Assessment and Benchmarking of Model Informed Approaches in Drug Development for Hemoglobinopathies: A Review of Scientific Advices From January 2000 to December 2024

Despite the fact that modeling and simulation are now recognized as promising innovative methodologies, their use in the context of development of drugs for sickle cell disease and Thalassemia has not yet been reviewed. Considering the challenges of conducting clinical trials for hemoglobinopathies, our work aims at exploring the current status of use of modeling and simulation by drug developers and their endorsement by regulators, based on European Medicines Agency scientific advices given to industry by the Committee for Medicinal Products for Human Use from January 2000 to December 2024. The present study describes different aspects of how modeling and simulation methods have been used and assessed. Our results highlight the need for an openly accessible structured framework that details the standards/criteria that make a method acceptable for regulators. The use of the ICH M15 credibility assessment framework is suggested for this purpose. Bearing in mind the question-centric approach, a repository of drug development questions and associated methods and data was built from 45 and 31 scientific advices for sickle cell disease and Thalassemia, respectively. The classification of the questions, methods and data based on the question-centric approach enabled modeling and simulation methods to be easily identified, objectively assessed and benchmarked against alternative methods used to address the same questions to evaluate their performance for characterizing benefit/risk of the different drugs.