Value-Generating Exploratory Trials in Neurodegenerative Dementias.
Value-Generating Exploratory Trials in Neurodegenerative Dementias.
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DOI：
10.1212/wnl.0000000000011774
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发表时间：
2021-05-18
期刊：
影响因子：
9.9
通讯作者：
Fillit HM
中科院分区：
文献类型：
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作者：
Friedman LG;McKeehan N;Hara Y;Cummings JL;Matthews DC;Zhu J;Mohs RC;Wang D;Hendrix SB;Quintana M;Schneider LS;Grundman M;Dickson SP;Feldman HH;Jaeger J;Finger EC;Ryan JM;Niehoff D;Dickinson SL;Markowitz JT;Owen M;Travaglia A;Fillit HM
治疗阿尔茨海默病和其他神经退行性痴呆(包括额颞痴呆)的药物开发经历了很长一段时间的2期和3期临床试验，但未能显示研究药物的疗效。尽管临床和行为特征不同，但这些疾病有着共同的病理基础，在设计预测晚期成功的早期试验方面面临着共同的挑战。在这里，我们讨论神经退行性痴呆的探索性临床试验。这些试验通常是1b期或2a期试验，旨在评估药理效应并依赖于生物标记物的结果，与传统的2期研究相比，治疗持续时间更短，患者更少。探索性试验可以建立通过/不通过的决策点，支持概念验证和剂量选择，并终止未能以适当的暴露和可接受的安全概况显示目标参与的药物。早期故障节省了宝贵的资源，包括机会成本。这对学术界和小型生物技术公司的项目尤其重要，但也可以应用于大型制药公司的高风险项目，以比传统方法更快、更低的成本实现概念证明。阶段性临床开发计划中的探索性研究可能提供有希望的数据，以保证通过后期开发推进化合物所需的大量资源。为了优化探索性试验的设计和应用，阿尔茨海默氏症药物发现基金会和额颞部退化协会召集了一个咨询小组，就这些类型的研究和研究设计的结果衡量标准和统计考虑提供建议，以提高临床开发的效率。
Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.