REMAP trials are characterised by five key features as described in table 2. These key features provide multiple advantages over conventional RCTs, collectively maximising trial efficiency and supporting rapid generation of new knowledge.25 These advantages are particularly impactful for rare diseases such as fILD that have a poor prognosis, few evidence-based treatment options and numerous potential treatments/interventions at the clinical trial phase of development.26

The distinct features of REMAP trials necessitate precise and standardised terminology. As defined in table 3, REMAP trials contain multiple mutually exclusive treatment factors. A factor describes the intervention being studied, which could be a medicinal or non-medicinal product. Examples of factors include existing standard of care treatments or active treatments. One or more factors may be grouped together into a treatment domain, with a domain describing a specific approach to clinical management. For example, an antifibrotic domain could include standard of care and one or more antifibrotic treatments, while an immunomodulatory domain could contain standard of care and one or more immunomodulatory treatments. A patient is randomised to a single factor within each domain of the adaptive platform trial and receives treatments in active domains for which they are eligible. Thus, a patient can be randomised to multiple factors across multiple domains. This collection of factors coming from separate domains administered to the individual patient is referred to as that patient’s regimen (figure 1). A stratum (for example, a diagnosis of IPF) captures a specific baseline disease characteristic that makes patients eligible or ineligible for particular domains, and can be used for stratified randomisation and/or strata-specific analyses. This means that not all patients entering the platform are eligible to be randomised to all platform domains. For example, an immunomodulatory domain is made unavailable for patients with IPF. REMAP trials also possess specific analytical characteristics, as described below, that can increase study efficiency.

Strengths and challenges of REMAP trials as compared with conventional randomised controlled trials. REMAP, Randomised Embedded Multifactorial Adaptive Platform.

Common terminology used in REMAP trials

REMAP trials are intended to operate as a perennial platform where new domains and/or factors (interventions) are added when understood to be a research priority and when additional funding to support such an addition is acquired (figure 2). They are randomised clinical trials centred around a core protocol that is embedded in routine patient care,15 17 reducing recruitment burden and increasing recruitment rate.27 The core protocol provides global details on trial design and conduct that is supplemented with domain-specific and region-specific appendices. These appendices describe prespecified protocol details for specific interventions and geographical regions; for example, details may include adaptations to treatment-specific exclusion criteria or specific healthcare system requirements.15 This modular structure allows rapid and efficient modification to individual components of the study with minimal disruption to overall study conduct, which includes the addition of new interventions or removal of ineffective interventions.

Study overview. Patients with fibrotic ILD will be assessed for platform eligibility criteria (step 1), after which, screening for domain-specific eligibility criteria will be performed (step 2). Patients who meet eligibility criteria for at least one domain will be randomised to an intervention (factor) from each domain (step 3), which could include a variety of different options depending on the available interventions (indicated by subscripts). Patients would then be initiated on therapy and complete study assessments that allow analysis of efficacy, safety and cost-effectiveness outcomes (step 4). Predefined stopping criteria for each intervention will be assessed throughout the study (step 5), with termination of completed interventions (factors) and/or domains and initiation of new interventions (factors) and/or domains. Patients will be continuously assessed throughout their participation in the study for eligibility of previously existing and newly added domains. Domain refers to a group of interventions that are mutually exclusive. Interventions are called factors in the REMAP terminology. Ctrl, control arm; ILD, interstitial lung disease; REMAP, Randomised Embedded Multifactorial Adaptive Platform.

The multifactorial aspect of a REMAP trial permits simultaneous assessment of several interventions across multiple therapeutic domains and different disease strata.25 28 Multifactorial designs facilitate efficient use of resources, leveraging patient data across multiple domains and providing support for important, but potentially less commercially appealing, research questions enabling these research questions to be answered simultaneously with questions for which funding may be more readily obtainable. A patient can be assigned to the control arm in one domain but to active treatments in other domains. This patient-centred approach decreases the number of trial participants who receive only standard of care or placebo, ensuring that more patients receive active treatments, which appeals to patients and increases trial attractiveness.

REMAP trials, like all RCTs, require a comprehensive statistical analysis plan (SAP) addressing typical issues, while also requiring additional work to arrive at the best adaptive features to be used prior to initiation of the trial. These design decisions are informed by extensive simulations whenever possible using real-world data.25 Design decisions are supported by the analysis of the trial performance characteristics under different simulated circumstances.

Multiple adaptive features can be employed, with the Bayesian statistical framework leveraging all available data, naturally enabling prespecified adaptations. These adaptive features include response-adaptive randomisation (RAR), which concentrates recruitment to therapies that appear to be beneficial, while minimising resource use and risks for enrolled patients.28 There is also greater potential to terminate a given factor or domain based on predetermined thresholds for success or futility.29 Similarly, should targeted therapies become available at some time in the future, the protocol can be adapted to incorporate stratified randomisation. All of these adaptive features are supported within a platform infrastructure that, once study start-up and site initiation are established, leverages the ongoing infrastructure to assess numerous therapies over time.

Not infrequently many patients are excluded from traditional clinical trials due to extensive inclusion and exclusion criteria.30 REMAP trials typically have broad eligibility criteria and simple study procedures that maximise patient recruitment while also retaining the ability to test heterogeneity of treatment effects across prespecified strata.29 Embedding the trial in routine clinical practice with minimal additional study visits also increases the likelihood that patients residing in more remote areas can participate. The simplified study protocol embedded within routine clinical care and the ability to randomise patients to multiple domains facilitate the retention of patients by reducing the burden of study visits and increasing the incentive to ongoing participation, respectively. To ensure that patients from low/middle-income countries can participate in REMAP-ILD, the core protocol is pragmatic, with minimally required data collection required to ensure successful delivery of the trial. This will reduce the burden of delivery and cost to ensure that more people can participate even in resource-scarce scenarios. All information and data collection tools will be translated into the languages of participating centres.

Initial power calculations and number needed to recruit are based whenever possible on simulated trials using real-world data. REMAP trials include frequent prespecified adaptive analyses, the timing and frequency of which are based on data obtained from simulated trials.28 Bayesian statistical methods are used during the trial to make prespecified changes to the protocol based on accruing data, including evaluation of differential treatment effects within prespecified strata, evaluation of prespecified intervention–intervention interactions and testing of multiple interventions.

An RAR algorithm may be used to preferentially randomise patients to interventions that have demonstrated a suggested benefit compared with other factors within a domain based on prespecified criteria that are assessed at interim analyses.28 The study continues until a statistical stopping rule for success, futility or harm has been triggered, or until complete follow-up for the predefined maximum sample size has been reached. Although a priori sample size estimates are generated, the exact sample size of REMAP trials is not fixed as in conventional RCTs. Instead, predefined minimum and maximum sample sizes are defined, with the potential to quickly declare success or futility, using prespecified statistical rules, based on accumulating data. Reaching study conclusions before reaching the maximum sample size, through triggering a prespecified statistical rule for success or futility, allows more efficient use of funding and leads to better patient care.21 31 32 This is an important advantage of REMAP trials, although it requires that regulatory agencies accept the employed analytical techniques.33

Funding global perennial adaptive platforms is a challenge as the current model for most funding organisations precludes fully integrated global collaboration by limiting the funds that can be transferred internationally. The funding structure is even more challenging for less-resourced countries and centres, as research funding is itself a source of research inequity. Further contributing to this challenge is the limited term for most funding sources, resulting in the need to frequently reapply for funding of a perennial international platform that tests multiple interventions over many years. Despite that, REMAP-CAP,24 an investigator-initiated global platform, was able to thrive and succeed. REMAP-ILD is being planned to adapt the learning and principles of REMAP-CAP to investigate therapies for fILD as outlined below. As per January 2024, various funding applications have been submitted. A REMAP trial design proposal has been submitted to the National Institute for Health and Care Research (UK). An investigator-initiated interventional trial activating the steroid domain has been submitted to the Swiss National Science Foundation (SNF) (Switzerland). A proposal to activate the antifibrotic and steroid domain is under negotiation with the Brazilian Ministry of Health, PROADI-SUS Programme (Brazil). In addition, the European Patient-driven Research Hub for Effective Interventions in Interstitial Lung Diseases analogue to the REMAP-ILD structure has been proposed in a first stage Horizon call submission (HORIZON-HLTH-2024-DISEASE-03-08-two-stage Comparative effectiveness research for healthcare interventions in areas of high public health need—European Union (EU)). The respective responses are currently pending. Additional submissions are currently under way to fund this global initiative and further sources of funding will be sought depending on the outcomes of these applications.

Governance policies within platform trials emphasise rapid and widespread dissemination of new knowledge through agreements on data sharing, data ownership and publication. The potential to reach earlier conclusions for success or futility contributes to the timely dissemination of evidence-based knowledge.