MEB Science Day 2026 - PhD's and abstracts

Streamlining the transition of Advanced Therapies: an introduction to CORE-AMTP

Thijs S. Rietveld^1,2, Chantal M.M.S. van Litsenburg^1,3, Manon A.A. Jansen², Marcel H.N. Hoefnagel⁴, Solange Levison⁵, Pauline Meij^1,3

1.    Leiden University Medical Center, Leiden, The Netherlands
2.    Centre for Human Drug Research, Leiden, The Netherlands
3.    The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, The Netherlands
4.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
5.    Central Committee on Research Involving Human Subjects, The Hague, The Netherlands

Background: The first administration in humans is a pivotal step in advanced therapy development, but remains a hurdle for developers to overcome. Challenges that developers face in the run-up to First-in-Human (FIH) trials relate to translating product interactions and determining the FIH dose. CORE-ATMP (Cutting-edge Optimization and Research Enhancement for Advanced Therapy Medicinal Products) connects academia (LUMC) and a clinical research organization (CHDR), supported by regulatory bodies (CBG-MEB and CCMO) in a quest to streamline translation of advanced therapies to FIH trials. 

Methods: Specifically, the partners aim to develop 1) a general methodology for the selection of (surrogate) potency assays for cell-based therapies, and 2) a tool that evaluates non-clinical data packages to de-risk clinical trials. EMA, FDA and TGA guidelines will be analyzed to identify common and diverging non-clinical data requirements, generating an overview of the regulatory landscape. Additionally, key product characteristics, best practices, and common pitfalls in product development will be based on aggregated and public information of products that hold marketing authorization or entered clinical trials. To ensure that the developed frameworks are regulator-informed and align with the current needs, interviews will be conducted with regulators and experts in the field. The tools will be validated through real-world cases, assuring scientific robustness and adherence to harmonized legislation. 

Conclusion: To maximize the project’s impact, CORE-AMTP strives to actively engage with stakeholders to foster synergy and knowledge exchange within the ATMP community. Ultimately, CORE-ATMP aims to de-risk FIH trials and accelerate the translation of advanced therapies through the development of novel methodologies.

Comparing in vitro and in vivo efficacy of anti-cancer drugs – how to bridge the translational gap? 

Puck Roos^1,2,3, Peter Theunissen^1,4, Peter van Meer^1,4, Anna M.G. Pasmooij^1,5, Rosalinde Masereeuw², Jarno Drost^3,6,7

1.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
2.    Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
3.    Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
4.    Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands
5.    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
6.    Oncode Institute, Utrecht, The Netherlands
7.    Division Cell Biology, Metabolism & Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

Background: Only 7% of anti-cancer drugs tested in clinical trials are approved for marketing, often due to inadequate clinical efficacy or safety. Standard preclinical models (2D tumor cell lines and cell line-derived xenograft models) may therefore lack clinical translatability. Here, we evaluated preclinical models to investigate anti-cancer drug efficacy. 

Methods: We collected data on anti-cancer drugs submitted for marketing in Europe (2020-2024) from the CBG-MEB internal database. For all drugs, we collected data on compound characteristics and study design of in vitro and in vivo efficacy studies. For a subset of drugs, we collected in-depth information on in vitro (IC50 for cell proliferation) and in vivo (% tumor growth) efficacy, to compare in vitro and in vivo efficacy. 

Results: The study included 72 anti-cancer drugs. The use of non-standard preclinical models was limited to 17/72 drugs for in vitro (patient-derived tumor tissue) and 34/72 drugs for in vivo (patient-derived xenografts and/or genetically-engineered mouse models) studies. No correlation was observed between in vitro and in vivo efficacy. Comparing in vitro and in vivo efficacy was challenging, due to differences in development strategy and study design, and lack of a threshold to determine whether a drug is effective. 

Conclusions: We show that preclinical development of anti-cancer drugs is heterogeneous. Our data stress the need for regulatory uptake of non-standard preclinical models, which may be more human-relevant than standard models. Lastly, our data suggest that a more streamlined preclinical development, with more human-relevant models and clinically translatable endpoints, may accelerate anti-cancer drug development. 

Regulatory roadmap for the development of Quality Control for pluripotent stem cell-derived medicinal products

Akvile Gasiunaite^1,*, Thijs S. Rietveld^{1, 2,*}, Mara Tihaya¹, Teun van Gelder³, Pauline Meij¹

1.    Center for Cell and Gene Therapy, Leiden University Medical Center, Leiden, The Netherlands
2.    Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands
3.    Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
* Authors contributed equally

This study was supported by a research grant from the Central Committee on Research Involving Human Subjects (CCMO).

Background: Cell-based medicinal products derived from embryonic or induced pluripotent stem cells (PSCs) must undergo Quality Control (QC) and non-clinical testing, similar to conventional small molecule pharmaceuticals. However, the framework for testing PSC-derived therapies is still evolving together with the increasing scientific advancement and clinical experience.

Methods: To facilitate the process of designing an appropriate quality testing strategy, we reviewed relevant guidelines applicable to cell-based medicinal products from regional and international authorities. The required or recommended tests related to product characteristics, such as identity, purity, safety, potency, and stability, were extracted. Tests were ranked using a custom-made system to distinguish their application across the different stages of product development and manufacturing timeline. Information was also collected on the objectives, study design, and animal models of non-clinical studies.

Results: The collected data represented quality testing applicable for cell banks, intermediate products, and final differentiated medicinal products. The distinction of tests between characterization, in-process control, and QC outlined the data that are required or suggested during product development or clinical batch manufacturing. Guidance for the non-clinical studies covered application of Good Laboratory Practice conditions and endpoints for short- and long-term evaluation of efficacy and safety, including tumorigenicity and toxicity. 

Conclusion: The resulting regulator-informed QC roadmap provides a resource showcasing the testing panels and methods that are accepted as fit-for-purpose in QC testing of cell-based medicinal products. It may aid both product developers and regulators in selecting and evaluating the non-clinical studies and QC strategies across different regulatory regions, contributing to the harmonization of the pre-clinical development.

A Holistic Risk Scoring Framework for ATMP Safety Assessment

Rafaella Buzatu^1,2, Tineke van den Hoorn², Marcel H.N. Hoefnagel², Christian Schröter¹, Micha Drukker^1,3

1.    Division of Cell Systems and Drug Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
2.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
3.    Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands

Background: Safety assessment of ATMPs requires identification of their potential tumorigenic risk. Existing approaches predominantly rely on detecting and evaluating genomic variants one-by-one, without clear standards for sequencing platforms or annotation databases for risk estimation. Despite the growing recognition that tumorigenicity is driven by coordinated gene network activity rather than single mutations, current variant-focused strategies do not probe for gene network dysregulation and may therefore overlook tumorigenic potential driven by non-genetic or environmental factors. 

Methods: To address these gaps, we propose a transcriptomics-based scoring platform that combines (i) a weight-of-evidence variant risk score based on curated annotations, variant effect and expression levels, and (ii) a gene programme-specific score assessing activation of tumorigenic pathways. 

Results: Preliminary comparative analyses across primary tissues, iPSCs, tumors and cancer cell lines revealed limited differences in high-risk variant counts, while pathway-level scoring captured the resulting cellular programme reconfiguration. 

Conclusion: Together, these complementary metrics enable holistic safety assessment of ATMPs.

Will the Weight-of-Evidence approach replace the need for carcinogenicity studies for oligonucleotide-based therapeutics? - a regulatory perspective

Clara Stock¹, Britt Duijndam¹, Kris Siezen¹, Anna M.G. Pasmooij^1,2

1.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
2.    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Background: The non-clinical safety assessment of oligonucleotide-based therapeutics (ONTs) lacks coherent regulatory guidance on a global level. This includes guidance on whether performing long-term rodent carcinogenicity studies are necessary to inform about their carcinogenic potential. To harmonize regulatory expectations, the ICH committed to drafting a new guideline addressing the non-clinical safety assessment of ONTs (ICH S13).

Methods: We collected the non-clinical study packages of all non-coding ONTs for which companies applied for EU marketing authorization to date, supplemented by data from ONTs receiving EU Scientific Advice (SA) between 2002-2025. Scientific Advice letters were analyzed regarding questions and positions of the Applicants and subsequent opinions and suggestions from the CHMP.

Results: We analyzed the carcinogenicity test strategies for 103 different ONT products of which the test strategy was determined and disclosed for 67 ONTs at time of SA request. For 25 ONTs, with a known carcinogenicity assessment strategy, Applicants conducted or proposed testing in two rodent species, whereas for 17 ONTs a study in a single rodent species and for 25 ONTs no studies were proposed. A preliminary analysis of SA reports indicated that Applicants and regulators see opportunities to use a Weight-of-Evidence (WoE) approach (ICH S1B (R1) addendum) supported by class experience from other similar products to waive not only the two-year rat study but also the mouse study. 

Conclusions: Our preliminary results suggest that the strategy for carcinogenicity assessment, at least for well-established ONT classes, is transforming towards a WoE approach that together with class experience might suffice to assess the carcinogenic potential of ONTs without the need for dedicated carcinogenicity studies. 

Platform technology in the EU regulation of medicines for human use: stakeholder perspectives on its definition and implementation

Stephanie M.P. Oskam^1,2, Lourens T. Bloem¹, Marcel H.N. Hoefnagel², Falk Ehmann³, Mike Broeders⁴, Anna M.G. Pasmooij^1,2

1.    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
2.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
3.    European Medicines Agency, Amsterdam, The Netherlands
4.    Centre for Future Affordable Sustainable Therapy Development (FAST), Leiden, The Netherlands

Background: The currently being revised European Union general pharmaceutical legislation will include a framework for “platform technologies”. A platform technology approach can be broadly understood as a development and manufacturing framework in which predefined fixed components are combined with adaptable variable components, enabling the development and manufacturing of multiple medicines within a shared regulatory framework. This may enable more efficient medicine development and regulatory evaluation, as well as increase patient access to new medicines. We investigated stakeholder perspectives on the definition and implementation of the platform technology approach for human medicines, including regulatory and clinical acceptability, to support the successful implementation of platform technology.

Methods: Four focus group discussions were organized, each representing a distinct stakeholder group: (i) regulators, (ii) pharmaceutical industry, (iii) not-for-profit medicine developers, and (iv) clinicians and patients/patient representatives. By means of thematic content analysis we identified various themes that represent the main findings.

Results: We identified 26 factors that may promote or hinder the successful implementation of platform technology across four themes: (i) defining (the scope of) platform technology, (ii) utility in medicine development, (iii) regulatory acceptability, and (iv) clinical acceptability. Stakeholders emphasized that regulatory acceptability depends on the availability of robust, platform-specific data, while clinical acceptability requires clear communication to ensure trust. Furthermore, we outlined future directions of platform technology as stated by stakeholders, including the establishment of a clear European Union regulatory framework and utilizing platform technology for treatments for rare diseases to improve patient access.

Conclusion: Effective collaboration among regulators, medicine developers, clinicians, and patients will be essential to establish a coherent European Union regulatory framework that supports the successful implementation of platform technology within the pharmaceutical landscape.

Artificial Intelligence for Regulatory Evidence: A Systematic Document Analysis of European Medicines Agency Regulatory Advice and Public Reports

Lucina-May Nollen^1,2, Gerard J.P. van Westen¹, Gabriel Westman^3,4, Anna M.G. Pasmooij^2,5 

1.    Division of Medicinal Chemistry, LACDR, Leiden University, Leiden, The Netherlands
2.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
3.    Swedish Medical Products Agency, Uppsala, Sweden
4.    Department of Medical Sciences, Uppsala University, Uppsala, Sweden
5.    Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Background: Artificial intelligence (AI) is receiving increasing attention across the entire lifecycle of medicines, from development to post-authorisation use. While various AI tools have been developed in commercial and academic settings, the extent of their use in regulatory contexts within the European Union remains unknown. 

Methods: In this study, we systematically analysed the use of AI for regulatory evidence by reviewing public reports and internal development advice documents from the European Medicines Agency (EMA). 

Results: Of 26,480 documents screened, 52 documents contained AI use, reflecting 43 unique AI tools used across quality, non-clinical, clinical and pharmacovigilance domains. The majority of AI tools were deployed in clinical applications, and outputs were used either directly as endpoints, in shaping clinical trial methodology, or in ancillary analyses. Comments and advice from the EMA regarding AI use varied according to use context and covered aspects of documentation, methodology, validation, and lifecycle management. 

Conclusion: Our findings indicate AI use in regulatory evidence is still limited but shows an increasing trend. As the field is still novel, there are limited regulatory precedents, and AI-specific guideline development and harmonisation across regulatory spheres is still ongoing. In this light, the quantitative characterisation of AI tools and AI-related regulatory comments captured in this analysis provide concrete insights into AI use and frequent regulatory considerations, aiding in both AI and AI-guideline development.

Physiologically-Based Pharmacokinetic Model Informed Evaluation of Gastric pH Interaction Studies: A Dabigatran Etexilate Case Example 

D. Esther Lubberts^1,2, Laurens F.M. Verscheijden^1,2, Frans G.M. Russel²

1.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
2.    Department Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands

Background: According to European Medicines Agency guidance, bioequivalence studies under acid-reducing agent (ARA) pre-treatment may be required for products with pH-dependent solubility, especially when containing pH-modifying excipients or different salt forms. This is relevant for innovator products where pH-related risks should explicitly be addressed in the product development, or generic formulations when bioequivalence studies under ARA pre-treatment may be required according to product-specific guidance. Currently, no harmonized regulatory framework exists for such studies.

Methods: Using dabigatran etexilate as a case example, this study applied physiologically-based pharmacokinetic (PBPK) modelling to simulate the impact of various ARA pre-treatment protocols on gastrointestinal pH changes and dabigatran etexilate absorption. Pre-treatment was performed with different ARA doses and treatment regimens, including pantoprazole, omeprazole and esomeprazole. In addition, sensitivity analyses identified formulation-specific parameters critical for quantifying interaction magnitude across different ARA scenarios.

Results: Preliminary simulations demonstrate measurable differences in absorption and systemic exposure with and without ARA pre-treatment, depending on the type of ARA, dosing frequency, and timing of concomitant administration. These findings indicate that PBPK modelling can potentially quantify the impact of ARA pre-treatment on pharmacokinetic profiles. 

Conclusions: These results could aid in optimizing ARA pre-treatment protocols in bioequivalence studies for both innovator and generic products, required during marketing authorization applications. Building on these findings, further work will focus on refining and verifying the PBPK model, including sensitivity analyses, to improve predictions of product-specific ARA effects across scenarios. Ultimately, the goal is to investigate the use of PBPK modelling as an alternative for clinical ARA bioequivalence studies.

Use of Asthma Medications in Pregnancy: A Drug Utilisation Study in the Netherlands

Donya Moslemzadeh¹, Katrien Oude Rengerink², Peter Mol², Katia Verhamme¹

1.    Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands
2.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands 

Background: Asthma affects 8–13% of pregnant women and poorly controlled asthma is associated with adverse maternal and perinatal outcomes. This study aimed to determine the prevalence and prescribing patterns of asthma medication use among women with pre-existing asthma before, during, and after pregnancy in the Netherlands.

Methods: We conducted a population-based cohort study using data from the Integrated Primary Care Information database (IPCI) in the Netherlands (2010-2023). Pregnant women with pre-existing asthma were identified. Drug exposure was assessed by means of prevalence of use (i.e. the proportion of women with ≥1 prescription) and prescription rates by drug class (prescriptions per person month). Exposure windows were one year before, during and one year after pregnancy. Analyses were conducted on data mapped to the Observational Medical Outcomes Partnership Common Data Model, using the IncidencePrevalence package developed by Darwin EU®.

Results: We identified 2,149 pregnant women with pre-existing asthma (2010-2023). Asthma medication use declined during pregnancy, especially short-acting β₂-agonists (SABA) (40.2% pre-pregnancy to 27.7%) and inhaled corticosteroids (ICS) (22.5% to 16.9%). Postpartum, SABA use slightly increased (28.9%), while ICS remained lower (15.6%). Prescription rates for ICS/long-acting β₂-agonists (ICS/LABA) increased during pregnancy and eventually surpassed ICS alone, while SABA remained the most frequently prescribed overall. Systemic corticosteroids prescriptions were higher before and during pregnancy and declined postpartum; other classes were rarely prescribed.

Conclusions: Asthma prescribing varied across the pre-pregnancy, pregnancy, and postpartum periods. ICS and SABA were the most prescribed drug classes throughout, with reduced use during pregnancy despite guidelines recommending continued treatment. 

Real-World Effectiveness of COVID-19 Vaccines in the Netherlands: A Test-Negative Case-Control Study within the PharmLines Initiative

Stefan Verweij^1,2*, Guiling Zhou^1*, Nina Dael¹, Spyros Balafas¹, Sumaira Mubarik¹, Jens Bos¹, Katrien Oude Rengerink², Maarten J. Bijlsma¹, Anna M.G. Pasmooij^2,3, Debbie van Baarle⁴, Peter G.M. Mol^2,5, Geertruida H. de Bock⁶, Eelko Hak¹

1.    Unit of Pharmaco-Therapy, -Epidemiology and -Economics (PTEE), Department of Pharmacy, University of Groningen, Groningen, The Netherlands
2.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
3.    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
4.    Virology and Immunology Research Group, Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
5.    Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
6.    Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
*Both authors contributed equally to this study

Background: In the Netherlands, high COVID-19 vaccine uptake was achieved early, yet waning immunity and emerging variants continue to challenge sustained protection. Understanding how vaccine effectiveness (VE) varies over longer periods of time, and by vaccination status or circulating variant, is crucial for informing ongoing public health strategies. This study aimed to estimate VE of different vaccines on preventing infection by different SARS-CoV-2 strains using a test-negative case-control design.

Methods: Data from the Pharmlines initiative and national COVID-19 vaccination records were linked. Adults with at least one reverse transcriptase polymerase chain reaction (RT-PCR) test between November 2020 and October 2022 were included. Cases were defined by a first positive RT-PCR test and matched to controls. VE was assessed using conditional logistic regression, and time-varying VE using nonlinear models.

Results: 1,987 cases and 4,004 controls had an average age of 57 years and 67.1% was female. The overall VE in preventing SARS-CoV-2 infection compared with unvaccinated individuals was 56.4% (95%CI: 29.0%; 73.2%) for partial vaccination, 59.7% (95%CI: 34.1%; 75.4%) for full vaccination, and 59.8% (95%CI: 36.2%; 74.6%) for booster vaccination(s). Vaccines had a protective effect against the alpha, delta and omicron strains. Time-varying VE increased up to 74.7% (95%CI: 61.6%; 83.3%) within six months following booster vaccination.

Conclusion: Booster vaccinations are important in sustaining high levels of protection against SARS-CoV-2 infections, but timing is essential. These findings support current vaccination strategies in the Netherlands and countries with similar healthcare settings.

Ethics framework for the evaluation of studies with controlled human infection models

Pepijn Al^1,2, Rieke van der Graaf¹, Marie-Astrid Hoogerwerf³, Martine C. de Vries^2,4

1.    Department of Bioethics and Health Humanities, Julius Center, University Medical Center Utrecht, Utrecht, The Netherlands
2.    Department of Medical Ethics and Health Law, Leiden University Medical Center, Leiden, The Netherlands
3.    Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
4.    Willem Alexander Pediatric Hospital (WAKZ), Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands

Background: In studies using controlled human infection models (CHIMs), participants are intentionally exposed to a pathogen as part of the medical research. Research protocols involving CHIMs often raise additional ethical and legal questions for review committees due to the intentional contamination of healthy participants. Given the increase in CHIMs and the ethical questions raised by medical ethics review committees, a clear framework for assessing protocols involving a CHIM in the Netherlands is essential. We have developed such a framework for the Central Committee on Research Involving Human Subjects (CCMO).

Methods: We developed an ethical framework through a combination of a literature review, focus groups, and ethical-normative research. First, a systematic literature review was conducted, which identified the relevant ethical questions and criteria proposed in the literature. Simultaneously, using CCMO’s and human research ethics committees’ archives, we examined which themes are currently considered important by review committees and which questions require further attention. Based on this, we developed an initial version of the framework and presented it to various stakeholders, namely members of review committees, CHI study researchers, and former participants, through focus groups. With the input from the focus groups, we finalized the framework for the ethical evaluation of CHIMs through the method of a reflective equilibrium, in which a balance is sought between ethical principles and practical considerations and implications. 

Results: We developed a framework with criteria that cover different ethical themes, including social value, risks for participants and third parties, respect for autonomy, compensation, location, and procedural aspects. 

Risk factors for medicine shortages in the Netherlands: A cross-sectional study of ten high-use pharmaceuticals

Doerine J. Postma^1,2, Kim Notenboom³,  Peter A.G.M. De Smet⁴, Hubert G.M. Leufkens¹, Aukje K. Mantel-Teeuwisse¹

1.    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
2.    Royal Dutch Pharmacists Association, The Hague, The Netherlands
3.    Medicines Evaluation Board, Utrecht, The Netherlands 
4.    Radboud University Medical Centre, Radboud Institute for Health Sciences, Departments of IQ Healthcare and Clinical Pharmacy, Nijmegen, The Netherlands

Background: Medicine shortages are structural and increasing globally. They are mainly caused by manufacturing and quality issues in upstream supply chains. 

Methods: A cross-sectional study on medicinal products containing ten pharmaceutical substances with the highest number of outpatients in the Netherlands (July 2022). We identified the marketing authorisation holders (MAHs), finished pharmaceutical product (FFP) and active pharmaceutical ingredient (API) manufacturers, indicated the commercial availability and occurrence of shortages and mapped the upstream pharmaceutical supply chains. Each pharmaceutical substance was examined for the presence of cascading shortages. Commercially available products were analysed to identify differences in supply chains, economic, and product characteristics between products with and without shortages. Products with a shortage were compared according to the cause of the shortage being manufacturing issues versus increased demand.

Results: Of 407 authorised medicinal products, 216 were commercially available, of which 59 faced a shortage in the Netherlands. For five substances the shortages displayed a cascading effect. The involved products had a total market share of 39-95% and concerned 25-100% of the MAHs.
Products with shortages (n = 59) more often had multiple FPP sources (51% vs. 27%, p = 0.001), a higher mean number of API manufacturers (2.36 vs. 1.89; p = 0.011) and were more frequently subject to maximum pricing (56% vs. 29%, p = 0.034).  

Conclusion: Effectively preventing and mitigating medicine shortages requires minimising risks on the micro-level of a product (such as sourcing and price policies) and on the macro-level of a substance (such as preventing cascading effects).

Contribution of Scientific Advisory Groups and Ad Hoc Expert Groups to regulatory decision making at the European Medicines Agency 

Audrey M.M. Hermans^1,2, Elisabeth Bakker², Viktoriia Starokozhko^1,2, Silja Sommer³, Peter G.M. Mol^1,2, Anna M.G. Pasmooij^1,4 

1.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands 
2.    Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands 
3.    European Medicines Agency, Amsterdam, The Netherlands 
4.    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

Background: Committees of the European Medicines Agency (EMA) that contribute to evaluating and supervising medicines in the European Union can consult external experts during procedures. For seven therapeutic areas Scientific Advisory Groups (SAGs) have been installed. In settings where relevant SAGs do not exist, Ad-Hoc Expert Groups (AHEGs) can be assembled. EMA has reported that external experts are consulted in about a quarter of all new medicine assessments, but there is no overview of what questions are asked to SAGs/AHEGs. This research aimed to identify topics on which advice was sought from SAGs and AHEGs by EMA’s committees, and to assess the impact of SAGs and AHEGs on the regulatory decision-making process.

Methods: This study reviewed European Public Assessment Reports (EPARs)(1995-2024) that mention SAGs or AHEGs. Characteristics such as type of procedure, type of registration, date of CHMP opinion, and therapeutic area were extracted. When available, questions to SAGs/AHEGs were extracted for qualitative analysis of the topics.

Results: In total, 363 procedures involving SAGs (n=242) or AHEGs (n=117) were identified between 1999-2024. In two procedures, both a SAG and an AHEG were consulted, and two procedures mentioned the consultation of a Therapeutic Advisory Group. Initially, external experts were only consulted for new Marketing Authorisation Applications, while from 2005 onwards also for variations and referrals. The most often assigned ATC-codes were L–Antineoplastics (n=139), J–Anti-infectives for systemic use (n=52), and N–Nervous system (n=34). The qualitative analysis is ongoing and will be presented on the poster at the Science Day.

Assessment of companion diagnostic consultation procedures at the European Medicines Agency between 2022 and 2025

Renske J. Grupstra^1,2, Elisabeth Bakker^1,2, Viktoriia Starokozhko^1,2, PGM Mol^1,2, Anna M.G. Pasmooij^1,3

1.    Dutch Medicines Evaluation Board, Utrecht, The Netherlands
2.    Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
3.    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

Background: Companion diagnostics (CDx) are in vitro diagnostics that support the optimised use of a specific medicinal product by identifying patients that are most suitable for the treatment. According to the In Vitro Diagnostic Medical Device Regulation (IVDR) that came into force in 2022, a Notified Body (NB) conducts a conformity assessment before a CDx can enter the European market. During this conformity assessment, a NB must seek the scientific opinion of a medicinal products authority in a so-called consultation procedure. Little is known about what is discussed during these consultation procedures and what their impact is. Therefore, this study aims to assess CDx consultation procedures conducted at the European Medicines Agency (EMA) between 2022 and 2025.

Methods: A review of regulatory documents (including non-public documents available at the EMA) was conducted. Information about procedural aspects, characteristics of the CDx and type of questions or issues raised during the procedure was collected and analysed descriptively.

Results: Between 2022 and 2025, 29 consultation procedures were completed. Most (90%) of the assays assessed in the procedures were intended for oncology indications. Overall, 6 major objections and 197 other concerns were raised by the CHMP during the procedures. Preliminary results demonstrate that issues commonly concerned the comparability and concordance studies, the assay's sensitivity and specificity, or the legal status of the CDx. Analysis of all data is expected to be completed in Q2 of 2026.

Conclusion: We anticipate to identify common bottlenecks from the completed consultation procedures. Insights therein may inform guidance on CDx certification. 

Quality concerns for cell, gene, and RNA therapies in clinical trial applications since the implementation of the European Clinical Trial Regulation

Christine C. van Hattem¹, Monique T.A. de Beijer², Sigrid Roosendaal², Thijs J. Giezen^1,2,3, Lourens T. Bloem¹, Toine C.G. Egberts^1,2,4

1.    Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
2.    Central Committee on Research Involving Human Subjects, The Hague, The Netherlands
3.    Department of Clinical Pharmacy, Spaarne Gasthuis, Haarlem, Hoofddorp, The Netherlands
4.    Department of Healthcare Innovation & Evaluation, Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands

Background: Cell, gene, and RNA therapies are innovative and complex modalities with therapeutic
promises for patients with unmet medical needs, but patient access remains complicated. One important issue is ensuring product quality. However, while developers raise many quality issues during development, regulators raise relatively few quality concerns upon marketing authorisation. Hence, quality concerns may be accepted or outweighed during this stage or may have been resolved in an earlier stage, such as upon the application to conduct a clinical trial. Therefore, we aim to evaluate the number and nature of concerns about the quality of cell, gene, and RNA therapies in initial applications of clinical trials that were intended to be conducted in the Netherlands since the implementation of the EU Clinical Trial Regulation (CTR).

Methods: We perform a retrospective cohort study including initial applications for clinical trials involving cell (including tissue), gene, and RNA therapies (i.e., products of interest) for which the Netherlands was involved in the assessment as either reporting or concerned Member State (2022-2025). Using the Clinical Trials Information System (CTIS), we collect the characteristics of the trials and products of interest, and the corresponding quality concerns. Data will be analysed qualitatively and quantitatively.

Conclusion: Insight in the quality concerns encountered in the applications for clinical trials with these complex modalities may offer worthwhile learnings for both developers and assessment committees. These findings may contribute to ensure a harmonised assessment process and high standards for both product quality and therewith participant safety under the CTR.