The clinical evaluation of new drugs for sepsis A prospective study design based on survival analysis

Authors: Knaus WA, Harrell FE, Fisher CJ Jr, Wagner DP, Opal SM, Sadoff JC, Draper EA, Walawander CA, Conboy K, Grasela TH
Publication: JAMA
Keywords: 80 and over, adolescent, adult, aged, analysis, child, classification, clinical trials, drug evaluation, drug therapy, female, hospitals, humans, infant, infection, male, methods, middle-aged, Phase II, Phase III, preschool
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

OBJECTIVE:

To develop a survival model and severity assessment method to estimate the 28-day mortality risk for patients with sepsis syndrome entering phase 2 and 3 drug evaluations.

DESIGN:

Retrospective analysis of intensive care unit admissions with sepsis syndrome by means of log-normal regression to identify risk factors for 28-day mortality. Prospective application of the model to patients with gram-negative infection meeting sepsis syndrome criteria from separate data collection (validation group).

PATIENTS:

A total of 58,737 intensive care unit admissions at 107 hospitals in the United States and Western Europe screened to yield 1195 patients meeting entry criteria for the sepsis syndrome study for the original model; 295 hospitalized patients with gram-negative infection meeting criteria for sepsis syndrome for validation.

MAIN OUTCOME MEASURES:

Survival time and mortality at 28 days after fulfillment of the sepsis syndrome criteria.

RESULTS:

Acute physiologic abnormalities were the most important prognostic factors influencing outcome (82% of total chi 2). Specific disease resulting in intensive care unit admission and the time the patient was in the hospital and intensive care unit before qualification were also independent risks, as were age and a clinical history of cirrhosis. The model’s overall classification accuracy was a Somers’ Dyx of .52 (rank correlation between predicted risk and 28-day mortality) (receiver operating characteristic area, 0.76), with equal accuracy (Dyx = .59; receiver operating characteristic area, 0.80) in the independent group of patients.

CONCLUSIONS:

We created an accurate independent estimate for 28-day mortality risk for patients with sepsis syndrome (severe sepsis). This estimate could improve the evaluation of new drugs by investigating whether the drug’s benefit varies by patient risk and then determining the amount of benefit for individual patients.

By Knaus WA, Harrell FE, Fisher CJ Jr, Wagner DP, Opal SM, Sadoff JC, Draper EA, Cynthia Walawander, Conboy K, Thaddeus H Grasela