Philip Maria, Benatar Michael, Fisher Marc, Savitz Sean I
Department of Neurology, University of Texas Houston Medical School, Houston, TX 77030, USA.
Stroke. 2009 Feb;40(2):577-81. doi: 10.1161/STROKEAHA.108.524330. Epub 2008 Dec 12.
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.
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.
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.
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.
众多神经保护剂在动物卒中研究中已被证明有效，但每种药物在进入临床试验时均未达到其主要研究终点。我们分析了支持NXY - 059及其他正在进行II/III期试验的神经保护剂疗效的动物研究的质量和充分性。
我们对所有处于II期或III期试验的神经保护药物进行了系统检索，并从在闭塞后24小时内全身给药的局灶性脑缺血试验药物的动物研究中收集数据。使用源自STAIR指南的5项标准评估每项研究的方法严谨性。然后，通过合并每种药物的所有研究结果，评估每种药物临床前“资料包”的充分性，以确定在从动物研究推进到人体研究之前，是否满足另外5项STAIR标准中的哪些标准。
我们的检索产生了13种药物，其中10种在同行评审期刊上发表了数据。临床前研究质量在药物内部存在很大差异，不同药物的临床前文献完整性也存在很大差异。自NXY - 059以来，动物研究质量几乎没有改善，目前的药物也没有接受更全面的临床前评估。
卒中神经保护剂的动物试验质量存在显著异质性。圣安东尼奥国际卒中试验（SAINT）时代后的药物尚未接受更彻底的临床前评估。
