Neurobehavioral Sciences, Charles River Laboratories, Mattawan, 49071, MI, USA.
Neurobehavioral Sciences, Charles River Laboratories, Mattawan, 49071, MI, USA.
Regul Toxicol Pharmacol. 2022 Mar;129:105116. doi: 10.1016/j.yrtph.2022.105116. Epub 2022 Jan 10.
Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.S. Regulatory Agencies and the International Commission on Harmonization. The validity and reliability of the Functional Observational Batter (FOB) is critically dependent on consistency and technical quality in each risk assessment plan. US Federal and International drug approval organizations have universally adopted the concept of principles of test construction rather than delineating specific behavioral assay endpoints for inclusion of the FOB in nonclinical safety protocols. The validity and reliability of behavioral observations in standardized neurotoxicity screening is critically dependent on the FOB developed by the Study Director with the Sponsor throughout all stages of testing.. The individual risk factors selected for observation to be included in the early Tier 1 safety program should be determined by the mechanism and mode of action of the test article. The results of Tier I testing are the basis for Tier II testing designs. Critical to the compliance with Good Laboratory Practices is the documentation of training of the operational staff scheduled to conduct all aspects of the established protocol.
去风险化并不是制药行业用来减少药物开发时间、精力或成本的策略。去风险化策略最初源自美国国立卫生研究院，是良好科学的前提。药物开发项目中有一种越来越强烈的情绪，认为在毒理学研究和美国监管机构以及国际协调委员会的分层安全评估计划中，减少行为措施的重要性。功能性观察电池（FOB）的有效性和可靠性严重依赖于每个风险评估计划中的一致性和技术质量。美国联邦和国际药物批准机构普遍采用了测试构建原则的概念，而不是为将 FOB 纳入非临床安全性方案而划定具体的行为测定终点。在标准化神经毒性筛选中的行为观察的有效性和可靠性严重依赖于研究主任与赞助商在整个测试阶段共同开发的 FOB。选择用于早期第 1 层安全计划观察的个体风险因素应根据测试物质的作用机制和作用模式确定。第 I 层测试的结果是第 II 层测试设计的基础。符合良好实验室规范的关键是记录计划进行所有既定方案方面的操作人员的培训。
