A review and re‐interpretation of a group‐sequential approach to sample size re‐estimation in two‐stage trials

In this paper, we review the adaptive design methodology of Li et al. (Biostatistics 3 :277–287) for two‐stage trials with mid‐trial sample size adjustment. We argue that it is closer in principle to a group sequential design, in spite of its obvious adaptive element. Several extensions are proposed that aim to make it even more attractive and transparent alternative to a standard (fixed sample size) trial for funding bodies to consider. These enable a cap to be put on the maximum sample size and for the trial data to be analysed using standard methods at its conclusion. The regulatory view of trials incorporating unblinded sample size re‐estimation is also discussed. © 2014 The Authors. Pharmaceutical Statistics published by John Wiley & Sons, Ltd.     

Blinded sample size re‐estimation in superiority and noninferiority trials: bias versus variance in variance estimation

The internal pilot study design allows for modifying the sample size during an ongoing study based on a blinded estimate of the variance thus maintaining the trial integrity. Various blinded sample size re‐estimation procedures have been proposed in the literature. We compare the blinded sample size re‐estimation procedures based on the one‐sample variance of the pooled data with a blinded procedure using the randomization block information with respect to bias and variance of the variance estimators, and the distribution of the resulting sample sizes, power, and actual type I error rate. For reference, sample size re‐estimation based on the unblinded variance is also included in the comparison. It is shown that using an unbiased variance estimator (such as the one using the randomization block information) for sample size re‐estimation does not guarantee that the desired power is achieved. Moreover, in situations that are common in clinical trials, the variance estimator that employs the randomization block length shows a higher variability than the simple one‐sample estimator and in turn the sample size resulting from the related re‐estimation procedure. This higher variability can lead to a lower power as was demonstrated in the setting of noninferiority trials. In summary, the one‐sample estimator obtained from the pooled data is extremely simple to apply, shows good performance, and is therefore recommended for application. Copyright © 2013 John Wiley & Sons, Ltd.     

Bayesian sample size determination for phase IIA clinical trials using historical data and semi‐parametric prior's elicitation

The Simon's two‐stage design is the most commonly applied among multi‐stage designs in phase IIA clinical trials. It combines the sample sizes at the two stages in order to minimize either the expected or the maximum sample size. When the uncertainty about pre‐trial beliefs on the expected or desired response rate is high, a Bayesian alternative should be considered since it allows to deal with the entire distribution of the parameter of interest in a more natural way. In this setting, a crucial issue is how to construct a distribution from the available summaries to use as a clinical prior in a Bayesian design. In this work, we explore the Bayesian counterparts of the Simon's two‐stage design based on the predictive version of the single threshold design. This design requires specifying two prior distributions: the analysis prior, which is used to compute the posterior probabilities, and the design prior, which is employed to obtain the prior predictive distribution. While the usual approach is to build beta priors for carrying out a conjugate analysis, we derived both the analysis and the design distributions through linear combinations of B‐splines. The motivating example is the planning of the phase IIA two‐stage trial on anti‐HER2 DNA vaccine in breast cancer, where initial beliefs formed from elicited experts' opinions and historical data showed a high level of uncertainty. In a sample size determination problem, the impact of different priors is evaluated.     

Sample size re‐estimation incorporating prior information on a nuisance parameter

Prior information is often incorporated informally when planning a clinical trial. Here, we present an approach on how to incorporate prior information, such as data from historical clinical trials, into the nuisance parameter–based sample size re‐estimation in a design with an internal pilot study. We focus on trials with continuous endpoints in which the outcome variance is the nuisance parameter. For planning and analyzing the trial, frequentist methods are considered. Moreover, the external information on the variance is summarized by the Bayesian meta‐analytic‐predictive approach. To incorporate external information into the sample size re‐estimation, we propose to update the meta‐analytic‐predictive prior based on the results of the internal pilot study and to re‐estimate the sample size using an estimator from the posterior. By means of a simulation study, we compare the operating characteristics such as power and sample size distribution of the proposed procedure with the traditional sample size re‐estimation approach that uses the pooled variance estimator. The simulation study shows that, if no prior‐data conflict is present, incorporating external information into the sample size re‐estimation improves the operating characteristics compared to the traditional approach. In the case of a prior‐data conflict, that is, when the variance of the ongoing clinical trial is unequal to the prior location, the performance of the traditional sample size re‐estimation procedure is in general superior, even when the prior information is robustified. When considering to include prior information in sample size re‐estimation, the potential gains should be balanced against the risks.     

TITE‐BOIN‐ET: Time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on both efficacy and toxicity outcomes

One of the primary purposes of an oncology dose‐finding trial is to identify an optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for subjects in subsequent clinical trials. In addition, it is quite important to accelerate early stage trials to shorten the entire period of drug development. However, it is often challenging to make adaptive decisions of dose escalation and de‐escalation in a timely manner because of the fast accrual rate, the difference of outcome evaluation periods for efficacy and toxicity and the late‐onset outcomes. To solve these issues, we propose the time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on cumulative and pending data of both efficacy and toxicity. The new design, named “TITE‐BOIN‐ET” design, is nonparametric and a model‐assisted design. Thus, it is robust, much simpler, and easier to implement in actual oncology dose‐finding trials compared with the model‐based approaches. These characteristics are quite useful from a practical point of view. A simulation study shows that the TITE‐BOIN‐ET design has advantages compared with the model‐based approaches in both the percentage of correct OD selection and the average number of patients allocated to the ODs across a variety of realistic settings. In addition, the TITE‐BOIN‐ET design significantly shortens the trial duration compared with the designs without sequential enrollment and therefore has the potential to accelerate early stage dose‐finding trials.     

A powerful test for Balaam's design

The crossover trial design (AB/BA design) is often used to compare the effects of two treatments in medical science because it performs within‐subject comparisons, which increase the precision of a treatment effect (i.e., a between‐treatment difference). However, the AB/BA design cannot be applied in the presence of carryover effects and/or treatments‐by‐period interaction. In such cases, Balaam's design is a more suitable choice. Unlike the AB/BA design, Balaam's design inflates the variance of an estimate of the treatment effect, thereby reducing the statistical power of tests. This is a serious drawback of the design. Although the variance of parameter estimators in Balaam's design has been extensively studied, the estimators of the treatment effect to improve the inference have received little attention. If the estimate of the treatment effect is obtained by solving the mixed model equations, the AA and BB sequences are excluded from the estimation process. In this study, we develop a new estimator of the treatment effect and a new test statistic using the estimator. The aim is to improve the statistical inference in Balaam's design. Simulation studies indicate that the type I error of the proposed test is well controlled, and that the test is more powerful and has more suitable characteristics than other existing tests when interactions are substantial. The proposed test is also applied to analyze a real dataset. Copyright © 2015 John Wiley & Sons, Ltd.     

Two‐stage phase II survival trial design

Recently, molecularly targeted agents and immunotherapy have been advanced for the treatment of relapse or refractory cancer patients, where disease progression‐free survival or event‐free survival is often a primary endpoint for the trial design. However, methods to evaluate two‐stage single‐arm phase II trials with a time‐to‐event endpoint are currently processed under an exponential distribution, which limits application of real trial designs. In this paper, we developed an optimal two‐stage design, which is applied to the four commonly used parametric survival distributions. The proposed method has advantages compared with existing methods in that the choice of underlying survival model is more flexible and the power of the study is more adequately addressed. Therefore, the proposed two‐stage design can be routinely used for single‐arm phase II trial designs with a time‐to‐event endpoint as a complement to the commonly used Simon's two‐stage design for the binary outcome.     

Weighted re‐randomization tests for minimization with unbalanced allocation

Re‐randomization test has been considered as a robust alternative to the traditional population model‐based methods for analyzing randomized clinical trials. This is especially so when the clinical trials are randomized according to minimization, which is a popular covariate‐adaptive randomization method for ensuring balance among prognostic factors. Among various re‐randomization tests, fixed‐entry‐order re‐randomization is advocated as an effective strategy when a temporal trend is suspected. Yet when the minimization is applied to trials with unequal allocation, fixed‐entry‐order re‐randomization test is biased and thus compromised in power. We find that the bias is due to non‐uniform re‐allocation probabilities incurred by the re‐randomization in this case. We therefore propose a weighted fixed‐entry‐order re‐randomization test to overcome the bias. The performance of the new test was investigated in simulation studies that mimic the settings of a real clinical trial. The weighted re‐randomization test was found to work well in the scenarios investigated including the presence of a strong temporal trend. Copyright © 2013 John Wiley & Sons, Ltd.     

Characterization of dose‐response for count data using a generalized MCP‐Mod approach in an adaptive dose‐ranging trial

Understanding the dose–response relationship is a key objective in Phase II clinical development. Yet, designing a dose‐ranging trial is a challenging task, as it requires identifying the therapeutic window and the shape of the dose–response curve for a new drug on the basis of a limited number of doses. Adaptive designs have been proposed as a solution to improve both quality and efficiency of Phase II trials as they give the possibility to select the dose to be tested as the trial goes. In this article, we present a ‘shapebased’ two‐stage adaptive trial design where the doses to be tested in the second stage are determined based on the correlation observed between efficacy of the doses tested in the first stage and a set of pre‐specified candidate dose–response profiles. At the end of the trial, the data are analyzed using the generalized MCP‐Mod approach in order to account for model uncertainty. A simulation study shows that this approach gives more precise estimates of a desired target dose (e.g. ED70) than a single‐stage (fixed‐dose) design and performs as well as a two‐stage D‐optimal design. We present the results of an adaptive model‐based dose‐ranging trial in multiple sclerosis that motivated this research and was conducted using the presented methodology. Copyright © 2015 John Wiley & Sons, Ltd.     

Adaptive designs for single‐arm phase II trials in oncology

Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two‐stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two‐stage design proposed by Chang et al. (Biometrics 1987; 43:865–874). However, the new design allows the use of mid‐course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology. Copyright © 2012 John Wiley & Sons, Ltd.     

START: single‐to‐double arm transition design for phase II clinical trials

Phase II clinical trials designed for evaluating a drug's treatment effect can be either single‐arm or double‐arm. A single‐arm design tests the null hypothesis that the response rate of a new drug is lower than a fixed threshold, whereas a double‐arm scheme takes a more objective comparison of the response rate between the new treatment and the standard of care through randomization. Although the randomized design is the gold standard for efficacy assessment, various situations may arise where a single‐arm pilot study prior to a randomized trial is necessary. To combine the single‐ and double‐arm phases and pool the information together for better decision making, we propose a Single‐To‐double ARm Transition design (START) with switching hypotheses tests, where the first stage compares the new drug's response rate with a minimum required level and imposes a continuation criterion, and the second stage utilizes randomization to determine the treatment's superiority. We develop a software package in R to calibrate the frequentist error rates and perform simulation studies to assess the trial characteristics. Finally, a metastatic pancreatic cancer trial is used for illustrating the decision rules under the proposed START design.     

Blinded sample size re‐estimation in crossover bioequivalence trials

In drug development, bioequivalence studies are used to indirectly demonstrate clinical equivalence of a test formulation and a reference formulation of a specific drug by establishing their equivalence in bioavailability. These studies are typically run as crossover studies. In the planning phase of such trials, investigators and sponsors are often faced with a high variability in the coefficients of variation of the typical pharmacokinetic endpoints such as the area under the concentration curve or the maximum plasma concentration. Adaptive designs have recently been considered to deal with this uncertainty by adjusting the sample size based on the accumulating data. Because regulators generally favor sample size re‐estimation procedures that maintain the blinding of the treatment allocations throughout the trial, we propose in this paper a blinded sample size re‐estimation strategy and investigate its error rates. We show that the procedure, although blinded, can lead to some inflation of the type I error rate. In the context of an example, we demonstrate how this inflation of the significance level can be adjusted for to achieve control of the type I error rate at a pre‐specified level. Furthermore, some refinements of the re‐estimation procedure are proposed to improve the power properties, in particular in scenarios with small sample sizes. Copyright © 2014 John Wiley & Sons, Ltd.     

Bayesian single-to-double arm transition design using both short-term and long-term endpoints

The choice between single-arm designs versus randomized double-arm designs has been contentiously debated in the literature of phase II oncology trials. Recently, as a compromise, the single-to-double arm transition design was proposed, combining the two designs into one trial over two stages. Successful implementation of the two-stage transition design requires a suspension period at the end of the first stage to collect the response data of the already enrolled patients. When the evaluation of the primary efficacy endpoint is overly long, the between-stage suspension period may unfavorably prolong the trial duration and cause a delay in treating future eligible patients. To accelerate the trial, we propose a Bayesian single-to-double arm design with short-term endpoints (BSDS), where an intermediate short-term endpoint is used for making early termination decisions at the end of the single-arm stage, followed by an evaluation of the long-term endpoint at the end of the subsequent double-arm stage. Bayesian posterior probabilities are used as the primary decision-making tool at the end of the trial. Design calibration steps are proposed for this Bayesian monitoring process to control the frequentist operating characteristics and minimize the expected sample size. Extensive simulation studies have demonstrated that our design has comparable power and average sample size but a much shorter trial duration than conventional single-to-double arm design. Applications of the design are illustrated using two phase II oncology trials with binary endpoints.     

Do single‐arm trials have a role in drug development plans incorporating randomised trials?

Often, single‐arm trials are used in phase II to gather the first evidence of an oncological drug's efficacy, with drug activity determined through tumour response using the RECIST criterion. Provided the null hypothesis of ‘insufficient drug activity’ is rejected, the next step could be a randomised two‐arm trial. However, single‐arm trials may provide a biased treatment effect because of patient selection, and thus, this development plan may not be an efficient use of resources. Therefore, we compare the performance of development plans consisting of single‐arm trials followed by randomised two‐arm trials with stand‐alone single‐stage or group sequential randomised two‐arm trials. Through this, we are able to investigate the utility of single‐arm trials and determine the most efficient drug development plans, setting our work in the context of a published single‐arm non‐small‐cell lung cancer trial. Reference priors, reflecting the opinions of ‘sceptical’ and ‘enthusiastic’ investigators, are used to quantify and guide the suitability of single‐arm trials in this setting. We observe that the explored development plans incorporating single‐arm trials are often non‐optimal. Moreover, even the most pessimistic reference priors have a considerable probability in favour of alternative plans. Analysis suggests expected sample size savings of up to 25% could have been made, and the issues associated with single‐arm trials avoided, for the non‐small‐cell lung cancer treatment through direct progression to a group sequential randomised two‐arm trial. Careful consideration should thus be given to the use of single‐arm trials in oncological drug development when a randomised trial will follow. Copyright © 2015 The Authors. Pharmaceutical Statistics published by JohnWiley & Sons Ltd.     

Practical approaches for design and analysis of clinical trials of infertility treatments: crossover designs and the Mantel–Haenszel method are recommended

Crossover designs have some advantages over standard clinical trial designs and they are often used in trials evaluating the efficacy of treatments for infertility. However, clinical trials of infertility treatments violate a fundamental condition of crossover designs, because women who become pregnant in the first treatment period are not treated in the second period. In previous research, to deal with this problem, some new designs, such as re‐randomization designs, and analysis methods including the logistic mixture model and the beta‐binomial mixture model were proposed. Although the performance of these designs and methods has previously been evaluated in large‐scale clinical trials with sample sizes of more than 1000 per group, the actual sample sizes of infertility treatment trials are usually around 100 per group. The most appropriate design and analysis for these moderate‐scale clinical trials are currently unclear. In this study, we conducted simulation studies to determine the appropriate design and analysis method of moderate‐scale clinical trials for irreversible endpoints by evaluating the statistical power and bias in the treatment effect estimates. The Mantel–Haenszel method had similar power and bias to the logistic mixture model. The crossover designs had the highest power and the smallest bias. We recommend using a combination of the crossover design and the Mantel–Haenszel method for two‐period, two‐treatment clinical trials with irreversible endpoints. Copyright © 2015 John Wiley & Sons, Ltd.     

Testing treatment‐by‐period interaction in four‐period crossover trials

Statistical analyses of crossover clinical trials have mainly focused on assessing the treatment effect, carryover effect, and period effect. When a treatment‐by‐period interaction is plausible, it is important to test such interaction first before making inferences on differences among individual treatments. Considerably less attention has been paid to the treatment‐by‐period interaction, which has historically been aliased with the carryover effect in two‐period or three‐period designs. In this article, from the data of a newly developed four‐period crossover design, we propose a statistical method to compare the effects of two active drugs with respect to two response variables. We study estimation and hypothesis testing considering the treatment‐by‐period interaction. Constrained least squares is used to estimate the treatment effect, period effect, and treatment‐by‐period interaction. For hypothesis testing, we extend a general multivariate method for analyzing the crossover design with multiple responses. Results from simulation studies have shown that this method performs very well. We also illustrate how to apply our method to the real data problem.     

Increasing the sample size at interim for a two‐sample experiment without Type I error inflation

For the case of a one‐sample experiment with known variance σ²=1, it has been shown that at interim analysis the sample size (SS) may be increased by any arbitrary amount provided: (1) The conditional power (CP) at interim is ?50% and (2) there can be no decision to decrease the SS (stop the trial early). In this paper we verify this result for the case of a two‐sample experiment with proportional SS in the treatment groups and an arbitrary common variance. Numerous authors have presented the formula for the CP at interim for a two‐sample test with equal SS in the treatment groups and an arbitrary common variance, for both the one‐ and two‐sided hypothesis tests. In this paper we derive the corresponding formula for the case of unequal, but proportional SS in the treatment groups for both one‐sided superiority and two‐sided hypothesis tests. Finally, we present an SAS macro for doing this calculation and provide a worked out hypothetical example. In discussion we note that this type of trial design trades the ability to stop early (for lack of efficacy) for the elimination of the Type I error penalty. The loss of early stopping requires that such a design employs a data monitoring committee, blinding of the sponsor to the interim calculations, and pre‐planning of how much and under what conditions to increase the SS and that this all be formally written into an interim analysis plan before the start of the study. Copyright © 2009 John Wiley & Sons, Ltd.     

The impact of period effects on dose level contrasts in alternating cross‐over designs for first‐time‐in‐human studies

For first‐time‐in‐human studies with small molecules alternating cross‐over designs are often employed and at study end are analyzed using linear models. We discuss the impact of including a period effect in the model on the precision with which dose level contrasts can be estimated and quantify the bias of least squares estimators if a period effect is inherent in the data that is not accounted for in the model. We also propose two alternative designs that allow a more precise estimation of dose level contrasts compared with the standard design when period effects are included in the model. Copyright © 2010 John Wiley & Sons, Ltd.     

The plan of enrichment designs for dealing with high placebo response

To deal with high placebo response in clinical trials for psychiatric and other diseases, different enrichment designs, such as the sequential parallel design, two‐way enriched design, and sequential enriched design, have been proposed and implemented recently. Depending on the historical trial information and the trial sponsors' resources, detailed design elements are needed for determining which design to adopt. To assist in making more suitable decisions, we perform evaluations for selecting required design elements in terms of power optimization and sample size planning. We also discuss the implementation of the interim analysis related to its applicability.     

Admissible two-stage designs for phase II cancer clinical trials that incorporate the expected sample size under the alternative hypothesis

two‐stage studies may be chosen optimally by minimising a single characteristic like the maximum sample size. However, given that an investigator will initially select a null treatment e?ect and the clinically relevant di?erence, it is better to choose a design that also considers the expected sample size for each of these values. The maximum sample size and the two expected sample sizes are here combined to produce an expected loss function to ?nd designs that are admissible. Given the prior odds of success and the importance of the total sample size, minimising the expected loss gives the optimal design for this situation. A novel triangular graph to represent the admissible designs helps guide the decision‐making process. The H ₀‐optimal, H ₁‐optimal, H ₀‐minimax and H ₁‐minimax designs are all particular cases of admissible designs. The commonly used H ₀‐optimal design is rarely good when allowing stopping for e?cacy. Additionally, the δ‐minimax design, which minimises the maximum expected sample size, is sometimes admissible under the loss function. However, the results can be varied and each situation will require the evaluation of all the admissible designs. Software to do this is provided. Copyright © 2012 John Wiley & Sons, Ltd.