| dc.description.abstract | To promote the use of authorized medical products for paediatrics, the Paediatric Regulation was implemented in the EU in 2007, requiring pharmaceutical companies to submit a paediatric investigation plan (PIP) to ensure appropriate data is gathered in the paediatric population to determine the benefit/risk balance. Modelling and simulation analyses are becoming increasingly more important in PIPs to provide valuable insights. However, it currently unclear whether the planned age range in compliant PIPs has also been approved. In addition, it is unclear whether there are differences between the regulatory route (full, partial or no extrapolation) taken and the overall approved age range. This study aims to provide a comprehensive overview on the use of extrapolation in compliant PIPs and identify the types and frequency of extrapolation in marketing applications for paediatric indications, and examine their impact on regulatory decision-making processes.
Methods: To extract data for all medical products approved by the European Medicines Agency, publicly available PIPs registered from 2007 to 2022 were extracted and filtered to only include compliant PIPs. Information was collected on the planned indication, types of studies conducted, and planned age range of the paediatric population involved. Subsequently, extracted information on age range approved in the indication and, if applicable, additional weight requirement from the Summary of Product Characteristics (SmPCs). Finally, information of the conducted paediatric studies was extracted from the European Public Assessment Report (EPAR).
Since the introduction of the paediatric regulation in 2007, 264 (10.1%) of the PIPs have been compliant. In the 264 compliant PIPs, 286 unique KBEs were extracted, of which 48 (16.8%) specified one or more extrapolation studies. Extrapolation studies were conducted to evaluate efficacy, pharmacokinetics (PK), pharmacokinetics/pharmacodynamics (PK/PD), and dose-finding. Interestingly, 35.6% of the indications applied extrapolation during marketing authorisation application, which is almost double the defined percentage in the KBEs. Marketing application procedures that used an extrapolation approach, lead to a reduction of 1.4 years in the average minimum approved age compared to procedures that did not use extrapolation. When extrapolation is not utilized, there is a difference of 3.2 years between the average minimum age specified in the PIP and the average minimum age approved in the SmPC. However, with extrapolation, both averages align at 3.8 years.
The role of paediatric extrapolation appears to be limited in publicly available paediatric investigation plans. However, from the marketing application procedures, it is apparent that paediatric extrapolation has a more pronounced role in the approval of paediatric indications. Interestingly, procedures that used extrapolation have a lower approved minimum age compared to procedures that did not use extrapolation. In addition, paediatric extrapolation procedures resulted, on average, in the same approved age range as planned in the paediatric investigation plans. These findings imply that the use of paediatric extrapolation could translate in broader approved paediatric age range and could therefore reduce off-label use. | |
