Unit of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, UK.
Health Technol Assess. 2010 Oct;14(Suppl. 2):19-26. doi: 10.3310/hta14suppl2/03.
This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of rituximab with chemotherapy compared to chemotherapy only for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. Evidence was available in the form of one open-label, ongoing, unpublished randomised controlled trial (RCT), REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia), conducted by the manufacturer, which compared rituximab with a fludarabine and cyclophosphamide combination (R-FC) to fludarabine and cyclophosphamide (FC) only. REACH was scheduled to run for 8 years; however, the data provided were immature, with a median observation time at the time of data analysis of 2.1 years. REACH provided evidence of prolonged progression free survival with R-FC compared to FC (10 months, investigators' data), but no evidence of an overall survival benefit with R-FC. Patients refractory to fludarabine and with prior rituximab exposure were excluded from REACH and no controlled studies were identified by the ERG for these patient groups. The ERG had concerns about the structure of the economic model submitted by the manufacturer, which did not allow improvement in quality of life from treatment while in a progressed state. The manufacturer's model further assumed a divergence in cumulative deaths between the R-FC and FC treatment arms from the outset, which did not accord with observed data from REACH. When the survival advantage was removed, the manufacturer's base-case incremental cost-effectiveness ratio (ICER) changed from 15,593 pounds to between 40,000 pounds and 42,000 pounds per quality-adjusted life-year (QALY). With no survival advantage, the ICER became sensitive to changes in utility. There was no good empirical evidence on the utility of CLL patients in different states. Allowing for the possibility of a survival advantage with rituximab (although not supported by current evidence), the ERG performed further modelling, which found that rituximab would be cost-effective at 20,000 pounds/QALY (30,000 pounds/QALY) if a reduction in survival advantage relative to the manufacturer's base case of 40% (80%) was assumed. The guidance issued by NICE in July 2010 as a result of the STA recommends rituximab with FC for people with relapsed or refractory chronic lymphocytic leukaemia, except when the condition is refractory to fludarabine or where there has been previous treatment with rituximab.
本文总结了制药公司向英国国家卫生与临床优化研究所（NICE）提交的申请文件中，关于利妥昔单抗联合化疗对比单纯化疗治疗复发/难治性慢性淋巴细胞白血病（CLL）的疗效和成本效益的循证医学评价组（ERG）报告。该申请是作为单个技术评估（STA）的一部分，用于评估利妥昔单抗联合氟达拉滨和环磷酰胺（R-FC）对比氟达拉滨和环磷酰胺（FC）单药治疗复发慢性淋巴细胞白血病的疗效。评估的依据是一份由制造商发起的、正在进行的、非公开的、开放性标签的、随机对照试验（RCT）REACH 研究的数据。REACH 研究计划开展 8 年，但数据分析时仅获得了 2.1 年的中期数据，因此数据不成熟。REACH 研究显示 R-FC 方案较 FC 方案可显著延长无进展生存期（10 个月，研究者数据），但 R-FC 方案并不能改善患者的总生存期。REACH 研究排除了先前使用过利妥昔单抗或对氟达拉滨耐药的患者，ERG 也没有找到针对这些患者群体的对照研究。ERG 对制造商提交的经济模型结构提出了质疑，该模型不允许在疾病进展时提高治疗质量。此外，制造商的模型还假设 R-FC 与 FC 治疗组之间的累积死亡率从一开始就存在差异，这与 REACH 研究中的观察数据不一致。当生存优势被去除后，制造商的基础增量成本效果比值（ICER）从 15593 英镑变为 40000 英镑至 42000 英镑每质量调整生命年（QALY）。当没有生存优势时，ICER 对效用的变化变得敏感。没有关于不同状态下 CLL 患者效用的良好经验证据。假设利妥昔单抗具有生存优势（尽管目前没有证据支持），ERG 进行了进一步的建模，发现如果相对于制造商的基础病例降低 40%（80%）的生存优势，则利妥昔单抗的成本效益将为 20000 英镑/QALY（30000 英镑/QALY）。NICE 于 2010 年 7 月发布的 STA 指南建议将利妥昔单抗联合 FC 用于治疗复发或难治性慢性淋巴细胞白血病患者，除非疾病对氟达拉滨耐药，或先前已使用过利妥昔单抗。
