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

尽管有效性和安全性证据不足，但儿童常用超说明书药物的安全性

• 批准号: 10503951
• 负责人: Daniel Benjamin Horton
• 金额: $ 66.64万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503951
• 关键词: Adult; Adverse effects; Age; Antibiotics; Antidepressive Agents; Antiepileptic Agents; Arrhythmia; Biology; Biometry; Bupropion; Cardiology; Child; Child Health; Child Psychiatry; Childhood; Clinical; Clinical Trials; Controlled Study; Data; Data Sources; Databases; Dermatology; Diagnosis; Disease; Dose; Drug Combinations; Drug Interactions; Drug usage; Effectiveness; Electronic Health Record; Escitalopram; FDA approved; Family; Fluoxetine; Goals; Health Insurance; Heart Arrest; Intervention; Intervention Trial; Label; Life; Light; Literature; Measurable; Medicaid; Medical; Medicine; Mood stabilizers; Outcome; Patients; Pharmaceutical Preparations; Pharmacoepidemiology; Polypharmacy; Population; Prevalence; Psychotropic Drugs; Reaction; Research; Retrospective cohort; Risk; Safety; Sample Size; Seizures; Skin; Subgroup; Sudden Death; Suicide; Therapeutic; Time; Translating; United Kingdom; United States; Ventricular Arrhythmia; Work; age group; alternative treatment; base; clinical decision-making; clinical practice; clinically relevant; drug efficacy; evidence base; gabapentin; high risk; improved; lamotrigine; medication safety; mortality risk; off-label drug; off-label use; programs; suicidal morbidity; suicidal risk; valproate; venlafaxine

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.

成人药物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，超过 40% 的儿童全身用药都是超说明书用药（在 FDA 批准之外使用） 批准的年龄、适应症等）。此外，儿童超说明书用药的比例正在上升，特别是 任何年龄的治疗指征均未经批准。标签外药物的使用、过度使用和联合使用（多药治疗） 用于不受支持的适应症的药物每年可能使数百万儿童面临严重与毒品相关的风险 危害超过治疗的不确定益处。该团队的长期目标是提高明智、 基于证据的药物使用将为临床决策提供信息并使儿童更健康 更安全。该项目的具体目标是描述严重毒品相关危害的风险特征 尽管疗效和安全性证据不足，但儿童仍然最常使用一些药物： 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。使用精神药物作为应用示例有多种原因：1） 儿童中未经支持的超说明书用药的流行率很高，而且还在不断上升； 2) 功效证据不足 孩子们; 3) 潜在的严重或致命伤害； 4）对儿童的潜在危害比对成人更大； 5）关键 治疗需求； 6) 可用的治疗替代方案（例如更安全的药物、非药物干预措施）； 7) 可衡量的成果。根据这些标准、文献中的空白和初步数据，本研究 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（例如文拉法辛）和抗癫痫药/情绪稳定剂（AED）（例如 拉莫三嗪）。具体来说，该提案旨在评估以下程度：1）某些抗抑郁药和 AED 会增加或降低儿童自杀死亡的风险（目标 1）； 2）某些抗抑郁药和 AED 会增加或降低儿童室性心律失常、心脏骤停或猝死的风险（目标 2）； 3) 某些抗癫痫药物/情绪稳定剂或药物组合会增加或降低风险 儿童严重皮肤反应（目标 3）。该项目团队将研究两个时期内不同的儿科人群 国家索赔和电子健康记录数据库来实现这些目标。这项研究将产生 目前缺乏可概括的、可操作的、临床相关的证据来证明严重的相对和绝对风险 药物和药物组合的危害越来越多地在儿童中超说明书使用且证据不足。 由于需要大量的数据，因此无法通过临床试验来研究这些罕见的结果。 样本大小。跨年龄组、诊断、药物剂量和联合用药的比较不仅可以 量化关键亚组的风险，但也将揭示潜在的生物学和机制。这个项目还 开始一项重要的新工作，这将有助于提高药物证据的整体质量， 尽管有效性和安全性证据不足，但儿童仍普遍使用。