Optimal allocation strategies in platform trials with continuous endpoints.

Platform trials are randomized clinical trials that allow simultaneous comparison of multiple interventions, usually against a common control. Arms to test experimental interventions may enter and leave the platform over time. This implies that the number of experimental intervention arms in the trial may change as the trial progresses. Determining optimal allocation rates to allocate patients to the treatment and control arms in platform trials is challenging because the optimal allocation depends on the number of arms in the platform and the latter typically varies over time. In addition, the optimal allocation depends on the analysis strategy used and the optimality criteria considered. In this article, we derive optimal treatment allocation rates for platform trials with shared controls, assuming that a stratified estimation and a testing procedure based on a regression model are used to adjust for time trends. We consider both, analysis using concurrent controls only as well as analysis methods using concurrent and non-concurrent controls and assume that the total sample size is fixed. The objective function to be minimized is the maximum of the variances of the effect estimators. We show that the optimal solution depends on the entry time of the arms in the trial and, in general, does not correspond to the square root of k allocation rule used in classical multi-arm trials. We illustrate the optimal allocation and evaluate the power and type 1 error rate compared to trials using one-to-one and square root of k allocations by means of a case study.

Regulatory Issues of Platform Trials: Learnings from EU-PEARL.

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

Systematic review of available software for multi-arm multi-stage and platform clinical trial design.

BACKGROUND: In recent years, the popularity of multi-arm multi-stage, seamless adaptive, and platform trials has increased. However, many design-related questions and questions regarding which operating characteristics should be evaluated to determine the potential performance of a specific trial design remain and are often further complicated by the complexity of such trial designs. METHODS: A systematic search was conducted to review existing software for the design of platform trials, whereby multi-arm multi-stage trials were also included. The results of this search are reported both on the literature level and the software level, highlighting the software judged to be particularly useful. RESULTS: In recent years, many highly specialized software packages targeting single design elements on platform studies have been released. Only a few of the developed software packages provide extensive design flexibility, at the cost of limited access due to being commercial or not being usable as out-of-the-box solutions. CONCLUSIONS: We believe that both an open-source modular software similar to OCTOPUS and a collaborative effort will be necessary to create software that takes advantage of and investigates the impact of all the flexibility that platform trials potentially provide.