今天和大家說說歐盟醫療器械臨床試驗。這個要求在歐盟醫療器械注冊中并不常見，因為絕大多數器械，特別是在MDD時代下，都是進行臨床文獻評估的路徑，并不是進行臨床試驗的。但是現在MDR時代，對臨床試驗有了更明確的要求了，而且小編發現大家都常常會搞混，今天就在這里好好分享一下。

**，不管是走臨床文獻評估路徑，還是臨床試驗，都還是要遵循meddev 2.7/1 rev4指南的要求，在寫臨床評估方案的時候就要決定是走scientific literature review還是走clinical investigation了。

其次，也是很重要的一點，MDD和MDR法規是不具備傳承性的，說這點可能大家都說知道知道。但單獨拎出來的時候，就開始犯糊涂了。很多制造商都會說我的產品在MDD時期可以進行臨床文獻評估，MDR時期應該能繼續走臨床文獻評估的路徑。那么既然大家都知道MDR不是MDD升級，而是全新注冊，那在MDR注冊就應該按照MDR法規來進行。況且MDD時期有多少放水，大家心里沒數么？

現在就開始正式說什么需要做臨床試驗，臨床文獻評估很難行得通的情況。

1. 植入類和3類的器械

MDR article 61.4明確規定，植入類和3類的器械都需要進行臨床試驗

In the case of implantable devices and class III devices（根據rule 8規定，所有的植入類器械分類至少是2b）, clinical investigations shall be performed

1.1. 與市面上已有產品比較，有技術調整的植入類和3類器械

此外，MDR article 61.4明確規定，植入類和3類的器械都需要進行臨床試驗，除了以下情況：

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（比對器械與擬注冊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 是關于比對器械一致性的討論，就是技術參數、生物相容性參數、臨床參數那三點，比對器械為別的制造商，一致性比較需要得到NB認可）

— 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.

第二點和第三點是遞進關系

老實說，小編認為61.4條是*有歧義的一條，也是制造商*容易走漏洞的一條。假設我已有高風險產品MDD上市，我是不是可以故意作一些整改來進行MDR注冊，已達到規避上市前臨床試驗的目的（這條走不走得通，還真的要拭目以待有沒有吃螃蟹的人了）？

但是哪怕是能規避上市前臨床試驗，上市后臨床試驗還是跑不掉的，重點看標紅句子。

1.2. 與別的制造商已上市產品比較，一致的植入類和3類器械

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

這兩點并不是二選一，而是遞進關系的。要與比對器械的制造商簽訂技術文檔評估授權書，并且該比對器械的臨床評估是要符合MDR法規的。其實**點都有可能做到，特別是在集團公司，A子公司和B子公司都有兩款一模一樣的產品，但是第二點比對器械的臨床評估要符合MDR，就有點懸了。

1.3. 植入類和3類器械的legacy device以及其他情況

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

這段說的就是*常碰到的MDD時期已上市銷售的產品，俗稱為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.

骨釘骨板那堆小玩意免臨床試驗就不啰嗦了，制造商自身比任何人還清晰這點。

討論*多的就是有關legacy device的sufficient clinical data問題，很多人都會問：我MDD沒做臨床試驗，但是我有收集上市后的臨床數據，行不行啊？

有這種疑惑歸根還是對法規指南沒全面了解，MDCG 2020-6對于legacy device的臨床數據等級已經清晰列明了，并且白紙黑字的規定只有等級1-4的臨床數據才能作為植入類和3類器械臨床評估中充足臨床數據使用。您MDD時期收集的那些上市后臨床數據，一比較就已經知道哪些能用哪些不能用了。

此外，注意a中的**點和第二點是并列關系。

2. 部分3類與部分有源2b類產品

2.1. 公告機構的責任

對于植入3類和2b有源類涉及藥物灌注或移除的產品，MDR ANNEX IX ? 5.1規定其制造商的臨床評估報告以及公告機構的CEAR報告都是需要給歐盟臨床專家小組審核的。

這里說的是符合rule 12的有源類產品，并不是所有2b類涉及藥物灌注或移除的產品都需要臨床專家小組審核，小編犯過這個錯誤，在這里提醒大家一下。

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. 制造商的責任

Article 61.2指出，所有3類以及部分2b類制造商可以，并且有義務在進行臨床文獻評估或臨床試驗前，給歐盟專家小組審核方案。

For all class III devices and for the class IIb devices（指的就是上文rule 12的有源涉及藥物灌注或轉移的產品） 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.

這里用的是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，其實并不是什么新內容，單純把MDR法規article 61逐條慢慢擰出來給大家解讀而已。真的挺繁雜的，而且歐盟法規指南的英語用法一直都沒FDA那么通俗易懂，包括小編自己，也常常會搞糊涂，今天寫出來，除了希望方便大家日常工作使用以外，也算是給自己一個歸納總結。

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