Supplementary Material for: Regulatory Measures to Improve the Safety of CAR-T-Cell Treatment

Introduction: Regulatory activities aim to facilitate the safe use of novel therapeutics such as genetically engineered chimeric antigen receptor (CAR)-T cells. Toxicities associated with CAR-T-cell therapies have led to modified safety management guidance in clinical trials and the implementation of post-marketing requirements. The aim of this study was to estimate the effect of individual risk-minimizing measures to evaluate the appropriateness of regulatory activities. Methods: We re-examined clinical trial data prior to and after the introduction of revised treatment guidelines; we analysed spontaneous adverse drug reaction (ADR) reports submitted to the EudraVigilance database in 2019/2020 regarding their completeness; and we performed a survey of treatment centres in Germany that have been qualified for the use of commercial CAR-T cells. Results: Lower combined incidences of severe cytokine release syndrome (CRS) as well as neurotoxicity occurred following CAR-T-cell treatment after a revision of management guidelines, suggesting earlier intervention compared to before (12.6% vs. 20.5%). Numerous post-marketing ADR reports lacked information important for case assessment. Full details on treatment indication, CRS onset, outcome, and grading were available for just 38.3% of CRS cases. Survey responses support the majority of regulatory requirements for centre qualification. Time investment was highest for training of healthcare professionals, which required an average of 6.5 staff members (range 2–20) and lasted more than 2 days per person in half of the facilities. The need to harmonize the regulatory requirements for the different CAR-T-cell therapeutics was emphasized. Conclusion: Defined regulatory measures can support the safe and effective use of new therapies and are indicated for structured recording of post-marketing data, and the evaluation of such measures appears to be necessary for the continuous improvement.

引言：监管活动旨在推动基因工程嵌合抗原受体（CAR，chimeric antigen receptor）-T细胞等新型治疗药物的安全应用。CAR-T细胞疗法相关的毒性反应，促使临床试验领域修订了安全管理指南，并推动了上市后监管要求的落地。本研究旨在评估个体风险最小化措施的实施效果，以论证相关监管活动的合理性。
方法：本研究重新审视了修订版治疗指南出台前后的临床试验数据；对2019至2020年提交至欧盟药品警戒数据库（EudraVigilance）的自发药品不良反应（ADR，adverse drug reaction）报告的完整性展开分析；同时对德国境内具备商用CAR-T细胞使用资质的治疗中心开展了问卷调查。
结果：治疗指南修订后，CAR-T细胞治疗后严重细胞因子释放综合征（CRS，cytokine release syndrome）与神经毒性的综合发生率有所降低，提示相较于指南修订前，临床干预时机更早（12.6% vs. 20.5%）。大量上市后ADR报告缺少对病例评估至关重要的信息。仅38.3%的CRS病例完整提供了治疗适应证、CRS发作时间、转归及分级的详细资料。问卷反馈结果显示，多数针对治疗中心资质的监管要求得到了临床机构的支持。医护人员培训的时间投入最高：半数受访机构中，平均需安排6.5名工作人员参与培训（范围2至20名），且每名参训人员的培训时长均超过2天。调研同时强调，亟需统一不同CAR-T细胞疗法的监管要求。
结论：明确的监管措施可助力新型疗法的安全有效应用，且对上市后数据的结构化记录具有重要支撑作用；而对这类监管措施开展评估，对于实现治疗方案的持续改进而言是必要之举。