1. Develop more informative studies using animal models |
2. Emphasize study of pathophysiology |
3. Identify biomarkers, molecular signals, or genetic markers to identify patients having an underlying causal process that might respond to the specific treatment being studied |
4. Develop networks of sepsis investigators experienced in clinical trial conduct |
5. Apply the recent Third International Consensus Definitions for Sepsis and Septic Shock [1, 37] when determining eligibility criteria |
6. Conduct targeted clinical trials in relatively homogeneous groups of patients with characteristics suggestive of treatment response |
7. Consider the addition of pre-specified covariate adjustment of the primary endpoint to address the issue of heterogeneity |
8. Exclude low-risk patients if appropriate for the intervention being studied |
9. Standardize care to reduce variability and random noise but not to the extent that results are not generalizable |
10. Develop realistic expectations for treatment effect and power trials accordingly |
11. Apply adaptive designs, especially when key variables are uncertain (e.g., event rates, expected treatment effect) |
12. Consider targeted primary endpoints with all-cause mortality reserved for safety |
13. Develop consensus in the field for standard trial definitions/criteria for interventions if used as endpoints (e.g., vasopressors, mechanical ventilation, renal replacement therapy) |
14. Collaborate with regulators to modify approach to clinical trial design in this field |
15. Develop robust registries to test external validity of the results of trials in broader patient populations |
16. Discovery and development of a diagnostic that predicts a higher chance of response to a specific intervention |