Increasing the efficiency of clinical trials of antimicrobials: the scientific basis of substantial evidence of effectiveness of drugs.

In the United States, drug sponsors must obtain approval from the US Food and Drug Administration before licensure and widespread clinical use of drugs. In this article, I discuss the definition and history of the regulatory requirement for "substantial evidence" of effectiveness from "adequate and well-controlled" clinical trials of drugs. These requirements apply to antimicrobials as they do to other therapeutic drug classes, and they may be even more important in their application to antimicrobials, given issues of antimicrobial resistance. I will discuss the evidence requirements, using examples from clinical trials in diseases such as acute otitis media, acute bacterial sinusitis, and acute exacerbations of chronic bronchitis. Examination of the principles of substantial evidence also points to opportunities to improve the efficiency of confirmatory clinical trials of antimicrobials to obtain more clinically relevant and useful information without increasing the uncertainty regarding the safety and efficacy of these drugs.