Table 3 Priorities for future sepsis clinical trials

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