenience sample of the population of patients potentially eligible for the trial, requiring a large proportion of cases with ascertainment does not facilitate generalizability of conclusions.
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