Weinreich Stephanie S, Vrinten Charlotte, Kuijpers Marja R, Lipka Alexander F, Schimmel Kirsten J M, van Zwet Erik W, Gispen-de Wied Christine, Hekster Yechiel A, Verschuuren Jan J G M, Cornel Martina C
Department of Clinical Genetics, Amsterdam Public Health research institute, VU University Medical Center, Amsterdam, The Netherlands.
Department of Care, National Health Care Institute, Diemen, The Netherlands.
Orphanet J Rare Dis. 2017 May 12;12(1):88. doi: 10.1186/s13023-017-0636-y.
Inexpensive medicines with a long history of use may currently be prescribed off-label for rare indications. Reimbursement is at the discretion of health insurance companies, and may be unpredictable. The example addressed was ephedrine as add-on treatment for myasthenia gravis. Stakeholders from academia, a patient organization, the Dutch National Health Care Institute (NHCI) and Dutch Medicines Evaluation Board (MEB) advised on the trial design. The NHCI and MEB agreed to provide scientific advice on the suitability of the evidence generated by the trial, for regulatory decisions. This paper describes the feasibility of the trial and the utility of its aggregated results.
The trialists experienced the trial as feasible. Retrospective interviews showed that the trial as performed was acceptable to patients. The treatment effect in the primary outcome measure, muscle strength, was statistically significant when inferred to the population level, though the effect size was modest. Secondary outcomes were statistically significant in a preplanned, fixed effects analysis within the four patients. The NHCI advised that it could potentially make reimbursement decisions based on the Fitting Evidence framework, should the trialists decide to apply for reimbursement. The MEB advised that for a licensing decision, the N-of-1 design is a last-resort option for demonstrating treatment benefit in a rare disease. N-of-1 trials alone do not provide enough evidence on potential risk. The MEB found the current trial inconclusive. It suggested doing a 2-armed trial of longer duration, possibly with a different outcome measure (postponement of corticosteroid use). It suggested engaging a consultancy or commercial sponsor, should the trialists decide to seek market authorization of the drug.
In theory, evidence from aggregated N-of-1 trials is suitable for use in licensing and reimbursement decisions. The current example illustrates differences in interpretation of N-of-1 results by health authorities. In the era of personalized medicine, consensus is required on the interpretation of data from study designs geared to small groups. Demonstrating effectiveness of inexpensive medicines in small populations may require involvement of non-commercial parties, to preserve affordability.
使用历史悠久的廉价药物目前可能会被用于罕见适应症的非标签处方。报销由健康保险公司自行决定，可能无法预测。所讨论的例子是麻黄碱作为重症肌无力的附加治疗。来自学术界、一个患者组织、荷兰国家医疗保健研究所（NHCI）和荷兰药品评估委员会（MEB）的利益相关者为试验设计提供了建议。NHCI和MEB同意就试验产生的证据对监管决策的适用性提供科学建议。本文描述了该试验的可行性及其汇总结果的效用。
试验人员认为该试验可行。回顾性访谈表明，所进行的试验对患者来说是可以接受的。在推断到总体水平时，主要结局指标肌肉力量的治疗效果具有统计学意义，尽管效应量较小。在对这四名患者进行的预先计划的固定效应分析中，次要结局具有统计学意义。NHCI建议，如果试验人员决定申请报销，它可能会根据“拟合证据”框架做出报销决定。MEB建议，对于许可决定，单病例试验设计是在罕见疾病中证明治疗益处的最后手段。仅单病例试验不能提供足够的潜在风险证据。MEB认为当前试验尚无定论。它建议进行一项持续时间更长的双臂试验，可能采用不同的结局指标（推迟使用皮质类固醇）。它建议，如果试验人员决定寻求该药物的市场授权，应引入咨询机构或商业赞助商。
理论上，汇总的单病例试验证据适用于许可和报销决策。当前的例子说明了卫生当局对单病例试验结果解释的差异。在个性化医疗时代，对于针对小群体的研究设计所产生数据解释需要达成共识。证明廉价药物在小群体中的有效性可能需要非商业方的参与，以保持药物的可负担性。
