title: Clinical and regulatory implications of active run-in phases in long-term studies for bipolar disorder.
abstract: OBJECTIVE
  The integration of new treatments into the market and routine clinical practice should be dependent on robustness of evidence from randomised controlled trials (RCTs). We assessed study designs of long-term studies for bipolar disorder of all second-generation antipsychotics (SGAs) submitted to the Food and Drug Administration (FDA) and the completeness of evidence submitted to the regulatory agency.
  
  
  METHODS
  Systematic review of double-blind RCTs comparing SGAs with placebo or active drugs in adults. FDA website and electronic databases were searched until July 2013.
  
  
  RESULTS
  Six placebo-controlled trials comparing aripiprazole, olanzapine, quetiapine and ziprasidone were found in the FDA website. Electronic searches found four additional RCTs about aripiprazole, olanzapine or quetiapine. All RCTs (either submitted to FDA or not) selected patients who responded to acute treatment to increase the treatment effect observed in the long-term phase (enrichment design). By contrast, in the prescribing information sheets for all SGAs, the reported indication was 'maintenance treatment of bipolar disorder'.
  
  
  CONCLUSIONS
  Extrapolation of results from enrichment studies to the more general population of patients should be carried out cautiously because average treatment benefits are likely to be less in unselected patients. Clear guidance for regulatory submission of RCTs is needed.
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, UK; Department of Public Health and Community Medicine, Section of Psychiatry, University of Verona, Verona, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cipriani
authors.forename: C
authors.initials: C
authors.lastname: Barbui
authors.forename: J
authors.initials: J
authors.lastname: Rendell
authors.forename: J R
authors.initials: JR
authors.lastname: Geddes
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000145:classification / Q000494:pharmacology; D001714:Bipolar Disorder / Q000188:drug therapy*; D017277:Drug Approval / Q000458:organization & administration; D055317:Evidence-Based Practice; D006801:Humans; D054539:Medication Therapy Management / Q000331:legislation & jurisprudence*; D020380:Needs Assessment; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000592:standards; D012107:Research Design / Q000592:standards
chemical_list: D014150:Antipsychotic Agents
keywords: affective disorders; antipsychotics; bipolar disorder; psychopharmacology; review of the literature