title: Benefits and harms in clinical trials of duloxetine for treatment of major depressive disorder: comparison of clinical study reports, trial registries, and publications.
abstract: OBJECTIVE
  To determine, using research on duloxetine for major depressive disorder as an example, if there are inconsistencies between protocols, clinical study reports, and main publicly available sources (journal articles and trial registries), and within clinical study reports themselves, with respect to benefits and major harms.
  
  
  METHODS
  Data on primary efficacy analysis and major harms extracted from each data source and compared.
  
  
  METHODS
  Nine randomised placebo controlled trials of duloxetine (total 2878 patients) submitted to the European Medicines Agency (EMA) for marketing approval for major depressive disorder.
  
  
  METHODS
  Clinical study reports, including protocols as appendices (total 13,729 pages), were obtained from the EMA in May 2011. Journal articles were identified through relevant literature databases and contacting the manufacturer, Eli Lilly. Clinicaltrials.gov and the manufacturer's online clinical trial registry were searched for trial results.
  
  
  RESULTS
  Clinical study reports fully described the primary efficacy analysis and major harms (deaths (including suicides), suicide attempts, serious adverse events, and discontinuations because of adverse events). There were minor inconsistencies in the population in the primary efficacy analysis between the protocol and clinical study report and within the clinical study report for one trial. Furthermore, we found contradictory information within the reports for seven serious adverse events and eight adverse events that led to discontinuation but with no apparent bias. In each trial, a median of 406 (range 177-645) and 166 (100-241) treatment emergent adverse events (adverse events that emerged or worsened after study drug was started) in the randomised phase were not reported in journal articles and Lilly trial registry reports, respectively. We also found publication bias in relation to beneficial effects.
  
  
  CONCLUSIONS
  Clinical study reports contained extensive data on major harms that were unavailable in journal articles and in trial registry reports. There were inconsistencies between protocols and clinical study reports and within clinical study reports. Clinical study reports should be used as the data source for systematic reviews of drugs, but they should first be checked against protocols and within themselves for accuracy and consistency.
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet Dept 7811, Copenhagen, Denmark em@cochrane.dk.
authors.forename: Emma
authors.initials: E
authors.lastname: Maund
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet Dept 7811, Copenhagen, Denmark.
authors.forename: Britta
authors.initials: B
authors.lastname: Tendal
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet Dept 7811, Copenhagen, Denmark.
authors.forename: Asbjørn
authors.initials: A
authors.lastname: Hróbjartsson
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet Dept 7811, Copenhagen, Denmark.
authors.forename: Karsten Juhl
authors.initials: KJ
authors.lastname: Jørgensen
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet Dept 7811, Copenhagen, Denmark Department of Infectious Diseases, Hvidovre University Hospital, Kettegårds Allé 30, 2650 Hvidovre, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundh
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet Dept 7811, Copenhagen, Denmark.
authors.forename: Jeppe
authors.initials: J
authors.lastname: Schroll
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet Dept 7811, Copenhagen, Denmark.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gøtzsche
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002985:Clinical Protocols / Q000592:standards; D002986:Clinical Trials as Topic / Q000592:standards*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D000068736:Duloxetine Hydrochloride; D006801:Humans; D012042:Registries / Q000592:standards; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D000068736:Duloxetine Hydrochloride; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes