TreeScan to Evaluate the Safety of New Drugs in Pediatric Populations

儿童不是小成人；然而，我们严重依赖以随机和 成人人群中的非随机研究，为儿科患者的治疗策略提供信息。 从历史上看，出于道德原因，儿童受到保护，不受研究的影响。然而，这口井- 有意识地保护儿童免受审判的风险和负担，这自相矛盾地让孩子们 容易受到日常实践中使用的药物的潜在风险的影响，经常是在标签外和 没有高质量的有效性、有效性或安全性的证据。重要的是 使用常规收集的医疗保健数据进行药物流行病学药物安全监测 越来越受到FDA、EMA和其他监管机构的认可，并构成了 作为国家药品安全监督系统的一个重要组成部分。然而，到目前为止， 这些倡议的重点一直是成年人的药物安全；目前没有 针对儿科人群用药安全的系统监测系统。要解决这个问题 证据差距--这会增加儿科患者的风险--我们建议开发和测试 基于TreeScan的系统性和并发性方法的性能 评估儿科人群中的多种潜在不良后果，并实施 这些方法用于儿科新药的前瞻性序贯监测。树扫描 方法使用包含数千个结果的层次结构树，并说明多个 检验相关的假设，同时系统地筛选潜在的不良影响。 该方法从未被用于评估儿科患者的药物安全性，在那里 与成年人口相比，是独一无二的挑战。因此，这些方法需要进一步 发展精细化。我们将基于真实世界的示例测试该方法 已确定的药物具有相对良好的安全性特征(目标1)以及血浆模式 探索儿科各种看似合理的临床背景的模拟(目标2)。这个 然后将实施性能测试方法，以前瞻性地监控 最近批准的药物和将在赠款最初几年获得批准的新药 (目标3)。将在全面的流行病学研究中进一步评估潜在的信号。这 项目将提供一个迫切需要的工具，可以及早发现可疑的 药物在儿科人群中的不良反应，如果存在，如果没有，则提供保证 检测到影响较大的安全问题。拟议的研究预计将有一个 通过提供对以下方面的全面评估，立即对公共卫生产生重要影响 儿科人群中新药的安全性概况。

Children are not small adults; yet we heavily rely on information collected in randomized and non-randomized studies in adult populations to inform treatment strategies for pediatric patients. Historically, children have been protected from research for ethical reasons. However, this well- intentioned protection from the risks and burdens of trials has paradoxically left children more susceptible to the potential risks of drugs used in everyday practice, frequently off-label and without high-quality evidence of efficacy, effectiveness, or safety. The importance of pharmacoepidemiologic drug safety monitoring using routinely collected healthcare data has been increasingly recognized by the FDA, EMA, and other regulators, and forms the backbone for a major component of the nation’s drug safety surveillance system. However, to date, the focus of these initiatives has been on drug safety in adult populations; there is currently no systematic surveillance system targeting drug safety in pediatric populations. To address this evidence gap – which puts pediatric patients at increased risk – we propose to develop and test the performance of TreeScan based approaches for the systematic and simultaneous evaluation of multiple potential adverse outcomes in pediatric populations, and to implement these methods for prospective sequential surveillance of new pediatric medications. TreeScan methods use a hierarchical tree comprising thousands of outcomes and account for multiple testing of correlated hypotheses while systematically screening for potential adverse effects. The methodology has never been used to evaluate drug safety in pediatric patients, where there are unique challenges compared to adult populations. Thus, the methods require further development and refinement. We will test the approach based on real-world examples of established drugs with relatively well characterized safety profiles (Aim 1) as well as plasmode simulations that explore a broad range of plausible clinical contexts in pediatrics (Aim 2). The performance tested approach will then be implemented to prospectively monitor the safety of recently approved drugs and new drugs that will be approved during the early years of the grant (Aim 3). Potential signals will be further evaluated in full-scale epidemiological studies. This project will provide a critically needed tool that could lead to early detection of unsuspected adverse effects of drugs in pediatric populations if they exist and provide reassurance if no safety issues with large effects are detected. The proposed studies are expected to have an immediate and important public health impact by providing comprehensive assessments of the safety profiles for new medications in pediatric populations.