Equivalence strategies can be used to efficiently demonstrate the safety of a medical device, limiting the need for new studies and testing. Given the level of investment that may be needed to achieve compliance with the EU Medical Device Regulation (MDR), leveraging equivalence may be a favorable route.
In principle, manufacturers can assess risk by comparing similarities and differences between their product and an equivalent device, and then determine whether these risks have an impact on the safety and performance profile of the product under review. However, under the MDR, demonstrating equivalence successfully may be more challenging, since expectations for the level and quality of clinical data are significantly higher. Manufacturers may be unsure whether their rationale for equivalence will stand up to notified body review, especially for demonstrating biological equivalence, which tends to be the toughest aspect of the overall equivalence story.
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EU MDR and the guidance document MDCG 2020-5 state that devices are biologically equivalent when they:
- use the same materials or substances
- are in contact with the same tissues or fluids
- are used for a similar kind and duration of contact
- and have similar release characteristics of substances.
Notified Body Expectations
Manufacturers familiar with the 510(k) process may refer to equivalence tables used by the U.S. FDA. These tables tend not to mention manufacturing-related differences, focusing instead on identifying same/similar elements. In contrast, notified bodies focus approximately 10% of their attention on understanding the items that are identical, 20% on similarities and the remaining 70% on differences between the two devices. They need to be satisfied that the risks arising out of differences—and the impact of these risks on the clinical evaluation of the subject device—have been thoroughly considered. The probability of acceptance depends on the nature and extent of the differences, the type of device and the impact of these factors on the clinical data.
In summary, to pass notified body review, manufacturers must ensure they have identified, acknowledged and addressed the differences between the designated equivalent device and the subject device, in terms of impact to device safety and performance.
Demonstrating Biological Equivalence
Biological equivalence strategies must center around biological safety and device performance parameters, in relation to the materials used. This does not mean that every non-patient contacting material difference needs to be mentioned; rather, the discussion should concentrate on items that impact clinical outcomes.
In the context of biological equivalence, the types of material differences include:
- Different grades/formulations of the same material
- Different types of the same material, e.g., varying densities of polyethylene
- Same materials, processed differently
- Different material
- Different processing or cleaning agent
- Different “minor” component
- Different colorant
For each different material or component, manufacturers should be able to explain the role of the material/component in relation to device safety and performance. They should also be able to discuss how material differences affect equivalence, and whether (and how) the clinical data remains relevant despite these differences. Where applicable, manufacturers should provide a risk assessment based on scientific justification or experimental evidence comprised of chemical and physical characterization data. It may even be useful to include the outcomes of toxicology risk assessments.
Example: Different Material
Differences in materials should be discussed in detail unless the component involved clearly has a minor or negligible role in terms of safety and performance. For implants, biological equivalence strategies will not be accepted if a different material is used. However, for short-term or transient devices, a different material may be acceptable. The justification should not rely solely on biological endpoint-based biocompatibility tests, and must show that chemical composition, release characteristics and consequent toxicological risk have been considered.
Where a different material is used, the risk assessment should focus on the following:
- Where in the body is the material going to be used? Typically, a large animal study designed to gather data around the typical relevant biological endpoints is sufficient.
- How long is the material going to be in contact with the body? The animal data is expected to be at least two times the expected duration.
- How much of the material is going to be in contact with the body or body fluids? For example, most vascular devices are blood contacting bringing quantitative and qualitative material characterization—especially extractables and leachables testing—prominently into focus.
- What effect is the material going to have on the body? As stated above, extractables and leachables testing and toxicological assessment must be considered.
- Is there any evidence that the materials are acceptable for the intended use? Have the materials been used previously in this intended use/application?
Biological Safety Testing & Biological Equivalence
Biological safety testing includes physical and chemical characterization of the medical device components, an assessment of the risk of injury and toxic effects to the human, and testing to assess all relevant biological endpoints. The biological safety evaluation should sit within manufacturers’ risk management process and Quality Management System. Manufacturers may be under the assumption that if a medical device has passed these safety tests, it is already biologically equivalent to existing products. Though biological safety testing does have a role to play in demonstrating equivalence, they are not synonymous. Elements of the safety testing process can be used in the justification for equivalence. For instance, chemical characterization helps to demonstrate how processing, design and the use environment may impact a material, though it is the same material used in the equivalent product.
Another important point relating to biological safety testing is that, though the test matrix provided in ISO 10993-1:2018 is a useful tool for endpoint selection, it is not comprehensive when it comes to biological safety. Strictly adhering to this matrix may result in an incomplete safety evaluation. The latest version of ISO 10993-1 has been revised to lay emphasis on material physical and chemical characterization (Annex A), so manufacturers should refer to both versions. The most recent version also provides clarity on biocompatibility testing for devices termed ‘transitory contacting devices’, which may include lancets, hypodermic needles or capillary tubes that are used for less than one minute. According to the standard, these generally do not require testing unless they are made with coatings or lubricants that could be left in contact with body tissues after the medical device is removed.
Providing a Clear Rationale
Leveraging clinical data from an equivalent device can be cost-effective, saving time and resources on sourcing new evidence. However, this strategy can only be successful if there is a clear rationale demonstrating why the safety and performance of the subject device are the same as that of the equivalent device, even if there are material differences. This will be the primary area of focus during notified body reviews. Manufacturers need to verify that they can take this route, as a weak rationale could lead to rejection from the notified body, unnecessarily prolonging the certification process, which currently is taking 12-18 months. In this case, manufacturers may have to carry out new clinical studies, creating further delays. Notified bodies cannot provide advice on manufacturers’ rationales, but manufacturers can refer to the latest guidance and standards for equivalence and biological safety testing to clarify requirements.
Manufacturers often struggle to answer the question, “What does ‘the same’ mean?” Materials that are essentially the same might have a different formulation or even a different manufacturing process when used in a different device. Ultimately, manufacturers should bear in mind that devices don’t necessarily have to be identical, but they must be the same to the extent that they are not different.