电子数据采集：临床试验的未来之路

 电子数据采集（electronic data capture,EDC）可以提高临床试验效率、保障数据质量、缩短研究周 期、降低研究成本。随着互联网的普及和临床试验行业对EDC认识的提高,临床试验电子化趋势将不可避免。本文首先 介绍了临床试验数据管理的现状及EDC的概念,然后对应用EDC系统带来的益处和面临的困难进行了分析,最后对药品研 发者应用EDC系统提供了建议。     

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准确而迅速地采集数据对成功完成临床研究至关重要,是新药研发和上市过程中的关键因素。《电子数据采集对我国临床研究的机遇和挑战》一文介绍了电子数据采集(EDC)的局长历程和优势,探讨了我国临床研究行业面临的挑战和解决方案,分享了临床研究中使用EDC的经验,对提高我国的临床试验水平有一定借鉴意义。     

基于电子源数据到电子数据采集系统的数据直连模式在远程数字化临床研究的应用

本文概述了数字化远程智能临床试验开展现状,重点介绍了电子源数据(eSource)到电子数据采集系统(EDC)的建设思路、应用情况以及成本效率、数据安全、流程合规等多维度价值。与传统模式相比,eSource to EDC(E2E)模式利用电子源数据平台、电子数据采集、远程监查等系统的有效融合,做到更小化人工干预,系统性地提升临床研究效率和数据质量。在保证数据安全与个人信息隐私的前提下,实现数据和操作的有效监管,达到国内外相关法律法规要求,为进一步探索临床研究信息化转型提供参考依据。     

电子化患者报告结局在新药临床试验疗效评价中的应用

患者报告结局（PRO）作为临床结局疗效评价最重要的指标之一,被广泛用于新药临床试验。在新药临床试验电子化的趋势下,电子化患者报告结局（ePRO）数据采集系统基于其种种可以推进新药临床评价的优势,迎来了快速发展。然而,ePRO在中国仍然处在初期发展阶段,因此将对ePRO的基本概念、功能、国内外临床应用情况及其在新药临床试验疗效评价中的价值等进行介绍;同时总结概括了目前ePRO在我国临床试验应用中存在的问题,最后对ePRO在中国的发展前景进行了探讨。     

智能化临床试验数据整合与质量控制平台的研发与应用效果评估

目的构建智能化临床试验数据整合与质量控制平台(简称iTrial平台),以提升临床试验实施效率及数据质量。方法构建以患者为中心的全生命周期的标准化数据集(PHSR),根据具体试验方案配置以受试者为中心的全生命周期的标准化数据集(SHSR),打造便捷的人机结合模式(HCIM)的iTrial平台。以2个已完成的临床试验(test01和test02)的人工采集数据及其分析结果为对照,验证iTrial平台实现医院内部试验相关数据自动采集并录入电子数据捕获(EDC)系统及试验过程自动化质控的可靠性和优越性。结果 PHSR实现了患者全生命周期院内全量临床数据实时汇总,在此基础上构建的SHSR可提供的时间和数据维度远大于传统受试者原始病历临床数据库;根据2个临床试验真实案例配置的SHSR比较结果显示,基于iTrial平台的HCIM模式提升了临床试验数据录入效率和质量,在监查或稽查数据的时效性上优于人工监查模式,同时可以实现基于风险的稽查和全量数据稽查。结论依托患者PHSR配置SHSR,构建HCIM的iTrial平台,在采集和上报临床试验数据和辅助完成监查或稽查方面优势明显,可提升临床试验质量和效率。     

我国药品临床试验数据清理问题及对策研究

目的：分析现阶段我国药物临床试验数据清理存在的问题,在借鉴发达国家经验的基础上,提出我国药物临床试验数据清理的对策和建议。方法：采用文献检索和典型国家经验分析的方法。结果：我国在药品临床试验数据清理法律法规、监督管理以及高素质专业数据清理人才培养等方面亟待发展和完善。结论：应进一步完善药物临床试验数据清理法规;保障EDC系统内的数据安全;CRF设计方案应更加专业化;数据转换实现标准化;加大培养高素质专业化临床试验数据清理人才队伍的力度。     

最小随机化分组系统在多中心临床试验中的应用

最小随机化分组方法以其突出的组间例数和预后因素的均衡能力,受到越来越多新药临床试验研究人员的关注.但由于计算复杂,实施难度大,该方法一直未得到大规模推广应用.本研究结合自主开发的一套基于网络的最小随机化分组系统在随机对照双盲新药临床试验中的应用,讨论了该系统的优点和不足,希望能为同行提供借鉴,并促进最小随机化方法以及中心随机化系统在多中心新药临床试验中的应用.     

确证性临床试验中数据缺失的处理指南

数据缺失是确证性临床试验研究中不可避免的问题,如何正确处理数据缺失是影响临床试验结论客观性的重要因素。临床试验中的数据缺失主要表现为病例脱落,根据其机制可分为完全随机缺失、随机缺失和非随机缺失。通过完善病例分析、谨慎选择缺失值处理方法(如填补法和混合效应模型法)和进行敏感性分析等尽量减少数据缺失所致的试验结论偏倚。欧洲医药产品管理局就临床试验中的数据缺失问题制订了指导原则,现已正式发布并实施。本文以该指导原则为核心阐述临床试验中数据缺失的主要处理方法,旨在为国内新药研发和临床研究提供有益参考。     

大数据和人工智能技术用于计算机辅助药物设计的研究进展

大数据和人工智能（AI）技术不仅可以对海量的生物医学数据进行准确和综合地分析,而且可以帮助构建药物设计领域的预测模型。随着算法和统计方法的发展,大数据和AI技术已应用于计算机辅助药物设计（CADD）。CADD可被用于有效克服药物设计领域的困难,从而高效地设计和开发新药。介绍了药物设计和发现过程中数据预处理和建模步骤、药物设计和发现过程中基于AI的建模方法、大数据和AI技术在CADD中的最新应用,以期为我国药物设计和开发提供参考。     

支持抗肿瘤新药进入临床试验的非临床评价要点及关注问题

新药非临床评价的主要目的是决策新药能否进入临床试验。抗肿瘤新药非临床评价中的利弊权衡需考虑到肿瘤疾病及其药物应用特点。多数抗肿瘤药物常伴有严重的不良反应,其临床受试对象多为临床治疗效果较差或根本无有效治疗方法的病人。若新药具有有效性的优势或特点,潜在毒性风险小于疾病自身危险,此时是可以考虑接受新药进入临床试验。本文主要根据该思路对非临床研究中的药效学、毒性实验、药动学进行技术审评,对临床前研究结果的支持性或存在问题进行评价。此外,本文也较为详细讨论了非临床评价的考虑要点及其关注问题。     

电子数据获取:实现更加优质与高效的临床研究

电子数据获取（EDC）是临床研究中电子化的数据获取方式。基于网络的电子数据获取方式将成为今后临床研究数据获取的主要方式。采用EDC的源数据分为书面源数据和电子源数据,书面源数据的源数据核查（SDV）要求核实书面原始记录与电子病历报告形式（e-CRF）,电子源数据一般认为可以免除SDV,但需要以录入时的逻辑检查与稽查轨迹查证的方式核实。EDC的使用可提高临床研究的效率与数据质量,降低成本,帮助解决基于书面病历报告形式的临床研究的一些问题。     

Living without a data management system

The implementation of a typical electronic data capture (EDC) system for clinical trials - encompassing data entry, validation and reporting tools - involves modeling electronic case report forms (eCRFs) for data that will be entered by investigative trial sites, providing web access for the sites to enter the data, managing a 'cleaning and locking' process (in which any queries against the data are resolved), and transmitting the final data to SAS datasets. Other clinical data not included in CRFs, such as laboratory data, are typically handled in a separate clinical data management system; this information is not directly linked back to the trial sites and therefore is inaccessible for review. Thus, activities such as seeking site feedback on out-of-range laboratory values can only be performed by manually transcribing queries from the data management system into the EDC system. As the number of studies using EDC systems escalates and the number of studies gathering data on paper diminishes, the inefficiencies of handling data across different systems are becoming increasingly apparent. This article explores the opportunities, risks and technical requirements needed for an integrated EDC environment to enable a discontinuation of the use of older data management systems.     

Deficits on a spatial navigation task following prenatal exposure to ethanol

Performance on a Morris water task was examined in young rats whose mothers consumed a liquid diet consisting of 35% ethanol-derived calories (EDC) during pregnancy. Offspring of pair-fed (0% EDC) and ad lib lab chow (LC) dams served as controls. Rats were required to find a platform submerged below the surface in a pool of opaque water. A trial ended when the rat remained on the platform for 15 sec, or had been in the tank for 180 sec without reaching the platform. Subjects received 5 trials daily for 3 consecutive days, followed by reversal training on Day 4. Groups did not differ in swimming ability. On Day 1 there were no group differences among females in latency to reach the platform or in distance traveled, but male 35% EDC and 0% EDC animals had shorter latencies than LC controls. On Day 2, latencies and distance traveled of LC and 0% EDC controls decreased while 35% EDC animals showed no change from Day 1, so that alcohol-exposed rats took longer to reach the platform and traveled a greater distance than controls. On Day 3, 35% EDC females took longer than controls to reach the platform, and 35% EDC animals of both sexes traveled a greater distance than controls. Search patterns on the first reversal trial on Day 4 suggest the differences are in spatial processing and not learning per se, but more so in alcohol-exposed males than females. The impaired performance on this task suggests that prenatal alcohol exposure alters the ability to process spatial information.     

临床试验CRF表-全息数据库-统计批处理“联姻”模式初报

目的:探讨临床试验CRF表-全息数据库-统计批处理"联姻"模式。方法:按纸版CRF表建立电子CRF表,并加载库操作程序和近10个常用统计模块,进而构成全息数据库。结果:以上海某大型临床试验资料作为本数据库试验运行之素材,共处理数据元约11万个,做出统计判断约1000份,调用统计工具8种,转换数据类型约10余次,运行时间仅半小时,出具大型试验综合性报告2份,统计归纳报告20余份。结论:此举既可作为电子数据获取系统EDC的应用过渡,也是EDC全面推广的前期实践。     

Neuroendocrine impacts of endocrine-disrupting chemicals in birds: life stage and species sensitivities

Assessing potential risk associated with exposure to endocrine-disrupting chemicals (EDC) has been difficult due to species specific variation in vulnerability and to both short- and long-term effects produced by EDC. In precocial birds, embryonic exposure to EDC impacts sexual differentiation of neuroendocrine systems and behavior. Often, detectable nonlethal effects of EDC diminish as the organism matures such that the chronic impact of EDC may appear relatively innocuous by the time an individual is sexually mature. In addition, studies have not addressed lifetime effects of EDC exposure on birds. Consequently, it is difficult to assess chronic effects of nonlethal exposure on the fitness of an individual and whether there is a potential risk to a wild population. Assessing behavioral and neuroendocrine consequences of exposure is complicated by individual and species variation in sensitivity as well as exposure to complex mixtures. Our studies are designed to examine effects of individual EDC administered to the embryo as well as in a multigenerational dietary study in which birds received low doses of the pesticide methoxychlor (MXC). The influence of dietary MXC exposure was also compared between Japanese quail and northern bobwhite quail. The effects of dietary exposures to 0.5, 5, or 10 ppm that are relatively environmentally low were determined. The selection of these doses was to mimic levels that might be encountered in the field and higher doses that might potentially reveal effects of exposure at relatively low exposures. These doses were also based on the regulations by the U.S. Environmental Protection Agency that mandate a limit 0.04 ppm MXC in drinking water, with a limit of no more than 0.05 ppm in water that children drink. Further there is a limit of 1-100 ppm for crops and other food for human and livestock consumption; bottled water has a 0.1 ppm limit for MXC content. Our data are discussed in the context of applicability of toxicological yardsticks, including the toxic equivalent (TEQ) and neurotoxic equivalent (NEQ) as predictive indices for short- and long-term outcomes to nonlethal concentrations of EDC. Other approaches have been developed to address inconsistencies in effects and incorporate diverse data into potency estimates. Perhaps it is time to develop a more inclusive estimation method for endocrine and neuroendocrine effects. An endocrine disruption index (EDI) would (1) complement other indices, (2) focus on endocrine disruption, and (3) include effects beyond those mediated by the aryl hydrocarbon receptor (AhR) for a comparative assessment of nonlethal EDC effects.     

Reaction of carbodiimide for the introduction of p-bis(2-chloroethyl)amino-L-phenylalanine to lysozyme

In the synthesis of new prodrugs with inhibitoring action of tumour growth, a new nitrogen mustard derivative was obtained, proceeding of the coupling between an egg-white lysozyme with an antitumor amine nucleophile, the methyl ester of p-bis-(2-chloroethyl)amino-L-phenylalanine (Melphalan), catalyzed by 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide (EDC), at pH 5.0 and room temperature. In that case, the mechanism for the modification isn't selective of Asp101 in lysozyme. As in cases of histamine and D-glucosamine [3], it is evident that Melphalan is one type of amine who doesn't cause a selective modification of Asp101 but causes somewhat random reaction, because Asp101 is modified followed by modifications of other carboxyls. In this case, we suggest that the amine (Melphalan) may also bind to the substrate binding site in competition with EDC. With this type of amine, enzyme-nucleophile interactions predominate, and the selective activation of Asp101 by EDC is reduced to lead a more random reaction.     

Pharmacokinetics and macromolecular interactions of ethylene dichloride in rats after inhalation or gavage

Ethylene dichloride (EDC) induces tumors in rats and mice when administered chronically by gavage. However, chronic inhalation of EDC vapor failed to induce any treatment-related tumors. To help understand the consequences of environmental exposure to EDC by either route, [¹⁴C]EDC was administered to male Osborne-Mendel rats by gavage (150 mg/kg in corn oil) or inhalation (150 ppm, 6 hr). EDC was extensively metabolized following either exposure. No significant differences were observed in the route of excretion of nonvolatile metabolites. In each case, ～85% of the total metabolites appeared in the urine, with 7 to 8, 4, and 2% found in the CO₂, carcass, and feces, respectively. The major urinary metabolites were thiodiacetic acid and thiodiacetic acid sulfoxide, suggesting a role for glutathione in biotransformation of EDC. Gross macromolecular binding (primarily protein binding) was studied after inhalation or gavage. No marked differences were noted between the two routes, or between “target” and “nontarget” tissues, after in vivo administration of EDC. Covalent alkylation of DNA by EDC was studied in Salmonella typhimurium and rats. DNA alkylation in S. typhimurium was directly related to the frequency of mutation in these bacteria. However, when DNA was purified from the organs of rats exposed in vivo to EDC, very little alkylation was observed after either gavage or inhalation (2 to 20 alkylations per million nucleotides). DNA alkylation after gavage was two to five times higher than after inhalation, but no marked differences were noted between target and nontarget organs. Pharmacokinetic studies indicated that peak blood levels of EDC were approximately five times higher after gavage than after inhalation. When pharmacokinetic data were modeled, it appeared that the elimination of EDC may become saturated when high blood levels are produced and that such saturation is more likely to occur when equivalent doses are administered by gavage versus inhalation. Since toxicity often occurs when the normal detoxification pathways are overwhelmed, this toxicity may represent the most reasonable explanation for the apparent differences between the two bioassays.     

Neuropeptides and enzymes are targets for the action of endocrine disrupting chemicals in the vertebrate brain

Endocrine-disrupting chemicals (EDC) are molecules that interfere with endocrine signaling pathways and produce adverse consequences on animal and human physiology, such as infertility or behavioral alterations. Some EDC act through binding to androgen or/and estrogen receptors primarily operating through a genomic mechanism regulating gene expression. This mechanism of action may induce profound developmental adverse effects, and the major targets of the EDC action are the gene products, i.e., mRNAs inducing the synthesis of various peptidic molecules, which include neuropeptides and enzymes related to neurotransmitters syntheses. Available immunohistochemical data on some of the systems that are affected by EDC in lower and higher vertebrates are detailed in this review.