A critical appraisal of the reporting of the National Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in acute spinal cord injury

From the beginning, the reporting of the results of National Acute Spinal C ord Injury Studies (NASCIS) II and III has been incomplete, leaving clinici ans in the spinal cord injury (SCI) community to use or avoid using methylp rednisolone in acute SCI on the basis of faith rather than a publicly devel oped scientific consensus. NASCIS II was initially reported by National Ins titutes of Health announcements, National Institutes of Health facsimiles t o emergency room physicians, and the news media. The subsequent report in t he New England Journal of Medicine implied that there was a positive result in the primary efficacy analysis for the entire 487 patient sample. Howeve r, this analysis was in fact negative, and the positive result was found on ly in a secondary analysis of the subgroup of patients who received treatme nt within 8 hours. In addition, that subgroup apparently had only 62 patien ts taking methylprednisolone and 67 receiving placebo. The NASCIS II and II I reports embody specific choices of statistical methods that have strongly shaped the reporting of results but have not been adequately challenged or or even explained. These studies show statistical artifacts that call thei r results into question. In NASCIS II, the placebo group treated before 8 h ours did poorly, not only when compared with the methylprednisolone group t reated before 8 hours but even when compared with the placebo group treated after 8 hours. Thus, the positive result may have been caused by a weaknes s in the control group rather than any strength of methylprednisolone. In N ASCIS III, a randomization imbalance occurred that allocated a disproportio nate number of patients with no motor deficit (and therefore no chance for recovery) to the lower dose control group. When this imbalance is controlle d for, much of the superiority of the higher dose group seems to disappear. The NASCIS group's decision to admit persons with minor SCIs with minimal or no motor deficit not only enables statistical artifacts it complicates t he interpretation of results from the population actually sampled. Perhaps one half of the NASCIS III sample may have had at most a minor deficit. Thu s, we do not know whether the results of these studies reflect the severely injured population to which they have been applied. The numbers, tables, a nd figures in the published reports are scant and are inconsistently define d, making it impossible even for professional statisticians to duplicate th e analyses, to guess the effect of changes in assumptions, or to supply the missing parts of the picture. Nonetheless, even 9 years after NASCIS II, t he primary data have not been made public. The reporting of the NASCIS stud ies has fallen far short of the guidelines of the ICH/FDA and of the Eviden ce-based Medicine Group. Despite the lucrative "off label" markets for meth ylprednisolone in SCI, no Food and Drug Association indication has been obt ained. There has been no public process of validation. These shortcomings h ave denied physicians the chance to use confidently a drug that many were e nthusiastic about and has left them in an intolerably ambiguous position in their therapeutic choices, in their legal exposure, and in their ability t o perform further research to help their patients.