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:

life-threatening illness or injury,

permanent physical damage or permanent impairment of a bodily function,

inpatient treatment or extension of the patient's inpatient treatment,

medical or surgical intervention to prevent a life-threatening illness or injury or permanent physical damage or permanent impairment of a bodily function,

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.

… “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 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.

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

Do you already have some initial questions?

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

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

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

Do you already have some initial questions?

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

As described in the outlook of the first article in October, the medXteam GmbH blog series now addresses the first type of clinical trials with medical devices: basic research - other clinical trials (MDR Article 82).

Other clinical investigations with medical devices

1 Introduction

Basic research has not only existed since EU Regulation 2017/745 (Medical Device Regulation, MDR), on the contrary. In general, this is about examining feasibility and clarifying fundamental questions. The aim of basic research is therefore:

research into technical fundamentals
research into medical principles
integration into the development of new products

Such activities usually take place in the laboratory:

Figure 1: Feasibility research project

But there are always questions that can only be clarified through tests/studies on humans.

This case was not previously regulated in the MPG. There are only clinical tests with medical devices in accordance with Sections 20 ff.

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.

2. Clarification of terms “medical product” and “prototype”

A medical device is defined in Article 2 of the MDR as follows:

„“Medical device” means an instrument, apparatus, device, software, implant, reagent, material or other item which, according to the manufacturer, is intended for human use and which, alone or in combination, fulfills one or more of the following specific medical purposes should:

Diagnosis, prevention, monitoring, prediction, prognosis, treatment or alleviation of diseases,
Diagnosing, monitoring, treating, alleviating or compensating for injuries or disabilities,
Examination, replacement or modification of anatomy or a physiological or pathological process or condition,
Obtaining information through in vitro examination of the human body
also from organ, blood and tissue donations
from samples and whose intended main effect in or on the human body is not achieved by pharmacological or immunological means or metabolically, but whose mode of action can be supported by such means.“

Fundamental to the definition of a product as a medical device is its intended purpose. According to Article 2 Sentence 12 of the MDR, this is “ … the use for which a product is intended in accordance with the information provided by the manufacturer on the labeling, in the instructions for use or in the advertising or sales material or the advertising or sales information and its information in the clinical evaluation is determined…”

The intended purpose must be formulated as part of the technical documentation by the manufacturer and is decisive for whether a product is simply a product or a medical device. In order for a medical device to be declared as such, it must be able to fulfill its intended purpose under normal conditions of use and correspond to the definition mentioned above.

If the intended purpose of a product does not correspond to the above definition and does not relate to one of the points mentioned above, it is not a medical product. In this case, the MDR requirements for development and initial use do not apply.

What is a medical device and what is not?

Table 1: Distinction between medical device and product

A product referred to as a “prototype” or “demonstrator” is a medical technology product in a very early phase of development. This means that it is a first test version of a new device, procedure or concept that has never been clinically tested. Accordingly, there is no experience with regard to a medical benefit, usability in everyday clinical practice, or the application/use protocol and possible risks associated with the application ".

An initial study with such a prototype/demonstrator is intended to collect initial and basic experience. Furthermore, the feasibility of the new concept/process is to be demonstrated and options for possible development as a medical product are to be made possible. The knowledge and experience gained form the basis on which further development of the prototype/demonstrator into a medical product can take place. This development process according to MDR can then be characterized by numerous changes to the design, equipment, technical functions and configuration in order to achieve sufficient usability and clinical/technical performance. Only a product that meets the demands placed on it in terms of safety and clinical performance can ultimately be placed on the market.

3. Clinical testing on humans – determining the appropriate study type

3.1 Clinical trial to demonstrate the conformity of products (Article 62 MDR) or other clinical trial (Article 82 MDR)

In order to differentiate a clinical trial ( approval study ) according to Article 62 of the MDR from a feasibility study ( other clinical trial ), the objectives of the regulatory requirements within the framework of the MDR must first be presented:

„Based on a high level of health protection for patients and users, this Regulation aims to ensure a smoothly functioning internal market for medical devices, taking into account small and medium-sized enterprises operating in this sector. This regulation also sets high standards for the quality and safety of medical devices, which are intended to address general safety concerns regarding these devices .“

In this context, determining the safety and performance of a medical product plays a fundamental role as a prerequisite for placing it on the market. Placing on the market “ means the initial provision of a product, with the exception of investigational products, on the Union market …” (MDR Article 2, sentence 28). The only exception is the supply of the medical device for the purpose of a clinical trial.

In order for a medical device to be placed on the market, it must have a CE marking. The CE mark indicates that the medical device complies with the legal requirements (is compliant) and that safety and performance have been demonstrated in accordance with the intended purpose under everyday clinical conditions during the evaluation process. The proof is provided by the manufacturer himself and is referred to as the conformity assessment procedure. This involves a clinical assessment of clinical data, the latter being the safety and performance data of the product. In contrast to pharmaceutical law, this data can also be obtained from the literature. The prerequisite is that the relevant data for similar products is available and similarity with your own medical device can be proven. This approach is also known as the literary route.

If this is not possible, performance and safety data must be generated by the manufacturer itself as part of a clinical test - currently the MPG test (§ 20 MPG) or the clinical test to demonstrate the conformity of products (Article 62 MDR). An MPG study is carried out in accordance with the “Regulation for the conduct of clinical trials with medical devices” (MPKPV), which, according to Section 1 (1) of the regulation, is always to be applied when conducting clinical trials in accordance with the MPG, the results of which are used to carry out a conformity assessment procedure in accordance with Medical Devices Regulation (MPV) should be used. After the MDR comes into force, this regulation will be replaced by Regulation (EU) 2017/745 of the European Parliament and of the Council (MDR) and the MPG by the MPEUAnpG (Medical Devices EU Adaptation Act). Clinical trials (Article 62 MDR) and other clinical trials (Article 82 MDR) are then planned and carried out in accordance with the requirements of the MDR and the supplementary national provisions of the MPEUAnpG. In the MDR, too, the focus is on the performance and safety of the medical device during clinical testing in accordance with Article 62:

“Clinical trial” means a systematic investigation involving one or more human subjects and conducted to evaluate the safety or performance of a device.”

The aim of a research project and an associated clinical application should not be to assess the performance and safety of a product in accordance with the current MPG (in conjunction with MPKPV) and MDR as part of a conformity assessment procedure, but rather to assess the medical/technical basis Research that may later be incorporated into the development of new medical products (testing a prototype) does not constitute a “clinical test” within the meaning of the regulations. Although a precise distinction and demarcation is missing in both the MPG and the MDD, this is provided by the MDR, which has been published since May 2017, in Articles 62 and 82:

Article 62: General requirements for clinical trials carried out to demonstrate the conformity of devices

to determine and verify that a product is designed, manufactured and packaged in such a way that, under normal conditions of use, it is suitable for one or more of the specific purposes listed in Article 2(1) and provides the intended performance as declared ;
to determine and verify the clinical benefit of a product as claimed by its manufacturer;
to establish and verify the clinical safety of the device and to determine any undesirable side effects of the device that may occur under normal conditions of use and to assess whether these represent acceptable risks compared to the benefits provided by the device.

Table 2: Objectives and timing of clinical trials to demonstrate product conformity

Article 82: Requirements for other clinical trials (basic research, in-vivo feasibility studies, ...)

Clinical trials which are not carried out for any of the purposes referred to in Article 62(1) shall comply with the provisions of Article 62(2) and (3), (4)(b), (c), (d), (f), (h) and (l) and paragraph 6.
In order to protect the rights, safety, dignity and well-being of subjects and to ensure compliance with scientific and ethical principles in clinical trials not carried out for any of the purposes referred to in Article 62(1), each Member State concerned shall: determine appropriate additional requirements for these tests.

And the MPEUAnpG, which comes into force with the MDR, also provides a definition for other clinical trials under Section 3 Sentence 4 Definitions:

"[...] a clinical trial that

not part of a systematic and planned product development process or product observation of a current or future manufacturer,
carried out with the aim of proving the conformity of a product with the requirements of Regulation (EU) 2017/745,
serves to answer scientific or other questions and
takes place outside of a clinical development plan in accordance with Annex XIV Part A Number 1 Letter a of Regulation (EU) 2017/745."

Table 3: Other clinical trials

The appropriate study format therefore clearly results from the objective of the clinical trial and the development status of the product to be used.

Therefore, if safety and performance data are to be collected that are used to assess the conformity of an existing prototype (ie the product must also be in an appropriately mature state), the MPG/MDR legal framework applies and a clinical trial must be carried out in accordance with MPKPV/MDR Article 62 are carried out.

On the other hand, if the product is still in an early research stage as a pre-prototype and first of all requires proof of the functionality and usefulness of the underlying concept, initial evidence of the effectiveness of the new process and the feasibility of a subsequent clinical intervention study should therefore be provided is not an MPG study (MDR Article 62), and clinical application does not take place in accordance with the MPKPV. The relevant requirements are described in the following chapter “Conducting a feasibility study”.

Other clinical trials are regulated in Article 82 of the MDR and in Chapter 4, Subsection 2, § 47 to § 61 of the MPEUAnpG (Medical Devices EU Adaptation Act).

3.2 Timing of another clinical trial

Another clinical test is always carried out when it is not intended to evaluate the performance and safety of the medical device. Rather, the focus is on answering scientific or other questions and this can be the case at all times in the “product life cycle”, even before the actual product (i.e. prototype, demonstrator). It may therefore also be the case that “ the other clinical trial is carried out within the scope of the intended purpose covered by the CE marking ” and therefore, it would be about performance/safety and/or benefit in relation to a PMCF study or clinical trial on products that bear the CE marking would be in accordance with Article 74 of the MDR.

3.3 Conducting a feasibility study

The other clinical examination is part of the collection of experience through various procedures for the additional acquisition of knowledge and improvement of specific methods. At the very beginning of such developments, for example, there is an idea that must first be tested for its feasibility, which is usually done within animal models (in vivo studies). In one of these testing phases, initial improvements and adjustments to the original idea take place, which are then tested on animal models. The implementation phase of the idea can include several cycles. The transition to a feasibility study occurs when there is evidence that the idea contributes to improving medical care (Kohnen, 2011).

Figure 2: Gaining knowledge in the empirical science of medicine. (Kohnen, 2011)

The aim of such other clinical trials on humans is to provide initial evidence on the effectiveness of a procedure and to examine the feasibility of a possible subsequent clinical intervention study.

If such other clinical trials were not taken into account in the MPG, the MDR now provides a clear definition in Article 82 (see above) and gives clear requirements for this form of clinical trial:

The commissioning of a product is not a legal vacuum, but is subject to extensive safety tests (technical safety, electrical safety, biological safety and standard compliance tests), the so-called “basic requirements” (Appendix I MDD) or “basic safety and performance requirements” (Appendix I MDR) , which must be verified by independent third parties. In addition, a comprehensive risk analysis must be presented and an ethically justifiable benefit-risk balance must be present.

This also follows from Article 82 MDR with reference to Article 62 paragraph 4 letter l:

„(4) A clinical trial in accordance with paragraph 1 can only be carried out if all of the following conditions are met: […]

(l) the investigational device or devices concerned comply with the essential safety and performance requirements set out in Annex I, with the exception of the points covered by the clinical trial; With regard to these points, all precautionary measures have been taken to protect the health and safety of the test participants. This includes, where appropriate, technical and biological safety tests and a pre-clinical assessment as well as provisions in the area of workplace safety and accident prevention, taking into account the latest knowledge .“

Since the other clinical trials are research projects that are part of basic medical research on humans, the general legal regulations and guidelines within medical research also apply. This applies to all other clinical trials, regardless of when they are carried out. To protect patients, users and third parties, a wide variety of requirements must be taken into account. This includes the

Declaration of Helsinki in its current version.

This means that the ethical standards of medical research on humans are taken into account. Particular attention should be paid to the following points within the project:

Obtaining informed consent from patients
Protection of patients unable to consent
The well-being of the “test subject” is put before the interests of science
Obtaining a positive vote from the responsible ethics committee This was included in the MDR in Article 82 as follows:

„Clinical trials which are not carried out for one of the purposes referred to in Article 62(1) shall comply with the provisions of Article 62(2) and (3), (4)(b), (c), (d), (f), (h) and (l) and paragraph 6."

This means in particular:

Article 62 paragraph 3

„Clinical trials are designed and conducted in such a way that the protection of the rights, safety, dignity and well-being of the subjects taking part in the trial is guaranteed and takes precedence over all other interests and that the clinical data obtained are scientifically sound, reliable and sound.

Clinical trials are subject to scientific and ethical review. The ethical review is carried out by an ethics committee in accordance with national law. Member States shall ensure that the procedures for review by the ethics committees are compatible with the procedures laid down in this Regulation for the assessment of the application for authorization of a clinical trial. At least one layperson participates in the ethical review .“

Article 62 paragraph 4

„A clinical trial in accordance with paragraph 1 can only be carried out if all of the following conditions are met: […]

(b) an ethics committee established under national law has not issued a negative opinion with regard to the clinical trial, which is valid for the entire territory of the Member State concerned under the national law of the Member State concerned;

(c) the sponsor or its legal representative or a contact person referred to in paragraph 2 is established in the Union;

(d) vulnerable populations and subjects shall be adequately protected in accordance with Articles 64 to 68;

(f) the subject or, if the subject is unable to give informed consent, his or her legal representative has given informed consent in accordance with Article 63;

h) the examinee's right to physical and mental integrity, privacy and protection of his or her personal data in accordance with Directive 95/46/EC is safeguarded.“

In addition, in accordance with Section 48 of the MPEUAnpG, the documents in accordance with Annex XV Chapter II of the MDR must be prepared and submitted to the Ethics Committee.

Subsection 2 with §§ 47 ff in the MPEUAnpG is dedicated to the topic of other clinical trials (requirements, procedures at the ethics committee, etc.) and provides clear national regulations on this.

It is also advisable to consider the application of ISO 14155 for the uniform implementation of a study with medical devices. Although the standard is aimed at clinical testing of medical devices and therefore does not correspond to the intention of a feasibility study, many of the contents can still be applied due to their usefulness. Within the standard, ethical principles have a primary position and Chapter 4 is dedicated to “Ethical Considerations”. Since it is important to protect the safety and well-being of the study participant in accordance with the Declaration of Helsinki (subject insurance, supplementary health care), the standard provides good further assistance in this regard.

The benefit-risk assessment and the justification of a “clinical trial” also play an important role. According to MDR and MPEUAnpG, ethical and safety-related requirements are to be viewed as binding.

For this purpose, ISO 14155 also equates the terms “clinical trial” and “clinical study” with “clinical trial”. To justify a clinical MPG trial, there must be an objective presentation of published and unpublished data as well as a detailed risk analysis and benefit-risk assessment. The justification for a clinical trial is reflected in the trial plan and serves as an evaluation criterion for the ethics committee in its review for a positive assessment. This applies equally to other clinical trials, although due to the early phase and the lack of clinical experience, one can only speak of a benefit-risk assessment with regard to the research project.

4. Outlook

The blog series on clinical trial types will be interrupted in December by our “ Christmas Special .” 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 with further changes are added every week.

DiGA studies will continue in January.

5. How we can help you

Do you already have some initial questions?

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

The medXteam GmbH blog series now begins with an overview of the different types of clinical trials that are possible for medical devices. These will then be described in more detail in the following episodes.

Types of clinical trials involving medical devices

1 Introduction

EU Regulation 2017/745 (Medical Device Regulation, MDR) emphasizes the need for medical device manufacturers to systematically collect and evaluate clinical data before and after approval of their products. Many manufacturers are unaware of the importance of clinical data in demonstrating the compliance of their products. This affects both the approval of the products and the “post-market activities”, in particular the “post-market clinical follow-up”.

In Article 2 (48) “Definitions” the MDR defines the term “clinical data” in more detail:

"Clinical data means information about safety or performance obtained during the use of a product from the following sources:

clinical trial(s) of the product in question,
clinical trial(s) or other studies reported in the scientific literature on a product whose similarity to the product in question can be demonstrated,
in peer-reviewed scientific literature published reports of other clinical experience either with the device in question or with a device whose similarity to the device in question can be demonstrated,
clinically relevant information from post-marketing surveillance, in particular from post-marketing clinical follow-up."

The MDR cites clinical trials as the first source. These will therefore continue to play an important role in the future. The following definition can also be found in the MDR:

"Clinical trial" means a systematic investigation involving one or more human subjects and conducted to evaluate the safety or performance of a product."

(Source: MDR, Article 2, Paragraph 45)

2. Types of clinical trials

All clinical studies with medical devices are clinical trials.

A distinction is made between the following types:

Basic research - other clinical trials (MDR Article 82)
Pilot study/approval study: clinical trials to demonstrate the conformity of products (MDR Article 62)
PMCF study: clinical trials related to products bearing the CE marking (MDR Article 74)

In addition, there is now the so-called DiGA study specifically in Germany:

Study with a digital health application ( DiGA ) to demonstrate positive care effects to achieve reimbursement status.
d. R. with CE marked medical device: PMCF study
If planned into the approval process, an approval study is also possible

(Sources: DiGAV, DVG, DiGA guidelines)

Figure 1: Different types of clinical trials

These different types differ in terms of the respective regulatory requirements, the approval procedures at the higher federal authority (BOB) and the Ethics Commission (EK) and the timing of implementation. This is briefly presented in the following subsections.

2.1 Clinical trials to demonstrate product conformity

The clinical test to prove the conformity of products is the classic approval study. It is regulated in Article 62 of the MDR and, with regard to national requirements for the start and significant changes and corrective measures, in Section 2 of the MPEUAnpG and here in particular in Subsection 1 in Sections 31 to 46.

Table 1: Objectives and timing of clinical trials to demonstrate product conformity

2.2 PMCF studies

Table 2: Objectives and timing of clinical trials related to products bearing the CE mark

Part of the PMCF studies are regulated in Article 74 of the MDR and are clinical trials carried out on a CE marked product: clinical trials related to products bearing the CE marking . However, the MDR in Article 74 only covers two specific cases of such PMCF studies, namely those that contain additional stressful examinations (Art. 74(1)) and those that are carried out outside the intended purpose of the medical device (Art. 74(2). )).

PMCF studies within the intended purpose and without additional burdensome examinations are regulated nationally.

2.3 Other clinical trials

Other clinical trials are regulated in Article 82 of the MDR and in Chapter 4, Subsection 2, § 47 to § 61 of the MPEUAnpG (Medical Devices EU Adaptation Act).

In Section 3 Sentence 4 of the MPEUAnpG it is defined as follows:

"[...] 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."

Table 3: Aims and timing of other clinical trials

2.4 DiGA studies

The area of DiGA studies (studies for digital health applications - DiGA) is a national special case.

According to the Digital Care Act (DVG), those insured under statutory health insurance are entitled to receive treatment with DiGA, which can be prescribed by doctors and psychotherapists and is then reimbursed by the health insurance company.

The prerequisite for this is that the DiGA have successfully completed a review process at the BfArM and are listed in a directory for these reimbursable digital health applications (DiGA directory). In order to include a DiGA in the DiGA directory, the positive care effect must be proven in a controlled study in accordance with the DiGA Ordinance This is usually carried out with a CE-marked product. However, it can also be carried out as part of the approval, but then it must meet the requirements for this study according to the DiGA guidelines .

2.5 Outlook

In the next blog post we will first go into detail about the “ other clinical trials ” that are now regulated by the MDR.

3. How we can help you

Do you already have some initial questions?

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

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Types of clinical trials involving medical devices

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