Drug development in spinal cord injury: what is the FDA looking for?

It has long been recognized that much of the post-traumatic degeneration of the spinal cord following injury is caused by a secondary injury process that occurs during the first minutes, hours, and days after spinal cord injury (SCI). A key biochemical event in that process is reactive oxygen-induced lipid peroxidation (LP). Indeed, the administration of a high-dose regimen of the glucocorticoid steroid methylprednisolone (MP) has been shown to inhibit post-traumatic LP in animal models of SCI, and to improve neurological recovery in spinal cord-injured humans. This resulted in the registration of high-dose MP for acute SCI in several countries, although not in the U.S. Nevertheless, this treatment quickly became the standard of care for acute SCI, since it was already on the U.S. market for many other indications. Subsequently, it was demonstrated that the nonglucocorticoid 21-aminosteroid tirilazad could duplicate the antioxidant neuroprotective efficacy of MP in SCI models, and evidence of human efficacy has been obtained. This article explains the process of the discovery, development, and Food and Drug Administration regulation of new drugs for SCI; reviews the past development of MP and tirilazad for acute SCI; identifies the regulatory complications involved in future SCI drug development; and suggests some promising therapeutic approaches that could either replace or be added to high-dose MP.