The adaptive platform trial toolbox

The  ACORD collaboration was formed in 2021 to encourage and support the development, running and reporting of Multi-arm, Multi-stage Platform Trials in four major neurodegenerative diseases: MND, Progressive MS, Parkinson’s Disease and ultimately Dementia.

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. In addition, REMAP-CAP provides an adaptive research platform for the evaluation of multiple treatment modalities in the event of a respiratory pandemic resulting in critical illness. Sponsored by University Medical Center Utrecht.

ALIC4E is the first publicly funded, multi-country, pragmatic study determining whether antivirals should be routinely prescribed for influenza-like illness in primary care. Taking ALIC4E as an example, this article aims to provide an accessible description of crucial aspects of the platform design, response adaptation of study arms, and pragmatic aspects in open-label trials.

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

This review discusses the European clinical trial, including the implementation of some EU platform trials for COVID-19, such as from DisCoVeRy 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 development of the most promising COVID-19 vaccines and treatments. Some trials including the STRIVE platform, are ongoing under this project.

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.

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.

The journal article introduces the main features of adaptive designs 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.

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 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.

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 objective and by stakeholders.

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.

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

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 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. 

This website includes a podcast series and case studies of adaptive platform trials performed in the United Kingdom. It is hosted by the National Institute of Health Research.

This article introduces some of the activities of the EU-PEARL consortium regarding the use of platform trials in NASH, in particular, the proposed trial design, decision rules and simulation results.

ECRAID is the first network of its kind in Europe that offers a single point of access to a pan-European clinical research network for infectious diseases. ECRAID was established as a not-for-profit foundation in 2023 as an envisaged, long-term successor of the European-funded projects COMBACTE and PREPARE. The webpage presents ECRAID-PRIME, the platform trial for COVID-19 primary care patients.

This learning course has been developed by The European Clinical Research Alliance on Infectious Diseases (ECRAID), which coordinates  Europe's largest 'warm-base' clinical research network for infectious diseases. The six modules, provided free of charge, introduce various types of adaptive designs and highlight their advantages and limitations. Additionally, experts in the field will articulate the challenges associated with implementing these trials in practice.

The journal article provides ten consensus recommendations to improve the conduct, quality and acceptability of complex oncology trials. While it has been prepared for oncology within the United Kingdom setting, the recommendations could be of general use for adaptive platform trials.

This paper reviews the designs of four ongoing platform trials (REMAP CAP. AGILE, RECOVERY, CAPE-COVID)

While the estimand framework is relevant to any study in which a treatment effect is estimated, discussion is needed regarding its application to complex designs. This article discussed possible ways of implementing the estimand framework for different complex innovative designs.    

This website, created by EU-PEARL, shows the information resources to support patient-centric platform trials. Resources are shown with each stakeholder category.

This EU-PEARL webinar discusses the topics around non-concurrent controls in platform trials. It includes a statistical consideration in sharing control arms or changing standard of care during platform trials.

The EU-SolidAct trial is a part of EU-Response, a pan-European research project involved with the rapid and coordinated investigation of new and repurposed medication to treat COVID-19 during the ongoing pandemic. EU-SolidAct is an adaptive platform trial sponsored by Oslo University Hospital, Norway. The master protocol is developed for evaluating treatments in hospitalised patients with COVID-19.

This deliverable ensures that the assessment and certification of data research platform / information and communications technology (ICT) systems are sustainable. 

This guidance document addresses several questions that users of the scientific advice or protocol assistance procedures may have. It provides an overview of the procedure to obtain scientific advice or protocol assistance and guides applicants in preparing their requests. It will enable applicants to submit requests that align with Scientific Advice Working Party (SAWP) requirements and can be validated and evaluated quickly and efficiently.

FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer, and it remains one of the first umbrella trial designs to be launched globally. This paper describes lessons learned from the trial delivery over the last ten years.

This paper presents the experiences of the Data Monitoring Committee (DMC) for the Randomised Evaluation of COVID therapy trial (RECOVERY), a large-scale randomised adaptive platform clinical trial of treatments for hospitalised patients with COVID-19.

The ICH E20 expert working group is working on the development of a new E20 Guideline on “Adaptive Clinical Trials” on the design, conduct, analysis, and interpretation of adaptive clinical trials. It aims to provide a transparent and harmonised set of principles for the regulatory review of these studies in a global drug development program. These principles should also provide the flexibility to discuss innovative approaches to clinical trial design throughout the development process.

This revision of the global harmonization regulatory guideline for GCP (ICH E6 R3) includes a risk-based approach to the design and conduct of clinical trials, increased reliance on electronic systems and non-traditional interventional clinical trials, such as pragmatic clinical trials, decentralized clinical trials, and those trials that incorporate real-world data sources.

The deliverable is a project review of the current platform trial landscape to understand which challenges have the most complexity and impact. It is developed within the EU-PEARL project and includes a literature search, a website review, and an outreach survey to trial teams.

In this commentary journal article, trial management and data management teams of STAMPEDE and FOCUS4 trials summarise the operational challenges and personal experiences of individual researchers to enable the broader clinical trials community to learn from their experiences