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 

UPDATE

In keeping with the first medXevent, the last blog post before our summer break is about the product register as part of the PMCF. Manufacturers of medical devices are obliged under the MDR to use various general and special methods and procedures as well as specific clinical follow-up during clinical follow-up (PMCF). The register is a very proactive method for obtaining your own clinical data from routine clinical practice. In this blog post we will show you what a register is and how you can use it for your medical device as part of your PMCF.

Abbreviations

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

PMCF (Post-Market Clinical Follow-up)

RCT (Randomized Controlled Trial)

1 Introduction

As part of the PMCF, the MDR requires the continuous collection of clinical data on the clinical performance, clinical benefit and safety of medical devices throughout the entire product life cycle. A register can be set up and used here in particular to record effectiveness data in the routine clinical use of the product and is therefore suitable for displaying the effectiveness in everyday care.

As part of the MDR, the registry is one of the proactive clinical follow-up activities (Post-Market Clinical Follow-up, PMCF). The evaluation of the register is referred to as a review of the register data, which is usually retrospective.

Fig. 1 Integration of the register into the market surveillance process according to MDR (source: General methods and procedures of PMS and PMCF (source: Keene A. Leveraging Post-Market Surveillance and Post-Market Clinical Follow-Up Data to Support EU Medical Device Regulation (MDR) compliance, white paper)

2. Definition of the register

2.1 Definition 1 

“A register is the most active, standardized data collection possible from observation units on predetermined but expandable questions, for which a precise reference to the source population can be transparently presented.”

(Source: German Institute for Vascular Health Research)

2.2 Definition 2

“An organized system that uses observational study methods to collect consistent data (clinical and other) to evaluate specific outcomes for a population defined by a particular disease, condition, or exposure, and one or more predetermined scientific, clinical, or policy Serves a purpose.”

(Source: Gliklich RE et al., 2010)

3. Product register

In principle, medical registers are sensible and useful because they generate necessary medical care data under everyday conditions. register

• create the conditions for safe medical operations and continuous quality improvement,
• create market observation knowledge and generate important product information for medical device manufacturers and knowledge for their market research and new developments,
• offer the opportunity of an “early warning system” to detect abnormalities at an early stage and avoid repeat damage,
• provide answers to the questions:
  • Where and why did the incident occur?
  • What role do the product, doctor and patient play?
  • Where can we learn about this?
  • What conclusions do we draw from this for quality improvements for the product in terms of its safety and performance/effectiveness?

In addition, effects from registry data can provide evidence of or evidence of clinical benefit and are therefore an important contribution to clinical follow-up (post-market clinical follow-up, PMCF).

3.1 Regulatory requirement

In Annex

“Post-marketing clinical follow-up shall be understood as an ongoing process to update the clinical assessment in accordance with Article 61 and Part A of this Annex and shall be addressed in the manufacturer's post-marketing surveillance plan. During post-market clinical follow-up, the manufacturer proactively collects and assesses clinical data resulting from the use in or on humans of a CE-marked product placed on the market or put into service in accordance with the relevant conformity assessment procedure for its intended purpose Body to confirm the safety and performance over the expected life of the product, to ensure the continued acceptability of the identified risks and to identify emerging risks on the basis of relevant evidence."

(MDR, Annex XIV Part B)

3.2 Differentiation from PMCF studies

The occasionally used term “registry study” should actually be avoided. Studies can have very different designs, but generally always include the immutability of the selected endpoints over the course of the study and, in addition to a time limit, usually also have a quantitative limit in relation to the population. In addition, you run within a defined framework (endpoints, inclusion and exclusion criteria, etc.). If you want to collect data from the routine clinical practice of a medical device, as is possible with a register, no framework conditions can prevail, since this can be done, for example. B. collecting off-label use data would lead to absurdity. But that is exactly what is possible with a register.

A registry therefore collects data from routine clinical practice without restrictions (ie without inclusion or exclusion criteria) without following a restricted and defined study structure.

A registry study as a non-interventional study therefore forms a complementary approach to a randomized clinical trial (RCT).

Table 1: Register study versus RCT (Source: Novustat, https://novustat.com/statistics-blog/registerstudien-professional-auswerte-die-essentials.html) 

In comparison to the registry, RCTs are often criticized for the lack of representativeness of everyday care due to a severely restricted population and artificial intervention scenarios. And of course this is one of the advantages of a register in order to comply with the PMCF requirements of the MDR:

3.3 Advantages of a register

Since registries collect data from routine clinical practice, they do not take place in the strictly regulated and controlled context of a PMCF study and can therefore also provide the manufacturer with important insights into the actual application of the product on the market. Other advantages include:

• scientific and empirical evidence
• Valid representation of trends from application observation
• All actually common forms of therapy and interventions are depicted
• No patient consent required, just privacy policy and consent to use the data

3.4 Data collection using registers 

A product register is used to collect data on specific clinical questions and, if applicable, data gaps (parameters) in a completely anonymized manner, both prospectively and retrospectively.

However, in order to make valid statements, the registers must be carefully planned and implemented. This planning is done via a register plan. This contains specifications for the parameters to be collected as well as their evaluation (also in terms of frequency). Based on this, a specific register database is built. The data is entered into this database, which is as independent as possible, completely anonymously and is first validated there with regard to completeness and plausibility. The entries in the register database are ideally validated by trained and trained external specialists. The validation and checking for completeness and compliance with the exclusion conditions is monitored and documented by a data manager.

GCP and ICH must also be adhered to, as well as the issue of data protection. Patients must be informed using patient information and must consent to data collection.

The data should not only be collected, but also statistically evaluated. When evaluating registry studies, methods are used that ensure the comparability of patients or patient groups. This allows, for example, matched pairs evaluations to be carried out. But evaluations based on the propensity score are also used in register studies. Matching comparison partners can be found based on defined criteria. Adjustment procedures with regard to different characteristics, e.g. B. the severity of an illness can be useful.

(Source: Novustat, https://novustat.com/statistics-blog/registerstudien-professional-auswerte-die-essentials.html . Accessed on June 25, 2021)

On the one hand, users of such a register are those who enter data into the register database in practices, clinics or when using the medical device. Other users are data managers who statistically evaluate and process the data. And of course the manufacturer, who can then use this data for the PMCF.

Fig. 3: Cycle of data collection, evaluation and use

3.4 What characterizes a good register?

What matters most here is the quality of the register:

What is important is the systematic and appropriate nature of data collection within the register.

The validity

• the sampling,
• data collection and
• statistical analyzes and reports

are further quality features. Likewise, other overarching quality requirements. These include:

• Dealing with limiting conditions
• Acceptance among reporters and patients
• Efficiency
• Transparency and scientific independence
• Flexibility and adaptability
• Actuality

Standardization is also an essential aspect if valid and evident clinical data is to be collected in this way. These include, for example:

• the establishment of standards in procedural instructions
• the training/review of data collection/capture

Registries provide an almost complete picture of the entire population and thus data from routine clinical practice. You therefore have the following advantages:

• Presentation of effectiveness in everyday care
• high number of patients with basic data
• heterogeneous study population
• Direct comparison to assess the benefits of different forms of therapy is possible
• possible use as a QM tool for benchmarking in long-term observation
• high case numbers can be achieved

(Source: Neugebauer, 2013. Establishment of a register for registers. Institute for Research in Operative Medicine (IFOM))

Instead of a PMCF study, manufacturers can generate long-term data on the safety, performance and benefits of their specific product as part of clinical follow-up.

Professional approaches to data collection and recording ensure high data quality. Professional support is also recommended with regard to medical statistics, analysis and the selection of suitable procedures.

4. What we can do for you

We act as a scientific, manufacturer-independent institution (CRO). As such, we will work with you to consider how we can best close any existing data gaps within the PMCF or continuously collect clinical data on your medical device.

One option here is the product register. This was also presented in detail in our first free medXevent on July 1st, 2021. recording is now available on our YouTube channel.

With this first live event we are going into the summer break in terms of blogs and events. Our second medX event on the topic of DiGA studies is planned for September. The next blog post will also appear. In this we will introduce our brand new GCP MDR training for auditors.

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. This also applies to your register!

Do you already have some initial questions?

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

The first blog post of 2021 was about the topic of “DiGA” and data collection. In this article we would like to go into the preparation task in more detail and that is why this time it is about the evaluation concept. This must also be submitted together with the test plan for the DiGA study with the application for inclusion in the reimbursement list. This blog post explains what it is all about, how it is best created and everything that needs to be taken into account.

Abbreviations

BOB (higher federal authority)

BtB (Business to Business)

BtC (Business to Customer)

DiGA (digital health application)

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

Underlying regulations

Digital Care Act (DVG)
Digital Health Applications Ordinance (DiGAV)
DiGA Guide
EU Regulation 2017/745 (MDR)
ISO 14155

1 Introduction

In order to be included as a DiGA in the reimbursement directory (DiGA directory), various requirements must be met and the review process at the BfArM must be successfully completed. This includes, among other things, if a study that meets the DiGA criteria has not yet been carried out, an evaluation concept and a clinical study based on it. January blog post important information about the DiGA study

This article deals with the evaluation concept for the positive care effect of the DiGA. The DiGA guidelines go into this in more detail in Chapter 4.5.2:

„With the application, the manufacturer also submits an evaluation concept drawn up in accordance with generally recognized scientific standards that appropriately takes into account the results of the systematic data evaluation. The study protocol of the intended study should be part of the evaluation concept. The choice of outcomes and study design of the selected comparison and the reality of care must be justified. It must be explained why and how the evidence of the desired pVE emerges from the selected evaluation concept. This must have been created by a manufacturer-independent scientific institute .“

“The scientific evaluation concept to be presented should appropriately take into account the results of the systematic data evaluation in accordance with Section 15 DiGAV.”

Excerpt from: Brönneke, Jan B. “DiGA VADEMECUM: What you need to know about digital health applications (German Edition).

The manufacturer does not have to create this himself because the law requires it to be created in the guidelines but also in the DVG by an independent scientific institute. Nevertheless, it contributes a significant part to the creation, because the study concept, including the endpoints to be proven for the positive care effect, require in-depth study of this topic. This article would like to explain in more detail what this means. At the same time, it is shown how the evaluation concept can be used for a DiGA (software as a medical product) that has been on the market for a long time or for a e.g. B. a DiGA that is currently in the development process or one that has just been approved under the MDD can be created.

2. DiGA evaluation concept

In the DiGA regulations, the evaluation concept is defined as follows:

„If an application for testing is to be submitted, it must be accompanied by a scientific evaluation concept. This must be prepared by a manufacturer-independent institution to demonstrate the positive care effect according to generally recognized scientific standards.”

(Source: DiGA Guide )

This includes in particular the following information on the planned study project in order to demonstrate the positive care effect of the DiGA:

• an indication of the testing period (maximum 12 months)
• systematic data evaluation with the DiGA itself
• Description using the PICO scheme in the short version of the positive supply effect
• Specifying the patient group by specifying the corresponding ICD codes
• Type of positive care effects of DiGA: medical benefits and/or patient-relevant procedural and structural improvements
• Information on research design and results
• Information on the quality-assured application of the DiGA and exclusion criteria
• Information about the scientific and manufacturer-independent institute involved

For example, we structure our evaluation concept as follows:

Fig. 1: Content and structure of the evaluation concept

An essential part of the scientific evaluation concept is systematic data evaluation as part of the application of the DiGA. Therefore, this data evaluation must be carried out with the approved medical product. This is not a problem if DiGA is already on the market and data has already been collected through its application. However, for products that are still in development or have just been approved, there may not yet be any data available for a corresponding evaluation. Such a survey phase must therefore be planned following approval before an application for provisional inclusion in the register can be submitted.

Regardless of this, the manufacturer must think about the planned supply path to be followed with the DiGA, for which the positive supply effect is to be proven. As part of the data collection for the evaluation concept, various endpoints should already be established that can be checked for validity in this context.

The aim and purpose of the data evaluation should be to define the endpoints of the DiGA study, which can be used to demonstrate the positive care effect on the intended care path. It therefore makes sense to have a selection option from the areas

• medical benefits
• patient-relevant process and structural improvements

But how should this data be collected so that it can then be evaluated for the evaluation concept?

2.1 Already approved DiGA

Many of the DiGAs already listed are approved medical devices that were already on the market. This means that it is possible to use a study that has already been carried out and that meets the DiGA criteria in order to be immediately and definitively included in the directory. In this case, we strongly recommend that you seek advice from the BfArM. Especially when there is uncertainty as to whether the data collected is sufficient and it is therefore unclear whether it is going in the right direction and whether an application should be submitted for provisional or final inclusion.

If no study has yet been carried out, in this case it is advisable to retrospectively evaluate data that was collected as part of the application with the DiGA and is available from the manufacturer via the app.

Note: This is possible without any problems if there is a BtC relationship between the manufacturer and the user. Doesn't this exist because the DiGA, for example, is not directly from the manufacturer, but e.g. B. is provided by therapists (with whom there is a BtB relationship with the manufacturer), the data is not held by the manufacturer.

If the manufacturer has access to the data that is automatically collected by DiGA as part of the application, it can be evaluated anonymously. In this case, this is done via a so-called observation plan; the collection refers to “real world data” and since it is completely anonymous, it can be collected accordingly without involving an ethics committee or authority. The observation plan defines the parameters to be collected, which relate to the above-mentioned aspects

• medical benefits
• patient-relevant process and structural improvements

should refer. Our March article “Medical products and real world data as well as real world evidence” is also recommended for real world data (link: https://www.medxteam.de/index.php/medxteam-blog/15-medizinprodukte-und-real-world -data and real-world evidence).

2.2 DiGAs that have not yet been approved or have just been approved

No personal data may have been collected using these products. In this case, the clinical assessment is usually also carried out using performance data (see also Article 61 Section 1 of the MDR), since clinical data can be dispensed with for these Class I or IIa products in order to meet the basic safety and performance requirements .

This means that no approval studies are usually carried out. Guidelines for state-of-the-art chapters in clinical assessment are usually only available for the underlying indications and alternative applications, as DiGAs are more innovative in nature and are not yet comprehensively anchored in guidelines.

However, for the clinical evaluation, claims for clinical performance, safety and clinical benefit must already be defined in the clinical evaluation plan and then supported with data in the clinical evaluation 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.

In addition, the DiGA process does not end with the listing in the DiGA directory. Negotiations with the health insurance companies then begin.

to include keywords from medical benefits or patient-relevant structural and process improvements, if possible, when defining the intended purpose of the medical product and in the claims This makes later negotiations easier. It’s also best not to talk about “software” but rather about digital health applications.

Therefore, once the medical device has been approved, data collection for the evaluation concept must be planned.

Here too, it is advisable to collect the data collected with the DiGA as part of its use by the manufacturer. This survey is not retrospective, but prospective into the future.

However, the data can also be evaluated retrospectively after a defined period of application of the DiGA.

Here too, it is important that the data

• with the DiGA itself and
• anonymous

be collected. This also works best in the BtC case. But even in the BtB case, if the manufacturer does not have direct access to the app data, an observation study and collection of real world data can be carried out. Essentially, all that needs to be ensured here is anonymized provision in the BtB ratio.

2.3 Summary

A key aspect of the evaluation concept is data on the care path taken and the necessary evidence of this

• medical benefit
• or patient-relevant procedural and structural improvements.

Parameters are therefore defined in advance that should be evaluated accordingly after data collection. These should come from the following areas:

Medical Benefits:

• improving health status,
• shortening the duration of illness,
• Prolonging survival or
• Improving the quality of life

Patient-relevant structural and procedural improvements:

• in the context of the detection, monitoring, treatment or mitigation of diseases or the detection, treatment, mitigation or compensation of injuries or disabilities and
• aimed at supporting the health care activities of patients or integrating the processes between patients and service providers and
• include in particular the areas of

1. coordination of treatment processes,
2. Alignment of treatment with guidelines and recognized standards,
3. adherence,
4. Facilitating access to care,
5. patient safety,
6. health literacy,
7. patient sovereignty,
8. Coping with illness-related difficulties in everyday life or
9. Reduction of therapy-related expenses and burdens on patients and their relatives.

3. What we can do for you

We act as a scientific, manufacturer-independent institution (CRO). As such, we create your evaluation concept and advise you in an interface-compliant manner in your early development phase with regard to your claims for the medical product or determination of the intended purpose. All of this is done with DiGA requirements in mind, so you can kill two birds with one stone.

If your technical documentation is already available, we look at possible DiGA endpoints either based on your documentation or based on the care path subsequently taken with the DiGA and make a sensible preliminary selection so that the data analysis for your evaluation concept is targeted and does not get out of hand. After all, we want clarity and not to fish in clouds.

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. This also applies to your evaluation concept and your DiGA study!

Do you already have some initial questions?

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