The scoring system, in essence, attempts to reflect how extensively a particular therapy has been studied, and any given treatment logically accrues points and a higher score as the body of peer-reviewed literature on it incrementally grows. For the subscores of “time window of efficacy” and “independent replication,” there is an ordinal progression of the weightings reflecting the simple concept that longer time windows and more independent studies would be more predictive of clinical efficacy. For the other subscores of “animal species,” “injury models,” and “demonstration of clinically meaningful efficacy,” the weightings are assigned categorically, reflecting the value in a therapy being studied in a multitude of settings and therefore accruing credit for the breadth of investigation. This scoring system also provides an objective perspective regarding the “translational readiness” of an SCI therapy that has been demonstrated in one single study from one lab. While such a “perspective” might seem obvious, human translation has proceeded in the past on the basis of this very limited peer-reviewed pre-clinical literature.

While scoring systems and checklists may have some “common sense” academic appeal, the SCI field has previously moved forward with clinical trials of a number of potential SCI treatments that have not met many of the criteria that are included in this grading scale (e.g., independent replication, demonstrated efficacy in more than one animal or injury model, time-window studies). Clearly, there are also other forces at play that influence the translation of a particular treatment into human patients.

• Studies in which the testing of the therapy was performed in an in-vivo animal model of SCI. Studies that were exclusively in-vitro experiments were excluded.
• Studies in which the spinal cord is traumatically injured. Non-traumatic local or global ischemia models and photochemical reaction models were excluded, as were traumatic root avulsion or dorsal root entry zone models.

• Studies in which the application of the therapy was via the systemic circulation. This included agents administered orally, or via subcutaneous, intraperitoneal, or intravenous injection. Studies in which the therapy was applied directly to the cord or via intrathecal injection/infusion were excluded.
• At least two peer-reviewed publications available on the therapy.
 

The most important points for clinical investigators to assess before considering participation in a trial with a new neuroprotective agent are: (1) an adequate dose-response curve with corresponding serum levels defining at least the minimally effective and maximally tolerated doses in at least 1 species, typically the rat; (2) time window studies showing benefit when therapy is initiated at delayed time points after stroke onset in animal models; (3) adequate physiological monitoring was performed in randomized, blinded animal studies and that treatment effects are reproducible in 2 laboratories, 1 of which is independent of the sponsoring company; (4) outcome measures should include both infarct volume and functional assessment in both acute and long-term phase animal studies; (5) initial studies should be done in smaller species such as rodents subjected to permanent occlusion models, unless the mechanism of drug action suggests that reperfusion will be necessary for drug effect. In this case, clinical development probably will be linked to reperfusion therapy. A second larger species (cats, primates) should be strongly considered for further preclinical assessment for novel, first-in-class drugs; (6) the data should be published or submitted for review in a peer-reviewed journal.

The mechanisms promoting functional recovery after ischemic stroke are not entirely clear but most likely depend on functional and/or structural reorganization of the remaining intact brain. Studies in humans with stroke show that recovery may be robust for at least the first 3 months after the stroke, but further recovery may continue thereafter. This prolonged time window of opportunity to intervene on the stroke recovery process offers a substantial and currently unexploited opportunity for drug development.