Jonathan A Cook1, Steven A Julious2, William Sones1, Lisa V Hampson3, Catherine Hewitt4, Jesse A Berlin5, Deborah Ashby6, Richard Emsley7, Dean A Fergusson8, Stephen J Walters2, Edward Cf Wilson9,10, Graeme MacLennan11, Nigel Stallard12, Joanne C Rothwell2, Martin Bland13, Louise Brown14, Craig R Ramsay15, Andrew Cook16, David Armstrong17, Douglas Altman1, Luke D Vale18. 1. Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. 2. Medical Statistics Group, School of Health and Related Research, University of Sheffield, Sheffield, UK. 3. Statistical Methodology and Consulting, Novartis Pharma AG, Basel, Switzerland. 4. York Trials Unit, Department of Health Sciences, University of York, York, UK. 5. Johnson & Johnson, Titusville, NJ, USA. 6. Imperial Clinical Trials Unit, Imperial College London, London, UK. 7. Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 8. Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada. 9. Cambridge Centre for Health Services Research, Cambridge Clinical Trials Unit University of Cambridge, Cambridge, UK. 10. Health Economics Group, Norwich Medical School, University of East Anglia, Norwich, UK. 11. Centre for Healthcare Randomised Trials, University of Aberdeen, Aberdeen, UK. 12. Warwick Medical School, Statistics and Epidemiology, University of Warwick, Coventry, UK. 13. Department of Health Sciences, University of York, York, UK. 14. MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK. 15. Health Services Research Unit, University of Aberdeen, Aberdeen, UK. 16. Wessex Institute, University of Southampton, Southampton, UK. 17. School of Population Health and Environmental Sciences, King's College London, London, UK. 18. Health Economics Group, Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK.
Abstract
BACKGROUND: The randomised controlled trial is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to its design is a calculation of the number of participants needed (the sample size) for the trial. The sample size is typically calculated by specifying the magnitude of the difference in the primary outcome between the intervention effects for the population of interest. This difference is called the 'target difference' and should be appropriate for the principal estimand of interest and determined by the primary aim of the study. The target difference between treatments should be considered realistic and/or important by one or more key stakeholder groups. OBJECTIVE: The objective of the report is to provide practical help on the choice of target difference used in the sample size calculation for a randomised controlled trial for researchers and funder representatives. METHODS: The Difference ELicitation in TriAls2 (DELTA2) recommendations and advice were developed through a five-stage process, which included two literature reviews of existing funder guidance and recent methodological literature; a Delphi process to engage with a wider group of stakeholders; a 2-day workshop; and finalising the core document. RESULTS: Advice is provided for definitive trials (Phase III/IV studies). Methods for choosing the target difference are reviewed. To aid those new to the topic, and to encourage better practice, 10 recommendations are made regarding choosing the target difference and undertaking a sample size calculation. Recommended reporting items for trial proposal, protocols and results papers under the conventional approach are also provided. Case studies reflecting different trial designs and covering different conditions are provided. Alternative trial designs and methods for choosing the sample size are also briefly considered. CONCLUSIONS: Choosing an appropriate sample size is crucial if a study is to inform clinical practice. The number of patients recruited into the trial needs to be sufficient to answer the objectives; however, the number should not be higher than necessary to avoid unnecessary burden on patients and wasting precious resources. The choice of the target difference is a key part of this process under the conventional approach to sample size calculations. This document provides advice and recommendations to improve practice and reporting regarding this aspect of trial design. Future work could extend the work to address other less common approaches to the sample size calculations, particularly in terms of appropriate reporting items. FUNDING: Funded by the Medical Research Council (MRC) UK and the National Institute for Health Research as part of the MRC-National Institute for Health Research Methodology Research programme.
BACKGROUND: The randomised controlled trial is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to its design is a calculation of the number of participants needed (the sample size) for the trial. The sample size is typically calculated by specifying the magnitude of the difference in the primary outcome between the intervention effects for the population of interest. This difference is called the 'target difference' and should be appropriate for the principal estimand of interest and determined by the primary aim of the study. The target difference between treatments should be considered realistic and/or important by one or more key stakeholder groups. OBJECTIVE: The objective of the report is to provide practical help on the choice of target difference used in the sample size calculation for a randomised controlled trial for researchers and funder representatives. METHODS: The Difference ELicitation in TriAls2 (DELTA2) recommendations and advice were developed through a five-stage process, which included two literature reviews of existing funder guidance and recent methodological literature; a Delphi process to engage with a wider group of stakeholders; a 2-day workshop; and finalising the core document. RESULTS: Advice is provided for definitive trials (Phase III/IV studies). Methods for choosing the target difference are reviewed. To aid those new to the topic, and to encourage better practice, 10 recommendations are made regarding choosing the target difference and undertaking a sample size calculation. Recommended reporting items for trial proposal, protocols and results papers under the conventional approach are also provided. Case studies reflecting different trial designs and covering different conditions are provided. Alternative trial designs and methods for choosing the sample size are also briefly considered. CONCLUSIONS: Choosing an appropriate sample size is crucial if a study is to inform clinical practice. The number of patients recruited into the trial needs to be sufficient to answer the objectives; however, the number should not be higher than necessary to avoid unnecessary burden on patients and wasting precious resources. The choice of the target difference is a key part of this process under the conventional approach to sample size calculations. This document provides advice and recommendations to improve practice and reporting regarding this aspect of trial design. Future work could extend the work to address other less common approaches to the sample size calculations, particularly in terms of appropriate reporting items. FUNDING: Funded by the Medical Research Council (MRC) UK and the National Institute for Health Research as part of the MRC-National Institute for Health Research Methodology Research programme.
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Keywords:
MINIMAL CLINICALLY IMPORTANT DIFFERENCE; PEER REVIEW; RANDOMISED CONTROLLED TRIALS; RESEARCH DESIGN; SAMPLE SIZE
Authors: Loretta Davies; Jonathan Cook; Jose Leal; Carlos Morgado Areia; Beverly Shirkey; William Jackson; Helen Campbell; Heidi Fletcher; Andrew Carr; Karen Barker; Sarah E Lamb; Paul Monk; Sean O'Leary; Fares Haddad; Chris Wilson; Andrew Price; David Beard Journal: Trials Date: 2020-05-14 Impact factor: 2.279
Authors: Lauren Burke; Elizabeth Littlewood; Samantha Gascoyne; Dean McMillan; Carolyn A Chew-Graham; Della Bailey; Claire Sloan; Caroline Fairhurst; Kalpita Baird; Catherine Hewitt; Andrew Henry; Eloise Ryde; Leanne Shearsmith; Peter Coventry; Suzanne Crosland; Elizabeth Newbronner; Gemma Traviss-Turner; Rebecca Woodhouse; Andrew Clegg; Tom Gentry; Andrew Hill; Karina Lovell; Sarah Dexter Smith; Judith Webster; David Ekers; Simon Gilbody Journal: PLoS One Date: 2022-03-24 Impact factor: 3.240