MDR
Clinical Evaluation

Principle of clinical evaluation

For all medical devices under the Medical Device Regulation (MDR), proof of safety, performance and clinical benefit must be provided. The so-called clinical evaluation serves this purpose.

Per MDR definition the following applies: A clinical evaluation [...] "means a systematic and planned process to continuously generate, collect, analyse and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer [MDR].”

Clinical evaluation essentially consists of two areas: (1) a plan addressing, inter alia, the establishment and updating of the clinical evaluation and (2) a report containing the activities carried out, such as the collection and analysis of clinical data, and the conclusions thereof.

Stages according to MEDDEV

MEDDEV 2.7-1 Revision 4 already provided a useful and established structure at the time of 93/42/EEC (MDD). This structure should also be used as a guideline under MDR - why reinvent the wheel?

If the stages are transferred to the document level, stage 0, as the graphic on the right suggests, is documented in the plan (CEP). The remaining stages describe the activities carried out and are documented in the report (CER).

Gathering, evaluating and analysing the data is an essential part of literature research and analysis. Please refer to the section "Literature and clinical data" further down on this page for more information.

Clinical evaluation plan (CEP)

The preparation of a CER has to be planned within a CEP - this is a mandatory requirement of the MDR. The exact contents of the plan are contained in Annex XIV, Part A, first item. These include the following points:

• an identification of the general safety and performance requirements that require support from relevant clinical data;
• a specification of the intended purpose of the device;
• a clear specification of intended target groups with clear indications and contra-indications;
• a detailed description of intended clinical benefits to patients with relevant and specified clinical outcome parameters;
• and some other requirements.

It quickly becomes clear that even the planning of a clinical evaluation is quite extensive. But the detailed requirements also have something good about them: the content to be delivered is relatively clearly addressed. In addition, MEDDEV 2.7-1 Revision 4 provides helpful information on many points. Although this refers to 93/42/EEC (MDD), the basic concept was not reinvented by MDR.

Clinical evaluation report (CER)

The CER records the work steps that have been carried out and planned in the CEP. Here, the defined and methodologically sound procedure required by Article 61 of the MDR is applied. As a result, a comprehensive document is produced which sets out the safety, performance and clinical benefit of the medical device.

The report brings together the data and findings from risk management, usability, biocompatibility, literature research and analysis, and post-marketing surveillance. On this sound basis, the safety and performance of the medical device is assessed. In addition, it is demonstrated that it has a clinical benefit, which is mandatory for the demonstration of clinical evidence.

The amount of different data alone shows how complex the CER of medical devices is. An author must be able to evaluate all this data in the right context and at the content level in order to draw correct and relevant conclusions.

Clinical data

As the name suggests, clinical evaluation is based on clinical data. Such data refers to "information concerning safety or performance that is generated from the use of a device [MDR]". The following sources of clinical data exist:

• "clinical investigation(s) of the device concerned,
• clinical investigation(s) or other studies reported in scientific literature, of a device for which equivalence to the device in question can be demonstrated,
• reports published in peer reviewed scientific literature on other clinical experience of either the device in question or a device for which equivalence to the device in question can be demonstrated,
• clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up; [MDR].”

A common method for identifying these data is a literature search. This involves a systematic search for published studies which can then be used as a data basis. How such a literature search is carried out is described in the following section.

Literature search

• Step 1: Analysis of the intended use and clinical claims, including patient population, indications, contraindications. Data on the aspects identified here will be collected in the literature search.
• Step 2: Identification of data sources from which clinical data can be obtained. For example pubmed, Cochrane, Embase.
• Step 3: Creation of search terms and objective filters to obtain data on the medical device under evaluation, the equivalent products and the state of the art.
• Step 4: The identified literature is first pre-filtered at the level of abstracts and assessed for potential relevance.
• Step 5: Potentially relevant literature is now analysed in depth at full text level.
• Step 6: The clinical data obtained in the analysis of the full texts will now be used to support the clinical evidence.

Lack of clinical data

What happens if, while creating the CER, you discover that there is not enough clinical data on your medical device?

Can you create a clinical evaluation without clinical data?

"[…] where the demonstration of conformity with general safety and performance requirements based on clinical data is not deemed appropriate, adequate justification for any such exception shall be given based on the results of the manufacturer's risk management and on consideration of the specifics of the interaction between the device and the human body, the clinical performance intended and the claims of the manufacturer. In such a case, the manufacturer shall duly substantiate in the technical documentation […] why it considers a demonstration of conformity with general safety and performance requirements that is based on the results of non-clinical testing methods alone, including performance evaluation, bench testing and pre-clinical evaluation, to be adequate [MDR]."

Fortunately for the patients, approval without sufficient data does not work. The principle is based on a sufficient data basis and without this, compliance with the general safety and performance requirements cannot be demonstrated.

Approval without clinical data only works in a few, special cases. However, what we have frequently observed with clients is that insufficient clinical data were identified during a clinical evaluation, which led to difficulties in obtaining approval.

The solution to the problem is ideally to adapt the literature search. It is quite possible that you have used an unfavorable combination of search terms and filters or equivalent devices. Actually, of course, you should already check during the creation of the search protocol whether it is suitable. Sometimes, however, this is difficult to do or it is simply forgotten.

If even this adaptation does not help, clinical studies or trials must be carried out to generate the necessary data. For manufacturers with valid MDD certificates, it is advisable to check during the period of validity of these certificates whether sufficient data is available for MDR.

In particular, it is much more difficult under MDR than it was under MDD to obtain data on equivalent devices. Therefore, the generation of sufficient clinical data should be started under the MDD in order not to be forced to conduct a clinical trial with an unapproved device. The associated costs for the approval of the ethics committee as well as in financial and time terms are enormous and should be avoided if possible.

Interface: Risk management

In the course of the analysis of identified data, it may happen that risks are identified in connection with the Company's own medical device or equivalent device that were not previously considered in risk management. Therefore, after the data analysis, a reconciliation between the risks identified in the CER and the existing risk analysis is to be performed.

If new risks have been identified, these are to be fed into the RM process for analysis.

Interface: Usability

It does not occur frequently, but is possible: Literature research has identified indications or even difficulties with regard to usability. In this situation, measures may have to be derived.

Interface: Post-market surveillance (PMS)

An important source of information is, for example, public databases in which incidents involving medical devices are reported. Has anything been reported about the device under evaluation that was not considered in risk management? Have there been incidents with reference products that could also occur with your own device and were not considered?

Interface: Post-market clinical follow-up (PMCF)

The medical device CER is closely linked to your PMCF activities. Through PMCF, you generate clinical data on your product that contribute to the clinical evaluation.

PMCF can be useful under the MDD to generate sufficient clinical data for the approval of your product under MDR. Feel free to contact us on this topic and we will show you how PMCF can make your life easier.

Clinical evaluation for class I medical devices

From manufacturers who only have Class I medical devices in their portfolio, we repeatedly receive the question: "Do I even need a clinical evaluation for a Class I medical device? Under the MDD, we didn't need it at all."

In Germany, the MDD was adopted into national law by the German Medical Devices Act (MPG). The MPG on §19 Clinical Evaluation stated, "The suitability of medical devices for their intended use shall be demonstrated by a clinical evaluation based on clinical data in accordance with §3 number 25, unless other data are sufficient in justified exceptional cases. The clinical evaluation includes the assessment of adverse effects as well as the acceptability of the benefit/risk ratio specified in the Essential Requirements of Directives 90/385/EEC and 93/42/EEC. The clinical evaluation shall be conducted in accordance with a defined and methodologically sound procedure and shall take into account, where appropriate, relevant harmonized standards."

The paragraph was not a backdoor way of not performing a clinical evaluation. It did, however, allow for data other than clinical data to be used in justified exceptional cases.

The same situation applies under the MDR (EU 2017/745). In Article 61 (10), this loophole for clinical evaluation without clinical data also exists. However, also only in justified exceptional cases.

So the answer to the question is: "Yes, you need a clinical evaluation for every medical device".

Clinical evaluation for software as a medical device

The clinical evaluation for software medical devices such as smartphone apps differs from the clinical evaluation for classic medical devices. This makes sense and is understandable because the interaction between software and the patient is different from that between a classic medical device and a patient.

A software provides information, which in turn can cause harm. However, software itself cannot, for example, cause physical harm to people. After all, the software does not touch anyone.

To illustrate the different processes of clinical evaluation on software, there is the document MDCG 2020-1. Below, we show its table of contents as an example for a first overview.

MDCG 2020-1 mainly describes three aspects

• valid clinical association
• technical Performance
• clinical Performance

The so-called "valid clinical association" is very similar to the so-called scientific validity of IVDs in the context of performance evaluation. To put it casually, it requires proof that the information provided by the software is related to a clinical condition or physiological state.

With an IVD, this is even more comprehensible. Imagine a COVID-19 rapid test. I want to use the test to detect COVID-19 infection. I now need proof of scientific validity for the IVD rapid test to prove that what I measure with the rapid test also has a correlation with a COVID-19 infection. Because if the connection does not exist, I cannot prove a COVID-19 infection with the measurement result. This then has nothing to do with the performance of the product, but simply with the fact that this type of detection is not possible.

So I also have to provide such proof for software as a medical device. Is the information provided related to the clinical condition or physiological state described in the intended purpose?

The "technical performance" describes the ability of a software to accurately and reliably provide the intended technical output from the input data made.

At this point, it is necessary to prove on a technical level that the software provides correct outputs from the respective inputs. These proofs are usually generated in the course of software development, when the algorithms of the software are checked and optimized

Therefore, the proof of clinical performance still remains. As with traditional medical devices, this requires data showing that the software has been tested for the intended use(s), target group(s), condition(s) of use, operating and usage environment(s), and with all intended user groups.

How exactly the evidence of clinical performance is to be provided must be decided on a case-by-case basis. It is important to note that Article 61 (10) of the MDR also applies here - the route for cases where evidence of compliance based on clinical data is not appropriate.

Clinical studies & investigations

The performance of clinical studies or PMCF studies is the necessary way to generate clinical data as a basis for approval for many existing products and especially for new developments. Due to the fact that there are extensive requirements in the area of GCP (Good Clinical Practice, ISO 14155 and at the legal level for the performance of clinical studies, an enormous amount of documentation is associated with this.

Some of our customers procure personnel who deal exclusively with planning and study coordination. Other customers rely on our study partner, who offers a convenient and cost-effective all-round solution for this.

Technical documentation

The clinical evaluation is an essential part of the technical documentation and thus the basis for the approval of any medical device on the European market. thinqbetter can support you in the preparation of CEP and CER - you will find an overview of our services in this area below.

Conformity assessment

Annex IX:
- Conformity assessment based on a quality management system and an assessment of the technical documentation - As the name suggests, you need complete technical documentation for your device.

Annex X:
- Conformity assessment based on a type-examination - "Als EU-Baumusterprüfung wird das Verfahren bezeichnet, mit dem eine Benannte Stelle feststellt und bescheinigt, dass ein Produkt einschließlich der technischen Dokumentation und der einschlägigen Prozesse während des Lebenszyklus sowie ein entsprechendes für die geplante Produktion des Medizinprodukts repräsentatives Exemplar den einschlägigen Bestimmungen dieser Verordnung entsprechen EU type-examination is the procedure whereby a notified body ascertains and certifies that a device, including its technical documentation and relevant life cycle processes and a corresponding representative sample of the device production envisaged, fulfils the relevant provisions of this Regulation [MDR]."

Annex XI:
- Conformity assessment based on product conformity verification - This procedure requires a successfully completed Annex X procedure and therefore also technical documentation.

Conclusion:
Without clinical evaluation, the technical documentation referred to in Annexes II and III is not complete. Therefore, the medical device cannot be approved, as all conformity assessment procedures require the completeness of the TD.

MDCG documents

Die klinische Bewertung erhält gesetzliche Vorgaben zwar ausschließlich aus der MDR, allerdings erwarten benannte Stellen, dass MDCG Dokumente entsprechend berücksichtigt werden. Darüber hinaus sind diese äußerst hilfreich, um ein besseres Verständnis davon aufzubauen, was erwartet wird. Eine gute Vorbereitung lohnt sich, da alle Abweichungen auf Seiten der benannten Stelle abverfolgt werden und somit Kosten erzeugen.

Document	Description
MEDDEV 2.7/1 Rev. 4	Although the document was already developed under 93/42/EEC (MDD), it still provides important information on the clinical evaluation process. MDCG 2020-6 mentions which parts of the MEDDEV are still applicable. Nevertheless, non-applicable parts may also contain helpful information.
MDCG 2020-1	Software as a medical device also requires a clinical evaluation. However, this process is somewhat different than for other products. MDCG 2020-1 provides helpful information in this regard
MDCG 2020-5	The popular equivalence route of clinical evaluation under MDD still exists. Under MDR, unfortunately, this is only possible for a few products.
MDCG 2020-6	Existing products, i.e. so-called legacy devices, can be transferred to the MDR more easily than complete new registrations. The document should definitely be read!
MDCG 2020-13	The Clinical Evaluation Assessment Report specifies what a notified body will review during the clinical evaluation review. Knowing this will help you prepare.

MDCG 2020-05 Equivalence

The use of data on equivalent products is a viable option to collect sufficient clinical data to demonstrate the applicable General Safety and Performance Requirements. Under 93/42/EEC (MDD), it was possible to use data from sources other than the device itself to a greater extent. At this point, the MDR leads to a situation where the data situation can become difficult for even established products.

In April 2020, the Medical Device Coordination Group (MDCG) published a document that provides guidance for notified bodies and manufacturers on equivalence.

The document aims in particular to highlight the differences between MEDDEV 2.7-1 Revision 4 and the requirements of the MDR.

Already under MEDDEV, equivalence was related to aspects of technical, biological and clinical properties of the devices. These properties are useful comparative values and remain the same under MDR.

The MDR requires the following with regard to biological properties: "The product uses the same materials or substances that come into contact with the same human tissues or body fluids, for a similar type and duration of contact and similar release properties of substances, including degradation products and leachables". Under the MEDDEV, variations in materials were possible at this point, e.g. for products in contact with intact skin. By means of a risk assessment, components with other materials could also be regarded as equivalent if necessary. The requirement that, for example, the duration and type of contact must be similar is also new. It becomes clear that MDR is much stricter with regard to biological properties.

Clinical properties: Products under the MDR must now be used by the same type of user, for example physicians or lay users.

Technical characteristics: Products under MDR must now be used under similar conditions of use. The MEDDEV demanded that these should be identical. Furthermore, MDR demands that in the case of software, the algorithms in the compared products must be similar.

Overall, it is clear that the Medical Devices Regulation makes it extremely difficult to use equivalent products from other manufacturers. Therefore, the importance of sufficient post-market surveillance data must be emphasized at this point. This data can be generated during the validity period of the MDD certificates and can be used as a basis for approval of the MDR.

If you could not prove equivalence, it is possible to use data from similar products. Often "no longer equivalent" products are well suited for this.

You can use such data for the following purposes:

• Ensure that the risk management system is comprehensive by identifying relevant hazards and clinical risks.
• Understanding the state of the art, the natural course of disease and alternative available treatments.
• Assist in defining the scope of the clinical evaluation by identifying design features of similar devices that raise particular performance or safety concerns.
• Provide input to the design of the clinical trial or the design of the post-market clinical follow-up (PMCF) and to the post-market surveillance system (PMS).
• Identification of relevant and specified clinical outcome parameters for the intended clinical benefit based on published clinical data relating to the similar product(s).
• Definition of minimum requirements for a quantified clinical benefit considered clinically relevant and/or identification of acceptable rates of occurrence of risks and adverse events.

MDCG 2020-06 Clinical evidence for legacy devices

This document provides valuable guidance for products that were already approved under the MDD and AIMD and for which a clinical evaluation according to MDR is now to be prepared.

For many of the legacy devices there is little usable data available under MDR. One reason is that it has become more difficult to prove equivalence and thus to use data from other products. Another aspect is the fact that too many products are simply not or hardly ever researched because of their simplicity. Thus, there are hardly any publications.

So how should the respective GSPRs (General Safety and Performance Requirements), be demonstrated for such products?

How is "sufficient clinical evidence" to be proven in this situation, especially since the term is not even defined?

Document MDCG 2020-06 states that "sufficient clinical evidence" is understood as the present result of the qualified assessment which has reached the conclusion that the product is safe and provides the intended benefit. This qualified assessment is performed as a continuous process within the clinical evaluation. The Medical Devices Regulation regards the generation of clinical data and the evaluation of these data as an important part of the "life cycle approach" of a medical device.

In the first conformity assessment procedure according to MDR of your product approved under the MDD or AIMD, the clinical pre-market and post-market data of the product can be used. These must have been generated within the framework of the valid MDD/AIMD certificates. It is possible that the existing clinical data may not be sufficient in terms of the MDR. For legacy devices that have undergone a conformity assessment procedure, it is assumed that these were supported by clinical data. Post-marketing clinical data, together with the clinical data generated for conformity assessment according to the MDD/AIMDDD, form the basis of the clinical assessment procedure for legacy devices according to the MDR.

For all medical devices, whether authorised under MDD, AIMD or already authorised under MDR, the requirements for post-market surveillance (PMS) and clinical follow-up (PMCF) apply. Thus, from the date of application of MDR, some requirements of MDR are also applicable to legacy devices.