Clinical trials of antibacterial agents: a practical guide to design and analysis. Statisticians in the Pharmaceutical Industry Working Party.

Guidelines on the conduct of clinical trials of antibacterial agents produced by the US Food and Drug Administration, the British Society for Antimicrobial Chemotherapy, the Infectious Diseases Society of America and a European Working Party have been reviewed. Although very informative, these guidelines provide limited practical guidance on the design and statistical aspects of phase III studies of antimicrobial agents. This paper describes the differences between antibacterial trials and clinical studies in other therapeutic areas with regard to subjective endpoints, dual clinical and bacteriological endpoints, frequent protocol violations and difficulty of using placebo controls. The importance of a detailed protocol and planned analysis strategy is emphasized. The choice of comparator agents, practical issues with the blinding of trial materials and the documentation of patients excluded from study entry are discussed. The use of different patient groups and different endpoints in analyses are described. The principles of equivalence and their application to trials of antibacterial agents are discussed, together with an approach to calculating sample size. A variety of statistical analyses of results are compared for different situations indicating some of the problems that can arise. Different methods of presentation of study data are included with emphasis on regulatory submissions rather than scientific publications. Some graphical presentations are recommended and issues regarding data across different studies are discussed.