Rare diseases are defined in the European Union as ones that affect fewer than one person in 2000. Although individually rare, there are more than 6000 rare diseases with more than half of them starting in childhood. As a result, there are approximately 3.5 million individuals with rare diseases in the UK. These rare diseases have significant impact on children and their families with more than 30% of children dying before the age of 5 years.1

Rare diseases in children generally lack focused development of new treatments. One of the important reasons behind this is the difficulty in doing clinical trials using traditional design: the number of patients available to recruit is often too limited to do well-powered randomised controlled trials (RCTs). Paediatric trials have significant complexities and very few patients/parents are keen on placebo controlled trials.2

With methodological developments in the past decade, there is now an array of alternative approaches that can be used to make clinical trials more efficient. Adaptive designs allow outcome data collected during the trial to make changes to the trial such that it is more efficient and patient-centric; master protocols allow combining of what would normally have been distinct trials into one, allowing more research questions to be answered with the same limited pool of patients; methods for using external data can be employed when it is impossible to do a traditional RCT.

In this viewpoint, we overview these approaches and discuss how they could transform rare paediatric disease research. All designs are overviewed in table 1.

Overview of innovative designs and their potential for rare diseases

Adaptive designs3 are a broad type of trial design that offer …