The adaptive platform trial toolbox

This paper describes the statistical considerations and challenges in platform trials for ALS. Since regulatory guidance specifically requires that survival be integrated into the primary outcome, the HEALEY ALS Platform Trial employs a Bayesian shared parameter model to manage shared controls dynamically using hierarchical models. 

This paper describes the design of an adaptive, parent protocol clinical trial for Ebola infection, such as the PREVAIL II—a "barely Bayesian" randomised controlled trial conducted during the 2014–2016 Ebola outbreak to evaluate experimental treatments. Although the trial was theoretically designed as a platform to evaluate multiple interventions, it ultimately assessed only one (ZMapp), due to the rapid decline in Ebola cases and operational constraints.

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.

This paper proposes a multi-arm multistage (MAMS) platform trial for progressive multiple sclerosis to speed up testing multiple treatments. It uses MRI brain atrophy as an interim outcome and clinical disability progression as the outcome. The design reduces trial size and duration compared to traditional trials and was supported by patient input.

EU-PEARL developed a suite of adaptable templates over 3.5 years (http://www.eu-pearl). These templates, based on TransCelerate’s CPT and enhanced with EU-PEARL input, help researchers design and manage complex, adaptive platform trials efficiently. A supporting user manual and best practices tool to make the IRP trial design easier and more standardised. This paper summarised the process and discussion on the development of a generic template for platform trials. 

DIAN; Dominantly Inherited Alzheimer Network (DIAN), conducted two platform trials for Alzheimer's disease. DIAN-TU Trial Platform (DIAN-TU-001), NCT01760005 and DIAN-TU NexGen (Next Generation Prevention Trial (NCT05269394)), based on the DIAN expanded registry. This website includes some trial information documents and webinars.

This systematic review examined how health economic analyses are used in designing and modifying multi arm, multistage (MAMS) adaptive and adaptive platform trials. Among 17 included studies, most were economic evaluation protocols, with only a few actual evaluations conducted during trials. Pretrial economic evaluations were not used in any case. Interim cost-effectiveness analyses were rare but did influence decisions in a few trials. Overall, while economic considerations are occasionally embedded in adaptive trials, their use remains limited despite their potential value in informing trial decisions.

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 the current information of ECRAID-PRIME, the platform trial for COVID-19 primary care patients, publication, meeting recording, and educational materials (Training modules on adaptive clinical trial designs: ERS-ECRAID initiative).

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 review discusses adaptive trial methodologies in the context of COVID-19, including group sequential, MAMS, Bayesian, and platform designs, such as the RECOVERY and REMAP-CAP platform trials. The paper emphasises the importance of simulation in evaluating design performance and addresses practical challenges such as ethics, regulation, data sharing, and statistical validation.

This rapid review found limited patient and public involvement reported in multiple sclerosis (MS) clinical trials over the past five years. The OCTOPUS trial in progressive MS is a case study where people affected by MS were deeply involved in governance, treatment selection, and trial design, leading the PPI strategy. The study concludes that meaningful PPI improves trial quality and relevance and offers recommendations to enhance PPI in future MS trials.

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 the 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 medications 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.

PLATCOV is a Phase 2 adaptive platform trial sponsored by the University of Oxford since 2021, focusing on early symptomatic COVID-19. It is distinct in being conducted through Oxford’s clinical research units based in low- and middle-income countries (LMICs) across Asia. Key trial documents, including the master protocol, are publicly available on the website of CERCLE (Coalition for Equitable Research in Low-Resource Settings), an initiative promoting fair and collaborative research in LMICs.

STAMPEDE is a platform trial that aims to provide evidence as to what is the best way of treating men with newly diagnosed advanced prostate cancer. Originally, there were five research and one control arm. This paper describes methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial.

The RESiLIENT trial is a platform trial, an adaptive, master‑protocol design using a smartphone CBT app. It delivers five CBT modules—cognitive restructuring, behavioural activation, problem-solving, assertion training, and insomnia therapy—through four parallel 2×2 factorial trials that efficiently evaluate each skill's effect, match modules to participant characteristics, and enable future additions. Recruiting around 3,520 adults with subthreshold depression and 1,700 without, it measures symptom reduction at week 6 (PHQ‑9) and incidence of major depressive episodes by week 50 (computerised CIDI).

This deliverable developed by EU-PEARL, covers the development of an organisational and business model for a scalable and sustainable data quality assessment service to assure future IRP studies and platforms that the data they reuse (e.g., from electronic health records –EHR – systems) is of satisfactory quality. 

This document explains the feasibility of protocol for patient recruitment using Communication Technology (ICT). This tool enables the reuse of Electronic Health Record (EHR) data, supporting an industry or public platform trial sponsor and contributing research organisations to undertake platform trials. 

Recruiting participants remains crucial to research efficiency in platform trials with more extensive and complicated trial designs. This document developed by EU-PEARL, describes a proposal for a generic process for gaining an estimate of patient numbers that match the clinical study inclusion criteria at hospitals, based on the analysis of hospitals' Electronic Health Records(EHR).

Global Coalition for Adaptive Research (GCAR) is a non-profit organisation in the US, committed to uniting stakeholders and developing and sponsoring Master Protocols and adaptive platform trials for facilitating the discovery of treatments for rare and deadly diseases, such as GBM AGILE for brain cancer, REMAP CAP US  for COVID. DDOG-M-PACT PTSD (Military and Veterans PTSD),  Neurofibromatosis (NF) Platform Trial- EU-PEARL, Ovarian CanceRx (ovarian cancer), ARBOR BTC (Biliary Tract Cancer), and IMPACT PDAC (Pancreatic Ductal Adenocarcinoma) are also being planned. The website presents several educational short videos and infographics about platform trials. 

This revision of the global harmonisation 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, decentralised clinical trials, and those trials that incorporate real-world data sources.

Guidance for a cover letter outlines the critical point when submitting a platform trial application to the regulatory authority. This guideline applies to the companion protocol templates, Master Protocol Template and Intervention Specific Appendix Template prepared within the EU-PEARL consortium.

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 tests multiple investigational products concurrently in people with ALS to identify novel treatments, biomarkers, and trial endpoints rapidly. This website includes a protocol paper (Paganoni et al. 2022, R2-131) , statistical consideration (Quintara M et al. 2023, see tool R131) and webinars.

HEAL-COVID is a national platform trial jointly sponsored by Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. It aims to evaluate the impact of treatments on longer-term morbidity, mortality, re-hospitalisation, symptom burden and quality of life associated with COVID-19. This website includes trial documents such as protocol, ICF, and SAP.

I-SPY-COVID is an extension of the I-SPY trial; a multi-centre open-label phase 2 platform trial in the USA designed to evaluate multiple therapeutics for severe COVID-19. As of December 2021, 11 investigational agent arms had been activated, and eight arms were complete. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial. 

This document describes internationally accepted principles and practices in conducting individual clinical trials and overall development strategies for new medical products. R1 contains statements for a wide range of study designs (platform trials etc.) and various data sources.

The ICH E20 expert working group is developing 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.

Between 2001 and 2019, 16 platform trials were initiated globally for the COVID-19 pandemic. This review was conducted to quantify and describe platform trials used in COVID-19.

This journal article presents the Bayesian, adaptive, platform trial INSIGhT to develop precision medicine approaches in glioblastoma. Detailed information on the statistical model, simulations, and randomisation algorithm is provided with expected benefits and challenges.

European Federation of Pharmaceutical Industries and Associations (EFPIA) Clinical Research Expert Group developed this white paper as a landscape review of innovation in clinical trial design, such as adaptive designs.

This white paper outlines key features of vaccine adaptive platform trials (APTs). It includes discussions from a two-day workshop organized by the VACCELERATE Consortium, exploring the concept and applicability of APT methodology in vaccine trials under both non-pandemic and pandemic conditions. It highlights the importance of pre-planned interim analyses, shared control groups, and flexible designs that can adapt as new data emerges. 

Clinical Trial Design Software for calculating sample size for basket and platform trials developed by the university of Texas MD Anderson Cancer Center.

This FDA document guides to sponsors and applicants in interacting with the FDA on complex innovative trial design proposals for drugs or biological products. It also covers some critical aspects of complex trial designs.

This intervention-specific appendix (ISA) template for platform trials contains instruction text, common/suggested text, variable text and examples. It is downloadable as a Microsoft Word document for readers' editing. This template is used with the Master Protocol Template, developed within the EU-PEARL project, based on TransCelerate Common Protocol Template CPT V8.0.

The I-SPY series of trials is changing the way new treatments are developed for breast cancer, helping make available new, better and more personalised treatments faster. ISPY-2 is an adaptive platform phase 2 trial, a Bayesian design to investigate neoadjuvant treatments of locally advanced breast cancer. It is sponsored by QuantumLeap Healthcare Collaborative. This website includes protocol concept papers, presentation/ education materials and other information, such as the expansion of the platform to COVID/ARDS.

This deliverable describes the value proposition of the IRP for NASH, the lessons learned during the project duration that affect the options available to fund and set up the IRP, and the proposed plan to implement such lessons in the future. 

This deliverable explains several tools developed by the EU-PEARL project to sustain the integrated research platform (IRP) for TB. Tools are a master protocol template including a design proposal for TB adaptive trials, an operational plan (a community engagement plan),  the Capacity Building and Assessment Handbook for sites to conduct TB drug development trials within the IRP environment, and a systematic review to identify and assess host and bacterial biomarkers able to predict end of treatment outcomes.

Drawing lessons from experiences in cancer and other neurodegenerative diseases, the authors discuss the opportunities and challenges of applying MAMS trials in Parkinson’s disease. They highlight considerations around trial design, patient recruitment, and regulatory aspects, emphasising how this adaptive approach could accelerate therapeutic development for Parkinson’s disease.

The PROTECT-CH trial aimed to test antiviral drugs for COVID-19 prevention in UK care homes but was halted before starting due to successful vaccination rollout and major logistical challenges, including delays in contracting, drug supply, and staffing. Though never launched, the trial highlighted the need for better infrastructure and planning to support future care home research during pandemics. This paper discusses the lessons learned from the PROTECT-CH experience.

This paper outlines the experience from the NHLBI's CONNECTS (Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies) program, which coordinated five multisite clinical trials during the COVID-19 pandemic. The program aimed to evaluate 18 interventions across outpatient, inpatient, and post-discharge settings, using an innovative, collaborative infrastructure to enable rapid trial implementation. Adaptive platform trial designs were a key component of this approach, enabling flexibility and efficiency in testing multiple therapies. However, the paper addresses a wide range of operational, regulatory, and logistical challenges encountered during execution, offering insights to inform future public health research responses.

The RECOVERY trial was launched as a streamlined, pragmatic randomised controlled trial to rapidly generate high-quality data on potential treatments. Within 100 days, it demonstrated that dexamethasone significantly improves survival in severe cases, saving countless lives. The trial also showed that other commonly used treatments, such as hydroxychloroquine and azithromycin, were ineffective. RECOVERY highlights the importance of integrating clinical trials with healthcare delivery, even in a pandemic setting.

This CTTI website includes a step-by-step tool for developing master protocols. It also contains guides for implementing the protocol and statistical considerations.

This template of the master protocol (MPT) for the platform trial contains instructional text, common / suggested text, variable text and examples, and it is downloadable as a Microsoft Word document for readers' editing. It is developed within the EU-PEARL project, based on TransCelerate Common Protocol Template CPT V8.0.

This FDA guidance provides advice to sponsors of drugs and biologics for cancer treatment regarding the design and conduct of clinical trials, other than first-in-human trials, intended to simultaneously evaluate more than one investigational drug and/or more than one cancer type within the same overall trial structure (master protocols) in adult and pediatric cancers.