Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative (Bogaerts et al., 2015)

Bogaerts J, Sydes MR, Keat N, et al - Bogaerts J, Sydes MR, Keat N, McConnell A, Benson A, Ho A, Roth A, Fortpied C, Eng C, Peckitt C, Coens C, Pettaway C, Arnold D, Hall E, Marshall E, Sclafani F, Hatcher H, Earl H, Ray-Coquard I, Paul J, Blay JY, Whelan J, Panageas K, Wheatley K, Harrington - 2015
  • Research question
  • Develop a protocol
  • Foundational design
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doi: 10.1016/j.ejca.2014.10.027

Experimental Designs for Small Randomised Clinical Trials

This publication reviews methodological approaches for designing randomised clinical trials in small populations and provides practical guidance on selecting trial designs that are appropriate for rare diseases. Recognising that conventional parallel-group randomised controlled trials are often difficult or impossible to conduct because of limited patient numbers, the paper discusses alternative experimental designs that can improve study efficiency while maintaining scientific validity. It is a valuable resource for researchers developing rare disease clinical trial protocols and complements existing regulatory and methodological guidance on studies in small populations.

The publication supports protocol development by describing the advantages, limitations and appropriate use of a range of study designs, including parallel-group, crossover, randomised withdrawal, delayed-start, factorial, adaptive, sequential and n-of-1 trials. It discusses the methodological considerations that influence design selection, such as disease characteristics, treatment effects, outcome variability, patient heterogeneity, ethical considerations, and recruitment constraints. The paper also highlights the importance of careful statistical planning, bias minimisation and prospective justification of design choices to ensure that evidence generated from small populations is robust and interpretable.

For researchers designing rare disease clinical trials, this resource provides practical support for selecting innovative and efficient study designs that maximise the information obtained from limited patient populations. It encourages early collaboration with statisticians and clinical experts to develop protocols that are scientifically rigorous, operationally feasible and capable of generating reliable evidence for clinical and regulatory decision-making.

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