臨床試驗中PD的上報流程和記錄

PD的定義

法規：

藥物臨床試驗必須遵循 GCP原則、依從倫理委員會(huì )批準的試驗方案; 任何有意或無(wú)意偏離或違反GCP原則和試驗方案的行為叫做偏離方案(protocol deviation，PD) 或違背方案( protocol violation， PV) 。

ICH GCP 對于偏離方案的規定［2］是: 研究者/ 研究機構應當依從由申辦者同意、管理當局(如有要求)批準，并已獲得倫理委員會(huì )批準的試驗方案。研究者/研究機構和申辦者應在試驗方案或類(lèi)似的合同(如在美國，研究者要求簽署 FDA1572 表) 上簽字以確認對方案的依從。如沒(méi)有和申辦者達成一 致并事先得到倫理委員會(huì )的審查和書(shū)面同意，研究者不能有任何偏離方案的行為，除非必須立即消除對受試者的傷害，或只是涉及事務(wù)上的或管理方面 的變化(如監查員變更，電話(huà)號碼的變更)。研究者/研究機構或申辦者方面有不依從方案/SOP/現行法規的行為時(shí)，申辦者應立即采取措施以保證對方案的依從。

總結：

方案偏離（Protocoldeviation，PD）

在研究者控制下的、未經(jīng)IRB批準的研究方案的試驗設計或程序的任何變化、分歧或者背離。

方案違背（Protocolviolation，PV）

方案違背是違反IRB批準的方案，它可影響到受試者的權益、安全性和獲益，或研究數據的完整性、精確性和可靠性。

發(fā)生方案違背的原因

一是方案設計的原因。包括方案對入選標準或者排除標準的設計不合理；設計的隨訪(fǎng)未留時(shí)間窗或者時(shí)間窗過(guò)短；臨床試驗相關(guān)檢查設計不合理；臨床試驗流程設計不合理等。

二是研究者方面的原因。主要是研究者對方案理解不深，未按照試驗方案操作實(shí)施，出現檢查漏開(kāi)、受試者隨訪(fǎng)丟失、隨機流程操作錯誤等情況。

三是受試者依從性差。這是臨床試驗操作過(guò)程中，普遍存在的問(wèn)題，表現為受試者未按時(shí)回院隨訪(fǎng)、不遵醫囑服用藥物或者使用醫療器械。

四是申辦方的原因。因為申辦方未及時(shí)提供有關(guān)資料、工具等造成的。例如器械項目中，可能出現器械缺陷未及時(shí)處理的情況。

PD的記錄與報告

1、研究者向申辦者報告；

2、研究者/申辦者向倫理委員會(huì )報告；

3、向政府藥品監督管理部門(mén)報告：申辦者在臨床總結報告中報告；申辦者將重大/持續PD 發(fā)生后中止了研究者/研究機構參與試驗的情況上報；研究者上報嚴重PD。

Tips

1、一般來(lái)說(shuō)，如果是輕微 PD，CRA 要做好記錄，和 PI 溝通和培訓，并在監查報告上體現，上報給上級，這是監查員的職責，即①；

2、申辦方匯總，定期向倫理報告，即②；

3、重大 PD，處理需要向申辦方匯報，申辦方如判定這是嚴重 PD 的話(huà)，需要通報PI 和通報倫理；視嚴重程度，選擇進(jìn)行步驟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.

偏離方案相關(guān)程序，威脅數據的完整性，對受試者產(chǎn)生不利影響和/或可能使項目（或部分項目）的可接受性失效。這種偏差需要立即采取行動(dòng)。

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.

偏離方案相關(guān)程序，可能影響數據的完整性或對受試者產(chǎn)生不利影響。這種偏差需要及時(shí)采取行動(dòng)。

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

偏離公認程序，不會(huì )對受試者或數據完整性產(chǎn)生不利影響，但應適當處理。

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.

討論 Q&A

修改建議

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：張遙