Antimicrobial Agents for Complicated Skin and Skin‐Structure Infections: Justification of Noninferiority Margins in the Absence of Placebo‐Controlled Trials

Abstract

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.

Systematic Review and Meta-Analysis To Estimate Antibacterial Treatment Effect in Acute Bacterial Skin and Skin Structure Infection

“…The TOC treatment effect estimations for linezolid (25.1%) and ceftaroline (27.8%) provide historical data for noninferiority margin justification in future noninferiority trial designs and for superiority trial designs that may include adaptive models and futility stopping criteria (56,57). Overall, our findings provide historical evidence of the sensitivity to drug effect (HESDE) at the TOC endpoint for ABSSSI and are consistent with prior estimations of the treatment effect (13).…”

“…The placebo search was extended to include clinical trials reporting a placebo treatment response in uncomplicated skin and soft tissue infections (uSSTI) as a proxy for placebo in ABSSSI (search A2). This strategy, which comprised use of a proxy for placebo effect estimation, has been recommended in the FDA guidance for noninferiority trials and has been used for placebo treatment effect estimation for trials in complicated urinary tract infections (13,21,22). Given that historical studies published in 1937 reported relatively high response rates in the treatment of erysipelas with UV light, an additional search (search C) was conducted to identify clinical trials of nonantibacterial treatment in uSSTI and in ABSSSI (4,23,24).…”

“…For trial endpoints, the traditional test-of-cure (TOC) endpoint, with the treatment success defined as total resolution of the infection at 7 to 14 days posttreatment, remains aligned with the European regulatory guidance, yet the treatment success for the primary efficacy endpoint aligned with the FDA guidance is defined as cessation of lesion spread after 48 to 72 h of treatment (9)(10)(11). Revisions to the enrollment and endpoint criteria in recent regulatory guidance for ABSSSI trials necessitate reevaluation of the antibacterial treatment effect estimation calculated from across-trials comparisons of existing data for noninferiority trial design (4,(12)(13)(14)(15)(16).…”

CANVAS 1 and 2: Analysis of Clinical Response at Day 3 in Two Phase 3 Trials of Ceftaroline Fosamil versus Vancomycin plus Aztreonam in Treatment of Acute Bacterial Skin and Skin Structure Infections

“…Evidence of an antimicrobial treatment effect was supported by reduced rates of recurrence and sepsis compared with control therapy. Of interest, others have recently attempted to define treatment effects for alternative endpoints and noninferiority margins for complicated skin and skin structure infections, without general acceptance (15).…”

U.S. bans antibiotics use for enhancing growth in livestock

“…The availability of effective antibiotics is necessary to enable modern medical advances that range from intensive care unit medicine to aggressive surgeries, cancer chemotherapy, care for premature neonates, and organ transplantation. Loss of antibiotic efficacy threatens to return society to a time when one in ten patients with a skin infection died and one in three patients with pneumonia died (greater than 10-fold higher death rates compared to the antibiotic era (Spellberg, 2010;Spellberg et al, 2008b;Spellberg et al, 2009). Without effective antibiotics, medicine would be paralyzed by an inability to treat infections resulting from intensive specialty care (Spellberg, 2010;Spellberg et al, 2008a;Spellberg et al, 2011;Spellberg et al, 2013).…”