Medical device manufacturers must conduct a clinical evaluation of their products in order to be allowed to market them in Europe. To do this, the manufacturer must use clinical data to determine whether the medical device is safe and performs well. The manufacturer then assesses whether the risks of an application are proportionate to the expected benefits. The European Medical Device Regulation (EU) 2017/745 (MDR) has changed the legal basis for clinical evaluations quite a bit. In addition, new experiences, guidelines and interpretations are constantly being added.
What is a clinical evaluation?
A clinical evaluation is a systematic collection and analysis of clinical data from a wide variety of sources (Art. 2 (44) MDR).
According to the MDR, the manufacturer is obliged to perform a clinical evaluation of a medical device (Art. 10 (3)).
The clinical evaluation process must be part of the quality management system (Art. 10 (9f) MDR) and is closely linked to the risk management process.
What does a clinical evaluation demonstrate?
Annex I of the MDR defines the essential requirements for safety and performance of medical devices.
If a manufacturer wants to market a medical device, he must prove that it meets the requirements of Annex I. Clinical evaluation is part of this demonstration and is explained in more detail in Art. 61 and Annex XIV MDR.
Consequently, the manufacturer should demonstrate that the medical device
- achieves the performance intended by the manufacturer
- has been designed and manufactured to be fit for purpose,
- is safe and effective
- does not compromise the clinical condition and safety of patients or the safety and health of users or third parties, as applicable,
- has an acceptable risk/benefit profile,
- is compatible with a high level of health protection and safety, and
- is based on the generally accepted state of the art.
The clinical risk/benefit profile therefore plays an important role. Here, manufacturers must balance the clinical benefits against the clinical risks, including undesirable side effects, according to
- Type of effect,
- intensity,
- duration and
- frequency
in the most precisely defined target group and indication qualitatively and, if possible, also quantitatively.
The strong focus on the risk/benefit assessment in the clinical evaluation is new. This directly relates to the risk management that the marketer must perform according to the MDR. It will be challenging for many companies to link the clinical evaluation and risk management processes in such a way that there are no unwanted overlaps or even contradictions.
There is also a link to the reimbursement of medical devices. This is also based on a risk/benefit assessment of a medical method, which includes the use of medical devices.
However, the concept of benefit must be differentiated at this point: "Benefit" according to Art. 2 (53) of the MDR has a different meaning than "benefit" in the context of reimbursement of medical services by the statutory health insurance.
The latter includes, in addition to the medical benefit, the consideration of the economic benefit and consequently requires a health economic discussion. With regard to the design of clinical trials, the question therefore arises as to the extent to which approval and reimbursement can be meaningfully linked at this point.
What is clinical data?
Clinical data is information about the safety or performance of a device and can come from the following sources ((Art. 2 (48) MDR):
- clinical trials of a device,
- other studies reported in the scientific literature on a device that can be shown to be similar to the device in question,
- peer-reviewed scientific literature on other clinical experience with either the device in question or a device that can be shown to be similar to the device in question; or
- clinically relevant information from post-market surveillance (especially clinical follow-up).
The MDR uses the term "clinical trial" instead of the more commonly used term "clinical study" in professional circles.
What is the scope of a clinical evaluation?
The manufacturer must specify and justify the scope of the clinical evidence based on the product characteristics and intended use. The newer or more initial a product is, the more comprehensive the clinical evaluation should be.
The clinical evaluation must follow a well-defined process and consider the following:
- a critical evaluation of the scientific literature,
- a critical evaluation of the results of all available clinical trials, and
- a consideration of other treatment options for the purpose.
The manufacturer can only omit clinical data in absolutely exceptional cases and must justify this with reference to the intended purpose, risk management and interaction between the product and the body.
When is a clinical trial required?
In principle, the manufacturer must carry out clinical trials if he
- wants to market a product with new functions and features,
- has modified a medical device in such a way that safety and performance are affected,
- market a medical device with a new intended purpose, or
- wishes to market implantable devices or devices in risk class III.
In the latter case, there are a number of exceptions:
- it is a modified medical device from the same manufacturer,
- it is a comparable product to a medical device from another manufacturer,
- it is a question of certain old products or
- it concerns certain (low-risk) product types, such as dental materials.
Details on the exceptions can be found in Art. 61 (4 ff.) of the MDR.
How does a clinical evaluation proceed?
At the beginning of a new project, it should be clear which specific medical application and medical need is being addressed and which product claim is derived from this. The clinical evaluation must confirm this and should therefore be considered from the beginning of the project. Therefore, clinical evaluation is best started at the same time as the development of a new product begins. For practical implementation, the manufacturer must prepare a clinical evaluation plan (CEP). At a minimum, this contains information on the following points:
- Determination of the essential safety and performance requirements,
- medical purpose of the product,
- Target groups with indications and contraindications,
- Presentation of the intended clinical benefit for patients,
- clinical outcome parameters,
- Presentation of the test methods,
- Parameters for determining the benefit/risk ratio,
- clinical development plan.
The manufacturer must then determine what clinical data are available, assess them for adequacy, and identify any gaps. Additional clinical data may be required, which the manufacturer must generate through a clinical trial.
The manufacturer must summarize the results of the clinical evaluation in a Clinical Evaluation Report (CER). This is a mandatory requirement for the initial CE mark.
Overall, the MDR contains comparatively little information on how exactly a clinical evaluation must be carried out. The "MEDDEV 2.7/1 Revision 4" guideline, which was published by the EU Commission in 2016 as a supplement to the European Medical Device Directive, goes much further here.
Thus, the MEDDEV guideline details the process of clinical evaluation based on a cycle of 5 stages, consisting of planning, data, evaluation, analysis and report. As a result of this cycle, the manufacturer generates and continuously updates the clinical evaluation report.
The clinical evaluation plan as the result of the "plan" stage and the clinical evaluation report as the result of the "report" stage are central documents and part of the technical documentation of a medical device. The clinical evaluation report also includes a clinical follow-up plan.
Even though the use of the MEDDEV Guide is not legally binding and it was not made explicit for the requirements of the current Medical Device Regulation, it should play an important role in the dialog with Notified Bodies for the time being.
Where can I find help for a clinical evaluation?
The Medical Devices Coordination Group (MDCG) of the EU Commission has written a number of guidance documents related to clinical evaluation. The MDCG 2020-6 guidance addresses the clinical evaluation of "established" medical devices ("Guidance on sufficient clinical evidence for legacy devices"). A key aspect is the definition of the term "well-established technology". According to this, established medical devices have already been on the market for several years and can be regarded as standard products whose safety and performance are demonstrably known. Furthermore, they are medical devices whose design has only been adapted in small steps.
Medical software represents a special use case for clinical evaluation. The MDCG 2020-1 guidance (Guidance on clinical evaluation (MDR) / Performance evaluation (IVDR) of medical device software) provides a set of guidance on how to demonstrate the scientific validity as well as the technical or clinical performance of an MDSW in the course of clinical evaluation. This also includes the questions in which framework equivalence data can be used or - if necessary - how a clinical trial should be structured with regard to the design and the level of evidence to be achieved.
How can comparative data be used for a clinical evaluation?
In principle, the manufacturer can use comparative data (equivalence data) for a clinical evaluation. The MDR requires at this point:
- The device that is the subject of the clinical evaluation for the intended use must be demonstrated to be similar to the device to which the data relate, and
- the data adequately demonstrate compliance with the relevant safety and performance requirements.
Comparator products must bear a CE mark. It is not permissible to use characteristics of multiple medical devices for an equivalence consideration but only those of one medical device.
The MDR also specifies 3 characteristics that manufacturers must consider when demonstrating equivalence with other medical devices:
- Technical (e.g., conditions of use, features, and algorithms),
- biological (e.g., same materials or removable substances), and
- clinical (e.g., clinical condition or purpose, population, and performance).
To demonstrate equivalence, the characteristics of the compared devices must match. There must be no clinically significant difference in the safety and clinical performance of the devices. It is therefore important that the demonstration be based on adequate scientific justification.
In addition, the manufacturer must clearly demonstrate that it has sufficient access to the comparative data. In most cases, this will require an appropriate contractual agreement with the company that clinically evaluated the compared device in compliance with the MDR. This aspect will prove particularly difficult to implement for obvious reasons.
The guideline "MDCG 2020-5: Guidance on clinical evaluation - Equivalence" supplements and specifies corresponding requirements from the MDR and the MEDDEV guideline by some specific aspects.
What is PMCF?
The MDR requires a clinical evaluation over the entire product life cycle in the sense of a continuous process (Art. 61 (11)). Thus, a clinical evaluation also includes a post-market clinical follow-up (PMCF) of the medical device and an update of the clinical evaluation report.
For this purpose, the manufacturer must again formulate a plan, the structure of which is described in the MDCG 2020-7 guideline. The PMCF plan qualifies methods to
- Confirm safety and performance of the medical device,
- Identify and monitor adverse reactions,
- identify and investigate risks,
- Monitor the benefit/risk ratio, and
- identify misuse.
In particular, the PMCF plan must specify "the general post-market clinical follow-up methods and procedures to be used" (No. 6.2 Annex XIV MDR). The required "justification of the appropriateness" of the methods and procedures also includes a needs assessment for a PMCF study. Examples of PMCF studies include continuation of a clinical study prior to CE certification (long-term follow-up of CE study participants), a new prospective clinical study, or review of retrospective patient data on the use of the medical device.
The manufacturer analyzes and documents the results in a post-market clinical follow-up assessment report (No. 7 Annex XIV MDR). Guideline MDCG 2020-8 explains the structure of the PMCF evaluation report, which, like the PMCF plan, is part of the technical documentation.
If, for example, it becomes apparent that new medical devices have been launched on the market by competitors that have a better risk/benefit profile than the manufacturer's own technology, the manufacturer must react and, if necessary, withdraw his medical device from the market.
Overall, the higher the risk class of the medical device in question, the more frequently clinical evaluation updates are required. Other factors include the degree of innovation, a changing medical evidence base, and market or competitive activity. The manufacturer must also continuously determine the specific need for PMS and PMCF and adjust them as necessary.
In addition to the documents already mentioned, the manufacturer must prepare the Summary of Safety and Clinical Performance (SSCP) for Class III and implantable devices (see MDCG 2019-9). The MDCG 2020-13 guideline provides a template for the Clinical Evaluation Assessment Report (CEAR), which is prepared by the Notified Body as part of the review of the manufacturer's documentation.
What are the professional requirements for authors of clinical evaluations?
The requirements for authors of clinical evaluations have increased significantly. They must have knowledge in the following areas:
- Technology of the product
- application of the product
- scientific work
- clinical study design
- biostatistics
- specific disease profile
- databases
- medical writing
- regulatory framework
In particular, medical knowledge in the relevant field of application requires relevant clinical experience at the specialist level.
The guideline MEDDEV 2.7/1 revision 4 specifies some aspects. Required are:
- an academic education in the relevant field and at least 5 years of proven specific professional experience (e.g., engineer, physicist, biologist, perfusionist)
- A specific specialist medical endorsement for high-risk devices (e.g., Class IIb implantable devices or Class III devices)
- A minimum of 10 years of demonstrated specific professional experience with non-academic training in the field (e.g., technician or master craftsman)
- knowledge of research methodology (study design, basics of biostatistics)
- special knowledge and experience with literature research as well as
- special knowledge and experience in the respective medical or clinical field with knowledge of the current state of the art and alternative treatment methods.
The high requirements make it clear that a major challenge on the part of both manufacturers and notified bodies should be to recruit suitable experts. There is also the question of the extent to which clinical evaluations should still be carried out professionally by just one author.
Conclusion
We recommend manufacturers to deal with clinical evaluation as early as possible and not to consider it only as a mandatory MDR task. A clearly elaborated clinical benefit (Art. 2 (53) MDR) is the basis for user acceptance of the product, successful marketing and competitive differentiation. Above all, it makes sense to dovetail the clinical evaluation with the other mandatory processes in the best possible way from the outset. This saves time and costs and increases the quality of their products. In addition, the audits benefit from a cleanly researched and documented clinical data situation. Please do not hesitate to contact us if you have any questions about clinical evaluation.
