K Number
DEN220017
Device Name
BioXmark
Manufacturer
Date Cleared
2022-12-23

(294 days)

Product Code
Regulation Number
892.5727
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdparty
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.
More Information

No Redacted Predicate, No Redacted Reference

Not Found

No
The device description and performance studies focus on the physical and chemical properties of the fiducial marker and its visibility in various imaging modalities. There is no mention of any software, algorithms, or data processing that would suggest the use of AI/ML.

No
The device is a marker used for radiation therapy planning and does not provide therapeutic benefit itself.

No

Explanation: The device is a fiducial marker used to make anatomical locations visible for radiation treatment planning and delivery; it does not aid in diagnosis.

No

The device description clearly states it is a single-use, implantable device consisting of a sterile transparent liquid in a glass ampoule, which forms a radiopaque gel-like fiducial marker in vivo. This is a physical, implantable medical device, not software.

Based on the provided information, this device is not an IVD (In Vitro Diagnostic).

Here's why:

  • IVD Definition: In Vitro Diagnostic devices are used to examine specimens taken from the human body (like blood, urine, or tissue samples) to provide information for diagnosis, monitoring, or screening.
  • BioXmark's Function: BioXmark is an implantable device that is injected directly into the patient's tissue. Its purpose is to act as a radiopaque marker within the body to aid in radiation treatment planning and delivery. It does not analyze samples taken from the body.

Therefore, BioXmark falls under the category of an implantable medical device, not an In Vitro Diagnostic device.

N/A

Intended Use / Indications for Use

The BioXmark is indicated as follows:

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.

Product codes

QUV

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. BioXmark is a mixture of ethanol, SAIB and x-SAIB in the ratio (b)(4) (w/w%). Upon injection, the 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. Based on performance data provided the rate of ethanol diffusion and formation of the marker is more dependent on the amount injected than the polarity of the tissue it is injected into. Ethanol diffusion rates do not vary significantly in different tissue types.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

fluoroscopy, CT, MRI, and ultrasound, 2D kV x-rays, CBCT, 4D CT

Anatomical Site

lung, bladder and lymph nodes, tissue adjacent to the tumor, healthy tissue

Indicated Patient Age Range

adult patients

Intended User / Care Setting

healthcare facility, gastroenterologists, interventional radiologists, advanced endoscopists, radiation oncologists, clinical support personnel, professional pulmonologists

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

SUMMARY OF BENCH STUDIES

BIOCOMPATIBILITY

Biocompatibility evaluation of the implant has been completed according to FDA Guidance, Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process." Cytotoxicity, sensitization, intracutaneous reactivity, acute systemic toxicity, genotoxicity, implantation, subacute/subchronic toxicity, and material-nediated pyrogenicity testing were conducted per the appropriate standards in the ISO-10993 series. Biocompatibility testing was performed on the sterlized device. A toxicological risk assessment was performed to evaluate the carcinogenicity endpoint for the subject device. No risk of carcinogenicity was identified. Based on all testing and evaluations, BioXmark was determined to be biocompatible.

STERILITY/PACKAGING/SHELF LIFE

Sterility: The device is sterilized by moist heat in accordance with ISO 17665-1:2006. The operation cycle selected was 121°C for 20 minutes. The sterilization cycle used for terminal sterilization of the device by moist heat achieved a F0≥15 and an SAL value of 10-6.
Packaging: The device is packaged in glass ampoules in a retail box with implant cards and instructions for use. Shipment integrity was conducted in accordance with ASTM D4169-16.
Shelf Life/Stability: Representative sterilized samples were aged two years. All tests were passed successfully.
Pyrogenicity: Bacterial endotoxin testing performed in accordance with ANSI/AAMI ST72:2019.

MAGNETIC RESONANCE (MR) COMPATIBILITY

The subject device is composed entirely of non-metallic components; per the FDA guidance document "Testing and Labeling Medical Devices for Safety in the Magnetic (MR) Environment," the device is MR Safe and poses no safety hazards in the MR environment.

HUMAN FACTORS TESTING

Usability testing was conducted to determine if use errors associated with use of the subject device have been reduced to an acceptable level. Across the sample of thirty (30) participants, a total of 241 critical user-device interactions were scored, including 61 simulated-use tasks with discernable outcomes and 180 comprehension questions. The overall success rate on critical tasks was 98.8%. In particular, the 241 critical user-device interactions yielded 238 successes (98.8%), 0 difficulties (0.0%), and only 3 use errors (1.2%).

PERFORMANCE TESTING - BENCH

  • Radiation effects on stability: No radiation effects shown on stability after exposure to 150 Gy.
  • Calculated mass attenuation curves: Mass attenuation curves showed that attenuation could be calculated based on elemental composition of BioXmark and X-Ray Mass Attenuation Coefficients from individual elements. High total iodine content of ~15 w/w% results in a high mass attenuation coefficient.
  • Effect of volume and shape on visibility under x-ray imaging: All markers (10 ul, elongated cylinder, flat cylinder, sphere) were clearly visible in x-ray imaging using clinically relevant settings in a thorax phantom. Mean contrast level for spherical BioXmark markers, flat cylindrical BioXmark markers and elongated cylindrical BioXmark markers were in the range of 700-1200 HU, 400-800 HU and 500-900 HU resulting in a contrast-to-noise ratio (CNR) of > 110 in all cases.
  • Artifacts: Data provided to support CNR and streaking artifacts. Contrast levels and streaking index were comparable to currently marketed fiducial markers. Artifacts did not impede the ability of the marker to be used for its intended purpose. The SI of BioXmark for volumes 2. No relevant artifacts were observed. The majority of BioXmark markers showed minimal change in the 3D vector length from the Center of Volume (CoV) of the tumor/lymph node and the CoV of the marker during the entire treatment period within the pre-defined criteria for migration ( 2. Based no observed migration with the twenty-nine (29) markers one can calculate with 95% certainty that migration of BioXmark in this use case is less than 15%.
    B. Bladder Cancer Study: Of the seventy-six (76) markers implanted, sixty (60) (79% (95% CI 70-88%) were visible on treatment planning CT scan. All (100%) of those visible markers (60) on CT scan remained detectable without displacement until the end of the treatment.

Predicate Device(s)

Not Found

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

N/A

0

DE NOVO CLASSIFICATION REQUEST FOR BIOXMARK

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Phase-changing fiducial marker for radiation therapy. A phase-changing fiducial marker for radiation therapy is a single-use. sterile liquid material that changes phase in situ when injected in tissue for the purposes of aiding radiation therapy treatment. The device is intended to be visualized using one or more radiologic imaging modalities.

NEW REGULATION NUMBER: 21 CFR 892.5727

CLASSIFICATION: Class II

PRODUCT CODE: OUV

BACKGROUND

DEVICE NAME: BioXmark

SUBMISSION NUMBER: DEN220017

DATE DE NOVO RECEIVED: March 4, 2022

SPONSOR INFORMATION:

Nanovi A/S Diplomvej 378 C/O DTU Science Park Kgs. Lyngby Denmark 2800

INDICATIONS FOR USE

The BioXmark is indicated as follows:

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.

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

LIMITATIONS

The sale, distribution, and use of the BioXmark are restricted to prescription use in accordance with 21 CFR 801.109.

The device is sterile, single-use and cannot be reprocessed.

Do not inject the device directly into the bloodstream.

A void injections into anatomical structures such as the heart, central nervous system, necrotic tissue, and air-filled cavities.

Do not inject into patients with hypersensitivity to iodine or other components of BioXmark.

Do not exceed maximum injection volume.

PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

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.

Image /page/1/Picture/11 description: The image shows a small glass ampule with a label on it. The label has the text "BioXmark" and "1 ml" printed on it. The ampule is clear and has a narrow neck. There is a small blue dot on the neck of the ampule.

Figure 1. BioXmark in single ampoule

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Table 1. BioXmark composition

Liquid

ComponentDescription(s)Nominal Content (w/w%)Function
SAIBSucrose acetate
isobutyrate(b)(4)Formation of marker in
vivo
x-SAIBIodinated and acylated
derivate of sucrose*Contrast component
providing radiopacity
EtOHEthanolSolvent, reducing the
viscosity of the liquid to
enable injection through
thin needles (≤25G)

*Sucrose 6.6'-di(2,4,6-triiodophenoxy) isobutyrate.

Primary Packaging

ComponentDescription(s)Nominal Content (w/w%)Function
Type 1 OPC Glass
ampouleBorosilicateN/ASterile barrier

BioXmark is a mixture of ethanol, SAIB and x-SAIB in the ratio | 00(4) (w/w%). Upon injection, the 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. Based on performance data provided the rate of ethanol diffusion and formation of the marker is more dependent on the amount injected than the polarity of the tissue it is injected into. Ethanol diffusion rates do not vary significantly in different tissue types.

SUMMARY OF BENCH STUDIES

BIOCOMPATIBILITY

As indicated in Table 1, BioXmark is a mixture of ethanol, SAIB and x-SAIB in the overall ratio of (0(4) (w/w%). Animal testing showed evidence of limited resorption occurring for 3-9 months followed by stabilization of the marker volume. It is characterized as a permanent (>30 days) implant, tissue/bone contacting. Biocompatibility evaluation of the implant has been completed according to FDA Guidance, Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process." Cytotoxicity, sensitization, intracutaneous reactivity, acute systemic toxicity, genotoxicity, implantation, subacute/subchronic toxicity, and material-nediated pyrogenicity testing were conducted per the appropriate standards in the ISO-10993 series. Biocompatibility testing was performed on the sterlized device. A toxicological risk assessment was performed to evaluate the carcinogenicity endpoint for the subject device. No risk of carcinogenicity was identified. Based on all testing and evaluations, BioXmark was determined to be biocompatible.

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Biocompatibility testing showed evidence of some resorption. Degradation appears to stop at the three-to-nine-month time point. The provided studies are sufficient to demonstrate lack of subchronic and chronic toxicity caused by the degradation products.

STERILITY/PACKAGING/SHELF LIFE

Sterility:

The subject device is provided sterile to the end user. The device is sterilized by moist heat in accordance with ISO 17665-1:2006. "Sterilization of health care products - Moist heat - Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices." The operation cycle selected was 121°C for 20 minutes. The sterilization cycle used for terminal sterilization of the device by moist heat achieved a F0≥15 and an SAL value of 10-6

Packaging:

The subject device is packaged in a glass ampoules are packaged in a retail box with implant cards and instructions for use.

Shipment integrity was conducted in accordance with ASTM D4169-16. "Standard Practice for Performance Testing of Shipping Containers and Systems." Packaging validation testing included stacking compression, loose load vibration, low pressure, random vibration, concentrated impact, handling, and visual inspection.

Shelf Life/Stability:

Representative sterilized samples were aged two years to determine the shelf life of the device. Testing was conducted to verify the devices still functioned as expected with two-year real time and accelerated-aged samples. Material and packaging properties did not degrade significantly during real time or accelerated aging. All tests were passed successfully.

Pyrogenicity:

Bacterial endotoxin testing performed in accordance with ANSI/AAMI ST72:2019 "Bacterial endotoxins - Test methods, routine monitoring, and alternatives to batch testing".

MAGNETIC RESONANCE (MR) COMPATIBILITY

The subject device is composed entirely of non-metallic components; per the FDA guidance document "Testing and Labeling Medical Devices for Safety in the Magnetic (MR) Environment," the device is MR Safe and poses no safety hazards in the MR environment.

HUMAN FACTORS TESTING

A human factors evaluation was conducted for the subject device in compliance with IEC 62366-1:2015+A1:2020 and FDA guidance document, "Applying Human Factors and Usability Engineering to Medical Device." Usability testing was conducted to determine if use errors associated with use of the subject device have been reduced to an acceptable level. The usability report described the validation study methods and findings that were used to evaluate the ability

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of the subject device to be used as intended by the intended users in the intended use environment. Percutaneous and endoscopic implantation methods were examined, and clinical users included gastroenterologists, interventional radiologists, advanced endoscopists, and radiation oncologists, and clinical support personnel with varying levels of experience.

The validation study consisted of user performance on comprehension questions that evaluated participants' understanding of device-specific knowledge presented in the technical documentation. Simulated-use tasks were also evaluated to promote the evaluation of the BioXmark for its intended use. Usability testing was performed for both percutaneous injections and endoscopic injections.

Across the sample of thirty (30) participants, a total of 241 critical user-device interactions were scored. including 61 simulated-use tasks with discernable outcomes and 180 comprehension questions. The overall success rate on critical tasks was 98.8% across all participants, types, and contexts. In particular. the 241 critical user-device interactions vielded 238 successes (98.8%). 0 difficulties (0.0%), and only 3 use errors (1.2%). The three (3) critical use errors were all committed by the same user group, on the same task, during the simulated endoscopic implantation procedure. Importantly, all 3 of the critical use errors are attributable to study artifacts and were associated with aspects of the procedure more generally, meaning they are not specific to BioXmark. Thus, these findings demonstrate that most critical user-device interactions attempted during device use were successfully completed without any form of difficulty or use error.

PERFORMANCE TESTING - BENCH

Bench testing was conducted to demonstrate that the BioXmark performs as expected under the anticipated conditions of use. The following bench testing was conducted to demonstrate the device performance characteristics:

TestPurposeResults
Radiation effects on stabilityTo determine if radiation
causes degradation of the
device when exposed to
appropriate energy and type of
beamsNo radiation effects shown on stability.
Calculated mass attenuation
curvesTo determine attenuation of the
subject deviceMass attenuation curves showed that attenuation
could be calculated based on elemental
composition of BioXmark and X-Ray Mass
Attenuation Coefficients from individual
elements
Effect of volume and shapeTo determine of marker
volume and shape affects
visibility on X-ray imagingAll markers were visible in X-ray imaging
ArtifactsTo assess marker visibility and
artifact evaluationData provided to support CNR and streaking
artifacts. Contrast levels, and streaking index
were comparable to currently marketed fiducial
markers. Artifacts did not impede the ability of
the marker to be used for its intended purpose.

Table 2. Performance testing completed for BioXmark

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Effects with proton beamsTo measure relative proton stopping powerEffects appear to be equivalent or smaller than solid markers.
BioXmark visibility and artifacts in MRTo evaluate marker visibility and artifactsAll volumes of markers tested were identified with low degrees of artifacts.
    1. Radiation effects on stability
      BioXmark markers were stress tested after exposure to a single irradiation dose of 150 Gy and compared to non-irradiated samples. HPLC analysis was performed at time: 0. ~ 30. ~60 and >90 days. Irradiation of BioXmark markers with a single dose of 150 Gy prior to storage had no effect on the hydrolysis rate. Marker degradation of non-irradiated samples was comparable to irradiated samples.

An additional study was performed, where 2.5-year-old samples were exposed to an irradiation dose of 150 Gy and compared to the non-irradiated samples. Visual inspection of BioXmark and High-performance liquid chromatography (HPLC) analysis were performed. Data showed no difference between BioXmark exposed to radiation versus the control product.

The stability of BioXmark was also studied under normo-fractionated and single-fraction proton beams to determine its stability if subjected to the conditions expected from proton beam therapy. Four markers were irradiated for a period of 51 days with 43 fractions ranging from 1.44-1.86 Gy resulting in an accumulated dose of 67.4 Gy. Four other markers were irradiated with a single dose of 155.4 Gy. BioXmark showed no signs of deterioration when exposed to proton beams.

In animal studies, absorption of the marker is seen and thought to be due to the increased inflammation following radiation therapy and increased vascularization and flow of fluid, which could lead to an increased resorption rate and a delayed formation of encapsulation typically observed in untreated animals, due to continued disturbance of the tissue. This increased resorption was not seen during the clinical testing in patients, though in some tissues, absorption was seen through months 3-9 followed by volume stabilization. Differences in resorption characterization between animal models and humans has been seen with other devices and in literature. It was concluded that this difference is not due to direct effect of radiation on the marker.

    1. Calculated mass attenuation curves
      Mass attenuation coefficients as a function of photon energy were calculated for BioXmark after complete ethanol efflux, gold and soft tissue (ICRU-44) based on the elemental composition of BioXmark and X-Ray Mass Attenuation Coefficients from individual elements. Mass attenuation curves were provided. The high total iodine content of ~15 w/w% results in a high mass attenuation coefficient of the marker.
    1. Effect of volume and shape on visibility under x-ray imaging

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The x-ray contrast of BioXmark markers with a volume of 10 ul shaped into an elongated cylinder (rod-like), a flat cylinder (plate-like) and a sphere was investigated in a thorax phantom using CT-imaging. All markers were casted into 10 w/w% gelatin to mimic the soft tissue environment in terms of background contrast level and an anthropomorphic thorax phantom was used to mimic clinical use in patients. All markers, irrespective of 3D marker shape, were clearly visible in x-ray imaging using clinically relevant settings. A mean contrast level for the spherical BioXmark markers, flat cylindrical BioXmark markers and elongated cylindrical BioXmark markers were in the range of 700-1200 HU, 400-800 HU and 500-900 HU depending on the contouring threshold, resulting in a contrast-to-noise ratio (CNR) of > 110 in all cases.

4. Artifacts

The visibility (contrast-to-noise ratio (CNR)) and evaluation of artifacts were investigated in a thorax phantom. BioXmark was filled into hollow polypropylene spheres. CT imaging was conducted using a clinical multi slice CT scanner. Images were acquired from three different gantry angles. Exposure settings were varied. Visibility of BioXmark and the included commercial markers were based on the CNR. CBCT scans were then performed for each marker using standard exposure settings. All scans were also performed with no marker present for a baseline image with no artifact. CBCT and CT scans were used to quantify artifacts introduced by the included markers in both imaging techniques based on the streaking index (SI). The SI of BioXmark in this study was comparable to solid fiducial markers included in the study.

A second study was performed to assess the visibility and artifacts of smaller volumes of BioXmark (10 ul, 25 ul, 50 ul, 100 ul, 200 ul, 300 ul, and 400 ul). Each marker was cast into gelatin in a hollow low-density polyethylene rod container. Imaging was performed with the filled rod container placed inside a CIRS IMRT thorax phantom. CT scans were performed using a standard clinical lung protocol. The SI of BioXmark for volumes 2 (160 HU or more). BioXmark does not migrate during radiotherapy using a predefined procedure for capturing and measuring BioXmark marker volume, contrast and positional stability.

Part B primary endpoint: Ouantification of risk of pneumonitis and cardiotoxicity estimated by V20 lung volume, mean lung dose and V40 heart volume and late lung tissue damage for DIBH versus free breathing technique (NTCP). These endpoints are not related to BioXmark performance.

Subjects: Twenty (20) subjects were screened, eighteen (18) subjects were found suitable for inclusion and fifteen (15) subjects gave their consent. Thirty-five (35) markers were implanted in the fifteen (15) subjects, 1-3 markers (100 -300 ul) in each subject. Eleven (11) markers were placed into or near the primary tumor and twenty-four (24) into the hilar or mediastinal lymph nodes. Imaging data were not recorded for two (2) subjects due to progression of their disease (3 markers). hence for these two subjects there are no medical imaging and data are available only for assessment of procedural safety. No subjects were withdrawn or discontinued from the investigation. Two (2) markers were lost between implantation and planning CT, and one marker was not suitable as a marker for radiotherapy (placed in the wall of a tumor cavity and was dispersed). Therefore, a total of twenty-nine (29) markers were followed from implantation through radiotherapy and follow up.

Thirteen (13) subjects completed the 2-month course of radiotherapy and the injected BioXmark markers were visible on all defined imaging modalities (ultrasound, CT, CBCT, 4D CT, 2D kV and fluoroscopy). The markers were visible during the entire treatment period with no change in marker contrast level over time, irrespective of placement (healthy lung tissue, primary tumor, or within PET positive lymph nodes). CT and CBCT scans were acquired during radiotherapy and each marker was automatically contoured in the Eclipse™ contouring software by using a Hounsfield Unit thresholding function with a lower limit of 500 HU. The CT and CBCT scans and the contoured markers were subsequently analyzed for marker radiopacity, marker volume and positional stability. Visibility was evaluated by the naked eve by scoring yes/no by the medical physicist and investigator. Constant marker visibility was evident from all scans.

Marker visibility using x-ray imaging was quantitatively assessed by measuring the contrast to noise ratio (CNR). All markers had a CNR > 2, the cutoff that determines whether the marker is visible. The CNR of the markers remained constant during the entire treatment period. The recorded clinical images were reviewed for potential artifacts by the investigator and the medical physicist independently. No relevant artifacts caused by the markers were observed.

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The majority of BioXmark markers showed minimal change in the 3D vector length from the Center of Volume (CoV) of the tumor/lymph node and the CoV of the marker during the entire treatment period within the pre-defined criteria for migration ( 0.75. H0 is rejected if the lower limit of the 95% CI for the observed performance success in the trial is lower than 0.75.

Patients: Approximately, 3-5 BioXmark liquid markers of ~0.1 ml (0.07-0.15 ml) each were injected in proximity to the bladder tumor, using flexible cystoscopy. Fluoroscopy after injection as visual quality control measurement was used only in the first five (5) patients (19 markers) but because the implantation with the endoscopic technique was successful, further use of fluoroscopy visualization was not deemed valuable. Visibility was evaluated on radiotherapy planning CT acquisition and weekly CBCT during treatment. Visibility was scored dichotomously (visible/non-visible). Serious adverse events (SAE) associated with BioXmark marker were recorded from the moment of injection until the end of chemoradiation treatment or at least 30 days after the marker implantation. Patients were assessed weekly during treatment and 4 weeks following treatment.

In total, seventy-six (76) markers were implanted in twenty (20) patients. One patient died after CT acquisition but before start of treatment from an intercurrent disease cause. There were twenty (20) evaluable patients for marker visibility on CT scan and nineteen (19) evaluable patients for marker visibility and stability on CBCT. All nineteen (19) patients finished treatment as planned.

Of the seventy-six (76) markers implanted, sixty (60) (79% (95% CI 70-88%) were visible on treatment planning CT scan. All separate spots were continuously classified as clearly visible without artifacts. The preset threshold of 75% was overlapped by the CIs, thereby this Phase 1 study failed to show a statistical difference with the prospectively defined test. However, the study showed a clear learning curve as visibility scored 58% for the first 5 patients and 86% for the next 15. The investigator concluded that the majority of the lost markers were the result

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of the implantation technique learning curve.

In patients where BioXmark was injected successfully, the fiducial marker was determined to be an easy and clinically applicable tool for IGRT in bladder-preserving chemoradiotherapy. Blurring, migration, and fading did not occur during treatment. Furthermore, this study resulted in continuous visibility of the fiducial markers. Positional stability was scored on CT scan and latest CBCT (with comparable bladder filling). Of those visible markers (60) on CT scan, all (100%) remained detectable without displacement until the end of the treatment, defined as visible on the last CBCT at week four of follow-up.

Results: BioXmark was safe to use for patients with non- metastasized unifocal muscle invasive bladder cancer. Two patients experienced grade 2 toxicity, but one of those events may be related to the implantation procedure itself and not the marker. One patient presented with urinary tract infection and the other with hematuria was present before the implantation and stopped during the radiation course.

Pediatric Extrapolation

In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric patient population.

LABELING

The labeling consists of Instructions for Use, device label, outer box label, and implant card.

The instructions for use include device description, storage instructions, indications for use, injection volumes and corresponding radiologic imaging modalities, warning and precaution statements, MR compatibility, shelf life, listing of adverse events, instructions for use (i.e., endoscopic assisted injections, percutaneous injection), disposal, treatment planning information and information related to patient follow-up.

The labeling meets the requirements of 21 CFR 801.109 for prescription devices.

RISKS TO HEALTH

The table below identifies the risks to health that may be associated with the use of Phasechanging fiducial markers for radiation therapy and the measures necessary to mitigate these risks:

Risks to HealthMitigation Measures
Adverse tissue reactionBiocompatibility evaluation
Animal performance testing

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| Interference with image-guided
radiation therapy or radiotherapy
response assessment | Clinical performance testing
Non-clinical performance testing
Labeling |
|-----------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|
| Treatment delays due to device
malfunction, marker migration, or
inability to locate marker on
imaging | Clinical performance testing
Non-clinical performance testing
Labeling |
| Infection | Sterilization validation
Shelf life testing
Labeling |
| Inaccurate radiation dose delivery
due to incorrect marker positioning.
marker migration, or implantation | Clinical performance testing
Non-clinical performance testing
Usability testing
Labeling |
| Complications due to implantation
of marker or marker migration | Clinical performance testing
Animal performance testing
Labeling |

SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the Phase-changing fiducial marker for radiation therapy is subject to the following special controls:

  • Clinical performance data under anticipated conditions of use must evaluate: (1)
    • (i) Risk of marker migration in tissue during the course of radiation therapy through post-treatment follow-up;
    • The ability to visualize the marker to allow for adequate localization during the (ii) course of radiation therapy through post-treatment follow-up;
    • (iii) Risk of device interference with tumor response assessment post-treatment; and
    • All adverse events. (iv)
  • (2) Animal performance data under anticipated conditions of use must evaluate device toxicity and the risk of marker migration.
  • (3) Non-clinical performance data under anticipated conditions of use must evaluate:
    • Maintenance of physical form throughout the course of therapy and post-treatment (i) follow-up;
    • (ii) Device visibility on one or more radiologic imaging modalities; and
    • Device interference with radiation dose delivery. (111)
  • (4) Performance testing must demonstrate the patient-contacting components of the device are biocompatible.
  • Performance testing must support the shelf life of the device by demonstrating continued (5) sterility, package integrity, and device functionality over the labeled shelf life.
  • Performance testing must demonstrate device sterility and non-pyrogenicity. (6)
  • Usability testing must demonstrate that the device can be positioned as indicated based (7) solely on reading the directions for use.
  • The labeling must include: (8)

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  • (i) A detailed description of the device including materials and composition, chemical and physical properties, a description of the mechanism of the change of phase, and timeframe for achieving final state:
  • (ii) Summary of all reported device-related adverse events from clinical testing:
  • (iii) Information describing the injection procedure, including any use of image guidance, and the range of compatible injection needle gauges; and
  • (iv) A shelf life.

BENEFIT-RISK DETERMINATION

The BioXmark is restricted to prescription use in accordance with 21 CFR 801.109 for the radiographic marking of the lung, bladder and lymph nodes.

Device risks and mitigations:

The risks include: 1) adverse tissue reaction, 2) interference with image-guided radiation therapy or radiotherapy response assessment, 3) treatment delays due to device malfunction, marker migration or inability to locate marker on imaging, 4) infection, 5) inaccurate radiation dose delivery due to incorrect marker positioning, marker migration, or implantation, 6) complications due to implantation of marker or marker migration.

Probable benefits:

In radiation therapy, it is crucial for the physician to accurately locate the intended target volumes in order to focus radiation on the target volumes and spare healthy tissue as much as possible. Accurate target volume localization is made more challenging by organ movement and lack of exact anatomic reference points. The implantation of a fiducial marker near the tumor, or target volume, can facilitate the ease, accuracy, and precision of the localization process. However, in some tissues, implantation can be difficult, and dislocation of implanted markers is observed. As a liquid fiducial marker, BioXmark has the probability to mitigate some of the challenges observed with traditional metal fiducial markers such as imaging artifacts, technical difficulties with implantation, and marker migration or dislodgement. BioXmark is visible on several imaging modalities and creates less interference than the metal fiducial markers. Lastly, evidence has shown that in some tissue types, the marker does not migrate out of the tissue.

Evidence of benefit has only been shown in lung, bladder, and lymph nodes.

Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

Benefit/Risk Conclusion

In conclusion, given the available information above, for the following indication statement:

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

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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.

The probable benefits outweigh the probable risks for BioXmark. The device provides benefits, and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

The De Novo request for the BioXmark is granted and the device is classified as follows:

Product Code: QUV Device Type: Phase-changing fiducial marker for radiation therapy Regulation Number: 21 CFR 892.5727 Class: II