The clinical trial types blog series will be interrupted by our “Christmas Special” in December. We would like to inform you comprehensively about the important changes to clinical trials due to the MDR this year so that you are prepared for 2021.

The special thing about our campaign is that the contribution grows until Christmas. New sections are added every week. The topic of DiGA studies will continue in January.

The first part of our December special gave you a guide to the application process for clinical trials as part of the conformity assessment procedure with the higher federal authority and the ethics committees. The second part dealt with the application process for clinical trials with CE-marked products. Today's third part is about the application process for other clinical trials.

Abbreviations.

BOB (higher federal authority)

EK (Ethics Commission)

KP (clinical examination)

MDR (medical device regulation; Regulation 2017/745)

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).

Part 3: Application procedure - approval process for other clinical trials - Article 82 MDR

1 Introduction

Currently and until the MDR comes into effect on May 21, 2021, the topic of “other clinical trials” is not regulated. And this despite the fact that basic research has not only existed since EU Regulation 2017/745 (Medical Device Regulation, MDR) in 2017. But clinical trials in the context of basic human research that are not carried out to assess clinical performance, safety and benefit often led to uncertainty among the respective ethics committees and to some projects that could not be implemented.

All of this is changing with the MDR: 

The MDR now regulates this in Article 82 with the so-called “other clinical investigations”, whose implementation at the national level in Germany via the MPEUAnpG (Medical Devices EU Adaptation Act) in Chapter 4, Subsection 2 , § 47 to § 61 is detailed. This also includes the application and approval procedures for this type of clinical trial, which can be carried out with a product in development, with a prototype or with CE-marked products. This depends on when the scientific or other question needs to be answered.

2. Approval process for other clinical trials with medical devices (Article 82 MDR and MPEUAnpG § 47-53)

2.1 Definition: Section 3 Sentence 4 of the MPEUAnpG

An “other clinical trial” of a product is a clinical trial that

a) is not part of a systematic and planned product development process or product observation of a current or future manufacturer,

b) is not carried out with the aim of demonstrating the conformity of a product with the requirements of Regulation (EU) 2017/745,

c) serves to answer scientific or other questions and

d) takes place outside of a clinical development plan in accordance with Annex XIV Part A Number 1 Letter a of Regulation (EU) 2017/745.

“Other clinical trials” are therefore NOT used to demonstrate performance, safety and benefits in accordance with Article 62 Section 1 MDR. They are therefore not to be equated with clinical trials as part of the conformity assessment procedure (Article 62 Para. 1 of the MDR) or with clinical trials in relation to products that bear the CE marking (Article 74 of the MDR) and thus PMCF studies!

In principle, however, it also applies to “other clinical trials” that the test product must meet the basic safety and performance requirements and be safe (Section 62 Paragraph 4, Letter l).

The “other KP” must comply with Section 62 MDR paragraphs 2, 3 and 4 letters b, c, d, f, h and l and paragraph 6.

Who will check this now?

2.2 Which applications must be submitted?

In order to check whether products/prototypes with which the other clinical trial is to be carried out are safe and meet the above requirements, the following must be observed:

• The requirements for other KP are regulated in Sections 47ff MPEUAnpG and described in the corresponding blog post from November (Other clinical trials with medical devices).
• Here too, an approving EC statement is required (= EC vote).
• According to Section 53 of the MPEUAnpG, a report to BfArM is now also required:

“According to Section 47 Paragraph 2 Number 2, any other clinical trial must be reported by the sponsor to the responsible higher federal authority via the German Medical Device Information and Database System in accordance with Section 86.”

• Changes must also be reported (Section 54 MPEUAnpG).

The deadlines for the EC statement are the same as for clinical trials according to Article 62 Para. 1 of the MDR (Part 1 of the Christmas special).

Informed regarding the report to BfArM

the Federal Institute for Drugs and Medical Devices [...] via an automated process, the authority responsible for the sponsor's registered office or the registered office of its legal representative and the authorities responsible for the testing centers via a notification.

So there is only information, but no assessment/approval etc. takes place.

Subsection 2 - Title 1 - Section 47 Paragraph 3 of the MPEUAnpG defines the procedure for other clinical trials with products that already bear the CE marking in accordance with Article 20 Paragraph 1 of Regulation (EU) 2017/745, insofar as the other clinical trial is carried out within the scope of the intended purpose covered by the CE marking and the test subjects are not subjected to any additional invasive or stressful procedures beyond the normal conditions of use of the product.

• In this case, no opinion from the ethics committee is required.
• A report to the higher federal authority does not have to be made either.

2.3 What does this mean?

For other clinical trials with prototypes, medical devices in development (without the CE mark) or with their components, a statement from the EC is required as with an approval study (see part 1 of the Christmas special). This means that once the MDR is valid, an EC vote is definitely required for other clinical trials. (Article 62 paragraph 4 sentence b) This other clinical trial must be reported to BfArM (Section 47 MPEUAnpG).

For CE-marked products, neither an EC vote nor a notification to BfArM is required for other clinical tests to answer scientific or other questions.

But be careful : If additional invasive or stressful procedures are used as part of the other clinical trial or if the medical device is used outside of its intended purpose, the sponsor must report the other clinical trial to BfArM and obtain a statement from the EC.

2.4 What effects does this have?

The EC vote required for other clinical trials with non-CE-marked medical devices means a full examination of the qualifications of the main investigator and examiner: The MDR itself says nothing about this; these requirements arise from the national regulations in Section 30 of the MPEUAnpG:

those who can demonstrate at least two years of experience in the clinical testing of medical devices can be appointed as head of a clinical trial or other clinical trial .

(5) Proof of the required qualifications must be provided through a current CV and other meaningful documents.

This means that two years of experience with medical device studies is also required as a qualification requirement for other clinical trials that require an EC vote. This therefore also represents a major hurdle for these clinical trials from May 2021.

3. Outlook

That was part 3 of our “ Christmas Special ” and this week there will be another article on safety reporting in clinical trials, which is regulated in detail in the guidance document MDCG 2020-10/1. We will once again provide you with comprehensive information about the important changes to clinical trials brought about by the MDR this year so that you are prepared for 2021.

The special thing about this campaign is that the contribution will continue to grow with part 4 this week until Christmas.

DiGA studies will continue in January.

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 

The clinical trial types blog series will be interrupted by our “Christmas Special” in December. We would like to inform you comprehensively about the important changes to clinical trials due to the MDR this year so that you are prepared for 2021.

The special thing about our campaign is that the contribution grows until Christmas. New sections are added every week. The topic of DiGA studies will continue in January.

The first part of our December special gave you a guide to the application process for clinical trials as part of the conformity assessment procedure with the higher federal authority and the ethics committees. The second part dealt with the application process for clinical trials with CE-marked products. The third part focused on the application process for other clinical trials. We will now conclude the Christmas special today with the topic of safety reporting in clinical trials , which is also explicitly regulated in the MDCG document 2020-10/1.

Abbreviations.

BOB (higher federal authority)

EK (Ethics Commission)

KP (clinical examination)

MDR (medical device regulation; Regulation 2017/745)

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).

Part 4: Safety reporting in clinical trials - Article 82 MDR

1. Definitions

During clinical trials, undesirable or even serious adverse events can occur at any time, the latter of which must be reported to the authorities. The MDR defines an adverse event as  

... an adverse medical event, unanticipated illness or injury, or adverse clinical symptoms, including abnormal laboratory findings, in subjects, users, or other persons in a clinical trial, even if unrelated to the investigational device. 

A serious adverse event is defined as follows:

“Serious adverse event” means an adverse event that resulted in any of the following:

a) death,

b) serious deterioration in the subject's health, which in turn resulted in any of the following consequences:

1. life-threatening illness or injury,
2. permanent physical damage or permanent impairment of a bodily function,
3. inpatient treatment or extension of the patient's inpatient treatment,
4. medical or surgical intervention to prevent a life-threatening illness or injury or permanent physical damage or permanent impairment of a bodily function,
5. chronic disease,

c) Fetal endangerment, fetal death or congenital physical or mental impairment or birth defect. 

In clinical trials, further “events” are now defined:

“Product defect” means an inadequacy in the identification, quality, durability, reliability, safety or performance of a test product, including malfunction, application error or inadequacy of information provided by the manufacturer.

The MDCG document also defines these three events in Chapter 3.

Adverse events are abbreviated “UE”. In English these are “Averse events”, the abbreviation for this is “AE”.

Serious adverse events are abbreviated “SAE”. In English we speak of “serious adverse events”, which are abbreviated as “SAE”.

2. What events need to be reported?

2.1 Clinical trials according to Article 62 of the MDR

First of all, all events in clinical trials must be documented. These include:

• all adverse events
• any serious adverse events
• any product defects that could have resulted in serious adverse events
• as well as any new information about the product in relation to the event that occurred 

Which events must now be reported can be seen from Article 80 of the MDR and the MDCG document:

The sponsor shall immediately report, via the electronic system referred to in Article 73, to all Member States in which the clinical trial is being conducted:

a) any serious adverse event that has a causal relationship with the investigational device, the comparator or the test method or for which a causal relationship appears to be entirely possible,

b) any product defect that could have resulted in serious adverse events in the absence of appropriate measures or intervention or under less favorable circumstances,

c) any new information relating to an event referred to in points (a) and (b). 

Reportable events must be reported by the sponsor of the clinical trial, which may be the manufacturer, the legal representative or another person6 or entity.

Reportable events must be reported at the same time to all authorities where the clinical trial was initiated. For this purpose, a list must be made in the table specified in the MDCG document.

The deadlines for reporting are defined in particular in MDCG-2020/1 in Chapter 8. The sponsor reports every reportable event to the authorities in whose jurisdiction the clinical trial is being carried out (including in other EU countries and in third countries),

• any reportable event that indicates an imminent threat of death, serious injury or serious illness and requires immediate remedial action for other patients/subjects, users or other persons or new knowledge thereof: immediately, but not later than 2 calendar days after the sponsor has become aware of a new reportable event or of new information in connection with an already reported event . This includes significant and unexpected events that may pose a potential threat to public health. Also included is the possibility of multiple deaths occurring at short intervals.
• Any other reportable event or a new finding/update thereto: immediately, but no later than 7 calendar days after the date on which the sponsor became aware of the new reportable event or of new information relating to an already reported event .

In order for the sponsor to be able to comply with the deadlines, the sponsor must ensure that the reportable events can be reported by the investigator to the sponsor immediately, but not later than 3 calendar days after the testing staff of the testing center became aware of the event. An appropriate system must be set up for this purpose.

2.2 Clinical trials according to Article 74 of the MDR

In accordance with Article 80 Section 5 of the MDR, the vigilance provisions of Articles 87 to 90 and the legal acts adopted pursuant to Article 91 apply to post-marketing clinical trials (PMCF studies).

A distinction is made here between the following “events”:

According to the MDR, an “incident” means

... a malfunction or deterioration in the characteristics or performance of a product already made available on the market, including errors in use due to ergonomic features, as well as an inadequacy of the information provided by the manufacturer or an undesirable side effect.

A

… “serious incident” means an event that has had, could have had or might have had, directly or indirectly, any of the following consequences: a) the death of a patient, user or other person, b) the temporary or permanent serious deterioration of the health status of a person patient, user or other persons, c) a serious threat to public health.

According to Article 87 Section 1 of the MDR

… any serious incident related to devices made available on the Union market, other than expected adverse reactions, which are clearly documented in the product information, quantified in the technical documentation and subject to trend reporting in accordance with Article 88 of the MDR,

Report to.

However, for those serious adverse events where a causal link has been established between the serious adverse event and the previous investigational procedure, the reporting procedures for clinical trials in accordance with Article 80 of the MDR apply.

The MDCG document therefore defines reportable events in clinical trials under the PMCF as those serious adverse events for which a causal relationship has been established between the serious adverse event and the previous investigational procedure.

According to Article 87 of the MDR

… the time limit within which the notification referred to in paragraph 1 of Article 87 must be made depends on the seriousness of the serious incident.

Section 3 of Article 87 states:

Manufacturers shall report any serious incident referred to in point (a) of paragraph 1 immediately after establishing a causal relationship or a reasonable possibility of a causal relationship between the incident and their product, but no later than 15 days after becoming aware of the incident.

Section 4:

Notwithstanding paragraph 3, in the event of a serious threat to public health, the notification referred to in paragraph 1 shall be made without delay, but no later than two days after the manufacturer becomes aware of that threat.

Section 5:

Notwithstanding paragraph 3, in the event of death or an unforeseen serious deterioration in the health of a person, the notification shall be made immediately after the manufacturer has established a causal link between the product and the serious incident or as soon as it suspects such a link, but no later than ten days after he became aware of the serious incident.

3. Causality

The relationship between the use of the medical device (including the medical-surgical procedure) and the occurrence of each adverse event must be assessed and categorized.
The assessment of causality is based on the investigator's clinical judgment.
The relevant documents, such as: For example, the Investigator's Brochure (IB), the clinical trial plan or the risk analysis and risk management report should be consulted. All foreseeable serious adverse events and potential risks are listed there and have been assessed accordingly. The presence of disruptive factors such as B. Concomitant medication/treatment, the natural history of the underlying disease, other concurrent medical conditions or risk factors should also be considered. The above considerations also apply to the serious adverse events occurring in the control group.
Each serious adverse event is classified according to four different levels of causality:

1. No connection
2. Possible connection
3. Probable connection
4. Causal connection

The following definitions apply to assess the relationship of the serious adverse event to the investigational product, control product or investigational procedure:

a. No context:

A connection with the product, the control product or the test procedure can be excluded if:

• the event has no temporal connection with the use of the investigational product or the procedures associated with the use of the investigational product, the investigational product is related,
• the serious adverse event does not follow a known reaction pattern to the medical device (if the reaction pattern was previously known) and is biologically implausible,
• Stopping use of the medical device or reducing the level of activation/exposure - if clinically feasible -
  and reintroducing use (or increasing the level of activation/exposure) do not affect the serious adverse event,
• the event relates to a part of the body or an organ that cannot be influenced by the product or procedure,
• the serious adverse event can be attributed to another cause (e.g. an underlying or concurrent disease/clinical condition, an effect of another product, drug, treatment or other risk factors),
• the event does not depend - if applicable - on an incorrect result of the test product used for diagnosis.

Determining non-relationship may not require all of the criteria listed above to be met simultaneously, depending on the type of device/procedure and the serious adverse event.

b. Possible connection:

The connection with the use of the test product or the control product or the connection with the procedures is weak, but cannot
be completely excluded. Alternative causes are also possible (e.g., an underlying or concurrent disease/clinical condition and/or an effect of another product, drug or treatment). Cases in which the connection cannot be assessed or no information is available should also be considered possible.

c. Likely connection:

The connection with the use of the investigational product or the control product or the connection with procedures appears relevant and/or the event cannot be reasonably explained by another cause.

d. Causal relationship:

The serious adverse event is clearly related to the investigational product, control product or procedures if:

• the event is a known adverse reaction to the product category of the investigational device or similar products and procedures,
• the event is temporally related to the use/application of the investigational product or the procedures,
• the event affects a part of the body or an organ,

          o on which the test product or the procedures are used

          o on which the test product or the procedures have/have an effect

• the serious adverse event follows a known reaction pattern to the medical device (if the reaction pattern is already known),
• interrupting the use of the medical device (or reducing the level of activation/exposure) and reintroducing its use
  (or increasing the level of activation/exposure) has an impact on the serious adverse event (if clinically possible),
• other possible causes (e.g. an underlying or concurrent disease/clinical condition and/or an effect of another product, drug or treatment) have been reasonably excluded,
• the damage to the study participant is due to an application error,
• the event depends on an incorrect result of the test product used for diagnosis.

To establish the association, all of the criteria listed above may not need to be met at the same time, depending on the type of device/procedure and the serious adverse event.

4. Outlook

That was part 4 of our “ Christmas Special ” and at the same time the conclusion of the divided blog post on changes caused by the MDR. We will once again provide you with comprehensive information about the important changes to clinical trials brought about by the MDR this year so that you are prepared for 2021.

If you have any questions about this, please feel free to get in touch. As always, our free initial consultation available. Now medXteam says goodbye to the Christmas break and wishes all readers a peaceful, contemplative Christmas. Have a healthy new year!

DiGA studies will continue in January.

5. 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 

The clinical trial types blog series will be interrupted by our “Christmas Special” in December. We would like to inform you comprehensively about the important changes to clinical trials due to the MDR this year so that you are prepared for 2021.

The special thing about our campaign is that the contribution grows until Christmas. New sections are added every week. The topic of DiGA studies will continue in January.

The first part of our December special gave you a guide to the application process for clinical trials as part of the conformity assessment procedure with the higher federal authority and the ethics committees. Today's second part deals with the application process for clinical trials with CE-marked products.

Abbreviations.

BOB (higher federal authority)

EK (Ethics Commission)

KP (clinical examination)

MDR (medical device regulation; Regulation 2017/745)

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).

Part 2: Application procedure - approval process for clinical trials with CE-marked products - Article 74 MDR

1 Introduction

Currently and until the MDR is valid from May 21, 2021, Sections 20 ff MPG currently apply to the approval of clinical trials for clinical trials carried out in Germany. For clinical trials with CE-marked products, the “exception” to clinical trials according to Section 20 MPG can be found in Section 23b MPG. This covers the so-called PMCF studies. The MEDDEV Guideline for Post-Market Clinical Follow-up Studies (MEDDEV 2.12/2 Rev. 2), which is subordinate to the MPG, also applies to this. This means that only an application for professional advice must be submitted to the ethics committee responsible for the test center and the examiner in accordance with Section 15 BO (professional regulations for doctors) and the ethics committee (EK) does not give a vote. However, this only applies if the product is used within the scope of this clinical trial for its intended purpose and/or no additional stressful examinations are carried out. If this is the case, Section 20 MPG applies again. The following two figures also show this:

Figure 1: Previous approval process before CE marking (changes due to the MDR article)

Figure 2: Previous approval process after CE marking (changes due to the MDR article)

All of this is now changing with the MDR, as the approval process and the national procedure for the ECs are described and defined in the associated MPDG. The corresponding articles from the MDR are already listed in both figures above. For example, this disappears B. Section 23b MPG completely. This is one of the biggest changes and effects of the MDR, as professional legal advice from the ethics committee is now no longer required. What needs to be taken into account here from May 2021 is now described below.

2. Approval process for clinical trials with CE marked products - Article 74 MDR

For the so-called “PMCF studies” (post-market follow-up = clinical follow-up after the product has been placed on the market), a distinction is made as to whether the test product is used within its intended purpose or not. So far, the above-mentioned § 23b MPG and § 7 of the MPKPV have been applied here. Neither was included in the MPAnpG (only the national application process at the EC is regulated here), but is covered in the MDR:

2.1 The medical product with the CE mark is used within the scope of its intended purpose

The following articles of the MDR apply:

• Article 74 paragraph 1 and
• then the rules of §  62 paragraph 4, letters b to k and m apply,
• Articles 75 to 77 Article 80 paragraph 5 (vigilance) as well
• the provisions of Annex XV of the MDR and here the required documents from Chapter II

What does that mean?

A statement is required from the EC as in an approval study (see part 1 of the Christmas special). This means that once the MDR is valid, an EC vote is also required for PMCF studies. (Article 62 paragraph 4 sentence b)

An application to the BOB still does not have to be submitted under these conditions.

Attention : If additional invasive or stressful procedures are used as part of the PCMF study, the sponsor must inform the BOB at least 30 days before the start of the clinical trial and submit the documents in accordance with Annex XV Chapter II. Until now, this was regulated by Section 23b MPG in conjunction with Section 7 of the MPKPV and BfArM only carried out a less extensive review, particularly with regard to the security aspects of the additional onerous investigation.

As above, an EC vote is required here, but the documents must also be submitted to BfArM via EUDAMED

What does that mean?

As above, a vote from the EC is still required and, in addition, an application must now also be submitted to BfArM via EUDAMED.

In this regard, the application deadlines are the same as for clinical trials as part of the conformity assessment procedure (see Part 1).

What impact does this have?

The change to the EC vote in PMCF studies means a full examination of the qualifications of the main examiner and examiner: The MDR says in Article 62 paragraph 4 sentence j:

the responsibility for the medical care of the subjects shall be a doctor with appropriate qualifications or, where appropriate, a qualified dentist or any other person authorized by national law to provide appropriate patient care in the context of a clinical trial...

And this is detailed nationally in Section 30 of the MPAnpG:

those who can demonstrate at least two years of experience in the clinical testing of medical devices can be appointed as head of a clinical trial or other clinical trial .

(5) Proof of the required qualifications must be provided through a current CV and other meaningful documents.

This means that in the future, two years of experience with medical device studies will also be required as a qualification requirement for PMCF studies. Since this was not required as part of the EC's professional legal advice in accordance with Section 23b MPG and Section 15 BO, this will also represent a major hurdle for the implementation of PMCF studies from May 2021.

2.2 The medical product with the CE mark is used outside of its intended purpose

If the CE-marked product is used outside of its intended purpose as part of the study (e.g. to collect clinical data for a new indication), Articles 62 to 81 also apply as in the case of a registration study. Until now, this was also regulated via Section 23b MPG in conjunction with Section 7 of the MPKPV and BfArM only carried out a less extensive review, particularly with regard to the security aspects of the extended intended purpose. This is now changing as part of the MDR and therefore applies :

• Articles 62 to 81, i.e. as in a registration study (part 1 of the Christmas special)
• Appendix XV and here documents from Chapter II

A statement is required from the EC as in an approval study (see part 1 of the Christmas special). In addition, as with approval studies, an application must be submitted to BfArM (via EUDAMED).

The application deadlines here are also the same as for clinical trials as part of the conformity assessment procedure (see Part 1).

3. Outlook

That was part 2 of our “ Christmas Special ” and next week we will continue with the approval process for other clinical trials. We will once again provide you with comprehensive information about the important changes to clinical trials brought about by the MDR this year so that you are prepared for 2021.

The special thing about our campaign is that the contribution grows until Christmas. New sections with further changes are added every week.

DiGA studies will continue in January.

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 

The clinical trial types blog series will be interrupted by our “Christmas Special” in December. We would like to inform you comprehensively about the important changes to clinical trials due to the MDR this year so that you are prepared for 2021.

The special thing about our campaign is that the contribution grows until Christmas. New sections are added every week. The topic of DiGA studies will continue in January.

The first part of our December special gives you a guide to the application procedures for various types of applications to the higher federal authority and the ethics committees:

Abbreviations.

BOB (higher federal authority)

EK (Ethics Commission)

KP (clinical examination)

MDR (medical device regulation; Regulation 2017/745)

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).

Part 1: Application procedure - Approval process for clinical trials as part of the conformity procedure (approval studies) - Article 62 paragraph 1 MDR

1 Introduction

Currently and until the MDR is valid from May 21, 2021, Sections 20 ff MPG currently apply to the approval of clinical trials for clinical trials carried out in Germany. For clinical trials with CE-marked products, the “exception” to clinical trials according to Section 20 MPG can be found in Section 23b MPG. This covers the so-called PMCF studies. The MEDDEV Guideline for Post-Market Clinical Follow-up Studies (MEDDEV 2.12/2 Rev. 2), which is subordinate to the MPG, also applies to this. This means that only an application for professional advice must be submitted to the ethics committee responsible for the test center and the examiner in accordance with Section 15 BO (professional regulations for doctors) and the ethics committee (EK) does not give a vote. However, this only applies if the product is used within the scope of this clinical trial for its intended purpose and/or no additional stressful examinations are carried out. If this is the case, Section 20 MPG applies again.  

All of this is now changing with the MDR, as the approval process and the national procedure for the ECs are described and defined in the associated MPDG.

2. Approval process for clinical trials as part of the conformity procedure (approval studies) - Article 62 paragraph 1 MDR

2.1 Application to the ethics committee according to § 33 MPDG via DIMDI (now BfArM)

Submission of documents from Annex XV Chapter II of the MDR

plus

• a German synopsis (short summary of the clinical trial)
• German documents for the exam participants: 
  • The documents for the test participants (test subjects, patients) must be written in German (§ 38 MPDG).

Application deadlines: (§ 36 MPDG)

The EC checks whether the application is correct and confirms it within 10 days.

In the event of defects, the sponsor has 10 days to correct them. The EC prepares its statement (vote) on the application. In the case of multicenter clinical trials, the statements of the other participating ECs are made within 20 days: " If the clinical trial is to be carried out in more than one testing center, the responsible ethics committee evaluates the application in consultation with the
ethics committees responsible for the ethics committees under state law Investigators or main investigators are responsible (ethics committees involved). The ethics committees involved check the qualifications of the examiners and the suitability of the testing bodies in their area of ​​responsibility.
The opinions of the ethics committees involved must be submitted to the responsible ethics committee within 20 days of receipt of the proper application are defects, the sponsor has 45 days to rectify them.

The EC “ sends its opinion to the sponsor within 30 days of receipt of the proper application .” This period is extended by 15 to 45 days if EK seeks advice from experts.

The EC examines: (§ 34 and § 35 MPDG)

• Is the application correct?
• The test plan and the required documents are discussed and checked, particularly from an ethical and legal perspective.
• In addition, the EC is obliged to give a clear vote (approval or rejection § 37 MPDG).

2.2 Application for approval of a clinical trial from the BOB in accordance with Article 70 MDR via EUDAMED

Documents to be submitted:

• Documents from Annex XV Chapter II, German or English.
• Statement by the EC (Section 37 MDG)

This means that the order in which the application for a clinical trial is submitted is now determined by the MDR: If the application was previously possible in parallel with BOB and EK, according to the MDR, the vote of the EK must first be obtained in accordance with national requirements. This positive vote must then be submitted to the BOB together with the other documents for the clinical trial. From now on, this procedure is subordinate to that of the ethics committee.

Application deadlines:

The BOB checks whether the application is complete and confirms it (within 10 days).

• If the application is incomplete: The sponsor has 10 days to resolve the additional requests from the authority.
• An extension of a maximum of 20 days is possible.

The BOB confirms the completeness within 5 days (can be extended for another 5 days): Date of validation of the application

• Checked by BOB
  • additional documents may be requested, the deadline is suspended for this period

A. Procedures for Class I and Non-Invasive Class IIa Devices

If the BOB has not objected within 10 days, the sponsor can begin the KP.

This procedure will now replace the procedure according to Section 7 MPKPV, which currently requires an application to the BOB for exemption from the approval requirement via DIMDI (BfArM) for Class I products and non-invasive Class II products. This is a shortened and simplified procedure for low-classified products.

B. Procedures for Class IIa (invasive), IIb and Class III devices

Once the BOB has informed the sponsor, he can begin the clinical trial.

• The BOB deadline for this is 45 days after the validation date.
• These 45 days will be extended by a further 20 to 65 days if the BOB seeks advice from experts.

The BOB checks:

The test plan and the submitted documents are checked in accordance with Article 71 Paragraphs 1-3 of the MDR.

3. Outlook

Our “ Christmas Special ” has just begun and will focus next week on changes to the approval process for PMCF studies. What happens to Section 23b MPG? We will once again provide you with comprehensive information about the important changes to clinical trials brought about by the MDR this year so that you are prepared for 2021.

The special thing about our campaign is that the contribution grows until Christmas. New sections with further changes are added every week.

DiGA studies will continue in January.

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