Keywords: interim monitoring, immuno-oncology
Introduction of new immune therapies that may have a delayed beneficial effect necessitates re-evaluation of traditional clinical trial designs in oncology. A key design feature of randomized trials is interim futility monitoring which allows stopping early if the accruing data convincingly demonstrate that the experimental treatment is detrimental or is very unlikely to be shown superior to the standard treatment. The appropriateness of futility monitoring is frequently questioned when the effect of the experimental treatment may be delayed, e.g., in trials of many immune agents. We examine the advisability of using futility monitoring when there is potential for a delayed treatment effect and make recommendations concerning its use.
We evaluated the loss of statistical power when using some common futility interim monitoring rules and a new proposed conservative rule via simulation under varying amounts of treatment-effect delay and varying accrual periods. We also considered scenarios where the experimental treatment starts out being worse than the standard treatment but ends up being better, as may sometimes be the case when an immune therapy is compared to an active standard therapy.
Some standard methods of futility monitoring can result in an unacceptable loss of power when there is a delayed treatment effect, especially if the accrual period is rapid or the experimental treatment is initially worse. The proposed conservative futility rule has a negligible loss of power in the situations considered.
Conclusion: Although care must be taken with the choice of futility monitoring when there is a delayed treatment effect, inclusion of appropriate rules can reduce the exposure of patients to ineffective therapies without reducing the probability of correctly identifying effective treatments.