A grading system to evaluate objectively the strength of pre-clinical data of acute neuroprotective therapies for clinical translation in spinal cord injury

Abstract

The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the "robustness" of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials.

FIG. 1.

Schematic of the methodological steps to developing the pre-clinical grading system.

FIG. 2.

The opinions of clinicians and scientists about animal species used in pre-clinical SCI research. Color image is available online at www.liebertonline.com/neu.

FIG. 3.

The opinions of clinicians and scientists about injury models used in pre-clinical SCI research. Color image is available online at www.liebertonline.com/neu.

FIG. 4.

The opinion of clinicians and scientists about the time window of efficacy requirements for acute neuroprotective therapies.

FIG. 5.

The opinion of clinicians and scientists about what constitutes “clinically meaningful efficacy.” Color image is available online at www.liebertonline.com/neu.

FIG. 6.

The opinion of clinicians and scientists about perceived bias in pre-clinical SCI research. Color image is available online at www.liebertonline.com/neu.