surrosurv: An R package for the evaluation of failure time surrogate endpoints in individual patient data meta-analyses of randomized clinical trials

Abstract

Background and objective: Surrogate endpoints are attractive for use in clinical trials instead of well-established endpoints because of practical convenience. To validate a surrogate endpoint, two important measures can be estimated in a meta-analytic context when individual patient data are available: the R_indiv² or the Kendall's τ at the individual level, and the R_trial² at the trial level. We aimed at providing an R implementation of classical and well-established as well as more recent statistical methods for surrogacy assessment with failure time endpoints. We also intended incorporating utilities for model checking and visualization and data generating methods described in the literature to date.

Methods: In the case of failure time endpoints, the classical approach is based on two steps. First, a Kendall's τ is estimated as measure of individual level surrogacy using a copula model. Then, the R_trial² is computed via a linear regression of the estimated treatment effects; at this second step, the estimation uncertainty can be accounted for via measurement-error model or via weights. In addition to the classical approach, we recently developed an approach based on bivariate auxiliary Poisson models with individual random effects to measure the Kendall's τ and treatment-by-trial interactions to measure the R_trial². The most common data simulation models described in the literature are based on: copula models, mixed proportional hazard models, and mixture of half-normal and exponential random variables.

Results: The R package surrosurv implements the classical two-step method with Clayton, Plackett, and Hougaard copulas. It also allows to optionally adjusting the second-step linear regression for measurement-error. The mixed Poisson approach is implemented with different reduced models in addition to the full model. We present the package functions for estimating the surrogacy models, for checking their convergence, for performing leave-one-trial-out cross-validation, and for plotting the results. We illustrate their use in practice on individual patient data from a meta-analysis of 4069 patients with advanced gastric cancer from 20 trials of chemotherapy.

Conclusions: The surrosurv package provides an R implementation of classical and recent statistical methods for surrogacy assessment of failure time endpoints. Flexible simulation functions are available to generate data according to the methods described in the literature.

Keywords: Copula; Individual patient data meta-analyses; Mixed models; R; Surrogate endpoints; Survival.