As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (GlaxoSmithKline [GSK]) of Benlysta (belimumab) to submit evidence regarding its clinical and cost effectiveness, for the review and possible extension of a previously conditionally approved intravenous formulation of belimumab for the treatment of active autoantibody-positive systemic lupus erythematosus (SLE). Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG’s critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the NICE Appraisal Committee.

This appraisal is different to the previous appraisal in three ways: (1). This appraisal expands its definition of ‘high disease activity’. (2). In TA397, belimumab was approved, with a managed access arrangement (MAA), for adults only. This appraisal includes subjects aged 5 years or older. (3). The original appraisal included an intravenous formulation only, but the current appraisal also includes a new subcutaneous formulation in the form of a prefilled pen.

The company was required to collect real-world data from the British Isles Lupus Assessment Group Biologics Register (BILAG-BR), including data on the efficacy, safety, and effect on health-related quality of life of belimumab versus rituximab. This appraisal considers these data as well as additional clinical trial evidence presented in the company’s updated submission to address uncertainties identified during the original appraisal. The ERG identified three major concerns with the evidence presented on the clinical effectiveness in the current submission; namely, short follow-up in the main comparative trials (BLISS-SC, BLISS-52 and BLISS-76); using the propensity score-matching (PSM) analysis in calibrating the cost-effectiveness model can severely bias the results in favour of belimumab; and BILAG-BR data are not suitable for a comparison of belimumab with rituximab.

The main issue in the economic analysis was the uncertainty about long-term disease activity progression and resulting organ damage. The company’s approach of calibrating modelled organ damage to longer-term data analysed using the PSM analysis was methodologically inappropriate. The final analysis comparing belimumab with standard treatment for the intravenous formulation resulted in an incremental cost-effectiveness ratio of £12,335 per quality-adjusted life-year (QALY) gained and £30,278 per QALY gained in the company’s and ERG’s base-case analyses, respectively. For the subcutaneous formulation, the final analysis resulted in £8480 per QALY gained and £29,313 per QALY gained in the company’s and ERG’s base-case analyses, respectively. NICE recommended belimumab in both intravenous and subcutaneous formulations as an add-on treatment option for active autoantibody-positive SLE in the HDA-2 subgroup.

作为单一技术评估 (STA) 流程的一部分，国家健康与护理卓越研究所 (NICE) 邀请 Benlysta（贝利木单抗）的制造商（葛兰素史克 [GSK]）提交有关其临床和成本效益的证据，以供审查以及可能扩展先前有条件批准的贝利尤单抗静脉制剂，用于治疗活动性自身抗体阳性系统性红斑狼疮（SLE）。Kleijnen Systematic Reviews Ltd 与马斯特里赫特大学医学中心+合作，受委托担任独立证据审查小组 (ERG)。本文总结了公司提交的材料 (CS)，介绍了 ERG 对 CS 中的临床和成本效益证据的严格审查，强调了关键的方法学考虑因素，并描述了 NICE 评估委员会制定的 NICE 指南。

本次评价与以往评价相比，有以下三点不同：（1）．该评估扩展了“高疾病活动度”的定义。（2）。在 TA397 中，贝利尤单抗 (belimumab) 获得批准，并有管理访问安排 (MAA)，仅用于成人。该评估包括 5 岁或以上的受试者。（3）。最初的评估仅包括静脉注射制剂，但当前的评估还包括预填充笔形式的新皮下制剂。

该公司被要求从不列颠群岛狼疮评估组生物制剂登记册 (BILAG-BR) 收集真实世界数据，包括贝利尤单抗与利妥昔单抗相比的疗效、安全性和对健康相关生活质量影响的数据。该评估考虑了这些数据以及公司更新的提交文件中提供的其他临床试验证据，以解决原始评估期间发现的不确定性。ERG 在当前提交的临床有效性证据中确定了三个主要问题；即主要比较试验（BLISS-SC、BLISS-52 和 BLISS-76）的短期随访；使用倾向评分匹配（PSM）分析来校准成本效益模型可能会使结果严重偏向于贝利尤单抗；和 BILAG-BR 数据不适用于贝利尤单抗与利妥昔单抗的比较。

经济分析的主要问题是长期疾病活动进展和由此产生的器官损伤的不确定性。该公司根据使用 PSM 分析分析的长期数据来校准模拟器官损伤的方法在方法上是不恰当的。在公司和 ERG 的基本案例分析中，将贝利木单抗与静脉制剂标准治疗进行比较的最终分析结果表明，每获得质量调整生命年 (QALY) 的成本效益比增加 12,335 英镑，每增加 QALY 成本效益比增加 30,278 英镑。分别。对于皮下制剂，在公司和 ERG 的基本案例分析中，最终分析结果分别为每 QALY 增加 8480 英镑和每 QALY 增加 29,313 英镑。NICE 推荐贝利木单抗静脉注射和皮下注射制剂作为 HDA-2 亚组活动性自身抗体阳性 SLE 的附加治疗选择。