Background The development of immuno-oncologic agents poses unique challenges, namely that both efficacy and safety profiles differ from previously characterized cytotoxic and pathway-specific agents. In addition, exponential distribution is usually assumed in study designs with time-to-event endpoints such as overall survival or progression-free survival. This assumption might lead to wrong estimates of study duration and statistical power if the phenomena of long term survival and delayed clinical effects are present. The aim here was to evaluate the magnitude of the impact caused by the violation of this assumption, and to describe new ways of analyzing efficacy and safety of immuno-oncologic agents. Methods Monte Carlo simulation was implemented to explore the impact of long term survivors and delayed treatment effect on study power and trial duration. Scenarios with various combinations of long term and delayed treatment effects were considered. Study power and duration were evaluated based on 10000 randomly generated trial data sets. The utility of group sequential study designs was discussed. A new set of immune-related response criteria (irRC) was considered for efficacy analysis. Two new methods for identifying adverse events, termed immune-related adverse events (irAE) and immune-mediated adverse reactions (imAR) were described. The key features of the safety profiles derived using these two methods were similar. Both methods were aimed at identifying inflammatory adverse events caused by immunotherapies. Results The presence of long term survivors usually lengthened the study duration. Depending on the treatment effect post survival curve separation, delayed clinical effect in general led to a loss of power. The irRC offered a new way of identifying clinical responses. Both safety analyses demonstrated higher sensitivity of identifying adverse events of immune system origin. Conclusion This simulation study showed the importance of accounting for the delayed treatment effect and long term survivors when these phenomena were expected. Interim analyses for the purpose of stopping the study for either positive or futile outcome should be implemented with caution in immuno-oncology trials. The new efficacy analysis offered a potential new way of assessing signs of activity in immunotherapies. While the irAE method facilitated prompt and effective management of adverse events, the imAR method captured truly immune-related events.
