Antimicrobial agents for complicated skin and skin-structure infections: justification of noninferiority margins in the absence of placebo-controlled trials.

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 >or= 50% of antibiotic efficacy versus placebo for these complicated SSSI subsets.