Efficiency of a Randomized Confirmatory Basket Trial Design Constrained to Control the False Positive Rate by Indication

PURPOSEMolecular oncology determines biomarker-defined niche indications. Basket trials pool histologic indications sharing molecular pathophysiology, potentially improving development efficiency. Currently basket trials have been confirmatory only for exceptional therapies. Our previous randomized basket design may be generally suitable in the resource-intensive confirmatory phase, maintains high power, and provides nearly k-fold increased efficiency for k indications, but controls false positives for the pooled result only. Since false positive control by indications (FWER) may sometimes be required, we now simulate a variant of this basket design controlling FWER at 0.025k, the total FWER of k separate randomized trials. METHODSThe previous design eliminated indications at an interim analysis, conducting a final pooled analysis of remaining indications. To control FWER, we rechecked individual indications at a prospectively defined level of statistical significance after any positive pooled result. We simulated this modified design under numerous scenarios varying design parameters. Only designs controlling FWER and minimizing estimation bias were allowable. RESULTSSequential analyses (interim, pooled, and post-individual tests)) result in cumulative power losses. Optimal performance results when k = 3,4. We report efficiency (expected # true positives/expected sample size) relative to k parallel studies, at 90% power ("uncorrected") or at the power achieved in the basket trial ("corrected", because conventional designs could also increase efficiency by sacrificing power). Efficiency and power (percentage active indications identified) improve with higher percentage of initial indications active. Up to 92% uncorrected and 38% corrected efficiency improvement is possible, with power {approx} 60%. CONCLUSIONSEven under FWER control, randomized confirmatory basket trials substantially improve development efficiency. Initial indication selection is critical. The design is particularly attractive when enrollment challenges preclude full powering of individual indications.