Lisa Hanquet1, Jean-Michel Dogné1,2, Flora Musuamba1,2
1Department of pharmacy, University of Namur, 2Federal Agency for Medicine and Health Products
Introduction/Objectives: Chimeric antigen receptor-engineered T-cells (CAR-T) are a type of modified T-cell that utilises synthetic receptors with monoclonal antibody specificity and signalling domains, thereby enabling the identification, targeting and elimination of specific cancer cells. At present, six CAR-T cell therapies were authorized at EU level, which are autologous and mainly indicated for haematological malignancies as third or fourth line treatments in relapsed or refractory cases. Abecma® and Carvykti® are used in the treatment of multiple myeloma (MM), while Kymriah® treats acute lymphoblastic leukaemia (ALL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Yescarta® is indicated for DLBCL, primary mediastinal B-cell lymphoma (PMBCL) and FL, while Tecartus® targets mantle cell lymphoma (MCL) and ALL. Breyanzi® is approved for DLBCL, PMBCL and FL. The first marketed was Kymriah®, which received conditional marketing authorisation in 2018 [2]. Most of the CART cells have an orphan designation as indicated for disease and/or lines of treatment where very limited alternative are available for concerned patients [3]. Modelling and simulation (M&S) have become a pivotal component of drug development and product lifecycle management. These models evolve from being considered supplementary evidence to becoming a primary source of information for the ultimate regulatory submissions. In the context of orphan drugs, this can have a great potential, given the challenging related to the limited number of patients and related clinical data. In these settings, M&S could be considered for addressing the gap left by lack of data and difficulty to use traditional approaches for drug development. Moreover, due to the nature and mode of actions of CAR-T cell, quantitative approaches such as M&S could increase the understanding of the dose requirement to maximize efficacy and improve their safety profile. Despite these theoretical advantages and potential described in the literature [4], the current use of M&S in CART cells development and related regulatory submissions has not yet been reviewed. Assessment of evidence generated using alternative or more 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 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.[1] The 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. We present here a repository of key regulatory questions answered in centralized procedures and evaluate the place of modeling and simulation methods in marketing authorization of CART cells from 2014 to 2024. Benchmarking of modeling and simulation 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 [5]. Subsequently, the credibility framework as described in the ICH M15 guideline and that is centred 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. Methods: A systematic review of regulatory documents was conducted, encompassing the original marketing authorisation and Type II variations for EPARs and eCTDs for the approved CAR-T cells. For the eCTDs, modules 2.4, 2.5, 2.6 and 2.7, corresponding to the overview and summary of non-clinical and clinical data, were extracted. Subsequently, a range of data elements were extracted from these documents, including the reference study number, the source of data, the aim of the study, the duration of the study, the type of samples, the analytical method used, and the statistical method used. The extracted data were then used to identify the regulatory questions to be answered, which were classified according to the desired objective (efficacy, safety, PK or modality). They were then compiled into a repository. The repository was developed for regulatory questions relevant for CART cells and related data and methods. These were organised under five categories including modalities of drug use, benefit/risk assessment, drug efficacy, safety and PK. Each heading was subsequently broken in subheadings. As an example, the modality contains questions related to the indication, population, formulation and dose. The different sections are interlinked with a clear branching from benefit-risk sections into efficacy and safety, and PK feeding both efficacy and safety assessment. The data and analytics (including M&S) were reviewed and organised around the concerned regulatory questions. Following the completion of the extraction process, the modelling and simulations used were identified through a subsequent screening process using the terms “model” excluding “in vitro” and “in vivo”. A credibility assessment was implemented for the identified models and the matrix as described in the ICH M15 guideline on General Principles for Model-Informed Drug Development implemented. Results: Based on the EPAR and submission data review, the modality of use, benefit/risk, efficacy, safety and PK comprised 26, 23, 50 and 18 questions, respectively. 11,0% of all questions have answers related to M&S methods, with the most commonly used models being Dose-exposure-response models and popPK models. The modelling objectives encompassed PK characterisation, prediction of the response or arrival of a CRS, and the examination of the relationship between various efficacy and safety endpoints at varying doses. Credibility matrices were implemented for the medium and high impact models leading to different conclusions on the acceptability of the models. To exemplify the implementation of the credibility assessment, we selected an exposure-response model with a medium model influence (complimentary model) and high consequence of wrong decision (dose selection). The model had medium regulatory impact because a confirmatory Phase 3 trial was proposed by the applicant. In the case of the popPK model, we selected a model with high influence and a low consequence of wrong decision led to medium model risk and medium regulatory impact, given that, the model is supported by several dataset. Conclusion: Based on the regulatory submissions the use of modelling in the process of marketing authorisations has not yet reached its maximum potential, when compared to what is described in the scientific literature. The models used most often have supporting roles. For the ones with medium or high 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 modeling and simulation in the context of pediatric drug development.
1. Bellino S, La Salvia A, Cometa MF, Botta R. Cell-based medicinal products approved in the European Union: current evidence and perspectives. Front Pharmacol. 2023;14:1200808. 2. Ali S, Kjeken R, Niederlaender C, Markey G, Saunders TS, Opsata M, et al. The European Medicines Agency Review of Kymriah (Tisagenlecleucel) for the Treatment of Acute Lymphoblastic Leukemia and Diffuse Large B-Cell Lymphoma. The Oncologist. 2020;25:e321–7. 3. Kalland ME, Pose-Boirazian T, Palomo GM, Naumann-Winter F, Costa E, Matusevicius D, et al. Advancing rare disease treatment: EMA’s decade-long insights into engineered adoptive cell therapy for rare cancers and orphan designation. Gene Ther. 2024;31:366–77. 4. Mc Laughlin AM, Milligan PA, Yee C, Bergstrand M. Model-informed drug development of autologous CAR-T cell therapy: Strategies to optimize CAR-T cell exposure leveraging cell kinetic/dynamic modeling. CPT Pharmacomet Syst Pharmacol. 2023;12:1577–90. 5. ICH harmonised guideline. General principles for model-informed drug development M15 [Internet]. International council for harmonisation of technical requirements for pharmaceuticals for human use; 2024. Available from: https://database.ich.org/sites/default/files/ICH_M15_EWG_Step2_DraftGuideline_2024_1031.pdf
Reference: PAGE 33 (2025) Abstr 11464 [www.page-meeting.org/?abstract=11464]
Poster: Drug/Disease Modelling - Oncology