New rules for clinical trials of patients with acute bacterial skin and skin-structure infections: do not let the perfect be the enemy of the good

Abstract

Over the past decade, the United States has witnessed an epidemic of acute bacterial skin and skin-structure infections (ABSSSIs) caused primarily by community-acquired methicillin-resistant Staphylococcus aureus. To address this medical need as well as the ongoing threat of increasing resistance, new antibiotics are being developed. Clinical trials involving patients with complicated ABSSSI are being implemented to understand the efficacy and safety of these new antibiotic agents. Because antibiotics clearly have an effect on the resolution of the majority of these infections, placebo-controlled trials have been replaced by noninferiority studies. However, to conduct noninferiority trials a noninferiority margin must be determined on the basis of the effect size of the comparator antibiotic. The lack of modern-day placebo-controlled studies of ABSSSI makes determining effect size/noninferiority margin--and as a result, trial design--challenging. The US Food and Drug Administration (FDA) in collaboration with the Foundation for the National Institutes of Health (FNIH) have been working hard to resolve these issues and develop a new guidance to aid investigators in the conduct of these trials. In this article, we first review the 1998 guidance and its shortcomings. Next, we address the ongoing discussion of the new 2010 guidance as we understand it, along with its perceived strengths and weaknesses. Throughout this process, we wish to emphasize that the continued development of antibiotics is essential. Thus, we hope that as the FDA and FNIH move forward they will strike a balance between "The Perfect" statistical solution and "The Good" practical clinical realities.