The NMPA granted innovation approvals to Medtronic’s Extravascular Implantable Cardioverter Defibrillator (EV-ICD) and issued a review report.
The published review reports like this one serve as important references for you to understand what the regulatory authorities are thinking and evaluating during their review process. We have been following the list for the past several years and review the relevant ones for our clients’ specific products to gain more clarity and be more efficient in their submission and approval process. As NMPA standardizes and streamlines the review process for fast-track approval, domestic and overseas players can benefit from our expertise and experience.
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Product overview
- Product structure and composition
- Intended Use
This product is used in conjunction with compatible extravascular implantable cardioverter defibrillator (EV-ICD) leads to automatically deliver therapies—including anti-tachycardia pacing, cardioversion, and defibrillation—for patients who have experienced or are at significant risk of life-threatening ventricular tachycardia.
This product is classified as an MRI-conditional medical device. Under specified conditions, and with special protective measures in place for both the patient and the implanted device, patients may undergo clinical magnetic resonance imaging (MRI) examinations at 1.5T and 3.0T field strengths. For detailed MRI examination requirements, please refer to the product’s instructions for use.
- Model/Specification
- Working principle
Pre-clinical
1. Product Performance
The performance evaluation assessed basic electrical characteristics such as pacing mode, pulse amplitude and width, lower rate limit, escape interval, sensitivity, input impedance, refractory periods, output voltage, pulse energy, anti-tachycardia pacing amplitude, and charging time. Functional characteristics included battery status indication, magnet application, emergency therapy, programmability, telemetry, and data transmission protocols. Sterility, residual ethylene oxide (EO), bacterial endotoxins, and the torque wrench accessory were also tested.
The applicant submitted technical specifications and corresponding test reports. All results complied with the product’s technical requirements, confirming that both general and specific performance expectations for active implantable devices were met.
2. Biocompatibility
As the device maintains long-term contact with patient tissue, a biological risk assessment was conducted in accordance with GB/T 16886.1-2022 (Biological Evaluation of Medical Devices – Part 1). Tests included cytotoxicity, sensitization, irritation, pyrogenicity, acute systemic toxicity, subacute/subchronic toxicity, chronic toxicity, implantation, genotoxicity, and carcinogenicity. The evaluation showed that biological risks were within acceptable limits.
3. Sterilization
The product is provided sterile using ethylene oxide. Sterilization validation confirmed a Sterility Assurance Level (SAL) of 10⁻⁶, consistent with regulatory requirements for sterile medical devices.
4. Shelf Life and Packaging
The device has a shelf life of 18 months. The applicant submitted stability data in accordance with the Guidance for Registration of Active Medical Devices with Defined Service Life. Shelf life is mainly influenced by battery, circuitry, and usage conditions. The applicant demonstrated that the product maintains performance throughout its expected service period.
5. Software Evaluation
The software is classified as high-risk (severity level: serious), with the current version labeled 8.1. Following the 2022 Guidance for Medical Device Software Registration Review, the applicant provided development documentation, GB/T 25000.51-2016 test results, and interoperability reports. These confirmed that the software development process was well controlled and all residual risks were acceptable.
In line with the 2022 Cybersecurity Guidance, the applicant also submitted documentation on cybersecurity risks and countermeasures. The current cybersecurity status was deemed acceptable, and an emergency response plan was in place.
6. Animal Studies
The applicant submitted animal study results from previous models involving substernal defibrillation and pacing. Additional studies specific to this product included:
- Morphological evaluation and lead displacement measurement in canine models;
- Long-term implant retrieval and performance in sheep models over a 3-year period.
These supported the device’s mechanical safety and long-term implantability.
7. Standards Compliance
The product complies with the following standards:
- GB 16174.1-2015: General requirements for safety, labeling, and manufacturer-provided information for active implantable devices.
- YY 0989.6-2016: Specific requirements for implantable devices used to treat tachyarrhythmias, including implantable defibrillators.
8. Other Studies
MRI compatibility testing demonstrated that the device is safe under specific conditions for use in 1.5T and 3.0T MRI environments, provided protective measures are taken. Supporting documentation confirmed system usability and safe operation in clinical settings.
Clinical
1. Exploratory Study
The exploratory study was a prospective, multicenter, single-arm trial involving 26 participants. Its primary goal was to preliminarily assess the safety and effectiveness of the EV ICD system.
- Primary Safety Endpoint: The proportion of subjects free from major EV ICD system- and/or procedure-related complications at 3 months post-implantation was 94.1% (95% CI: 83.6%–100%).
- Primary Effectiveness Endpoint: Among the 21 participants who underwent defibrillation testing at implantation, 20 successfully received defibrillation, with 18 (90%) meeting the success criteria.
- Secondary Endpoints included:
- Appropriate/Inappropriate Shocks: One patient experienced 5 spontaneous monomorphic VT/VF episodes. Two were terminated via ATP, and three by successful 40J shocks. Seven participants underwent elective defibrillation re-testing post-implant, all passing.
- Electrical Performance Over Time: Measurements such as pacing threshold, impedance, and sensing amplitude across different body positions and respiration phases remained stable across follow-ups.
- Pacing Capture and Sensing: At 3 months, 100% of participants had at least one vector with successful capture. The most commonly tested vector (Ring 1 to Coil 2) maintained consistent capture thresholds.
- Lead Position Stability: Among 16 participants with imaging data, 12 had lead curvature changes <5mm; 3 experienced notable displacements, with only one affecting therapy.
- ATP Performance: One patient had 5 monomorphic VT episodes. After initial programming failure, reprogrammed ATP led to intermittent capture in subsequent episodes.
- Adverse Events (AEs): Within 36 months, 56 AEs were reported among 16 participants; 10 were system/procedure-related, including 3 major complications that led to system explant.
2. Pivotal Study
The pivotal trial was also a prospective, multicenter, single-arm study, enrolling 356 participants to comprehensively assess the safety and effectiveness of the EV ICD system.
- Implantation Outcomes: 316 participants attempted implantation; 299 had a complete system successfully implanted.
- Primary Safety Endpoint: The 6-month rate of freedom from system/procedure-related major complications was 92.6% (95% CI lower bound: 89.0%), significantly above the prespecified 79% performance goal (p<0.0001).
- Primary Effectiveness Endpoint: Among 302 participants undergoing defibrillation testing, 298 succeeded (success rate: 98.7%; 95% CI lower bound: 96.6%), surpassing the 88% benchmark (p<0.0001). At ≤20J and ≤15J, effective defibrillation was achieved in 72.5% and 72.6% of applicable cases, respectively.
- Secondary Endpoints:
- Shock Appropriateness: In 2,068 spontaneous arrhythmic episodes reviewed by an adjudication committee, 149 received therapy (ATP and/or shock). Of these, 66 were appropriate and 83 inappropriate. At 180 days, the cumulative incidence of the first appropriate shock was 3.1%, and that of the first inappropriate shock was 8.5%.
- Electrical Performance:
- Pacing Thresholds: The most tested vector (Ring 1 to Coil 2) showed stable thresholds from pre-discharge (5.0V) to 6 months (5.5V). About 21.8% of patients could not be tested at 6 months due to sensing issues.
- Impedance: Impedance increased from pre-discharge to 6 months across vectors. For Ring 1–Ring 2, impedance rose from 339.6Ω to 512.1Ω.
- Sensing Amplitude: At pre-discharge, average R-wave amplitudes across postures were approximately 2.5–2.6 mV, remaining stable through follow-up.
- Pacing Perception and Therapy Adjustments:
- ATP Deactivation: By 6 months, 25.4% had ATP turned off due to intolerance; 41 patients in total had ATP disabled at some point due to pacing sensation.
- Asystole Prevention Pacing: Deactivated or set to monitor in 90.1% of patients at 6 months; 53 had therapy disabled or monitored due to sensation issues.
- Post-Shock Pacing: Deactivated in 21.1% of patients at 6 months, with 24 disabling it due to sensation concerns.
- Asystole Prevention: Among 29 patients, 173 asystolic episodes were identified. In 3 patients with therapy activated, 2 experienced 7 episodes that were successfully treated with 1–19 pacing pulses.
- ATP Efficacy in Spontaneous VT: Among 10 patients with ATP-enabled devices, 53 adjudicated VT episodes occurred. In 46 monomorphic VT cases, 32 were successfully terminated with ATP (69.9% success).
- Chronic Defibrillation Testing: All 36 patients who completed the protocol passed defibrillation testing at 30–40J. Real-world episodes (n=26 in 8 patients) were also successfully terminated with EV ICD therapy.
- Adverse Events: A total of 756 AEs occurred in 243 patients. Among 231 patients who underwent implantation, 731 AEs were recorded, including 331 serious AEs, 144 system/procedure-related (90 surgical, 92 device-related), and 31 related to accessories. Of these, 50 were complications (27 major, 23 minor), and 94 were observations without clinical consequences.