Journal of Clinical Epidemiology
Volume 61, Issue 3 , Pages 241-246 , March 2008

Early stopping of randomized clinical trials for overt efficacy is problematic

  • Dirk Bassler

      Affiliations

    • Department of Neonatology, University Children's Hospital, Tübingen, Germany
    • ,
  • Victor M. Montori

      Affiliations

    • Knowledge and Encounter Research Unit, Division of Endocrinology and Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
    • ,
  • Matthias Briel

      Affiliations

    • CLARITY Research Group, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
    • Basel Institute for Clinical Epidemiology, University Hospital, Basel, Switzerland
    • ,
  • Paul Glasziou

      Affiliations

    • Centre for Evidence-Based Medicine, Department of Primary Health Care, University of Oxford, Oxford, UK
    • ,
  • Gordon Guyatt

      Affiliations

    • CLARITY Research Group, Department of Clinical Epidemiology and Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
    • Corresponding Author InformationCorresponding author. Department of Clinical Epidemiology and Biostatistics, Health Sciences Centre, Room 2C12, McMaster University, Hamilton, Ontario, Canada. Tel.: +905-525-9140 ext. 22900; fax: +905-524-3841.

,Accepted 22 July 2007.

References 

  1. Peltoniemi O, Kari MA, Heinonen K, Saarela T, Nikolajev K, Andersson S, et al. Pretreatment cortisol values may predict responses to hydrocortisone administration for the prevention of bronchopulmonary dysplasia in high-risk infants. J Pediatr. 2005;146:632–637
  2. Thistle P, Spitzer RF, Glazier RH, Pilon R, Arbess G, Simor A, et al. A randomized, double-blind, placebo-controlled trial of combined nevirapine and zidovudine compared with nevirapine alone in the prevention of perinatal transmission of HIV in Zimbabwe. Clin Infect Dis. 2007;44:111–119Epub 2006 Nov 22
  3. Laupacis A, Connolly SJ, Gent M, Roberts RS, Cairns J, Joyner C. How should results from completed studies influence ongoing clinical trials? The CAFA study experience. Ann Intern Med. 1991;115:818–822
  4. Smith MR, Manola J, Kaufman DS, Oh WK, Bubley GJ, Kantoff PW. Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol. 2006;24:2691–2693
  5. Papanikolaou EG, Camus M, Kolibianakis EM, Van Landuyt L, Van Steirteghem A, Devroey P. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med. 2006;354:1190–1193
  6. Draft guidance for clinical trial sponsors on the establishment and operation of clinical trial data monitoring committees. 66 Federal Register 58151–58153 (2001).
  7. Sydes MR, Altman DG, Babiker AB, Parmar MK, Spiegelhalter DJ. Reported use of data monitoring committees in the main published reports of randomized controlled trials: a cross-sectional study. Clin Trials. 2004;1:48–59
  8. DAMOCLES Study Group . NHS health technology assessment programme: a proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet. 2005;365:711–722
  9. Slutsky AS, Lavery JV. Data safety and monitoring boards. N Engl J Med. 2004;350:1143–1147
  10. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317:141–145
  11. Berry DA. Bayesian clinical trials. Nat Rev Drug Discov. 2006;5:27–36
  12. Montori VM, Devereaux PJ, Adhikari NK, Burns KEA, Eggert CH, Briel M, et al. Randomized trials stopped early for benefit: a systematic review. JAMA. 2005;294:2203–2209
  13. 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
  14. Bassler D, Ferreira-Gonzalez I, Briel M, Cook DJ, Devereaux PJ, Heels-Ansdell D, et al. Systematic reviewers neglect bias that results from trials stopped early for benefit. J Clin Epidemiol. 2007;60:869–873
  15. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999;354:1896–1900
  16. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:549–556
  17. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observations of each patient. I. Introduction and design. Br J Cancer. 1976;34:585–612
  18. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 1971;44:793–797
  19. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70:659–663
  20. Schulz KF, Grimes DA. Multiplicity in randomised trials. II: Subgroup and interim analyses. Lancet. 2005;365:1657–1661
  21. Pocock S, White I. Trials stopped early: too good to be true?. Lancet. 1999;353:943–944
  22. Hughes MD, Pocock SJ. Stopping rules and estimation problems in clinical trials. Stat Med. 1988;7:1231–1242
  23. Pocock SJ, Hughes MD. Practical problems in interim analyses, with particular regard to estimation. Control Clin Trials. 1989;10(4 Suppl):209S–221S
  24. Yusuf S, Collins R, Peto R. Why do we need some large, simple, randomized trials?. Stat Med. 1984;3:409–420
  25. Ioannidis J, Lau J. Evolution of treatment effects over time: empirical insight from recursive cumulative metaanalyses. Proc Natl Acad Sci USA. 2001;98:831–836
  26. Trikalinos TA, Churchill R, Ferri M, Leucht S, Tuunainen A, Wahlbeck K, et al. EU-PSI project Effect sizes in cumulative meta-analyses of mental health randomized trials evolved over time. J Clin Epidemiol. 2004;57:1124–1130
  27. Mueller PS, Montori VM, Bassler D, Koenig BA, Guyatt GH. Ethical issues in stopping randomized trials early because of apparent benefit. Ann Intern Med. 2007;146:878–881
  28. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical?. JAMA. 2000;283:2701–2711
  29. Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341:1789–1794
  30. Devereaux PJ, Yusuf S, Yang H, Choi PT, Guyatt GH. Are the recommendations to use perioperative beta-blocker therapy in patients undergoing noncardiac surgery based on reliable evidence?. CMAJ. 2004;171:245–247
  31. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2:349–360
  32. Auvert B, Taljaard D, Lagarde E, Sobngwi-Tambekou J, Sitta R, Puren A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 trial. Epub 2005 Oct 25 PLoS Med. 2005;e298
  33. Bailey RC, Moses S, Parker CB, Agot K, Maclean I, Krieger JN, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007;369:643–656
  34. Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F, et al. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007;369:657–666
  35. Pocock SJ. Current controversies in data monitoring for clinical trials. Clin Trials. 2006;3:513–521

PII: S0895-4356(07)00292-2

doi: 10.1016/j.jclinepi.2007.07.016

Journal of Clinical Epidemiology
Volume 61, Issue 3 , Pages 241-246 , March 2008

Article Tools