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Antimicrobial Agents for Complicated Skin and Skin-Structure Infections: Justification of Noninferiority Margins in the Absence of Placebo-Controlled Trials
Clinical Infectious Diseases, 07/08/09

Spellberg B et al. - 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.

Exclusive Author Commentary
Dr. Brad Spellberg, 07/08/09

Regulatory confusion regarding appropriate clinical trial designs is creating a major barrier to the development of badly needed new antibiotics. A primary cause of regulatory confusion relates to the complexities of non-inferiority trial design. Because placebo is not tested in a non-inferiority trial, there are two possible conclusions to be drawn when an experimental drug is found to be "non-inferior" to the comparator drug in a clinical trial: 1) both the experimental and comparator drugs are superior in efficacy to placebo; and 2) neither the experimental or comparator drug are superior in efficacy to placebo. The only way to exclude the latter possibility is to be certain, based on a previously published placebo-controlled study, that the comparator drug used in the non-inferiority study is superior in efficacy to placebo. Unfortunately, antibiotics became available in an era prior to the use placebo-controlled studies, and most serious forms of infections have never been studied in placebo-controlled studies. This fact makes regulatory review of non-inferiority studies of infections very complicated. We sought to provide an alternative mechanism to establishing the magnitude of superiority of standard antibiotic therapy to placebo/no therapy. We conducted a systematic literature review of literature from the pre- and immediate post-antibiotic era and calculated weighted average cure rates for complicated skin and skin structure infections treated with anti-bacterials or non antibiotic treatments. By comparing cure rates with and without anti-bacterials, we were able to provide a conservative estimate of the magnitude of antibiotic efficacy for these infections, thereby enabling justification of non-inferiority margins to be used in modern non-inferiority studies of complicated skin and skin structure infections. It is hoped that these results will provide clarity to appropriate trial design for these infections.

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