NIOX VERO® measures Nitric Oxide (NO) in human breath. Nitric Oxide is frequently increased in some airway inflammatory processes such as asthma. The fractional NO concentration in expired breath (FeNO), can be measured by NIOX VERO according to guidelines for NO measurement established by the American Thoracic Society.

Measurement of FeNO by NIOX VERO is a quantitative, non-invasive, simple and safe method to measure the decrease in FeNO concentration in asthma patients that often occurs after treatment with anti-inflammatory pharmacological therapy, as an indication of the therapeutic effect in patients with elevated FeNO levels. NIOX VERO is suitable for children, 7- 17 years, and adults 18 years and older.

NIOX VERO 10 second test mode is for age 7 and up
NIOX VERO 6 second test mode is for ages 7-10 only who cannot successfully complete a 10 second test.

FeNO measurements provide the physician with means of evaluating an asthma patient's response to anti-inflammatory therapy, as an adjunct to the established clinical and laboratory assessments in asthma. The NIOX VERO is intended for prescription use and should only be used as directed in the NIOX VERO User Manual by trained healthcare professionals. NIOX VERO cannot be used with infants or by children under the age of 7 as measurement requires patient cooperation.

NIOX VERO should not be used in critical care, emergency care or in anesthesiology.

Device Description

NIOX VERO is a portable system for the non-invasive, quantitative measurement of the fraction of exhaled nitric oxide (NO) in expired human breath (FeNO). NO levels increase during allergic airway inflammation. Measurement of changes in FeNO concentration is used in evaluating a patient's response to antiinflammatory therapy, as an adjunct to established clinical and laboratory assessments.

The NIOX VERO system is comprised of the NIOX VERO unit with AC adapter, a rechargeable battery, an electrochemical NO sensor, disposable patient filters, and an exchangeable handle containing an internal NO scrubber filter. The NIOX Panel is an optional PC application for operation of the NIOX VERO from a PC and access to electronic medical record systems. The device can connect to the PC via a standard USB cable or wirelessly via Bluetooth.

The patient empties their lungs, inhales deeply through the patient filter to total lung capacity and then slowly exhales for 10 seconds. A 6 second mode is available for children aged 7 – 10 who cannot perform a 10 second exhalation. In approximately one minute, the NO concentration is displayed in parts per billion (ppb).

The NIOX VERO unit includes a sampling and gas conditioning system and a man-machine interface (MMI). The instrument controls the inhaled sample appropriately via the electronics and software program. Filtering of inhaled air elimination from ambient NO levels. A built-in flow control keeps exhalation standardized at 50 ml/s so that it is standardized for all patients. The sample enters an electromechanical sensor and interacts with an electrolyte. A chemical reaction takes place where electrons are generated proportional to the number of NO molecules.

Results are processed using dedicated software. In order to verify the device's performance and reliability of measurements, there are built-in system control procedures and a Quality Control procedure to be performed on a daily basis.

AI/ML Overview

The Circassia NIOX VERO device measures the fractional nitric oxide concentration in expired breath (FeNO) to evaluate an asthma patient's response to anti-inflammatory therapy. The 510(k) submission (K170983) is specifically for the activation of an existing 6-second measurement mode for children aged 7-10, in addition to the previously cleared 10-second mode.

Here's a breakdown of the acceptance criteria and study information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria for the NIOX VERO are compared against the predicate device (NIOX VERO, K150233), and for the 6-second mode, the performance was found to be identical to these established criteria.

Acceptance Criteria	Specified by Predicate (K150233)	Reported Device Performance (NIOX VERO 6s mode)
Analytical limits (low levels, limit of detection)	5 ppb	Identical to predicate (5 ppb)
Precision	< 3 ppb for values < 30 ppb; < 10% for values ≥ 30 ppb	Identical to predicate
Accuracy	±5 ppb for values ≤ 30 ppb; 10% of measured value for values > 30 ppb	Identical to predicate
Measurement Range	5 - 300 ppb	Identical to predicate
Linearity, reportable range	Squared correlation coefficient $r^2$ ≥ 0.998, slope 0.95 - 1.05, intercept ±3 ppb	Identical to predicate
Measurement Mode	10s mode for patients 7 to 17 and adults 18+	10s mode (7 to 17, adults 18+); 6s mode (7 to 10 only)

2. Sample Size and Data Provenance

Test Set (Clinical Study AER-047):
- Sample Size: 43 male and female subjects.
- Data Provenance: Not explicitly stated, but the study was described as a "single-center" study. This suggests the data originated from one specific location. It was a "single-visit, point-of-care clinical validation study," indicating it was a prospective study.

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

This information is not provided in the document. The study focuses on comparing the 6s mode against the 10s mode in children for their ability to successfully perform the test and maintain similar analytical performance characteristics, rather than expert-adjudicated ground truth for a diagnostic outcome.

4. Adjudication Method (Test Set)

This information is not provided. The clinical study described in the document is a validation study demonstrating the feasibility and performance equivalence of the 6s mode. It does not appear to involve a diagnostic outcome requiring expert adjudication.

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

An MRMC study was not conducted as this device measures a quantitative physiological biomarker (FeNO). The study performed was a clinical validation to demonstrate the equivalence of the 6s measurement mode. The device does not involve human readers interpreting images, so the concept of "human readers improve with AI vs without AI" is not applicable.

6. Standalone Performance (Algorithm Only)

Yes, a standalone (algorithm only) performance assessment was done. The performance bench testing (precision, accuracy, linearity) of the NIOX VERO in 6s mode was conducted independently and demonstrated to be within the specifications of the original NIOX VERO performance. This refers to the device's inherent ability to accurately measure FeNO, irrespective of human interaction beyond operating the device as intended.

7. Type of Ground Truth Used

Clinical Study (AER-047): The "ground truth" for the clinical study was the successful completion and measurement of FeNO for the 6-second mode in children aged 7-10, and the comparison of these measurements to the established performance characteristics of the 10-second mode. It was about patient cooperation and the device's ability to consistently provide measurements in this cohort.
Bench Testing: The ground truth for bench testing (precision, accuracy, linearity) was established by using certified calibration gas of known concentrations (5ppb, 25ppb, 75ppb, and 200ppb) as reference standards.

8. Sample Size for the Training Set

This information is not applicable and therefore not provided. The NIOX VERO is a measurement device, not an AI/ML-driven diagnostic algorithm that requires a training set in the conventional sense. The "6s measurement mode" was an existing functionality in the predicate device, not a newly developed algorithm requiring extensive training data.

9. How the Ground Truth for the Training Set Was Established

This information is not applicable as there is no mention of a training set for an AI/ML algorithm. The device measures a physical parameter using electrochemical sensing.

Summary

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November 30, 2017

Circassia AB William Sammons Manager, Global Regulatory Affairs Hansellisgatan 13 SE-754 50 Uppsala, Sweden

Re: K170983

Trade/Device Name: NIOX VERO Regulation Number: 21 CFR 862.3080 Regulation Name: Breath nitric oxide test system Regulatory Class: Class II Product Code: MXA Dated: October 19, 2017 Received: October 23, 2017

Dear William Sammons:

This letter corrects our substantially equivalent letter of November 22, 2017.

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

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803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Courtney H. Lias -S

Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K170983

Device Name NIOX VERO

Indications for Use (Describe)

NIOX VERO 10 second test mode is for age 7 and up NIOX VERO 6 second test mode is for ages 7-10 only who cannot successfully complete a 10 second test.

NIOX VERO should not be used in critical care, emergency care or in anesthesiology.

Type of Use (Select one or both, as applicable)
Prescription Use (Part 21 CFR 801 Subpart D)	Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) SUMMARY

The assigned 510(k) number is: K170983

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SDMA 1990 and 21 CFR 807.92.

Preparation Date:	22 Nov 2017
510(k) Applicant:	Circassia ABHansellisgatan 13SE-754 50 UppsalaSwedenPhone: +46-8-629-0780Fax: +46-8-629-0781
Contact Person:	Susanne ParksGlobal Director Regulatory Affairs & Quality Assurance
Trade Name:	NIOX VERO®
Common Name:	Airway Inflammation Monitor
Classification Name:	System, Test, Breath Nitric Oxide
Regulatory Class:	Class II
Product Code:	MXA
CFR Section:	21 CFR 862.3080
Predicate Device:	NIOX VERO® Airway Inflammation Monitor
510(k) Clearance Number:	K150233Class II under 21 CFR 862.3080, Product Code MXA

Circassia AB

Registered Address: P.O. Box 3006, SE75003 Uppsala, Sweden. Company number: 556549-105601.

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Device Description

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Intended Use/Indications for Use

NIOX VERO 10 second test mode is for age 7 and up

NIOX VERO 6 second test mode is for ages 7 - 10 only who cannot successfully complete a 10 second test

NIOX VERO should not be used in critical care, emergency care or in anesthesiology.

	SubjectNIOX VERO®	PredicateNIOX VERO®
Trade Name	10 s and 6s Measurement Modes	10 Measurement Mode
510(k) Number	K170983	K150233
Regulatory Class	Class II	Class II
RegulationNumber	21 CFR 862.3080	21 CFR 862.3080
Product Code	MXA	MXA

Technological Characteristics Compared to Predicate

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Indications forUse	NIOX VERO® measures Nitric Oxide(NO) in human breath. Nitric Oxide isfrequently increased in some airwayinflammatory processes such asasthma. The fractional NOconcentration in expired breath(FeNO), can be measured by NIOXVERO according to guidelines for NOmeasurement established by theAmerican Thoracic Society.Measurement of FeNO by NIOX VEROis a quantitative, non-invasive, simpleand safe method to measure thedecrease in FeNO concentration inasthma patients that often occursafter treatment with anti-inflammatory pharmacologicaltherapy, as an indication of thetherapeutic effect in patients withelevated FeNO levels. NIOX VERO issuitable for children, 7 - 17 years, andadults 18 years and older.NIOX VERO 10 second test mode isfor age 7 and upNIOX VERO 6 second test mode is forages 7 - 10 only who cannotsuccessfully complete a 10 secondtestFeNO measurements provide thephysician with means of evaluatingan asthma patient's response to anti-inflammatory therapy, as an adjunctto the established clinical andlaboratory assessments in asthma.The NIOX VERO is intended forprescription use and should only beused as directed in the NIOX VEROUser Manual by trained healthcareprofessionals. NIOX VERO cannot beused with infants or by childrenunder the age of 7, as measurementrequires patient cooperation.NIOX VERO should not be used incritical care, emergency care or in	NIOX VERO measures Nitric Oxide (NO) inhuman breath. Nitric Oxide is frequentlyincreased in some inflammatoryprocesses such as asthma. The fractionalNO concentration in expired breath(FeNO), can be measured by NIOX VEROaccording to guidelines for NOmeasurement established by theAmerican Thoracic Society.Measurement of FeNO by NIOX VERO is aquantitative, non-invasive, simple andsafe method to measure the decrease inFeNO concentration in asthma patientsthat often occurs after treatment withanti-inflammatory pharmacologicaltherapy, as an indication of thetherapeutic effect in patients withelevated FeNO levels. NIOX VERO issuitable for children, approximately 7 - 17years, and adults 18 years and older.FeNO measurements provide thephysician with means of evaluating anasthma patient's response to anti-inflammatory therapy, as an adjunct tothe established clinical and laboratoryassessments in asthma. The NIOX VERO isintended for prescription use and shouldonly be used as directed in the NIOX VEROUser Manual by trained healthcareprofessionals. NIOX VERO cannot beused with infants or by childrenapproximately under the age of 7, asmeasurement requires patientcooperation.NIOX VERO should not be used in criticalcare, emergency care or inanesthesiology.
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	anesthesiology.
Analytical limitsat low levels,(limit ofdetection)	Identical to predicate	5 ppb
Precision	Identical to predicate	< 3 ppb of measured value for values < 30ppb< 10% of measured value for values ≥30ppb
Accuracy	Identical to predicate	±5 ppb for measured values ≤ 30ppb or10% of measured value for values > 30ppb.
MeasurementRange	Identical to predicate	5 - 300 ppb
Linearity,reportable range	Identical to predicate	Squared correlation coefficient $r^2$ ≥ 0.998,slope 0.95 - 1.05, intercept ±3ppb
MeasurementMode	10s mode for patients 7 to 17 and foradults age 18 and over; 6s measurementmode for patients 7 to 10 only	10s measurement mode for patients 7 to17

The scope of this 510(k) application is the activation of the existing 6s measurement mode on the predicate device. The 6s measurement mode was present in the previously cleared device, but not activated for the US market. The 6s measurement mode is used to aid the performance of patients that are younger and unable to successfully achieve a 10s breath sample for testing purposes.

Performance Testing:

Performance testing was repeated for the NIOX VERO device in 6s mode. The 6s exhalation mode is technically identical to the standard 10s exhalation mode for which all other verification is made, except for the timing counter that controls how long time the patient should exhale into the device. When bench testing is performed, certified calibration gas of approximately 200 ppb is mixed with nitrogen gas in a gas mixer, connected with the NIOX VERO instrument, to produce 5ppb, 25 ppb and 75ppb. 200ppb is produced directly from the gas bottle.

The precision, accuracy, and linearity bench testing was repeated with the NIOX VERO in 6s mode. All results were found to be within specifications for the original NIOX VERO performance specifications.

Clinical Testing:

This 510(k) submission supports the use of an alternative 6s mode to the currently approved 10 second test for use in children aged 7 to 10.

The evidence to support use of the 6 second mode is demonstrated by the clinical study conducted and provided in the submission.

AER-047 Use of 6s in ages 7 to 10 years

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A randomized, single-center, single-visit, point-of-care clinical validation study was conducted in 43 male and female subjects age 7 to 10 years. Data supports use of 6s mode in children under age of 10.

Conclusions:

The updated NIOX VERO has the same intended use as the predicate device and the Indications for Use have been updated to reflect the 6s mode usage. The device modifications do not affect the device's fundamental scientific technology, clinical performance, hardware or software as the functionality was previously implemented in the predicate, but not activated in the US market.

Performance bench testing was repeated in the 6s mode to demonstrate that the use of the NIOX VERO in 6s mode does not change the fundamental performance properties of the device and the new measurement mode is as safe and effective as the predicate 10s mode.

Clinical testing has been performed to demonstrate that the NIOX VERO in 6s mode for patients between the ages of 7 and 10 years old is substantially equivalent to 10s mode use in this patient population. The patient ages for the 6s mode are ages 7 - 10 year age range. This data supports substantial equivalence and the changes to the NIOX VERO Indications for Use to support this new measurement mode.

Regulation Number and Section

§ 862.3080 Breath nitric oxide test system.

(a)
Identification. A breath nitric oxide test system is a device intended to measure fractional nitric oxide in human breath. Measurement of changes in fractional nitric oxide concentration in expired breath aids in evaluating an asthma patient's response to anti-inflammatory therapy, as an adjunct to established clinical and laboratory assessments of asthma. A breath nitric oxide test system combines chemiluminescence detection of nitric oxide with a pneumotachograph, display, and dedicated software.(b)
Classification. Class II (special controls). The special control is FDA's guidance entitled “Class II Special Controls Guidance Document: Breath Nitric Oxide Test System.” See § 862.1(d) for the availability of this guidance document.