如何使用 frailtypack 验证来自随机对照试验荟萃分析的个体患者数据的失效时间替代终点。

How to use frailtypack for validating failure-time surrogate endpoints using individual patient data from meta-analyses of randomized controlled trials.

机构信息

Biostatistics team, INSERM BPH-U1219, Bordeaux, France.

ISPED, Université de Bordeaux, Bordeaux, France.

出版信息

PLoS One. 2020 Jan 28;15(1):e0228098. doi: 10.1371/journal.pone.0228098. eCollection 2020.

DOI:10.1371/journal.pone.0228098

PMID:31990928

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6986733/

Abstract

BACKGROUND AND OBJECTIVE

The use of valid surrogate endpoints can accelerate the development of phase III trials. Numerous validation methods have been proposed with the most popular used in a context of meta-analyses, based on a two-step analysis strategy. For two failure time endpoints, two association measures are usually considered, Kendall's τ at individual level and adjusted R2 ([Formula: see text]) at trial level. However, [Formula: see text] is not always available mainly due to model estimation constraints. More recently, we proposed a one-step validation method based on a joint frailty model, with the aim of reducing estimation issues and estimation bias on the surrogacy evaluation criteria. The model was quite robust with satisfactory results obtained in simulation studies. This study seeks to popularize this new surrogate endpoints validation approach by making the method available in a user-friendly R package.

METHODS

We provide numerous tools in the frailtypack R package, including more flexible functions, for the validation of candidate surrogate endpoints using data from multiple randomized clinical trials.

RESULTS

We implemented the surrogate threshold effect which is used in combination with [Formula: see text] to make decisions concerning the validity of the surrogate endpoints. It is also possible thanks to frailtypack to predict the treatment effect on the true endpoint in a new trial using the treatment effect observed on the surrogate endpoint. The leave-one-out cross-validation is available for assessing the accuracy of the prediction using the joint surrogate model. Other tools include data generation, simulation study and graphic representations. We illustrate the use of the new functions with both real data and simulated data.

CONCLUSION

This article proposes new attractive and well developed tools for validating failure time surrogate endpoints.

摘要

背景与目的

有效的替代终点的使用可以加速 III 期临床试验的发展。已经提出了许多验证方法，最流行的方法是在荟萃分析的背景下，基于两步分析策略。对于两个失效时间终点，通常考虑两种关联度量，个体水平的 Kendall's τ 和试验水平的调整 R2([Formula: see text])。然而，[Formula: see text]并不总是可用，主要是由于模型估计的限制。最近，我们提出了一种基于联合脆弱性模型的一步验证方法，目的是减少对替代评价标准的估计问题和估计偏差。该模型具有很好的稳健性，在模拟研究中获得了令人满意的结果。本研究旨在通过在一个用户友好的 R 包中提供该方法，推广这种新的替代终点验证方法。

方法

我们在 frailtypack R 包中提供了许多工具，包括更灵活的功能，用于使用来自多个随机临床试验的数据验证候选替代终点。

结果

我们实现了替代阈值效应，它与[Formula: see text]结合使用，以便对替代终点的有效性做出决策。还可以使用 frailtypack 根据替代终点上观察到的治疗效果，预测新试验中真实终点的治疗效果。还可以使用交叉验证来评估使用联合替代模型进行预测的准确性。其他工具包括数据生成、模拟研究和图形表示。我们使用真实数据和模拟数据来说明新功能的使用。