Table 2 Reasons for past failures in stroke and TBI drug discovery and development

Inadequate understanding of secondary injury mechanisms

Lack of definition of time course of NMDA receptor functional changes

Lack of definition of the sources and spatial and temporal characteristics of reactive oxygen generation — inability to rationally determine therapeutic window and optimum treatment duration Lack of understanding of the integration of secondary injury mechanisms

Focus on secondary injury mechanisms with short therapeutic windows — need to identify and target injury mechanisms with longer therapeutic windows

Lack of understanding of the relative therapeutic windows in animal models and humans. Is the time course of secondary injury in mice, rats, and humans similar? Inadequate preclinical testing Lack of testing in multiple models Failure to compare efficacy in male and female animals Incomplete dose-response and definition of therapeutic plasma levels Incomplete definition of therapeutic window

Lack of definition of pharmacokinetics, timing of needed maintenance dosing, and optimum treatment duration Poor clinical trial design

Gross mismatch between preclinical and clinical testing

Imprecise endpoints (e.g., Glasgow Coma Scale, Glasgow Outcome Scale, and ASIA scale) Lumping together of all kinds of ischemic strokes or moderate and severe TBIs Lack of identification of an a priori plan to analyze subgroups (e.g., tSAH)

Lack of a biomarker to follow the progression of the pathophysiology and to monitor mechanistic drug effects Lack of standardization of neurorehabilitation protocols

6. determination of the therapeutic window to determine how early treatment must begin (this may vary between TBI, ischemic stroke, SAH, and SCI)

7. comparison of neuroprotective pharmacology in multiple injury models in order to determine whether the agent in question only works in certain types of injuries

8. determination of pharmacodynamic and pharmacokinetic interactions with other commonly used ancillary treatments (e.g., anticonvulsants).

Thirdly, in retrospect, there were several flaws in the early design of neuroprotective clinical trials in terms of the use of imprecise and insensitive endpoints, lumping together of all types of patients, failure to stratify according to subgroups, lack of a suitable biomarker (with which to monitor the progression of the pathophysiology and drug effects thereon) for use in early phase dose-response trials, and the failure to include and standardize neurorehabilitative techniques across all patients in the trials. The detailed preclinical evaluation of neuroprotective agents in stroke, TBI, or SCI models called for above should then be followed by a clinical trial design that is consistent with the results of preclinical trials. One of the most glaring examples of how this has not been done in the past concerns the fact that, even with agents in which the therapeutic efficacy window has been determined, the trials typically involved an enrollment window that far exceeded the postinsult time at which a particular agent can be expected to retain neuroprotective potential. It has been argued that even if a particular agent only has a 1-h window in a rat stroke, TBI, or SCI model, the window in humans with the corresponding condition is likely to be much longer. However, there is little or no evidence to support this assumption. Consequently, in the author's opinion, clinical trial design should take seriously the preclinical therapeutic window definition for a particular agent with regard to how soon the compound may need to be given to patients. With this in mind, a failure to demonstrate a clinically practical therapeutic window for a particular agent may mean that this agent and its corresponding secondary injury mechanism may be too short to be effectively addressed in real-world therapeutics.

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