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Masahiro Kojima

Publications and source records attributed to Masahiro Kojima.

At least 19 recordsLinked to original sources

Feedback-Aware Tuning of Recursive Q-Learning

Model choice in backward Q-learning is recursive because a later-stage choice changes the response supplied to an earlier regression and can alter its model-comparison statistic. Separate stagewise criteria do not directly assess the target-stage prediction risk of a completed Q-learning fit. We address this mismatch by treating the entire backward-fitting rule as the unit of comparison and propose feedback-aware soft tuning for sequential multiple assignment randomised trials. Each backward fit uses its own generated responses and is assessed at a common prediction target. The risk criterion retains downstream effects on upstream comparisons, while a separate correction accounts for estimating the final exponential weights from the same observations. For a fixed finite library of smooth recursive maps, we establish an exact risk identity under a Gaussian shift model and an oracle inequality with an explicit adaptation remainder. Under coordinate-representation and moment conditions, these guarantees transfer to prediction risk at any prespecified stage, with the number of stages fixed as sample size increases. A two-stage construction supplies an explicit observable implementation. Numerical studies examine risk estimation and finite-sample performance, and a simulated attention-deficit/hyperactivity-disorder trial illustrates the relation between comparison feedback and treatment recommendations.

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Finite-Boundary Reduction and Exact Verification of Strong Familywise Error in Active-Count-Coupled Multi-Arm Efficacy-Toxicity Monitoring

Randomized dose-optimization trials may screen several candidate doses using binary efficacy and toxicity outcomes. A dose is inadmissible if efficacy is insufficient or toxicity is excessive, so each dose-specific null hypothesis is a union region and strong familywise error control must hold across arbitrary mixtures of inadmissible and promising doses. We study exact verification of multistage monitoring rules in which armwise decisions may be coupled through the number of active arms remaining at each interim analysis. For uncoupled rules, we derive an exact product representation and show that a complete-null boundary configuration is least favourable. Under active-count coupling, this factorization no longer holds because a promising dose can remain active and alter future boundaries for null doses. Assuming independent sampling across arms, prespecified per-dose analysis schedules, analysis timing not driven by the observed efficacy or toxicity outcomes, arm-specific monitoring statistics, and stagewise monotonicity, we establish an exact finite-boundary characterization without parametric restrictions on the within-arm joint efficacy-toxicity distribution. Each dose need only be evaluated at an efficacy-null boundary, a toxicity-null boundary, or a maximally favourable alternative. A deterministic finite-state recursion then verifies a fixed decision table without Monte Carlo error. Numerical studies confirmed the prespecified strong familywise error control and showed that active-count coupling can shift the least-favourable configuration away from the complete null while improving joint retention of multiple promising doses. A published randomized dose-ranging trial was used as a clinical illustration of how the framework could be prospectively implemented. The framework separates monitoring-rule construction from rigorous error verification.

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A staggered seamless dose-optimization design for co-developing monotherapy and combination therapy

Contemporary oncology drug development increasingly requires efficient dose-optimization strategies that evaluate monotherapy (Mono) and combination therapy (Combo) while balancing activity, efficacy, and tolerability. We propose a staggered seamless phase I/II design for settings in which a novel agent is evaluated alone and in combination with an established therapy. In phase I, Mono dose finding begins first, and Combo subtrials can be opened adaptively once a prespecified combination-initiation signal based on early clinical or biological information is observed. Dose assignment uses a model-assisted rule based on toxicity and early activity, with backfilling at tolerable and potentially promising regimens. At the end of phase I, two candidate regimens are selected from the evaluated Mono and Combo regimens using an efficacy-toxicity utility based on accumulated toxicity and treatment-response data. Phase II seamlessly carries forward patients treated at the selected regimens, enrolls additional patients as needed, and applies Bayesian futility and efficacy stopping boundaries to identify a final recommended optimal biological dose (OBD). Simulation studies showed that the proposed design shortened phase I trial duration relative to the comparator designs while maintaining competitive OBD-selection performance and acceptable safety. The seamless phase II component further reduced the need for additional enrollment and supported efficient final OBD selection.

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A seamless dose-optimization design for monotherapy and combination therapy

The emergence of molecular-targeted agents and immune-oncology therapies has fundamentally transformed oncology drug development, necessitating evolution beyond traditional dose-finding approaches designed for cytotoxic agents. While conventional agents exhibit predictable monotonic dose-response relationships, novel anticancer agents often demonstrate plateau-effect patterns where higher doses may compromise therapeutic benefit, requiring identification of optimal biological doses that balance efficacy and tolerability. The FDA's Project Optimus initiative emphasizes comprehensive dose optimization through parallel randomized cohorts and patient backfilling to better understand pharmacological profiles across multiple dose levels. Contemporary drug development increasingly prioritizes combination therapy alongside monotherapy evaluation, yet existing designs typically assume equivalent roles for both agents, diverging from clinical practice where novel agents combine with established treatments having limited dose options. This paper proposes a seamless dose-optimization design that adaptively evaluates both monotherapy and combination therapy based on efficacy and toxicity outcomes through adaptive subtrials with patient backfilling capabilities. The model-assisted framework employs predetermined Bayesian optimal boundaries, eliminating real-time model fitting while accommodating evaluation of both monotherapy and combination therapy and enabling sequential enrollment with strategic backfilling. Simulation studies demonstrate robust performance across diverse dose-response patterns relevant to contemporary oncology. The design addresses critical gaps between methodological assumptions and clinical reality, offering a practical approach that integrates monotherapy and combination therapy evaluation with efficacy-toxicity-based backfilling.

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A Globally Calibrated Bayesian Optimal Phase II Design for Adaptive Enrichment Trials

Adaptive enrichment allows development of an experimental treatment to continue when its activity is insufficient in an all-comer population but remains promising in a prespecified biomarker-positive subgroup. However, sequential application of separately calibrated phase II designs can inflate the probability of a false-positive efficacy conclusion. We develop a globally calibrated Bayesian optimal phase II (BOP2) design for branching adaptive enrichment trials. At prespecified all-comer interim analyses, the trial either continues all-comer enrollment or, after crossing the all-comer futility boundary, evaluates the accumulated biomarker-positive data. Enrichment is initiated only when a prespecified minimum number of biomarker-positive patients is available and the biomarker-positive futility boundary is not crossed; otherwise, the trial stops. The all-comer and biomarker-positive thresholds are jointly calibrated for the union of the two possible efficacy claims while accounting for the random subgroup sample size available when enrichment is considered. All decision rules are prespecified before trial initiation. For a binary endpoint, an exact finite-state recursive enumeration enables calibration and operating-characteristic evaluation without Monte Carlo error. Under the prespecified point global null, the proposed design controlled the global type I error rate over the prespecified set of biomarker-positive prevalence values while achieving higher power than the independently calibrated BOP2 comparator across the evaluated alternative scenarios. In the numerical study, the independently calibrated comparator exceeded the nominal global type I error level after its components were embedded in the branching procedure. The framework is also extended to complex categorical endpoints using a Dirichlet--multinomial formulation, with calibration and evaluation performed by simulation.

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Fast Power Evaluation under Biased-Coin Minimization: Sampling and Randomization Calibration

Design-stage power and sample-size evaluation under biased-coin minimization can be computationally intensive when a prespecified randomization test is reproduced within every simulated trial. We develop a reusable stratum-imbalance Gaussian approximation (SIGA) framework by exactly decomposing a fixed-score statistic into joint-stratum imbalance and orthogonal within-stratum components. Under explicit allocation-copy limit conditions for the same absolute-imbalance rule, the sampling-calibrated procedure, SIGA-S, consistently estimates the repeated-sampling variance at a marginal mean- or risk-difference boundary. At a nonsharp boundary, the conditional variance of a fixed-score randomization test can differ because the score contains the observed allocation path. To characterize this distinction, we express the first-order variance gap as a quadratic form involving pair-path covariance and introduce the randomization-calibrated procedure, SIGA-R, based on a reusable paired allocation-only calibration to approximate the conditional reference distribution. Separate comprehensive benchmarks showed close agreement between each SIGA procedure and the corresponding reference randomization test. A trial-inspired simulation based on published aggregate planning characteristics likewise produced similar power for SIGA-S, SIGA-R and the reference randomization test, while both reusable calibration procedures substantially reduced computation relative to nested rerandomization.

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Covariate-Adaptive Sample Size Re-estimation for Population-Standardized Historical Control Designs in Single-Arm Trials

Externally controlled single-arm trials are increasingly considered when randomized controls are infeasible, but baseline imbalance between the active-arm trial and historical controls complicates both estimation and sample size planning. We propose a population-standardized design framework in which the target estimand is defined for the actually enrolled active-arm population and historical-control outcomes are standardized to that population through a pre-specified balancing score. Building on this estimand, we develop an outcome-blinded, covariate-adaptive sample size re-estimation (SSR) procedure that updates the required sample size using only accumulating baseline covariates, without using active-arm outcomes during enrollment. The method combines an initial scenario-based design with sequential updates of the enrolled-population score distribution, standardized control parameters, and target sample size under pre-specified stopping rules. We give conditional and unconditional power interpretations and sufficient conditions for approximate type I error control under repeated blinded SSR. In simulation studies with distributional shifts between planned and true active-arm populations, fixed designs based only on planning assumptions lost power, whereas the proposed SSR maintained power near the target level and performed similarly to an oracle design. In an illustrative ADCS-based example, the proposed procedures yielded different final sample sizes across adjustment sets, reflecting evolving enrolled-population covariate profiles. These results support covariate-adaptive, outcome-blinded SSR as a practical design strategy for externally controlled single-arm trials that target population-standardized treatment effects.

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Likelihood-Ratio E-Value Monitoring for Benchmark-Based Decisions in Early-Phase Oncology Trials

Early-phase oncology trials often require protocol-ready interim rules for deciding whether an experimental regimen shows sufficient activity relative to prespecified clinical benchmarks. Existing Bayesian optimal phase II designs provide calibrated count boundaries for such decisions, but evidence is quantified through posterior probabilities and sample-size-dependent cutoff functions. We propose calibrated e-value monitoring (CEVAM), a likelihood-ratio evidence framework that defines monitoring evidence directly relative to prespecified clinical benchmarks, without requiring a Bayesian analysis prior or sample-size-dependent posterior-probability cutoff functions. For a binary efficacy endpoint, CEVAM constructs efficacy and reverse-futility e-processes targeted to clinically meaningful benchmark rates and converts them into monotone response-count boundaries. We distinguish a fixed-threshold e-process version, which has an anytime-valid interpretation under optional monitoring, from planned-look calibrated versions designed for conventional finite-look phase II trials. In simulations based on binary benchmark settings used in existing posterior-cutoff phase II designs, the proposed tuned planned-look rule controlled the nominal type I error and achieved the smallest expected sample size across all evaluated settings while retaining similar rejection probabilities. In an application to an actual phase II breast cancer trial, CEVAM classified the reported pathological complete response result as sufficient evidence for early success stopping. Extensions to categorical and multicomponent endpoints are provided in the Supplementary Material. CEVAM offers an analysis-prior-free, protocol-ready likelihood-ratio evidence scale for binary benchmark monitoring in early-phase oncology trials.

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A Clustering Approach for Basket Trials Based on Treatment Response Trajectories

Heterogeneity in efficacy is sometimes observed across baskets in basket trials. In this study, we propose a model-free clustering framework that groups baskets based on transition probabilities derived from the trajectories of treatment response, rather than relying solely on a single efficacy endpoint such as the objective response rate. The number of clusters is not predetermined but is automatically determined in a data-driven manner based on the similarity structure among baskets. After clustering, baskets within the same cluster are analyzed using a hierarchical Bayesian model. This framework aims to improve the estimation precision of efficacy endpoints and enhance statistical power while maintaining the type~I error rate at the nominal level. The performance of the proposed method was evaluated through simulation studies. The results demonstrated that the proposed method can accurately identify cluster structures in heterogeneous settings and, even under such conditions, maintain the type~I error rate at the nominal level while improving statistical power.

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Hybrid Non-informative and Informative Prior Model-assisted Designs for Mid-trial Dose Insertion

In oncology phase I trials, model-assisted designs have been increasingly adopted because they enable adaptive yet operationally simple dose adjustment based on accumulating safety data, leading to a paradigm shift in dose-escalation methodology. In practice, a single mid-trial dose insertion may be considered to examine safer doses and/or to collect more informative efficacy data. In this study, we investigate methods to improve dose assignment and the selection of the maximum tolerated dose (MTD) or the optimal biological dose (OBD) when a new dose level is added during an ongoing trial under a model-assisted framework, by assigning informative prior information to the inserted dose. We propose a hybrid design that uses a non-informative model-assisted design at trial initiation and, upon dose insertion, applies an informative-prior extension only to the newly added dose. In addition, to address potential skeleton misspecification, we propose two adaptive extensions: (i) an online-weighting approach that updates the skeleton over time, and (ii) a Bayesian-mixture approach that robustly combines multiple candidate skeletons. We evaluate the proposed methods through simulation studies.

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Seamless Phase I--II Cancer Clinical Trials Using Kernel-Based Covariate Similarity

In response to the U.S.\ Food and Drug Administration's (FDA) Project Optimus, a paradigm shift is underway in the design of early-phase oncology trials. To accelerate drug development, seamless Phase I/II designs have gained increasing attention, along with growing interest in the efficient reuse of Phase I data. We propose a nonparametric information-borrowing method that adaptively discounts Phase I observations according to the similarity of covariate distributions between Phase I and Phase II. Similarity is quantified using a kernel-based maximum mean discrepancy (MMD) and transformed into a dose-specific weight incorporated into a power-prior framework for Phase II efficacy evaluation, such as for the objective response rate (ORR). Considering the small sample sizes typical of early-phase oncology studies, we analytically derive a confidence interval for the weight, enabling assessment of borrowing precision without resampling procedures. Simulation studies under four toxicity scenarios and five baseline-covariate settings showed that the proposed method improved the probability that the lower bound of the 95\% credible interval for ORR exceeded a prespecified threshold at efficacious doses, while avoiding false threshold crossings at weakly efficacious doses. A case study based on a metastatic pancreatic ductal adenocarcinoma trial illustrates the resulting borrowing weights and posterior estimates.

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Sample size re-estimation in blinded hybrid-control design using inverse probability weighting

With the increasing availability of data from historical studies and real-world data sources, hybrid control designs that incorporate external data into the evaluation of current studies are being increasingly adopted. In these designs, it is necessary to pre-specify during the planning phase the extent to which information will be borrowed from historical control data. However, if substantial differences in baseline covariate distributions between the current and historical studies are identified at the final analysis, the amount of effective borrowing may be limited, potentially resulting in lower actual power than originally targeted. In this paper, we propose two sample size re-estimation strategies that can be applied during the course of the blinded current study. Both strategies utilize inverse probability weighting (IPW) based on the probability of assignment to either the current or historical study. When large discrepancies in baseline covariates are detected, the proposed strategies adjust the sample size upward to prevent a loss of statistical power. The performance of the proposed strategies is evaluated through simulation studies, and their practical implementation is demonstrated using a case study based on two actual randomized clinical studies.

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Integrate Meta-analysis into Specific Study (InMASS) for Estimating Conditional Average Treatment Effect

Randomized controlled trials are the standard method for estimating causal effects, ensuring sufficient statistical power and confidence through adequate sample sizes. However, achieving such sample sizes is often challenging. This study proposes a novel method for estimating the average treatment effect (ATE) in a target population by integrating and reconstructing information from previous trials using only summary statistics of outcomes and covariates through meta-analysis. The proposed approach combines meta-analysis, transfer learning, and weighted regression. Unlike existing methods that estimate the ATE based on the distribution of source trials, our method directly estimates the ATE for the target population. The proposed method requires only the means and variances of outcomes and covariates from the source trials and is theoretically valid under the covariate shift assumption, regardless of the covariate distribution in the source trials. Simulations and real-data analyses demonstrate that the proposed method yields a consistent estimator and achieves higher statistical power than the estimator derived solely from the target trial.

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Bayesian Parametric Methods for Deriving Distribution of Restricted Mean Survival Time

We propose a Bayesian method for deriving the distribution of restricted mean survival time (RMST) using posterior samples, which accounts for covariates and heterogeneity among clusters based on a parametric model for survival time. We derive an explicit RMST equation by devising an integral of the survival function, allowing for the calculation of not only the mean and credible interval but also the mode, median, and probability of exceeding a certain value. Additionally, We propose two methods: one using random effects to account for heterogeneity among clusters and another utilizing frailty. We developed custom Stan code for the exponential, Weibull, log-normal frailty, and log-logistic models, as they cannot be processed using the brm functions in R. We evaluate our proposed methods through computer simulations and analyze real data from the eight Empowered Action Group states in India to confirm consistent results across states after adjusting for cluster differences. In conclusion, we derived explicit RMST formulas for parametric models and their distributions, enabling the calculation of the mean, median, mode, and credible interval. Our simulations confirmed the robustness of the proposed methods, and using the shrinkage effect allowed for more accurate results for each cluster.

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Random Effect Restricted Mean Survival Time Model

The restricted mean survival time (RMST) model has been garnering attention as a way to provide a clinically intuitive measure: the mean survival time. RMST models, which use methods based on pseudo time-to-event values and inverse probability censoring weighting, can adjust covariates. However, no approach has yet been introduced that considers random effects for clusters. In this paper, we propose a new random-effect RMST. We present two methods of analysis that consider variable effects by i) using a generalized mixed model with pseudo-values and ii) integrating the estimated results from the inverse probability censoring weighting estimating equations for each cluster. We evaluate our proposed methods through computer simulations. In addition, we analyze the effect of a mother's age at birth on under-five deaths in India using states as clusters.

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Adjusting confidence intervals under covariate-adaptive randomization in non-inferiority and equivalence trials

Regulatory authorities guide the use of permutation tests or randomization tests so as not to increase the type-I error rate when applying covariate-adaptive randomization in randomized clinical trials. For non-inferiority and equivalence trials, this paper derives adjusted confidence intervals using permutation and randomization methods, thus controlling the type-I error to be much closer to the pre-specified nominal significance level. We consider three variable types for the outcome of interest, namely normal, binary, and time-to-event variables for the adjusted confidence intervals. For normal variables, we show that the type-I error for the adjusted confidence interval holds the nominal significance level. However, we highlight a unique theoretical challenge for non-inferiority and equivalence trials: binary and time-to-event variables may not hold the nominal significance level when the model parameters are estimated by models that diverge from the data-generating model under the null hypothesis. To clarify these features, we present simulation results and evaluate the performance of the adjusted confidence intervals.

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Introduction of accelerated BOIN design and facilitation of its application

Purpose: During discussions at the Data Science Roundtable meeting in Japan, there were instances where the adoption of the BOIN design was declined, attributed to the extension of study duration and increased sample size in comparison to the 3+3 design. We introduce an accelerated BOIN design aimed at completing a clinical phase I trial at a pace comparable to the 3+3 design. Additionally, we introduce how we could have applied the BOIN design within our company, which predominantly utilized the 3+3 design for most of its clinical oncology dose escalation trials. Methods: The accelerated BOIN design is adaptable by using efficiently designated stopping criterion for the existing BOIN framework. Our approach is to terminate the dose escalation study if the number of evaluable patients treated at the current dose reaches 6 and the decision is to stay at the current dose for the next cohort of patients. In addition, for lower dosage levels, considering a cohort size smaller than 3 may be feasible when there are no safety concerns from non-clinical studies. We demonstrate the accelerated BOIN design using a case study and subsequently evaluate the performance of our proposed design through a simulation study. Results: In the simulation study, the average difference in the percentage of correct MTD selection between the accelerated BOIN design and the standard BOIN design was -2.43%, the average study duration and the average sample size of the accelerated BOIN design was reduced by 14.8 months and 9.22 months, respectively, compared with the standard BOIN design. Conclusion: We conclude that our proposed accelerated BOIN design not only provides superior operating characteristics but also enables the study to be completed as fast as the 3+3 design.

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Dynamic Borrowing Method for Historical Information Using a Frequentist Approach for Hybrid Control Design

Information borrowing from historical data is gaining attention in clinical trials of rare and pediatric diseases, where statistical power may be insufficient for confirmation of efficacy if the sample size is small. Although Bayesian information borrowing methods are well established, test-then-pool and equivalence-based test-then-pool methods have recently been proposed as frequentist methods to determine whether historical data should be used for statistical hypothesis testing. Depending on the results of the hypothesis testing, historical data may not be usable. This paper proposes a dynamic borrowing method for historical information based on the similarity between current and historical data. In our proposed method of dynamic information borrowing, as in Bayesian dynamic borrowing, the amount of borrowing ranges from 0% to 100%. We propose two methods using the density function of the t-distribution and a logistic function as a similarity measure. We evaluate the performance of the proposed methods through Monte Carlo simulations. We demonstrate the usefulness of borrowing information by reanalyzing actual clinical trial data.

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