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