Abstract：
Chronic repeated-dose toxicity studies are required to support long-term dosing in late-stage clinical trials, providing data to adequately characterize adverse effects of potential concern for human safety. Different regulatory guidances for the design and duration of chronic toxicity studies are available, with flexibility in approaches often adopted for specific drug modalities. These guidances may provide opportunities to reduce time, cost, compound requirement and animal use within drug development programs if applied more broadly and considered outside their current scopes of use. This article summarizes presentations from a workshop at the 43rd Annual Meeting of the American College of Toxicology (ACT) in November 2022, discussing different approaches for chronic toxicity studies. A recent industry collaboration between the Netherlands Medicines Evaluation Board (MEB) and UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) illustrated current practices and the value of chronic toxicity studies for monoclonal antibodies (mAbs) and evaluated a weight of evidence (WOE) model where a 3-month study rather than a 6-month study might be adequate. Other topics included potential opportunities for single-species chronic toxicity studies for small molecules, peptides and oligonucleotides and whether a 6-month duration non-rodent study can be used more routinely than a 9-month study (similar to ICH S6(R1) for biological products). Also addressed were opportunities to optimize recovery animal use if warranted and whether restriction to one study only (if at all) can be applied more widely within and outside ICH S6(R1).
摘要：
需要进行慢性重复剂量毒性研究，以支持后期临床试验中的长期给药。提供数据来充分描述潜在关注人类安全的不利影响。慢性毒性研究的设计和持续时间有不同的监管指导，具有特定药物模式通常采用的方法的灵活性。这些指南可以提供减少时间的机会，成本,药物开发计划中的化合物要求和动物使用，如果应用更广泛，并在其当前使用范围之外考虑。本文总结了2022年11月在美国毒理学学会（ACT）第43届年会上的研讨会上的演讲，讨论了慢性毒性研究的不同方法。荷兰药品评估委员会（MEB）和英国国家替代中心之间最近的行业合作，研究中的动物的改良和减少（NC3R）说明了当前的实践和单克隆抗体（mAb）的慢性毒性研究的价值，并评估了证据重（WOE）模型，其中3个月的研究而不是6个月的研究可能是足够的。其他主题包括单物种小分子慢性毒性研究的潜在机会，肽和寡核苷酸，以及6个月的非啮齿动物研究是否可以比9个月的研究更常规地使用（类似于用于生物制品的ICHS6（R1））。还讨论了优化恢复动物使用的机会（如果有必要），以及是否可以在ICHS6（R1）内外更广泛地应用仅限制一项研究（如果有的话）。
