Assessing methods for dealing with treatment switching in clinical trials: A follow-up simulation study

• Published in: Statistical methods in medical research Vol. 27; no. 3; pp. 765 - 784
• Main Authors: Latimer, Nicholas R, Abrams, Keith R, Lambert, Paul C, Morden, James P, Crowther, Michael J
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01-03-2018; Sage Publications Ltd
• Subjects: Adjustment; Bias; Biostatistics - methods; Clinical research; Clinical Trial Protocols as Topic; Clinical trials; Computer Simulation; Cross-Over Studies; Data Interpretation, Statistical; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Medical prognosis; Medical research; Medicin och hälsovetenskap; Models, Statistical; Proportional Hazards Models; Randomization; Randomized Controlled Trials as Topic - methods; Randomized Controlled Trials as Topic - statistics & numerical data; Sample Size; Severity; Simulation; Standardized patients; Statistical analysis; Statistical methods; Structural failure; Survival Analysis; Switching; treatment crossover; health technology assessment; Treatment switching; survival analysis; time-to-event outcomes; overall survival; prediction; oncology
• ISSN: 0962-2802; 1477-0334; 1477-0334
• DOI: 10.1177/0962280216642264

When patients randomised to the control group of a randomised controlled trial are allowed to switch onto the experimental treatment, intention-to-treat analyses of the treatment effect are confounded because the separation of randomised groups is lost. Previous research has investigated statistical methods that aim to estimate the treatment effect that would have been observed had this treatment switching not occurred and has demonstrated their performance in a limited set of scenarios. Here, we investigate these methods in a new range of realistic scenarios, allowing conclusions to be made based upon a broader evidence base. We simulated randomised controlled trials incorporating prognosis-related treatment switching and investigated the impact of sample size, reduced switching proportions, disease severity, and alternative data-generating models on the performance of adjustment methods, assessed through a comparison of bias, mean squared error, and coverage, related to the estimation of true restricted mean survival in the absence of switching in the control group. Rank preserving structural failure time models, inverse probability of censoring weights, and two-stage methods consistently produced less bias than the intention-to-treat analysis. The switching proportion was confirmed to be a key determinant of bias: sample size and censoring proportion were relatively less important. It is critical to determine the size of the treatment effect in terms of an acceleration factor (rather than a hazard ratio) to provide information on the likely bias associated with rank-preserving structural failure time model adjustments. In general, inverse probability of censoring weight methods are more volatile than other adjustment methods.