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   Rosenblum, Michael; Fang, Ethan X.; Liu, Han (July 2020, Journal of the Royal Statistical Society: Series B (Statistical Methodology))

   null (Ed.)
2. Seamless Clinical Trials with Doubly Adaptive Biased Coin Designs

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   Zhu, Hongjian; Yu, Jun; Lai, Dejian; Wang, Li (March 2023, The New England Journal of Statistics in Data Science)

   In addition to scientific questions, clinical trialists often explore or require other design features, such as increasing the power while controlling the type I error rate, minimizing unnecessary exposure to inferior treatments, and comparing multiple treatments in one clinical trial. We propose implementing adaptive seamless design (ASD) with response adaptive randomization (RAR) to satisfy various clinical trials’ design objectives. However, the combination of ASD and RAR poses a challenge in controlling the type I error rate. In this paper, we investigated how to utilize the advantages of the two adaptive methods and control the type I error rate. We offered the theoretical foundation for this procedure. Numerical studies demonstrated that our methods could achieve efficient and ethical objectives while controlling the type I error rate. 

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4. Dynamic Programming for Response-Adaptive Dose-Finding Clinical Trials

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   Nasrollahzadeh, Amir Ali; Khademi, Amin (July 2022, INFORMS Journal on Computing)

   Identifying the right dose is one of the most important decisions in drug development. Adaptive designs are promoted to conduct dose-finding clinical trials as they are more efficient and ethical compared with static designs. However, current techniques in response-adaptive designs for dose allocation are complex and need significant computational effort, which is a major impediment for implementation in practice. This study proposes a Bayesian nonparametric framework for estimating the dose-response curve, which uses a piecewise linear approximation to the curve by consecutively connecting the expected mean response at each dose. Our extensive numerical results reveal that a first-order Bayesian nonparametric model with a known correlation structure in prior for the expected mean response performs competitively when compared with the standard approach and other more complex models in terms of several relevant metrics and enjoys computational efficiency. Furthermore, structural properties for the optimal learning problem, which seeks to minimize the variance of the target dose, are established under this simple model. Summary of Contribution: In this work, we propose a methodology to derive efficient patient allocation rules in response-adaptive dose-finding clinical trials, where computational issues are the main concern. We show that our methodologies are competitive with the state-of-the-art methodology in terms of solution quality, are significantly more computationally efficient, and are more robust in terms of the shape of the dose-response curve, among other parameter changes. This research fits in “the intersection of computing and operations research” as it adapts operations research techniques to produce computationally attractive solutions to patient allocation problems in dose-finding clinical trials. 

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5. Optimal Stopping of Adaptive Dose-Finding Trials

   https://doi.org/10.1287/serv.2020.0261  

   Nasrollahzadeh, Amir Ali; Khademi, Amin (June 2020, Service Science)

   null (Ed.)

   The primary objective of this paper is to develop computationally efficient methods for optimal stopping of an adaptive Phase II dose-finding clinical trial, where the decision maker may terminate the trial for efficacy or abandon it as a result of futility. We develop two solution methods and compare them in terms of computational time and several performance metrics such as the probability of correct stopping decision. One proposed method is an application of the one-step look-ahead policy to this problem. The second proposal builds a diffusion approximation to the state variable in the continuous regime and approximates the trial’s stopping time by optimal stopping of a diffusion process. The secondary objective of the paper is to compare these methods on different dose-response curves, particularly when the true dose-response curve has no significant advantage over a placebo. Our results, which include a real clinical trial case study, show that look-ahead policies perform poorly in terms of the probability of correct decision in this setting, whereas our diffusion approximation method provides robust solutions. 

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