Off-label prescribing in pediatrics: between regulatory gaps and clinical evidence

Despite important regulatory progress, evidence supporting the use of medicines in children remains limited, and off-label prescribing continues to be common in pediatric practice. Regulatory initiatives such as the United States Pediatric Research Equity Act (PREA) and the European Pediatric Regulation were designed to increase the labelling information relevant to paediatric use, yet important gaps persist because studies are often delayed, incomplete, or absent for many conditions and formulations. This article addresses the common misconception that off-label prescribing is always inappropriate or unsupported and argues that this interpretation is not supported by the current evidence. In reality, many off-label treatments in pediatrics are supported by scientific evidence, clinical guidelines, and consolidated experience, even when formal regulatory approval is lacking. Examples involving pediatric oncology, child psychiatric disorders, and supportive care illustrate how effective therapies may remain off-label despite becoming standards of care. The Italian experience reflects these broader challenges. Studies have shown that off-label prescribing is structural rather than exceptional in pediatrics, while national initiatives such as Law 648/96 and pediatric formularies have sought to support evidence-based prescribing beyond regulatory boundaries. It is necessary to overcome the simplistic distinction between prescriptions that comply with the indications and appropriate prescriptions. A more rational framework should distinguish unsupported off-label use from evidence-based off-label prescribing. Reducing the pediatric evidence gap therefore requires not only more pediatric research, but also recognition of rational off-label prescribing as an essential component of pediatric clinical practice.