Dataset Information

A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development.

ABSTRACT:

Background

Adverse drug effects (ADEs) in children are common and may result in disability and death, necessitating post-marketing monitoring of their use. Evaluating drug safety is especially challenging in children due to the processes of growth and maturation, which can alter how children respond to treatment. Current drug safety-signal-detection methods do not account for these dynamics.

Methods

We recently developed a method called disproportionality generalized additive models (dGAMs) to better identify safety signals for drugs across child-development stages.

Findings

We used dGAMs on a database of 264,453 pediatric adverse-event reports and found 19,438 ADEs signals associated with development and validated these signals against a small reference set of pediatric ADEs. Using our approach, we can hypothesize on the ontogenic dynamics of ADE signals, such as that montelukast-induced psychiatric disorders appear most significant in the second year of life. Additionally, we integrated pediatric enzyme expression data and found that pharmacogenes with dynamic childhood expression, such as CYP2C18 and CYP27B1, are associated with pediatric ADEs.

Conclusions

We curated KidSIDES, a database of pediatric drug safety signals, for the research community and developed the Pediatric Drug Safety portal (PDSportal) to facilitate evaluation of drug safety signals across childhood growth and development.

Funding

This study was supported by grants from the National Institutes of Health (NIH).

SUBMITTER: Giangreco NP

PROVIDER: S-EPMC9378670 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development.

Giangreco Nicholas P NP Tatonetti Nicholas P NP

Med (New York, N.Y.) 20220624 8

<h4>Background</h4>Adverse drug effects (ADEs) in children are common and may result in disability and death, necessitating post-marketing monitoring of their use. Evaluating drug safety is especially challenging in children due to the processes of growth and maturation, which can alter how children respond to treatment. Current drug safety-signal-detection methods do not account for these dynamics.<h4>Methods</h4>We recently developed a method called disproportionality generalized additive mode ...[more]

PMID: 35752163

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Project description:Introduction and background"Pediatric Drug Development" is being used to describe not the development of drugs for children, but rather the planning & conducting separate efficacy and safety (E&S) studies requested/demanded by regulatory authorities designed to produce pediatric labels. Pediatric studies required for drug approval enroll "children"; defined as <17 years of age (US Food and Drug Administration [FDA])/ <18 years (European Union [EU]). The medical rationale for study designs was examined.Material & methodsInternational industry-sponsored pediatric E&S studies registered in www.clinicaltrials.gov were analysed along with the history of US/EU laws, published literature, internet-retrieved regulatory documents, and regulatory/ American Academy of Pediatrics (AAP) justifications for doing separate pediatric E&S studies.ResultsUS/EU regulators utilize an official, but non-physiological definition of childhood based on an age limit of 17/18 years. This definition, which blurs the interface between medicine and law, emerged after clinical studies became required for drug approval in 1962 prompting drug manufacturers to insert pediatric warnings into product information. Intended largely as legal protection against liability, they were interpreted medically. Absorption, distribution, metabolism, excretion mature rapidly. Drug toxicities seen in newborns during the first months of life were cited by AAP/FDA in warnings of dangers of drugs in all "children" including in adolescents who are physiologically no longer children. Warnings were/are exaggerated, exploit/ed parents' protective instincts and fears, and increase/d pediatric clinical trial activity. Conflicts of interest created by this increased activity involve research funding, career status & advancement, commercial profits.DiscussionFDA/EMA-requested/demanded "pediatric" studies were identified which lack medical sense at best, others actually harm young patients by impeding use of superior, effective treatments. Separate labels for different indications make medical sense; separate approval in persons above/below 17/18 years of age does not.ConclusionsPediatric medical research should be restricted to studies which meet important medical needs of all recruited young patients, which generate information that cannot be obtained by other study designs, and do not limit access to superior alternative therapies. Clinical centers, investigators, and IRBs/ECs should more carefully examine studies for unjustified regulatory demands, prevention of subjects' access to superior treatments, and undeclared COI's. Questionable studies should not be approved and ongoing ones should be suspended.

Dataset Information

A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development.

Background

Methods

Findings

Conclusions

Funding

Publications

A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development.

Similar Datasets

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