今天和大家说说欧盟医疗器械临床试验。这个要求在欧盟医疗器械注册中并不常见，因为绝大多数器械，特别是在MDD时代下，都是进行临床文献评估的路径，并不是进行临床试验的。但是现在MDR时代，对临床试验有了更明确的要求了，而且小编发现大家都常常会搞混，今天就在这里好好分享一下。
**，不管是走临床文献评估路径，还是临床试验，都还是要遵循meddev 2.7/1 rev4指南的要求，在写临床评估方案的时候就要决定是走scientific literature review还是走clinical investigation了。
其次，也是很重要的一点，MDD和MDR法规是不具备传承性的，说这点可能大家都说知道知道。但单独拎出来的时候，就开始犯糊涂了。很多制造商都会说我的产品在MDD时期可以进行临床文献评估，MDR时期应该能继续走临床文献评估的路径。那么既然大家都知道MDR不是MDD升级，而是全新注册，那在MDR注册就应该按照MDR法规来进行。况且MDD时期有多少放水，大家心里没数么？
现在就开始正式说什么需要做临床试验，临床文献评估很难行得通的情况。
1. 植入类和3类的器械
MDR article 61.4明确规定，植入类和3类的器械都需要进行临床试验
In the case of implantable devices and class III devices（根据rule 8规定，所有的植入类器械分类至少是2b）, clinical investigations shall be performed
1.1. 与市面上已有产品比较，有技术调整的植入类和3类器械
此外，MDR article 61.4明确规定，植入类和3类的器械都需要进行临床试验，除了以下情况：
In the case of implantable devices and class III devices, clinical investigations shall be performed, except if:
— the device has been designed by modifications of a device already marketed by the same manufacturer（比对器械与拟注册器械需要同一制造商）,
— the modified device has been demonstrated by the manufacturer to be equivalent to the marketed device, in accordance with Section 3 of Annex XIV and this demonstration has been endorsed by the notified body, and （Annex XIV 3 是关于比对器械一致性的讨论，就是技术参数、生物相容性参数、临床参数那三点，比对器械为别的制造商，一致性比较需要得到NB认可）
— the clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements.
In this case, the notified body shall check that the PMCF plan is appropriate and includes post market studies to demonstrate the safety and performance of the device.
第二点和第三点是递进关系
老实说，小编认为61.4条是*有歧义的一条，也是制造商*容易走漏洞的一条。假设我已有高风险产品MDD上市，我是不是可以故意作一些整改来进行MDR注册，已达到规避上市前临床试验的目的（这条走不走得通，还真的要拭目以待有没有吃螃蟹的人了）？
但是哪怕是能规避上市前临床试验，上市后临床试验还是跑不掉的，重点看标红句子。
1.2. 与别的制造商已上市产品比较，一致的植入类和3类器械
MDR Article 61.5提到：A manufacturer of a device demonstrated to be equivalent to an already marketed device not manufactured by him, may also rely on paragraph 4 in order not to perform a clinical investigation provided that the following conditions are fulfilled in addition to what is required in that paragraph:
— the two manufacturers have a contract in place that explicitly allows the manufacturer of the second device full access to the technical documentation on an ongoing basis, and
— the original clinical evaluation has been performed in compliance with the requirements of this Regulation, and the manufacturer of the second device provides clear evidence thereof to the notified body
这两点并不是二选一，而是递进关系的。要与比对器械的制造商签订技术文档评估授权书，并且该比对器械的临床评估是要符合MDR法规的。其实**点都有可能做到，特别是在集团公司，A子公司和B子公司都有两款一模一样的产品，但是第二点比对器械的临床评估要符合MDR，就有点悬了。
1.3. 植入类和3类器械的legacy device以及其他情况
MDR Article 61.6 提到：The requirement to perform clinical investigations pursuant to paragraph 4 shall not apply to implantable devices and class III devices:
(a) which have been lawfully placed on the market or put into service in accordance with Directive 90/385/EEC or Directive 93/42/EEC and for which the clinical evaluation:
— is based on sufficient clinical data, and
— is in compliance with the relevant product-specific CS for the clinical evaluation of that kind of device, where such a CS is available; or
这段说的就是*常碰到的MDD时期已上市销售的产品，俗称为legacy device。
(b) that are sutures, staples, dental fillings, dental braces, tooth crowns, screws, wedges, plates, wires, pins, clips or connectors for which the clinical evaluation is based on sufficient clinical data and is in compliance with the relevant product-specific CS, where such a CS is available.
骨钉骨板那堆小玩意免临床试验就不啰嗦了，制造商自身比任何人还清晰这点。
讨论*多的就是有关legacy device的sufficient clinical data问题，很多人都会问：我MDD没做临床试验，但是我有收集上市后的临床数据，行不行啊？
有这种疑惑归根还是对法规指南没全面了解，MDCG 2020-6对于legacy device的临床数据等级已经清晰列明了，并且白纸黑字的规定只有等级1-4的临床数据才能作为植入类和3类器械临床评估中充足临床数据使用。您MDD时期收集的那些上市后临床数据，一比较就已经知道哪些能用哪些不能用了。
此外，注意a中的**点和第二点是并列关系。
2. 部分3类与部分有源2b类产品
2.1. 公告机构的责任
对于植入3类和2b有源类涉及药物灌注或移除的产品，MDR ANNEX IX 5.1规定其制造商的临床评估报告以及公告机构的CEAR报告都是需要给欧盟临床专家小组审核的。
这里说的是符合rule 12的有源类产品，并不是所有2b类涉及药物灌注或移除的产品都需要临床专家小组审核，小编犯过这个错误，在这里提醒大家一下。
5.1. Assessment procedure for certain class III and class IIb devices
(a) For class III implantable devices, and for class IIb active devices intended to administer and/or remove a medicinal product as referred to in Section 6.4. of Annex VIII (Rule 12), the notified body shall, having verified the quality of clinical data supporting the clinical evaluation report of the manufacturer referred to in Article 61(12), prepare a clinical evaluation assessment report which sets out its conclusions concerning the clinical evidence provided by the manufacturer, in particular concerning the benefit-risk determination, the consistency of that evidence with the intended purpose, including the medical indication or indications and the PMCF plan referred to in Article 10(3) and Part B of Annex XIV.
The notified body shall transmit its clinical evaluation assessment report, along with the manufacturer's clinical evaluation documentation, referred to in points (c) and (d) of Section 6.1 of Annex II, to the Commission. The Commission shall immediately transmit those documents to the relevant expert panel referred to in Article 106.
2.2. 制造商的责任
Article 61.2指出，所有3类以及部分2b类制造商可以，并且有义务在进行临床文献评估或临床试验前，给欧盟专家小组审核方案。
For all class III devices and for the class IIb devices（指的就是上文rule 12的有源涉及药物灌注或转移的产品） referred to in point (b) of Article 54(1), the manufacturer may, prior to its clinical evaluation and/or investigation, consult an expert panel as referred to in Article 106, with the aim of reviewing the manufacturer's intended clinical development strategy and proposals for clinical investigation. The manufacturer shall give due consideration to the views expressed by the expert panel. Such consideration shall be documented in the clinical evaluation report referred to in paragraph 12 of this Article.
这里用的是may，不是should，不然又有很多制造商要哭哭了。
以上就是今天的分享了，其实并不是什么新内容，单纯把MDR法规article 61逐条慢慢拧出来给大家解读而已。真的挺繁杂的，而且欧盟法规指南的英语用法一直都没FDA那么通俗易懂，包括小编自己，也常常会搞糊涂，今天写出来，除了希望方便大家日常工作使用以外，也算是给自己一个归纳总结。
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