Simon Richard
a National Cancer Institute , Rockville , Maryland , USA.
J Biopharm Stat. 2014;24(5):1011-21. doi: 10.1080/10543406.2014.931411.
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.
本文探讨了在接受生物标志物阳性和阴性患者的临床试验中，根据生物标志物值进行治疗分配分层的作用，这些试验的主要目标是分别评估标志物阳性亚组的治疗效果。本文还研究了生物标志物值不完全确定的问题，以及这如何影响对生物标志物阳性患者亚组治疗效果的推断。我发现，对生物标志物进行随机化分层可确保所有患者都能采集到组织，但如果生物标志物值完全确定，对于生物标志物阳性亚组推断的有效性而言，这并非必要条件。如果生物标志物值未完全确定，那么确定生物标志物的确定与治疗分配无关就很重要。对于确定生物标志物阳性患者治疗评估的内部有效性而言，有很大比例的病例确定生物标志物并非必要条件；确定与治疗的独立性才是重要因素。有很大比例的病例确定生物标志物，会使已确定生物标志物的阳性患者更有可能代表临床试验中（无论是否已确定）的生物标志物阳性患者，但由于临床试验中的患者是可能符合试验条件的患者群体的便利样本，要求有很大比例的病例确定生物标志物并不能促进结论的推广。
