The adaptive platform trial toolbox

RAMPART (Renal Adjuvant MultiPle Arm Randomised Trial) is an international investigator-led phase III multi-arm multi-stage, multi-centre randomised controlled platform trial of adjuvant therapy in patients with resected primary renal cell carcinoma at high or intermediate risk of relapse.

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. It is sponsored by the University of Oxford.

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.

This document describes the recommended ethical, information governance and security policies for integrated research platforms (IRPs) of the IMI EU-PEARL project. The deliverable identifies the documents required and the reasons why they are needed. It also identifies existing templates within the EU-PEARL catalogue of products or elsewhere where possible.

For the first anniversary of RECOVERY in 2021, Peter Horby, co-lead on the RECOVERY platform trial, was interviewed about the history and future.  RECOVERY recruited 40000 patients into 13 treatment arms. It demonstrated the benefits of the steroid dexamethasone and tocilizumab while showing the lack of efficacy of azithromycin, colchicine, convalescent plasma hydroxychloroquine and lopinavir-ritonavir.

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.

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 generalizability 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 University of Liverpool.

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

A major outcome of the EU-PEARL Tuberculosis (TB) work package is the development of a TB master protocol outline to conduct platform trials in the context of an IRP with the final goal of expediting treatment regimen development. EU-PEARL developed a template for the master protocol that guides the protocol author(s).

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 designed to overcome these issues by simultaneously evaluating multiple COVID-19 treatments in the outpatient setting in one common platform with shared controls.  

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 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 (OPtimizing Treatment and Impact of Monoclonal antibodies through Evaluation for COVID-19), an open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization. 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.

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.

The TOGETHER clinical trial started in June 2020 as an international collaboration in response to the worsening pandemic of SARS-CoV-2 / COVID-19. Utilizing 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 disease progression of COVID-19.

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.  

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 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. 

This guidance was developed to implement the request of the Director General in the WHA resolution 75.8. It is under public consultation (accessed on 21 Sep 2023).