Contents

Part 3: What is a Protocol Amendment?

Part 4: What is a Protocol Violation?

Part 5: Summary of Key Points

Part 3: What is a protocol amendment?

A protocol amendment is a written description of a change to some aspect(s) of the study as described in the research protocol.

方案修订是对研究方案中所述研究某些方面的变更的书面说明。

Protocol amendments must be submitted in writing to the designated Institutional Review Board (IRB) and must be approved by the IRB before they can be implemented, except when necessary to eliminate immediate hazards to the participants or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)). If the study involves a product that is regulated by the U.S. Food and Drug Administration (FDA), the amendment must be submitted to FDA as well as to the IRB, prior to enacting the amendment (21 CFR 312.30).

方案修订案必须以书面形式提交给指定的机构审查委员会（IRB），并在实施前必须得到IRB的批准，除非有必要消除对参与者的直接危害，或者变更仅涉及试验的后勤或行政方面（例如，变更监查员，电话号码）。如果研究涉及的产品受美国食品和药物管理局（FDA）监管，则必须在颁布修正案之前将修订提交给FDA和IRB（21 CFR 312.30）。

Protocol Amendments and Informed Consent  议定书修正案和知情同意

Study participants must be informed of protocol amendments. Depending on the nature and extent of the amendment, the Informed Consent Form may be revised, and participants will need to complete and sign a new Informed Consent Form.

研究参与者必须被告知方案修订。根据修改的性质和范围，可能会修改知情同意书，参与者需要填写并签署新的知情同意书。

A protocol amendment is not to be confused with a “protocol clarification.” A protocol clarification aids in the implementation or conduct of the study and provides internal guidance. It does not change the protocol or alter the risk-benefit ratio of the study. A protocol clarification generally does not need to be submitted to the IRB. A clarification should be provided in writing to all investigators.

不得将议定书修正案与“议定书澄清”混淆。议定书澄清有助于研究的实施或进行，并提供内部指导。它不会改变研究方案或改变研究的风险效益比。议定书澄清通常不需要提交给IRB。应以书面形式提供澄清给所有调查人员。

Part 4: What is a protocol violation?

A protocol violation occurs whenever a study staff person performs any action that does not adhere to the research protocol. Protocol violations are sometimes referred to as protocol "deviations." Although "deviations" may sound less serious than “violation,” the two terms are identical.

当研究人员执行任何不遵守研究方案的行为时，就会发生违反方案的情况。违反协议有时被称为协议“偏差”，虽然“偏差”听起来不如“违反”严重，但这两个词是相同的。

Protocol Violations Policy

A protocol violation may be the result of a problem with study oversight, training of study personnel, or site study procedures.

违反方案可能是研究监督、研究人员培训或现场研究程序出现问题的结果。

A protocol violation may be:

Ⅰ、An omission (i.e., failure to do something required in the protocol)

Ⅱ、An addition (i.e., any action that is not required in the protocol).

Ⅲ、A change in any procedure described in the protocol.

违反协议可能是：

1、遗漏（即未按协议要求执行）

2、补充（即协议中不要求的任何行动）

3、协议中描述的任何程序的变更。

Protocol violations may occur due to human error. However, every attempt should be made to keep them at a minimum. Each violation and the action taken to correct the situation that led to the violation must be documented and submitted to the IRB.

由于人为错误，可能会发生违反协议的情况。然而，应尽一切努力将其控制在最低限度。必须记录每次违规行为以及为纠正导致违规的情况而采取的行动，并将其提交给IRB。

Repeated protocol violations may indicate the need for additional training of research staff or the need for a protocol amendment (e.g. to allow more flexibility in a follow-up plan that participants are having a difficult time adhering to).

反复违反方案可能表明需要对研究人员进行额外培训或需要修改方案（例如，在参与者难以遵守的后续计划中允许更大的灵活性）。

What to Do When a Protocol Violation Occurs

When a protocol violation occurs:

Ⅰ、Any concerns regarding participant safety must be addressed immediately by staff at the study site.

Ⅱ、The violation and a plan for corrective action must be documented.

Ⅲ、The violation must be reported to the principal investigator at the site, the study investigator, project management (if applicable), and the sponsor, and the FDA if the study is under an IND, in accordance with established procedures.

Ⅳ、The local IRB must be notified in a manner that conforms to the IRB's documented procedures.

发生协议冲突时：

1、研究现场的工作人员必须立即解决与参与者安全有关的任何问题。

2、必须记录违规行为和纠正措施计划。

3、必须按照既定程序向现场主要研究者、研究研究者、项目管理人员（如适用）和申办方报告违规行为，如果研究处于IND中，则必须向FDA报告违规行为。

4、必须以符合IRB书面程序的方式通知当地IRB。

(For a more detailed discussion of the roles of the principal investigator and lead investigator, see the Roles and Responsibilities module.)

（有关首席研究员和首席研究员角色的更详细讨论，请参阅角色和责任模块）

Interactive: IS THIS A PROTOCOL VIOLATION OR NOT?  互动：这是一个违规的协议吗？

Users are instructed as follows: Consider each of the five scenarios described below. Then, classify the occurrence as a protocol violation by choosing Violation or not by choosing No Violation。

对用户的指示如下: 分别考虑下述五种情景。然后，通过选择违反或不违反来将事件分类为违反协议。

Scenario 1

The clinic is approaching the end of the day. The Research Coordinator has a patient there that is eligible for the study, and he wants to quickly get through screening procedures. He decides to streamline procedures and collect the screening urine specimen before the patient has an opportunity to discuss, review, and sign the Informed Consent.

诊所快结束了。研究协调员在那里有一名符合研究条件的患者，他希望能够快速通过筛查程序。他决定简化程序，在患者有机会讨论、审查和签署知情同意书之前收集筛查尿液样本。

Feedback: Is this a Violation or No Violation? This is a Violation. The informed consent process communicates all of the information that the individual needs to make an informed decision about taking part in the study, before any study procedures are performed.

反馈：这是违规还是不违规？这是违法行为。知情同意程序传达了在进行任何研究程序之前，个体需要就参与研究做出知情决定的所有信息。

Scenario 2

The study protocol indicates that cash incentives are awarded based on a payment schedule, which will occur over the 12 months of the study. At each of the six study visits, the participant will receive 15 dollars in cash at the end of the visit. If the participant missed a visit or withdrew participation before the end of the study, they would not receive the reward for the missed visit(s).

The study staff at the ABC Research Clinic enrolled two participants at their site in the first week of study launch. At the first study visit, the PI determined that each participant and all future participants enrolled would receive the entire incentive ($90) at the last visit at the end of the study if the participants completed all six study visits. When the protocol monitor arrived weeks later for an interim monitoring visit, the site staff described these site procedures for applying incentives for the enrolled participants.

研究方案表明，现金奖励是根据付款计划授予的，付款计划将在研究的12个月内进行。在六次研究访问中，参与者将在访问结束时收到15美元现金。如果参与者在研究结束前错过了一次访问或退出了参与，他们将不会收到错过访问的奖励。

ABC研究诊所的研究人员在研究启动的第一周在他们的研究地点招募了两名参与者。在第一次研究访视时，PI确定，如果参与者完成了所有六次研究访视，则每位参与者和所有未来参与者在研究结束时的最后一次访视时将获得全部奖励（$90）。当方案监督员在几周后抵达进行临时监测访问时，现场工作人员描述了这些现场程序，以对登记的参与者实施激励。

Feedback: Is this a Violation or No Violation? This is a Violation. Site staff did not follow the incentive payment schedule outlined in the protocol. Also, incentive payments should not be conditional on the participant’s completion of the study.

反馈：这是违规还是不违规？这是违法行为。现场工作人员未遵守协议中概述的奖励付款计划。此外，奖励金不应以参与者完成研究为条件。

Scenario 3

The protocol indicates that at the third and sixth study visits, the participant will have urine collected for drug testing. If the urine was not collected on the scheduled visit, study staff should collect at the following study visit.

At the Mercy Hospital, the clinician forgot to collect the urine specimen for drug testing on Visit 3. She collected the urine and performed the drug testing at Visit 4.

方案表明，在第三次和第六次研究访视时，参与者将收集尿液进行药物检测。如果计划访视时未收集尿液，研究人员应在下一次研究访视时收集。

在Mercy医院，临床医生在第3次就诊时忘记收集尿液样本进行药物检测。她在第4次就诊时收集尿液并进行药物测试。

Feedback: Is this a Violation or No Violation? This is No Violation. The site staff completed the urine drug testing according to the procedures outlined in the protocol.

反馈：这是违规还是不违规？这不是违反规定。现场工作人员根据方案中概述的程序完成尿液药物检测。

Scenario 4

A participant receives the wrong dose of the study medication.

参与者服用了错误剂量的研究药物。

Feedback: Is this a Violation or No Violation? This is a Violation. Research that is not conducted in a standardized manner is unethical because it may put research participants at risk unnecessarily while yielding invalid data.

反馈：这是违规还是不违规？这是违法行为。未以标准化方式进行的研究是不道德的，因为它可能会使研究参与者处于不必要的风险中，同时产生无效数据。

Scenario 5

Participants are enrolled in the study although they do not meet the inclusion or exclusion criteria.

参与者虽然不符合纳入或排除标准，但仍被纳入研究。

Feedback: Is this a Violation or No Violation? This is a Violation. Enrolling participants into a study that they are not eligible to participate in may put research participants at risk unnecessarily while yielding invalid data.

反馈：这是违规还是不违规？这是违法行为。将参与者纳入他们没有资格参与的研究可能会使研究参与者面临不必要的风险，同时产生无效数据。

How to Avoid Protocol Violations

Care should be taken when writing a protocol to avoid unnecessary rigidity in schedules and procedures and to allow for flexibility whenever it does not compromise the integrity of the study or the safety of participants. This is the first step in avoiding protocol violations.

在编写方案时应注意避免时间表和程序中不必要的僵化，并在不损害研究完整性或参与者安全的情况下允许灵活性。这是避免违反协议的第一步。

Then, every member of the research team must be familiar with the protocol and aware of the importance of following it at all times. The following steps can help to ensure that protocol violations are minimized.

然后，研究团队的每个成员都必须熟悉该协议，并意识到始终遵守该协议的重要性。以下步骤有助于确保协议冲突最小化。

Ⅰ、Provision of thorough protocol training as well as periodic refresher training for all members of the study team.

Ⅱ、Notification to all members of the study team of a protocol amendment.

Ⅲ、Updating research materials when changes occur such as the Informed Consent Form or Operations Manual reflecting the changes to the protocol or procedures.

Ⅳ、Reminders about protocol requirements during regular study team meetings.

1、为研究小组所有成员提供全面的协议培训和定期进修培训。

2、向研究小组所有成员发出方案修订通知。

Ⅲ、在发生变化时更新研究材料，如反映方案或程序变化的知情同意书或操作手册。

Ⅳ、定期研究小组会议期间关于方案要求的提醒。

Again, protocol violations will occur in spite of the best intentions of research staff. Violations must be documented and corrective actions taken to prevent re-occurrences.

同样，尽管研究人员的意图是好的，但仍会发生违反协议的情况。必须记录违规行为，并采取纠正措施防止再次发生。

Part 5: Summary of Key Points

Ⅰ、Standardization of procedures is critical in a clinical research study. Research that is not conducted in a standardized manner is unethical because it may put research participants at risk while yielding invalid data.

1、程序标准化在临床研究中至关重要。不以标准化方式进行的研究是不道德的，因为它可能会使研究参与者处于风险之中，同时产生无效数据。

Ⅱ、All research staff involved in a clinical study must be familiar with, and must strictly adhere to, the procedures described in the research protocol.

2、参与临床研究的所有研究人员必须熟悉并严格遵守研究方案中描述的程序。

Ⅲ、The research protocol is one of the main documents that must be approved by a designated Institutional Review Board before a research study can begin. The research protocol provides a plan for the essential aspects of the proposed research.

3、 研究方案是研究开始前必须由指定机构审查委员会批准的主要文件之一。研究方案为拟议研究的基本方面提供了计划。

Ⅳ、The Good Clinical Practice guidelines of the International Council for Harmonization require a research protocol for any study that involves human participants. In addition, Title 21 Part 312 of the Code of Federal Regulations requires a research protocol for studies conducted under an Investigational New Drug application.

4、国际协调理事会的《良好临床实践指南》要求对任何涉及人类参与者的研究制定研究方案。此外，《联邦法规》第21篇第312部分要求在试验性新药申请下进行研究的研究方案。

Ⅴ、A protocol amendment is a change to some aspect of the study. Amendments must be approved by the IRB before they can be implemented, unless there is an immediate safety concern for participants. If the study is to be submitted to the FDA, such as being under an IND, the amendment must be submitted to the FDA as well as to the IRB.

5、方案修订是对研究某些方面的改变。修正案在实施前必须得到IRB的批准，除非对参与者有直接的安全顾虑。如果该研究要提交给FDA，比如IND，则修订必须提交给FDA和IRB。

Ⅵ、A protocol violation occurs whenever any study staff member performs any action that does not adhere to the study description in the research protocol. Each violation must be documented and action must be taken to correct the situation that led to the violation. Repeated protocol violations may indicate the need for additional staff training or a protocol amendment.

6、当任何研究人员执行任何不符合研究方案中研究描述的行为时，就会发生违反方案的情况。必须记录每次违规行为，并采取措施纠正导致违规的情况。反复违反协议可能表明需要额外的员工培训或协议修订。