Quality control should be applied to each stage of data handling to
ensure that all data are reliable and have been processed
correctly.
5.1.4
Agreements, made by the sponsor with the
investigator/institution and any other parties involved with the
clinical trial, should be in writing, as part of the protocol or in
a separate agreement.
5.1.1-5.1.4申办方必须建立质量保证（QA）和质量控制(QC)体系以确保临床试验的执行、数据的产生、数据的记录是按照研究方案、GCP、相关的法规执行的。而这种QA/QC体系必须是写入SOP的。E6R1规定了QC适用于所有的临床研究数据。因此为了可以QC临床研究数据，申办方需要与临床试验的所有缔约方（包含研究者/研究机构、中心实验室、其他临床试验的供应商）签订协议，以协议的形式来允诺申办方的此项权利。
关于QA/QC 其含义是什么呢？其实我们可以将临床试验想象成一个数据生产的过程，QA 和QC 都是产品（数据）质量管理（Quality
Management）体系的一部分。有一个非常经典的例子，话说某学校食堂每天中午供应鱼香肉丝给学生，突然某天有学生反映吃完鱼香肉丝后胃部不适。于是校领导约谈了食堂的承包人，责令其整改。那么食堂是怎么整改的呢。食堂员工开始了一次头脑风暴。
首先，有人提出菜品销售前需要确认菜品的新鲜度及口味。
于是专门请一个小师傅每日菜品制作完成后，取样试吃一下，看菜品是否有问题，并且留一部分样本，以便安全问题发生后可提供检验。另外，又有人提出，食品的质量是生产出来的，不是检验出来。所以我们要确保食材新鲜、食材制作工艺规范。于是食堂的大师傅，专门撰写了一个鱼香肉丝的制作工艺丢给手下的人。制作工艺中写到：每日采购土豆、菌菇、胡萝卜XX斤，严禁使用有霉菌、腐烂的，食材配比XX调料配比XX。至此，食堂的师傅均按照大师傅的制作工艺执行。某日那个专门试尝菜品的小师傅向大师傅提到，鱼香肉丝中土豆未削皮且土豆丝粗细不一，影响美感和口感。于是大师傅又在其独门配方中加上一句：所有土豆必须必须在切丝前削皮，并用5mm过筛器切丝。就这样，食堂的鱼香肉丝产品在师傅们的不断完善基础上，成为食堂的一味独特的菜品。
通过这个案例，大家应该QA和QC
之间的千丝万缕的哲学关系了吧。学习过GMP的或者从事过药品生产的同学应该对QA/QC不会陌生。
5.2 Contract Research Organization (CRO)
5.2.1 A sponsor may transfer any or all of the sponsor's
trial-related duties and functions to a CRO, but the ultimate
responsibility for the quality and integrity of the trial data
always resides with the sponsor. The CRO should implement quality
assurance and quality control.
5.2.2 Any trial-related duty and function that is transferred to
and assumed by a CRO should be specified in writing.
5.2.3 Any trial-related duties and functions not specifically
transferred to and assumed by a CRO are retained by the
sponsor.
5.2.4 All references to a sponsor in this guideline also apply to a
CRO to the extent that a CRO has assumed the trial related duties
and functions of a sponsor.
5.2 规定了CRO 与申办方之间的关系。身在CRO公司的你一般如何跟家人介绍自己的公司呢？
我一般说我公司的性质就类似于会计事务所、律师事务所， 我们帮药厂做临床试验。
对于CRO公司的CRA 来讲，
你肯定经常会被医院伦理要求提交CRO公司的授权书（一般申办方和CRO公司的合作协议不会提供给研究中心）、CRA
的委托书。这些文件就包含了各委托方和被委托方之间的权责义务，通过授权书你可以了解申办方将哪些权利和义务委托给CRO公司。
在与医院签署研究协议时候，我们常常被要求签署三方协议，或者直接是申办方和医院的两方协议，这主要也是因为5.2.1，
申办方对临床试验赋有最终的责任。申办方的责任中有一个非常重要的责任就是“受试者补偿”，受试者因参加临床试验发生的损害，与研究药物相关或者与研究操作相关的情况下，需要向申请索赔。相信没有一家CRO公司会愿意承担申办方的这一职责，所以很多研究中心，也是基于此项顾虑要求申办方加入成为协议的缔约方。
5.3 Medical Expertise
The sponsor should designate appropriately qualified medical
personnel who will be readily available to advise on trial related
medical questions or problems. If necessary, outside consultant(s)
may be appointed for this purpose.
5.3 传说中的Medical Monitor
(MM)。根据二丘的经验，启用MM的好处在于他可以在整个研究中起到协调的作用，对于医学问题有一个总体的把控。比如某方案规定受试者在用药期间禁止使用抗癌中药，那么具体哪些药物属于抗癌中药呢，medical
monitor 会将各家中心提出的问题汇总成一个清单，然后再动态共享给所有参与中心。这个活并不是CRA
或者项目经理能干的来的哦。
另外一个MM的好处，当你和研究者因为医学方面的问题产生矛盾时，可以请MM作为中间人，进行协调。一方面研究者与MM专业人员之间的对话，会让研究者觉得重视，从而也更重视我们的研究；另一方面重大的医学决策由MM和研究者直接沟通避免CRA
传达出现误差。简而言之，随着临床试验分工的细化，我们要好好把握我们的同事MM在项目执行方面能够提供给我们的帮助。
5.4 Trial Design
5.4.1 The sponsor should utilize qualified individuals (e.g.
biostatisticians, clinical pharmacologists, and physicians) as
appropriate, throughout all stages of the trial process, from
designing the protocol and CRFs and planning the analyses to
analyzing and preparing interim and final clinical trial
reports.
5.4.2 For further guidance: Clinical Trial Protocol and Protocol
Amendment(s) (see 6.), the ICH Guideline for Structure and Content
of Clinical Study Reports, and other appropriate ICH guidance on
trial design, protocol and conduct.
5.4申办方需要聘请有资质的生物统计家、药理学家、医生等有专业背景的人员进行临床研究方案、CRF、统计报告、总结报告等资料的撰写。这些专业人士的工作其实都可以被外包出去，成为CRO
的部分职能。甚至二丘有经历过直接请研究者撰写方案的。
5.5 Trial Management, Data Handling, and Record
Keeping
5.5.1 The sponsor should utilize appropriately qualified
individuals to supervise the overall conduct of the trial, to
handle the data, to verify the data, to conduct the statistical
analyses, and to prepare the trial reports.
5.5.1与5.4内容基本一致，申办方的人员配备。
5.5.2 The sponsor may consider establishing an independent
data-monitoring committee (IDMC) to assess the progress of a
clinical trial, including the safety data and the critical efficacy
endpoints at intervals, and to recommend to the sponsor whether to
continue, modify, or stop a trial. The IDMC should have written
operating procedures and maintain written records of all its
meetings.
5.5.2
申办方可以建立数据安全监测委员会（IDMC）以阶段性审查临床试验的安全和疗效数据，根据审查结果来给出申办方是否继续试验、修改试验或者停止试验的建议。IDMC
需要有自己的工作章程同时也需保留所有的会议记录。
提问，IDMC 的成员一般如何配置？欢迎小伙伴们踊跃发言。
5.5.3 When using electronic trial data handling and/or remote
electronic trial data systems, the sponsor should:
(a) Ensure and document that the electronic data processing
system(s) conforms to the sponsor’s established requirements for
completeness, accuracy, reliability, and consistent intended
performance (i.e. validation).
(b) Maintains SOPs for using these systems.
(c) Ensure that the systems are designed to permit data changes in
such a way that the data changes are documented and that there is
no deletion of entered data (i.e. maintain an audit trail, data
trail, edit trail).
(d) Maintain a security system that prevents unauthorized access to
the data.
(e) Maintain a list of the individuals who are authorized to make
data changes (see 4.1.5 and 4.9.3).
(f) Maintain adequate backup of the data.
(g) Safeguard the blinding, if any (e.g. maintain the blinding
during data entry and processing).
5.5.3 如果申办方采用电子数据处理系统（EDC）采集、保存、处理临床试验数据，那么这款EDC 需要具备以下功能：
1）该系统被验证过；
2）有SOP 指导该系统的操作；
3）有稽查轨迹；
4）需要有账户和密码登录，安全性能高；
5）有使用者清单；
6）数据可以备份；
7）保证盲法。
看完这一条，我们来回想我们之前使用的EDC 系统上述条件是否均具备了呢。
5.5.4 If data are transformed during processing, it should always
be possible to compare the original data and observations with the
processed data.
5.5.4 数据的转换需要有记录。
5.5.5 The sponsor should use an unambiguous subject identification
code (see 1.58) that allows identification of all the data reported
for each subject.
5.5.5
申办方需要给受试者独特的编码，以便于识别每位受试者的信息。编码就比如受试者编号、药物号等都属于受试者的独特的编码用来替代受试者的姓名。
5.5.6 The sponsor, or other owners of the data, should retain all
of the sponsor-specific essential documents pertaining to the trial
(see 8. Essential Documents for the Conduct of a Clinical
Trial).
5.5.6申办方需要保留所有临床试验必须文件（申办方需要保存的那部分）；研究者保存的必须文件存放于研究者文件夹（ISF）中，申办方保存的放在Trial
Master File,TMF. 文件列表在本法规的第八章。
5.5.7 The sponsor should retain all sponsor-specific essential
documents in conformance with the applicable regulatory
requirement(s) of the country(ies) where the product is approved,
and/or where the sponsor intends to apply for approval(s).
5.5.7
这一条是将除了本法规第八章规定的essential
documents以外，也要遵循拟（以）上市国家或地区当地法规，其要求的文件也要保存。
5.5.8 If the sponsor discontinues the clinical development of an
investigational product (i.e. for any or all indications, routes of
administration, or dosage forms), the sponsor should maintain all
sponsor-specific essential documents for at least 2 years after
formal discontinuation or in conformance with the applicable
regulatory requirement(s).
5.5.8
如果申办者决定终止某项研究，则与该研究相关的文件应该保存至其正式决定终止发布后的两年或者按照当地法规一致。
即，文件至少保存两年。
5.5.9 If the sponsor discontinues the clinical development of an
investigational product, the sponsor should notify all the trial
investigators/institutions and all the regulatory
authorities.
5.5.9
如果申办者决定终止某项研究，需要通知各临床试验的相关方。
这与研究者一致。不同的是伦理应该由申办方通知研究者然后由研究者告知。
5.5.10 Any transfer of ownership of the data should be reported to
the appropriate authority(ies), as required by the applicable
regulatory requirement(s).
5.5.10
申办方的变更或者试验数据所有权的变更应该根据当地法律法规，告知相关法规部门。
5.5.11 The sponsor specific essential documents should be retained
until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or
contemplated marketing applications in an ICH region or at least 2
years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents should
be retained for a longer period however if required by the
applicable regulatory requirement(s) or if needed by the
sponsor.
5.5.11 申办方保存的文件的保存年限，最后一个国家或地区上市后的两年，或者终止发布后的两年。
两年都是最低年限，应该遵循各个国家的规定。 比如在中国就是5年。 所以就时间长的那个计算。
5.5.12 The sponsor should inform the investigator(s)/institution(s)
in writing of the need for record retention and should notify the
investigator(s)/institution(s) in writing when the trial related
records are no longer needed.
5.5.12
申办方除了管好自己的文件，研究者保管的文件的保存年限，以及何时销毁也要及时告知。比如一般研究文件保存年限会写入合同，在年限到达时候，申办方应当书面通知研究中心/研究者与本试验相关的文件可以被销毁。所以对于研究中心而言，千万不可擅自销毁研究文件，一定要联系上申办方，获得其书面确认后方可销毁。
5.5 是关于试验的管理、数据的处理、记录的保存，这其中涉及到有资质的人员、合格的系统、以及制度等。
5.6 Investigator Selection
5.6.1 The sponsor is responsible for selecting the
investigator(s)/institution(s). Each investigator should be
qualified by training and experience and should have adequate
resources (see 4.1, 4.2) to properly conduct the trial for which
the investigator is selected. If organization of a coordinating
committee and/or selection of coordinating investigator(s) are to
be utilized in multicentre trials, their organization and/or
selection are the sponsor's responsibility.
5.6.2 Before entering an agreement with an investigator/institution
to conduct a trial, the sponsor should provide the
investigator(s)/institution(s) with the protocol and an up-to-date
Investigator's Brochure, and should provide sufficient time for the
investigator/institution to review the protocol and the information
provided.
5.6.3 The sponsor should obtain the investigator's/institution's
agreement:
(a) to conduct the trial in compliance with GCP, with the
applicable regulatory requirement(s) (see 4.1.3), and with the
protocol agreed to by the sponsor and given approval/favourable
opinion by the IRB/IEC (see 4.5.1);
(b) to comply with procedures for data recording/reporting;
(c) to permit monitoring, auditing and inspection (see 4.1.4)
and
(d) to retain the trial related essential documents until the
sponsor informs the investigator/institution these documents are no
longer needed (see 4.9.4 and 5.5.12). The sponsor and the
investigator/institution should sign the protocol, or an
alternative document, to confirm this agreement.
5.6 研究者/研究中心的选择
5.6.1研究者/研究中心相对于申办方来说属于乙方，所以临床试验供应商的选择当然是甲方的职责。申办方需要确保选择的研究者具备E6R2《研究者》一章中所述的职责：
有临床经验、资质、培训、有一定的患者资源。申办方也负责选择牵头的研究单位或者研究者。
提问：如果你作为申办方的决策者，你在选择牵头单位和牵头研究者时会考虑哪些因素？
二丘经历过的一些研究，有设立组长单位和牵头PI，
这种配置的多中心研究，很多分中心伦理在材料审查时需要提供组长单位的审批批件，哪怕只是审查一个知情同意书仍然需要组长单位的批件。从申办方角度这一要求大大复杂了伦理审查的流程、降低了伦理审查的效率。当然从分中心角度，跟着组长老大哥的步伐迈进，一般不会出啥大错。这对于一些新成立的伦理单位而言是一个保障。总之，设立组长单位，有蔽有利。二丘遇到一些比较成熟的伦理单位，一般会自己审查，出具审查意见，同时仅要求组长单位的意见备案，二丘要给这些伦理单位好评。设立组长单位的另一优势，部分分中心的伦理单位认可组长单位的审查结果，在本中心可以免审查，
当然这些单位是少之又少，早些年那些做四期的单位会这样操作。但是二丘还真遇到一家不小的中心，接受组长单位的审查结果免除伦理审查，但是伦理费也一分不少的收。
二丘猜测，可能是因为设立组长单位的一些弊端，大大降低了临床试验的效率。有些机智的申办方开始设立牵头PI，
但是牵头PI所在的单位不作为组长单位。所有的中心均为平行单位。这种做法真的太机智了，一石二鸟。既能依赖牵头PI的资源联系各家中心，同时由于每家单位是平行单位，加快了伦理审查效率。临床试验的项目组统一出一份《本研究不设立组长单位申明》递交至各家中心，大家都开心。
5.6.2-5.6.3 申办方在和研究中心确立合作关系的时，需要具备一系列条件：
申办方要将自己的研究方案、研究者手册发送给研究者审阅，这个审阅的过程也是请研究者确认一下其是否可以承接这个项目。
正式确立合作关系时，合作方需要签订合约来约定双方在这一合作中各自承担的职责，研究者的职责都会列入合同中。值得注意的是，研究方案也可以被认为是一种合约，申办方和主要研究者均需要在研究方案中签字，签字即代表认可，签字方会按照方案的要求执行研究。说到签字，我们来思考一下研究者应该何时在研究方案中签字？一般如果在做中心筛选时，研究者对方案没有任何质疑，可以签字。再不济，等到双方意向基本确立，方案递交伦理时，研究者需要将自己认可的方案递交伦理，所以至少递交伦理时签字。
5.7 Allocation of Responsibilities
Prior to initiating a trial, the sponsor should define, establish,
and allocate all trial-related duties and functions.
5.7 人员、权责的分配。临床试验是一个团队的事情。必须依靠合作达成。
5.8 Compensation to Subjects and Investigators
5.8.1 If required by the applicable regulatory requirement(s), the
sponsor should provide
insurance or should indemnify (legal and financial coverage) the
investigator/the
institution against claims arising from the trial, except for
claims that arise from
malpractice and/or negligence.
5.8.2 The sponsor's policies and procedures should address the
costs of treatment of trial
subjects in the event of trial-related injuries in accordance with
the applicable regulatory
requirement(s).
5.8.3 When trial subjects receive compensation, the method and
manner of compensation
should comply with applicable regulatory requirement(s).
5.8对受试者和研究者的补偿，这一条肯定是写入研究协议：如果因临床试验的原因而非临床医生操作不当引起的医疗事故，申办方应当为研究者或研究机构提供经济保证；受试者因参与临床研究发生的损害，申办方应当承担相应的治疗费用。对受试者的经济补充应当按照相关法规执行。正是因为这一条的存在，很多研究机构要求即使在CRO存在的条件下，申办方需要参与协议的缔约。原因是受试者因临床试验发生的损害，任何CRO也无法承担相应的责任，责任主体还在申办方。
5.9 Financing
The financial aspects of the trial should be documented in an
agreement between the sponsor and the
investigator/institution.
5.9 申办方为临床研究提供资金支持。这是金主爸爸最有魅力的地方。
5.10 Notification/Submission to Regulatory
Authority(ies)
Before initiating the clinical trial(s), the sponsor (or the
sponsor and the investigator, if required by the applicable
regulatory requirement(s)) should submit any required
application(s) to the appropriate authority(ies) for review,
acceptance, and/or permission (as required by the applicable
regulatory requirement(s)) to begin the trial(s). Any
notification/submission should be dated and contain sufficient
information to identify the protocol.
5.10
临床试验需要获得监管部门的批准。在中国临床试验需要获得药监局的批件方可实施。这个批件基本上是药品走上临床的第一步，也是最关键的一步。没有这个批件，其余的都免谈。很久之前二丘在CRO做商务助理时就天天扒着CDE的网站，看每周又有哪些厂家拿到批件了，
是否有机会进行临床合作。现在这种商务合作方法估计早已被淘汰了吧。商务精英们应该早在临床申请提交之时拿下订单了。最近有消息透露临床试验申请的审批今后可能会从审批制改为备案制。备案制即申报临床的申请申报后在规定的时间内如果没有监管部门的反对意见即代表可以实施。这也是效仿国外的监管方案，加速药品审评的一条途径。
5.11 Confirmation of Review by IRB/IEC
5.11.1 The sponsor should obtain from the
investigator/institution:
(a) The name and address of the investigator's/institution’s
IRB/IEC.
(b) A statement obtained from the IRB/IEC that it is organized and
operates according to
GCP and the applicable laws and regulations.
(c) Documented IRB/IEC approval/favourable opinion and, if
requested by the sponsor,
a current copy of protocol, written informed consent form(s) and
any other written
information to be provided to subjects, subject recruiting
procedures, and documents
related to payments and compensation available to the subjects, and
any other
documents that the IRB/IEC may have requested.
5.11.2 If the IRB/IEC conditions its approval/favourable opinion
upon change(s) in any aspect of the trial, such as modification(s)
of the protocol, written informed consent form and any other
written information to be provided to subjects, and/or other
procedures, the
sponsor should obtain from the investigator/institution a copy of
the modification(s)
made and the date approval/favourable opinion was given by the
IRB/IEC.
5.11.3 The sponsor should obtain from the investigator/institution
documentation and dates of any IRB/IEC reapprovals/re-evaluations
with favourable opinion, and of any withdrawals
or suspensions of approval/favourable opinion.
5.11申办方与伦理委员会的关系。
伦理委员会一般不直接与申办方联系，二者之间的桥梁会是研究者。所以我们看到申办方的任何决定都是通过研究者传达给伦理委员会。那么反向地，伦理委员会的任何决定都是通过研究者传达。在我们国内，只有部分特别轴的伦理委员会会严禁申办方人员直接沟通，当然大部分伦理都会很nice
的接受申办方人员的沟通，实际也是只有这样，双方的工作效率才能提高。
无论什么样的工作方式，申办方需要从伦理那边拿到对研究审查的意见，即伦理批件。拿到伦理批件后，申办方需要确认批件以下信息：
-伦理审查的内容；
-伦理审查的结果；
-伦理审查结果的日期；
-伦理委员会的名称，伦理委员会的地址；
-伦理委员会遵守GCP和相关法规的申明。
如果伦理出具的意见是修正后同意，那么申办方也需要协助研究者递交修正后的文件，直至获得伦理同意的批件。话说，你如果是一名监查员，你刚入门的时候有没有做过伦理批件找茬的游戏呢？关于伦理批件的要素，详细内容，二丘将会在《伦理委员会的职责》一章详细讲解。
5.12 Information on Investigational Product(s)
5.12.1 When planning trials, the sponsor should ensure that
sufficient safety and efficacy data from nonclinical studies and/or
clinical trials are available to support human exposure by the
route, at the dosages, for the duration, and in the trial
population to be studied.
5.12.2 The sponsor should update the Investigator's Brochure as
significant new information becomes available (see 7.
Investigator's Brochure).
5.12
研究者手册的更新也是申办方是职责。申办方需要在研究者手册中详细记录从临床前试验以及现有的临床试验中获得的关于研究产品的安全性和有效性的信息。在有重大安全性信息更新时，应当及时更新知情同意书。研究者手册的更新频率一般按各家公司的SOP执行，大多为一年一次，做的好的申办方一年内即使没有更新内容也会出个说明告知研究者。由于研究者手册无法做到高频率更新，所以研究期间的SUSAR,
SAE等安全性信息的及时报告就显得尤为重要。
关于研究安全性报告，几乎所有的项目经理都会及其重视是否有及时递交，然而这也是一个实效性的文件，就算没有及时递交，研究者手册更新了，所有安全性信息涵盖在更新的研究者手册中，研究者手册递交给研究者了，之前的旧账也可以翻篇。安全性信息和研究者手册是一个具有法律效益的文件，你递交给研究者了，说明你通知给研究者了，今后受试者发生任何安全性事件，研究者可以参考你提供的文件，协助其处理那些安全性时间。然而，如果你万一没有递交，似乎这个事情就很难说清楚了。所以，无论怎样，二丘忠告，一定要重视安全性报告、研究者手册的递交。
5.13 Manufacturing, Packaging, Labelling, and Coding
Investigational Product(s)
5.13.1 The sponsor should ensure that the investigational
product(s) (including active
comparator(s) and placebo, if applicable) is characterized as
appropriate to the stage of
development of the product(s), is manufactured in accordance with
any applicable GMP,
and is coded and labelled in a manner that protects the blinding,
if applicable. In addition,
the labelling should comply with applicable regulatory
requirement(s).
5.13.2 The sponsor should determine, for the investigational
product(s), acceptable storage
temperatures, storage conditions (e.g., protection from light),
storage times,
reconstitution fluids and procedures, and devices for product
infusion, if any. The
sponsor should inform all involved parties (e.g., monitors,
investigators, pharmacists,
storage managers) of these determinations.
5.13.3 The investigational product(s) should be packaged to prevent
contamination and
unacceptable deterioration during transport and storage.
5.13.4 In blinded trials, the coding system for the investigational
product(s) should include a mechanism that permits rapid
identification of the product(s) in case of a medical
emergency, but does not permit undetectable breaks of the
blinding.
5.13.5 If significant formulation changes are made in the
investigational or comparator
product(s) during the course of clinical development, the results
of any additional studies
of the formulated product(s) (e.g., stability, dissolution rate,
bioavailability) needed to
assess whether these changes would significantly alter the
pharmacokinetic profile of the
product should be available prior to the use of the new formulation
in clinical trials.
5.13.1申办方需要按照GMP的要求生产临床试验用药品，药品的包装、标签等。由于涉及临床研究用药，如果涉及到盲法，标签还需要编盲信息，如药物号等。药品的标签需要符合当地的法律法规要求。比如中国的临床试验用药，必须清晰地标注：仅供临床试验使用。
5.13.2申办方需要决定药品的存储条件，如存储温度、湿度、是否需要避光、效期，如果需要静配，静配的要求等。这些信息如果在方案里面不能详尽的描述，则需要单独出具一个药品使用手册，以书面的方式将这些信息传达给研究中心的相关人员。
5.13.3药品包装的应当独立、防止在运输中产生混淆、污染。这个跟流通的药品同样的要求。
5.13.4如果研究设立盲法，应当建立揭盲的机制，同时也能避免意外揭盲。比如以前用应急信封的揭盲方法，应急信封应当由专人专管，同时有backup的人员，应急信封存放地点要安全，需要达成某个条件，应急信封方可被开启。如果是盲态系统，则需要固定的账号和密码，以及系统的确认才可以揭盲。
5.13.5此条所述，二丘尚未经历过类似事件。如果在试验进程中，试验药品的成分信息有更改，则需要一系列药物分析的结果（如稳定性、溶解度、生物利用度等），这些变化是否会影响药代动力学。这些信息均需要在临床使用前提供。那么由于这种药物成分改变，是与受试者安全性息息相关的变化，在新的药品使用前肯定也是需要经过伦理审批同意的。
5.14 Supplying and Handling Investigational Product(s)
5.14.1 The sponsor is responsible for supplying the
investigator(s)/institution(s) with the
investigational product(s).
5.14.2 The sponsor should not supply an investigator/institution
with the investigational
product(s) until the sponsor obtains all required documentation
(e.g., approval/favourable
opinion from IRB/IEC and regulatory authority(ies)).
5.14.1-5.14.2
药品供应是申办方的职责。药品供应只有在获得伦理批准或相关部门的批准后方可运送至研究中心。关于这一条，E6R2只是明确了伦理批件是药品供应的先决条件。但是在实际操作中，我们一般是合同签署完成并且研究中心启动启动后方可运送药物至研究中心。
这是什么原因呢？原因是按照公司的SOP 是需要这么操作的。当然，这只是表象，可是公司SOP
为何有这个要求？我们不妨来思考一下，如果合同不签署，研究药物在研究中心被误使用导致的安全性问题谁来承担法律责任？启动会不开启，研究者或相关授权人员没有被培训过药品管理内容，就来接收或保管药品，是否违反了GCP？
二丘在《研究者的职责》一章中有讲述，任何参与研究的人员均需要接受培训才可以承担相应的职责。所以作为一名小A，如果你的公司没有明确的SOP
要求，并且你的项目经理要求中心启动前（合同已经签署完成的背景下）运送药品，你能做的是给接收药品的老师提前做好药品管理的培训，并且提前请PI
给该老师授权。如果中心启动完成（合同尚未签署），当然这种情况及其少数，作为一名小A，
你需要与机构和你的项目经理联系，获得双方的书面允许。
5.14.3 The sponsor should ensure that written procedures include
instructions that the
investigator/institution should follow for the handling and storage
of investigational
product(s) for the trial and documentation thereof. The procedures
should address
adequate and safe receipt, handling, storage, dispensing, retrieval
of unused product from
subjects, and return of unused investigational product(s) to the
sponsor (or alternative
disposition if authorized by the sponsor and in compliance with the
applicable regulatory
requirement(s)).
5.14.3 申办方需要提供一个书面的详尽的药品管理说明，如IP
manual(药品管理手册)。这个手册中需要写明，药品从申请、接收、发放（给受试者）、回收（从受试者）、存储、返回（至申办方）一系列药品在研究中心管理的操作指南。作为一名小A，一定要确保药品管理人员熟悉药品管理手册中的内容，一份好的药品管理手册可以大大提高药品管理的效率。当然，如果你的项目没有药品管理手册，仅在研究方案中描述药品管理的要求，此时也建议小A能够自己结合方案以及项目组要求，制作一份可以一目了然的药品管理的指导文件给药品管理员，这样我们会减少很多沟通成本。比如，作为一个监查员，如果你每天都会接到研究中心无数个电话，此时你就得思考一个问题，中心的研究者/研究人员是不是对流程不熟悉，我是不是培训不到位？其实古人有一句话说的十分有道理，授人与予鱼不如授人予渔。你与其反复地跟site
老师解释遇到各种情况应该如何处理，不如一开始就提供一个指南性的文件给他们，告诉他们如何使用这个文件，遇到什么问题，怎么在指南中找寻答案。如果你同时管理好几个项目，你的记忆肯定是不如白纸黑字的文件来的更准确和及时。同样，再插一句题外话，与药品管理手册类似，请一定要教会我们的研究者们学会使用中心实验室手册、病历报告表填写指南等指导性文件。
5.14.4 The sponsor should:
(a) Ensure timely delivery of investigational product(s) to the
investigator(s).
(b) Maintain records that document shipment, receipt, disposition,
return, and
destruction of the investigational product(s) (see 8. Essential
Documents for the
Conduct of a Clinical Trial).
(c) Maintain a system for retrieving investigational products and
documenting this
retrieval_r(e.g., for deficient product recall, reclaim after trial
completion, expired
product reclaim).
(d) Maintain a system for the disposition of unused investigational
product(s) and for the
documentation of this disposition.
5.14.4申办方需要确保研究药品及时的供应，需要保留所有的药品流转的过程性文件，建立药品返回、药品返回后处理（销毁）的机制。总之，在药品的管理流程中要保存好所有记录，没有记录就没有发生，一份好的记录，可以清晰地帮我们重现药品流转的过程。所以这种记录性文件，一定要确保其ALCOAC原则，这个很重要。
5.14.5 The sponsor should:
(a) Take steps to ensure that the investigational product(s) are
stable over the period of
use.
(b) Maintain sufficient quantities of the investigational
product(s) used in the trials to
reconfirm specifications, should this become necessary, and
maintain records of
batch sample analyses and characteristics. To the extent stability
permits, samples
should be retained either until the analyses of the trial data are
complete or as
required by the applicable regulatory requirement(s), whichever
represents the longer
retention period.
5.14.5关于药品的效期问题。如果申办方认为，过了复验期的药品仍然可以使用，一定要出具相关稳定性的说明文件，并且给药品重新贴更新的标签。这一条也解释了，所有的研究中心均需要提供研究药品的药检报告，没有药检报告，我如何判定这个药品是检验合格的，其有效成分是稳定的，是可以被使用的。所有的试验药品均需要留样，这一点GMP对于非试验用药品也是同样的要求。
5.15 Record Access
5.15.1 The sponsor should ensure that it is specified in the
protocol or other written agreement that the
investigator(s)/institution(s) provide direct access to source
data/documents for trial-related monitoring, audits, IRB/IEC
review, and regulatory inspection.
5.15.2 The sponsor should verify that each subject has consented,
in writing, to direct access to his/her original medical records
for trial-related monitoring, audit, IRB/IEC review, and regulatory
inspection.
5.15
申办方需要与研究中心/研究者达成一致，研究中心的与本临床试验相关的医疗记录是允许被监查、稽查、核查、伦理委员会相关人员查看的。这一契约可以通过研究方案或者研究协议的形式达成。通常我们可以看到这一条件在研究方案和研究协议中均有，属于双重保障。
试验相关医疗记录查阅的权限仅仅获得研究中心的允许还不够，我们也需要获得受试者的同意。所以受试者在进入研究前签署的知情同意书肯定也会有相关描述：受试者同意其试验相关医疗记录可供监查、稽查、核查、伦理委员会相关人员查看。只有受试者同意这一条，签署知情同意书了，才可以进入研究，对其执行研究的相关操作。对申办方而言，其需要确认，研究者是否已经从受试者那里取得相关同意。这一条也引申了一个话题，监查员作为申办方的代表，在查阅受试者资料最先查阅的是知情同意书，如果没有受试者的知情同意书，从法律层面，我们是无权查阅受试者的其他医疗记录的。
5.16 Safety Information
5.16.1 The sponsor is responsible for the ongoing safety evaluation
of the investigational
product(s).
5.16.2 The sponsor should promptly notify all concerned
investigator(s)/institution(s) and the regulatory authority(ies) of
findings that could affect adversely the safety of subjects,
impact the conduct of the trial, or alter the IRB/IEC's
approval/favourable opinion to
continue the trial.
5.16此条基本与5.12所述内容一致。申办方应当及时将与研究有关的安全性信息传达给研究者/研究中心。
5.17 Adverse Drug Reaction Reporting
5.17.1 The sponsor should expedite the reporting to all concerned
investigator(s)/institutions(s), to the IRB(s)/IEC(s), where
required, and to the regulatory authority(ies) of all adverse drug
reactions (ADRs) that are both serious and unexpected.
5.17.2 Such expedited reports should comply with the applicable
regulatory requirement(s) and with the ICH Guideline for Clinical
Safety Data Management: Definitions and Standards for Expedited
Reporting.
5.17.3 The sponsor should submit to the regulatory authority(ies)
all safety updates and periodic reports, as required by applicable
regulatory requirement(s).
5.17不良反应报告
不良反应（ADR），并且严重的Serious ,
并且非预期的Unexpected,这三个要素的集合，就是我们常说的SUSAR，suspected unexpected serious
adverse reaction。如何理解这个SUSAR呢， SUSAR 一定是具有他的三个要素的特点的：
1）ADR 的特点： 判定与研究用药的使用具有相关性的。基本除了判定为肯定无关的其他所有的判定都是具有相关性的。
2）Serious的特点：符合SAE的范畴。
3）Unexpected：研究者手册中尚未描述过的，或者尚未报道过的。其实个人认为判定unexpected以研究者手册的登记为准，因为毕竟研究者手册是作为一个具有法律地位的文件存在的。如果研究者或者监查员实在无法明确某一事件是否属于unexpected,建议请申办方作为判断。所以SUSAR翻译成中文就是严重的非预期的不良反应。
E6R2要求SUSAR的报告应当遵循当地的法规以及ICH Guideline for Clinical Safety Data
Management。在中国，根据中国GCP, 不等到SUSAR, 所有事件在serious
(SAE)的时候均已经报告了。随着中国成为ICH的成员，相信研究中心的伦理会、中国的法规部门对SAE、SUSAR的报告要求会重新的调整和界定。毕竟SUSAR才是对临床研究最具有研究价值的信息。
5.18 Monitoring
5.18
这一条是与我们监查员的工作息息相关的条款。纵览ICH有四个模块，每个模块又下设N多指南。而与我们监查员相关的仅是指南E6R2中的某一条。虽然这是一个螺丝钉的活，但是这并不意味这我们的认知也需要停留在螺丝钉的工作范畴。因为有一天，你可能会从研究者成长为申办方的医学顾问、你可能从一个监查员成长为项目经理。而成长必须由见识作为支撑，如果希望成长，就必须跳出我们熟悉的领域，尝试了解我们不熟悉的。但是反向思考，在我们跨出熟悉领域的第一步，我们首先要对自己所在的领域足够熟悉。
5.18.1 Purpose
The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are
protected.
(b) The reported trial data are accurate, complete, and verifiable
from source documents.
(c) The conduct of the trial is in compliance with the currently
approved protocol/amendment(s), with GCP, and with the applicable
regulatory requirement(s).
5.18.1
监查的目的：1）受试者的安全和权利是被保护的2）数据是准确、完整、可靠的3）临床研究是严格按照研究方案、GCP和相关的法规执行的。我们讲GCP
有两大原则，安全性和有效性。安全性是受试者的安全性，有效性是指数据的有效性，那么什么才能确保安全性和有效性是得到保障或者在控制范围内呢？方案、SOP、GCP以及相关的法规。所以，我们做的所有关于监查的工作都是围绕“受试者安全”“数据有效”这两个目的执行的。这两个原则如果产生冲突时，哪一个排第一？
当然是“安全”，人权永远是临床试验的第一位。所有临床试验的受试者都会受到赫尔辛基宣言的保护：While the primary
purpose of medical research is to generate new knowledge, this goal
can never take precedence over the rights and interests of
individual research subjects.
5.18.2 Selection and Qualifications of Monitors
(a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the
scientific and/or
clinical knowledge needed to monitor the trial adequately. A
monitor’s qualifications
should be documented.
(c) Monitors should be thoroughly familiar with the investigational
product(s), the
protocol, written informed consent form and any other written
information to be
provided to subjects, the sponsor’s SOPs, GCP, and the applicable
regulatory
requirement(s).
5.18.2 监查员的条件。
-监查员需要是来自申办方委派的。
-监查员在上岗前需要经过培训、并且具有科学或临床相关知识背景以确保其可以胜任监查的工作。监查员的资质需要有书面记录。
-监查员必须熟悉方案、知情同意书或者其他提供给受试者的材料、申办方的SOP、GCP和相关当地的法规要求。
如果申办方已经将监查的工作由CRO代理，CRO则需要履行此条所述申办方的职责。这一条解释了我们去研究中心监查前，一定要确认一下自己是否拿到申办方的监查员委派函、自己的简历是否通过申办方的批准、自己对于研究方案、研究流程是否熟悉、是否完成了研究方案、GCP的培训、是否有培训记录。有些研究中心也会要求监查员提供上述材料，其实这也是研究中心代替申办方履行其职责、自我保障的途径。如果你被研究中心要求提供这些材料，不要奇怪，最好是自己在进入某项研究前，自己准备好这些材料。
5.18.3 Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored.
The sponsor should
determine the appropriate extent and nature of monitoring. The
determination of the
extent and nature of monitoring should be based on considerations
such as the objective,
purpose, design, complexity, blinding, size, and endpoints of the
trial. In general there is
a need for on-site monitoring, before, during, and after the trial;
however in exceptional
circumstances the sponsor may determine that central monitoring in
conjunction with
procedures such as investigators’ training and meetings, and
extensive written guidance
can assure appropriate conduct of the trial in accordance with GCP.
Statistically
controlled sampling may be an acceptable method for selecting the
data to be verified.
ADDENDUM
The sponsor should develop a systematic, prioritized, risk-based
approach to monitoring
clinical trials. The flexibility in the extent and nature of
monitoring described in this
section is intended to permit varied approaches that improve the
effectiveness and
efficiency of monitoring. The sponsor may choose on-site
monitoring, a combination of
on-site and centralized monitoring, or, where justified,
centralized monitoring. The
sponsor should document the rationale for the chosen monitoring
strategy (e.g., in the
monitoring plan).
On-site monitoring is performed at the sites at which the clinical
trial is being conducted.
Centralized monitoring is a remote evaluation of accumulating data,
performed in a
timely manner, supported by appropriately qualified and trained
persons (e.g., data
managers, biostatisticians).
Centralized monitoring processes provide additional monitoring
capabilities that can
complement and reduce the extent and/or frequency of on-site
monitoring and help
distinguish between reliable data and potentially unreliable
data.
Review, that may include statistical analyses, of accumulating data
from centralized
monitoring can be used to:
(a) identify missing data, inconsistent data, data outliers,
unexpected lack of variability
and protocol deviations.
(b) examine data trends such as the range, consistency, and
variability of data within and
across sites.
(c) evaluate for systematic or significant errors in data
collection and reporting at a site
or across sites; or potential data manipulation or data integrity
problems.
(d) analyze site characteristics and performance metrics.
(e) select sites and/or processes for targeted on-site
monitoring.
5.18.3 监查的范畴。监查员工作的范畴是由申办方根据自己项目的实际情况进行的。比如申办方可以决定：
-监查的形式：onsite MV 还是remote MV；
-监查的频率；
-监查的数据点：哪些数据点必须做核对的，哪些是非必须的。E6R2认可非100%数据核对的形式，然而中国是要求100%数据核对。
ADDENDUM
的内容是相对于E6R1增加的内容.随着科技的进步、管理手段的更新E6R2提倡申办方建立自己的监查管理体系，比如设立监查计划，以此更具体的指导监查员的工作。
同时，随着电子病历系统（EDC）的引入，给中心化监查（in house
monitoring）提供了便利。其实很多数据管理员（DM）也分担着监查员的活。CRA通过现场、DM通过远程。中心化监查的引入使得申办方可以及时有效地了解各家中心的数据情况，对监查员工作复核，同时也降低差旅成本。中心化监查的结果指导申办方决定是否需要对相关研究中心再次进行实地监查或者稽查等。借助现代科学的管理手段，E6R2提倡建立基于风险管理的监查模式，这是临床试验的一个很大的进步，由人为决策，到借助数据模型决策。如果你将来有志于项目经理方向，不妨畅想一下未来你的监查员的工作方式会有何变化。你能开发出哪些管理模式可以更大程度提高监查员的工作效率。
5.18.4 Monitor's Responsibilities
The monitor(s) in accordance with the sponsor’s requirements should
ensure that the trial
is conducted and documented properly by carrying out the following
activities when
relevant and necessary to the trial and the trial site:
(a) Acting as the main line of communication between the sponsor
and the investigator.
(b) Verifying that the investigator has adequate qualifications and
resources (see 4.1,
4.2, 5.6) and remain adequate throughout the trial period, that
facilities, including
laboratories, equipment, and staff, are adequate to safely and
properly conduct the
trial and remain adequate throughout the trial period.
(c) Verifying, for the investigational product(s):
(i) That storage times and conditions are acceptable, and that
supplies are
sufficient throughout the trial.
(ii) That the investigational product(s) are supplied only to
subjects who are
eligible to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on
properly using,
handling, storing, and returning the investigational
product(s).
(iv) That the receipt, use, and return of the investigational
product(s) at the trial
sites are controlled and documented adequately.
(v) That the disposition of unused investigational product(s) at
the trial sites
complies with applicable regulatory requirement(s) and is in
accordance with
the sponsor.
(d) Verifying that the investigator follows the approved protocol
and all approved
amendment(s), if any.
(e) Verifying that written informed consent was obtained before
each subject's
participation in the trial.
(f) Ensuring that the investigator receives the current
Investigator's Brochure, all
documents, and all trial supplies needed to conduct the trial
properly and to comply
with the applicable regulatory requirement(s).
(g) Ensuring that the investigator and the investigator's trial
staff are adequately
informed about the trial.
(h) Verifying that the investigator and the investigator's trial
staff are performing the
specified trial functions, in accordance with the protocol and any
other written
agreement between the sponsor and the investigator/institution, and
have not
delegated these functions to unauthorized individuals.
(i) Verifying that the investigator is enroling only eligible
subjects.
(j) Reporting the subject recruitment rate.
(k) Verifying that source documents and other trial records are
accurate, complete, kept
up-to-date and maintained.
(l) Verifying that the investigator provides all the required
reports, notifications,
applications, and submissions, and that these documents are
accurate, complete,
timely, legible, dated, and identify the trial.
(m) Checking the accuracy and completeness of the CRF entries,
source documents and
other trial-related records against each other. The monitor
specifically should verify
that:
(i) The data required by the protocol are reported accurately on
the CRFs and are
consistent with the source documents.
(ii) Any dose and/or therapy modifications are well documented for
each of the
trial subjects.
(iii) Adverse events, concomitant medications and intercurrent
illnesses are
reported in accordance with the protocol on the CRFs.
(iv) Visits that the subjects fail to make, tests that are not
conducted, and
examinations that are not performed are clearly reported as such on
the CRFs.
(v) All withdrawals and dropouts of enrolled subjects from the
trial are reported
and explained on the CRFs.
(n) Informing the investigator of any CRF entry error, omission, or
illegibility. The
monitor should ensure that appropriate corrections, additions, or
deletions are made,
dated, explained (if necessary), and initialled by the investigator
or by a member of
the investigator's trial staff who is authorized to initial CRF
changes for the
investigator. This authorization should be documented.
(o) Determining whether all adverse events (AEs) are appropriately
reported within the
time periods required by GCP, the protocol, the IRB/IEC, the
sponsor, and the
applicable regulatory requirement(s).
(p) Determining whether the investigator is maintaining the
essential documents (see 8.
Essential Documents for the Conduct of a Clinical Trial).
(q) Communicating deviations from the protocol, SOPs, GCP, and the
applicable
regulatory requirements to the investigator and taking appropriate
action designed to
prevent recurrence of the detected deviations.
5.18.4 监查员的职责。
这一条真的很长。由此可见，作为监查员，我们是肩负重任。如果你已经监查，完成过至少一次监查报告，建议你打开监查报告，看一下你们监查报告的checklist里面是否已经包含上述全部的内容？如果你的监查报告模板不能囊括上述的全部要求，建议你可以和你的领导谈谈。5.18.4所述的每一条都是我们的谋生的本领，对于没有监查经验的人来讲理解真的很难，但是对于一般有一年左右监查经验的朋友应该能够如数家珍。不仅在工作，在面试中也都会用到。监查的几个模块：药品、样本（如有）、知情、原始病历、CRF、ISF。这每一个环节都会有很多话题点、很多注意点。一名有心的监查员，肯定会在这些模块有着自己独到的工作技巧。二丘曾经在面试中被问及，你通过什么方法来保证临床试验的质量的。这个问题真的是太宏观了，但是这就像写一篇议论文，我们需要从宏观走向微观，找一个切入点，谈谈你是如何工作的。当然面试问题的回答（除了是非题）是仁者见仁智者见智的，也许你的回答并不能得到面试官的满意，但是那也未必是你的错，只能说明你们的观点不合而已。
5.18.5 Monitoring Procedures
The monitor(s) should follow the sponsor’s established written SOPs
as well as those
procedures that are specified by the sponsor for monitoring a
specific trial.
5.18.5 监查流程 监查员需要根据申办方/CRO的SOP执行监查。
5.18.6 Monitoring Report
(a) The monitor should submit a written report to the sponsor after
each trial-site visit or
trial-related communication.
(b) Reports should include the date, site, name of the monitor, and
name of the
investigator or other individual(s) contacted.
(c) Reports should include a summary of what the monitor reviewed
and the monitor's
statements concerning the significant findings/facts, deviations
and deficiencies,
conclusions, actions taken or to be taken and/or actions
recommended to secure
compliance.
(d) The review and follow-up of the monitoring report with the
sponsor should be
documented by the sponsor’s designated representative.
ADDENDUM
(e) Reports of on-site and/or centralized monitoring should be
provided to the sponsor
(including appropriate management and staff responsible for trial
and site oversight)
in a timely manner for review and follow up. Results of monitoring
activities should
be documented in sufficient detail to allow verification of
compliance with the
monitoring plan. Reporting of centralized monitoring activities
should be regular
and may be independent from site visits.
5.18.6
监查员完成监查后需要撰写监查报告，监查报告中需要记录监查的问题以及跟进的措施。二丘深刻感觉，监查员与稽查员最大的区别就是监查员不仅发现问题还要给出解决方案，一个既要挖坑、又要填坑的活。但是即使就是这样的一份工作，我们也能痛并快乐地干着，因为这份工作相对于稽查更能感受到人间烟火的气息。
ADDENDUM
5.18.7 Monitoring Plan
The sponsor should develop a monitoring plan that is tailored to
the specific human
subject protection and data integrity risks of the trial. The plan
should describe the
monitoring strategy, the monitoring responsibilities of all the
parties involved, the
various monitoring methods to be used, and the rationale for their
use. The plan should
also emphasize the monitoring of critical data and processes.
Particular attention
should be given to those aspects that are not routine clinical
practice and that require
additional training. The monitoring plan should reference the
applicable policies and
procedures.
5.18.7 以及5.18.6 最后一条是E6R2新增加的内容。其要求临床试验的申办方提供监查计划（monitoring
plan），监查计划的内容包含所有E6R2在5.18讲述的内容。及通过书面化的文件，将法规的要求落到实处。坦白来讲，监查计划就是CRA的manual,有了这个manual,我们再也不用什么事情都去找项目经理了。
5.19 Audit
If or when sponsors perform audits, as part of implementing quality
assurance, they should
consider:
5.19.1 Purpose
The purpose of a sponsor's audit, which is independent of and
separate from routine
monitoring or quality control functions, should be to evaluate
trial conduct and
compliance with the protocol, SOPs, GCP, and the applicable
regulatory requirements.
5.19.2 Selection and Qualification of Auditors
(a) The sponsor should appoint individuals, who are independent of
the clinical
trials/systems, to conduct audits.
(b) The sponsor should ensure that the auditors are qualified by
training and experience
to conduct audits properly. An auditor’s qualifications should be
documented.
5.19.3 Auditing Procedures
(a) The sponsor should ensure that the auditing of clinical
trials/systems is conducted in
accordance with the sponsor's written procedures on what to audit,
how to audit, the
frequency of audits, and the form and content of audit
reports.
(b) The sponsor's audit plan and procedures for a trial audit
should be guided by the
importance of the trial to submissions to regulatory authorities,
the number of
subjects in the trial, the type and complexity of the trial, the
level of risks to the trial
subjects, and any identified problem(s).
(c) The observations and findings of the auditor(s) should be
documented.
(d) To preserve the independence and value of the audit function,
the regulatory
authority(ies) should not routinely request the audit reports.
Regulatory authority(ies)
may seek access to an audit report on a case by case basis when
evidence of serious
GCP non-compliance exists, or in the course of legal
proceedings.
(e) When required by applicable law or regulation, the sponsor
should provide an audit
certificate.
5.19稽查
稽查和监查是两份独立的工作。打个比方，如果监查员是依附于人间烟火，那么稽查员就是不识人间烟火。稽查的工作某种程度是基于完美理论来开展的，尽情地挖坑、没有填坑的后顾之忧。既然对于监查员来讲，稽查这么铁面无情，申办方为何又要找人来稽查呢。那是因为稽查是对监查员工作的监督，研究者工作的复核。申办方需要这样一个中立的人员来尽早发现问题，确保项目的质量，降低后期核查的风险。
稽查人员首先要独立于研究，其资质要求与监查员类似。稽查人员的工作应该按照申办方的稽查计划的范畴开展。稽查结束后，稽查报告一般不放于研究中心，取而代之的是稽查证书。法规部门核查时一般也不会要求查阅稽查报告，除非是发生一些严重的GCP违规或者违反法规的事件。所以，提醒小A们，不需要将稽查报告存放于研究中心。
5.20 Noncompliance
5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or
applicable regulatory
requirement(s) by an investigator/institution, or by member(s) of
the sponsor's staff
should lead to prompt action by the sponsor to secure
compliance.
ADDENDUM
If noncompliance that significantly affects or has the potential to
significantly affect
human subject protection or reliability of trial results is
discovered, the sponsor should
perform a root cause analysis and implement appropriate corrective
and preventive
actions.
5.20.2 If the monitoring and/or auditing identifies serious and/or
persistent noncompliance on the part of an
investigator/institution, the sponsor should terminate the
investigator's/
institution’s participation in the trial. When an
investigator's/institution’s participation
is terminated because of noncompliance, the sponsor should notify
promptly the
regulatory authority(ies).
5.20 违规
在临床试验中，如果是对方案、SOP、GCP以及当地适用法规的不遵循被视为违规。如果这个违规对受试者的安全、数据的有效性已经产生了影响，或者可能产生影响，这两种情况下，申办方需要进行事件的归因分析，并且提供相应的纠正和预防措施，就是我们常说的CAPA。如果研究中心上述违规操作达到严重和（或者）持续违规，申办方有权终止在该中心的研究，并且上报相关法规部门。
5.21 Premature Termination or Suspension of a Trial
If a trial is prematurely terminated or suspended, the sponsor
should promptly inform the
investigators/institutions, and the regulatory authority(ies) of
the termination or suspension and the reason(s) for the termination
or suspension. The IRB/IEC should also be informed promptly and
provided the reason(s) for the termination or suspension by the
sponsor or by the investigator/institution, as specified by the
applicable regulatory requirement(s).
5.21
如果申办方需要提前终止或者暂停某项研究，需要及时通知其他试验参与方，研究者/研究机构、法规部门、研究中心的伦理。关于研究中心的伦理，伦理不接受申办方直接沟通，可以通过研究者传达这一决定。
5.22 Clinical Trial/Study Reports
Whether the trial is completed or prematurely terminated, the
sponsor should ensure that the clinical trial reports are prepared
and provided to the regulatory agency(ies) as required by the
applicable regulatory requirement(s). The sponsor should also
ensure that the clinical trial reports in marketing applications
meet the standards of the ICH Guideline for Structure and Content
of Clinical Study Reports. (NOTE: The ICH Guideline for Structure
and Content of Clinical Study Reports specifies that abbreviated
study reports may be acceptable in certain cases.)
5.22
不管研究正常结束还是提前终止，申办方均需按照当地法规要求出具研究总结报告。如果是ICH成员国，研究总结报告需按照ICH相关指南的要求撰写。
5.23 Multicentre Trials
For multicentre trials, the sponsor should ensure that:
5.23.1 All investigators conduct the trial in strict compliance
with the protocol agreed to by the sponsor and, if required, by the
regulatory authority(ies), and given approval/favourable
opinion by the IRB/IEC.
5.23.2 The CRFs are designed to capture the required data at all
multicentre trial sites. For those investigators who are collecting
additional data, supplemental CRFs should also be
provided that are designed to capture the additional data.
5.23.3 The responsibilities of coordinating investigator(s) and the
other participating
investigators are documented prior to the start of the trial.
5.23.4 All investigators are given instructions on following the
protocol, on complying with a uniform set of standards for the
assessment of clinical and laboratory findings, and on
completing the CRFs.
5.23.5 Communication between investigators is facilitated.
5.23 关于开展多中心试验的要求
-所有研究中心遵循申办方、伦理和（或）法规部门批准的研究方案；
-所有研究中心使用同样的CRF模板，如果个别中心收集额外的数据，CRF应当设计一个额外数据采集点；
-关于协调研究者（leading PI）和参与研究者的职责应当在项目启动前明确，这一点一般合同中会进行界定；
-所有研究中心按照同一套标准执行研究，如适用同一个方案，遵循相同的实验室评估标准，遵循相同的CRF填写要求，此条具有非常重要的实践意义，多中心研究的研究评估和数据录入如果不统一规范，那么申办方收到的数据将会很难精确，对研究结果的影响也很大。
我们熟悉的用来评估AE 的CTCAE的标准应该也是应运而生的吧；
-促进多中心研究者的交流， 申办方的协调职责。
E6R2关于申办方职责的23条已经全部介绍完毕，这一章是与我们监查员工作息息相关的，甚至与项目经理的工作也是息息相关。法规表述很宽泛，精炼，重要的还是对法规的诠释和实践。对于本章节如果您有建议或者意见，欢迎补充
。
