Use of pharmacokinetics and pharmacodynamics in a failure analysis of community-acquired pneumonia: implications for future clinical trial study design.

Regulatory uncertainty has led to the cessation of antimicrobial agent drug development for some community-acquired respiratory tract infections. This uncertainty stems from the fact that many people, including individuals within government, are unsure about the magnitude of drug effect relative to no treatment in patient populations perceived to be at low-to-moderate risk of mortality. Without such information, it is not possible to power noninferiority studies, which, in turn, necessitates the need for superiority study designs. Moreover, many believe that current categorical clinical trial end points (success or failure), determined 7-14 days after therapy, are insensitive measures of drug benefit and that new outcome measures are needed. To date, characterization of the magnitude of treatment effect relative to that of no treatment has not been accomplished through traditional examinations of existing clinical trial databases or evaluations of historical data. However, pharmacokinetic-pharmacodynamic analyses of existing clinical trial data may provide a new context to inform the debate. Herein, we examine pharmacokinetic-pharmacodynamic relationships for efficacy derived from recent clinical drug development programs involving agents for the treatment of community-acquired respiratory tract infections. Through a collective understanding of these data, it may be possible to estimate the no-treatment response rate without exposing patients to any risk incurred by conducting clinical trials with alternative designs (e.g., placebo-controlled studies or studies using suboptimal dose ranges or comparator regimens). Finally, the value and potential of adding continuous, numeric clinical trial end points to those currently used are discussed.