Group Sequential Survival Trial Design and Monitoring Using the Log-Rank Test

ABSTRACT

For randomized group sequential survival trial designs with unbalanced treatment allocation, the widely used Schoenfeld formula is inaccurate, and the commonly used information time as the ratio of number of events at interim look to the number of events at the end of trial can be biased. In this article, a sample size formula for the two-sample log-rank test under the proportional hazards model is proposed that provides more accurate sample size calculation for unbalanced survival trial designs. Furthermore, a new information time is introduced for the sequential survival trials such that the new information time is more accurate than the traditional information time when the allocation of enrollments is unbalanced in groups. Finally, we demonstrate the monitoring process using the sequential conditional probability ratio test and compare it with two other well-known group sequential procedures. An example is given to illustrate unbalanced survival trial design using available software. Supplementary materials for this article are available online.

KEYWORDS:

• Group sequential trial design
• Information time
• Proportional hazards model
• Sample size
• Time-to-event
• Unequal allocation

Supplementary Materials

The supplementary materials contain the appendices.

Acknowledgments

The author acknowledges anonymous reviewers and associate editor for their valuable comments that improved an earlier version of the article.

Funding

This work was supported in part by National Cancer Institute (NCI) support grant P30CA021765 and ALSAC.