Dynamic enrichment of Bayesian small sample, sequential, multiple assignment randomized trial (snSMART) design using natural history data: A case study from Duchenne muscular dystrophy
Presented by Satrajit Roychoudhury, Executive Director, Statistical Research and Innovation Group, Pfizer, Inc.
Wednesday, April 26, 2023
4:00 PM ET
Webex Meeting Link
In Duchenne muscular dystrophy (DMD) and other rare diseases, recruiting patients into clinical trials is challenging. Additionally, assigning patients to long-term, multi-year placebo arms raises ethical and trial retention concerns. This poses a significant challenge to the traditional sequential drug development paradigm. In this article, we propose a small sample, sequential, multiple assignment, randomized trial (snSMART) design that combines dose selection and confirmatory assessment into a single trial. This multi-stage design evaluates the effects of multiple doses of a promising drug and rerandomizes patients to appropriate dose levels based on their stage 1 dose and response. Our proposed approach increases the efficiency of treatment effect estimates by i) enriching the placebo arm with external control data, and ii) using data from all stages. Data from external control and different stages are combined using a robust Meta-Analytic Combined (MAC) approach to consider the various sources of heterogeneity and potential selection bias. We reanalyze data from a DMD trial using the proposed method and external control data from the Duchenne Natural History Study (DNHS). Our method's estimators show improved efficiency compared to the original trial. Also, the robust MAC-snSMART method most often provides more accurate estimators than the traditional analytic method. Overall, the proposed methodology provides a promising candidate for efficient drug development in DMD and other rare diseases.
Satrajit Roychoudhury is an Executive Director and member of Statistical Research and Innovation group in Pfizer Inc. He has 15+ years of extensive experience of working in different phases of clinical trials for drug and vaccine. Satrajit is a recipient of young statistical scientist award from the International Indian Statistical Association in 2019 and elected as ASA fellow in 2022.