TOOLBOX
The Adaptive Platform Trial Toolbox
Objective of this toolbox
The Adaptive Platform Trial Toolbox aims to collect the accumulated knowledge, experience, and resources (collectively termed as ‘tools’) from multiple projects and trials into a practical and guided toolbox to facilitate planning and conduct of future adaptive platform trials in any therapeutic area.
Why should you use the toolbox?
Adaptive platform trials constitute a dynamic topic in the current clinical research environment. Design, conduct, and even the naming of adaptive platform trials are in active discussion. Therefore, the toolbox has been structured as a practical aid to support complex clinical research. If you need resources regarding adaptive platform trials including, general information as well as specific resources for the different steps in the design or conduct, you can look for recommendations within the toolbox. You can consult the toolbox for training purposes as well.
How should you use the toolbox?
The toolbox has been structured with different categories for different trial steps. Each tool is presented with a brief explanation and a resource type, indicating the tool's format and level of validation. The tools are grouped into categories, each with its own tab. On the reference for each tool, the link to access the outside source is included. Further information is also available within the references section. The tools have been selected for their relevance and utility, but the views and opinions expressed in the tools may not represent the specific opinions of the EU-RESPONSE and RECOVER consortia.
The toolbox is still under development and is currently available in a beta version. If you would like to provide feedback or gather more information about the rationale and methodology of the toolbox, please contact us.
| Name | Explanation | Type | Year | Reference |
|---|---|---|---|---|
| Report on terminology, references and scenarios for platform trials and master protocols | 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. Developed within EU-PEARL project. | Document, project deliverable, review | 2020 | Parke et al. 2020 |
| Project: master protocol studies. Using master protocol studies to drive medical product development | A set of project resources that guide the appropriate use of master protocols, developed by CTTI. | Document, project outcome, guide | 2020 | CTTI 2020a |
| The evolution of master protocol clinical trial designs: a systematic literature review | 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. | Document, journal article, systematic review | 2020 | Meyer et al. 2020 |
| Clinical operations best practices report | 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 EU-PEARL project and includes a literature search, website review, and an outreach survey to trial teams. | Document, project deliverable, review | 2020 | Parke et al. 2020ba |
| Advancing the use of complex innovative trial designs (CID): introduction | This video introduces FDA’s Complex Innovative Trial Designs (CID) program. It also covers some key aspects of complex trial designs with examples. | Video, regulatory guide by health authority | 2019 | FDA 2019a |
| Adaptive designs for clinical 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. | Document, journal article, review | 2016 | Bhatt and Mehta 2016 |
| Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs | The journal article introduces the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials. | Document, journal article, correspondence | 2020 | Burnett et al. 2020 |
| Adaptive trial designs - introduction for non-statisticians | This video introduces adaptive trial design options for non-statisticians with trial examples. Presented by Cytel. | Video, presentation by private company | 2019 | Cytel 2019 |
| New approaches to clinical trials: adaptive designs | The document and attached presentation discuss adaptive design elements for clinical trials, including advantages, disadvantages, rare diseases, and involvement of patients. Prepared by EUPATI. | Document, website, article and presentation | 2015 | EUPATI 2015 |
| Clinical trials in global health | This Lancet Global Health Series of four papers and a commentary show the challenges in clinical trial research in global health and offers solutions that can optimise statistical efficiency and sustainability, including adaptive trial designs and master protocols, with considerations for the required clinical research infrastructure. | Document, journal article, discussion and comment | 2021 | Bhandari et al. 2021, Dron et al. 2021, Park et al. 2021a, Park et al. 2021b, Park et al. 2021c |
| The COMET handbook: version 1.0 | A key consideration for platform trials is to designate appropriate outcomes. These outcomes must be relevant for new interventional arms and suitable for adaptive elements. This journal article of Core Outcome Measures in Effectiveness Trials (COMET) Initiative addresses issues to consider when selecting or developing a core outcome set. Available outcome or data element repositories are also identified. | Document, journal article, review | 2017 | Williamson et al. 2017 |
| Effective delivery of Complex Innovative Design (CID) cancer trials—a consensus statement | 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. | Document, journal article, consensus statement | 2020 | Blagden et al. 2020 |
| Delivering complex and innovative trials: case study library | This website includes podcast series and case studies of adaptive platform trials performed in the United Kingdom. Hosted by the National Institute of Health Research. | Document, video, and podcast, website, case study library | 2020 | NIHR 2020 |
| PARADIGM patient engagement toolbox | This project deliverable centralises all PARADIGM’s co-created recommendations, tools and relevant background information to make patient engagement in medicines development easier for all. The toolbox could help develop clinical trials with a further enhanced patient-focus and improve the experience of patients participating in the trials. Developed by PARADIGM project. | Document, project deliverable, guide, checklist, and article | 2020 | PARADIGM 2020 |
| Name | Explanation | Type | Year | Reference |
|---|---|---|---|---|
| Complex clinical trials - Questions and answers | This document aims to address challenges sponsors may face as regards scientific and operational aspects of complex clinical trials in the EU/EEA and to encourage considering choices in development as early as possible, in order to generate useful evidence and inform clinical and regulatory decision making | Document, regulatory questions and answers | 2022 | EC,EMA, HMA 2022 |
| Recommendation paper on the initiation and conduct of complex clinical trials | This key document provides recommendations for sponsors regarding the authorisation and conduct of complex clinical trials. It describes the current perspective of the CTFG on these trials and outlines the major issues that sponsors should address in the process of initiating and conducting complex clinical trials in the EU/EEA. | Document, regulatory guide by health authority | 2019 | CTFG 2019 |
| Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design | The document outlines some general considerations for studies incorporating interim analyses. A set of minimal requirements is outlined that must be fulfilled whenever confirmatory clinical trials are planned with an adaptive design. Later sections comment on specific design modifications. Published by EMA. | Document, regulatory guide by health authority | 2007 | CHMP 2007 |
| Adaptive designs in clinical trials: from scientific advice to marketing authorisation to the European Medicine Agency | The journal article assesses scientific advice letters containing questions related to adaptive clinical trials in phases II or III, issued by EMA. It also examines relevant regulatory aspects. | Document, journal article, research paper | 2018 | Collignon et al. 2018 |
| Master protocols: efficient clinical trial design strategies to expedite development of oncology drugs and biologics - draft guidance for industry | 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. | Document, regulatory guide by health authority | 2018 | FDA 2018 |
| Interacting with the FDA on complex innovative trial designs for drugs and biological products - guidance for industry | This FDA document provides guidance to sponsors and applicants on interacting with the FDA on complex innovative trial design proposals for drugs or biological products. It also covers some key aspects of complex trial designs. | Document, regulatory guide by health authority | 2020 | FDA 2020 |
| COVID-19: master protocols evaluating drugs and biological products for treatment or prevention | FDA is issuing this guidance to provide recommendations to sponsors of master protocols evaluating drugs for the treatment or prevention of COVID-19. | Document, regulatory guide by health authority | 2021 | FDA 2021 |
| Name | Explanation | Type | Year | Reference |
|---|---|---|---|---|
| Master protocol content development guide | A step-by-step tool to develop an engagement strategy for engaging all relevant stakeholders early in the master protocol development process, developed by CTTI. | Document, project outcome, guide | 2020 | CTTI 2020b |
| Clinical ICF - Study information and informed consent form | An informed consent form template harmonised for clinical studies and further research. It is meant to cover all information required by the General Data Protection Regulation (GDPR) within a traditional (non-electronic) informed consent document to be signed by patients or healthy volunteers before participating in a clinical study; it does not address country specific requirements. Developed within DO->IT project. | Document, project deliverable, template | 2019 | Norwegian Institute of Public Health and Boehringer Ingelheim 2019 |
| Guidelines for tailoring the informed consent process in clinical studies | These guidelines have been designed to provide information and evidence to assist with the development, or review of the consent process for use in clinical studies with human participants. Developed within i-CONSENT project. | Document, project deliverable, guide and checklist | 2021 | i-CONSENT 2021 |
| Adaptive platform trials: scalable from breast cancer to COVID | This video with attached slides summarizes how the adaptive platform I-SPY trials 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, operations, infrastructure, intervention selection, data collection, added value, and publications. Hosted by NIH Collaboratory. | Video, presentation, discussion | 2020 | NIH Collaboratory 2020 |
| Lessons from COVID-19: the first year of the REMAP-CAP global adaptive platform trial | The video with slides discusses the accumulated experience from REMAP-CAP COVID-19 platform trial with a focus on design, Bayesian statistical model, data management, interpretation of results, funding, and challenges for publication and trial logistics. Hosted by NIH Collaboratory. | Video, presentation, discussion | 2021 | NIH Collaboratory 2021 |
| Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial | The journal article describes methodological and practical experience arising with stopping recruitment to research arms following a pre-planned intermediate analysis and adding a new research arm during STAMPEDE, an adaptive platform oncology trial. It also includes criteria for assessing potential new intervention arms. | Document, journal article, methodology | 2012 | Sydes et al. 2012 |
| Mind the gap? The platform trial as a working environment | In this commentary journal article, trial management and data management teams of STAMPEDE and FOCUS4 trials summarise the operational challenges and personal experience of individual researchers, to enable the broader clinical trials community to learn from their experiences. | Document, journal article, commentary | 2019 | Morrell et al. 2019 |
| This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols | 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. | Document, journal article, methodology | 2019 | Schiavone et al. 2019 |
| Name | Explanation | Type | Year | Reference |
|---|---|---|---|---|
| Statistical simulation in master protocols: components & communications considerations |
This tool provides early adopters with an overview of components of statistical simulation and tips for how to organize presentations of simulated trials to key stakeholder groups. Developed by CTTI. |
Document, project outcome, guide | 2020 | CTTI 2020c |
| Systematic review of available software for multi-arm multi-stage and platform clinical trial design | This systematic research reviews existing software for the design of platform trials. Developed within EU-PEARL project. | Document, journal article, systematic review | 2021 | Meyer et al. 2021 |
| Adaptive design clinical trials for drugs and biologics - guidance for industry | 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. | Document, regulatory guide by health authority | 2019 | FDA 2019b |
| Statistical consideration when adding new arms to ongoing clinical trials: the potentials and the caveats | The journal article reviews the impact on 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. | Document,journal article, commentary | 2021 | Lee et al. 2021 |
| The adaptive platform trial - the statistical efficiencies | The video provides statistical and methodological aspects of adaptive platform trials. It also covers case studies. Prepared by Berry Consultants. | Video, presentation by private company | 2015 | Berry Consultants 2015 |
| Data, data all around | This news article from the Lancet Digital Health highlights the complex routine data collection machinery behind the RECOVERY trial, simplifying site operations. | Document, journal article, news | 2021 | McCall 2021 |
| Individualized screening trial of innovative glioblastoma therapy (INSIGhT): a Bayesian adaptive platform trial to develop precision medicines for patients with glioblastoma | 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 randomization algorithm is provided with expected benefits and challenges. | Document, journal article, methodology | 2019 | Alexander et al. 2019 |
| Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons | 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, number of case report form changes, database amendments and database growth are discussed. | Document, journal article, methodology | 2019 | Hague et al. 2019 |
| Name | Explanation | Type | Year | Reference |
|---|---|---|---|---|
| The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design | This CONSORT extension is meant to provide reporting guidance for any randomised trial that was designed using an adaptive design. | Document, website and journal article, statement and checklist | 2020 | Dimairo et al. 2020 |
| An overview of platform trials with a checklist for clinical readers | The objective of this journal review is 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 example use of the checklist for platform trials. | Document, journal article, review and checklist | 2020 | Park et al. 2020 |
| Name | Explanation | Type | Year | Reference |
|---|---|---|---|---|
| Accelerating COVID-19 therapeutic interventions and vaccines (ACTIV) trials | 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 prioritizing and speeding development of the most promising COVID-19 vaccines and treatments. | Document, trial website, protocol | 2020 | NIH 2020 |
| A randomised, embedded, multi-factorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) | REMAP-CAP is a randomised, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia. In addition, REMAP-CAP provides and adaptive research platform for evaluation of multiple treatment modalities in the event of a respiratory pandemic resulting in critical illness. Sponsored by University Medical Center Utrecht. | Document, video, and podcast, trial website, protocol, statistical plan, and statistical model | 2015 | University Medical Center Utrecht 2015 |
| Investigation of serial studies to predict your therapeutic response with imaging and molecular analysis (I-SPY) trials | Adaptive platform phase 2 trials family with a Bayesian design to investigate treatments for breast cancer or COVID-19. Sponsored by QuantumLeap Healthcare Collaborative. | Document and video, trial website, presentation | 2010 | QuantumLeap Healthcare Collaborative 2010 |
| Randomised evaluation of COVID-19 therapy (RECOVERY) | An adaptive platform clinical trial design to accelerate the process of identifying effective treatments for COVID-19 patients who enter the United Kingdom’s National Health Service hospitals. Sponsored by University of Oxford. | Document and video, trial website, protocol, statistical plan, consent form, manual, patient engagement material, and presentation | 2020 | University of Oxford 2020a |
| Helping alleviate the longer-term consequences of COVID-19 (HEAL-COVID) | 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. | Document, trial website, protocol and consent form | 2021 | Cambridge University Hospitals NHS Foundation Trust 2021 |
| Platform randomised trial of interventions against COVID-19 In older people (PRINCIPLE) | This study is a platform, randomised controlled trial in primary care that can rapidly test low-risk treatments for people at higher risk of complications from COVID-19. The intent is to establish an on-going trial infrastructure within a master protocol. Sponsored by University of Oxford. | Document, trial website. protocol, guidance, and patient information sheet | 2020 | University of Oxford 2020b |
| Molecular selection of therapy in colorectal cancer: a molecularly stratified randomised controlled trial programme (FOCUS4) | FOCUS4 is an adaptive, molecularly stratified trial which aims to improve the efficiency with which new novel agents can be tested in the colorectal cancer setting. It has a multi-arm, multi-stage design with a master protocol. Sponsored by University College London. | Document, trial website, protocol and patient information sheet | 2013 | University College London 2013 |
| Seamless phase I/IIa platform for the rapid evaluation of candidates for COVID-19 treatment (AGILE) | 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. Sponsored by University of Liverpool. | Document and video, trial website, protocol and manual | 2021 | University of Liverpool 2021 |
| An open-label, multicentre, randomised, adaptive platform trial of the safety and efficacy of several therapies, including antiviral therapies, versus control in mild/moderate cases of COVID-19 (ANTICOV) | 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 progression of COVID-19 to severe disease and potentially limit transmission. Sponsored by Drug for Neglected Diseases Initiative and others. | Document and video, trial website, protocol, patient information, informed consent form, and standard operating procedure | 2020 | Drugs for Neglected Diseases Initiative et al. 2020 |
|
References |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|