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

基本信息

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
项目类别：
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

项目摘要

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.

成人的药物安全和有效性不能确保儿童同一药物的安全性和有效性。在美国，有40％为儿童订购的全身药物不在标签外（在FDA-之外使用批准的年龄，指示等）。此外，儿童的标签外使用率正在上升，特别是任何年龄段的治疗迹象都不批准。使用，过度使用和联合使用（多药）的标签不受支持的迹象的药物可能会使数百万儿童每年遭受与药物有关的严重危险危害这超过治疗的不确定益处。该团队的长期目标是改善明智的，基于证据的药物使用，这些药物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表征严重与毒品有关的危害的风险来自某些药物的儿童使用了最常见的dospite效率和安全性证据不足：精神药物。中心假设是在儿童中使用某些精神药物严重危害的风险增加。精神药物被用作应用示例的许多原因：1）儿童不受支持的非标签使用率高； 2）效率不足的证据孩子们; 3）可能造成严重或致命的伤害； 4）儿童的危害可能比成年人更大； 5）关键治疗需求； 6）可用的治疗替代方法（例如，安全药物，非药物干预措施）； 7）可测量的结果。基于这些标准，文献差距和初步数据，这提案重点是可能的严重危害（即自杀，心律不齐和严重的皮肤反应）与抗抑郁药（例如Venlafaxine）和抗癫痫药/情绪稳定剂（AEDS）（例如，例如， lamotrigine）。特别是，该提案旨在评估以下程度：1）某些抗抑郁药和 AEDS增加或减少儿童自杀死亡的风险（AIM 1）； 2）某些抗抑郁药和 AEDS增加或减少儿童心律不齐，心脏骤停或猝死的风险（AIM 2）; 3）某些抗癫痫药/情绪稳定剂或药物组合会增加或降低儿童的严重皮肤反应（AIM 3）。项目团队将在两个内研究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。这项研究将产生现在缺乏严重的相对风险和绝对风险，可概括，可操作，临床上相关的证据药物和药物组合造成的危害越来越多地使用了标签，儿童的证据不足。由于需要大量较大的临床试验，这些罕见的结果不能在临床试验中进行可行的研究。样本量。在年龄组，诊断，药物剂量和伴随药物之间进行比较，不仅将量化关键亚组的风险，但也将阐明潜在的生物学和机制。这个项目也是如此开始了一项重要的新工作，将为改进提供毒品证据的总体证据质量儿童通常使用效率和安全性的证据不足。