07session 6 理解临床试验的风险管理understanding the risk managment of clinical trials mm cn 医疗器械临床试验管理与统计分析培训班讲义

第六部分：理解临床试验的风险管理,Institute 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 Consultant 助理顾问Global Medical Qualtiy, Eli Lilly & Company, USA 全球医药质量部，美国礼来制药公司,Session 6： Understanding the Risk Management of Clinical Trials,What is Quality?什么是质量？,Information/Data sufficient to support the decision making process throughout the clinical development and post-market approval足以支持临床研发全过程和上市批准后决策的信息/数据Collecting data, generating information, enabling decision making by:收集数据，产生信息，使得下列人员可以做出决策：Sponsors 申办者Ethics Committees 伦理委员会Regulators 监管者Investigators 研究者Healthcare Professionals 卫生保健专业人员Study Subjects 研究受试者,2,Clinical Quality How its evolving临床质量 如何演变而来,Identifying the Problems鉴别问题,Enforcement actions with clear messages on deficiencies缺陷清晰信息的强制行动Lack of confidence in data due to poor quality由于质量不佳缺乏对数据的信心Insufficient monitoring of investigation sites不充分的研究机构监查Questioning if sponsors have CROs in control疑虑申办者是否有CRO在管理Corrections failed to be systemic or effective纠正不成功系统或无效,Discussions about the Solutions解决方案讨论,Discussions on quality and how to improve the deficiencies讨论质量和如何改善缺陷Build quality into the program构建质量于程序中Apply risk management to target resources appropriately应用适当的风险管理到目标资源中Define controls to prevent errors明确监控来预防错误Identify problems and intervene before issues become endemic鉴别问题并在变得严重前解决它,3,Parallel to ICH Q10, Q9, & Q8相关ICH Q10、Q9和Q8,Quality Management Systems (QMS Q10)质量管理体系Not a GCP requirement but, if you have one, you are more likely to meet expectations不是GCP要求，但如果您已经做的化，则更可能符合预期Defines the required controls明确所要求的监控“Say what you do, do what you say, prove it, improve it”“说了您要做什么，做您所说的，证明它，改善它”Quality Risk Management (QRM Q9)质量风险管理Target resources to highest risk: data quality, data integrity, and human research subject protection高度风险的目标资源：数据质量，数据完整性和人体研究受试者保护Initial efforts apply to monitoring最初的努力应用于监查Quality by Design (QbD Q8)设计质量Well designed studies reduce systemic errors设计良好的研究减少系统错误Focus on protocols and case report forms重点在试验方案和病例报告表,4,Principles to Assure Quality保证质量的原则,Determine the factors that are critical to quality确定关键性的质量要素Use a risk-based approach to determine where quality should be improved (i.e., where does quality matter)运用风险管理方法来确定什么地方的质量应当改善Build in quality up front, rather than inspect at the end构建质量在先，而不是在最后进行视察Develop a “closed loop system” to manage quality, including a feedback mechanism to check that the mitigating plans are working, and modify the risks and plans as necessary发展“封闭循环系统”来管理质量，包括反馈机制来检查减缓计划的实施，并在必要时改善风险和计划,5,Determining Factors Critical to Quality确定关键的质量要素,Voice of the Customer客户的声音Quality Objectives质量目标Patient Safety病人安全性Data Quality / Integrity数据质量完整性Protocol Compliance试验方案依从性,6,Example: Critical to Quality例证：关键性质量,7,Identifying & Managing Quality Risks鉴别和管理质量风险,8,Quality Risk Management in the GCP Environment环境中质量风险管理,Say what you do说您要做的 Do what you say做您所说的 Prove it证明它 Improve it改善它,9,PLAN计划,Prospectively define processes & responsibilities for key clinical trial activities, starting with protocol development从试验方案开始，前瞻性地规定关键临床试验活动的程序和责任Pre-identify the procedures and data critical to reliability of study findings预先确定规程和对研究结果可靠性有关键性意义的数据Identify critical measurements 鉴别关键的量化点Determine how errors and deviations will be detected and prevented确定如何发现和预防错误和偏离,10,Identifying Risks - Questions to Ask鉴别风险提问,What could go wrong?什么可能出错？What must go right for us to succeed?我们要成功的话什么必须做对？Where are we vulnerable?我们的弱点在哪里？How do we know whether we are achieving our objectives?如何知道我们是否正在达到我们的目标What activities are most complex?什么活动最复杂？Is there a predicate rule?有现有的条例吗？,11,Using the Failure Modes and Effects Analysis (FMEA) to Identify and Manage Risks采用失效模式和效应分析来鉴别和管理风险,Process for analysis of potential failure modes within a system for classification by the severity and likelihood of the failures. 在分类失败的严重性和可能性系统中潜在失效模式分析的程序A successful FMEA activity helps a team to identify potential failure modes based on past experience, enabling the team to design those failures out of the system with the minimum of effort and resource expenditure, thereby reducing development time and costs成功的活动有助于团队依据过去的经验鉴别潜在的失效模式，使之能用最小的努力和资源成本排除那些失败因素在系统之外，因而减少研发的时间和费用,What is FMEA?什么是？,12,Quality Risk Identification and Mitigation Planning : FMEA质量风险鉴别和预防计划：,Identify鉴别Failure Mode What could go wrong?失效模式什么可能出错？Failure Effect What could happen if it did go wrong失效效应如果出错什么可能发生？Potential Cause What are the possible causes of the issues潜在原因问题可能的原因是什么？,Assessment & Prioritization评价和优化Severity How bad would it be if the risk happened严重性如果风险发生它会糟糕到什么程度？Occurrence How frequently does the cause occur发生起因发生的频率怎样？Detection How easy is it to detect the issue if it occurs检出如果发生的发现它的容易程度如何？,13,Potential Risks Examples潜在风险案例,System Level系统水平Organization structures and responsibilities体制机构和职责Quality systems of organizations体制的质量系统Computer systems计算机系统Human resources including personnel qualifications包括人员资质的人力资源Compliance metrics, quality audits and/or inspection outcomes依从性指标，质量稽查和或视察结果Project Level项目水平Device properties器械性能Investigational product manufacturing process研究产品生产程序Safety and clinical trials安全性和临床试验Study budget, clinical trial site selection and management, CRO involvement, laboratory setup, study databases, safety data monitoring etc.研究预算、临床试验机构选择和管理、合同研究组织介入、实验室建立、研究数据库、安全性数据监查等Complexity of trial design, subject population etc.实验设计复杂性，受试者群等,14,“Traditional” Methods Dont Work传统方法无效,Whos in the room 谁在其中Experience/ “Gut” 经验/“胆量”Memory and “filters” 记忆和“过滤”Gaps / selective recall 差异/选择性回忆Optimism bias 乐观主义偏爱Isolated fixes or “one-off” solutions孤立地修正或“一次性”解决方案,Traditional methods depend on:传统方法取决于,Challenges 挑战:,15,A New Approach.新的方法,Organizational analysis method: structured multidimensional input & interdependencies体制分析方法：有计划的多方位投入和相互关联Risk-find techniques 寻求风险技术Risk assessment (FMEA) （风险评价）Systematic reviews of sources of risk 来源或风险的系统审阅Explores unfamiliar territory 探索不熟悉的领域Identifies and challenges assumptions 鉴别和挑战设想,Integrated “holistic” approach:整合“整体”方法,Benefits 效益:,16,Techniques for Identifying Risks鉴别风险的技术,Asking questions and questioning assumptions “5 WHYS”提问和质问设想 5个为什么“,Comparison with reference standards/history与参照标准/史料对比,Checklists or questionnaires 清单或问答卷,Structure & process mapping/mindmapping构架和程序对映/想法对映,Asking questions RACI charts, governance documents提问RACI图标，管理文件,Algorithms/ decision trees 推算/决策树,Virtual walkthrough 有效预排,17,Risk Identification Biggest Challenge风险鉴别 最大的挑战,Quality by Design depends on reliable identification of risks in advance质量设计取决于预先可靠的风险识别Greatest challenge in areas with little precedent of risk detection, such as:在没有发现风险先例的领域中的最大风险，例如：New or reorganized structures and processes新的或重组机构和程序Innovative projects and clinical programs创新项目和临床规划Innovative methodology 创新方法Changes in external environment 外部环境的变化,18,Quality Risk Identification and Mitigation Planning : FMEA质量风险识别和预防计划：FEMA,Identify 识别Failure Mode What could go wrong?失效模式 什么出错？Failure Effect What could happen if it did go wrong失效效应 如果出错什么可能发生？Potential Cause What are the possible causes of the issues 可能原因 问题的可能根源是什么？,Assessment & Prioritization 评价和优先排序Severity How bad would it be if the risk happened严重性 如果风险发生它将会糟糕到什么程度Occurrence How frequently does the cause occur发生 原因出现的频率会怎样Detection How easy is it to detect the issue if it occurs探测 如果问题出现发现的容易程序如何,19,Risk Prioritization 风险优先排序,Whats the likelihood the risk will occur?风险会出现的可能性是什么？,If the risk does occur, how easy can it be detected?如果风险出现，它能被发现的容易程度怎样？,If the risk occurs, how severe is the impact?如果风险出现，影响的严重性会怎样？,20,Risk Assignment and Prioritization风险划分和优先排序,H高M中L低,L 低 M 中 H 高,Impact影响度,Probability概率,Activity has risk assigned & quantified by probability of occurrence and impact if it occurs通过出现概率和出现的影响度来划分和量化活动的风险 Prioritization to focus on Tier 1 events first优先排序先集中在第一级事件上,21,DO 进行,Specific requirements, and responsibilities are communicated prospectively to:特殊要求和责任要预先交流给：Affected sponsor staff 相关申办者人员CRO and service provider personnel, and合同研究组织和服务提供商人员和Clinical investigators and their staff临床研究者和他们的雇员Execute the plan 实施计划Protocol 试验方案Monitoring Plan 监查计划Other 其它,22,CHECK/ACT 检查/行动,Risk-based monitoring 基于风险的监查Verify critical activities, including QC, are carried out ac