病原体特异性M型免疫球蛋白定性检测试剂注册技术审查指导原则

病原体特异性M型免疫球蛋白定性检测试剂注册技术审查指导原则 附件2 病原体特异性M型免疫球蛋白定性检测试剂 注册技术审查指导原则 一、前言 本指导原则旨在指导注册申请人对病原体特异性M型免疫球蛋白,Immunoglobulin M～IgM,定性检测试剂注册申报资料的准备及撰写～同时也为技术审评部门对注册申报资料的技术审评提供参考。 本指导原则是对病原体特异性IgM抗体定性检测试剂的一般要求～申请人应依据产品的具体特性确定其中内容是否适用～若不适用～需具体阐述理由及相应的科学依据～并依据产品的具体特性对注册申报资料的内容进行充实和细化。 本指导原则是对申请人和审查人员的指导性文件～但不包括注册审批所涉及的行政事项～亦不作为法规强制执行～如果有能够满足相关法规要求的其他方法～也可以采用～但需要提供详细的研究资料和验证资料～相关人员应在遵循相关法规的前提下使用本指导原则。 本指导原则是在现行法规和标准体系以及当前认知水平下制定的～随着法规和标准的不断完善～以及科学技术的不断发展～本指导原则相关内容也将适时进行调整。 二、适用范围 病原体特异性IgM抗体定性检测试剂是指利用酶联免疫吸附法、化学发光法或磁微粒酶免疫技术等基于抗原抗体反应原理～以特定病原体的特异性IgM抗体为检测目标～对人血清或血浆样本中病原体特异性IgM抗体进行体外定性检测的试剂。本指导原则适用于进行首次注册申报和相关许可事项变更的产品。 根据结构不同～人免疫球蛋白可分为G型免疫球蛋白,IgG,、M型免疫球蛋白 — 25 — ,IgM,、A型免疫球蛋白,IgA,、E型免疫球蛋白,IgE,和D型免疫球蛋白,IgD,5种类型～ IgM占血清免疫球蛋白总量的5%,10%。分泌型IgM为五聚体～是分子量最大的免疫球蛋白分子～一般不能通过血管壁～主要存在于血液中。五聚体IgM含10个抗原结合片段,Fab段,～有很强的抗原结合能力～含5个可结晶化片段,Fc段,～比G型免疫球蛋白,IgG,更易激活补体～IgM抗体一般为保护性抗体～具有免疫性。IgM是个体发育过程中最早合成和分泌的抗体～在胚胎发育晚期的胎儿即能产生IgM～且由于IgM分子量大～不能通过母血进入胎儿体内～故脐带血或新生儿血液中特异性IgM升高常提示胎儿或新生儿存在宫内或围生期感染。在病原体感染的初次体液免疫应答中(原发性感染)～特异性IgM抗体首先出现～但其普遍反应短暂～一般几周后即不易再测到。病原体特异性IgM抗体阳性常提示早期感染～可用于感染急性期的辅助判断。人血液样本中病原体特异性IgM抗体的定性检测～对某些传染病如甲型肝炎、乙型肝炎、TORCH,弓形虫、风疹病毒、巨细胞病毒及单纯疱疹病毒,类病原体感染等有较高的临床参考价值。不具备病原体分离培养鉴定实验室的临床检测机构常将病原体特异性IgM抗体的检测作为早期感染的唯一依据～因此～病原体特异性IgM抗体检测结果的准确性显得颇为重要。假阳性结果可能导致病人接受不必要的抗病原体治疗而假阴性结果则有可能造成患者治疗的延误～由特异性IgM抗体检测造成的误诊或漏诊对孕妇或胎儿可能造成很大伤害。相关生产企业必须充分意识到该类产品的潜在风险～根据本指导原则的要求对该类试剂的安全性和有效性进行科学合理的验证。 三、基本要求 ,一,综述资料 综述资料主要包括产品临床适用症背景情况、预期用途、产品描述、有关生物安全性的说明、研究结果的评价以及同类产品上市情况介绍等内容～其中同类产品上市情况介绍部分应着重从方法学及临床适用范围等方面写明拟申报产品与目 — 26 — 前市场上已获批准的同类产品之间的主要区别。综述资料注册申报资料的重要组分之一～其内容应符合《体外诊断试剂注册,试行,》,国食药监械„2007?229号,和《体外诊断试剂注册申报资料基本要求》,国食药监械„2007?609号,的相关要求。另外～建议申请人对以下几方面内容进行着重介绍: 1(特定病原体的生物学特性、结构与功能、感染过程、潜伏期、特异性IgM抗体产生及可持续存在时间、病理背景等。 2(特定病原体感染相关的疾病情况、流行病学以及易患,高危,人群的说明。 3(对申报试剂检测结果可能带来的风险进行合理评估～即由申报试剂的假阳性/假阴性结果导致的对患者临床诊治、孕妇或胎儿的不恰当处理、疫苗接种、流行病学等方面的负面影响。 4(用于特定病原体特异性IgM抗体检测方法的发展历程摘要及各种检测方法的优缺点评价。 ,二,产品说明书 说明书承载了产品预期用途、标本采集及处理、实验方法、检测结果解释以及注意事项等重要信息～是指导实验室工作人员正确操作、临床医生针对检验结果给出合理医学解释的重要依据～因此～产品说明书是体外诊断试剂注册申报最重要的文件之一。产品说明书的格式应符合《体外诊断试剂说明书编写指导原则》,国食药监械„2007?240号,的要求～境外试剂的中文说明书除格式要求外～其内容应尽量保持与原文说明书的一致性～翻译力求准确且符合中文表达习惯。产品说明书的所有内容均应与申请人提交的注册申报资料中的相关研究结果保持一致～如某些内容引用自参考文献～则应以规范格式对此内容进行标注～并单独注明文献的相关信息。 结合《体外诊断试剂说明书编写指导原则》,国食药监械„2007?240号,的要求～下面对病原体特异性IgM抗体定性检测试剂说明书的重点内容进行详细说明～以指导注册申报人员更合理地完成说明书编制。 — 27 — 1.【预期用途】 应至少包括以下几部分内容: ,1,试剂盒用于体外定性检测人血清和/或血浆样本中xx的特异性IgM抗体。 ,2,简单介绍待测目标的特征～如特定病原体的生物学性状、潜伏期、易感人群、感染后的临床表现等临床背景相关的信息介绍,适用于对哪些患者人群的检测～如具有何种症状/体征的患者、相关的密切接触者、地域要求或年龄限制,如有,等。 ,3,病原体特异性IgM抗体的产生、持续时间、与特异性IgG、病原体核酸等其他检测指标的关联, ,4,该试剂盒的应用是否需要配套使用的专用仪器～与靶抗体检测相关的其他检测技术的介绍。 2.【主要组成成分】 ,1,说明试剂盒包含组分的名称、数量、比例或浓度等信息～阴性/阳性对照品可能含有人源组分～应提供其生物学来源、灭活方法及无传染性确认的方法等。 ,2,对检测中使用的抗原及抗体的信息进行简单介绍。 ,3,试剂盒中不包含但对该项检测必须的组分～企业应列出相关试剂/耗材的名称、货号及其他相关信息。 3.【储存条件及有效期】 对试剂盒的效期稳定性、开封稳定性、运输稳定性等信息做详细介绍。 胶体金试纸条产品应对开封后未使用产品允许暴露于空气中的温度、湿度及期限等条件予以明确。 4.【样本要求】 重点明确以下内容: ,1,样本采集前对患者的要求:如采集时间、采集顺序等～是否受临床症状、用药情况等因素的影响。 ,2,样本采集:说明采集方法及样本类型～如有血浆样本～应注明对抗凝剂的要求。 — 28 — ,3,样本处理及保存:样本处理方法、保存条件及期限,短期、长期,、运输条件等。冷藏/冷冻样本检测前是否须恢复室温～冻融次数。经热处理样本是否可用、对储存样本的添加剂要求等。 ,4,如果检测系统含有某种IgG抗体的去除技术,IgG吸附剂,～如抗人IgG抗体等～则应包括IgG吸附剂使用相关的注意事项。例如:经IgG吸附剂处理的样本不能用于 IgG类抗体的检测,在检测IgM类抗体的同时～检测处理过的混合物中的IgG类抗体～以证实对IgG、类风湿因子,RF,等去除的有效性等。 5.【检验方法】 详细说明试验操作的各个步骤: ,1,实验环境:温、湿度条件～检测试剂及样本的复温要求及相关注意事项。例如:冻存样本在复融后应经过充分的混匀再行检测。 ,2,试剂配制方法、注意事项～试剂开封后使用方法及注意事项等。 ,3,试验条件:操作步骤、温度、时间、仪器波长等以及试验过程中的注意事项。不同型号产品～加样方法如有差异～建议分别以图示方式描述清楚。 6.【检验结果的解释】 结果判断或计算:详细描述对检测结果的判定或计算方法、对质控品,对照品,的检测结果要求,试验有效性的判断,等。如果质控品和病人样本的使用方法不同～生产商应注明必要的指导和解释。建议在质控品,对照品,结果解释环节注明以下字样:“如果质控结果与预期不符～实验室不应出具检测报告。” 7.【检验方法局限性】 综合产品的预期用途、临床背景、检测方法及适用范围等信息～对可能出现的局限性进行相关说明～主要包括以下描述～请申请人选择适用的条款在产品说明书中予以阐述。 ,1,本产品检测结果仅供临床参考～不应作为临床诊治的唯一依据～对患者的临床管理应结合其症状/体征、病史、其他实验室检查,尤其是病原学检测,、治疗 — 29 — 反应及流行病学等信息综合考虑。 ,2,感染初期～病原体特异性IgM抗体未产生或滴度很低会导致阴性结果～如怀疑有病原体感染～应提示患者在7,14天内复查～抽取第二份样本～并和第一份样本在同条件下同时检测～以确定是否有初次感染的血清转化或病原体特异IgM或IgG抗体滴度明显升高。 ,3,高滴度病原体特异性IgG抗体会与特异性IgM抗体竞争抗原结合部位～会使检测的敏感性降低～IgM结果可能会出现假性低值或阴性结果。尤其是怀疑先天性病原体感染的新生儿样本～他们的血清中可能含有母亲来源的高水平病原体特异的IgG抗体和胎儿产生的相对低水平的病原体特异IgM抗体～因此～对于该类样本的阴性结果应慎重分析。 ,4,由于脐带血中可能含有源于母体的病原体特异性IgM抗体,胎盘渗漏,～因此～最好在出生后5天内再对婴儿的后续样本进行检测～以证实脐带血样本病原体特异性IgM抗体的阳性结果。建议将新生儿与母亲的血清样本平行进行测试～如果是胎儿的先天性感染,其IgM抗体水平(以及IgG抗体水平) 会持续存在或呈上升趋势, 反之,如果抗体来源于母体～则在在平行实验中婴儿的抗体水平会逐渐下降或消失。 ,5,由于孕妇的实验室检查不能可靠地鉴定胎儿患病的风险～故不建议采用本试剂对无症状的母体感染进行筛查～不得将本试剂的检测结果单独作为终止妊娠的依据。 ,6,免疫功能受损或接受免疫抑制治疗的患者～如人类免疫缺陷病毒,HIV,感染患者或器官移植后接受免疫抑制治疗的患者～其血清学IgM抗体检测的参考价值有限～可能会导致错误的医学解释。 ,7,在近几个月内接受过输血或其他血液制品治疗的人群～对其阳性检测结果的分析应慎重。 — 30 — ,8,病原体特异性IgM抗体不仅出现于初次感染～当二次感染和复发感染时也可能出现。 ,9,当疾病的流行程度降低时阳性预测值降低～对低危人群阳性结果的解释应当谨慎。建议对申报试剂临床研究中的病例人群特征进行说明～并对适用人群的性别、年龄、地域等特征进行明示。 8.【产品性能指标】 详述以下性能指标: ,1,对相应国家参考品,如有,检测的符合情况。 ,2,最低检测限,分析灵敏度,:说明试剂的最低检测浓度或滴度～简单介绍最低检测限的确定方法。 ,3, 企业内部阳性/阴性参考品符合率～简单介绍阳性参考品的来源、浓度梯度、阴性参考品组成、来源以及浓度梯度设臵等信息。 ,4, 精密度:精密度参考品的组分、浓度及评价标准。 ,5, 分析特异性 ?交叉反应:对易产生交叉反应的其他病原体的高水平IgM抗体、特异性IgG抗体等的验证情况。 ?干扰物质:样本中常见干扰物质对检测结果的影响～如溶血、高脂、黄疸等干扰因子研究,结果应量化表示～禁用轻度、严重等模糊表述,～有关高浓度总IgM和IgG抗体、自身抗体、类风湿因子,RF,、嗜异型性抗体等的干扰验证。 ?药物影响:较常见的用于病原体感染治疗的外用或内服药物对检测结果的影响。 ,6,钩状,HOOK,效应:对高浓度特异性IgM抗体的钩状效应验证情况。 ,7,对比试验研究,如有,:简要介绍参比试剂,方法,的信息、所采用的统计学方法及统计分析结果。 9.【注意事项】应至少包括以下内容: — 31 — ,1,有关试剂盒内人源组分,如有,生物安全性的警告。 ,2,有关实验操作、样本保存及处理等其他注意事项。 ,三,拟定产品标准及编制说明 拟定产品标准应符合国食药监械„2007?229号和国食药监械„2007?609号文件的相关规定。另外～对于国产试剂～应参考《中国生物制品规程》,2000年版,～将拟申报产品的主要原材料、生产工艺及半成品检定等内容作为附录附于标准正文后～并在正文的“产品分类”项中引出该附录内容。 病原体特异性IgM抗体检测试剂的注册检测应主要包括以下性能指标:物理性状、阳性参考品符合率、阴性参考品符合率、精密度、最低检测限,分析灵敏度,等。阳性参考品主要考察对不同滴度情况下的检测符合性。阴性参考品则是对分析特异性,交叉反应,的验证～应主要包括易发生交叉反应的其他病原体特异性IgM抗体的假阳性情况的考核。 行业标准发布～则企业标准的要求不得低于上如果拟申报试剂已有相应的国家/ 述标准要求。 ,四,注册检测 根据国食药监械„2007?229号文件要求～首次申请注册的第三类产品应该在国家食品药品监督管理局认可的、具有相应承检范围的医疗器械检测机构进行连续三个生产批次样品的注册检测。对于已经有国家参考品的病原体特异性IgM抗体项目～在注册检测时应采用相应的国家参考品进行,对于目前尚无国家参考品的项目～生产企业应自行建立稳定的质控体系并提供相应的内部参考品。 ,五,主要原材料研究资料 1(试剂盒所用病原体抗原的制备、筛选、纯化以及鉴定等详细试验资料～主要包括以下两方面: ,1,企业自制抗原 — 32 — 如为天然抗原～则应对病原体毒株选择、病原体培养、抗原提取及纯化、鉴定等实验过程予以详述,如为重组抗原～则应提交有关特定基因选择、基因序列、基因克隆、抗原表达及抗原纯化鉴定等详细内容～并对基因克隆的整个过程进行详述～如特定脱氧核糖核酸,DNA,分子的体外处理、重组连接、导入宿主细胞、宿主细胞繁殖以及重组子表达等实验过程。 ,2,企业外购抗原～则应详述抗原的名称及生物学来源～外购方名称～提交外购方出具的抗原性能指标及检验证书～详述申请人对该抗原技术指标的要求以及申请人确定该抗原作为主要原材料的依据。供货商应相对固定～不得随意更换。 2(试剂盒所用抗体,如抗IgM-μ链抗体,的制备、筛选、纯化以及鉴定等详细试验资料～主要包括以下两方面: ,1,企业自制抗体 如使用天然抗原作为免疫原则应明确该天然抗原的来源,如使用重组抗原或其他人工合成抗原作为免疫原～应提供相应的核酸组分及重组抗原的序列信息。申请人对所选抗体的技术指标要求,如外观、纯度、蛋白浓度、效价等,～确定该抗体作为主要原材料的依据。 ,2,企业外购抗体～应详述抗体的名称及生物学来源～外购方名称～提交外购方出具的抗体性能指标及检验证书～详述申请人对该抗抗体技术指标的要求以及申请人确定该抗体作为主要原材料的依据。供货商应相对固定～不得随意更换。 申请人应对主要生物原料质控标准的技术要求如外观、纯度、蛋白浓度、效价等进行确认～并对制备完成的抗原成品进行质量检验以确认其符合标准要求～整个生产工艺稳定可靠。 3.其他主要原辅料的选择及验证资料～如固相载体、硝酸纤维素膜、反应缓冲液等～该类原辅料一般均为外购～应详述每一原辅料的外购方名称～提交外购方出具的每一原辅料性能指标及检验证书～详述申请人对每一原辅料技术指标的要求以 — 33 — 及申请人确定该原辅料作为主要原辅料的依据。 4(企业内部参考品的原料选择、制备、定值、统计学分析及相关的实验验证资料。应提供对参考品性质确认的其他方法或试剂,建议采用国内已上市的、临床上普遍认为质量较好的同类试剂,的相关信息。 ,六,主要生产工艺及反应体系的研究资料 1.主要生产工艺介绍～可用图方式表示～并简要说明主要生产工艺的确定依据。 2.产品基本反应原理介绍。 3.包被工艺研究～申请人应考虑如包被液量、浓度、时间等指标对产品性能的影响～通过试验确定上述指标的最佳组合。 4.显色,发光,系统、酶作用底物等的介绍。 5.实验体系反应条件确定:申请人应考虑反应时间、反应温度、洗涤次数等条件对产品性能的影响～通过试验确定上述条件的最佳组合。 6. 酶催化底物,发光或变色,的最适条件研究。 7.体系中样品加样方式及加样量确定:申请人应考虑样品加样方式、加样量对产品检测结果的影响～通过实验确定最佳的加样方式及加样量。如样本需采取稀释或其他必要的方法进行处理后方可用于最终检测～申请人还应对可用于样本稀释的基质或处理方法进行研究～通过试验确定最终选择的用于样本稀释的基质或处理方法。 ,七,分析性能评估资料 企业应提交原厂在产品研制或成品验证阶段对试剂盒进行的所有性能验证的研究资料～包括具体研究方法、内控标准、试验数据、统计分析等详细资料。对于病原体特异性IgM抗体检测试剂～建议着重对以下分析性能进行研究。 1.最低检测限,分析灵敏度, — 34 — 选取特定滴度的病原体特异性IgM抗体样本～做系列倍比稀释～将检测结果的阳性率在90%，95%,n?20,的最大稀释倍数作为试剂盒的最低检测限。 2.分析特异性 ,1,交叉反应 用于病原体特异性IgM抗体检测试剂交叉反应验证主要考虑以下几方面可能性: ?对抗原结构相近或临床症状相似的其他病原体高水平IgM抗体血清进行交叉反应研究～如乙型肝炎病毒核心抗体,HBc,IgM、甲型肝炎病毒,HAV,IgM、弓形虫、风疹病毒、单纯疱疹病毒以及巨细胞病毒IgM抗体等。 ?高浓度病原体特异性IgG抗体与特异性IgM抗体的交叉反应验证。 申请人应提交所有用于交叉反应验证的病原体来源、浓度或滴度确认等信息。建议申请人将有关交叉反应验证的信息以列表的方式在产品说明书的【产品性能指标】项中列出。 ,2,干扰物质 ?内源性干扰 对样本中常见的内源性干扰物质进行检测～如溶血、高脂、黄疸、类风湿因子,RF,、抗核抗体,ANA,、抗线粒体抗体,AMA,、高浓度非特异性IgG和IgM抗体,血清总IgG和IgM,等。方法为对病原体特异性IgM抗体阴性、弱阳性,临界浓度,的临床或模拟添加样本分别进行验证～样本量选择应体现一定的统计学意义～说明样本的制备方法及干扰实验的评价标准～确定可接受的干扰物质极限浓度。 ?抗凝剂的干扰 如果试剂盒适用样本类型包括血浆样本～应采用各种适用抗凝剂抗凝的血浆样本分别与血清样本进行对比实验研究。方法为对不少于50例源自同一患者的病原体特异性IgM抗体阴性、弱阳性,略高于临界值,的血清和血浆样本,不同抗凝剂各50例,进行检测以验证申报试剂对于血清和血浆样本的检测结果的一致性。 — 35 — ?目前～病原体特异性IgM抗体检测试剂通常采用捕获法,又称双夹心法,和间接法两种原理。后者是将病原体抗原包被在固相载体上～加入含待测IgM抗体的样本后～待抗原抗体结合后～再加入酶标记的抗IgM抗体进行反应～孵育后洗去未结合的酶结合物再加入酶底物显色以反应“抗原-抗体-酶标二抗”复合物的存在。该方法在检测特异性IgM抗体时存在一定不足～由于血清中存在的IgM类类风湿因子能与IgG抗体结合～然后结合到酶标二抗上～易造成假阳性～高效价的病原体特异性IgG抗体也可与IgM抗体竞争抗原结合位点而导致假阴性。因此～采用间接法,固相包被病原体抗原,的试剂～需要在病原体特异性IgM检测前采用一定的方法去除样本中的IgG类抗体～例如～在样本缓冲液中加入抗人IgG抗体～可以特异性地结合血清或血浆中的IgG并沉淀～如果样本中存在类风湿因子～也将被抗人IgG-IgG的复合物所吸附而去除干扰。 基于上述理论～使用间接法原理的试剂盒～在样本处理环节应该设臵一定的IgG消除体系以降低实验中假阳性或假阴性的可能性。如果反应体系中使用了相关的IgG吸附技术,IgG吸附剂,来去除类风湿因子、抗核抗体或病原体特异性IgG抗体的干扰～应以mg/dL为单位注明IgG吸附剂对样本中人IgG抗体的吸附能力～并进行以下的实验研究:对至少10份临界值附近的病原体特异性IgM抗体弱阳性并含有多水平病原体特异性IgG抗体的样本进行检测～比较去除总IgG前后的结果～验证IgG吸附剂消除干扰的效果～以上实验可以采用人工制备的样本进行。 ?对至少10份含有病原体特异性IgM抗体的样本进行IgM破坏实验研究～方法为采用特定的化学制剂,如2,巯基乙醇或二硫苏糖醇,处理样本后～重新进行检测～IgM检测结果应为阴性。 5.精密度 企业应对每项精密度指标的评价标准做出合理要求～如标准差或变异系数的范围等～针对本类产品的精密度评价主要包括以下要求。 — 36 — ,1,对可能影响检测精密度的主要变量进行验证～除申报试剂本身外～还应对操作者、实验地点等要素进行相关的验证。 ,2,设定合理的精密度评价周期～如有条件～建议申请人选择不同的实验室进行重复实验以对室间精密度进行评价。 ,3,用于精密度评价的质控品应至少包括三个水平: ?阴性质控品:待测物浓度低于试剂盒的临界值,cut-off value,或背景值较高的零浓度质控品～阴性检出率应为100%,n?20,。 ?弱阳性质控品:待测物浓度略高于试剂盒的临界值,cut-off value,～阳性检出率应在90%，95%范围,n?20,。 ?阳性质控品:待测物浓度呈中到强阳性～阳性检出率为100%～且CV?15%,n?20,。 另外～建议选择适量临床采集的新鲜病人样本,包括所有样本类型,作为无靶值质控品进行精密度评价～以更好地模仿临床检测环境。 6.阳性/阴性参考品 如申报产品有相应的国家参考品～则企业内部阳性/阴性参考品应参考国家参考品的项目设臵。在不低于国家参考品要求的前提下～申请人可以结合实际情况设臵合理的内部阳性/阴性参考品。对于没有国家参考品的产品～申请人应根据产品性能验证的实际情况自行设定企业内部参考品～阳性参考品应着重考虑抗体滴度要求～阴性参考品则主要涉及对分析特异性,交叉反应,的验证情况。 申请人应对内部阳性/阴性参考品的来源、抗体滴度等信息进行精确的实验验证～并提交详细的验证资料。 7.钩状,HOOK,效应 须采用高滴度的病原体特异性IgM抗体的血清进行梯度稀释后由低浓度至高浓度开始检测～每个梯度的稀释液重复3，5份～对钩状效应进行合理的验证。建议在 — 37 — 产品说明书上明示对钩状效应的研究结果。 ,八,参考值,范围,确定资料 重点提交对申报试剂阴性/灰区/阳性等结果判断的临界值确定的实验研究资料～应包括具体的试验、评价标准、统计学分析、研究数据等研究资料。建议采用受试者工作特征曲线,ROC,的分析方式来选择确定合理的临界值～如实验结果分析存在灰区,equivocal zone,～则应明确灰区建立的基础。临界值建立的样本来源选择应考虑到地域性、年龄、不同生理状态等因素的影响～并明确临界值在不同的样本类型是否有差异。对临界值建立后所产生的临床灵敏度和特异性进行充分判断～使产生假阴性或假阳性结果的可能性均降至最低。 ,九,稳定性研究资料 稳定性研究资料主要涉及两部分内容～申报试剂的稳定性和适用样本的稳定性研究。前者主要包括实时稳定性、高温加速破坏稳定性、运输稳定性及开瓶稳定性,如涉及,等研究～申请人可根据实际需要选择合理的稳定性研究方案。稳定性研究资料应包括研究方法的确定依据、具体的实施方案、详细的研究数据以及结论。对于实时稳定性研究～应提供至少三批样品在实际储存条件下保存至成品有效期后的研究资料。 考虑到低温条件下长时间保存可能造成病原体特异性IgM抗体的活性减弱～申请人应对样本稳定性进行合理的验证～主要是对冷藏和冷冻两种条件下的有效期进行验证～以确认不同类型样本的短期、长期保存条件及效期。需要冷冻保存的样本应对冻融次数,重要指标,进行合理的验证。某些用于防腐、冷冻用途或起稳定保护作用的添加剂,如叠氮化物,可能会对IgM抗体的检测造成影响～如涉及～请对该添加剂的影响进行合理验证。 另外～如果要用于加热样本,如热灭活,的检测～则应对加热前后的病原体特异性IgM抗体阳性及阴性样本进行加热因素的干扰验证。方法为对临界值附近的至 — 38 — 少10份弱阳性加热和未加热样本进行对比检测～比较检测结果的差异,对至少10份阴性加热和未加热的样本进行对比检测～比较检测结果的差异。 试剂稳定性和样本稳定性两部分内容的研究结果均应在说明书【储存条件及有效期】和【样本要求】两项中进行详细说明。 ,十,临床试验资料 1. 研究方法 ,1,对于已有同类产品上市的试剂临床研究～选择境内已批准上市、临床普遍认为质量较好的同类产品作为参比试剂～采用拟申报产品,以下称考核试剂,与之进行对比试验研究～证明本品与已上市产品等效或优于已上市产品。考虑到试剂盒的预期用途～阳性样本中应包括一定量的新鲜样本比例。 另外～申请人还应选择不少于30例、感染急性期患者采集的样本进行考核试剂与病原体分离培养鉴定方法的比较研究～以确定申报试剂检测结果与金标准方法比较的符合率并以此判断其临床灵敏度和特异性。如果病原体分离培养鉴定的方法不可行也可以采用其他用于感染急性期判断的方法进行比对研究～例如:病原体IgG抗体的血清学转换,动态监测2份或以上的血清IgG～恢复期与急性期比较IgG呈4倍以上升高,、病原体核酸检测或直接抗原检测等方法～对于病原体感染急性期的判断应密切结合患者的临床诊断综合进行。 ,2,对于无同类产品上市的申报试剂的临床研究～则必须选择病原体感染检测的金标准方法并结合临床诊断进行相应的对比试验研究～如病原体分离培养鉴定、病原体IgG抗体的血清学转换、病原体核酸检测或直接抗原检测等方法。 2.临床研究单位的选择 申请人在国内不同区域选择临床单位～尽量使各单位的临床样本有一定的区域代表性,临床研究单位应具有特定病原体感染疾患诊疗、病原体分离培养鉴定方法或分子生物学方法检测的优势～实验操作人员应有足够的时间熟悉检测系统的各环 — 39 — 节,仪器、试剂、质控及操作程序等,～熟悉评价方案。在整个实验中～考核试剂和参比方法都应处于有效的质量控制下～最大限度保证试验数据的准确性及可重复性。 3.临床试验方案 临床试验实施前～研究人员应从流行病学、统计学、临床医学、检验医学等多方面考虑～科学合理的临床研究方案。各临床研究机构的方案设臵应基本一致～且保证在整个临床试验过程中遵循预定的方案实施～不可随意改动。整个试验过程应在临床研究机构的实验室内并由本实验室的技术人员操作完成～申报单位的技术人员除进行必要的技术指导外～不得随意干涉实验进程～尤其是数据收集过程。 试验方案中应确定严格的病例纳入/排除标准～任何已经入选的病例再被排除出临床研究都应记录在案并明确说明原因。在试验操作过程中和判定试验结果时应采用盲法以保证试验结果的客观性。各研究单位选用的参比试剂应保持一致～以便进行合理的统计学分析。另外～考核试剂的样本类型不应超越参比试剂对样本类型的检测要求～如果选择了参比试剂适用样本类型以外的样本～则应采用病原体分离培养鉴定或其他合理方法对额外的样本类型进行验证。 4.病例选择及样本类型 临床试验应选择具有特定病原体感染症状/体征、相似症状或有密切接触史等人群作为研究对象。企业在建立病例纳入标准时～应考虑到不同人群的差异～尽量覆盖各类适用人群。在进行结果统计分析时～除总体病例数的要求外～建议对各类人群分层进行数据统计分析。考虑到大样本统计学的要求～临床研究中病原体特异性IgM抗体的阳性样本例数以不少于120例为宜。对于阴性病例的选择～也应考虑到交叉反应的需要～对靶病原体之外的其他病原体感染急性期的患者样本进行检测～以从临床角度考察其分析特异性。 5.统计学分析 对临床试验结果的统计应选择合适的统计方法～如检测结果一致性分析、受试 — 40 — 者工作特征,ROC,曲线分析、阴性/阳性符合率等。对于本类产品对比实验的等效性研究～常选择交叉四格表的形式总结两种试剂的定性检测结果～对定性结果进行四格表卡方或kappa检验以验证两种试剂定性结果的一致性～统计学分析应可以证明两种方法的检测结果无明显统计学差异。在临床研究方案中应明确统计检验假设～即评价考核试剂与参比试剂是否等效的标准。 6.结果差异样本的验证 在数据收集过程中～对两种试剂检测结果明显不一致的样本～应采用“金标准”方法或临床上普遍认为质量较好的第三种同类试剂,国内已上市,进行复核～同时结合患者的临床病情对差异原因及可能结果进行分析。如果申报试剂与参比试剂的检测结果显示不一致样本均是位于二者的临界值附近且例数很少,如低于总例数的1%,～则对不一致原因作简要分析即可～不须进行第三方复核。注意～如果有必要选择第三方试剂复核～建议先采用第三方试剂对一定数量的申报试剂和参比试剂检测结果一致的样本,包括阳性和阴性结果,进行检测～以对第三方试剂选择的合理性进行评估。 7. 临床试验总结报告撰写 根据《体外诊断试剂临床研究技术指导原则》,国食药监械„2007?240号,的要求～临床试验报告应该对试验的整体设计及各个关键点给予清晰、完整的阐述～应该对整个临床试验实施过程、结果分析、结论等进行条理分明的描述～并应包括必要的基础数据和统计分析方法。建议在临床总结报告中对以下内容进行详述。 ,1,临床试验总体设计及方案描述 ? 临床试验的整体管理情况、临床研究单位选择、临床主要研究人员简介等基本情况介绍。 ? 病例纳入/排除标准、不同人群的预期选择例数及标准。 ? 样本类型～样本的收集、处理及保存等。 — 41 — ? 统计学方法、统计软件、评价统计结果的标准。 ,2, 具体的临床试验情况 ? 申报试剂和参比试剂的名称、批号、有效期等信息。 ? 对各研究单位的病例数、人群分布情况进行综合～建议以列表或图示方式给出具体例数及百分比。 ? 质量控制～试验人员培训、质控品检测情况～对检测精密度、质控品测量值的抽查结果评估。 ? 具体试验过程～样本检测、数据收集、样本长期保存、结果不一致样本的校验等。 ,3, 统计学分析 ? 数据预处理、差异数据的重新检测或第三方验证以及是否纳入最终数据统计、对异常值或缺失值的处理、研究过程中是否涉及对方案的修改。 ? 定性结果的一致性分析 阳性符合率、阴性符合率、总体符合率及其95%,或99%,的臵信区间。以交叉表的形式总结两种试剂的定性检测结果～对定性结果进行四格表卡方或kappa检验以验证两种试剂定性结果的一致性。另外考虑到对不同样本类型以及不同人群的检测结果可能存在一定差异～故建议对不同样本类型及不同人群分别进行统计分析～ 以对考核试剂的临床性能进行综合分析。 ,4, 讨论和结论 对总体结果进行总结性描述并简要分析试验结果～对本次临床研究有无特别说明～最后得出临床试验结论。 四、名词解释 1.分析特异性,analytical Specificity,:测量程序只测量被测量物的能力。分析特异性用于描述检测程序在样本中有其他物质存在时只测量被测量物的能力。 — 42 — 通常以一个被评估的潜在干扰物清单来描述～并给出在特定医学相关浓度值水平的分析干扰程度。 注:潜在干扰物包括干扰物和交叉反应物。 2.精密度,precision,:在规定条件下～相互独立的测试结果之间的一致程度。精密度的程度是用统计学方法得到的测量不精密度的数字形式表示～如标准差,SD,和变异系数,CV,。 五、 参考文献 1.《体外诊断试剂注册管理办法,试行,》～,国食药监械„2007?229号,～2007年4月19日。 2.《体外诊断试剂临床研究技术指导原则》～,国食药监械„2007?240号,～2007年4月28日。 3.《体外诊断试剂说明书编写指导原则》～,国食药监械„2007?240号,～2007年4月28日。 4.Review Criteria for In Vitro Diagnostic Devices for Detection of IgM Antibodies to Viral Agents, CDRH FDA, USA February 27, 1997。 5.National Committee for Clinical Laboratory Standards. Specifications for immunological testing for infectious diseases, proposed guideline. 2001. Order code I/LA18-A2。 6.彭文伟～《传染病学》～第五版～人民卫生出版社～2001。 7.刘艳芳、张勇建、苏明～临床病原体学检验～军事医学科学出版社～2009。 8.陈敬贤～《诊断病原体学》～第一版～人民卫生出版社～2008年4月。 9.冯仁丰～《临床检验质量管理技术基础》～第二版～上海科学技术文献出版社～2007年4月。 10.《中国生物制品规程》,2000年版,～化学工业出版社。 — 43 — 11(李洪源～王志玉～《病原体学检验》～第一版～人民卫生出版社～2006年7 月。 12(Nathanson.N～《病原体致病与免疫》～第2版～科学出版社～2008年1月。 13(曹雪涛～《免疫学技术及其应用》～第一版～科学出版社～2010年5月。 — 44 — (英文版 ) Two regulations promulgated for implementation is in the party in power for a long time and the rule of law conditions, the implementation of comprehensive strictly strategic plan, implementation in accordance with the rules and discipline to manage the party, strengthen inner-party supervision of major initiatives. The two regulations supporting each other, the < code > adhere to a positive advocate, focusing on morality is of Party members and Party leading cadres can see, enough to get a high standard; < rule > around the party discipline, disciplinary ruler requirements, listed as "negative list, focusing on vertical gauge, draw the party organizations and Party members do not touch the" bottom line ". Here, the main from four square face two party rules of interpretation: the first part introduces two party Revised regulations the necessity and the revision process; the second part is the interpretation of the two fundamental principles of the revision of laws and regulations in the party; the third part introduces two party regulations modified the main changes and needs to grasp several key problems; the fourth part on how to grasp the implementation of the two regulations of the party. < code > and < Regulations > revised the necessity and revised history of the CPC Central Committee the amendment to the Chinese Communist Party members and leading cadres honest politics several guidelines > and < Chinese Communist Party discipline and Punishment Regulations > column 1 by 2015 to strengthen — 45 — party laws and regulations focus. Two party regulations revision work lasted a Years, pooling the wisdom of the whole party, ideological consensus, draw historical experience, respect for the wisdom of our predecessors, which reflects the unity of inheritance and innovation; follow the correct direction, grasp the limited goals, adhere to the party's leadership, to solve the masses of the people reflect a focus on the problem. The new revision of the < code > and < rule >, reflects the party's 18 and the eighth session of the third, the spirit of the fourth plenary session, reflecting the experience of studying and implementing the General Secretary Xi Jinping series of important speech, reflects the party's eighteen years comprehensive strictly practice. (a) revised two regulations of the party need of < the ICAC guidelines > in < in 1997 Leaders as members of the Communist Party of China clean politics certain criteria (Trial) > based on revised, the promulgation and implementation of January 2010, to strengthen the construction of the contingent of leading cadres play an important role. But with the party to manage the party strictly administering the deepening, has not been able to fully meet the actual needs. Content is too complicated, "eight prohibition, 52 are not allowed to" hard to remember, and also difficult to put into practice; the second is concisely positive advocated by the lack of prohibited provisions excessive, no autonomy requirements; the third is banned terms and discipline law, both with the party discipline, disciplinary regulations — 46 — repeat and Criminal law and other laws and regulations repeat; the fourth is to "clean" the theme is not prominent, not for the existing problems, and is narrow, only needle of county-level leading cadres above. < rule > is in 1997 < Chinese Communist Party disciplinary cases (Trial) > based on revision, in December 2003 the promulgation and implementation, to strengthen the construction of the party play very important role. Along with the development of the situation, which many provisions have been unable to fully meet the comprehensive strictly administering the practice needs. One is Ji law, more than half of the provisions and criminal law and other countries laws and regulations Repetition; two is the political discipline regulations is not prominent, not specific, for violation of the party constitution, damage the authority of Party Constitution of misconduct lack necessary and serious responsibility to pursue; third is the main discipline for the leading cadres, does not cover all Party members. Based on the above situation, need to < the criterion of a clean and honest administration > and < rule > the two is likely to be more relevant regulations first amendment. By revising, really put the authority of Party discipline, the seriousness in the party tree and call up the majority of Party members and cadres of the party constitution of party compasses party consciousness. (II) two party regulations revision process the Central Committee of the Communist Party of China attaches great importance to two regulations revision . Xi Jinping, general books recorded in the Fifth — 47 — Plenary Session of the eighth session of the Central Commission for Discipline Inspection, on the revised regulations < > made clear instructions. According to the central deployment, the Central Commission for Discipline Inspection from 2014 under six months begin study two regulations revision. The Standing Committee of the Central Commission for Discipline Inspection 4 review revised. Comrade Wang Qishan 14 times held a special meeting to study two regulations revision, amendment clarifies the direction, major issues of principle, path and target, respectively held a forum will listen to part of the province (area) secretary of the Party committee, Secretary of the Discipline Inspection Commission, part of the central ministries and state organs Department The first party committee is mainly responsible for people, views of experts and scholars and grassroots party organizations and Party members. Approved by the Central Committee of the Communist Party of China, on 7 September 2015, the general office of the Central Committee of the Party issued a notice to solicit the provinces (autonomous regions, municipalities) Party, the central ministries and commissions, state ministries and commissions of the Party (party), the General Political Department of the military, every 3 people organization of Party of two regulations revision opinion. Central Commission for Discipline Inspection of extensive solicitation of opinions, careful study, attracting, formed a revised sent reviewers. In October 8 and October 12, Central Committee Political — 48 — Bureau Standing Committee and the Political Bureau of the Central Committee After consideration of the two regulations revised draft. On October 18, the Central Committee of the Communist Party of China formally issued two regulations. Can say, two laws amendment concentrated the wisdom of the whole party, embodies the party. Second, < code > and < Regulations > revision of the basic principles of two party regulations revision work and implement the party's eighteen, ten eight plenary, the spirit of the Fourth Plenary Session of the Eleventh Central Committee and General Secretary Xi Jinping important instructions on the revised < low political criterion > and < Regulations >, highlighting the ruling party characteristics, serious discipline, the discipline quite in front of the law, based on the current, a long-term, advance as a whole, with Bu Xiuding independent < rule > and < rule >. Main principle is: first, adhere to the party constitution to follow. The constitution about discipline and self-discipline required specific, awaken the party constitution of party compasses party consciousness, maintaining the authority of the constitution. General Secretary Xi Jinping pointed out that "no rules, no side round. Party constitution is the fundamental law, the party must follow the general rules. In early 2015 held the eighth session of the Central Commission for Discipline Inspection Fifth Plenary Session of the 16th Central Committee, Xi Jinping again pointed out that constitution is the party must follow the general rules, but also the general rules." the revision — 49 — of the < code > and < rule > is Method in adhere to the regulations established for the purpose of combining rule of virtue is to adhere to the party constitution as a fundamental to follow, the constitution authority set up, wake up the party constitution and party rules the sense of discipline, the party constitution about discipline and self-discipline specific requirements. 4 second is to adhere to in accordance with the regulations governing the party and the party. The Party of rule of virtue "de", mainly refers to the party's ideals and beliefs, excellent traditional style. The revised the < code > closely linked to the "self-discipline", insisting on the positive initiative, for all members, highlight the "vital few", emphasized self-discipline, focusing on the morality, and the majority of Party members and the ideological and moral standards. The revised < > Ji method separately, Ji, Ji Yan to Method, as a "negative list", emphasizing the heteronomy, focusing on vertical gauge. Is this one high and one low, a positive reaction, the strict party discipline and practice results transformation for the integration of the whole party to observe moral and discipline requirements, for the majority of Party members and cadres provides benchmarking and ruler. Third, insist on to. In view of the problems existing in the party at the present stage, the main problems of Party members and cadres in the aspect of self-discipline and abide by the discipline to make clearly defined, especially the party's eighteen years strict political discipline and political rules, organization and discipline and — 50 — to implement the central eight provisions of the spirit against the four winds and other requirements into Disciplinary provisions. Not one pace reachs the designated position, focusing on in line with reality, pragmatic and effective. After the revision of major changes, major changes in the < code > and < rule > modified and needs to grasp several key problems (a) < code > < code > adhere to according to regulations governing the party and party with morals in combination, for at the present stage, the leadership of the party members and cadres and Party members in existing main problems of self-discipline, put forward principles, requirements and specifications, showing Communists noble moral pursuit, reflected at all times and in all over the world ethics from high from low 5 common requirements. One is closely linked to the "self-discipline", removal and no direct relation to the provisions of . the second is adhere to a positive advocate, "eight prohibition" 52 are not allowed to "about the content of the" negative list moved into synchronization amendment < cases >. Three is for all the party members, will apply object from the leadership of the party members and cadres to expand to all Party members, fully embodies the comprehensive strictly required. The fourth is prominent key minority, seize the leadership of the party members and cadres is the key, and put forward higher requirements than the ordinary Party members. Five is to simplify, and strive to achieve concise, easy to understand, easy to remember. The revised < code > is the ruling Party since the first insists on — 51 — a positive advocate forAll Party members and the self-discipline norms, moral declaration issued to all members of the party and the National People's solemn commitment. > < criterion of a clean and honest administration consists of 4 parts, 18, more than 3600 words. After the revision of the < code >, a total of eight, 281 words, including lead, specification and Party member cadre clean fingered self-discipline norms, etc. Part 3 members low-cost clean and self-discipline, the main contents can be summarized as "four must" "eight code". Lead part, reiterated on ideal and faith, fundamental purpose, the fine traditions and work style, noble sentiments, such as "four must" the principle of requirements, strong tone of self-discipline, The higher request for 6 and supervised tenet, the foothold in permanent Bao the party's advanced nature and purity, to reflect the revised standards requirements. Members of self-discipline norms around the party members how to correctly treat and deal with the "public and private", "cheap and rot" thrifty and extravagance "bitter music", put forward the "four norms". Party leader cadre clean fingered self-discipline norms for the leadership of the party members and cadres of the "vital few", around the "clean politics", from civil servant of the color, the exercise of power, moral integrity, a good family tradition and other aspects of the leadership of the party members and cadres of the "four norms" < > < norm norm. "The Party member's self-discipline norms" and "party members and leading cadre clean fingered self-discipline norms," a — 52 — total of eight, collectively referred to as the "eight". "Four must" and "eight" of the content from the party constitution and Party's several generation of leaders, especially Xi Jinping, general secretary of the important discussion, refer to the "three discipline and eight points for attention" statements, and reference some embody the Chinese nation excellent traditional culture essence of epigrams. (2) the revised regulations, the main changes in the revised Regulations > to fully adapt to the strictly requirements, reflects the according to the regulations governing the law of recognition of deepening, the realization of the discipline construction and Jin Ju. < rule > is party a ruler, members of the basic line and follow. And the majority of Party members and cadres of Party organizations at all levels should adhere to the bottom line of thinking, fear discipline, hold the bottom line, as a preventive measure, to keep the party's advanced nature and purity. 1, respect for the constitution, refinement and discipline. Revised < rule > from comprehensive comb physical constitution began, the party constitution and other regulations of the Party of Party organizations and Party discipline requirements refinement, clearly defined in violation of the party constitution will be in accordance with regulations to give the corresponding disciplinary action. The original 10 categories of misconduct, integration specification for political discipline, discipline, honesty and discipline masses Ji Law and discipline and discipline and other six categories, the content of < rule > — 53 — real return to Party discipline, for the majority of Party members and listed a "negative list. 7 2, highlighting the political discipline and political rules. > < Regulations according to the stage of the discipline of outstanding performance, emphasizing political discipline and political rules, organization and discipline, in opposition to the party's leadership and the party's basic theory, basic line, basic program and basic experience, the basic requirement of behavior made prescribed punishment, increase the cliques, against the organization such as violation of the provisions, to ensure that the central government decrees and the Party of centralized and unified. 3, adhere to strict discipline in the law and discipline In front, Ji separated. Revised < Regulations > adhere to the problem oriented, do Ji separated. Any national law existing content, will not repeat the provisions, the total removal of 79 and criminal law, repeat the content of the public security management punishment law, and other laws and regulations. In the general reiterated that party organizations and Party members must conscientiously accept the party's discipline, die van comply with national laws and regulations; at the same time, to investigate violations of Party members and even criminal behavior of Party discipline and responsibility, > < Regulations distinguish five different conditions, with special provisions were made provisions, so as to realize the connection of Party discipline and state law. 4, reflect Wind building and anti-corruption struggle of the latest achievements. < rule > the party's eighteen years — 54 — implement the spirit of the central provisions of the eight, against the requirements of the "four winds" and transformation for disciplinary provisions, reflecting the style construction is always on the road, not a gust of wind. In the fight against corruption out of new problems, increase the trading rights, the use of authority relatives profit and other disciplinary terms. Prominent discipline of the masses, the new against the interests of the masses and ignore the demands of the masses and other disciplinary terms and make provisions of the disposition and the destruction of the party's close ties with the masses. Discipline to protect the party's purpose. 8 of these regulations, a total of three series, Chapter 15, 178, more than 24000 words, after the revision of the regulations a total of 3 series, Chapter 11, 133, 17000 words, divided into "general" and "special provisions" and "Supplementary Provisions" Part 3. Among them, add, delete, modify the provisions of the proportion of up to nearly 90%. 1, the general general is divided into five chapters. The first chapter to the regulations of the guiding ideology, principles and scope of application of the provisions, highlight the strengthening of the party constitution consciousness, maintenance the authority of Party Constitution, increase the party organizations and Party members must abide by the party constitution, Yan Centralized centralized, would examine at all levels of the amended provisions implementing and maintaining Party discipline, and consciously accept the party discipline, — 55 — exemplary compliance with national laws and regulations. The second chapter of discipline concept, disciplinary action types and effects of the regulations, will be a serious warning from the original a year for a year and a half; increase the Party Congress representative, by leaving the party above (including leave probation) punishment, the party organization should be terminated its representative qualification provisions. The third chapter of the disciplinary rules of use prescribed in the discipline rectifying process, non convergence, not close hand classified as severely or heavier punishment. "Discipline straighten "At least eighteen years of five years, these five years is to pay close attention to the provisions of the central eight implementation and anti -" four winds ". The fourth chapter on suspicion of illegal party disciplinary distinguish five different conditions, with special provisions were made provisions, to achieve effective convergence of Party and country 9 method. < rule > the provisions of Article 27, Party organizations in the disciplinary review found that party members have committed embezzlement, bribery, dereliction of duty dereliction of duty and other criminal law act is suspected of committing a crime shall give cancel party posts, probation or expelled from the party. The second is < Regulations > Article 28 the provisions of Party organizations in the disciplinary review But found that party members are stipulated in the criminal law, although not involved in a crime shall be investigated for Party discipline and responsibility should — 56 — be depending on the specific circumstances shall be given a warning until expelled punishment. This situation and a difference is that the former regulation behavior has been suspected of a crime, the feeling is quite strict, and the latter for the behavior not involving crime, only the objective performance of the provisions of the criminal code of behavior, but the plot is a crime to slightly. < Regulations > the 29 provisions, Party organizations in the discipline review found that party members and other illegal behavior, affect the party's image, the damage to the party, the state and the people's interests, we should depend on the situation Seriousness given disciplinary action. The loss of Party members, seriously damaging the party's image of behavior, should be given expelled from the party. At this article is party member is in violation of the criminal law outside the other illegal acts, such as violates the public security administration punishment law, customs law, financial laws and regulations behavior. The fourth is < cases > Article 32 stipulates, minor party members and the circumstances of the crime, the people's Procuratorate shall make a decision not to initiate a prosecution, or the people's court shall make a conviction and exempted from criminal punishment shall be given within the party is removed from his post, probation or expelled from the party. Party members and crime, sheets were fined in accordance with For acts; the principal Ordinance amended the provisions of the preceding paragraph. This is the new content, in order to achieve Ji method effective — 57 — convergence. Five is < > the thirty third article 10 of the provisions, the Party member due to an intentional crime is sentenced to criminal law (including probation) sheets or additional deprivation of political rights; due to negligence crime and was sentenced to three years or more (excluding three years) a penalty, shall give expelled punishment. Due to negligence crime is convicted and sentenced to three years (including three years) in prison or be sentenced to public surveillance, detention, shall in general be expelled from the party. For the individual may not be expelled from the party, should control Approval. This is followed and retained the original > < Regulations the provisions of punishment party authorization rules and report to a level party organizations. For is "party members with criminal acts, and by the criminal punishment, generally should be expelled from the party". The fifth chapter of probationary Party member of the discipline and discipline after missing members of the treatment and punishment decisions, such as the implementation of the provisions, clear the related party discipline and punishment decision made after, for duties, wages and other relevant alteration formalities for the longest time. 2, sub sub section will the original regulations of 10 categories of acts of violation of discipline integration revised into 6 categories, respectively, in violation of the punishments for acts of political discipline "in violation of discipline behavior of punishment" in violation of integrity of disciplinary action points "of violation punishments for acts — 58 — of mass discipline" "the violation of work discipline, punishment" in violation of discipline of life behavior punishment "6 chapters. 3, annex" Supplementary Provisions "clear authority making supplementary provisions of, cases of interpretative organ, as well as regulations implementation time and retroactivity etc.. 11 (3) learning understanding > < regulations needs to grasp several key problems The first problem -- about the violation of political discipline behavior > < new ordinance chapter 6 the political discipline column for the six disciplines, that is the main opposition to Party leadership and the opposition of the basic theory, basic line, basic program and basic experience, basic requirements of misconduct made provisions of the disposition, especially the eighteen since the CPC Central Committee put forward the Yan Mingzheng treatment of discipline and political rules requirements and practical achievements transformation for Discipline article, increase the false debate central policies, cliques, against the organization review, make no discipline of the principle of harmony terms. These are the party's eighteen years in comprehensive strictly Process combined with the practice of rich content. (1) false debate the central policies and undermine the Party of centralized and unified the problem is made in accordance with the provisions of the party constitution. Constitution in general programme requirements adhere to democratic centralism is one of the requirements of the construction of the party must adhere to the four cardinal. Application — 59 — of this principle is not only the party the basic organization principle and is also the mass line in party life, it requires that we must fully develop inner-party democracy, respect for the dominant position of Party members, safeguarding the Party member democratic rights, give full play to the enthusiasm and creativity of the party organizations at all levels and Party members, at the same time, also must implement the right concentration, ensure the party's mission < the chaos in unity and concerted action to ensure that the party's decision to get quickly and effectively implementing. The Party Central Committee formulated the major principles and policies, through different channels and ways, fully listen to the party organizations and Party members of the opinions and suggestions, but 12 is some people face to face not to say back blather "" will not say, after the meeting said, "" Taiwan does not say, and nonsense ", in fact, not only disrupt the people thought, some causing serious consequences, the damage to the Party of the centralized and unified, hinder the central policy implementation, but also a serious violation of the democratic system of principles. There is no doubt that shall, in accordance with the Regulations > 4 Specified in Article 6 to give the appropriate punishment. For did not cause serious consequences, to give criticism and education or the corresponding tissue processing. (2) about the destruction of the party's unity < New Regulations > the forty eighth to fifty second article, to damage Party's unity unified and violation of political discipline, punishment situation — 60 — made explicit provisions. Article 52 of the new "in the party get round group, gangs seek private gain, cliques, cultivate private forces or through the exchange of interests, for their own to create momentum and other activities to gain political capital, given a serious warning or withdraw from their party posts disposition; if the circumstances are serious, to give Leave a party to observation or expelled from the party. (3) on against the organization review of the provisions of the constitution, party loyalty honesty is party members must comply with the obligations. Members must obey the organization decision, shall not violate the organization decided encounters by asking questions to find organization, rely on the organization, shall not deceive the organization, against the organization. For example, after the investigation does not take the initiative to explain the situation, but to engage in offensive and defensive alliance, hiding the stolen money is against survey organization, is a violation of the behavior of political discipline. Article 24 of the original > < Regulations, although the provisions of the interference, hinder group review the behavior of the fabric can be severely or 13 Aggravated punishment, but did not put this kind of behavior alone as a discipline for qualitative amount of discipline. > < new regulations increase the Article 57, "anti organization review, one of the following acts, given a warning or serious warning; if the circumstances are relatively serious, giving removed from or placed on probation within the party post; if the circumstances are serious, give — 61 — expelled from the party: (a) on supply or forged, destroyed, transfer, conceal evidence; (II) to prevent others expose, providing evidence Material; (III) harboring co personnel; (4) to the organization to provide false information, to hide the fact; (5) the him against the acts of the organization review. "< rule > add this clause to the Constitution requires more specific, the previous no punishment in accordance with the definite list and put forward clear punishment in accordance with. (4) about organizing or participating in superstitious activities as < Regulations > about engage in activities of feudal superstition obstruction of social management order" violations of Article 164 the provisions, but according to the original < rule > only in disrupting production, work, social life order The case to be disciplinary treatment, in other words, alone make the feudal superstition, organize or participate in the activities of feudal superstition of, does not constitute a violation. Which is not consistent with the requirements of our party's political party. > < new regulations in this change is, superstitious activities on the political discipline, increase the Article 58, is the organization of Party members, in superstitious activities included in violation of the negative list of political discipline deserves punishment, which and Party members should adhere to the correct political principle, political standpoint and viewpoint is consistent. 14 the second question about organization and discipline violation behavior of democratic centralism is our The party's fundamental — 62 — organizational system. < New Regulations > Chapter 7 "in violation of the behavior of organizational discipline punishment" mainly for violation of democratic centralism, contrary to the "four obey the discipline behavior for source classification rules. Increased not in accordance with the relevant provisions or requirements to the organization for instructions to report on major issues; do not report truthfully report about personal matters; falsify personal archives; hide before joining the party serious mistakes; leading cadres in violation of the relevant provisions of the organization, will participate in the spontaneous formation of the old Xiang, Alumni Association, comrades in arms; to obtain illegal country residence abroad or foreign nationality, illegal for private frontier Documents such as discipline terms. (1) on the report truthfully report personal matters in 2010 the Central Committee of the Communist Party of China office, office of the State Council introduced < provisions on issues related to the leading cadres to report personal >, is clear about the request, deputy division level and above leading cadres should truthfully report changes in my marriage and spouse, children, moved to the country (territory), practitioners, income, real estate, investment and other matters, for failing to report, do not report, concealed and unreported, according to the seriousness of the case, giving criticism and education, and to make a correction within a time limit, shall be ordered to make a check, the commandment Jiemian conversation, informed criticism or jobs, free Post — 63 — processing, constitute violations, in accordance with the relevant provisions shall be given a disciplinary sanction. But since the original < Regulations > and there is no corresponding specific terms, the violation of the regulations, do not report, as a false report about personal matters, there is no corresponding disciplinary action terms, in practice it is difficult to operate. In this regard, in order to solve is not reported, as a false report about personal matters 15 asked censure, the new < Regulations > add the Article 67 of violation of personal matters related to reporting requirements, report truthfully report the clear punishment basis, making this kind of violation behavior is no longer free drilling for Exhibition on matters of personal checks to verify and supervision of cadres, discipline review provides a powerful discipline guarantee. (2) about the illegal organization, to fellow, alumni, friends of the war will < regulations stipulated in Article 68 of >, leading cadres of the party in violation of relevant provisions of the organization, will participate in the spontaneous formation of fellow, Alumni Association, comrade in arms to give the punishment according to the seriousness of the case. Here special needs note is three points: this provision for only the leading cadres ", reflecting the high requirements of leading cadres; second violation in 2002, the Central Commission for Discipline Inspection, the central Organization Department and the The relevant provisions of the General Political Department jointly issued the < off in leading cadres not to participate in — 64 — the initiative to set up "the villagers would be" alumni "" comrades in arms organization notice >. That is to say, to the spontaneous formation of fellow, Alumni Association, comrades in arms will constitute the premise of discipline is a violation of the provisions of this. The notification specified, leading cadres are not allowed to participate in the spontaneous incorporation of fellow, alumni, between comrades association would like the organization and shall not bear the sorority Human and the organizer shall not hold the corresponding position in the sorority; shall not borrow machine woven "network" and engage in kiss sparsely, round and round the gangs, but not "align" "Jieyi Gold Orchid" behavior. The third is to emphasize here that shall be organized to participate in the initiative to set up the villager, Alumni Association, comrades in arms. The so-called 16 spontaneous was established mainly means without registration. Therefore, Party members include leading cadres in the normal range of fellow, alumni, comrades in the party is not a violation of the rules of Party discipline. The three problem about integrity violations discipline Lian Jie discipline has been eighteen years clean government and anti The focus of the work of corruption. This Ordinance to amend, honesty and discipline this biggest adjustment, the new content, most of which prescribed by the original < criterion of a clean and honest administration > 8 ban and 52 are not allowed into the basic this part. (1) the central eight provisions of the spirit and requirements into < New > in — 65 — the regulations of the party's eighteen years, central resolutely implement the provisions of the eight and pay close attention to the node and intensive briefing, on public funds, private bus, public funds tourism, gifts of public funds, the big parade and lavish weddings and festive, illegal payment allowances and subsidies, illegal construction of buildings such as the original masses reflects the relatively strong, "four winds" problem of the Resolute rectification. But original < Regulations > to eat and drink, super standard reception and no clear and specific expression, new < rule > will implement eight Central provisions of the spirit of the problem increased to "clean cheap self-discipline" chapter, clear to exceed the standard, beyond the scope of the reception or borrow machine eating and drinking etc. some in violation of the provisions of the spirit of the eight central relevant persons responsible for punishment, once the violation will be according to the < rule > severely punished, binding, enhanced significantly. One is to add Article 87, about to obtain illegal, hold, and the actual use of the sports card, golf ball cards and other consumer card. Illegal access to private clubs made the punishment provisions. The second is increase the Article 97, has made provisions of the disposition of illegal self pay or 17 spamming allowances, subsidies and bonuses. The third is added to the Article 99, on violation of super standard, beyond the scope of the reception or borrow machine eat and drink to make the provisions of punishment. The fourth is to increase the Article 101, on the management — 66 — of conference activities in violation of the provisions made sanctions regulations. The fifth is the increased Article 102, for violation of office space management provisions made the punishment provisions. Six is to split the original < rule > Article 78, formed article 98, Article 100 of public Models of tourism, violate the provisions on the administration of the use of discipline of the bus through the list of made a more detailed provisions, apply more operational. Seven is increased the article 96, in violation of the relevant provisions of the, to participate in public funds to pay for dinner, high consumption of entertainment, fitness activities and public funds to buy gift, send gifts to make the provisions of the disposition. On the violation of the central provisions of the spirit of the eight, in addition to > < new regulations into "violation of honesty and self-discipline" misconduct outside, is different with the original < Regulations >, revised < rule > clearly defined not only to disposition of the directly responsible persons, but also dispose of collar Guide responsibilities. (2) increased trading rights, use of authority or position influence as relatives and close to profit violation of the terms of the < New Regulations > absorption < clean politics several guidelines > the relevant provisions spirit, increase the "negative list, including trading rights, the functions and powers or duties of influence as relatives and staff around profit. Increase Article 81" mutual use of office or authority ring for each other and their spouses, children and their spouses and other relatives, — 67 — around 18 personnel and other specific relationship between the people to seek benefits engage in trading rights, given a warning or serious warning Sanctions; if the circumstances are relatively serious, giving removed from or placed on probation within the party post; if the circumstances are serious, shall be expelled from the party. Increase Article 82 "connivance, acquiescence to the spouse, children and spouse etc. relatives and staff around the effect of Party members and cadres personal authority or position for personal gain, if the circumstances are relatively minor, given a warning or a serious warning; if the circumstances are relatively serious, giving removed from or placed on probation within the party post; if the circumstances are serious, the given Expelled from the party. Party members and cadres of the spouses, children and their spouses does the actual work and get salary or although the actual work but to receive significantly beyond the same rank salary standard, Party members and cadres informed fails to correct, in accordance with the provisions of the preceding paragraph. "(3) about the gifts, gifts misconduct from handling practices in recent years, engaged in official cadres received gifts, gifts problems more prominent. This has seriously affected the image of Party members and cadres, damaged the relations between the party and the masses, and is a hotbed of corruption, is really necessary for this kind of behavior to be disciplined. < rule > no on accepting gifts, gifts, Card consumption behavior to engage in simple "one — 68 — size fits all", but the difference between the different separately. One is in accordance with the provisions of Article 83, accepting may affect the impartial enforcement of the official gifts, gifts, consumer cards to depending on the seriousness of the case shall be given disciplinary sanctions. That is to say, for may affect the fair execution of business gifts, gifts, consumer cards are not allowed to accept. 19 is in accordance with the provisions of Article 83, accepting was significantly higher than normal ceremony is still exchanges of gifts, gifts, consumer card to disciplinary action. This is new regulations that daily life is purely reciprocity, accepting the same thing, boys , fellow friends gifts, gifts, shopping cards, although and fair execution of business has nothing to do, also want to as the case shall be dealt with, the situation is obviously beyond normal reciprocity ". The so-called" reciprocity ", one is emphasizes the reciprocal in protocol. In other words is you to me how, I to you how, not only does not go. The second is to significantly exceeded the normal local economy level, customs and habits, economic capacity of individual gifts, gift value. Specific sanctions to according to the processing of a variety of factors to consider, as appropriate. The third is the root according to the provisions of Article 84," to Engaged in public service personnel and their spouses and children, children's spouses and other relatives and other specific relationship presented Ming Xianchao normal reciprocity of gifts, gifts, consumer card, if the circumstances are — 69 — relatively serious, given a warning until probation. "In accordance with the above provisions, gift giving significantly beyond the normal reciprocity, giver constitute the discipline. (4) on illegal trading of stocks or of other regulations of securities investment < > Article 88 is engaged in punishment regulation of camp and activity in violation of the relevant provisions on. Among them, 3 will" buying and selling stocks or in other securities investment "column as one of disciplinary cases Out. First need to be clear, > < regulations did not change the provisions of the Ordinance. The ordinance of the provisions of the second paragraph of Article 77 provisions "who, in violation of the provisions of the sale of stocks" is one of the violation, and at the beginning of the first paragraph of this article "violation of 20 against the relevant provisions of the" textual representation of the repeat revision. In, just from the legislative technique removed the "personal" in violation of the provisions, content and not to change the original provisions. Need to clear is, "buy or sell a stock or of other securities investment" refers to violation of the relevant provisions refers to in April 2001, the Party Central Committee, the State Council promulgated the On the work of the party and government organs staff's personal investment in securities if dry provisions >. According to the provisions of Article 3, use of work time, office facilities, the sale of stocks and securities investment fund belongs to illegal behavior. The fourth question, about the violation of the masses of the disciplinary actions < — 70 — new regulations > would violate public discipline behavior of a single set of a class of restored "three rules of discipline and eight note" in the discipline of the masses of excellent traditional. < New Regulations > Chapter 9 "to violate the masses of disciplinary action", mainly the destruction of the party's close ties with the masses of misconduct made provisions on disciplinary; enrich and perfect the super standard, beyond the scope of Xiang Qun < All to raise fund and labor, in for involving the public affairs deliberately, chinakayao, in social security, policy support, disaster relief funds and materials and other matters assigned any kind and affectionate friends, obviously unfair acts against the interests of the masses of the disciplinary terms; increase the terms not in accordance with the provisions of the public party provided, government, factory and village (neighborhood) provided etc. violation of the people's right to know the behavior of the discipline. The fifth issue, on the violation of work discipline violation of work discipline added "negative list, including Party organizations carry out strictly Main responsibility for poor discipline terms. (1) the new party organization comprehensive strictly the main responsibility of the party does not fulfill the 21 or perform poor disciplinary terms < New Regulations > has a lead people to pay attention to the new terms, that is, in chapter ten "on the violation of work discipline behavior punishment" increase in the one hundred and fourteenth "party fail to perform — 71 — comprehensive strictly the main responsibility of the party or to perform comprehensive strictly the main responsibility for administering the ineffective, resulting in serious damage or serious adverse effects, to the person directly responsible and the responsibility of leadership and give a warning or serious warning. The situation is serious, giving removed from their party posts or on probation Punishment. "Here the changes. For the first time, the main responsibility write < rule >. (2) new shall report does not report or false reporting discipline shall increase the 117 bar" in the higher level units to check to inspect the work or report to the parent unit, work report of shall report the matters do not report or do not report, cause serious damage or serious adverse effects of, to the person directly responsible and the responsibility of leadership, to give warning or a serious warning; if the circumstances are serious, giving removed from their party posts or placed on probation. "For example, during the tour visits to the region, the unit Members the obligation to the inspection teams to reflect the true situation, to conceal not reported or intentionally to the inspection teams to provide false information, causing serious damage or serious adverse effects of, the person directly responsible and the responsibility of leadership should be in accordance with the provisions of < rule > Article 117 to give the appropriate punishment. (3) the new not granted in accordance with the provisions of punishment, not according to the provisions of the implementation of disciplinary measures 22 violation — 72 — of the provisions of Article 115 "Party organizations have one of the following circumstances, the direct leadership responsibility. Probation: members were sentenced punished, in accordance with the provisions give disciplinary action or in violation of state law Rules of behavior should be given disciplinary punishment and dispose of; disciplinary punishment by decision or complaint review the decision made, not in accordance with the provisions of the implementation decisions on punishment of the party, position, rank, and the treatment of the matters; Party members subject to disciplinary action, not in accordance with the cadre management authority and organizational relationships of by dispose of Party members to carry out education and supervision of daily management. "What needs to be pointed out is," cliff "demoted with cars, housing, secretary problem, implementation is not a discipline and party posts and ranks treatment by the organization department is responsible for the implementation, with cars, housing by the logistics department is responsible for the implementation of, Ji Commission responsible oversight responsibilities. The six questions, about the acts violating the discipline of life "in violation of discipline of life behavior punishment", mainly to "four winds" problems and a serious violation of social morality, family virtue acts of misconduct made provisions on disciplinary, an increase of extravagant life, contrary to the social public order and good customs disciplinary terms. Worth mentioning is, > < Regulations in Article 150 — 73 — about "adultery" "mistress (Cardiff) formulation in the new < rule > is removed, to expand the scope of Article 127 provisions" and others hair improper sexual relations, let face disciplinary action Wider more strict. Four, and earnestly do a good job in the < code > and < rule > implement system of life lies in execution. < code > and < Regulations > is 23 Party organizations at all levels of a strong constraint and all Party members follow. Learning and implementing the < code > and < rule > is party committees (party), commission for discipline, discipline inspection group), the majority of Party members and cadres of the common responsibility, must party caught together, the party one execution. () Party committees (party) and play and implement comprehensive strictly the main responsibility, pays special attention to the two party regulations learning cross penetration. One is to Adhere to the party constitution is fundamental to follow, and resolutely safeguard the authority of the Party Chapter. The second is to adhere to the problem oriented, to strictly political discipline and political rule moments in the first place. The third is to adhere to the discipline and rules quite in front must not allow the bottom line to break the discipline. The fourth is to seriously organize the study of propaganda and education, in the city party members to create a disciplined, about the rules of the strong atmosphere. (II) Commission for Discipline Inspection at all levels (Discipline Inspection Group) to an important basis for the revised two party regulations as, adhere to easily — 74 — blame, strengthen supervision and enforcement And early method in combining Ji, increase accountability efforts. One is to two regulations within the party important basis, adhere to the party constitution duties, with strict discipline to maintain the constitution authority. The second is to adhere to high standards and keep the bottom line, adhere to Ji Yan in law and discipline, the discipline and rules quite in front, grasping grasping small, easily blame, comprehensive use of supervision and discipline of "four kinds of form" in the discipline embodies the strict requirements and care for the discipline, tighten up, Yan. According to discipline in accordance with regulations to carry out disciplinary review. Increase the violations punishment, clues can initiate an investigation on the trial of cases According to the discipline on the provisions of the proportion of processing and control manager maintains discipline. To focus on investigating non convergence, don't accept hand serious disciplinary violations at the same time, pay more attention to the general review of discipline 24 behavior, and gradually increase the lighter punishment. Four is to illuminate two party regulations, combined with the local district of the Department of party conduct Lianzheng to relevant laws and regulations system clean, timely research proposes to establish, change, waste release opinion, avoid conflict, and the fasten system of cage, and gradually formed not rot, not rot, not want to rot system and working mechanism. (3) the leadership of the party members and cadres — 75 — should play an exemplary role. The rate of higher consciousness of the front of the Ordinance to lead practice self-discipline norms, leading to maintain discipline of seriousness and authority. One is the above rate, demonstration and guidance, take the lead in learning and mastering the < code > and < > the requirements and regulations, do the deep understanding, learning to use. The second is to play an exemplary role in abiding by discipline rate, take the lead in practicing self-discipline norms, firmly establish before the discipline are equal, the system has no privilege, discipline is no exception, and consciously do standards, require more strict measures more practical. Third is to consciously accept supervision, conscientiously participate in the democratic life and debriefing honesty responsibility, such as Real to the party organization to report personal matters, and to accept the supervision of the work and life of the normal, habits under the supervision of the exercise of power, to carry out the work. The fourth is to set an example for the strict enforcement of discipline. Leading cadres should take the lead in the maintenance of discipline of seriousness and authority, to dare to seriously, dare to struggle, dare to offend people, for misconduct not laissez faire, but do not indulge, not tolerate to ensure the party constitution of party compasses party put in place. (4) the majority of Party members and cadres to set high standards and hold the bottom line, consciously abide by the < code > and < rule >. One is to control the < standard > and < 25 cases >, tight Close connection — 76 — with their own thoughts, practical work and life, efforts to solve the problems, to enhance the study and implement of the effectiveness and pertinence. The second is to establish a high standard and hold the bottom line, consciously in the self-discipline pursuit of high standards, strictly in the party away from the red line discipline, discipline, about the rules and know fear, distrust, the formation of the honor system, comply with the system, safeguard system of good habits. Regulations and discipline regulations of < < New Revision of the Communist Party of China clean fingered self-discipline criterion > and < Chinese Communist Party Disciplinary Regulations > is the Party Central Committee in the new situation to promote the comprehensive strictly root of the lift, the regulations of the party construction of keeping pace with the times. We should study and implement the Standards > and < > as the primary political task, adhere to the party constitution duties, adhere to the discipline of, Ji Yan in law, the full implementation of supervision and discipline accountability responsibilities for coordination and promotion "four overall" strategic layout in XX District vivid practice to provide a strong guarantee. - Si Jian Wu, and effectively enhance the implementation of the implementation of the < code > < > The consciousness of General Secretary Xi pointed out that the party is in charge of the party, to manage the party; strictly, it can cure good party. Criterion > and < rule > keep pace — 77 — with the times is our party to form a new potential strictly rules, to deepen understanding of the ruling law, is a comprehensive strictly, and strengthen the supervision within the party important grasper. Criterion > closely linked to the theme of self-discipline, self-discipline intensity-modulated, focusing on morality, for the majority of Party members and cadres set to see, feel the high standard, show the Communists noble moral sentiment; District Ordinance < < rule > the constitution of discipline integration into a political discipline, organization and discipline, honesty and discipline, discipline of the masses, work discipline, discipline, emphasize discipline, focusing on established rules, to draw the party organizations and Party members do not touch the bottom line. Party committees (party) to effectively strengthen the study and publicize the implementation of the < code > and < rule > the organization and leadership of criterion > and < > a full range, multi angle, deep publicity, the formation of study and publicize and implement the boom, in order to consolidate the development of good political environment to create a positive environment and atmosphere. The majority of Party members and cadres to strict requirements, the < rule > and < Ordinance cases > as a guide to action and behavior criterion, adhere to the moral standards and discipline of the bottom line, to maintain the discipline of worship and awe, learning, compliance, and maintain party discipline and rules of the model. The discipline inspection and supervision organs and cadres to the < code > and < > as the deepening of — 78 — the "three", and strengthen supervision and discipline of accountability is important to follow correctly grasp the use of supervision and discipline of "four types", promote the comprehensive strictly in new roots. Strict discipline, adhere to the discipline and rules quite in front of the enterprise in the implementation of expensive to implement to execute. The discipline inspection and supervision organs to implement the < code > and < Efforts to investigate cases > as an opportunity, adhere to the party should manage the party strictly, serious performance of their duties to promote two regulations implementation. Change discipline concept. From the simple "investigation of illegal" to a comprehensive "stare at violate discipline"; from the business case to prosecute the big cases and timely solve the signs of tilt to. From the orientation to the normal supervision; from the tube "minority" to resist the "most". Guide Party members and cadres to seriously implement the < code > and < rule >, consciously abide by the political, organizational, honest people, work, life six discipline. Urge the leadership cadres sent to play an exemplary role, take the lead in strictly enforced. Relaxation and rest Strong wind is Su Ji, closely linked to the "four winds" prone to multiple, the masses reflect the strong important nodes and, glued to the four winds "new form, new trends, seriously investigate and deal with violations of the central eight provisions of the spirit, to increase the bulletin exposure intensity, the formation of Chajiu" four winds "loudly, continue to release and discipline — 79 — must be strict signal. At the same time, extended supervision tentacles, through the development of the rural and fishery party conduct Lianzheng construction inspection, issued in a timely manner, Chajiu occurred in grassroots side of corruption and unhealthy, and earnestly safeguard the interests of the masses and social stability. The creativity and discipline. Grasp and make good use of the supervision and discipline of" four types ", to ensure the Promoting clues to lots of discipline and the law of the vacuum tube, strict together. Not only to the "less" and "very few" thorough investigation severely punished, but also the "most" to maintain zero tolerance trend through layers of conductive pressure, let the discipline about the rules for each party members and cadres consciously follow. At present, it is necessary to implement the "list" management, strictly follow the clues to the disposal of five standards, make the classification of disposal, dynamic cleanup. Zadok Party committees at all levels to implement the main responsibility, comprehensive use of disciplinary action and tissue processing and other means to effectively curb the commonplace, used to see do not blame the "small problem", not because of "practice" and "exception". Prominent Discipline characteristics, the problems of violation of discipline and rules into the focus of supervision and discipline and disciplinary review. At the same time, increase case double check the intensity, the serious problems of discipline violations or "four winds" ban but not absolutely, not only to be — 80 — held directly responsible, but also held leadership responsibility; not only to pursue studies the main responsibility of the Party committee, and to pursue Commission for Discipline Inspection and supervision responsibilities and promote accountability to become the new norm. The implementation of supervisory responsibility. Maintain < code > and < rule > the seriousness and authority of the discipline and rules and truly become the party's ruler. Discipline as supervision within the party the specialized agency, we must strengthen the responsibility to act, adhere to the Impartial discipline accountability, earnestly will be strict discipline, discipline must be punished, and severely punish the acts in violation of rules and regulations. — 81 —