K Number
DEN170056
Device Name
Parathyroid Detection (Model PTeye) System
Manufacturer
Date Cleared
2018-11-02

(403 days)

Product Code
Regulation Number
878.4550
AI/MLSaMDIVD (In Vitro Diagnostic)TherapeuticDiagnosticis PCCP AuthorizedThirdparty
Intended Use
The AiBiomed Parathyroid Detection System (PTeye) is an adjunctive tool intended to aid in the identification of parathyroid tissue by confirming parathyroid tissue already visually located by the surgeon.
Device Description
The Parathyroid Detection (PTeye) System aids surgeons in differentiating parathyroid tissue during common surgical procedures. The handheld probe assembly includes one glass fiber-optic element that emits non-ionizing radiation at 785 nm in the near IR range (NIR) and one fiber optic detector element that collects and transmits the fluorescence emitted by the tissue to a photo detector. The Parathyroid Detection (PTeye) System consists of the following components: 1. A console that includes: An LED display that indicates if the laser is on. A display for visual feedback. A speaker for auditory feedback. 2. A handheld fiber-optic probe assembly that interfaces into the console unit using two unique connectors. One connector plugs into the laser output and the other plugs into the photo detector input (fluorescent signal). 3. A foot pedal attached by a cable to the rear of the unit, used to control power to the laser and initiate data collection. 4. An external power supply and power cord that plugs into the power supply. Tissue detection is based on the ratio of the fluorescent response of parathyroid to thyroid tissue; with the assumption that the fluorescence of thyroid tissue is much lower than parathyroid. During surgery, five thyroid data points are collected by touching thyroid tissue with the probe assembly. The system calculates a baseline median for the thyroid tissue based on those points. The baseline value establishes a reference point for distinguishing parathyroid tissue, which produces a higher level of fluorescence. Once the baseline thyroid value has been calculated, a new operational screen will display to support continuous parathyroid search mode. To operate in this mode, the foot switch must be pressed in order to activate the laser. When laser emission is taking place, the LASER ON LED at the front of the system will illuminate. Responses indicating parathyroid tissue are communicated to the user through a bar graph, a detection percentage, a detection ratio, and audio feedback.
More Information

Not Found

Not Found

No
The device description outlines a system based on measuring and comparing fluorescence ratios, with a simple calculation of a baseline median. There is no mention of AI, ML, or complex algorithms for pattern recognition or learning from data.

No
The device is described as an "adjunctive tool intended to aid in the identification of parathyroid tissue by confirming parathyroid tissue already visually located by the surgeon," indicating it is for diagnostic or identification purposes, not for treating a disease or condition.

Yes

The device aids in the identification of parathyroid tissue by providing real-time feedback (visual and auditory) based on the fluorescence of the tissue, which helps surgeons differentiate parathyroid tissue from other tissues during surgery. This function directly supports a diagnostic decision (identifying specific tissue type).

No

The device description clearly outlines multiple hardware components including a console, handheld fiber-optic probe assembly, foot pedal, and external power supply. It is not solely software.

No, this device is not an IVD (In Vitro Diagnostic).

Here's why:

  • IVD Definition: In Vitro Diagnostics are tests performed on samples taken from the human body, such as blood, urine, or tissue, to detect diseases, conditions, or infections. They are used outside of the living body (in vitro).
  • PTeye Function: The PTeye system operates in vivo (within the living body) during surgery. It uses a handheld probe to directly interact with and measure the fluorescence of tissues in situ (in their original location).
  • Intended Use: The intended use is to aid in the identification of parathyroid tissue during surgical procedures by confirming tissue already visually located by the surgeon. This is a real-time, intraoperative assessment, not a laboratory test on a removed sample.

The PTeye is a medical device used for real-time tissue differentiation during surgery, not an in vitro diagnostic test.

N/A

Intended Use / Indications for Use

The AiBiomed Parathyroid Detection System (PTeye) is an adjunctive tool intended to aid in the identification of parathyroid tissue by confirming parathyroid tissue already visually located by the surgeon.

Product codes

QDF

Device Description

The Parathyroid Detection (PTeye) System aids surgeons in differentiating parathyroid tissue during common surgical procedures. The handheld probe assembly includes one glass fiber-optic element that emits non-ionizing radiation at 785 nm in the near IR range (NIR) and one fiber optic detector element that collects and transmits the fluorescence emitted by the tissue to a photo detector.

The Parathyroid Detection (PTeye) System consists of the following components: 1. A console that includes:

  • An LED display that indicates if the laser is on. ●

  • A display for visual feedback. ●

  • A speaker for auditory feedback. ●
    The console is multiple patient reusable device.

    1. A handheld fiber-optic probe assembly that interfaces into the console unit using two unique connectors. One connector plugs into the laser output and the other plugs into the photo detector input (fluorescent signal). Fiber optic is sterile single use device.
    1. A foot pedal attached by a cable to the rear of the unit, used to control power to the laser and initiate data collection.
    1. An external power supply and power cord that plugs into the power supply.

The single use ethylene oxide (EtO) sterilized fiber-optic probe will also be sold separately.

Tissue detection is based on the ratio of the fluorescent response of parathyroid to thyroid tissue; with the assumption that the fluorescence of thyroid tissue is much lower than parathyroid. During surgery, five thyroid data points are collected by touching thyroid tissue with the probe assembly. The system calculates a baseline median for the thyroid tissue based on those points. The baseline value establishes a reference point for distinguishing parathyroid tissue, which produces a higher level of fluorescence.

Once the baseline thyroid value has been calculated, a new operational screen will display to support continuous parathyroid search mode. To operate in this mode, the foot switch must be pressed in order to activate the laser. When laser emission is taking place, the LASER ON LED at the front of the system will illuminate. Responses indicating parathyroid tissue are communicated to the user through a bar graph, a detection percentage, a detection ratio, and audio feedback. The highest percentage (100%), full bar graph, and the highest frequency beeps indicate 2.5-times the median of the 5 thyroid measurements taken during the baseline stage. The on-screen bar graph and detection percentage, and detection ratio correlate directly with the audio. When using the probe on non-parathyroid tissue, the display shows mostly yellow and a low detection ratio. When using the probe on parathyroid tissue, the display feedback shows primarily green and a high detection ratio.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Parathyroid tissue, thyroid tissue, neck muscle, trachea

Indicated Patient Age Range

Adults (18-99 years of age)

Intended User / Care Setting

Surgeons performing parathyroid or thyroid surgical procedures, in a hospital or surgical center setting.

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

A clinical study was conducted at two centers, Vanderbilt and Ohio State University Medical Center. The study was single blinded and non-randomized. 82 patients were tested with the PTeye in its final design. Subjects included both men (23.5%) and women (76.5%) over the age of 18. Measurements were taken intraoperatively by surgeons who were blinded to PTeye device output. During the surgical procedure, five thyroid data points were initially collected by touching the probe tip to the thyroid tissue. The system used these 5 points to calculate a baseline near infrared autofluorescence (NIRAF) median value and this established the reference baseline for each individual patient. If no thyroid tissue was present due to a previous thyroidectomy/thyroid ablation, baseline NIRAF median was alternatively obtained on neck muscle or trachea for that particular patient. Subsequent tissue NIRAF measurements in the patient were then normalized to this NIRAF baseline for obtaining the detection ratio. Upon visualizing a tissue of interest, the surgeon first stated the degree of confidence in having identified tissue as parathyroid gland with high, moderate or low confidence, based solely on visual inspection of the tissue-in-situ and without relying on the PTeye device. This information was recorded for assessing the performance of the PTeye as compared to the surgeon's visual assessment. The surgeon then placed the probe of the PTeye on the suspect tissue site and pressed the foot-pedal, resulting in tissue NIRAF intensity and detection ratio being displayed only to the study investigator and not surgeon in real-time.

For effectiveness analysis, 181 PGs and 546 non-PG tissues (194 thyroid, 116 fat, 119 neck muscle, and 117 trachea) were measured in 81 patients. Of the 181 PGs measured, fluorescence measurements of 68 PGs (68/181, 37.6%) were confirmed with histology. The remaining 113 PGs could not be confirmed with histology and were validated based on high or medium confidence of the surgeon's visual assessment. Tissues identified with low confidence by the surgeon were excluded from further analysis unless histological validation was obtained from those tissues.

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

Study Type: Clinical study (single blinded, non-randomized) and bench studies.
Sample Size:

  • Clinical Study: 81 patients (40 from Site A, 41 from Site B) for effectiveness data analysis (originally 133 enrolled, 82 with final PTeye design).
    • 181 PGs and 546 non-PG tissues (194 thyroid, 116 fat, 119 neck muscle, and 117 trachea) were measured.
    • 68 PGs (37.6%) confirmed by histology, 113 PGs by surgeon's visual assessment (high/medium confidence).
  • Bench Studies:
    • Biocompatibility: Tested per FDA guidelines for biocompatibility and ISO 10993-1.
    • Sterility/Packaging/Shelf Life: Evaluated after accelerated aging equivalent to one year.
    • Electrical/Mechanical/Thermal Safety, and Electromagnetic Compatibility (EMC): Tested per IEC 60601-1, IEC 60601-1-2, IEC 60601-1-6.
    • Laser/Light Safety: Tested per IEC 60825-1.
    • Software: Provided documentation as outlined in FDA's guidance documents.
    • Performance Testing - Bench: Short term variation in laser intensity, Change in laser intensity due to aging or different environmental condition, Effect of surgical and ambient light on the device performance.
    • Effect of blood on NIRAF ex vivo: 3 fresh frozen specimens each of normal thyroid and PG adenoma (total 18 NIRAF measurements per group).
    • Effect of blood on NIRAF in vivo: 4 PGs from 3 patients (at least 6 NIRAF measurements per group).
    • Effect of probe-to-tissue contact pressure: Excised fresh frozen human PG (n=3) and thyroid (n=2) tissues.

Standalone Performance:

  • Safety: No device or procedure related adverse events (AEs), serious adverse events (SAEs), or unanticipated adverse device effects (UADEs) were observed in the clinical study. Additional total procedure time was approximately one minute, which was under the 5-minute pre-defined cut-off.
  • Effectiveness (Primary Endpoint - PG identification rate):
    • Normalized NIRAF Intensity: PG tissue NIRAF was about 5.4 times higher than that of the measured thyroid, while muscle, fat and trachea showed little to no NIRAF intensity (p-value = 1.21 × 10-4).
    • Accuracy of PG identification (based on histology/surgeon validation, all diagnoses combined):
      • Sensitivity: 92.3% (167/181)
      • Specificity: 97.3% (531/546)
      • Overall Accuracy: 96%
      • Kappa: 0.89
      • False Positive Rate: 2.7%
      • False Negative Rate: 7.7%
      • PPV: 91.8%
      • NPV: 97.4%
    • Accuracy of PG identification (excluding secondary hyperparathyroidism patients):
      • Sensitivity: 93.6% (162/173)
      • Specificity: 97.1% (510/525)
      • Overall Accuracy: 96.3%
      • Kappa: 0.90
      • False Positive Rate: 2.9%
      • False Negative Rate: 6.4%
      • PPV: 91.5%
      • NPV: 97.9%

Key Results:

  • The PTeye could successfully identify PGs with high sensitivity and specificity.
  • Normalized NIRAF intensity of PGs was significantly higher than non-PG tissues.
  • Performance was improved when patients with renal-induced secondary hyperparathyroidism (r-SHPT) were excluded. The device is not recommended for use in patients with secondary hyperparathyroidism.
  • Influence of blood had no statistically significant effect on PG NIRAF measurements (in vivo p=0.95, ex vivo p=0.53, though thyroid NIRAF was lower with blood ex vivo p=0.007).
  • Probe-to-tissue contact pressure (mild, moderate, or high) did not notably affect tissue NIRAF measurements for PG or thyroid specimens.
  • Diseased PGs exhibited lower normalized NIRAF intensity compared to healthy PGs (p=0.00012).
  • No significant difference in normalized NIRAF intensity between healthy and diseased thyroid glands (p=0.96).

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Overall Performance (combined histology and surgeon's eye, all diagnoses):

  • Sensitivity: 92.3%
  • Specificity: 97.3%
  • Accuracy: 96.0%
  • Kappa: 0.89
  • PPV: 91.8%
  • NPV: 97.4%
  • False Positive Rate: 2.7%
  • False Negative Rate: 7.7%

Overall Performance (combined histology and surgeon's eye, excluding secondary hyperparathyroid patients):

  • Sensitivity: 93.6%
  • Specificity: 97.1%
  • Accuracy: 96.3%
  • Kappa: 0.90
  • PPV: 91.5%
  • NPV: 97.9%
  • False Positive Rate: 2.9%
  • False Negative Rate: 6.4%

Histology only:

  • Sensitivity: 89.7%; Specificity: 80.0%; PPV: 98.4%; NPV: 36.4%; False Positive Rate: 20.0%; False Negative Rate: 11.3% (All Diagnoses)
  • Sensitivity: 93.3%; Specificity: 80.0%; PPV: 98.3%; NPV: 50.0%; False Positive Rate: 20.0%; False Negative Rate: 6.7% (Excluding secondary hyperparathyroid patients)

Surgeon's eye only:

  • Accuracy: 96.8%; k: 0.89; Sensitivity: 93.8%; Specificity: 97.4%; PPV: 88.3%; NPV: 98.7%; False Positive Rate: 2.6%; False Negative Rate: 6.2% (All Diagnoses)
  • Accuracy: 96.7%; k: 0.89; Sensitivity: 93.8%; Specificity: 97.3%; PPV: 88.3%; NPV: 98.6%; False Positive Rate: 2.7%; False Negative Rate: 6.2% (Excluding secondary hyperparathyroid patients)

Predicate Device(s)

Not Found

Reference Device(s)

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information

Not Found

§ 878.4550 Autofluorescence detection device for general surgery and dermatological use.

(a)
Identification. An autofluorescence detection device for general surgery and dermatological use is an adjunct tool that uses autofluorescence to detect tissues or structures. This device is not intended to provide a diagnosis.(b)
Classification. Class II (special controls). The special controls for this device are:(1) In vivo testing under anticipated conditions of use must characterize the ability of the device to detect autofluorescent signals from tissues or structures consistent with the indications for use.
(2) The patient-contacting components of the device must be demonstrated to be biocompatible.
(3) Performance testing must demonstrate the electromagnetic compatibility and electrical, mechanical, and thermal safety of the device.
(4) Software verification, validation, and hazard analysis must be performed.
(5) Performance testing must demonstrate the sterility of patient-contacting components of the device.
(6) Performance testing must support the shelf life of device components provided sterile by demonstrating continued sterility and package integrity over the labeled shelf life.
(7) Performance testing must demonstrate laser and light safety for eye, tissue, and skin.
(8) Labeling must include the following:
(i) Instructions for use;
(ii) The detection performance characteristics of the device when used as intended; and
(iii) A shelf life for any sterile components.

0

DE NOVO CLASSIFICATION REQUEST FOR PARATHYROID DETECTION (MODEL PTEYE) SYSTEM

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Autofluorescence detection device for general surgery and dermatological use. An autofluorescence detection device for general surgery and dermatological use is an adjunct tool that uses autofluorescence to detect tissues or structures. This device is not intended to provide a diagnosis.

NEW REGULATION NUMBER: 21 CFR 878.4550

CLASSIFICATION: Class II

PRODUCT CODE: ODF

BACKGROUND

DEVICE NAME: Parathyroid Detection (Model PTeye) System

SUBMISSION NUMBER: DEN170056

DATE OF DE NOVO: September 27, 2017

CONTACT: AiBiomed. Corp. 107 West Gutierrez Street Santa Barbara, CA 93101

INDICATIONS FOR USE

The AiBiomed Parathyroid Detection System (PTeye) is an adjunctive tool intended to aid in the identification of parathyroid tissue by confirming parathyroid tissue already visually located by the surgeon.

LIMITATIONS

The sale, distribution, and use of the Biomed Parathyroid Detection System (PTeye) are restricted to prescription use in accordance with 21 CFR 801.109.

The AiBiomed Parathyroid Detection System (Model PTeye) has no contraindications.

Due to limitations in parathyroid detection of autofluorescence by the PTeye System in certain disease states, the device is not recommended for use in patients with secondary hyperparathyroidism and in patients with parathyroid cysts.

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The PTeye System is intended to be an aid in the identification of parathyroid tissue and not as a parathyroid locator. The use of this device has not been evaluated as a parathyroid tissue locator.

Due to a small sample size, limited clinical data is available regarding the safety and effectiveness of the PTeye System for rare disease states such as tertiary hyperparathyroidism, concomitant thyroid-parathyroid diseases, malignant parathyroid diseases, or other circumstances when prophylactic thyroidectomies are performed in individuals at high-risk for certain diseases such as MEN2A.

The PTeye requires the probe to be in direct contact with the tissue of interest for proper signal recording as its detection depth is only a few millimeters. If parathyroid tissue is covered by fat or other tissues, the fat and tissues must be manually moved out the way and/or the probe maneuvered around these tissues to make direct contact with area of interest.

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

DEVICE DESCRIPTION

The Parathyroid Detection (PTeye) System aids surgeons in differentiating parathyroid tissue during common surgical procedures. The handheld probe assembly includes one glass fiber-optic element that emits non-ionizing radiation at 785 nm in the near IR range (NIR) and one fiber optic detector element that collects and transmits the fluorescence emitted by the tissue to a photo detector.

Image /page/1/Picture/6 description: The image shows a medical device with a screen displaying numerical values. The device is connected to a probe via a cable. There is also a black box-shaped object next to the device. The image also includes a diagram of a similar device, highlighting its various components such as the screen display, laser connector, detector connector, and power switch.

The Parathyroid Detection (PTeye) System consists of the following components: 1. A console that includes:

  • An LED display that indicates if the laser is on. ●
  • A display for visual feedback. ●
  • A speaker for auditory feedback. ●

2

The console is multiple patient reusable device.

    1. A handheld fiber-optic probe assembly that interfaces into the console unit using two unique connectors. One connector plugs into the laser output and the other plugs into the photo detector input (fluorescent signal). Fiber optic is sterile single use device.
    1. A foot pedal attached by a cable to the rear of the unit, used to control power to the laser and initiate data collection.
    1. An external power supply and power cord that plugs into the power supply.

The single use ethylene oxide (EtO) sterilized fiber-optic probe will also be sold separately.

Tissue detection is based on the ratio of the fluorescent response of parathyroid to thyroid tissue; with the assumption that the fluorescence of thyroid tissue is much lower than parathyroid. During surgery, five thyroid data points are collected by touching thyroid tissue with the probe assembly. The system calculates a baseline median for the thyroid tissue based on those points. The baseline value establishes a reference point for distinguishing parathyroid tissue, which produces a higher level of fluorescence.

Once the baseline thyroid value has been calculated, a new operational screen will display to support continuous parathyroid search mode. To operate in this mode, the foot switch must be pressed in order to activate the laser. When laser emission is taking place, the LASER ON LED at the front of the system will illuminate. Responses indicating parathyroid tissue are communicated to the user through a bar graph, a detection percentage, a detection ratio, and audio feedback. The highest percentage (100%), full bar graph, and the highest frequency beeps indicate 2.5-times the median of the 5 thyroid measurements taken during the baseline stage. The on-screen bar graph and detection percentage, and detection ratio correlate directly with the audio. When using the probe on non-parathyroid tissue, the display shows mostly yellow and a low detection ratio. When using the probe on parathyroid tissue, the display feedback shows primarily green and a high detection ratio.

Image /page/2/Picture/8 description: The image shows a medical device with a digital display. The display shows a detection percentage of 71% and a detection level of 296. There is also a reading of 2.0 on the right side of the screen. The device has labels for 'Detector Input,' 'Laser Aperture,' and 'Laser On,' along with a power switch.

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Table 1: PTeye Regulatory Information
Device Trade/Proprietary NameParathyroid Detection (Model PTeye) System
Device Common NameParathyroid Autofluorescence Detection Device
Device ClassClass II
Classification Regulation878.4550
Product CodeQDF

Table 1: PTeve Requiatory Information

SUMMARY OF NONCLINICAL/BENCH STUDIES

BIOCOMPATIBILITY/MATERIALS

The PTeve fiber-optic assembly will be in direct contact with organ tissue. The sterile PTeye fiber-optic assembly was tested per FDA guidelines for biocompatibility and ISO 10993-1 according to FDA guidance document, "Use of International Standard ISO 10993-1, 'Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process". The testing showed that the optical probe passed the biocompatibility requirements for cytotoxicity, sensitization, irritation or intracutaneous reactivity, acute systemic toxicity, and material-mediated pyrogenicity.

The PTeye fiber-optic assembly was tested for Limulus Amebocyte Lysate (LAL) evaluation for three product lots on the final product, post-sterilization. The results show that the test article met the requirement of less than 20 EU/device. In addition, the LAL endotoxin testing will be conducted on 3 samples as part of each product lot release criteria.

STERILITY/PACKAGING/ SHELF LIFE

The PTeye optical probe is a sterile, single use component of the device system. The cartridge is sterilized using EO sterilization and sterilant residuals were quantified and under the acceptable limits for EO and ethylene chlorohydrin (ECH). The sterilization method was validated per ISO 11135:2014 (Sterilization of health care products --Ethylene oxide: "Requirements for development, validation and routine control of a sterilization process for medical devices"). The Sterility Assurance Level (SAL) for the optical probe is 10-6.

The primary packaging consists of one probe assembly seated and secured inside an inner tray which is heat sealed to a Tyvek lid. The sealed primary packaged probe is placed inside a poly/Tyvek pouch which is heat sealed. The sealed outer pouch is placed inside the bottom half of the unit box. The top half of the unit box covers the bottom half of the unit box and the seals of the unit box are secured with tamper proof seals.

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The shelf-life of the optical probe was evaluated after accelerated aging equivalent to one year. The cartridge was evaluated by visual inspection, peel test, and bubble leak testing. The test article met the acceptance criteria for each test.

ELECTROMAGNETIC COMPATIBILITY AND ELECTRICAL SAFETY

The following Electrical/Mechanical/Thermal Safety, and electromagnetic compatibility (EMC):

  • IEC 60601-1: 2005 +CORR.1:2006+CORR.2: 2007 + AM1:2012 or IEC 60601-. 1:2012 with US deviations, Medical electrical equipment - Part 1: General requirements for basic safety and essential performance.
  • . IEC 60601-1-2: 2007 (Edition 3), Medical electrical equipment Part 1-2 – General requirements for basic safety and essential performance - Electromagnetic compatibility.
  • IEC 60601-1-6: Collateral Standard: Medical electrical equipment Part 1-6 - General requirements for basic safety and essential performance - Usability.

LASER/LIGHT SAFETY

The following laser safety testing has been performed:

  • IEC 60825-1: Safety of laser products Part 1: Equipment classification and . requirements

MAGNETIC RESONANCE (MR) COMPATIBILITY

Device is not compatible for Magnetic resonance (MR) environment.

SOFTWARE

The software controls the PTeye system hardware including the laser firing after pressing the foot-pedal. It calculates the background level based on five data points from thyroid tissue and determines the median values of those points. It then calculates the ratio of autofluorescence signal from the background level to demonstrate if the tissue is parathyroid or not.

The software GUI includes an on-screen bar graph, detection percentage and detection ratio which correlate directly with the audio feedback. When using the probe on nonparathyroid tissue, the display shows mostly yellow and a low detection ratio. When using the probe on parathyroid tissue. the display feedback shows primarily green and a high detection ratio. The audio feedback for non-parathyroid tissue sounds with slow beep frequency (one beep per second). As the ratio of autofluorescence to background increases, the beeps are emitted more rapidly.

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Device does not have wireless capability or a communication port.

The agency considers the software to be a moderate level of concern (LOC) because inadvertent software errors could result in injury to the patient or delay in procedure time.

All of the elements of software and cybersecurity information as outlined in FDA's guidance documents "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices" (issued May 11, 2005) and "Content of Premarket Submissions for Management of Cybersecurity in Medical Devices" (issued June 14, 2013) were provided.

Overall, the software documentation included in the De Novo request is in sufficient detail to provide reasonable assurance that the software will operate in a manner described in the specifications.

TestPurposeAcceptance CriteriaResults
Short term variationTo demonstrate the influence of shortPassed
in laser intensityterm variation in laser intensity on the
device performance during a surgery
Change in laserTo demonstrate the influence of thePassed
intensity due to agingdevice ageing and degradation (like
or differentdecrease in laser intensity over time or
environmentaldue to different environmental
conditioncondition) on the performance of the
device
Effect of surgical andTo demonstrate the influence of thePassed
ambient light on thesurgical and ambient light on the
device performanceperformance of the device

PERFORMANCE TESTING - BENCH

SUMMARY OF CLINICAL INFORMATION

A. Study Design

A clinical study was conducted to support the safety and effectiveness of the AiBiomed Parathyroid Detection System (PTeve) to aid in the identification of parathyroid (PG) tissue during thyroid and parathyroid surgical procedures.

The single blinded non-randomized study was conducted at two centers, Vanderbilt and Ohio State University Medical Center and included tissue measurements during thyroid and parathyroid surgical procedures. Measurements were taken intraoperatively by surgeons who were blinded to PTeye device output. During the surgical procedure, five thyroid data points were initially collected by touching the probe tip to the thyroid tissue. The system used these 5 points to calculate a baseline near infrared autofluorescence (NIRAF) median value and this established the reference baseline for each individual patient. If no thyroid tissue was present due to a previous thyroidectomy/thyroid ablation. baseline NIRAF median was alternatively obtained on neck muscle or trachea for that particular patient. Subsequent tissue NIRAF measurements in the patient were then

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normalized to this NIRAF baseline for obtaining the detection ratio. Upon visualizing a tissue of interest, the surgeon first stated the degree of confidence in having identified tissue as parathyroid gland with high, moderate or low confidence, based solely on visual inspection of the tissue-in-situ and without relying on the PTeye device. This information was recorded for assessing the performance of the PTeye as compared to the surgeon's visual assessment. The surgeon then placed the probe of the PTeye on the suspect tissue site and pressed the foot-pedal. resulting in tissue NIRAF intensity and detection ratio being displayed only to the study investigator and not surgeon in real-time.

The study was originally designed to compare the performance of the PTeye to a prior prototype parathyroid detection system. Of the original 133 patients enrolled, 82 patients were tested with the PTeye in its final design. There are technological differences between the PTeye and the prototype device, including ambient light interference and peak intensity to determine baseline (NIRAF), which may alter the device effectiveness results. Therefore, effectiveness results only for the PTeye final design were considered. However, for the safety results, both treatment groups are included in the summary below. Of note, there were no reported surgery or device related adverse events for the 51 patients whose results have been excluded from the final effectiveness analysis.

Subjects enrolled in the study included both men (23.5%) and women (76.5%) over the age of 18.

| Demographic

VariablesSite ASite BOverall
Number of
patients40
(38- excluding 2
patients with
secondary
hyperparathyroidism)4181
(79- excluding 2
patients with
secondary
hyperparathyroidism)
Gender
Female28 (70.0%)34 (82.9%)62 (76.5%)
Male12 (30.0%)7 (17.1%)19 (23.5%)
Race
Caucasian34 (85.0%)39 (95.1%)73 (90.1%)
Non-Caucasian6 (15.0%)2 (4.9%)8 (9.9%)
Age (years)54.3 ± 15.852.3 ± 16.453.8 ± 19.9
BMI (kg/m²)29.3 ± 6.231.6 ± 9.230.5 ± 7.9

Table 1: Summary of Demographic Information

Clinical Inclusion and Exclusion Criteria

Inclusion Criteria:

To be eligible for study enrollment, a subject was required to satisfy each of the following criteria.

    1. Adults (18-99 years of age) scheduled to undergo parathyroid or thyroid surgery.

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    1. Willing to sign the informed written consent form.

Exclusion Criteria:

A subject was not eligible to participate if they met any of the following exclusion criteria.

    1. Pregnant
    1. Unsuitable for study participation in the opinion of the Investigator- attending surgeon.

The study was initially designed to evaluate the performance of the PTeye in differentiating between parathyroid gland and non-parathyroid gland tissue once a potential candidate tissue was surgically exposed during the procedure. This was subsequently corroborated by the surgeon's visual identification for in situ parathyroid glands using an unvalidated confidence scale (low, medium, or high) and with histological examination for the excised parathyroid gland tissues.

Primary effectivenessPerformance measured by the ability of the PTeye to accurately identify
endpointsparathyroid glands [PG detection rate].
Secondary effectivenessIntra-patient and inter-patient variability of NIRAF in thyroid and PGs.
endpoints
Effect of thyroid and PG pathology on intraoperative parathyroid
Identification.
In-vivo and ex-vivo effect of blood on NIRAF intensity of PG and
thyroid with the PTeye system to assess if a hemorrhagic surgical field
would affect parathyroid identification.
Ex-vivo effect of probe-to-tissue contact pressure on PG fluorescence
intensity.
Safety EndpointSafe use as determined by a lack of (serious) adverse events.
The addition of no more than 5 minutes to the total procedure time
during normal use of the device.

Table 2: Study Endpoints

Table 3: Subject Accountability

All SubjectsFinal PTeye System
Enrolled subjectsN = 133N = 82
Completed subjects-82
Discontinued subjects51 (prototype device)3
Reason for discontinuation
Protocol deviationa1
Previously identified disease stateb2

a Protocol deviation due to communication error between study coordinator and surgeon regarding the timing of depressing the PTeye foot pedal leading to incorrect baseline NIRAF measurements.

b Patients with secondary hyperparathyroidism were determined to exhibit in prior studies and thus, were excluded from the final effectiveness performance assessment.

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The ability of the PTeye to accurately identify parathyroid glands [PG detection rate] included the following assessments using objective histology and subjective expert surgeon opinion:

PTeve Performance Data Analysis:

    1. Sensitivity- Number of true positives. (as determined by PTeye and validated by histology or surgeon's visual identification with high/moderate confidence) divided by actual positives (PG sites – total number of positives as determined by histology or surgeon's visual identification with high/moderate confidence)
    1. Specificity: Number of true negatives, (as determined by PTeye and validated by histology or surgeon's visual identification with high/moderate confidence) divided by actual negatives (non-PG sites - total number of negatives as determined by histology or surgeon's visual identification with high/moderate confidence)
    1. PPV: Number of true positives, (as determined by PTeye and validated by histology or surgeon's visual identification with high/moderate confidence) divided by number of device positives (total number of positives as determined by PTeye alone)
    1. NPV: Number of true negatives, (as determined by PTeye and validated by histology or surgeon's visual identification with high/moderate confidence) divided by number of device negatives (total number of negatives as determined by PTeye alone)
    1. False positive rate: Rate of device positive measurements when tested on actual negatives (number of negatives validated by histology or surgeon's visual identification with high/moderate confidence).
    1. False negative rate: Rate of device negative measurements when tested on actual positives (number of positives validated by histology or surgeon's visual identification with high/moderate confidence).

Based on these parameters, overall accuracy of the PTeye in PG identification and associated kappa values were accordingly calculated.

Statistical significance of NIRAF intensities between thyroid, parathyroid gland, fat, muscle and trachea were determined using a two-tailed Student's t-test for unequal variance, with an alpha (level of significance) of 0.01. The same statistical approach was adopted to determine if there was a significant difference between NIRAF measured from normal and diseased thyroid and parathyroid glands.

Comparison of surgeon's visual determination versus the PTeye as validated with histology-based gold standard:

The performance accuracy of the participant surgeons in differentiating between parathyroid gland (PG) and non-PG tissues relying on their visual skills were compared to that of the PTeye. This was performed in those cases when in vivo measurements were performed on tissues that were later excised for histological validation via frozen section or Hematoxylin-Eosin stained tissue section analysis by the pathologists that could serve as the gold standard. Due to lack of histological validation of in-situ tissues, these were not considered for comparing performance accuracy between the surgeons and the PTeye. In addition, comparison of surgeon versus PTeye

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were evaluated for each investigational site/study center. All participant surgeons at both centers were high-volume surgeons (who perform >25 thyroid surgeries per year and >15 parathyroid surgeries per vear).

Assessing variability and associated factors within patient data acquired with the PTeye:

Following data acquisition and analysis, the report also investigated: (i) the distribution of demographic variables at both study centers including: age (18- 99 years of age), gender (male or female), race (Caucasian or non-Caucasian), body-mass index (BMI) at time of surgery, (ii) Intra-patient and inter-patient variability of NIRAF in thyroid and PGs respectively and (iii) the effect of thyroid and parathyroid disease on intraoperative PG identification.

Influence of blood on NIRAF of thyroid and PG:

A. Ex vivo Validation:

The effect of blood on the NIRAF intensity of PG and thyroid was assessed ex vivo with the PTeye in order to determine if a hemorrhagic surgical field would affect PG identification. Three fresh frozen specimens each, of normal thyroid and PG adenoma were obtained from the NIH funded Co-operative Human Tissue Network (Vanderbilt University Medical Center, Nashville, TN). After thawing the specimens, at least six NIRAF measurements were obtained from each specimen ex vivo. To simulate a hemorrhagic surgical field, 0.5 cc of heparinized murine blood was introduced on to the specimen surface. NIRAF intensity of each specimen was measured with the PTeye and normalized to the thyroid NIRAF and grouped into four categories: (i) thyroid without blood (n, (ii) thyroid with blood, (iii) PG without blood and (iv) PG with blood, with each group consisting of 18 NIRAF measurements. Statistical significance was determined using a two-tailed Student's t-test for unequal variance, with an alpha level of significance, alpha of 0.01.

B. In vivo validation:

The influence of a hemorrhagic surgical field on PG identification with the PTeye was also tested in vivo using 4 PGs from 3 patients. The surgeon upon identifying a tissue thought to be the PG with high/moderate confidence, obtained PTeye measurement from the tissue. In these three patients -1-2 measurements were taken when the PG was covered with blood, which routinely occurs during the surgical procedure. After the measurement, the surgeon suctioned the blood away, rinsed the tissue with saline and repeated the PTeye measurement on the same tissue site. Detection ratios were grouped for three categories: (i) PG with blood and (iii) PG without blood, with each group consisting of at least 6 NIRAF measurements. Statistical significance between (i) thyroid and PG without blood and (ii) thyroid and PG with blood were determined by a 2-tailed Student's t-test for unequal variance, with an alpha level of significance of 0.01.

Effect of probe-to-tissue contact pressure on tissue NIRAF measurements with the PTeye:

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The effect of probe-to-tissue contact pressure on tissue NIRAF intensity was examined in vitro on excised fresh frozen human PG (n=3) and thyroid (n=2) tissues. NIRAF measurements with the PTeve were collected where the user reported the probe contact pressures qualitatively to be 'mild', 'moderate', and 'high'. Differences in PG detection ratios were correlated with the degree of probe-to-tissue contact pressure.

Schedule of assessments:

There were no formal follow-up assessments or visits for the patient: subjects exit the study at the conclusion of standard recovery from the surgical procedure.

Safety definitions and reporting requirements:

All adverse events (AEs), regardless of seriousness, severity, or relationship to the study device, were to be recorded in the Case Report Forms (CRF) by the investigators and/or study coordinators and reported to corresponding IRBs at the two centers and to the Principal Investigator. The evaluation was to include a determination of the seriousness and severity of the event, whether the event or the severity of the event was anticipated or unanticipated, and the relationship of the event to the study device.

A serious adverse event (SAE) is defined according to ISO 14155:2003 as any adverse event that:

  • Led to a death
  • Led to a serious deterioration in the health of the subject that ●
  • Resulted in a life-threatening illness or injury ●
  • . Resulted in a permanent impairment of a body structure or a body function
  • Required in-patient hospitalization or prolongation of existing hospitalization
  • . Resulted in medical or surgical intervention to prevent permanent impairment to body structure or a body function

An unanticipated adverse device effect (UADE) is defined per 21 CFR 812.3 as any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects.

SAE and UADE were to be reported by the investigators to the IRB and to AiBiomed within 24 hours. Serious AEs and UADEs were documented on the Serious Adverse Event Form.

Safety and Effectiveness Results

    1. Safety Results

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At the end of patient follow-up period of two weeks, no adverse events related to the procedure or during the study period were reported. There were no adverse events, SAE's, or UADE's reported in the 81 patients considered for effectiveness data analysis. No clinical issues or adverse events related to the intra-operative use of the device description of procedural difficulties, or device complaints were reported at the closure of the study.

Individual measurements once the PTeye device is set up take approximately 2 seconds. (5) thyroid baseline measurements, (4) extra thyroid measurements, (8) PG measurements, (2) fat measurements, (2) trachea measurements, and (2) muscle measurements per patients took approximately one minute of additional total procedure time during normal use of the device, this was under the 5-minute pre-defined cut-off.

2. Effectiveness Results

Primary endpoint parathyroid identification rate:

Measurements were obtained using the final design of the PTeye on 181 PGs and 546 non-PG tissues (194 thyroid, 116 fat. 119 neck muscle, and 117 trachea) in 81 patients. Individual performance data was populated for all 81 patients (40 from site A and 41 from site B). Of the 181 PGs measured, fluorescence measurements of 68 PGs (68/181, 37.6%) were confirmed with histology. The remaining 113 PGs could not be confirmed with histology and were validated based on high or medium confidence of the surgeon's visual assessment. Tissues identified with low confidence by the surgeon were excluded from further analysis unless histological validation was obtained from those tissues.

A. Normalized NIRAF Intensity:

Testing with the PTeve system vielded 362 measurements from 181 PGs and 546 measurements from non-PG locations in 81 patients undergoing parathyroidectomy and/or thyroidectomy.

Figure 1: Normalized NIRAF Intensity to Tissues:

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Image /page/12/Figure/0 description: This bar graph shows the tissue NIRAF normalized to thyroid NIRAF. The x-axis shows the different tissues, including thyroid, parathyroid, muscle, fat, and trachea. The y-axis shows the NIRAF values, with parathyroid having the highest value of approximately 3.5, while the other tissues have values less than 1.

NIRAF measured with the PTeye on different neck tissues normalized to NIRAF of the thyroid. Error bar – Standard Error. **p-value