R01HD109335

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

Drug safety and effectiveness in adults does not assure the safety and effectiveness of the same drugs in children. In the United States, over 40% of systemic drugs ordered for children are off-label, meaning they are 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. The 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 the 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, specifically psychotropic drugs. The central hypothesis is that the 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 in the overall quality of evidence for drugs that children commonly use despite insufficient evidence of efficacy and safety.

Rutgers The State University Of New Jersey

NOT APPLICABLE

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Newark, New Jersey 071073001 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 05/30/27 to 05/31/27 and the total obligations have increased 398% from $666,419 to $3,318,985.