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

BMC Medical Research Methodology
Xiaqing Huang, Byron Gajewski

Abstract

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. 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. 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(...Continue Reading

References

Nov 12, 2005·Clinical Trials : Journal of the Society for Clinical Trials·Andrew P Grieve, Michael Krams
May 10, 2019·Statistics in Medicine·Byron J GajewskiRenee' H Martin
Oct 22, 2019·Clinical Trials : Journal of the Society for Clinical Trials·Kert VieleBenjamin R Saville

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Software Mentioned

pMAX
HOBIT
OpenBUGS
EMAX

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