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

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