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Orphanet J Rare Dis. 2018 Nov 6;13(1):195. doi: 10.1186/s13023-018-0931-2.

Recommendations for the design of small population clinical trials.

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Clinical Trials Consulting & Training Limited, 53 Portway, North Marston, Buckingham, Buckinghamshire, MK18 3PL, UK.
IRDiRC Scientific Secretariat, Inserm US-14, Paris, France.
Department of Medical Statistics, RWTH Aachen University, Aachen, Germany.
Center for Biologics Evaluation and Research/ Office of Tissues and Advanced Therapies, US Food and Drug Administration, Silver Spring, USA.
Orphan Medicines, European Medicines Agency, London, UK.
Julius Center for Health Sciences and Primary Care, UMC Utrecht, Utrecht, The Netherlands.
Statistics and Epidemiology, Warwick Medical School, University of Warwick, Coventry, UK.



Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases.


The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients' engagement in study design.


Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy's safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered.


Clinical trials; IRDiRC; Patient engagement; Rare diseases; Recommendations; Small population studies; Small populations; Statistical methods

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