At medXteam, clinical data is our core focus. We collect this data through literature searches or directly with the medical device during clinical trials. This article demonstrates how literature searches serve as an interface and how 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 Devices Implementation Act (MPDG)

1 Introduction

Clinical data is indispensable 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 data from post-market surveillance, in particular from post-market clinical follow-up.

(SOURCE: MDR, Article 2)

How clinical data will be collected should be defined at the very beginning of every product development process. On behalf of manufacturers, we collect this data as needed through clinical trials or literature reviews, which in turn also serve as the basis for clinical trial designs, evaluation concepts for digital health applications (DiGA) studies, and descriptions of the state of the art (SotA).

The collected clinical data are summarized in the clinical evaluation or as part of its update. Clinical evaluation is therefore central to every data collection process; or, put another way, every piece of data collected contributes to the clinical evaluation, which then analyzes and assesses this data.

This article presents our solution for collecting clinical data digitally and automatically 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 types of clinical trials:

Fig. 1 Clinical trial types

This article focuses in particular on clinical trials to demonstrate the conformity of products (Articles 62 ff of the MDR, also called "approval study"), clinical trials relating to products bearing the CE marking (Article 74 of the MDR or exception thereto, also called "PMCF study") and DiGA studies.

Other clinical investigations (Article 82 of the MDR) primarily serve to advance scientific knowledge and take place outside the conformity assessment procedure and outside of post-market clinical follow-up (PMCF). Therefore, they are not included in the clinical evaluation. Nevertheless, a literature search must also be conducted for the protocols of these other studies.

2.1 Clinical trial to demonstrate product conformity

Such a clinical trial is also called a registration study. In this case, clinical data are collected directly for the medical device as part of a clinical trial. These data, along with state-of-the-art data, are then incorporated into the initial clinical evaluation of the medical device.

Such a clinical trial must include, among other things, a preclinical evaluation. This includes:

• preclinical/verification data for the product
• State of the art data

To obtain data on the state of the art, a literature search is required.

This preclinical assessment also serves as the basis for the clinical investigation plan (CIP), as this provides a

"Description of the relevance of the clinical trial in the context of the state of the art in clinical practice"

must contain (Annex XV, Chapter II, paragraph 3.4 of the MDR).

The clinical data summarized in the clinical investigation report (Annex XV, Chapter II, paragraph 3.17 of the MDR) as part of this clinical investigation are incorporated into the clinical evaluation, which also includes a chapter on the state of the art, which can be updated from the preclinical evaluation.

The literature search here 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 bearing the CE marking (Article 74 of the MDR) and exempt PMCF studies, a study plan must also be drawn up, which – unlike for registration studies – is based on the most recently completed clinical evaluation, its possible data gaps and remaining questions.

A literature search was also conducted as part of the clinical evaluation in this regard.

2.3 DiGA studies

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

For this purpose, an evaluation concept prepared according to generally accepted scientific standards must be submitted in advance of the fast-track procedure, which adequately takes into account the results of the systematic data analysis.

"The systematic data analysis includes not only a systematic literature search and evaluation but also the inclusion of our own systematically evaluated data obtained in the application of DiGA."

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

This literature may, to some extent, originate from clinical evaluations. However, since the endpoints of the DiGA study can cover not only the claims of the clinical evaluation regarding clinical performance, safety, and clinical benefit (via the demonstration of the medical benefit of the DiGA), but also endpoints relating to patient-relevant structural and procedural improvements, a separate literature search is recommended.

3. Digitized literature search

The previous section shows:

Fig. 2 Literature search in the center

Literature searches can sometimes be very time-consuming and lengthy. Therefore, as part of the digitization of technical documentation, clinical evaluation, and in particular literature searches, were also digitized and the process automated.

Since medXteam focuses primarily on clinical data, literature searches are central. We implemented this process through our partner avasis , 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

Conducting objective searches in PubMed and PubMed Central can be partially automated using digital software solutions to ensure traceable and reproducible search documentation and to reduce the effort required to document search results. The solution used (Polarion with the 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 review 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 Digitized clinical evaluation

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

Its core feature is the literature search, which can be performed digitally (like this). Embedded within Polarion as a subsystem, it can also be digitized itself. The following figure provides an overview of the content of the documents for clinical evaluation

• 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 Digitized clinical trial

And with the close integration of clinical trials (whether for approval, within the framework of clinical evaluation or within the framework of a DiGA study) with the literature search process and thus with the clinical evaluation, digitization of the essential documents of the clinical trial, such as...

• 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 therefore essential technical documentation must be prepared.

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

Therefore, we support you throughout your entire project with your medical device, always with primary reference to the clinical data on the product: from the beginning to the end.

Please note the following two events:

October 6, 2021, 4:00 PM – 8:00 PM Start-up Night of the Healthcare Industry

Q&A session on Regulatory & Clinical Affairs – Innovation and technology meet regulation, approval and market surveillance (Hans Wenner, VDE and Daniela Penn, medXteam)

November 11, 2021, 2:00 PM – 3:00 PM: 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