White paper: recommendations on the conduct of superiority and organism-specific clinical trials of antibacterial agents for the treatment of infections caused by drug-resistant bacterial pathogens

Abstract

There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper's drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents.

Figure 1.

Flow diagram of a hierarchical noninferiority–superiority study.

Figure 2.

Flow diagram depicting trial designs based on randomization before or after knowing the infecting pathogen. Abbreviation: XDR/PDR, extreme drug resistant/pandrug resistant.

Figure 3.

Flow diagram of a nested superiority–noninferiority trial. Abbreviation: XDR/PDR, extreme drug resistant/pandrug resistant.

Figure 4.

Flow diagram of a historically controlled superiority trial. Abbreviation: XDR/PDR, extreme drug resistant/pandrug resistant.

Figure 5.

Relationship between drug exposure and response to therapy. The treatment effect is the difference between maximum and minimum drug effect. The y-intercept of the functional relationship between exposure and response is an estimate of the placebo response. Abbreviations: PK-PD, pharmacokinetics-pharmacodynamics; AUC:MIC, area under the curve–minimum inhibitory concentration ratio. Figure adapted from Ambrose PG, et al, Lancet Infect Dis 2012; 12:265–6.