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Review
. 2024 Dec;25(18):2375-2384.
doi: 10.1080/14656566.2024.2426678. Epub 2024 Nov 14.

Therapeutic orphans, off-label, pediatric drug development: towards reasonable pharmacotherapy for minors

Klaus Rose  1 , Jane M Grant-Kels  2 , Pasquale Striano  3
Affiliations
Review

Therapeutic orphans, off-label, pediatric drug development: towards reasonable pharmacotherapy for minors

Klaus Rose et al. Expert Opin Pharmacother. 2024 Dec.

Abstract

Introduction: The concept that children are therapeutic orphans emerged in the 1960s, triggering eventually worldwide legislation to facilitate pediatric studies, called 'Pediatric Drug Development (PDD).' However, PDD's true aim is not better medicines for children but labels in minors; minors are not another species.

Areas covered: Absorption, distribution, metabolism, and excretion (ADME) differ in preterm newborns, but babies mature. With the exception of neonatology, the justifications for clinical, pharmacokinetic, and safety studies were and are exaggerated.

Expert opinion: PDD reflects an artificial regulatory challenge, reflecting mankind's transition into a world of effective new drugs compared to previous millennia when only materials taken from nature were available. Minors need dose assessment and proof of safety; there is a tendency to exaggerate the scope of pharmacokinetic and safety studies before and after the eighteenth birthday, potentially motivated not by industry's greed, but by researchers' desire for funding and regulatory authorities' desire for recognition, specifically as since 2007 the European Medicines Agency (EMA) augmented and expanded PDD: a new type of conflict of interest in medicines' administration and mainstream medical science.

Keywords: Pediatric drug development (PDD); children as therapeutic orphans; conflict of interests; developmental pharmacology; international council of medical journal editors (ICMJE); off-label.

Plain language summary

The concept that children are therapeutic orphans claims that children are disadvantaged in drug treatment if drugs are not specifically approved for children. The concept arose when new drug legislation in the U.S.A. required that medicines had to be proven safe and effective before applying for approval. This legislation was the result of the thalidomide disaster. In order to avoid lawsuits for damages, manufacturers now included warnings in drug labels that the respective drug had not been tested on children. This was the time of many new discoveries and medical breakthroughs. One such breakthrough was the realization that the body of very young children works differently than it does when it gets older. Developmental pharmacology learned, for example, how the liver enzymes involved in processing medication change massively in the days after birth. But after the first few weeks and months, the child’s body matures and the differences to adults are no longer so dramatic. The concept that children are therapeutic orphans demanded pediatric studies for all minors. This demand is called ‘Pediatric Drug Development’ (PDD). The European Medicines Agency (EMA) in particular requires pediatric studies long before approval, regardless of whether they make medical sense or not. But adolescents’ bodies are no longer as different from adults as babies are. Nevertheless, the EMA also requires pediatric studies for adolescents. Also, for younger children, EMA`s insistence on repeating safety and efficacy studies is exaggerated. The origins and impact of the children-are-therapeutic-orphans concept can only be understood by considering that modern drug development is only half century old and that for the regulatory authorities drugs are only safe with a label. However, the major therapeutic breakthroughs in pediatrics were not caused by pediatric labels, but because courageous researchers used everything that was available. Pediatric oncology saved hundreds of thousands of children from death decades before the discussion about pediatric labels had even begun. PDD reflects a regulatory challenge and mankind’s transition into a world of new drugs in contrast to previous millennia when only materials taken from nature were available. Minors need reasonable assessment of doses and safety, not large international regulatory studies. Such expensive pointless and exaggerated studies are primarily not triggered by industry’s greed, but by researchers’ desire for funding and regulatory authorities’ desire for recognition. A new type of conflict of interest in medicines’ administration and in mainstream medical science.

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