Dynamic enrichment of Bayesian small‐sample, sequential, multiple assignment randomized trial design using natural history data: a case study from Duchenne muscular dystrophy

Sidi Wang, Kelley M. Kidwell and Satrajit Roychoudhury

Biometrics, 2023, vol. 79, issue 4, 3612-3623

Abstract: 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 paper, 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 re‐randomizes 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://doi.org/10.1111/biom.13887

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:bla:biomet:v:79:y:2023:i:4:p:3612-3623

Ordering information: This journal article can be ordered from
http://www.blackwell ... bs.asp?ref=0006-341X

Access Statistics for this article

More articles in Biometrics from The International Biometric Society
Bibliographic data for series maintained by Wiley Content Delivery ().