Visualizing hypothesis tests in survival analysis under anticipated delayed effects.

What can be considered an appropriate statistical method for the primary analysis of a randomized clinical trial (RCT) with a time-to-event endpoint when we anticipate non-proportional hazards owing to a delayed effect? This question has been the subject of much recent debate. The standard approach is a log-rank test and/or a Cox proportional hazards model. Alternative methods have been explored in the statistical literature, such as weighted log-rank tests and tests based on the Restricted Mean Survival Time (RMST).

Stratified modestly weighted log-rank tests in settings with an anticipated delayed separation of survival curves.

Delayed separation of survival curves is a common occurrence in confirmatory studies in immuno-oncology. Many novel statistical methods that aim to efficiently capture potential long-term survival improvements have been proposed in recent years. However, the vast majority do not consider stratification, which is a major limitation considering that most large confirmatory studies currently employ a stratified primary analysis.

Design and analysis of group-sequential clinical trials based on a modestly weighted log-rank test in anticipation of a delayed separation of survival curves: A practical guidance.

Background: A common feature of many recent trials evaluating the effects of immunotherapy on survival is that non-proportional hazards can be anticipated at the design stage. This raises the possibility to use a statistical method tailored towards testing the purported long-term benefit, rather than applying the more standard log-rank test and/or Cox model. Many such proposals have been made in recent years, but there remains a lack of practical guidance on implementation, particularly in the context of group-sequential designs.