预防用疫苗临床试验不良反应分级标准指导原则

预防用疫苗临床试验不良反应分级标准指导原则 (国食药监注[2005]493号) 各省、自治区、直辖市食品药品监督管理局(药品监督管理局): 为疫苗研发行为，指导疫苗研究单位科学地开展研究工作，根据《药品管理法》、《药品管理法实施条例》及《药品注册》，我局组织制定了《预防用疫苗临床前研究技术指导原则》、《生物制品生产工艺过程变更管理技术指导原则》、《联合疫苗临床前和临床研究技术指导原则》、《多肽疫苗生产及质控技术指导原则》、《结合疫苗质量控制和临床研究技术指导原则》和《预防用疫苗临床试验不良反应分级标准指导原则》等6个技术指导原则，现印发给你们，并请转发辖区内各有关单位。 国家食品药品监督管理局 二??五年十月十四日 预防用疫苗临床试验不良反应分级标准指导原则 前 言 疫苗系一类特殊的药品，通常用于健康人群的预防疾病。大多数预防性疫苗的各阶段临床试验均选择健康的受试者，并且多数疫苗用于健康儿童，因此，在预防性疫苗临床研究过程中，对安全性方面的考虑尤为重要，其要求应高于一般治疗性药物。 标准化的不良反应评价分级标准，已逐渐被广泛用于评估治疗用药物在特定疾病的患者人群中的安全fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 性，但这些分级标准适用于患者，本身的疾病过程经历了轻度、中度或重度临床和实验室指标异常的不良事件，故其参数可能并不适于健康志愿者。本指导原则针对预防性疫苗制定不良反应分级标准的目的，就是最大程度地降低健康受试者在临床试验中的风险，本不良反应分级标准中所采用参数的界定值，系基于已上市疫苗临床试验中所获得的和已公开的信息，并结合当前国情的考虑。 一、概述 本指导原则适于创新性预防性疫苗，并适用于临床试验的受试者为健康成人及青少年时，对试验中发生的临床和实验室指标异常的严重程度即不良反应强度进行评估，并可作为一般预防性疫苗临床试验设计中规定的破盲标准，以及作为是否停止临床研究的参考。同时，本指导原则提供的统一不良反应分级标准也有助于预防性疫苗的同一临床试验不同试验组间或不同临床试验间的安全性数据的比较。 预防性疫苗的临床试验应严格遵守《药物临床试验质量管理规范》(GCP)并符合相关的法规要求，管理法规要求疫苗临床研究中发生的不良事件需接受有关管理当局的监查和相关主体(注册申请人、伦理委员会和研究人员)的监控，并适时备报。 预防性疫苗的临床试验研究者必须适时、全面、客观而准确地记录所有安全性观察值及相关数据，从而进行不良事件或不良反应的评价，注册申请人必须监测临床研究的全程进展，本不良反应的分级标准有助于进行安全性监控，并及时做出判断和按要求适时。 本指导原则及已发布的疫苗临床试验相关指导原则的目的旨在为预防性疫苗进行临床试验的安全性评估时提供参考，本文中不良反应的分类和分级标准为临床研究中安全性资料的完整性提供补充。 二、基本内容 本指导原则提供的预防性疫苗临床试验中不良反应的分级指标包括两部分(详见毒性分级表)，第一部分为临床指标(局部反应、全身反应、生命体征检测);第二部分为实验室指标(血生化、血常规、尿常规检测)，但并非涵盖所有预防性疫苗临床试验中所需观察的安全性指标，对于一些开发中的特殊疫苗fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 可能需要增加额外的监控指标，或修改表中参数的具体界定值。例如，额外的参数基于临床前毒理研究的安全性提示或先前类似已上市产品的经验。 不同疫苗在进行临床试验时，可根据疫苗的特性，从本文的不良反应分级表中选择适合的观察指标。根据疫苗的各自特征和疾病流行情况，进行合理的安全性监测与评价。 (一)不良反应分级表 1(临床观察指标(表1,3) 表 1 局部反应分级表 局部反应 轻度( 1 级) 中度( 2 级) 严重( 3 级) 潜在的生命危胁( 4 级) 疼痛 不影响活动 影响活动或多次使用非麻醉性止痛药 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 影响日常活动或多次使用麻醉性止痛药 急诊或住院 皮肤粘膜 红，瘙痒 弥散，斑丘疹样皮疹，干，脱屑 泡状，潮湿，脱屑或溃疡 脱皮性皮炎，累及粘膜，或多型性红斑，或疑似 Stevens-Johnsons 综合症 硬结 * <15 mm 15 , 30 mm >30 mm 坏疽或剥脱性皮炎 红 * <15 mm 15 , 30 mm >30 mm 坏疽或剥脱性皮炎 肿 ** fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the <15 mm 且不影响活动 15 , 30 mm 或影响活动 >30 mm 或限制日常活动 坏疽 疹(注射部位) <15 mm 15 , 30 mm >30 mm 瘙痒 注射部位微痒 注射肢中度痒 全身痒 *除了最直接地通过测量直径来分级评价局部反应，还要记录测量结果的发展变化。 **肿的评价和分级应根据功能等级和实际测量结果 表 2 生命体征分级表 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 生命体征 * 轻度( 1 级) 中度( 2 级) 严重( 3 级) 潜在的生命危胁( 4 级) 发热，腋温 * 37.1 , 37.5 ? 37.6 , 39.0? >39.0? 口温 ** 37.7 , 38.5 38.6 , 39.5? 39.6 , 40.5? , 40 ? 心动过速(次 /min ) 101 , 115 116 , 130 >130 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 由于心率不齐就急诊或住院 心动过缓(次 /min ) 50 , 54 45 , 49 <45 由于心率不齐就急诊或住院 高血压(收缩压 mmHg ) *** 141 , 150 151 , 155 >155 由于严重高血压就急诊或住院 高血压(舒张压 mmHg ) *** 91 , 95 96 , 100 >100 由于严重高血压就急诊或住院 低血压(收缩压) mmHg*** 85 , 89 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 80 , 84 <80 由于低血压休克就急诊或住院 呼吸频率(次 /min ) 17 , 20 21 , 25 >25 需气管插管 引自中国预防接种手册， 受试者应在静止状态进行检测 * ** 口温;检测前没有喝热的或冷的饮料或吸烟 *** 血压异常的判断需与使用疫苗前的基线血压值对比，进行具体。 表 3 全身反应分级表 全身反应 轻度( 1 级) 中度( 2 级) 严重( 3 级) 潜在的生命危胁( 4 级) fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 变态反应 瘙痒无皮疹 局部荨麻疹 广泛荨麻疹，血管性水肿 严重变态反应 头痛 不影响活动，无需治疗 一过性，稍有影响活动，需治疗(多次使用非麻醉性止痛药) 严重影响日常活动，初始麻醉剂治疗有反应 顽固性，重复麻醉剂治疗。急诊或住院 疲劳、乏力 正常活动减弱, 48 小时，不影响活动 正常活动减弱 20% , 50% , 48 小时，稍影响活动 正常活动减弱, 50% ，严重影响日常活动，不能工作 不能自理，急诊或住院 恶心、呕吐 1 , 2 次 /24 小时，摄入基本正常且不影响活动 2 , 5 次 /24 小时，摄入显著降低，或活动受限 24 小时内, 6 次，无明显摄入，需静脉输液 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 由于低血压休克需要住院或其他途径营养 腹泻 轻微或一过性， 2 , 3 次稀便 / 天，或轻微腹泻持续小于 1 周 中度或持续性， 4 , 5 次 / 天，或腹泻, 1 周 , 6 次水样便 / 天，或血样腹泻，直立性低血压，电解质失衡，需静脉输液, 2L 低血压休克，需 住院治疗 肌肉痛 不影响日常活动 非注射部位肌肉触痛，稍影响日常活动 重度肌肉触痛，严重影响日常活动 症状明显，肌肉坏死，急诊或住院 咳嗽 一过性，无需治疗 持续咳嗽，治疗有效 阵发咳嗽，治疗无法控制 急诊或住院 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 其它不适或临床上的不良反应 ( 依据相应的判断标准 ) 不影响活动 稍有影响活动不需药物治疗 严重影响日常活动需要药物治疗 2、实验室指标(表4 , 6) 由于实验室所有指标作为参考标准须依据所规定的正常值而定 , 因此需提供规定的正常 值范围来证明其合理可行性，以下仅供参考。 表 4 血生化指标分级表 血清 轻度( 1 级) 中度( 2 级) 严重( 3 级) 潜在的生命危胁( 4 级) 肝功能, ALT,AST 由影响因素引起的升高 1.25 , 2.5 ×ULN* 2.6 , 5 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the ×ULN 5.1 , 10 ×ULN >10×ULN 肌酐 1.1 , 1.5×ULN 1.6 , 3.0×ULN 3.1 , 6×ULN >6×ULN BUN 1.25 , 2.5×ULN 2.6 , 5×ULN 5.1 , 10×ULN >10×ULN 胆红素 : 由影响因素引起的升高但功能检查正常 1.1 , 1.5×ULN 1.6 , 2.0×ULN 2.0 , 3.0×ULN >3.0×ULN fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 胆红素 : 由影响因素引起的升高伴随肝功能检查指标的升高 1.1 , 1.25×ULN 1.26 , 1.5×ULN 1.51 , 1.75×ULN >1.75×ULN 胰酶 - 淀粉酶，脂肪酶 1.1 , 1.5×ULN 1.6 , 2.0×ULN 2.1 , 5.0×ULN >5.0×ULN CPK-mg/dL 1.25 , 1.5×ULN 1.6 , 3.0×ULN 3.1 , 10×ULN >10×ULN *“ULN”:为正常值范围之上限 #在毒性评价和结论中的临床症状需与每项实验室参数共同描述，并在研究中进行监查 表 5 血液检查分级表 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 血液 轻度( 1 级) 中度( 2 级) 严重( 3 级) 潜在的生命危胁( 4 级) 血红蛋白(女性)( g/dL ) 12.0 , 13.0 10.0 , 11.9 8.0 , 9.9 <8.0 血红蛋白(女性)与试验前比较的变化( gm/dL ) 增长, 1.5 1.6 , 2.0 2.1 , 5.0 >5.0 血红蛋白(男性)( gm/dL ) 12.5 , 14.5 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 10.5 , 12.4 8.5 , 10.4 <8.5 血红蛋白(男性)与试验前比较的变化( gm/dL ) 增长, 1.5 1.6 , 2.0 2.1 , 5.0 >5.0 白细胞升高 (个 /mm 3 ) >13,000/mm3 13,000 , 15,000/mm3 15,000 , 30,000/mm3 >30,000 白细胞降低 (个 /mm 3 ) 2500 , 3500 1500 , 2499 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 1000 , 1499 <1000 凝血时间,由影响因素引起的延长 1.0 , 1.10×ULN 1.11 , 1.20×ULN 1.21 , 1.25×ULN >1.25×ULN 局部促凝血酶原激酶时间,由影响因素引起的延长 1.0 , 1.2×ULN 1.21 , 1.4×ULN 1.41 , 1.5×ULN >1.5×ULN **“ULN”:为正常值范围之上限 表 6 尿液检查分级表 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 尿 轻度( 1 级) 中度( 2 级) 严重( 3 级) 潜在的生命危胁( 4 级) 蛋白 微量 1+ 2+ >2+ 尿糖 微量 1+ 2+ >2+ 血细胞(镜检) 每个高倍视野下的红细胞数( rbc/hpf ) 1 , 10 11 , 50 >50 或 / 和密布血细胞 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 住院治疗或需输入浓缩血细胞 以上表中的分级指标并不推荐用于所有疫苗临床试验的健康志愿者的安全性监测，也不代表涵盖了所有安全性的监测指标，建议选取适宜的监测指标用于相应的预防性疫苗的临床试验受试者。 鉴于健康婴幼儿的部分生理指标与成人明显不同，建议在具体应用时结合临床研究的具体情况进行相应的调整。 (二)不良反应强度分级的一般评估原则 对于上面分级表中未涉及的临床异常情况，按照下列标准对不良反应进行强度分级评估: 1级 轻度 短时间的不适(,48小时)，无需医疗; 2级 中度 轻度到中度限制日常活动，不需要或只需要少量的医疗干预; 3级 重度 显著地限制日常活动，需要日常生活照顾，需要医疗，可能需要住院; 4级 危及生命 极度限制日常活动，显著地需要日常生活照顾，需要医疗和住院; (三)严重的或危及生命的不良反应 预防性疫苗的临床研究中，发生由临床医师认定的任何严重的或危及生命的临床事件，其强度均被认为是4级，包括:癫痫、昏迷、手足抽搐、糖尿病酮酸中毒、弥散性血管内凝血、弥散性瘀斑、麻痹或瘫痪、急性精神病、严重抑郁症等。 严重的或罕见的不良反应常需要大量样本的临床研究才能发现，有时可能需通过上市后进行进一步评价。但在上市前的临床研究中，应尽可能的增大样本量，以期发现少见或罕见的严重不良反应。而作为主fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the 要适用人群为健康个体并包括婴幼儿的疫苗而言，对其安全性的要求较其他药品更为严格，考虑更为慎重。 如在必要的情况下，还可进行以安全性观察指标作为临床评价终点的临床研究，样本量最低则需符合统计 学的要求。 国家食品药品监督管理局将根据预防性疫苗临床研究的情况，适时对本指导原则进行修订和完善。 fertility better. Site preparation before planting, clearing rubble, if conditions for soil disinfection can be carried out. Thickness of planting soil: Arbor thickness not less than 90cm, shrubs not less than 60cm, to be not less than 20cm. Poor quality of the soil, should enlarge the hole (hole) specifications, and debris picked up by clearing encountered lime slag, against the growth substances such as stone, asphalt, you should pit (hole) diameter increased 1 to twice times, harmful substances removal clean and put on suitable planting soil. F, green natural trees found in the planting hole dug seriously affect the operation of the underground obstacle, get in touch with designers, the appropriate changes. ?, seedling quality of trees dug a well ... C, trees have been delivered to the site in a given place, to turn the roots covered with straw to prevent water loss. ? trees planted seedlings before planting quality requirements: should be checked according to the design drawings and seedling varieties, specifications and plant location. Principles of plant "outside the high to low, the first after the first" grown order "big tree---small tree---shrub-plants" before the tree into planting holes, you should check the planting hole size and depth, while root system requirements are not met, trimming plants dibble. A, seedling rate should be commensurate with the speed of planted seedlings, planted along, kind of finish, minimizing root exposure. On planting trench, remaining seedling exposed roots should be kept buried with soil. B, depending on the specific seedlings, good seedlings and planting depth should be identified, roots with soil plug solid rear mud balls can be under the