Subgroup analysis in clinical trials

Department of Physiology, University of Sydney, Sydney, NSW. David I Cook, MD, FRACP, Professor of Cellular Physiology. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW. Val J Gebski, BA, MStat, Associate Professor and Principal Research Fellow; Anthony C Keech, MScEpid, FRACP, Deputy Director. Reprints will not be available from the authors. Correspondence: Professor David I Cook, Department of Physiology (F-13), University of Sydney, Sydney, NSW 2006. davidc@physiol.usyd.edu.au The Medical Journal of Australia ISSN: 0025-729X 15 March 2004 180 6 289-291 ©The Medical Journal of Australia 2004 www.mja.com.au EBM: Trials on Trial whether there are subgroups of trial participants who a more (or less) likely to be helped (or harmed) by th intervention under investigation, and a recent survey trials published over 3 months in four leading journa found that 70% included subgroup analyses. Furthe more, regulatory guidance documents (such as the Comm CLINICAL TRIALS REPRESENT A MAJOR INVESTMENT by investigators, sponsors and participants, and it is reasonable to attempt to gain the maximum information from them. Practitioners and regulatory agencies are keen to know re e of ls rittee for Proprietary Medicinal Products September 2002 document Points to consider on multiplicity issues in clinical trials3) strongly encourage appropriate subgroup analyses. The results of subgroup analyses can also drive changes in practice guidelines. For example, the United States National Institutes of Health issued a clinical alert following the unexpected finding in the BARI (Bypass Angioplasty Revascularisation Investigation) trial that mortality after angioplasty in patients with diabetes was nearly double that after bypass-graft surgery (P = 0.003).4 Meaningful information from subgroup analyses within a randomised trial is restricted by multiplicity of testing and low statistical power. There is therefore a tension between our wish to identify heterogeneity in the responses of trial participants to trial interventions and our technical capacity for doing so. Surveys on the adequacy of the reporting of clinical trials consistently find the reporting of subgroup analysis to be characterised by poor practice.2,5-7 Item 18 of the CONSORT checklist (Box 1) deals with the multiplicity issues that arise in subgroup analysis.8