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: 10491120
• 负责人: LARA A. RAY
• 金额: $ 22.5万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491120
• 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 酒精使用障碍（AUD）的药物开发是一个耗时且昂贵的过程。不幸的是， 在过去的二十年里，尽管有大量的投资，但没有新的AUD药物被批准。一 开发AUD新药的典型途径包括在动物中进行测试，然后进行安全性测试。 人类，然后是随机临床试验。最近，有人提出，在人类中使用 实验精神药理学范例可以检测化合物的初始功效， 发展因此，最初在动物模型中确定了药物优于安慰剂的“信号”， 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。本质上，在 在测试的每个阶段，科学家的任务是对候选人做出“去/不去”的决定 药物治疗在这种情况下，FDA的批准构成了最终的“通过”决定，并要求 在随机对照试验中得到令人信服的疗效证明，这是金标准。虽然有一系列因素参与， 在做出“进行/不进行”的决定时，在动物和人类测试中用于检测功效信号的范例是 这对药物开发的成功至关重要。此外，如何评估临床前和人体证据 对于一个化合物，以决定，是至关重要的。到目前为止，哪些模型应该 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如何 评价仍然是非常主观的。科学家们可以用他们最熟悉的模型来论证， 初步数据可以用一系列合理的解释来呈现，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的荟萃分析模型，以测试 在动物模型、人类实验室模型和随机临床试验中获得的AUD药物效应量 试验（RCT）。这些分析将测试在药物治疗的每个阶段使用模型的程度 AUD的开发可预测RCT中的临床结局，这是改善医疗保健的金标准。