Marco Dionisi1, Jean-Michel Dogné1,2, Flora Musuamba1,2
1University of Namur , 2Federal Agency for Medicines and Health Products
Introduction and objectives Pain in pediatric population is a common clinical symptom, often not properly managed. Despite the need for better utilization and development of analgesics in this population, off-label use is common and associated with a risk of lack of efficacy and/or safety issues. Many challenges arise throughout the development of pediatric analgesics, including clinical trial enrollment, standardization of pain model and pain scale for all age groups. Model Informed Drug Development (MIDD) is often used to overcome these limitations [1]. Assessment of evidence generated by alternative or innovative methods by regulatory authorities can be challenging due to a lack of systematic and integrated approach to assess and establish the acceptability of these methods. The ICHM15 as well as the ERAMET project (Horizon Europe grant 101137141) aim to define the framework for assessment of MIDD evidence to inform decision-making [2]. ERAMET project aims to build an ecosystem including a repository of key regulatory questions linking the questions with the data and the methods used to answer them and benchmarking the use of MIDD in the regulatory setting. The aim of this work was to build a repository of regulatory questions raised in PIPs for pediatric analgesics development answered by M&S approaches. Subsequently, we applied the MIDD evidence assessment framework described by ICH M15 guideline to evaluate and benchmark M&S implementation for MIDD pediatric analgesics. Methods PIPs of analgesic drugs submitted to EMA from November 2008 to December 2024 were analyzed. PIPs presented for full waiver and/or withdrawn were excluded. A repository of questions of interest (QOI), extracted from the documentation, was created. QOI is defined as the regulatory question that M&S or other methods intend to answer. A categorization of QOI, based on modalities (formulations, dose, population), efficacy, safety and PK was applied. The framework for assessment of MIDD evidence was applied for each M&S approach. Furthermore, a technical model evaluation including verification, validation and applicability of the models was performed whenever data was available. Results A total of 32 PIPs related to 28 analgesic drugs were selected. However, PIPs were excluded due to reasons such as drug withdrawal, full waiver, or incorrect indications. As a result, 14 PIPs related to 13 analgesic drugs were included in the analysis. A total of 181 distinct QOI were extracted from the selected documentation. If required, each QOI was repeated for the different drugs selected. M&S were used for all products, except for two, and the proportion of QOI answered by M&S ranged from nearly 0,5% to 32% of QOI for each drug. M&S methods were used predominantly to answer QOI related to PK and modalities. The most common M&S approach used was NLME model for POPPK analysis, used to characterize the PK, for dosing recommendation and for extrapolation of efficacy to younger age groups. Other approaches widely applied were PK/PD models and PBPK. Credibility assessment of MIDD evidence was implemented and applied to each M&S selected. Specifically, context of use, model influence, consequence of wrong decision, model risk and model impact were evaluated in relation with the QOI to be answered. To exemplify the implementation of the credibility assessment we selected a POPPK and an exposure-response models with medium to high patient risk, model influence (complimentary model) and consequence of wrong decision (safety concerns). These models had medium to high regulatory impact. We located the positioning of modeling and simulation approaches and benchmarked them against alternative approaches used in different aspects during the development of pediatric pain drugs. For models with medium or high regulatory impact, the credibility assessment reveals varying levels of maturity, resulting in correspondingly variable regulatory acceptance. Conclusions We examined the use of M&S in the context of pediatric analgesic development by analyzing PIPs submitted to the EMA. M&S was commonly employed to support dosing recommendations and to extrapolate efficacy to specific age groups. Additionally, we applied the ICH M15 framework to assess the MIDD evidence selected. This framework can help standardize and enhance the application of M&S in pediatric analgesic development, thereby facilitating regulatory interactions and decision-making processes.
Reference: PAGE 33 (2025) Abstr 11409 [www.page-meeting.org/?abstract=11409]
Poster: Oral: MIDD: Innovations, Successes and Lessons