TreeScan to Evaluate the Safety of New Drugs in Pediatric Populations

儿童不是小的成年人;然而，我们严重依赖随机和 在成人人群中进行的非随机研究，为儿科患者提供治疗策略。 从历史上看，出于道德原因，儿童一直受到保护。不过，这口井- 有意保护儿童免受审判的风险和负担， 易受日常实践中使用的药物的潜在风险的影响，经常超说明书使用， 没有高质量的疗效、有效性或安全性证据。的重要性 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性监测， 越来越多地得到FDA、EMA和其他监管机构的认可， 作为国家药品安全监督系统的主要组成部分。然而，迄今为止， 这些举措的重点是成年人的药物安全;目前没有 针对儿科人群的药物安全性的系统监测系统。为了解决这个 证据缺口-这使得儿科患者的风险增加-我们建议开发和测试 基于TreeScan的方法在系统和同时 评估儿科人群中的多种潜在不良结局，并实施 这些方法用于对新儿科药物的前瞻性连续监测。TreeScan 方法使用包括数千个结果的分层树， 相关假设的检验，同时系统地筛选潜在的不良反应。 该方法从未用于评估儿科患者的药物安全性， 与成年人相比是一个独特的挑战。因此，所述方法还需要 发展和完善。我们将基于以下真实示例来测试该方法： 具有相对良好安全性特征的已确立药物（目标1）以及plasmode 模拟，探索广泛的合理的儿科临床背景（目标2）。的 然后将实施性能测试方法，以前瞻性地监测 最近批准的药物和将在赠款的最初几年批准的新药 (Aim 3）。将在全面流行病学研究中进一步评价潜在信号。这 该项目将提供一个迫切需要的工具，可以导致早期发现未知的 药物在儿科人群中的不良反应（如果存在），并提供保证（如果不存在） 检测到具有大影响的安全问题。拟议的研究预计将有一个 通过全面评估对公共卫生的直接和重要影响， 儿科人群中新药的安全性特征。

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.