Design and Interpretation of Noninferiority Trials

Design and Interpretation of Noninferiority Trials 1 2 Scott K. Aberegg, MD, MPH and Andrew M. Hersh, MD 1 2 Division of Pulmonary and Critical Care Medicine , University of Utah School of Medicine, Salt Lake City, UT, USA; Brooke Army Medical Center, San Antonio, TX, USA. J Gen Intern Med can be adapted at the level of the patient or the population, DOI: 10.1007/s11606-018-4505-8 holds promise for shared decision-making using the re- © Society of General Internal Medicine 2018 sults of randomized trials of all types. Application of these methods will be facilitated by reliable estimates of effects from well designed and executed trials, and from a focus on actual confidence intervals of beneficial and harmful effects, rather than arbitrary and potentially misleading uthors’ reply: We are grateful for the correspondents’ conclusions such as Bnoninferior^ or Binconclusive.^ interest in our descriptive study of noninferiority trials. Turgeon et al. have retrospectively extended the part of our analysis comparing ITT (intention-to-treat) and PP (per- Corresponding Author: Scott K. Aberegg, MD, MPH; Division of protocol) methodologies to 2004. While we found that 64% Pulmonary and Critical Care Medicine University of Utah School of Medicine, Salt Lake City, UT, USA (e-mail: scottaberegg@gmail.com). of trials in our cohort from 2011 to 2016 reported both ITT and PP analyses, they found that only 45% of trials in the same Compliance with Ethical Standards: journals between 2004 and 2014 reported both analyses. These results are consistent with those found in other reports, Conflict of Interest: The authors declare that they do not have a with modest increases over time in the reporting of both conflict of interest. –4 analyses. Regarding discordant results between analyses, both of our results reinforce the observation that the theoretical claim that PP analyses are more conservative than ITT analy- REFERENCES ses is empirically ungrounded. Ideally, both PP and ITT meth- 1. Aberegg SK, Hersh AM, Samore MH. Empirical Consequences of Current odologies should be carefully described and reported with an a Recommendations for the Design and Interpretation of Noninferiority Trials. Journal of general internal medicine 2018;33(1):88–96. https://doi. priori plan for handling discordant results when they occur. org/10.1007/s11606-017-4161-4 Vach et al. highlight our finding that a fundamental 2. Wangge G, Klungel OH, Roes KC, et al. Room for improvement in conducting and reporting non-inferiority randomized controlled trials on ethical tenet of noninferiority trials, namely that the NT drugs: a systematic review. PLoS One 2010;5(10):e13550. https://doi.org/ (new treatment) have some secondary benefit, is frequent- 10.1371/journal.pone.0013550 [published Online First: 2010/11/05] ly unmet. We regret that we neglected to reference their 3. Rehal S, Morris TP, Fielding K, et al. Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals. BMJ systematic review of this specific issue, which showed 5 Open 2016;6(10) https://doi.org/10.1136/bmjopen-2016-012594 similar results to ours. In their study, 51% of trials ex- 4. Le Henanff A, Giraudeau B, Baron G, et al. Quality of reporting of noninferiority and equivalence randomized trials. JAMA plicitly reported the purported secondary advantages of 2006;295(10):1147–51. https://doi.org/10.1001/jama.295.10.1147 [pub- the NT, and an additional 25% vaguely or indirectly lished Online First: 2006/03/09] mentioned secondary advantages. The corresponding per- 5. Gladstone BP, Vach, W. Analyzing noninferiority trials: it is time for advantage deficit assessment—an observational study of published non- centages in our trial were 70 and 20%. In their article, inferiority trials. Open Access J Clin Trials 2015;2015(7):11–21. https:// Vach et al. propose the integration of measures of benefits doi.org/10.2147/OAJCT.S74821 and harms of NT versus active control in a manner con- sistent with expected utility theory. This approach, which http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of General Internal Medicine Springer Journals

Design and Interpretation of Noninferiority Trials

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Springer US
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Copyright © 2018 by Society of General Internal Medicine
Subject
Medicine & Public Health; Internal Medicine
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0884-8734
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1525-1497
D.O.I.
10.1007/s11606-018-4505-8
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Abstract

1 2 Scott K. Aberegg, MD, MPH and Andrew M. Hersh, MD 1 2 Division of Pulmonary and Critical Care Medicine , University of Utah School of Medicine, Salt Lake City, UT, USA; Brooke Army Medical Center, San Antonio, TX, USA. J Gen Intern Med can be adapted at the level of the patient or the population, DOI: 10.1007/s11606-018-4505-8 holds promise for shared decision-making using the re- © Society of General Internal Medicine 2018 sults of randomized trials of all types. Application of these methods will be facilitated by reliable estimates of effects from well designed and executed trials, and from a focus on actual confidence intervals of beneficial and harmful effects, rather than arbitrary and potentially misleading uthors’ reply: We are grateful for the correspondents’ conclusions such as Bnoninferior^ or Binconclusive.^ interest in our descriptive study of noninferiority trials. Turgeon et al. have retrospectively extended the part of our analysis comparing ITT (intention-to-treat) and PP (per- Corresponding Author: Scott K. Aberegg, MD, MPH; Division of protocol) methodologies to 2004. While we found that 64% Pulmonary and Critical Care Medicine University of Utah School of Medicine, Salt Lake City, UT, USA (e-mail: scottaberegg@gmail.com). of trials in our cohort from 2011 to 2016 reported both ITT and PP analyses, they found that only 45% of trials in the same Compliance with Ethical Standards: journals between 2004 and 2014 reported both analyses. These results are consistent with those found in other reports, Conflict of Interest: The authors declare that they do not have a with modest increases over time in the reporting of both conflict of interest. –4 analyses. Regarding discordant results between analyses, both of our results reinforce the observation that the theoretical claim that PP analyses are more conservative than ITT analy- REFERENCES ses is empirically ungrounded. Ideally, both PP and ITT meth- 1. Aberegg SK, Hersh AM, Samore MH. Empirical Consequences of Current odologies should be carefully described and reported with an a Recommendations for the Design and Interpretation of Noninferiority Trials. Journal of general internal medicine 2018;33(1):88–96. https://doi. priori plan for handling discordant results when they occur. org/10.1007/s11606-017-4161-4 Vach et al. highlight our finding that a fundamental 2. Wangge G, Klungel OH, Roes KC, et al. Room for improvement in conducting and reporting non-inferiority randomized controlled trials on ethical tenet of noninferiority trials, namely that the NT drugs: a systematic review. PLoS One 2010;5(10):e13550. https://doi.org/ (new treatment) have some secondary benefit, is frequent- 10.1371/journal.pone.0013550 [published Online First: 2010/11/05] ly unmet. We regret that we neglected to reference their 3. Rehal S, Morris TP, Fielding K, et al. Non-inferiority trials: are they inferior? A systematic review of reporting in major medical journals. BMJ systematic review of this specific issue, which showed 5 Open 2016;6(10) https://doi.org/10.1136/bmjopen-2016-012594 similar results to ours. In their study, 51% of trials ex- 4. Le Henanff A, Giraudeau B, Baron G, et al. Quality of reporting of noninferiority and equivalence randomized trials. JAMA plicitly reported the purported secondary advantages of 2006;295(10):1147–51. https://doi.org/10.1001/jama.295.10.1147 [pub- the NT, and an additional 25% vaguely or indirectly lished Online First: 2006/03/09] mentioned secondary advantages. The corresponding per- 5. Gladstone BP, Vach, W. Analyzing noninferiority trials: it is time for advantage deficit assessment—an observational study of published non- centages in our trial were 70 and 20%. In their article, inferiority trials. Open Access J Clin Trials 2015;2015(7):11–21. https:// Vach et al. propose the integration of measures of benefits doi.org/10.2147/OAJCT.S74821 and harms of NT versus active control in a manner con- sistent with expected utility theory. This approach, which

Journal

Journal of General Internal MedicineSpringer Journals

Published: May 29, 2018

References

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