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Novel Framework (Target Trial Emulation) in Observational Causal Inference Research Based on Real-world Data and Its Application Prospects in Traditional Chinese Medicine
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摘要: “目标试验模拟”(target trial emulation)作为一种新的真实世界研究框架在近年来被正式确立，其可用于指导基于真实世界数据开展观察性因果推断研究，继而进行医疗干预有效性和安全性评价。该框架的核心思想是参照随机对照试验的原则，利用真实世界数据模拟相应的随机对照试验，进而得出干预措施与临床结局间因果关联的结论。其主要实施要点可总结为“3-7-2”，即声明因果问题、制订模拟方案和模拟目标研究3个实施步骤，纳排标准、治疗策略、干预分配、随访期、结局指标、因果比较和分析计划7个设计要素，对永恒时间偏倚和现用药者偏倚2个关键偏倚的控制。本文通过对该框架的历史与现状、实施要点、经典案例、优势与局限性及其在中医药领域中的应用前景进行概述，以期帮助中医药学者开展中医药真实世界研究，并为构建具有中医药特色的临床评价体系提供新思路。Abstract: "Target trial emulation" (TTE), as a new framework in real-world research, has been formally established in recent years. It can be used to guide the evaluation of the effectiveness and safety of medical interventions based on real-world data for observational causal inference. The core idea of this framework is to follow the principles of randomized controlled trial (RCT), emulate a corresponding RCT using real-world data, and then draw conclusions about the causal relationship between interventions and outcomes. The main implementation tips of TTE can be summarized as "3-7-2": 3 implementation steps including formulating the causal question, designing the emulation plan, and emulating the target study; 7 design elements including eligibility criteria, treatment strategies, intervention allocation, follow-up period, outcome, causal contrast of interest, and analysis plan; and control of 2 critical biases including immortal time bias and prevalent user bias. In this article, we present an overview of the development, current status, implementation steps, classic examples, advantages and limitations of TTE, and its application prospects in traditional Chinese medicine (TCM). It is hoped that this article can assist researchers in TCM to utilize this method for real-world research and contribute to the construction of a clinical evaluation system with distinctive features of TCM.
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近年来，关于如何界定缓和医疗照护对象的讨论正在悄然展开，并已引起多个领域(包括但不限于临床专业、政策制定、医疗体制改革、法律伦理和投资实业等)专家的关注。本文从推广生前预嘱(living will)的角度就这一问题展开讨论。
北京生前预嘱推广协会是于2013年注册成立的公益性社团组织。生前预嘱是指人们在健康或意识清楚时事先签署的指示性文件，阐明当其在不可治愈的伤病末期或临终时要或不要哪种医疗照护[1]。目前，世界上所有提供缓和医疗服务的国家和地区，均将生前预嘱以及具有表达个人意愿功能的相似文件作为开展此项医疗服务的合法性前提[2]。缓和医疗相关国家政策、临床实践与理论的发展，则是生前预嘱推广的必要条件。因此，本协会将推广生前预嘱和缓和医疗作为并驾齐驱的两项日常工作。
2010—2016年，本协会委托多名两会代表(胡定旭、凌峰、陶斯亮、顾晋等)连续数年提案，在中国现有法律环境下推广生前预嘱，以期建立政府指导下全方位分层次的缓和医疗服务。2015年，本协会受邀参加由时任全国政协主席俞正声支持、全国政协教科文卫体委员会开展的全国调研，该项工作围绕如何“推动安宁疗护发展”展开，对多地进行了为期8个月的走访和深度观察。2016年4月，俞正声主持并召开全国政协第49次双周协商座谈会，围绕“推进安宁疗护工作”建言献策。时任协会总干事罗峪平和香港医管局局长、协会专委会主席胡定旭参加会议并发言[3]。在调研和会议准备的过程中，我们竭力主张中国现代缓和医疗应从一开始就把照护对象尽量扩大化，主要依据是缓和医疗的定义一直在变化。
最广为人知和接受的缓和医疗定义由世界卫生组织(World Health Organization，WHO) 于2002年制定：缓和医疗是一种提供给患有危及生命疾病的患者和家庭的，旨在提高其生活质量及应对危机能力的系统方法；通过对痛苦和疼痛的早期识别，以严谨的评估和有效管理，满足患者及家庭的所有(包括心理和精神)需求[4]。2020年WHO发布了该定义的修订版，简化了语言表述，之前难以翻译成各国语言的措辞也得到纠正：缓和医疗是一种改善患有危及生命疾病的患者(成人和儿童)及其家人生活质量的方法；其通过早期识别，正确评估、治疗疼痛和其他身体、心理、精神问题以预防和减轻痛苦[5]。更新版定义列出了可能需要缓和医疗的最常见病症，但这些常见病症并无一份详尽的清单，疾病本身的诊断也并非获得缓和医疗服务的标准，因此对于缓和医疗照护对象的界定仍存在争议。
与此同时，国际安宁缓和医疗协会(International Association for Hospice & Palliative Care，IAHPC)提出了更具专业视角的缓和医疗新定义：缓和医疗是对因严重疾病而遭受严重健康损害的所有年龄段的个人，尤其是对生命终末期患者，所进行的积极全面的照护。该定义旨在提高个人及其家属和照护者的生活质量[6]。尽管这一定义与WHO的定义存在差异，但优先考虑舒适、尊严和共同决策，界定的目标人群为“患有严重疾病的人，不论年龄大小”，并不强调疾病的死亡率，而仅强调其严重性，建议从疾病一开始就实施缓和医疗，此表述符合多数人对缓和医疗的期盼，其一经发布即得到全球180个安宁疗护与缓和医疗组织和学术中心的支持[7]。
通过与调研专家团进行充分讨论，最终大家一致认为，从国家目前医疗体制的实际情况出发，对以癌症为主的终末期患者进行照护(后来被命名为“安宁疗护”)开始，可更快地使国家职能部门找到推广的抓手，具有更好的操作性，也更符合我国国情。而医保支付系统和商业保险等各相关领域在逐步积累数据的过程中，也能够留出充足的计算和决策空间，从而促使缓和医疗理念以更合理的速度长入复杂社会的“肌体”。随后，国家卫生健康委正式发布了安宁疗护标准和管理规范，并陆续推出三批安宁疗护试点城市。自此，安宁疗护作为现代缓和医疗的一部分开始快速发展，使更多人在了解安宁疗护的同时也对缓和医疗理念有了深入了解。从目前所取得的成果来看，这一“小切口”的决策更趋合理，使得缓和医疗的推广更易落实和操作。
全球老龄化日益加剧、感染性疾病大流行以及战争和气候变化带来的人道灾难，均将继续影响缓和医疗照护对象的界定。各国政府和各类组织将依据自身所处的不同环境作出不同决策，并不断修正和完善。不仅如此，生前预嘱的概念和推广方式也在经历一轮又一轮的更新和变化。
预立照护计划(advance care planning，ACP)是针对原有生前预嘱概念的迭代性文件。完整的ACP一般包括充分的个人意愿表达、指定的医疗代理人和可被执行的临床医嘱三部分，旨在通过患者、家属(或医疗代理人)和临床医生的充分协商，对诸如临终是否使用生命支持系统、是否充分镇痛等作出最大限度优化患者利益的共同决策。其优点在于可最大限度保障在长期照护机构、养老院、护理院、紧急医疗部门和医院各科室之间完整信息的传送和使用。目前，此类由医护人员主张形成的具有专业特点的措施，已经展现出良好的效果。2019年，由美国政府购买服务的美国生前预嘱注册中心(U.S. Living Will Registry)也因此改名为美国预立照护计划注册中心(U.S. Advance Care Plan Registry)[1]。
鉴于此，未来本协会的生前预嘱推广工作将增添新的重要内容——积极推动在现有法律环境下，在医政医管职权范围内，将统一制作的ACP文本放入住院病案首页，纳入病案级管理。这不仅有利于缓和医疗照护全过程的正确对接，还能够指导临床医护人员深入了解和掌握缓和医疗的基本概念和技能。标准ACP制作流程见图 1。
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缓和医疗的本质是对人的尊重，是在科技时代人们对生命本质重新认识的产物，而缓和医疗照护对象的界定亦无可争议地会随着国家经济和文明水平的发展而不断被修正和完善。北京生前预嘱推广协会作为推广生前预嘱和“尊严死”理念的社会组织，秉承“推广生前预嘱，让更多人知道，按照本人意愿，尽量以自然和有尊严的方式离世，是对生命的珍惜和热爱”的使命，殷切而充满信心地期待安宁缓和医疗在不久的将来，能够成为人人享有的基本权利。
作者贡献：卢存存负责查阅资料、论文撰写；陈子佳负责论文修订；王志飞负责论文修订与审校。利益冲突：所有作者均声明不存在利益冲突 -
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