The changes in physiology during growth, the different pharmacodynamic and pharmacokinetic parameters in pediatric subjects compared to adults, the immaturity of some organ systems, the changes in body composition and the greater sensitivity to pharmacologically active excipients cause that pediatric patients have different reactions than adults. Therefore, drugs expressly formulated for this specific age group must be developed.

Moreover, the risk of adverse events can potentially increase in some specific cases:
– long-term exposure: it could have effects on the development of organs, for example on skeletal growth, on sexual maturation or on neurobehavioral development, and can become evident, visible or identifiable only after several years, even in adulthood. It is therefore necessary to perform long-term follow-up to observe the effects in several stages of development.
– off label use: given the lack of specific drugs for children in the past, it was common to administer medicines for adults, thus going beyond the terms and conditions of the marketing authorization and exposing them to additional risks.
– pharmaceutical error: involuntary failure in the pharmacological treatment process that may occur when a medicine is prescribed, stored, dispensed, prepared or administered. Due to the limited availability of drugs with pediatric indication or appropriate pharmaceutical form, children can be treated at dosages deduced from adult patients or with inadequate pharmaceutical forms.
– insufficient safety data: pediatric clinical studies are limited to a sample that is not sufficiently populated and due to the limited duration, this leads to a lack of knowledge of the real risks.
– erroneousness or lack of clinical presentation of ADR: this may in fact be non-specific or misinterpreted, or worse may not be found and therefore not reported: non-specific symptoms, such as vomiting, diarrhea, drowsiness or crying, are the only ones manifestations observed in newborns and infants, while symptoms that depend on the patient’s ability to communicate, such as nausea, pain, mood changes etc., in younger children may be underestimated or reported incorrectly.

The pharmacovigilance activity must pay attention to different specific aspects in the various phases.
Risk management plan: the methods used to minimize risk in the adult population should be evaluated and adapted to pediatric patients.
ADR management and reporting. ICSRs must include:

• precise information on age by noting day, month, year or indicating the subset of pediatric age (Preterm New-born Neonates, Term and Post-term Neonates, Infants, Children, Adolescents)
• main development parameters such as prematurity, pubertal developmental stage, cognitive or motor development – indication of use, pharmacological form, dosage and weight and height of patients.
  The missing information must be followed up to ensure the quality and the integrity of the data.

Periodic safety update report (PSUR). The PSUR is a tool for the continuous monitoring of the risk-benefit ratio and the cumulative analysis of information on pediatric use, therefore the topics that must be discussed are:

• any new safety problem identified in the pediatric population
• off-label use, including the use of non-age-appropriate formulations or use in pediatric subgroups for which the product is not authorized
• any identified signal of a pediatric adverse reaction
• exposure of pediatric patients during the PSUR signaling interval, exposure per age subgroup
• safety results from ongoing or completed pediatric clinical trials, including those included in the PIP.
  All sources must be included: clinical studies, post-authorization use, spontaneous reporting, literature.

Post-authorization safety studies (PASS). For paediatrics, PASS can be of particular value when developmental effects are expected to occur only years after drug exposure, when long-term safety data are needed due to chronic use, when there is it was an off-label use and a security problem was suspected.

Signal management. For signal detection it is essential to distinguish and analyze the differences in reactions between pediatric and adult patients and to go into the sub-category of belonging, without dwelling on the pediatric range in general.

Security communication. To ensure that even children can understand the information on the drug, it is good that the communication is personalized and adapted to their age, especially if they are teenagers or children who can use the drug independently, for example infographics, comics and social media.

Despite the progress made in this area, thanks also to the most recent regulations and guidelines, difficulties persist for the pharmacovigilance activities, mostly due to the underestimation of the suspected adverse reactions in children, from the frequent and more serious therapeutic errors in the population to the difficulty of demonstrating the risk minimization efficacy of new drugs available to the pediatric population.