Manufacturers of medical devices must carry out 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 check whether the medical device is safe and efficient. The manufacturer then assesses whether the risks of use are in reasonable proportion to the expected benefits.
The European Medical Device Regulation (EU) 2017/745 (MDR) has changed the legal basis for clinical evaluations. In addition, new experiences and interpretations are constantly being added. This article gives an overview of the current status of the requirements and their implementation.
- What is a Clinical Evaluation?
- What does a clinical evaluation prove?
- What is clinical data?
- What is the extent of a clinical evaluation?
- When is a clinical investigation necessary?
- How does a clinical evaluation work?
- How can equivalent data be used for a clinical evaluation?
- What is Post-Market-Clinical-Follow-Up (PMCF)?
- How is a clinical evaluation documented?
- What are the technical requirements for the authors of clinical evaluations?
What is a Clinical Evaluation?
A clinical evaluation is a systematic collection and evaluation of clinical data from various sources.
According to the MDR, the manufacturer is obliged to carry out a clinical evaluation during the entire life cycle of a medical device. Thus, a clinical evaluation also includes a clinical follow-up of the medical device in the market (Post Market Clinical Follow-Up, PMCF). The clinical evaluation must be part of the quality management system and is closely connected with the obligatory risk management.
What does a clinical evaluation prove?
Annex I of the MDR defines the general requirements for safety and performance of medical devices.
If a manufacturer wishes to market a medical device, he must prove that it meets the requirements as defined by Annex I. The clinical evaluation is part of this proof.
The manufacturer should therefore demonstrate that the medical device:
- achieves the performance intended by the manufacturer,
- has been designed and manufactured to be suitable for its intended use,
- is safe and effective,
- does not compromise the clinical condition or safety of patients or the safety or health of users or third parties,
- has an acceptable risk/benefit profile,
- is compatible with a high level of health and safety protection, and
- is based on the generally accepted state of the art.
The clinical risk/benefit profile therefore plays an important role. Manufacturers must assess the clinical benefit against the clinical risks including undesirable side effects according to:
- type of effect,
- duration, and
in the target group and indication defined as precisely as possible, both qualitatively and quantitatively.
The strong focus on risk/benefit considerations in clinical evaluation is new. This results in a direct reference to risk management, which the manufacturer must carry out in accordance with the MDR. It will be challenging for many companies to link the processes of clinical evaluation and risk management in such a way that there are no unwanted overlaps or even contradictions.
There is also a relationship to the reimbursement of medical devices. This is also based on a risk/benefit analysis of medical methods that includes the use of medical devices.
However, at this point the concept of benefit must be differentiated since benefit in the context of the MDR has a different meaning than benefit in the context of reimbursement of medical services by health insurance.
The latter includes not only the medical benefit but also the economic benefit and therefore requires a health economic discussion. With regard to the design of clinical investigations, the question arises to what extent 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 product and may be derived from the following sources:
- clinical investigations of a medical device,
- other studies reproduced in scientific literature relating to a product which can be shown to be equivalent to the product concerned,
- scientific literature (peer review) on other clinical experiences either with the product concerned or with a product whose equivalence with the product concerned can be demonstrated, or
- clinically relevant information from PMCF.
The MDR uses the term clinical investigation instead of the more commonly used terms clinical study or trial.
What is the extent of a clinical evaluation?
The manufacturer must specify and justify the extent of clinical evaluation on the basis of product characteristics and intended purpose (Article 61, MDR). The newer or the more initial a product is, the more extensive the clinical evaluation should be.
The clinical evaluation shall follow a well-defined procedure and take into account the following:
- a critical evaluation of the scientific literature,
- a critical evaluation of the results of all available clinical investigations, and
- a consideration of other treatment options for the respective purpose.
The manufacturer can only forgo clinical data in absolutely exceptional cases and must justify this with reference to intended purpose, risk management and interaction between product and body.
When is a clinical investigation necessary?
The manufacturer must in principle carry out clinical investigations 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
- wants to market implantable products or products 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 an equivalent product to a medical device of another manufacturer,
- it concerns certain well-established products or
- certain (low risk) product types are involved, such as dental materials.
Details on the exceptions can be found in Art. 61 (4 ff.), MDR.
How does a clinical evaluation work?
At the beginning of a new project it should be clear which specific medical application and need is being addressed and which product claim is derived from it. The clinical evaluation must confirm this and should therefore be considered from the beginning of the project. Therefore, the clinical evaluation ideally starts at the same time as the development of a new product starts. To implement this, the manufacturer must prepare a Clinical Evaluation Plan (CEP). The CEP shall contain at least the following information:
- determination of general safety and performance requirements,
- medical purpose of the product,
- target groups with indications and contraindications,
- presentation of the intended clinical benefit for patients,
- parameters for the clinical outcome,
- presentation of the examination methods,
- parameters for determining the benefit/risk ratio, and
- a clinical development plan.
The manufacturer must then determine which clinical data are available, assess their suitability and identify any gaps. Additional clinical data may be required, which the manufacturer must generate through a clinical investigation.
The manufacturer must summarize the results of the clinical evaluation in a Clinical Evaluation Report (CER). This is a mandatory prerequisite for the initial CE mark.
Overall, the MDR contains comparatively little information on how exactly a clinical evaluation must be carried out. The guideline MEDDEV 2.7/1 Revision 4, which was published by the EU Commission in 2016 as a supplement to the “old” Medical Devices Directive, goes much further here.
The MEDDEV guideline details the process of clinical evaluation based on a cycle of 5 steps consisting of planning, data, evaluation, analysis and report. As a result of this cycle, the manufacturer generates the clinical evaluation report and updates it continuously.
The clinical evaluation plan as the outcome of the “planning” stage and the clinical evaluation report as the outcome of the “reporting” stage are central documents and are part of the technical documentation of a medical device. The clinical evaluation report shall also include a clinical follow-up plan.
Even if the use of the MEDDEV guideline is not legally binding and has not been made explicit for the requirements of the current Medical Devices Regulation, it should play an important role in the dialogue with the Notified Bodies until further notice.
The Medical Devices Coordination Group (MDCG) has recently published MDCG 2020-6, a supplementary guideline dealing with the clinical evaluation of “established” medical devices (“Guidance on sufficient clinical evidence for legacy devices“). An essential aspect of MDCG 2020-6 is the definition of the term “well-established technology”. According to this definition, established medical devices have already been on the market for several years and can be considered as standard products whose safety and performance have been proven. Furthermore, they are medical devices whose design has been adapted only in small steps.
Medical software represents a special use case for a clinical evaluation. The Medical Devices Coordination Group has provided the MDCG 2020-1 (Guidance on clinical evaluation (MDR) / Performance evaluation (IVDR) of medical device software). In the definition of medical software, the guideline refers directly to the term “Medical Device Software (MDSW)”, which is newly introduced with the guideline MDCG 2019-11 (Qualification and classification of software – Regulation (EU) 2017/745 and Regulation (EU) 2017/746) and is discussed in detail in our article “Medical software: classification and approval as medical device“.
MDCG 2020-1 provides a number of tools 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 investigation should be structured with regard to design and evidence level to be achieved.
How can equivalent data be used for a clinical evaluation?
In principle, the manufacturer may use equivalent data for a clinical evaluation. The MDR demands:
- The product which is the subject of the clinical evaluation for the intended purpose must be demonstrably equivalent to the product to which the data relate and
- the data adequately demonstrate compliance with the relevant safety and performance requirements.
Comparable products must carry a CE mark. It is not allowed to use properties of several medical devices for an equivalence consideration but only those of one medical device.
The MDR defines 3 characteristics that manufacturers must consider if they are to demonstrate equivalence with medical devices already on the market:
- technical (e.g. conditions of use, characteristics and algorithms),
- biological (e.g. identical materials or leachable substances) and
- clinical (e.g. clinical condition or purpose, population and performance).
To demonstrate equivalence, the characteristics of the compared devices must match. There shall be no clinically significant difference in the safety and clinical performance of the devices. It is therefore important that the demonstration is based on adequate scientific justification.
In addition, the manufacturer must clearly demonstrate that he has sufficient access to the equivalence data. Usually, this requires a corresponding contractual agreement with the company that has already performed the clinical evaluation of the product in an MDR compliant way. This aspect will prove to be particularly difficult to implement for obvious reasons.
The Medical Device Coordination Group (MDCG) has published a current guideline “MDCG 2020-5: Guidance on clinical evaluation – Equivalence” on this question. This guideline supplements and specifies requirements from the MDR and the MEDDEV guidelines by some specific aspects.
What is Post-Market-Clinical-Follow-Up (PMCF)?
The manufacturer monitors the market (Post Market Surveillance, PMS) and systematically collects clinical data on his medical product (Post Market Clinical Follow-Up, PMCF), evaluates it and updates the clinical evaluation.
To do this, the manufacturer must formulate a new plan. This plan qualifies methods to
- confirm the safety and performance of the medical device,
- identify and monitor side effects,
- identify and investigate risks,
- monitor the benefit/risk ratio, and
- find a misuse.
The manufacturer analyses and documents the results in an assessment report. This report forms part of the clinical assessment report and technical documentation.
The MDR requires a clinical evaluation over the entire product life cycle as a continuous process. This means that the manufacturer must proactively update the clinical evaluation report.
If, for example, it turns out that new medical devices have been brought onto the market by market competitors that exhibit 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 a medical device, the more frequently updates of the clinical evaluation are required. Further factors are the degree of innovation, a changed medical evidence situation and market or competitive developments. The manufacturer must also continuously determine the concrete need for market surveillance or clinical follow-up and adjust it if necessary.
How is a clinical evaluation documented?
In addition to the plans and reports already mentioned, the manufacturer must provide and maintain more documents.
In summary, the documentation contains the following components:
- Clinical Evaluation Plan (CEP),
- Clinical Evaluation Report (CER),
- Clinical Follow-Up Plan as part of Post Market Surveillance (PMS),
- Clinical Follow-Up Report for Class I devices as part of PMS,
- a plan for clinical investigations as part of Post Market Clinical Follow-Up (PMCF) or a justification why a PMCF is not applicable,
- Periodic Safety Update Report (PSUR) for Class IIa equipment (every 2 years), Class IIb equipment (annual update) and Class III equipment (annual update),
- Evaluation Report for PMCF studies with annual updates for Class III and implantable devices,
- Summary of Safety and Clinical Performance (SSCP) for Class III and implantable devices,
- Clinical Evaluation Assessment Report (CEAR) prepared by the Notified Body.
The MDCG has provided a number of templates and explanations:
- MDCG 2020-7: Guidance on PMCF plan template
- MDCG 2020-8: Guidance on PMCF evaluation report template
- MDCG 2019-9: Summary of safety and clinical performance
- MDCG 2020-10/1: Guidance on safety reporting in clinical investigations
- MDCG 2020-10/2: Appendix: Clinical investigation summary safety report form
- MDCG 2020-13: Clinical evaluation assessment report template
The demands on the authors of clinical evaluations have increased considerably. They must have knowledge in the following areas:
- technology of the product
- application of the product
- scientific work
- clinical study design
- respective disease
- medical writing
Particularly, relevant clinical experience at specialist level is required in the field of the respective diseases.
The MEDDEV 2.7/1 Revision 4 guideline specifies some aspects. The following is required:
- an academic education in the respective field and at least 5 years of proven specific professional experience (e.g. engineer, physicist, biologist, cardio technician)
- specific medical knowledge with respect to high-risk products (e.g. implantable class IIb or class III products)
- at least 10 years of proven specific professional experience in non-academic training in the specialist 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, both on the part of the manufacturers and on the part of the Notified Bodies, should be to recruit suitable specialists. The question also comes up as to whether clinical evaluations should be carried out by just one author at all.
We recommend that manufacturers keep up to date with the latest developments in clinical evaluation. In view of the many interpretations, lack of clarity and poorly established workflows, it is wise to seek contact with other concerned parties and to work together.