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Subgroup analysis in clinical trials

David I Cook, Val J Gebski and Anthony C Keech
Med J Aust 2004; 180 (6): . || doi: 10.5694/j.1326-5377.2004.tb05928.x
Published online: 15 March 2004

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 whether there are subgroups of trial participants who are more (or less) likely to be helped (or harmed) by the intervention under investigation, and a recent survey of trials published over 3 months in four leading journals found that 70% included subgroup analyses.1,2 Furthermore, regulatory guidance documents (such as the Committee 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


  • 1 Department of Physiology, University of Sydney, Sydney, NSW.
  • 2 NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW.


Correspondence: 

Acknowledgements: 

We thank Rhana Pike for expert assistance in preparation of this manuscript and Dr Jonathan Craig for helpful advice and comments.

Competing interests:

None identified.

  • 1. Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other mis(uses) of baseline data in clinical trials. Lancet 2000; 255: 1064-1069.
  • 2. Pocock SJ, Assmann SE, Enos LE Kasten LE. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting. Stat Med 2000; 21: 2917-2930.
  • 3. Committee for Proprietary Medicinal Products. Points to consider on multiplicity issues in clinical trials. September 2002. Available at: www.emea.eu.int\pdfs\human\ewp\090899en.pdf (accessed Feb 2004).
  • 4. Bypass Angioplasty Revascularisation Investigation (BARI). Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996; 335: 217-225.
  • 5. Pocock SJ, Hughes MD, Lee RJ. Statistical problems in reporting of clinical trials: a survey of three medical journals. N Engl J Med 1987; 317: 426-432.
  • 6. Yusuf S, Wittes J, ProbstfieldJ, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991; 266: 93-98.
  • 7. Parker AB, Naylor CD. Subgroups, treatment effects and baseline risks: some lessons from major cardiovascular trials. Am Heart J 2000; 139: 952-961.
  • 8. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet 2001; 357: 1191-1194.
  • 9. Burgess DC, Gebski VJ, Keech AC. Baseline data in clinical trials. Med J Aust 2002; 179: 105-107.<eMJA full text>
  • 10. Brookes ST, Whitley E, Peters TJ, et al. Subgroup analyses in randomised controlled trials: quantifying the risks of false positives and false negatives. Health Technol Assess 2001; 5: 1-56.
  • 11. Lee KL. Clinical judgement and statistics. Lessons from a simulated randomized trial in coronary artery disease. Circulation 1980; 61: 508-515.
  • 12. ISIS-2 Collaborative Group Randomized trial of IV streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction. Lancet 1988; 2: 349-360.
  • 13. Hoffman SN, TenBrook JA, Wolf MP, et al. A meta-analysis of randomized controlled trials comparing coronary artery bypass graft with percutaneous transluminal coronary angioplasty: one- to eight-year outcomes. J Am Coll Cardiol 2003; 41: 1293-1304.
  • 14. Niles NW, McGrath PD, Malenka D, et al. Survival of patients with diabetes and multivessel coronary artery disease after surgical or percutaneous coronary revascularization: results of a large regional prospective study. Northern New England Cardiovascular Disease Study Group. J Am Coll Cardiol 2001; 37: 1008-1015.
  • 15. Peto R. Clinical trials. In: Price P, Sikara K, editors. Treatment of cancer. 3rd ed. London: Chapman and Hall, 1995: 1039-1044.
  • 16. Coates AS, Goldhirsch A, Gelber RD. Overhauling the breast cancer overview: are subsets subversive? Lancet Oncology 2002; 3: 525-526.
  • 17. Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 3rd ed. New York: Springer, 1998: 289-293.
  • 18. Hahn S. Assessing the potential for bias in meta-analysis due to selective reporting of subgroup analyses within studies. Stat Med 2000; 19: 3325-3336.
  • 19. Matthews JNS, Altman DG. Interaction 2: compare effect sizes not P values. BMJ 1996; 313; 808.
  • 20. Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ 2003; 326: 219.
  • 21. Frasure-Smith N, Lesperance F, Prince RH, et al. Randomised trial of home-based psychosocial nursing intervention for patients recovering from myocardial infarction. Lancet 1997; 350: 473-479.
  • 22. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002; 347: 1403-1411.
  • 23. Altman DG. Within trial variation — a false trail? J Clin Epidemiol 1998; 51: 301-303.
  • 24. Helgason T, Jonasson MR. Evidence for a food additive as a cause of ketosis-prone diabetes. Lancet 1981; 2: 716-720.
  • 25. Dijkstra BKS. Origin of carcinoma of the bronchus. J Natl Cancer Inst 1963; 31: 511-519.

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