Table 2.

Potential Peasons for the Failure of Clinical Trials for Therapies for TBI: Reasons Related to Pre-Clinical Testing

Reason	Summary	References
Translational issues	Inadequate understanding of differences in therapeutic window, pharmacokinetics, dosages, etc., between humans and experimental animals	Hawryluk et al.15; Margulies and Hicks121
Multiple injury models	Limited evidence of efficacy in different species, genders, ages, etc.	Hawryluk et al.15; Margulies and Hicks121
Injury mechanisms	Mismatch between primary injury mechanisms in humans and experimental animals (e.g., diffuse vs. focal, DAI)	Hawryluk et al.15; Margulies and Hicks121; Saatman et al.8
End-points	Differences in types of end-points in clinical vs. experimental studies	Agoston et al.9
Sample size/power	Inadequate sample size to produce adequate statistical power	Button et al.77
Time intervals	Experimental studies measure acute effects (<1 month); RCTs measure long-term (>1 month) outcomes	Agoston et al.9
Inadequate scientific rigor/Inadvertent bias/Confounders	Inadequate blinding, selective analyses, reporting bias, randomization, attrition	Holman et al.158; Fanelli et al.159; Vogt et al.160; Tsilidis et al.161; O'Collins et al.162

Modified from: Hawryluk et al.¹⁵; Margulies and Hicks¹²¹.

DAI, diffuse axonal injury; RCT, randomized clinical trial.