1. Nov 30, 2020

Broad methodological approaches needed for rare disease randomized controlled trials

Due to the small patient populations found in rare diseases, researching these disease states can be difficult. Although it is feasible to complete randomized controlled trials (RCTs) in rare diseases, a more varied methodological approach is needed, including the use of adaptive trials, cross-over trials, and early escape designs, according to a new study.

Researchers conducted a review of available methodological approaches and found 3 algorithms for matching study design to rare disease or intervention characteristics.

Methodological and analytic approaches were summarized.

The researchers suggested that “an effective research infrastructure can set an agenda, prioritize studies, accelerate accrual, catalyze patient engagement, and terminate poorly performing studies.”

In the Patient-Centered Outcomes Research Institute, there were 24 rare disease projects, 11 of which were RCTs using standard designs and 13 observational studies using case-control, prospective cohort, or natural history designs. There are 9 Patient-Powered Research Networks (PPRNs) focused on rare diseases supported by the Patient-Centered Outcomes Research Institute.


Whicher D, Philbin S, Aronson N. An overview of the impact of rare disease characteristics on research methodology. Orphanet J Rare Dis. 2018;19;13(1):14. DOI: 10.1186/s13023-017-0755-5. PMID: 29351763; PMCID: PMC5775563.