TO THE EDITOR—Despite their designation, noninferiority study designs allow for small ( presumably inconsequential) decrements in efficacy of the investigational drug relative to the established comparator [1–4]. Once deemed noninferior, the newer agent often assumes the role of standard of care in subsequent clinical trials. Consequently, selection of a comparator is critical to interpretation and extrapolation of the results, but suboptimal choices and successive rounds of noninferiority testing may lead to creeping erosion of the gold-standard bearer. Recent active comparator trials of novel long-acting lipoglycopeptides for acute bacterial skin and skin structure infections illustrate this slippery slope [5–7]. Specifically, protocol-mandated empirical use of vancomycin as the comparator may lower the therapeutic bar because persuasive (albeit not incontrovertible) evidence indicates that penicillinase-resistant
1290
•
CID 2015:60 (15 April)
•
CORRESPONDENCE
Downloaded from http://cid.oxfordjournals.org/ at University of California, Santa Barbara on June 22, 2015
Trials and Tribulations of Noninferiority: Caveat Emptor
Notes Disclaimer. The opinions expressed in this report represent the views of the author and do not necessarily reflect the formal position of Merck. Potential conflict of interest. Merck develops and markets antibacterial drugs. The author is an employee of Merck and owns stock and stock options in the company. Merck formally reviewed a penultimate draft of this manuscript. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Mark J. DiNubile Office of the Chief Medical Officer, Merck, Upper Gwynedd, Pennsylvania
References
6. Corey GR, Kabler H, Mehra P, et al. Singledose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med 2014; 370:2180–90. 7. Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med 2014; 370:2169–79. 8. Deresinski S. Vancomycin: does it still have a role as an antistaphylococcal agent? Expert Rev Anti Infect Ther 2007; 5:393–401. 9. Stryjewski ME, Szczech LA, Benjamin DK Jr, et al. Use of vancomycin or firstgeneration cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis 2007; 44:190–6. 10. Kim SH, Kim KH, Kim HB, et al. Outcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2008; 52:192–7. 11. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355: 653–65. 12. Schweizer ML, Furuno JP, Harris AD, et al. Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillinsusceptible Staphylococcus aureus bacteremia. BMC Infect Dis 2011; 11:279.
Downloaded from http://cid.oxfordjournals.org/ at University of California, Santa Barbara on June 22, 2015
penicillins outperform vancomycin for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia [8–12]. Of course, antibiotic resistance, adverse events, overall expense, and convenience also prominently enter into the cost-benefit equation. Although the available data convincingly demonstrate that both dalbavancin and oritavancin have efficacy generally similar to that of vancomycin in routine skin infections, the untested penicillinase-resistant penicillins should still be regarded as the parenteral drugs of choice for definitive treatment of lifeor limb-threatening MSSA infections, especially in bacteremic patients.
Correspondence: Mark J. DiNubile, MD, FIDSA, UG3C-06, PO Box 1000, North Wales, PA 19454-1099 (mark_dinubile@ merck.com). Clinical Infectious Diseases® 2015;60(8):1290–1 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/civ022
1. Powers JH, Ross DB, Brittain E, Albrecht R, Goldberger MJ. The United States Food and Drug Administration and noninferiority margins in clinical trials of antimicrobial agents. Clin Infect Dis 2002; 34: 879–81. 2. Fleming TR, Powers JH. Issues in noninferiority trials: the evidence in communityacquired pneumonia. Clin Infect Dis 2008; 47(suppl 3):S108–20. 3. DiNubile MJ, Sklar P, Lupinacci RJ, Eron JJ. Paradoxical interpretations of non-inferiority studies: violating the excluded middle. Fut Virol 2012; 7:1055–63. 4. DiNubile MJ. Bias and asymmetry in sequential noninferiority-superiority trial designs. Clin Infect Dis 2013; 56:1841–2. 5. Corey GR, Good S, Jiang H, et al. Single-dose oritavancin compared to 7–10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study. Clin Infect Dis 2015; 60:254–62.
CORRESPONDENCE
•
CID 2015:60 (15 April)
•
1291
1290
•
CID 2015:60 (15 April)
•
CORRESPONDENCE
Downloaded from http://cid.oxfordjournals.org/ at University of California, Santa Barbara on June 22, 2015
Trials and Tribulations of Noninferiority: Caveat Emptor
Notes Disclaimer. The opinions expressed in this report represent the views of the author and do not necessarily reflect the formal position of Merck. Potential conflict of interest. Merck develops and markets antibacterial drugs. The author is an employee of Merck and owns stock and stock options in the company. Merck formally reviewed a penultimate draft of this manuscript. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Mark J. DiNubile Office of the Chief Medical Officer, Merck, Upper Gwynedd, Pennsylvania
References
6. Corey GR, Kabler H, Mehra P, et al. Singledose oritavancin in the treatment of acute bacterial skin infections. N Engl J Med 2014; 370:2180–90. 7. Boucher HW, Wilcox M, Talbot GH, Puttagunta S, Das AF, Dunne MW. Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med 2014; 370:2169–79. 8. Deresinski S. Vancomycin: does it still have a role as an antistaphylococcal agent? Expert Rev Anti Infect Ther 2007; 5:393–401. 9. Stryjewski ME, Szczech LA, Benjamin DK Jr, et al. Use of vancomycin or firstgeneration cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis 2007; 44:190–6. 10. Kim SH, Kim KH, Kim HB, et al. Outcome of vancomycin treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia. Antimicrob Agents Chemother 2008; 52:192–7. 11. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355: 653–65. 12. Schweizer ML, Furuno JP, Harris AD, et al. Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillinsusceptible Staphylococcus aureus bacteremia. BMC Infect Dis 2011; 11:279.
Downloaded from http://cid.oxfordjournals.org/ at University of California, Santa Barbara on June 22, 2015
penicillins outperform vancomycin for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia [8–12]. Of course, antibiotic resistance, adverse events, overall expense, and convenience also prominently enter into the cost-benefit equation. Although the available data convincingly demonstrate that both dalbavancin and oritavancin have efficacy generally similar to that of vancomycin in routine skin infections, the untested penicillinase-resistant penicillins should still be regarded as the parenteral drugs of choice for definitive treatment of lifeor limb-threatening MSSA infections, especially in bacteremic patients.
Correspondence: Mark J. DiNubile, MD, FIDSA, UG3C-06, PO Box 1000, North Wales, PA 19454-1099 (mark_dinubile@ merck.com). Clinical Infectious Diseases® 2015;60(8):1290–1 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/civ022
1. Powers JH, Ross DB, Brittain E, Albrecht R, Goldberger MJ. The United States Food and Drug Administration and noninferiority margins in clinical trials of antimicrobial agents. Clin Infect Dis 2002; 34: 879–81. 2. Fleming TR, Powers JH. Issues in noninferiority trials: the evidence in communityacquired pneumonia. Clin Infect Dis 2008; 47(suppl 3):S108–20. 3. DiNubile MJ, Sklar P, Lupinacci RJ, Eron JJ. Paradoxical interpretations of non-inferiority studies: violating the excluded middle. Fut Virol 2012; 7:1055–63. 4. DiNubile MJ. Bias and asymmetry in sequential noninferiority-superiority trial designs. Clin Infect Dis 2013; 56:1841–2. 5. Corey GR, Good S, Jiang H, et al. Single-dose oritavancin compared to 7–10 days of vancomycin in the treatment of gram-positive acute bacterial skin and skin structure infections: the SOLO II noninferiority study. Clin Infect Dis 2015; 60:254–62.
CORRESPONDENCE
•
CID 2015:60 (15 April)
•
1291
