Embracing Biological and Methodological Variance in a New Approach to Pre-Clinical Stroke Testing.
Embracing Biological and Methodological Variance in a New Approach to Pre-Clinical Stroke Testing.
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DOI：
10.1007/s12975-016-0463-9
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发表时间：
2016-08
影响因子：
6.9
通讯作者：
Mandava P
中科院分区：
文献类型：
--
作者：
Kent TA;Mandava P
中风临床试验中引人注目的失败阻碍了神经保护剂的临床转化。虽然有几个合理的解释，这些失败，我们认为，根本问题是临床和临床前研究的设计和分析异质性疾病，如中风，由于先天的生物和方法的变异性，目前的方法无法捕捉。最近的努力，以解决临床前的严谨性和设计，而重要的是，无法解释的变异性，即使在遗传同质的啮齿动物。事实上，尽量减少变异性的努力可能会减少临床前模型的临床相关性。我们提出了一种新的方法，认识到基线中风严重程度和其他因素在影响结果中的重要作用。类似于临床试验，我们建议报告影响结果的基线因素，然后适应临床前设置的方法开发的临床试验分析，其中基线因素的影响进行数学建模和方差量化。然后相对于其自身基线条件下的汇总结果方差来评估新疗法的有效性。通过这种方式，可以建立稳健性的客观阈值，必须克服该阈值，以表明其在扩展到PI实验室受控环境之外的更广泛人群时的有效性。该方法是模型中性的，并包含了基线因素（如初始卒中严重程度）中反映的方差来源。我们建议，这种新的方法值得考虑提供一个客观的方法来选择值得的时间和资源的承诺，在翻译到临床试验的代理。
High-profile failures in stroke clinical trials have discouraged clinical translation of neuroprotectants. While there are several plausible explanations for these failures, we believe that the fundamental problem is the way clinical and pre-clinical studies are designed and analyzed for heterogeneous disorders such as stroke due to innate biological and methodological variability that current methods cannot capture. Recent efforts to address pre-clinical rigor and design, while important, are unable to account for variability present even in genetically homogenous rodents. Indeed, efforts to minimize variability may lessen the clinical relevance of preclinical models. We propose a new approach that recognizes the important role of baseline stroke severity and other factors in influencing outcome. Analogous to clinical trials, we propose reporting baseline factors that influence outcome and then adapting for the pre-clinical setting a method developed for clinical trial analysis where the influence of baseline factors is mathematically modeled and the variance quantified. A new therapy’s effectiveness is then evaluated relative to the pooled outcome variance at its own baseline conditions. In this way, an objective threshold for robustness can be established that must be overcome to suggest its effectiveness when expanded to broader populations outside of the controlled environment of the PI’s laboratory. The method is model neutral and subsumes sources of variance as reflected in baseline factors such as initial stroke severity. We propose that this new approach deserves consideration for providing an objective method to select agents worthy of the commitment of time and resources in translation to clinical trials.