FDA基于風險監查方法（RBM）的問題與解答

?

　　2019年3月FDA發布了基于風險監查方法（RBM）的問題與解答（Q&A）指南草案。分別從監查方法、監查計劃內容、監查結果的后續行動和溝通三個方面，共8個問題進行了詳細解答。

　　FDA強調基于風險的監查是一個重要的工具。此問答的目的在于幫助申辦者規劃和實施基于風險的監查方法，為申辦者實施RBM提供額外的指導。通過8個問題的解答，FDA具體澄清了記錄風險應包含哪些方面；風險監控的重點不僅在影響研究質量的重要和可能的風險，還應監控不太可能發生但可能對研究質量產生重大影響的風險；早期監查的好處；制訂監查抽樣計劃的具體考量等。

　　指南草案部分重點內容翻譯請見下文：

　　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.
　　本指南擴展了行業指南：臨床研究監督-基于風險的監查方法（2013年8月）（RBM指南），為促進申辦者實施基于風險的監查提供額外的指導。

　　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指南討論了識別影響受試者保護和研究完整性的關鍵數據和過程、進行風險評估以及制定針對研究的監查計劃的重要性。RBM指南還鼓勵申辦者根據研究需求定制監查計劃，描述制定監查計劃時要考慮的因素，并提供監查方法和技術的實例。

　　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認為基于風險的監查是一個重要的工具，可以讓申辦者在進行臨床研究時識別和解決問題。FDA自2013年發布RBM指南以來的經驗表明，對于FDA的建議——規劃監查方法，制定監查計劃內容以及處理和溝通監查結果，FDA給予額外的指導將是有益的。以下問題和答案旨在幫助申辦者規劃和實施基于風險的監查方法。

　　III．QUESTIONS AND ANSWERS
　　問題和解答

　　A.Monitoring Approach 監查方法

　　Q1. What is the purpose of the risk assessment and should sponsors document their methodologies and activities for assessing risk？
　　風險評估的目的是什么？申辦者應該記錄他們評估風險的方法和活動嗎？

　　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RBM指南，申辦者應識別并執行對關鍵數據和流程（對人類受試者保護和對于研究完整性是必需的）的風險評估。

　　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.
　　風險評估用于識別和理解可能影響關鍵數據收集或關鍵過程執行的風險的性質、來源、可能性和潛在原因。風險評估可以為監查計劃的制定提供信息，也可以支持臨床研究（例如，通過修改方案設計或實施）或跨產品開發計劃中的風險管理。因此，申辦者應記錄其風險評估，包括用于風險評估的方法，風險評估的結論，以及如何使用評估來管理所識別的風險。任何上述此類文件都應該可供審查。

　　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.
　　監查計劃應包括已識別風險以及監查方法如何應對這些風險的信息。（有關詳細信息，請參閱Q6。）將這些組件包含在監查計劃中，通過明確說明已識別的風險以及如何監控、管理和減輕風險來提高監查計劃的實用性。

　　Q2. Should sponsors monitor only risks that are important and likely to occur？
　　申辦者是否應僅監控重要且可能發生的風險？

　　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.
　　基于風險的監查方法應將申辦者監督活動的重點放在預防或減輕影響研究質量的重要和可能的風險上，包括影響受試者保護和數據完整性的風險。申辦者還應考慮監控不太可能發生但可能對研究質量產生重大影響的風險。申辦者應確定最適合解決已識別風險的監查活動的類型和強度。此外，監查計劃應允許監查活動依據在研究過程中可能發現的其他額外問題和風險而發展變化。

　　Q3. What factors should sponsors consider when determining the timing, types, frequency, and extent of monitoring activities？
　　在確定監查活動的時間，類型，頻率和范圍時，申辦者應考慮哪些因素？

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

　　• Complexity of the study design
　　研究設計的復雜性

　　• Types of study endpoints
　　研究終點的類型

　　• 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）
　　研究人群的臨床復雜性（例如，研究人群病情嚴重，有多種合并癥或更易受傷害，可能需要更加密集的監查甚至考慮現場監查訪視，以確保提供了適當的保護）

　　• 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，如可能存在醫療實踐標準差異或臨床試驗基礎設施較不成熟的中心

　　• Relative experience of the CI and of the sponsor with the CI
　　CI及申辦方與CI合作的相關經驗

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

　　• Relative safety of the investigational product
　　研究產品的相對安全性

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

　　• Quantity of data
　　數據質量

　　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所在中心的工作負載

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

　　•Similar to workload, high personnel turnover may cause unintended disruptions to conduct of the investigation and sponsor oversight.
　　與工作量相似，高人員流動率可能會導致非預期的研究和申辦者監查中斷。

　　• 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以及是否需要在多個地點查看受試者完成研究程序（例如，需在成像中心，當地醫生辦公室或受試者家中收集數據）

　　•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）.
　　在設計監查計劃時，申辦者應考慮研究中數據收集的地點和方式，以及相應的申辦者實施監督活動的地點（例如，確認適當的控制、說明和培訓工具已到位）。

　　• Benefit of an early monitoring visit or other early monitoring activities
　　早期監查訪視或其他早期監查活動的好處

　　•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.
　　通過安排早期監查訪視（例如，在首例試驗受試者入組后不久）或通過執行其他早期監查活動（例如，通過遠程過程），申辦者可幫助確保在研究早期，研究流程在CI所在中心被正確執行?；蛘?，如果早期監查發現問題，則可以更快地實施糾正措施。

　　• Experience and qualifications of the research coordinator
　　研究協調員的經驗和資格

　　•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.）
　　研究協調員在確保研究中心的研究實施質量方面發揮著重要作用（例如，研究協調員經常招募受試者、收集和評估研究數據，并維護研究記錄。）

　　• Safety profile of the investigational product
　　研究產品的安全性概況

　　•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.
　　在制定監查計劃時，申辦者應考慮已知的安全概況，包括該產品和同類別產品已有的人體和非臨床安全信息，以及作用機制。

　　• Characteristics of data to be collected
　　需收集的數據的特征

　　•When developing a monitoring plan, sponsors should consider the amount and complexity of the data collected.
　　在制定監查計劃時，申辦者應考慮數據收集的數量和復雜程度。

　　Q4. How can a risk-based approach to monitoring that includes centralized monitoringhelp minimize missing data, protocol violations, or protocol deviations？
　　基于風險的監查方法（包括中心化監查）如何最大限度地幫助減少數據丟失，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，不良的試驗實施行為或未遵守研究計劃會導致不完整的數據收集。因此，通過對CI所在中心重要研究活動的實時審查，申辦者可能能夠識別丟失數據、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在其他臨床研究部分發生的可能性。

　　Q5. Should the risk-based monitoring approach include processes to ensure that appropriate blinding is maintained？
　　基于風險的監查方法是否應包括確保適當盲法保持的過程？

　　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，對于盲法將用于干預和/或結果評估的研究，確保研究盲態保持是一個關鍵過程，申辦者應在其風險評估中考慮這一過程。

　　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.
　　風險評估中確定的對于盲態維持的特定風險，應在研究開始之前減輕該風險（如可行）。此外，在研究過程中識別和跟蹤可能導致無意中揭示治療分配的偏離，應作為監查計劃的一部分，以確保在CI所在中心和申辦者保持適當的盲態。例如，在盲法研究中，若要求研究中心一個工作人員以非盲態管理、發放研究測試產品，則應監控維持研究中心其他工作人員和申辦者盲態的流程。

　　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認識到數據監測委員會（DMC）可以訪問DMC章程中描述的非盲數據。（有關DMC的其他信息，請參閱臨床試驗申辦者指南：臨床試驗數據監測委員會的建立和運行（2006年3月）。

　　B. Monitoring Plan Content
　　監查計劃內容

　　Q6. What elements should sponsors include in monitoring plans？
　　申辦者應該在監查計劃中包括哪些要素？

　　The following elements （discussed in detail in section IV.D of the RBM guidance） are summarized here to assist sponsors in developing monitoring plans:
　　這里總結了以下要素（在RBM指南第IV.D節中詳細討論），以協助申辦者制定監查計劃：

　　• A synopsis of the study
　　研究概要

　　• Study objectives
　　研究目標

　　• Identification of critical data and study procedures
　　確定關鍵數據和研究程序

　　• Trial-specific risks to be addressed by monitoring
　　通過監查解決特定的試驗風險

　　• Monitoring methods and rationale for use of the monitoring methods, including how the methods address identified risks
　　監查方法和使用監查方法的合理性，包括該方法如何處理已識別的風險

　　• Criteria for determining the timing, types, frequency, and extent of monitoring activities
　　確定監查活動的時間、類型、頻率和范圍的標準

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

　　• 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）
　　可觸發監查活動變化的事件或結果的定義（例如，方案偏離如何作為可觸發監查活動變化的事件進行監測）

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

　　• Format, content, timing, and archiving requirements for documentation of monitoring activities
　　監查活動文檔的格式、內容、時間和歸檔要求

　　• Processes for communicating routine monitoring results to appropriate parties
　　將常規監查結果傳達給相關方的流程

　　• Processes for immediate reporting of significant monitoring issues to appropriate parties
　　向適當的各方立即報告重大監查問題的流程

　　• 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方到監查員的適當溝通流程

　　• Processes to address unresolved or significant issues identified by monitoring
　　處理通過監查確定的未解決或重大問題的流程

　　• Processes to ensure that root cause analyses are conducted where important deviations are discovered and that corrective and preventative actions are implemented
　　確保在發現重要偏離并實施糾正和預防措施的情況下，進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量管理實踐（例如，參考描述針對不合規的適當行動的其他文件）

　　• Training for personnel who carry out monitoring activities
　　為開展監查活動的人員提供培訓

　　• Planned audits of monitoring activities
　　計劃對監查活動進行稽查

　　• Process for updating monitoring plans
　　更新監查計劃的流程

　　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，FDA建議監查計劃還包括以下項目，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險。

　　• A description of the investigation design and the blinding and randomization procedures, if applicable
　　描述研究設計以及盲法和隨機化流程（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
　　當通過監查確定隨機化為需解決的風險時，確認隨機化根據方案和研究計劃執行的流程

　　• 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
　　監測抽樣計劃（該抽樣計劃用于確定需要監控的具體記錄和數據），包括抽樣計劃如何有代表性（代表整體信息），以及如何實施抽樣計劃

　　• A description of the types of significant issues identified through monitoring that would trigger immediate issue escalation
　　描述通過監查確定的、可立即引發問題升級的重大問題類型

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

　　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.
　　監查計劃應詳細描述這些項目中的每一項。申辦者還應酌情參考相關文件。鼓勵申辦者制定監查計劃，強調最有可能對研究質量產生不利影響的關鍵風險，包括研究受試者的權利，安全和福利，以及研究安全性和療效終點等臨床數據的收集或分析。

　　C. Follow-Up and Communication of Monitoring Results
　　監查結果的后續行動和溝通

　　Q7. How should sponsors follow up on significant issues identified through monitoring, including communication of such issues？
　　申辦者應如何跟蹤通過監查發現的重大問題，包括溝通此類問題？

　　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.
　　通過監查確定的重大問題（例如，嚴重不依從方案）應及時進行徹底評估（如監查計劃中所述的適當級別，例如，申辦方，CI所在中心）。
　　應采取適當的糾正和預防措施。應酌情記錄、跟蹤研究計劃的偏離，并將其上報給相關人員。
　　應及時發現并解決相關的系統性問題，以確保研究質量，包括維護研究受試者的權利，安全和福利以及數據完整性。

　　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，但一些糾正和預防措施的例子可能需要對CI和研究中心工作人員等進行再培訓；通過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.
　　通過監查確定的重大問題和應采取的行動應記錄在案并傳達給相關方，其中可能包括但不限于以下方面：（1）申辦者管理層，（2）申辦者團隊，（3）CI所在中心，（4）機構審查委員會，（5）其他相關方（例如，DMC和相關合同研究組織），以及（6）FDA，適當時。

　?。⊿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申辦者在監查計劃中應包括的要素的說明，請參見Q6關于重大問題的跟進和溝通。）

　　Q8. How should centralized monitoring activities and the results of these activities be documented and shared with those involved in the investigation？
　　如何記錄中心化監查活動和這些活動的結果，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，監查活動的文件通常應包括以下內容：（1）活動日期； （2）進行和參與活動的個人；（3）審查的數據或活動摘要； （4）對任何不依從、潛在不依從、數據違規或其他缺陷的描述；（5）對已采取、將采取或建議采取的任何行動的描述（詳情見RBM指南第五節）。此類文件應包括足夠詳細的中心化監查活動的結果，以便核實描述的活動對監查計劃的遵守情況。

　　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.
　　應及時向適當的管理層提供中心化監查活動的報告（包括負責研究和監督研究中心的申辦方人員），以便進行審查和跟進。此外，申辦者應將中心化監查發現的、與CI活動相關的問題向CI通報。