Helen Prior, Paul Baldrick, David O Clarke, Elisa Passini, Fiona Sewell, Peter van Meer
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引用次数: 0
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用药,提供数据以充分描述可能对人体安全造成影响的不良反应。慢性毒性研究的设计和持续时间有不同的监管指南,通常针对特定药物模式采用灵活的方法。如果能更广泛地应用这些指导原则,并在其现有使用范围之外加以考虑,就有可能在药物开发项目中减少时间、成本、化合物需求和动物用量。本文总结了 2022 年 11 月美国毒理学会 (ACT) 第 43 届年会的研讨会发言,讨论了慢性毒性研究的不同方法。荷兰药品评估委员会(MEB)和英国国家研究动物替代、改进和减少中心(NC3Rs)最近开展了一项行业合作,说明了单克隆抗体(mAbs)慢性毒性研究的现行做法和价值,并评估了证据权重(WOE)模型,在该模型中,3个月的研究而不是6个月的研究可能就足够了。其他主题包括小分子、肽和寡核苷酸单物种慢性毒性研究的潜在机会,以及为期 6 个月的非啮齿动物研究是否比为期 9 个月的研究更常规(类似于生物制品的 ICH S6(R1))。此外,还讨论了在有必要的情况下优化回收动物使用的机会,以及在 ICH S6(R1)内外是否可以更广泛地应用仅限一项研究的限制(如果有的话)。
Exploring Greater Flexibility for Chronic Toxicity Study Designs to Support Human Safety Assessment While Balancing 3Rs Considerations.
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).
期刊介绍:
The International Journal of Toxicology publishes timely, peer-reviewed papers on current topics important to toxicologists. Six bi-monthly issues cover a wide range of topics, including contemporary issues in toxicology, safety assessments, novel approaches to toxicological testing, mechanisms of toxicity, biomarkers, and risk assessment. The Journal also publishes invited reviews on contemporary topics, and features articles based on symposia. In addition, supplemental issues are routinely published on various special topics, including three supplements devoted to contributions from the Cosmetic Review Expert Panel.