How to Justify Excluding Biocompatibility Endpoints in Your BEP

Not every biological endpoint needs to be tested for every device. That has always been the intent of ISO 10993-1: the standard provides a framework for identifying which biological effects are relevant, not a mandate to test them all. The challenge is that excluding an endpoint without adequate justification is one of the most common deficiency findings in biological evaluation documentation.

ISO 10993-1:2025 makes this requirement explicit. The standard now uses the term "biological effects" rather than "endpoints," and the restructured evaluation tables require assessors to justify their selections based on device-specific characteristics, not simply check boxes on a matrix.¹ If your biological evaluation plan excludes an effect from evaluation, the plan must document why.

This article covers what constitutes an adequate justification for excluding a biological effect, the most common justification errors, and how to structure your rationale so it holds up under notified body or FDA review.

The standard's position on exclusions

ISO 10993-1:2025 replaces the single Table A.1 from the 2018 edition with four separate tables organized by contact type. These tables identify which biological effects should be considered for each device category and contact duration.¹ The key word is "considered." The tables indicate what needs to be evaluated or addressed in your documentation. They do not automatically require testing for every listed effect.

The standard allows for effects to be addressed through means other than new testing: existing test data, literature review, chemical characterization combined with toxicological risk assessment, biological equivalence, or a documented rationale that the effect is not relevant to the device. Any of these can be valid, but only if the justification is specific, documented, and scientifically supportable.

The FDA's guidance on ISO 10993-1 reinforces this. The FDA-modified matrix is described as a framework for endpoint selection, not a comprehensive checklist. Variations from the framework should be justified, and existing data can be used where it adequately addresses the biological risk.²

In the EU, the legal basis for endpoint selection is the General Safety and Performance Requirements (GSPR) in Annex I of the Medical Device Regulation (EU 2017/745). While ISO 10993-1 provides the evaluation framework, notified bodies assess biological evaluation documentation as part of the broader technical documentation review. EU reviewers tend to place heavier emphasis on the completeness of the biological evaluation plan and the quality of justifications for excluded effects than the FDA process, which is more structured around the FDA-modified matrix. Additionally, the MDR requires specific attention to CMR (carcinogenic, mutagenic, reproductive toxic) substances under Annex I, Section 10.4.1, which may require endpoints to be addressed that would not be flagged by the ISO 10993 tables alone.^2b

What a strong justification looks like

A well-documented endpoint exclusion has three components: what you are excluding, why it is not relevant or is already adequately addressed, and what evidence supports that conclusion.

Exclusion based on contact type and duration

The simplest justifications are those tied directly to the device's categorization. If your device has limited contact with intact skin and the biological effects tables do not indicate a particular effect for that category, the justification writes itself. Reference the applicable table, state the device's contact type and duration, and note that the effect is not indicated for that category.

Be careful with contact duration calculations under the 2025 standard. The revision changes how duration is calculated: any portion of a day now counts as a full day, and cumulative contact from multiple exposures can push a device into a longer-duration category than manufacturers expect.¹ If your categorization is wrong, every endpoint decision that follows is built on a flawed foundation.

Exclusion based on existing data

If testing has already been performed on the same device or an equivalent device, you can reference that data rather than repeating the test. The justification should identify the specific test report, confirm that the test was conducted on a representative test article under relevant conditions, and explain why the existing data remains applicable. If the device or its materials have changed since the testing was performed, the justification must address whether those changes affect the relevance of the existing data.

Exclusion based on chemical characterization and TRA

Chemical characterization under ISO 10993-18 combined with toxicological risk assessment under ISO 10993-17 can serve as an alternative to biological testing for several effects. The FDA guidance explicitly identifies this as an acceptable approach for evaluating acute, subacute, subchronic, and chronic systemic toxicity, as well as genotoxicity, carcinogenicity, and reproductive/developmental toxicity.³

This is one of the most valuable pathways for reducing testing scope because it addresses multiple biological effects simultaneously. If your chemical characterization identifies all relevant extractable and leachable substances, and the toxicological risk assessment demonstrates adequate margins of safety for each, you have a documented basis for concluding that these effects are adequately addressed without additional animal testing.

ISO 10993-1:2025 reinforces the stepwise approach: material characterization and in vitro testing should be performed first, and in vivo testing should only be conducted if the data obtained from earlier steps is insufficient.⁴ This means a robust chemical characterization and TRA is not just an alternative to testing; it is the preferred first step in the evaluation hierarchy.

Exclusion based on biological equivalence

If your device can be demonstrated as biologically equivalent to a comparator device with existing biocompatibility data, that equivalence can justify excluding certain effects from new testing. The 2025 revision provides a more structured framework for equivalence, shifting the focus from input similarity (same material, same process) to output similarity: whether the biological risk profile is sufficiently comparable.¹

Equivalence arguments are heavily scrutinized. The justification must identify the comparator, document the basis of comparison, address any differences, and explain why those differences do not affect the biological risk profile. If the comparator data is not accessible or not adequately documented, the equivalence argument will not hold.

The most common justification errors

Referencing the wrong table or outdated categorization

A BEP that references "Table A.1" from the 2018 standard without addressing the restructured 2025 categorization will be flagged. The four new tables organize devices differently, and some devices may fall into different categories than they did under the 2018 framework. If your device category has changed, your endpoint evaluation must reflect the new category.

Excluding newly added effects without acknowledgment

The 2025 revision expands the scope of several biological effects. Genotoxicity is now a required consideration for devices with prolonged or long-term contact with all tissues except intact skin. This means devices that previously did not require genotoxicity evaluation may now need to address it.¹ Similarly, foreseeable misuse must now be addressed in the BEP. Excluding these without acknowledging they are new requirements suggests the BEP was not updated for the 2025 standard.

Generic material safety claims

Statements like "this material is widely used in medical devices" or "silicone is a well-known biocompatible material" are not justifications. They are assertions without evidence. A reviewer reading this has no way to verify the claim, no specific data to evaluate, and no traceability to the device under review. Every exclusion must reference specific data, whether that is a test report, a published study, a chemical characterization, or a documented risk assessment.

Cost-driven exclusions presented as scientific decisions

Reviewers can recognize when an endpoint was excluded to save money rather than because the risk was adequately addressed. If your BEP excludes chronic systemic toxicity for a long-term implant with no chemical characterization data and no existing test data, the justification problem is obvious regardless of how it is worded. The evaluation must be driven by the device's risk profile, not by the testing budget.

A practical framework for documenting exclusions

For each biological effect indicated in the applicable table that you are not addressing through new testing, document the following:

The effect being excluded. Name the specific biological effect as described in the 2025 tables.

The basis for exclusion. State which category applies: not indicated for this device category, addressed by existing test data, addressed by chemical characterization and TRA, addressed through biological equivalence, or not relevant based on a device-specific rationale.

The supporting evidence. Reference the specific document, report, or data that supports the justification. This should be traceable: a reviewer should be able to locate and evaluate the referenced evidence.

The assessment of continued relevance. If the evidence is from a prior evaluation cycle, confirm that no changes to the device, its materials, or its manufacturing have occurred that would affect the relevance of the existing data.

What this means for your BEP

The 2025 standard does not require more testing. It requires better justification. Many devices that were adequately evaluated under the 2018 framework will remain adequately evaluated under the 2025 framework. But the documentation must now explicitly address each biological effect, explain why excluded effects were excluded, and trace each decision to specific supporting evidence.

Before submitting your BEP, review every excluded effect and ask whether your justification would satisfy a reviewer who has no prior knowledge of your device. If the answer is uncertain, the justification needs strengthening. BioEvalPro checks every exclusion for documented rationale, referenced evidence, and consistency with the rest of your package, and scores the strength of each justification so you know exactly where to focus your effort. request a gap analysis for early access, or reach out to discuss your evaluation plan.