Is There a Role for Surrogate Markers in the Evaluation of Sepsis Trials?
Part of the
Yearbook of Intensive Care and Emergency Medicine
book series (YEARBOOK, volume 1998)
The successive failure of a number of clinical trials of experimental agents in sepsis or septic shock is now an all too familiar theme, and one which has generated much discussion. Many investigators have given considerable thought to possible explanations, including incorrect reasoning (i.e., poor basic science), ineffective drugs, and poor trial design. One aspect is the question of endpoints, and the use of 28-day mortality as the ‘gold standard’ of success or failure of a new drug. Many have questioned the wisdom of this approach, arguing that death is too blunt a tool, and that we may be missing potentially useful therapies by demanding too much efficacy, too soon. The way to avoid this problem, they say, is to accept surrogate markers as valid endpoints, i.e., to find a more amenable measurement than death. In this paper, I will discuss some of the issues raised by this proposal, and show some of the advantages, and disadvantages, that it might offer.
KeywordsSeptic Shock Surrogate Marker Acute Respiratory Distress Syndrome Acquire Immune Deficiency Syndrome Negative Blood Culture
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
to read the full conference paper text
Fleming TR, DeMets DL (1996) Surrogate end points in clinical trials: are we being misled? Ann Intern Med 125: 605–613PubMedGoogle Scholar
Fleming TR (1994) Surrogate markers in AIDS and cancer trials. Stat Med 13: 1423–1435PubMedCrossRefGoogle Scholar
De Gruttola V, Fleming T, Lin DY et al (1997) Perspective: validating surrogate markers - are we being naive? J Infect Dis 175: 237–246PubMedCrossRefGoogle Scholar
Marshall JC, Cook DJ, Sibbald WJ, Roy PD, Christou NV (1995) Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 23: 1638–1652PubMedCrossRefGoogle Scholar
Abraham E, Wunderink R, Silverman H, et al (1995) Efficacy and safety of monoclonal antibody to human tumor necrosis factor a in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. JAMA 273: 934–941PubMedCrossRefGoogle Scholar
Cohen J, Carlet J, INTERSEPT Study Group (1996) INTERSEPT: An international multicentrer placebo-controlled trial of monoclonal antibody to human TNF-a in patients with sepsis. Crit Care Med 24: 1431–1440Google Scholar
Waage A, Halstensen A, Shalaby R, et al (1989) Local production of tumor necrosis factor alpha, interleukin 1, and interleukin 6 in meningococcal meningitis. Relation to the inflammatory response. J Exp Med 170: 1859–1867PubMedCrossRefGoogle Scholar
Lemm G, Carlet J, Cohen J, et al (1995) Cytokine levels in patients with the sepsis syndrome treated with a monoclonal antibody to human TNF a (INTERSEPT trial). Clin Intensive Care 6: 68 (Abst)Google Scholar
Fisher Jr CJ, Agosti JM, Opal SM, et al (1996) Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. N Engl J Med 334: 1697–1702PubMedCrossRefGoogle Scholar
Reinhart K, Wiegand-Lohnert C, Grimminger F, et al (1996) Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study. Crit Care Med 24: 733–742PubMedCrossRefGoogle Scholar
Parsons PE,Moss M,Vannice JL,et al (1997) Circulating IL-lra and 11-10 levels are increased but do not predict the development of acute respiratory distress syndrome in at-risk patients. Am J Respir Crit Care Med 155: 1469–1473PubMedGoogle Scholar
de Werra I, Jaccard C, Corradin SB, et al (1997) Cytokines, nitrite/nitrate, soluble tumor necrosis factor receptors, and procalcitonin concentrations: comparisons in patients with septic shock, cardiogenic shock, and bacterial pneumonia. Crit Care Med 25: 607–613PubMedCrossRefGoogle Scholar
Cummings CJ, Sessler CN, Beall LD, et al (1997) Soluble E-selectin levels in sepsis and critical illness. Correlation with infection and hemodynamic dysfunction. Am J Respir Crit Care Med 156: 431–437PubMedGoogle Scholar
Danner RL, Elin RJ, Hosseini J, et al (1991) Endotoxemia in human septic shock. Chest 99: 169–175PubMedCrossRefGoogle Scholar
© Springer-Verlag Berlin Heidelberg 1998