This is a systematic rapid review published in Wellcome Open Research (2023; 8:194). It analyses evidence on community engagement and informed consent in adaptive platform and alternative design trials conducted during public health emergencies (PHEs) such as Ebola and COVID-19. The review includes 49 publications and guidance documents, highlighting key ethical and communication challenges in explaining complex trial designs under emergency conditions.

The Cochrane Central Register of Controlled Trials (CENTRAL) is a database within the Cochrane Library that provides a highly concentrated source of reports of randomized and quasi‑randomized controlled trials. It contains bibliographic records with citation details and usually an abstract, but not the full text, and is updated monthly. Records are drawn from multiple sources, including PubMed/MEDLINE, Embase, CINAHL, ClinicalTrials.gov, WHO trial registries and Cochrane Review Groups’ specialized registers, and are included regardless of language or publication year. CENTRAL is developed and maintained by Cochrane and is particularly useful for investigators who need to identify controlled trials for inclusion in systematic reviews and evidence syntheses to inform clinical studies.

This guideline extends the SPIRIT recommendations for clinical trial protocols to N-of-1 trials by providing a checklist of protocol items specific to individualised crossover studies. It supports protocol development by addressing trial objectives, treatment sequencing, randomisation, blinding, outcome measurement, statistical analysis, and reporting considerations unique to N-of-1 designs. The guideline is particularly relevant for rare diseases in which conventional randomised controlled trials are not feasible and individualised evidence generation may provide a rigorous alternative for evaluating treatment effects.

EUPATIConnect is a fee‑for‑service matchmaking platform that connects trained EUPATI Patient Experts with researchers for meaningful patient involvement in medicines research and development. Researchers submit a request describing their project and needs and are matched to patient experts whose profiles, experience and disease areas fit the aims of the collaboration. Engagement can include protocol and document review, advisory boards, focus groups, speaking engagements, co‑creation workshops and other patient engagement activities. The platform is operated by EUPATI, the European Patients’ Academy on Therapeutic Innovation, which coordinates a large network of trained patient experts and national platforms.

European YPAG Network (eYPAGnet) provides expertise and support for meaningful Patient and Public Involvement and Engagement (PPIE) with children, young people and families in paediatric clinical research. Through Young Persons Advisory Groups (YPAGs), it supports protocol development by enabling young patients and families to contribute to study design, patient priorities, endpoints, recruitment strategies and patient-facing materials. The resource helps researchers develop more relevant, feasible and age-appropriate clinical trials by integrating the perspectives and experiences of children and young people affected by health conditions.

The ECRIN Paediatric Tools – Outcomes provide practical guidance for planning efficacy and safety outcome assessment in paediatric and neonatal clinical trials. The collection supports protocol development by offering recommendations and examples for selecting short- and long-term outcomes, defining data items and planning outcome measurement throughout the study. These tools help researchers develop clinically meaningful, feasible and standardised outcome assessment strategies that are adapted to paediatric populations and particularly relevant for rare disease clinical trials.

This guidance provides practical recommendations for incorporating pharmacovigilance and risk management into neonatal clinical trial protocols. It supports protocol development by outlining key considerations for planning safety monitoring, adverse event collection and reporting, risk identification, and safety oversight in neonatal studies. The tool helps researchers address the specific safety challenges of neonatal clinical trials and develop protocols that support effective pharmacovigilance while meeting regulatory and ethical expectations.

This document is a mapping and forward-looking overview of all scientific/regulatory advice mechanisms in the EU medicines system, with a strong focus on coordination, early engagement, and support for better clinical development. The document is essentially a framework overview. It explains what advice exists, how to access it and how the system is evolving.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) can issue qualification opinions or qualification advice on novel methodologies used in medicine development, such as biomarkers, imaging methods and digital tools, within a defined context of use in non‑clinical or clinical studies. 

The Protocol Development Toolkit, part of the EDCTP Knowledge Hub, is an online resource developed by the European & Developing Countries Clinical Trials Partnership (EDCTP) and The Global Health Network to support high‑quality health research protocols, particularly for clinical studies in low‑resource settings. It combines step‑by‑step guidance on protocol development with examples, templates and interactive tools, including the Concept Protocol Crowd Review Tool, the SEPTRE electronic protocol builder and the Study Walk‑through toolkit. Linked training materials cover scientific, ethical, regulatory, operational and data‑management aspects of study design, helping investigator‑initiated studies move from a research question to a complete, robust protocol.

The EURORDIS Community Advisory Board (CAB) Programme provides a structured framework for involving patient representatives and expert patients in clinical research and development. It supports protocol development by facilitating dialogue between patient communities and research sponsors on topics such as unmet needs, trial design, feasibility, outcome selection, recruitment strategies and participant burden. The programme helps researchers integrate patient perspectives early in the clinical trial planning process, supporting the development of more relevant, acceptable and patient-centred rare disease clinical trials.

The Patient Engagement Toolbox, developed under the IMI‑PARADIGM (Innovative Medicines Initiative – Patients Active in Research and Dialogues for an Improved Generation of Medicines) project, centralises co‑created recommendations, practical tools and background materials to make patient engagement in medicines development easier, more consistent and more impactful. The toolbox is organised around three key phases of patient engagement: planning, conduct, reporting and evaluation. 

This guide supports the meaningful involvement of patients, caregivers and patient organisations during protocol development. It provides practical recommendations for establishing effective patient partnerships, including identifying appropriate partners, defining roles and expectations, planning communication, and recognising contributions. The guide also highlights how patient input can improve the relevance, feasibility and participant-centredness of a clinical trial by informing the research question, study procedures, outcome selection, recruitment strategies and participant-facing materials. It is a useful resource for researchers seeking to embed patient perspectives from the earliest stages of trial design.
 

This publication provides practical recommendations for incorporating health-related quality of life (HRQoL) and patient-reported outcomes (PROs) into rare disease research. It supports protocol development by discussing the selection of appropriate outcome measures, instrument validity, patient relevance, data collection strategies, and interpretation of HRQoL data in small and heterogeneous patient populations. The resource helps researchers identify meaningful patient-centred endpoints and select fit-for-purpose PRO instruments that strengthen the clinical relevance and quality of rare disease clinical trials.

This review provides guidance on the use of patient-reported outcome measures (PROMs) in rare disease research and clinical trials. It supports protocol development by addressing the selection, development and evaluation of PROMs, including considerations of validity, reliability, responsiveness, feasibility and relevance to patients. The resource helps researchers identify meaningful patient-centred endpoints and incorporate appropriate outcome measures into rare disease clinical trial protocols, particularly when disease heterogeneity and small populations create challenges for outcome assessment.

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.

The ERICA PROMs Repository provides a centralised resource to identify patient-reported outcome measures (PROMs), observer-reported outcome measures (ObsROs) and other patient-centred clinical outcome assessment tools relevant to rare diseases. It supports protocol development by helping researchers select appropriate outcome measures based on disease area, patient population, age group and assessment type. The repository facilitates the integration of meaningful patient-centred endpoints into rare disease clinical trials and promotes the use of standardised, fit-for-purpose outcome measurement instruments.

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 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 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 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.

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.

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.

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 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.

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 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 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.

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.