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Critically appraising noninferiority randomized controlled trials: a primer for emergency physicians

Published online by Cambridge University Press:  02 June 2015

Mohammad Al Deeb ,
Aftab Azad  and
David Barbic
Mohammad Al Deeb
Affiliation:
Department of Emergency Medicine, McGill University Health Centre, Montreal, QC Department of Emergency Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia
Aftab Azad
Affiliation:
Department of Emergency Medicine, McGill University Health Centre, Montreal, QC Department of Emergency Medicine, Hamad Medical Corporation, Doha, Qatar
David Barbic*
Affiliation:
Department of Emergency Medicine, Sunnybrook Health Sciences Centre, Toronto, ON
*
Correspondence to: Dr. David Barbic, Department of Emergency Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto,ON M4N 3N5; david.barbic@gmail.com

Abstract

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Noninferiority (NI) trials aim to show that a new treatment or drug is not inferior to a standard, accepted treatment. The rapid proliferation of NI trials within the literature makes it imperative for emergency physicians to be able to read, interpret, and appraise critically this type of research study. Using several emergency medicine examples from the recent literature, this article outlines the key differences between traditional, superiority randomized controlled trials and NI trials. We summarize four important points that an emergency physician should consider when critically appraising an NI trial: 1) Does the new treatment have tangible benefits over the standard treatment? 2) Was the choice of the NI margin appropriate? 3) Was the effect of the standard treatment preserved? Does the trial have assay sensitivity? and 4) What type of analysis strategy was employed: intention-to-treat (ITT) or per protocol (PP)?

Résumé

Les essais de non-infériorité (ENI) visent à démontrer qu’un nouveau traitement ou un nouveau médicament n’est pas inférieur au traitement de référence, reconnu. La prolifération des ENI dans la documentation rend impérative la capacité des urgentologues à comprendre, à interpréter et à évaluer d’un oeil critique ce type de recherche. Ainsi, l’article fera ressortir, à l’aide de plusieurs exemples tirés de la documentation récente en médecine d’urgence, les principales différences qui existent entre le modèle classique d’essai comparatif, hasardisé , de supériorité , et le modèle d’ENI. Seront résumés quatre points importants qu’un urgentologue devrait envisager lorsqu’il évalue de façon critique un ENI: 1) Le nouveau traitement offre-t-il des avantages tangibles comparativement au traitement habituel? 2) Le choix de l’intervalle de non-infé riorité est-il pertinent? 3) L’effet du traitement de référence est-il conservé ? L’essai est-il sensible? 4) Quel type de straté gie d’analyse a été employé : selon l’intention de traiter ou selon le protocole?

Type
Editorial/Commentary
Information
Canadian Journal of Emergency Medicine , Volume 17 , Issue 3 , May 2015 , pp. 231 - 236
Copyright
Copyright © Canadian Association of Emergency Physicians 2015 

References

1. Dellinger, RP, Levy, MM, Rhodes, A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580–637, doi:10.1097/CCM.0b013e31827e83af.CrossRefGoogle ScholarPubMed
2. Rivers, E, Nguyen, B, Havstad, S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368–1377, doi:10.1056/NEJMoa010307.Google Scholar
3. Jones, A, Kline, JA. Use of goal-directed therapy for severe sepsis and septic shock in academic emergency departments. Crit Care Med 2005;33:1888–1889, doi:10.1097/01.CCM.0000166872.78449.B1.CrossRefGoogle ScholarPubMed
4. Jones, AE, Shapiro, NI, Roshon, M. Implementing early goaldirected therapy in the emergency setting: the challenges and experiences of translating research innovations into clinical reality in academic and community settings. Acad Emerg Med 2007;14:1072–1078, doi:10.1111/j.1553-2712.2007.tb02391.x.Google Scholar
5. Jones, AE, Shapiro, NI, Trzeciak, S, et al. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA 2010;303:739–746, doi:10.1001/jama.2010.158.CrossRefGoogle ScholarPubMed
6. Wangge, G, Roes, KC, de Boer, A, et al. The challenges of determining noninferiority margins: a case study of non inferiority randomized controlled trials of novel anticoagulants. CMAJ 2012;185:222–227, doi:10.1503/cmaj.120142.Google Scholar
7. Piaggio, G, Elbourne, DR, Altman, DG, et al. Reporting of noninferiority and equivalence randomized trials. JAMA 2006;295:1152–1160, doi:10.1001/jama.295.10.1152.Google Scholar
8. 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, doi:10.1002/sim.1425.Google Scholar
9. Mulla, SM, Scott, IA, Jackevicius, CA, et al. How to use a noninferiority trial: users’ guides to the medical literature. JAMA 2012;308:2605–2611, doi:10.1001/2012.jama.11235.CrossRefGoogle ScholarPubMed
10. Schumi, J, Wittes, JT. Through the looking glass: understanding non-inferiority. Trials 2011;12(1):106 doi:10.1186/1745-6215-12-106.CrossRefGoogle ScholarPubMed
11. Center for Biologics Evaluation and Research, US Food and Drug Administration. Guidance for industry non-inferiority clinical trials February 24, 2010 Silver Spring (MD) US Food and Drug Administration; 2010.Google Scholar
12. Huitfeldt, B, Hummel, J. The draft FDA guideline on noninferiority clinical trials: a critical review from European pharmaceutical industry statisticians. Pharm Stat 2011;10:414–419, doi:10.1002/pst.508.Google Scholar
13. Wangge, G, de Boer, A, Klungel, OH, et al. Expert-opinion on non-inferiority margin: a case study of oral anti-coagulant agents for prophylaxis of venous thromboembolic events after orthopaedic surgery. Thromb Res 2013;131:368–371, doi:10.1016/j.thromres.2013.01.013.CrossRefGoogle Scholar
14. Altman, DG, Schulz, KF, Moher, D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001;134:663–694, doi:10.7326/0003-4819-134-8-200104170-00012.Google Scholar
15. Tamayo-Sarver, JH. Advanced statistics: how to determine whether your intervention is different, at least as effective as, or equivalent: a basic introduction. Acad Emerg Med 2005;12:536–542, doi:10.1111/j.1553-2712.2005.tb00897.x.CrossRefGoogle ScholarPubMed
16. ICH Expert Working Group. Statistical principles for clinical trials. ICH harmonised tripartite guideline. Statistics in Medicine 1999;18:1905–1942.Google Scholar
17. Ferguson, JJ, Califf, RM, Antman, EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-STsegment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45–54.Google Scholar
18. Silbergleit, R, Durkalski, V, Lowenstein, D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591–600, doi:10.1056/NEJMoa1107494.Google Scholar
19. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–2510, doi:10.1056/NEJMoa1007903.Google Scholar
20. Schulman, S, Kearon, C, Kakkar, AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2013;361:2342–2352, doi:10.1056/NEJMoa0906598.CrossRefGoogle Scholar
21. Kearon, C, Akl, EA, Comerota, AJ, et al. Antithrombotic therapy for VTE disease, Antithrombotic therapy and prevention of thrombosis, 9th edition. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e4195.Google Scholar
22. Kaul, S, Diamond, GA. Good enough: a primer on the analysis and interpretation of noninferiority trials. Ann InternMed 2006;145:62–69, doi:10.7326/0003-4819-145-1-200607040-00011.Google Scholar
23. Fleming, TR. Current issues in non-inferiority trials. Stat Med 2008;27:317–332, doi:10.1002/sim.2855.Google Scholar
24. Rivers, EP, Elkin, R, Cannon, CM. Counterpoint: should lactate clearance be substituted for central venous oxygen saturation as goals of early severe sepsis and septic shock therapy? No. Chest 2011;140:1408–1413, doi:10.1378/chest.11-2563.Google Scholar
25. Jones, AE. Point: should lactate clearance be substituted for central venous oxygen saturation as goals for early severe sepsis and septic shock therapy? Yes. Chest 2011;140:1406–1407, doi:10.1378/chest.11-2560.CrossRefGoogle ScholarPubMed
26. Committee for Proprietary Medicinal Products. Points to consider on switching between superiority and non-inferiority. London (UK) European Agency for the Evaluation of Medicinal Products; 2000.Google Scholar