Lack of formal regulatory definitions of off-label medication use in children: an analysis using agency inquiry and text mining

Objectives: This study investigates the formal definitions of “off-label” medication use among five major Western regulatory authorities—FDA, EMA, Health Canada, MHRA, and TGA. The primary research question is whether these agencies provide explicit, official definitions of off-label use.

Design: The study employs a mixed-methods design, combining direct inquiries via standardized questionnaires with AI-assisted text mining of publicly available regulatory documents.

Setting: Regulatory agencies at a national level across North America, Europe, and Oceania.

Participants: Five agencies, with data collected through direct contact and automated document analysis; no human participants were involved.

Intervention: Analysing agency webpages and documents for sentences that resemble formal definitions, followed by manual review and categorization based on linguistic and contextual criteria.

Main outcome: The presence or absence of official definitions, the content and clarity of any definitional statements, and their prominence within regulatory documents.

Result: None of the agencies provide a formal, official definition of off-label use. However, all agencies’ publicly available documents contain statements that resemble definitions, generally describing off-label use as prescribing beyond the conditions approved by the drug’s marketing authorization. Despite similarities in language, the clarity and prominence of these statements vary across agencies.

Conclusion: The lack of formal off-label definitions may contribute to legal ambiguity, clinical uncertainty, and challenges in guideline development, particularly affecting paediatric populations where off-label prescribing is common. The regulatory agencies should adopt clear, standardized official definitions of off-label use to improve transparency, legal coherence, and patient safety.