Clinical trial design for mild-to-moderate community-acquired pneumonia--an industry perspective.

The use of noninferiority clinical trials is problematic unless one can establish the benefit of the active control versus no treatment. In community-acquired pneumonia, there are no placebo-controlled clinical trials establishing the benefit of antibiotic treatment, because the observed benefit of sulfapyridine and, subsequently, penicillin was established before the advent of randomized clinical studies. Historical data and observational cohort studies have established the marked decrease in mortality resulting from antimicrobial therapy; however, mortality is not a suitable end point for contemporary clinical trials for mild-to-moderate community-acquired pneumonia that is treated with oral antimicrobial drugs in ambulatory patients. There are historical clinical data that describe the timing of spontaneous recovery in patients with documented pneumonia caused by Streptococcus pneumoniae. In addition, there is one contemporary clinical trial that demonstrated superiority in clinical response of levofloxacin versus a cephalosporin regimen of ceftriaxone and/or cefuroxime for treatment of mild-to-moderate community-acquired pneumonia. Using either the historical data or the superiority study of levofloxacin, one can justify a noninferiority margin of 10% for the per-protocol population and 15% for the microbiologically evaluable population for future noninferiority clinical trials for mild-to-moderate community-acquired pneumonia.