Non-inferiority studies

Recent years have seen a considerable increase in the number of non-inferiority studies. Unlike superiority studies, these studies aim to show that a new drug is not less effective than an existing one.
However, the appropriateness of non-inferiority studies is still being debated. Advocates of such studies claim that this type of research is justified in certain situations, for instance when a drug is expected to have the same efficacy but to have fewer side-effects, or to be more convenient to use (e.g. lower dosage frequency) or is cheaper. One may question, however, whether such assumed advantages should not also be examined and proven (in a superiority study). Non-inferiority studies can also be used to expand the range of therapeutic options. For some life-threatening indications it may be sufficient to prove that drugs are not less effective than the standard therapy.
Some opponents regard non-inferiority studies as unethical, as patients taking part in such studies are exposed to potential side-effects while no added benefits are to be expected from the new drug. Nearly all relevant research questions regarding new drugs need to be answered in a superiority study, viz. those to assess whether the new drugs perform better than the current standard therapy. Studies of a new drug whose only purpose is to prove that it does not perform worse than the standard treatment should not be undertaken, for ethical and financial reasons. In other words, researchers will have to clearly justify their decision to start a non-inferiority study in their publications. Medical ethics committees and registration authorities should also assess these studies more critically.
The design and analyses of non-inferiority studies differ from those of superiority studies. There are certain methodological drawbacks to non-inferiority studies, such as the arbitrarily chosen non-inferiority margin (delta: δ or ∆), that is, the maximum negative effect at which a drug can still be regarded as not less effective. The larger this margin, the easier it becomes to establish non-inferiority.
In reading and evaluating publications on non-inferiority studies, doctors, pharmacists and registration authorities should keep the concerns listed in the box on page 33 in mind. If one or more of these requirements are not being met, caution is warranted in interpreting the study results.

1. D’Agostino RB, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues – the
encounters of academic consultants in statistics. Stat Med 2003; 22: 169-186.
2. Wangge G, Roes KC, Boer A de, Hoes AW, Knol MJ. The challenges of determining noninferiority margins : a case study of noninferiority randomized controlled trials. CMAJ 2013; 185: 222-227.
3. Soonawala D, Middelburg R, Egger M, Vandenbroucke JP, Dekkers OM. Efficacy of experimental treatments compared with standard treatments in non-inferiority trials: a meta-analysis of randomized controlled trials. Int J Epidemiol 2010; 39: 1567-1581.
4. Sterne JAC, Smith GD. Sifting the evidence ─what’s wrong with significance tests? BMJ 2001; 322: 226-231.
5. Soonawala D, Dekkers OM. ’Non-inferiority’-studies: mogelijkheden en kanttekeningen. Ned Tijdschr Geneeskd. 2012; 156: A4665.
6. Wangge G, Klungel OH, Roes KCB, Boer A de, Hoes AW, Knol MJ. Room for improvement in conducting and reporting non-inferiority randomized controlled trials on drugs: a systematic review. PloS One 2010; 5: e13550.
7. Garattini S. Bertele V. Ethics in clinical research. J Hepatol 2009; 51: 792-797.
8. Dühmke E, Franklin J, Pfreundschuh M, Sehlen S, Willich N, Rühl U, et al. Low-dose radiation is sufficient for the noninvolved extended-field treatment infavorable early-stage Hodgkin’s disease: long-term results of a randomized trial of radiotherapy alone. J Clin Oncol 2001; 19: 2905-2914.
9. Inagaki N, Atsumi Y, Oura T, Saito H, Imaoka T. Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority trial. Clin Ther 2012; 34: 1892-1908.
10. Stolpman DR, Solem C A, Eastlick D, Adlis S, Shaw MJ. A randomized controlled trial comparing a low-residue diet versus clear liquids for colonoscopy preparation: impact on tolerance, procedure time, and adenoma detection rate. Journal of Clin Gastroenterol 2014; 48: 851-855.
11. Powers JH, Cooper CK, Lin D, Ross DB. Sample size and the ethics of non-inferiority trials. Lancet 2005; 366: 24-25.
12. Tauber E, Kollaritsch H, Korinek M, Rendi-Wagner P, Jilma B, Firbas C, et al. Safety and immunogenicity of a Vero-cell-derived, inactivated Japanese encephalitis vaccine: a non-inferiority, phase III, randomised controlled trial. Lancet 2007; 370: 1847-1853.
13. Garattini S, Bertele V, Bassi L li. How can research ethics committees protect patients better? BMJ 2003; 326: 1199-1201.
14. Garattini S, Bertele V. Non-inferiority trials are unethical because they disregard patients’ interests. Lancet 2007; 370: 1875-1877.
15. Anoniem. Tests for equivalence or non-inferiority--why? Drug Ther Bull 2008; 46: 55-56.
16. Aberegg S. Reporting noninferiority trials. JAMA 2013; 309: 1584-1585.
17. Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). Guidance for industry antibacterial drug products: use of non-inferiority trials to support approval [document op het internet]. US Food and Drug Administration. Via:
18. Discussion paper on the clinical investigation of medicines for the treatment of Alzheimer’s disease and other dementias [document op het internet]. European Medicines Agency. Via:
19. Guideline on the choice of the non-inferiority margin [document op het internet]. European Medicines Agency. Via:
20. Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). Draft guidance: guidance for industry non-inferiority clinical trials [document op het internet]. US Food and Drug Administration. Via:
21. Henanff AL, Giraudeau B, Baron G, Ravaud Ph. Quality of reporting of noninferiority and equivalence randomized trials. JAMA 2006; 295: 1147-1151.
22. Wangge G, Klungel OH, Roes KC, Boer A de, Hoes AW, Knol MJ. Interpretation and inference in noninferiority randomized controlled trials in drug research. Clin Pharmacol Ther 2010; 88: 420-423.
23. Wangge G, Boer A de, Klungel OH, Hoes AW, Knol MJ. Expert-opinion on non-inferiority margin: a case study of oral anti-coagulant agents for prophylaxis of venous thromboembolic events after orthopedic surgery. Thromb Res 2013; 131: 368-371.
24. Wangge G, Klungel OH, Roes KC, Boer A de, Hoes AW, Knol MJ. Should non-inferiority drug trials be banned altogether? Drug Discov Today 2013; 18: 601-604.
25. Piaggio G, Elbourne DR, Pocock SJ, Evans SJW, Altman DG. Reporting of noninferiority and equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA 2012; 308: 2594-2604.
26. Gopal AD, Desai NR, Tse T, Ross JS. Reporting of noninferiority trials in and corresponding publications. JAMA 2015; 313: 1163-1165.
27. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 2009; 373: 2125-2135.
28. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, et al. Extended use of dabigatran, warfarin or placebo in venous thromboembolism. N Engl J Med 2013; 368: 709-718.
29. Dekkers OM, Soonawala D, Vandenbroucke JP, Egger M. Reporting of noninferiority trials was incomplete in trial registries. Journal of Clinical Epidemiology 2011; 64: 1034-1038.
30. Gøtzsche PC. Lessons from and cautions about noninferiority and equivalence randomized trials. JAMA 2006; 295: 1172-1174.

*The literature refers to the Dutch tekst


  • dr O.M. Dekkers