Ramaiah Lila, Tomlinson Lindsay, Tripathi Niraj K, Cregar Laura C, Vitsky Allison, Beust Barbara von, Barlow Valerie G, Reagan William J, Ennulat Daniela
1 Bristol-Myers Squibb, New Brunswick, New Jersey, USA.
2 Pfizer Worldwide Research and Development, Andover, Massachusetts, USA.
Toxicol Pathol. 2017 Feb;45(2):260-266. doi: 10.1177/0192623316681646. Epub 2017 Jan 5.
There is limited direction in the literature or regulatory guidance on determination of adversity for clinical pathology (CP) biomarkers in preclinical safety studies. Toxicologic clinical pathologists representing the American Society for Veterinary Clinical Pathology-Regulatory Affairs Committee and Society of Toxicologic Pathology-Clinical Pathology Interest Group identified principles, overall approach, and unique considerations for assessing adversity in CP data interpretation to provide a consensus opinion. Emphasized is the need for pathophysiologic context and a weight-of-evidence approach. Most CP biomarkers do not have the potential to be adverse in isolation, regardless of magnitude of change. Rather, they quantify or describe the impact of effects, provide adjunct or supportive information regarding a process or pathogenesis, and provide translational biomarkers of effect. Most often, CP changes are part of a constellation of findings that collectively are adverse. Thus, most CP changes must be interpreted in conjunction with other study findings and require contextual and integrative interpretation. Exceptions include critical CP changes without correlates that indicate a health risk in the tested species. Overall, CP changes should not be interpreted in isolation and their adversity is best addressed with an integrated approach.
在临床前安全性研究中，关于确定临床病理学（CP）生物标志物的有害性，文献或监管指南中提供的指导有限。代表美国兽医临床病理学会监管事务委员会和毒理病理学会临床病理兴趣小组的毒理临床病理学家确定了在CP数据解释中评估有害性的原则、总体方法和独特考量因素，以提供共识意见。强调了病理生理背景和证据权重方法的必要性。大多数CP生物标志物无论变化程度如何，孤立来看都没有产生有害影响的可能性。相反，它们量化或描述效应的影响，提供有关过程或发病机制的辅助或支持信息，并提供效应的转化生物标志物。大多数情况下，CP变化是一系列共同构成有害情况的发现的一部分。因此，大多数CP变化必须结合其他研究发现进行解释，需要进行背景和综合解释。例外情况包括无相关因素的关键CP变化，这些变化表明受试物种存在健康风险。总体而言，CP变化不应孤立地进行解释，其有害性最好通过综合方法来解决。
