Efficient ways exist to obtain the optimal sample size in clinical trials in rare diseases.
OBJECTIVE
Recruitment of pediatric patients in randomized clinical trials is hampered by the rarity of many conditions and by ethical constraints. The objective of this paper is to give an overview of design options to obtain a statistically valid result while including a minimum number of subjects.


METHODS
Overview and discussion of several approaches to conduct valid randomized clinical trials in rare diseases and vulnerable populations.


RESULTS
Sequential designs have been developed as efficient ways to evaluate accumulating information from a clinical trial, thereby reducing the average size of trials. Different sequential procedures exist, including group sequential designs, boundaries designs, and adaptive designs. The sample size attained at the end of the trial is unknown at the start. The sample size for a given set of alpha, beta, and effect size may turn out to be larger than with a classical fixed sample size approach. Simulations have shown that on average, sample sizes are smaller.


CONCLUSIONS
There are several possibilities to optimize the number of subjects in a clinical trial. The rarity of many disorders in children and the ethical requirements in this patient population should not obstruct the performance of well-designed research to support clinical decision making.
van der Lee
J H
JH
Department of Pediatric Clinical Epidemiology, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. j.h.vanderlee@amc.uva.nl
Wesseling
J
J
Tanck
M W T
MW
Offringa
M
M
D002648:Child; D015340:Epidemiologic Research Design; D026690:Ethics, Clinical; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000941:ethics / Q000379:methods*; D035583:Rare Diseases; D018401:Sample Size