The difficulties of clinical trials evaluating therapeutic agents in patients with severe sepsis

Introduction Although the pathophysiology of sepsis has been extensively studied, the disease remains a common cause of death in the critically ill patient. It thus remains one of the most pressing clinical and economic problems of modern medicine. A vast amount of inflammatory mediators have been identified as key factors in driving sepsis. Therapeutic agents designed to target these mediators have so far failed to demonstrate significant clinical benefit. Methods Clinical trials are the standard for assessing safety and efficacy of novel agents but are made difficult by the heterogeneous nature of septic patients. This review aims to highlight the complex nature of sepsis and the inherent difficulties encountered in designing clinical trials in these patients. The major factors contributing to the difficulties in improving internal and external validity will be discussed with the aim of guiding future study design. Conclusions The design of clinical trials on the septic patient remains a challenge. Methodology must be rigorous if seemingly positive clinical trials which are widely implemented are later discredited as a result of poor study design. Many lessons can be learnt from the study design of the PROWESS trial, however there remains room for improvement. This review serves as a stimulus and guide in motivating much needed high quality clinical trials in sepsis.