On Stopping a Randomized Clinical Trial for Futility

Chapter
First Online:
Part of the Applied Bioinformatics and Biostatistics in Cancer Research book series (ABB)

Abstract

This chapter reviews the art and science of planned interim futility analyses in clinical trials that test a superiority hypothesis. Our goal is to recommend “best practices.” We briefly describe situations where we find terminating trials for futility advisable and not advisable. This chapter outlines four statistical methods of interim futility analysis – conditional power, predictive power, group sequential testing, and basing an interim futility analysis on a Phase 2 outcome or biomarker instead of on the primary efficacy variable. We distinguish between trials where the locus of control resides in the investigators from those where the commercial sponsor controls the trial. We provide guidance, based on our experience and opinion, as to types of trials where each method is preferable. We describe several practical issues that arise in the use of interim futility analysis, for example, lag in treatment effect, time patterns in development of evidence of efficacy, unreliability of early data, efficacy endpoints that take long follow-up to observe, and choice of timing of futility analysis. Finally, we consider the ethics of futility analyses including public disclosure of their results. A conclusion section summarizes our recommendations for the use of interim futility analysis.

Keywords

Interim Analysis Vagus Nerve Stimulator Data Monitoring Committee Conditional Power Drift Parameter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Notes

Acknowledgements

We thank Catherine Conlon for preparing Fig. 5.4. We are grateful to David Sackett for his insightful comments on an earlier version of this chapter.

References

  1. .
    Abraham E., Reinhart K, Opal S et al (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis. JAMA 290:238–247PubMedCrossRefGoogle Scholar
  2. .
    Abraham E, Laterre, P-F, Garg R et al (2005) Drotrecogin-alfa (activated) for adults with severe sepsis and a low risk of death. New Engl J Med 353:1332–1341PubMedCrossRefGoogle Scholar
  3. .
    Ajani JA, Winter KA, Gunderson LL et al (2008) Fluorouracil, mitomycin and radiotherapy vs. fluorouracil, cisplatin and radiotherapy for carcinoma of the anal canal: A randomized controlled trial. JAMA 299:1914–1921PubMedCrossRefGoogle Scholar
  4. .
    Alling DW (1963) Early decision in the Wilcoxon two-sample test. J Am Stat Assoc 58:713–720CrossRefGoogle Scholar
  5. .
    Alling DW (1966) Closed sequential tests for binomial probabilities. Biometrika 53:73–84; with correction note Biometrika 55:268 (1968)Google Scholar
  6. .
    Anderson JR (2007) Correspondence: Persistent coronary occlusion after myocardial infarction. New Engl J Med 356:1681PubMedCrossRefGoogle Scholar
  7. .
    Ashcroft R (2001) Responsibilities of sponsors are limited in premature discontinuation of trials. BMJ 323:53PubMedCrossRefGoogle Scholar
  8. .
    Boyd K (2001) Commentary: Early discontinuation violates Helsinki principles. BMJ 322:605–606PubMedGoogle Scholar
  9. .
    Bretz F, Koenig F, Brannath W et al (2009) Adaptive designs for confirmatory clinical trials. Stat Med 28:1181–1217PubMedCrossRefGoogle Scholar
  10. .
    Bryant J, Day R (1995) Incorporating toxicity considerations into the design of two-stage Phase 2 clinical trials. Biometrics 51:1372–83PubMedCrossRefGoogle Scholar
  11. .
    Burzykowski T, Molenberghs G, Buyse M (eds) (2005) The evaluation of surrogate endpoints. Springer, New YorkGoogle Scholar
  12. .
    Bussel JB, Cheng G, Saleh MN et al (2007) Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. New Engl J Med 357:2237–2247PubMedCrossRefGoogle Scholar
  13. .
    Cairns JA, Wittes J, Wyse DG et al (2008) Monitoring the ACTIVE-W trial: Some issues in monitoring a noninferiority trial. Am Heart J 155:33–41PubMedCrossRefGoogle Scholar
  14. .
    Cannistra SA (2004) The ethics of early stopping rules: Who is protecting whom? J Clin Oncol 22:1542–1545PubMedCrossRefGoogle Scholar
  15. .
    Chuang-Stein C, Gallo PA et al (2006) Sample size reestimation: A review and recommendations. Drug Inf J 40:475–484Google Scholar
  16. .
    Curley MA, Hibberd PL, Fineman RN (2005) Effect of prone positioning on clinical outcomes in children with acute lung injury: A randomized controlled trial. JAMA 294:229–237PubMedCrossRefGoogle Scholar
  17. .
    D’Agostino RB, Massaro JM, Sullivan LM (2003) Non-inferiority trials: Design concepts and issues – the encounters of academic consultants in statistics. Stat Med 22:169–186PubMedCrossRefGoogle Scholar
  18. .
    Ellenberg SS, Fleming TR, DeMets DL (2002) Data monitoring committees in clinical trials: A practical perspective. Wiley, New YorkCrossRefGoogle Scholar
  19. .
    Emerson SS, Fleming TR (1989) Symmetric group sequential designs. Biometrics 45:905–923PubMedCrossRefGoogle Scholar
  20. .
    Emerson SS, Kittelson JM, Gillen DL (2007) Frequentist evaluation of group sequential clinical trial designs. Stat Med 26:5047–5080PubMedCrossRefGoogle Scholar
  21. .
    Evans S, Pocock SJ (2001) Editorial: Societal responsibilities of clinical trial sponsors: lack of commercial pay off is not a legitimate reason for stopping a trial. BMJ 322:569–570PubMedCrossRefGoogle Scholar
  22. .
    Falanga V, Sabolinski M (1999) A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen 7:201–207PubMedCrossRefGoogle Scholar
  23. .
    Fleming TR (1982) One-sample multiple testing procedures for Phase 2 clinical trials. Biometrics 38:143–151PubMedCrossRefGoogle Scholar
  24. .
    Freedman LS, Spiegelhalter DJ (1989) Comparison of Bayesian with group sequential methods for monitoring clinical trials. Contr Clin Trials 10:357–367CrossRefGoogle Scholar
  25. .
    Gennari A, Amadori D, De Lena M et al (2006) Lack of benefit of maintenance paclitaxel in first-line chemotherapy in metastatic breast cancer. J Clin Oncol 24:3912–3918PubMedCrossRefGoogle Scholar
  26. .
    Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. New Engl J Med 355:2733–2743PubMedCrossRefGoogle Scholar
  27. .
    Goldman B, LeBlanc M, Crowley J (2008) Interim futility analysis with intermediate endpoints. Clin Trials 5:14–22PubMedCrossRefGoogle Scholar
  28. .
    Gorelick PB, Richardson D, Kelly M et al (2003) Aspirin and ticlopidine for prevention of recurrent stroke in black patients: A randomized trial. JAMA 289:2947–2957PubMedCrossRefGoogle Scholar
  29. .
    Gragoudas ES, Adamis AP, Cunningham ET et al (2004) Pegaptanib for neovascular age-related macular degeneration. New Engl J Med 351:2805–2816PubMedCrossRefGoogle Scholar
  30. .
    Gray A, Raff AB, Chiriva-Internati M et al (2008) A paradigm shift in therapeutic vaccination of cancer patients: the need to apply therapeutic vaccination strategies in the preventive setting. Immunol Rev 222:316–327PubMedCrossRefGoogle Scholar
  31. .
    Grunkenmeier GL, Johnson DM, Naftel DC (1994) Sample size requirements for evaluating heart valves with constant risk events. J Heart Valve Dis 3:53–58Google Scholar
  32. .
    Herson J (2009) Data and safety monitoring committees in clinical trials. Chapman and Hall, FLCrossRefGoogle Scholar
  33. .
    Hochman JS, Lamas GA, Buller CE et al (2006) Coronary intervention for persistent occlusion after myocardial infarction. New Engl J Med 355:2395–2407PubMedCrossRefGoogle Scholar
  34. .
    Hochman JS, Forman S, Reynolds HR (2007) Correspondence: Persistent coronary occlusion after myocardial infarction. New Engl J Med 356:1683CrossRefGoogle Scholar
  35. .
    Iltis AS (2005) Stopping trials early for commercial reasons: The risk-benefit relationship as a moral compass. J Med Ethics 31:410–414PubMedCrossRefGoogle Scholar
  36. .
    Inoue LYT, Thall PF, Berry DA (2002) Seamlessly expanding a randomized Phase 2 trial to Phase 3. Biometrics 58:823–831PubMedCrossRefGoogle Scholar
  37. .
    International Conference on Harmonisation (1998). E9: Statistical Principles for Clinical Trials. http://www/ich.org/LOB/media/MEDIA485.pdf
  38. .
    Jennison C, Turnbull BW (2007) Adaptive seamless designs: selection and prospective testing of hypotheses. J Biopharm Stat 17:1135–1161PubMedCrossRefGoogle Scholar
  39. .
    Jennison CM, Turnbull BW (2006) Confirmatory seamless Phase 2II/III clinical trials with hypotheses selection at interim: Opportunities and limitations. Biometr J 48:650–655CrossRefGoogle Scholar
  40. .
    Kiel DP, Magaziner J, Zimmerman S (2007) Efficacy of a hip protector to prevent hip fracture in nursing home residents: the HIP PRO randomized controlled trial. JAMA 298:413–422PubMedCrossRefGoogle Scholar
  41. .
    Lan KKG, DeMets DL (1983) Discrete sequential boundaries for clinical trials. Biometrika 70:659–663CrossRefGoogle Scholar
  42. .
    Lan K, Wittes J (1988) The B-value: A tool for monitoring data. Biometrics 44:579–585PubMedCrossRefGoogle Scholar
  43. .
    Lan KK, Trost DC (1997) Estimation of parameters and sample size re-estimation. American Statistical Association Proceedings of the Biopharmaceutical SectionGoogle Scholar
  44. .
    Lan KK, Simon R, Halperin M (1982) Stochastically curtailed tests in long-term clinical trials. Commun Statist Sequential Anal 1:207–219CrossRefGoogle Scholar
  45. .
    Lanciano R, Calkins A, Bundy BN et al (2005) Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: A gynecologic oncology group study. J Clin Oncol 23:8289–8295PubMedCrossRefGoogle Scholar
  46. .
    Lee JJ, Feng L (2005) Review article: Randomized Phase 2 designs in cancer clinical trials: current status and future directions. J Clin Oncol 23:4450–4457PubMedCrossRefGoogle Scholar
  47. .
    Levy MM (2004) PEEP in ARDS – How much is enough?. New Engl J Med 351:389–391PubMedCrossRefGoogle Scholar
  48. .
    Lewis PA, O’Sullivan MM, Rumfield WR (1988) Significant changes in Ritchie scores. Rheumatology 27:32–26CrossRefGoogle Scholar
  49. .
    Lievre M, Menard J, Bruckert E et al (2001) Premature discontinuation of clinical trials for reasons not related to efficacy, safety or feasibility. BMJ 322:603–606PubMedCrossRefGoogle Scholar
  50. .
    Lorigan P, Verweij J, Papai Z et al (2007) PhaseIII trial of two investigation schedules of ifosfamide compared with standard dose doxorubicin in advanced or metastatic soft tissue sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study. J Clin Oncol 25:3144–3150PubMedCrossRefGoogle Scholar
  51. .
    Loughlin KR (2008) Immunotherapy: A new paradigm for androgen-refractory prostate cancer. Urol Oncol 26:575PubMedCrossRefGoogle Scholar
  52. .
    Malec (2001) A closer look at combining data among a small number of binomial experiments. Stat Med 20:1811–1824Google Scholar
  53. .
    Mas J-L, Catellier G, Beyssen B et al (2006) Endaterectomy versus stenting in patients with symptomatic severe carotid stenosis. New Engl J Med 355:1660–1671PubMedCrossRefGoogle Scholar
  54. .
    Mehta C (2005) EaST user manual, version 4. Cytel, Inc, Cambridge MAGoogle Scholar
  55. .
    Mehta C (2010) Sample size re-estimation for confirmatory trials. In:(Harrington D (ed) Current issues in the design of clinical trials. Springer, New YorkGoogle Scholar
  56. .
    Pampallona SM, Tsiatis AA (1994) Group sequential designs for one-sided and two-sided hypothesis testing with provision for early stopping in favor of the null hypothesis. J Stat Plann Inference 42:19–35CrossRefGoogle Scholar
  57. .
    Pepe MS, Anderson GL (1992) Two-stage experimental designs: Early stopping with a negative result. Appl Stat 41:180–190CrossRefGoogle Scholar
  58. .
    Pepe MS, Feng Z, Longton G et al (2009) Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility. Stat Med 28:762–779PubMedCrossRefGoogle Scholar
  59. .
    Proschan MA, Lan KKG, Wittes JT (2006) Statistical monitoring of clinical trials: A unified approach. Springer, New YorkGoogle Scholar
  60. .
    Psaty BM, Rennie D (2003) Stopping medical research to save money: A broken pact with researchers and patients. JAMA 289:2128–2131PubMedCrossRefGoogle Scholar
  61. .
    Robbins JA, Gensler G, Hind J et al (2008) Comparison of 2 interventions for liquid aspiration on pneumonia incidence: A randomized trial. Ann Internal Med 148:509–518Google Scholar
  62. .
    Robins SJ, Collins D, Wittes JT et al (2001) Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT, a randomized controlled trial. JAMA 285:1585–1591PubMedCrossRefGoogle Scholar
  63. .
    Rubins HB et al (1999) Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. New Engl J Med 341:410–418PubMedCrossRefGoogle Scholar
  64. .
    Rush AJ, Marangell LB, Sackheim HA et al (2005) Vagus nerve stimulation for treatment-resistant depression: A randomized controlled acute phase trial. Biol Psychiatry 58:347–354PubMedCrossRefGoogle Scholar
  65. .
    Sargent DJ, Chan V, Goldberg RM (2001) A three-outcome design for Phase 2 clinical trials. Contr Clin Trials 22:117–125CrossRefGoogle Scholar
  66. .
    Simon R (1989) Optimal two-stage designs for Phase 2 clinical trials. Contr Clin Trials 10:1–10CrossRefGoogle Scholar
  67. .
    Simon R, Wittes RE, Ellenberg SS (1985) Randomized Phase 2 clinical trials. Canc Treat Rep 69:1375–1381Google Scholar
  68. .
    Singh AK, Szczech L, Tang LT et al (2006) Correction of anemia with epoetin-alfa in chronic kidney disease. New Engl J Med 355:2085–2098PubMedCrossRefGoogle Scholar
  69. .
    Spiegelhalter DJ, Freedman LS, Blackburn PR (1986) Monitoring clinical trials: Conditional or predictive power? Contr Clini Trials 7:8–17CrossRefGoogle Scholar
  70. .
    Spriggs DR, Brady MF, Vaccarello L (2007) Phase 3 randomized trial of intravenous cisplatin plus a 24 or 96-hour infusion of paclitaxel in epithelial ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 25:4466–4471PubMedCrossRefGoogle Scholar
  71. .
    Stadler WM, Rosner G, Small E (2005) Successful implementation of the randomized discontinuation trial design: An application to the study of the putative antiangiogenic agend carboxyaminomidazole in renal cell carcinoma – CALGB 69901. J Clin Oncol 23:3726–3732PubMedCrossRefGoogle Scholar
  72. .
    Sternberg CN, Petrylak DP, Sartor O et al (2009) Multinational double-blind phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after chemotherapy: The SPARC trial. J Clin Oncol 27(32):5431–5438PubMedCrossRefGoogle Scholar
  73. .
    Teerlink JR, McMurray JJV, Bourge RC (2005) Tezosentan in patients with acute heart failure: design of the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study (VERITAS). Am Heart J 150:46–53PubMedCrossRefGoogle Scholar
  74. .
    Thall PF, Simon R, Ellenberg SS (1988) Two-stage selection and testing designs for comparative clinical trials. Biometrika 75:303–310CrossRefGoogle Scholar
  75. .
    Trotta F, Apolone G, Garattini S et al (2008) Stopping a trial early in oncology; for patients or for industry? Ann Oncol 9:1347–1353CrossRefGoogle Scholar
  76. .
    US Food and Drug Administration (2006) Guidance for trial sponsors: Establishment and operation of clinical trial data monitoring committees. http://www.fda.gov/cber/gdlns/clintrialdmc.pdf
  77. .
    US National Heart, Lung and Blood Institute ARDS Clinical Trials Network (2004) Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. New Eng J Med 351:327–336Google Scholar
  78. .
    Wittes J, Barrett-Connor E, Braunwald E et al (2007) Monitoring the randomized trials of the Women’s Health Initiative: the experience of the Data and Safety Monitoring Board. Clin Trials 4:218–234PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of BiostatisticsJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  2. 2.IDDI ConsultantsInternational Drug Development InstituteLouvain-la-NeuveBelgium
  3. 3.Department of BiostatisticsHasselt UniversityDiepenbeekBelgium
  4. 4.Statistics Collaborative, Inc.WashingtonUSA

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