In Part 2 of our Christmas special, we discussed the application and approval process for clinical trials with CE-marked products and assumed that this, along with Article 74, applied to all PMCF studies with medical devices already on the market. However, a virtual event hosted by the BfArM (Federal Institute for Drugs and Medical Devices) in conjunction with the Federal Ministry of Health and the Working Group of Ethics Committees has now clarified the regulations regarding this article, at least as far as Germany is concerned.

Abbreviations

BOB (higher federal authority)

EK (Ethics Commission)

KP (clinical examination)

MDR (medical device regulation; EU Regulation 2017/745)

MPG (Medical Devices Act)

MPAnpG-EU (Medical Devices Adaptation Act)

MPDG (Medical Devices Implementation Act)

BO (Professional Code of Conduct for Physicians)

Underlying regulations

EU Regulation 2017/745 (MDR)

The Medical Devices EU Adaptation Act (MPEUAnpG) was passed by the German Bundestag on May 25, 2020. Article 1 of this MPAnpG-EU describes the Medical Devices Implementation Act (MPDG)

MPDG (the MPDG will gradually replace the Medical Devices Act (MPG) from May 26, 2021 and will be legally binding for all manufacturers and operators of medical devices in Germany).

1 Introduction

The European Medical Device Regulation (MDR) has been in force since 2017, and its application was originally scheduled to begin on May 26, 2020. Due to the COVID-19 pandemic, this date, as well as that of the German Medical Devices Law Implementation Act (MPDG), was postponed to May 26, 2021. As is well known, this also entails changes to many legal requirements and practical frameworks for the authorization and conduct of clinical trials of medical devices. The Federal Institute for Drugs and Medical Devices (BfArM), together with the Federal Ministry of Health and the Working Group of Ethics Committees, provided information on this at a virtual event on May 5, 2021.

Assuming that Article 74 of the MDR :

"Clinical trials relating to products bearing the CE marking

1. If a clinical investigation is conducted for the further evaluation of a product already bearing the CE marking in accordance with Article 20(1) within the scope of its intended purpose (hereinafter referred to as a ‘post-marketing clinical investigation’), and if, as part of this investigation, participants are subjected to additional procedures beyond those carried out under normal conditions of use of the product, and if these additional procedures are invasive or burdensome, the sponsor shall notify the Member States concerned at least 30 days before the start of the investigation via the electronic system referred to in Article 73. The sponsor shall transmit the documentation in accordance with Chapter II of Annex XV as part of the notification. For post-marketing clinical investigations C1, Article 62(4)(b) to (k) and (m), Articles 75, 76 and 77 and Article 80(5) and (6) and the relevant provisions of Annex XV shall apply.
2. If a clinical investigation is carried out for the purpose of evaluating a product which already bears the CE marking in accordance with Article 20(1) outside of its intended purpose, Articles 62 to 81 shall apply

For all medical devices bearing the CE mark, the majority assumed that from May 26, 2021, ethics approval would be required for PMCF studies and that professional consultation according to Section 15 of the Professional Code of Conduct for Physicians (BO) would no longer be necessary. This is no longer the case.

2. Different types of PMCF studies

2.1 Definition of PMCF studies

There is no actual definition of PMCF studies. This is true neither in the directive, the Medical Devices Act (MPG), nor in any of the regulations or MEDDEVs, nor in the Medical Devices Regulation (MDR) or the Medical Devices Act (MPDG). Article 74 of the MDR only states that such a clinical investigation is called post-marketing clinical

“If a clinical investigation is carried out for the further evaluation of a product which already bears the CE marking in accordance with Article 20(1) within the scope of its intended purpose (hereinafter referred to as ‘post-market clinical investigation’) […].”

A PMCF study is therefore a clinical investigation conducted with the CE-marked product, providing clinical data on the product as part of post-market clinical follow-up (PMCF). Clinical follow-up is regulated in Annex XIV, Part B of the MDR.

Clinical follow-up encompasses not only PMCF studies but also other potential activities for collecting clinical data on the product. Examples include real-world data, as described in the last blog post, as well as registry data and other activities. The following figure provides an overview of these activities and the entire post-market surveillance process according to the MDR, specifically Articles 83-85:

Figure 1. General methods and procedures of PMS and PMCF (Source: Keene A. Leveraging Post-Market Surveillance and Post-Market Clinical Follow-Up Data to Support EU Medical Device Regulation (MDR) Compliance, Whitepaper)

2.2 PMCF studies within the scope of their intended purpose and without invasive examinations

Previous regulation:

Previously, these PMCF studies were regulated according to § 23b MPG :

"Section 23b Exceptions to clinical trials

Sections 20 to 23a shall not apply if a clinical investigation is carried out with medical devices which are permitted to bear the CE marking in accordance with Sections 6 and 10, unless this investigation concerns a different intended purpose of the medical device or additional invasive or other burdensome examinations are carried out

Such a study previously fell under the category of "other studies" and was conducted outside the scope of the Medical Devices Act (MPG). The Ethics Committee of the Bavarian State Medical Association, for example, states the following:

Figure 2: Types of study at the BLÄK (Bavarian State Medical Association)

In Baden-Württemberg, a "free application" is submitted for such a study:

Figure 3: Free application for such a study at the Baden-Württemberg Medical Association

For PMCF studies within the intended purpose of the medical device, professional ethics consultation according to Section 15 of the Professional Code of Conduct for Physicians was therefore required. Previously, an application for this consultation was submitted directly to the ethics committee. Some ethics committees required multiple paper copies and one copy on CD-ROM. Others (e.g., Hesse, Bavaria) have a portal through which applications can be uploaded electronically. In this case, only one paper copy is required.

For these studies, in addition to certain study documents (study protocol, patient information and informed consent form, questionnaires, etc.), the investigator's CV must be submitted. A qualification demonstrating at least two years of experience in clinical trials with medical devices, as required for ethics approval, is not verified here.

Regulations effective from the start of the MDR

Up to now, our assumption and interpretation of Article 74 of the MDR was that all PMCF studies fall under this and therefore an ethics vote would be required from 26 May 2021.

At the aforementioned event, Article 74 was interpreted for Germany as follows:

• It only applies to clinical trials with CE-marked products that are conducted outside their intended purpose.
• It also applies to clinical trials with CE-marked products if additional stressful investigations are carried out as part of these trials.

This means that the procedure described above for other studies and open applications (professional legal advice according to § 15 BO) will continue to apply!

Figure 4: Article 74 of the MDR (Source: Presentation slides, BfArM event, https://www.bfarm.de/DE/Service/Veranstaltungen/Dialogveranstaltungen/2021/210505-klinische_Pruefungen_von_MP.html)

Article 74 of the MDR thus excludes PMCF studies from the scope of the intended purpose and continues to regard them, as in the MPG, as an exception to clinical trials.

Therefore, apart from the terminology in the study protocol relating to the German Medical Devices Act (MPG) and, where applicable, Directive 92/43/EEC (amended in the Medical Devices Regulation (MDR), as it is no longer valid), nothing changes here. The procedure remains the same, and manufacturers still have the option of collecting their clinical data more easily within the framework of the PMCF study.

2.3 PMCF studies with stressful examinations

Previous regulation:

These PMCF studies have also been regulated to date in accordance with Section 23b of the German Medical Devices Act (MPG) :

"Section 23b Exceptions to clinical trials

Sections 20 to 23a shall not apply if a clinical investigation is carried out with medical devices which may bear the CE marking in accordance with Sections 6 and 10, unless this investigation concerns a different intended purpose of the medical device or additional invasive or other burdensome examinations are carried out .

In the case of additional burdensome examinations, the provisions of Sections 20 et seq. of the Medical Devices Act (MPG) and, in this case, in conjunction with Section 7 of the Medical Devices Patient Regulations (MPKPV) with Section 1 Sentence 3, have so far applied to such a study:

are permitted to bear the CE marking in accordance with Sections 6 and 10 of the Medical Devices Act , unless this investigation concerns a different intended purpose of the medical device."

In this case, an application for exemption from the approval requirement had to be submitted to BfArM via the Medical Device Information System (MPI, formerly DIMDI), and an application for an opinion (vote) had to be submitted to the Ethics Committee, also via the MPI.

Regulations effective from the start of the MDR

With the entry into force of the MDR, this procedure will be replaced by the new one regulated in Article 74 of the MDR:

• The sponsor shall inform the Federal Higher Authority (BOB, in Germany: BfArM) at least 30 days before the start of the study about the MPI (in Germany).
• Article 62, paragraph 4, letters b to k and m, Articles 75, 76 and 77 and Article 80, paragraphs 5 and 6 apply
• The relevant provisions of Annex XV also apply

This means that the BOB must be informed and an ethics opinion must be obtained from the Ethics Committee in accordance with Article 62 paragraph 4 letter b.

Furthermore, Chapter 4 of the MPDG, specifically Sections 1 and 2, and in the latter, Subsection 1, apply with regard to application, approval, and the respective deadlines. See also the blog post in the Christmas Special, Part 2 .

2.4 PMCF studies outside their intended purpose

Previous regulation:

These PMCF studies have also been regulated to date in accordance with Section 23b of the German Medical Devices Act (MPG) :

"Section 23b Exceptions to clinical trials

Sections 20 to 23a shall not apply if a clinical investigation is carried out with medical devices which are permitted to bear the CE marking in accordance with Sections 6 and 10, unless this investigation concerns a different intended purpose of the medical device or additional invasive or other burdensome examinations are carried out.

Previously, if the clinical trial with the CE-marked product related to a new intended purpose (e.g., also to new indications), then Sections 20 et seq. of the German Medical Devices Act (MPG) also applied to such a study. This means that a classic registration study was conducted in accordance with Sections 20 et seq. of the MPG

• Application submitted via the MPI to BfArM and EK

Regulations effective from the start of the MDR

With the entry into force of the MDR, Article 74, paragraph 2 now applies:

“(2) Where a clinical investigation is carried out for the purpose of evaluating a product which already bears the CE marking in accordance with Article 20(1) outside of its intended purpose, Articles 62 to 81 shall apply.”

This means that a classic clinical investigation in accordance with Article 62ff of the MDR must also be carried out in this case.

Furthermore, Chapter 4 of the MPDG, specifically Sections 1 and 2, and in the latter, Subsection 1, apply with regard to application, approval, and the respective deadlines. See also the blog post in the Christmas Special, Part 1 .

Application for authorization of a clinical trial pursuant to Article 70(7) of the MDR:

Abbreviated procedure paragraph 7a

For medical devices without CE marking and for CE-marked products when the clinical investigation is carried out outside the intended purpose (Class I and IIa non-invasive)

The application must include the documents from Annex XV Chapter II of the MDR as well as the positive opinion of the EC.

Full application procedure paragraph 7b

For medical devices without CE marking and for CE-marked products when the clinical investigation is carried out outside the intended purpose (Class IIa invasive, IIb* and III)

The application must include the documents from Annex XV Chapter II of the MDR as well as the positive opinion of the EC.

* Exception in Germany, normally the abbreviated procedure also applies to products of class IIb, only in Germany does the full application procedure apply here.

3. What we can do for you

We will first help you find the right data collection method within the framework of PMCF. If a PMCF study is to be conducted, we will work with you to find the right way to implement it.

4. How we can help you

At medXteam we clarify whether and if so which clinical trial needs to be carried out under what conditions and according to what requirements during the pre-study phase: In 3 steps we determine the correct and cost-effective strategy in relation to the clinical trial required in your case Data collection.

Do you already have some initial questions?

You can get a free initial consultation here: free initial consultation