现实世界研究的机遇与挑战

现实世界研究(real world research，RWR)作为随机对照研究的补充，受到越来越多关注。如何能有效地利用高质量现实世界数据产生可靠的现实世界证据存在着机遇与挑战。本文从数据管理与利用以及获取证据的技术两方面对近年来的相关研究现状进行总结与评述，以期为RWR及应用提供参考。     

反常性痤疮的中文期刊文献证据等级评价

目的分析有关反常性痤疮的中文期刊文献证据的等级现状。方法通过检索中文数据库主题为"反常性痤疮"的期刊文献,分析其文献类型、发表时间、期刊来源等要素,根据牛津大学循证医学中心证据等级标准来评价文献的评价证据等级。结果共纳入文献99篇,来源于52种中文期刊,出版时间分布于1995年~2015年。无推荐等级为A的文献;推荐等级为B的文献4篇,证据等级均为3b;推荐等级为C的文献78篇,证据等级均为4;推荐等级为D的文献17篇,证据等级均为5。其中,《中华皮肤病杂志》《临床皮肤科杂志》及《中国皮肤性病学杂志》各有8篇,均为证据等级4和5的文献。结论关于反常性痤疮的中文文献绝大多数属于低证据等级文献,对临床工作的指导意义存在明显的局限性,提示当前国内学者需重视对现有低证据等级文献资料的整理分析和学习借鉴,同时积极开展高证据等级的临床研究。     

目标仿真试验的基本原理、设计要素及其优缺点

队列研究往往具有研究对象代表性好、样本量大、随访时间长等独特优势,但混杂因素控制困难是其因果推断不够严密的主要障碍。相反随机对照试验（RCT）研究则在混杂因素的控制上有着绝对的优势,但其组织实施往往会受到人力、物力和伦理等方面的限制。近年来,随着真实世界队列研究数据的积累,在大型队列研究中遵照RCT研究的设计原则开展目标仿真试验（ETT）愈发受到关注。基于队列数据的ETT研究能够得到较为准确的研究结论,也为真实世界队列数据分析提供了新的思路。本文旨在介绍ETT研究的基本原理、设计要素和优缺点,以期为医学研究者开展ETT提供参考。     

卫生装备环境模拟试验的几个问题

一种卫生装备品的环境适应能力究竟如何，怎么揭示其缺陷和不足，通常不可能都把装备放在实际环境中加以试验考核，但通过环境仿真，预先选定环境因素及其时间历程，进行环境模拟试验，以评价装备在未来寿命期内所遇到的自然的和诱发的环境条件下的适应能力，却是能够做得到的。三环境试验类型的确定1·三环境剖面的分析卫生装备环境剖面分析，是装备环境试验中确定试验类型、严酷等级及时间历程的依据。从总体看，卫生装备全寿命期内的环境过程包括：设计、制造、装卸、运输、储存、使用、维修直至退役等阶段。而装备从出厂到使用维修过程…     

鸡胚绒毛尿囊膜血管试验在化妆品安全性评价中的应用研究

目的 将鸡胚绒毛尿囊膜血管试验（CAMVA）与家兔眼刺激试验进行比较,探讨在化妆品安全性评价中的应用。方法 将11种化妆品原料和8种化妆产品分别进行鸡胚绒毛尿囊膜血管试验和家兔眼刺激试验,结果进行分析比较。结果 CAMVA试验分级标准和动物试验评级标准具有较高的等级相关性和一致性。结论 CAMVA是一种较好的体外眼刺激替代方法,但需和其他体外试验组合评价更加可靠。     

健康指数指标筛选的因果推断方法

健康指数体系的构建与发展对于推动健康中国目标的实现具有重要的战略意义。从现实世界数据入手,通过一系列的因果推断方法,筛选和确定对健康/疾病结局具有确凿因果关系且可干预的健康指数指标,从而为健康/疾病管理提供更贴近实践、更有价值的现实世界证据是至关重要的。本文针对健康指数构建的循证医学需求,介绍了目前常用的现实世界研究中人群水平评估的因果推断方法,为健康指数指标筛选提供方法支撑。     

成人冠心病患者焦虑抑郁管理的最佳证据总结CSCD

目的总结成人冠心病患者焦虑抑郁管理的最佳证据。方法计算机检索BMJ最佳临床实践、UpToDate、国际指南协作网、英国国家卫生与临床优化研究所、苏格兰院际指南网、加拿大安大略注册护士协会网、Cochrane图书馆、JBI循证卫生保健中心数据库、PubMed、Embase、Medline、Web of Science、中国知网数据库、万方数据库中关于成人冠心病患者焦虑抑郁管理的所有证据,包括指南、系统评价、专家共识、证据总结等。检索时间范围为建库至2021年9月13日,检索词为"coronary heart disease""psychology""anxiety""depression""冠心病""焦虑""抑郁"等,数据整理时间为2021年9月14—23日。由2名研究者根据AGREEⅡ和JBI循证卫生保健中心的评价工具独立进行文献质量评价和资料提取,使用JBI循证卫生保健中心的证据预分级系统和证据推荐级别系统对证据等级进行划分,在JBI的证据结构指导下结合研究组讨论及专家意见确定证据推荐强度并进行最佳证据的提取、汇总和分析。结果共纳入22篇文献,其中指南5篇、系统评价14篇、专家共识2篇、证据总结1篇;指南3篇质量等级为B,2篇质量等级为A;系统评价5篇质量等级为B,9篇质量等级为A,95%的条目评价结果为"是";专家共识质量等级均为A,所有条目评价结果均为"是";证据总结汇总心理健康管理模式、风险因素评估与预防、心理问题识别与筛查、心理调试与干预、药物治疗5大方面共32条最佳证据,其中60%为1类证据,34%推荐强度为A。结论成人冠心病患者焦虑抑郁管理文献总体质量较高,证据级别较高;创新心理健康管理模式,做好风险因素评估与预防、心理问题识别与筛查、心理调试与干预以及药物治疗是冠心病患者焦虑抑郁管理的关键。     

鸡胚尿囊膜绒毛膜试验与动物试验结果的比较

外来化学物眼刺激毒性评价是化合物质安全性毒理学评价的重要组成部分。长期以来，传统的动物眼刺激实验是全世界公认的评价外来化合物眼刺激性的唯一金标准，但该方法存在着评分系统主观性、动物个体差异等问题并且由于大量使用试验动物、对试验动物造成损害而受到各种动物保护组织的反对，因此，自上世纪八十年代开始，欧、美、     

妊娠期补铁对妊娠糖尿病发病率影响的meta分析

目的:用meta分析方法探讨妊娠期补铁对妊娠糖尿病发病率的影响。方法:计算机检索Cochrane Library(1980-2015)、PubMed(1980-2015)、Web of Knowledge(1980-2015)、CBMdisc(1980-2015)、中国知网(1980-2015)、万方(1980-2015)、维普(1980-2015)并结合手工检索相关杂志,收集国内外有关妊娠期补铁对妊娠糖尿病发病率影响的随机对照试验(RCT)。对于检索到的文献由两位研究者独立地按照纳入排除标准进行资料提取及方法学质量评价,并采用RevMan 5.2软件对妊娠糖尿病发病率进行meta分析,GRADE系统进行证据质量评价和等级推荐。结果:共检索到315篇文献,排除非随机对照试验、干预措施不符合纳入标准、失访情况不明确、重复发表的研究,共纳入2项RCT,累计调查人数1824例,其中补铁干预组921例,常规对照组903例。meta分析显示与常规对照组相比,补铁干预组妊娠糖尿病的发生率无差异(RR=0.95,95%CI:0.68~1.33,P=0.77)。基于GRADE系统的证据推荐等级评价结果显示妊娠糖尿病发生率证据质量为高级。结论:非贫血孕妇妊娠期间补铁不会引起妊娠糖尿病发病率的增加,但仍需更多大规模高质量的随机对照研究进一步确认。     

碘盐预防碘缺乏病随机对照试验的系统评价

目的 评价碘盐预防碘缺乏病的效果。方法 采用Cochrane系统评价的方法。结果 全世界约500篇相关文献中，4项研究为随机对照试验，符合纳入标准，按照年龄，干预措施和对照措施的不同进行亚组分析，8-12岁儿童组使用分发碘盐和市场碘盐加碘油胶囊均能有效降低甲状腺肿患病率（甲肿率），接近5%控制线，并明显优于市场碘盐（OR=0.10,95%CI:0.02-0.17)；市场碘盐虽能使甲肿率下降，但仍不能达到甲肿率控制线（14.7%)，使用市场碘盐时，儿童尿碘日排量在不同地区有不同结果，中国的研究结果尿碘水平随市场碘盐浓度的变化而变化，一般能达到100μg/L以上；德国和印度尼西亚的研究结果均不能达到碘缺乏病控制线，孕妇组使用市场碘盐预防碘营养不足基本有效，但仍应注意有相当部分孕妇达不到碘营养标准。结论 严格控制质量的碘盐和市场碘盐加碘油制剂能有效消除碘缺乏病；但对于市场碘盐消除碘缺乏病，尤其是消除儿童的碘缺乏病的效果评价。尚需更充分的证据。     

Emulating Target Trials With Real-World Data to Inform Health Technology Assessment: Findings and Lessons From an Application to Emergency Surgery

ObjectivesInternational health technology assessment (HTA) agencies recommend that real-world data (RWD) are used in some circumstances to add to the evidence base about the effectiveness and cost-effectiveness of health interventions. The target trial framework applies the design principles of randomized-controlled trials to RWD and can help alleviate inevitable concerns about bias and design flaws with nonrandomized studies. This article aimed to tackle the lack of guidance and exemplar applications on how this methodology can be applied to RWD to inform HTA decision making.MethodsWe use Hospital Episode Statistics data from England on emergency hospital admissions from 2010 to 2019 to evaluate the cost-effectiveness of emergency surgery for 2 acute gastrointestinal conditions. We draw on the case study to describe the main challenges in applying the target trial framework alongside RWD and provide recommendations for how these can be addressed in practice.ResultsThe 4 main challenges when applying the target trial framework to RWD are (1) defining the study population, (2) defining the treatment strategies, (3) establishing time zero (baseline), and (4) adjusting for unmeasured confounding. The recommendations for how to address these challenges, mainly around the incorporation of expert judgment and use of appropriate methods for handling unmeasured confounding, are illustrated within the case study.ConclusionsThe recommendations outlined in this study could help future studies seeking to inform HTA decision processes. These recommendations can complement checklists for economic evaluations and design tools for estimating treatment effectiveness in nonrandomized studies.     

Approaches for Enhanced Extrapolation of Long-Term Survival Outcomes Using Electronic Health Records of Patients With Cancer

ObjectivesThis study aimed to demonstrate enhanced survival extrapolation methods using electronic health record-derived real-world data (RWD).MethodsThe study population included patients diagnosed of ER+/HER2? metastatic breast cancer who started first-line treatment with anastrozole or letrozole between November 18, 2014, and November 18, 2015. Two patient cohorts were constructed: a clinical trial cohort from digitized MONARCH-3 clinical trial results and a RWD cohort from a deidentified electronic health record-derived database. RWD patients were weighted to trial baseline covariate distributions. Standard parametric approaches were applied to trial data and a “best-fit” model was selected. We demonstrate traditional and enhanced hybrid (pooling with weighted RWD at start, 75%, or end of trial) extrapolation approaches.ResultsObserved and estimated 5-year progression-free survival (PFS) rates in extrapolating the trial control arm (n = 165) were comparable across all methods. Compared with the observed 5-year mean PFS in the RWD cohort (n = 118) of 20.4 months (95% confidence interval [CI] 16.9-23.8), there was some variation among studied methods. Best-fit standard parametric model (log-normal) had 5-year mean PFS of 21.3 months (95% CI 18.2-24.9), and for the hybrid methods in order of estimate conservativeness was start of trial (20.8 months; 95% CI 18.5-23.2), 75% of trial (21.3 months; 95% CI 18.1-24.5), and end of trial (21.8 months; 95% CI 18.8-25.2).ConclusionsOur study leverages RWD to enhance long-term survival extrapolation. Future use cases should include applying patient eligibility criteria, weighting on baseline characteristics, and choice of time window to add RWD to trial data.     

Can Observational Analyses of Routinely Collected Data Emulate Randomized Trials? Design and Feasibility of the Observational Patient Evidence for Regulatory Approval Science and Understanding Disease Project

ObjectivesThe Observational Patient Evidence for Regulatory Approval Science and Understanding Disease (OPERAND) project examines whether real-world data (RWD) can be used to inform regulatory decision making.MethodsOPERAND evaluates whether observational analyses using RWD to emulate index trials can produce effect estimates similar to those of the trials and examines the impact of relaxing the eligibility criteria of the observational analyses to obtain samples that more closely match the real-world populations receiving the treatments. In OPERAND, 2 research teams independently attempt to emulate the ROCKET Atrial Fibrillation and LEAD-2 trials using OptumLabs data. This article describes the design of the project, summarizes the approaches of the 2 research teams, and presents feasibility results for 2 emulations using new-user designs.ResultsThere were differences in the teams’ conceptualizations of the emulation, design decisions for cohort identification, and resulting RWD cohorts. These differences occurred even though both teams were guided by the same index trials and had access to the same source of RWD.ConclusionsReasonable alternative design and analysis approaches may be taken to answer the same research question, even when attempting to emulate the same index trial. Researcher decision making is an understudied and potentially important source of variability across RWD analyses.     

Replication of Randomized,Controlled Trials Using Real-World Data: What Could Go Wrong?

With the growing interest in using real-world evidence (RWE) for regulatory purposes, researchers and policy makers are considering how best to assess the credibility of RWE. Because the randomized controlled trial (RCT) has long been regarded as the gold standard for high-quality research, one approach being pursued is to see to what extent findings from RCTs can be replicated based on analyses of nonrandomized real-world data (RWD). If findings are congruent, the reasoning goes, this would bolster confidence in the underlying RWD sources and validity of the RWE generated. But it is well known that medical interventions perform differently in experimental clinical trials versus real-world clinical practice, reflecting a phenomenon known as the “efficacy-effectiveness gap.” So even with the highest-quality RWD sources and strongest analytic methods, we can and should expect to observe discrepancies in findings between RCTs and RWE. This calls into question the objectives of RCT replication efforts and makes clear that impugning RWD sources and analytic methods for failing to align with RCT findings is inappropriate and, worse, potentially harmful to the growing acceptance of RWE in stakeholder decision making.     

Specifying a target trial prevents immortal time bias and other self-inflicted injuries in observational analyses

Many analyses of observational data are attempts to emulate a target trial. The emulation of the target trial may fail when researchers deviate from simple principles that guide the design and analysis of randomized experiments. We review a framework to describe and prevent biases, including immortal time bias, that result from a failure to align start of follow-up, specification of eligibility, and treatment assignment. We review some analytic approaches to avoid these problems in comparative effectiveness or safety research.     

真实世界数据作为外部对照用于药械临床评价的特殊考虑

随机对照试验(RCT)被视为药械临床疗效评价的"金标准"。但针对罕见、重大且无有效治疗方式等疾病, 考虑伦理、成本等因素, RCT并不适宜。此时, 采用真实世界数据(RWD)作为试验的外部对照支持药械临床评价, 可降低患者招募难度、缩减研发时间及成本。本文基于国内外最新发布的RWD有关的指导原则, 并结合团队前期研究经验, 介绍了采用RWD作为外部对照用于支持药械临床评价的常见应用场景、数据来源、研究设计、外部对照选择基本原则和统计分析方法, 以期为相关学者、申办方开展RWD研究提供参考与借鉴。     

真实世界数据适用性评价方法的研究进展与前景挑战

对真实世界数据开展适用性评价是从数据使用角度出发,保证健康医疗大数据质量并确保数据范畴与研究假设紧密相关的重要途径。基于此开展的研究也将具有更好的样本代表性和证据外推性,产出高可信度的真实世界证据。本文总结各国家、国际组织真实世界数据适用性文件,对真实世界数据适用性的概念、范畴、评价维度、指标细则、评价方式及已开展研究...     

The value of explicitly emulating a target trial when using real world evidence: an application to colorectal cancer screening

Observational analyses for causal inference often rely on real world data collected for purposes other than research. A frequent goal of these observational analyses is to use the data to emulate a hypothetical randomized experiment, i.e., the target trial, that mimics the design features of a true experiment, including a clear definition of time zero with synchronization of treatment assignment and determination of eligibility. We review a recent observational analysis that explicitly emulated a target trial of screening colonoscopy using insurance claims from U.S. Medicare. We then compare this explicit emulation with alternative, simpler observational analyses that do not synchronize treatment assignment and eligibility determination at time zero and/or do not allow for repeated eligibility. This empirical comparison suggests that lack of an explicit emulation of the target trial leads to biased estimates, and shows that allowing for repeated eligibility increases the statistical efficiency of the estimates.     

开发专病临床数据交换标准协会病例报告表助力我国真实世界数据生态建设

真实世界数据是指在日常医疗活动、生活与工作等环境下产生的数据。真实世界数据在临床与公共卫生研究中一直被广泛应用,但真实世界数据质量相关问题,如不完整性、不一致性和准确性等会影响真实世界研究的真实性。为了应对真实世界源数据缺乏标准化带来的挑战,本文基于当前被广泛应用的数据标准,即临床数据交换标准协会（CDISC）开发的CDISC标准开发了专病CDISC-病例报告表（CRF）,以提高真实世界源数据标准化水平,助力我国真实世界数据生态建设。我们阐述了如何应用数据标准弥补真实世界数据到真实世界证据之间的裂痕;设计了基于专病CDISC-CRF建设真实世界数据生态的流程,重点介绍了CDISC-CRF表单的开发技术;并就基于专病CDISC-CRF建设真实世界数据的应用前景及意义进行了描述。     

What Is Real-World Data? A Review of Definitions Based on Literature and Stakeholder Interviews

Background

Despite increasing recognition of the value of real-world data (RWD), consensus on the definition of RWD is lacking.