Does the low prevalence affect the sample size of interventional clinical trials of rare diseases An analysis of data from the aggregate analysis of clinicaltrials.govReport as inadecuate

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Orphanet Journal of Rare Diseases

, 12:44

First Online: 02 March 2017Received: 13 December 2016Accepted: 14 February 2017DOI: 10.1186-s13023-017-0597-1

Cite this article as: Hee, S.W., Willis, A., Tudur Smith, C. et al. Orphanet J Rare Dis 2017 12: 44. doi:10.1186-s13023-017-0597-1


BackgroundClinical trials are typically designed using the classical frequentist framework to constrain type I and II error rates. Sample sizes required in such designs typically range from hundreds to thousands of patients which can be challenging for rare diseases. It has been shown that rare disease trials have smaller sample sizes than non-rare disease trials. Indeed some orphan drugs were approved by the European Medicines Agency based on studies with as few as 12 patients. However, some studies supporting marketing authorisation included several hundred patients. In this work, we explore the relationship between disease prevalence and other factors and the size of interventional phase 2 and 3 rare disease trials conducted in the US and-or EU. We downloaded all clinical trials from Aggregate Analysis of AACT and identified rare disease trials by cross-referencing MeSH terms in AACT with the list from Orphadata. We examined the effects of prevalence and phase of study in a multiple linear regression model adjusting for other statistically significant trial characteristics.

ResultsOf 186941 trials only 1567 0.8% studied a single rare condition with prevalence information from Orphadata. There were 19 1.2% trials studying disease with prevalence <1-1,000,000, 126 8.0% trials with 1–9-1,000,000, 791 50.5% trials with 1–9-100,000 and 631 40.3% trials with 1–5-10,000. Of the 1567 trials, 1160 74% were phase 2 trials. The fitted mean sample size for the rarest disease prevalence <1-1,000,000 in phase 2 trials was the lowest mean, 15.7; 95% CI, 8.7–28.1 but were similar across all the other prevalence classes; mean, 26.2 16.1–42.6, 33.8 22.1–51.7 and 35.6 23.3–54.3 for prevalence 1–9-1,000,000, 1–9-100,000 and 1–5-10,000, respectively. Fitted mean size of phase 3 trials of rarer diseases, <1-1,000,000 19.2, 6.9–53.2 and 1–9-1,000,000 33.1, 18.6–58.9, were similar to those in phase 2 but were statistically significant lower than the slightly less rare diseases, 1–9-100,000 75.3, 48.2–117.6 and 1-5-10,000 77.7, 49.6–121.8, trials.

ConclusionsWe found that prevalence was associated with the size of phase 3 trials with trials of rarer diseases noticeably smaller than the less rare diseases trials where phase 3 rarer disease prevalence <1-100,000 trials were more similar in size to those for phase 2 but were larger than those for phase 2 in the less rare disease prevalence ≥1-100,000 trials.

KeywordsAggregate analysis of Orphadata Orphanet Prevalence Orphan disease Rare disease Sample size AbbreviationsAACTAggregate analysis of

CHMPCommittee for medicinal products for human use

CIConfidence interval

DMCData monitoring committee

EMAEuropean medicines agency

FDAFood and drug administration

ICD-1010 International classification of diseases

ICMJEInternational committee of medical journal editors

INSERMFrench National Institute of Health and Medical Research

IQRInterquartile range

MedDRaMedical dictionary for regulatory activities

MeSHMedical subject headings

NLMNational library of medicine

OMIMOnline mendelian inheritance in man

RCTRandomised controlled trial

UMLSUnited medical language system

Author: Siew Wan Hee - Adrian Willis - Catrin Tudur Smith - Simon Day - Frank Miller - Jason Madan - Martin Posch - Sarah Zohar -


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