1、临床试验的知情同意与SAE审查,江苏省人民医院南京医科大学第一附属医院汪秀琴,TuskegeeSyphilisStudy,Study in Jewish Chronic Disease Hospital in Brooklyn, New York,NO Informed Consent,NO Informed Consent,Nazi Experiment,尼日利亚“特洛芬” 试验制药公司赔偿7500万美元,NO Informed Consent,Nuremberg Code 纽伦堡法典,Voluntary consent of the human subject is absolutely
2、essential 强调必须获得受试者的知情同意。,知情同意,为什么？尊重受试者的自主决定权All human beings are born free and equal in dignity and rights. 人生来平等自由。Report of the International Bioethics Committee of UNESCO on Consent (2009)自主决定与承担责任Autonomy implies responsibility. The power to decide for ones self entails ipso facto acceptance o
3、f the consequences of ones actions. 为自己做决定意味着同意承担行为的后果.Report of the International Bioethics Committee of UNESCO on Consent (2009),是不是签署知情同意了，研究者就没有责任了？,知情同意有关法规,SFDA，药物临床试验质量管理规范第8条：在药物临床试验的过程中，必须对受试者的个人权益给予充分的保障，并确保试验的科学性和可靠性。受试者的权益、安全和健康必须高于对科学和社会利益的考虑。 伦理委员会与知情同意书是保障受试者权益的主要措施。,什么是知情同意？,A proces
4、s by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subjects decision to participate 指向受试者告知一项试验的各方面情况后，受试者自愿确认其同意参加该项临床试验的过程。ICH GCP 1.28,知情同意原则(principle of informed c
5、onsent),充分理解,完全告知,自主决定,信息（Information）理解 (understanding) 3个要素 自愿 (voluntariness),完全告知,SFDA，药物临床试验质量管理规范第14条：研究者或其指定的代表必须向受试者说明有关临床试验的详细情况：（一）受试者参加试验应是自愿的，而且有权在试验的任何阶段随时退出试验而不会遭到歧视或报复，其医疗待遇与权益不会受到影响；（二）必须使受试者了解，参加试验及在试验中的个人资料均属保密。必要时，药品监督管理部门、伦理委员会或申办者，按规定可以查阅参加试验的受试者资料；（三）试验目的、试验的过程与期限、检查操作、受试者预期可能的
6、受益和风险，告知受试者可能被分配到试验的不同组别；,完全告知,SFDA，药物临床试验质量管理规范第14条：研究者或其指定的代表必须向受试者说明有关临床试验的详细情况： （四）必须给受试者充分的时间以便考虑是否愿意参加试验，对无能力表达同意的受试者，应向其法定代理人提供上述介绍与说明。知情同意过程应采用受试者或法定代理人能理解的语言和文字，试验期间，受试者可随时了解与其有关的信息资料；（五）如发生与试验相关的损害时，受试者可以获得治疗和相应的补偿。,完全告知SFDA药物临床试验伦理审查工作指导原则 （2010）,4. 知情同意书告知的信息4.1 试验目的、应遵循的试验步骤（包括所有侵入性操作）、
7、试验期限。4.2 预期的受试者的风险和不便。4.3 预期的受益。当受试者没有直接受益时，应告知受试者。4.4 受试者可获得的备选治疗，以及备选治疗重要的潜在风险和受益。4.5 受试者参加试验是否获得报酬。4.6 受试者参加试验是否需要承担费用。,完全告知SFDA药物临床试验伦理审查工作指导原则 （2010）,4. 知情同意书告知的信息4.7 能识别受试者身份的有关记录的保密程度，并说明必要时，试验项目申办者、伦理委员会、政府管理部门按规定可以查阅参加试验的受试者资料。4.8 如发生与试验相关的损害时，受试者可以获得的治疗和相应的补偿。4.9 说明参加试验是自愿的，可以拒绝参加或有权在试验的任何
8、阶段随时退出试验而不会遭到歧视或报复，其医疗待遇与权益不会受到影响。4.10 当存在有关试验和受试者权利的问题，以及发生试验相关伤害时，有联系人及联系方式。,完全告知,理智人的角度从受试者决定参加研究前可能想要知道的信息的角度，判断哪些信息应该在知情同意过程告知，如：心脏导管插入术死亡风险的统计概率很小，从研究者角度看这并不重要，但对于受试者，这种风险可能显得很严重育龄期妇女对影响受孕或胎儿的风险十分敏感血液保存进行基因研究与试验有关的对配偶或伴侣的风险,知情同意是一个“过程”，不是“一次”事件,充分理解,在获得知情同意的过程中，应注意以下几点：文字应简明易懂，避免使用晦涩难懂的医学术语；语言
9、表达：以适合个体理解水平的语言来表达；受试者理解能力取决于个体的发育、智力和受教育程度如果研究具有重大风险，建议使用视听资料和小册子帮助理解，或使用口头的或书面的测验来判断受试者是否理解。,自主选择,SFDA，药物临床试验质量管理规范第15条：经充分和详细解释试验的情况后获得知情同意书：（一）由受试者或其法定代理人在知情同意书上签字并注明日期，执行知情同意过程的研究者也需在知情同意书上签署姓名和日期；（二）对无行为能力的受试者，如果伦理委员会原则上同意、研究者认为受试者参加试验符合其本身利益时，则这些病人也可以进入试验，同时应经其法定监护人同意并签名及注明日期；（三）儿童作为受试者，必须征得其
10、法定监护人的知情同意并签署知情同意书，当儿童能做出同意参加研究的决定时，还必须征得其本人同意；,自主选择,SFDA，药物临床试验质量管理规范第15条：经充分和详细解释试验的情况后获得知情同意书： （四）在紧急情况下，无法取得本人及其合法代表人的知情同意书，如缺乏已被证实有效的治疗方法，而试验药物有望挽救生命，恢复健康，或减轻病痛，可考虑作为受试者，但需要在试验方案和有关文件中清楚说明接受这些受试者的方法，并事先取得伦理委员会同意；（五）如发现涉及试验药物的重要新资料则必须将知情同意书作书面修改送伦理委员会批准后，再次取得受试者同意。,自主选择 SFDA药物临床试验伦理审查工作指导原则 （201
11、0）,5. 知情同意的过程5.1 知情同意应符合完全告知、充分理解、自主选择的原则5.2 知情同意的表述应通俗易懂，适合该受试者群体理解的水平5.3 对如何获得知情同意有详细的描述，包括明确由谁负责获取知情同意，以及签署知情同意书的规定。5.4 计划纳入不能表达知情同意者作为受试者时，理由充分正当，对如何获得知情同意或授权同意有详细说明。5.5 在研究过程中听取并答复受试者或其代表的疑问和意见的规定。,免除知情同意免除知情同意签字,知情同意的特殊情况,利用以往临床诊疗中获得的医疗记录和生物标本的研究，并且符合以下全部条件，可以申请免除知情同意研究目的是重要的研究对受试者的风险不大于最小风险免除
12、知情同意不会对受试者的权利和健康产生不利的影响受试者的隐私和个人身份信息得到保护若规定需获取知情同意，研究将无法进行（病人/受试者拒绝或不同意参加研究，不是研究无法实施、免除知情同意的理由）只要有可能，应在研究后向受试者提供适当的有关信息若病人/受试者先前已明确拒绝在将来的研究中使用其医疗记录和标本，则该受试者的医疗记录和标本只有在公共卫生紧急情况需要时才可被使用,免除知情同意,利用以往研究中获得的医疗记录和生物标本的研究（研究病历/生物标本的二次利用），并且符合以下全部条件，可以申请免除知情同意以往研究已获得受试者的书面同意，允许其他的研究项目使用其病历或标本本次研究符合原知情同意的许可条件
13、受试者的隐私和身份信息的保密得到保证,免除知情同意,当一份签了字的知情同意书会对受试者的隐私构成不正当的威胁联系受试者真实身份和研究的唯一记录是知情同意文件，并且主要风险就来自于受试者身份或个人隐私的泄露要求：1）遵循每一位受试者本人的意愿，签署或不签署书面知情同意文件；2）向受试者或其法定代理人提供书面告知信息，告知信息要求参照“知情同意审查工作表”；3）获得受试者或其法定代理人的口头知情同意。,免除知情同意签字,研究对受试者的风险不大于最小风险并且如果脱离“研究”背景，相同情况下的行为或程序不要求签署书面知情同意例如，访谈研究，邮件/电话调查要求：1）向受试者或其法定代理人提供书面告知信息
14、，告知信息要求参照“知情同意审查工作表”；2）获得受试者或其法定代理人的口头知情同意。,免除知情同意签字,Adverse Events,Report,What are unanticipated problems?,OHRP considers unanticipated problems, in general, to include any incident, experience, or outcome that meets all of the following criteria:unexpected (in terms of nature, severity, or frequen
15、cy) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;（性质、严重程度或频率）非预期related or possibly related to participation in the
16、 research (in this guidance document, possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and与参加研究相关或可能相关suggests that the research places subjects or others at a greater risk of harm (in
17、cluding physical, psychological, economic, or social harm) than was previously known or recognized.对受试者或其他人更大的伤害风险,How to determine which adverse events are unanticipated problems?,Assessing whether an adverse event is unexpectedAssessing whether an adverse event is related or possibly related to pa
18、rticipation in researchAssessing whether an adverse event suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized,How to determine which adverse events are unanticipated problems?,Assessing whether an adverse event is unexpectedAssessing
19、 whether an adverse event is related or possibly related to participation in researchAssessing whether an adverse event suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized,问题1,Any adverse event occurring in one or more subjects parti
20、cipating in a research protocol, the nature, severity, or frequency of which is NOT consistent with either: (1) the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the protocol-related documents, such as the IRB-approved r
21、esearch protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and (b) other relevant sources of information, such as product labeling and package inserts; or与试验程序相关的预期不良事件，方案、IB、ICF有说明，或药品说明书(2) the expected natural progression of any underlying dise
22、ase, disorder, or condition of the subject(s) experiencing the adverse event and the subjects predisposing risk factor profile for the adverse event.基础疾病的自然进展，不良事件危险因素,问题1,Examples,liver failure due to diffuse hepatic necrosis occurring in a subject without any underlying liver disease would be an u
23、nexpected adverse event (by virtue of its unexpected nature) if the protocol-related documents and other relevant sources of information did not identify liver disease as a potential adverse event.弥漫性肝坏死，没有基础肝脏疾病，方案等没有提及导致肝损liver failure due to diffuse hepatic necrosis occurring in a subject without
24、 any underlying liver disease would be an unexpected adverse event (by virtue of its unexpected greater severity) if the protocol-related documents and other relevant sources of information only referred to elevated hepatic enzymes or hepatitis as potential adverse events related to the procedures i
25、nvolved in the research.弥漫性肝坏死，没有基础肝脏疾病，方案提及转氨酶升高,How to determine which adverse events are unanticipated problems?,Assessing whether an adverse event is unexpectedAssessing whether an adverse event is related or possibly related to participation in researchAssessing whether an adverse event suggest
26、s that the research places subjects or others at a greater risk of harm than was previously known or recognized,问题2,Adverse events may be caused by one or more of the following:(1) the procedures involved in the research;研究程序(2) an underlying disease, disorder, or condition of the subject; or基础疾病(3)
27、 other circumstances unrelated to either the research or any underlying disease, disorder, or condition of the subject.与研究和基础疾病都无关的其他情况,In general, adverse events that are determined to be at least partially caused by (1) would be considered related to participation in the researchwhereas adverse ev
28、ents determined to be solely caused by (2) or (3) would be considered unrelated to participation in the research.,问题2,Examples,subjects with cancer participating in oncology clinical trials testing chemotherapy drugs, neutropenia and anemia are common adverse events related to participation in the r
29、esearch. Likewise, if a subject with cancer and diabetes mellitus participates in an oncology clinical trial testing an investigational chemotherapy agent and experiences a severe hypoglycemia reaction that is determined to be caused by an interaction between the subjects diabetes medication and the
30、 investigational chemotherapy agent, such a hypoglycemic reaction would be another example of an adverse event related to participation in the research.肿瘤患者化疗药临床试验，嗜中性白血球减少症和贫血，研究相关同时患有肿瘤和糖尿病的受试者参加化疗药临床试验，严重的低血糖反应，认定由糖尿病药物和化疗药的相互作用引起，研究相关,问题2,Examples,subjects with cancer enrolled in a non-intervent
31、ional, observational research registry study designed to collect longitudinal morbidity and mortality outcome data on the subjects, the death of a subject from progression of the cancer would be an adverse event that is related to the subjects underlying disease and is unrelated to participation in
32、the research. Finally, the death of a subject participating in the same cancer research registry study from being struck by a car while crossing the street would be an adverse event that is unrelated to both participation in the research and the subjects underlying disease.肿瘤患者参加非干预、观察性研究，目的采集发病率和死亡
33、率数据，肿瘤进展导致的受试者死亡，与基础疾病有关，与参加研究无关。车祸引起的受试者死亡，与参加研究以及与受试者基础疾病都无关。,How to determine which adverse events are unanticipated problems?,Assessing whether an adverse event is unexpectedAssessing whether an adverse event is related or possibly related to participation in researchAssessing whether an adverse
34、 event suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized,问题3,OHRP defines serious adverse event as any adverse event that:results in death;is life-threatening (places the subject at immediate risk of death from the event as it occu
35、rred);results in inpatient hospitalization or prolongation of existing hospitalization;results in a persistent or significant disability/incapacity;results in a congenital anomaly/birth defect; orbased upon appropriate medical judgment, may jeopardize the subjects health and may require medical or s
36、urgical intervention to prevent one of the other outcomes listed in this definition (examples of such events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the developme
37、nt of drug dependency or drug abuse).,OHRP considers adverse events that are unexpected, related or possibly related to participation in research, and serious to be the most important subset of adverse events representing unanticipated problems because such events always suggest that the research pl
38、aces subjects or others at a greater risk of physical or psychological harm than was previously known or recognized and routinely warrant consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, wel
39、fare, or rights of subjects.,哪些情况要报告？何时？,SFDA GCP第十条试验中发生严重不良事件，应及时向伦理委员会报告。卫生部“涉及人的生物医学研究伦理审查办法”22条 在实施过程中发生严重不良反应或者不良事件的，应当及时向伦理委员会报告。,与研究有关非预期的严重不良事件,严重不良事件,案例1,治疗骨质疏松的中药期临床试验1例受试者因重住院，后死亡另有数例受试者不同程度肝损,案例1,审查考虑是否预期？与参加研究是否有关？,案例1,是否预期？试验已知和可能发生的不良事件？ 研究方案、ICF、IB等都没有提到肝损受试者基础疾病的自然进展？不良事件的倾向性危险因素？受
40、试者既往身体健康，无合并疾病和合并用药，病毒指标等检查均无阳性发现。,案例1：与参加研究是否有关？,案例1：与参加研究是否有关？,案例1：与参加研究是否有关？,案例1：与参加研究是否有关？,与研究有关非预期的严重不良事件,严重不良事件,区分内部不良事件和外部不良事件,内部不良事件有责任进行充分分析 提出相应的安全性措施或纠正措施 告知其他伦理委员会外部不良事件一般而言，研究者和伦理委员会并不被要求评估外部个案不良事件的意义,It is the duty of the physician to promote and safeguard the health of patients, including those who are involved in medical research.,谢谢！,
