Why advanced therapy medicinal products struggle in clinical translation: an in-depth analysis of developmental challenges in the EU

Advanced Therapy Medicinal Products (ATMPs) can offer unprecedented therapeutic benefit for patients with limited treatment options. However, their clinical translation and early-stage clinical development remain highly complex, particularly for academic developers and small- and medium-sized enterprises (SMEs). This study presents a comprehensive analysis of the different types of challenges that ATMP developers face in initiating clinical trials, based on a scoping literature review, conducted according to the JBI methodology for scoping reviews and reported according to PRISMA-ScR. PubMed, Embase and Scopus were searched for peer-reviewed literature covering the last decade, focusing on publications discussing regulatory challenges for ATMP developers at the stage of clinical trial initiation. Our findings show that key challenges exist in four areas, comprising (a) preclinical evidence and product characteristics, (b) cell sourcing and manufacturing, (c) clinical trials and (d) regulatory landscape. Early engagement with regulators and the availability of up-to-date guidance documents emerged as key strategies to align developer efforts with regulatory expectations, while the review also identifies practical recommendations to support more efficient and harmonized clinical translation. In line with the objectives of JOIN4ATMP, these insights are valuable for developers and informative for regulators to foster more efficient and aligned ATMP development pathways.