1、Session 2：Fundamentals of Quality Compliance of Clinical trials: QC/QA Elements and QMS,Institute of Executive Development State Food and Drug Administration of China Training Program of Clinical Trial Management in Medical Device Development Nanjing, China September 28-29, 2012Mary Ann Morris Assoc
2、iate Consultant Global 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,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 trialData
3、 integrity is the assurance of the trustworthiness and reliability of data,Why 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,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)。然而Indus
4、try 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,A set of policies, processes and procedures re
5、quired 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 various co
6、re 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 9001:2008,One Definition of a Quality System 质量体系的定义,4,The most widely ac
7、cepted 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被实施。,QMS According
8、 to ICH GCP E6 ICH GCP E6定义的QMS,5,Management Support/InvolvementTrained/Qualified PersonnelQuality Control (QC)Quality Assurance (QA)Continual Improvement,Quality 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,Management should establish a quality system that
9、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 properly done, it will all
10、ow 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,Management responsibilities: define the scope of the QMS supply the resources resources money establish and maintain the system make key decisions hold people accountable de
11、fine clear roles and responsibilities,Management 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,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 generate procedures to pa
12、ss 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 responsibilities so all know who
13、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,Qualifications The 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 done by a n
14、urse, 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. Training The 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确承担某项特殊任务的人员应该具有什么样
15、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。,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 are generated, documented (re
16、corded), 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,QC ensures accountability exists for qualityQC 确
17、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,The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities h
18、ave 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，以确保所有的数据都是可靠的，并且已被正确地处理,Quality Control is 质量控
19、制是,13,QC checks are:usually completed by the individual or team managing the clinical trialnot unbiased,Quality Control 质量控制,14,QC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,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 inclusion/exclusion criteria are written in the co
20、rrect 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 results are entered in the correct units检查测试结果及其
21、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 Like QC看起来像什么,15,Metrics can be used to measure different parameters during the conduct of the t
22、rial 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 observations or corrections identified by monitors or aud
23、itors (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,Metrics usually are collected and analyzed by the QC functio
24、n 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 不同的原因可能存在 protocol or CRF design defect where data do
25、 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。,Quality Control through Metrics 通过指标进行质量控制,17
26、,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 documents and data.,Quality Control through Monitoring
27、 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。,All those planned and systematic actions established to ensure the trial is performed and the data are generated, documented (recorded), and reported in compliance with GCP and the applicable regulatory requirement(s)履行为
28、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,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 common method used is an audit最常用的方法是稽查 Per ICH GCP E6 5.19.1, t
29、he 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 requirements.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
30、、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,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 developed based on: QA计划的发展应当依据: management input 管理层的投入 regulatory
31、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 laboratories, 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: devi
32、ce 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,Every QMS should have a method to ensureit is being followed people are alerted when it is headed in out of control The metric tool is used to establish a state of cont
33、rol 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,Metrics are standards for measuring performance within a system or processThey are at the heart of a robust QMS directed at continuous improvement. Metrics as part of the
34、 QMS must be able to adapt and evolve along with the organizations business, regulatory and quality objectives,Continuous 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、监管和质量目标一起发展,The concepts of root cause analysis and corrective and preventive
35、actions are fundamental to quality systems. CAPA is fundamental to continuous improvement, a principle of an effective clinical quality system.CAPA = Corrective and Preventive Actions,Continuous Improvement throughCAPA 通过CAPA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
36、预防行动方案（Corrective and Preventive Actions）,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 action process is designed to prevent the recurrence of nonconformities or undesirabl
37、e 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.,Preventive actions 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
38、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 objective of preventive action is to prevent the occurrence of an error in a process or
39、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,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 ultimate responsibility for the quality and integrity of the trial data always resides with
40、 the sponsor. The CRO should implement quality assurance and quality control.,What About CROs? 合同研究组织(CRO)是什么?,27,E6 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。,Data quality can benefit significantly from the use of computerized systems.数据质量可以主要受益于
41、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，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 con
42、sistency 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 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性、完整性和保密性,Ways to Impr
43、ove Data QualityComputerized Systems 改善数据质量的方法计算计化体系统,28,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所在。 Creating a culture of quality begins with management and is directed down through the organiz
44、ation. 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,Bu
45、ilding 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 each investigational activity. Every organization is responsible for setting up their quality management s
46、ystem and to ensure continuous improvement.,Quality is a Culture 质量是一种文化,30,构建质量于临床研究之中是全体相关人员的责任。 从事临床研究过程的人员需要懂得质量为每个研究活动内在属性部分。每一个组织机构都需要建立它们的质量管理体系并确保持续改善。,Total quality only can be achieved by all parties involved in the clinical research paradigm working together while focused on the same endp
47、oints: data integrity and subject safety. Quality is not something achieved in a single point in time, rather the consequence of a series of activities.,Summary 总结,31,总体质量只有通过所有参与临床研究领域的各方共同努力才能实现，其着重于相同的终极目标：数据完整性和受试者安全性。质量不是在某一刻的单独点上可以实现的事情，而是一系列活动的结果。,Quality management systems ensure that the or
48、ganizations management is involved in the system qualified people are trained in and follow the organizations procedures quality control steps are implemented quality assurance audits assure the processes are followed metrics aid in the continual improvement process,Summary 总结,32,质量管理体系确保 组织机构的管理层介入
49、体系中 合格的人员经过机构程序的培训并遵循机构的程序 实施质量控制步骤 质量保障稽查确任程序被遵循 指标有助于持续改善程序。,Experience shows that planning and doing it right the first time, in the end, costs significantly less than trying to fix or salvage it later. Reputation of quality is difficult to build but easy to destroy. Quality and the resulting reputation is what consumers trust and rely upon when they make a decision.,Summary 总结,33,经验表明计划和自始至终做正确的事可以使最后需要纠正或挽救所需的花费努力要少得多。质量的信誉难于建立但易于被毁坏。质量及其结果的信誉是消费者信赖所在并依赖于作出决策的时机。,
