最近众多有关欧盟待决的新医疗器械法规的报道刺激着医疗器械制造商们开始为即将在年底成为欧盟新法律的大规模改革而准备。届时,该医疗器械法规(MDR)将取代现行的医疗器械指令(MDD)和有源植入医疗器械指令(AIMDD)。


体外诊断医疗器械新定义

那么作为医疗器械一部分的体外诊断医疗器械(IVD)呢?一项新的体外诊断医疗器械法规(IVDR)已经被提议用来取代现行的体外诊断医疗器械指令。该拟议法规可以在欧盟法规索引Eur-Lex上搜索并阅读。在这次扩展的法规中,IVDR被定义为:


是指制造商预期用于体外检查从人体提取的样本,包括捐献的血液及组织,单独使用或组合使用的试剂、试剂产品、校准物品、控制材料、成套工具、仪器、器具、设备、软件或系统,其唯一目的或主要目的是提供以下信息:

 ·有关生理学或病理学状态;

 ·有关先天性异常;

 ·有关健康状况或疾病的易感性;

 ·确定安全性以及与可能接受治疗者的相容性;

 ·预测治疗效果或反应;

 ·明确或监控治疗措施。




IVDR将如何影响器械的分类

IVDR将从根本上改变CE标志的机制。这个机制将决定哪些IVD能够加贴CE标志。首先从一个基于风险的新分类机制开始,这种机制将“普通体外诊断试剂”这一分类替换为四种新的器械类别:A、B、C和D类(分别对应最低级风险到最高级风险)。B类到D类产品的技术文档要经过公告机构的评估。技术文档必须包括三种类型的临床证据:

 1.科学有效性:一个分析物与一种临床疾病或生理状态相关联

 2.分析性能IVD器械正确检测和测量分析物(检测限(LOD)、定量限(LOQ)、准确度、精确度和可复制性)的能力

 3.临床性能:器械依据目标人群产生与预期用途特定的临床疾病相关和与预期用户(若适用)相关的结果的能力


新法规强调对供应链的格外监督,包括公告机构对关键供应商和分包商的突击审核。此外,新法规规定了进口商、分销商和授权代表的监管作用以及对他们的要求。进口商是指在欧盟范围内建立,将第三国的器械投放在欧盟市场的任何自然人或法人。分销商是指除了供应链的制造商和进口商之外,使得器械在市场可获得的任何自然人或法人。在某些情况下,进口商也可充当分销商。


制造商必须为其产品投保责任保险;但是,进口商有责任验证保险是否充分,否则进口商必须购买额外的保险。除了法定制造商,授权代表必须指定专人负责其组织内部的法规遵从工作。这个专人必须在IVD领域受到过适当的教育以及具有IVD领域的经验。而且,他还必须对技术文档负责,确保符合性声明、性能评估和监测要求及时更新。


此外,新的IVDR对伴随诊断作了特别的规定。其中最主要的一条要求是,由公告机构审核完技术文档后必须向主管当局咨询。我们预计在IVDR正式发表之后,有关伴随诊断的具体指南也将发布。


最后,IVDR并不仅限于生产加贴CE标志的IVD试剂盒的制造商。如果你是一家位于美国经CLIA认证的实验室,并且打算在欧盟销售自建试剂,那么你需要作出一番努力,因为同样的分类规则和符合性评估路径也适用于实验室自建试剂(LDTs)。此时很可能需要符合国际标准的全面质量体系的要求,并且你的设计文档/技术文档接受公告机构的审查。



IVDR法规的转换

IVDR是由欧盟委员会拟议并经欧洲议会和理事会认可的法律。一旦采用,法规将立即在所有的成员国生效。这意味着该法律不会转换成各个成员国的法律。


当前的法规草案规定了5年的转换期,并且在2021年之前全面实施该法规。在转换期间,制造商可以选择依照现行的指令将产品投放市场,或者遵从新的法规。目前还不清楚在全面实施日期之前市场上是否会有关于自我保证声明类型的产品的额外指南,所以,制造商还是有可能继续在实施的前一天投放其自我保证声明类型的IVD产品,并保持在市场上的销售直到产品过期。


根据英国标准协会(BSI)的说法,在转换期间取得公告机构发放证书的产品可以在实施日期开始后的两年内在市场上继续销售,或者在证书发放的5年之内,以较早日期为准。目前还不清楚是否会有针对那些在新法规下需要公告机构证书的自我保证声明类型的产品的额外限制。



如何准备

鉴于未来暗淡监管形势,建议制造商在新法规变成法律的预期下采取以下的措施:

 ·根据新的分类规则进行IVD器械的分类

 ·对现有的技术文档执行差距分析

 ·识别重要的供应商和关键分包商,增强现有的供应商质量控制

 ·评价现有的临床证据,为进一步研究做准备


IVDR将从根本上改变欧盟监管IVD器械的方式。鉴于当前仅10-20%的诊断试剂需要接受公告机构的审查,新IVDR将对现行指令下自我认证的80-90%的IVD进行法规监管。建议制造商们提前做好规划,要有灵活性,为应对新模式做好准备。



英语原文

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.

来源:博济医疗