Introduction: Schoenfeld et al. (2009) proposed Bayesian design and analysis for a pediatric randomize controlled trial (RCT), to be informed by adult data, using a pre-specified borrowing fraction parameter (BFP). This incorrectly assumes that the BFP is intuitive and corresponds to the degree of similarity between the populations. Methods: We generalize the results of Schoenfeld et. al to K>1 historical datasets, derive simple expressions and show that it leads to Empirical Bayes meta-analysis (EBMA, Raudenbush & Byrk, 1985). We also show that the powers of the induced power-prior approach (Ibrahim & Chen 2000) are driven by uncertainty, rather than affinity between datasets. We proceed to offer power and sample size calculations for a future RCT, to be informed by K historical RCTs. The method is applied to simulated datasets with a dichotomous outcome. Results: We demonstrate how designing RCTs with EBMA in mind, can save resources and improve estimation accuracy. Conclusion: Bridging Schoenfeld’s design and EBMA can help inform inference on treatment effects for independent trials involving either different patient populations or various therapies from a common class.
Adoptive cell therapy (ACT), such as chimeric antigen receptor (CAR) T-cell therapy, has demonstrated promising therapeutic effects with potentially non-monotonic dose–response curves. Building upon the i3 + 3 design for cytotoxic agents (Liu et al., 2020), we propose a new method – joint i3 + 3 (Ji3 + 3) that takes into account of both safety and efficacy outcomes in making dosing recommendations. This allows for efficient dose escalation and identification of biological optimal dose of ACTs which may not be cytotoxic. The Ji3 + 3 design is rule based, easy to understand for clinicians, and is simple to implement. Simulation results show that Ji3 + 3 outperforms existing designs when monotonic dose–response assumption is violated, and still achieves comparable performance when the assumption holds. The simplicity and superior operating characteristics make Ji3 + 3 a good candidate for phase I/II ACT dose-finding trials in the clinical community when toxicity and efficacy are both considered as binary endpoints.
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