A review and re-interpretation of a group-sequential approach to sample size re-estimation in two-stage trials.
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ABSTRACT:
SUBMITTER: Bowden J
PROVIDER: S-EPMC4288989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSample size re-estimation (SSR) is a method used to recalculate sample size during clinical trial conduct to address a lack of adequate information and can have a significant impact on study size, duration, resources, and cost. Few studies to date have summarized the conditions and circumstances under which SSR is applied. We therefore performed a systematic review of the literature related to SSR to better understand its application in clinical trial settings.MethodsPubMed was used as the primary search source, supplemented with information from ClinicalTrials.gov where necessary details were lacking from PubMed. A systematic review was performed according to a pre-specified search strategy to identify clinical trials using SSR. Features of SSR, such as study phase and study start year, were summarized.ResultsIn total, 253 publications met the pre-specified search criteria and 27 clinical trials were subsequently determined as relevant in SSR usage. Among trials where the study phase was provided, 2 (7.4%) trials were Phase I, 5 (18.5%) trials were Phase II, 11 (40.7%) trials were Phase III, and 2 (7.4%) trials were Phase IV.ConclusionOur results showed that SSR is also used in Phase I and II, which involve earlier decision making. We expect that SSR will continue to be used in early-phase trials where sufficient prior information may not be available. Furthermore, no major trends were observed in relation to therapy area or type of SSR, meaning that SSR may become a feasible and widely applied method in the future.
| S-EPMC10568275 | biostudies-literature
Project description:BackgroundNon-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. These advantages however are not included in the classic frequentist approach of sample size calculation for non-inferiority trials. In contrast, the decision theory approach of sample size calculation does include these factors. The objective of this study is to compare the conceptual and practical aspects of the frequentist approach and decision theory approach of sample size calculation for non-inferiority trials, thereby demonstrating that the decision theory approach is more appropriate for sample size calculation of non-inferiority trials.MethodsThe frequentist approach and decision theory approach of sample size calculation for non-inferiority trials are compared and applied to a case of a non-inferiority trial on individually tailored duration of elastic compression stocking therapy compared to two years elastic compression stocking therapy for the prevention of post thrombotic syndrome after deep vein thrombosis.ResultsThe two approaches differ substantially in conceptual background, analytical approach, and input requirements. The sample size calculated according to the frequentist approach yielded 788 patients, using a power of 80% and a one-sided significance level of 5%. The decision theory approach indicated that the optimal sample size was 500 patients, with a net value of €92 million.ConclusionsThis study demonstrates and explains the differences between the classic frequentist approach and the decision theory approach of sample size calculation for non-inferiority trials. We argue that the decision theory approach of sample size estimation is most suitable for sample size calculation of non-inferiority trials.
| S-EPMC4468148 | biostudies-literature
Project description:BackgroundCrossover designs are commonly utilised in randomised controlled trials investigating treatments for long-term chronic illnesses. One problem with this design is its inherent repeated measures necessitate the availability of an estimate of the within-person standard deviation (SD) to perform a sample size calculation, which may be rarely available at the design stage of a trial. Interim sample size re-estimation designs can be used to help alleviate this issue by adapting the sample size mid-way through the trial, using accrued information in a statistically robust way.MethodsThe AIM HY-INFORM study is part of the Informative Markers in Hypertension (AIM HY) Programme and comprises two crossover trials, each with a planned recruitment of 600 participants. The objective of the study is to test whether blood pressure response to first line antihypertensive treatment depends on ethnicity. An interim analysis is planned to reassess the assumptions of the planned sample size for the study. The aims of this paper are: (1) to provide a formula for sample size re-estimation in both crossover trials; and (2) to present a simulation study of the planned interim analysis to investigate alternative within-person SDs to that assumed.ResultsThe AIM HY-INFORM protocol sample size calculation fixes the within-person SD to be 8 mmHg, giving > 90% power for a primary treatment effect of 4 mmHg. Using the method developed here and simulating the interim sample size reassessment, if we were to see a larger within-person SD of 9 mmHg at interim, 640 participants for 90% power 90% of the time in the three-period three-treatment design would be required. Similarly, in the four-period four-treatment crossover design, 602 participants would be required.ConclusionsThe formulas presented here provide a method for re-estimating the sample size in crossover trials. In the context of the AIM HY-INFORM study, simulating the interim analysis allows us to explore the results of a possible increase in the within-person SD from that assumed. Simulations show that without increasing the planned sample size of 600 participants, we can reasonably still expect to achieve 80% power with a small increase in the within-person SD from that assumed.Trial registrationClinicalTrials.gov, NCT02847338. Registered on 28 July 2016.
| S-EPMC6889633 | biostudies-literature
Project description:We discuss sample size determination in group-sequential designs with two endpoints as co-primary. We derive the power and sample size within two decision-making frameworks. One is to claim the test intervention's benefit relative to control when superiority is achieved for the two endpoints at the same interim timepoint of the trial. The other is when superiority is achieved for the two endpoints at any interim timepoint, not necessarily simultaneously. We evaluate the behaviors of sample size and power with varying design elements and provide a real example to illustrate the proposed sample size methods. In addition, we discuss sample size recalculation based on observed data and evaluate the impact on the power and Type I error rate.
| S-EPMC4082481 | biostudies-literature
Project description:Repeated testing in a group sequential trial can result in bias in the maximum likelihood estimate of the unknown parameter of interest. Many authors have therefore proposed adjusted point estimation procedures, which attempt to reduce such bias. Here, we describe nine possible point estimators within a common general framework for a two-stage group sequential trial. We then contrast their performance in five example trial settings, examining their conditional and marginal biases and residual mean square error. By focusing on the case of a trial with a single interim analysis, additional new results aiding the determination of the estimators are given. Our findings demonstrate that the uniform minimum variance unbiased estimator, whilst being marginally unbiased, often has large conditional bias and residual mean square error. If one is concerned solely about inference on progression to the second trial stage, the conditional uniform minimum variance unbiased estimator may be preferred. Two estimators, termed mean adjusted estimators, which attempt to reduce the marginal bias, arguably perform best in terms of the marginal residual mean square error. In all, one should choose an estimator accounting for its conditional and marginal biases and residual mean square error; the most suitable estimator will depend on relative desires to minimise each of these factors. If one cares solely about the conditional and marginal biases, the conditional maximum likelihood estimate may be preferred provided lower and upper stopping boundaries are included. If the conditional and marginal residual mean square error are also of concern, two mean adjusted estimators perform well.
| S-EPMC9896306 | biostudies-literature
Project description:Cluster-level dynamic treatment regimens can be used to guide sequential treatment decision-making at the cluster level in order to improve outcomes at the individual or patient-level. In a cluster-level dynamic treatment regimen, the treatment is potentially adapted and re-adapted over time based on changes in the cluster that could be impacted by prior intervention, including aggregate measures of the individuals or patients that compose it. Cluster-randomized sequential multiple assignment randomized trials can be used to answer multiple open questions preventing scientists from developing high-quality cluster-level dynamic treatment regimens. In a cluster-randomized sequential multiple assignment randomized trial, sequential randomizations occur at the cluster level and outcomes are observed at the individual level. This manuscript makes two contributions to the design and analysis of cluster-randomized sequential multiple assignment randomized trials. First, a weighted least squares regression approach is proposed for comparing the mean of a patient-level outcome between the cluster-level dynamic treatment regimens embedded in a sequential multiple assignment randomized trial. The regression approach facilitates the use of baseline covariates which is often critical in the analysis of cluster-level trials. Second, sample size calculators are derived for two common cluster-randomized sequential multiple assignment randomized trial designs for use when the primary aim is a between-dynamic treatment regimen comparison of the mean of a continuous patient-level outcome. The methods are motivated by the Adaptive Implementation of Effective Programs Trial which is, to our knowledge, the first-ever cluster-randomized sequential multiple assignment randomized trial in psychiatry.
| S-EPMC5802435 | biostudies-literature
Project description:BackgroundThe sample size calculation in a confirmatory diagnostic accuracy study is performed for co-primary endpoints because sensitivity and specificity are considered simultaneously. The initial sample size calculation in an unpaired and paired diagnostic study is based on assumptions about, among others, the prevalence of the disease and, in the paired design, the proportion of discordant test results between the experimental and the comparator test. The choice of the power for the individual endpoints impacts the sample size and overall power. Uncertain assumptions about the nuisance parameters can additionally affect the sample size.MethodsWe develop an optimal sample size calculation considering co-primary endpoints to avoid an overpowered study in the unpaired and paired design. To adjust assumptions about the nuisance parameters during the study period, we introduce a blinded adaptive design for sample size re-estimation for the unpaired and the paired study design. A simulation study compares the adaptive design to the fixed design. For the paired design, the new approach is compared to an existing approach using an example study.ResultsDue to blinding, the adaptive design does not inflate type I error rates. The adaptive design reaches the target power and re-estimates nuisance parameters without any relevant bias. Compared to the existing approach, the proposed methods lead to a smaller sample size.ConclusionsWe recommend the application of the optimal sample size calculation and a blinded adaptive design in a confirmatory diagnostic accuracy study. They compensate inefficiencies of the sample size calculation and support to reach the study aim.
| S-EPMC9019976 | biostudies-literature
Project description:Individual randomized trials (IRTs) and cluster randomized trials (CRTs) with binary outcomes arise in a variety of settings and are often analyzed by logistic regression (fitted using generalized estimating equations for CRTs). The effect of stratification on the required sample size is less well understood for trials with binary outcomes than for continuous outcomes. We propose easy-to-use methods for sample size estimation for stratified IRTs and CRTs and demonstrate the use of these methods for a tuberculosis prevention CRT currently being planned. For both IRTs and CRTs, we also identify the ratio of the sample size for a stratified trial vs a comparably powered unstratified trial, allowing investigators to evaluate how stratification will affect the required sample size when planning a trial. For CRTs, these can be used when the investigator has estimates of the within-stratum intracluster correlation coefficients (ICCs) or by assuming a common within-stratum ICC. Using these methods, we describe scenarios where stratification may have a practically important impact on the required sample size. We find that in the two-stratum case, for both IRTs and for CRTs with very small cluster sizes, there are unlikely to be plausible scenarios in which an important sample size reduction is achieved when the overall probability of a subject experiencing the event of interest is low. When the probability of events is not small, or when cluster sizes are large, however, there are scenarios where practically important reductions in sample size result from stratification.
| S-EPMC7247053 | biostudies-literature
Project description:BACKGROUND: The group testing method has been proposed for the detection and estimation of genetically modified plants (adventitious presence of unwanted transgenic plants, AP). For binary response variables (presence or absence), group testing is efficient when the prevalence is low, so that estimation, detection, and sample size methods have been developed under the binomial model. However, when the event is rare (low prevalence <0.1), and testing occurs sequentially, inverse (negative) binomial pooled sampling may be preferred. METHODOLOGY/PRINCIPAL FINDINGS: This research proposes three sample size procedures (two computational and one analytic) for estimating prevalence using group testing under inverse (negative) binomial sampling. These methods provide the required number of positive pools ([Formula: see text]), given a pool size (k), for estimating the proportion of AP plants using the Dorfman model and inverse (negative) binomial sampling. We give real and simulated examples to show how to apply these methods and the proposed sample-size formula. The Monte Carlo method was used to study the coverage and level of assurance achieved by the proposed sample sizes. An R program to create other scenarios is given in Appendix S2. CONCLUSIONS: The three methods ensure precision in the estimated proportion of AP because they guarantee that the width (W) of the confidence interval (CI) will be equal to, or narrower than, the desired width ([Formula: see text]), with a probability of [Formula: see text]. With the Monte Carlo study we found that the computational Wald procedure (method 2) produces the more precise sample size (with coverage and assurance levels very close to nominal values) and that the samples size based on the Clopper-Pearson CI (method 1) is conservative (overestimates the sample size); the analytic Wald sample size method we developed (method 3) sometimes underestimated the optimum number of pools.
| S-EPMC3310835 | biostudies-literature
Project description:Group sequential design has been widely applied in clinical trials in the past few decades. The sample size estimation is a vital concern of sponsors and investigators. Especially in the survival group sequential trials, it is a thorny question because of its ambiguous distributional form, censored data and different definition of information time. A practical and easy-to-use simulation-based method is proposed for multi-stage two-arm survival group sequential design in the article and its SAS program is available. Besides the exponential distribution, which is usually assumed for survival data, the Weibull distribution is considered here. The incorporation of the probability of discontinuation in the simulation leads to the more accurate estimate. The assessment indexes calculated in the simulation are helpful to the determination of number and timing of the interim analysis. The use of the method in the survival group sequential trials is illustrated and the effects of the varied shape parameter on the sample size under the Weibull distribution are explored by employing an example. According to the simulation results, a method to estimate the shape parameter of the Weibull distribution is proposed based on the median survival time of the test drug and the hazard ratio, which are prespecified by the investigators and other participants. 10+ simulations are recommended to achieve the robust estimate of the sample size. Furthermore, the method is still applicable in adaptive design if the strategy of sample size scheme determination is adopted when designing or the minor modifications on the program are made.
| S-EPMC3434206 | biostudies-literature