How To Approach Biological Equivalence Under The EU MDR

By Jaishankar Kutty, Ph.D., VP of clinical services, RQM+

The EU Medical Device Regulation (MDR) has significantly raised notified body expectations of the level and quality of clinical data for medical devices. For this reason, an equivalence strategy can save businesses time and resources, as clinical data from an equivalent device can be used to demonstrate the safety of a device undergoing review. Using this strategy, manufacturers can assess the risks arising from any potential similarities or differences with the equivalent device, and then evaluate the impact on the safety and performance profile of their product. However, the criteria for demonstrating equivalence are more stringent than under the preceding Medical Device Directive, so manufacturers must be able to make a strong case to pass notified body review.

The MDR requires that technical, biological, and clinical characteristics are considered when demonstrating equivalence to another device.¹ In connection with biological equivalence, the MDR demands that the subject device uses the same materials or substances in contact with the same human tissues or body fluids as the equivalent device. Additionally, this must be for a similar kind and duration of contact and similar release characteristics of substances, including degradation products and leachables. Many medical device manufacturers are mystified by this aspect of the MDR and are uncertain about the acceptability of their biological equivalence strategies.  

To shed light on this topic, this article will provide an overview of the MDR requirements for biological safety evaluation, practical advice on how to approach biological equivalence, and an example of how to demonstrate biological equivalence for a material difference.

Biological Safety Testing

Typically, medical devices comprise multiple components, each with mutually exclusive physical and chemical profiles. To address this inherent varying complexity, risk of injury, and toxic effects to the human, notified bodies expect a biological safety evaluation process. This must include physical and chemical characterization and biocompatibility testing to assess all relevant biological endpoints.  However, it is important to bear in mind that biological safety is not the same as biological equivalence.  In other words, even if you pass all the biocompatibility tests, it does not necessarily mean the device under evaluation is biologically equivalent. 

Limitations of ISO 10993-1:2018

The biological safety evaluation should sit within a manufacturer’s risk management process and quality management system, and the recommendations of the ISO 10993 series should be applied. Figure 1 of ISO 10993-1:2018² provides a matrix of tests per device categorization. It is important to bear in mind that though this test matrix is a useful tool for endpoint selection, it is not a conclusive set of activities when it comes to biological safety. For example, for a non-implantable device, strict adherence to only the test matrix of biocompatibility tests may result in a lack of quantitative and qualitative chemical characterization addressing the presence of colorants, fillers, plasticizers, etc. Consequently, the latest version of ISO 10993-1 has been revised to lay emphasis on material physical and chemical characterization (Annex A).

Chemical Characterization

Although it is not synonymous with biological equivalence, biological safety testing is important when a manufacturer wants to claim biological equivalence to another device. As explained by the MDCG 2020-5 guidance document on equivalence,³ the MDR distinguishes between “same materials or substances” and “similar release characteristics of substances” to account for the fact that processing, design, and the use environment may introduce small changes even when the raw materials are the same. Chemical characterization, which assesses factors such as processing, storage conditions, and sources of contamination, must therefore be considered when evaluating biological equivalence.

Transitory Contacting Devices

A final point is that the release characteristics of materials may be less relevant when assessing devices with extremely limited contact with patients. Such devices, termed “transitory contacting devices” by ISO 10993-1:2018, may include lancets, hypodermic needles, or capillary tubes that are used for less than 1 minute. The most recent version of ISO 10993-1 states that these generally do not require testing to address biocompatibility unless they are made with coatings or lubricants that could be left in contact with body tissues after the medical device is removed.

How To Approach Equivalence Evaluation

The EU’s process of evaluating equivalence is very different from a typical equivalence table used in the U.S. FDA’s 510K process. These tables tend to stop at an identification of same/similar, and manufacturing related differences may be ignored. Irrespective of device classification, EU notified body reviewers approach equivalence (whether technical, clinical, or biological) in three phases:

• Phase 1 is a review of items that are identical with the equivalent device.
• Phase 2 is a review of items that are similar (but not identical).
• Phase 3 is where the reviewer seeks to identify the risks arising out of differences between the devices and the impact of these risks on successfully leveraging the clinical data of the equivalent device.

To this end, any approach to biological equivalence must be focused on the most relevant material-based device performance parameters, their impact on corresponding device performance parameters, and, eventually, the clinical outcomes. Manufacturers must avoid the temptation to mention every non-patient-contacting “cyanoacrylate glue” that may be different, as this will have been comprehensively addressed via the overall biological safety evaluation prior to the biological equivalence discussion. Rather, the equivalence discussion should concentrate on clinically relevant items.

Demonstrating Biological Equivalence

For each different material or component, manufacturers should be able to answer two key questions:

• What role does the material/component have with respect to device safety and performance?
• What is the expected impact of the material differences on leveraging the clinical data of the equivalent device?

Where applicable, the manufacturer should provide a risk assessment based on scientific justification or experimental evidence that comprises chemical and physical characterization data. It may even be useful to include the outcomes of toxicology risk assessments.

Example: Subject Device Uses A Different Type Of The Same Material

One common scenario is where the subject and equivalent devices use different types of the same material, e.g., varying densities of polyethylene or different types of patient-contacting adhesive resins. For a short-term/transient device, which will be used on the patient for less than 60 minutes, this material difference may be acceptable. However, to demonstrate that the difference does not impact biological equivalence, the discussion should place particular focus on the risks arising out of differences in the material specifications, including:

• overall chemistry,
• surface area,
• surface morphology,
• processing/cleaning aids,
• sterilization, and
• biological safety evaluation at the end of the device shelf life.

For an implant, if the subject device uses a different type of the same material, this is likely to be unacceptable, unless it is possible to conclusively show that there is no impact on clinical outcomes. The manufacturer would need to demonstrate that, despite the different chemical and physical properties, the local tissue response and long-term effects are not different.

Conclusion

Drawing on clinical data for an equivalent device can be an efficient way to gain notified body approval. However, the criteria are complex, and manufacturers still need to invest time and resources to pass notified body review. They should first leverage available guidance and standards for equivalence and biological safety testing. These will help to clarify the requirements and what is deemed acceptable. Secondly, manufacturers should make sure they are focused on clinical outcomes throughout their biological equivalence discussion and avoid including irrelevant information. Lastly, this may be an area where third-party expert support may be especially valuable, as specialists in this area are likely to have reviewed a wide variety of submissions and can advise on the acceptability of equivalence strategies and methodologies.

For further potential methodologies to demonstrate biological equivalence, download the RQM+ guide here.

References

1. Medical Device Coordination Group, MDCG 2020-5: Clinical Evaluation – Equivalence, A guide for manufacturers and notified bodies, April 2020
2. International Organization for Standardization, ISO 10993-1:2018, Biological evaluation of medical devices
3. Medical Device Coordination Group, MDCG 2020-5: Clinical Evaluation – Equivalence, A guide for manufacturers and notified bodies, April 2020

About The Author:

Jaishankar Kutty, Ph.D., is vice president of clinical services at RQM+. His expertise combines cardiovascular product development and CE marking (technical & clinical) leadership with a keen appreciation for the evolving regulations landscapes. His cardiovascular device experience spans product development, advanced biomechanical testing, preclinical model development, physician training, FDA interactions, implantable device commercialization, and patents. Previously, he worked in CE marking technical and clinical leadership roles at BSI.