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Journal of Chinese Integrative Medicine Free Full Text
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Editorial
Journal of Chinese Integrative Medicine: Volume 5   May, 2007   Number 3

DOI: 10.3736/jcim20070302
A review of international clinical trial registration
1. He YU (Evidence-based Chinese Medicine Centre for Clinical Research and Evaluation, Beijing University of Chinese Medicine, Beijing 100029, China Beijing 100029 )
2. Jian-ping LIU (Evidence-based Chinese Medicine Centre for Clinical Research and Evaluation, Beijing University of Chinese Medicine, Beijing 100029, China Beijing 100029 E-mail: jianping_l@hotmail.com)

ABSTRACT: Clinical trials play a critical role in medical research. However, only a few clinical trials conducted at present have been registered at various clinical trial registries. Clinical trial registration can prevent bias in these registered trials effectively and avoid unnecessary waste of resources due to meaningless repeats. Moreover, it will benefit the development of evidence-based medicine, and promote human welfare. Great attention has been paid to the importance and necessity of clinical trial registration. This review briefly introduced the definition, justification, contents, history, current status of clinical trial registration, and introduced the information regarding important international clinical trial registries in detail. Clinical trial registration should be developed toward a transparent, compulsory and comprehensive stage.

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Yu H, Liu JP. J Chin Integr Med / Zhong Xi Yi Jie He Xue Bao. 2007; 5(3): 234-242. Received December 14, 2006; published online May 15, 2007. Free full text (PDF) is available at www.jcimjournal.com

Correspondence: Jian-ping LIU, MD, Professor; Tel: 010-64286757; E-mail: jianping_l@hotmail.com

基金项目: 973国家重点基础研究发展计划资助项目(No. 2006CB504602)

Jump to Section
-   Top
-   Article & Author Info
-   Introduction
-   临床试验注册概述
-   临床试验注册的国际机构
-   国际临床试验资料库
-   国际临床试验注册的未来
-   References
   

       在医学研究领域,临床试验是推动人类健康事业向前发展的重要手段,临床试验注册的重要性和必要性已日益凸显,也越来越引起人们的重视。现就临床试验注册的有关内容论述如下。

 
   
1 临床试验注册概述
1.1 临床试验注册的定义 一种新药或干预措施的临床试验注册,指在试验的起始阶段将试验的重要信息在公开的临床试验注册机构进行登记,以便向公众、卫生从业人员、研究者和赞助者提供可靠的信息,使临床试验的设计和实施透明化 1 ,并使所有人都可以通过网络免费查询和评价注册的临床试验。临床试验在注册时应逐一列出计划中的、正在进行的和已经完成的各阶段的关键信息 2
1.2 临床试验注册的原因 最初是因为未注册和未发表的临床试验不能对循证医学做出贡献,系统综述和meta分析仅仅收录了少部分获得发表的、却可能有偏倚的临床试验。近年来,医学界强烈呼吁临床试验应进行注册并公开其试验结果,避免选择性偏倚和报告偏倚。患者、研究者、赞助者、政府以及出版商等社会各界均赞成临床试验应在国际上注册,以促进循证医学的发展和信息的自由获取
3 ,临床试验注册还能使所有试验的结果得到保留2。从伦理学角度看,病人参与临床试验,承担了一定的风险,因此,病人有权获悉试验结果,以及他们为人类健康事业的发展和卫生保健决策的制定所做出的贡献。所以,临床试验注册是必须的。
      通过临床试验注册,人们可以在试验的起始阶段就获得试验的重要信息,而不是来自于滞后发表的文章。人们可以知道谁在做什么研究,方法为何,以避免不必要的重复研究,但不排除鼓励适当的重复验证试验;临床试验注册还有助于促进国际协作,使赞助者将资金用于最有意义的项目;避免发表偏倚,防止由于未报道阴性结果或结果不明确而产生的报告不全,误导研究人员做出有偏倚的系统综述,影响医生进行临床决策。通过注册将试验信息直接面向公众,有助于招募志愿者,容易被公众接受,提高公众对制药企业的信任度4,使公众对疗效的真实性有更多的了解,强调公众参与医药研究的义务1
1.3 临床试验注册的要求 国际医学杂志编辑委员会(International Committee of Medical Journal Editors, ICMJE)、世界卫生组织(World Health Organization, WHO)以及国家政府组织都支持临床试验注册。要求临床试验在招募受试者之前应将试验具体措施向公众开放,并以此作为允许试验结果发表的条件。大多数重要医学杂志都要求临床试验进行注册,如《美国医学协会杂志》(JAMA)、《新英格兰医学杂志》(New England Journal of Medicine)、《内科学年鉴》(Annals of Internal Medicine)等13个重要世界医学杂志5。2004年9月,ICMJE成员联合发表述评1,明确提出只有当某项试验在征集首位患者之前就进行了注册,才会考虑发表其研究结果。该政策适用于在2005年7月1日及以后开始征募患者的试验。由于许多正在进行中的试验开始时都没有注册,已将这些试验注册的截止时间延长到2005年9月13日以前。当前和今后的目标是推动建立一个全面的、公众可及的临床试验数据库6。因此,确保所有临床试验证据发挥其有效性的唯一途径就是将每一个临床试验在其初始阶段就进行注册7
1.4 临床试验注册的内容 2004年,由6名具有国际知名度的临床试验专家共同起草、修订和发表了临床试验注册的宣言,即著名的《渥太华宣言》,80多名国际临床学家、杂志编辑和研究人员共同签署了该项声明。宣言要求任何临床试验的研究方案及随后的试验结果都应当进行注册,并使公众能够获取。国内学者刘建平经授权将《渥太华宣言Ⅰ》译成中文并发表8,《渥太华宣言Ⅰ》主要介绍人体健康相关干预临床试验方案的信息与结果的国际注册原则,旨在为临床试验注册建立国际认可的标准。《渥太华宣言Ⅱ》旨在规范有关人体医疗干预试验的研究方案信息和结果的国际注册操作原则。涉及要点如下:(1)介绍唯一注册号(Unique ID);(2)最低要求的研究方案条目;(3)注册确认标准;(4)查询平台;(5)试验结果。原文可以在渥太华小组网站上获取。2005年4月WHO协约成员会议上提出了临床试验进行注册时应完成WHO最低要求的资料集,共有20项,分列如下:(1)全球唯一的试验注册号;(2)试验注册日期;(3)次级注册号;(4)资金来源;(5)主办者;(6)协办者;(7)责任联系人;(8)研究联系人;(9)研究的题目;(10)正式的科学题目;(11)伦理许可;(12)条件;(13)干预措施;(14)关键的纳入、排除标准;(15)研究类型;(16)预计试验启动日期;(17)目标样本量;(18)招募情况;(19)主要结局;(20)关键的次要结局。
       WHO规定以上20项条目对于临床试验注册是非常必要的,注册时必须详细说明以上信息(详请查阅《渥太华宣言Ⅱ》),即使这样,仍不能满足《渥太华宣言Ⅰ》对试验透明度的要求。《渥太华宣言》还要求临床试验的注册信息必须以英语提交,最好同时也采用主要试验地或地区的主流语言。高质量、无偏倚的试验注册包含以上国际间承认的最少资料集,能够对多次注册进行相互对比和控制以避免重复注册。只有在国际承认或符合标准的注册处进行注册的临床试验才被视为一项试验注册得以完成。
1.5 临床试验注册的历史与现状 1970年正式提出临床试验注册,当时是为了发展美国尼克松总统的“抗癌运动”(the war on cancer)和减少临床试验结果的发表偏倚9。现在看来,它不仅可以为医生和患者提供某种新疗法的信息,还可以为研究者提供系统综述的证据。因在试验结果尚未发表的情况下,研究者就可以获得相关信息,这就大大方便了系统综述的完成10
       当前,世界范围内广泛存在发表偏倚。发表偏倚歪曲了整个试验的科学信息,甚至使系统综述失去参考价值。更严重的是受试者将面临试验所带来的潜在危险11。医生、研究者、患者、公众以及赞助商都深受发表偏倚的影响,消除或减少发表偏倚可以促进科学进步和卫生事业的发展,也符合伦理学要求。加拿大卫生研究院(Canadian Institutes of Health Research, CIHR)主席Alan Bernstein说:“临床试验注册将会实现新兴知识的共享,促进更安全有效疗法的发展。”
       临床试验注册一直受到企业的阻挠。企业赞助者往往具有两面性,他们虽然声称反对发表偏倚,但考虑到企业利益,又每每促进了发表偏倚的产生。加之政府部门缺乏有效措施,公众知之甚少,所以,即使医学杂志一直呼吁临床试验注册,并提出辉煌的目标和响亮的口号,但谈到如何实现,他们也可能同样存在一部分抵触情绪,茫然无措。BMJ曾考虑过要求强制实行临床试验注册,但临床试验注册库种类繁多、秩序紊乱,容易忽略注册,而且他们也不希望因为注册费用阻碍研究者在BMJ上发表论文。BMJ主题专栏曾经报道了医生和药厂之间的纠葛,提出应建立透明的、相互信任的新型关系以保护广大患者的利益12
       ICMJE没有明确支持一个专门的注册库,只是建议研究者在WHO注册平台中进行注册。目前已有几百个注册库,如Clinical Trials注册库和Current Controlled Trials注册库,它们运行良好,一项临床试验在2~3 h内就可以完成注册11
       尽管临床试验注册目前还存在许多问题,但是在国际各界人士的共同努力下,临床试验注册制度正在不断发展完善当中。例如,“国际临床试验日”的提出就是国际临床试验注册向前迈进的一个重要标志。1747年5月20日,英国苏格兰航海医生詹姆斯林德进行了著名的坏血病(维生素C缺乏症)临床试验,开创了临床试验的先河,这项研究奠定了循证医学的基石。为了纪念这一历史性事件,欧洲临床研究基础网络(European Clinical Research Infrastructures Network, ECRIN)联合美国和加拿大,倡议将2005年5月20日定为第一个国际临床试验日,以后每年5月20日被定为国际临床试验日13。WHO在布鲁塞尔举行了第一个国际临床试验日,由ECRIN、欧盟、WHO组成,每年举办此次活动以引起公众重视临床研究的方法和挑战14
      2006年12月1日,在日本神户,世界卫生组织国际临床试验注册平台(WHO International Clinical Trial Registration Platform, WHO ICTRP)邀请了来自8个国家的9个国家级临床试验注册中心参加WHO ICTRP秘书组和WHO ICTRP科学指导委员会(SAG)举行的工作会议,参会组织包括澳大利亚临床试验注册中心(Australian Clinical Trial Registry, ACTR),中国临床试验注册中心,美国临床试验注册中心、国家癌症研究所(National Cancer Institute, NCI)、医师数据咨询(Physician Data Query, PDQ)和癌症临床试验注册中心(Cancer Clinical Trials Registry),德国体细胞基因转录临床试验数据库(Somatic Gene Transfer Clinical Trial Database),印度临床试验注册中心,日本临床试验注册中心(UMIN-CTR),英国国际标准随机对照临床试验编号(International Standard Randomized Controlled Trial Number Register, ISRCTN)以及荷兰国家毒理学研究中心(National Center for Toxicological Research, NCTR)15
Jump to Section
-   Top
-   Article & Author Info
-   Introduction
-   临床试验注册概述
-   临床试验注册的国际机构
-   国际临床试验资料库
-   国际临床试验注册的未来
-   References
   
2 临床试验注册的国际机构
      临床试验注册要求在临床试验开始前就将其有关信息在公共数据库上公布,该公共数据库称临床试验注册库,也叫临床试验注册中心,世界上已有几百个临床试验注册中心。1987年,美国布朗大学建立了一个包括500多个临床试验注册中心的注册系统。在Trials CentralTM上也列出了400多个注册中心,这些中心在注册目的、内容、质量以及是否对公众开放等方面各不相同。
      目前,国际上比较重要的临床试验注册机构主要有:美国的Clinical Trials注册资料库,英国的国立研究注册库(Britain's National Research Register, BNRR),澳大利亚临床试验注册中心等;企业性的有英国当前对照试验注册库(Current Controlled Trials, CCT)及其建立的《国际标准随机对照临床试验编号》注册系统(ISCTRN),葛兰素史克(Glaxo Smith Kline)资助的临床试验注册库(Glaxo Smith Kline Register)等。完全独立的注册机构有Trials Central注册库等。
      WHO为使国际上临床试验的注册符合伦理学要求并具备科学性,制定了相应的规范和标准,建立了WHO临床试验注册平台( http://www.who.int/ictrp/en/ ),与以上注册机构不同,它是WHO于2005年8月成立的全球性临床试验注册网,总的目标是通过提高透明度来加强临床试验的可信度。WHO ICTRP不同于“临床试验注册库”,目前尚未提供临床试验注册服务,但可以为临床试验在相应国家和地区注册提供指导。该注册平台功能如下:(1)提供临床试验注册的规范、标准、注册的信息及试验的主要责任人等;(2)链接到符合WHO特定质量标准的注册网站;(3)为辨认和解决重复注册设立协作程序,为国际上每一项临床试验指定全球唯一的临床试验编号;(4)建立世界范围内的注册检索查询平台。WHO ICTRP可以检索所有主要的注册库,可通过临床试验编号或WHO临床试验数据集中的项目进行检索,如:条件和干预措施等。WHO ICTRP能够显示所有与之匹配的条目216
      所有国家或地区的注册中心都应将其试验记录提交WHO ICTRP。WHO ICTRP向公众公开全球所有临床试验。2006年后半年,WHO注册平台创办了网络查询平台,使科学家、患者、临床医生和任何对此感兴趣的人都可以在世界各地实现检索注册库中正在进行的或已经完成的临床试验。这是数据库最大限度发挥其效能的重要标准。
2.1 主要的国际临床试验注册库
2.1.1 Clinical Trials注册资料库 Clinical Trials注册资料库(http://www.clinicaltrials.gov)可提供临床试验的注册服务,因收录了大量临床试验信息和数据,同时也是重要的临床试验资料库。
2.1.2 英国国立研究注册库英国国立研究注册库 (BNRR, http://www.nrr.nhs.uk )可检索正在进行的或新近完成的临床试验,由英国国家卫生服务部出资建立,共有来自英国、苏格兰和威尔士等350个组织对其进行赞助。BNRR会不断增加数据并收录新注册的试验记录,且每3个月对现有试验记录进行一次更新17。BNRR可以在线注册当前和新近完成的由英国国立卫生服务部(National Health Service, NHS)支持的项目,列出近50 000项临床试验。该注册库提供免费注册,并提供主要研究者的联系方式以及与研究相关的问题、方法学和关键词。该库可直接检索,而且可以同时得到其他英国数据库中的试验资料,如医学研究委员会临床试验目录(Medical Research Council's Clinical Trials Directory)、卫生经济学中心(Centre for Health Economics)和NHS评价与传播中心(Centre for Reviews and Dissemination)数据库。缺点是尚不完善,且仅限于英国1
2.1.3 澳大利亚临床试验注册库 2005年5月,澳大利亚政府出资150万美元在悉尼大学的全国卫生与医学研究委员会临床试验研究中心建立澳大利亚临床试验注册库(ACTR,
http://www.actr.org.au/)。该中心符合ICMJE和WHO的标准,而且已于2005年6月底开始接收注册[18
2.1.4 英国当前对照试验注册库 英国当前对照试验注册库(CCT, http://www.controlled-trials.com)创办于2000年,由当代科学协会出版公司Current Science Group成立,2003年5月正式运行。CCT允许用户免费检索和使用临床随机对照试验的资料,还可以向CCT申请注册的全部费用而享受免费注册服务。会员公司生物医学中心杂志出版社还可提供出版服务。CCT在网上链接了50多家注册库和对照试验的meta分析资料注册库。它能简化试验识别并提供唯一编号以记录所有临床试验所报告的结果,即《国际标准随机对照临床试验编号》注册系统(ISRCTN)。Meta分析注册库的6个赞助商包括加拿大HIV临床试验网(Canadian HIV Trials Network)、先灵健康护理(Schering Health Care)、英国医学研究委员会(Medical Research Council)、英国癌症研究协作委员会(Coordinating Committee for Cancer Research)、英国国家研究注册库(National Research Register)、医学编辑试验补遗(Medical Editor's Trials Amnesty)1。2005年9月,其所有权移交为非盈利性组织,目前它已符合所有ICMJE的注册要求19
      统一所有注册库并通过网络建立链接,实现资源共享,以实现同步检索所有注册库是最为理想的手段,英国的CCT的meta分析注册库就是一个范例19。许多注册库为了满足各种需要正在不断进行改进,ISRCTN注册库和Clinical Trials注册库在WHO、渥太华组织、ICMJE进行决策时有着重要地位20
2.1.5 葛兰素史克注册库 葛兰素史克注册库(Glaxo Smith Kline Register, http://ctr.gsk.co.uk/welcome.asp)由葛兰素史克公司建立。葛兰素史克公司是由在研发新药方面享有盛誉的葛兰素威康(Glaxo Wellcome)和史克美占(SmithKline Beecham)公司合并而成。葛兰素威康1998年开办了一项药物试验注册库( http://ctr.glaxowellcome.co.uk/ ),所有葛兰素史克公司资助的临床试验均在该注册库注册。它提供该公司赞助的临床试验(Ⅰ~Ⅳ期)研究的详细资料21、参考文献和摘要等。该注册库设有密码,只有科学家和卫生保健行业人员才能获取,且每年更新注册资料,重要的资料变动可能处于两次更新之间而不能及时获得1。试验结果除发表于期刊的常规报道外,还包括试验方案设计中主要、次要疗效终点指标和不良事件。该注册库注册的试验结果和注册招募均为开放性22。该注册库开创了制药公司公开注册正在进行中试验资料的先河。
2.1.6 Trials Central注册库 Trials Central 注册库(
http://www.trialscentral.org/ )提供免费、保密服务。检索系统使用方便,可进行病名检索,也可以地区进行限制。提供常见问题的解决方法,还与许多卫生保健信息网站建立了链接,如医学字典、已发表或最近发表的文章以及循证医学网站等23
2.1.7 中国临床试验注册中心 中国临床试验注册中心(Chinese Clinical Trial Register, ChiCTR,
www.chictr.org)由卫生部中国循证医学中心、中国Cochrane中心、四川大学华西医院组建,是渥太华工作组的成员单位,是一个非赢利的学术和服务机构。卫生部中国循证医学中心、中国Cochrane中心、循证医学教育部网上合作研究中心、英国Cochrane中心为中国临床试验注册中心提供技术支撑。中国临床试验注册中心网站上公布的服务项目包括临床试验注册、临床研究设计咨询、产生和隐藏中心随机分配序列、临床科研论文评审、培训临床科研和论文评审专家。该中心已于2005年10月正式开始运行
       此外,世界上许多国家都拥有临床试验注册库,虽然有些起步较晚,但目前正在不断完善中。除了欧洲临床试验资料库(European Clinical Trial Database, EudraCT)和国际标准随机对照临床试验编号(ISRCTN)以外,对公众开放的国家级临床试验注册库在中国、日本、澳大利亚以及欧洲等国相继建立。目前,特殊疾病临床试验注册库也呈增长趋势。除了公开的注册库,法国、意大利、西班牙、荷兰还建立了不公开的临床试验注册库。如果这些数据库向大众公开,将极大地丰富现有临床试验的信息含量。但是有些国家目前还没有设立针对国内临床试验的注册库。比如印度目前还缺少国家级别的临床试验注册库,因此公众和研究者们可能无法掌握印度境内进行过哪些临床试验及其具体信息。这可能会导致重复试验和资源的浪费,更严重的是由于这些试验所取得的不良事件和阴性结果没有公开发表,可能导致受试者受到不必要的危害。国立财政机构由于不清楚是否有相同的试验正在进行或曾经进行过而可能会为相似的研究给予资金投入24
2.2 临床试验注册库标准 研究者所面临的问题是在何处注册以及这些注册库的标准。显然,为避免利益冲突和提高公众信任度,临床试验注册库的创建和管理应该达到一定的要求。
      ICMJE为临床试验注册库制定了一系列标准25。这些标准有:免费向公众开放,向所有注册者开放,由非盈利性机构负责管理,可以实现电子检索,包含有效资料和最少资料(唯一识别编号、干预措施和试验假说、主要和次要结局测量、合格性评价标准、关键时间点、目标样本量、资金来源及主要负责人的联系方式)。
      ICMJE制定的标准和要求一方面有效地促进了临床试验的注册,如Zarin等26发现ICMJE标准对临床试验注册产生了巨大影响。2005年夏,临床试验注册数目大幅增长,到10月份注册库中的资料较5月份时更为完善,2005年5月20日到10月11日期间,Clinical Trials注册库中的试验数从13 153增长到22 714。使用者还可以在ICMJE网站http://www.icmje.org/faq.pdf上了解有关临床试验注册的一些常见问题。另一方面,由于临床试验注册还处于刚刚起步的发展阶段,也有人提出不应该对其进行更多的限制。目前,只有Clinical Trials注册库、ISRCTN注册库、ACTR、欧洲儿童药物评价注册库(European Register of Clinical Trials in Children)满足ICMJE的标准25。Cochrane肾脏病组临床试验注册库、英国国立研究注册库(BNRR)、欧洲临床试验数据库(EudraCT, http://eudract.emea.eu.int/ 27只达到其中一部分要求。即使Clinical Trials作为应用最广泛的注册库,它的一些纳入标准仍会令许多临床试验因为不能达到其要求而无法注册。在发展中国家进行的许多非药物试验和非政府支持的试验就有可能达不到注册的要求12
Jump to Section
-   Top
-   Article & Author Info
-   Introduction
-   临床试验注册概述
-   临床试验注册的国际机构
-   国际临床试验资料库
-   国际临床试验注册的未来
-   References
   
3 国际临床试验资料库
      临床试验资料库收集了国家或地区间临床试验的详细资料,可通过检索获得某项试验的具体资料。有的临床试验资料库还同时具备注册功能,如Clinical Trials注册资料库,大大方便了临床试验的注册和资料保存及公开。
3.1 Cochrane对照试验注册中心 Cochrane协作网是在英国合法注册的一个非盈利性国际学术组织,以已故英国著名流行病学家和内科医生Archie Cochrane的姓氏命名。Cochrane对照试验注册中心(Central Register of Controlled Clinical Trials, CENTRAL)是目前最丰富的临床对照试验数据库,包括MEDLINE、EMBASE或是其他数据库没有收录的一些对照试验。CENTRAL对试验的质量控制非常严格,只收录符合标准的随机对照试验(Randomized Control Trial, RCT)或对照临床试验(Controlled Clinical Trial, CCT)。Cochrane协作组成员手工和计算机检索医学杂志、会议论文或通过其他渠道来收集RCT或CCT的资料,按规定的格式标准提交至CENTRAL。目前CENTRAL已收录了1948年以来全世界已发表的所有RCT和CCT,总数超过50万条,其中也包括在中国发表的RCT28
3.2 Clinical Trials注册资料库 ClinicalTrials.gov于1997年由美国国家医学图书馆(National Medical Library, NML)与美国食品与药物管理局(Food and Drug Administration, FDA)共同创建,范围涵盖各种疾病及其症状20。ClinicalTrials.gov是美国政府创建的第一个临床试验资料库,而且同时提供试验注册服务,由NML负责运行29。初期仅限于美国由国立卫生研究院(National Institutes of Health, NIH)资助的正在进行的临床研究项目与成果,是NIH独具特色的信息资源,2004年后开始对国际上的临床试验开放20。ClinicalTrials.gov可以提供关于政府或私人资助的临床研究最新信息,包括该研究的参与者、位置以及电话等一系列详细信息,且均免费。ClinicalTrials.gov被列为公开化、国际化临床试验注册的典范,而且达到了ICMJE的要求59。1997年FDA现代化法案要求所有危重疾病的临床试验均应在公众可免费获取的数据库中说明,这也是最初创办ClinicalTrials.gov的宗旨10
      注册时需登录 http://prsinfo.clinicaltrials.gov/gettingOrgAccount.html 网站。个人PRS账号通常由研究者持有并用于临床试验的注册,两个工作日之内,ClinicalTrials.gov就可生成账号并通过电子邮件说明如何在PRS上注册临床试验30。但是,ClinicalTrials.gov也存在一些有待完善的地方。如,尽管早期的试验信息可通过各种信息渠道获得,但患者却难以利用这些渠道,因为试验注册信息不容易被患者理解,或者存在语言障碍,如仅提供英语版本。ClinicalTrials.gov收录的Ⅰ期临床试验资料大部分在美国进行,其他国家的患者很难检索到在本国进行的早期临床试验资料,这种现象难以较好地体现公平的原则31。ClinicalTrials.gov开始仅限于美国国内获准的临床试验注册,直至2004年才向全世界开放。ICMJE认为欧洲临床试验资料库(EudraCT)尚未达到国际注册的标准,因为该注册库不向公众开放。2004年5月以后,在欧盟成员国内进行的临床试验要求必须在EudraCT进行注册,因此,欧洲的研究者将不得不面临多重注册的问题32,从而导致一些欧洲研究者们放弃在ClinicalTrials.gov上注册19
      总之,自2004年以来,为适应近年来越来越频繁的国际间的交流与合作,每一个资料库都在根据不同需要进行改进。其中包括扩大研究领域,实现资源共享,为所有试验的注册提供便捷的服务20
Jump to Section
-   Top
-   Article & Author Info
-   Introduction
-   临床试验注册概述
-   临床试验注册的国际机构
-   国际临床试验资料库
-   国际临床试验注册的未来
-   References
   
4 国际临床试验注册的未来
     国际临床试验的注册任重而道远,需要各方面的努力与支持,以及国家或地区间的团结与协作。未来的发展趋势将主要表现在以下几方面。
4.1 透明化 目前,国际临床试验已经越来越趋向透明化,逐渐取得了公众信任。自2004年葛兰素史克公司发生诉讼案后,制药企业、杂志编辑、学术界、消费者协会、政府和WHO都表示应提高临床试验的透明度。制药企业已经尝试进一步加大透明度和研究信息的使用权限。一些较大的企业还把他们的试验结果在企业网站上公布,这些都是重要的进步。然而,公众因仍然无法判断是否存在报告偏倚,而未给予充分信任
33 。目前,临床试验的公开情况各异,有的公司将信息全部公开,有的则相反。一些较敏感的信息经常可以通过一些技术轻易地在一些收费网站上获取,试验参与者也可能透露试验信息。尚无证据支持资料的公开会有碍于竞争,事实上,信息公开有可能促进创新。有专家指出,在Ⅰ、Ⅱ期临床试验中,我们可以理解药厂希望为其所生产的药物作用机制保密,但是到了Ⅲ期临床试验,所有业内人士都应对其试验有所了解。
      WHO ICTRP致力于取得公众信任的全球卫生保健研究,此举具有划时代意义。它为实现所有临床试验能公平统一地公开资料而努力探索一套运行机制,为达到一定的透明度起到了积极的作用。期待在不久的将来,该平台能促进患者人群、现有注册库、企业、学术团体以及其他重要成员之间的合作,有效地完善全球临床试验的注册34,最终实现所有临床试验及结果的公开化19
      近两年来,WHO ICTRP所有利益相关方的代表,包括制药业、生物技术产业、医疗器材产业、患者和消费者群体、政府、医学杂志编辑、伦理委员会以及学术界进行了协商。WHO助理总干事Timothy Evans博士说:“注册所有临床试验,并在注册时充分公开重要信息,对于确保医学研究的透明度和履行对患者及研究参与者的道德义务至关重要。”
       WHO认为对临床试验进行注册并公开注册信息是唯一能够确保试验透明化和符合伦理学要求的方法。WHO ICTRP代表陈安文博士说:“这是向前迈进的重要一步,我们希望可使临床试验注册更加透明化并增强公众的信任度。”WHO表示,截止至2006年5月19日,所有进行临床试验的公司或其他研究组织都应将20个注册条目公开35。加利福尼亚大学旧金山分校医学信息学系副主任兼注册平台行动协调人Ida Sim博士说:“我们的目的是使临床研究透明化并加强公众对科学的信任,而我们正与所有利益相关方一起从事一项公正和公开的工作。我们希望在推行注册平台时就注册试验和报告结果问题持续对话2。”我们相信所有成员都能真诚地达成共识,这将增加临床试验的透明度和增强试验推行者的责任感。WHO提供了国际支持和法规,为继续乐观地推进试验的国际注册和报告奠定了坚实的基础33
4.2 强制性 强制性在一定程度上是实现综合性临床试验注册库的条件36。已有学者提出将来对临床试验注册实行强制性措施,而不再是采取自愿的原则,甚至会采取一定的处罚措施37。由于大量的阴性结果和试验中出现的不良事件未得到报道,甚至有意对公众隐瞒,产生了严重的后果38,因此,应当强制实行临床试验注册。临床试验的注册应当尽可能保证资料的完整性、可靠性,并做好合理的解释和说明工作19。尽管ISRCTN的唯一试验编号系统已经使临床试验注册向前迈进了一大步,但是仍未能解决使所有临床试验均进行注册的问题。
      尽管现在的临床试验注册仍属自愿,但强制性临床试验注册已初露端倪。临床试验注册的支持者们认为应该很好地衡量注册的益处,并提出只有全部的试验均进行注册,那才有意义,而且他们对自愿原则持怀疑态度。美国医学会(American Medical Association, AMA)、ICMJE和民主立法者都认同对临床试验实行强制性措施。AMA建议政府创建一个综合注册库以便所有在美国进行的临床试验都可以进行注册。ICMJE声明将是否注册作为今后发表论文的条件,要求试验必需在招募参与者之前完成注册5
      印度临床试验的趋势将跟随ICMJE的步伐,印度的专家提出,临床试验注册应当是强制性的,这样能最大程度地避免低质量的临床研究24,但强制性注册制度障碍重重,私人研究能够自主决定是否注册,如果没有国家指令性要求,他们将不愿进行注册539。所以,要想实现国际临床试验注册强制性原则,还需要国际社会共同协调努力以及立法机关的介入。
      2004年英国学者提出在英国创建类似ClinicalTrials.gov的公共注册库,由非盈利性机构运行,并呼吁英国的立法机构强制性要求所有临床试验在该注册库注册,只有这样才有望建立一个综合性数据库36。目前,可以对临床试验注册实行强制性措施的组织有伦理委员会、国家政府和各种提供资金的组织机构。伦理委员会有权要求临床试验在适当的注册库进行注册,国家政府可以提出同样的要求以使临床试验注册成为例行程序,此外,立法机构也可对临床试验注册进行约束,前提是注册库应向公众免费开放。自1982年起,西班牙药物试验法规开始支持临床试验注册,但是西班牙政府却一直迟迟未将注册库对公众和研究者开放4。我们始终乐观地认为,强制性临床试验注册一定会实现,只是时间问题38
4.3 综合性 目前,距离我们实现创建公共注册库的目标还很远,注册库中的资料和公开程度都不统一,参与注册的临床试验仍为少数。ICMJE提出了建立综合临床试验注册库解决多重注册的问题40
      20世纪80年代临床试验有了长足的发展。然而,目前由政府、医院、企业协会等筹建的注册库种类繁多,它们的功能互不兼容,各个注册库之间缺乏互相协作,导致许多临床试验并未在公开性的注册库上登记。在英国,研究管理准则要求所有临床试验必须在国家卫生部公开注册。英国国立卫生服务部(NHS)中所有非企业资助的试验注册已经取得了很大进步,但是那些企业资助的试验注册却止步不前。2003年4月,英国制药工业协会创办了自愿参加的试验注册库,并提出“如果不能实现全球性,至少应该覆盖英国境内的临床试验,以避免重复10”。同时,制度制定者和注册库创办者应保证注册库具有较高的实用性,并为所有大大小小的研究团体所了解,这样,才能保证注册库的综合性。临床试验注册库的广泛使用将促进阴性结果和不良结果的发表,从而避免发表偏倚19
      谁来创建综合性临床试验注册数据库将是未来面临的另一个挑战。从企业的利益角度看,一些企业认为实行注册是明智之举。虽然目前已经取得了一定的进步,但是以往的经验表明,由于利益冲突根深蒂固,依靠企业创建一个大规模、共有、完备、实用、可靠、最新、并且使用方便和长期维护的注册库似乎不太可能41,而且并不易于取得公众信任。渥太华宣言中呼吁全球成立国际性、中立性和非赢利性机构为所有临床试验进行国际编号,以赋予每项试验唯一编号,WHO显然是最理想的机构。未来期待着国际社会创建一个公开、公正、完备、可靠、实用而且兼容性良好的综合性国际试验注册库。WHO支持国家、地区和国际间建立符合WHO国际标准的注册库协作网络。为减少重复注册所造成的浪费和保护资源,WHO鼓励应用最小条目数据的国际标准进行注册。渥太华宣言中关于公开临床试验方案的详细资料的论述已远较WHO最小数据资料前进了一步,并已获得了100多个学者和组织的赞同,但由于多方原因,还没有一家制药公司参与19
      当今国际需要建立具有良好透明度、高效、综合的临床试验注册库,以避免发表偏倚和重复。目前WHO已经建立的ICTRP为国际注册创造了一个良好的注册途径。欧洲临床研究基础网络负责人Christian Gluud博士建议,目前中国的临床试验注册可以在WHO的注册平台以及美国的ClinicalTrials.gov上进行注册,获取全球唯一的试验注册号,便于将来在国际医学期刊上发表高质量的临床试验研究结果。相信通过所有关心临床试验注册的人们的齐心协力,营造一个良好的国际协作环境,将有助于为人类健康事业做出贡献。
Jump to Section
-   Top
-   Article & Author Info
-   Introduction
-   临床试验注册概述
-   临床试验注册的国际机构
-   国际临床试验资料库
-   国际临床试验注册的未来
-   References
   
References
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Jump to Section
-   Top
-   Article & Author Info
-   Introduction
-   临床试验注册概述
-   临床试验注册的国际机构
-   国际临床试验资料库
-   国际临床试验注册的未来
-   References
   
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Browsing the airport get out of, Fan Ye tend to be viewing the river increase in the state of this kind of metropolis, his / her mouth area murmured:. "My domain is back, this is one more regarding my personal brilliant Fan Ye, I swear, I'll let the men and women in the condition of water I remember fondly the brand regarding Supporter Ye. "night, since Lu Wei Dong, within Huang Ye Fan golf club evening meal. Supporter Ye couple of messages or calls during the past, your idea of the whole introduction around. Zhao Tiehai, devil stick Enthusiast Team, Yu Jian Chen, Yu Tai, Lu Yun, Ape, They Hai Wei, who had been both upwards. "Iron Seashore, We seen anyone l Deputy Commissioner, very good ah! Don't know will probably be heard, just isn't prolonged chicken wings tough.Inch Lover Ye appeared laugh. "I care the boss, you cannot draw myself our skin.Inches Zhao Tiehai grimaces, as well as said, appear, looked at the building reverend mentioned, "This is one area we are obligated to repay from Mexico, they ended up being fishing to get a photo Deputy Commissioner situation. Normally, I wouldn't understand ok now what nook colony when a main cried and cried just a little. "" Also. "Yu Jian Chen smiled along with mentioned,Inches This is something you must give thanks to my own son foliage brother Don't think involving other individuals From the japanese losers cannot handle things Minamifuku simple fact, every time he'd see us a few bothering, I protected anyone refer to it as. often gave their long-winded as well sick of that, a person marine is actually his / her flat iron sibling, it really is not our friends? "" I am aware my own boss will not forget about, even so, pertaining to help in Cr, the particular metal ocean to be able to heart. "赵铁??oral cavity this slide. Leaves, within the two took in training course are very at ease with the. "Fan Company, went up by Zhengke right?Inches Supporter Ye looked just a enthusiast, giggled. "Hey, merely m A smaller area chief practically nothing.In . Fan Bunch useless giggle noisally, mentioned. "Little Key, nonetheless nothing! My oh my you just young adults. Finished a few years, at your age, once i used to be a new rural authorities stop to dawdle. Those days, a lot battling, managing each day are based on a small grouping of block Aunt Eastern side mother and father Western side family quick. nearly all satisfied thing would be to get guess there time for you to aid the cousin to some tree to trap the particular chicken, broke up with nearly ten several weeks Yang pay. "Yu Jian Chen snappily, hum. Unfortunately, I wouldn't recognize how kind house maid. Supporter Ye looked Lover Bunch, considered his or her initial girl * Lin Shih Supporter Chunxiang recipe Comes. These days a lot of people, is hard must this. "Good work, over the years, you're also the Commissioner." Fan Ye Enthusiast Gang patted the neck, said. "I be worried about this particular, you will find your government, the actual Director shall Shoudaoqinlai in order to Shihai.In . Lover Gang worthwhile promises 'demon stick', your head bum appears extremely cardiovascular Lishu Bronze Ye Enthusiast. That deal with, do not have to perish giggling. Effectively guy, have got these chop pride, can perform the main things for your female's loved ones really feel when confronted with a female's stomach direct post has to be whole lot. Moreover, following your computer intestinal tract battle, will definitely become especially delicate, pleasurable female. Bit males gallop war, has to be desire Eden. "Brother, on this occasion to HL, certain to be considered a large struggle.Inches Kamu Wei chuckled. "A large struggle, Let me, though the circumstance HL Are you aware this specific provincial money with the Admin." Supporter Ye mentioned gently, their deal with would not while positive. "HL, the particular identify sounds very good, today nearly success lotus, unfortunately ......In . This individual Hoi-wai somewhat worried, along with sighed. "It are not therefore bad.In . Enthusiast Ye smiled. "Worse compared to anyone imagined." In this case, Kamu Wei unity have a good laugh, mentioned. "How is it?" Supporter Ye looked down, requested. "Made a mess, Gu Yiwu is designed. Successive introduction of countless expenditure because of this, not just a liar can be heavily polluting companies in order to pull all of them in, Gu Gu Yiwu can be a smaller amount. Offers stated absolutely no income taxes with regard to 5 years even book almost all no cost so many positive aspects, along with, within a more metropolitan preparing is a bit of a mess. 顾一??stick them just about all on the 'Shunde company', Shunde, the corporation is really a non-public business, just how can individuals baby? his or her eyes just pursuits an end result, the new developing, the street can also be organizing wreck simply silly. lotus riverside most severe can be a result of large polluting companies as well sloppy. appropriately HL river is currently almost as any waste get rid of. "Lu Wei sighed along with mentioned. "Yes, paralysis! Pond one final time I went to HL Xiaoqu Ban circumstance. Practically accidentally caught up from the water." Zhao Tiehai angrily swore strong. "Big day time, you are a fantastic living, the forest will certainly fall under the particular lure involving flat iron seashore, you'll not return to residing lengthier, correct?" Supporter Ye accomplish not consider, nonetheless banging his / her mind. "Ye buddy does not feel isn't this? Call for ended up given birth to when.Inch Zhao Tiehai having a laugh loudly. "In the finish how is that?" Supporter Ye frowned, asked. "How could it be? Filter water in which workplace. Estimations on the leftover 20 or so feets broad, outcome was most inhabitants from the regional community of waste accumulated. River full of cellular levels regarding waste, what plastic material luggage, munch son, cigarette box every thing. merely can't begin to see the water, and i also thought it was a garbage moment, did not and then Italy, with ft through to your cross. got a number of measures pishi not necessarily, has gone seven or eight measures in any concave Community ft down a step merely sense Kit Kat. The good news is, powering an old person shouted the yowl, or perhaps truly their new mother fell in to the pond to move pungent trash bass. "Zhao Tiehai quit here whooped unfortunate. "That pond there are fish? Roach variations loads.In . Lorrie just smiled. "Section not maintain a near eye it?Inches Lover Ye do not really understand, ask Lu Wei Road. "Paid shut interest, you'll find a lot of activities to do area, how could i get through to buy. Besides, these items are generally things folks 顾一??share in this particular part baton regarding demand regarding the weapon could it be, can't also issue in addition loaded round ought to water line up. Gu Yiwu in addition used to do in which? Apart from, normal water Area Mayor Zhou solid wood is a powerful figure, paragraph even though typically hanging provincial subject, but Zhou can also be substantial using wood sub-provincial cadres. section times instead of very easy for much better and, following the Provincial eyelids, by some means some scruples, right? "after HE Hai Wei concluded, concentrating instead sipped wines. The following day, Enthusiast Ye towards the provincial business division reported. As soon as the Minister involving Provincial Corporation Kamu Ming Chu personally achieved Ye Supporter, Lover Ye describe the main things to ask while all set. Enthusiast Ye looked over the time, declared that in case are able to do this immediately down. Provincial past an acceptable limit to HL zone, absolutely no congested zones, after that ten mins drive coming from Bale, generally Haitian part was critical indication. Lu Ming Chu flipped your calendar, said to be no cost, in order to go along with YeFan trip with each other. Supporter Ye heart definitely appreciate it. Exactly what can the actual Minister involving Manual work who required place of work personally, together with provincial celebration businesses, these kinds of treatment solutions are generally only took place in the public level management get this sort of options. Moreover, you will have to discover how a new a friendly relationship along with her. Associated with Deputy Reverend could prepare a serious high regular. RO! ~!Reputation 1412th Section HL region chanel online shop http://flukeipkqy.blog.com/2014/02/12/the-good-reputation-for-handbags/ (2014-2-15 0:00:00)

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