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Recently, interest has grown in the development of dose-finding methods that consider both toxicity and efficacy as endpoints. Along with responses on these, the incorporation of pharmacokinetic (PK) data can be beneficial in terms of patients’ safety and can also increase the efficiency of the design for finding the best dose for the next phase. In this paper, the maximum concentration (${C_{\max }}$Cmax) is used as the PK measure guiding the dose selection. The ethically attractive approach, which is based on the probability of efficacy, is used as a dose optimisation criterion. At each stage of an adaptive trial, that dose is selected for which the criterion is maximised, subject to the constraints imposed on the ${C_{\max }}$Cmax and the probability of toxicity. The inter-patient variability of the PK model parameters is considered, and population $D$D-optimal sampling time points for measuring the concentration of a drug in the blood are calculated. The method is illustrated with a one-compartment PK model with first-order absorption, with the parameters being assumed to be random. The Cox model for bivariate binary responses is employed to model the dose–response outcomes. The results of a simulation study for several plausible dose–response scenarios show a significant gain in the efficiency of the design, as well as a reduction in the proportion of toxic responses. [ABSTRACT FROM AUTHOR]

Adaptive seamless phase 2/3 subgroup enrichment design plays a pivotal role in streamlining efficient drug development within a competitive landscape, while also enhancing patient access to promising treatments. This design approach identifies biomarker subgroups with the highest potential to benefit from investigational regimens. The seamless integration of Phase 2 and Phase 3 ensures a timely confirmation of clinical benefits. One significant challenge in adaptive enrichment decisions is determining the optimal timing and maturity of the primary endpoint. In this paper, we propose an adaptive seamless 2-in-1 biomarker-driven subgroup enrichment design that addresses this challenge by allowing subgroup selection using an early intermediate endpoint that predicts clinical benefits (i.e. a surrogate endpoint). The proposed design initiates with a Phase 2 stage involving all participants and can potentially expand into a Phase 3 study focused on the subgroup demonstrating the most favorable clinical outcomes. We will show that, under certain correlation assumptions, the overall type I error may not be inflated at the end of the study. In scenarios where the assumptions may not hold, we present a general framework to control the multiplicity. The flexibility and efficacy of the proposed design are highlighted through an extensive simulation study and illustrated in a case study in multiple myeloma. [ABSTRACT FROM AUTHOR]

Adaptive designs, such as group sequential designs (and the ones with additional adaptive features) or adaptive platform trials, have been quintessential efficient design strategies in trials of unmet medical needs, especially for generating evidence from global regions. Such designs allow interim decision making and making adjustment to study design when necessary, meanwhile maintaining study integrity and operating characteristics. However, driven by the heightened competitive landscape and the desire to bring effective treatment to patients faster, innovation in the already functional designs is still germane to further propel drug development to a more efficient path. One way to achieve this is by leveraging external real-world data (RWD) in the adaptive designs to support interim or final decision making. In this paper, we propose a novel framework of incorporating external RWD in adaptive design to improve interim and/or final analysis decision making. Within this framework, researchers can prespecify the decision process and choose the timing and amount of borrowing while maintaining objectivity and controlling of type I error. Simulation studies in various scenarios are provided to describe power, type I error, and other performance metrics for interim/final decision making. A case study in non-small cell lung cancer is used for illustration on proposed design framework. [ABSTRACT FROM AUTHOR]

Combination therapy, a treatment modality that involves multiple treatment agents, has become imperative for improving treatment effectiveness and addressing resistance in the field of oncology. However, determining the most effective dose for these combinations, particularly when dealing with intricate drug interactions and diverse toxicity patterns, presents a substantial challenge. This paper introduces a novel Bayesian dose-finding design for combination therapies with information borrowing, named the DOD-Combo design. Leveraging historical single-agent trials and the meta-analytic-predictive (MAP) power prior, our approach utilizes a copula-type model to connect individual drug priors with joint toxicity probabilities in combination treatments. The MAP power prior allows the integration of information from multiple historical trials, constructing informative priors for each agent. Extensive simulations confirm our method’s superior performance compared to combination designs with no information borrowing. By adaptively incorporating historical data, our approach reduces sample sizes and enhances efficiency in selecting the maximum tolerated dose (MTD), effectively addressing the intricate challenges presented by combination trials. [ABSTRACT FROM AUTHOR]

The propensity score‐integrated composite likelihood (PSCL) method is one method that can be utilized to design and analyze an application when real‐world data (RWD) are leveraged to augment a prospectively designed clinical study. In the PSCL, strata are formed based on propensity scores (PS) such that similar subjects in terms of the baseline covariates from both the current study and RWD sources are placed in the same stratum, and then composite likelihood method is applied to down‐weight the information from the RWD. While PSCL was originally proposed for a fixed design, it can be extended to be applied under an adaptive design framework with the purpose to either potentially claim an early success or to re‐estimate the sample size. In this paper, a general strategy is proposed due to the feature of PSCL. For the possibility of claiming early success, Fisher's combination test is utilized. When the purpose is to re‐estimate the sample size, the proposed procedure is based on the test proposed by Cui, Hung, and Wang. The implementation of these two procedures is demonstrated via an example. [ABSTRACT FROM AUTHOR]

In theory, offering each sample member the mode sequence that maximizes their response propensity should increase the response rate and/or reduce the amount of nonresponse follow-up relative to a design that offers all sample members the same mode sequence. However, for this sort of tailoring to be feasible in a cross-sectional survey, it must be possible to use data available prior to data collection (e.g. on the sampling frame) to predict sample members' "mode-sensitivity"—the effect of the offered mode sequence on response propensity. Using data from randomized experiments incorporated into the 2016 and 2019 cycles of the National Household Education Survey, we evaluate whether data appended to an address-based sampling (ABS) frame can accurately predict the sensitivity of household-level response behavior to the initial offer of a paper questionnaire instead of a web instrument and whether a modeled-mode design that tailors the offered mode sequence (web-push vs. paper-only) based on the resulting predictions improves household-level data collection outcomes relative to a uniform web-push design. We find that several characteristics available on the ABS frame show statistically significant interactions with the offered mode sequence in determining the probability of response to initial survey mailings. Consequently, relative to a uniform web-push design, the modeled-mode design increased the response rate to early mailings and reduced the number of mailings required per response. However, the modeled-mode design did not meaningfully increase the final response rate, nor did it lead to a substantial reduction in indicators of nonresponse bias. [ABSTRACT FROM AUTHOR]

The adoption of emerging technologies under the Industry 4.0 paradigm has resulted in an increased quantity of data projected on the human-machine interface (HMI). This complexity is imposed in combination with users' limited cognitive capabilities to interpret such data quantity. We foresee this limitation fails to address the human-centric approach of the Industry 5.0 paradigm. To overcome this challenge, an automated approach is proposed to enable user-guided ad hoc visualization forms, which ultimately increases users' situational awareness of supervised industrial processes. In this paper, we present a framework for introducing automated HMI design as a custom feature of standard SCADA-based HMI functionality and showcase an example of how open technology may be used for such purposes, thus opening new avenues for rapid innovation on SCADA HMI. The framework enables integration of the user-initiated additions for loosely coupled visualization components configurable and integrated into the standard HMI runtime layer to meet changing user needs. [ABSTRACT FROM AUTHOR]

Due to the small sample sizes in early-phase clinical trials, the toxicity and efficacy profiles of the dose-schedule regimens determined for subsequent trials may not be well established. The recent development of novel anti-tumor treatments and combination therapies further complicates the problem. Therefore, there is an increasing recognition of the essential place of optimizing dose-schedule regimens, and new strategies are now urgently needed. Bayesian adaptive designs provide a potentially effective way to evaluate several doses and schedules simultaneously in a single clinical trial with higher efficiency, but real-world implementation examples of such adaptive designs are still few. In this paper, we cover the critical factors associated with dose-schedule optimization and review the related innovative Bayesian adaptive designs. The assumptions, characteristics, limitations, and application scenarios of those designs are introduced. The review also summarizes some unresolved issues and future research opportunities for dose-schedule optimization. [ABSTRACT FROM AUTHOR]

Adaptive survey designs are increasingly used by survey practitioners to counteract ongoing declines in household survey response rates and manage rising fieldwork costs. This paper reports findings from an evaluation of an early-bird incentive (EBI) experiment targeting high-effort respondents who participate in the 2019 wave of the US Panel Study of Income Dynamics. We identified a subgroup of high-effort respondents at risk of nonresponse based on their prior wave fieldwork effort and randomized them to a treatment offering an extra time-delimited monetary incentive for completing their interview within the first month of data collection (treatment group; N  = 800) or the standard study incentive (control group; N  = 400). In recent waves, we have found that the costs of the protracted fieldwork needed to complete interviews with high-effort cases in the form of interviewer contact attempts plus an increased incentive near the close of data collection are extremely high. By incentivizing early participation and reducing the number of interviewer contact attempts and fieldwork days to complete the interview, our goal was to manage both nonresponse and survey costs. We found that the EBI treatment increased response rates and reduced fieldwork effort and costs compared to a control group. We review several key findings and limitations, discuss their implications, and identify the next steps for future research. [ABSTRACT FROM AUTHOR]

Conditional power (CP) is a commonly used tool to inform interim decision‐making in clinical trials, but the conventional approach using only primary endpoint data to calculate CP may not perform well when the primary endpoint requires a long follow‐up period, or the treatment effect size changes during the trial. Several methods have been proposed to use additional short term auxiliary data observed at the interim analysis to improve the CP estimation in these situations, however, they may rely on strong assumptions, have limited applications, or use ad hoc choices of information fraction. In this paper we propose a general framework where the true CP formula is first derived in the presence of auxiliary data, and CP estimation is obtained by substituting the unknown parameters with consistent estimators. We conducted extensive simulations to examine the performance of both proposed and conventional approaches using the true CP as the benchmark. As the proposed approach is based on the true underlying CP, the simulations confirmed its superiority over the conventional approach in terms of efficiency and accuracy, especially if observed auxiliary data reflect the change of treatment effect size. The simulations also indicate that the magnitude of improvement in CP estimation is associated with the correlation between auxiliary and primary endpoints and/or the magnitude of the effect size change during the trial. [ABSTRACT FROM AUTHOR]

The binary endpoint and the time-to-event (TTE) endpoint are the main staple for clinical evaluation. The TTE endpoint is typically utilized when the follow-up is long, and the attrition rate is substantial. In the latter case, if the constant hazard ratio condition is approximately accurate, typically the Cox regression is applied to all available information by accommodating early terminations. However, if the treatment effect is fluctuating over time to such a degree that the proportional hazard ratio assumption is seriously violated, alternative approaches need to be considered, including in the setting of adaptive trial design. Due to the lack of literature focusing on application of the Com-Nougue method in the adaptive trial design, this paper is to highlight the unique features of sample size re-estimation under the Com-Nougue approach in contrast to some typical statistical techniques, with some representative simulations. In most scenarios of the simulations, including both superiority and non-inferiority (NI) tests, constant and piecewise hazard ratio under the exponential distribution, the Com-Nougue method performs well with the adaptive design. Cox regression excels in the proportional hazard ratio setting due to the use of all available data. This paper illustrates the utility of the Com-Nougue method in adaptive clinical trial design. It also provides a simple and convenient approach to calculate the conditional power and sample size under arbitrary underlying true parameter assumptions. [ABSTRACT FROM AUTHOR]

Background: Adaptive designs offer added flexibility in the execution of clinical trials, including the possibilities of allocating more patients to the treatments that turned out more successful, and early stopping due to either declared success or futility. Commonly applied adaptive designs, such as group sequential methods, are based on the frequentist paradigm and on ideas from statistical significance testing. Interim checks during the trial will have the effect of inflating the Type 1 error rate, or, if this rate is controlled and kept fixed, lowering the power.Results: The purpose of the paper is to demonstrate the usefulness of the Bayesian approach in the design and in the actual running of randomized clinical trials during phase II and III. This approach is based on comparing the performance of the different treatment arms in terms of the respective joint posterior probabilities evaluated sequentially from the accruing outcome data, and then taking a control action if such posterior probabilities fall below a pre-specified critical threshold value. Two types of actions are considered: treatment allocation, putting on hold at least temporarily further accrual of patients to a treatment arm, and treatment selection, removing an arm from the trial permanently. The main development in the paper is in terms of binary outcomes, but extensions for handling time-to-event data, including data from vaccine trials, are also discussed. The performance of the proposed methodology is tested in extensive simulation experiments, with numerical results and graphical illustrations documented in a Supplement to the main text. As a companion to this paper, an implementation of the methods is provided in the form of a freely available R package 'barts'.Conclusion: The proposed methods for trial design provide an attractive alternative to their frequentist counterparts. [ABSTRACT FROM AUTHOR]

The recent development of novel anticancer treatments with diverse mechanisms of action has accelerated the detection of treatment candidates tremendously. The rapidly changing drug development landscapes and the high failure rates in Phase III trials both underscore the importance of more efficient and robust phase II designs. The goals of phase II oncology studies are to explore the preliminary efficacy and toxicity of the investigational product and to inform future drug development strategies such as go/no-go decisions for phase III development, or dose/indication selection. These complex purposes of phase II oncology designs call for efficient, flexible, and easy-to-implement clinical trial designs. Therefore, innovative adaptive study designs with the potential of improving the efficiency of the study, protecting patients, and improving the quality of information gained from trials have been commonly used in Phase II oncology studies. Although the value of adaptive clinical trial methods in early phase drug development is generally well accepted, there is no comprehensive review and guidance on adaptive design methods and their best practice for phase II oncology trials. In this paper, we review the recent development and evolution of phase II oncology design, including frequentist multistage design, Bayesian continuous monitoring, master protocol design, and innovative design methods for randomized phase II studies. The practical considerations and the implementation of these complex design methods are also discussed. [ABSTRACT FROM AUTHOR]

Traditional vaccine efficacy trials usually use fixed designs with fairly large sample sizes. Recruiting a large number of subjects requires longer time and higher costs. Furthermore, vaccine developers are more than ever facing the need to accelerate vaccine development to fulfill the public's medical needs. A possible approach to accelerate development is to use the method of dynamic borrowing of historical controls in clinical trials. In this paper, we evaluate the feasibility and the performance of this approach in vaccine development by retrospectively analyzing two real vaccine studies: a relatively small immunological trial (typical early phase study) and a large vaccine efficacy trial (typical Phase 3 study) assessing prophylactic human papillomavirus vaccine. Results are promising, particularly for early development immunological studies, where the adaptive design is feasible, and control of type I error is less relevant. [ABSTRACT FROM AUTHOR]

In modern oncology drug development, adaptive designs have been proposed to identify the recommended phase 2 dose. The conventional dose finding designs focus on the identification of maximum tolerated dose (MTD). However, designs ignoring efficacy could put patients under risk by pushing to the MTD. Especially in immuno‐oncology and cell therapy, the complex dose‐toxicity and dose‐efficacy relationships make such MTD driven designs more questionable. Additionally, it is not uncommon to have data available from other studies that target on similar mechanism of action and patient population. Due to the high variability from phase I trial, it is beneficial to borrow historical study information into the design when available. This will help to increase the model efficiency and accuracy and provide dose specific recommendation rules to avoid toxic dose level and increase the chance of patient allocation at potential efficacious dose levels. In this paper, we propose iBOIN‐ET design that uses prior distribution extracted from historical studies to minimize the probability of decision error. The proposed design utilizes the concept of skeleton from both toxicity and efficacy data, coupled with prior effective sample size to control the amount of historical information to be incorporated. Extensive simulation studies across a variety of realistic settings are reported including a comparison of iBOIN‐ET design to other model based and assisted approaches. The proposed novel design demonstrates the superior performances in percentage of selecting the correct optimal dose (OD), average number of patients allocated to the correct OD, and overdosing control during dose escalation process. [ABSTRACT FROM AUTHOR]

An important issue for many economic experiments is how the experimenter can ensure sufficient power in order to reject one or more hypotheses. The paper illustrates how methods for testing multiple hypotheses simultaneously in adaptive, two-stage designs can be used to improve the power of economic experiments. We provide a concise overview of the relevant theory and illustrate the method in three different applications. These include a simulation study of a hypothetical experimental design, as well as illustrations using two data sets from previous experiments. The simulation results highlight the potential for sample size reductions, maintaining the power to reject at least one hypothesis while ensuring strong control of the overall Type I error probability. [ABSTRACT FROM AUTHOR]

Unblinded sample size re‐estimation (SSR) is often planned in a clinical trial when there is large uncertainty about the true treatment effect. For Proof‐of Concept (PoC) in a Phase II dose finding study, contrast test can be adopted to leverage information from all treatment groups. In this article, we propose two‐stage SSR designs using frequentist conditional power (CP) and Bayesian predictive power (PP) for both single and multiple contrast tests. The Bayesian SSR can be implemented under a wide range of prior settings to incorporate different prior knowledge. Taking the adaptivity into account, all type I errors of final analysis in this paper are rigorously protected. Simulation studies are carried out to demonstrate the advantages of unblinded SSR in multi‐arm trials. [ABSTRACT FROM AUTHOR]

Adaptive planning of clinical trials allows modifying the entire trial design at any time point mid‐course. In this paper, we consider the case when a trial‐external update of the planning assumptions during the ongoing trial makes an unforeseen design adaptation necessary. We take up the idea to construct adaptive designs with defined features by solving an optimization problem and apply it to the situation of unplanned design reassessment. By using the conditional error principle, we present an approach on how to optimally modify the trial design at an unplanned interim analysis while at the same time strictly protecting the type I error rate. This linking of optimal design planning and the conditional error principle allows sound reactions to unforeseen events that make a design reassessment necessary. [ABSTRACT FROM AUTHOR]

Abstract Background Adaptive designs offer added flexibility in the execution of clinical trials, including the possibilities of allocating more patients to the treatments that turned out more successful, and early stopping due to either declared success or futility. Commonly applied adaptive designs, such as group sequential methods, are based on the frequentist paradigm and on ideas from statistical significance testing. Interim checks during the trial will have the effect of inflating the Type 1 error rate, or, if this rate is controlled and kept fixed, lowering the power. Results The purpose of the paper is to demonstrate the usefulness of the Bayesian approach in the design and in the actual running of randomized clinical trials during phase II and III. This approach is based on comparing the performance of the different treatment arms in terms of the respective joint posterior probabilities evaluated sequentially from the accruing outcome data, and then taking a control action if such posterior probabilities fall below a pre-specified critical threshold value. Two types of actions are considered: treatment allocation, putting on hold at least temporarily further accrual of patients to a treatment arm, and treatment selection, removing an arm from the trial permanently. The main development in the paper is in terms of binary outcomes, but extensions for handling time-to-event data, including data from vaccine trials, are also discussed. The performance of the proposed methodology is tested in extensive simulation experiments, with numerical results and graphical illustrations documented in a Supplement to the main text. As a companion to this paper, an implementation of the methods is provided in the form of a freely available R package ’barts’. Conclusion The proposed methods for trial design provide an attractive alternative to their frequentist counterparts.

Background: Current dose-finding designs for phase I clinical trials can correctly select the MTD in a range of 30-80% depending on various conditions based on a sample of 30 subjects. However, there is still an unmet need for efficiency and cost saving.Methods: We propose a novel dose-finding design based on Bayesian stochastic approximation. The design features utilization of dose level information through local adaptive modelling and free assumption of toxicity probabilities and hyper-parameters. It allows a flexible target toxicity rate and varying cohort size. And we extend it to accommodate historical information via prior effective sample size. We compare the proposed design to some commonly used methods in terms of accuracy and safety by simulation.Results: On average, our design can improve the percentage of correct selection to about 60% when the MTD resides at a early or middle position in the search domain and perform comparably to other competitive methods otherwise. A free online software package is provided to facilitate the application, where a simple decision tree for the design can be pre-printed beforehand.Conclusion: The paper proposes a novel dose-finding design for phase I clinical trials. Applying the design to future cancer trials can greatly improve the efficiency, consequently save cost and shorten the development period. [ABSTRACT FROM AUTHOR]

An immunotherapy trial often uses the phase I/II design to identify the optimal biological dose, which monitors the efficacy and toxicity outcomes simultaneously in a single trial. The progression‐free survival rate is often used as the efficacy outcome in phase I/II immunotherapy trials. As a result, patients developing disease progression in phase I/II immunotherapy trials are generally seriously ill and are often treated off the trial for ethical consideration. Consequently, the happening of disease progression will terminate the toxicity event but not vice versa, so the issue of the semi‐competing risks arises. Moreover, this issue can become more intractable with the late‐onset outcomes, which happens when a relatively long follow‐up time is required to ascertain progression‐free survival. This paper proposes a novel Bayesian adaptive phase I/II design accounting for semi‐competing risks outcomes for immunotherapy trials, referred to as the dose‐finding design accounting for semi‐competing risks outcomes for immunotherapy trials (SCI) design. To tackle the issue of the semi‐competing risks in the presence of late‐onset outcomes, we re‐construct the likelihood function based on each patient's actual follow‐up time and develop a data augmentation method to efficiently draw posterior samples from a series of Beta‐binomial distributions. We propose a concise curve‐free dose‐finding algorithm to adaptively identify the optimal biological dose using accumulated data without making any parametric dose–response assumptions. Numerical studies show that the proposed SCI design yields good operating characteristics in dose selection, patient allocation, and trial duration. [ABSTRACT FROM AUTHOR]

Adaptive designs are an increasingly popular method for the adaptation of design aspects in clinical trials, such as the sample size. Scoring different adaptive designs helps to make an appropriate choice among the numerous existing adaptive design methods. Several scores have been proposed to evaluate adaptive designs. Moreover, it is possible to determine optimal two‐stage adaptive designs with respect to a customized objective score by solving a constrained optimization problem. In this paper, we use the conditional performance score by Herrmann et al. (2020) as the optimization criterion to derive optimal adaptive two‐stage designs. We investigate variations of the original performance score, for example, by assigning different weights to the score components and by incorporating prior assumptions on the effect size. We further investigate a setting where the optimization framework is extended by a global power constraint, and additional optimization of the critical value function next to the stage‐two sample size is performed. Those evaluations with respect to the sample size curves and the resulting design's performance can contribute to facilitate the score's usage in practice. [ABSTRACT FROM AUTHOR]

Compared with the traditional sustainable design that optimizes physical materials and components to extend product life-cycle time period, adaptive design aims at creating a dynamic design process to satisfy changes of product requirements in life-cycle time periods. In this paper, we discuss the key features of sustainable adaptive design to optimize the product design process. An adaptive design method is proposed to analyze the ever-changing requirements to reduce resource consumption and waste. Accordingly, two appropriate mechanisms are proposed to achieve product improvement in sustainability, (1) an approach of product requirements classification is used to dynamically identify and classify customer perceptions, and (2) a mapping between functions and requirements is introduced to represent the ability of existing design to adapt to the changing requirements. A case study of vehicle is conducted to show the effectiveness of the introduced method. [ABSTRACT FROM AUTHOR]

Wind turbines work in harsh environments and have changeable loads. The reliability and service life of the wind turbine gearbox has become an important factor for maintaining its safe, stable, and reliable economic operation. The production practice shows that the failure of the wind turbine gearbox is closely related to the structure and performance of the lubrication system. In this paper, the fault tree of the wind turbine gearbox lubrication system is established. It is pointed out that the temperature, state, and lubrication intensity of the lubricating oil are not well adapted to the working condition of the gear box, which leads to frequent gearbox breakdowns until its failure. The heat dissipation power consumption of the lubrication system is determined by calculating the heat balance of the lubrication system. By introducing the AI control method, the adaptive lubrication system framework of the wind turbine gear box is constructed from the aspects of oil temperature, oil pressure, oil level, and oil quality, which can automatically adjust the lubrication intensity according to the working condition of the wind turbine, so as to improve the lubrication effect of the wind turbine gear box. The research work in this paper plays an important role in optimizing the performance of the lubrication system, reducing the failure of the lubrication system, and reducing the operation and maintenance cost of wind turbines. [ABSTRACT FROM AUTHOR]

Automobile traffic, which is considered one of the permanent major sources of various types of pollution in the urban environment, gives a special contribution to urban ecological problems. The establishment of roadside green spaces can greatly reduce the negative ecological consequences that urban traffic produces. In the process of planning and management of urban green spaces, information on the types of biophysical structures of the green spaces and their characteristics in relation to the degree of modification of unfavorable ecological factors are of great importance. This paper investigates the impact of the type of biophysical structure of green roadside spaces in the area of Belgrade on the ecological factors with the highest impact on people's quality of life in the city, including air temperature, air humidity, the urban noise level and wind speed. The results and conclusions of this paper are part of a research of the adaptive design, which provides guidelines for the planning of urban landscape development in the conditions of unpredictable climate change. [ABSTRACT FROM AUTHOR]

Asymptotic distribution theory for maximum likelihood estimators under fixed alternative hypotheses is reported in the literature even though the power of any realistic test converges to one under fixed alternatives. Under fixed alternatives, authors have established that nuisance parameter estimates are inconsistent when sample size re-estimation (SSR) follows blinded randomization. These results have helped to inhibit the use of SSR. In this paper, we argue for local alternatives to be used instead of fixed alternatives. We treat unavailable treatment assignments in blinded experiments as missing data and rely on single imputation from marginal distributions to fill in for missing data. With local alternatives, it is sufficient to proceed only with the first step of the EM algorithm mimicking imputation under the null hypothesis. Then, we show that blinded and unblinded estimates of the nuisance parameter σ θ 2 are consistent, and re-estimated sample sizes converge to their locally asymptotically optimal values. This theoretical finding is confirmed through Monte-Carlo simulation studies. Practical utility is illustrated through a multiple logistic regression example. We conclude that, for hypothesis testing with a predetermined minimally clinically relevant local effect size, both blinded and unblinded SSR procedures lead to similar sample sizes and power. [ABSTRACT FROM AUTHOR]

Adaptive two-stage designs for clinical trials are well understood from a statistical perspective. However, there is still few research on how the stage-two sample size looks like when it is regarded as a function of the first-stage test statistic. In this paper, a formal proof on the concavity of the sample size function is provided if the design's second stage is optimized such that it minimizes the expected sample size under the alternative under constraints on maximal type I error rate and minimal power. [ABSTRACT FROM AUTHOR]