Animal Studies & FDA: When Animal Studies May Be Required and How to Justify Study Scope

The FDA (U.S. Food and Drug Administration) does not require animal studies in general.

Missing or inadequately justified animal studies can lead to inquiries and significant delays in the premarket review process. This is because the agency does not merely verify whether a study was conducted; it evaluates whether the justification for the study’s scope, model, and endpoints is sound.

Anyone developing medical devices for the U.S. market faces a key question early on: When may in vivo animal studies be expected from a regulatory perspective, and how do you justify the scope of the study in a way that withstands a technical review by the FDA?

This article offers structured guidance for R&D leads, RA/QA managers, and startup teams facing this very decision. It is based on publicly available FDA guidance documents and international standards but does not replace project-specific regulatory advice.

Note: The term “human animal studies” refers to an academic field of research and search terminology. This article focuses on preclinical animal studies in the regulatory medical device context.

What the FDA Expects from Animal Studies: Safety and Performance

FDA Guidance: “General Considerations for Animal Studies”

A key FDA reference is the guidance document “General Considerations for Animal Studies Intended to Evaluate Medical Devices.” It contains non-binding recommendations for animal studies to evaluate medical devices, particularly when no suitable alternative is available. It supplements product-specific guidance documents and relevant standards for medical devices of all classes.

The document describes a risk-based decision-making pathway: First, the team conducts a risk analysis in accordance with ISO 14971. This is followed by nonclinical bench testing of the device in its final form. Only if safety issues are identified during this process that cannot be adequately addressed through bench testing or other methods does an animal study become a regulatory consideration.

Where the appropriate study scope is uncertain, the Q-Submission process (a formalized FDA process for early regulatory alignment of study designs prior to submission) is available to seek early FDA feedback on the proposed study scope.

Evidence Category	Focus of the Study	Regulatory Reference
Safety	Local tissue reaction, systemic toxicity, immune response, thrombogenicity.	ISO 10993-6, ISO 10993-11
Performance	Functional integrity, mechanical stability in vivo, user handling.	FDA Guidance (March 2023)
Handling	Insertability, visibility under imaging, controllability, retrievability.	FDA Guidance (March 2023)

Safety Evidence: Biocompatibility, Toxicity, Local Tissue Reaction

The FDA expects adequate evidence of biological safety, particularly biocompatibility in accordance with ISO 10993, systemic toxicity, and local tissue reaction following implantation (ISO 10993-6). The assessment is based on semi-quantitative histopathological evaluation systems. Crucially, the safety evidence must directly address the hazards identified in the risk analysis. Generic test batteries without reference to the risk assessment are insufficient.

Performance Evidence: Function Under Physiological Conditions

In addition to safety, the FDA evaluates whether the device functions under physiological use conditions, i.e., under blood flow, mechanical stress, or tissue interaction. Performance endpoints must be clinically relevant and have predefined acceptance criteria. The FDA emphasizes that studies should reflect all steps of the clinical procedure, from surgical access to the final placement of the device.

When Animal Studies Are Warranted: Trigger Criteria

Not every medical device requires an animal study. However, certain scenarios may make in vivo animal studies more likely from a regulatory perspective. Three trigger criteria occur particularly frequently in practice.

Intended Use: Tissue Interaction, Implant, Blood Contact

For implantable devices, devices with direct blood contact, or otherwise biologically invasive devices, an animal study may become a regulatory consideration, particularly if significant safety or handling issues remain unresolved following risk analysis, bench testing, and other nonclinical methods.

Novel Technologies: No Predicate Device, No Literature Basis

If there is no reliable reference to a predicate device and no robust comparative data, an animal study may become significantly more likely from a regulatory perspective. However, what evidence is considered appropriate from a regulatory standpoint depends on the risk profile, the technology, the intended premarket submission pathway, and the remaining questions regarding testing and alternative methods. In the FDA preclinical pathway, early coordination regarding the Q-Submission process is recommended in such cases. This applies in particular to Class III devices in the PMA (Premarket Approval) pathway with novel mechanisms of action or materials for which no sufficient data basis exists.

Size and Surgical Application: Devices Requiring In Vivo Handling

Some questions may be difficult to address through bench testing alone and may require in vivo evaluation: Can the device be placed anatomically correctly? How does it behave under real-world handling conditions, from insertion through final placement? Particularly with catheter-based systems or minimally invasive instruments, such questions often cannot be resolved on a test bench alone.

When Animal Studies May Not Be the Primary Evidence Pathway

The trigger criteria indicate when an animal study becomes a regulatory priority. Equally important is the counter perspective: In which scenarios are other evidence pathways sufficient?

Three scenarios in which animal studies are generally not the primary focus:

Sufficient Predicate Data Available

If a device is submitted via the 510(k) pathway and a robust predicate device product with a documented safety history exists, the combination of bench testing, biocompatibility data, and literature review may be sufficient. Prerequisite: The technological differences from the comparator do not raise new safety questions that can only be answered in vivo.

Purely External Contact Devices with Short Contact Duration

For devices that merely touch the intact skin surface and are intended for a contact duration of less than 24 hours (e.g., diagnostic sensors or external electrodes), animal studies are generally not a priority, provided there are no additional risk factors. Here, the focus is generally on a risk-based biological assessment, including existing data, material, and contact evaluation, and—if necessary—appropriate biocompatibility tests. In vivo animal studies are usually not warranted in the absence of additional risk factors. In accordance with the current state of standardization (ISO 10993-23), in vitro methods for testing irritation are also preferred over traditional in vivo rabbit models.

Validated In Silico or Ex Vivo Methods Available

For specific issues, such as mechanical fatigue strength, hemodynamic flow conditions, or thermal effects, computational modeling—such as finite element analysis (FEA) or computational fluid dynamics (CFD)—can provide regulatory evidence, provided that model validation and credibility assessment for the respective context of use are convincingly documented. Comprehensible model validation and credibility assessment based on the FDA CM&S framework are required; ASME V&V 40 can serve as an important reference for this, where applicable. Cadaveric testing or complex ex vivo tissue models can also address questions regarding surgical handling and placement without the need for a live animal model.

Principle: In all three cases, the following remains crucial: The justification for why no animal study was conducted must be just as clearly documented as the justification for conducting a study. The risk-based decision path according to ISO 14971 applies in both directions.

How to Clearly Justify the Scope of the Study: The Rationale Canvas

The FDA evaluates not only the results but also the logic behind the study design. A compelling rationale for animal studies encompasses four dimensions that together define the scope of the study: The Rationale Canvas, or structured rationale framework.

Graphic: “The Rationale Canvas – the structured rationale framework”

01	Model Selection: Which Animal? Rationale and Alternatives The choice of animal model must be scientifically sound. Depending on the research question, porcine, ovine, or small animal models may be suitable, for example. What matters is not the animal species itself, but the scientific justification that the anatomy, physiology, and study design adequately reflect the defined study objectives and the intended clinical application. The FDA expects a documented justification for why this specific model was chosen, including known limitations and an explanation of why alternatives were not suitable.
02	Endpoints: What is Being Measured and Why? Primary endpoints typically include histopathological evaluations according to ISO 10993-6 and device safety parameters such as adverse events and structural integrity. Secondary endpoints may include imaging (radiography, micro-CT), biomechanical tests, or blood parameters. Each endpoint must be traceable to a specific risk identified in the risk analysis. Acceptance criteria must be defined in advance and scientifically justified, not retrospectively.
03	Sample Size: How Many Animals and Why? Regulatory expectations for preclinical animal studies require a transparent justification of the sample size. It should be study-objective-specific and transparently justified, ideally based on exploratory data, variability, and the clinically relevant effect size. Method-specific minimum requirements of individual standards do not replace this justification. A sample size that is too small risks yielding uninterpretable data due to unexpected animal losses or statistical outliers. Additional reserve animals should only be planned where scientifically justified by the risk of loss, duration of observation, or procedural complexity.
04	Worst-case Scenario: Are Extreme Clinical Situations Covered? The FDA assesses whether the test conditions reflect the most demanding clinical scenarios: the most challenging anatomical configuration, the longest intended duration of use, and the most aggressive clinical usage parameters. If demanding clinical usage scenarios are not clearly accounted for in the study design, the risk of inquiries regarding the adequacy of the design increases. This aspect is most frequently underestimated in practice, yet it is often the decisive factor for the FDA’s assessment of the animal study design.

Typical FDA Questions During Review and How to Anticipate Them

Answering the following questions in the submission can help reduce the risk of review questions:

• Why this animal model and not an alternative?
• Does the test sample correspond to the final commercial product, and if not, what differences exist, and have their effects been evaluated?
• Are the endpoints clinically relevant and pre-specified?
• How was the sample size determined?
• Have all relevant ISO standards been taken into account?

Typical weaknesses identified in review comments include insufficient model justification, lack of rationale for the sample size, and test samples that do not correspond to the final device. GLP requirements under 21 CFR Part 58 should also be considered early on if nonclinical laboratory studies are planned to support an FDA submission.

Data integrity and documentation aligned with GLP requirements, where applicable, remain a sensitive area of scrutiny. Accordingly, the selection and oversight of external testing facilities should be documented with particular care in the context of regulatory submissions. Structured preparation using the Rationale Canvas helps proactively address these typical weaknesses in animal studies.

What 3Rs/NAMs Mean as Alternatives: Clearly Categorized

3R (Replace, Reduce, Refine) and New Approach Methodologies (NAMs; non-animal or alternative methodological approaches) are gaining regulatory significance as alternatives to animal studies, both at the FDA and under the EU MDR. This shift is changing how teams plan and justify preclinical animal studies.

ISO 10993-1 requires a clearly defined stepwise approach: material characterization and in vitro testing take precedence. An animal study is only considered if, after these steps, gaps in the evidence remain that cannot be closed by other means. Validated or established in vitro alternatives may be available for certain biocompatibility endpoints, such as cytotoxicity, genotoxicity, or hemolysis, where applicable. Computational modeling is also gaining acceptance. The FDA has published guidelines for the evaluation of computational models.

For implantation studies according to ISO 10993-6, complex tissue-device interactions, and novel products without robust predicate data, animal studies may still be scientifically justified from a regulatory perspective if alternative methods do not sufficiently address the remaining safety or performance questions. The crucial question is therefore not “Animal study, yes or no?” but rather, “What evidence can be generated without using animals?” and “Where are animal studies scientifically necessary and justified from a regulatory perspective?”

Those who ask the right questions early on (model, endpoints, sample size, worst-case scenario) and document the answers before the FDA requests them can support a more efficient review process and strengthen the credibility of the submission rationale in the review process.

Frequently Asked Questions (FAQ)

Do I have to conduct an animal study for every medical device?

No. The FDA does not require animal testing across the board. The decision is based on a risk analysis in accordance with ISO 14971. If bench testing and other nonclinical methods sufficiently address all identified risks, an animal study may be dispensable. The Q-Submission process offers the opportunity to seek FDA feedback on this in advance.

Which FDA guidance applies to animal studies for medical devices?

The key document is “General Considerations for Animal Studies Intended to Evaluate Medical Devices” (Final, March 2023). It applies to all device classes and describes requirements for study design, GLP requirements, where applicable, and reporting. Additionally, ISO 10993-6 applies to implantation studies and ISO 14971 applies to the underlying risk analysis.

Can I replace an animal study with in vitro tests?

In some cases. ISO 10993-1 requires a stepwise approach in which in vitro tests take priority. Validated alternatives exist for certain endpoints, such as cytotoxicity or genotoxicity. For implantation studies and complex tissue-device interactions, in vivo models may still be scientifically justified or expected from a regulatory perspective, provided that alternative evidence pathways do not sufficiently address the relevant risks.

How do I determine the correct sample size for an animal study?

Ideally, through a formal power analysis based on expected effect sizes and variability from preliminary studies. If this basis is lacking, the risk of failure, observation duration, and/or procedural complexity must be factored into the assessment, and the sample size must be thoroughly justified.

Sources & Further Links

External References

• FDA – “General Considerations for Animal Studies Intended to Evaluate Medical Devices” (Final Guidance, March 2023)
• ISO – ISO 10993-6:2016 “Biological Evaluation of Medical Devices – Part 6: Tests for Local Effects After Implantation”
• ISO – ISO 10993-1:2025 “Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing Within a Risk Management Process”
• ISO 10993-23:2021 “Biological Evaluation of Medical Devices – Part 23: Tests for Irritation”
• ISO 14971:2019: “Medical devices — Application of risk management to medical devices”

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Updated: May 2026 | Last reviewed: May 2026