The adaptive platform trial toolbox

The national ACORD collaboration was formed in 2021 to encourage and support the development, running and reporting of multi-arm, multi-stage (MAMS) platform trials (with their associated scientific and infrastructure projects) in four major neurodegenerative diseases (MND), progressive multiple sclerosis (MS), Parkinson’s disease and dementia; Currently, the ACORD collaboration has two clinical trials open for recruitment, in MND (MND-SMART) and progressive MS (OCTOPUS). A third, in Parkinson’s disease (EJS ACT-PD) will open in 2025, and a trial in Alzheimer’s disease (MASTODON) is currently in development. This website includes brief information on those 4 MMRS design examples. it also links to UCLMRC websites, which provide some tools for MMMS design and conduct.

FOCUS4 is an adaptive, molecularly stratified trial that aims to improve the efficiency with which new novel agents can be tested in colorectal cancer. It has a multi-arm, multi-stage design with a master protocol. It is sponsored by University College London. FOCUS4 started recruitment in January 2014, and closed to recruitment in October 2020. This website includes the FOCUS4 master protocol and intervention-specific appendix.

The TOGETHER clinical trial started in June 2020 as an international collaboration in response to the worsening pandemic of SARS-CoV-2 / COVID-19. Utilising an adaptive platform trial design, the international researchers and teams in Brazil, Canada, Australia, and the United States sought to identify evidence-informed therapeutics by repurposing existing medications to identify effective repurposed therapies to prevent the progression of COVID-19. This is a master protocol paper of the TOGETHER trial.

VACCELERATE is a clinical research network for coordinating and conducting COVID-19 vaccine trials. The network is comprised of academic institutions from all over Europe. University Hospital Cologne, Germany, led the consortium. This protocol paper presents the design of  EU-COVAT-1-AGED, an adaptive platform conducted within the VACCELERATE network, to test different vaccine immunogenicity and reactogenicity in adults ≥75.

PANDA is a toolkit developed by a collaborative initiative in the UK funded by NIHR. It presents critical information for adaptive design development and trial conduct, and it provides resources to help researchers use adaptive design in practice, such as statistical software, guidance to enhance the reporting, and case studies/ examples of different types of adaptive design.

REMAP-CAP is a randomised, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia. The REMAP-CAP also provides an adaptive research platform for the evaluation of multiple treatment modalities in the event of a respiratory pandemic resulting in critical illness. It is sponsored by the University Medical Center Utrecht. This webpage includes trial information, protocols, SAPs and publications (experience and protocol concept).

This rapid review examines how engagement and informed consent were handled in alternative and adaptive trial designs during public health emergencies, such as Ebola and COVID-19. The authors analysed 49 publications, including guidance documents and trial protocols, and found that while APTs are valued for their efficiency in emergency research, specific guidance on engagement and consent is lacking, especially in middle- and low-income countries. The study emphasises the need for clear communication about complex trial designs and suggests incorporating best practices for community engagement and consent into future research guidance.

Report and presentations from a multi-stakeholder workshop organised by EFPIA to develop shared solutions for the use of complex clinical trials to optimise drug development in Europe

Success was driven by a strong public–private partnership involving the US government, academia, and industry. Decades of prior NIH-funded research and coordinated trial designs enabled quick evaluation of candidates. Harmonised protocols and regulatory alignment allowed independent assessments and meaningful comparisons across vaccine platforms. This collaborative approach resulted in safe, effective vaccines within a year and offers a model for developing future vaccines for public health needs.

This review discusses the European clinical trial, including the implementation of some EU platform trials for COVID-19, such as from DisCoVeRy(DisCoVeRy (an add-on trial of the WHO Solidarity consortium) and the EU-SolidAct. 

A public-private partnership in the United States led by the National Institutes of Health (NIH) and coordinated by the Foundation for the National Institutes of Health (FNIH) to develop a research strategy for prioritising and speeding the development of the most promising COVID-19 vaccines and treatments. ACTIV conducted 6 (ACTIVE 1 to 6) Platform trials, 10 FDA-approved master protocols. The trial is ongoing all over the world, including US, Europe, South America, Africa and Asia. This FNIH webpage includes short videos for trial introduction, trial documents( all PRTs, eCRF, SDV form, and eCRF(COA) and protocol papers.

EJS ACT-PD is a consortium led by King’s College London that supports a platform trial evaluating multiple treatments for Parkinson’s disease. The platform trial is scheduled to begin participant recruitment across multiple sites in the UK in 2025. The official website publishes some posters as key elements including the treatment selection criteria, and patient and public involvement reports. 

This FDA document provides guidance to sponsors and applicants submitting investigational new drug applications, new drug applications, biologics licensing applications, or supplemental applications on the appropriate use of adaptive designs for clinical trials to provide evidence of the effectiveness and safety of a drug or biologic.

The journal article reviews the characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials.

This journal review focuses on adaptive designs of confirmatory clinical trials. It discusses the benefits and limitations of such designs, using four case studies that highlight the statistical and operational considerations.

The journal article assesses and reviews scientific advice letters issued by EMA containing questions related to adaptive clinical trials in phases II or III. It also examines relevant regulatory aspects.

GBM AGILE is a global, multi-arm, adaptive platform trial designed to efficiently evaluate therapies for glioblastoma, sponsored by the Global Coalition for Adaptive Research (GCAR). This concept paper outlines its two-stage Bayesian/fixed design, integration of biomarkers, and collaborative development to address the challenges of translating molecular insights into clinical benefit.

PICOBOO is a novel, innovative randomised clinical trial being conducted across multiple Australian sites that investigates the impacts of different COVID-19 vaccination strategies. This trial is designed to generate high-quality evidence to inform COVID-19 immunisation practice. This webpage includes MPT, ISA, ICF and statistical documents. Publications such as the master protocol concept (Macleod C et al, 2023) or statistical considerations (Dymoc M et al, 2024) are also available on the website

The platform trial approach is now being employed more often in neurology. This paper describes a newly launched platform trial for ALS. The Healey ALS Platform Trial is testing multiple investigational products concurrently in people with ALS to identify novel treatments, biomarkers, and trial endpoints rapidly.

This video with attached slides summarises how the adaptive platform I-SPY trial has been developed for breast cancer and how it is replicated as a COVID trial. It depicts the life cycle of an adaptive platform trial with rationale, design, infrastructure, intervention selection, data collection, added value, and publications. It was hosted by NIH Collaboratory.

This video introduces adaptive trial design options for non-statisticians with example trials. It is presented by Cytel, a statistical software provider. The parent website also includes other adaptive design lectures.

Dal-Ré R et al, (2023). Adaptive, platform trials assessing therapies for hospitalized COVID-19 patients: Informed consent forms omitted a few important elements of information. J Glob Health. 2023 May 12:13:06019. doi: 10.7189/jogh.13.06019.

The journal article introduces the main features of adaptive designs, including MAMS and commonly used terminology, highlighting their utility and pitfalls, and illustrating their use through case studies of adaptive trials.

ANTICOV is an open-label, randomised, comparative, adaptive platform trial that will test the safety and efficacy of treatments in 2,000 to 3,000 mild-to-moderate COVID-19 patients. ANTICOV aims to identify early treatments that can prevent the progression of COVID-19 to severe disease and potentially limit transmission. It is sponsored by the Drug for Neglected Diseases Initiative and others. It was launched in September 2020 in 13 countries, including Europe, Brazil, and African countries. This website shared the master protocol. CRF, ICF and other essential trial documents.

This journal review aims to outline key considerations for general clinical readers when critically evaluating publications on platform trials and for researchers when designing these types of clinical trials. Supplementary tables provide examples of the use of the checklist for platform trials.

This protocol paper describes the ALIC4E trial, a multinational, pragmatic, adaptive-platform randomized controlled trial assessing the clinical and cost-effectiveness of adding oseltamivir to usual primary care for influenza-like illness (ILI). The trial will recruit at least 2,500 participants (aged ≥1 year) with ILI symptoms of ≤72 hours’ duration over three influenza seasons. The primary outcome is time to return to usual daily activities with mild symptoms. The trial has completed recruitment and follow-up.

ASCOT is a clinical trial that will generate clinical evidence about treatment for COVID-19 that can be applied during the pandemic to reduce mortality or the need for mechanical ventilation in hospitalised but not yet critically ill patients with COVID-19. ASCOT has been endorsed by the Thoracic Society of Australia and New Zealand (TSANZ) and the Australasian Society for Infectious Diseases (ASID), through collaboration with REMAP CAP as a federal trial. The website includes other trial documents such as master protocol, SAP, and protocol papers (Denholm, JT et.al. 2022). Some domains have been already closed.

Berry Consultants is a scientific consulting company specialising in innovative adaptive clinical trial design, analysis, implementation. This YouTube channel includes statistical and methodological aspects of adaptive platform trials. It also covers case studies, such as 'The adaptive platform trial - The statistical efficiencies', 'I-SPY2 and other platform trials', and  'NHLBI ICTR Short Video #7: Sharing Controls and Platform Trials '. It also includes some video for the simulation software. 

This website features free biostatistical software developed by the University of Texas MD Anderson Cancer Center for use in the design and conduct of clinical trials in the medical field. The software is available for download and supports data analysis and statistical calculations. Some programs are specifically designed for adaptive trial designs.

ERA4Health is a 7-year EU-funded initiative to boost transnational health research by jointly funding studies that tackle diseases, improve healthcare, and promote prevention. This deliverable is a recommendation booklet aimed at helping investigators and sponsors conduct multi-country investigator-initiated clinical studies (IICS) using innovative trial designs. It addressed challenges in designing and conducting multi-country IICS using novel trial methods, including platform trials, based on systematic literature reviews and expert input.

This handbook represents an innovative approach that will help to prepare sites for future Integrated Research Platform (IRP) for TB, as discussed within one of the work packages of the EU-PEARL project.

The journal article shares experiences from FOCUS4 and STAMPEDE trials from the operational aspects of running these adaptive trials, focusing on data management. Adding and closing intervention arms, a number of case report form changes, database amendments and database growth are discussed.

Platform trials (PTs) are increasingly used in clinical research for testing multiple treatments flexibly. A review identified 189 PTs, mainly in infectious diseases and cancer. Many used Bayesian or frequentist statistical designs, but transparency—like sharing protocols or simulation details—was often limited. Greater transparency and better reporting are needed to build trust in PTs.

This systematic review examined 127 randomized platform trials, mostly in oncology and COVID-19, assessing their design, progression, and output. It found that key platform trial features, such as the use of adaptive designs and nonconcurrent controls, were often poorly reported or not used, with adaptive features included in only about half of the trials. Results were available for 65.2% of completed arms, and premature closure due to recruitment issues was rare. The study highlights the need for better planning, reporting, and transparency in platform trials to enhance their contribution to clinical research.

The paper discussed how the UK government funded a portfolio of platform trials to develop new treatments for COVID-19. A key feature was the independent prioritisation of candidate drugs with central coordination to prevent duplication, accelerating recruitment to deliver definitive trial results. 

This deliverable presents our approach to defining site selection criteria for the network of sites that could run the platform trials for NF. The deliverable focuses on the network for the NF1 platform trial. 

A vital aspect of the platform trials' success is establishing a Clinical Research Network (CRN) comprising healthcare providers, researchers, and relevant stakeholders. This deliverable describes the survey results to provide future directions and guidance on establishing a CRN for a future NASH platform trial.

This paper provides corresponding regulatory perspectives on approval and reimbursement. It notes that the optimal design of a platform trial will differ through our societal objectives and by stakeholders.

This study proposes a combined factorial and multi-arm multi-stage trial design to efficiently test multiple treatments. It is suited for situations where some treatments can be given together without interaction. The design allows shared efficiencies from both methods but requires careful planning, especially for timing, eligibility, and analysis using concurrent controls.

This article describes the experience of the EU-PEARL project in engaging community members and patients in tuberculosis research. It outlines how a Community Advisory Group was involved from early protocol development stages to ensure meaningful and non-tokenistic participation. The authors reflect on challenges and successes in fostering trust and inclusivity in clinical research design. This approach is presented as a model for future patient-centric platform trials.

This document aims to address challenges sponsors may face regarding scientific and operational aspects of complex clinical trials in the EU/EEA and to encourage considerations in development as early as possible to generate valuable evidence and inform clinical and regulatory decision-making.

The FDA program to facilitate drug development using complex innovative trial design met. Five cases were selected and the master protocols were discussed. This webpage presents public meeting records and discussion minutes. 

This is a concept paper for platform trials published by EMA.

This article presents a mock costing exercise amongst seven clinical trial units (CTUs) in the UK. This work outlines the additional resources required to support a high-quality adaptive trial. The percentage increase in costs for supporting an adaptive trial was generally modest and should allow adaptive designs to be cost-effective in practice.

This thematic issue of the Journal of Clinical and Translational Science focuses on lessons learned from COVID-19 therapeutic platform trials, with particular emphasis on the ACTIV initiative. The series includes 10 articles—comprising editorials, reviews, perspectives, research articles, and special communications—that explore study design, statistical approaches, and operational challenges in this field.

The FDA issued this guidance to provide recommendations to sponsors of master protocols evaluating drugs for the treatment or prevention of COVID-19.

The EU-PEARL project developed new methodologies and collaborative tools to support broader adoption of platform trials in Europe, involving stakeholders like patients and regulatory agencies. This review highlights key challenges in infrastructure, design, and regulation, and offers guidance for planning platform trials based on lessons from the EU-PEARL project. Early involvement of regulators and patients is crucial for successful implementation.

This template of the Data Monitoring Committee Charter is for a platform trial. EU-PEARL developed the template.

This news article from the Lancet Digital Health highlights the complex routine data collection machinery behind the RECOVERY trial, simplifying site operations.

The definition of error rates in a platform trial is not straightforward, as classical error rate concepts are not applicable. This article discusses error rates and operating characteristics. Then, it uses these to compare design parameters under a range of simulation assumptions for an open-entry, exploratory platform trial design comparing combination therapies to the respective monotherapies and standard-of-care.