Table 3. Translational challenges in TBI and suggestions.
| Challenges in TBI trial | Comments and potential solutions |
|---|---|
| Complex secondary injury mechanisms |
Important to investigate secondary injury mechanisms at molecular, and cellular levels, and to develop and test multifunctional agents or combination treatments |
| Choice of species, sex and age |
Test therapeutic agents in higher-species animals of TBI, in young and aged subjects of both sexes |
| Comorbidities | Incorporate hypoxia, ischemia, hematoma, alcohol and drug use, systemic trauma and other diseases (e.g., Diabetes) into animal models of TBI |
| Lack of pharmacokinetics and pharmacodynamic |
Obtain pharmacokinetics, pharmacodynamics and brain concentration of the tested treatment, obtain data on dose response, therapeutic window, route, duration, interaction with other drugs |
| Diverse injury type | Test agents in different types of TBI: focal, diffuse, open vs closed, and blast head injury mild, moderate, and severe, repetitive mTBI |
| Neuron-centered neuroprotection |
Block the molecular cascade of injury following TBI. A major limitation of neuroprotection strategies is the short time window in which to deliver the therapy. Test of neuroprotection on neurons alone is inadequate; also require testing on non-neuronal cells. |
| Neurorestoration | Unlike neuroprotection which solely reduces cell death or lesion volume, neurorestorative approaches aim to remodel brain tissue by promoting endogenous neurogenesis, axonal sprouting, synaptogenesis, oligodendrogenesis and angiogenesis, which in concert enhance neuroplasticity and improves functional recovery. Neurorestorative therapy could potentially have a high clinical impact by extending the therapeutic window and targeting an expanded population of patients with TBI. |
| Outcome measures and long-term study |
The outcomes (e.g., mortality, GOS or GOSe) are often measured at 3 or 6 months post injury in TBI patients. Development of new outcome measures and use of well-characterized outcome measures to assess long- term effects of the treatment in animal models of TBI and clinical trials are warranted. |
| Study design and statistical analyses |
Whereas clinical trials generally employ an intent-to-treat analysis, this is virtually never conducted pre-clinically. Whereas clinical studies usually include a range of injury severities with various comorbidities (heterogeneity of the population), preclinical studies employ well- defined, highly controlled animal models of predetermined severity. There is a need to enlarge sample sizes and to improve power as well as to conceal treatment allocation or blinded outcome assessment. |
| Lack of biomarkers | There is a need to identify specific and sensitive biomarkers/imaging makers which are important for the diagnosis, prognosis, and evaluation of treatment efficacy for TBI. |
| Publication bias | Report/publish negative results of preclinical studies on efficacy of therapeutic treatments. |