Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre+ (MUMC+), PO Box 5800, 6202 AZ, Maastricht, The Netherlands.
Centre of Economic Evaluation, Trimbos Institute (Netherlands Institute of Mental Health and Addiction), Utrecht, The Netherlands.
Pharmacoeconomics. 2020 Oct;38(10):1043-1053. doi: 10.1007/s40273-020-00932-4.
GW Research Ltd. provided two separate, but similar, submissions to the National Institute for Health and Care Excellence (NICE) on the clinical and cost-effectiveness of cannabidiol (CBD) 10 mg/kg/day, trade name Epidyolex, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). This paper highlights important methodological issues related to the company submissions, the Evidence Review Group (ERG) reports, and the subsequent development of the NICE guidance by the Appraisal Committee (AC) for the use of CBD. The company identified four randomised controlled trials (RCTs) of CBD (GWPCARE1 and GWPCARE2 for DS, and GWPCARE3 and GWPCARE4 for LGS) and an ongoing open-label extension study (GWPCARE5) as relevant to both submissions. In these RCTs, CBD in addition to current clinical management (CCM) was compared to CCM without CBD (i.e. CCM plus placebo). GWPCARE2 and GWPCARE3 were three-arm studies and compared two dosages of CBD (10 mg/kg/day and 20 mg/kg/day) in addition to CCM and CCM plus placebo. GWPCARE1 and GWPCARE4 compared CBD (20 mg/kg/day) in addition to CCM and CCM plus placebo. Both DS patients in GWPCARE2 and LGS patients in GWPCARE3 who received 10 mg/kg/day CBD in addition to CCM achieved better seizure frequency outcomes than those who received CCM plus placebo. In the company's base case, use of CBD for LGS patients resulted in an incremental cost-effectiveness ratio (ICER) of £31,107 per quality-adjusted life year (QALY) gained and, for DS patients, £36,046 per QALY gained versus CCM. The ERG considered that these ICERs were extremely uncertain and suffered from validity issues concerning model structure (e.g. patients receiving CCM moved back to baseline drop seizure frequency), input (e.g. inclusion of caregivers' QALYs), and transparency issues (e.g. hidden worksheets and coding in Visual Basic for Applications), and hence incorporated adjustments to the original base case which increased the ICERs. During the process, the European Medicines Agency (EMA) licence granted marketing authorisation for CBD only in conjunction with clobazam. Hence, the company provided evidence from this subgroup in an additional submission, which resulted in an ICER of £33,721 per QALY gained for LGS and an ICER of £32,471 per QALY gained for DS. In this submission and clarifications, the ERG was able to verify and validate most of the company's responses to the ERG's concerns. However, some issues remained regarding the face validity of model assumptions on patient pathways after treatment discontinuation. Finally, the AC recommended CBD with clobazam as an option for treating seizures associated with LGS and DS in patients aged 2 years and older only if (1) the frequency of drop seizures is checked every 6 months and CBD is stopped if the frequency has not fallen by at least 30% compared with 6 months before starting treatment and (2) the company provides CBD according to the commercial arrangement.
GW 研究有限公司向英国国家卫生与保健优化研究所（NICE）提交了两份关于大麻二酚（CBD）10mg/kg/天（商品名 Epidyolex）辅助治疗 Lennox-Gastaut 综合征（LGS）和 Dravet 综合征（DS）相关癫痫发作的临床和成本效益的独立但相似的报告。本文重点介绍了与公司提交材料、证据审查小组（ERG）报告以及随后评估委员会（AC）制定有关 CBD 使用的 NICE 指南相关的重要方法学问题。该公司确定了四项 CBD 的随机对照试验（RCT）（GWPCARE1 和 GWPCARE2 用于 DS，GWPCARE3 和 GWPCARE4 用于 LGS）和一项正在进行的开放标签扩展研究（GWPCARE5），这两项研究与两份报告均相关。在这些 RCT 中，CBD 联合现行临床管理（CCM）与 CCM 不联合 CBD（即 CCM 加安慰剂）进行了比较。GWPCARE2 和 GWPCARE3 为三臂研究，比较了两种剂量的 CBD（10mg/kg/天和 20mg/kg/天）联合 CCM 和 CCM 加安慰剂。GWPCARE1 和 GWPCARE4 比较了 CBD（20mg/kg/天）联合 CCM 和 CCM 加安慰剂。GWPCARE2 中的 DS 患者和 GWPCARE3 中的 LGS 患者接受 10mg/kg/天的 CBD 联合 CCM 治疗的癫痫发作频率结果优于接受 CCM 加安慰剂的患者。在公司的基本案例中，LGS 患者使用 CBD 的增量成本效益比（ICER）为每获得 1 个质量调整生命年（QALY）31,107 英镑，DS 患者为每获得 1 个 QALY 36,046 英镑，而 CCM 为 36,046 英镑。ERG 认为这些 ICER 非常不确定，并且在模型结构（例如，接受 CCM 的患者返回基线时癫痫发作频率下降）、输入（例如，包括照顾者的 QALY）和透明度问题（例如，隐藏的工作表和 Visual Basic for Applications 中的编码）方面存在有效性问题，因此对原始基本案例进行了调整，增加了 ICER。在此过程中，欧洲药品管理局（EMA）仅在与氯巴占联合的情况下授予 CBD 的营销授权。因此，该公司在附加报告中提供了来自这一组患者的证据，结果显示 LGS 的 ICER 为每获得 1 个 QALY 33,721 英镑，DS 的 ICER 为每获得 1 个 QALY 32,471 英镑。在这份报告和澄清文件中，ERG 能够验证和验证公司对 ERG 关注的大多数回应。然而，在治疗停止后患者路径的模型假设的表面有效性方面，仍存在一些问题。最后，AC 建议，如果（1）每 6 个月检查发作性癫痫发作的频率，如果与开始治疗前 6 个月相比频率没有下降至少 30%，则停止 CBD 治疗，并且（2）公司按照商业安排提供 CBD，则在 2 岁及以上的 LGS 和 DS 相关癫痫发作患者中，将氯巴占联合 CBD 作为一种治疗选择。
