PMCF studies and Article 74 of the MDR

As part of our Christmas special, we wrote in Part 2 about the application procedure and the approval process for clinical trials with CE-marked products and assumed that this and Article 74 apply to all PMCF studies with medical devices that have already been placed on the market. The virtual event by BfArM together with the Federal Ministry of Health and the working group of ethics committees shed light on this article as part of a virtual event as far as the regulation is concerned, at least in Germany.

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 regulations for doctors)

Underlying regulations

EU Regulation 2017/745 (MDR)

MPEUAnpG (the Medical Devices EU Adaptation Act was passed as law by the Bundestag on May 25, 2020. This MPAnpG-EU describes the Medical Devices Implementation Act (MPDG) in Article 1)

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 entry into force was scheduled for May 26, 2020. Due to Corona, this start of application and that of the Medical Devices Law Implementation Act (MPDG) was postponed to May 26, 2021. As is well known, this means that many legal requirements and practical framework conditions for the approval and conduct of clinical trials of medical devices are changing. The BfArM provided information about this on May 5, 2021 together with the Federal Ministry of Health and the working group of the ethics committees as part of a virtual event.

Assuming that Article 74 of the MDR :

“Clinical trials relating to products bearing the CE marking

If a clinical trial is carried out to further evaluate a device which already bears the CE marking in accordance with Article 20(1) within the scope of its intended purpose (hereinafter “post-market clinical trial”) and would be subjects within the framework of that trial subject to additional procedures to those carried out under normal conditions of use of the device, and if those additional procedures are invasive or burdensome, the sponsor shall inform the Member States concerned via the electronic system referred to in Article 73 at least 30 days before the start of the test. The sponsor shall submit the documents set out in Chapter II of Annex XV as part of the notification. For post-marketing clinical trials 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 apply.
If a clinical trial designed to evaluate a device which already bears the CE marking in accordance with Article 20(1) is carried out outside its intended purpose, Articles 62 to 81 shall apply."

applies to all medical devices that bear the CE mark, the majority assumed that from May 26, 2021 an ethics vote is required for PMCF studies and that there is no longer any professional advice according to Section 15 of the Professional Code for Doctors (BO). This is not the case now.

2. Different types of PMCF studies

2.1 Definition of PMCF studies

There is no actual definition of the PMCF studies. Neither in the directive, MPG or in one of the regulations or MEDDEVs, nor in the MDR or MPDG. The MDR only says in Article 74 that such a clinical trial is called post-market clinical

"If a clinical trial is carried out to further evaluate a device which already bears the CE marking in accordance with Article 20(1) within the scope of its intended purpose (hereinafter 'post-market clinical trial') [...]."

A PMCF study is a clinical trial that is carried out on the CE-marked product and provides clinical data on the product as part of the post-market clinical follow-up (PMCF). Clinical follow-up is regulated in the MDR in Annex XIV Part B.

The clinical follow-up does not only include PMCF studies, but also other possible activities to collect clinical data on the product. An example is real-world data, which was described in the last blog post. Or register data and other activities. The following figure provides an overview of this and of the entire market surveillance (post-market surveillance) according to MDR according to Articles 83 - 85:

Figure 1. General methods and procedures 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 the intended purpose and without burdensome examinations

Previous regulation:

To date, these PMCF studies have been regulated in accordance with Section 23b MPG :

“§ 23b Exceptions to clinical trials

§§ 20 to 23a do not apply if a clinical test is carried out with medical devices that may bear the CE marking in accordance with §§ 6 and 10, unless this test has a different purpose for the medical device or it Additional invasive or other stressful examinations are carried out.”

Such a study previously fell under the category of other studies and was carried out outside the MPG. On the website of the Ethics Committee of the Bavarian State Medical Association, for example: E.g. like this:

Figure 2: Types of EC studies at BLÄK

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

Figure 3: Free application for such a study at LÄK BW

For PMCF studies within the intended purpose of the medical device, professional advice was required in accordance with Section 15 of the Professional Code for Doctors. To date, an application has been sent directly to the Ethics Committee. Some ethics committees required multiple paper copies and one copy as a CD-ROM. Others (e.g. Hesse, Bavaria) have a portal through which applications can be uploaded electronically. Then all that is required is a simple paper copy.

For these studies, in addition to certain study documents (test plan, patient information and consent form, questionnaires, etc.), the examiner's CV must be submitted. A qualification proven by the examiner having at least two years of experience in clinical trials with medical devices, as required for an ethics vote, is not checked here.

Regulation from the MDR’s entry into force

So far our acceptance and interpretation of Article 74 of the MDR has been; that this includes all PMCF studies and therefore an ethics vote would be required from May 26, 2021.

At the above-mentioned event, Article 74 for Germany was interpreted as follows:

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

This means that the procedure described above for other studies and free applications (professional legal advice in accordance with Section 15 BO) still applies!

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

Article 74 of the MDR thus separates the PMCF studies within the intended purpose and continues to view them as an exception to clinical trials, as in the MPG.

So nothing changes here except for designations in the test plan for MPG and, if applicable, Directive 92/43/EEC (change in MDR, as it is no longer valid). The process remains the same and manufacturers continue to have the opportunity to collect their clinical data as part of the PMCF study in a more straightforward manner.

2.3 PMCF studies with stressful examinations

Previous regulation:

To date, these PMCF studies have also been regulated in accordance with Section 23b MPG :

“§ 23b Exceptions to clinical trials

§§ 20 to 23a do not apply if a clinical test is carried out with medical devices that may bear the CE marking in accordance with §§ 6 and 10, unless this test has a different purpose for the medical device or it Additional invasive or other stressful examinations are carried out .”

In the case of additional incriminating investigations, Sections 20ff of the MPG and in this case in conjunction with Section 7 of the MPKPV with Section 1 Sentence 3 applied to such a study:

may bear the CE marking in accordance with Sections 6 and 10 of the Medical Devices Act , unless this testing has a different purpose for the medical device."

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

Regulation from the MDR’s entry into force

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

The sponsor informs the higher federal authority (BOB, in Germany: BfArM) about the MPI (in Germany) at least 30 days before the start of the examination.
Articles 62(4)(b) to (k) and (m), Articles 75, 76 and 77 and Article 80(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.

In addition, Chapter 4 with Sections 1 and 2 and in the latter with Subsection 1 apply in the MPDG with regard to the application, approval and respective deadlines. See also the blog post in the Christmas special part 2 .

2.4 PMCF studies outside of intended purpose

Previous regulation:

To date, these PMCF studies have also been regulated in accordance with Section 23b MPG :

“§ 23b Exceptions to clinical trials

§§ 20 to 23a do not apply if a clinical test is carried out with medical devices that may bear the CE marking in accordance with §§ 6 and 10, unless this test has a different purpose for the medical device or it Additional invasive or other stressful examinations are carried out.”

If the clinical trial with the CE-marked product previously referred to a new intended purpose (e.g. also to new indications), Section 20ff of the MPG also applied again to such a study. This means that a classic approval study was carried out in accordance with Sections 20ff of the MPG:

Application via the MPI to BfArM and EK

Regulation from the MDR’s entry into force

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

"(2) If a clinical trial designed to evaluate a device which already bears the CE marking in accordance with Article 20(1) is carried out outside its intended purpose, Articles 62 to 81 shall apply."

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

Application for approval of a clinical trial in accordance with Article 70 paragraph 7 of the MDR:

Shortened procedure paragraph 7a

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

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

Full application process paragraph 7b

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

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

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

3. What we can do for you

We initially support you in finding the right data collection method within the framework of the PMCF. If a PMCF study is to be carried out, 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

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