1、Institute of Executive Development Institute of Executive Development State Food and Drug Administration of ChinaState Food and Drug Administration of ChinaTraining Program of Clinical Trial Management in Medical Device DevelopmentTraining Program of Clinical Trial Management in Medical Device Devel
2、opmentNanjing, ChinaNanjing, ChinaSeptember 28-29, 2012September 28-29, 2012Mary Ann MorrisAssociate ConsultantGlobal Medical Quality，Eli Lilly & Company, United StatesThe goal of quality in clinical research is to ensure the collection of data in integrity in an ethical manner that protects and saf
3、eguards subjects throughout the life of a clinical trialData integrity is the assurance of the trustworthiness and reliability of data2临床研究中质量的目的是临床研究中质量的目的是为了为了 确保数据采集的完整性确保数据采集的完整性 伦理要求伦理要求 保护和保障受试者保护和保障受试者 贯穿于临床试验的生命贯穿于临床试验的生命 周期周期 中中数据完整性是保障试验数据完整性是保障试验数据的可信度和可靠度数据的可信度和可靠度There is no regulation
4、that says a company must have a Quality Management System, or QMS. However没有法规说一个公司必须有质量管理体系（没有法规说一个公司必须有质量管理体系（QMS)QMS)。然。然而而Industry best practice is for companies to have a quality management system appropriate to their size, the products they produce, and their company culture.业界最佳实践就是需要公司针对他们的规
5、模、生产的产业界最佳实践就是需要公司针对他们的规模、生产的产品和公司文化建立质量管理体系。品和公司文化建立质量管理体系。3A set of policies, processes and procedures required for planning and executionin the core business area of an organization. QMS integrates the various internal processes within the organization and intends to provide a process approach fo
6、r project execution. QMS enables the organizations to identify, measure, control and improve the various core business processes that will ultimately lead to improved business performance. as defined by ISO 9001:2008.一套计划和运营所要求的政策、流程和规程一套计划和运营所要求的政策、流程和规程在一家组织机在一家组织机构的核心商务领域中。构的核心商务领域中。QMSQMS整合组织内部的
7、各个流程，并可提整合组织内部的各个流程，并可提供项目运营的流程途径。供项目运营的流程途径。QMSQMS可使组织机构鉴别、权衡、监控可使组织机构鉴别、权衡、监控和改善最终可导致商务绩效得以提高的各种核心商务流程成和改善最终可导致商务绩效得以提高的各种核心商务流程成为可能为可能 。 载自ISO 9001:20084The most widely accepted model for a QMS is ICH GCP E6 最广为接受的最广为接受的QMSQMS模式源于模式源于ICH GCP ICH GCP E6E6E6 does not have a section on clinical qual
8、ity systems but E6 E6 并没有临床质量体并没有临床质量体系，但是系，但是Section 2.13 states:第第2.13 2.13 部分指出部分指出: :Systems with procedures that assure the quality of every aspect of the trial should be implemented.确保试验每一个方面质量的规程体系应当被实施。确保试验每一个方面质量的规程体系应当被实施。5Management Support/InvolvementTrained/Qualified PersonnelQuality Co
9、ntrol (QC)Quality Assurance (QA)Continual Improvement6管理层的支持和介入管理层的支持和介入经过培训的经过培训的/ /合格的人员合格的人员质量控制质量控制 (QC)(QC)质量保障质量保障 (QA)(QA)持续改善持续改善Management should establish a quality system that includes policies, procedures and processes to meet the regulatory, quality control, and quality assurance expect
10、ations管理层应当建立包括政策、规程和流程在内的质量体系，管理层应当建立包括政策、规程和流程在内的质量体系，以满足监管、质量控制和质量保障的期许以满足监管、质量控制和质量保障的期许As part of the QMS, management should also establish a process to capture, quantify and analyze performance. If properly done, it will allow for continual improvement.作为作为QMSQMS的部分的部分, , 管理层也应当建立能采集、量化和分析管理层也
11、应当建立能采集、量化和分析绩效的程序。如果正确运用，它可以使得持续改善成为可绩效的程序。如果正确运用，它可以使得持续改善成为可能。能。7Management responsibilities:define the scope of the QMSsupply the resources resourcesmoneyestablish and maintain the systemmake key decisionshold people accountabledefine clear roles and responsibilities8管理层的职责管理层的职责: :规定规定QMSQMS的范畴
12、的范畴提供资源提供资源 物力物力财力财力建立和维护体系建立和维护体系作出主要决策作出主要决策明确人员归属明确人员归属规范清晰的角色和责规范清晰的角色和责任任Management should ensure procedures in the QMS are to ensure people know what to do. 管理层应当确保管理层应当确保QMSQMS中的规程人人皆知如何去做。中的规程人人皆知如何去做。Sometimes organizations generate procedures to pass regulatory inspections or third-party a
13、udits. 有时组织机构产生的规程能经得起监管视察或第三方稽有时组织机构产生的规程能经得起监管视察或第三方稽查。查。The real purpose behind having a procedure is so employees know how to do a task consistently time after time. 规程背后的真实目的是要雇员知道如何时刻恒定地完成所规程背后的真实目的是要雇员知道如何时刻恒定地完成所担负的职责。担负的职责。These procedures should clearly define roles and responsibilities so
14、 all know who is doing what and when.这些规程应当清楚地规定角色和责任，以至于所有人员都知道谁在做什么和这些规程应当清楚地规定角色和责任，以至于所有人员都知道谁在做什么和何时要做。何时要做。9QualificationsThe quality management system should define what the qualifications or requirements of the person conducting a specific task should be. For example, if a task should be don
15、e by a nurse, there should be documentation typically found in a job description that a nurse with X number of years of experience should fill the role for this procedure. TrainingThe system should explain how training will be done. 10资质资质质量管理体系应当明确承质量管理体系应当明确承担某项特殊任务的人员应担某项特殊任务的人员应该具有什么样的资质和要该具有什么样
16、的资质和要求。求。 例如，如果一项任务应当例如，如果一项任务应当有护士来做的化，通常应有护士来做的化，通常应当在岗位责任说明中表明当在岗位责任说明中表明具有具有X X年经验的护士应当年经验的护士应当担任这个规程中的角色。担任这个规程中的角色。培训培训体系应当解释如何进行培体系应当解释如何进行培训。训。 Per ICH GCP E6, 5.1.1:The sponsor is responsible for implementing and implementing and maintaining quality assurance and quality control maintaining
17、 quality assurance and quality control systems systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). 根据ICH GCP E6, 5.1.1:申办者负责用书面SOP的形式实施和维护质量保障和质量实
18、施和维护质量保障和质量控制体系控制体系，以便确保试验的进行、数据的产生，文档记录和报告都符合试验方案、GCP和相应的监管要求。11QC ensures accountability exists for qualityQC QC 确保责任制存在于质量之中确保责任制存在于质量之中QA ensures that appropriate quality controls have occurredQA QA 确保有相应的质量监控确保有相应的质量监控12The operational techniques and activities undertaken within the quality ass
19、urance systemwithin the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled运营技术和活动在质量保障体系中在质量保障体系中进行，以便证明试验有关的活动的质量已按照要求完成Per ICH GCP E6 5.3.1, quality control should be applied to each stage of data handling to ensure that all dat
20、a are reliable and have been processed correctly依据ICH GCP E6 5.3.1, 质量控制应当运用于处理数据的每一个阶段，以确保所有的数据都是可靠的，并且已被正确地处理13QC checks are:usually completed by the individual or team managing the clinical trialnot unbiased 14QCQC检查是检查是: :通常由管理临床试验通常由管理临床试验的个人或团队完成的个人或团队完成不是无偏见的不是无偏见的 Examples of QC Activities o
21、n a Clinical Study Team临床研究团队中临床研究团队中QCQC活动的案例活动的案例Protocol试验方案试验方案checking that inclusion/exclusion criteria are written in the correct units 检查入组检查入组/ /排出标准在正确的段落中被写出排出标准在正确的段落中被写出checking that all laboratory tests in the body of the protocol are included in the schedule of events检查试验方案中所有化验检测都包括在
22、试验事件流程中检查试验方案中所有化验检测都包括在试验事件流程中Case Report Forms 病例报告表病例报告表( (CRF) CRF) checking for missing data on CRFs 检查检查CRFCRF中的缺失数据中的缺失数据checking that test results are entered in the correct units检查测试结果及其单位输入正确检查测试结果及其单位输入正确Regulatory Reports 监管报告监管报告checking that all studies in scope for the report are incl
23、uded检查所有研究项目都包括在报告范畴中检查所有研究项目都包括在报告范畴中checking that information is consistent throughout the report检查整个报告中信息的一致性检查整个报告中信息的一致性15Metrics can be used to measure different parameters during the conduct of the trial to ensure quality.指标可用于量化试验进行过程中的不同参数以确保质量。指标可用于量化试验进行过程中的不同参数以确保质量。These metrics are som
24、etimes called Key Performance Indicators 这些指标有时被称为关键绩效指标这些指标有时被称为关键绩效指标 Examples of typical quality control metrics include:典型质量控制指标例证包括典型质量控制指标例证包括: :Time to enter and report data 输入和报告数据的时间输入和报告数据的时间Number of observations or corrections identified by monitors or auditors (observations should be ra
25、ted according to their criticality)监查员或稽查员鉴别出的问题或矫正问题的数量（观察应当按照它们的严重监查员或稽查员鉴别出的问题或矫正问题的数量（观察应当按照它们的严重程序定级程序定级) )Time for query resolution 质疑解决的时间质疑解决的时间Time for CRF review 质疑解决的时间质疑解决的时间Number of data errors 数据错误的数量数据错误的数量16Metrics usually are collected and analyzed by the QC function 指标通常由指标通常由QCQC
26、职能部门收集和分析职能部门收集和分析The goal is to identify areas for quality improvement and potential risks. 其目的是为了鉴别质量改善的领域和可能的风险度。其目的是为了鉴别质量改善的领域和可能的风险度。For example, a significant amount of missing data should prompt an investigation. 例如，大量缺失数据应当提示进行调查例如，大量缺失数据应当提示进行调查。 different reasons may exist 不同的原因可能存在不同的原因可
27、能存在protocol or CRF design defect where data do not exist as anticipated试验方案或试验方案或CRFCRF设计的缺陷，使数据如预期一样不存在设计的缺陷，使数据如预期一样不存在lack of compliance with defined protocol assessments 不遵循规定的试验方不遵循规定的试验方案评价案评价data deliberately omitted by the investigator 研究者有意遗漏数据研究者有意遗漏数据 Impact will vary, but all impact data
28、 quality and integrity. 影响程度不一，但都影响数据质量和完整性。影响程度不一，但都影响数据质量和完整性。17Monitors watch over a portion of the clinical trial. Monitoring is the function most often thought of when quality control of clinical research is mentioned. The clinical monitoring of the data involves the review and verification of
29、the source documents and data.18监查员监督部分临床试监查员监督部分临床试验的过程。验的过程。 监查就是要经常监督什监查就是要经常监督什么时候进行临床研究的么时候进行临床研究的质量控制。质量控制。临床数据的监督涉及到临床数据的监督涉及到源文件和数据的审阅和源文件和数据的审阅和查证。查证。All those planned and systematic actions established to ensure the trial is performed and the data are generated, documented (recorded), and
30、reported in compliance with GCP and the applicable regulatory requirement(s)履行为确保试验所建立的全部计划或履行为确保试验所建立的全部计划或系统计划，和数据的产生，文档记录系统计划，和数据的产生，文档记录和报告都是按照和报告都是按照GCPGCP和相关监管要求被和相关监管要求被执行执行19The main function of quality assurance is to provide an independent evaluation of the clinical research for management
31、 质量保障的主要功能是为了向管理层提供临床研究的独立评价质量保障的主要功能是为了向管理层提供临床研究的独立评价The most common method used is an audit最常用的方法是稽查最常用的方法是稽查Per ICH GCP E6 5.19.1, the purpose of a sponsors audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and c
32、ompliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.依据依据ICH GCP E6 5.19.1, ICH GCP E6 5.19.1, 申办者稽查的目的应当是为了证实临床申办者稽查的目的应当是为了证实临床试验的行为遵循试验方案、试验的行为遵循试验方案、SOPSOP、GCPGCP和相关监管要求，其应当独立和相关监管要求，其应当独立于并且不同于常规的监查或质量控制职能。于并且不同于常规的监查或质量控制职能。 20The quality assurance group should pr
33、epare and implement a plan for evaluating each of the steps in the clinical research program质量保障团队应当准备和实施质量保障团队应当准备和实施QAQA计划，以评价临床研究计划中的每一步计划，以评价临床研究计划中的每一步The QA plan should be developed based on: QAQA计划的发展应当依据计划的发展应当依据: :management input 管理层的投入管理层的投入regulatory requirements 监管要求监管要求trial-specific a
34、ttributes 试验专属特性试验专属特性Examples of quality assurance activities involving computerized systems are: 涉及计算机化系统的质量保障活动例涉及计算机化系统的质量保障活动例证：证：audit types: vendor, electronic archives, datacenters, clinical sites, central laboratories, etc. 稽查类别稽查类别: : 服务商、电子档案、数据中心、临床研究机构、中心实验室等服务商、电子档案、数据中心、临床研究机构、中心实验室等P
35、rocess reviews: device program, functional area, trial-specific程序审评程序审评: : 器械计划、功能区域、试验专属器械计划、功能区域、试验专属Continuous Improvement: CAPA programs 持续改善持续改善: CAPA: CAPA计划计划21Every QMS should have a method to ensure it is being followed people are alerted when it is headed in out of control The metric tool
36、is used to establish a state of control and monitor when that state changes.22每一个每一个QMSQMS应当由途径确应当由途径确保保它正在被遵循它正在被遵循 当进入失控时可以警告当进入失控时可以警告 人员人员 指标工具用于当状态变指标工具用于当状态变化时可以建立控制和监化时可以建立控制和监督状态督状态Metrics are standards for measuring performance within a system or processThey are at the heart of a robust QMS
37、 directed at continuous improvement. Metrics as part of the QMS must be able to adapt and evolve along with the organizations business, regulatory and quality objectives23指标是量化体系或程序指标是量化体系或程序绩效的标准。绩效的标准。它们是针对持续改善的它们是针对持续改善的强健强健QMSQMS的要点。的要点。作为作为QMSQMS一部分的指标一部分的指标必须能够适应和随着机必须能够适应和随着机构商务、监管和质量目构商务、监管和
38、质量目标一起发展标一起发展The concepts of root cause analysis and corrective and preventive actions are fundamental to quality systems. CAPA is fundamental to continuous improvement, a principle of an effective clinical quality system.CAPA = Corrective and Preventive Actions24根源分析和纠偏和防根源分析和纠偏和防偏偏(CAPA)(CAPA)的概念是
39、质的概念是质量体系的基础。量体系的基础。 CAPA CAPA 是持续改善的基是持续改善的基础，为有效的临床质础，为有效的临床质量体系的原则。量体系的原则。CAPA = CAPA = 纠正和预防行纠正和预防行动方案（动方案（Corrective Corrective and Preventive and Preventive ActionsActions）Corrective actions steps that are taken to remove the root causes of an existing nonconformity or undesirable situation an
40、d to identify any affected systems. The corrective action process is designed to prevent the recurrence of nonconformities or undesirable situations ISO 9001:2008.25纠偏行动方案纠偏行动方案 针对消除已有不规范根源或不理想情形和针对消除已有不规范根源或不理想情形和鉴别任何受影响的体系所需采取的步骤。鉴别任何受影响的体系所需采取的步骤。纠偏行动过程是为了防止不规范或不理想纠偏行动过程是为了防止不规范或不理想情形再次出现情形再次出现IS
41、O 9001:2008.ISO 9001:2008.Preventive actions 防偏行动方案防偏行动方案steps that are taken to remove the causes of potential nonconformities or potential situations that are undesirable.针对消除可能不规范或潜在不理想情形所采取的步骤针对消除可能不规范或潜在不理想情形所采取的步骤The preventive action process is designed to prevent the occurrence of nonconform
42、ities or situations that do not yet exist.防偏行动过程是为了预防还没有发生的不规范行为或情形出防偏行动过程是为了预防还没有发生的不规范行为或情形出prevent occurrence by eliminating causes. 通过消除根源来预防发通过消除根源来预防发生生 The objective of preventive action is to prevent the occurrence of an error in a process or multiple processes 防偏行动的目的是为了防止多个程序中的某一个程序出现错防偏行动
43、的目的是为了防止多个程序中的某一个程序出现错误误ISO 9001:2008.26E6 Section 5.2.1 A sponsor may transfer any or all of the sponsors 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 as
44、surance and quality control. 27E6 E6 第第5.2.1 5.2.1 部分部分申办者可以转移任何或全部申办者的试验相申办者可以转移任何或全部申办者的试验相关的职责和职能给一家合同研究组织关的职责和职能给一家合同研究组织(CRO),(CRO), 但是试验数据的质量和完整性的最终责任总但是试验数据的质量和完整性的最终责任总是由申办者承担。是由申办者承担。CROCRO应当实施质量保障和应当实施质量保障和质量控制。质量控制。Data quality can benefit significantly from the use of computerized system
45、s.数据质量可以主要受益于计算机化系统的使用。数据质量可以主要受益于计算机化系统的使用。Well-designed and tested computerized systems automate tasks and streamline processes such as the creation, distribution, completion, management, and analysis of data.设计良好和验证的计设计良好和验证的计算化系统使得任务完成自动化成为可能，并且流程化程序，如数据的建算化系统使得任务完成自动化成为可能，并且流程化程序，如数据的建立、分发、完成、管
46、理和分析等立、分发、完成、管理和分析等 Such automation can 这种自动化过程可以这种自动化过程可以reduce human error 减少人为错误减少人为错误improve consistency and data quality 改善一致性和数据质量改善一致性和数据质量 increase efficiency 增加效率增加效率reduce cost and cycle time. 减少费用和循环时间。减少费用和循环时间。To assist with this task, regulatory bodies have special requirements to assu
47、re the reliability, integrity and confidentiality of electronic data.为了协助这一过程，监管部门颁布了专门的要求来确保电子数据的可靠为了协助这一过程，监管部门颁布了专门的要求来确保电子数据的可靠性、完整性和保密性性、完整性和保密性28All employees of an organization are responsible for quality - it is not just the function of the quality department. 机构中所有的雇员对质量都负有责任机构中所有的雇员对质量都负有责
48、任 它不只是质量部门的职能它不只是质量部门的职能所在。所在。Creating a culture of quality begins with management and is directed down through the organization. 创建质量文化始于管理层并通过组织机构自上而下贯穿。创建质量文化始于管理层并通过组织机构自上而下贯穿。The quality culture is built into the quality system: 质量文化构建于质量体系之中质量文化构建于质量体系之中: :well-defined and documented processes
49、 定义明确的和记录良好的程定义明确的和记录良好的程序序measurement of process performance 程序绩效的量化程序绩效的量化Training 培训培训validation of processes and applicable systems程序和相关体系的验证程序和相关体系的验证29Building quality into clinical research is the responsibility of all stakeholders. Individuals contributing to the clinical research process ne
50、ed to understand quality as an integral attribute of each investigational activity. Every organization is responsible for setting up their quality management system and to ensure continuous improvement. 30构建质量于临床研究之中构建质量于临床研究之中是全体相关人员的责任。是全体相关人员的责任。 从事临床研究过程的人员从事临床研究过程的人员需要懂得质量为每个研究需要懂得质量为每个研究活动内在属性
