Rare diseases clinical trials toolbox - public resources and main considerations to set up a clinical trial on medicinal products for humans in Europe

Abstract

Aim: Drug development programs in rare diseases face many challenges, such as the scarcity and geographic dispersion of patients, limited natural history data, the need for novel study designs, and sensitive outcome measures.

Over the past years, tools supporting clinical research have been developed in the context of different projects and for diverse purposes. Therefore, they have not yet been structured to encompass the conduct of rare disease (RD) clinical trials as a whole. To address this issue, the European Joint Program for Rare Diseases (EJP RD) has developed the Rare Diseases Clinical Trial Toolbox. This toolbox collates the accumulated knowledge (collectively termed “tools”) generated by projects/organizations into a structured and guided instrument. By structuring and making resources discoverable, we aim to help RD clinical trialists and trial managers.

Methods: We have designed and developed a toolbox structured around the definition of the clinical trial pathway. It is organized into five domains. Each domain describes one or several activities to be considered throughout the clinical trial pathway. Selection criteria were then defined to include existing resources that are relevant to those activities. Rare disease-specific resources are highlighted as such and include those especially relevant to pediatric clinical research.

Results: The current version of the Toolbox includes 121 resources tagged as relevant to any of the 18 activities within the clinical trial pathway. Overall, 60% of all resources are relevant to any clinical trial while 40% are tagged as “rare disease-specific”.

Conclusion: Access to public resources relevant to the development of clinical trials for rare diseases is sometimes challenged by limited awareness and/or the absence of an adequate framework that enables their findability. This Toolbox aims to build a framework supporting the optimal use of existing tools.

Keywords

Rare diseases / clinical trial / pediatric / toolbox / resources / academic-sponsored / investigator-initiated

References

[1] Rath A,Peixoto S.A systematic literature review of evidence-based clinical practice for rare diseases: what are the perceived and real barriers for improving the evidence and how can they be overcome?.Trials2017;18:556 PMCID:PMC5700662

[2] Griggs RC,Dunkle M.Rare Diseases Clinical Research NetworkClinical research for rare disease: opportunities, challenges, and solutions.Mol Genet Metab2009;96:20-6 PMCID:PMC3134795

[3] Morel T.Measuring what matters to rare disease patients - reflections on the work by the IRDiRC taskforce on patient-centered outcome measures.Orphanet J Rare Dis2017;12:171 PMCID:PMC5667521

[4] Del Álamo M,Fisher D.Identifying obstacles hindering the conduct of academic-sponsored trials for drug repurposing on rare-diseases: an analysis of six use cases.Trials2022;23:783 PMCID:PMC9479412

[5] den Berg S, de Visser S, Leufkens HGM, Hollak CEM. Drug repurposing for rare diseases: a role for academia.Front Pharmacol2021;12:746987 PMCID:PMC8564285

[6] Del Álamo M,Nieto C.Funding multinational investigator-initiated clinical studies in Europe: why and how?.Trials2024;25:689 PMCID:PMC11487848

[7] Djurisic S,Gaber S.Barriers to the conduct of randomised clinical trials within all disease areas.Trials2017;18:360 PMCID:PMC5539637

[8] Rare diseases clinical trials toolkit. Available from: https://ecrin.org/rare-diseases-clinical-trials-toolbox. [Last accessed on 20 Mar 2025]

[9] The European Parlament and the European Union. Regulation (EU) No 536/2014 OF the european parliament and of the council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing directive 2001/20/EC. Published online 2014. Available from: https://health.ec.europa.eu/medicinal-products/clinical-trials/clinical-trials-regulation-eu-no-5362014_en. [Last accessed on 21 Mar 2025]

[10] EU CORDIS. Available from: https://cordis.europa.eu/. [Last accessed on 20 Mar 2025]

[11] IRDiRC recognized resources. Available from: https://irdirc.org/resources-2/irdirc-recognized-resources/. [Last accessed on 20 Mar 2025]

[12] ECRIN Rare Diseases Toolbox Full List of Tools. Available from: https://ecrin.org/sites/default/files/Ecrin/pdf/Toolkit_November_2024.pdf. [Last accessed on 20 Mar 2025]

[13] ECRIN rare diseases toolbox instructional video. Available from: https://www.youtube.com/watch?v=_f8y3WUFGTA. [Last accessed on 20 Mar 2025]

[14] Hechtelt Jonker A,Gabaldo M.Boosting delivery of rare disease therapies: the IRDiRC orphan drug development guidebook.Nat Rev Drug Discov2020;19:495-6

[15] NIA NIH clinical research study investigator’s toolbox. Available from: https://www.nia.nih.gov/research/grants-funding/ocr/clinical-research-study-investigators-toolbox. [Last accessed on 20 Mar 2025]

[16] NIHR clinical trials toolkit. Available from: https://www.ct-toolkit.ac.uk/. [Last accessed on 20 Mar 2025]

[17] Malaria clinical trials toolkit. Available from: https://www.iddo.org/wwarn/tools-resources/malaria-clinical-trials-toolkit. [Last accessed on 20 Mar 2025]

[18] ICH harmonised guideline. General considerations for clinical studies E8 (R1). 2021. Available from: https://database.ich.org/sites/default/files/E8-R1_Guideline_Step4_2021_1006.pdf. [Last accessed on 20 Mar 2025]

[19] Chan AW,Gøtzsche PC.SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials.BMJ2013;346:e7586 PMCID:PMC3541470

[20] Chan AW,Altman DG.SPIRIT 2013 statement: defining standard protocol items for clinical trials.Ann Intern Med2013;158:200-7 PMCID:PMC5114123

[21] Day S,Lau LPL.Recommendations for the design of small population clinical trials.Orphanet J Rare Dis2018;13:195 PMCID:PMC6219020

[22] Hilgers RD,Burman CF.Lessons learned from IDeAl-33 recommendations from the IDeAl-net about design and analysis of small population clinical trials.Orphanet J Rare Dis2018;13:77

[23] Mitroiu M,Pontes C.Applicability and added value of novel methods to improve drug development in rare diseases.Orphanet J Rare Dis2018;13:200 PMCID:PMC6233569

[24] Friede T,Zohar S.Recent advances in methodology for clinical trials in small populations: the InSPiRe project.Orphanet J Rare Dis2018;13:186 PMCID:PMC6203217

[25] ERICA PROMs Repository. Available from: https://erica-rd.eu/work-packages/patient-centred-research/proms-repository/. [Last accessed on 20 Mar 2025]

[26] ERA4Health partnership. Available from: https://era4health.eu/. [Last accessed on 20 Mar 2025]

[27] NIRO. Navigating innovation and research opportunities. Available from: https://niroglobal.com/. [Last accessed on 20 Mar 2025]

[28] Scientify research. Available from: https://www.scientifyresearch.org/. [Last accessed on 20 Mar 2025]

[29] ACT EU. Accelerating clinical trials in the EU. Available from: https://accelerating-clinical-trials.europa.eu/index_en. [Last accessed on 20 Mar 2025]