Multistate models as a framework for estimand specification in clinical trials of complex processes.

Intensity-based multistate models provide a useful framework for characterizing disease processes, the introduction of interventions, loss to followup, and other complications arising in the conduct of randomized trials studying complex life history processes. Within this framework we discuss the issues involved in the specification of estimands and show the limiting values of common estimators of marginal process features based on cumulative incidence function regression models. When intercurrent events arise we stress the need to carefully define the target estimand and the importance of avoiding targets of inference that are not interpretable in the real world. This has implications for analyses, but also the design of clinical trials where protocols may help in the interpretation of estimands based on marginal features.

Recurrent disability progression endpoints in multiple sclerosis clinical trials.

BACKGROUND: The current standard endpoint to assess disability accumulation in multiple sclerosis (MS) clinical trials is the time to the first confirmed disability progression, which excludes subsequent progression events. Including recurrent progression events may permit a more comprehensive assessment of treatment effects on disability progression. OBJECTIVE: To propose a definition of recurrent disability progression events and to compare time-to-first and recurrent event analysis. METHODS: Recurrent disability progression events were defined by expanding the recommended first event definition. Marginal recurrent event methods (negative binomial model, Lin-Wei-Yang-Ying model) were compared with Cox regression in data from three randomized controlled trials in relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS), and in simulated randomized controlled trial data. RESULTS: The recurrent event analyses included a substantially larger number of progression events compared with the time-to-first-event analyses (+7.5% and +9.9% in the RMS trials and +22.7% in the PPMS trial). The increase in the number of events resulted in more precise treatment effect estimates and a corresponding gain in statistical power. CONCLUSION: Our results support the use of recurrent event data analysis, especially in progressive MS trials, to improve estimates of treatment effects, increase statistical power, and better capture the clinically meaningful long-term disability progression experience.