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

Award Number: R01HD109335
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/19/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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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 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $663,345 )
2026	2026	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Child Health and Human Development Extramural Research	000	5	5/15/2026	NON-COMPETING CONTINUATION	$663,345
														Subtotal = $663,345

Issue Date FY: 2025 ( Subtotal = $664,492 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Child Health and Human Development Extramural Research	000	4	5/14/2025	NON-COMPETING CONTINUATION	$664,492
														Subtotal = $664,492

Issue Date FY: 2024 ( Subtotal = $658,627 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Child Health and Human Development Extramural Research	000	3	7/3/2024	NON-COMPETING CONTINUATION	$658,627
														Subtotal = $658,627

Issue Date FY: 2023 ( Subtotal = $666,102 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Child Health and Human Development Extramural Research	001	2	6/6/2023	NON-COMPETING CONTINUATION	$666,102
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Child Health and Human Development Extramural Research	000	1	12/15/2022	NEW	$0
														Subtotal = $666,102

Issue Date FY: 2022 ( Subtotal = $666,419 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Child Health and Human Development Extramural Research	000	1	9/19/2022	NEW	$666,419
														Subtotal = $666,419

Grand Total All Awards = $3,318,985

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

Award Number: R01HD109335

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/19/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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