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510(k) Data Aggregation

    K Number
    DEN220017

    Validate with FDA (Live)

    Device Name
    BioXmark
    Manufacturer
    Nanovi A/S
    Date Cleared
    2022-12-23

    (294 days)

    Product Code
    QUV,OUV
    Regulation Number
    892.5727
    Type
    Direct
    Panel
    Radiology
    Age Range
    All
    Reference & Predicate Devices
    N/A
    Predicate For
    N/A
    AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticPediatricDiagnosticis PCCP AuthorizedThirdpartyExpeditedreview
    Intended Use

    BioXmark is indicated for use to radiographically mark lung, bladder and lymph nodes in adult patients for whom it has been determined that radiographical marking of tissue for radiation treatment is indicated for their cancer treatment.

    BioXmark is implanted via image guided injection into tissue relevant for radiotherapy planning at a healthcare facility. BioXmark can be implanted in the tumor, lymph nodes or tissue adjacent to the tumor subject to irradiation or healthy tissue which should not be irradiated.

    BioXmark is intended to mark tissue for at least 3 months after implantation.

    Device Description

    The device is a single-use, implantable device consisting of a sterile transparent liquid in a onepoint-cut (OPC) glass ampoule. Upon injection of the liquid into soft tissue, efflux of alcohol leads to the formation of a radiopaque, sticky, gel-like fiducial marker in vivo, which is visible using fluoroscopy, CT. MRI, and ultrasound. The subject device is a mixture of ethanol, sucrose acetate isobutyrate (SAIB) and an iodinated and acylated derivative of sucrose (x-SAIB). Each ampoule contains 1 mL of liguid and is steam sterilized. On injection, a miniscule amount of ethanol diffuses in 1 to 2 hours, causing an increase in marker viscosity and resulting in a hydrophobic semisolid gel-like marker at the injection site.

    AI/ML Overview

    Here's a summary of the acceptance criteria for BioXmark and the studies performed to demonstrate that the device meets those criteria, based on the provided text:

    Acceptance Criteria and Device Performance for BioXmark

    1. Table of Acceptance Criteria and Reported Device Performance

    Acceptance Criteria (Special Controls & Clinical Study Endpoints)Reported Device Performance (as demonstrated by studies)
    Risk of marker migration in tissue during the course of radiation therapy through post-treatment follow-up.Lung Cancer Study (310-01): Migration of BioXmark in lung cancer patients in this use case is less than 15% (calculated with 95% certainty). No migration observed in any of the 29 markers followed. Positional shifts were observed only in patients with large anatomical changes, with markers still at the anatomically right spot. Bladder Cancer Study: All 60 visible markers (from a total of 76 implanted) remained detectable without displacement through week four of follow-up. Blurring, migration, and fading did not occur during treatment. Animal Study (Porcine model): BioXmark markers did not migrate and retained their 3D shape over the course of a 6-week study. Animal Study (Pancreatic tumor mouse model): Position of BioXmark was stable over 4 months. Animal Study (Mice subcutaneous implantation): Followed positional stability at 1 hour, 24 hours, 1 month, and 5 months without adverse events.
    Ability to visualize the marker to allow for adequate localization during the course of radiation therapy through post-treatment follow-up.Lung Cancer Study (310-01): BioXmark was visible on all defined imaging modalities (ultrasound, CT, CBCT, 4D CT, 2D kV, fluoroscopy) during the entire treatment period. All markers had a Contrast-to-Noise Ratio (CNR) > 2 (cutoff for visibility), and CNR remained constant. Bladder Cancer Study: 79% (95% CI 70-88%) of implanted markers were visible on treatment planning CT scan. All separate spots were continuously classified as clearly visible without artifacts. All visible markers remained detectable through treatment. Bench Study (X-ray imaging): All markers (10 ul, various shapes) were clearly visible with mean contrast levels in the range of 700-1200 HU (spherical), 400-800 HU (flat cylindrical), and 500-900 HU (elongated cylindrical), resulting in CNR > 110. Bench Study (MR): All volumes of markers tested (10 ul, 25 µl, 50 µl, 100 ul) were identified with low degrees of artifacts as hypo-intense spots in both T1w FFE and T2w MRI. Animal Study (Porcine model): Visualizable using Ultrasound, fluoroscopy, and CT-imaging. Animal Study (Pancreatic tumor mouse model): Detectable by CBCT (SARRP and Skyscan).
    Risk of device interference with tumor response assessment post-treatment.Bench Study (Artifacts): Data support CNR and streaking artifacts comparable to currently marketed fiducial markers. SI of BioXmark for volumes < 200 ul (range 10.79-20.14) was significantly lower than commercial solid soft tissue markers (range 16.23-62.36) while maintaining high contrast. No relevant artifacts observed in clinical studies. Bench Study (MR): Low degree of artifacts compared to solid soft tissue markers.
    All adverse events.Lung Cancer Study (310-01): 15 SAEs and 25 AEs reported in Part A, none device-related. One AE, likely marker-related due to protocol violation (no image guidance, possible placement in a vessel/vascularized area), resulted in mild pain. 59 SAEs in Part B, no Adverse Device Effects or Serious Adverse Device Effects. Bladder Cancer Study: Two patients experienced grade 2 toxicity, one possibly related to the implantation procedure, not the marker (urinary tract infection, hematuria).
    Device toxicity (Animal performance data).Biocompatibility: Determined to be biocompatible based on cytotoxicity, sensitization, intracutaneous reactivity, acute systemic toxicity, genotoxicity, implantation, subacute/subchronic toxicity, material-mediated pyrogenicity, and toxicological risk assessment for carcinogenicity. No risk of carcinogenicity identified. Animal Safety Studies: BioXmark was well tolerated in a pancreatic tumor mouse model (no changes in physical condition or toxic side effects). No adverse events or withdrawal of animals in mice with subcutaneous implantation.
    Maintenance of physical form throughout the course of therapy and post-treatment follow-up.Lung Cancer Study (310-01): Marker volume and density were stable through the treatment period. Volume slowly reduced by ~35% over the first 9 months due to resorption, then stabilized. Contrast level remained constant for 24 months, indicating degradation from surface to interior. Animal Study (Resorption): Resorption via chemical hydrolysis, gradually degrading the surface. Degradation appears to stop at 3-9 months.
    Device interference with radiation dose delivery.Clinical Study (Dose distribution): Effect on dose distribution from BioXmark was negligible for 6 lung cancer patients treated with photon therapy. Bench Study (Proton beams): Effects appear to be equivalent or smaller than solid markers. One large BioXmark marker perturbed the proton beam by a maximum of 4.8%; no influence after the phantom. Calculated and measured Relative Proton Stopping Power (RSP) showed good agreement (1.174 calculated vs 1.164 measured).
    Biocompatibility of patient-contacting components.Biocompatibility Evaluation: Extensive testing according to ISO 10993-1 demonstrated biocompatibility.
    Continued sterility, package integrity, and device functionality over the labeled shelf life.Sterility: Sterilized by moist heat (ISO 17665-1:2006) achieving SAL of 10-6. Packaging: Shipment integrity tested per ASTM D4169-16. Shelf Life/Stability: Representative samples aged two years (real-time and accelerated) confirmed continued functionality, material, and packaging properties.
    Device sterility and non-pyrogenicity.Sterility: Demonstrated with SAL of 10-6. Pyrogenicity: Bacterial endotoxin testing per ANSI/AAMI ST72:2019.
    Usability testing (device can be positioned as indicated).Human Factors Testing: Overall success rate on critical tasks was 98.8% across 30 participants, types, and contexts (241 critical user-device interactions). Only 3 critical use errors (1.2%), attributed to study artifacts and general procedure, not specific to BioXmark.

    2. Sample Size for Test Set and Data Provenance

    • Lung Cancer Study (310-01):
      • Subjects: 15 subjects
      • Markers: 29 (analyzable) out of 35 implanted markers.
      • Provenance: Retrospective, collected from patients having BioXmark implanted prior to radiotherapy. The study started in February 2014 and was completed in October 2018. Country of origin not explicitly stated, but Nanovi A/S is based in Denmark.
    • Bladder Cancer Study:
      • Subjects: 20 patients (20 evaluable for CT scan, 19 evaluable for CBCT).
      • Markers: 76 implanted markers (60 evaluable for visibility on CT, 60 evaluable for stability on CBCT).
      • Provenance: Prospective Phase I-II trial conducted between July 2018 and July 2019 at a tertiary university medical center. Country of origin not explicitly stated, but Nanovi A/S is based in Denmark.

    3. Number of Experts and Qualifications for Test Set Ground Truth

    • Lung Cancer Study (310-01):
      • Number of Experts: At least two (a medical physicist and an investigator).
      • Qualifications: "Medical physicist" and "investigator" are stated. Specific years of experience or additional details are not provided.
    • Bladder Cancer Study:
      • Not explicitly stated for establishing ground truth for visibility and stability. "Investigator" is mentioned in the context of the study. Visual scoring was dichotomous (visible/non-visible).

    4. Adjudication Method for Test Set

    • Lung Cancer Study (310-01):
      • Visibility was evaluated by "the naked eye by scoring yes/no by the medical physicist and investigator."
      • Potential artifacts were reviewed "by the investigator and the medical physicist independently."
      • For markers with decreased 3D vector length (indicating potential migration), "Independent manual assessment by both the medical physicist and the investigator resulted in their judgement that the markers had in fact not migrated." This suggests an unblinded consensus or discussion approach.
    • Bladder Cancer Study:
      • Visibility was scored dichotomously (visible/non-visible). No explicit adjudication method described beyond this.

    5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

    • No MRMC comparative effectiveness study was explicitly mentioned in the provided text, nor was an effect size for human readers improving with AI vs. without AI assistance. The studies focused on the performance of the BioXmark device itself, its visibility, stability, and safety, rather than comparing human reader performance with and without AI assistance in reading images with BioXmark.

    6. Standalone (Algorithm Only) Performance Study

    • No standalone (algorithm only) performance study was described. The performance data for BioXmark focuses on its physical properties, visibility by human assessment (medical physicist/investigator), and integration into clinical workflows.

    7. Type of Ground Truth Used

    • Lung Cancer Study (310-01):
      • Expert Consensus: For visibility, artifacts, and particularly for the re-assessment of potential migration, a joint judgment/consensus of a medical physicist and investigator was used.
      • Quantitative Measurements: Contrast-to-Noise Ratio (CNR) for visibility, Hounsfield Unit (HU) thresholding for automatic contouring, and 3D vector length changes for positional stability were objective measurements.
    • Bladder Cancer Study:
      • Visual Assessment/Expert Judgment: Visibility scored dichotomously (visible/non-visible). Positional stability scored on CT scan and latest CBCT by experts (investigators).
      • Quantitative Measurements: The "preset threshold of 75%" for visibility suggests a quantitative benchmark.
    • Animal Studies: Primarily based on direct observation, necropsy findings, and specialized imaging techniques (CBCT, SARRP, Skyscan).
    • Bench Studies: Objective measurements of physical properties, attenuation coefficients, contrast levels (HU, CNR), streaking index (SI), and RSP.

    8. Sample Size for the Training Set

    • The provided text does not describe a "training set" in the context of a machine learning algorithm. The studies mentioned (clinical, animal, bench) are performance evaluations of the physical device. Therefore, a sample size for a training set is not applicable here as no AI/ML algorithm is being 'trained'.

    9. How Ground Truth for the Training Set Was Established

    • As there is no mention of an AI/ML algorithm or a "training set," the method for establishing ground truth for a training set is not applicable to the information provided.
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