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Background Platform trials can evaluate the efficacy of several experimental treatments compared to a control. The number of experimental treatments is not fixed, as arms may be added or removed as the trial progresses. Platform trials are more efficient than independent parallel group trials because of using shared control groups. However, for a treatment entering the trial at a later time point, the control group is divided into concurrent controls, consisting of patients randomised to control when that treatment arm is in the platform, and non-concurrent controls, patients randomised before. Using non-concurrent controls in addition to concurrent controls can improve the trial’s efficiency by increasing power and reducing the required sample size, but can introduce bias due to time trends. Methods We focus on a platform trial with two treatment arms and a common control arm. Assuming that the second treatment arm is added at a later time, we assess the robustness of recently proposed model-based approaches to adjust for time trends when utilizing non-concurrent controls. In particular, we consider approaches where time trends are modeled either as linear in time or as a step function, with steps at time points where treatments enter or leave the platform trial. For trials with continuous or binary outcomes, we investigate the type 1 error rate and power of testing the efficacy of the newly added arm, as well as the bias and root mean squared error of treatment effect estimates under a range of scenarios. In addition to scenarios where time trends are equal across arms, we investigate settings with different time trends or time trends that are not additive in the scale of the model. Results A step function model, fitted on data from all treatment arms, gives increased power while controlling the type 1 error, as long as the time trends are equal for the different arms and additive on the model scale. This holds even if the shape of the time trend deviates from a step function when patients are allocated to arms by block randomisation. However, if time trends differ between arms or are not additive to treatment effects in the scale of the model, the type 1 error rate may be inflated. Conclusions The efficiency gained by using step function models to incorporate non-concurrent controls can outweigh potential risks of biases, especially in settings with small sample sizes. Such biases may arise if the model assumptions of equality and additivity of time trends are not satisfied. However, the specifics of the trial, scientific plausibility of different time trends, and robustness of results should be carefully considered.

Background Platform trials are innovative clinical trials governed by a master protocol that allows for the evaluation of multiple investigational treatments that enter and leave the trial over time. Interest in platform trials has been steadily increasing over the last decade. Due to their highly adaptive nature, platform trials provide sufficient flexibility to customize important trial design aspects to the requirements of both the specific disease under investigation and the different stakeholders. The flexibility of platform trials, however, comes with complexities when designing such trials. In the past, we reviewed existing software for simulating clinical trials and found that none of them were suitable for simulating platform trials as they do not accommodate the design features and flexibility inherent to platform trials, such as staggered entry of treatments over time. Results We argued that simulation studies are crucial for the design of efficient platform trials. We developed and proposed an iterative, simulation-guided “vanilla and sprinkles” framework, i.e. from a basic to a more complex design, for designing platform trials. We addressed the functionality limitations of existing software as well as the unavailability of the coding therein by developing a suite of open-source software to use in simulating platform trials based on the R programming language. To give some examples, the newly developed software supports simulating staggered entry of treatments throughout the trial, choosing different options for control data sharing, specifying different platform stopping rules and platform-level operating characteristics. The software we developed is available through open-source licensing to enable users to access and modify the code. The separate use of two of these software packages to implement the same platform design by independent teams obtained the same results. Conclusion We provide a framework, as well as open-source software for the design and simulation of platform trials. The software tools provide the flexibility necessary to capture the complexity of platform trials.

While platform trials have several benefits with their adaptive features, randomization challenges become of central relevance to the design and execution of a platform trial. This paper intends to address these challenges and explore some potential solutions. A platform type of clinical trial is a clinical trial design where multiple interventions are investigated simultaneously often against partly or fully shared controls, with new treatment arms added and completed treatment arms removed. Unequal allocation is often used in platform trials to improve statistical efficiency, deliver benefits to trial participants, and control the speed of enrollment in different treatment arms. Changes to the allocation ratio may be required after an interim analysis even when the number of treatment arms remains constant, for example, in a platform trial with response-adaptive randomization. To deliver the design efficiencies promised by the carefully optimized allocation ratio or simply to ensure a pre-determined allocation ratio, randomization methods that keep allocation proportions close to the target allocation ratio throughout randomization are helpful. Other situations commonly occurring in platform trials require special considerations for randomization methods and in some cases new classes of randomization methods. Such specific platform features include the requirement to accommodate differences in eligibility for different treatments, the need to ensure partial blinding with a 2-step randomization when mode of administration for different interventions is conspicuously different and full blinding is unfeasible, the objective to balance through dynamic randomization multiple prognostic factors or the need to accommodate limited drug supplies at the numerous trial centers, among others. The key to a successful execution of a complex randomization in the platform trial is the expert design of the Interactive Response Technology (IRT) system, where the system is built at the master protocol level and existing and potential randomization needs are incorporated from the outset. An additional, often overlooked, challenge when working with unequal allocation ratios and randomization methods to attain these, is the importance of preserving the unconditional allocation ratio at every allocation. Failure to do so might lead to a selection and evaluation bias even in double-blind trials, accidental bias, and reduced power of the re-randomization test.

In this paper we propose an approach for solving problems of optimal resource capacity allocation to a collection of stochastic dynamic competitors. In particular, we introduce the knapsack problem for perishable items, which concerns the optimal dynamic allocation of a limited knapsack to a collection of perishable or non-perishable items. We formulate the problem in the framework of Markov decision processes, we relax and decompose it, and we design a novel index-knapsack heuristic which generalizes the index rule and it is optimal in some specific instances. Such a heuristic bridges the gap between static/deterministic optimization and dynamic/stochastic optimization by stressing the connection between the classic knapsack problem and dynamic resource allocation. The performance of the proposed heuristic is evaluated in a systematic computational study, showing an exceptional near-optimality and a significant superiority over the index rule and over the benchmark earlier-deadline-first policy. Finally we extend our results to several related revenue management problems.

In the UK, the Medicines and Healthcare products Regulatory Agency consulted on proposals “to improve and strengthen the UK clinical trials legislation to help us make the UK the best place to research and develop safe and innovative medicines”. The purpose of the consultation was to help finalise the proposals and contribute to the drafting of secondary legislation. We discussed these proposals as members of the Trials Methodology Research Partnership Adaptive Designs Working Group, which is jointly funded by the Medical Research Council and the National Institute for Health and Care Research. Two topics arose frequently in the discussion: the emphasis on legislation, and the absence of questions on data sharing. It is our opinion that the proposals rely heavily on legislation to change practice. However, clinical trials are heterogeneous, and as a result some trials will struggle to comply with all of the proposed legislation. Furthermore, adaptive design clinical trials are even more heterogeneous than their non-adaptive counterparts, and face more challenges. Consequently, it is possible that increased legislation could have a greater negative impact on adaptive designs than non-adaptive designs. Overall, we are sceptical that the introduction of legislation will achieve the desired outcomes, with some exceptions. Meanwhile the topic of data sharing — making anonymised individual-level clinical trial data available to other investigators for further use — is entirely absent from the proposals and the consultation in general. However, as an aspect of the wider concept of open science and reproducible research, data sharing is an increasingly important aspect of clinical trials. The benefits of data sharing include faster innovation, improved surveillance of drug safety and effectiveness and decreasing participant exposure to unnecessary risk. There are already a number of UK-focused documents that discuss and encourage data sharing, for example, the Concordat on Open Research Data and the Medical Research Council’s Data Sharing Policy. We strongly suggest that data sharing should be the norm rather than the exception, and hope that the forthcoming proposals on clinical trials invite discussion on this important topic.

Many real-world situations involve queueing systems in which customers may abandon if service does not start sufficiently quickly. We study a comprehensive model of multi-class queue scheduling accounting for customer abandonment, with the objective of minimizing the total discounted or time-average sum of linear waiting costs, completion rewards, and abandonment penalties of customers in the system. We assume the service times and abandoning times are exponentially distributed. We solve analytically the case in which there is one server and there are one or two customers in the system and obtain an optimal policy. For the general case, we use the framework of restless bandits to analytically design a novel simple index rule with a natural interpretation. We show that the proposed rule achieves near-optimal or asymptotically optimal performance both in single- and multi-server cases, both in overload and underload regimes, and both in idling and non-idling systems.

In this paper we introduce the knapsack problem for perishable inventories concerning the optimal dynamic allocation of a collection of products to a limited knapsack. The motivation for designing such a problem comes from retail revenue management, where different products often have an associated lifetime during which they can only be sold, and the managers can regularly select some products to be allocated to a limited promotion space that is expected to attract more customers than the standard shelves. Another motivation comes from scheduling of requests in modern multiserver data centers so that quality-of-service requirements given by completion deadlines are satisfied. Using the Lagrangian approach we derive an optimal index policy for the Whittle relaxation of the problem in which the knapsack capacity is used only on average. Assuming a certain structure of the optimal policy for the single-inventory control, we prove indexability and derive an efficient, linear-time algorithm for computing the index values. To the best of our knowledge, our paper is the first to provide indexability analysis of a restless bandit with bi-dimensional state (lifetime and inventory level). We illustrate that these index values are numerically close to the true index values when such a structure is not present. We test two index-based heuristics for the original, nonrelaxed problem: (1) a conventional index rule , which prescribes to order the products according to their current index values and promotes as many products as fit in the knapsack, and (2) a recently proposed index-knapsack heuristic , which employs the index values as a proxy for the price of promotion and proposes to solve a deterministic knapsack problem to select the products. By a systematic computational study we show that the performance of both heuristics is nearly optimal, and that the index-knapsack heuristic outperforms the conventional index rule.