EU‑X‑CT initiative aims to improve safe and equitable access to clinical trials in Europe when suitable options are not available in a patient’s home country. The document shares practical approaches to cross‑border recruitment, conduct and follow‑up and is linked to the wider EU‑X‑CT online resources for patients, caregivers and clinical trial professionals, including a trial preparator and country profiles for selected European states.The initiative has developed general recommendations on key aspects of clinical trial management and conduct to address the challenges faced by participants who travel across borders to join a study. These recommendations were developed through a multi‑stakeholder process coordinated by the European Forum for Good Clinical Practice (EFGCP) and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

This publication provides practical guidance on selecting appropriate randomised clinical trial designs for studies involving small patient populations, making it particularly relevant for rare disease research. It supports protocol development by comparing conventional and innovative designs, including crossover, randomised withdrawal, adaptive, sequential and n-of-1 trials, and discusses the circumstances in which each design is most appropriate. The resource helps researchers maximise the scientific value of limited patient populations while maintaining methodological rigour, feasibility and reliable evidence generation.

This ERA4Health report  presents a structured mapping of organisations that can support at national or international level the planning, design, and conduct of multicountry Investigator Initiated Clinical Studies (IICS) in Europe. It compiles information on the services offered by clinical trial units (CTUs), academic clinical research centres, national coordinating centres, disease‑specific networks, and other non‑commercial infrastructures that provide services for investigator‑led clinical trials. For each organisation, the report documents core competencies, target trial phases, therapeutic focus (where applicable), geographic scope, and experience with multinational trials.

The GA4GH Regulatory & Ethics Toolkit provides internationally applicable guidance, frameworks and practical resources to support the responsible governance, ethical oversight and sharing of genomic and health-related data in research. The toolkit addresses key aspects of trial management, including consent, data access, privacy, governance and responsible data sharing. It is particularly relevant for rare disease clinical trials, where genomic information, international collaboration and secondary use of research data are often essential for improving diagnosis, developing therapies and enabling efficient multicentre studies. Although focused on genomics, the principles and resources are broadly applicable to paediatric and rare disease clinical research.

This guideline provides a harmonised framework for using extrapolation to support paediatric drug development when existing evidence from adults or other paediatric populations can be scientifically justified. During protocol development, it helps researchers determine the extent of new clinical data required, identify evidence gaps, and plan efficient study designs using approaches such as modelling and simulation, pharmacokinetic/pharmacodynamic data, and targeted evidence generation. The guideline is particularly relevant for rare diseases, where limited patient populations require innovative and scientifically robust strategies to minimise unnecessary studies while ensuring reliable evidence of safety and efficacy.

This PedCRIN guidance provides practical recommendations for obtaining informed consent in neonatal clinical trials. It addresses specific challenges related to parental decision-making, communication of study information, timing of consent discussions, and ethical considerations when enrolling newborns into research. Although developed for neonatal studies, the principles are highly relevant to paediatric and rare disease clinical trials, where families may face complex decisions, limited treatment options and emotionally challenging circumstances requiring carefully designed consent processes.

This guidance supports protocol development for paediatric clinical trials by providing recommendations on trial preparedness before study initiation. It highlights key aspects of study design, feasibility assessment, patient recruitment, endpoint selection, participant burden, operational planning, and stakeholder engagement. The recommendations are particularly relevant for rare disease trials, where early planning, collaboration with patient organisations, and consideration of small patient populations are essential to ensure feasible, efficient and patient-centred study protocols.

This Enpr-EMA guidance provides practical recommendations for developing informed consent and assent processes in paediatric clinical trials. It supports researchers and sponsors in preparing age-appropriate information and consent materials for children, adolescents and their parents or legal representatives, considering the specific needs of different paediatric age groups. Developed within the European paediatric research framework, the guidance is particularly relevant to rare disease clinical trials, where many conditions have a childhood onset and meaningful involvement of children and families is essential for ethical and successful study conduct.

This guideline provides recommendations for designing clinical studies involving children and is particularly relevant for rare diseases with paediatric onset. It supports protocol development by addressing key considerations such as age-appropriate study design, selection of endpoints, dose selection, ethical aspects, safety monitoring, formulation, and the use of extrapolation and modelling where appropriate. The guideline also promotes strategies to minimise the burden on children and their families while ensuring the generation of robust evidence. It is a valuable resource for researchers developing paediatric rare disease clinical trial protocols in line with international regulatory expectations.

This European Commission guidance provides recommendations on the ethical aspects of conducting clinical trials involving children and adolescents. It addresses key considerations for protocol development and trial conduct, including risk–benefit assessment, informed consent from parents or legal representatives, child assent, age-appropriate information, protection of vulnerable participants and involvement of minors in research decisions. Although developed within the European regulatory framework, the principles are broadly applicable to paediatric and rare disease clinical trials, where ethical considerations, family involvement and participant-centred approaches are essential for successful study implementation.

The SPIRIT‑Outcomes 2022 extension to the SPIRIT 2013 statement is an international, evidence‑ and consensus‑based guideline that specifies 9 outcome‑specific items to be addressed in all clinical trial protocols. Developed within the InsPECT project using the EQUATOR framework, it supplements the SPIRIT 2013 checklist with minimum essential standards for defining, justifying, measuring, and analyzing trial outcomes. Applying SPIRIT‑Outcomes can enhance trial utility, reproducibility, and transparency and may help reduce selective nonreporting of trial results, making it particularly valuable for investigator‑initiated clinical studies.

The COSMIN database of systematic reviews of outcome measurement instruments is an online, searchable collection of systematic reviews that evaluate the quality of health‑related outcome measures in humans. It is developed by the international COSMIN (COnsensus‑based Standards for the selection of health Measurement INstruments) initiative to support research and clinical practice. The database helps investigators identify existing systematic reviews on patient‑reported outcomes and other measurement instruments, see which tools have evidence on reliability, validity and responsiveness, and spot gaps in the evidence. This makes it a useful starting point when selecting and justifying outcome measurement instruments in investigator‑initiated clinical studies.

This PedCRIN guidance provides practical recommendations for planning participant enrolment during the development of neonatal clinical trial protocols. It addresses key factors that influence successful recruitment, including enrolment pathways, communication with parents and families, informed consent, site preparation and investigator engagement. Although developed for neonatal trials, the guidance addresses recruitment challenges that are common across paediatric and rare disease clinical research, where small patient populations and complex study procedures require careful planning to optimise enrolment and study feasibility.

PANDA (Practical Adaptive & Novel Designs and Analysis toolkit) is an open‑access, online educational resource developed by the University of Sheffield and collaborators to support researchers in using adaptive designs, their practical application, potential benefits and limitations. Aimed at trialists across disciplines, it explains when and how to use key adaptive approaches—sample size re‑estimation, group sequential, multi‑arm multi‑stage, adaptive population enrichment and response adaptive randomisation—and outlines their practical, statistical and operational implications. It is particularly relevant for statisticians, clinicians, trial managers, data managers and grant developers working on complex or innovative trial designs.

Trials@Home is a public–private partnership funded by the Innovative Medicines Initiative that has developed recommendations for decentralised clinical trial approachesl.The consortium explored how to move trial activities from traditional sites to the participant’s immediate surroundings using digital and operational innovations. Investigator‑initiated studies can use these recommendations to design, implement and evaluate decentralised or hybrid trials, improve participant accessibility and retention, and ensure appropriate oversight, data protection and site support. Its main and in‑depth recommendations cover methodological, regulatory, ethical, operational and social aspects of decentralised clinical trials.

The SPIRIT‑Outcomes 2022 extension to the SPIRIT 2013 statement is an international, evidence‑ and consensus‑based guideline that specifies 9 outcome‑specific items to be addressed in all clinical trial protocols. Together, these two guidelines create a clear reporting continuum from the trial protocol to the final trial report, helping researchers prepare protocols and reports more consistently and making it easier to assess adherence to the planned protocol. It supplements the SPIRIT 2013 checklist with minimum essential standards for defining, justifying, measuring, and analyzing trial outcomes. Applying SPIRIT‑Outcomes can enhance trial utility, reproducibility, and transparency and may help reduce selective nonreporting of trial results.

This recommendation paper provides harmonised guidance on introducing decentralised elements into clinical trials with investigational medicinal products in the EU/EEA, beyond any specific health‑crisis context. Developed under the Accelerating Clinical Trials in Europe (ACT EU) initiative by the Heads of Medicines Agencies Clinical Trials Coordination Group (HMA CTCG), the European Commission Clinical Trial Expert Group (CTEG) and the European Medicines Agency Good Clinical Practice Inspectors Working Group (EMA GCP IWG), it reflects the common view of the European medicines regulatory network but is not legally binding. The document includes investigator oversight, informed consent (including electronic methods), delivery and home administration of investigational medicinal products, trial‑related procedures at home, data collection and management, and trial monitoring in decentralised settings, supported by an appendix with an overview of national provisions per EU Member State. Investigator‑initiated and academically sponsored trials can use this paper to plan and document risk‑proportionate decentralised or hybrid designs while protecting participants and ensuring robust data.

Hosted by the Global Health Trials Knowledge Hub (TGHN), this open-access library provides over 100 ready-to-use templates and tools spanning the full clinical trial lifecycle. Categories cover protocol development, participant enrolment and retention, informed consent, IMP management, data management, site management, ethics, safety reporting, staff management, and quality assurance. Designed primarily for trials in global health settings, templates are directly adaptable for investigator-led studies.

This ICH guideline (2017) outlines principles for planning multi-regional clinical trials (MRCTs) to support global regulatory acceptance by evaluating treatment effects and safety across populations. It provides a framework for designing trials that generate evidence acceptable to multiple regulators and facilitate efficient global drug development, including single multinational trials for rare diseases.

The COMET (Core Outcome Measures in Effectiveness Trials) Initiative brings together people interested in developing and applying agreed standardised sets of outcomes, known as core outcome sets (COS). These represent the minimum that should be measured and reported in all clinical trials of a specific condition, and can also be used in routine care, clinical audit and other types of research. COMET provides an international hub and searchable database of COS‑related studies, along with methodological resources to support their development and use in clinical research.

The INCLUDE Project Guidance provides practical recommendations and resources to help researchers design and conduct more inclusive clinical studies by identifying and addressing barriers to participation for under-served populations. Developed by the UK National Institute for Health and Care Research (NIHR), the guidance covers recruitment strategies, participant communication, informed consent, study design and operational considerations that support equitable access to research. Although developed within the UK research context, its principles are broadly applicable to international clinical research and are particularly relevant to rare disease trials, where small, geographically dispersed populations and barriers to participation can significantly affect recruitment, retention and study representativeness.

The Enpr-EMA Network Database is a searchable directory of paediatric research networks and centres recognised by the European Medicines Agency for their expertise in conducting clinical studies in children. It enables researchers and sponsors to identify potential collaborators, specialised trial sites and research infrastructures based on therapeutic expertise, research experience, quality management and geographical coverage. Although developed for paediatric clinical research, the database is highly relevant to rare disease trials, as many rare diseases have a paediatric onset and require multinational collaboration between specialised centres. It provides a practical resource for identifying experienced partners to support the planning and management of multicentre rare disease clinical trials.

This guidance provides an overview of the scientific and regulatory support mechanisms available through the European Medicines Agency (EMA) and national competent authorities to assist medicine developers throughout the development process. It helps investigators identify the most appropriate regulatory interactions during protocol development, including innovation meetings, scientific advice, protocol assistance and qualification procedures. The resource is particularly relevant for rare disease clinical trials, where early regulatory engagement can support innovative study designs, small population methodologies and efficient protocol development.

This EMA guidance (2025) explains to users, in the form of FAQs how to request EMA scientific advice and protocol assistance, outlining the procedures, scope, and nature of these services so that applications can be prepared, validated, and evaluated efficiently. Applicants are guided through the different steps of the procedure and receive useful information on how to prepare a possible discussion meeting with the Scientific Advice Working Party (SAWP).

This PedCRIN guidance provides practical recommendations for assessing the feasibility of neonatal clinical trials and selecting appropriate investigator sites and study centres. It outlines key considerations for evaluating study feasibility, site capabilities, patient availability, infrastructure, clinical expertise and local operational requirements before trial initiation. Although developed for neonatal studies, the principles are broadly applicable to paediatric and rare disease clinical trials, where successful study delivery often depends on identifying specialised centres with the expertise, patient population and research capacity needed to conduct complex multicentre studies.

This publication provides practical recommendations for designing and analysing clinical trials in small populations, with a particular focus on rare diseases. It supports protocol development by addressing study design, endpoint selection, statistical methodology, randomisation, adaptive and Bayesian approaches, use of external information, and strategies to maximise the value of limited patient data. The recommendations encourage efficient, scientifically robust and patient-centred trial designs that improve the quality and interpretability of evidence while acknowledging the challenges of recruiting small populations.

This guideline provides methodological recommendations for designing clinical trials when patient populations are limited, making it particularly relevant for rare disease research. It supports protocol development by addressing study design, statistical considerations, sample size justification, choice of control groups, endpoint selection, randomisation, and the use of external data or surrogate endpoints where appropriate. The guideline encourages researchers to justify methodological decisions prospectively and to consider innovative approaches that maximise the scientific value of limited data while ensuring reliable and interpretable evidence for regulatory decision-making.

The Portico Center Toolkit Modules provide practical resources, templates and training materials to support the management and conduct of clinical trials. Developed within the context of paediatric musculoskeletal disease research, the toolkit covers key operational aspects such as participant recruitment and retention, informed consent, participant engagement, health literacy, diversity and inclusion, and decentralized trial approaches. Although developed for paediatric musculoskeletal research, the tools address common operational challenges encountered across paediatric and rare disease clinical trials and can be readily applied to support participant-centred and efficient trial conduct in a wide range of rare disease settings.

The SPIRIT-C Extension provides additional protocol development recommendations for randomised clinical trials involving children and adolescents. It complements the general SPIRIT guidance by addressing paediatric-specific considerations, including age-appropriate interventions, outcome selection, safety monitoring, participant burden and involvement of young people and caregivers. The tool is particularly relevant for paediatric rare disease trials, where limited populations, developmental differences and challenges in selecting meaningful outcomes require carefully adapted protocol approaches.

SPIRIT and SPIRIT extensions are internationally endorsed reporting guidelines for clinical trials that support protocol development and trial reporting across the full research lifecycle. CONSORT 2025 provides a 30-item checklist for reporting randomized trial results, including title and abstract, trial registration, protocol and statistical analysis plan, participant flow, recruitment, harms, outcomes, interpretation, limitations, and other open science elements.  

The website hosts two online tools: SEPTRE and COBWEB:

• SEPTRE: the SPIRIT Electronic Protocol Tool & Resource, is an online trial protocol writing and management tool that helps users create, register, and manage protocols in line with SPIRIT guidance.
• COBWEB: the CONSORT-based WEB tool, is an online manuscript writing aid that guides authors through structured templates to write, edit, share, and export randomised trial reports in line with CONSORT and its extensions.

The UKTMN Guide to Efficient Trial Management is a practitioner‑written reference for those involved in managing non‑commercial, academically initiated clinical trials in the UK. Hosted by the Nottingham Clinical Trials Unit, University of Nottingham, and overseen by the UK Trial Managers’ Network Editorial Board, it describes the process of understanding and managing randomised trials and outlines the trial management framework, both legal and operational, providing pragmatic advice, hints, tips and links to external resources. It is written primarily for new trial managers as an essential reference tool, and also serves as an aide‑mémoire and induction resource for more experienced staff. Although some elements are specific to the UK national infrastructure, many sections on trial planning and development are also relevant to European researchers conducting investigator‑initiated studies.

Developed by the Good Clinical Trials Collaborative (GCTC), this guidance sets out the underpinning principles of good randomised controlled trials (RCT): reliably informative, ethical, and efficient. It  is organised around five guiding principles with detailed sub‑principles that cover design, conduct, oversight, and reporting. The guidance is accompanied by a structured evaluation tool to help users reflect on how well their trials align with these principles in their specific context. An online learning course further explores the fundamental principles of what makes a good trial and supports all those involved in planning, conducting, regulating, funding, or using the results of randomised trials to apply the guidance in practice.

Developed by the ICH Expert Working Group, the ICH E8 (R1) Guideline is an internationally recognized guidance document from the  that defines core principles and general considerations for designing and conducting clinical studies, including exploratory and confirmatory trials. It provides a broad framework for trial planning, quality‑by‑design, risk‑based approaches, ethical considerations, statistical thinking, and meaningful interpretation of study outcomes.

This three‑hour programme familiarises investigators and site teams with the specific challenges of initiating and managing multinational rare‑disease trials. It is solution‑oriented, addressing common barriers such as differing national implementations of European clinical research Regulations and ethical requirements.

This ECRIN-developed ERDERA training course provides practical guidance on planning and managing multinational clinical trials in rare diseases. The course addresses key operational challenges, including trial preparation, stakeholder roles and responsibilities, regulatory and ethical considerations, budget planning and coordination across participating countries. Designed specifically for rare disease clinical research teams, it supports investigators, study coordinators and project managers in improving the feasibility and successful implementation of multinational trials involving small and geographically dispersed patient populations.