title: Assessing methods to specify the target difference for a randomised controlled trial: DELTA (Difference ELicitation in TriAls) review.
abstract: BACKGROUND
  The randomised controlled trial (RCT) is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to the design and validity of a RCT is a calculation of the number of participants needed (the sample size). The value used to determine the sample size can be considered the 'target difference'. From both a scientific and an ethical standpoint, selecting an appropriate target difference is of crucial importance. Determination of the target difference, as opposed to statistical approaches to calculating the sample size, has been greatly neglected though a variety of approaches have been proposed the current state of the evidence is unclear.
  
  
  OBJECTIVE
  The aim was to provide an overview of the current evidence regarding specifying the target difference in a RCT sample size calculation. The specific objectives were to conduct a systematic review of methods for specifying a target difference; to evaluate current practice by surveying triallists; to develop guidance on specifying the target difference in a RCT; and to identify future research needs.
  
  
  METHODS
  The biomedical and social science databases searched were MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, Education Resources Information Center (ERIC) and Scopus for in-press publications. All were searched from 1966 or the earliest date of the database coverage and searches were undertaken between November 2010 and January 2011. There were three interlinked components: (1) systematic review of methods for specifying a target difference for RCTs - a comprehensive search strategy involving an electronic literature search of biomedical and some non-biomedical databases and clinical trials textbooks was carried out; (2) identification of current trial practice using two surveys of triallists - members of the Society for Clinical Trials (SCT) were invited to complete an online survey and respondents were asked about their awareness and use of, and willingness to recommend, methods; one individual per triallist group [UK Clinical Research Collaboration (UKCRC)-registered Clinical Trials Units (CTUs), Medical Research Council (MRC) UK Hubs for Trials Methodology Research and National Institute for Health Research (NIHR) UK Research Design Services (RDS)] was invited to complete a survey; (3) production of a structured guidance document to aid the design of future trials - the draft guidance was developed utilising the results of the systematic review and surveys by the project steering and advisory groups.
  
  
  METHODS
  Methodological review incorporating electronic searches, review of books and guidelines, two surveys of experts (membership of an international society and UK- and Ireland-based triallists) and development of guidance.
  
  
  METHODS
  The two surveys were sent out to membership of the SCT and UK- and Ireland-based triallists.
  
  
  METHODS
  The review focused on methods for specifying the target difference in a RCT. It was not restricted to any type of intervention or condition.
  
  
  METHODS
  Methods for specifying the target difference for a RCT were considered.
  
  
  RESULTS
  The search identified 11,485 potentially relevant studies. In total, 1434 were selected for full-text assessment and 777 were included in the review. Seven methods to specify the target difference for a RCT were identified - anchor, distribution, health economic, opinion-seeking, pilot study, review of evidence base (RoEB) and standardised effect size (SES) - each having important variations in implementation. A total of 216 of the included studies used more than one method. A total of 180 (15%) responses to the SCT survey were received, representing 13 countries. Awareness of methods ranged from 38% (n =69) for the health economic method to 90% (n =162) for the pilot study. Of the 61 surveys sent out to UK triallist groups, 34 (56%) responses were received. Awareness ranged from 97% (n =33) for the RoEB and pilot study methods to only 41% (n =14) for the distribution method. Based on the most recent trial, all bar three groups (91%, n =30) used a formal method. Guidance was developed on the use of each method and the reporting of the sample size calculation in a trial protocol and results paper.
  
  
  CONCLUSIONS
  There is a clear need for greater use of formal methods to determine the target difference and better reporting of its specification. Raising the standard of RCT sample size calculations and the corresponding reporting of them would aid health professionals, patients, researchers and funders in judging the strength of the evidence and ensuring better use of scarce resources.
  
  
  BACKGROUND
  The Medical Research Council UK and the National Institute for Health Research Joint Methodology Research programme.
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Cook
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hislop
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Temitope E
authors.initials: TE
authors.lastname: Adewuyi
authors.affiliation: Medical Statistics Team, University of Aberdeen, Aberdeen, UK.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Harrild
authors.affiliation: Centre for Statistics in Medicine, University of Oxford, Oxford, UK.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Altman
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Ramsay
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Fraser
authors.affiliation: Department of General Practice, National University of Ireland, Galway, Ireland.
authors.forename: Brian
authors.initials: B
authors.lastname: Buckley
authors.affiliation: Population Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Fayers
authors.affiliation: Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Harvey
authors.affiliation: Health Economics and Health Technology Assessment, University of Glasgow, Glasgow, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Briggs
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Norrie
authors.affiliation: Ottawa Hospital Research Institute, Ontario, Canada.
authors.forename: Dean
authors.initials: D
authors.lastname: Fergusson
authors.affiliation: Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Luke D
authors.initials: LD
authors.lastname: Vale
mesh_terms: D001291:Attitude of Health Personnel; D015982:Bias; D003362:Cost-Benefit Analysis; D003625:Data Collection; D015340:Epidemiologic Research Design; D019317:Evidence-Based Medicine / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D006801:Humans; D038622:Internationality; D007494:Ireland; D017060:Patient Satisfaction; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D012108:Research Personnel; D018401:Sample Size; D012958:Societies, Scientific; D013223:Statistics as Topic / Q000379:methods; D006113:United Kingdom