Safety of Drugs Commonly Used Off-Label in Children Despite Insufficient Evidence of Efficacy and Safety

药物在成人中的安全性和有效性并不能保证相同药物在儿童中的安全性和有效性。 在美国，>40%的儿童全身用药是标签外使用的（在FDA之外使用）。 年龄、适应症等）。此外，儿童的标签外使用率正在上升，特别是 治疗适应症在任何年龄都未经批准。超说明书使用、过度使用和联合使用（多种药物） 用于无支持适应症的药物每年可能使数百万儿童面临与药物有关的严重风险。 危害大于治疗的不确定益处。这个团队的长期目标是改善明智的， 循证使用药物，为临床决策提供信息，使儿童更健康， 更安全本项目的具体目标是描述以下方面的严重药物相关危害风险： 儿童最常用的一些药物，尽管疗效和安全性的证据不足： 精神药物中心假设是，儿童使用某些精神药物与 严重伤害的风险增加。精神药物被用作应用实例的原因有很多：1） 儿童无支持的超说明书使用的高流行率和不断上升的流行率; 2）疗效证据不足， 儿童; 3）严重或致命伤害的可能性; 4）儿童的潜在伤害大于成人; 5）关键 治疗需要; 6）可用的治疗替代方案（例如，更安全的药物，非药物干预）; （7）可衡量的结果。根据这些标准、文献中的空白和初步数据， 提案重点关注可能的选定严重伤害（即自杀、心律失常和严重皮肤反应） 与抗抑郁药相关（例如，文拉法辛）和抗癫痫药/情绪稳定剂（AED）（例如， 拉莫三嗪）。具体而言，该提案旨在评估以下方面的程度：1）某些抗抑郁药， AED增加或减少儿童自杀死亡的风险（目标1）; 2）某些抗抑郁药， AED增加或减少儿童室性心律失常、心脏骤停或猝死的风险（Aim 2）;和3）某些抗癫痫药物/情绪稳定剂或药物组合增加或降低 儿童严重皮肤反应（目标3）。该项目小组将研究两个不同的儿科人群， 国家索赔和电子健康记录数据库，以实现这些目标。这项研究将产生 目前缺乏可推广的、可操作的、临床相关的证据，表明严重 越来越多的药物和药物组合在儿童中使用标签外且证据不足。 这些罕见的结果无法通过临床试验进行可行的研究，因为需要大量的 样本量。年龄组、诊断、药物剂量和伴随药物之间的比较不仅 量化关键亚组的风险，但也将揭示潜在的生物学和机制。该项目还 开始了一项重要的新工作，这将有助于改善药物证据的整体质量， 儿童普遍使用，尽管没有足够的证据证明其有效性和安全性。

Drug safety and effectiveness in adults does not assure safety and effectiveness of the same drugs in children. In the United States, >40% of systemic drugs ordered for children are off-label (used outside of an FDA- approved age, indication, etc.). Furthermore, rates of off-label use in children are rising, particularly for treatment indications unapproved at any age. Use, overuse, and combined use (polypharmacy) of off-label medicines for unsupported indications may put millions of children at risk each year for serious drug-related harms that outweigh uncertain benefits of treatment. This team’s long-term goal is to improve the judicious, evidence-based use of medicines that will inform clinical decision-making and make children healthier and safer. The specific objective of this project is to characterize the risks for serious drug-related harms in children from some of the drugs used most commonly despite insufficient evidence of efficacy and safety: psychotropic drugs. The central hypothesis is that use of certain psychotropic drugs in children is associated with increased risks of serious harms. Psychotropic drugs are used as applied examples for many reasons: 1) high and rising prevalence of unsupported off-label use in children; 2) insufficient evidence of efficacy in children; 3) potential for serious or fatal harms; 4) potentially greater harms in children than in adults; 5) critical therapeutic needs; 6) available therapeutic alternatives (e.g., safer drugs, non-pharmacologic interventions); and 7) measurable outcomes. Based on these criteria, gaps in the literature, and preliminary data, this proposal focuses on selected serious harms (namely, suicide, arrhythmias, and severe skin reactions) possibly associated with antidepressants (e.g., venlafaxine) and antiepileptic drugs/mood stabilizers (AEDs) (e.g., lamotrigine). Specifically, this proposal aims to evaluate the extent to which: 1) certain antidepressants and AEDs increase or decrease the risk of death by suicide in children (Aim 1); 2) certain antidepressants and AEDs increase or decrease the risk of ventricular arrhythmias, cardiac arrest, or sudden death in children (Aim 2); and 3) certain antiepileptic drugs/mood stabilizers or drug combinations increase or decrease the risk of severe skin reactions in children (Aim 3). The project team will study distinct pediatric populations within two national claims and electronic health records databases to accomplish these aims. This research will produce generalizable, actionable, clinically relevant evidence now lacking on relative and absolute risks of serious harms from drugs and drug combinations increasingly used off-label and with insufficient evidence in children. These rare outcomes cannot be feasibly studied with clinical trials due to the need for prohibitively large sample sizes. Comparisons across age groups, diagnoses, drug doses, and concomitant drugs will not only quantify risks in key subgroups but will also shed light on underlying biology and mechanisms. This project also begins an important new line of work that will inform improvements the overall quality of evidence for drugs that children commonly use despite insufficient evidence of efficacy and safety.