What routes of clinical evaluation of medical devices are there?

At medXteam, the focus is on clinical data. In this context, as CRO, we not only carry out clinical trials with medical devices in accordance with MDR and ISO 14155, but also offer all other options and forms of data collection and product approval as well as market surveillance. The focus is always on clinical evaluation, both during product approval and during clinical follow-up. But how can a clinical evaluation be carried out? What options are there to provide clinical evidence? And what role do the different routes of clinical assessment play in this? In this blog post we explore these questions, explaining in particular what the three routes of clinical evaluation mean, when they can be used and how they impact different product groups.

Abbreviations

MDR Medical Device Regulation; EU Regulation 2017/745

PMCF Post-Market Clinical Follow-up, clinical follow-up

CEP Clinical Evaluation Plan

CDP Clinical Development Plan

Underlying regulations

EU Regulation 2017/745 (MDR)

1 Introduction

Clinical evaluation is an essential step for every medical device manufacturer. It is necessary to create a comprehensive Clinical Evaluation Report (CER) for each medical device, which includes a thorough literature search. This was already standard procedure before Regulation (EU) 2017/745 (MDR) came into force. According to Article 61 of the MDR, the planning and implementation of a clinical evaluation for all medical devices - from Class I to Class III - is required:

“ The manufacturer shall determine and justify the scope of clinical evidence to demonstrate compliance with the relevant essential safety and performance requirements. The level of clinical evidence must be appropriate to the characteristics of the device and its intended purpose. For this purpose, manufacturers shall carry out, plan and document a clinical assessment in accordance with this Article and Part A of Annex XIV .” (See Article 61 of the MDR)

This process begins early in the development process. The clinical evaluation plan (CEP) is usually created shortly after the product idea, intended purpose and initial risk analysis of the medical device have been determined.

During planning in the CEP, the route of which data should be included for the clinical assessment is determined. This includes initial literature research depending on the defined product as well as a market assessment with regard to similar products and possibly existing clinical data in publications and the state of the art in the area of ​​application of the medical device.

This information makes it possible to define a clinical strategy for the product and record this in the clinical development plan (CDP).

Early timing is critical as the clinical strategy and resulting route for clinical evaluation have a significant impact on the time and cost of the entire development project. It makes a significant difference whether a clinical trial still has to be integrated into the validation part. This can delay the completion of the conformity assessment procedure and the CE marking of the medical device for years.

Early planning is also important because the intended purpose can still change. Since this forms the basis of the development process, changes made at an advanced stage can have a significant impact on the time and cost of the project. (see also our blog post on clinical strategy)

Therefore, every manufacturer should address the following questions as early as possible:

What product class does the medical device have? In our experience, for implantable products in Class IIb and all Class III products, it is essential to use your own clinical data.

What is the difference to existing products? The degree of innovation of the product is crucial here.

This blog post provides the answers to these questions.

2. The 3 routes of clinical assessment

According to the MDR, clinical evaluation refers to a structured and planned process for the ongoing generation, collection, analysis and evaluation of clinical data of a product in order to verify its safety, performance and clinical benefit when used as intended by the manufacturer (MDR Art. 2, Sentence 44). Clinical data is defined as follows: “Clinical data” is information about the safety or performance of a product that is obtained during its use and can come from various sources (MDR Art. 2, Sentence 48):

Clinical studies of the product in question.

• Clinical studies or other studies in the scientific literature that can demonstrate similarity to the product in question.
• Reports of clinical experience with the product or similar products that have been published in the scientific literature after peer review.
• Clinically relevant information from post-marketing surveillance, including post-marketing clinical follow-up.

This results in three possible routes for clinical assessment:

Own clinical data: This route involves conducting a clinical trial with the product in question in accordance with Article 62 of the MDR, which requires careful planning and execution.

Clinical data on equivalent products: Clinical data on similar products from the specialist literature are used here or there is already a clinical study with an equivalent product.

Use of performance data: This route is used when a human clinical trial is not possible or appropriate. Instead, performance data, also called verification data, is used. This data is based on non-clinical testing methods, including performance evaluation, technical testing and pre-clinical evaluation.

Fig. 1 The three routes of clinical assessment

It is important to note that the third route, although specified in the MDR, was already similarly established in Directive 93/42/EEC, MDD. The following sections describe all three routes in detail, with particular attention to the third route.

2.1 Own clinical data

For class IIb implantable medical devices in particular, the generation of own clinical data is the predominant method under the MDR. While under Directive 93/42/EEC the clinical assessment for these products could still be carried out using clinical data on equivalent products, this approach is under no longer possible due to the massively stricter requirements of the MDR. In particular, the requirement to conclude a contract with the manufacturer of the potentially equivalent product in order to obtain full access to its technical documentation (MDR, Art. 61, Section 5) completely excludes the option of using equivalent products:

„A manufacturer of a product which is proven to be similar to a product which has already been placed on the market and which he has not manufactured may also rely on paragraph 4 in order to avoid having to carry out a clinical trial, provided that, in addition to the requirements of that paragraph, the following conditions are met : – The two manufacturers have concluded a contract in which the manufacturer of the second product is expressly permitted unrestricted access to the technical documentation throughout, (…)“

This proprietary clinical data route is mandatory not only for Class IIb and Class III implantable devices, but also for innovative devices with clinical claims regarding the benefit or effectiveness of the device. There are usually no equivalent products for such innovative products, and the performance/verification data route cannot be chosen either, as clinical claims must necessarily be proven by own clinical data.

A concrete example would be a product whose clinical benefit is to reduce pain or improve quality of life. The choice of route for clinical evaluation depends on the degree of innovation of the product, regardless of its classification. This can even apply to Class I products.

2.2 The Equivalence Route

Under Directive 93/42/EEC, MDD or before the introduction of the MDR, the equivalence route was considered the standard procedure - the so-called gold standard - for clinical assessments. However, if one wishes to use clinical data on an equivalent product to support claims about the safety, clinical performance, and clinical benefit of one's product, one must first determine through a literature search whether any clinical data on that product is available. If this is not the case, a mandatory equivalence assessment is not possible. If there is data on this potential equivalent product, then in such a case it is first analyzed whether the potential equivalent product is actually equivalent. Previously, evaluation criteria were used for this analysis, which were set out in the MEDDEV 2.7/1 Rev. 4.3 guide for clinical assessments until the MDR came into force in May 2021.

These criteria targeted the clinical, technical and biological characteristics of the equivalent product, which were compared with the own product to determine whether they are the same or just similar in some aspects. For example, they may have had to be used for the same indications (clinical characteristics), while technical characteristics such as diameter and size could be similar.

With the introduction of the MDR and the associated MDCG document 2020-05 (“Clinical Evaluation – Equivalence: A guide for manufacturers and notified bodies”), these criteria were drastically tightened. Particularly with regard to technical and biological equivalence, the products now have to be identical in terms of their characteristics much more often than before. For example, assessing the equivalence of one software as a medical device may require access to complete algorithms and source codes of the other software, in which case these features would have to be identical. In the case of material medical devices, both products must consist of exactly the same substances and be present in the same concentration, and the product residues must also be identical.

Such detailed data on the potential equivalent product is usually not available because no one has access to such details of a software or exact material concentrations and residues of a product. And that is exactly what makes the equivalence route increasingly difficult or even impossible.

2.3 Performance data

The way to demonstrate the clinical performance of a product through performance data has always been possible and remains so under the MDR (Article 61):

„If demonstration of compliance with essential safety and performance requirements based on clinical data is considered inappropriate, any such exception shall be based on the manufacturer's risk management and taking into account the specific characteristics of the interaction between the device and the human body, the intended clinical performance and the information provided by the manufacturer; this applies without prejudice to paragraph 4. In this case, the manufacturer shall duly justify in the technical documentation set out in Annex II why he demonstrates compliance with essential safety and performance requirements solely on the basis of the results of non-clinical testing methods, including performance evaluation, technical testing ( “bench testing”) and preclinical evaluation, is considered suitable .“

The decision is based on various considerations:

• the result of risk management
• the specifics of the interaction between body and product
• proof of performance based on product tests (technical, in-vitro)
• the result of the preclinical assessment (initial literature search, verification tests, etc.)

This decision must be adequately justified and documented in the clinical evaluation plan.

This route is chosen when a clinical trial makes little sense. A classic example of this is the wooden tongue depressor, for which clinical data are not available in the literature. In such cases, technical data such as breaking strength and workmanship prove the safety and performance of the product.

Although this route has been less used in the past because it was often less well known and the route via an equivalent product was commonly used, it is suitable for a wide range of products.

2.3.1 Example – Medical Software

Most software products (Class I and IIa) are examples of products where performance data makes sense. The reasoning for this decision is as follows:

The product has been fully verified as part of the software life cycle process in accordance with IEC 62304 and all tests have been successfully completed. The testing included unit testing, integration testing, system testing and usability testing. Based on these tests, it can be shown that the product works effectively.

According to MDCG-2020-1 (Guidance on Clinical Evaluation (MDR)/Performance Evaluation (IVDR) of Medical Device Software), scientific validity is defined as the extent to which the output of the software product is valid based on the selected inputs and algorithms is associated with the desired physiological state or clinical disease. In order to provide proof of scientific validity, a literature search is carried out, which also includes proof of benefit according to the MDR as well as determining the state-of-the-art and identifying the safety and performance of the medical device.

The clinically relevant components of the system are the implementations of the algorithms/questionnaires for diagnosis or the course of therapy. The literature search focuses on scores/detection algorithms as well as on the general use of digital products in the diagnosis/therapy of the indicated indications.

Table 1: Clinical evaluation of a software product

2.3.2 Example – dentist chair

Another product whose clinical performance, safety and benefits can be easily assessed using performance data and for which a clinical test makes no sense is the dental treatment unit: the dental chair.

Such products are active medical devices that are used to treat children and adults in the dental field. These products are dental treatment devices according to ISO 7494 with a dental patient chair according to ISO 6875. They are intended exclusively for use in dentistry and may only be operated by medical professionals. The dental treatment unit is used as an aid for patient positioning and for treatment in the dental field. Depending on whether dental instruments are part of this treatment unit and, if so, which ones, these products are classified in class IIa or IIb.

Due to the clear intended purpose of these products, the question of whether a clinical trial should be carried out on humans is unnecessary. The claims about the product relate to the ergonomics for both the patient and the practitioner and user of the product. It also emphasizes efficiency and ease of operation, and prescribed procedures and supporting components to facilitate infection control and maintain water quality. These statements are not suitable endpoints for a clinical trial. However, they can be supported with performance data. For example, the topic of ergonomics and ease of use can be proven via the usability test (DIN EN 62366-1). Compliance with the relevant standards and regulations on water hygiene and quality also confirms these claims about the product. The reason for choosing the path based on performance data is now listed here in Table 2:

Table 2: Clinical evaluation of an active product

2.3.3 Example – Heart rhythm detector

Another example is a Class IIa product that can detect episodes of irregular heart rhythm suggestive of atrial fibrillation through long-term monitoring of pulse parameters over several days to four weeks. It therefore supports the diagnosis by providing evidence of atrial fibrillation.

This product is based on embedded software whose algorithm recognizes the episodes and displays them accordingly. The verification and validation of the software already provides crucial data on how this medical device works. Despite the possibility of conducting a clinical trial on humans, ethical concerns must also be taken into account. An ethics committee examines precisely these aspects. However, there are alternative ways to generate clinical data to support the clinical performance and function of the product. For example, episodes can be played via simulation tests to check whether the algorithm recognizes them correctly. Here, too, no human study is required to provide this proof. The rationale for this route is shown in the table below:

Table 3: Clinical evaluation of cardiac rhythm detector

2.3.4 Example – Dental Implant

Even with an implantable product, this can be a viable option, as our last example from dental technology shows: The titanium base is part of a dental implant, a class IIb implantable medical device. The titanium base is used to create an individually manufactured implant prosthetic structure. After bonding with a CAD/CAM milled structure, it represents the connecting element to the implant. It can also be sold individually, so that a clinical evaluation must also be prepared for this product.

When conducting a literature search in the field of dental implants, you quickly come across the limitations of such system components. There is still no human study that has exclusively examined the titanium base as a test product. Only in vitro studies or studies on material properties (titanium), etc. were published. How the choice of route based on performance data is justified in this case is shown in Table 4:

Table 4: Clinical evaluation titanium base

2.3.5 Conclusion from the examples

In all of these examples, the section on the clinical assessment of the state of the art is also very important. Many product features or functions and in many cases also the clinical benefit can be proven via guidelines, technical documents and standards. What also helps in these examples is the data collection as part of the clinical follow-up (Post-Market Clinical Follow-up, PMCF) - after the product has been placed on the market and bears the CE mark. A clinical assessment based on performance data usually results in measures within the framework of clinical follow-up. These can range from focused literature searches and product registers to application observations and PMCF studies. This makes it possible to specifically close gaps that have not yet been fully documented in the performance data. Such an approach is also recognized and accepted by the notified bodies if the reasons are correct.

3. Conclusion

To date, for many medical devices the equivalence route and the use of clinical data on one or more equivalent devices have been chosen, regardless of the class of the medical device. However, this has changed completely when the MDR came into force. Due to stricter regulations, especially for implantable and Class III devices, this route is hardly possible anymore. This is due to both the difficulty in proving equivalence and the specific regulations, such as the conclusion of a contract between the manufacturers (MDR, Art. 61 Paragraph 5). This change was probably the desired goal of the makers of MDR.

It is therefore crucial to carry out initial literature searches and rethink the clinical strategy at the beginning of the development process. This enables a comprehensive view of the data situation and the state of the art for the product. Determining the intended purpose at an early stage can mean that the route can be taken via performance data, which is now becoming increasingly important and is being used in more and more products. The examples in this article show that this is possible if it can be justified. Nevertheless, a literature search should not be neglected even in a clinical evaluation based on performance data. Data on the state of the art, guideline recommendations and technical standards make a significant contribution to the assessment.

4. How we can help you

As CRO, we support you throughout the entire process of generating and evaluating clinical data and in the approval and market monitoring of your product. And we start with the clinical strategy! We also create the complete clinical evaluation file for you.

In the case of clinical trials, we consider together with you whether and, if so, which clinical trial needs to be carried out, under what conditions and in accordance with what requirements. We clarify this as part of the pre-study phase: In 3 steps, we determine the correct and cost-effective strategy with regard to the clinical data collection required in your case.

If a clinical trial is to be carried out, basic safety and performance requirements must first be met. The data from the clinical trial then flow into the clinical evaluation, which in turn forms the basis for post-market clinical follow-up (PMCF) activities (including a PMCF study if necessary).

In addition, all medical device manufacturers require a quality management system (QMS), including when developing Class I products.

We support you throughout your entire project with your medical device, starting with a free initial consultation, help with the introduction of a QM system, study planning and implementation through to technical documentation - always with primary reference to the clinical data on the product: from the beginning to the end End.

Do you already have some initial questions?

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

Why is clinical strategy so important in medical device development?

 At medXteam, the focus is on clinical data. In this context, as CRO, we not only carry out clinical trials with medical devices in accordance with MDR and ISO 14155, but also offer all other options and forms of data collection and product approval as well as market surveillance. Right from the very beginning of a product idea, but also with regard to the MDR transfer of existing products, the clinical strategy plays an important role. It not only paves the way for the collection and evaluation of the necessary clinical data, but is also the basis for time and cost planning. This blog post looks at exactly this fundamental role: What is the clinical strategy and why is it so crucial?

Abbreviations

MDR Medical Device Regulation; EU Regulation 2017/745

PMCF Post-Market Clinical Follow-up, clinical follow-up

CEP Clinical Evaluation Plan

CDP Clinical Development Plan

Underlying regulations

EU Regulation 2017/745 (MDR)

1 Introduction

The development of a new product or the MDR transfer of an existing product presents medical device manufacturers with extensive challenges. One of these is the early development of a clinical strategy. The MDR explicitly requires the creation of a clinical development plan in Annex XIV. This plan is intended to cover all phases from idea to market and beyond, including exploratory studies, feasibility studies, pilot studies, confirmatory studies such as pivotal clinical trials and post-marketing clinical surveillance. The definition of milestones and the description of possible acceptance criteria are essential components.

The importance of such a clinical strategy can be attributed to several key factors. On the one hand, it enables clear structuring and planning of the development process. By defining goals and criteria at an early stage, development time and costs can be controlled efficiently and potential risks can be minimized. On the other hand, the clinical strategy serves not only to meet regulatory requirements, but also to ensure that the product will later bring the greatest possible benefit to patients. It supports manufacturers in making evidence-based decisions at an early stage and in being able to classify the product in terms of its clinical performance, safety and benefit.

In addition, the clinical strategy provides valuable input for risk management. A key part of the strategy includes conducting a comprehensive literature search to integrate existing knowledge about similar products or technologies and identify potential risks at an early stage. This information is crucial to assess, manage and ultimately minimize risks.

How this works and what needs to be taken into account is described below.

2. Product idea, start of development or new beginning with the MDR

Regardless of whether it is a new product, an idea for a new product has been born or the existing product needs to be adapted to the MDR requirements, it is always necessary to check which data and clinical data are required to create the initial clinical assessment become. Once this has been created, it must then be updated regularly and clinical data must be collected in the area of ​​clinical follow-up (Post-Market Clinical Follow-up, PMCF). In addition, a so-called clinical development plan (CDP) must be created in the clinical evaluation plan (CEP), which basically contains exactly that, namely which data are needed and must be collected. In order to be able to determine this, a clinical strategy is needed.

2.1 What is the clinical strategy?

The clinical strategy is a comprehensive, systematic approach that guides the identification, collection, analysis and updating of clinical data throughout the entire life cycle of a medical device. It is used to evaluate and document the safety, effectiveness and performance of the product, both during initial development and when adapting to regulatory requirements such as the Medical Device Regulation (MDR). The core of the clinical strategy is the creation and regular updating of an initial clinical assessment. This evaluation requires careful consideration of what specific data and clinical evidence is needed to support the benefits and risks of the product.

The clinical strategy forms the basis for the Clinical Evaluation Plan (CEP), which includes a Clinical Development Plan (CDP). This CDP defines in detail what data and clinical evidence is required to create the clinical assessment and how it should be collected. This includes both the planning and execution of pre-market studies (such as first-in-man studies, feasibility studies, pilot studies and pivotal clinical trials) as well as the ongoing collection of post-market data through Post-Market Clinical Follow-up (PMCF ) Measures.

The clinical strategy is therefore the basis for the continuous collection of (clinical) data throughout the entire product life cycle. By planning clinical data and assessments early and systematically, the clinical strategy helps to minimize risks, increase development efficiency, identify existing gaps and ultimately accelerate the market launch or MDR transfer of medical devices.

2.2 Building a clinical strategy

The development of a clinical strategy is a complex and indispensable process that covers wide-ranging areas and is deeply embedded in the planning and implementation of the development and evaluation of medical devices. The methodological structure and content of such a strategy are discussed in detail below. The clinical strategy is a comprehensive concept that covers various aspects to ultimately enable well-founded conclusions regarding the product.

2.2.1 Product description with intended purpose

The clinical strategy begins with the detailed product description. This covers the intended purpose of the product, including the technical features as well as the intended indications and contraindications. In addition, the target groups, i.e. patients and users, are defined. This initial classification is fundamental in order to correctly position the product in the medical context and forms the basis for all further steps.

2.2.2 Specific development process

The specific development process for the product is then shown. The relevant performance and safety regulations in accordance with Annex I of the MDR are taken into account. This means that the product is classified further in order to be able to draw the right conclusions for further action.

2.2.3 Documents and evidence

Another essential component of the clinical strategy is the definition of the documents to be created and the evidence required in accordance with Annex II and III of the MDR for the technical documentation of the product. These documents include in particular the necessary documents and test procedures for verification and validation of the product, as this may be important for deciding on the correct route of clinical evaluation.

2.2.4 Identification of similar products

An important step within the clinical strategy is the identification of similar or even equivalent products. This analysis makes it possible to use existing knowledge and data to support the development and evaluation of your own product. By comparing with similar products or applications in the same area of ​​application, it is possible to better estimate what clinical data is already available or required and how it can best be collected.

2.2.5 Literature and safety database search

The clinical strategy then naturally includes a literature search and a search in safety databases for similar or equivalent products. This research serves to record the current state of the art and to ensure that all relevant clinical data and information about safety aspects and similar applications, the area of ​​application of the medical device, etc. are taken into account.

2.2.6 Classification of the product in the application context

The targeted classification of the product in its application context is based on the knowledge gained from the previous steps. In particular, the comprehensive literature search makes a significant contribution to this. By analyzing existing data on similar or equivalent products and assessing the current state of the art, important insights into the practical application conditions and the needs of the target group can be gained.

The integration of this diverse information makes it possible to classify the product in the application context. This not only takes into account the theoretical intended purpose of the product, but also reflects its use in real clinical or home environments. This allows a realistic assessment of product performance under typical application conditions, which in turn optimizes product development and evaluation.

2.3 Conclusions from the clinical strategy

The careful development of a clinical strategy for medical devices brings with it far-reaching conclusions that are crucial to the direction of the product and its explicit strategy. These conclusions not only provide guidance for the clinical evaluation and development process, but also help to optimally prepare the product for market and use or for MDR transfer.

2.3.1 Foundation for the clinical assessment route

The clinical strategy lays the foundation for the clinical evaluation route and strategically aligns the planning of the development process. There are three possible ways to do this:

1. Clinical assessment using your own clinical data

The decision to conduct our own clinical trials is necessary if no alternative routes via performance data or data on equivalent products are viable, or if the product has innovative clinical claims that must be clearly supported with clinical data. This approach often involves higher costs and a longer time frame.

2. Performance/verification data (MDR Art. 61(10))

Using verification and performance data, as well as additional literature on similar products, is another possible route whenever direct demonstration of compliance with essential safety and performance requirements based on clinical data is deemed inappropriate. This approach is typically time and cost effective, but requires sound justification as to why it is considered appropriate.

3. Data on equivalent products

The use of data on equivalent products is another possibility, provided such products exist and clinical data on them are available. This route has long been the gold standard of clinical evaluation. Due to the increased MDR requirements in particular

• implantable class IIb and
• all Class III products

as well as increased requirements for proof of equivalence, e.g. B. for software, this hardly takes place anymore. If this route is nevertheless possible, the need for own clinical data can of course be avoided, which of course potentially accelerates the development process.

2.3.2 Identification of further risks and side effects

The comprehensive collection and analysis of data as part of the clinical strategy helps to identify further, previously unknown risks and side effects. These insights are also of great value for risk management and enable a more precise assessment of alternative uses of the product. By identifying potential risks early, measures to minimize risks can be implemented and the safety of the product for users and patients can be maximized.

2.3.3 Identification and closure of gaps in clinical data

Another critical aspect of the clinical strategy is the identification of possible gaps in the required clinical data. The early detection of such deficits makes it possible to take targeted measures to adequately close these gaps. This can be done through additional in-house data collection (e.g. planning a clinical trial, as a clinical claim cannot yet be proven using clinical data), the collection of post-market or PMCF data or the re-analysis of existing data.

3. Literature search for clinical strategy

On the one hand, the literature search as the core of the clinical strategy makes it easier to classify the product into its area of ​​application. It also leads to the identification of potential risks and helps in the development of risk mitigation strategies. It ultimately supports the formulation of a long-term clinical and development strategy based on the exact data it collects.

The literature search process takes place in several steps:

Fig. 1: Literature search process

Defining the search strategy : The first step is to carefully plan the search strategy. Relevant keywords and search terms are defined that form the framework of the research.

Choosing the right databases : Because of the wealth of information, choosing the right databases is crucial. Each database has its own strengths and specializations that need to be taken into account.

Carrying out the search : The databases are systematically searched using the defined keywords. This phase requires patience and care to ensure that no relevant information is missed.

Analysis and selection of data : After collecting the information, the results are critically evaluated. The most relevant and well-founded studies and reports are selected that help answer the question.

The analysis of “state of the art” data required for the clinical strategy captures the current state of the art.

The literature search includes four steps:

Fig. 2: Literature search step by step

4. Conclusion

Developing and implementing a clinical strategy for medical devices is a crucial step that goes far beyond simply meeting regulatory requirements. It offers a structured approach to systematically evaluate and document the safety, effectiveness and performance of a product. This process makes a significant contribution to optimally adapting the product to the needs of users and patients while at the same time meeting the regulatory framework.

Through the detailed planning and analysis that a clinical strategy requires, medical device developers and manufacturers can make informed decisions that impact the entire life cycle of the product. From initial product conception through market launch to post-market monitoring, the strategy enables ongoing evaluation and adaptation of the product to changing clinical and regulatory requirements. This applies both to new developments and product ideas and to the MDR transfer of an existing product.

The choice of route for clinical evaluation, be it through own clinical data, performance data or data on equivalent products, lays the foundation for the development process and largely determines the time and costs involved. In addition, the systematic detection and assessment of risks and side effects as well as the identification and closure of gaps in the clinical data enable continuous improvement of the product and its (planned) use.

In summary, it can be said that the creation and implementation of a clinical strategy is not only a regulatory necessity, but also represents an opportunity to optimize medical devices and ensure their success in the market. It promotes an in-depth examination of the product and its application context, improves quality and safety for end users and patients and supports efficient product development. In an industry characterized by innovation and constant change, clinical strategy is a central pillar for the long-term success of medical devices.

5. How we can help you

As CRO, we support you throughout the entire process of generating and evaluating clinical data and in the approval and market monitoring of your product. And we start with the clinical strategy!

In the case of clinical trials, we consider together with you whether and, if so, which clinical trial needs to be carried out, under what conditions and in accordance with what requirements. We clarify this as part of the pre-study phase: In 3 steps, we determine the correct and cost-effective strategy with regard to the clinical data collection required in your case.

If a clinical trial is to be carried out, basic safety and performance requirements must first be met. The data from the clinical trial then flow into the clinical evaluation, which in turn forms the basis for post-market clinical follow-up (PMCF) activities (including a PMCF study if necessary).

In addition, all medical device manufacturers require a quality management system (QMS), including when developing Class I products.

We support you throughout your entire project with your medical device, starting with a free initial consultation, help with the introduction of a QM system, study planning and implementation through to technical documentation - always with primary reference to the clinical data on the product: from the beginning to the end End.

Do you already have some initial questions?

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

From data to insights: trend reports and the requirements of the MDR

At medXteam, the focus is on clinical data. In this context, as CRO we not only carry out clinical trials with medical devices in accordance with MDR and ISO 14155, but also offer all other options and forms of data collection. This is where the topic of trends in accordance with Article 88 of the MDR comes into play: data must also be collected and evaluated for this purpose. That's exactly what this blog post is about.  

Abbreviations

MDR Medical Device Regulation;
EU Regulation 2017/745 PMS Post-Market Surveillance

Underlying regulations

EU Regulation 2017/745 (MDR)

1 Introduction

In the world of medical devices, safety and effectiveness are paramount, making it crucial to identify trends early and respond appropriately.

A trend report in accordance with Article 88 of the Medical Device Regulation (MDR) may be required if statistically significant negative trends are identified in the data collected. Provided that the criterion defined in Article 88 of the MDR is met, manufacturers of medical devices are obliged to prepare regular trend reports and, if necessary, take measures to minimize potential risks and ensure the safety of their products.

2. Trend reports

2.1 What is a trend report?

A trend report can be a part of the post-market surveillance (PMS) report.
The PMS plan and PMS report are based on Articles 84 and 85 of the MDR. The trend report is a tool for the early identification of trends and developments related to the safety and performance of medical devices. This report is intended to identify and assess potential risks or safety concerns associated with a medical device. According to Article 88 of the MDR, a trend report is required when a statistically significant increase in the frequency or severity of non-serious incidents or expected adverse reactions is identified that could have an impact on the benefit-risk analysis and result in risks to the health or safety of Lead or may lead to patients, users or others that is unacceptable in light of the intended use.

2.2 Importance of Trend Reports

Trend reports are critical to medical device manufacturers for several reasons:

• Early identification of risks: By regularly analyzing trends, potential risks or safety concerns can be identified early and appropriate measures taken to ensure patient safety.
• Informed decision making: Manufacturers can make informed decisions based on trend reports, both in terms of product development and ongoing monitoring of products already on the market.
• Compliance with legal requirements: Article 88 of the MDR makes the creation of trend reports a legal requirement. Compliance with this provision is therefore essential for manufacturers to meet regulatory requirements and maintain marketing authorization for their products.

3. Implementation of trend reports in accordance with Article 88 of the MDR

The implementation of trend reports in accordance with Article 88 of the MDR requires a structured and systematic approach.

3.1 Data analysis

As part of the data analysis, the data collected is evaluated with regard to its development over time using a suitable statistical method. The following points, among others, are taken into account:

3.2 Data collection and analysis

Manufacturers must continually collect and analyze data that reflects relevant trends and developments related to their products. This may include evaluation of clinical trials, user feedback, post-market surveillance data and regulatory updates.

• • The collected data is evaluated and first checked for a statistically significant increase in frequency or severity to evaluate whether further analysis of the trend and a resulting trend report are necessary.
  • Statistical significance occurs when an observed effect or difference in data is highly unlikely to be due to chance, but rather indicates an actual connection or difference between the variables examined. This is typically expressed by a p-value, where a p-value smaller than the specified significance level indicates that the observed results are statistically significant.
  • An observed trend in the data may or may not be a causal connection to the use of the product being evaluated. The existence of a causal relationship will be checked in the further course of the evaluation of a significant trend.
  • A trend is determined by evaluating the data from the individual survey times and thus analyzing the development over time in more detail.
  • For this purpose, various statistical methods can be used to evaluate the data collected over time and to adequately check for statistical significance.
    Which statistical method is suitable in a specific case depends on several factors. This includes, among other things, the type of data collected, the size and structure of the sample and the underlying assumptions about the distribution of the data.
  • As part of data analysis, trends are also graphically represented using diagrams or graphics as an effective means of making complex statistical results more understandable and clear.

3.3 Documentation

The results of data analysis must be documented in the form of trend reports as part of the post-market surveillance reports or separately. These results reports should be clearly structured and contain relevant information on identified trends, their root cause analysis and potential impacts, as well as the proposed risk mitigation measures:

• Description of the trend:
  A clear description of the identified trend including its potential impact on the safety and performance of the medical device.
• Root cause analysis:
  An analysis of the causes or factors that could contribute to the development of the trend, including possible technical, clinical or regulatory aspects.
• Impact Assessment:
  An assessment of the potential impact of the trend on the safety and performance of the medical device, as well as on users and patients.
• Suggested actions:
  Suggestions of appropriate actions to minimize or eliminate potential risks, including updates to the risk management plan, changes to product design or instructions for use, and user training.
• Action Plan:
  A plan to implement the proposed actions, including timelines and responsibilities.

4. Review and Update

Trend reports must be reviewed regularly and updated as necessary to ensure they reflect current trends and developments.

5. Application example

To illustrate the concepts and processes associated with trend reports in accordance with Article 88 of the MDR, we consider fictitious data on sales figures and complaints from a medical device manufacturer (Table 1).

Table 1: Number of sales and complaints over time

The collected data on sales and complaints can now be checked for a trend and a significant change using suitable statistical methods (Table 2).

Table 2: Results of the statistical analysis of the data collected

At a defined significance level of 0.05, the number of sales from year 1 to year 11 is a significantly positive increase with a p-value of 0.0126. For complaints with a p-value of 0.8205, which is greater than the significance level of 0.05, the change cannot be demonstrated to be statistically significant.

Since the results of the evaluations do not represent negative, statistically significant trends, a root cause analysis and the consideration of further measures are not necessary.

However, if there is a negative, statistically significant trend, this trend is analyzed thoroughly. The data collected is evaluated in detail with regard to a causal connection to the use of the product, the causes and the effects of the trend. This also includes a thorough examination of the complaints, their distribution in the complaint categories and their influence on the identified trend for the derivation of measures and, if necessary, adjustments to the risk analysis. The results of these evaluations and appropriate measures to be taken are documented as part of the post-market surveillance report or separately.

6. Conclusion

Trend reports in accordance with Article 88 of the MDR play a crucial role in ensuring the safety and performance of medical devices. By systematically analyzing trends, manufacturers can identify potential risks early and take appropriate measures to ensure the safety of patients, users and third parties. Compliance with this legal requirement is therefore essential for all manufacturers who want to sell medical devices on the European market.

7. How we can help you

Our statisticians accompany you from data collection through analysis to documentation, the trend report! Be safe!

Clinical trials:

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.

If a clinical trial is to be carried out, basic safety and performance requirements must first be met. The data from the clinical trial then feed into the clinical evaluation, which in turn forms the basis for post-market clinical follow-up (PMCF) activities (including a PMCF study).

In addition, all medical device manufacturers require a quality management system (QMS), including when developing Class I products.

We support you throughout your entire project with your medical device, starting with a free initial consultation, help with the introduction of a QM system, study planning and implementation through to technical documentation - always with primary reference to the clinical data on the product: from the beginning to the end End.

Do you already have some initial questions?

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

Literature search for medical devices

At medXteam, the focus is on clinical data. In this context, as CRO we not only carry out clinical trials with medical devices in accordance with MDR and ISO 14155, but also offer all other options and forms of data collection. The literature search plays an important role in this context. Because it is not only essential in connection with the clinical evaluation of medical devices. This blog post shows when, where and why you need a literature search in other situations.

Abbreviations

MDR Medical Device Regulation; EU Regulation 2017/745

DiGA Digital Health Application

PMCF Post-Market Clinical Follow-up, clinical follow-up

QMS quality management system

Underlying regulations

EU Regulation 2017/745 (MDR)
Medical Device Implementation Act (MPDG)
ISO 14155

1 Introduction

In the regulatory environment of medical devices, the literature search is an elementary process that takes place in different phases of the life cycle. It is relevant not only in clinical assessment, but also in context

• the clinical strategy,
• the development strategy,
• of risk management
• in connection with clinical trials, PMCF studies
• at DiGAs with regard to systematic data collection

This article therefore first answers the question: When do I carry out a literature search for medical devices? The different contextual situations and the design of the search in the respective situation are discussed.

In addition, we also show how to conduct an effective literature search and offer practical examples for designing the search strategy in different situations.

2. Literature search and clinical data

When it comes to the topic of “literature search”, clinical data obviously plays an important role. Clinical data is the heart of medical research and refers to the collection of information about the product when used on humans. They include a wide range of information obtained from clinical studies, patient observations, research results and other medical sources. This data is essential for assessing the effectiveness, safety and quality of medical devices. They form the basis for regulatory decisions and make a significant contribution to the development of innovative medical solutions.

Clinical data is defined in connection with medical devices in the MDR in Art. 2 as follows:

“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."

The literature search is therefore the process of finding clinical data. This leads us into the world of medical databases. The most important sources include PubMed, the Cochrane Library and EMBASE. These databases provide access to a variety of publications, journals, conference proceedings and systematic reviews, meta-analyses, guidelines and much more.

The literature search process takes place in several steps and is the same in every regulatory situation:

Fig. 1: Literature search process

Defining the search strategy : The first step is to carefully plan the search strategy. Relevant keywords and search terms are defined that form the framework of the research.

Choosing the right databases : Because of the wealth of information, choosing the right databases is crucial. Each database has its own strengths and specializations that need to be taken into account.

Carrying out the search : The databases are systematically searched using the defined keywords. This phase requires patience and care to ensure that no relevant information is missed.

Analysis and selection of data : After collecting the information, the results are critically evaluated. The most relevant and well-founded studies and reports are selected that help answer the question.

A possible technique that can be used in this process is e.g. B. the PICO technique: It helps to make search queries more precise and more effective. PICO stands for Population, Intervention, Comparison and Outcome. This method makes it possible to focus the research on the most important aspects, thereby providing more precise and relevant results.

This technology is used in particular in the context of

• Patient care
• Treatment

and for determination

• the accuracy of diagnostic tests
• prognostic factors

used.

3. Literature search in practice

The literature search enables well-founded decisions to be made, in this context we also speak of “evidence-based” decisions. It is therefore an indispensable part of the development and evaluation of medical devices because it

• provides a structured basis for decision-making and
• which ensures the quality, clinical performance and safety of medical devices.

There are various situations in the product life cycle of a medical device in which a literature search is necessary. Each has specific goals and foci:

• Context Clinical Assessment: Plan, Report
• Context Clinical strategy, development strategy, risk management
• Context Clinical trial, PMCF study, systematic data collection

These are discussed in detail below.

3.1 The literature search in the context of clinical evaluation

The clinical evaluation of medical devices (Article 61 of EU Regulation 2017/745 (MDR)) is a core element of technical documentation and, as part of the validation of clinical data, confirms the safety of the medical device, its clinical performance and its benefit-risk ratio. The literature search is an integral part of providing this information. The process of "assessing" clinical data is a defined sequence of actions to analyze the various sources, including clinical trials, not only in terms of content but also methodologically. Evaluation criteria include the relevance of the publication, the quality and scientific validity as well as the weighting of the data with regard to the clinical evaluation.

The analysis of “state of the art” data captures the current state of the art. In contrast, the data of the product being evaluated is provided to substantiate the claimed clinical performance and safety of the product.

The literature search includes four steps:

Fig. 2: Literature search step by step

The aim of the clinical evaluation is to create a sound basis for market approval and to ensure the quality, safety and effectiveness of the medical device. This requires careful documentation of the entire process, including literature search plan, protocol and report, to ensure transparency and traceability for audits and regulatory reviews.

3.2 Context clinical strategy, development strategy, risk management

Clinical strategy:

In these areas, literature searches facilitate the identification of potential risks and the development of risk mitigation strategies. It also supports the formulation of a long-term clinical and development strategy based on current research and existing data. It thus lays the foundation for the clinical evaluation route and sets the course for the entire planning of the development process in terms of costs and time.

Risk management:

Risk management is the systematic application of management strategies to identify and control product risks. There is a close interface between risk management and clinical assessment, especially when incorporating the current medical and technological state of the art.

The literature search in the context of the clinical strategy is also carried out in four steps (see Figure 2).

A focus is on searching for similar products to assess equivalence, identify side effects and incorporate market data. The product's intended use is also examined, including the prevalence and incidence of relevant conditions or diseases, alternative forms of use, and current medical guidelines.

3.3 Context clinical trial, PMCF study, systematic data collection

Clinical test:

The clinical trial is designed in the project planning phase and carried out with the final product as part of product validation. The collected data flows into the Clinical Evaluation Report (CER) and is crucial for the product's market entry. It is carried out in accordance with legal requirements such as MDR and ISO 14155.

The literature search in the context of clinical testing is again carried out in four steps (see Figure 2). The focus here is on identifying relevant endpoints on the basis of which the research question should be answered. Furthermore, ideas for a potential study design should be collected.

DiGA:

For digital health applications (DiGAs), a literature search for the "minimally important difference/change" (MCID) is crucial for the systematic data collection and evaluation of the data collected on the product in order to assess the clinical significance of the data and classify it accordingly. But the DiGA guidelines require a systematic literature search, particularly for the evaluation concept: it should provide evidence of the positive care effect.

4. Digital literature search

We have seen how important and central the literature search is in connection with medical devices, across the entire product life cycle.

medXteam specializes in the collection and evaluation of clinical data: our focus is on literature searches. 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.

4.1 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)

4.2 Documentation of the analysis

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

4.3 Report on the literature search

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

4.4 Digitalized clinical assessment

Digitalization is of course particularly effective here:

The core of the clinical assessment 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:

4.5 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.

5. Conclusion

According to MDR Art. 2, clinical data includes information on safety and performance derived from clinical trials, specialist literature, clinical experience reports and post-market surveillance. These data sources are crucial for an effective literature search. Searching the literature where we find clinical data and the importance of this data to various aspects of medical device development illustrates how fundamental literature searching is to the entire development process.

The literature search for medical devices is more than just a step in the development process; it is a continuous process that has a decisive influence on the quality and safety of medical devices. It enables manufacturers, researchers and clinical experts to make informed decisions based on the latest scientific evidence. In an ever-evolving industry, literature searches remain an essential part of ensuring innovative and safe medical devices.

A literature search is essential for all medical devices over the entire product life cycle, namely: To obtain clinical data!

6. How we can help you

Due to high demand, we have produced a special online training:

This training is designed to provide medical device professionals with comprehensive guidance on effective literature searches in various settings with a focus on clinical evaluation. The training is divided into four lessons, which include both theoretical basics and practical application examples.

Lesson 1: Literature search and clinical data

Lesson 2: Literature search in practice

Lesson 3: Getting started in practice: First practical example

Lesson 4: More practical examples

Clinical trials:

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.

If a clinical trial is to be carried out, basic safety and performance requirements must first be met. The data from the clinical trial then feed into the clinical evaluation, which in turn forms the basis for post-market clinical follow-up (PMCF) activities (including a PMCF study).

In addition, all medical device manufacturers require a quality management system (QMS), including when developing Class I products.

We support you throughout your entire project with your medical device, starting with a free initial consultation, help with the introduction of a QM system, study planning and implementation through to technical documentation - always with primary reference to the clinical data on the product: from the beginning to the end End.

Do you already have some initial questions?

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