The blog series continues this year during Advent with our three-part “Advent Special”. We would like to provide you with comprehensive information about the important interfaces between the various types of clinical trials and the technical documentation and the relevant documents.

The special thing about our campaign is that the contribution is spread over the first three weeks of Advent. Each week, one type of clinical trial and the respective interfaces are examined in detail. The topic of risk management in clinical trials will continue in January.  

The first part of our blog special dealt with the interfaces in the “approval study” (clinical trials in accordance with Article 62 of the MDR). The second part 2 now examines the PMCF studies (Article 74 of the MDR, MPDG, ISO 14155). This third and final part now explains the interfaces in DiGA studies .

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: Interfaces to technical documentation in PMCF studies and connection to MDR

1 Introduction

The correct term for a clinical trial involving medical devices is “clinical trial”.

A distinction is made between the following types of clinical trials:

• 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, especially in Germany:

• Study with a digital health application (DiGA) to demonstrate positive care effects in order to obtain 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)

Fig. 1: Types of clinical trials

These different types differ in terms of the respective regulatory requirements and thus in terms of the different interfaces to the technical documentation of the medical device to be examined.

A DiGA study is a PMCF study. That's why the same special features apply here:

A DiGA and thus PMCF study that takes place with a CE-marked medical device within the scope of its intended purpose and without stressful examinations represents an exception to Article 74 of the MDR:

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

Regardless of this, the documents according to Annex XV Chapter II and Articles 80ff of the MDR are still binding.

2. Documents to be submitted for DiGA studies

The additional phase in a DiGA study includes the creation of the evaluation concept based on a systematic literature search, data collection with the DiGA itself on the user and the systematic evaluation of this data.

The clinical assessment - and in this case ideally the most recent one - serves as essential input. It lists the various claims for the medical device and it is important to find the right ones for the DiGA concept: The claims for clinical performance, safety and clinical benefit required for the clinical evaluation have already been included in the plan for the clinical evaluation defined and then documented with data in the clinical assessment report.

Note: This is exactly where it is recommended to use the interface on the DiGA topic of “medical benefits” or patient-relevant structural and procedural improvements, because this data can then be used to update the clinical assessment after the DiGA study.

We have already reported on this in detail in our blog post on the evaluation concept this year.

And then after creating the evaluation concept and finding the appropriate endpoints for the DiGA study, it's time to create the study documents. As with the PMCF study, the following documents must also be created for DiGA studies. Depending on whether Article 74 of the MDR applies, it will be submitted to the EC for a vote and to BfArM. If Article 74 does not apply, all that is required is professional advice from the responsible ethics committee in accordance with Section 15 of the Professional Code of Conduct for Doctors (BO). No matter which application is submitted, the following documents must be created and these are related to the technical documentation:

• Test plan - attachments according to appendix XV chapter. II 3 MDR.
• Clinical Investigator's Handbook - Appendices as per Annex XV Chapter. II 2 MDR.

The following documents are required from the technical documentation:

• clinical assessment - in accordance with Article 61 of the MDR.
• Instructions for use
• Biological safety test results
• How MP works/information about the MP (how MP works)
• How it works and further information about the medical device.
• Risk analysis and assessment including residual risks
• List basic security and performance requirements
• If necessary, suitable processing or sterilization processes
• Proof of CE marking (Required if the test product bears a CE marking.)

2.1 Interfaces to technical documentation

The following table lists the above-mentioned documents to be submitted as well as the elements contained therein and the respective correspondence in the technical documentation:

Table 1: Clinical trial documents and technical documentation

Since this is a CE-marked product, all of these documents are already present in the technical documentation and are particularly included in the test plan and the clinical examiner's manual.

The CE-marked medical device is therefore the test product tested in the PMCF study for which the clinical data is collected. I.e. the documents and results must refer to exactly this product and not to an earlier version!

Technical Documentation:

• Product description
• Intended use
• product specification
• Final clinical assessment with state of the art chapters and literature and risk-benefit assessment
• Risk management documentation according to ISO 14971: PHA, risk analysis, risk management report
• Instructions for use
• Classification
• Checklist of basic performance and security requirements
• List of standards
• Verification test reports
• Biosafety report (if applicable)
• Sterilization process documentation (if applicable)

2.2 Synergies

If you look at the list above, you will notice that this is almost all of the technical documentation.

A good example of using synergies when creating documents is the test plan. Many sections contain the same content as in other technical documentation documents. The intended purpose, the product description, etc. are just a few examples. In addition, the final clinical assessment includes state-of-the-art clinical data, which can also be used for the protocol and the clinical investigator's manual.

And here the digitalization of clinical trials plays a role again:

With the close integration of the clinical trial not only with the process of literature search and thus with the clinical assessment as reported in the penultimate blog post, but also with the technical documentation, digitalization of the essential documents of the clinical trial such as: b.

• Clinical trial plan (Appendix XV, Chapter II, Section 3 of the MDR)
• Clinical Investigator's Manual (Appendix XV, Chapter II, Section 2 of the MDR)
• clinical evaluation

possible.

The advantages of digitalization are obvious:

• more efficient work
• Target-oriented use of capacities
• Elimination of inefficiencies in the creation, maintenance and modification of technical documentation content, clinical evaluation and literature searches
• long-term reduction in care costs

Using the “Polarion” software application, interfaces such as purpose, risk management, usability, clinical evaluation, clinical testing can be assigned to projects and reused if necessary. The creation and maintenance of documents is thus significantly simplified and accelerated. In addition, redundancies and inconsistencies are avoided.

3. Outlook

Our “ Advent special ” is now over. We wish all readers a peaceful and relaxing Christmas ahead and plenty of time to do something other than deal with medical devices.

In the new year we will start again with the topic of “risk management in clinical trials”.

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 blog series continues this year during Advent with our three-part “Advent Special”. We would like to provide you with comprehensive information about the important interfaces between the various types of clinical trials and the technical documentation and the relevant documents.

The special thing about our campaign is that the contribution is spread over the first three weeks of Advent. Each week, one type of clinical trial and the respective interfaces examined in detail. The topic of risk management in clinical trials will continue in January.

The first part of our blog special now presents the interfaces in the “approval study” (clinical trials in accordance with Article 62 of the MDR). Part 2 then highlights the PMCF studies (Article 74 of the MDR, MPDG, ISO 14155) and the third and final part explains the interfaces in DiGA studies .

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: Interfaces to technical documentation in clinical trials as part of the conformity procedure (approval studies) - Article 62 paragraph 1 MDR

1 Introduction

The correct term for a clinical trial involving medical devices is “clinical trial”.

A distinction is made between the following types of clinical trials:

• 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, especially in Germany:

• Study with a digital health application (DiGA) to demonstrate positive care effects in order to obtain 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)

Fig. 1: Types of clinical trials

These different types differ in terms of the respective regulatory requirements and thus in terms of the different interfaces to the technical documentation of the medical device to be examined.

2. Documents to be submitted for approval studies

The following documents must be submitted for clinical trials in accordance with Article 62 of the MDR and are related to the technical documentation:

• Test plan - attachments according to appendix XV chapter. II 3 MDR.
• Clinical Investigator's Handbook - Appendices as per Annex XV Chapter. II 2 MDR.
• Preclinical assessment - systems according to Annex XV Chapter. II 2.3 MDR.
• Instructions for use - Appendices in accordance with Annex XV Chapter. II 2.2 MDR.
• Assessment of risks - investments in accordance with Annex XV Chapter. II 2.5 or 4.6 MDR.
• Insurance basic safety and performance requirements (Insurance Basic Requirements) - Annexes in accordance with Annex XV Chapter II 4.1 MDR.
• Results of biological safety testing - facilities in accordance with Annex XV Chapter. II 2.3 MDR.
• Proof of safety-related harmlessness - systems in accordance with Annex XV Chapter. II 2.5 or 4.6 MDR.
• How the MP works/information about the MP (how the MP works) - systems in accordance with appendix XV chap. II 2.2. MDR.
• How it works and further information about the medical device.
• Risk analysis and assessment including residual risks - investments in accordance with Annex XV Chapter. II 2.5 or 4.6 MDR.
• List of basic safety and performance requirements - systems in accordance with Annex XV Chapter. II 2.7 MDR.
• If necessary, suitable processing or sterilization processes
• Proof of CE marking (Required if the test product bears a CE marking.)
• Clinical evaluation plan - appendices in accordance with Annex XV Chapter II 1.5 MDR;
• Technical documentation - systems in accordance with Annex XV Chapter II 3.18 and 4.6 MDR on request

The last point (appendices in accordance with Annex XV Chapter II 3.18 and 4.6 MDR) must only be submitted upon request and includes:

• List of technical and functional characteristics of the product, with particular reference to those to which the test relates.
• Full details of the available technical documentation, for example detailed risk analysis/management documents or specific test reports, will be provided upon request to the competent authority reviewing an application.

2.1 Interfaces to technical documentation

The following table lists the above-mentioned documents to be submitted as well as the elements contained therein and the respective correspondence in the technical documentation:

Table 1: Clinical trial documents and technical documentation

The result from this table is that the following documents from the technical documentation must be created with the final medical device before the application for the clinical trial is submitted. The final medical device is therefore the test product tested in the clinical trial for which the clinical data is collected. I.e. the documents and results must refer to exactly this product and not to a prototype!

Technical Documentation:

• Product description
• Intended use
• product specification
• Clinical Evaluation Plan (CEP)
• Preclinical assessment as a preliminary stage of the final clinical assessment with state of the art chapters and literature and risk-benefit assessment
• Risk management documentation according to ISO 14971: PHA, risk analysis, risk management report
• Instructions for use 
• Classification
• Checklist of basic performance and security requirements
• List of standards
• Verification test reports
• Biosafety report (if applicable)
• Sterilization process documentation (if applicable)

Only in the case of medical devices that contain drugs or tissues, cells or derivatives, detailed information, which is also contained in the technical documentation, must the following information also be provided:

Information about the medicinal product or the tissues, the cells or their derivatives and the fulfillment of the relevant essential safety and performance requirements and the specific risk management relating to the medicinal product or the tissues or cells or their derivatives and evidence of the incorporation of these components the clinical benefit and/or safety of the product.

2.2 Synergies

If you look at the documentation that must be created before applying for a clinical trial in accordance with Article 62 of the MDR, you will notice that this is almost the entire technical documentation. And that is intentional, because the clinical test is already part of the validation of the final product, so the requirements must already have been checked. Additionally, the product must be proven safe before it is used on humans. I.e. All basic performance and safety requirements are met except for those examined in the clinical trial.

A good example of using synergies when creating documents is the test plan. Many sections contain the same content as in other technical documentation documents. The intended purpose, the product description, etc. are just a few examples. In addition, clinical data on the state of the art are already listed in a so-called preclinical assessment (a document that contains the chapters of the clinical assessment except for the clinical data on the product and PMS etc.), which are also used for the test plan and the clinical examiner's manual can be used.

Such a preclinical assessment can also be part of the clinical investigator's manual, although it is advisable to create a separate document (preclinical assessment), as this is already half the battle to the final initial clinical assessment.

And here the digitalization of clinical trials plays a role again:

With the close integration of the clinical trial not only with the process of literature search and thus with the clinical assessment as reported in the last blog post, but also with the technical documentation, digitalization of the essential documents of the clinical trial such as: b.

• Clinical trial plan (Appendix XV, Chapter II, Section 3 of the MDR)
• Clinical Investigator's Manual (Appendix XV, Chapter II, Section 2 of the MDR)
• preclinical assessment

possible.

The advantages of digitalization are obvious:

• more efficient work
• Target-oriented use of capacities
• Elimination of inefficiencies in the creation, maintenance and modification of technical documentation content, clinical evaluation and literature searches
• long-term reduction in care costs

Using the “Polarion” application, interfaces such as purpose, risk management, usability, clinical evaluation, clinical trial can be assigned to projects and reused if necessary. The creation and maintenance of documents is thus significantly simplified and accelerated. In addition, redundancies and inconsistencies are avoided.

3. Outlook

our “ Advent special ” will focus on the interfaces to technical documentation in PMCF studies.

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 

At medXteam, the focus is on clinical data. We collect this through literature searches or directly with the medical device as part of clinical trials. This article shows how the literature search represents an interface and how the data can be collected digitally.

Abbreviations

CEP Clinical Evaluation Plan

CER Clinical Evaluation Report

CIP Clinical investigation plan

DiGA digital health application

MDR Medical Device Regulation; EU Regulation 2017/745

PMCF Post-market clinical follow-up

SotA State of the Art

Underlying regulations

EU Regulation 2017/745 (MDR)
Medical Device Implementation Act (MPDG)

1 Introduction

Clinical data is essential for every medical device manufacturer and for every medical device:

“Clinical data” means safety or performance information obtained through 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.

(SOURCE: MDR, Article 2)

How the clinical data is collected should be determined at the beginning of every product development. If necessary, we collect data on behalf of the manufacturers via clinical investigations or literature searches, which in turn also serve as the basis for clinical investigation concepts, evaluation concepts for DiGA studies and descriptions of the state of the art (SotA).

The clinical data collected is summarized in the clinical evaluation or as part of its updating. The clinical evaluation is therefore at the center of every data collection or, to put it another way, every data collection flows into the clinical evaluation, which then analyzes and assesses this data.

This article shows our solution for digitally and automatically collecting clinical data for clinical evaluation or as input for a clinical trial.

2. Types of clinical trials

For medical devices, a distinction is made between four different clinical test types:

Fig. 1 Clinical examination types

The focus of this article is in particular on the clinical trial to demonstrate the conformity of products (Article 62 ff of the MDR, also called “authorization study”) and the clinical trial in relation to products that bear the CE marking (Article 74 of the MDR or exception of which, also called the “PMCF study”) as well as the DiGA studies.

Other clinical trials (Article 82 of the MDR) serve primarily to gain scientific knowledge and take place outside of the conformity assessment procedure and outside of clinical follow-up (Post Market Clinical Follow-up, PMCF). They are therefore not included in the clinical evaluation. Nevertheless, a literature search must also be carried out for test plans for these other studies.

2.1 Clinical testing to demonstrate product conformity

Such a clinical trial is also called an approval study. In this case, the clinical data is collected directly on the medical device as part of a clinical trial. In addition to state-of-the-art data, these are then included in the initial clinical evaluation of the medical device.

For such a clinical trial, a preclinical evaluation must, among other things, be submitted. This contains:

• preclinical/verification data on the product
• Data on the state of the art

In order to obtain data on the state of the art, a literature search is necessary.

This preclinical assessment also serves as the basis for the Clinical Investigation Plan (CIP), as this is a

“Description of the relevance of the clinical trial in the context of the state of the art in clinical practice”

must contain (Appendix XV, Chapter II, sentence 3.4 of the MDR).

The clinical data summarized in the clinical test report (Appendix .

The literature search focuses on clinical data on the state of the art, alternative procedures and their outcomes.

2.2 PMCF study

For clinical trials relating to products that bear the CE marking (Article 74 of the MDR) and PMCF studies excluded from it, a trial plan must also be drawn up which - unlike registration studies - is based on the most recently created clinical assessment and its possible data gaps and remaining questions.

A literature search was also carried out as part of the clinical evaluation.

2.3 DiGA studies

DiGA studies serve to demonstrate the positive healthcare effect of the digital health application (DiGA).

For this purpose, an evaluation concept drawn up in accordance with generally recognized scientific standards must be presented in advance of the fast-track procedure, which appropriately takes into account the results of the systematic data evaluation.

“In addition to a systematic literature search and evaluation, the systematic data evaluation also includes the inclusion of our own systematically evaluated data that was obtained using the DiGA.”

Therefore, in the context of a planned DiGA study, a systematic literature search must be carried out, which then also flows into the CIP of the DiGA study.

On the one hand, this literature can partly come from clinical evaluation. Since the endpoints of the DiGA study can not only cover the claims of the clinical assessment on clinical performance, safety and clinical benefit (via proof of the medical benefit of the DiGA), but can also include endpoints on patient-relevant structural and procedural improvements, recommends a separate literature search.

3. Digitized literature search

The previous section shows:

Fig. 2 Literature search in the center

The literature search can sometimes be very time-consuming and tedious. As part of the digitization of the technical documentation, the clinical assessment and therefore in particular the literature search were digitized and the process was automated.

Since medXteam focuses on clinical data, the focus is on literature searches. We implemented this process through our partner avasis as a certified Smart Expert Partner of Siemens Digital Industries Software in the areas of Teamcenter and Polarion.

3.1 Digitized literature search via Polarion

Literature search is the core process of clinical evaluation.

When searching for literature via Polarion, a direct connection is established to the database sources (e.g. directly to PubMed).

The literature search is carried out and documented in the form of the following documents:

• Literature Search and Review Plan

The literature search and review plan describes the objective search and describes the identification of publications. It includes:

• Sources of publications
• Search terms
• defined filters
• Assessment criteria and process for identified publications
• Process for analyzing the relevant publications
• Literature Search Execution Protocol

The implementation protocol provides details of the research carried out and an overview of the history of the research. It includes:

• Search queries and results used
• Deviations from the literature search and review plan
• Overview of searches carried out and search results
• Literature Review Report

The report contains a summary of the search carried out, as well as the evaluation and analysis. It includes:

• Summary of objective search execution and results
• conducted search and selection procedures for identification by other means
• Evaluation of the identified publications
• Analysis of the relevant publications (see following section)

Documentation of the analysis

The execution of objective research in Pubmed and Pubmed Central can be partially automated with digital software solutions to ensure comprehensible and reproducible research documentation and to reduce the effort required for documenting the research results. The solution used (Polarion with avaPubmed extension) offers a direct, validated interface to Pubmed and Pubmed Central.

The full text of each potentially relevant publication is read and analyzed with regard to the scope of the literature search and the relevant clinical assessment topics in the respective clinical assessment plan. The extracted statements about safety, performance, benefits, demands or state of the art are documented.

The analysis of a single "publication" is documented in the form of a single "publication evaluation" (see diagram below): The "publication" is linked to the "publication evaluation" and the evaluation is linked to the respective "clinical evaluation object" linked in the clinical evaluation plan. The following graphic explains the connection between the individual work item types:

Fig. 3: Analysis

Literature search report

The literature search report provides an overview and summary of the analysis:

For each clinical assessment topic, it is listed which publication was identified as being relevant to this topic and which specific statements were extracted in the publication assessment.

Based on these results, it is analyzed whether the relevant data sets as a whole show evidence for the respective clinical evaluation subject (the respective claim, see figure above). The aim is to look for consistency of results across specific clinical assessment topics. If different results are observed across datasets, it is helpful to determine the reason for these differences.

The following graphic visualizes the connection between the documents and the digital content they contain in the form of work items:

Fig. 4 Interfaces and work items

3.2 Digitalized clinical assessment

The clinical assessment is an essential part of the technical documentation (initially as part of the conformity assessment process and updates as part of the clinical follow-up).

Its core is the literature search, which can be carried out digitally (see above). Embedded in Polarion as a subsystem, it can also be digitized itself. The following figure provides an overview of the content of the clinical assessment documents

• CEP,
• CERIUM,
• Literature search documents – plan, minutes, report

embedded as a subsystem in the overall technical documentation system:

Fig. 5 Overall system technical documentation

3.3 Digitalized clinical trial

And with the close integration of the clinical trial (whether for approval, as part of the clinical evaluation or as part of a DiGA study) with the process of literature search and thus with the clinical evaluation, digitalization of the essential documents of the clinical trial, such as e.g . b.

• Clinical trial plan (Appendix XV, Chapter II, Section 3 of the MDR)
• Clinical Investigator's Manual (Appendix XV, Chapter II, Section 2 of the MDR)
• preclinical assessment

possible.

3.4 Advantages of digitalization

The digitalization of technical documentation for medical devices and thus clinical evaluation and literature search is the future!

The advantages of digitalization are obvious:

• more efficient work
• Target-oriented use of capacities
• Elimination of inefficiencies in the creation, maintenance and modification of technical documentation content, clinical evaluation and literature searches
• long-term reduction in care costs

Via Polarion, interfaces such as purpose, risk management, usability, clinical evaluation, clinical trial can be assigned to projects and reused if necessary. The creation and maintenance of documents is thus significantly simplified and accelerated. In addition, redundancies and inconsistencies are avoided.

4. What we can do for you

If a clinical trial is to be carried out, basic safety and performance requirements must first be met and essential technical documentation must therefore be created.

The clinical trial leads to the clinical evaluation, which then forms the basis for PMCF activities (including a PMCF study).

We therefore support you throughout your entire project with your medical device with primary reference to the clinical data on the product: from start to finish.

Please note two events:

October 6th, 2021, 4:00 p.m. – 8:00 p.m. Start-up Night for the healthcare industry

Question time Regulatory & Clinical Affairs – Innovation and technology meet regulation, approval and market surveillance (Hans Wenner, VDE and Daniela Penn, medXteam)

November 11th, 2021, 2:00 p.m. – 3:00 p.m.: Second free medXevent:

Digitalized clinical assessment from the perspective of clinical trials

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

In the first blog post after the summer break, we include the new MDCG documents, which specifically concern clinical trials with medical devices. In this article we present both documents and address the points that may be of concern to sponsors and therefore also manufacturers.

Abbreviations

CE Marking on a product to signify that it meets the legal requirements to be sold on the extended Single Market in the European Economic Area (EEA).

CIP Clinical investigation plan

DMIDS German medical device information and database system

EUDAMED European database on medical devices

GSLA Basic Security and Performance Requirements

IVDR Regulation (Eu) 2017/746 of the European Parliament and of the Council on in vitro diagnostic medical devices

MDCG Medical Device Coordination Group

MDR Medical Device Regulation; EU Regulation 2017/745

MPI Medical Device Information System

MS Member State

NCA National Competent Authority

PMCF Post-market clinical follow-up

REC Research ethics committee

Underlying regulations

EU Regulation 2017/745 (MDR)
MDCG 2021-6
MDCG 2021-8

1 Introduction

The Medical Device Coordination Group (MDCG) regularly and continuously publishes so-called guidance documents for the MDR. This is done in accordance with Article 105 of the MDR and Article 99 of the IVDR. The documents are prepared in collaboration with interested parties represented in the various groups and are given in the following format: "MDCG Year Number Revision".

The MDCG is composed of representatives from all Member States and is chaired by a representative of the European Commission. The documents are not European Commission documents and cannot be regarded as the official position of the European Commission. Any views expressed in this document are not legally binding and only the Court of Justice of the European Union can give a binding interpretation of Union law.

They simply represent a common view on how the MDR and the IVDR should be applied in practice in order to achieve an effective and harmonized implementation of the legislation.

This article now deals with the two newly published MDCG documents 2021-6 and 2021-8.

MDCG 2021-6 is aimed at sponsors of clinical trials of medical devices that are carried out within the scope of Regulation (EU) 2017/745 (MDR). It covers questions and answers and may be supplemented with further questions and answers in due course.

The document MDCG 2021-8 “Clinical investigation application/notification documents”, on the other hand, addresses the documents to be submitted when applying for a clinical trial.

2. New MDCG documents

2.1 MDCG 2021-6

This MDCG document, published last April, contains a total of 28 general questions and related answers:

On the one hand, the differences between the MDR and the previous Directive 93/42/EEC are discussed:

What are the general differences and improvements related to clinical investigations under the new Regulation (EU) 2017/745 (MDR) as compared to the Directives 93/42/EEC and 90/385/EEC?

Basically there is none here, except that the MDR represents a different, more binding set of rules that is intended to ensure a more uniform and predictable feasibility of clinical trials.

In addition to the definition of the clinical trial, which was taken from the MDR (question 2), the third question is interesting again:

What is the difference between the performance, clinical performance and clinical benefit?

According to the MDR, the performance (definition see Article 2(22) of the MDR) of a product is the ability of the product to fulfill its intended purpose as specified by the manufacturer. In a broader sense, the clinical performance (definition see Article 2(52) of the MDR) of a medical device is the ability of the product to fulfill its intended purpose and thereby provide a clinical benefit when used as intended (definition see Article 2(53) of the MDR) to provide. Clinical benefit is the positive impact of a product on a person's health, expressed in the form of a meaningful, measurable, patient-relevant clinical outcome (including diagnostic-related outcomes) or a positive impact on patient management or public health.

Fig. 1 Definition of performance, clinical performance and clinical benefit.

Until now, a distinction has never been made so precisely between performance (to fulfill the intended purpose) and clinical performance (performance to provide the clinical benefit, i.e. the clinical aspects of the service).

But this is important, not only with regard to clinical trials when choosing the primary and secondary endpoints, but also when defining the claims about clinical performance within the framework of the clinical evaluation.

The ninth question covers the subject of “additional incriminating investigations” and defines these in accordance with Article 74.

“Additional procedures that are stressful may include a variety of different procedures, including procedures that may cause pain, discomfort, anxiety, potential risks or complications/side effects, disruption to life and personal activities, or other unpleasant experiences. It is usually determined from the perspective of the person bearing the burden.

Other invasive procedures include penetration into the interior of the body through the body surface, including through the mucous membranes of body openings, or penetration into a body cavity through a body opening.”

These include, for example, blood samples or biopsies that are also carried out as part of the clinical trial and are not part of routine clinical practice.

However, there is still uncertainty here and it is advisable to contact the ethics committee and also the authorities as part of the respective clinical trial in order to be able to make the right decision regarding the application if there are any controversial questions regarding the additional burden.

Overall, many questions concern the correct regulatory path that must be followed in the respective constellation of the medical device with regard to a clinical trial. This is about Articles 62, 74 and 82 of the MDR. We would be happy to provide individual advice on this as part of our free initial consultation .

From question 15 up to and including question 20, changes to the clinical trial plan (amendments) are discussed and questions 21 to 28 deal with deadlines and transition periods.

As a basic overview, this MDCG document is certainly suitable for briefly addressing fundamental questions. However, detailed information or explanations cannot be found and must be clarified as part of the consultation in relation to the individual case.

2.2 MDCG 2021-8

A clinical trial, except in the case of a PMCF clinical trial not covered by Article 74 of the MDR, must be submitted with an application containing the documents referred to in Chapter II of Annex

Since the European Medical Devices Database (EUDAMED) does not yet exist, the MDCG has now created a series of clinical trial application/notification documents to support the clinical trial procedures under the MDR.

Attention: In Germany, clinical trials are applied for via the medical device information system, now the German Medical Device Information and Database System ( DMIDS ), at BfArM (formerly DIMDI ), which already contains the templates listed in the MDCG document as queries.

These documents include:

• Clinical examination - application/reporting form within the framework of the MDR
• Addendum to the application/reporting form for clinical trials for:
  • Additional test product(s) (Section 3)
  • Additional comparator(s) (Section 4)
  • Additional testing body(s) (Section 5)
• Supporting documents for the clinical trial - Appendix of documents to be attached
• Checklist of general safety and performance requirements, standards, common specifications and scientific recommendations

As far as possible, the clinical trial application/notification form contains the same data fields as the EUDAMED system, which is still under development.

The templates are listed in the MDCG document and can be accessed via the following links:

Clinical investigation – application form under Medical Device Regulation

Additional investigational device(s) (section 3)

Additional comparator device(s) (section 4)

Additional investigation site(s) (section 5)

This document also contains a link to a list of the required documents, which is based on ISO 14155:2020.

Finally, you receive a template for the checklist of the basic safety and performance requirements (GSLA), standards, common specifications, etc., which is based on the MDR checklist:

Fig. 2 List of standards, CS and scientific references, except those examined in the clinical trial

Fig. 3 Matrix for fulfilling the GSLA

Apart from the two Word templates, this MDCG document does not provide any new information for clinical trials carried out in Germany, as everything can be entered and applied for via the DMIDS.

3. What we can do for you

We act as a scientific, manufacturer-independent institution (CRO). As such, we support you throughout your entire clinical trial project - from the initial idea to the evaluation and the clinical trial report.

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