?

　　2019年3月FDA發(fā)布了基于風(fēng)險(xiǎn)監(jiān)查方法（RBM）的問(wèn)題與解答（Q&A）指南草案。分別從監(jiān)查方法、監(jiān)查計(jì)劃內(nèi)容、監(jiān)查結(jié)果的后續(xù)行動(dòng)和溝通三個(gè)方面，共8個(gè)問(wèn)題進(jìn)行了詳細(xì)解答。

　　FDA強(qiáng)調(diào)基于風(fēng)險(xiǎn)的監(jiān)查是一個(gè)重要的工具。此問(wèn)答的目的在于幫助申辦者規(guī)劃和實(shí)施基于風(fēng)險(xiǎn)的監(jiān)查方法，為申辦者實(shí)施RBM提供額外的指導(dǎo)。通過(guò)8個(gè)問(wèn)題的解答，F(xiàn)DA具體澄清了記錄風(fēng)險(xiǎn)應(yīng)包含哪些方面；風(fēng)險(xiǎn)監(jiān)控的重點(diǎn)不僅在影響研究質(zhì)量的重要和可能的風(fēng)險(xiǎn)，還應(yīng)監(jiān)控不太可能發(fā)生但可能對(duì)研究質(zhì)量產(chǎn)生重大影響的風(fēng)險(xiǎn)；早期監(jiān)查的好處；制訂監(jiān)查抽樣計(jì)劃的具體考量等。

　　指南草案部分重點(diǎn)內(nèi)容翻譯請(qǐng)見(jiàn)下文：

　　I．INTRODUCTION
　　介紹

　　This guidance expands on the guidance for industryOversight of Clinical Investigations – A Risk-Based Approach to Monitoring（August 2013） （the RBM guidance） providing additional guidance to facilitate sponsors’ implementation of risk-based monitoring.
　　本指南擴(kuò)展了行業(yè)指南：臨床研究監(jiān)督-基于風(fēng)險(xiǎn)的監(jiān)查方法（2013年8月）（RBM指南），為促進(jìn)申辦者實(shí)施基于風(fēng)險(xiǎn)的監(jiān)查提供額外的指導(dǎo)。

　　II. BACKGROUND
　　背景

　　The RBM guidance discusses the importance of identifying critical data and processes necessary for human subject protection and integrity of the investigation, conducting a risk assessment, and developing a monitoring plan specific to the investigation. The RBM guidance also encourages sponsors to tailor monitoring plans to the needs of the investigation, describes factors to consider in developing a monitoring plan, and provides examples of monitoring methods and techniques.
　　RBM指南討論了識(shí)別影響受試者保護(hù)和研究完整性的關(guān)鍵數(shù)據(jù)和過(guò)程、進(jìn)行風(fēng)險(xiǎn)評(píng)估以及制定針對(duì)研究的監(jiān)查計(jì)劃的重要性。RBM指南還鼓勵(lì)申辦者根據(jù)研究需求定制監(jiān)查計(jì)劃，描述制定監(jiān)查計(jì)劃時(shí)要考慮的因素，并提供監(jiān)查方法和技術(shù)的實(shí)例。

　　FDA believes risk-based monitoring is an important tool to allow sponsors to identify and address issues during the conduct of clinical investigations. FDA’s experience since finalizing the RBM guidance in 2013 suggests that additional guidance would be beneficial regarding FDA’s recommendations for planning a monitoring approach, developing the content of monitoring plans, and addressing and communicating monitoring results. The following questions and answers are intended to assist sponsors in planning and conducting risk-based approaches to monitoring
　　FDA認(rèn)為基于風(fēng)險(xiǎn)的監(jiān)查是一個(gè)重要的工具，可以讓申辦者在進(jìn)行臨床研究時(shí)識(shí)別和解決問(wèn)題。FDA自2013年發(fā)布RBM指南以來(lái)的經(jīng)驗(yàn)表明，對(duì)于FDA的建議——規(guī)劃監(jiān)查方法，制定監(jiān)查計(jì)劃內(nèi)容以及處理和溝通監(jiān)查結(jié)果，F(xiàn)DA給予額外的指導(dǎo)將是有益的。以下問(wèn)題和答案旨在幫助申辦者規(guī)劃和實(shí)施基于風(fēng)險(xiǎn)的監(jiān)查方法。

　　III．QUESTIONS AND ANSWERS
　　問(wèn)題和解答

　　A.Monitoring Approach 監(jiān)查方法

　　Q1. What is the purpose of the risk assessment and should sponsors document their methodologies and activities for assessing risk？
　　風(fēng)險(xiǎn)評(píng)估的目的是什么？申辦者應(yīng)該記錄他們?cè)u(píng)估風(fēng)險(xiǎn)的方法和活動(dòng)嗎？

　　Consistent with the RBM guidance, sponsors should identify and perform a risk assessment on those critical data and processes that are necessary for human subject protection and integrity of the investigation.
　　根據(jù)RBM指南，申辦者應(yīng)識(shí)別并執(zhí)行對(duì)關(guān)鍵數(shù)據(jù)和流程（對(duì)人類(lèi)受試者保護(hù)和對(duì)于研究完整性是必需的）的風(fēng)險(xiǎn)評(píng)估。

　　The risk assessment serves to identify and understand the nature, sources, likelihood of detection, and potential causes of risks that could affect the collection of critical data or performance of critical processes. The risk assessment informs the development of a monitoring plan and may also support efforts to manage risks across a clinical investigation （for example, through modifying the protocol design or implementation） or across a product’s development program. Therefore, sponsors should document their risk assessment, including methodologies used for the risk assessment, conclusions from the risk assessment, and how the assessment was used to make decisions on the management of the risks identified. Any such document should be available for review.
　　風(fēng)險(xiǎn)評(píng)估用于識(shí)別和理解可能影響關(guān)鍵數(shù)據(jù)收集或關(guān)鍵過(guò)程執(zhí)行的風(fēng)險(xiǎn)的性質(zhì)、來(lái)源、可能性和潛在原因。風(fēng)險(xiǎn)評(píng)估可以為監(jiān)查計(jì)劃的制定提供信息，也可以支持臨床研究（例如，通過(guò)修改方案設(shè)計(jì)或?qū)嵤┗蚩绠a(chǎn)品開(kāi)發(fā)計(jì)劃中的風(fēng)險(xiǎn)管理。因此，申辦者應(yīng)記錄其風(fēng)險(xiǎn)評(píng)估，包括用于風(fēng)險(xiǎn)評(píng)估的方法，風(fēng)險(xiǎn)評(píng)估的結(jié)論，以及如何使用評(píng)估來(lái)管理所識(shí)別的風(fēng)險(xiǎn)。任何上述此類(lèi)文件都應(yīng)該可供審查。

　　The monitoring plan should include information regarding the identified risks and how the monitoring methods will address those risks. （See Q6 for further details.） The inclusion of these components in the monitoring plan will enhance the utility of the plan by providing a clear explanation of the identified risks and how they will be monitored, managed, and mitigated.
　　監(jiān)查計(jì)劃應(yīng)包括已識(shí)別風(fēng)險(xiǎn)以及監(jiān)查方法如何應(yīng)對(duì)這些風(fēng)險(xiǎn)的信息。（有關(guān)詳細(xì)信息，請(qǐng)參閱Q6。）將這些組件包含在監(jiān)查計(jì)劃中，通過(guò)明確說(shuō)明已識(shí)別的風(fēng)險(xiǎn)以及如何監(jiān)控、管理和減輕風(fēng)險(xiǎn)來(lái)提高監(jiān)查計(jì)劃的實(shí)用性。

　　Q2. Should sponsors monitor only risks that are important and likely to occur？
　　申辦者是否應(yīng)僅監(jiān)控重要且可能發(fā)生的風(fēng)險(xiǎn)？

　　A risk-based approach to monitoring should focus sponsor oversight activities on preventing or mitigating important and likely risks to investigation quality, including risks to human subject protection and data integrity. Sponsors also should consider monitoring risks that are less likely to occur but could have a significant impact on the investigation quality. Sponsors should determine the types and intensity of monitoring activities best suited to address the identified risks. In addition, monitoring plans should permit monitoring activities to evolve based on additional issues and risks that may be identified during the conduct of an investigation.
　　基于風(fēng)險(xiǎn)的監(jiān)查方法應(yīng)將申辦者監(jiān)督活動(dòng)的重點(diǎn)放在預(yù)防或減輕影響研究質(zhì)量的重要和可能的風(fēng)險(xiǎn)上，包括影響受試者保護(hù)和數(shù)據(jù)完整性的風(fēng)險(xiǎn)。申辦者還應(yīng)考慮監(jiān)控不太可能發(fā)生但可能對(duì)研究質(zhì)量產(chǎn)生重大影響的風(fēng)險(xiǎn)。申辦者應(yīng)確定最適合解決已識(shí)別風(fēng)險(xiǎn)的監(jiān)查活動(dòng)的類(lèi)型和強(qiáng)度。此外，監(jiān)查計(jì)劃應(yīng)允許監(jiān)查活動(dòng)依據(jù)在研究過(guò)程中可能發(fā)現(xiàn)的其他額外問(wèn)題和風(fēng)險(xiǎn)而發(fā)展變化。

　　Q3. What factors should sponsors consider when determining the timing, types, frequency, and extent of monitoring activities？
　　在確定監(jiān)查活動(dòng)的時(shí)間，類(lèi)型，頻率和范圍時(shí)，申辦者應(yīng)考慮哪些因素？

　　As described in detail in the RBM guidance, factors sponsors should consider include the following:
　　如RBM指南中所詳述，申辦者應(yīng)考慮的因素包括以下內(nèi)容：

　　• Complexity of the study design
　　研究設(shè)計(jì)的復(fù)雜性

　　• Types of study endpoints
　　研究終點(diǎn)的類(lèi)型

　　• Clinical complexity of the study population （for example, study populations that are seriously ill, have multiple co-morbidities, or are more vulnerable and may require more intensive monitoring and consideration of on-site monitoring visits to be sure appropriate protection is being provided）
　　研究人群的臨床復(fù)雜性（例如，研究人群病情嚴(yán)重，有多種合并癥或更易受傷害，可能需要更加密集的監(jiān)查甚至考慮現(xiàn)場(chǎng)監(jiān)查訪(fǎng)視，以確保提供了適當(dāng)?shù)谋Ｗo(hù)）

　　• Geographic location of clinical investigator （CI） sites where there may be differences in standards of medical practice or less established clinical trial infrastructure
　　臨床研究者（CI）所在中心的地理位置，如可能存在醫(yī)療實(shí)踐標(biāo)準(zhǔn)差異或臨床試驗(yàn)基礎(chǔ)設(shè)施較不成熟的中心

　　• Relative experience of the CI and of the sponsor with the CI
　　CI及申辦方與CI合作的相關(guān)經(jīng)驗(yàn)

　　• Electronic data capture to be utilized
　　EDC的利用程度

　　• Relative safety of the investigational product
　　研究產(chǎn)品的相對(duì)安全性

　　• Stage of the study （progress of the study）
　　研究階段（研究進(jìn)展）

　　• Quantity of data
　　數(shù)據(jù)質(zhì)量

　　FDA also recommends that sponsors consider the following additional factors:
　　FDA還建議申辦者考慮以下其他因素：

　　•Workload at the CI site
　　CI所在中心的工作負(fù)載

　　• Turnover of personnel at the CI site or among monitoring staff
　　CI所在中心研究人員或監(jiān)查人員的流動(dòng)

　　•Similar to workload, high personnel turnover may cause unintended disruptions to conduct of the investigation and sponsor oversight.
　　與工作量相似，高人員流動(dòng)率可能會(huì)導(dǎo)致非預(yù)期的研究和申辦者監(jiān)查中斷。

　　• Location where subjects will be seen and whether they will be seen at more than one location to complete investigation procedures （for example, data collection at the imaging center, at a local physician’s office, or at the subject’s home）
　　需查看受試者的地點(diǎn)以及是否需要在多個(gè)地點(diǎn)查看受試者完成研究程序（例如，需在成像中心，當(dāng)?shù)蒯t(yī)生辦公室或受試者家中收集數(shù)據(jù)）

　　•When designing the monitoring plan, sponsors should take into consideration where and how the data are going to be collected in the investigation relative to where the sponsor oversight activities will be conducted （for example, to confirm that appropriate controls, instructions, and training tools are in place）.
　　在設(shè)計(jì)監(jiān)查計(jì)劃時(shí)，申辦者應(yīng)考慮研究中數(shù)據(jù)收集的地點(diǎn)和方式，以及相應(yīng)的申辦者實(shí)施監(jiān)督活動(dòng)的地點(diǎn)（例如，確認(rèn)適當(dāng)?shù)目刂?、說(shuō)明和培訓(xùn)工具已到位）。

　　• Benefit of an early monitoring visit or other early monitoring activities
　　早期監(jiān)查訪(fǎng)視或其他早期監(jiān)查活動(dòng)的好處

　　•By scheduling an early monitoring visit （for example, soon after the first trial subject（s） enrolls in the investigation） or by carrying out other early monitoring activities （for example, through remote processes）, sponsors can help ensure early in the investigation that procedures are being performed correctly at CI sites. Alternatively, if early monitoring identifies issues, corrective action（s） can be implemented sooner.
　　通過(guò)安排早期監(jiān)查訪(fǎng)視（例如，在首例試驗(yàn)受試者入組后不久）或通過(guò)執(zhí)行其他早期監(jiān)查活動(dòng)（例如，通過(guò)遠(yuǎn)程過(guò)程），申辦者可幫助確保在研究早期，研究流程在CI所在中心被正確執(zhí)行?；蛘?，如果早期監(jiān)查發(fā)現(xiàn)問(wèn)題，則可以更快地實(shí)施糾正措施。

　　• Experience and qualifications of the research coordinator
　　研究協(xié)調(diào)員的經(jīng)驗(yàn)和資格

　　•The research coordinator serves an important role in ensuring the quality of the execution of the investigation at the investigation site （for example, the research coordinator often recruits subjects, collects and evaluates study data, and maintains study records.）
　　研究協(xié)調(diào)員在確保研究中心的研究實(shí)施質(zhì)量方面發(fā)揮著重要作用（例如，研究協(xié)調(diào)員經(jīng)常招募受試者、收集和評(píng)估研究數(shù)據(jù)，并維護(hù)研究記錄。）

　　• Safety profile of the investigational product
　　研究產(chǎn)品的安全性概況

　　•When developing a monitoring plan, sponsors should consider the known safety profile, including the available human and non-clinical safety information for the product and the class, and the mechanism of action.
　　在制定監(jiān)查計(jì)劃時(shí)，申辦者應(yīng)考慮已知的安全概況，包括該產(chǎn)品和同類(lèi)別產(chǎn)品已有的人體和非臨床安全信息，以及作用機(jī)制。

　　• Characteristics of data to be collected
　　需收集的數(shù)據(jù)的特征

　　•When developing a monitoring plan, sponsors should consider the amount and complexity of the data collected.
　　在制定監(jiān)查計(jì)劃時(shí)，申辦者應(yīng)考慮數(shù)據(jù)收集的數(shù)量和復(fù)雜程度。

　　Q4. How can a risk-based approach to monitoring that includes centralized monitoringhelp minimize missing data, protocol violations, or protocol deviations？
　　基于風(fēng)險(xiǎn)的監(jiān)查方法（包括中心化監(jiān)查）如何最大限度地幫助減少數(shù)據(jù)丟失，方案違背或方案偏離？

　　There may be situations in which poor trial conduct or adherence to the investigational plan causes or contributes to incomplete data collection. Therefore, by reviewing important investigation activities, in real-time across CI sites, sponsors may be able to identify the reasons for missing data, protocol violations, or protocol deviations and take corrective actions to minimize the likelihood of these occurring during the remainder of the clinical investigation.
　　在某些情況下，不良的試驗(yàn)實(shí)施行為或未遵守研究計(jì)劃會(huì)導(dǎo)致不完整的數(shù)據(jù)收集。因此，通過(guò)對(duì)CI所在中心重要研究活動(dòng)的實(shí)時(shí)審查，申辦者可能能夠識(shí)別丟失數(shù)據(jù)、方案違背或方案偏離的原因，并采取糾正措施最大限度地降低這些活動(dòng)在其他臨床研究部分發(fā)生的可能性。

　　Q5. Should the risk-based monitoring approach include processes to ensure that appropriate blinding is maintained？
　　基于風(fēng)險(xiǎn)的監(jiān)查方法是否應(yīng)包括確保適當(dāng)盲法保持的過(guò)程？

　　Yes. As identified in the RBM guidance, for investigations in which blinding will be used for interventions and/or outcome assessments, ensuring that the investigation blind is maintained is a critical process that sponsors should consider in their risk assessment.
　　是。正如在RBM指南中所指出的，對(duì)于盲法將用于干預(yù)和/或結(jié)果評(píng)估的研究，確保研究盲態(tài)保持是一個(gè)關(guān)鍵過(guò)程，申辦者應(yīng)在其風(fēng)險(xiǎn)評(píng)估中考慮這一過(guò)程。

　　Specific risks to the maintenance of the blind that are identified during the risk assessment should be mitigated in advance of investigation initiation, when feasible. In addition, identifying and tracking deviations during investigation conduct that could result in unintentional unblinding of treatment assignment should be considered as a part of the monitoring plan to ensure that appropriate blinding is maintained at CI sites and by the sponsor. For example, in a blinded investigation that requires a site staff member to be unblinded to administer the test article, the site processes for maintaining the blind for the remainder of the site staff and the sponsor should be monitored.
　　風(fēng)險(xiǎn)評(píng)估中確定的對(duì)于盲態(tài)維持的特定風(fēng)險(xiǎn)，應(yīng)在研究開(kāi)始之前減輕該風(fēng)險(xiǎn)（如可行）。此外，在研究過(guò)程中識(shí)別和跟蹤可能導(dǎo)致無(wú)意中揭示治療分配的偏離，應(yīng)作為監(jiān)查計(jì)劃的一部分，以確保在CI所在中心和申辦者保持適當(dāng)?shù)拿B(tài)。例如，在盲法研究中，若要求研究中心一個(gè)工作人員以非盲態(tài)管理、發(fā)放研究測(cè)試產(chǎn)品，則應(yīng)監(jiān)控維持研究中心其他工作人員和申辦者盲態(tài)的流程。

　　FDA recognizes that Data Monitoring Committees （DMC） may access unblinded data as described in the DMC Charter. （For additional information about DMC, see the guidance for clinical trial sponsors Establishment & Operation of Clinical Trial Data Monitoring Committees （March 2006.）
　　FDA認(rèn)識(shí)到數(shù)據(jù)監(jiān)測(cè)委員會(huì)（DMC）可以訪(fǎng)問(wèn)DMC章程中描述的非盲數(shù)據(jù)。（有關(guān)DMC的其他信息，請(qǐng)參閱臨床試驗(yàn)申辦者指南：臨床試驗(yàn)數(shù)據(jù)監(jiān)測(cè)委員會(huì)的建立和運(yùn)行（2006年3月）。

　　B. Monitoring Plan Content
　　監(jiān)查計(jì)劃內(nèi)容

　　Q6. What elements should sponsors include in monitoring plans？
　　申辦者應(yīng)該在監(jiān)查計(jì)劃中包括哪些要素？

　　The following elements （discussed in detail in section IV.D of the RBM guidance） are summarized here to assist sponsors in developing monitoring plans:
　　這里總結(jié)了以下要素（在RBM指南第IV.D節(jié)中詳細(xì)討論），以協(xié)助申辦者制定監(jiān)查計(jì)劃：

　　• A synopsis of the study
　　研究概要

　　• Study objectives
　　研究目標(biāo)

　　• Identification of critical data and study procedures
　　確定關(guān)鍵數(shù)據(jù)和研究程序

　　• Trial-specific risks to be addressed by monitoring
　　通過(guò)監(jiān)查解決特定的試驗(yàn)風(fēng)險(xiǎn)

　　• Monitoring methods and rationale for use of the monitoring methods, including how the methods address identified risks
　　監(jiān)查方法和使用監(jiān)查方法的合理性，包括該方法如何處理已識(shí)別的風(fēng)險(xiǎn)

　　• Criteria for determining the timing, types, frequency, and extent of monitoring activities
　　確定監(jiān)查活動(dòng)的時(shí)間、類(lèi)型、頻率和范圍的標(biāo)準(zhǔn)

　　• Specific activities necessary for each monitoring method used
　　使用的每種監(jiān)查方法所必需的具體活動(dòng)

　　• Definitions of events or results that would trigger changes in monitoring activities （for example, how protocol deviations may be monitored as events that would trigger changes in monitoring activities）
　　可觸發(fā)監(jiān)查活動(dòng)變化的事件或結(jié)果的定義（例如，方案偏離如何作為可觸發(fā)監(jiān)查活動(dòng)變化的事件進(jìn)行監(jiān)測(cè)）

　　• Identification of protocol deviations and failures that, if occurred, would affect study integrity, and how they will be recorded, tracked, and reported
　　識(shí)別可影響研究完整性的方案偏離和失敗，如果發(fā)生，以及如何記錄，跟蹤和報(bào)告

　　• Format, content, timing, and archiving requirements for documentation of monitoring activities
　　監(jiān)查活動(dòng)文檔的格式、內(nèi)容、時(shí)間和歸檔要求

　　• Processes for communicating routine monitoring results to appropriate parties
　　將常規(guī)監(jiān)查結(jié)果傳達(dá)給相關(guān)方的流程

　　• Processes for immediate reporting of significant monitoring issues to appropriate parties
　　向適當(dāng)?shù)母鞣搅⒓磮?bào)告重大監(jiān)查問(wèn)題的流程

　　• Processes for appropriate communication from study management and other stakeholders to monitors
　　從研究管理方和其他利益相關(guān)方到監(jiān)查員的適當(dāng)溝通流程

　　• Processes to address unresolved or significant issues identified by monitoring
　　處理通過(guò)監(jiān)查確定的未解決或重大問(wèn)題的流程

　　• Processes to ensure that root cause analyses are conducted where important deviations are discovered and that corrective and preventative actions are implemented
　　確保在發(fā)現(xiàn)重要偏離并實(shí)施糾正和預(yù)防措施的情況下，進(jìn)行根本原因分析的流程

　　• Other quality management practices applicable to the clinical investigation （for example, reference to other documents describing appropriate actions regarding non-compliance）
　　適用于臨床研究的其他質(zhì)量管理實(shí)踐（例如，參考描述針對(duì)不合規(guī)的適當(dāng)行動(dòng)的其他文件）

　　• Training for personnel who carry out monitoring activities
　　為開(kāi)展監(jiān)查活動(dòng)的人員提供培訓(xùn)

　　• Planned audits of monitoring activities
　　計(jì)劃對(duì)監(jiān)查活動(dòng)進(jìn)行稽查

　　• Process for updating monitoring plans
　　更新監(jiān)查計(jì)劃的流程

　　In addition, FDA recommends that monitoring plans also include the following items, which will help explain how the sponsor intends to address the risks that could affect the clinical investigation.
　　此外，F(xiàn)DA建議監(jiān)查計(jì)劃還包括以下項(xiàng)目，這將有助于解釋申辦者打算如何解決可能影響臨床研究的風(fēng)險(xiǎn)。

　　• A description of the investigation design and the blinding and randomization procedures, if applicable
　　描述研究設(shè)計(jì)以及盲法和隨機(jī)化流程（如果適用）

　　• Processes for confirming that randomization is performed according to the protocol and investigational plan when randomization is identified as a risk to be addressed by monitoring
　　當(dāng)通過(guò)監(jiān)查確定隨機(jī)化為需解決的風(fēng)險(xiǎn)時(shí)，確認(rèn)隨機(jī)化根據(jù)方案和研究計(jì)劃執(zhí)行的流程

　　• Sampling plan（s） that will be used to identify the specific records and data that will be monitored, including the rationale for how the sampling plan provides a representative picture of the overall information, and how the sampling plan will be implemented
　　監(jiān)測(cè)抽樣計(jì)劃（該抽樣計(jì)劃用于確定需要監(jiān)控的具體記錄和數(shù)據(jù)），包括抽樣計(jì)劃如何有代表性（代表整體信息），以及如何實(shí)施抽樣計(jì)劃

　　• A description of the types of significant issues identified through monitoring that would trigger immediate issue escalation
　　描述通過(guò)監(jiān)查確定的、可立即引發(fā)問(wèn)題升級(jí)的重大問(wèn)題類(lèi)型

　　• An approach for determining if issues identified at a site also exist at other CI sites and an approach for correcting these issues
　　確定某個(gè)中心發(fā)現(xiàn)的問(wèn)題是否也存在于其他CI所在中心的方法以及糾正這些問(wèn)題的方法

　　The monitoring plan should describe each of these items in sufficient detail. Sponsors also should reference related documents, when appropriate. Sponsors are encouraged to develop monitoring plans that emphasize critical risks that have the greatest potential to adversely affect investigation quality, including the rights, safety, and welfare of investigation subjects, and the collection or analysis of clinical data such as investigation safety and efficacy endpoints.
　　監(jiān)查計(jì)劃應(yīng)詳細(xì)描述這些項(xiàng)目中的每一項(xiàng)。申辦者還應(yīng)酌情參考相關(guān)文件。鼓勵(lì)申辦者制定監(jiān)查計(jì)劃，強(qiáng)調(diào)最有可能對(duì)研究質(zhì)量產(chǎn)生不利影響的關(guān)鍵風(fēng)險(xiǎn)，包括研究受試者的權(quán)利，安全和福利，以及研究安全性和療效終點(diǎn)等臨床數(shù)據(jù)的收集或分析。

　　C. Follow-Up and Communication of Monitoring Results
　　監(jiān)查結(jié)果的后續(xù)行動(dòng)和溝通

　　Q7. How should sponsors follow up on significant issues identified through monitoring, including communication of such issues？
　　申辦者應(yīng)如何跟蹤通過(guò)監(jiān)查發(fā)現(xiàn)的重大問(wèn)題，包括溝通此類(lèi)問(wèn)題？

　　Significant issues identified through monitoring （for example, significant non-compliance with the protocol） should be thoroughly evaluated in a timely manner at the appropriate level （for example, sponsor, CI site（s）） as described in the monitoring plan. Appropriate corrective and preventative actions should be taken. Deviations from the investigational plan should be documented, tracked, and escalated to relevant personnel, as appropriate. Related systemic issues should be identified and resolved promptly to ensure that investigation quality, including the rights, safety, and welfare of investigation subjects and data integrity, is maintained.
　　通過(guò)監(jiān)查確定的重大問(wèn)題（例如，嚴(yán)重不依從方案）應(yīng)及時(shí)進(jìn)行徹底評(píng)估（如監(jiān)查計(jì)劃中所述的適當(dāng)級(jí)別，例如，申辦方，CI所在中心）。
　　應(yīng)采取適當(dāng)?shù)募m正和預(yù)防措施。應(yīng)酌情記錄、跟蹤研究計(jì)劃的偏離，并將其上報(bào)給相關(guān)人員。
　　應(yīng)及時(shí)發(fā)現(xiàn)并解決相關(guān)的系統(tǒng)性問(wèn)題，以確保研究質(zhì)量，包括維護(hù)研究受試者的權(quán)利，安全和福利以及數(shù)據(jù)完整性。

　　Although not an exhaustive list, some examples of corrective and preventive actions that may be needed include retraining CI and site staff；clarifying protocol requirements through protocol amendment（s）；or revision（s） to informed consent documents or procedures.
　　雖然不是詳盡的清單，但一些糾正和預(yù)防措施的例子可能需要對(duì)CI和研究中心工作人員等進(jìn)行再培訓(xùn)；通過(guò)方案修正以澄清方案要求；或修訂知情同意文件或程序。

　　Significant issues identified through monitoring and the actions to be taken should be documented and communicated to the appropriate parties, which may include, but are not limited to, the following: （1） sponsor management, （2） sponsor teams, （3） CI sites, （4） institutional review board（s）, （5） other relevant parties （for example, DMCs and relevant contract research organizations）, and （6） FDA, when appropriate.
　　通過(guò)監(jiān)查確定的重大問(wèn)題和應(yīng)采取的行動(dòng)應(yīng)記錄在案并傳達(dá)給相關(guān)方，其中可能包括但不限于以下方面：（1）申辦者管理層，（2）申辦者團(tuán)隊(duì)，（3）CI所在中心，（4）機(jī)構(gòu)審查委員會(huì)，（5）其他相關(guān)方（例如，DMC和相關(guān)合同研究組織），以及（6）FDA，適當(dāng)時(shí)。

　?。⊿ee Q6 for a description of elements that sponsors should include in monitoring plans regarding follow up and communication of significant issues.）
　?。ㄓ嘘P(guān)申辦者在監(jiān)查計(jì)劃中應(yīng)包括的要素的說(shuō)明，請(qǐng)參見(jiàn)Q6關(guān)于重大問(wèn)題的跟進(jìn)和溝通。）

　　Q8. How should centralized monitoring activities and the results of these activities be documented and shared with those involved in the investigation？
　　如何記錄中心化監(jiān)查活動(dòng)和這些活動(dòng)的結(jié)果，并與參與研究的人員分享？

　　As described in the RBM guidance, documentation of monitoring activities should generally include the following: （1） the date of the activity； （2） the individual（s） conducting and participating in the activity； （3） a summary of the data or activities reviewed； （4） a description of any noncompliance, potential noncompliance, data irregularities, or other deficiencies identified； and （5） a description of any actions taken, to be taken, or recommended （see section V of the RBM guidance for details）. Such documentation should include the results of centralized monitoring activities in sufficient detail to allow verification of adherence to the monitoring plan describing those activities.
　　如RBM指南所述，監(jiān)查活動(dòng)的文件通常應(yīng)包括以下內(nèi)容：（1）活動(dòng)日期； （2）進(jìn)行和參與活動(dòng)的個(gè)人；（3）審查的數(shù)據(jù)或活動(dòng)摘要； （4）對(duì)任何不依從、潛在不依從、數(shù)據(jù)違規(guī)或其他缺陷的描述；（5）對(duì)已采取、將采取或建議采取的任何行動(dòng)的描述（詳情見(jiàn)RBM指南第五節(jié)）。此類(lèi)文件應(yīng)包括足夠詳細(xì)的中心化監(jiān)查活動(dòng)的結(jié)果，以便核實(shí)描述的活動(dòng)對(duì)監(jiān)查計(jì)劃的遵守情況。

　　Reports of centralized monitoring activities should be provided to appropriate management, including sponsor staff responsible for investigation and site oversight, in a timely manner for review and follow up. In addition, sponsors should inform a CI of monitoring findings from centralized monitoring activities that are relevant to the CI’s activities.
　　應(yīng)及時(shí)向適當(dāng)?shù)墓芾韺犹峁┲行幕O(jiān)查活動(dòng)的報(bào)告（包括負(fù)責(zé)研究和監(jiān)督研究中心的申辦方人員），以便進(jìn)行審查和跟進(jìn)。此外，申辦者應(yīng)將中心化監(jiān)查發(fā)現(xiàn)的、與CI活動(dòng)相關(guān)的問(wèn)題向CI通報(bào)。