title: The ethics of cluster-randomized trials requires further evaluation: a refinement of the Ottawa Statement.
abstract: OBJECTIVE
  The Ottawa Statement is the first guidance document for the ethical and scientific conduct of cluster-randomized trials (CRTs). However, not all recommendations are straightforward to implement. In this paper we will reflect in particular on the recommendation on identifying human research subjects and the issue to what extent the randomization process should be disclosed if there is a risk of contamination.
  
  
  METHODS
  The Ottawa Statement was thoroughly evaluated within a multidisciplinary research team, consisting amongst others of epidemiologists and ethicists.
  
  
  RESULTS
  Patients in a CRT may also be considered as research subjects if they are indirectly affected by the studied interventions in a CRT. Second, health care workers are research subjects in CRTs but have a different moral status compared with ordinary research participants. This different status has implications for withdrawal and the choice of the primary objective. Third, modified informed consent for CRTs may be obtained when researchers can demonstrate that disclosure of the randomization process would affect the validity of a CRT.
  
  
  CONCLUSIONS
  Recommendations of the Ottawa Statement on identifying the research subject and providing informed consent can and should be refined.
authors.affiliation: Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, PO Box 85500, Utrecht 3508 GA, The Netherlands. Electronic address: r.vandergraaf@umcutrecht.nl.
authors.forename: Rieke
authors.initials: R
authors.lastname: van der Graaf
authors.affiliation: Department of Health Technology Assessment, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Koffijberg
authors.affiliation: Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Diederick E
authors.initials: DE
authors.lastname: Grobbee
authors.affiliation: Department of Biostatistics and Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: de Hoop
authors.affiliation: Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Karel G M
authors.initials: KG
authors.lastname: Moons
authors.affiliation: Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Ghislaine J M W
authors.initials: GJ
authors.lastname: van Thiel
authors.affiliation: Department of Health Technology Assessment, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: G Ardine
authors.initials: GA
authors.lastname: de Wit
authors.affiliation: Department of Medical Humanities, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Johannes J M
authors.initials: JJ
authors.lastname: van Delden
mesh_terms: D032984:Ethics, Research; D020793:Gatekeeping / Q000941:ethics; D006801:Humans; D007258:Informed Consent / Q000941:ethics*; D018579:Patient Selection / Q000941:ethics; D016032:Randomized Controlled Trials as Topic / Q000941:ethics*; D012107:Research Design / Q000592:standards; D035842:Research Subjects
keywords: Cluster-randomized trials; Disclosure of randomization; Informed consent; Modified informed consent; Research ethics; Research participants