Comparison of hierarchical EMAX and NDLM models in dose-response for early phase clinical trials

Abstract

Background: Phase II clinical trials primarily aim to find the optimal dose and investigate the relationship between dose and efficacy relative to standard of care (control). Therefore, before moving forward to a phase III confirmatory trial, the most effective dose is needed to be identified. Methods: The primary endpoint of a phase II trial is typically a binary endpoint of success or failure. The EMAX model, ubiquitous in pharmacology research, was fit for many compounds and described the data well, except for a single compound, which had nonmonotone dose-response (Thomas et al., Stat Biopharmaceutical Res. 6:302-317 2014). To mitigate the risk of nonmonotone dose response one of the alternative options is a Bayesian hierarchical EMAX model (Gajewski et al., Stat Med. 38:3123-3138 2019). The hierarchical EMAX adapts to its environment. Results: When the dose-response curve is monotonic it enjoys the efficiency of EMAX. When the dose-response curve is non-monotonic the additional random effect hyperprior makes the hierarchical EMAX model more adjustable and flexible. However, the normal dynamic linear model (NDLM) is a useful model to explore dose-response relationships in that the efficacy at the current dose depends on the efficacy of the previous dose(s). Previous research has compared the EMAX to the hierarchical EMAX (Gajewski et al., Stat Med. 38:3123-3138 2019) and the EMAX to the NDLM (Liu et al., BMC Med Res Method 17:149 2017), however, the hierarchical EMAX has not been directly compared to the NDLM. Conclusions: The focus of this paper is to compare these models and discuss the relative merit for each of their uses for an ongoing early phase dose selection study.