TY - JOUR
T1 - Antimicrobial agents for complicated skin and skin-structure infections
T2 - Justification of noninferiority margins in the absence of placebo-controlled trials
AU - Spellberg, Brad
AU - Talbot, George H.
AU - Boucher, Helen W.
AU - Bradley, John S.
AU - Gilbert, David
AU - Michael Scheld, W.
AU - Edwards, John
AU - Bartlett, John G.
N1 - Funding Information:
Potential conflicts of interest. B.S. has received research grant support from Astellas, Gilead, Novartis, Merck, and Pfizer; serves on the scientific advisory board of Merck; has consulted for Arpida, Basilea, Advanced Life Sciences, Novo Nordisk, and Theravance; owns equity in NovaDigm Therapeutics; and has previously received speaker’s honoraria from Merck, As-tellas, and Pfizer. G.T. serves, or has recently served, as a consultant to the Actelion, Avera, Bausch and Lomb, Calixa, Cempra, Cerexa, Cubist, Ipsat, Middlebrook, Nabriva, PTC, Rib-X, Shire, Targanta, Tetraphase, Thera-vance, ViroPharma, and Wyeth; and owns equity in Calixa and Mpex. J.B.’s employer has received research grants from AstraZeneca, Cubist, Johnson & Johnson, and Wyeth, and has received reimbursement for J.B.’s role in consulting for AstraZeneca, Cubist, Johnson & Johnson, Wyeth, Forest/ Cerexa, Pfizer, Schering Plough, and Trius. H.B. serves as an advisor/consultant to Astellas, Basilea, Cubist, Johnson & Johnson, Merck, Pfizer, Rib-X, Targanta, and Theravance and has owned shares of Pfizer and Cubist. D.G. serves as an advisor/consultant to Pfizer, Advanced Life Sciences, Pacific Bioscience, Schering-Plough, Roche, Wyeth, and Pfizer and is on the speakers’ bureau for Merck. W.M.S. serves on advisory boards of Pfizer, Cubist, and GlaxoSmithKline. J.E.E. serves on the scientific advisory boards of Pfizer, Merck, and Gilead; has participated in educational programs regarding fungal infections funded by Pfizer, Merck, and Astellas; has received research laboratory support from Pfizer, Merck, and Gilead; and has participated in the Bristol-Myers Squibb Freedom to Discovery research program. J.G.B. serves on the HIV advisory boards for Bristol-Myers Squibb, Abbott Laboratories, and GlaxoSmithKline.
PY - 2009/8/1
Y1 - 2009/8/1
N2 - Background. The United States Food and Drug Administration requires clinical trial noninferiority margins to preserve a fraction (eg, 50%) of the established comparator drug's efficacy versus placebo. Lack of placebo-controlled trials for many infections complicates noninferiority margin justification for and, hence, regulatory review of new antimicrobial agents. Noninferiority margin clarification is critical to enable new antimicrobial development. In the absence of placebo-controlled trials, we sought to define the magnitude of efficacy of antimicrobial agents and resulting noninferiority margins for studies of complicated skin and skin-structure infection (SSSI). Methods. We systematically reviewed literature on complicated SSSI published during 1900-1950 (before widespread penicillin resistance) to define treatment outcomes and confidence intervals (CIs). Antimicrobial efficacy was calculated as the lower limit CI of the cure rate with antimicrobials minus the upper limit CI of the cure rate without antimicrobials. Results. We identified 90 articles describing >28,000 patients with complicated SSSI. For cellulitis/erysipelas, cure rates were 66% (95% CI, 64%-68%) without antibiotics and 98% (95% CI, 96%-99%) for penicillin-treated patients, and penicillin reduced mortality by 10%. Cure rates for wound/ulcer infections were 36% (95% CI, 32%-39%) without antibiotics and 83% (95% CI, 81%-85%) for penicillin-treated patients. For major abscesses, cure rates were 76% (95% CI, 71%-80%) without antibiotics and 96% (95% CI, 94%-98%) for penicillin-treated patients; penicillin reduced mortality by 6%. Conclusion. Systematic review of historical literature enables rational noninferiority margin justification in the absence of placebo-controlled trials and may facilitate regulatory review of noninferiority trials. Noninferiority margins of 14% for cellulitis/erysipelas, 21% for wound/ulcer infections, and 7% for major abscesses would preserve ≥50% of antibiotic efficacy versus placebo for these complicated SSSI subsets.
AB - Background. The United States Food and Drug Administration requires clinical trial noninferiority margins to preserve a fraction (eg, 50%) of the established comparator drug's efficacy versus placebo. Lack of placebo-controlled trials for many infections complicates noninferiority margin justification for and, hence, regulatory review of new antimicrobial agents. Noninferiority margin clarification is critical to enable new antimicrobial development. In the absence of placebo-controlled trials, we sought to define the magnitude of efficacy of antimicrobial agents and resulting noninferiority margins for studies of complicated skin and skin-structure infection (SSSI). Methods. We systematically reviewed literature on complicated SSSI published during 1900-1950 (before widespread penicillin resistance) to define treatment outcomes and confidence intervals (CIs). Antimicrobial efficacy was calculated as the lower limit CI of the cure rate with antimicrobials minus the upper limit CI of the cure rate without antimicrobials. Results. We identified 90 articles describing >28,000 patients with complicated SSSI. For cellulitis/erysipelas, cure rates were 66% (95% CI, 64%-68%) without antibiotics and 98% (95% CI, 96%-99%) for penicillin-treated patients, and penicillin reduced mortality by 10%. Cure rates for wound/ulcer infections were 36% (95% CI, 32%-39%) without antibiotics and 83% (95% CI, 81%-85%) for penicillin-treated patients. For major abscesses, cure rates were 76% (95% CI, 71%-80%) without antibiotics and 96% (95% CI, 94%-98%) for penicillin-treated patients; penicillin reduced mortality by 6%. Conclusion. Systematic review of historical literature enables rational noninferiority margin justification in the absence of placebo-controlled trials and may facilitate regulatory review of noninferiority trials. Noninferiority margins of 14% for cellulitis/erysipelas, 21% for wound/ulcer infections, and 7% for major abscesses would preserve ≥50% of antibiotic efficacy versus placebo for these complicated SSSI subsets.
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U2 - 10.1086/600296
DO - 10.1086/600296
M3 - Review article
C2 - 19555285
AN - SCOPUS:67651119706
SN - 1058-4838
VL - 49
SP - 383
EP - 391
JO - Clinical Infectious Diseases
JF - Clinical Infectious Diseases
IS - 3
ER -