How to use the Equivalence Pathway under MDR

The topic of this article is the equivalence pathway under the European Medical Device Regulation (MDR) 2017/745. The MDR provides possibilities to use clinical data related to an equivalent device in the clinical evaluation. This article explains how to use this pathway to demonstrate conformity of a medical device with the general safety and performance requirements based on the MDR, the MEDDEV 2.7/1 revision 4 and the new guideline published by the Medical Device Coordination Group MDCG 2020-5, as well as contractual aspects of equivalence.

The equivalence pathway allows a manufacturer of a medical device to use the technical documentation, post-market surveillance (PMS), post-market clinical follow-up (PMCF) and the scientific literature related to an already marketed device, thereby avoiding the time and cost for performing clinical studies to fulfill the safety and performance requirements as defined in the clinical evaluation.

To answer the question whether or not the equivalence pathway can be used, you must consider the device class and the regulatory status of the device.

Equivalence for implantable devices and class III devices

According to Article 61 (4), a manufacturer of implantable devices and class III devices shall perform clinical investigations, except if the device has been designed by modifications of a device already marketed by the same manufacturer, and equivalence can be demonstrated according to MDR. In this context, a marketed device is a device already placed on the market and CE-marked with respect to either MDR, the medical device directive (MDD) 93/42/EEC or the active implantable medical device directive (AIMD) 90/385/EEC. The CE mark should still be valid and should be based on an updated clinical evaluation, the benefit/risk ratio for this device should be favorable, and the equivalence should be endorsed by the notified body.

For a manufacturer of implantable devices and class III devices claiming equivalence to an already marketed device not manufactured by them, in addition to the requirements in MDR Article 61 (4), the manufacturer must have a contract in place that explicitly allows full access to the technical documentation on ongoing basis and that the second manufacturer provides clear evidence thereof to the notified body. In addition, the equivalent device must have been certified under MDR. As such, it will not be possible to claim equivalence to an implantable device or class III device certified with respect to the MDD if the manufacturers are different. However, it may be possible to use the equivalence pathway using an equivalent device certified under MDD if the manufacturer of both devices is the same.

Contractual aspects of equivalence

Trying to understand better the exact meaning of having a contract in place, it can be beneficial to revisit the wording of other available guidelines. In the published MDCG 2020-13 “Clinical evaluation assessment report template”, it is stated that the notified body should “confirm that there is a current valid contract between the two manufacturers allowing ongoing access to the technical documentation in accordance with Article 61 (5) of the MDR”. Notified bodies will therefore request a current valid contract by the second manufacturer. As notified body reviewers are normally technical experts, it can be foreseen that it will be a challenge for the notified body to be able to verify that a contract is valid.

In regard to full access to the technical documentation, further guidance can be found in the MEDDEV 2.7/1 rev 4: “The notified body should challenge the ability of the manufacturer to access information that is relevant to the demonstration of equivalence. Demonstration of equivalence might be difficult or impossible in case of limited access to the technical documentation of the devices.” Combined with the text in the MDCG 2020-13, where it states that the notified body is to “confirm that access to data is sufficient to provide the manufacturer with enough information about the equivalent devices to support equivalence claims, including any testing which may have been undertaken to confirm equivalence of specifications/performance/etc.” which can be interpretated as the full access means sufficient access to the Annex II and III technical documentation, including Annex XIV describing the requirement for PMCF and periodic safety update report (PSUR) for confirmation of equivalence. The access should be as stated on an ongoing basis, meaning for as long as the equivalent device is going to be placed on the market.

What contractual format can be used?

The access to another manufacturers (meaning competitors) technical documentation is very unlikely to happen, but between manufacturers in a corporate group, this is an opportunity. The format most likely to be of use would be the Virtual Manufacturing Agreement (Art. 10(8) in the MDR). The contract will include as a minimum the following details:

• Scope of devices for which the second manufacturer may rely on data in the technical documentation; for example, whether line extensions are allowed.
• How to control access to data and keeping confidentiality?
• How to maintain intellectual property, e.g. what the manufacturer may disclose to the notified body without the need for additional non-disclosure agreements? Additionally, how to maintain intellectual property in case of device improvements or clinical data?
• How to disclose data to third parties, such as authorities, notified bodies, or other entities like crucial suppliers or critical subcontractors.
• Ongoing access to MDR-compliant clinical evaluation, PMS, vigilance, PMCF data – Annex XIV requires evaluation of clinical data relating to the equivalent device. How to work with new data and what to share?
• Change management - when can each party implement what changes for the equivalence to remain valid.
• Allowing unannounced audits.
• Termination provisions taking into account the equivalent device’s presence on the market.

The contract will also need to contain the normal clauses to make it operable, where intellectual property and confidentiality provisions will also play an important role, as they must be drafted in a way as to allow for access to the relevant data on an ongoing basis.

Equivalence for legacy devices

For legacy devices, which are defined as those previously CE marked under MDD or AIMDD, the need to conduct clinical investigations will depend on whether there is sufficient clinical evidence for the device being evaluated. Under Article 61 (6), the requirements to perform clinical investigations shall not apply to implantable devices and class III devices which (a) have been lawfully placed on the market or put into service in accordance with the MDD or AIMDD and for which the clinical evaluation is based on sufficient clinical data and is in compliance with the relevant product-specific common-specifications, if applicable, or (b) for certain types of devices belonging to well-established technologies (WET). If this is not the case, CER remediation will be required, or the certification will not be transitioned to MDR.

For WET devices, the clinical evaluation might be based on data from similar devices without the need of conducting clinical investigations on the actual device. Detailed information on this is provided in the MDCG 2020-6 guideline on sufficient clinical evidence for legacy devices.

If none of the above situations applies, and the use of the equivalence pathway is not possible according to the MDR, then a clinical investigation is needed for implantable devices and class III devices. In general, the notified body shall check whether the PMCF plan is appropriate and includes post-market studies to confirm the safety and performance of the device.

Equivalence for risk class other than class III and implantable devices

For devices other than implantable devices and class III devices and where the manufacturer wants to claim equivalence, MDR Article 61 (3) is applicable. This means that it is possible to claim equivalence to a device certified under MDD, AIMDD or MDR, and in exceptional cases to non-CE marked devices, provided that all relevant MDR requirements regarding equivalence and clinical evaluation can be met. Therefore, the manufacturer shall have sufficient access to the data relating to the equivalent device. If the presumed equivalent device is from another manufacturer, there is no need for a contract between the manufacturers for regulating the access to the technical documentation. In addition, clinical investigations must have been conducted in accordance with international guidelines. The clinical data must meet the MDR requirements and must be applicable to the European population.

Evaluation based on non-clinical data

Clinical data may not be required for some lower classes of devices according to Article 61 (10) and as previously mentioned for devices of well-established technologies. To use Article 61 (10), the manufacturer shall justify any such exception 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 referred to in Annex II 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.

Demonstrating equivalence

According to MDR Annex XIV Part A (3), a clinical evaluation may be based on clinical data of an already marketed device if equivalence can be demonstrated. For every feature a manufacture claims as equivalent, proper data and evidence must be provided. When demonstrating equivalence according to Annex XIV, technical, biological and clinical similarities must be presented. The three characteristics are defined within the article as:

1. Technical: similarities in design, usage, specifications, properties, deployment methods, principles of operation and critical performance requirements.
2. Biological: similarities in the materials/substances, human tissues/fluids, duration and way of contact with the subject.
3. Clinical: similarities in clinical condition, severity and stage of disease, user, clinical effect and patient’s characteristics (e.g. weight, age, gender, physiology).

All three characteristics, clinical, technical and biological, need to be fully appraised when demonstrating equivalence. They shall be similar to the extent that there would be no clinically significant difference in the safety and clinical performance between the two devices. Considerations of equivalence shall be based on proper scientific justification.

Demonstration of equivalence is also the subject of Appendix A1 of the MEDDEV 2.7/1 revision 4. There are, however, slight differences in the criteria for equivalence between MDR and MEDDEV. For instance, the conditions of use shall be the same according to MEDDEV but can be only similar according to MDR. In terms of clinical characteristics, the MDR clearly points out that a user means any person who uses the device, be healthcare professional or lay person. Manufacturers must therefore consider whether the intended user’s competence or knowledge can have any implication for the safety, clinical performance and outcomes of the device. Also, the device must deliver similar relevant or critical performance in view of their expected clinical effect.

Bearing the slight differences between MDR and MEDDEV in mind, we can use Appendix A1 of the MEDDEV 2.7/1 guidance for the equivalence pathway. This guidance says that equivalence can only be based on a single device. If referring to several devices, equivalence to each single device should be fully investigated, demonstrated and described in the clinical evaluation report. Any differences between the devices need to be identified, fully disclosed and evaluated. Explanations should be given as to why the differences are not expected to significantly affect the clinical performance and safety of the device.

If measurements are possible, clinically relevant specifications and properties should be measured in both devices and presented in comparative tabulations. Comparative pictures should be included to compare shapes and sizes of elements that are in contact with the body.

In addition, the manufacturer is expected to include supporting non-clinical information in the technical documentation as well as a summary of this in the clinic evaluation report. Please note that, for the evaluation of the technical characteristics, devices that achieve the same therapeutic results by different means cannot be considered equivalent.

The only clinical data considered relevant are the data obtained when the equivalent device is used in accordance with its intended purpose, as documented in the IFU. Ideally the easiest way of comparing the device on the evaluation in the equivalent device is by using a table format. An example is shared below:

In the table, the clinical, technical and biological characteristics of the device under evaluation are compared to the device for which equivalence is being claimed. In the analysis column, the scientific justification, why there will be no clinically significant differences in the safety and clinical performance of the device or a description of the impact on safety and clinical performance should be provided.

The demonstration of equivalence is what allows the manufacturer to use clinical data from an equivalent device in the clinical evaluation to comply with the general safety and performance requirements of the MDR. The notified body will test the manufacturer’s ability to access information important to the demonstration of equivalence. Therefore, it is crucial to have sufficient access to technical documentation of the already marketed device. The notified body must document their conclusions on the claimed equivalence and the suitability of the data for demonstrating conformity.

This article describes the requirements for using the equivalence pathway for your device in accordance with MDR 2017/745, MEDDEV 2.7/1 rev 4 and the recently published MDCG guideline 2020-5. We are still gathering information on how the different notified bodies are appraising equivalence analyses, especially for lower risk class products, as well as when real clinical investigations for these products are requested and how they will audit the validity and sufficiency of access agreements.

If you have any questions or comments, please feel free to reach out to us: Helene (hq@qmed-consulting.com), Diana (diana.nogueira@Qservegroup.com) or Erik (erik.vollebregt@axonlawyers.com).

Helene Quie, Managing Director, Qmed Consulting A/S, Copenhagen, Denmark

Diana Nogueira, Senior Consultant, Qserve Group Germany, Mannheim, Germany

Erik Vollebregt, Lawyer, Axon Lawyers, Axon Lawyers, Leiden, The Netherlands