title: Systematic reviews in paediatric multiple sclerosis and Creutzfeldt-Jakob disease exemplify shortcomings in methods used to evaluate therapies in rare conditions.
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.
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, 37073, Göttingen, Germany. steffen.unkel@med.uni-goettingen.de.
authors.forename: Steffen
authors.initials: S
authors.lastname: Unkel
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, 37073, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Röver
authors.affiliation: Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Stallard
authors.affiliation: Biostatistics and Special Pharmacokinetics Unit, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Benda
authors.affiliation: Section of Medical Statistics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Posch
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Service 1138, Team 22, Centre de Recherche des Cordeliers, Université Paris 5 et Université Paris 6, Paris, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Zohar
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Humboldtallee 32, 37073, Göttingen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Friede
mesh_terms: D007562:Creutzfeldt-Jakob Syndrome / Q000175:diagnosis* / Q000188:drug therapy*; D006801:Humans; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic