今天和大家說(shuō)說(shuō)歐盟醫(yī)療器械臨床試驗(yàn)。這個(gè)要求在歐盟醫(yī)療器械注冊(cè)中并不常見(jiàn)，因?yàn)榻^大多數(shù)器械，特別是在MDD時(shí)代下，都是進(jìn)行臨床文獻(xiàn)評(píng)估的路徑，并不是進(jìn)行臨床試驗(yàn)的。但是現(xiàn)在MDR時(shí)代，對(duì)臨床試驗(yàn)有了更明確的要求了，而且小編發(fā)現(xiàn)大家都常常會(huì)搞混，今天就在這里好好分享一下。

**，不管是走臨床文獻(xiàn)評(píng)估路徑，還是臨床試驗(yàn)，都還是要遵循meddev 2.7/1 rev4指南的要求，在寫(xiě)臨床評(píng)估方案的時(shí)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(diǎn)，MDD和MDR法規(guī)是不具備傳承性的，說(shuō)這點(diǎn)可能大家都說(shuō)知道知道。但單獨(dú)拎出來(lái)的時(shí)候，就開(kāi)始犯糊涂了。很多制造商都會(huì)說(shuō)我的產(chǎn)品在MDD時(shí)期可以進(jìn)行臨床文獻(xiàn)評(píng)估，MDR時(shí)期應(yīng)該能繼續(xù)走臨床文獻(xiàn)評(píng)估的路徑。那么既然大家都知道MDR不是MDD升級(jí)，而是全新注冊(cè)，那在MDR注冊(cè)就應(yīng)該按照MDR法規(guī)來(lái)進(jìn)行。況且MDD時(shí)期有多少放水，大家心里沒(méi)數(shù)么？

現(xiàn)在就開(kāi)始正式說(shuō)什么需要做臨床試驗(yàn)，臨床文獻(xiàn)評(píng)估很難行得通的情況。

1. 植入類(lèi)和3類(lèi)的器械

MDR article 61.4明確規(guī)定，植入類(lèi)和3類(lèi)的器械都需要進(jìn)行臨床試驗(yàn)

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

1.1. 與市面上已有產(chǎn)品比較，有技術(shù)調(diào)整的植入類(lèi)和3類(lèi)器械

此外，MDR article 61.4明確規(guī)定，植入類(lèi)和3類(lèi)的器械都需要進(jìn)行臨床試驗(yàn)，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(duì)器械與擬注冊(cè)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(guān)于比對(duì)器械一致性的討論，就是技術(shù)參數(shù)、生物相容性參數(shù)、臨床參數(shù)那三點(diǎn)，比對(duì)器械為別的制造商，一致性比較需要得到NB認(rèn)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(diǎn)和第三點(diǎn)是遞進(jìn)關(guān)系

老實(shí)說(shuō)，小編認(rèn)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(shè)我已有高風(fēng)險(xiǎn)產(chǎn)品MDD上市，我是不是可以故意作一些整改來(lái)進(jìn)行MDR注冊(cè)，已達(dá)到規(guī)避上市前臨床試驗(yàn)的目的（這條走不走得通，還真的要拭目以待有沒(méi)有吃螃蟹的人了）？

但是哪怕是能規(guī)避上市前臨床試驗(yàn)，上市后臨床試驗(yàn)還是跑不掉的，重點(diǎn)看標(biāo)紅句子。

1.2. 與別的制造商已上市產(chǎn)品比較，一致的植入類(lèi)和3類(lèi)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(diǎn)并不是二選一，而是遞進(jìn)關(guān)系的。要與比對(duì)器械的制造商簽訂技術(shù)文檔評(píng)估授權(quán)書(shū)，并且該比對(duì)器械的臨床評(píng)估是要符合MDR法規(guī)的。其實(shí)**點(diǎn)都有可能做到，特別是在集團(tuán)公司，A子公司和B子公司都有兩款一模一樣的產(chǎn)品，但是第二點(diǎn)比對(duì)器械的臨床評(píng)估要符合MDR，就有點(diǎn)懸了。

1.3. 植入類(lèi)和3類(lèi)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(shuō)的就是*常碰到的MDD時(shí)期已上市銷(xiāo)售的產(chǎn)品，俗稱(chēng)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(yàn)就不啰嗦了，制造商自身比任何人還清晰這點(diǎn)。

討論*多的就是有關(guān)legacy device的sufficient clinical data問(wèn)題，很多人都會(huì)問(wèn)：我MDD沒(méi)做臨床試驗(yàn)，但是我有收集上市后的臨床數(shù)據(jù)，行不行啊？

有這種疑惑歸根還是對(duì)法規(guī)指南沒(méi)全面了解，MDCG 2020-6對(duì)于legacy device的臨床數(shù)據(jù)等級(jí)已經(jīng)清晰列明了，并且白紙黑字的規(guī)定只有等級(jí)1-4的臨床數(shù)據(jù)才能作為植入類(lèi)和3類(lèi)器械臨床評(píng)估中充足臨床數(shù)據(jù)使用。您MDD時(shí)期收集的那些上市后臨床數(shù)據(jù)，一比較就已經(jīng)知道哪些能用哪些不能用了。

此外，注意a中的**點(diǎn)和第二點(diǎn)是并列關(guān)系。

2. 部分3類(lèi)與部分有源2b類(lèi)產(chǎn)品

2.1. 公告機(jī)構(gòu)的責(zé)任

對(duì)于植入3類(lèi)和2b有源類(lèi)涉及藥物灌注或移除的產(chǎn)品，MDR ANNEX IX ? 5.1規(guī)定其制造商的臨床評(píng)估報(bào)告以及公告機(jī)構(gòu)的CEAR報(bào)告都是需要給歐盟臨床專(zhuān)家小組審核的。

這里說(shuō)的是符合rule 12的有源類(lèi)產(chǎn)品，并不是所有2b類(lèi)涉及藥物灌注或移除的產(chǎn)品都需要臨床專(zhuān)家小組審核，小編犯過(guò)這個(gè)錯(cuò)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(zé)任

Article 61.2指出，所有3類(lèi)以及部分2b類(lèi)制造商可以，并且有義務(wù)在進(jìn)行臨床文獻(xiàn)評(píng)估或臨床試驗(yàn)前，給歐盟專(zhuān)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(zhuǎn)移的產(chǎn)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(shí)并不是什么新內(nèi)容，單純把MDR法規(guī)article 61逐條慢慢擰出來(lái)給大家解讀而已。真的挺繁雜的，而且歐盟法規(guī)指南的英語(yǔ)用法一直都沒(méi)FDA那么通俗易懂，包括小編自己，也常常會(huì)搞糊涂，今天寫(xiě)出來(lái)，除了希望方便大家日常工作使用以外，也算是給自己一個(gè)歸納總結(jié)。

醫(yī)療器械檢測(cè)及臨床試驗(yàn)等可咨詢

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