如何利用真实世界证据(Real-world evidence,RWE)评价药物的有效性和安全性,已成为国内外药物研发和监管决策等方面共同关注的热点话题.真实世界研究(Real-world research/study,RWR/RWS)不同于临床实践,作为临床研究的一种类型,仍须基于医学伦理并科学开展,保护受试者权益仍是重中之重.知情同意是保障受试者权益的重要路径,做好知情同意非常关键.传统的知情同意方式在开展RWR/RWS过程中可能会导致招募困难或选择偏倚而降低研究结果的普适性,因此作者结合RWR/RWS的实际特点,探讨了在RWR/RWS范式下的知情同意方式的相关问题.

在中医药发展的新时代背景下,强化中医专业硕士研究生中医药临床科研思维,提升临床科研能力是推动中医药传承创新的基石.中医药临床试验设计与方法作为中医药临床与科研的衔接课程,对学生临床科研能力的提升有着重要作用,课程教学质量关系到学生今后进入临床开展临床科研的能力.教学组2013-2020年来结合临床实践,通过设置合理的教学内容,采用多元化的教学方法,注重培养学生科研思维,使之初步掌握中医临床研究的科研思路、基本原则和方法,为学生今后走入工作岗位开展临床和科研工作打下良好的基础.

目的 探讨基于临床数据获取协调标准(CDASH)的中医药临床试验病例报告表(CRF)的设计原则、方法及内容.方法 对照最新版CDASH v 2.0,结合中医药临床试验数据特点,设计符合中医药临床试验实际需求的标准化CRF.结果 将CDASH引入中医药临床试验CRF的设计中,规范中医药临床试验数据采集字段和变量,达到CRF设计的标准化,提高数据质量的目的.结论 执行CDASH进行中医药临床试验CRF设计,可以促进中医药临床研究数据的交换与共享.

目的 观察珍枣胶囊对阴虚火旺型老年失眠患者的血清MT、NE及睡眠时相的影响,并探讨珍枣胶囊治疗失眠的有关机制.方法 按照纳入标准及排除标准,选取将50例老年失眠患者按照随机、单盲的方法分为治疗组和对照组,4周为一个观察周期,分别在治疗前后检测患者的血清MT、NE水平和多导睡眠图检测,进行比较分析.结果 珍枣胶囊组患者经治疗后血清MT水平较前升高(P<0.01),且优于对照组(P<0.05);NE水平较前均有下降(P<0.01),优于对照组(P<0.05);治疗组睡眠总时间(P<0.05)、深睡眠时间延长(P<0.05),睡眠潜伏期时间缩短(P<0.05).结论 珍枣胶囊能够增加MT分泌,抑制中枢神经递质-NE释放,改善失眠;并可通过延长睡眠总时间、深睡眠时间,缩短睡眠潜伏期时间进一步优化睡眠结构,改善睡眠症状.

目的: 观察益肾清利和络方颗粒剂治疗慢性肾脏病3 期的临床疗效.方法: 采用随机双盲对照的研究方法,选择2014 年4 月～2016 年8 月江苏省中医院门诊和住院患者随机纳入观察组和对照组,观察组给予西医基础治疗+益肾清利和络方颗粒剂,对照组给予西医基础治疗+益肾清利和络方颗粒安慰剂,随访24 周,比较两组间实验室指标和疗效.结果: 共纳入88 例,观察组和对照组各44 例,两组患者的年龄、性别、病程、血压、尿蛋白定量、肾功能、肝功能差异无统计学意义(P>0. 05).观察24 周后,观察组血肌酐水平显著低于对照组(P<0. 05),观察组总有效率为69. 23％,对照组为35. 90％,组间差异有统计学意义(P<0. 05),且观察组总体及3a、3b 期逆转恢复率显著高于对照组(P<0. 05).结论: 益肾清利和络方可降低血肌酐升高速率,延缓慢性肾脏病3 期进展.

Along with the increase of clinical application,the safety of traditional Chinese medicine gained more and more attentions.In particular,the safety evaluation of Chinese medical injections has become a mandatory task should be completed by pharmaceutical companies under the supervision of China Food and Drug Administration (CFDA).Due to the weak foundation of previous studies,the safety issues of Chinese medical injections have not been fully understood,and lack of scientific and rational risk management programs.Clinical safety centralized monitoring(CSCM) is an important method for post-market safety evaluation of Chinese medicine.Due to the lack of appropriate norms and procedures,the quality of similar research is uneven,and the results vary.Combined with practical experience with experts' suggestions,we developed this expert consensus on the design and implementation of CSCM from three stages (design,implementation and report) with 20 technical points,which will provide technical support for future CSCM studies.

笔者通过分析开展大数据时代中医药临床研究的必要性及存在的困难,探讨利用计算机信息化手段,以就诊患者为对象,以临床数据为导向,以解决临床实际问题为出发点,建立基于中医结构化电子病历的大数据管理体系,利用数据挖掘的理念与方法,构建基于临床大数据真实世界的中医药临床科研模式,评价并分析所有专科专病中医药的疗效,为达成中医专科专病治疗方案的共识,形成中医专科特色,解决临床关键问题提供有效的科研模式.

Problems revealed by verification of bioequivalence trial data for authenticity, integrity and standardability were sorted and summarized. By analyzing their causes, relevant countermeasures were put forward as reference for bioequivalence clinical trials.

OBJECTIVES:To assess the safety and tolerance of healthy volunteers to as tragalosides injection (AGI), and to determine a safe dose range for phase II clinical trial.METHODS:A total of 62 healthy volunteers participated in this study, with 26 being given a single AGI of 100 mL, 200 mL, 300 mL, 400 mL, 500 mL, or 600 mL and 36 subjects being given 500 mL, 400 mL, 200 mL or 300 mL of AGI once a day for 7 d. Discomfortsymptoms, vital signs and safety problems were recorded 3 d and 7 d after the administration of AGI. The results were analyzed.RESULTS:Of the 62 participants, 40 adverse events (AEs) were reported by 31 participants, which included 23 mild adverse reactions (ADRs) and 4 moderate ADRs. Nine AEs were reported by 9 participants with single AGI, including 7 ADRs. Fourteen AEs were reported by 10 participants with 500 mL and 400 mL multiple AGI, including 12 ADRs occurred in 9 participants.Seventeen AEs were reported by 12 participants with 300 mL and 300 mL multiple AGI, including 3 mild ADRs. The main ADRs included abnormal liver function [slightly elevated glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST),and serum total bilirubin (TBil)], low blood potassium, increased urine red blood cell count, rash, and phlebitis.CONCLUSIONS:The maximum tolerance is 600 mL for single-dose treatment, and 400 mL for multiple-dose (7 d). The dose guidance given in this study should be examined its effects and safety in patients with coronary heart disease in phase II clinical trial.

Objective: To investigate the tolerance and preliminary safety of Cicada mycelium capsule in human body. Methods: According to the results of animal experiments, initial and maximum doses were calculated to carry out the single and cumulative tolerance tests. Trials involved 46 healthy human subjects, including 34 cases for single dose tolerance test in 6 dose groups, respectively, taking 3 (330 mg/capsule), 6, 12, 18, 24 or 30 capsules; and 12 cases for cumulative (multiple dosing) tolerance test in 2 dose groups, respectively, taking 8 or 10 capsules/time, 3 times daily for seven days. Clinical symptoms, vital signs and physical and chemical inspection index were observed. The SAS 9.13 statistical software was applied for data processing. Results: For the 46 subjects tested, a total of six cases of adverse events happened, in which 2 cases were judged on the relation with the experimental drug as impossible, 4 cases were judged as suspicious. The adverse reactions were mainly weak positive fecal occult blood, moderately elevated urine MDI red blood cell count, moderately elevated urine red blood cell count or cheek red papules. Conclusion: The maximum tolerated single dose of Cicada mycelium capsule is 30 capsules; the multiple dosing is 10 capsules/time, 3 times a day. The recommended phase Ⅱ safe dose range for clinical trials is 24-30 capsules per day. In phase Ⅱ and Ⅲ clinical trials, observation of adverse reactions is recommended.

目的 考察人体对派能达胶囊(人参二醇组皂苷提取物,40 mg/粒)的耐受性和初步安全性,为该药Ⅱ期临床试验提供安全的剂量范围.方法 选择健康人为受试对象,顺序开展单次给药耐受性试验和累积性耐受性试验.单次给药耐受性试验42例,7个剂量组,分别为1、2、4、8、12、16、20粒,每日1次给药.累积性耐受性试验12例,2个剂量组,分别为每次5粒和每次6粒,每日2次给药,连续7d.观察指标为临床症状、生命体征和安全性指标等,采用SAS 9.13统计软件进行统计学处理.结果 54例受试者其中19人出现28次轻度不良反应.本试验单次给药16粒剂量组6人中出现1例轻度不良反应,单次给药20粒剂量组6例均出现轻度不良反应;多次给药12粒剂量组6人均出现轻度不良反应,10粒剂量组未出现不良反应.不良反应主要表现为牙龈出血、失眠、口干、出汗、体温轻度升高、血清总胆红素升高、血清甘油三酯偏高等.结论 单次给药最大耐受量为640 mg(16粒),多次给药安全剂量为400 mg(10粒/d×7 d),推荐Ⅱ期临床试验的安全剂量范围为每日6～ 10粒,建议在Ⅱ、Ⅲ期临床试验中注意对不良反应的观察.

目的:考察人体对南五味子软胶囊的耐受性和初步安全性,为该药Ⅱ期临床试验提供安全的剂量范围.方法:选择健康人为受试者,依据动物实验结果推算初始及最大剂量,从安全的初始剂量开始,顺序开展单次给药耐受性试验和累积性耐受性试验.共纳入36例受试者,其中单次给药耐受性临床试验24例,5个剂量组,分别为1(含南五味子木脂素提取物132mg g)、2、3、4、6粒,每日1次给药.累积性(多次给药)耐受性试验12例,2个剂量组,分别为4粒/次和3粒/次,每日1次,连续给药7天.观察指标为临床症状、生命体征和理化检查指标等,采用SAS 9.13统计软件进行统计学处理.结果:36名受试者共发生15例次轻度不良反应,主要表现为:血清白/球蛋白(A/G)轻度下降、CD3+、CD4+、CD8+降低,大便隐血弱阳性,血清总胆红素升高,血AST轻度升高,血Cl-降低,等.结论:南五味子软胶囊Ⅰ期临床试验最大耐受剂量单次给药为4粒/日,多次给药为3粒/日.推荐Ⅱ期临床试验的安全剂量范围为每日3粒,建议在Ⅱ期临床试验中注意对不良反应的观察.

目的 通过观察冠心平治疗冠状动脉粥样硬化性心脏病(CHD,简称冠心病)心绞痛患者超氧化物歧化酶(SOD)、过氧化脂质(LPO)、超敏C反应蛋白(hs-CRP)和谷胱甘肽过氧化物酶(GSH-Px)水平以及心绞痛症状和心电图等疗效指标的改变,评估冠心平治疗CHD心绞痛的临床疗效,探索其抗氧化、抗炎症反应功能的作用机制.方法 选择120例符合条件的CHD心绞痛患者,应用随机数字表法分入治疗组和对照组各60例.治疗组基础治疗加用冠心平片,每次4片,每日3次;对照组基础治疗加用心可舒片,每次4片,每日3次.2组均连续服药4周,为1个疗程.观察CHD心绞痛患者临床症状、心电图和综合疗效及血浆SOD、LPO、hs-CRP、GSH-Px治疗前后水平变化.结果 2组CHD心绞痛患者在CHD的临床症状总有效率和综合疗效方面,治疗组改善更显著,P＜0.05.2组患者心电图、心绞痛疗效、发作次数及持续时间均较治疗前改善,P＜0.05;治疗后2组比较,P＜0.05.2组患者治疗后血浆SOD、GSH-Px水平均较治疗前升高,2组比较,P＜0.05;2组患者治疗后血浆LPO、hs-CRP水平下降,2组比较,P＜0.05.结论 冠心平对CHD心绞痛患者的中医临床症状改善明显,缩短了心绞痛发作持续时间、减少了发作次数,提高了心电图疗效,临床疗效显著;其治疗机理可能是通过提高CHD心绞痛患者血浆SOD、GSH-Px水平以及降低血浆LPO、hs-CRP含量,而发挥保护其抗氧化、抗炎症反应功能,进而达到治疗CHD的作用.

目的 通过观察珍枣胶囊治疗老年阴虚火旺型失眠患者中医临床症状的变化以及血浆5-羟色胺(5-HT)、多巴胺(DA)含量的改变,评价其临床疗效,并探究其作用机制.方法 将60例符合失眠诊断标准以及阴虚火旺证中医辨证标准的原发性失眠患者,按照随机分组、单盲以及平行对照的方式,分为治疗组和对照组各30例.治疗组患者睡前0.5h服用珍枣胶囊,每日1次、5粒/次,对照组患者睡前0.5h服用舒眠胶囊,每日1次、5粒/次.各组均连续服药4周为1个疗程,每7天复诊1次.观察时间为1个疗程.观测治疗前后血浆5-HT和DA水平的变化;并对2组患者的临床疗效以及中医证候疗效进行评定.结果 2组老年阴虚火旺型失眠患者改善失眠的临床疗效相当,P＞0.05;但在改善中医证候疗效方面,治疗组改善更明显,与对照组比较,P＜0.05.2组患者治疗前后相比,5-HT水平皆提高且DA含量皆降低,治疗组调节幅度优于对照组,P＜0.05.结论 珍枣胶囊改善了老年阴虚火旺型失眠患者的中医临床症状,临床疗效显著;其治疗机理可能与提高5-HT水平以及降低DA含量有关.

目的 改进中医临床科研机制,提高医院中医临床研究水平;方法 梳理中医医院临床研究体系中存在的问题;根据中医临床医学的规律和医院的特点,调整学科整体布局;并围绕核心规章制度,将标准操作规程(Standard Operating Procedure,SOP)以及现代信息化技术引入科研管理;建立以需求为导向,围绕研究方向建立研究模式;整合资源,搭建高水平科研平台;采用灵活的研究型临床人才机制.探索创新完善中医临床研究机制及科研管理机制;结果 通过机制的完善,使学科能够发挥整体效应,高效利用资源,使我院的中医临床研究取得了明显的成效.结论 机制的创新和完善,对促进中医临床研究,推动医院建设发展能够起到重要的作用.

How to promote the standardization of new drug clinical researches and guarantee the authenticity and scientificity of the results of clinical studies,is currently the focus of quality management of new drug clinical trials.In this paper,authors summarized the working experience of clinical trial project management in recent years from the points of laws and guide learning,project evaluation,work team creating, implementation training,original data recording,quality control,the use of research coordinator,the management of test drug and so on.

In this study, 4116 traditional Chinese medicine(TCM) prescriptions of 994 outpatients of gastric cancer from the Jiangsu Provincial Hospital of Traditional Chinese Medicine were analyzed with the use of Clinical Research Information Sharing System and the data mining method of scale- free networks. The core drugs and compatibility were visually displayed on diagrams which revealed the characteristics of gastric cancer treatment with TCM prescriptions in this hospital with high credibility. This method has certain meaning and value for the study of TCM prescriptions.

Scientific review,time schedule of ethical review,standards of review,the compensation for injuries of subjects in clinical research and the relation between the ethical review and scientific integrity are common issues in ethical review of clinical research.This paper had an in-depth discussion on issues mentioned above.The international rules were referred and the personal suggestions were also provided for the reference in further discussion.

如何执行方案、保证临床试验的质量是困扰研究管理人员的难题。中药Ⅱ、Ⅲ期临床试验的数据管理可以分为两个阶段:一是源数据的现场管理,二是数据报告后的管理。执行方案的关键环节之一是设计一份完整、良好的中药Ⅱ、Ⅲ期临床试验执行文件。执行方案的另一个关键环节是源数据的现场管理。采用计算机系统,基于医疗流程,设计一份电子源文件(病历),将数据管理前移,实现对中药Ⅱ、Ⅲ期临床试验源数据的现场管理,将大大提高法规的依从性与研究方案的执行力,保证新药临床试验的质量,提高临床研究结果的科学性,为中药临床试验研究真实性提供循证医学证据。

Objective:Research the effect of Guanxinping on TCM symptoms of coronary heart disease(CHD),ECG,blood lipids(TC,TG,HDL-C,LDL-C),anti-oxidative stress indexes(SOD,GSH),and the association between them before and after treatment,then evaluate the mechanism of its improvement of CHD endothelial dysfunction(EDF)and the clinical effect.Methods:By using random,blind,parallel control,and independent evaluation clinic research methods,160 patients of Angina Pectoris were enrolled and randomly divided into 2 groups:the treatment group and the control group,80 patients in each group.Based on routine therapy,Guanxinping was added in the treatment group,4 pills for each time by 3 times a day.While Xinkeshu Tablet was added in the control group,4 pills for each time by 3 times a day.Each group was continuously treated for 4 weeks as a course,and patients were asked to return visit every 7 days.Observation time lasted for a course.Effect of comprehensive therapy to Angina Pectoris,effect of clinical symptoms,effect of ECG,and content variation of TC,TG,HDL-C,LDL-C,SOD,GSH before and after treatment were observed.Results:Compared with the control group,the treatment group had a better improvement of comprehensive therapeutic effect and total effective rates(P0.05).After treatment,TCM symptoms such as thoracic stuffiness,palpitation,short breath,weakness and tiredness,tongue picture and pulse condition in both groups had been improved(P0.05),and compared with the control group,the treatment group was better(P0.05).All patients' ECGs revealed ST segment depression,T wave low-flat and inversion were some corrected after treatment(comparing with pre-treatment,P0.05),but there was no statistical significance between the two groups(P0.05).Levels of TC and LDL-C in both post-treatment groups decreased significantly(P0.05),which were even lower in the treated group than those in the control group,and the decreasing trend was significantly different(P0.05).Level of TG in the treated group had a decreasing trend,but no statistical significance between pre and post treatment(P0.05).Level of TC in control group had a rising trend after treatment(comparing with pre-treatment,P0.05),which was better in the treatment group than that in the control group.Levels of HDL-C,SOD and GSH in both groups had a rising trend after treatment,compared with pre-treatment there was no significance for HDL-C(P0.05),while for SOD and GSH there were significances(P0.05),but levels of SOD and GSH in control group was opposite to the treatment group,the decreasing trend also had no significance(P0.05).There was significant difference of all indexes between two groups(P0.05),which was better improved in the treatment.Conclusion:For Angina Pectoris,Guanxinping can obviously improve the TCM symptoms,ECG expression,blood lipid and anti-oxidative stress indexes.Probably by regulating blood lipid metabolism,anti-oxidation,etc,Guanxinping could protect VEC,improve EDF,and then treat CHD.It may be the therapeutic mechanism,and offer molecular biology basis for further interpretation to mechanism of treating CHD according to TCM syndrome differentiation.