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Non-inferiority Randomized Controlled Trials

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Evidence-Based Surgery

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Abstract

Clinical trialists may explore competing interventions , not to demonstrate the superiority of one over the other, but instead to determine if a new therapy that is less burdensome, costly, or with lower risks of harms is not substantially less effective than the existing standard of care. This type of study is called a non-inferiority trial . This chapter describes an approach to assessing the validity of non-inferiority trials, interpreting results, and applying their findings. Clinicians, in consultation with their patients, should determine whether the loss in effectiveness suggested by the upper boundary of the 95% CI associated with the treatment effect of the novel approach is acceptable, regardless of a specific trial’s non-inferiority threshold.

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References

  1. Cadeddu M, Farrokhyar F, Levis C, Cornacchi S, Haines T, Thoma A. users’ guide to the surgical literature. Understanding confidence intervals. Can J Surg. 2012;55(3):207–11.

    Article  Google Scholar 

  2. Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet. 2015;386(9990):249–57.

    Article  Google Scholar 

  3. Alberts DS, Hannigan EV, Liu PY, Jiang C, Wilczynski S, Copeland L, et al. Randomized trial of adjuvant intraperitoneal alpha-interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: an intergroup study. Gynecol Oncol. 2006;100(1):133–8.

    Article  CAS  Google Scholar 

  4. Bothwell LE, Greene JA, Podolsky SH, Jones DS. In: Malina D, editor. Assessing the gold standard—lessons from the history of RCTs. N Engl J Med. 2016;374(22):2175–81.

    Google Scholar 

  5. Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med. 2001;134(8):663–94.

    Article  CAS  Google Scholar 

  6. Hahn S. Understanding noninferiority trials. Korean J Pediatr. 2012;55(11):403–7.

    Article  Google Scholar 

  7. Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: Ethical and scientific issues. Ann Intern Med. 2000;133(6):455–63.

    Google Scholar 

  8. Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: Practical issues and specific cases. Ann Intern Med. 2000;133(6):464–70.

    Google Scholar 

  9. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Non-inferiority clinical trials to establish effectiveness: guidance for industry. [internet]. 2016. [cited 2018 July 5]. Available from https://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf.

  10. Althunian TA, de Boer A, Groenwold RHH, Klungel OH. Defining the noninferiority margin and analysing noninferiority: an overview. Br J Clin Pharmacol. 2017;83(8):1636–42.

    Article  Google Scholar 

  11. Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG, For the CONSORT Group. Reporting of noninferiority and equivalence randomized trials. JAMA. 2012;308(24):2594–604.

    Google Scholar 

  12. Aberegg SK, Hersh AM, Samore MH. Empirical consequences of current recommendations for the design and interpretation of noninferiority trials. J Gen Intern Med. 2018;33(1):88–96.

    Article  Google Scholar 

  13. Thoma A, Farrokhyar F, Bhandari M, Tandan V, Evidence-Based Surgery Working Group. Users’ guide to the surgical literature. How to assess a randomized controlled trial in surgery. Can J Surg. 2004;47(3):200–8.

    Google Scholar 

  14. Thoma A, Farrokhyar F, Waltho D, Braga LH, Sprague S, Goldsmith CH. Users’ guide to the surgical literature: how to assess a noninferiority trial. Can J Surg. 2017;60(6):426–32.

    Article  Google Scholar 

  15. Anthon CT, Granholm A, Perner A, Laake JH, Møller MH. No firm evidence that lack of blinding affects estimates of mortality in randomized clinical trials of intensive care interventions: a systematic review and meta-analysis. J Clin Epidemiol. 2018;100:71–81.

    Article  Google Scholar 

  16. Seidman JD, Yemelyanova A, Cosin JA, Smith A, Kurman RJ. Survival rates for international federation of gynecology and obstetrics stage III ovarian carcinoma by cell type. Int J Gynecol Cancer. 2012;22(3):367–71.

    Article  Google Scholar 

  17. Gupta SK. Intention-to-treat concept: a review. Perspect Clin Res. 2011;2(3):109–12.

    Article  Google Scholar 

  18. Vergote I, Tropé CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363(10):943–53.

    Article  CAS  Google Scholar 

  19. Herzog TJ, Armstrong DK, Brady MF, Coleman RL, Einstein MH, Monk BJ, et al. Ovarian cancer clinical.

    Google Scholar 

  20. Shimokawa M, Kogawa T, Shimada T, Saito T, Kumagai H, Ohki M, et al. Overall survival and post-progression survival are potent endpoint in phase III trials of second/third-line chemotherapy for advanced or recurrent epithelial ovarian cancer. J Cancer. 2018;9(5):872–9.

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada

    Yaad Shergill, Atefeh Noori, Ngai Chow & Jason W. Busse

  2. Department of Anesthesia, McMaster University, Hamilton, ON, Canada

    Jason W. Busse

  3. Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, ON, Canada

    Jason W. Busse

  4. Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University, Hamilton, ON, Canada

    Jason W. Busse

Authors
  1. Yaad Shergill
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  2. Atefeh Noori
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  3. Ngai Chow
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  4. Jason W. Busse
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Corresponding author

Correspondence to Jason W. Busse .

Editor information

Editors and Affiliations

  1. Department of Surgery, Division of Plastic Surgery, Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada

    Achilles Thoma

  2. Department of Surgery, Division of Orthopaedic Surgery, Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada

    Sheila Sprague

  3. Department of Surgery, Division of Plastic Surgery, McMaster University, Hamilton, ON, Canada

    Sophocles H. Voineskos

  4. Department of Health Research Methods, Evidence and Impact (HEI), McMaster University, Hamilton, ON, Canada

    Charles H. Goldsmith

Appendix

Appendix

  1. 1.

    Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet. 2015;386(9990):249–57.

  2. 2.

    Ledermann JA. Primary chemotherapy: the future for the management of advanced ovarian cancer? Int J Gynecol Cancer. 2010;11(Suppl 2):S17–9.

  3. 3.

    Kayikcioglu F, Kose MF, Boran N, Caliskan E, Tulunay G. Neoadjuvant chemotherapy or primary surgery in advanced epithelial ovarian carcinoma. Int J Gynecol Cancer. 2001;11(6):466–70

  4. 4.

    Milam MR, Tao X, Coleman RL, Harrell R, Bassett R, Dos Reis R, et al. Neoadjuvant chemotherapy is associated with prolonged primary treatment intervals in patients with advanced epithelial ovarian cancer. Int J Gynecol Cancer. 2011;21(1):66–71.

  5. 5.

    Munstedt K, Franke FE. Role of primary surgery in advanced ovarian cancer. World J Surg Oncol. 2004;2:32.

  6. 6.

    Hegazy MA, Hegazi RA, Elshafei MA, Setit AE, Elshamy MR, Eltatoongy M, et al. Neoadjuvant chemotherapy versus primary surgery in advanced ovarian carcinoma. World J Surg Oncol. 2005;3:57.

  7. 7.

    Alberts DS, Hannigan EV, Liu PY, Jiang C, Wilczynski S, Copeland L, et al. Randomized trial of adjuvant intraperitoneal alpha interferon in stage III ovarian cancer patients who have no evidence of disease after primary surgery and chemotherapy: an intergroup study. Gynecol Oncol. 2006;100(1):133–8.

  8. 8.

    Eisenhauer EL, Tew WP, Levine DA, Lichtman SM, Brown CL, Aghajanian C, et al. Response and outcomes in elderly patients with stages IIIC-IV ovarian cancer receiving platinum–taxane chemotherapy. Gynecol Oncol. 2007;106(2):381–7.

  9. 9.

    Drews F, Bertelli G, Lutchman-Singh K. Management of advanced ovarian cancer in South West Wales—a comparison between primary debulking surgery and primary chemotherapy treatment strategies in an unselected, consecutive patient cohort. Cancer Epidemiol. 2017;49:85–91.

  10. 10.

    Jarnagin WR, Dematteo RP, D’Angelica MI, Barakat RR, Chi DS. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer. Gynecol Oncol. 2006;103(3):1083–90.

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Shergill, Y., Noori, A., Chow, N., Busse, J.W. (2019). Non-inferiority Randomized Controlled Trials. In: Thoma, A., Sprague, S., Voineskos, S., Goldsmith, C. (eds) Evidence-Based Surgery. Springer, Cham. https://doi.org/10.1007/978-3-030-05120-4_13

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  • DOI: https://doi.org/10.1007/978-3-030-05120-4_13

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-05119-8

  • Online ISBN: 978-3-030-05120-4

  • eBook Packages: MedicineMedicine (R0)

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