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Multi-armed bandit problems (MABPs) are a special type of optimal control problem well suited to model resource allocation under uncertainty in a wide variety of contexts. Since the first publication of the optimal solution of the classic MABP by a dynamic index rule, the bandit literature quickly diversified and emerged as an active research topic. Across this literature, the use of bandit models to optimally design clinical trials became a typical motivating application, yet little of the resulting theory has ever been used in the actual design and analysis of clinical trials. To this end, we review two MABP decision-theoretic approaches to the optimal allocation of treatments in a clinical trial: the infinite-horizon Bayesian Bernoulli MABP and the finite-horizon variant. These models possess distinct theoretical properties and lead to separate allocation rules in a clinical trial design context. We evaluate their performance compared to other allocation rules, including fixed randomization. Our results indicate that bandit approaches offer significant advantages, in terms of assigning more patients to better treatments, and severe limitations, in terms of their resulting statistical power. We propose a novel bandit-based patient allocation rule that overcomes the issue of low power, thus removing a potential barrier for their use in practice.

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented. We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

The use of digital health technologies to measure outcomes in clinical trials opens new opportunities as well as methodological challenges. Digital outcome measures may provide more sensitive and higher-frequency measurements but pose vital statistical challenges around how such outcomes should be defined and validated and how trials incorporating digital outcome measures should be designed and analysed. This article presents eight methodological questions, exploring issues such as the length of measurement period, choice of summary statistic and definition and handling of missing data as well as the potential for new estimands and new analyses to leverage the time series data from digital devices. The impact of key issues highlighted by the eight questions on a primary analysis of a trial are illustrated through a simulation study based on the 2019 Bellerophon INOPulse trial which had time spent in MVPA as a digital outcome measure. These eight questions present broad areas where methodological guidance is needed to enable wider uptake of digital outcome measures in trials.

We introduce a non-myopic, covariate-adjusted response adaptive (CARA) allocation design for multi-armed clinical trials. The allocation scheme is a computationally tractable procedure based on the Gittins index solution to the classic multi-armed bandit problem and extends the procedure recently proposed in Villar et al. (2015). Our proposed CARA randomization procedure is defined by reformulating the bandit problem with covariates into a classic bandit problem in which there are multiple combination arms, considering every arm per each covariate category as a distinct treatment arm. We then apply a heuristically modified Gittins index rule to solve the problem and define allocation probabilities from the resulting solution. We report the efficiency, balance, and ethical performance of our approach compared to existing CARA methods using a recently published clinical trial as motivation. The net savings in terms of expected number of treatment failures is considerably larger and probably enough to make this design attractive for certain studies where known covariates are expected to be important, stratification is not desired, treatment failures have a high ethical cost, and the disease under study is rare. In a two-armed context, this patient benefit advantage comes at the expense of increased variability in the allocation proportions and a reduction in statistical power. However, in a multi-armed context, simple modifications of the proposed CARA rule can be incorporated so that an ethical advantage can be offered without sacrificing power in comparison with balanced designs.

The Gittins index provides a well established, computationally attractive, optimal solution to a class of resource allocation problems known collectively as the multi‐arm bandit problem. Its development was originally motivated by the problem of optimal patient allocation in multi‐arm clinical trials. However, it has never been used in practice, possibly for the following reasons: (1) it is fully sequential, i.e., the endpoint must be observable soon after treating a patient, reducing the medical settings to which it is applicable; (2) it is completely deterministic and thus removes randomization from the trial, which would naturally protect against various sources of bias. We propose a novel implementation of the Gittins index rule that overcomes these difficulties, trading off a small deviation from optimality for a fully randomized, adaptive group allocation procedure which offers substantial improvements in terms of patient benefit, especially relevant for small populations. We report the operating characteristics of our approach compared to existing methods of adaptive randomization using a recently published trial as motivation.

Background The StratosPHere 2 trial will evaluate the efficacy of hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2 by focussing on the novel biomarker and other endpoints including safety. Study design StratosPHere 2 is a three armed, placebo-controlled, phase 2 trial with two strata based on the mutation groups. It is response adaptive where the allocation of treatments follows a Bayesian response-adaptive randomisation algorithm. An expected number of 20 patients will be randomised in each stratum to one of the three arms containing hydroxychloroquine, phenylbutyrate and placebo. The primary outcome is a novel endpoint considering the change in the bone morphogenetic receptor type 2 (BMPR2). Method The final primary analysis on the efficacy of each active treatment against control is assessed using a one-sided nonparametric Wilcoxon test computed on the continuous biomarker data collected up to 8 weeks from the start of treatment. Discussion This manuscript presents the key elements of the StratosPHere 2 implementation and statistical analysis plan. This is submitted to the journal before the first interim analysis to preserve the scientific integrity under a response-adaptive design framework. The StratosPHere 2 trial closely follows published guidelines for the content of Statistical Analysis Plans in clinical trials. Trial registration The ISRCTN Registry ISRCTN10304915 (22/09/2023)

Background Obstructive sleep apnoea is caused by closure of the upper airway during sleep due to excessive muscle relaxation. It is treated with continuous positive airway pressure (CPAP), a machine connected to a mask worn by a patient during sleep, which generates pressure to keep the throat open. CPAP is highly effective, but often not tolerated, sometimes due to the required pressure of the machine. Mandibular advancement devices advance the lower jaw, increasing airway space. Using such a device may open the airway enough to allow CPAP pressure to be reduced, resulting in more patients being able to tolerate using the CPAP machine. Methods/design The PAPMAT trial is a multicentre, randomised controlled crossover trial. It will measure CPAP machine adherence for participants with obstructive sleep apnoea, comparing their adherence when using a CPAP machine alone to using a CPAP machine in conjunction with a mandibular advancement device. The sample size will be re-estimated after at least 50% of participants have completed follow-up. This document is the statistical analysis plan, which gives details of the planned analysis, including the sample size re-estimation. Trial registration ISRCTN 33966032. Registered 18th February 2022.

Background There is evidence that during the COVID pandemic, a number of patient and HCW infections were nosocomial. Various measures were put in place to try to reduce these infections including developing asymptomatic PCR (polymerase chain reaction) testing schemes for healthcare workers. Regularly testing all healthcare workers requires many tests while reducing this number by only testing some healthcare workers can result in undetected cases. An efficient way to test as many individuals as possible with a limited testing capacity is to consider pooling multiple samples to be analysed with a single test (known as pooled testing). Methods Two different pooled testing schemes for the asymptomatic testing are evaluated using an individual-based model representing the transmission of SARS-CoV-2 in a ‘typical’ English hospital. We adapt the modelling to reflect two scenarios: a) a retrospective look at earlier SARS-CoV-2 variants under lockdown or social restrictions, and b) transitioning back to ‘normal life’ without lockdown and with the omicron variant. The two pooled testing schemes analysed differ in the population that is eligible for testing. In the ‘ward’ testing scheme only healthcare workers who work on a single ward are eligible and in the ‘full’ testing scheme all healthcare workers are eligible including those that move across wards. Both pooled schemes are compared against the baseline scheme which tests only symptomatic healthcare workers. Results Including a pooled asymptomatic testing scheme is found to have a modest (albeit statistically significant) effect, reducing the total number of nosocomial healthcare worker infections by about 2 % in both the lockdown and non-lockdown setting. However, this reduction must be balanced with the increase in cost and healthcare worker isolations. Both ward and full testing reduce HCW infections similarly but the cost for ward testing is much less. We also consider the use of lateral flow devices (LFDs) for follow-up testing. Considering LFDs reduces cost and time but LFDs have a different error profile to PCR tests. Conclusions Whether a PCR-only or PCR and LFD ward testing scheme is chosen depends on the metrics of most interest to policy makers, the virus prevalence and whether there is a lockdown.

Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely.

In a rare life-threatening disease setting the number of patients in the trial is a high proportion of all patients with the condition (if not all of them). Further, this number is usually not enough to guarantee the required statistical power to detect a treatment effect of a meaningful size. In such a context, the idea of prioritizing patient benefit over hypothesis testing as the goal of the trial can lead to a trial design that produces useful information to guide treatment, even if it does not do so with the standard levels of statistical confidence. The idealized model to consider such an optimal design of a clinical trial is known as a classic multi-armed bandit problem with a finite patient horizon and a patient benefit objective function. Such a design maximizes patient benefit by balancing the learning and earning goals as data accumulates and given the patient horizon. On the other hand, optimally solving such a model has a very high computational cost (many times prohibitive) and more importantly, a cumbersome implementation, even for populations as small as a hundred patients. Several computationally feasible heuristic rules to address this problem have been proposed over the last 40 years in the literature. In this paper, we study a novel heuristic approach to solve it based on the reformulation of the problem as a Restless bandit problem and the derivation of its corresponding Whittle Index (WI) rule. Such rule was recently proposed in the context of a clinical trial in Villar, Bowden, and Wason [16]. We perform extensive computational studies to compare through both exact value calculations and simulated values the performance of this rule, other index rules and simpler heuristics previously proposed in the literature. Our results suggest that for the two and three-armed case and a patient horizon less or equal than a hundred patients, all index rules are a priori practically identical in terms of the expected proportion of success attained when all arms start with a uniform prior. However, we find that a posteriori, for specific values of the parameters of interest, the index policies outperform the simpler rules in every instance and specially so in the case of many arms and a larger, though still relatively small, total number of patients with the diseases. The very good performance of bandit rules in terms of patient benefit (i.e., expected number of successes and mean number of patients allocated to the best arm, if it exists) makes them very appealing in context of the challenge posed by drug development and treatment for rare life-threatening diseases.