Is each egg alike the other in the box? The guidance MDCG 2020-5 “Clinical Evaluation – Equivalence: A guide for manufacturers and notified bodies”, which has been available in its original version since April 2020, addresses the requirements for and the actual drafting of the equivalence assessment when preparing clinical evaluations. Generally speaking, the equivalence assessment should be carried out according to the valid rules of the MDR. The specifications and recommendations of MEDDEV 2.7/1 Rev. 4 continue to have their justification even three years after the MDR came into force; nevertheless, there are deviations from MDR which are discussed in the MDCG 2020-5 document without introducing new aspects and specifications. Only the MDR remains legally binding, but the guidelines are to be understood and taken into account as “state of the art”.
In the same wording as the MDR, MEDDEV 2.7/1 Rev. 4 requires that technical, biological and clinical characteristics must be taken into account when assessing equivalence when preparing a clinical evaluation based on the equivalence principle. The differences between the MDR criteria and the MEDDEV 2.7/1 Rev. 4 criteria regarding the evaluation of these three characteristics are addressed in the MDCG 2020-5 document.
Technical aspects of the equivalence assessment
While MEDDEV 2.7/1 Rev. 4 requires that the medical device under assessment and the equivalent product must be used under the same conditions of use with regard to technical characteristics, MDR only refers to similar conditions of use. If according to MDCG 2020-5 no clinically significant difference in safety and performance is to be expected, the conditions of use are to be assessed similarly.
The MDCG 2020-5 also points out that the MDR emphasizes the aspect of software algorithms (in contrast to MEDDEV 2.7/1 Rev. 4), both for software that is necessary for the operation of a medical device and for software that is itself classified as a medical device. In order to be able to prove and evaluate equivalence in the sense of the MDR, MDCG 2020-5 states that in this case both the functional principle of the software – or more precisely of the underlying algorithm – and the clinical performance as well as the defined purpose must be taken into account.
Biological aspects of the equivalence assessment
While the introductory sentence is still congruent between MDR and MEDDEV 2.7/1 Rev. 4 to a large extent (“use of the same materials or substances in contact with the same human tissues or body fluids”), subsequently crucial differences come up, toughening the biological equivalence assessment as per MDR:
- The exceptions in MEDDEV 2.7/1 Rev. 4 for the assessment of equivalence with regard to medical devices that only have contact with intact skin areas or for individual components of the medical device that are only of minor importance are dropped in the course of the MDR. The procedure of being able to rely in these cases on the results of the risk analysis with regard to these materials, based on the biological properties and the corresponding use and the thus postulated similarity, is no longer permitted in the legal framework of the MDR. MDCG 2020-5 explicitly refers to this.
- In addition to the introductory sentence above, the MDR also requires at least a similar application period and a similar release mechanism of substances used, including degradation products and leachables, to demonstrate biological equivalence. The MDCG 2020-5 provides the background information that this formulation is intended to take into account the fact that changes may occur due to external influences or the processing of certain substances or materials, even if the raw materials used are identical.
- For medical devices that are composed of several substances or represent a combination of substances and are absorbed or dissolved in the human body, the same substances must also be used to demonstrate equivalence. Even if these products do not constitute medicinal products, the MDCG 2020-5 points out that compliance with the relevant requirements of Annex 1 of Directive 2001/83/EC must nevertheless be taken into account in order to claim biological equivalence within the scope of the MDR.
Clinical aspects of the equivalence assessment
With regard to clinical equivalence, the MDCG 2020-5 describes two aspects that differ in wording and meaning from MEDDEV 2.7/1 Rev. 4:
- Both the medical device to be evaluated and the equivalent product must be used or applied by the same user group; from the point of view of MDR, it is irrelevant whether this is a health professional or a layperson without medical training. Ultimately, this requirement represents a tightening of the specifications compared to MEDDEV 2.7/1 Rev. 4.
- While MEDDEV 2.7/1 Rev. 4 clearly states that the medical devices to be compared must be used for the same medical indication, sex and duration of use, the MDR formally describes this in a less strict way, requiring “the same clinical condition of the patient or for the same purpose”. However, the interpretation in the context of the MDCG-2020-5 document concludes that, despite the different wording, this aspect corresponds to the same level of equivalence comparison as in MEDDEV 2.7/1 Rev. 4.
Objective of the MDCG 2020-5
According to the MDCG 2020-5, the global preparation of the equivalence comparison primarily serves to present all characteristics of a technical, biological and clinical nature required and listed in the MDR in a verifiable and justified manner in order to conclude – in the best case – that there is no clinically significant difference in terms of safety and clinical performance compared to the equivalent product. Still, it is not ruled out to present several equivalent products in the clinical evaluation, but each of these products must comply with the requirements of the MDR in the three categories mentioned above. A combination of features of different devices is not permitted, as already in MEDDEV 2.7/1 Rev. 4.
Furthermore, in its assessment of the MDR, the MDCG 2020-5 points out that differences of a technical, biological or clinical nature that result from the equivalence comparison can be conclusively assessed on the basis of scientific evidence and ideally be considered not clinically significant. Preclinical data, in turn, can be very helpful, especially when considering technical and biological equivalence characteristics. These must of course relate to the current version/generation of the medical device under consideration.
Limits of the equivalence assessment
The MDCG 2020-5 also deals with the limits of the fundamental permissibility of the equivalence assessment. This concerns manufacturers of class III products and implantable products. The equivalence assessment is only permissible in the following two case constellations, irrespective of the content of the equivalence assessment:
- The manufacturer refers to a predecessor product from his own company that is already CE-approved and sold according to the directives MDR or 93/42/EEC or 90/385/EEC.
- The manufacturer refers to an equivalent product of a competitor with whom there is a contractual agreement that allows unlimited and continuous access to the technical documentation of this equivalent product. In addition, there must be access to the clinical evaluation carried out in accordance with the MDR, which implies that this medical device has already been certified under the MDR.
In all other cases, proof of safety and clinical performance will only be possible with clinical trials. However, this does not apply to special product groups as listed in Article 61(6b) of the MDR, where clinical trials may continue to be waived provided that the clinical evaluation is based on sufficient clinical data.
With regard to access to data and information for preparing the demonstration of equivalence, the following guidance is recommended: The MDCG Guidance 2023-7 deals in particular with the topic of access to data required to justify claims of equivalence. For manufacturers with medical devices outside risk class III and in the non-implantable area, no contractual agreement is required, but “it shall be clearly demonstrated that manufacturers have sufficient levels of access to the data relating to devices with which they are claiming equivalence in order to justify their claims of equivalence.” This guidance document depicts various case constellations and points out possible restrictions that need to be taken into account when justifying claims of equivalence.
For devices without a medical purpose as defined in Annex XVI of the MDR, such as contact lenses or devices for transcranial stimulation of the brain, clinical investigations should in principle be carried out unless clinical data of an analogue medical device are available. Analogue means a device with a similar technical basis and risk profile but with a medical use. Thus, in a large number of cases, even low-level devices can be expected to be subject to clinical trials, since possible equivalent products are difficult or impossible to identify.
In addition to one of the central elements of the clinical evaluation, the demonstration of equivalence (provided that the clinical evaluation is based on this principle), it is also important to identify relevant hazards or clinical risks, to describe the state of the art, alternative treatment methods and the clinical background of the underlying disease in a scientifically sound manner. This can be based on scientific publications of similar medical devices belonging to the same generic product group as the medical device under evaluation.
Finally, a note on the identification of appropriate clinical data : For both the medical device under evaluation and the equivalent product, all available data should be used, whether favourable or unfavourable to the safety and clinical performance of the medical device. The analysis of the data is ultimately aimed at reconciling or establishing conformity of the clinical evidence with the relevant essential safety and performance requirements. The procedure for identification, evaluation and analysis of clinical data is still found in MEDDEV 2.7/1 Rev. 4; these rules continue to apply under MDR, provided that the clinical data comply with the definition of MDR, see Article 2, point 48 of MDR.
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