Operational burden and fragmented implementation in CAR T‐cell therapy: Insights from a multinational survey by the GoCART Coalition and the JACIE Quality Managers Committee

Chimeric-antigen-receptor (CAR) T-cells have rapidly become a cornerstone in the treatment of advanced hematological malignancies,1 offering transformative outcomes for patients. Since the approval of the first two products in 2017, the number of authorized CAR T-cell therapies has steadily increased, with at least seven now approved worldwide.2 This expansion has brought not only clinical progress but also growing complexity in the organizational processes required to ensure the safe and effective delivery of CAR T-cell therapies, including the conduct of post-registration studies captured through the European Society for Blood and Marrow Transplantation (EBMT)'s CAR T-cell registry.3, 4 A growing challenge is not only the increasing number of new CAR T-cell products entering clinical testing5, 6 but also the fact that each approved product is tied to a proprietary platform, requiring distinct onboarding protocols, electronic systems, documentation procedures, and post-infusion monitoring requirements. Importantly, many of these demands are shaped by formal regulatory documents. In the United States, these include the Food and Drug Administration (FDA)'s Biologics-License-Application (BLA) letters and Risk-Evaluation-and-Mitigation-Strategies (REMS); in Europe, analogous requirements are outlined in the European Medicines Agency (EMA)'s European-Public-Assessment-Reports (EPARs), Risk-Management-Plans (RMPs), and Annex II of the marketing authorization.7, 8 These documents define marketing authorization holder (MAH)-specific obligations related to manufacturing, traceability, pharmacovigilance, and controlled distribution. As a result, MAHs interpret and implement regulatory expectations through their own systems, leading to significant variability in comparable clinical procedures. While the core workflow (patient selection, apheresis, shipment, conditioning, infusion, and follow-up) is broadly consistent, its implementation varies substantially by product. This divergence adds significant operational and administrative burdens to hospitals, particularly those managing multiple CAR T-cell therapies, by diverting time and resources away from direct clinical care. A major contributor to this burden is the increasing number and overlapping tenor of these inspections and audits required for the implementation and ongoing maintenance of CAR T-cell programs, with some centers facing more than nine inspections per year. These include inspections by MAHs, certification/accreditation bodies (e.g., Joint Accreditation Committee [JACIE]/Foundation for the Accreditation of Cellular Therapy [FACT]), national regulatory agencies, and internal onboarding teams with the introduction of each new product. To better understand how the interpretation and implementation of defined regulatory requirements by MAHs translate into real-world operational challenges, experts representing the JACIE Quality Management Committee, Cellular Therapy & Immunobiology Working Party (CTIWP), and the GoCART Coalition conducted a survey targeting hospitals involved in CAR T-cell delivery. The objective was to capture hospital perspectives on inspection burden, identify operational inefficiencies, and inform ongoing efforts to harmonize regulatory, certification, and implementation frameworks. A survey was distributed in early 2025 to CAR T-cell program leads. Survey responses were considered valid if respondents answered at least one question besides their country of origin and role. Participating countries (n = 32) included a global mix, with most from Europe (n = 22), alongside contributions from Asia (n = 6), South America (n = 2), North America (n = 1), and Oceania (n = 1). European centers accounted for the majority of survey responses; as a result, the findings predominantly reflect the experiences and practices of European institutions. Within Europe, participation varied by country, with some contributing more than 13 centers (Italy, Germany, the United Kingdom, Spain), while others were represented by only one. Figure 1A illustrates this imbalance, which we further normalized to national population size (Figure S1), underscoring that the survey findings are primarily shaped by European practice. A total of 183 valid responses were received from 142 hospitals (Table S1), reflecting input from a range of professionals involved in CAR T-cell therapy implementation and delivery (Figure 1B). The majority of responding centers (65%) reported that JACIE certification was required to perform CAR T-cell infusions, either due to national regulatory mandates (43.8%) or as a condition set by the MAH (21.6%) (Figure 1C). The questionnaire comprised 25 items covering system usability and communication with MAHs, patient preparation and apheresis, courier logistics and documentation, data sharing and post-product delivery handling, training, onboarding, and annual audits, as well as JACIE and MAH inspection overlap. System usability and MAH communication were generally viewed positively, but with important caveats. Communication with MAHs was described as “generally good” by 58% of respondents and “easy and smooth” by 34%, reflecting that most interactions were constructive and supportive. Likewise, 46.8% found the use of MAH platforms for ordering, booking slots, and scheduling apheresis straightforward. However, nearly the same proportion (46.6%) reported occasionally needing assistance, and a smaller subset experienced persistent challenges. Training on ordering systems was mostly adequate, 53% considered it “mostly sufficient” and 30% “sufficient”, yet 15.3% judged it only somewhat sufficient and 1.7% found it inadequate. Figure 1D illustrates this divide, showing that while many centers navigate systems smoothly, a notable minority still encounter barriers that demand targeted support and clearer training. Patient preparation and apheresis emerged as comparatively well aligned across MAHs. Preparation materials were considered clear or mostly clear by 89% of respondents, though several highlighted differences in style and depth across products that created confusion for patients (Figure 1E). Similarly, the apheresis process was rated “fully aligned” by 46.5% and “mostly aligned” by 31.7%, but 15.2% observed slight variations and 6.6% felt procedures “differ a lot” between MAHs. Figure 1F demonstrates this pattern: most processes are harmonized, but variability in materials and procedures still undermines full standardization. Training content was broadly valued but not consistently comprehensive. Education on side effects and complications was described as “helpful but could be improved” by 41.5% of respondents, “valuable training per ATMP” by 31.3%, and “somewhat useful but not essential” by 22.9%, while only 4.3% considered it unnecessary. This suggests that training is seen as essential but often fails to prepare staff for the full spectrum of real-world toxicity management. Figure 1G reinforces this finding, highlighting the strong recognition of training's importance but also clear dissatisfaction with its depth and uniformity. Onboarding was widely regarded as resource-intensive, with 47.3% of respondents describing it as “somewhat time consuming” and 12% as “very time consuming.” Nearly half (45.3%) rated the process as “somewhat repetitive or similar to existing processes,” while 8.9% considered it outright duplicative, leaving only a minority who viewed it as bringing fresh perspectives. Figure 1H,I captures this perception, emphasizing onboarding as both time-intensive and of limited added value, thereby underscoring the need for streamlined approaches aligned with existing certifications. As shown in Figure 1J, data sharing showed marked variability across the CAR T-cell process. Overall, 36.7% of respondents reported full sharing and 40% some sharing, but 17.2% experienced limited sharing and 6.1% reported no sharing at all. A stage-specific analysis revealed the best exchange occurred before apheresis (41.3% full sharing), dropped slightly after apheresis (39.5%), and fell more substantially after infusion (29.2%), when communication is most critical for safety and follow-up. Audits and dry runs added further administrative strain. While intended to ensure quality, 43.2% of respondents described dry runs as “somewhat repetitive” and 10% as duplicative, with similar perceptions for onboarding audits. Overlap between JACIE and MAH requirements was also widely noted: 46% of respondents reported “some overlap” and 41.3% “lots of overlap,” with only 12.7% perceiving minimal or no overlap. Likewise, 44.8% saw “few differences” between the two frameworks, 35.2% “some differences,” and 14.5% considered them identical. Figure 1K underscores this redundancy, showing how audits frequently duplicate JACIE criteria rather than complement them, thereby fueling inspection fatigue. Collectively, the figures reveal a consistent theme: while core processes are aligned, variability in implementation across MAHs generates inefficiencies, inconsistent training, and redundant oversight, creating an operational burden that diverts hospitals from patient care. Greater harmonization is underway, with some MAHs reducing onboarding for JACIE-certified centers,7 whose standards already cover most onboarding criteria (EBMT News). The GoCART Coalition, promoted by EBMT and EHA, is implementing a number of initiatives to face these challenges, including introducing innovations like best practice recommendations9 and the evolving EU CAR T Handbook that offer practical support, the CAR T Passport and the GoCART Coalition Observership Program to standardize education of healthcare professionals, and potentially replacing the majority of the non-product-specific training provided by MAHs. We aim to expand access through the observership program, which supports structured training and long-term mentorship between experienced and emerging CAR T centers, while also fostering sustainable partnerships with non-CAR T centers to enable early referral and shared care. Notably, the FDA eliminated REMS for commercial products in June 2025, which will facilitate access to CAR T-cell therapy for every eligible patient, but also raises concern in our global capability to maintain high levels of safety and optimal management. Supporting centralized, clinician-led initiatives through platforms like the EBMT Registry, JACIE, and the CAR T Passport could streamline CAR T-cell delivery, realizing that this vision will require coordinated action across healthcare providers, MAHs, and regulators. Nick van Sinderen: Conceptualization; investigation; data curation; supervision; project administration; writing—review and editing; methodology; formal analysis. Julie Dolva: Methodology; validation; supervision; data curation; formal analysis. Caterina Riillo: Writing—original draft; writing—review and editing; data curation; validation; formal analysis; visualization. Raquel Espada: Data curation; project administration; software. Christof Scheid: Supervision; writing—review and editing. Suzanne van Dorp: Supervision; writing—review and editing. Marten Nijziel: Supervision; writing—review and editing. Margot Jak: Supervision; writing—review and editing. Florent Malard: Supervision; writing—review and editing. Christian Chabannon: Supervision; writing—review and editing. Andrea Egan: Supervision; writing—review and editing. Chiara Bonini: Supervision; writing—review and editing. Julio Delgado: Supervision; writing—review and editing. Martin Dreyling: Supervision; writing—review and editing. Annalisa Ruggeri: Supervision; writing—review and editing. Marion Subklewe: Supervision; writing—review and editing. Anna Sureda: Supervision; writing—review and editing. Yolanda Cabrerizo: Supervision; writing—review and editing. Ibrahim Yakoub-Agha: Supervision; writing—review and editing. Tuula Rintala: Supervision; writing—review and editing. Lynn Manson: Supervision; writing—review and editing. Laurel Anderson: Supervision; writing—review and editing. Olivier Urbain: Supervision; writing—review and editing. Rachel Luke: Supervision; writing—review and editing. Lea Brandt Kristensen: Supervision; writing—review and editing. Anne Emmett: Supervision; data curation; investigation; conceptualization; writing—review and editing; formal analysis; methodology. Jürgen Kuball: Writing—original draft; writing—review and editing; supervision; conceptualization; validation; formal analysis; data curation. J.K. is cofounder and shareholder of Gadeta Founders B.V., inventor on patents with γδTCR/ligand and genetic engineering related topics, and has received research funding from Novartis, Miltenyi Biotech, and Gadeta. For full disclosure, go to https://researchinformation.umcutrecht.nl/en/persons/jurgen-kuball.