欧盟GMP附录13对投诉和召回的影响

一沙一叶

Julia法规翻译
                                 Effect of the newAnnex 13 on Complaints and Recalls新附录13对投诉和召回的影响

As previously reported the final "Detailed Commissionguidelines on GMP for IMPs for human use" have beenpublished in December 2017 in Annex 13 of the EU GMP-Guidelines.

正如之前所报道的，“人药IMP的GMP详细EC指南”终稿已于2017年12月在EU GMP指南附录13发布。

The sections 10 and 11 of the Detailed Commission Guideline coverthe topicsComplaintsand Recalls.What has changed in comparison to the previous Annex 13 (Manufacture ofInvestigational Medicinal Products, IMPs)?

详细EC指南第10部分和第11部分覆盖了投诉和召回主题。相比于之前的附录13（IMP生产），有哪些改变呢？

Pertaining to Complaints andRecalls theDetailedCommission Guideline contains references to:
• EU-GMP-Guidelines, Part1, Chapter 8 (Complaints and Product Recall),
• DelegatedRegulation (EU) 2017/1569,
• EUGCP Regulation 536/2014 (Clinical Trials Regulation, CTR).

关于投诉和召回，详细EC指南包括以下引用：

EU-GMP指南第1部分第8章（投诉和产品召回）

托管法案（EU）2017/1569

EU GCP法规536/2014（临床试验规范，CTR）

Overall, there seems to be some lack of clarity betweensponsor /manufacturer responsibility. For example, some of the activities areusually under the sponsor´s responsibility (e.g. according to Part1, Chapter 8 of the EU GMP-Guidelines) but have now been placed under themanufacturer´s responsibility (e.g emergencyunblinding, destruction) or have been deleted or moved from GMPto GCP.

总体来说，貌似对于申办人/生产商的职责澄清有所缺乏。例如，有些活动通常是申办人的职责（例如，依据EUGMP指南第1部分第8章），但现在放在了生产商的职责下面（例如，应急揭盲、销毁）或者是删除或从GMP中移到了GCP中。

A more detailed comparison concerning thechanges in the guidelines in regard to complaints and recalls can befound below:

指南中对投诉和召回更为详细的变化对照如下：

Section 10. COMPLAINTS of the Detailed Commission Guideline

详细EC指南第10部分投诉
Thefollowing specific requirements have been added:

增加了以下具体要求：

• "written procedures describing the actions to be taken upon receipt of a complaint at the manufacturing, storage or importation site."
• “描述在生产场所、存贮或进口场所收到投诉时所采取的措施的书面程序”
• "All complaints should be documented and assessed to establish if they represent a potential quality defect or other issue."
• “所有投诉均应记录和评估以识别其是否代表有潜在的质量缺陷或其它问题”
• "The procedures should ensure that the sponsor is able to assess the complaints to determine if they justify the reporting of a serious breach, as required by Article 52 of Regulation (EU) No     536/2014" (Clinical Trials Regulation, CTR).
• “生产商应确保申办人可以获得投诉信息以确定其是否认为应依据法规EU     536/2014（临床试验法规，CTR）第52条所要求的报告为严重偏离”
  
  

Article 52 "Reporting of serious breaches"of the CTR states: "1.Thesponsor shall notify the Member Statesconcerned about a serious breach of this Regulation or of the version of theprotocol applicable at the time of the breach through the EU portal withoutundue delay but notlater than seven daysof becoming aware of that breach. 2. For the purposes of this Article, a ‘serious breach’ means a breach likely to affect to asignificant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial."

第52条“报告为CTR严重偏离”要求“1、申办人应立即，或在知晓偏离之后不迟于7天内通知相关成员国对此法规的严重偏离，或者是在知晓偏离之时通过EU端口提交适用的方案版本。2、在本条中，“严重偏离”指可能影响受试对象安全和权利，或影响临床试验产生的数据的可靠性和稳定度使其达到严重程度的偏离”。

• "The investigation of quality defects should be performed in accordance with  the principles detailed in the EU GMP Guidelines, Part I, Chapter 8 (Complaints and Product     Recall)".
• 质量缺陷的调查应依据EU GMP指南第1部分第8章（投诉和产品召回）中的详细原则执行
  
  

The following section is compromised in the previousAnnex 13 and has been slightly amended in theDetailed Commission Guideline:

以下部分包括了之前的附录13，在详细EC指南中略有修改：

• "The conclusions of the investigation should be discussed between the manufacturer and thesponsor, if different, in a timely manner"(the previous Annex 13 also includes the importer). "This should involve the Qualified Person (QP) and those responsible for the     relevant clinical trial in order to asses any potential impact on the trial, product development and on subjects."
• 如果调查的结论不一致，生产商和申办人应及时进行讨论（之前的附录13还包括有进口商）。QP和相关临床试验负责人应参与此讨论以评估是否对试验、产品开发和受试对象有潜在影响
  
  

Section 11. RECALLS AND RETURNS of the Detailed Commission Guideline

详细EC指南第11部分召回和退货
11.1.Recalls 召回

• "Procedures for retrieving investigational medicinal products and documenting this retrieval should in line with Article 14 of the Delegated     Regulation be agreed by the sponsor in  cooperation with the manufacturer, where different" (the previous Annex 13 also includes theimporter).   
• 收回临床试验药品的程序及收回所做记录应符合托管法案第14条规定，并由申办人同意，如果生产商不同于申办人，则申办人应与生产商协作（之前的附录13还包括进口商）
  
  

Article 14 "Complaints,product recall and emergency unblinding" of the Delegated Regulationstates:

托管法案第14条“投诉、产品召回和应急揭盲”称：

1. The manufacturer shall, in cooperation with the sponsor, implement a system for recording andreviewing complaints together with an effective system for recallinginvestigational medicinal products which have already entered the distributionnetwork promptly and at any time. Themanufacturer shall record and investigate anycomplaint concerning a defect and shall inform thesponsor and the competent authority of the Member States concerned of anydefect that could result in a recall or abnormal restriction on supply. Alltrial sites shall be identified and, in so far as possible, the countries ofdestination shall be indicated. In the case of an authorised investigationalmedicinal product, the manufacturer shall, in cooperation with the sponsor, inform the marketing authorisationholder of any defect that could be related to that product.

生产商应与申办人协作实施一套记录和审核投诉的系统，连同一个有效的已即时快速录入销售网络的召回临床试验药品的系统一起运作。生产商应记录和调查所有与缺陷相关的投诉，并将可能导致召回和供应异常限制的任何缺陷通知申办人和相关成员国药监当局。应识别所有试验场所，并尽可能指明目的国。如果是经批准的临床试验药品，生产商应与申办人协作，将可能与该产品有关的任何缺陷通知MAH。

2. Where blinding ofinvestigational medicinal products is required by the protocol of a clinicaltrial, themanufacturer inconjunction with the sponsor shallimplement a procedure for the rapid unblinding of blinded products, where thisis necessary for a prompt recall as referred to in paragraph 1. Themanufacturer shall ensurethat the procedure discloses the identity of the blinded product only in so faras it is necessary.

如果临床试验方案要求对临床试验药品揭盲，则生产应与申办人一起对加盲药品实施快速揭盲，必要时按段1要求执行快速召回。生产商应确保只有在必要时才会公开加盲药品的识别方式。

However, the EU GMP Guidelines, Part I, Chapter 8 (Complaintsand Product Recall) states:"Thesponsor should implement a procedure for therapid unblinding of blinded products, where this is necessary for a promptrecall. The sponsor should ensure that the procedurediscloses the identity of the blinded product only in so far as isnecessary."

EU GMP指南第一部分第8章（投诉和产品召回）中说“如果快速召回需要，申办人应对加盲药品执行快速揭盲程序。申办人应确保只有在必要时才会公开加盲药品的识别方式

• "The manufacturer, investigator and the sponsor's representative need to understand their obligations under the retrieval procedure" (previously:  "The investigator and monitor need to understand their obligations under the retrieval procedure").
• 生产商、临床试验调查员和申办方代表需要理解其在收回程序中的义务（之前是：调查员和监管员需要了解其在收回程序中的义务）
• "The procedures for retrieval of investigational medicinal products should be in accordance with the principles detailed in EU GMP Guidelines, Part I,  Chapter 8".
• 收回临床试验药品的程序应符合EU GMP指南第1部分第8章中的详细原则
• "To     facilitate recall, a detailed     inventory of the shipments made by the manufacturershould be maintained."   
• 为便于召回，应保存生产商所制订的详细运输清单
  
  

The following sentence of the previous Annex 13 hasbeen deleted in the DetailedCommission Guideline:

以下原附录13中的句子在详细EC指南中已被删除

• "TheSponsor should ensure that the supplier of any comparator or other medication to be used in a clinical trial has a system for communicating to the Sponsor the need to recall any product supplied."
• 申办人应确保临床试验中所用的所有对照药品和其它药品的供应商具备一套沟通系统，与申办人沟通召回其所供应的产品事宜
  
  

As defined in the CTR"IMP" means a medicinal product which is being tested or used as a reference(comparator), including asa placebo, in a clinical trial. Therefore, the comparator is included inthe above mentioned requirements for the IMP.

由于在CTR中定义IMP为临床试验中受测或用作对照（比较）的药品，包括空白剂。因此，对照药品包括在上述IMP要求中。

11.2. Returns 退货

• As it is also written in the previous Annex 13: "Returned investigational medicinal products (IMPs) should be clearly identified and stored in an appropriately controlled, dedicated area. Inventory records of returned products should be kept."
• 在原附录13中也写到：退回的临床试验药品（IMP）应清楚识别并存贮在恰当受控的专用区域。应保存退货的库存记录
  
  

The following sentence of the previous Annex 13 hasbeen deleted in the DetailedCommission Guideline:

以下原附录13中的句子已在详细EC指南中删除

• "IMPs should be returned on agreed conditions defined by the sponsor, specified in approved written     procedures."
• “IMP应在申办人所定义的条件下经批准的书面程序退回”
  
  

This requirement has been moved from GMP to GCP, nowpresented in Article 51(Traceability, storage, return and destruction of investigational medicinalproducts) of the CTR: 1. "IMPs shall be traceable. They shall be stored, returned and/or destroyed as appropriate and proportionate to ensure the safety of the subjectand the reliability and robustness of the data generated in the clinical trial,in particular, taking into account whether the IMP is an authorised IMP,and whether the clinical trial is a low-intervention clinical trial. The first subparagraph shall alsoapply to unauthorised auxiliary medicinal products" (according to the CTRauxiliary medicinal products are medicinal products used in the context of aclinical trial but not as IMPs, such as medicinal products used for backgroundtreatment). 2."Therelevant information regarding the traceability, storage, return anddestruction of medicinal products referred to in paragraph 1 shall be containedin theapplicationdossier."

此要求已从GMP中移至GCP中，现在出现在CTR的第51条（IMP的追溯、存贮、退货和销毁）：1、IMP均可追溯。其存贮、退回和/或销毁应恰当以确保受试对象的安全和临床试验中所产生数据的可靠性与稳定度，尤其是要考虑该IMP是否经批准的IMP，以及该临床试验是否是低干扰度临床试验。第一子段也应适用于未经批准的辅助药品（依据CTR定义，辅助药品是指在临床试验用中使用但并不作为IMP，例如用于背景治疗的药品）。2、依据段1的IMP的相关追溯、存贮、退货和销毁信息均应包括在申报文档中。

11.3 Destruction销毁

• "Themanufacturer or sponsor’s representative should destroy IMPs only with     prior written authorisation by the sponsor. The arrangements for destruction of IMPs have to be described in the protocol. Any arrangement between sponsor and manufacturer in this regard should be defined in their technical agreement."
• 生产商或申办人代表应在申办人授权后方可销毁IMP。IMP销毁安排必须有方案描述。申办人和生产商在此方面的所有安排均应在其技术协议中写明
• "Records of destruction operations should be retained, including a dated certificate of destruction or a receipt for destruction to the sponsor."
• 应保存销毁记录，包括有日期的销毁证明或销毁收据给申办人
  
  

According to the previous Annex 13 the sponsor is responsiblefor the destruction of unused and/or returned IMPs and records should be keptby the sponsor:

依据原附录13，申办人负责未使用和/或退回IMP的销毁并保存销毁记录：

• "The Sponsor is responsible for the destruction of unused and/or returned investigational medicinal products.  Investigational medicinal products should therefore not be destroyed without prior written authorisation by the Sponsor."
• 申办人负责销售未使用的和/或退回的临床试验药品。因此临床试验药品未得申办人书面批准不得销毁。
• "The records should be kept by the Sponsor".   
• 记录应由申办人保存
  
  

The CTR and the DetailedCommission Guideline are expected to become applicable in the second half of2019. More information on Annex 13 and the DetailedCommission Guideline can be found inEudraLex, Volume 4.

CTR和详细EC指南有望在2019年下半年执行。更多信息参见EC官网。

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