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.

摘要 开发治疗酒精使用障碍(AUD)的药物是一个既耗时又昂贵的过程。不幸的是， 在过去的20年里，尽管进行了大量的投资，但没有批准治疗AUD的新药。一个 开发一种治疗AUD的新药的典型途径包括在动物身上进行试验，然后在 人类，随后进行随机临床试验。最近，有人建议在人体上进行测试，使用 实验精神药理学范式可以检测一种化合物在 发展。因此，药物益处超过安慰剂的“信号”最初是在动物模型中确定的， 随后进行人体实验室测试，并最终在随机临床试验(RCT)中进行测试。从本质上讲，在 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 药物疗法。在这种情况下，FDA的批准构成了最终的“通过”决定，并要求 在随机对照试验中的令人信服的疗效演示，这是黄金标准。虽然涉及到许多因素， 做出“去/不去”的决定，在动物和人体试验中用来检测疗效信号的范例是 对药物开发的成功至关重要。此外，如何评估临床前和人类证据 对于一个化合物来说，要想决定，是至关重要的。到目前为止，哪些车型应该 用于临床前研究和人体实验室研究，以及它们提供的证据应该如何 评估仍然具有很高的主观性。科学家们可以为他们最熟悉的模型争辩 初步数据可以用一系列似是而非的解释来呈现，所有这些解释本身都是主观的。 建议的R21应用程序寻求进行新的元分析模型，以测试 在动物模型、人体实验室模型和随机临床试验中获得的药物效应大小 试验(RCT)。这些分析将测试模型在每个用药阶段的使用程度 AUD的发展可以预测RCT的临床结果，RCT是改善医疗保健的黄金标准。