Semiparametric copula-based analysis for treatment effects in the presence of treatment switching

Chia Hui Huang, Yi Hau Chen, Jinn Li Wang, Mey Wang

Research output: Contribution to journalArticlepeer-review


In controlled trials, “treatment switching” occurs when patients in one treatment group switch to alternative treatments during the trial, and poses challenges to treatment effect evaluation owing to crossover of the treatments groups. In this work, we assume that treatment switching can occur after some disease progression event and view the progression and death events as two semicompeting risks. The proposed model consists of a copula model for the joint distribution of time-to-progression (TTP) and overall survival (OS) up to the earlier of the two events, as well as a conditional hazard model for OS subsequent to progression. The copula model facilitates assessing the marginal distributions of TTP and OS separately from the association between the two events, and, in particular, the treatment effect on OS in the absence of treatment switching. The proposed conditional hazard model for death subsequent to progression allows us to assess the treatment switching (crossover) effect on OS given occurrence of progression and covariates. Semiparametric proportional hazards models are employed in the marginal models for TTP and OS. A nonparametric maximum likelihood procedure is developed for model inference, which is verified through asymptotic theory and simulation studies. The proposed analysis is applied to a lung cancer dataset to illustrate its real utility.

Original languageEnglish
Pages (from-to)2936-2948
Number of pages13
JournalStatistics in Medicine
Issue number22
Publication statusPublished - Sept 30 2020


  • maximum likelihood
  • oncology trial
  • semicompeting risks

ASJC Scopus subject areas

  • Epidemiology
  • Statistics and Probability


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