title: Reducing bias in open-label trials where blinded outcome assessment is not feasible: strategies from two randomised trials.
abstract: BACKGROUND
  Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios.
  
  
  METHODS
  We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias.
  
  
  RESULTS
  TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination).TAPPS was an open-label trial whose primary outcome was whether the patient was referred for a pleural drainage procedure. Allowing a blinded assessor to decide whether to refer the patient for a procedure was not feasible as many clinicians may be reluctant to enrol patients into the trial if they cannot be involved in their care during follow-up. Assessment by an adjudication committee was not possible, as the outcome either occurred or did not. Therefore, the decision pathway for procedure referral was modified. If a chest x-ray indicated that more than a third of the pleural space filled with fluid, the patient could be referred for a procedure; otherwise, the unblinded clinician was required to reach a consensus on referral with a blinded assessor. This process allowed the unblinded clinician to be involved in the patient's care, while reducing the potential for bias.
  
  
  CONCLUSIONS
  When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias.
  ISRCTN85757829. Registered 26 July 2012.TAPPS: ISRCTN47845793. Registered 28 May 2012.
authors.affiliation: Pragmatic Clinical Trials Unit, Queen Mary University of London, E1 2AB London, UK. b.kahan@qmul.ac.uk.
authors.forename: Brennan C
authors.initials: BC
authors.lastname: Kahan
authors.forename: Suzie
authors.initials: S
authors.lastname: Cro
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Doré
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bratton
authors.forename: Sunita
authors.initials: S
authors.lastname: Rehal
authors.forename: Nick A
authors.initials: NA
authors.lastname: Maskell
authors.forename: Najib
authors.initials: N
authors.lastname: Rahman
authors.forename: Vipul
authors.initials: V
authors.lastname: Jairath
mesh_terms: D015982:Bias; D004322:Drainage; D023381:Endpoint Determination; D017707:Erythrocyte Transfusion / Q000379:methods; D006471:Gastrointestinal Hemorrhage / Q000175:diagnosis / Q000209:etiology / Q000628:therapy; D006801:Humans; D016066:Pleural Effusion, Malignant / Q000175:diagnosis / Q000628:therapy; D018700:Pleurodesis; D012008:Recurrence; D012017:Referral and Consultation; D012107:Research Design; D013997:Time Factors; D016896:Treatment Outcome