Integrating findings across stages of medication development for AUD

整合 AUD 药物开发各个阶段的发现

• 批准号: 10353926
• 负责人: LARA A. RAY
• 金额: $ 21.28万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353926
• 关键词: Alcohol consumption; Alcohols; Animal Model; Animals; Clinical; Clinical Trials; Code; Consumption; Cues; Data; Development; Ethanol dependence; Gold; Healthcare; Heavy Drinking; Human; Integration Host Factors; Investments; Laboratories; Laboratory Study; Least-Squares Analysis; Literature; Methods; Modeling; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebos; Pre-Clinical Model; Process; Psychopharmacology; Randomized Clinical Trials; Relapse; Scientist; Sedation procedure; Self Administration; Signal Transduction; Stress; Testing; Time; Work; alcohol cue; alcohol effect; alcohol use disorder; analytical method; cost; craving; cue reactivity; design; drinking; human model; improved; novel; pre-clinical; preclinical study; predict clinical outcome; predictive modeling; preservation; safety testing; success

ABSTRACT Medication development for alcohol use disorder (AUD) is a time-consuming and costly process. Unfortunately, no new medications for AUD have been approved in the past two decades, despite significant investments. A typical path to developing a new medication for AUD includes testing in animals, followed by safety testing in humans, followed by randomized clinical trials. Recently, it has been proposed that testing in humans using experimental psychopharmacology paradigms can detect the initial efficacy of a compound under development. As such, the “signal” of medication benefit over placebo is initially identified in animal models, followed by human laboratory testing, and ultimately tested in randomized clinical trials (RCT). In essence, at each phase in testing, scientists are tasked with making “go/no-go” decisions about candidate pharmacotherapies. In this context, approval by the FDA constitutes the final “go” decision and requires compelling efficacy demonstration in RCTs, which is the gold standard. While a host of factors are involved in making “go/no-go” decisions, the paradigms used in animal and human testing to detect an efficacy signal are crucial to the success of medication development. Further, how to evaluate the preclinical and human evidence for a compound in order to decide, is of paramount importance. To date, the question of which models should be used in preclinical studies and human laboratory studies and how the evidence they provide should be evaluated remains highly subjective. Scientists can argue for models they are most familiar with and preliminary data can be presented with a range of plausible interpretation, all of which is inherently subjective. The proposed R21 application seeks to conduct novel meta-analytic models to test the relationship between AUD medication effect sizes obtained in animal models, human laboratory models, and randomized clinical trials (RCTs). These analyses will test the degree to which models used at each stage of medication development for AUD are predictive of clinical outcomes in RCTs, the gold standard for improving healthcare.

抽象的 不幸的是，针对酒精使用障碍（AUD）的药物开发是一个耗时且昂贵的过程。 尽管进行了大量投资，但在过去二十年中尚未批准用于 AUD 的新药物。 AUD 新药的典型开发路径包括在动物身上进行测试，然后进行安全性测试 最近，有人提出在人体中进行测试。 实验精神药理学范式可以检测化合物在以下条件下的初始功效 因此，药物优于安慰剂的“信号”最初是在动物模型中发现的。 随后进行人体实验室测试，最终在随机临床试验（RCT）中进行测试。 在测试的每个阶段，科学家的任务是对候选人做出“通过/不通过”的决定 在这种情况下，FDA 的批准构成最终的“继续”决定，并且需要进行。 随机对照试验中令人信服的功效证明，这是黄金标准，同时涉及许多因素。 做出“继续/不继续”决策时，动物和人体测试中用于检测功效信号的范式是 此外，如何评估临床前和人体证据对于药物开发的成功至关重要。 迄今为止，对于一个化合物来说，应该选择哪些模型是至关重要的。 用于临床前研究和人体实验室研究以及它们的证据应该如何 评估仍然非常主观。科学家们可以争论他们最熟悉和最熟悉的模型。 初步数据可以通过一系列看似合理的解释来呈现，所有这些解释本质上都是主观的。 拟议的 R21 应用程序旨在进行新颖的元分析模型来测试之间的关系 在动物模型、人体实验室模型和随机临床中获得的 AUD 药物效应大小 这些分析将测试模型在药物治疗的每个阶段使用的程度。 AUD 的开发可以预测 RCT 的临床结果，这是改善医疗保健的黄金标准。