Developmental physical, metabolic and psychological processes reveal that children cannot be considered small adults, nor can they be considered a homogeneous group in themselves. It is therefore necessary that tailor-made medicines are developed and that paediatric pharmacovigilance activity is more targeted. Here is what Laura Boga, QPPV at Dompè Pharmaceutical, reported during her speech on pediatric patients at the European Pharmacovigilance Congress 2019.

Paediatric patients

Pediatric patients are identified as individuals in the age group from 0 to 18 years. This category falls within the so-called special populations, i.e. potentially more fragile categories due to their characteristics. Pediatric patients are in fact characterized by changes in physiology during growth, by different pharmacodynamic and pharmacokinetic parameters compared to adults, by immaturity of some organ systems, by changes in body mass and composition and by greater sensitivity to pharmacologically active excipients. All of this causes pediatric patients to have different reactions than adults.

Paediatric clinical trials

To obtain Marketing Authorisation, each drug must undergo in-depth studies, including preclinical tests and clinical trials in order to guarantee its safety, efficacy and quality. Often, however, the pediatric population is not included in these studies. What follows is a limited availability of medicines suitable for children who are therefore given medicines not authorized for this use. Pediatric pharmacovigilance in is therefore a valid aid for improving the safety profile of a drug.

Paediatric regulation

In January 2007, Regulation (EC) 1901/2006 of the European Parliament and of the Council on medicinal products for pediatric use came into force, amending Regulation (EEC) 1768/92, Directive 2001/20/EC and Regulation (EC) 726/2004.

The objective of the Paediatric Regulation is the optimization of pediatric health in the European Union. This is intended to facilitate the development and availability of medicines for children, ensure the quality of medicines by subjecting them to ethical research and authorizing them appropriately, and improve the availability of information on the use of medicines for children. All this while respecting the health of patients, i.e. trying as much as possible to avoid unnecessary tests for children and without delaying the authorization of medicines for use in adults.

Guidelines for paediatrics pharmacovigilance

In November 2018, the GVP (Guideline on Good Pharmacovigilance Practices) relating to paediatrics (GVP – Product – or population – Specific Consideration IV: Pediatric Population) entered into force.

The guidelines mainly deal with medicinal products with pediatric indications, with indications for adults and pediatric development in progress and with indications for adults, for which there is evidence of use in the pediatric population. However, it does not deal with vaccines and the safety surveillance of pediatric outcomes after exposure to drugs in utero.

You might be interested in: Pharmacovigilance: what is it

The role of EMA for paediatric pharmacovigilance

In 2007, the PDCO (Paediatric Committee) was set up at EMA. It is a multidisciplinary scientific committee mainly responsible for the evaluation and approval of PIP (Pediatric Investigation Plans).

The PDCO interacts with other committees, in particular the CHMP (Committee for Medicinal Products for Human Use), the PRAC (Pharmacovigilance Risk Assessment Committee) and the COMP (Committee for Orphan Medicinal Products) on any issue related to the development of medicines for pediatric use.

The responsibilities of the PDCO also include applications for full or partial exemption from the PIP and for study referrals.

The PDCO and PRAC interact on promoting the early development of risk management strategies, understand the impact of emerging safety issues on pediatric development, gain information on pediatric needs and generally ensure that, when needed, pharmacovigilance activities are adapted to address the specific challenges of collecting data safety measures in the pediatric population.

Risk of adverse events in pediatric patients

The risk of adverse events can potentially increase in some specific cases.

Long-term effects. Administration of a particular drug may have effects on organ development, skeletal growth, sexual maturation, and neurobehavioral development. These effects can become evident, visible or identifiable only after several years, even only in adulthood. Long-term follow-ups are therefore needed to observe effects at multiple stages of development.

Off-label use. The administration of a non-specific drug for this age group may expose the patient to further risks of adverse events or treatment ineffectiveness. Fortunately, thanks to studies, today there are more and more specific medicines for children and therefore the administration of medicines for adults is no longer so common.

Medication error. A further potential risk may arise as a result of an unintended failure in the drug treatment process. It may occur when a medicine is prescribed, stored, dispensed, prepared or administered. Due to the limited availability of drugs with pediatric indications or appropriate pharmaceutical forms, children may be treated with dosages derived from adult patients or with inappropriate pharmaceutical forms.

Insufficiency of safety data. Pediatric clinical studies are limited to an insufficiently large sample and moreover related to a limited period of time. What follows is a lack of knowledge of the real risks and therefore a lack of awareness in the administration.

Misreporting or lack of clinical reporting of ADR (Adverse Drug Reaction). Adverse reaction reporting may sometimes be incomplete, nonspecific, or misinterpreted. In some cases, the reaction may even not be detected, and consequently not reported, as non-specific symptoms, such as vomiting, diarrhea, drowsiness or crying, are the only manifestations observed in newborns and infants and therefore may be underestimated.

RMP (Risk Management Plan)

The methods used to minimize the risk of adverse reactions in the adult population must be evaluated and adapted to pediatric patients, taking into account specific aspects:

  • preclinical evidence. Findings from juvenile animal toxicology studies may have predictive value in terms of effects in the pediatric population and may support prioritization of pharmacovigilance research questions;
  • clinical data. These should support in the identification of important potential risks, in the characterization of the safety profile as well as in the description of the tools to reduce the risk related to the use of the product in the pediatric population;
  • lack of previous clinical data in adults. Where a medicinal product has been authorized exclusively for pediatric patients or simultaneously for adult and pediatric patients, there is a lack of clinical data and this leads to a gap in the RMP.

You might be interested in: Pharmacovigilance during pregnancy

Paediatric pharmacovigilance management: ADR reporting

ICSRs must include:

  • precise information on age with annotation of day, month and year or indicating the subset of pediatric age (Preterm New-born Neonates, Term and Post-term Neonates, Infants, Children, Adolescents);
  • weight and height of the patient;
  • main developmental parameters such as prematurity, stage of pubertal development, cognitive or motor development;
  • indication for use, pharmacological form and dose of the drug.

Any missing information should be followed up to ensure data quality and integrity.

PSUR (Periodic Safety Update Report)


The PSUR is a tool for continuous benefit-risk monitoring and cumulative analysis of information on pediatric use. The topics to be covered are:

  • any new safety issue identified in the pediatric population;
  • off-label use, including the use of age-inappropriate formulations or use in pediatric subgroups for which the product is not authorised;
  • any identified signal of a pediatric adverse reaction;
  • exposure of pediatric patients during the PSUR reporting interval, reported by age subgroups;
  • safety results from ongoing or completed pediatric clinical trials, including those included in the Pediatric Investigation Plan (PIP).
  • sources: clinical trials, post-authorisation use, spontaneous reporting, literature.

PASS (Post-Authorisation Safety Studies)

For paediatrics, PASS may be of particular value when developmental effects are expected to occur only years after exposure to the drug, when long-term safety data are needed due to chronic use, or when there is it was an off-label use and a safety issue was suspected.

In the PASS it is advisable to integrate the data prior to marketing authorization with those collected in post-marketing surveillance.

You might be interested in: Geriatrics pharmacovigilance

Signal detection

For Signal Detection it is essential to distinguish and analyze the diversity of reactions between pediatric and adult patients and to enter into the merits of the sub-category to which they belong, without dwelling on the pediatric range in general.

Difficulties and improvements

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

A potential help could be to give greater awareness to pediatric patients able to independently take their medicines through personalized communication such as infographics, comics and social media.

The most effective measure certainly remains the development of more and more drugs specially formulated for this specific age group.