Pharmacometrics Modelling-Based Dose-Finding and Synthetic Control Arms Established Using Longitudinal Analyses - Numerical analysis - Mathematical sc

肿瘤学领域的进步正在迅速改变许多癌症患者的预期寿命。治疗性干预逐渐从向大群体施用细胞毒性药物直至进展或死亡的短间歇周期转变为在较小群体中靶向和/或免疫调节分子组合的终身慢性治疗。这些进展提出了肿瘤药物开发的几个挑战，将在本项目中解决：1。基于药物计量学的超过最大耐受剂量（MTD）的剂量发现，平衡长期疗效和安全性，是否为肿瘤学临床药物开发提供了可行且具有成本效益的方法？使用基于系统建模、估计和优化的方法，将探讨肿瘤药物开发中的几种剂量发现策略。这将基于虚拟开发计划，但设置将反映目前在肿瘤学中看到的情况。将传统MTD范式与更广泛的剂量范围、长期疗效和安全性评价进行比较，并根据纵向分析做出决策。这将与成本分析挂钩，以评估可行性和附加值。2.是否可以利用历史临床试验数据和真实世界数据集的纵向分析来建立I/II期试验的合成对照组，以提高肿瘤临床药物开发的效率并最大限度地降低成本？将确定几个内部AZ数据集和外部数据库，并用于纵向建模，将药物暴露、生物标志物、遗传学和其他信息与相关临床试验结局联系起来。这些努力将与正在进行的开发项目保持一致，重点将是应用现有的建模和统计方法，促进决策，并防止负面的关键试验。

Advancements in the field of oncology are rapidly changing the life expectancy of patients across many cancers. Therapeutic interventions are gradually shifting, from short intermittent cycles of cytotoxic drugs administered to large populations until progression or death, to the life-long chronic treatment of combinations of targeted and/or immunomodulating molecules in smaller populations. These advances raise several challenges in oncology drug development that will be tackled in this project: 1. Do pharmacometrics based dose findings beyond the Maximum Tolerated Dose (MTD), balancing longer-term efficacy and safety, provide a feasible and cost-effective approach to clinical drug development in oncology? Using a systems modelling estimation and optimisation based approach several dose-finding strategies in oncology drug development will be explored. This will be based on virtual development programmes, but the settings will reflect what is currently seen across oncology. The traditional MTD-paradigm will be compared with more extensive dose-ranging, longer-term efficacy and safety evaluations, with decision-making based on the longitudinal analysis. This will be tied in with an analysis of costs to evaluate the feasibility and added value. 2. Can longitudinal analyses of historical clinical trial data and real-world datasets be leveraged to establish synthetic control arms for phase I/II trials to increase efficiency and minimise costs in oncology clinical drug development? Several internal AZ datasets and external databases will be identified and used for longitudinal modelling, linking drug exposure, biomarkers, genetics and other information to relevant clinical trial outcomes. These efforts will be aligned with ongoing development projects and the focus will be on the application of existing modelling and statistical approaches, facilitation decision-making, and preventing negative pivotal trials.