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Activity Number: 346
Type: Topic Contributed
Date/Time: Tuesday, August 2, 2016 : 10:30 AM to 12:20 PM
Sponsor: Biopharmaceutical Section
Abstract #320784 View Presentation
Title: Regulatory and Practical Considerations for an Adaptive Trial in the Context of Evaluating a Combination Product: An Example Using Two Human MAbs to Prevent Recurrence of CDI
Author(s): Kenneth Koury* and Robert Tipping
Companies: Merck Research Laboratories and Merck Research Laboratories
Keywords: adaptive design ; FDA combination product rules ; multiplicity strategy ; interim analysis
Abstract:

Human monoclonal antibodies (mAb) targeting C. difficile toxins A and B were evaluated in earlier Phase 2 trials. Results suggest that A alone is inadequate, but A+B reduced C. difficile infection (CDI) recurrence relative to placebo. Since human data for the individual mAbs were limited, an adaptive approach was considered to assess the 2 individual mAbs, as well as the combination and placebo (to satisfy FDA combination product rules). The Phase 3 design included a planned interim analysis to evaluate individual mAb therapies relative to combined therapy (but virtually all Type I error was allocated to the final analysis based on FDA recommendations). A 4-stage multiplicity strategy provides control of Type 1 error across multiple comparisons at two analysis times. Simulations confirmed that Type 1 error is controlled at planned levels, and there is high power to select an effective regimen. But the probability of dropping an individual mAb arm is only 36%, even for a substantial difference versus the combination. This raises the question of whether more Type I error should have been allocated to the interim analysis, even in the context of evaluating a combination product.


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