Role of clinical evaluation committees in sepsis trials: from 'valid cohort' assessment to subgroup analysis

In this issue of Critical Care, the study from Laterre and colleagues offers suggestions for the role of clinical evaluation committees (CECs) in future sepsis trials. Despite encouraging preliminary results, all randomized controlled trials (RCTs) devoted to potential compounds in severe sepsis have failed to show survival benefit. One of the reasons might be related to RCT-related factors that inevitably occur within a heterogeneous septic patient population. A patient population free from confounding events would seem to provide the most suitable platform upon which to judge therapeutic effect. To solve this issue, CECs have been introduced into RCTs in sepsis to ensure uniform data for analysis and to identify such 'optimal cohorts' for which the therapy was initially designed to treat. More recently, some RCTs have reported positive results in sepsis. The role of CECs has shifted to become a more integral part of the detailed analysis of drug safety and efficacy in large databases, and to identify subgroups of patients in which a therapy might be less or more effective and/or safe. As an example, the retrospective analysis by Laterre and colleagues focuses on patients with severe community-acquired pneumonia (sCAP) within a large, failed RCT (on recombinant tissue factor pathway inhibitor (rTFPI)). However, the results should be interpreted with great caution, and should be viewed as exploratory and a hypothesis-generating activity. This question of potential benefit of rTFPI in patients with sCAP will be definitively answered by the results of the recently completed RCP.