Abstract
Despite some recent success with clinical trials studying innovative therapies in sepsis, the field remains predominantly one of failure despite compounds with significant preclinical activity. Preclinical animal experimentation remains an important component of drug development, and a portfolio approach is recommended. Failure in animals is more likely to predict failure in humans; however, success in animals often does not predict success in humans. Because the signal with innovative therapy of sepsis is likely to be low, an oncology model clinical trial approach, in which studies start with a high-risk homogeneous population and look for a large treatment effect with smaller numbers of patients, is likely to be more relevant than the commonly used cardiology model, in which studies search for a small treatment effect using large, heterogeneous, low-risk populations. With certain rules in place, improvement in organ function may be a worthwhile alternative to mortality as a clinical end point. Once a therapy is approved, adopting less stringent but still appropriate criteria for the use of that therapy in clinical practice may be appropriate.
References
Dec 6, 1990·Nature·K OhlssonR C Thompson
Aug 1, 1995·Shock·D RemickG Wollenberg
Oct 1, 1993·Critical Care Medicine·M BodmerL B Hinshaw
Jul 1, 1996·Intensive Care Medicine·J L VincentL G Thijs
Apr 2, 1997·JAMA : the Journal of the American Medical Association·A A QuartinP N Peduzzi
Nov 21, 1998·Critical Care Medicine·J L VincentS Blecher
Feb 11, 1999·The New England Journal of Medicine·P C HébertE Yetisir
Dec 10, 1999·American Journal of Respiratory and Critical Care Medicine·J P KressJ B Hall
May 4, 2000·The New England Journal of Medicine·UNKNOWN Acute Respiratory Distress Syndrome NetworkArthur Wheeler
Mar 10, 2001·The New England Journal of Medicine·G R BernardUNKNOWN Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group
Apr 20, 2001·Intensive Care Medicine·P Arndt, E Abraham
Jun 16, 2001·European Surgical Research. Europäische Chirurgische Forschung. Recherches Chirurgicales Européennes·E Otero-AntónL F Pérez
Oct 12, 2001·JAMA : the Journal of the American Medical Association·F L FerreiraJ L Vincent
Mar 11, 2003·Critical Care Medicine·Jean-Louis VincentUNKNOWN Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group
May 1, 2004·Critical Care Medicine·Charles T Esmon
Dec 24, 2005·Shock·John C Marshall
Citations
Nov 20, 2009·Critical Care Medicine·Edward Abraham
May 31, 2008·American Journal of Respiratory and Critical Care Medicine·Hector R WongMark D Williams
Aug 4, 2011·Expert Review of Anti-infective Therapy·Jean-Louis VincentAikaterina Dimoula
Jul 25, 2008·The Journal of Emergency Medicine·H Bryant NguyenStephen W Corbett
Feb 15, 2011·The Journal of Surgical Research·Zhifeng LiuLei Su
Jul 11, 2007·Shock·James L WynnLyle L Moldawer