Stochastic curtailment tests for phase II trial with time-to-event outcome using the concept of relative time in the case of non-proportional hazards

ABSTRACT

As part of the drug development process, interim analysis is frequently used to design efficient phase II clinical trials. A stochastic curtailment framework is often deployed wherein a decision to continue or curtail the trial is taken at each interim look based on the likelihood of observing a positive or negative treatment effect if the trial were to continue to its anticipated end. Thus, curtailment can take place due to evidence of early efficacy or futility. Traditionally, in the case of time-to-event endpoints, interim monitoring is conducted in a two-arm clinical trial using the log-rank test, often with the assumption of proportional hazards. However, when this is violated, the log-rank test may not be appropriate, resulting in loss of power and subsequently inaccurate sample sizes. In this paper, we propose stochastic curtailment methods for two-arm phase II trial with the flexibility to allow non-proportional hazards. The proposed methods are built utilizing the concept of relative time assuming that the survival times in the two treatment arms follow two different Weibull distributions. Three methods – conditional power, predictive power and Bayesian predictive probability – are discussed along with corresponding sample size calculations. The monitoring strategy is discussed with a real-life example.

KEYWORDS:

• Non-proportional hazards
• relative time
• interim analysis
• time-to-event
• Weibull distribution
• stochastic curtailment tests

Disclaimer

Although the examples discussed in this manuscript represent real-life clinical situations, the effect size definition(s) used in this manuscript is purely hypothetical in nature. We have not used any original datasets from our collaborations on previously funded grants, but we occasionally rely on our published results for parameter estimates used in this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/10543406.2023.2244056.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.