Treatment switching occurs when patients in the control group of a clinical trial are allowed to switch onto the experimental treatment at some point during follow-up. Switching is common in clinical trials of cancer treatments and can also occur in trials of treatments for other diseases. When switching occurs, an “intention to treat” (ITT) analysis – whereby the data are analysed according to the arms to which patients were randomised – of the overall survival (OS) advantage associated with the new treatment will be biased: If control group patients switch treatments and benefit from the new treatment the OS advantage of the new treatment will be underestimated. For interventions that impact upon survival, health technology assessment (HTA) bodies such as the National Institute for Health and Care Excellence (NICE) require that economic evaluations consider a lifetime horizon. This is problematic in the presence of treatment switching, because standard ITT analyses are likely to be inappropriate.
Various statistical methods are available to adjust survival estimates in the presence of treatment switching, but each makes important assumptions and is subject to limitations. “Simple” adjustment methods such as censoring switchers at the point of switch, or excluding them entirely from the analysis, are highly prone to selection bias because switching is likely to be associated with prognosis. More complex adjustment methods, which are theoretically unbiased given certain assumptions are satisfied, are also available. Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm represent randomisation-based methods for estimating counterfactual survival times (i.e. survival times that would have been observed in the absence of switching). The Inverse Probability of Censoring Weights (IPCW) method represents an observational-based approach, whereby data for switchers are censored at the point of switch and remaining observations are weighted with the aim of removing any censoring-related selection bias.
This Technical Support Document (TSD) introduces the RPSFTM, IPE, IPCW and other adjustment methods that may be used in the presence of treatment switching. The key assumptions and limitations associated with each method are described, and the use of these in past NICE technology appraisals and their performance in simulation studies is reviewed. Based upon this, advice is offered in the form of an analysis framework, to help analysts determine adjustment methods that are likely to be appropriate on a case-by-case basis.