Kerr Kathleen F, Roth Jeremy, Zhu Kehao, Thiessen-Philbrook Heather, Meisner Allison, Wilson Francis Perry, Coca Steven, Parikh Chirag R
1 Department of Biostatistics, University of Washington, Seattle, WA, USA.
2 Program of Applied Translational Research, Yale University School of Medicine and VA Medical Center, New Haven, CT, USA.
Clin Trials. 2017 Dec;14(6):629-638. doi: 10.1177/1740774517723588. Epub 2017 Aug 10.
BACKGROUND/AIMS: A potential use of biomarkers is to assist in prognostic enrichment of clinical trials, where only patients at relatively higher risk for an outcome of interest are eligible for the trial. We investigated methods for evaluating biomarkers for prognostic enrichment.
We identified five key considerations when considering a biomarker and a screening threshold for prognostic enrichment: (1) clinical trial sample size, (2) calendar time to enroll the trial, (3) total patient screening costs and the total per-patient trial costs, (4) generalizability of trial results, and (5) ethical evaluation of trial eligibility criteria. Items (1)-(3) are amenable to quantitative analysis. We developed the Biomarker Prognostic Enrichment Tool for evaluating biomarkers for prognostic enrichment at varying levels of screening stringency.
We demonstrate that both modestly prognostic and strongly prognostic biomarkers can improve trial metrics using Biomarker Prognostic Enrichment Tool. Biomarker Prognostic Enrichment Tool is available as a webtool at http://prognosticenrichment.com and as a package for the R statistical computing platform.
In some clinical settings, even biomarkers with modest prognostic performance can be useful for prognostic enrichment. In addition to the quantitative analysis provided by Biomarker Prognostic Enrichment Tool, investigators must consider the generalizability of trial results and evaluate the ethics of trial eligibility criteria.
背景/目的：生物标志物的一个潜在用途是协助临床试验进行预后富集，即只有对感兴趣的结局具有相对较高风险的患者才有资格参加试验。我们研究了评估用于预后富集的生物标志物的方法。
在考虑生物标志物和用于预后富集的筛选阈值时，我们确定了五个关键因素：（1）临床试验样本量，（2）招募试验的日历时间，（3）患者总筛选成本和每位患者的总试验成本，（4）试验结果的可推广性，以及（5）对试验入选标准的伦理评估。因素（1）-（3）适用于定量分析。我们开发了生物标志物预后富集工具，用于在不同筛选严格程度下评估用于预后富集的生物标志物。
我们证明，使用生物标志物预后富集工具，中度预后和高度预后的生物标志物均可改善试验指标。生物标志物预后富集工具可作为网络工具在http://prognosticenrichment.com获取，也可作为R统计计算平台的一个包获取。
在某些临床环境中，即使是预后性能中等的生物标志物也可用于预后富集。除了生物标志物预后富集工具提供的定量分析外，研究人员还必须考虑试验结果的可推广性，并评估试验入选标准的伦理问题。
