Challenges of Demonstrating Biological Equivalence

ISO 10993-18 and EU MDR

In the European Union (EU), a device is considered equivalent if it fulfills all the requirements of technical, clinical, and biological equivalence. Of these, demonstrating biological equivalence tends to be the toughest aspect of the overall equivalence argument. Biological equivalence is a concept that allows medical device manufacturers to reduce or avoid animal testing for their products by demonstrating that they are biologically equivalent to another device that has already been tested and approved for the market. This concept assumes that if two devices have the same chemical composition, surface characteristics, and intended use, they will have the same biological response in the human body. Demonstrating biological equivalence, however, is not a simple task.

Regulatory Challenges

One of the main challenges of biological equivalence is the lack of harmonized and clear guidance from the regulatory authorities. Different regions and countries have different definitions, criteria, and expectations for biological equivalence. For example, the International Organization for Standardization (ISO) published the standard ISO 10993-18 in 2020, which provides a framework for the chemical characterization of medical devices and the assessment of biological equivalence (see Part 18, Annex C). The revision built a framework for identifying and quantifying medical device materials and constituents in concentrations that could potentially cause toxicological concern. However, this standard is not mandatory and may not be accepted by all regulators. Regulatory bodies in both the U.S. and the EU have taken a stepwise approach to recognize, adopt, and implement ISO 10993-18:2020. The U.S. FDA partially recognized 10993-18:2020 in July 2020 but stopped short of full recognition. The EU Regulation 2017/745 (EU MDR) accepts the revised ISO 10993-18:2020 as “state of the art” and holds manufacturers to the standard but the EU has yet to harmonize the standard across member states. While the EU MDR empowers notified bodies to interpret the meaning of “state of the art”, what constitutes “state of the art” analytical chemistry is not explicitly defined. Differences in resources, expertise, and regulatory priorities across member states lead to variations in interpretation and application.

ISO 10993-18:2020 presents some of the biggest challenges manufacturers face and the EU MDR has even stricter and more specific requirements for biological equivalence. EU MDR Annex XIV Part A(3) outlines the requirements for demonstrating equivalence. This text states that devices are biologically equivalent when they have the same materials (not just the same ISO 10993 biological response), in contact with the same tissues – even “similar release characteristics of substances, including degradation products and leachables.” This is in stark contrast to the EU Medical Device Directive 93/42/EEC (MDD) which allowed more liberty for material differences. This is especially challenging because materials that are closely related might have a different formulation or even a different manufacturing process. Due to materials characterization requirements outlined in the EU MDR applicable to most devices, regardless of contact duration or risk class, manufacturers need to disclose whether any carcinogens, mutagens, reproductive toxicants or endocrine disrupters (CMRs) are present in their devices in amounts ≥0.1% w/w. Addressing CMRs presents additional challenges, including thorough identification, scientific justification for their use, and extensive documentation. Materials characterization compliant with ISO 10993-18:2020 will be the best approach for addressing CMRs for many manufacturers.

The EU MDR requires manufacturers to provide a detailed justification for the choice of the proposed equivalent device, to perform a comprehensive comparison of the physical, chemical, and biological properties of the two devices, and to conduct additional testing if there are any differences or uncertainties. Chemical characterization and toxicological risk assessment can help manufacturers provide a rationale for the acceptability of devices with material differences.

The EU MDR also imposes more stringent criteria for the acceptance of existing data, such as the relevance, validity, and reliability of the data sources, the traceability of the data, and the ethical aspects concerning animal testing. Manufacturers who want to demonstrate biological equivalence for their products in the EU market must comply with these requirements, which may not be aligned with the ISO standard or other regulatory frameworks.

Technical Challenges

Another challenge of demonstrating biological equivalence is the complexity and variability of the technical methods and instruments used to perform the chemical characterization of medical devices. Chemical characterization involves the identification and quantification of the substances that are used in the construction of the device or that can be released from the device during its use. This process requires the use of sophisticated analytical techniques, such as gas chromatography, mass spectrometry, and infrared spectroscopy, which can have different levels of sensitivity and specificity. Moreover, the chemical characterization can be influenced by several factors, such as sample preparation or extraction conditions. It is essential to ensure that the chemical characterization is performed in a standardized and reproducible manner, and that the results are comparable between the subject and proposed equivalent devices.

Expert Guidance and Support

Realistically, no two devices are identical. It is important to bear in mind that biological safety is not the same as biological equivalence. To pass notified body review, manufacturers must identify, acknowledge, and address the differences between the subject and proposed equivalent devices in terms of impact to device safety and performance. Acceptance of the equivalency demonstration depends on the nature and extent of the differences, the type of device, and the impact of these factors on the clinical data. Manufacturers should be able to explain how material differences affect biological equivalence, and whether 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 as well as the outcomes of relevant toxicological risk assessments.

Biological equivalence is a useful and ethical concept that can help medical device manufacturers to reduce or avoid animal testing for their products. However, biological equivalence is not a straightforward concept, as it involves several challenges related to the regulatory requirements, the scientific methods, and the data analysis. Our team can help; contact us today to discuss your biological safety evaluation needs 855.463.1633.