Structural heart technologies encompass a diverse family of devices that restore or support cardiovascular function through repair, replacement, occlusion, or mechanical assistance. These devices support patients with conditions ranging from congenital heart disease to advanced heart failure.
NAMSA brings extensive global expertise and experience to deliver a comprehensive preclinical testing pathway for valve technologies, septal and appendage-related implants, circulatory support systems (LVAD, TAH, ECMO), structural reconstruction (patches), and ablation and electrophysiology (EP) platforms.
These devices and their associated delivery systems operate at the intersection of complex anatomy, high-energy hemodynamics, and long-term blood contact. This combination makes preclinical medical device testing both indispensable and uniquely challenging.
Strategy First: Your Regulatory Pathway Shapes the Preclinical Plan
Even the most sophisticated bench setups cannot fully replicate cardiac anatomy, physiologic hemodynamics, thrombo-inflammation, and device-tissue interactions in living systems. For long-term blood-contacting implants—like structural heart devices—regulators typically expect in vivo confirmation of safety and performance before first-in-human implants and marketing submissions. Before locking endpoints and selecting animal models, first confirm your regulatory route:
- The FDA uses risk-based classification to determine your route: 510(k) (predicate-based), De Novo (novel, low–moderate risk), or PMA (high-risk). Structural heart devices are frequently classified as PMA, but innovative access systems, accessories, or lower-risk ancillaries may pursue 510(k) or De Novo. Get the class, product code, and pathway right first—your preclinical program depends on this decision.
- Under EU MDR, manufacturers must provide detailed technical documentation (per Annex II) including results and critical analyses of all verification & validation activities (engineering, simulated use, animal tests). These data, along with a clinical evaluation, must map to each relevant General Safety and Performance Requirement (GSPR). In all cases, in vivo studies must be well-justified and traceable from raw data to conclusions.
Pro tip: Build a Biological Evaluation Plan (BEP) that ties materials and blood-path, long-term exposure to ISO 10993-1 endpoints using the FDA’s contact-duration tables. This becomes your blueprint for required testing and scientific justifications.
Designing an In Vivo Study for a Structural Heart Device
With the regulatory route determined, the next step is to design a robust in vivo preclinical study addressing key safety and performance risks.
Study Objectives Anchored to Residual Risk
Preclinical animal testing should be purposeful, risk-based, and focused on demonstrating that a device is safe, functional, durable, and physiologically compatible before first-in-human use.
Structural heart preclinical study objectives typically include:
- Demonstration of Acute and Chronic Safety
- Assess immediate procedural safety during device implantation or deployment
- Confirm absence of major adverse events such as perforation, embolization, or arrhythmias
- Evaluate hemodynamic stability immediately post-implant and during follow-up
- Validation of Functional Performance in a Living Cardiovascular System
- Demonstrate proper deployment, positioning, anchoring, and stability of the device in vivo
- Confirm effective restoration or support of cardiovascular function
- Evaluate hemodynamic performance under physiologic conditions (e.g., regurgitation, pressure gradients, qualitative/quantitative flow behavior)
- Assessment of Device–Tissue Interaction and Healing Response
- Characterize the biological response to the device, including inflammatory reaction, fibrosis, or neo-endothelialization
- Confirm absence of tissue damage, erosion, perforation, or abnormal remodeling
- Evaluate integration of the device with native anatomy
- Evaluation of Thrombogenic and Hemocompatibility Behavior
- Assess presence or absence of thrombus on, near, or downstream of the device
- Monitor systemic markers of hemolysis and/or inflammation
- Confirm appropriate blood-device interface behavior during follow-up
- Confirmation of Structural Integrity and Device Durability
- Identify fractures, tears, deformation, or wear
- Evaluate chronic stability of seals, anchors, and other components
- Characterization of Systemic and Organ-Level Effects
- Evaluate potential off-target effects (e.g., renal or pulmonary emboli, myocardial injury)
- Assess overall clinical condition and survival of the animal
- Perform necropsy and histopathology to evaluate downstream organs for embolic or inflammatory sequelae
- Validation of Imaging and Procedural Usability
- Demonstrate device visibility under fluoroscopy, angiography, ultrasonography, CT, or MRI
- Confirm the ability to navigate, position, and deploy the device using a clinically relevant access route
- Assess procedural workflow and operator usability
Finally, it is critically important to turn your risk analysis and study objectives into testable, quantitative endpoints by defining how success or failure will be measured and which tests will produce the necessary evidence to support safety and performance. Make primary endpoints your pass/fail criteria (e.g., hemodynamics, structural integrity, thrombus formation, deployment success) and secondary endpoints your supporting evidence (e.g., usability, imaging).
Model Selection & Justification
Animal model selection for preclinical testing of structural heart devices is driven by the need to replicate human cardiac anatomy, physiology, and hemodynamic loading as closely as possible. Large animal species, most commonly porcine (pig) and ovine (sheep), are selected because their cardiovascular dimensions, tissue properties, and valve mechanics approximate those of humans and allow realistic assessment of device deployment, anchoring, and functional performance.
The chosen model must provide sufficient anatomical access for the intended delivery route (e.g., transcatheter, transapical, transseptal), and the target structure must be large enough to accommodate the device. Additional considerations include the animal’s healing response, thrombotic tendency, chronic survivability, and compatibility with imaging modalities used for real-time assessment.
Ultimately, the selected model must enable evaluation of both acute procedural performance and chronic tissue-device interactions to reduce residual risk before first-in-human studies.
It is important to explicitly state model limitations, if any, and how they affect interpretation of your study results—e.g., healthy sheep hearts are smaller and stiffer than dilated human hearts; wall-contact lesions or conduction effects may be exaggerated in ovine compared to clinical reality. Regulatory authorities expect this kind of critical analysis in your preclinical documentation.
In addition to animal models, consider incorporating in silico modeling and benchtop 3D or biosimulation models early in the development process. These tools can help identify potential failure modes, optimize device design, and reduce the number of animals required—supporting the 3R principles (Replace, Reduce, Refine).
Sample Size and Bias Control
Sample size in large animal preclinical studies is generally driven by regulatory expectations, scientific rigor, and ethical considerations rather than formal statistical powering. Because structural heart devices are often evaluated in complex, resource-intensive models, the goal is to use the minimum number of animals needed to generate reliable safety and performance data.
Key considerations include:
- Study objectives and regulatory risk
- Variability of the animal model
- Acute versus chronic evaluation
- Number of timepoints
- Device sizes
- Ethical considerations (adhering to the 3R principles)
While studies testing structural heart devices often cannot be blinded in the same way as drug trials, several well-established practices—such as protocol standardization, animal randomization, blinding of histopathology or imaging assessments, and the use of objective, quantitative endpoints—help ensure scientific rigor and reduce operator bias.
Choice of Predicate Device
For PMA, De Novo, and EU MDR pathways, animal studies are generally risk-driven rather than predicate-driven. However, the FDA’s 510(k) framework requires demonstrating that a new device is substantially equivalent to a legally marketed device.
Substantial equivalence means the new device is at least as safe and effective as the predicate device and does not raise new questions of safety or effectiveness. This is distinct from a non-inferiority claim, which is a statistical concept used in clinical trials.
Choosing a predicate device requires alignment on intended use, technological characteristics (mechanism of action, material and structural similarity), risk profile, and availability of high-quality preclinical and clinical data. The closer the predicate matches the test device in design and function, the more meaningful and defensible the preclinical comparison will be.
The FDA also requests a narrative justification explaining how the predicate was chosen and how it adheres to best-practice criteria. For guidance, consult the FDA’s 2023 draft guidance on predicate selection.
Study Duration
Study duration should be selected to adequately capture both acute procedural risks and longer-term biological and mechanical behaviors of the device. This should be justified based on the device’s intended use, blood-contact duration, and risk profile.
For structural heart devices, durations are typically aligned with ISO 10993-1 exposure categories:
- Prolonged exposure (>24 hours to 30 days): Evaluate acute procedural safety, early hemodynamic performance, thrombus formation, and initial tissue response.
- Long-term exposure (>30 days): Assess healing and endothelialization, chronic hemodynamics, thrombogenicity, anchoring stability, fatigue or wear, and device durability.
Use multiple survival timepoints (e.g., 30, 90, and 180 days) when different biological processes evolve at different rates. Incorporate longitudinal imaging (e.g., echocardiography, fluoroscopy, CT) to maximize data yield per animal and support the 3R principle of Reduction.
GLP or Non-GLP
Both GLP and non-GLP studies play essential and complementary roles in preclinical development.
- Non-GLP (pilot or feasibility) studies are used to:
- Refine access routes, delivery techniques, and deployment steps
- Optimize anticoagulation and peri-procedural management
- Validate imaging modalities and follow-up cadence
- Identify unanticipated failure modes early
- GLP studies are reserved for pivotal evaluations intended to support regulatory submissions (FDA IDE, PMA, De Novo, or EU MDR technical documentation)
Common Pitfalls and Practical Mitigations
A well-designed preclinical program for structural heart devices is risk-based, duration-appropriate, and strategically staged. A clear justification of animal model, sample size, study duration, and transparent translation of animal data into regulatory evidence are critical to progress toward first-in-human implants and market approval.
Common pitfalls and strategies to mitigate them include:
- Unaddressed Model–Human Differences: Clearly discuss anatomical and physiological differences and their impact on data interpretation.
- Skipping Pilot Studies: Proceeding directly to GLP increases the likelihood of deployment failures or protocol deviations. Well-designed non-GLP pilots reduce overall animal use and program risk.
- Vague or Non-Quantitative Endpoints: Claims such as “hemocompatible” or “durable” must be supported by predefined, measurable criteria (e.g., thrombus scoring, gradient thresholds, histological coverage).
- Incomplete GLP Documentation: Missing QAU inspections, weak raw data traceability, or insufficient article characterization are common causes of regulatory delay.
By proactively addressing these issues—and with experienced partners to guide you—you can streamline the path to first-in-human studies and regulatory approval.
Conclusion
In summary, developing a sound preclinical strategy—from aligning with the right regulatory pathway to carefully designed animal studies (complemented by bench and in silico methods)—is critical for the success of structural heart devices. By addressing key safety and performance questions early and avoiding common pitfalls, innovators can accelerate time-to-clinic and approval.
Partnering with an experienced CRO like NAMSA can help ensure all bases are covered, from regulatory planning to executing robust preclinical studies, ultimately increasing confidence in your device’s safety, performance, and regulatory success.
Frequently Asked Questions
Do all structural heart implants require animal studies?
Regulators in both the U.S. and EU do not mandate animal studies for every structural heart device. However, for long-term, blood-contacting, implantable devices, in vivo studies are often expected because bench, in vitro, or in silico testing alone cannot fully address key risks.
Are healthy animal models acceptable for diseased human indications?
Yes. Healthy large-animal models are commonly accepted, but regulators expect:
- A clear justification for model selection
- A transparent discussion of model limitations
- An explanation of how those limitations impact data interpretation
Explicitly addressing these gaps strengthens the credibility of the preclinical package.
Can I ask regulators if my study design is appropriate before starting?
Yes. Regulators explicitly allow—and strongly encourage—you to ask for feedback on your proposed animal study before you start it. Although the feedback is non-binding, this is considered good regulatory practice and often saves time, animals, and rework.
- The FDA allows sponsors to request formal, written feedback through the Q-Submission (Q-Sub) Program.
- Under EU MDR, early interaction is expected, typically via pre-submission meetings with your Notified Body.
Can one animal study support both FDA and EU MDR submissions?
Yes. A single well-designed animal study can often support both FDA and EU MDR submissions, provided that:
- The study objectives and endpoints are clearly defined
- The study is conducted under GLP when required
- The data are reported in a way that allows mapping to FDA risk closure and EU MDR GSPRs
Early alignment of study design with both regulatory frameworks is strongly recommended to avoid duplication.
