Sepsis is a severe and complex form of infection associated with a systemic inflammatory response syndrome (SIRS). However, in numerous patients who demonstrate all findings suggestive of sepsis, a source of infection cannot be confirmed. Although infection is the predominant etiology in the intensive care unit (ICU), SIRS may also develop after different types of injuries such as trauma, burns, acute pancreatitis, ischemia-reperfusion and major surgery including cardio-pulmonary bypass and abdominal surgery. The response involves a complex network of circulating mediators such as pro-inflammatory cytokines and changes of the coagulation/fibrinolysis systems. According to current understanding the critical pathophysiological trigger is a disturbance in equilibrium between pro-inflammatory response and concomitant anti-inflammatory mechanisms, which is closely linked to alterations in the haemostasis system.

The generation of accurate statistics about sepsis is confounded by the imprecise and highly variable terminology used to describe sepsis by clinicians around the world. Recent European epidemiological studies indicate that up to about 20% of all ICU patients are admitted with or progress to sepsis during their stay in the ICU (with large differences between ICUs). The management of sepsis based on elimination of the causative infection by surgery, where possible, antibiotics, and supportive treatment (fluids, inotropes, vasopressors, replacement therapy of failing organ functions) has not sufficiently changed the mortality rate over the past decades. Sepsis remains an important and life-threatening problem and the most common cause of death in the ICU with mortality between 20 to 50% for severe sepsis and 45 to 80% for septic shock.

The remarkably diverse spectrum of illness encompassed under the term ‘sepsis’ – ranging in severity from mild systemic inflammation without significant clinical consequences to multi-system failure in septic shock with an exceedingly high mortality rate – and the many factors related to the pathogenesis of (severe) sepsis have made it difficult to effectively design clinical trials for the management of this disease. Planning, implementation and assessment of results of intervention studies on sepsis thus present enormous challenges. A number of large prospective randomized trials with various types of therapeutic intervention undertaken to modify the inflammatory response has been unsuccessful in improving the outcome. Given the high degree of complexity and the obvious difficulty to demonstrate that a certain medicinal product adds clinical benefit to the usually multimodal treatment of sepsis, a need for regulatory guidance on the design and analyses of medicinal products intended for the treatment of sepsis is identified.