产生现实世界证据的现实世界数据应用现状及展望

现实世界数据（real-world data，RWD）在医药卫生领域的应用日益广泛。在RWD转化为现实世界证据（real-world evidence，RWE）的过程中也涌现了大量问题，其中主要关注点在于RWD相关的数据质量和数据标准问题。本文着眼于RWD来源、数据合规性，讨论其数据标准及其质量控制问题，并对其未来可能的发展途径作一展望。     

不同领域现实世界临床研究证据转化的应用策略

参考已发布的政策法规指导意见，通过文献检索现实世界研究相关的专家共识指南，总结国内外现实世界临床研究不同领域的研究现况，归纳不同领域现实世界临床研究证据转化的观点，结合典型案例，为现实世界数据转化为现实世界证据的应用提供策略支持。     

基于现实世界研究中临床随访数据的两种动态预测建模方法的实证研究

目的： 针对现实世界研究（real-world study，RWS）中常见的具有纵向测量属性的动态观察指标，探讨界标法和联合建模法2种动态预测方法的应用价值。方法： 基于358例某重症肺炎患者预后数据，分别采用界标法和联合建模法，基于R软件，对于第5天、第10天、第15天尚处于观察期的某重症肺炎患者，预测其未来的死亡风险。结果： 2种方法均能在各时间点预测个体未来发生结局事件的概率。第5天、第10天和第15天，利用界标法进行动态预测的AUC分别为81.64%、85.89%和82.15%；而联合建模法的AUC分别为81.11%、85.07%和72.09%。结论： 在针对动态历史数据的现实世界研究中，可采用动态预测模型分析法，从而获得更为丰富的信息。     

GLUT1在子宫颈鳞状上皮病变中的表达和意义

葡萄糖转化酶1（GLUT1）属于活化的葡萄糖转化蛋白家族（GLUT1—7），在许多肿瘤的葡萄糖摄取中起主要作用。生理状态下GLUT1主要表达在红细胞膜、脑毛细血管内皮（血脑屏障）、外周神经的神经束膜及良性鳞状上皮基底细胞。研究表明，GLUT1在许多葡萄糖代谢率高的实质性肿瘤中有较高的表达，并且与肿瘤的进展及预后有关。[第一段]     

腹腔镜下肝脏手术增强现实三维影像导航平台的构建与应用

目的 实现腹腔镜下肝脏手术增强现实三维影像实时导航方案，构建平台雏形并评估其运行效果。方法 通过编写术前CT影像三维重建自动化算法、三维模型二维平面投影轮廓点集采集算法、基于人工智能的腹腔镜手术视野肝脏轮廓点集识别采集算法、“一对多”匹配算法、坐标系转换算法以及视频实时渲染增强融合算法，组成腹腔镜下肝脏手术增强现实三维影像实时导航软件，配合光学定位系统硬件和双目光学信息采集硬件，构建出导航平台雏形。在实验室仿真模型和大型动物中进行平台试运行，引入配准误差参数，评估运行效果并进行优化调整。结果 腹腔镜下肝脏手术导航软件基本实现：三维模型重建（CT图像自动分割和异色掩膜处理），手术室观测坐标系、腹腔镜视角坐标系和三维重建模型坐标系的建立及三者之间的信息转换，三维重建模型与手术视频所见结构实时配准导航，导航平台雏形构建。实验室仿真模型中的试运行配准误差为（4.1±0.4）mm，大型动物试运行2次的配准误差分别为4.6 mm和5.8 mm。结论 通过腹腔镜下肝脏手术增强现实三维影像实时导航平台雏形的设计、研发、构建以及使用，导航配准精度已经基本可以达到临床需求，未来进一步优化调整之后，有望广泛...     

对有关女阴（外阴）白斑临床问题的梳理和思考

长期以来人们把女阴（外阴）皮肤粘膜有白斑表现的病症，诊断为女阴（外阴）白斑病，并一般倾向于认为它是癌前期的变化。通过几乎是一个世纪以来，在世界范围的临床和病理学科的实践发现，女阴（外阴）皮肤粘膜有白斑表现的病症，在诊断及评估其性质及预后方面，均有进一步的认识。并认为女阴（外阴）皮肤粘膜有白色变化的疾病，多数为慢性良性过程，继发或伴发癌变的仅为较少数。现对有关女阴（外阴）皮肤粘膜有白斑表现的疾病进一步地梳理及思考如下。     

基于现实冲击理论的心理课程在新入职护士培训中的应用

目的 分析基于现实冲击理论的心理课程在新入职护士培训中的应用效果。方法 采用整群抽样方法，选取新入职于上海交通大学医学院附属第九人民医院的护士作为研究对象。根据护士入职时间分组，将2018年7月入职的护士设为对照组（n=71），将2019年7月入职的护士设为观察组（n=64）。对照组参照《新入职护士培训大纲（试行）》进行培训，观察组在其基础上增加基于现实冲击理论的心理培训。培训1年后，比较两组新入职护士的职业认同感水平、护士工作压力及心理弹性情况。结果 干预后，观察组新护士职业认同高于对照组（P<0.05），心理弹性优于对照组（P<0.05），工作压力小于对照组（P<0.05）。结论 基于现实冲击理论的心理培训能帮助新入职护士增加职业认同感、缓解工作压力、增强心理弹性，值得临床推广。     

转化医学概述及其在护理领域的研究与思考

近年来，转化医学（translational medicine）在人类健康领域迅速兴起并席卷全球，成为继循证医学（evidence—based medicine）之后世界医学研究的新浪潮。事实上，转化医学并不是一种新的研究方法，而是一种医学研究理念，它倡导将基础研究成果快速转向临床应用，再从临床中发现和提出问题，由基础研究人员深入研究，实现双向转化（bench to bedside，简称B2B模式）。     

想象-现实暴露疗法在慢性心力衰竭合并高血压患者运动恐惧中的应用

目的：探讨想象-现实暴露疗法在慢性心力衰竭合并高血压患者运动恐惧中的应用效果。方法：便利抽样法选取2020年2月至2022年1月心内科住院的慢性心力衰竭合并高血压的运动恐惧患者126例。按随机数字表法分为观察组和对照组各63例。对照组给予常规护理干预，观察组在对照组基础上进行想象-现实暴露疗法干预，干预12周。干预前后比较两组中文版心脏病运动恐惧量表（TSK-Heart-C）、运动自我效能量表（SEE）、心理弹性量表（CD-RISC）评分。结果：研究期间，观察组脱落2例，对照组脱落2例，最终两组各61例完成研究。干预后，观察组运动回避、感知危险、自我功能失调、运动恐惧、TSK-Heart-C总分均低于对照组，差异有统计学意义（P<0.05）；观察组SEE评分、CD-RISC评分高于对照组，差异有统计学意义（P<0.05）。结论：想象-现实暴露疗法能够提高慢性心力衰竭合并高血压患者的运动自我效能与心理弹性水平，降低运动恐惧。     

人Toll样受体4胞浆内段融合蛋白表达载体的构建与表达

目的：构建人Toll样受体4胞浆内段（hTLR4C)His融合蛋白表达载体并在原核表达与纯化，以研究其功能及鉴定与其相互作用的蛋白。方法：采用PCR方法扩增hTLR4基因编码区的胞浆内段，并将其重组于pET-DsbA2.0载体中。重组质粒经酶切、序列鉴定分析后，转化大肠杆菌BL21（DE3）。结果：用异丙基β－D硫代半乳糖（IPTG）诱导产生hTLR4胞浆内段的His-DsbA融合蛋白，继而纯化获得了分子量约42kd的融合蛋白。结论：本研究成功地构建了hTLR4胞浆内段融合蛋白表达载体并获得高效表达，为进一步研究提供了重要的实验材料。     

The Case for Real-world Evidence in the Future of Clinical Research on Chronic Myeloid Leukemia

Purpose

In light of recently published guidelines from the US Food and Drug Administration (FDA) on the communication of real-world data (RWD) and real-world evidence (RWE) to support regulatory decision making, it is important to understand how such data are developed, the limitations of these data, and how to best use RWD to improve patient care. Historically, the use of RWE has been approached with skepticism because of its often-retrospective nature compared with data from conventional randomized controlled trials (RCTs). This review discusses the role and function of RWE and RWD in clinical research. We summarize the types of RWE used in clinical research, outline the challenges and limitations involved with these data, and suggest how these types of analyses can supplement results from clinical trials to foster a more complete understanding of a drug or disease area of interest. In particular, we focus on the role of RWE in investigating chronic myeloid leukemia (CML) and tyrosine kinase inhibitor therapy for CML.

Real-World Evidence for Regulatory Decision-Making: Guidance From Around the World

PurposeInterest in leveraging real-world evidence (RWE) to support regulatory decision making for product effectiveness has been increasing globally as evident by the increasing number of regulatory frameworks and guidance documents. However, acceptance of RWE, especially before marketing for regulatory approval, differs across countries. In addition, guidance on the design and conduct of innovative clinical trials, such as randomized controlled registry studies, pragmatic trials, and other hybrid studies, is lacking.MethodsWe assessed the global regulatory environment with regard to RWE based on regional availability of the following 3 key regulatory elements: (1) RWE regulatory framework, (2) data quality and standards guidance. and (3) study methods guidance.FindingsThis article reviews the available frameworks and existing guidance from across the globe and discusses the observed gaps and opportunities for further development and harmonization.ImplicationsCross-country collaborations are encouraged to further shape and align RWE policies and help establish frameworks in countries without current policies with the goal of creating efficiencies when considering RWE to support regulatory decision-making globally.     

Hybrid clinical trials to generate real-world evidence: design considerations from a sponsor's perspective

Randomized controlled trials have traditionally been the gold standard for evaluating efficacy and safety of medical products and for regulatory decision-making. With the advancement of information technologies, vast amounts of data pertinent to patient health status and health care delivery are becoming available from a variety of real-world sources, including electronic health records, medical claims, patient registries, and patient-generated data. In 2016, the United States Congress passed the 21st Century Cures Act, mandating the U.S. FDA to establish a program to evaluate the potential use of real-world evidence (RWE) for regulatory purposes. In 2018, the FDA published the framework on its RWE program. One particular study type identified in the framework is the hybrid design – integration of a traditional randomized controlled trial with pragmatic design aspects to collect real-world data on patients. This design preserves the benefit of randomization, provides real-world outcome data while potentially accelerating product development and lowering the cost of data collection and patient follow-up. Here we focus on design considerations for hybrid trials to support regulatory decisions and provide a sponsor's perspective. While applicable to all medical products, we emphasize vaccine development where such hybrid designs are particularly useful given the low incidence rate of some vaccine-preventable clinical outcomes. We propose program strategies on how such hybrid designs may be integrated into a clinical development plan, illustrated by three examples. Major challenges are discussed and recommendations provided. Given the promise of hybrid designs and the challenges in implementation, we encourage proactive discussion with health authorities.     

Key considerations in the design of real-world studies

Randomized controlled clinical trials (RCTs) are the gold standard for evaluating the safety and efficacy of pharmaceutical drugs, but in many cases their costs, duration, limited generalizability, and ethical or technical feasibility have caused some to look for real-world studies as alternatives. However, real-world studies may be less convincing due to the lack of randomization and blinding. In this article, we discuss some key considerations in the design of real-world studies, which include experimental studies (e.g., hybrid or pragmatic clinical trials and non-randomized single-arm clinical trials with external controls) and non-experimental studies (e.g., cohort studies, cross-sectional studies, and case-control studies). Causal inference plays a critical role in the derivation of robust real-world evidence (RWE) from the analysis of real-world data (RWD). Therefore, we apply the hypothetical strategy, along with the concept of potential outcome, to lay out these key considerations, and we hope these considerations are helpful for the design, conduct, and analysis of real-world studies.     

A review and critique of published real-world weight management program studies

Background: Beyond the essential but somewhat artificial conditions that typify formal clinical studies, real-world evidence (RWE) of weight loss program effectiveness is paramount for an accurate assessment of such programs and refinement of best practices.

Objectives: To evaluate the current state of RWE studies and publications on weight loss, identify the range of weight loss components being used in RWE programs, and to provide a general overview of the consistency or lack of consistency with regard to measuring and reporting outcomes.

Methods: A structured search of PubMed was performed to identify relevant English-language publications from 2006 to December 2017 that reported real-world studies of weight loss among adults. Duplicates, non-relevant publications, articles on weight loss surgery, pediatric studies, randomized controlled trials, studies with self-reported weight loss, no objective weight measures, or that failed to include weight loss results were excluded.

Results: This review included 62 RWE publications. Forty-nine studies included dietary intervention, 37 included exercise, 29 included motivational counseling, and 5 contained some patients who had pharmacologic treatment as part of their weight loss regimen. The numbers of participants per study ranged from 10 to more than 3 million. The interventions reported in the publications included diet, exercise, counseling to promote diet and/or exercise, motivational counseling, and pharmacotherapy, and various combinations of these.

Conclusions: Despite general acceptance that weight loss programs are capable of facilitating successful outcomes, this review revealed substantial inconsistency in the design and reporting of such programs, making it very difficult to draw conclusions about the comparative merits of different real-world weight loss strategies/components. In addition, there was a marked lack of congruence with current weight loss management guidelines, and notably few studies incorporating anti-obesity medications. There clearly is a need for greater rigor and standardization among designing and reporting RWE weight-loss studies.     

Non-medical Switching from Originator Tumor Necrosis Factor Inhibitors to Their Biosimilars: Systematic Review of Randomized Controlled Trials and Real-World Studies

Tumor necrosis factor (TNF) inhibitors are widely used biologics for the treatment of several chronic inflammatory diseases. The launch of anti-TNF biosimilars has introduced the possibility of non-medical switching between originator biologics and their biosimilars. However, the potential clinical and patient-reported consequences of non-medical switching remain largely unknown, as much of the evidence comes from poorly or uncontrolled real-world evidence (RWE) studies that often have an element of bias and nonstandardized outcome measures. To appropriately evaluate the safety, efficacy, and immunogenicity of non-medical switching from an originator to its biosimilar, we propose that seven key study design elements should be considered when assessing the existing evidence: studies should be (1) randomized and double-blind, (2) adequately controlled, and (3) adequately powered; include (4) multiple switching, (5) an assessment of immunogenicity, and (6) adequate follow-up duration; and (7) report individual patient-level outcomes. This systematic review assessed the robustness and consistency of the current non-medical switching evidence, with a focus on TNF inhibitors. A comprehensive literature search (January 2012–February 2018) identified 98 publications corresponding to 91 studies (17 randomized controlled trials and 74 RWE studies) describing non-medical switching from a TNF inhibitor originator to its biosimilar. When assessing the totality of this evidence, none of the non-medical switching studies conducted to date were found to use all seven of the key design elements, and the absence of these elements dilutes the robustness of the data. Furthermore, discontinuation rates varied widely among studies (0–87%), suggesting heterogeneity and inconclusiveness of the current efficacy, safety, and immunogenicity evidence, particularly at an individual patient level. Therefore, patients should not be indiscriminately switched from an originator TNF inhibitor to its biosimilar for non-medical reasons. Switching decisions should remain between the treating physicians and their patients and be made on a case-by-case basis, relying upon robust scientific evidence.Funding: AbbVie.Plain Language Summary: Plain language summary available for this article.     

Ustekinumab in psoriatic arthritis: need for studies from real-world evidence

Ustekinumab (UST) is a recently approved drug for the treatment of psoriatic arthritis (PsA). The ACR response rates in randomized clinical trials (RCTs) with this drug have been slightly lower than that reported in RCTs of anti-TNF and anti-IL17 therapies. Therefore, the position that this drug may occupy in the treatment algorithms of PsA is not clear. More information is needed on the true efficacy of this agent under real clinical practice conditions. In this review of real-world evidence studies, it is shown that UST is effective and safe to treat PsA; nevertheless, it is necessary to homogenize the way in which the main outcomes and treatment objectives of these studies are presented.     

Practical considerations of utilizing propensity score methods in clinical development using real-world and historical data

In recent years, with the rapid increase in the volume and accessibility of Real-World-Data (RWD) and Real-World-Evidence (RWE), we have seen the unprecedented opportunities for their use in drug clinical development and life-cycle management. RWD and RWE have demonstrated the significant potential to improve the design, planning, and execution of clinical development. Furthermore, they can feature in the designs as either a substitute or compliment to traditional clinical trials. However, to utilize RWD and RWE appropriately and wisely, it is critical to apply rigorous statistical methodologies that enable the robustness of results to be characterized and ascertained. Several statistical methodologies including exact matching, propensity score methods, matching-adjusted indirect comparisons and meta-analysis have been proposed for analyzing RWD. Among them, propensity score method is one of the most commonly used methods for non-randomized trials with indirect comparison. Although massive methodologies and examples have been published and discussed since propensity score methods were introduced, systematic review and discussion of how to rigorously use propensity score methods in the practical clinical development is still deficient. This paper introduces commonly used and emerging propensity score methods with detailed discussions of their pros and cons. Three different case studies are presented to illustrate the practical considerations of utilizing propensity score methods in the study design and evaluation using real-world and historical data. Additional considerations including selection of patient populations, endpoints, baseline covariates, propensity score methods, sensitivity analysis and practical implementation flow in clinical development will be discussed.