临床试验中PD的上报流程和记录

PD的定义

法规：

药物临床试验必须遵循 GCP原则、依从伦理委员会批准的试验方案; 任何有意或无意偏离或违反GCP原则和试验方案的行为叫做偏离方案(protocol deviation，PD) 或违背方案( protocol violation， PV) 。

ICH GCP 对于偏离方案的规定［2］是: 研究者/ 研究机构应当依从由申办者同意、管理当局(如有要求)批准，并已获得伦理委员会批准的试验方案。研究者/研究机构和申办者应在试验方案或类似的合同(如在美国，研究者要求签署 FDA1572 表) 上签字以确认对方案的依从。如没有和申办者达成一 致并事先得到伦理委员会的审查和书面同意，研究者不能有任何偏离方案的行为，除非必须立即消除对受试者的伤害，或只是涉及事务上的或管理方面 的变化(如监查员变更，电话号码的变更)。研究者/研究机构或申办者方面有不依从方案/SOP/现行法规的行为时，申办者应立即采取措施以保证对方案的依从。

总结：

方案偏离（Protocoldeviation，PD）

在研究者控制下的、未经IRB批准的研究方案的试验设计或程序的任何变化、分歧或者背离。

方案违背（Protocolviolation，PV）

方案违背是违反IRB批准的方案，它可影响到受试者的权益、安全性和获益，或研究数据的完整性、精确性和可靠性。

发生方案违背的原因

一是方案设计的原因。包括方案对入选标准或者排除标准的设计不合理；设计的随访未留时间窗或者时间窗过短；临床试验相关检查设计不合理；临床试验流程设计不合理等。

二是研究者方面的原因。主要是研究者对方案理解不深，未按照试验方案操作实施，出现检查漏开、受试者随访丢失、随机流程操作错误等情况。

三是受试者依从性差。这是临床试验操作过程中，普遍存在的问题，表现为受试者未按时回院随访、不遵医嘱服用药物或者使用医疗器械。

四是申办方的原因。因为申办方未及时提供有关资料、工具等造成的。例如器械项目中，可能出现器械缺陷未及时处理的情况。

PD的记录与报告

1、研究者向申办者报告；

2、研究者/申办者向伦理委员会报告；

3、向政府药品监督管理部门报告：申办者在临床总结报告中报告；申办者将重大/持续PD 发生后中止了研究者/研究机构参与试验的情况上报；研究者上报严重PD。

Tips

1、一般来说，如果是轻微 PD，CRA 要做好记录，和 PI 沟通和培训，并在监查报告上体现，上报给上级，这是监查员的职责，即①；

2、申办方汇总，定期向伦理报告，即②；

3、重大 PD，处理需要向申办方汇报，申办方如判定这是严重 PD 的话，需要通报PI 和通报伦理；视严重程度，选择进行步骤③。

PD Severity Classification

Critical Protocol Deviation: A deviation from Protocol-related procedures that threatens integrity of data, adversely affects subjects and/or could invalidate acceptability of a project (or part of it). Such deviations require immediate action.

偏离方案相关程序，威胁数据的完整性，对受试者产生不利影响和/或可能使项目（或部分项目）的可接受性失效。这种偏差需要立即采取行动。

Major Protocol Deviation: A deviation from Protocol-related procedures that could affect integrity of the data or adversely affect subjects. Such deviations require timely action.

偏离方案相关程序，可能影响数据的完整性或对受试者产生不利影响。这种偏差需要及时采取行动。

Minor Protocol Deviation: A deviation from accepted procedures that will not adversely affect subjects or data integrity but should be dealt with appropriately.

偏离公认程序，不会对受试者或数据完整性产生不利影响，但应适当处理。

PD Description

Must be measurable so that any person reading the information (site manager/CRA, site staff, PM/COL, Sponsor, etc.) will know exactly what is meant and root cause:

1、WHO(which Subject or investigator is involved)

2、WHAT(objectively describe the content of the protocol deviation, from a thirdpersonperspective)

3、WHEN(which visit is involved and indicate date）

4、WHY(indicate the root cause, and objectively analyze the occurrence of the protocol deviation)

5、WHERE(indicate the place where the protocol deviation occurred, such as the site number involved, the relevant department, or the subject himself, etc.)

For example:

Minor PD: Subject 1000X00X local chemical testing result for week 16 visit was reported at 12:04 am on 09Feb2022(ALT/AST results were normal), however the IP was randomly assigned at 08:33 am and administered at 09:56 am on 09Feb2022. Root cause: that was because the investigators (name) ignored a protocol requirement that dosing should be started after all safety evaluation were available.

Major PD: The subject performed the week 16 visit on 01Apr2022. Due to the error of IXRS system operation, the IP for Week12 was randomly assigned and injection to this subject. Root cause:1. Week 12 was skipped due to the impact of the epidemic, but the site staff did not register "SKIP" in the IWRS system. As a result, the visit of Week 12 was wrongly registered in the system when Week 16 visited, and drugs of Week 12 were used. 2. Sub-idid not review the IP number in a timely manner after the randomization and before the subject took the IP.

PD- Describe the action taken

Action Items must be measurable/executable so that any person reading the information (site manager/CRA, site staff, sponsor, Auditor, etc.) will know exactly what is meant and take the action accordingly:

1、WHO (Roll or Roll+ full name) is responsible for the action?

2、WHAT exact action is required?

3、WHEN should the AI be resolved?

Example:

The new sub-Investigator, Dr. Smith (who), will need to sign the delegation log (what) as soon as possible and no later than 01Sep2013 (when).

For the Action Item owner (WHO): “site staff” or role (e.g. SC.) is acceptable.

Only name without the person role, is not acceptable Each Subject-specific Action Item must include: - Subject and visit identification - Outstanding issue and responsible party (Dr. Smith (Sub-I) or Ms. Jones (SC)

Example:

SC or Dr. Smith (Sub-I) to re-consent the Subject 100123/ABC on the latest Informed Consent (version 2.1;15Sep2013) at the subject next scheduled visit (Visit 4 on 01Oct2013).

PD end date

CRA should ensure that all the PD end date is added.

PD end date is the date that deviation has ended, it can same day as PD happened date or after the PD start date.

For example:

if a PD is subject visit out of window, the PD start date should be the last planned date of this scheduled visit, and the PD end date is the actual date the subject completed visit.

讨论 Q&A

修改建议

1、Start date error，The end date then precedes the start date。

2、Subject number needs to be added。

3、add how the investigator confirmed that the subject was not pregnant during the visit.

4、as per the protocol the urine/blood pregnancy test is required;

5、Type should be Laboratory Assessment

6、add EC submission expected date or specific date (DD-MMM-YYYY, or before the end of MMM-YYYY, etc.)

7、add the action on providing the relevant training to investigator;

8、Root Cause for Important PDsshould be Site Staff Error

9、Not yet submitted to EC and GCP should open an AI

10、The information needs to be updated again after completing the submission

作者：张遥