title: Subgroup analyses in confirmatory clinical trials: time to be specific about their purposes.
abstract: BACKGROUND
  It is well recognized that treatment effects may not be homogeneous across the study population. Subgroup analyses constitute a fundamental step in the assessment of evidence from confirmatory (Phase III) clinical trials, where conclusions for the overall study population might not hold. Subgroup analyses can have different and distinct purposes, requiring specific design and analysis solutions. It is relevant to evaluate methodological developments in subgroup analyses against these purposes to guide health care professionals and regulators as well as to identify gaps in current methodology.
  
  
  METHODS
  We defined four purposes for subgroup analyses: (1) Investigate the consistency of treatment effects across subgroups of clinical importance, (2) Explore the treatment effect across different subgroups within an overall non-significant trial, (3) Evaluate safety profiles limited to one or a few subgroup(s), (4) Establish efficacy in the targeted subgroup when included in a confirmatory testing strategy of a single trial. We reviewed the methodology in line with this "purpose-based" framework. The review covered papers published between January 2005 and April 2015 and aimed to classify them in none, one or more of the aforementioned purposes.
  
  
  RESULTS
  In total 1857 potentially eligible papers were identified. Forty-eight papers were selected and 20 additional relevant papers were identified from their references, leading to 68 papers in total. Nineteen were dedicated to purpose 1, 16 to purpose 4, one to purpose 2 and none to purpose 3. Seven papers were dedicated to more than one purpose, the 25 remaining could not be classified unambiguously. Purposes of the methods were often not specifically indicated, methods for subgroup analysis for safety purposes were almost absent and a multitude of diverse methods were developed for purpose (1).
  
  
  CONCLUSIONS
  It is important that researchers developing methodology for subgroup analysis explicitly clarify the objectives of their methods in terms that can be understood from a patient's, health care provider's and/or regulator's perspective. A clear operational definition for consistency of treatment effects across subgroups is lacking, but is needed to improve the usability of subgroup analyses in this setting. Finally, methods to particularly explore benefit-risk systematically across subgroups need more research.
authors.affiliation: Julius Center for Health Sciences and Primary Care, UMC Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands. j.tanniou@umcutrecht.nl.|College ter Beoordeling van Geneesmiddelen, Dutch Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH, Utrecht, The Netherlands. j.tanniou@umcutrecht.nl.
authors.forename: Julien
authors.initials: J
authors.lastname: Tanniou
authors.affiliation: Julius Center for Health Sciences and Primary Care, UMC Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands. I.vanderTweel@umcutrecht.nl.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: van der Tweel
authors.affiliation: College ter Beoordeling van Geneesmiddelen, Dutch Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH, Utrecht, The Netherlands. s.teerenstra@cbg-meb.nl.|Department of Health Evidence, Section Biostatistics, Radboud University Medical Centre, Geert Grooteplein 21, 6525 GA, Nijmegen, The Netherlands. s.teerenstra@cbg-meb.nl.
authors.forename: Steven
authors.initials: S
authors.lastname: Teerenstra
authors.affiliation: Julius Center for Health Sciences and Primary Care, UMC Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands. K.C.B.Roes@umcutrecht.nl.|College ter Beoordeling van Geneesmiddelen, Dutch Medicines Evaluation Board, Graadt van Roggenweg 500, 3531 AH, Utrecht, The Netherlands. K.C.B.Roes@umcutrecht.nl.
authors.forename: Kit C B
authors.initials: KC
authors.lastname: Roes
mesh_terms: D035843:Biomedical Research / Q000379:methods* / Q000706:statistics & numerical data; D002986:Clinical Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D019317:Evidence-Based Medicine / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D017063:Outcome Assessment, Health Care / Q000379:methods* / Q000706:statistics & numerical data; D015203:Reproducibility of Results; D012107:Research Design