中国临床试验注册中心建成并运行

[本刊讯]据《中国循证医学杂志》2007年第7期报道,2007年5月,世界卫生组织国际临床试验注册平台(World Health Organization International Clinical Trial Registration Platform,WHO ICTRP)正式运行,澳大利亚-新西兰临床试验注册中心(Australian and New Zealand Clinical Trials Registry,ACTR),美国国立医学图书馆临床试验注册中心(National Library of Medicine)(Clinical Trials.gov),英国国际标准随机对照试验号注册库(International Standard Randomised Controlled Trial Number Register,ISRCTN)成为首批一级注册机构.

急性心肌梗死介入治疗进展

血栓形成确认为急性心肌梗死的病理基础后，80年代起再灌注治疗开创了急性心肌梗死（AMI）治疗的里程脾。多项临床试验证实静脉溶栓治疗显著降低了心肌梗死（MI）的死亡率，大大改善了心肌梗死患者的预后。然而，静脉溶栓治疗仍有不足之处，如能接受溶栓治疗的患者仅1/3，血管再通率只有60％～80％，而实际上溶栓后梗死相关血管冠状动脉造影达TIMI 3级血流（即完全再灌注）的仅50％～55％，TIMI 2级血流（即部分再灌注）虽达再灌注标准，但并不降低死亡率，Anderson等报告90min梗死相关血管达TIMI 3级血流者30d死亡率才降低（3.7%），而部分再灌注TIMI 2级的死亡率和血管未灌注者一样（TIMI 2级和TIMI 0/l级的死亡率分别为7％和8％）［1］。溶栓治疗患者还要冒出血，特别是颅内出血的风险。 80年代初，Hartzler等首先报道直接经皮冠状动脉腔内成型术（PTCA）的机械再灌注代替药物溶栓治疗急性心肌梗死取得了良好效果［2］，然而，对急性心肌梗死急诊PTCA治疗长期以来一直存在争议，但经过大量随机临床对比研究，与药物静脉溶栓比较，直接PTCA在增加血管再通率，降低死亡率，减少再梗死及出血并发症方面确实优于溶栓治疗。AMI急诊PTCA近年来已逐渐广泛应用于临床。AMI时机械再灌注方法按其目的和进行时间分为直接、补救性、立即和延迟PTCA。1 直接PTCA 直接PTCA指急性心肌梗死不采用药物溶栓而直接进行PTCA。直接PTCA登记(The Primary Angioplasty registry，PAR)［3］包括6个中心，271例AMI，发病12h内行直接PTCA，成功率(达TIMI 3级血流及残余狭窄＜50％)高达92％，死亡率4％，再梗死3％及卒中1%，效果相当满意。Weaver等［4］综合分析13项临床试验比较AMI溶栓和直接PTCA结果，出院时或30d直接PTCA降低死亡相对危险性34％，死亡+非致命性再梗42％以及非致命性再梗47%，绝对危险性分别降低21％，4.6％和24％。GUSTO-IIb［5］比较t-PA溶栓与直接PTCA治疗AMI的效果，AMI发病时间分别为18和19h，但开始治疗时间PTCA比溶栓延迟了50min。直接PTCA组TIMI 3级血流达80％，并显著降低了30d死亡率、再梗或非致命性卒中的发生率。但PTCA的益处随时间的延长而减少，6个月的死亡率两者无显著差异（PTCA为14.1％，t-PA为16.1％），非致命性再梗也无减少。 急性心肌梗死合并心源性休克常规治疗死亡率高，平均为70％［6］。溶栓治疗未能明显降低死亡率［7］。近年报道机械性再灌注治疗降低心源性休克死亡率。1995年公布的一组251例心源性休克的前瞻性登记资料，急诊血管重建组和保守组死亡率分别为51％和85％［8］。1999年公布多中心随机研究休克结果，302例AMI伴心源性休克患者随机分为6h内血管重建（PTCA或冠状动脉搭桥术）和药物溶栓组，两组均应用主动脉内球囊反搏（IABP）。结果显示30d死亡率两组无差别，但6个月死亡率在早期血管重建组（50.3％）显著低于药物治疗组（63.1％,P＜0.05）。30d早期直接PTCA成功者的死亡率（33％）显著低于不成功者（79％，P＜0.01）。故对AMI合并心源性休克者提倡早期血管重建治疗。 直接PTCA也存在一些问题，如延长了再灌注时间，梗死相关血管病变复杂（夹层、痉挛或血栓），技术设备条件要求高，还需要一组能行直接PTCA的高技术。随时应召的队伍以及价格昂贵等。即使在美国，能实施每天24h行急诊PTCA的医院不到10％。目前推荐AMI首选直接PTCA的适应症是：①溶栓禁忌；②高龄（＞70岁）；③心功能Killip 3级及心源性休克；④既往MI史或冠状动脉搭桥术（CABG）史；⑤梗死部位在左前降支（LAD）近端。

How to design clinical trials for medical devices is a problem plaguing the industry today. As there are many differences in clinical trials of medical devices and drugs. This paper describes the differences of the two points from the perspectivs of defi-nition of medical devices and drugs, scope, phasing, subjects and design of clinical trials in details, aiming to help the related personnel make scientific decisions while conduct-ing clinical trial design for medical devices.

IMMPACT推荐的慢性痛临床治疗转归的测量方法

1.概述许多慢性痛病人并没有从现有治疗中得到适当的缓解,甚至还要承受药物副作用的折磨.当临床治疗宣布正性转归时,这些治疗措施是否真的具有长远利益也并不知晓.因此,努力开创更好的治疗手段以获得更佳的治疗效果乃是疼痛研究者的当务之急.由于不同的临床过程采用不同的预后评测指标,因而妨碍了对治疗效果的评价.针对这一情况,IMMPACT(Initiative on Methods,Measurement,and Pain Assessment in Clinical Trials)近推荐了六项评价治疗转归的核心内容,包括:(1)疼痛状况;(2)躯体功能;(3)情绪状态;(4)被试者对治疗效果和满意度的评分;(5)异常症状和意外事件;(6)被试者的选择和安排.

设计决定成败——来自国际大型临床试验的经验和教训

与过去的几年相比,逝去的2010年对于全世界的糖尿病医生和患者是极为不平静的一年.糖尿病控制心血管危险行动(ACCORD)研究[1]的意外发现、那格列奈和缬沙坦治疗在糖耐量受损人群的预后研究(NAVlGATOR)[2-3]中降血糖药物那格列奈在糖尿病预防中的不作为……每一条、每一款都让人感到莫名其妙的云遮雾绕.为数不少缺乏长期临床实践磨练的医生在治疗中感到犹豫和茫然,许多糖尿病患者让媒体惊人的标题新闻弄得不知在多大程度上该相信医生.这和前几年言之凿凿的证据给人们的鼓舞大相径庭,也和某些靠跟着感觉走治病多年的老医生的自我感觉相去甚远,于是甚至有人开始不再相信循证医学的神圣.

临床试验的里程碑事件

2007年5月,世界卫生组织国际临床试验注册平台(World Health Organization International Clinical Trial Registration Platform,WHO ICTRP)正式运行,澳大利亚-新西兰临床试验注册中心(Australian and New Zealand Clinical Trials Registry,ACTR),美国国立医学图书馆临床试验注册中心(National Library of Medicine)(ClinicalTrials.gov),英国国际标准随机对照试验号注册库(International Standard Randomised Controlled Trial Number Register,ISRCTN)成为首批一级注册机构.

China and clinical research in international nephrology

"China has the opportunity to lead the world not only in research quantity, but also in quality" Lancet has affirmed[1].There is no reason to exclude the possibility that the above authoritative prediction could be applied to the research in Nephrology.However, how to comply with this goal? Methodologically rigorous randomized controlled trials have the ability to address relevant research questions on safety and efficacy of new interventions.Indispensable conditions for successful conduct of clinical trials rely on the two major principles on which Good Clinical Practice is based[2]: One is strict ethical rules to safeguard the rights and safety of patients and another is high level of validity and credibility of trial data.However, absence of formal training in research ethics and methodology for investigators, reduced time for research activities, lack of adequate infrastructures, bureaucratic limitations and poor financial resources still represent major barriers to the successful performance of high quality randomized controlled trials[3].

乳腺癌手术前后化疗对手术次数和范围影响的随机临床试验研究

乳腺癌术前化疗正在广泛地用于临床.研究表明行术前化疗的乳腺癌患者其存活率与行术后化疗的相同.但是手术前化疗有其优势:它可以在体内评估肿瘤对化疗的反应,提高保乳术率且不增加局部复发的危险.

美国重症肌无力基金会关于重症肌无力临床试验的建议

由美国重症肌无力基金会(MGFA)的医学科学建议委员会(MSAB)组成工作组,于2010年在美国和2011年在意大利召开专家共识会议讨论重症肌无力(MG)临床试验的问题,与会代表包括来自美国和欧洲的神经科医生、统计学家、企业界代表、MG患者以及MGFA和欧洲重症肌无力协会的平民代表.会议总结以往的MG临床试验存在的问题包括:(1)大多数试验入组患者的病情发展较预期明显缓慢;(2)单独使用泼尼松改善肌无力症状的疗效可能比预期明显,所以较难发现联用免疫抑制剂而产生的疗效;(3)为减少激素剂量,大多数的临床试验时间过短,难以发现疗效;(4)入组标准太窄,在结果推广时会产生困难;(5)预后指标不够敏感或定义的太窄以至于无法发现重要的临床效应.

临床试验安全数据管理介绍

根据药品临床试验质量管理规范要求(GCP),对药品上市前和上市后的临床试验安全信息进行收集、监测、速报和综合分析是临床研究中的重要内容.

Alpinia zerumbet,a ginger plant with a multitude of medicinal properties:An update on its research findings

In this review,the botany and uses ofAlpinia zerumbet (yan shan jiang) are described,and the current knowledge of its phytochemistry,pharmacological properties,and clinical trials is summarized.An important ginger crop in East Asia,A.zerumbet has many uses,both medicinal and non-medicinal.Leaves are used to produce essential oils and herbal teas.Rhizomes are consumed as spices,and stem fibers are made into paper,fabrics,and handicrafts.In Brazil,tea from A.zerumbet leaves is believed to have hypotensive,diuretic,and anti-ulcerogenic properties.This species possesses many medicinal properties due to its chemical constituents,including flavonoids,phenolic acids,phenylpropanoids,kava pyrones,sterols,and terpenoids.Extracts of A.zerumbet display antioxidant,antimicrobial,insecticidal,anthelmintic,tyrosinase and melanogenesis inhibitory,anti-atherogenic,anti-aging,anti-glycation,integrase and neuraminidase inhibitory,lifespan prolongation,hair growth promotion,anticancer,antidepressant,anxiolytic,anti-obesity,analgesic,anti-inflammatory,hypolipidemic,anti-ulcerogenic,anti-platelet,osteoblastic,osteogenic,thrombolytic,and cardiac arrhythmogenic activities.Essential oils ofA.zerumbet leaves have antimicrobial,larvicidal,antinociceptive,hypotensive,vasorelaxant,myorelaxant,antispasmodic,antidepressant,anxiolytic,anti-neuraminidase,anti-atherogenic,anti-aging,anti-melanogenic,anti-tyrosinase,cytoprotective,cardiodepressive,antipsychotic,analgesic,anti-inflammatory,and tissue healing activities.Clinical trials conducted in Brazil showed that extracts of A.zerumbet have hypotensive and diuretic effects whereas topical application of the essential oil has positive therapeutic effects on patients with fibromyalgia.Spanning two continents of Asia and South America,A.zerumbet is truly a multi-purpose ginger plant with promising medicinal properties.

Interventional therapy for congenital heart disease (CHD)was introduced in the 1960s following animal experiments and clinical studies using transluminal technique. However,it was not widely accepted in clinical applications until the 1990s because of the limitations of interventional devices and catheter technique. Interventional therapy is now well developed as a result of successful animal studies and clinical trials. It has a higher success rate than that of surgery in some CHD cases such as patent ductus arteriosus (PDA), pulmonary valve stenosis (PS), atrial septial defect (ASD) and coarctation of the aorta (CoA), and it may palliate some CHDs by atrial septostomy and interventional embolization of the pulmonary arteriovenous fistula.

临床研究质量控制体系设计的目标和原则

临床研究质量不高是制约我国临床研究整体水平提高的重要环节,提高研究质量是当前迫切需要解决的问题.在提高临床研究质量的工作中,首先要做顶层设计,在目标和原则上达成共识,但至今未见对这一问题的系统论述.现笔者提出如下看法,供学术界讨论.

达肝素与普通肝素对危重症患者静脉血栓栓塞的预防作用比较

静脉血栓栓塞是危重症思看的重妥开发症,危重症患有是静脉血栓栓塞的高危人群.目前尚不肯定在危重症患者中应用低分子肝素比普通肝素具有优势.加拿大危重症试验组和新西兰危重症学会临床试验组进行的危重症患者血栓栓塞预防试验(The PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group,C00k D,Meade M,et al.Dalteparin versus unfraetionated heparin in critically ill patients.N Engl J Med,2011,364:1305-1314.),对达肝素(Dalteparin)和普通肝素的作用进行了比较.

违背随机分组方案时的临床试验统计分析方法研究

目的 在临床试验出现随机分组被部分破坏的情况下,探索适合的统计分析方法.方法 利用随机模拟的方法考察三种分析方法的第一类错误发生概率是否小于α;比较第一类错误发生概率不大于α的分析方法的功效.结果 对违背随机分组方案的情况,按客观分组的t检验是的第一类错误发生概率远大于α;ITT方法和协方差分析方法的第一类错误发生概率的95%置信区间包含α;协方差分析方法的第二类错误发生概率显著小于ITT方法的第二类错误发生概率.结论 对违背随机分组方案的情况,按客观分组的t检验是不合适的;ITT方法和协方差分析方法能较好地控制第一类错误的概率在α附近;协方差分析方法的功效高于TTT方法的功效.

脂质体作为疫苗佐剂和给药系统的应用

Liposomes are artificial, spherical, closed vesicles consisting of one or more lipid bilayer (s). Liposomes made from ester phospholipids have been studied extensively over the last 3 decades as artificial membrane models. Considerable interest has been generated for applications of liposomes in medicine, including their use as diagnostic reagents, as carrier vehicles in vaccine formulations, or as delivery systems for drugs,genes, or cancer imaging agents[1]. There are now liposomal formulations of conventional drugs that have received clinical approval and many others in clinical trials that bring benefits of reduced toxicity and enhanced efficacy for the treatment of cancer and other life-threatening diseases[2].

IntroductionIn clinical trials of the efficacy of manualtreatments like surgery or acupuncture,control groups are commonly given'sham' procedures. Sham procedures, inorder to be true placebos, must be 1) in-distinguishable from the real treatmentand 2) inactive.

Angiogenesis is a very complex physiological process, which involves multiple pathways that are dependent on the homeostatic balance between the growth factors (stimulators and inhibitors). This tightly controlled process is stimulated by angiogenic factors, which are present within the tumor and surrounding tumor-associated stromal cells. The dependence of tumor propagation, invasion and metastasis on angiogenesis makes the inhibitors of new blood vessel formation attractive drugs for treating the malignancies. Angiogenesis can be disrupted by several distinct mechanisms:by inhibiting endothelial cells, by interrupting the signaling pathways or by inhibiting other activators of angiogenesis. This strategy has shown therapeutic beneift in several types of solid tumors, leading to Food and Drug Administration (FDA) approval of anti-angiogenic agents in the treatment of kidney, non-small cell lung, colon and brain cancers. Although no angiogenesis inhibitors have been approved for patients with metastatic prostate cancer, therapies that target new blood vessel formation are still an emerging and promising area of prostate cancer research.

理性地看待我国急性卒中临床试验的结果

循证医学要求对治疗的推荐应该具有临床证据,大样本的随机对照临床试验(randomized control trial,RCT)被公认为佳证据的"金标准"[1,2].自20世纪80年代中期起,我国也逐步开展了与脑卒中相关的大样本RCT,如卒中后抗高血压治疗研究(PATS)[3]和著名的早期应用阿司匹林治疗急性缺血性脑卒中的随机安慰剂对照试验(CAST)[4]等.

Current treatment in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is defined by fixed airflow limitation associated with an abnormal pulmonary and systemic inflammatory response of the lungs to cigarette smoke. COPD represents an increasing burden worldwide, reported to be the sixth leading cause of death in 1990 and the fourth in 2000. Discouragingly, it is projected to jump to third place by the year 2020.There is increasing evidence that COPD is a more complex systemic disease than an airway and lung disease. In particular, cachexia, skeletal muscle abnormalities, diabetes, coronary artery disease, heart failure, cancer and pulmonary vascular disease are the most common comorbidities. It is associated with a wide variety of systemic consequences, most notably systemic inflammation. Because COPD patients have in general ahigher cardiovascular risk than the average population, cardiovascular safety in a COPD medication is of critical importance.SINGH et al performed a systematic review and recta-analysis of 17 clinical trials enrolling 14 783 patients treated with inhaled anticholinergic drugs used for the treatment of COPD. Inhaled anticholinergics significantly increased the risk of cardiovascular death, MI, or stroke ( 1.8 % vs 1.2 % for control; RR, 1.58 (95 % CI,1.21 - 2.06); P < 0.001 ). However, UPLIIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium) , a large, 4-year, placebo controlled clinical trial with tiotropium in approximately 6 000 patients with COPD. The preliminary results of UPLIFT showed that there was no increased risk of stroke with tiotropium bromide compared to placebo.A meta-analysis is always considered less convincing than a large prospective trial designed to assess the outcome of interest. However, COPD is a systemic disease. COPD management needs to focus on four major areas: smoking cessation, pharmacologic therapy, exercise training, and pulmonary rehabilitation. Clinicians and patients should always carefully consider any potential risks of intervention in the treatment of COPD.