最近眾多有關歐盟待決的新醫療器械法規的報道刺激著醫療器械制造商們開始為即將在年底成為歐盟新法律的大規模改革而準備。屆時,該醫療器械法規(MDR)將取代現行的醫療器械指令(MDD)和有源植入醫療器械指令(AIMDD)。


體外診斷醫療器械新定義

那么作為醫療器械一部分的體外診斷醫療器械(IVD)呢?一項新的體外診斷醫療器械法規(IVDR)已經被提議用來取代現行的體外診斷醫療器械指令。該擬議法規可以在歐盟法規索引Eur-Lex上搜索并閱讀。在這次擴展的法規中,IVDR被定義為:


是指制造商預期用于體外檢查從人體提取的樣本,包括捐獻的血液及組織,單獨使用或組合使用的試劑、試劑產品、校準物品、控制材料、成套工具、儀器、器具、設備、軟件或系統,其唯一目的或主要目的是提供以下信息:

 ·有關生理學或病理學狀態;

 ·有關先天性異常;

 ·有關健康狀況或疾病的易感性;

 ·確定安全性以及與可能接受治療者的相容性;

 ·預測治療效果或反應;

 ·明確或監控治療措施。




IVDR將如何影響器械的分類

IVDR將從根本上改變CE標志的機制。這個機制將決定哪些IVD能夠加貼CE標志。首先從一個基于風險的新分類機制開始,這種機制將“普通體外診斷試劑”這一分類替換為四種新的器械類別:A、B、C和D類(分別對應最低級風險到最高級風險)。B類到D類產品的技術文檔要經過公告機構的評估。技術文檔必須包括三種類型的臨床證據:

 1.科學有效性:一個分析物與一種臨床疾病或生理狀態相關聯

 2.分析性能IVD器械正確檢測和測量分析物(檢測限(LOD)、定量限(LOQ)、準確度、精確度和可復制性)的能力

 3.臨床性能:器械依據目標人群產生與預期用途特定的臨床疾病相關和與預期用戶(若適用)相關的結果的能力


新法規強調對供應鏈的格外監督,包括公告機構對關鍵供應商和分包商的突擊審核。此外,新法規規定了進口商、分銷商和授權代表的監管作用以及對他們的要求。進口商是指在歐盟范圍內建立,將第三國的器械投放在歐盟市場的任何自然人或法人。分銷商是指除了供應鏈的制造商和進口商之外,使得器械在市場可獲得的任何自然人或法人。在某些情況下,進口商也可充當分銷商。


制造商必須為其產品投保責任保險;但是,進口商有責任驗證保險是否充分,否則進口商必須購買額外的保險。除了法定制造商,授權代表必須指定專人負責其組織內部的法規遵從工作。這個專人必須在IVD領域受到過適當的教育以及具有IVD領域的經驗。而且,他還必須對技術文檔負責,確保符合性聲明、性能評估和監測要求及時更新。


此外,新的IVDR對伴隨診斷作了特別的規定。其中最主要的一條要求是,由公告機構審核完技術文檔后必須向主管當局咨詢。我們預計在IVDR正式發表之后,有關伴隨診斷的具體指南也將發布。


最后,IVDR并不僅限于生產加貼CE標志的IVD試劑盒的制造商。如果你是一家位于美國經CLIA認證的實驗室,并且打算在歐盟銷售自建試劑,那么你需要作出一番努力,因為同樣的分類規則和符合性評估路徑也適用于實驗室自建試劑(LDTs)。此時很可能需要符合國際標準的全面質量體系的要求,并且你的設計文檔/技術文檔接受公告機構的審查。



IVDR法規的轉換

IVDR是由歐盟委員會擬議并經歐洲議會和理事會認可的法律。一旦采用,法規將立即在所有的成員國生效。這意味著該法律不會轉換成各個成員國的法律。


當前的法規草案規定了5年的轉換期,并且在2021年之前全面實施該法規。在轉換期間,制造商可以選擇依照現行的指令將產品投放市場,或者遵從新的法規。目前還不清楚在全面實施日期之前市場上是否會有關于自我保證聲明類型的產品的額外指南,所以,制造商還是有可能繼續在實施的前一天投放其自我保證聲明類型的IVD產品,并保持在市場上的銷售直到產品過期。


根據英國標準協會(BSI)的說法,在轉換期間取得公告機構發放證書的產品可以在實施日期開始后的兩年內在市場上繼續銷售,或者在證書發放的5年之內,以較早日期為準。目前還不清楚是否會有針對那些在新法規下需要公告機構證書的自我保證聲明類型的產品的額外限制。



如何準備

鑒于未來暗淡監管形勢,建議制造商在新法規變成法律的預期下采取以下的措施:

 ·根據新的分類規則進行IVD器械的分類

 ·對現有的技術文檔執行差距分析

 ·識別重要的供應商和關鍵分包商,增強現有的供應商質量控制

 ·評價現有的臨床證據,為進一步研究做準備


IVDR將從根本上改變歐盟監管IVD器械的方式。鑒于當前僅10-20%的診斷試劑需要接受公告機構的審查,新IVDR將對現行指令下自我認證的80-90%的IVD進行法規監管。建議制造商們提前做好規劃,要有靈活性,為應對新模式做好準備。



英語原文

EU's New In Vitro Diagnostic Regulations


Much has been written recently about the European Union’s pending new medical device regulations, encouraging medical device manufacturers to begin preparing for the broad changes that may become EU law later this year. This Medical Devices Regulation (MDR) will replace both the existing Medical Devices Directive and the Active Implantable Medical Devices Directive .



A New Definition For In Vitro Diagnostic Devices

But what about that subset of medical devices that are in vitro diagnostic devices (IVDs)? A new In Vitro Diagnostic Devices Regulation (IVDR) has been proposed to replace the existing In Vitro Diagnostic Devices Directive. Useful reading on the proposed regulation can be found at Eur-Lex, an index of European Law. In this expanded regulation, IVDRs are now defined as:


a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:

 ·concerning a physiological or pathological state;

 ·concerning a congenital abnormality;

 ·concerning the predisposition to a medical condition or a disease;

 ·to determine the safety and compatibility with potential recipients;

 ·to predict treatment response or reactions;

·to define or monitor therapeutic measures.




How IVDR Will Impact Device Classification

The IVDR will substantially change the mechanism by which IVDs may bear the CE mark. For starters, a new risk-based classification scheme will replace the "general IVD" category with four new device classes: A, B, C, and D (lowest risk to highest risk, respectively). Classes B through D will require an assessment of the technical documentation by a Notified Body. This technical documentation must include three types of clinical evidence:

 1.Scientific Validity: association of an analyte to a clinical condition or physiological state

 2.Analytical Performance: ability of an IVD to correctly detect and measure the analyte (LOD, LOQ, accuracy, precision and reproducibility)

 3.Clinical Performance: ability of the device to yield results that relate to a particular clinical condition for the intended use and in accordance with target population, and to the intended user (if applicable)


The new regulation emphasizes additional oversight of the supply chain, which includes unannounced audits of critical suppliers and subcontractors by the Notified Bodies. Additionally, the new regulation requires regulatory roles and requirements for importers, distributors, and authorized representatives. Importers are defined as any natural or legal person, established within the EU, who places a device from a third country in the European market. A distributor is defined as any natural or legal person in the supply chain, other than the manufacturer or importer, who makes the device available on the market. In some instances, the importer may also act as the distributor.


Manufacturers must have liability insurance for their products; however, it is the responsibility of the importers to verify that the insurance is adequate, or additional insurance must be taken out by the importer. The authorized representatives, in addition to the legal manufacturer, are required to designate a person responsible for regulatory compliance within their organization. This person must have the proper education and experience within the field of IVDs. Furthermore, this individual is responsible for the technical documentation, ensuring the declaration of conformity, performance evaluations, and vigilance requirements are kept up-to-date.


Additionally, the new IVDR makes special provisions for companion diagnostics. Chief among these is the requirement for a consultation with a Competent Authority after review of the technical documentation by a Notified Body. We expect there will be specific guidance issued regarding companion diagnostics following official publication of the IVDR.


Finally, the IVDR is not limited to manufacturers of CE-marked IVD kits. If you are a US-based, CLIA-licensed laboratory intending to market your in-house developed tests in the EU, you also may have some work to do, as the same classification rules and conformity assessment routes will apply to laboratory developed tests (LDTs). This will likely require full quality system compliance with an international standard and a review of the design dossier/technical documentation file by a Notified Body.



Transitionary IVDR Regulation

The IVDR is a law proposed by the European Commission and agreed upon by the European Parliament and Council. Upon adoption, the regulation immediately enters into force in all the member states. This means there is no transposition into Member State law.


The current draft regulation provides for a five-year transitionary period and full implementation by 2021. During the transitionary period, manufacturers can choose to place products on the market under the existing directive, or to comply with the new regulation. It is unclear whether any additional guidance regarding self-declared products will be placed on the market before the full implementation date, so it is possible that manufacturers may continue to release self-declared IVDs through the day before implementation, and keep them on the market until they expire.


According to BSI, products issued a certificate from a Notified Body during the transition period may remain on the market for two years after the implementation date, or five years from issue, whichever is earlier. It currently is unclear whether there will be any additional restrictions placed on self-declared products that require a certificate issued by a Notified Body under the new regulation.



How To Prepare

In light of murky regulatory waters ahead, we recommend that manufacturers take the following steps in anticipation of this new regulation becoming law:

 ·Classify your IVD device according to the new classification rules.

 ·Perform a gap analysis of your existing technical documentation.

 ·Identify your crucial suppliers and critical subcontractors and augment your existing supplier quality controls.

 ·Evaluate your existing clinical evidence and plan for additional studies.


The IVDR will fundamentally change the way IVDs are regulated in the EU. Whereas currently only 10-20 percent of diagnostics currently require review by a Notified Body, the new IVDR will require regulatory oversight for 80-90 percent of all IVDs that are self-certified under the existing Directive. Mapping out your path ahead of time, including preparing to be flexible, will equip you to respond to this new paradigm.

來源:博濟醫療