Grace Shalom Govere1,2, Jean-Michel Dogne1,2, Flora Musuamba1,2
1Department of Pharmacy, University of Namur, 2Federal Agency for Medicines and Health Products (FAMHP)
Introduction: Haemoglobinopathies are genetic diseases that result in the synthesis of defective hemoglobin. Annually, 500,000 children are born with sickle cell disease (SCD) and 60,000 people are diagnosed with transfusion-dependent ß Thalassemia (TDT). [1] As compared to more common diseases, modeling and simulation (M&S) methods have been less extensively used in the therapeutic area of haemoglobinopathies, namely SCD and Thalassemia. Important barriers still exist for them to be fully embraced, including a lack of standardized methodology for integrating evidence from modeling studies into treatment guidelines.[2] Assessment of evidence generated using alternative or more innovative methods by regulatory authorities can be challenging due to a lack of systematic and integrated approaches to assess and establish the acceptability of these methods. The ICH M15 as well as the ERAMET project (Horizon Europe grant 101137141) aim to define the framework for assessment of Model Informed Drug Development (MIDD) evidence to inform decision-making.[3] The ERAMET project aims to build an ecosystem including a repository of key regulatory questions linking the questions with the methods and data used to answer them. We present here a repository of key regulatory questions answered in centralized procedures and evaluate the place of M&S methods in marketing authorization and drug development for sickle cell disease and thalassemia, from applicants that requested scientific advice (SA) from EMA from January 2014 to December 2024. Benchmarking of M&S methods versus traditional methods is performed by assessing their quality using the table for assessment of MIDD evidence; a communication tool between applicant and regulatory authorities that has been set up in the ICH M15 guideline.[3] Assessment of evidence generated using alternative or more innovative methods by regulatory authorities can be challenging due to a lack of systematic and integrated approaches to assess and establish the acceptability of these methods. The ICH M15 as well as the ERAMET project (Horizon Europe grant 101137141) aim to define the framework for assessment of MIDD evidence to inform decision-making.[3] This approach was applied to drug development questions for SCD and Thalassemia. For this purpose, drug development questions for SCD and Thalassemia were extracted from SAs, with the methods and data used to answer them. M&S methods were identified, assessed and compared to standard methods. Objectives: To assess the value of M&S methods in drug development and regulatory decision-making, in relation to alternative or more commonly used methods. Methods: The SAs were manually retrieved from EMA Scientific explorer using the search field “agreed condition” and the key words “sickle cell disease” and “thalass(a)emia”. We reviewed the SA letters for these treatments and translated the information into essential regulatory questions. These questions were classified and organized based on the level of the questions (i.e. cellular, molecular, tissular, individual or population) and their granularity. A graphical representation of the questions and a table listing data and methods used to answer these questions in the MAAs was built. Statistics of the place of M&S methods in these MAAs were computed. The credibility framework which is described in the ICH M15 guideline and which is centered around drug development questions was implemented to assess the quality of these model based approaches in relation to their context of use, the patient risk and the regulatory impact. Results: 295 questions were found for SCD, while 215 were found for Thalassemia. Approximately 45% of the Benefit/Risk questions were on efficacy/safety and 72% of the questions were population level- questions. 11% of SCD and 5,5% of Thalassemia questions were related to M&S methods. The most common models were Exposure-response and POPPK. To exemplify the implementation of the credibility assessment we selected an exposure-response model for a drug being developed in Thalassemia with a medium patient risk owing to medium model influence (complimentary model) and high consequence of wrong decision (safety concerns). The model had medium regulatory impact because a confirmatory Phase 3 trial was proposed by the applicant. The information on the model’s technical criteria was scarce and model evaluation showed a few AUC concentrations not captured by the POPPK model. For SCD we selected a model with medium influence (complimentary model) and a high consequence of wrong decision which led to medium model risk but high regulatory impact, given that, if qualified, the proposed POPPK model would be used instead of Bioequivalence to compare the drug exposure from different dosage forms. Conclusion: We locate the positioning of M&S and benchmark it for drug products under development for haemoglobinopathies, for which SAs were requested from EMA from January 2014 to December 2024. For the models with medium or high regulatory impact, credibility assessment reveals various levels of maturity and therefore the regulatory acceptance is also variable. This repository will be completed by searching pediatric investigation plans to assess the place of M&S in the context of pediatric drug development. Overall, the use of M&S methods to address drug development and regulatory questions for haemoglobinopathies is promising, if sufficient data can be provided to develop and qualify the M&S models.
[1] Locatelli F et al. 2024. Autologous gene therapy for hemoglobinopathies: From bench to patient’s bedside. Molecular Therapy, pp. 1202-1218. [2] Tsakalozou E et al. 2025. Considering Opportunities and Challenges When Implementing the Model Master File Framework – a Meeting Report. Pharmaceutical Research. [3] International Council for Harmonisation, 2024. General Principles for Model-Informed Drug Development M15, Amsterdam: European Medicines Agency.
Reference: PAGE 33 (2025) Abstr 11451 [www.page-meeting.org/?abstract=11451]
Poster: Methodology - Other topics