Re-randomization tests as sensitivity analyses to confirm immunological noninferiority of an investigational vaccine: Case study.

ABSTRACT

Here we present as case study how re-randomization tests were performed in two randomized, controlled clinical trials as sensitivity analyses, as recommended by the United States Food and Drug Administration in the context of adaptive randomization. This was done to confirm primary conclusions on immunological noninferiority of an investigational new fully liquid presentation of a quadrivalent cross-reacting material conjugate meningococcal vaccine (MenACWY-CRM), over its licensed lyophilized/liquid presentation. In two phase 2b studies (Study #1 NCT03652610; Study #2 NCT03433482), noninferiority of the fully liquid presentation of MenACWY-CRM to the licensed presentation was assessed and demonstrated for immune responses against meningococcal serogroup A (MenA), the only vaccine component modified from lyophilized to liquid in the new presentation. The original vaccine assignment algorithm, with a minimization procedure accounting for center or center within age strata, was used to re-randomize participants belonging to the fully liquid and licensed vaccine groups while keeping antibody responses, covariates and entry order as observed. Test statistics under re-randomization were generated according to the ANCOVA model used in the primary analysis. To confirm immunological noninferiority following re-randomization, the corresponding p-values had to be <0.025. For both studies and all primary objective evaluations, the re-randomization p-values were well below 0.025 (0.0004 for Study #1; 0.0001 for the two co-primary endpoints in Study #2). Re-randomization tests performed to comply with a regulatory request confirmed the primary conclusions of immunological noninferiority for the MenA of the fully liquid compared to the licensed vaccine presentation.