BioPETsurv: Methodology and open source software to evaluate biomarkers for prognostic enrichment of time-to-event clinical trials.

Si Cheng,Chirag R Parikh,Steven G Coca,Heather Thiessen-Philbrook,Kathleen F Kerr,Qin Liu

doi:10.1371/journal.pone.0239486

Abstract

Biomarkers can be used to enrich a clinical trial for patients at higher risk for an outcome, a strategy termed "prognostic enrichment." Methodology is needed to evaluate biomarkers for prognostic enrichment of trials with time-to-event endpoints such as survival. Key considerations when considering prognostic enrichment include: clinical trial sample size; the number of patients one must screen to enroll the trial; and total patient screening costs and total per-patient trial costs. The Biomarker Prognostic Enrichment Tool for Survival Outcomes (BioPETsurv) is a suite of methods for estimating these elements to evaluate a prognostic enrichment biomarker and/or plan a prognostically enriched clinical trial with a time-to-event primary endpoint. BioPETsurv allows investigators to analyze data on a candidate biomarker and potentially censored survival times. Alternatively, BioPETsurv can simulate data to match a particular clinical setting. BioPETsurv's data simulator enables investigators to explore the potential utility of a prognostic enrichment biomarker for their clinical setting. Results demonstrate that both modestly prognostic and strongly prognostic biomarkers can improve trial metrics such as reducing sample size or trial costs. In addition to the quantitative analysis provided by BioPETsurv, investigators should consider the generalizability of trial results and evaluate the ethics of trial eligibility criteria. BioPETsurv is freely available as a package for the R statistical computing platform, and as a webtool at www.prognosticenrichment.com/surv.

Highlights

Biomarkers are used for various purposes across research and clinical contexts
We identified key considerations for evaluating a biomarker for prognostic enrichment, including: clinical trial sample size; number of patients to screen to enroll the trial; total patient screening costs and the total of per-patient costs for patients in the trial
Total Screened is the total number of patients who would need to be screened to enroll the trial, which depends on the sample size and level of enrichment

Summary

Introduction

Biomarkers are used for various purposes across research and clinical contexts. In a clinical trial of an intervention intended to prevent or delay some unwanted clinical event, a biomarker may be useful for “prognostic enrichment” of the trial [1,2,3,4,5]. A prognostically enriched trial uses a biomarker to enroll only patients at relatively higher risk of the unwanted clinical. Evaluating biomarkers for prognostic enrichment of time-to-event clinical trials

Methods

Results

Conclusion