Noninferiority Trials

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

  Article  Google Scholar 

• Bratton DJ, Williams HC, Kahan BC, Phillips PP, Nunn AJ (2012) When inferiority meets non-inferiority: implications for interim analyses. Clin Trials 9(5):605–609

  Article  Google Scholar 

• Chan AW, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA et al (2013) SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 346:e7586

  Article  Google Scholar 

• Committee for Proprietary Medicinal Products (2000) Points to consider on switching between superiority and non-inferiority. https://www.ema.europa.eu/en/documents/scientific-guideline/points-consider-switching-between-superiority-non-inferiority_en.pdf

• Committee for Proprietary Medicinal Products (2002) Points to consider on multiplicity issues in clinical trials. https://www.ema.europa.eu/en/documents/scientific-guideline/points-consider-multiplicity-issues-clinical-trials_en.pdf

• Committee for Proprietary Medicinal Products (2006) Guideline on the choice of the non-inferiority margin. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-choice-non-inferiority-margin_en.pdf

• D’Agostino RB Sr, Massaro JM, Sullivan LM (2003) Non-inferiority trials: design concepts and issues - the encounters of academic consultants in statistics. Stat Med 22(2):169–186

  Article  Google Scholar 

• Dorman SE, Nahid P, Kurbatova EV, Goldberg SV, Bozeman L, Burman WJ et al (2020) High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial. Contemp Clin Trials 90:105938

  Article  Google Scholar 

• Dunn DT, Copas AJ, Brocklehurst P (2018a) Superiority and non-inferiority: two sides of the same coin? Trials 19(1):499

  Article  Google Scholar 

• Dunn DT, Glidden DV, Stirrup OT, McCormack S (2018b) The averted infections ratio: a novel measure of effectiveness of experimental HIV pre-exposure prophylaxis agents. Lancet HIV 5(6):e329–e334

  Article  Google Scholar 

• Evans SR, Rubin D, Follmann D, Pennello G, Huskins WC, Powers JH et al (2015) Desirability of outcome ranking (DOOR) and response adjusted for duration of antibiotic risk (RADAR). Clin Infect Dis 61(5):800–806

  Article  Google Scholar 

• Farrington CP, Manning G (1990) Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 9(12):1447–1454

  Article  Google Scholar 

• Floyd K, Hutubessy R, Kliiman K, Centis R, Khurieva N, Jakobowiak W et al (2012) Cost and cost-effectiveness of multidrug-resistant tuberculosis treatment in Estonia and Russia. Eur Respir J 40(1):133–142

  Article  Google Scholar 

• Food and Drug Administration Center for Biologics Evaluation and Research (CBER) (2020) Guidance for industry. Development and licensure of vaccines to prevent COVID-19. U.S. Department of Health and Human Services. https://www.fda.gov/media/139638/download

• Food and Drug Administration Center for Drug Evaluation and Research (CDER) (2013) Guidance for industry. Pulmonary tuberculosis: developing drugs for treatment, draft guidance. U.S. Department of Health and Human Services. https://www.fda.gov/media/87194/download

• Food and Drug Administration Center for Drug Evaluation and Research (CDER) (2016) Guidance for Industry. Non-inferiority clinical trials to establish effectiveness. U.S. Department of Health and Human Services. https://www.fda.gov/media/78504/download

• Gamalo-Siebers M, Gao A, Lakshminarayanan M, Liu G, Natanegara F, Railkar R et al (2016) Bayesian methods for the design and analysis of noninferiority trials. J Biopharm Stat 26(5):823–841

  Article  Google Scholar 

• Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Dore C et al (2017) Guidelines for the content of statistical analysis plans in clinical trials. JAMA 318(23):2337–2343

  Article  Google Scholar 

• Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR et al (2014) Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med 371(17):1577–1587

  Article  Google Scholar 

• Gomberg-Maitland M, Frison L, Halperin JL (2003) Active-control clinical trials to establish equivalence or noninferiority: methodological and statistical concepts linked to quality. Am Heart J 146(3):398–403

  Article  Google Scholar 

• Hernan MA, Robins JM (2017) Per-protocol analyses of pragmatic trials. N Engl J Med 377(14):1391–1398

  Article  Google Scholar 

• Holmgren EB (1999) Establishing equivalence by showing that a specified percentage of the effect of the active control over placebo is maintained. J Biopharm Stat 9(4):651–659

  Article  MATH  Google Scholar 

• Horsburgh CR, Shea KM, Phillips P, Lavalley M (2013) Randomized clinical trials to identify optimal antibiotic treatment duration. Trials 14(1):88

  Article  Google Scholar 

• Ibrahim JG, Chen M-H (2000) Power prior distributions for regression models. Stat Sci 15(1):46–60

  MathSciNet  Google Scholar 

• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals For Human Use (1998) Statistical principles for clinical trials (E9). https://database.ich.org/sites/default/files/E9_Guideline.pdf

• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals For Human Use (2000) Choice of control group and related issues in clinical trials (E10). https://database.ich.org/sites/default/files/E10_Guideline.pdf

• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals For Human Use (2019) Estimands and sensitivity analysis in clinical trials. E9(R1). https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf

• James Hung HM, Wang SJ, Tsong Y, Lawrence J, O’Neil RT (2003) Some fundamental issues with non-inferiority testing in active controlled trials. Stat Med 22(2):213–225

  Article  Google Scholar 

• Jindani A, Harrison TS, Nunn AJ, Phillips PP, Churchyard GJ, Charalambous S et al (2014) High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med 371(17):1599–1608

  Article  Google Scholar 

• Jones B, Jarvis P, Lewis JA, Ebbutt AF (1996) Trials to assess equivalence: the importance of rigorous methods. BMJ 313(7048):36–39

  Article  Google Scholar 

• Kaji AH, Lewis RJ (2015) Noninferiority trials: is a new treatment almost as effective as another? JAMA 313(23):2371–2372

  Article  Google Scholar 

• Kirby S, Burke J, Chuang-Stein C, Sin C (2012) Discounting phase 2 results when planning phase 3 clinical trials. Pharm Stat 11(5):373–385

  Article  Google Scholar 

• Korn EL, Freidlin B (2018) Interim monitoring for non-inferiority trials: minimizing patient exposure to inferior therapies. Ann Oncol 29(3):573–577

  Article  Google Scholar 

• Machin D, Campbell MJ, Tan SB, Tan SH (2018) Sample size tables for clinical, laboratory and epidemiology studies, 4th edn. Wiley, Hoboken

  Book  Google Scholar 

• Mauri L, D’Agostino RB Sr (2017) Challenges in the design and interpretation of noninferiority trials. N Engl J Med 377(14):1357–1367

  Article  Google Scholar 

• Mayer KH, Molina JM, Thompson MA, Anderson PL, Mounzer KC, De Wet JJ et al (2020) Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. Lancet 396(10246):239–254

  Article  Google Scholar 

• Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ (2010) Summarizing historical information on controls in clinical trials. Clin Trials 7(1):5–18

  Article  Google Scholar 

• Ng T-H (2015) Noninferiority testing in clinical trials: issues and challenges. Taylor & Francis/CRC Press, Boca Raton, xvii, 190 p

  MATH  Google Scholar 

• Nunn AJ, Phillips PPJ, Gillespie SH (2008) Design issues in pivotal drug trials for drug sensitive tuberculosis (TB). Tuberculosis 88:S85–S92

  Article  Google Scholar 

• Nunn AJ, Rusen I, Van Deun A, Torrea G, Phillips PP, Chiang CY et al (2014) Evaluation of a standardized treatment regimen of anti-tuberculosis drugs for patients with multi-drug-resistant tuberculosis (STREAM): study protocol for a randomized controlled trial. Trials 15(1):353

  Article  Google Scholar 

• Nunn AJ, Phillips PPJ, Meredith SK, Chiang CY, Conradie F, Dalai D et al (2019) A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med 380(13):1201–1213

  Article  Google Scholar 

• Phillips PP, Morris TP, Walker AS (2016) DOOR/RADAR: a gateway into the unknown? Clin Infect Dis 62(6):814–815

  Article  Google Scholar 

• Piaggio G, Elbourne D, Altman D, Pocock S, Evans S (2006) Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA 295(10):1152

  Article  Google Scholar 

• Piaggio G, Elbourne DR, Pocock SJ, Evans SJ, Altman DG, Group C (2012) Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA 308(24):2594–2604

  Article  Google Scholar 

• Quartagno M, Walker AS, Carpenter JR, Phillips PP, Parmar MK (2018) Rethinking non-inferiority: a practical trial design for optimising treatment duration. Clin Trials 15(5):477–488. https://doi.org/10.1177/1740774518778027

  Article  Google Scholar 

• Quartagno M, Walker AS, Babiker AG, Turner RM, Parmar MKB, Copas A et al (2020) Handling an uncertain control group event risk in non-inferiority trials: non-inferiority frontiers and the power-stabilising transformation. Trials 21(1):145

  Article  Google Scholar 

• Rehal S, Morris TP, Fielding K, Carpenter JR, Phillips PP (2016) Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals. BMJ Open 6(10):e012594

  Article  Google Scholar 

• Rothmann MD, Tsou HH (2003) On non-inferiority analysis based on delta-method confidence intervals. J Biopharm Stat 13(3):565–583

  Article  MATH  Google Scholar 

• Rothmann MD, Wiens BL, Chan ISF (2012) Design and analysis of non-inferiority trials. Chapman & Hall/CRC, Boca Raton, xvi, 438 p

  MATH  Google Scholar 

• Sankoh AJ (2008) A note on the conservativeness of the confidence interval approach for the selection of non-inferiority margin in the two-arm active-control trial. Stat Med 27(19):3732–3742

  Article  MathSciNet  Google Scholar 

• Simon R (1999) Bayesian design and analysis of active control clinical trials. Biometrics 55(2):484–487

  Article  MATH  Google Scholar 

• Snapinn S, Jiang Q (2008) Preservation of effect and the regulatory approval of new treatments on the basis of non-inferiority trials. Stat Med 27(3):382–391

  Article  MathSciNet  Google Scholar 

• Spiegelhalter DJ, Freedman LS, Parmar MK (1994) Bayesian approaches to randomized trials. J R Stat Soc A Stat Soc 157(3):357–387

  Article  MathSciNet  MATH  Google Scholar 

• Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ (2011) Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One 6(4):e17601

  Article  Google Scholar 

• Treadwell JR, Uhl S, Tipton K, Shamliyan T, Viswanathan M, Berkman ND et al (2012) Assessing equivalence and noninferiority. J Clin Epidemiol 65(11):1144–1149

  Article  Google Scholar 

• Tsui M, Rehal S, Jairath V, Kahan BC (2019) Most noninferiority trials were not designed to preserve active comparator treatment effects. J Clin Epidemiol 110:82–89

  Article  Google Scholar 

• Tweed CD, Wills GH, Crook AM, Amukoye E, Balanag V, Ban AYL et al (2021) A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB. Int J Tuberc Lung Dis 25(4):305–314

  Article  Google Scholar 

• Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P et al (2010) Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 182(5):684–692

  Article  Google Scholar 

• Wellek S (2010) Testing statistical hypotheses of equivalence and noninferiority, 2nd edn. CRC Press, Boca Raton, xvi, 415 p

  Book  MATH  Google Scholar 

• White IR, Carpenter J, Horton NJ (2012) Including all individuals is not enough: lessons for intention-to-treat analysis. Clin Trials 9(4):396–407

  Article  Google Scholar 

• Wiens BL, Zhao W (2007) The role of intention to treat in analysis of noninferiority studies. Clin Trials 4(3):286–291

  Article  Google Scholar 

• Williams HC, Wojnarowska F, Kirtschig G, Mason J, Godec TR, Schmidt E et al (2017) Doxycycline versus prednisolone as an initial treatment strategy for bullous pemphigoid: a pragmatic, non-inferiority, randomised controlled trial. Lancet 389(10079):1630–1638

  Article  Google Scholar 

• World Health Organization (2011) Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update. World Health Organization

  Google Scholar 

• World Health Organization (2019) WHO consolidated guidelines on drug-resistant tuberculosis treatment. World Health Organization, Geneva

  Google Scholar 

• World Health Organization (2020) Global tuberculosis report 2020. World Health Organization, Geneva

  Google Scholar 

Download references