Unkel, Steffen, Röver, Christian, Stallard, Nigel, Benda, Norbert, Posch, Martin, Zohar, Sarah and Friede, Tim (2016) Systematic reviews in paediatric multiple sclerosis and Creutzfeldt-Jakob disease exemplify shortcomings in methods used to evaluate therapies in rare conditions. Orphanet Journal of Rare Diseases, 11 (1). 16. doi:10.1186/s13023-016-0402-6 ISSN 1750-1172.

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Abstract

Background
Randomized controlled trials (RCTs) are the gold standard design of clinical research to assess interventions. However, RCTs cannot always be applied for practical or ethical reasons. To investigate the current practices in rare diseases, we review evaluations of therapeutic interventions in paediatric multiple sclerosis (MS) and Creutzfeldt-Jakob disease (CJD). In particular, we shed light on the endpoints used, the study designs implemented and the statistical methodologies applied.

Methods
We conducted literature searches to identify relevant primary studies. Data on study design, objectives, endpoints, patient characteristics, randomization and masking, type of intervention, control, withdrawals and statistical methodology were extracted from the selected studies. The risk of bias and the quality of the studies were assessed.

Results
Twelve (seven) primary studies on paediatric MS (CJD) were included in the qualitative synthesis. No double-blind, randomized placebo-controlled trial for evaluating interventions in paediatric MS has been published yet. Evidence from one open-label RCT is available. The observational studies are before-after studies or controlled studies. Three of the seven selected studies on CJD are RCTs, of which two received the maximum mark on the Oxford Quality Scale. Four trials are controlled observational studies.

Conclusions
Evidence from double-blind RCTs on the efficacy of treatments appears to be variable between rare diseases. With regard to paediatric conditions it remains to be seen what impact regulators will have through e.g., paediatric investigation plans. Overall, there is space for improvement by using innovative trial designs and data analysis techniques.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Statistics and Epidemiology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Rare diseases -- Research -- Statistical methods, Multiple sclerosis -- Research -- Statistical methods, Creutzfeldt-Jakob disease -- Research -- Statistical methods, Systematic reviews (Medical research)
Journal or Publication Title:	Orphanet Journal of Rare Diseases
Publisher:	BioMed Central Ltd.
ISSN:	1750-1172
Official Date:	20 February 2016
Dates:	Date Event 20 February 2016 Available 12 February 2016 Accepted 29 September 2015 Submitted
Volume:	11
Number:	1
Article Number:	16
DOI:	10.1186/s13023-016-0402-6
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	11 January 2017
Date of first compliant Open Access:	12 January 2017
Funder:	Seventh Framework Programme (European Commission) (FP7)
Grant number:	FP HEALTH 2013 – 602144 (FP7)

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