Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials.
OBJECTIVE
Numerous neuroprotective agents have proven effective in animal stroke studies, but every drug has failed to achieve its primary outcome when brought forward to clinical trials. We analyzed the quality and adequacy of animal studies supporting the efficacy of NXY-059 and other neuroprotective agents that are currently being investigated in phase II/III trials.


METHODS
We conducted a systematic search of all neuroprotective drugs in Phase II or III trials and collected data from animal studies of focal cerebral ischemia testing agents systemically administered within 24 hours of occlusion. The methodological rigor of each individual study was evaluated using 5 criteria derived from the STAIR guidelines. The adequacy of the preclinical "package" for each drug was then evaluated by combining the results of all studies for each drug to determine which of a further 5 STAIR criteria were met before moving forward from animal to human studies.


RESULTS
Our search yielded 13 agents of which 10 had published data in peer-reviewed journals. There is substantial within-drug variability in the quality of preclinical studies as well as substantial variation in the completeness of the collective preclinical literature for different drugs. There has been little or no improvement in the quality of animal studies since NXY-059, and current agents have not been subjected to a more complete preclinical evaluation.


CONCLUSIONS
There is significant heterogeneity in the quality of animal testing for neuroprotective agents in stroke. Drugs in the post-SAINT era have not been subjected to more thorough preclinical evaluation.
Philip
Maria
M
Department of Neurology, University of Texas Houston Medical School, Houston, TX 77030, USA.
Benatar
Michael
M
Fisher
Marc
M
Savitz
Sean I
SI
D000208:Acute Disease; D000818:Animals; D001557:Benzenesulfonates / Q000627:therapeutic use; D002545:Brain Ischemia / Q000150:complications*; D002317:Cardiovascular Agents / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D004195:Disease Models, Animal; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012106:Research / Q000592:standards / Q000706:statistics & numerical data; D012107:Research Design; D012306:Risk; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology
D001557:Benzenesulfonates; D002317:Cardiovascular Agents; D018696:Neuroprotective Agents; C120851:disufenton sodium