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Table 1 Main barriers to the conduct of randomised clinical trials (RCTs) on rare diseases

From: 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?

Special barriers to RCTs on rare diseases Comments
Difficult to recruit patients due to rarity Improve patient identification through appropriate codification. Develop registries. Establish rare disease research cohorts. Improve collaboration among clinical centres. Rely on clinical research networks. And develop multinational controlled trials
Incomplete understanding of natural history to inform trial design Develop clinical research infrastructure preparatory to clinical trials. Develop registries
Need for trial designs adapted to the small population size and clinical heterogeneity In-depth knowledge of trial methodology, including design of n-of-1 trials as well as other methods designed for clinical research into rare diseases. Develop innovative, controlled study designs adapted to small population sizes and clinical heterogeneity that are acceptable by regulatory bodies. Develop clinical research infrastructure preparatory to clinical trials. Providing methodological support
Organisational challenges as a consequence from the need for multinational randomised clinical trials Comply to Voluntary Harmonisation Procedures and to common EU regulation
Need for more sensitive outcome measures to quantify disease. Construct rare disease-specific clinical outcome measures
Need for involvement of all the stakeholders in the study design and conduct Involve patients as research partners to include patients’ views. Rely on European Reference Networks
  1. Barriers as identified by European Clinical Infrastructure Network (ECRIN)