The adaptive platform trial toolbox

The document published by EMA outlines some general considerations for studies incorporating interim analyses. A set of minimal requirements must be fulfilled whenever confirmatory clinical trials are planned with an adaptive design. Later sections comment on specific design modifications.

The EU-PEARL project systematically reviewed EU and US guidelines, engaged with regulatory bodies, and gathered input from stakeholders, including ethics committees and HTA bodies, to address these challenges. A master protocol template was developed alongside the identification of unresolved issues, such as clinical trial submissions, multiplicity control, non-concurrent controls, and randomisation schemes. Early dialogue with stakeholders remains essential to effectively implement platform trials and mitigate their complexities.

A problem unique to platform trials is deciding not just which investigational medicinal product should be added to the trial but also the correct timing and procedure to avoid a negative impact on external validity and generalisability of the conclusion(s), as well as to minimise delays in the evaluation of ongoing investigational medicinal products. The EU-PEARL framework suggests that independent experts within the Investigational Medical Product Selection Scientific Committee should decide to include a new investigational medicinal product.

An adaptive platform trial brings new challenges due to its increased operational, logistical and statistical complexity. Regulators, ethics committees and health technology assessment bodies face difficulties assessing these challenges. This report summarises these challenges and potential solutions, focusing on regulatory, ethical and HTA-related aspects.

The project deliverable contains a selective glossary of terms for complex trials and platform trials. It also lists the current published platform trials and contains a curated and rated set of seminal publication references for platform Trials. It was developed within the EU-PEARL project.

Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need inclinical research and drug development. Platform trials might help accelerate drug development This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape.

AGILE is a multicentre, multi-arm, multi-dose, multi-stage open-label, adaptive, seamless phase I/II Bayesian randomised platform trial to determine the optimal dose, activity and safety of multiple candidate agents for the treatment of COVID-19. It is sponsored by the University of Liverpool. This webpage includes essential trial document (protocol, protocol papers, ICF and lab manual), and short videos.

This study explored using response-adaptive randomisation (RAR) in the RECOVERY trial. Simulations showed RAR would have allocated more patients to dexamethasone, reduced mortality, and maintained unbiased results. Though it sometimes lowered statistical power, it could have identified effective treatments sooner. The findings highlight ethical trade-offs between benefiting current and future patients.

The Staphylococcus aureus bacteraemia Network Adaptive Platform Trial is an innovative trial to evaluate a range of interventions with the aim of improving outcomes for patients with Staphylococcus aureus bacteraemia (AKA bloodstream infections). The study includes sites from throughout Australia, New Zealand, Singapore, Canada, Israel and the UK and has the potential to include sites elsewhere in the world. This website includes trial documents, such as core protocol, the domain-specific protocol and the SAP 

This is a template of the statistical plan for the platform trial. It is developed within EU-PEARL and based on TransCelerate Statistical Analysis Plan SAP V3.0

The journal article reviews the impact on the statistical inference of adding arms. It also covers changing the control arm and how patient eligibility would complicate the trial design and analysis, the more generic statistical literature, and statistical considerations for different phases and funders.

This is a protocol paper of STIMULATE-ICP; a pragmatic, nested, Phase III, open-label, adaptive platform randomised drug trial in individuals with Long COVID. The trial is being carried out in 6–10 LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes at 3 months. The recruitment was closed in 2024.

This systematic research reviews existing software for the design of platform trials. It was developed within the EU-PEARL project.

EU-PEARL developed an adaptive platform trial for tuberculosis (TB) to accelerate the development of new treatment regimens. This master protocol provides a framework for its implementation within the IRP structure. 

This consensus document resulted from two very productive meetings held in 2022, which brought together researchers, academics, technical partners, TB drugs and regimens developers, trialists, regulators, guideline developers, programme managers, community representatives and nongovernmental organisations.

Alongside the master protocol, the EU-PEARL Tuberculosis (TB) work package developed operational standards and a set of best practices for planning, conducting, and reporting on IRPs. This report addresses the best practices, among these are crucial aspects of implementing an operational plan, mainly focusing on Community Engagement in the context of a TB IRP. 

This CONSORT extension provides reporting guidance for any randomised trial using an adaptive design.

The video provides statistical and methodological aspects of adaptive platform trials. It also covers case studies. It was prepared by Berry Consultants.

This is a protocol paper of the COVID-19 Outpatient Pragmatic Protocol Study (COPPS), a flexible phase 2, multi-site, randomised, blinded trial based at Stanford University. It is designed to overcome these issues by simultaneously evaluating multiple COVID-19 treatments in the outpatient setting in one common platform with shared controls. The trial website is also available in Dutch but the English version of the protocol and PIC are can be found on the website: https://covidkids.nl/english-intro/

The concept paper presents the DIAN-TU Next Generation (NexGen) Alzheimer's prevention trial, an adaptive platform study focused on autosomal dominant Alzheimer's disease (ADAD). It aims to evaluate the efficacy of disease-modifying therapies—such as anti-amyloid and anti-tau agents- using an innovative disease progression model and a cognitive composite endpoint tailored for ADAD. The trial incorporates adaptive design elements including dose adjustment, early interim analyses, and self-administered cognitive testing to enhance efficiency. Its broader goal is to accelerate therapeutic development for both familial and sporadic Alzheimer’s by serving as a public-private research platform.

This review assesses the characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials.

The journal review identifies existing master protocol studies and summarizes their characteristics. The review also identifies articles relevant to the design of master protocol trials, such as proposed trial designs and related methods.

This article presents the concept and structure of the NCI-MATCH trial, a precision oncology study that combines features of both a basket trial—matching therapies to molecular alterations regardless of tumor type—and a platform trial—allowing multiple treatment arms to be added or closed over time. It also outlines the extension of this approach to pediatric populations through the NCI-COG Pediatric MATCH trial. Both adult and pediatric arms have completed recruitment.

(https://www.cancer.gov/research/infrastructure/clinical-trials/nci-supported/nci-match. Accessed on June 30, 2025)

This paper describes the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma. Using an innovative adaptive platform trial design, the PrecISE Network simultaneously evaluates up to 6 interventions in biomarker-defined subgroups of subjects. 

This paper presents the protocol for OPTIMISE-C19 (Optimising Treatment and Impact of Monoclonal antibodies through Evaluation for COVID-19), an open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomisation. The primary objective is to evaluate the comparative effectiveness of COVID-19-specific monoclonal antibodies (mABs) with US FDA Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs.

VACCELERATE is a clinical research network established to coordinate and conduct COVID-19 vaccine trials. Under this consortium, three platform trials—AGED, BOOSTAVAC, and COVAC—were conducted. The consortium recruited 100,000 participants across 250 sites in 57 countries. All platform trials completed recruitment by 2025. The consortium’s website provides information on each trial, training webinars, short videos for participants, trial documents, and related publications.

The journal article provides experiences gathered in FOCUS4 and STAMPEDE adaptive platform trials from a trial management perspective, highlighting the challenges and successes encountered in running adaptive platform trials.

In mental health, treatment approvals are fewer, treatment effects vary, and comparative data are limited. Platform trials, which use shared infrastructure, control groups, and master protocols, offer a more efficient and flexible way to generate evidence. This expert perspective paper discusses examples in mental health, highlighting their potential to improve speed, reduce costs, and enhance statistical power and comparability.

EU-PEARL developed an adaptive platform trial for treatment-resistant depression (TRD) and partially responsive depression (PRD). This platform trial allows new treatments to be added to the trial anytime they become available for testing, increases the speed by which we can provide the best treatments, and requires fewer participants overall. The present document describes the master design of this platform trial.  A summary of longitudinal natural history study (LNHS) / Readiness cohort protocol for MDD platform is included in another deliverable.

The report presents a draft of how EU-PEARL envision an integrated research platform for depression. This draft has been discussed formally with the European Medicines Agency (EMA), and feedback has been received from EMA experts to ensure that the trial yields speedy results on the benefit of any new drug tested and maintains the highest ethical and safety standards.

This article describes the prototype tools and guidance documents created to help build the hospital network as part of an integrated research platform that can conduct platform trials. 

This review examined the use of master protocols in paediatric drug development. While their use is growing—mainly in oncology and early-phase trials since 2020—it remains limited. Platform and basket trials are more common than umbrella trials. Broader adoption is hindered by challenges like infrastructure and data interpretation.

This review examined the uptake of registered, late-phase MAMS platforms in the EU clinical trials register, etc., highlighting the potential scope of MAMS platform trials and may assist research teams considering using this approach in the late-phase randomised clinical trial setting.

These are the recommendations presented by WHA 75.8 for best practices and other measures to improve the global clinical trials ecosystem, taking into account existing initiatives. This may include the role of WHO, Member States and non-State actors. 

Adaptive platform trials have had limited uptake in cardiovascular medicine due to several challenges. These include unfamiliarity with adaptive methods like Bayesian statistics and response-adaptive randomisation, which can complicate interpretation. The risk of bias from time trends and non-concurrent controls is a particular concern in long-running cardiovascular trials. Additionally, the field’s reliance on traditional fixed designs makes it slower to adopt innovative trial frameworks.

This guideline was published ON 24 Sep 2024, in response to requests by the World Health Assembly to the Director-General in resolution WHA75.8 (2022) . This guidance updates and adapts the previous work of the World Health Organization (WHO) on research capacity for the context of well-designed and well-implemented clinical trials as framed in resolution WHA75.8 (2022). It aims to enhance clinical research efficiency, minimize research waste and provide guidance on sustained clinical trials that are always functional and active for endemic conditions and can pivot in time of emergency or pandemics.

Existing clinical trial simulation tools were found inadequate for modelling Platform trials with flexible designs, especially features like staggered treatment entry. This paper developed an iterative “vanilla and sprinkles” framework and created a suite of open-source R-based software specifically for simulating platform trials. These tools support key design features and enable transparent, reproducible simulations, aiding in the efficient design of platform trials.