Session2临床试验质量依从性的基础：QAQC要素和质量管理体系医疗器械临床试验管理与统计分析培训班讲义课件

1、SESSION 2：FUNDAMENTALS OF QUALITY COMPLIANCE OF CLINICAL TRIALS: QC/QA ELEMENTS AND QMSInstitute of Executive Development State Food and Drug Administration of ChinaTraining Program of Clinical Trial Management in Medical Device DevelopmentNanjing, ChinaSeptember 28-29, 2012Mary Ann MorrisAssociate

2、ConsultantGlobal Medical Quality，Eli Lilly & Company, United States第二部分：临床试验质量依从性的基础： QA/QC要素和质量管理体系第1页，共33页。The goal of quality in clinical research is to ensure the collection of data in integrity in an ethical manner that protects and safeguards subjects throughout the life of a clinical trialDat

3、a integrity is the assurance of the trustworthiness and reliability of dataWHY QULAITY?为什么要质量?2临床研究中质量的目的是为了 确保数据采集的完整性 伦理要求 保护和保障受试者 贯穿于临床试验的生命 周期 中数据完整性是保障试验数据的可信度和可靠度第2页，共33页。There is no regulation 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（QMS)。然

4、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模、生产的产品和公司文化建立质量管理体系。HOW DO WE ENSURE QUALITY IN CLINICAL RESEARCH?如何确保临床研究中的质量?3第3页，共33页。A set of policies, processes and pr

5、ocedures 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 for project execution. QMS enables the organizations to identify, measure, control and improve the

6、 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、流程和规程在一家组织机构的核心商务领域中。QMS整合组织内部的各个流程，并可提供项目运营的流程途径。QMS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为可能 。 载自ISO 9001:2008ONE DEFINITION OF A QUALITY SYSTEM质量体系的定义4第4页，共33页。

7、The most widely accepted model for a QMS is ICH GCP E6 最广为接受的QMS模式源于ICH GCP E6E6 does not have a section on clinical quality systems but E6 并没有临床质量体系，但是Section 2.13 states:第2.13 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

8、被实施。QMS ACCORDING TO ICH GCP E6ICH GCP E6定义的QMS5第5页，共33页。Management Support/InvolvementTrained/Qualified PersonnelQuality Control (QC)Quality Assurance (QA)Continual ImprovementQUALITY COMPONENTS OF A SUCCESSFUL QMS成功QMS的质量内涵6管理层的支持和介入经过培训的/合格的人员质量控制 (QC)质量保障 (QA)持续改善第6页，共33页。Management should estab

9、lish a quality system that includes policies, procedures and processes to meet the regulatory, quality control, and quality assurance expectations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As part of the QMS, management should also establish a process to capture, quantify and analyze performance. If

10、 properly done, it will allow for continual improvement.作为QMS的部分, 管理层也应当建立能采集、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能。MANAGEMENT SUPPORT/INVOLVEMENT管理层的支持/介入7第7页，共33页。Management responsibilities:define the scope of the QMSsupply the resources resourcesmoneyestablish and maintain the systemmake key decisions

11、hold people accountabledefine clear roles and responsibilitiesMANAGEMENT SUPPORT/INVOLVEMENT管理层的支持和介入8管理层的职责:规定QMS的范畴提供资源 物力财力建立和维护体系作出主要决策明确人员归属规范清晰的角色和责任第8页，共33页。Management should ensure procedures in the QMS are to ensure people know what to do. 管理层应当确保QMS中的规程人人皆知如何去做。Sometimes organizations gene

12、rate procedures to pass regulatory inspections or third-party audits. 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。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担负的职责。These procedures should clearly define roles and responsibilit

13、ies so 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何时要做。MANAGEMENT SUPPORT/INVOLVEMENT管理层的支持和介入9第9页，共33页。QualificationsThe quality management system should define what the qualifications or requirements of the person conducting a specific task should be. For example, if a ta

14、sk should be done 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. TRAINED/QUALIFIED PERSONNEL经过培训的/合格的人员10资质质量管理体系应当明

15、确承担某项特殊任务的人员应该具有什么样的资质和要求。 例如，如果一项任务应当有护士来做的化，通常应当在岗位责任说明中表明具有X年经验的护士应当担任这个规程中的角色。培训体系应当解释如何进行培训。 第10页，共33页。Per ICH GCP E6, 5.1.1:The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data a

16、re 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。QUALITY CONTROL AND QUALITY ASSURANCE质量控制和质量保障11第11页，共33页。QC ensures acc

17、ountability exists for qualityQC 确保责任制存在于质量之中QA ensures that appropriate quality controls have occurredQA 确保有相应的质量监控QUALITY CONTROL VS. QUALITY ASSURANCE质量控制与质量保障12第12页，共33页。The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for q

18、uality of the trial-related activities have been fulfilled运营技术和活动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 data 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

19、数据都是可靠的，并且已被正确地处理QUALITY CONTROL IS质量控制是13第13页，共33页。QC checks are:usually completed by the individual or team managing the clinical trialnot unbiased QUALITY CONTROL质量控制14QC检查是:通常由管理临床试验的个人或团队完成不是无偏见的 第14页，共33页。Examples of QC Activities on a Clinical Study Team临床研究团队中QC活动的案例Protocol试验方案checking that

20、 inclusion/exclusion criteria are written in the correct units 检查入组/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试验事件流程中Case Report Forms 病例报告表(CRF) checking for missing data on CRFs 检查CRF中的缺失数据checking that test

21、results are entered in the correct units检查测试结果及其单位输入正确Regulatory Reports 监管报告checking that all studies in scope for the report are included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WHAT DOES QC LOOK LIKEQC看起来像什么15第15页，共33页。Metrics can be used to measu

22、re 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。These metrics are sometimes called Key Performance Indicators 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:Time to enter and report data 输入和报告数据的时间Number of observat

23、ions or corrections identified by monitors or auditors (observations should be rated 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程序定级)Time for query resolution 质疑解决的时间Time for CRF review 质疑解决的时间Number of data errors 数据错误的数量QUALITY CONTROL VIA METRICS通过指标进行质量控制16第16页，共33页。Metrics

24、usually are collected and analyzed by the QC function 指标通常由QC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。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。 different reasons may exist 不同的

25、原因可能存在protocol or CRF design defect where data do not exist as anticipated试验方案或CRF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案评价data deliberately omitted by the investigator 研究者有意遗漏数据 Impact will vary, but all impact data quality and integrity. 影响程度不一，但都影响数据质量和完整性

26、。QUALITY CONTROL THROUGH METRICS通过指标进行质量控制17第17页，共33页。Monitors 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 the source d

27、ocuments and data.QUALITY CONTROL THROUGH MONITORING通过监查进行质量控制18监查员监督部分临床试验的过程。 监查就是要经常监督什么时候进行临床研究的质量控制。临床数据的监督涉及到源文件和数据的审阅和查证。第18页，共33页。All those planned and systematic actions established to ensure the trial is performed and the data are generated, documented (recorded), and reported in complianc

28、e with GCP and the applicable regulatory requirement(s)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，文档记录和报告都是按照GCP和相关监管要求被执行QUALITY ASSURANCE IS质量保障是19第19页，共33页。The main function of quality assurance is to provide an independent evaluation of the clinical research for management 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 c

29、ommon method used is an audit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 compliance with the protocol, SOPs, GCP, and the applicable regulatory requ

30、irements.依据ICH GCP E6 5.19.1, 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、SOP、GCP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。 QA 质量保障20第20页，共33页。The quality assurance group should prepare 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QA计划，以评价临床研究计划中的每一步The QA plan should be

31、 developed based on: QA计划的发展应当依据:management input 管理层的投入regulatory requirements 监管要求trial-specific attributes 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证：audit types: vendor, electronic archives, datacenters, clinical sites, central laboratori

32、es, etc. 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Process reviews: device program, functional area, trial-specific程序审评: 器械计划、功能区域、试验专属Continuous Improvement: CAPA programs 持续改善: CAPA计划QA PLANS QA计划21第21页，共33页。Every QMS should have a method to ensure it is being followed people are alerted when it is headed

33、in out of control The metric tool is used to establish a state of control and monitor when that state changes.CONTINUOUS IMPROVEMENT持续改善22每一个QMS应当由途径确保它正在被遵循 当进入失控时可以警告 人员 指标工具用于当状态变化时可以建立控制和监督状态第22页，共33页。Metrics are standards for measuring performance within a system or processThey are at the heart

34、 of a robust QMS 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 objectivesCONTINUOUS IMPROVEMENT THROUGHMETRICS通过.指标持续改善23指标是量化体系或程序绩效的标准。它们是针对持续改善的强健QMS的要点。作为QMS一部分的指标必须能够适应和随着机构商务、监管和质量目标

35、一起发展第23页，共33页。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 ActionsCONTINUOUS IMPROVEMENT THROUGHCAPA通过C

36、APA持续改善24根源分析和纠偏和防偏(CAPA)的概念是质量体系的基础。 CAPA 是持续改善的基础，为有效的临床质量体系的原则。CAPA = 纠正和预防行动方案（Corrective and Preventive Actions）第24页，共33页。Corrective actions steps that are taken to remove the root causes of an existing nonconformity or undesirable situation and to identify any affected systems. The corrective

37、action process is designed to prevent the recurrence of nonconformities or undesirable situations ISO 9001:2008.CORRECTIVE ACTION纠偏方案25纠偏行动方案 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。纠偏行动过程是为了防止不规范或不理想情形再次出现ISO 9001:2008.第25页，共33页。Preventive actions 防偏行动方案steps that are taken to remove the causes of pote

38、ntial 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The preventive action process is designed to prevent the occurrence of nonconformities 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prevent occurrence by eliminating causes. 通过消除根源来预防发生 The obj

39、ective 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误ISO 9001:2008.PREVENTIVE ACTIONS防偏方案26第26页，共33页。E6 Section 5.2.1 A sponsor may transfer any or all of the sponsors trial-related duties and functions to a CRO, but the u

40、ltimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control. WHAT ABOUT CROS?合同研究组织(CRO)是什么?27E6 第5.2.1 部分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(CRO), 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。CRO应当实施质量保障和质量控制。第

41、27页，共33页。Data quality can benefit significantly from the use of computerized systems.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算化系统使得任务完成自动化成为可能，

42、并且流程化程序，如数据的建立、分发、完成、管理和分析等 Such automation can 这种自动化过程可以reduce human error 减少人为错误improve consistency and data quality 改善一致性和数据质量 increase efficiency 增加效率reduce cost and cycle time. 减少费用和循环时间。To assist with this task, regulatory bodies have special requirements to assure the reliability, integrity a

43、nd 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性、完整性和保密性WAYS TO IMPROVE DATA QUALITYCOMPUTERIZED SYSTEMS改善数据质量的方法计算计化体系统28第28页，共33页。All 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 它不只是质量部门的职能

44、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。The quality culture is built into the quality system: 质量文化构建于质量体系之中:well-defined and documented processes 定义明确的和记录良好的程序measurement of process performance 程序绩效的量化Training 培训validation of processes and applicable systems程序和相关体系的验证QUALITY IS A CULTURE质量是一种文化29第29页，共33页。Building quality into clinical research is the responsibility of all stakeholders. Individuals contributing to the clinical research process need to understand quality as an integral attribute of