Dose Escalation with Over-dose and Under-dose Controls for Phase I/II Clinical Trials Open Access

Abstract

To save time and resources in new drug development, Phase I/II clinical trials with toxicity response and drug efficacy as dual primary endpoints have become increasingly popular. Escalation with over dose control (EWOC) is a leading Bayesian adaptive Phase I clinical trial design that can accurately estimate maximum tolerated dose (MTD) and control the probability of overdosing patients during dose allocation. To adapt EWOC to Phase I/II clinical trials, we have used it as a framework to incorporate the Gumbel Copula model and additional under-dosing control to guarantee minimum drug efficacy for patients. A utility function is proposed to estimate the composite effect of toxicity and efficacy. The final recommended dose is determined by maximizing this utility. Late onset and missing efficacy data are common in Phase I/II clinical trials, especially during early stages when patients are treated at low doses. Therefore, we further employed the Bayesian data augmentation (DA) algorithm to impute values for late onset or delayed efficacy data. The resulting new Phase I/II design, which can monitor toxicity and efficacy simultaneously, is named Dose Escalation with Over-Dose and Under-Dose Control using Data Augmentation (EWOUC-DA). The underlying theory of EWOUC-DA is elaborated and extensive simulations are conducted to evaluate its performance and operating characteristics. EWOUC-DA has been demonstrated to provide better over-dose control, optimize utility, and reduce the risk of failure in Phase III clinical trials compared to EWOC. Hence, EWOUC-DA can address the new requisites of Phase I/II clinical trials, reduce the cost of clinical trials, and largely shorten the duration of new drug development.

Table of Contents

1. Introduction................................................................................................................................. 1

2. Methods....................................................................................................................................... 5

2.1 Outcome Model and Re-parameterization......................................................................... 5

2.2 Overdose-Control and Under-dose Control...................................................................... 7

2.3 Accommodate Delayed Efficacy..................................................................................... 10

3 Simulation................................................................................................................................... 13

3.1 Simulation Plans and Model Setting................................................................................ 13

3.2 Dose Recommendation.................................................................................................... 15

3.3 Therapeutic Effects.......................................................................................................... 16

3.4 Expected Trial Duration................................................................................................... 17

3.5 Sensitivity Study.............................................................................................................. 18

4. Conclusion and Discussion........................................................................................................ 19

References..................................................................................................................................... 21

Appendix A................................................................................................................................... 23

Appendix B................................................................................................................................... 27

About this Master's Thesis

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School	Rollins School of Public Health
Department	Biostatistics and Bioinformatics
Subfield / Discipline	Biostatistics - MPH & MSPH
Degree	MSPH
Submission	Master's Thesis
Language	English
Research Field	Biology, Biostatistics Health Sciences, Public Health
Keyword	Phase I/II clinical trial Escalation with overdose control Gumbel Copula model
Committee Chair / Thesis Advisor	Chen, Zhengjia , Emory University
Partnering Agencies	Does not apply (no collaborating organization)

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