A Bayesian approach to pilot-pivotal trials for bioequivalence assessment.

BACKGROUND: To demonstrate bioequivalence between two drug formulations, a pilot trial is often conducted prior to a pivotal trial to assess feasibility and gain preliminary information about the treatment effect. Due to the limited sample size, it is not recommended to perform significance tests at the conventional 5% level using pilot data to determine if a pivotal trial should take place. Whilst some authors suggest to relax the significance level, a Bayesian framework provides an alternative for informing the decision-making. Moreover, a Bayesian approach also readily permits possible incorporation of pilot data in priors for the parameters that underpin the pivotal trial. METHODS: We consider two-sequence, two-period crossover designs that compare test (T) and reference (R) treatments. We propose a robust Bayesian hierarchical model, embedded with a scaling factor, to elicit a Go/No-Go decision using predictive probabilities. Following a Go decision, the final analysis to formally establish bioequivalence can leverage both the pilot and pivotal trial data jointly. A simulation study is performed to evaluate trial operating characteristics. RESULTS: Compared with conventional procedures, our proposed method improves the decision-making to correctly allocate a Go decision in scenarios of bioequivalence. By choosing an appropriate threshold, the probability of correctly (incorrectly) making a No-Go (Go) decision can be ensured at a desired target level. Using both pilot and pivotal trial data in the final analysis can result in a higher chance of declaring bioequivalence. The false positive rate can be maintained in situations when T and R are not bioequivalent. CONCLUSIONS: The proposed methodology is novel and effective in different stages of bioequivalence assessment. It can greatly enhance the decision-making process in bioequivalence trials, particularly in situations with a small sample size.

The Infant KIdney Dialysis and Utrafiltration (I-KID) Study: A Stepped-Wedge Cluster-Randomized Study in Infants, Comparing Peritoneal Dialysis, Continuous Venovenous Hemofiltration, and Newcastle Infant Dialysis Ultrafiltration System, a Novel Infant Hemodialysis Device.

OBJECTIVES: Renal replacement therapy (RRT) options are limited for small babies because of lack of available technology. We investigated the precision of ultrafiltration, biochemical clearances, clinical efficacy, outcomes, and safety profile for a novel non-Conformité Européenne-marked hemodialysis device for babies under 8 kg, the Newcastle Infant Dialysis Ultrafiltration System (NIDUS), compared with the current options of peritoneal dialysis (PD) or continuous venovenous hemofiltration (CVVH). DESIGN: Nonblinded cluster-randomized cross-sectional stepped-wedge design with four periods, three sequences, and two clusters per sequence. SETTING: Clusters were six U.K. PICUs. PATIENTS: Babies less than 8 kg requiring RRT for fluid overload or biochemical disturbance. INTERVENTIONS: In controls, RRT was delivered by PD or CVVH, and in interventions, NIDUS was used. The primary outcome was precision of ultrafiltration compared with prescription; secondary outcomes included biochemical clearances. MEASUREMENTS AND MAIN RESULTS: At closure, 97 participants were recruited from the six PICUs (62 control and 35 intervention). The primary outcome, obtained from 62 control and 21 intervention patients, showed that ultrafiltration with NIDUS was closer to that prescribed than with control: sd controls, 18.75, intervention, 2.95 (mL/hr); adjusted ratio, 0.13; 95% CI, 0.03-0.71; p = 0.018. Creatinine clearance was smallest and least variable for PD (mean, sd ) = (0.08, 0.03) mL/min/kg, larger for NIDUS (0.46, 0.30), and largest for CVVH (1.20, 0.72). Adverse events were reported in all groups. In this critically ill population with multiple organ failure, mortality was lowest for PD and highest for CVVH, with NIDUS in between. CONCLUSIONS: NIDUS delivers accurate, controllable fluid removal and adequate clearances, indicating that it has important potential alongside other modalities for infant RRT.

Residual Disease Threshold After Primary Surgical Treatment for Advanced Epithelial Ovarian Cancer, Part 1: A Systematic Review and Network Meta-Analysis.

BACKGROUND: We present a systematic review and network meta-analysis (NMA) that is the precursor underpinning the Bayesian analyses that adjust for publication bias, presented in the same edition in AJT. The review assesses optimal cytoreduction for women undergoing primary advanced epithelial ovarian cancer (EOC) surgery. AREAS OF UNCERTAINTY: To assess the impact of residual disease (RD) after primary debulking surgery in women with advanced EOC. This review explores the impact of leaving varying levels of primary debulking surgery. DATA SOURCES: We conducted a systematic review and random-effects NMA for overall survival (OS) to incorporate direct and indirect estimates of RD thresholds, including concurrent comparative, retrospective studies of ≥100 adult women (18+ years) with surgically staged advanced EOC (FIGO stage III/IV) who had confirmed histological diagnoses of ovarian cancer. Pairwise meta-analyses of all directly compared RD thresholds was previously performed before conducting this NMA, and the statistical heterogeneity of studies within each comparison was evaluated using recommended methods. THERAPEUTIC ADVANCES: Twenty-five studies (n = 20,927) were included. Analyses demonstrated the prognostic importance of complete cytoreduction to no macroscopic residual disease (NMRD), with a hazard ratio for OS of 2.0 (95% confidence interval, 1.8-2.2) for <1 cm RD threshold versus NMRD. NMRD was associated with prolonged survival across all RD thresholds. Leaving NMRD was predicted to provide longest survival (probability of being best = 99%). The results were robust to sensitivity analysis including only those studies that adjusted for extent of disease at primary surgery (hazard ratio 2.3, 95% confidence interval, 1.9-2.6). The overall certainty of evidence was moderate and statistical adjustment of effect estimates in included studies minimized bias. CONCLUSIONS: The results confirm a strong association between complete cytoreduction to NMRD and improved OS. The NMA approach forms part of the methods guidance underpinning policy making in many jurisdictions. Our analyses present an extension to the previous work in this area.

Point estimation following a two-stage group sequential trial.

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.

A hybrid approach to comparing parallel-group and stepped-wedge cluster-randomized trials with a continuous primary outcome when there is uncertainty in the intra-cluster correlation.

BACKGROUND/AIMS: To evaluate how uncertainty in the intra-cluster correlation impacts whether a parallel-group or stepped-wedge cluster-randomized trial design is more efficient in terms of the required sample size, in the case of cross-sectional stepped-wedge cluster-randomized trials and continuous outcome data. METHODS: We motivate our work by reviewing how the intra-cluster correlation and standard deviation were justified in 54 health technology assessment reports on cluster-randomized trials. To enable uncertainty at the design stage to be incorporated into the design specification, we then describe how sample size calculation can be performed for cluster- randomized trials in the 'hybrid' framework, which places priors on design parameters and controls the expected power in place of the conventional frequentist power. Comparison of the parallel-group and stepped-wedge cluster-randomized trial designs is conducted by placing Beta and truncated Normal priors on the intra-cluster correlation, and a Gamma prior on the standard deviation. RESULTS: Many Health Technology Assessment reports did not adhere to the Consolidated Standards of Reporting Trials guideline of indicating the uncertainty around the assumed intra-cluster correlation, while others did not justify the assumed intra-cluster correlation or standard deviation. Even for a prior intra-cluster correlation distribution with a small mode, moderate prior densities on high intra-cluster correlation values can lead to a stepped-wedge cluster-randomized trial being more efficient because of the degree to which a stepped-wedge cluster-randomized trial is more efficient for high intra-cluster correlations. With careful specification of the priors, the designs in the hybrid framework can become more robust to, for example, an unexpectedly large value of the outcome variance. CONCLUSION: When there is difficulty obtaining a reliable value for the intra-cluster correlation to assume at the design stage, the proposed methodology offers an appealing approach to sample size calculation. Often, uncertainty in the intra-cluster correlation will mean a stepped-wedge cluster-randomized trial is more efficient than a parallel-group cluster-randomized trial design.

Residual Disease After Primary Surgical Treatment for Advanced Epithelial Ovarian Cancer, Part 2: Network Meta-analysis Incorporating Expert Elicitation to Adjust for Publication Bias.

BACKGROUND: Previous work has identified a strong association between the achievements of macroscopic cytoreduction and improved overall survival (OS) after primary surgical treatment of advanced epithelial ovarian cancer. Despite the use of contemporary methodology, resulting in the most comprehensive currently available evidence to date in this area, opponents remain skeptical. AREAS OF UNCERTAINTY: We aimed to conduct sensitivity analyses to adjust for potential publication bias, to confirm or refute existing conclusions and recommendations, leveraging elicitation to incorporate expert opinion. We recommend our approach as an exemplar that should be adopted in other areas of research. DATA SOURCES: We conducted random-effects network meta-analyses in frequentist and Bayesian (using Markov Chain Montel Carlo simulation) frameworks comparing OS across residual disease thresholds in women with advanced epithelial ovarian cancer after primary cytoreductive surgery. Elicitation methods among experts in gynecology were used to derive priors for an extension to a previously reported Copas selection model and a novel approach using effect estimates calculated from the elicitation exercise, to attempt to adjust for publication bias and increase confidence in the certainty of the evidence. THERAPEUTIC ADVANCES: Analyses using data from 25 studies (n = 20,927 women) all showed the prognostic importance of complete cytoreduction (0 cm) in both frameworks. Experts accepted publication bias was likely, but after adjustment for their opinions, published results overpowered the informative priors incorporated into the Bayesian sensitivity analyses. Effect estimates were attenuated but conclusions were robust in all analyses. CONCLUSIONS: There remains a strong association between the achievement of complete cytoreduction and improved OS even after adjustment for publication bias using strong informative priors formed from an expert elicitation exercise. The concepts of the elicitation survey should be strongly considered for utilization in other meta-analyses.

Bayesian sample size determination in basket trials borrowing information between subsets.

Basket trials are increasingly used for the simultaneous evaluation of a new treatment in various patient subgroups under one overarching protocol. We propose a Bayesian approach to sample size determination in basket trials that permit borrowing of information between commensurate subsets. Specifically, we consider a randomized basket trial design where patients are randomly assigned to the new treatment or control within each trial subset ("subtrial" for short). Closed-form sample size formulae are derived to ensure that each subtrial has a specified chance of correctly deciding whether the new treatment is superior to or not better than the control by some clinically relevant difference. Given prespecified levels of pairwise (in)commensurability, the subtrial sample sizes are solved simultaneously. The proposed Bayesian approach resembles the frequentist formulation of the problem in yielding comparable sample sizes for circumstances of no borrowing. When borrowing is enabled between commensurate subtrials, a considerably smaller trial sample size is required compared to the widely implemented approach of no borrowing. We illustrate the use of our sample size formulae with two examples based on real basket trials. A comprehensive simulation study further shows that the proposed methodology can maintain the true positive and false positive rates at desired levels.

Design and analysis of umbrella trials: Where do we stand?

Background: The efficiencies that master protocol designs can bring to modern drug development have seen their increased utilization in oncology. Growing interest has also resulted in their consideration in non-oncology settings. Umbrella trials are one class of master protocol design that evaluates multiple targeted therapies in a single disease setting. Despite the existence of several reviews of master protocols, the statistical considerations of umbrella trials have received more limited attention. Methods: We conduct a systematic review of the literature on umbrella trials, examining both the statistical methods that are available for their design and analysis, and also their use in practice. We pay particular attention to considerations for umbrella designs applied outside of oncology. Findings: We identified 38 umbrella trials. To date, most umbrella trials have been conducted in early phase settings (73.7%, 28/38) and in oncology (92.1%, 35/38). The quality of statistical information available about conducted umbrella trials to date is poor; for example, it was impossible to ascertain how sample size was determined in the majority of trials (55.3%, 21/38). The literature on statistical methods for umbrella trials is currently sparse. Conclusions: Umbrella trials have potentially great utility to expedite drug development, including outside of oncology. However, to enable lessons to be effectively learned from early use of such designs, there is a need for higher-quality reporting of umbrella trials. Furthermore, if the potential of umbrella trials is to be realized, further methodological research is required.

Residual disease after primary surgery for advanced epithelial ovarian cancer: expert elicitation exercise to explore opinions about potential impact of publication bias in a planned systematic review and meta-analysis.

OBJECTIVES: We consider expert opinion and its incorporation into a planned meta-analysis as a way of adjusting for anticipated publication bias. We conduct an elicitation exercise among eligible British Gynaecological Cancer Society (BGCS) members with expertise in gynaecology. DESIGN: Expert elicitation exercise. SETTING: BGCS. PARTICIPANTS: Members of the BGCS with expertise in gynaecology. METHODS: Experts were presented with details of a planned prospective systematic review and meta-analysis, assessing overall survival for the extent of excision of residual disease (RD) after primary surgery for advanced epithelial ovarian cancer. Participants were asked views on the likelihood of different studies (varied in the size of the study population and the RD thresholds being compared) not being published. Descriptive statistics were produced and opinions on total number of missing studies by sample size and magnitude of effect size estimated. RESULTS: Eighteen expert respondents were included. Responders perceived publication bias to be a possibility for comparisons of RD <1 cm versus RD=0 cm, but more so for comparisons involving higher volume suboptimal RD thresholds. However, experts' perceived publication bias in comparisons of RD=0 cm versus suboptimal RD thresholds did not translate into many elicited missing studies in Part B of the elicitation exercise. The median number of missing studies estimated by responders for the main comparison of RD<1 cm versus RD=0 cm was 10 (IQR: 5-20), with the number of missing studies influenced by whether the effect size was equivocal. The median number of missing studies estimated for suboptimal RD versus RD=0 cm was lower. CONCLUSIONS: The results may raise awareness that a degree of scepticism is needed when reviewing studies comparing RD <1 cm versus RD=0 cm. There is also a belief among respondents that comparisons involving RD=0 cm and suboptimal thresholds (>1 cm) are likely to be impacted by publication bias, but this is unlikely to attenuate effect estimates in meta-analyses.

Subgroup analyses in randomized controlled trials frequently categorized continuous subgroup information.

BACKGROUND AND OBJECTIVES: To investigate how subgroup analyses of published Randomized Controlled Trials (RCTs) are performed when subgroups are created from continuous variables. METHODS: We carried out a review of RCTs published in 2016-2021 that included subgroup analyses. Information was extracted on whether any of the subgroups were based on continuous variables and, if so, how they were analyzed. RESULTS: Out of 428 reviewed papers, 258 (60.4%) reported RCTs with a subgroup analysis. Of these, 178/258 (69%) had at least one subgroup formed from a continuous variable and 14/258 (5.4%) were unclear. The vast majority (169/178, 94.9%) dichotomized the continuous variable and treated the subgroup as categorical. The most common way of dichotomizing was using a pre-specified cutpoint (129/169, 76.3%), followed by a data-driven cutpoint (26/169, 15.4%), such as the median. CONCLUSION: It is common for subgroup analyses to use continuous variables to define subgroups. The vast majority dichotomize the continuous variable and, consequently, may lose substantial amounts of statistical information (equivalent to reducing the sample size by at least a third). More advanced methods that can improve efficiency, through optimally choosing cutpoints or directly using the continuous information, are rarely used.

Adaptive Designs: Benefits and Cautions for Neurosurgery Trials.

BACKGROUND: It is well accepted that randomized controlled trials provide the greatest quality of evidence about effectiveness and safety of new interventions. In neurosurgery, randomized controlled trials face challenges, with their use remaining relatively low compared with other clinical areas. Adaptive designs have emerged as a method for improving the efficiency and patient benefit of trials. They allow modifications to the trial design to be made as patient outcome data are collected. The benefit they provide is highly variable, predominantly governed by the time taken to observe the primary endpoint compared with the planned recruitment rate. They also face challenges in design, conduct, and reporting. METHODS: We provide an overview of the benefits and challenges of adaptive designs, with a focus on neurosurgery applications. To investigate how often an adaptive design may be advantageous in neurosurgery, we extracted data on recruitment rates and endpoint lengths for ongoing neurosurgery trials registered in ClinicalTrials.gov. RESULTS: We found that a majority of neurosurgery trials had a relatively short endpoint length compared with the planned recruitment period and therefore may benefit from an adaptive trial. However, we did not identify any ongoing ClinicalTrials.gov registered neurosurgery trials that mentioned using an adaptive design. CONCLUSIONS: Adaptive designs may provide benefits to neurosurgery trials and should be considered for use more widely. Use of some types of adaptive design, such as multiarm multistage, may further increase the number of interventions that can be tested with limited patient and financial resources.

Mind the gap: covariate constrained randomisation can protect against substantial power loss in parallel cluster randomised trials.

BACKGROUND: Cluster randomised trials often randomise a small number of units, putting them at risk of poor balance of covariates across treatment arms. Covariate constrained randomisation aims to reduce this risk by removing the worst balanced allocations from consideration. This is known to provide only a small gain in power over that averaged under simple randomisation and is likely influenced by the number and prognostic effect of the covariates. We investigated the performance of covariate constrained randomisation in comparison to the worst balanced allocations, and considered the impact on the power of the prognostic effect and number of covariates adjusted for in the analysis. METHODS: Using simulation, we examined the Monte Carlo type I error rate and power of cross-sectional, two-arm parallel cluster-randomised trials with a continuous outcome and four binary cluster-level covariates, using either simple or covariate constrained randomisation. Data were analysed using a small sample corrected linear mixed-effects model, adjusted for some or all of the binary covariates. We varied the number of clusters, intra-cluster correlation, number and prognostic effect of covariates balanced in the randomisation and adjusted in the analysis, and the size of the candidate set from which the allocation was selected. For each scenario, 20,000 simulations were conducted. RESULTS: When compared to the worst balanced allocations, covariate constrained randomisation with an adjusted analysis provided gains in power of up to 20 percentage points. Even with analysis-based adjustment for those covariates balanced in the randomisation, the type I error rate was not maintained when the intracluster correlation is very small (0.001). Generally, greater power was achieved when more prognostic covariates are restricted in the randomisation and as the size of the candidate set decreases. However, adjustment for weakly prognostic covariates lead to a loss in power of up to 20 percentage points. CONCLUSIONS: When compared to the worst balanced allocations, covariate constrained randomisation provides moderate to substantial improvements in power. However, the prognostic effect of the covariates should be carefully considered when selecting them for inclusion in the randomisation.

When is a two-stage single-arm trial efficient? An evaluation of the impact of outcome delay.

BACKGROUND: Simon's two-stage design is a widely used adaptive design, particularly in phase II oncology trials due to its simplicity and efficiency. However, its efficiency can be adversely affected when the primary end-point takes time to observe, as is common in practice. METHODS: We propose an optimal design, taking the delay in observing treatment outcome into consideration and compare the efficiency gained from using Simon's design over a single-stage design for real-life oncology trials. Based on the results, we provide a general rule-of-thumb for determining whether a two-stage single-arm design can provide any added advantage over a single-stage design, given the recruitment rate and primary end-point length. RESULTS: We observed an average 15-30% loss in the estimated efficiency gain in real oncology trials that used Simon's design due to the delay in observing the treatment outcome. The delay-optimal design provides some advantage over Simon's design in terms of reduced sample size when the delay is large compared to the recruitment length. DISCUSSION: Simon's two-stage design provides large benefit over a single-stage design, in terms of reduced sample size, when the primary end-point length is no more than 10% of the total recruitment time. It provides no efficiency advantage when this ratio is above 50%.

Optimised point estimators for multi-stage single-arm phase II oncology trials.

The uniform minimum variance unbiased estimator (UMVUE) is, by definition, a solution to removing bias in estimation following a multi-stage single-arm trial with a primary dichotomous outcome. However, the UMVUE is known to have large residual mean squared error (RMSE). Therefore, we develop an optimisation approach to finding estimators with reduced RMSE for many response rates, which attain low bias. We demonstrate that careful choice of the optimisation parameters can lead to an estimator with often substantially reduced RMSE, without the introduction of appreciable bias.

Conditional power and friends: The why and how of (un)planned, unblinded sample size recalculations in confirmatory trials.

Adapting the final sample size of a trial to the evidence accruing during the trial is a natural way to address planning uncertainty. Since the sample size is usually determined by an argument based on the power of the trial, an interim analysis raises the question of how the final sample size should be determined conditional on the accrued information. To this end, we first review and compare common approaches to estimating conditional power, which is often used in heuristic sample size recalculation rules. We then discuss the connection of heuristic sample size recalculation and optimal two-stage designs, demonstrating that the latter is the superior approach in a fully preplanned setting. Hence, unplanned design adaptations should only be conducted as reaction to trial-external new evidence, operational needs to violate the originally chosen design, or post hoc changes in the optimality criterion but not as a reaction to trial-internal data. We are able to show that commonly discussed sample size recalculation rules lead to paradoxical adaptations where an initially planned optimal design is not invariant under the adaptation rule even if the planning assumptions do not change. Finally, we propose two alternative ways of reacting to newly emerging trial-external evidence in ways that are consistent with the originally planned design to avoid such inconsistencies.

Improving power in PSA response analyses of metastatic castration-resistant prostate cancer trials.

BACKGROUND: To determine how much an augmented analysis approach could improve the efficiency of prostate-specific antigen (PSA) response analyses in clinical practice. PSA response rates are commonly used outcome measures in metastatic castration-resistant prostate cancer (mCRPC) trial reports. PSA response is evaluated by comparing continuous PSA data (e.g., change from baseline) to a threshold (e.g., 50% reduction). Consequently, information in the continuous data is discarded. Recent papers have proposed an augmented approach that retains the conventional response rate, but employs the continuous data to improve precision of estimation. METHODS: A literature review identified published prostate cancer trials that included a waterfall plot of continuous PSA data. This continuous data was extracted to enable the conventional and augmented approaches to be compared. RESULTS: Sixty-four articles, reporting results for 78 mCRPC treatment arms, were re-analysed. The median efficiency gain from using the augmented analysis, in terms of the implied increase to the sample size of the original study, was 103.2% (IQR [89.8,190.9%]). CONCLUSIONS: Augmented PSA response analysis requires no additional data to be collected and can be performed easily using available software. It improves precision of estimation to a degree that is equivalent to a substantial sample size increase. The implication of this work is that prostate cancer trials using PSA response as a primary endpoint could be delivered with fewer participants and, therefore, more rapidly with reduced cost.

Response adaptive intervention allocation in stepped-wedge cluster randomized trials.

BACKGROUND: Stepped-wedge cluster randomized trial (SW-CRT) designs are often used when there is a desire to provide an intervention to all enrolled clusters, because of a belief that it will be effective. However, given there should be equipoise at trial commencement, there has been discussion around whether a pre-trial decision to provide the intervention to all clusters is appropriate. In pharmaceutical drug development, a solution to a similar desire to provide more patients with an effective treatment is to use a response adaptive (RA) design. METHODS: We introduce a way in which RA design could be incorporated in an SW-CRT, permitting modification of the intervention allocation during the trial. The proposed framework explicitly permits a balance to be sought between power and patient benefit considerations. A simulation study evaluates the methodology. RESULTS: In one scenario, for one particular RA design, the proportion of cluster-periods spent in the intervention condition was observed to increase from 32.2% to 67.9% as the intervention effect was increased. A cost of this was a 6.2% power drop compared to a design that maximized power by fixing the proportion of time in the intervention condition at 45.0%, regardless of the intervention effect. CONCLUSIONS: An RA approach may be most applicable to settings for which the intervention has substantial individual or societal benefit considerations, potentially in combination with notable safety concerns. In such a setting, the proposed methodology may routinely provide the desired adaptability of the roll-out speed, with only a small cost to the study's power.

A stochastically curtailed single-arm phase II trial design for binary outcomes.

Phase II clinical trials are a critical aspect of the drug development process. With drug development costs ever increasing, novel designs that can improve the efficiency of phase II trials are extremely valuable.Phase II clinical trials for cancer treatments often measure a binary outcome. The final trial decision is generally to continue or cease development. When this decision is based solely on the result of a hypothesis test, the result may be known with certainty before the planned end of the trial. Unfortunately, there is often no opportunity for early stopping when this occurs.Some existing designs do permit early stopping in this case, accordingly reducing the required sample size and potentially speeding up drug development. However, more improvements can be achieved by stopping early when the final trial decision is very likely, rather than certain, known as stochastic curtailment. While some authors have proposed approaches of this form, these approaches have various limitations.In this work we address these limitations by proposing new design approaches for single-arm phase II binary outcome trials that use stochastic curtailment. We use exact distributions, avoid simulation, consider a wider range of possible designs and permit early stopping for promising treatments. As a result, we are able to obtain trial designs that have considerably reduced sample sizes on average.

Characterising the allergic profile of children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a genetic condition that affects multiple organ systems. Allergic bronchopulmonary aspergillosis (ABPA) is a well-recognised problem but other allergic conditions are less well documented in CF. OBJECTIVE: To characterise the allergic profile of a cohort of children with CF, with a focus on those with ABPA. METHODS: A cohort of children with CF were interviewed and retrospective data were collected regarding their allergic histories and other relevant clinical features. RESULTS: The cohort included 37 children with median age of 9 years (interquartile range: 6-12). There was a history of ≥1 allergic condition(s) in 28/37 children (76%). The most common allergic condition was allergic rhinitis (AR) in 21/37 (57%) and 16 of these 21 children (76%) had another allergic condition. All children with ABPA (8) had another allergic condition. In some children ABPA exacerbations appeared to be seasonal, suggesting possible cross-sensitisation between Aspergillus fumigatus and aeroallergens associated with seasonal AR. Allergic conditions were also common in children with Pseudomonas aeruginosa infection.

Advantages of multi-arm non-randomised sequentially allocated cohort designs for Phase II oncology trials.

BACKGROUND: Efficient trial designs are required to prioritise promising drugs within Phase II trials. Adaptive designs are examples of such designs, but their efficiency is reduced if there is a delay in assessing patient responses to treatment. METHODS: Motivated by the WIRE trial in renal cell carcinoma (NCT03741426), we compare three trial approaches to testing multiple treatment arms: (1) single-arm trials in sequence with interim analyses; (2) a parallel multi-arm multi-stage trial and (3) the design used in WIRE, which we call the Multi-Arm Sequential Trial with Efficient Recruitment (MASTER) design. The MASTER design recruits patients to one arm at a time, pausing recruitment to an arm when it has recruited the required number for an interim analysis. We conduct a simulation study to compare how long the three different trial designs take to evaluate a number of new treatment arms. RESULTS: The parallel multi-arm multi-stage and the MASTER design are much more efficient than separate trials. The MASTER design provides extra efficiency when there is endpoint delay, or recruitment is very quick. CONCLUSIONS: We recommend the MASTER design as an efficient way of testing multiple promising cancer treatments in non-comparative Phase II trials.