Improved estimation of overall survival and progression-free survival for state transition modeling

Aim: National Institute for Health and Care Excellence guidance (Technical Support Document 19) highlights a key challenge of state transition models (STMs) being their difficulty in achieving a satisfactory fit to the observed within-trial endpoints. Fitting poorly to data over the trial period can then have implications for long-term extrapolations. A novel estimation approach is defined in which the predicted overall survival (OS) and progression-free survival (PFS) extrapolations from an STM are optimized to provide closer estimates of the within-trial endpoints. Materials & methods: An STM was fitted to the SQUIRE trial data in non-small-cell lung cancer (obtained from Project Data Sphere). Two methods were used: a standard approach whereby the maximum likelihood was utilized for the individual transitions and the best-fitting parametric model selected based on AIC/BIC, and a novel approach in which parameters were optimized by minimizing the area between the STM-predicted OS and PFS curves and the corresponding OS and PFS Kaplan-Meier curves. Sensitivity analyses were conducted to assess uncertainty. Results: The novel approach resulted in closer estimations to the OS and PFS Kaplan-Meier for all combinations of parametric distributions analyzed compared with the standard approach. Though the uncertainty associated with the novel approach was slightly larger, it provided better estimates to the restricted mean survival time in 10 of the 12 parametric distributions analyzed. Conclusion: A novel approach is defined which provides an alternative STM estimation method enabling improved fits to modeled endpoints, which can easily be extended to more complex model structures. Plain language summary: A key challenge of state transition models is their difficulty in achieving a satisfactory fit to the observed within-trial endpoints (such as overall survival [OS] and progressionfree survival [PFS]). This can have implications for long-term extrapolations and, therefore, for medical decision making as well. A novel approach is defined which provides an alternative estimation method that enables improved fits to modeled endpoints. This approach resulted in closer estimations to the OS and PFS Kaplan-Meier curves for all combinations of parametric distributions analyzed compared with the standard approach. This addresses some of the challenges that are discussed when modeling state transition models, and can easily be extended to more complex model structures. Tweetable abstract: A key challenge of state transition models is their difficulty in achieving a satisfactory fit to the observed within -trial endpoints, with implications for long-term extrapolations and medical decision making. In this new Methodology article, the authors explore a novel method that helps address some of these challenges.