Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Abstract

Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients.

Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

Keywords: Adaptive designs; Clinical research; Integrated research platform; Master protocols; Patient-centred.

Fig. 1

Platform Trials: Simultaneously, sequentially and adaptively. A simplified illustration of a platform trial over time. It starts with a control and 2 treatment arms. The blue arrows indicate the timing of pre-planned adaptive interim analyses. Interim decisions may include early stopping (either for efficacy or futility—see intervention 1) or design adaptations such as the change of allocation ratio (see intervention 2 and 3), sample size reassessment (see intervention 4) or subgroup selection (not illustrated). For example, intervention 1 is stopped after the first interim analysis and at the same time a new arm is added (intervention 3). At the second interim analysis the allocation ratio is changed, e.g., by allocating more patients to intervention 3 compared to 2. At the interim analysis for intervention 4 a sample size re-assessment is performed (the extension is indicated by the darker colour).

Fig. 2

Elements of Integrated Research Platforms for drug development in the context of EU-PEARL. Three different layers describe the foundation which should be put in place and are the basis to conduct a platform trial for a certain disease. Layer one encompasses the generic framework to develop a platform trial, which are the same in any Integrated Research Platform (IRP) or disease. Layer two indicates the stakeholders which should be engaged in the building of the IRP very early but are disease specific. On top is the disease specific master protocol for the platform trial, e.g., in EU-PEARL both generic templates and (illustrated by the shared operational framework) and disease specific templates (top circle) have been developed for major depressive disorder (MDD), tuberculosis (TB), non-alcoholic steatohepatitis (NASH), and neurofibromatosis (NF).