Fenom Pro™ Nitric Oxide Test is a portable, non-invasive device to measure fractional exhaled nitric oxide (FeNO) in human breath. FeNO is increased in some airway inflammatory processes, such as asthma, and often decreases in response to anti-inflammatory treatment of FeNO by Fenom Pro™ is a 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 therapeutic effect in patients with elevated FeNO levels. FeNO measurements are to be used as an adjunct to established clinical assessments. Fenom Pro™ is suitable for children, approximately 7-17 years, and adults 18 years and older.

Testing using the Fenom Pro™ should only be done in a point-of-care healthcare setting under professional supervision. Fenom Pro™ should not be used in critical care, emergency care or in anesthesiology.

Device Description

Fenom Pro™ is a point-of-care breath analyzer that uses solid-state electrochemical technology to measure the fraction of exhaled nitric oxide (FeNO), a marker for airway inflammation, in human exhaled breath. Measurement of FeNO by Fenom Pro is a quantitative and non-invasive method to indicate therapeutic effects of anti-inflammatory pharmacological therapy in patients with elevated FeNO levels. Fenom Pro™ is suitable for children, approximately 7-17 years, and adults 18 years and older.

Fenom Pro uses solid state, potentiometric, sensor technology sensitive to nitric oxides (NO) compounds. The solid state sensor is fluidly preceded by a reactive filter material that renders (oxidizes) potentially confounding species such as carbon monoxide (CO), ammonia (NH4), and methanol (CH4O) inactive, or inert, to the NO sensor. Fenom Pro provides visual and audible feedback during its use. The visual and audible feedback is especially important during the FeNO measurement such that the user can modulate their breath speed within the flow parameters required by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) standards.

Fenom Pro is comprised of four major components. The main unit contains a touch screen interface for the use as well as houses the nitric oxide sensor and pneumatics needed to sample the patient's breath. The patient interfaces with Fenom though the mouthpiece which is attached to the handpiece. The handpiece is connected to the main unit via a breath tube. The handpiece contains a breath conditioning cartridge which prepares the breath sample from the patient for proper analysis in the main unit. Both the mouthpiece and the breath conditioning cartridge are consumables.

AI/ML Overview

Here's an analysis of the provided text, extracting the acceptance criteria and the study details for the Fenom Pro™ Nitric Oxide Test.

Device: Fenom Pro™ Nitric Oxide Test (K182874)
Intended Use: Portable, non-invasive device to measure fractional exhaled nitric oxide (FeNO) in human breath. FeNO measurements are used as an adjunct to established clinical assessments to indicate therapeutic effect in patients with elevated FeNO levels after anti-inflammatory pharmacological therapy. Suitable for children (approx. 7-17 years) and adults (18+ years).

1. Table of Acceptance Criteria and Reported Device Performance

The provided document details non-clinical (analytical) and clinical studies. We will parse the acceptance criteria and performance from these sections.

Non-Clinical (Analytical) Performance:

Study Category	Acceptance Criteria	Reported Device Performance	Pass/Fail (based on stated performance)
Accuracy	For 15 ppb: +/- 5 ppb	Across 5 environmental conditions for 2 devices and 5 replicates each, all results for 15 ppb target concentration were within +/- 5 ppb. (e.g., Ambient T/RH: GP18 had upper 95% error limit of 0.17ppb and lower of -1.97ppb; GP35 had upper 0.44ppb and lower -3.84ppb).	Pass
	For 75 ppb & 200 ppb: +/- 10%	Across 5 environmental conditions for 2 devices and 5 replicates each, all results for 75 ppb and 200 ppb target concentrations were within +/- 10%. (e.g., Ambient T/RH: GP18 had upper 1.83% and lower -2.12% for 75ppb; High T/Low RH: GP35 had upper -1.63% and lower -3.38% for 200ppb).	Pass
Precision (Repeatability)	Not explicitly stated as a pass/fail criterion in the table, but reported as SD (ppb) and %CV.	For 10 ppb: SDs ranged from 1.1 to 1.9 ppb. For 25 ppb: SDs ranged from 1.2 to 2.3 ppb. For 75 ppb: %CVs ranged from 3.2% to 7.1%. For 200 ppb: %CVs ranged from 3.0% to 7.3%.	N/A (Data Reported)
Precision (Within-Device)	Not explicitly stated as a pass/fail criterion in the table, but reported as SD (ppb) and %CV.	For 10 ppb: SDs ranged from 1.2 to 2.3 ppb. For 25 ppb: SDs ranged from 1.2 to 3.3 ppb. For 75 ppb: %CVs ranged from 4.3% to 7.5%. For 200 ppb: %CVs ranged from 3.4% to 8.5%.	N/A (Data Reported)
Linearity	Slope between 0.95 and 1.05 and R (correlation coefficient) presumably close to 1.0.	Device GammaPrime42: Slope 1.03, Intercept 2.32, R 0.999. Device GammaPrime49: Slope 1.02, Intercept 0.231, R 0.999. Combined: Slope 1.02, Intercept 1.27, R 0.998.	Pass
Limit of Detection (LoD)	< 10 ppb	Device #1: LoD = 1.8 ppb. Device #2: LoD = 4.6 ppb.	Pass
Interference (Other Gases)	Change in response <= 4 ppb NO equivalent	For acetaldehyde, acetone, ammonia, carbon dioxide, carbon monoxide, ethanol, hydrogen, hydrogen sulfide, isoprene, oxygen: all interferences were <= 4 ppb NO equivalent. Acetonitrile showed 120.8 ppb interference, but is only present in exhaled breath when recently smoked, and the device is labeled for use not after smoking.	Pass (with labeling mitigation for acetonitrile)
Interference (Exogenous Substances)	Mean difference between 60 minutes and baseline values <= 5 ppb. Lower and upper 95% confidence intervals around the means must include zero.	All 7 tested substances (Alcohol Free Mouthwash, Caffeinated Soda, Caffeine Free Soda, Menthol Lozenge, Mouthwash with Alcohol, Non-Menthol Lozenge, Toothpaste) showed mean differences <= 5 ppb and 95% CIs that included zero at 60 minutes.	Pass

Clinical Performance:

Study Category	Acceptance Criteria	Reported Device Performance	Pass/Fail (based on stated performance)
Clinical Precision (User Bias)	No explicit numerical acceptance criteria given, but the objective was to confirm no user bias. The text implies a "very high quantitative agreement."	Maximum mean bias observed was only 1.2 ppb between pairs of HCPs. Deming regression, correlation (Pearson R > 0.9873 for all HCP pairs), and all bias analyses demonstrated very high quantitative agreement.	Pass (Implied)
Clinical Precision (Within-subject Variability)	Less than 5 ppb by mean standard deviation for FeNO values below 50 ppb. %CVs for FeNO values greater than 50 ppb were maintained at less than 10%, "unless sample size was small."	Across both clinical precision studies and all age groups: - For FeNO < 50ppb (excluding 0-<10ppb where N=0): Mean SDs were generally less than 5 ppb. Exceptions occurred in small N subgroups (e.g., All ages Visit 1 20-<30ppb where N=5, Mean SD 4.97). - For FeNO >= 50ppb: Mean CVs were generally less than 10%. Exceptions also occurred with small N (e.g., 5-17 Visit 1 75-<100ppb where N=3, Mean CV 18.73%). The document mitigates these by stating "unless sample size was small".	Pass (with noted small N exceptions)
Clinical Efficacy (Concordance with established measures)	Implicitly, significant concordance between Fenom Pro and other established asthma-related outcome measures (FEV1, ACQ/pACQ).	Significant differences between the two visits were achieved for all three modalities (FeNO, spirometry, asthma questionnaires). Kendall's Tau p-values were 0.0370 for FeNO vs. FEV1 and 0.0125 for FeNO vs. ACQ/pACQ, indicating statistically significant correlations (concordance) given typical alpha levels of 0.05.	Pass

2. Sample Sizes Used for the Test Set and Data Provenance

Non-Clinical (Analytical):
- Accuracy and Environmental Testing: 2 devices, 3 concentrations (15, 75, 200 ppb), 5 replicates per concentration, 5 environmental conditions. Total of 150 tests.
- Precision: 5 devices, 5 operating days, 2 sessions per day, 4 runs per session, 2 replicates per concentration (10, 25, 75, 200 ppb). This calculates to 80 replicates per sample per device according to CLSI EP05-A3.
- Linearity: 2 devices, 8 NO concentration levels (5, 10, 15, 30, 50, 100, 150, 200 ppb), 5 replicates per concentration. Total 80 tests.
- Limit of Detection: 2 devices, 0 ppb (60 replicates), 5 ppb (30 replicates), 10 ppb (30 replicates) over three days. Total 120 replicates.
- Interference (Other Gases): Tested in a laboratory setting. No specific number of tests/replicates provided, but states "The applicable concentration of each substance was generated... and the sensor signal was measured."
- Interference (Exogenous Substances): Minimum of 10 volunteers per substance (7 substances). This means at least 70 volunteers.
- Data Provenance: The document does not explicitly state the country of origin for the non-clinical data. It is implied to be laboratory-based and likely retrospective as it's presented as completed tests.
Clinical:
- Clinical Precision (User Bias Study): 127 subjects (44 pediatric, 83 adults). Each subject yielded 6 evaluations (2 Fenom Pro measurements with assistance of 3 HCPs). Data provenance not explicitly stated (e.g., country), but implied prospective data collection for this study.
- Clinical Precision (Within-subject Variability/Longitudinal Study): 82 subjects (37 pediatric, 45 adults). Each subject provided replicate (n=2) FeNO measurements at Visit 1 (baseline) and Visit 2 (after approx. two weeks). Data provenance not explicitly stated, but implied prospective data collection.
- Clinical Efficacy (Concordance Study): 82 subjects in longitudinal study (matches the precision study's subject count) - 37 pediatric, 45 adults. 80 subjects for regression analysis (due to missing asthma symptom scores for 2 subjects). Data provenance not explicitly stated, but implied prospective data collection.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

Non-Clinical Studies:
- Accuracy, Precision, Linearity, LoD: Ground truth was established using calibrated reference instruments/methods. Specifically, a chemiluminescence device calibrated against a NIST (National Institute of Standards and Technology) traceable NO tank was used to measure the actual concentration of nitric oxide in simulated breath mixtures. This does not involve human experts in the same way as, for example, image interpretation.
- Interference (Other Gases): Ground truth was based on the controlled generation of specific gas concentrations and measurement by the device.
- Interference (Exogenous Substances): The ground truth for this was the subjects' baseline Fenom Pro levels before exposure to the substances, acting as their own control for comparison.
Clinical Studies:
- Clinical Precision (User Bias Study) and Clinical Precision (Within-subject Variability/Longitudinal Study): The ground truth was effectively the FeNO measurements themselves, as performed by the device. The study evaluated agreement between HCPs and within subjects. The study used three healthcare professionals (HCPs) to assist with measurements. Their specific qualifications (e.g., type of healthcare professional, years of experience) are not provided in the summary.
- Clinical Efficacy (Concordance Study): The "ground truth" for showing clinical efficacy was the change in FeNO, which was correlated with changes in established asthma-related outcome measures (spirometry - FEV1, and asthma questionnaires - ACQ/pACQ). These established measures themselves serve as the comparative ground truth. The expertise in interpreting FEV1 and ACQ/pACQ would be inherent in the clinicians applying these standard assessments but is not explicitly detailed as part of "ground truth establishment" for the device's performance.

4. Adjudication Method for the Test Set

Non-Clinical Studies: No adjudication method is applicable as these are instrumental measurements against calibrated standards.
Clinical Studies: No formal adjudication method involving multiple experts resolving discrepancies is described for the clinical studies. The "user bias" study quantifies bias between HCPs rather than adjudicating a "true" FeNO value. The other clinical studies compare the device's output to standard clinical measures rather than relying on a panel for ground truth adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, What was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

This device is a breath test system, not an imaging AI system that assists human readers (like radiologists). Therefore, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study focusing on human reader improvement with AI assistance is not applicable to this device.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

The Fenom Pro™ is a point-of-care device that directly measures FeNO. Its non-clinical (analytical) performance tests (Accuracy, Precision, Linearity, LoD, Interference) are essentially standalone performance of the device's measurement algorithm/sensor. While human operators perform the physical test, the output (FeNO value) is generated by the device's internal algorithms from the sensor data, without human interpretation or intervention in the measurement result itself.

The "user bias" clinical study specifically explores human-in-the-loop variance (i.e., how different operators' assistance impacts measurements), which is a crucial aspect for a point-of-care device. However, the core measurement itself, once the breath sample is collected, is standalone.

7. The Type of Ground Truth Used

Non-Clinical (Analytical) Studies:
- Calibrated Reference Standard: For Accuracy, Precision, and Linearity, the ground truth was established using a chemiluminescence device calibrated against a NIST traceable NO tank measuring specific concentrations of nitric oxide mixed in simulated breath.
- Controlled Input: For Limit of Detection and Interference (other gases), known, controlled concentrations of gases were presented to the device.
- Self-reference (Baseline): For Interference (Exogenous Substances), each subject's own baseline Fenom Pro measurement before exposure served as the ground truth for evaluating the impact of the substances.
Clinical Studies:
- Comparative Assessment: For the Clinical Efficacy study, the "ground truth" for demonstrating the device's utility was established by comparison with established clinical assessments: FEV1 (spirometry) and ACQ/pACQ (asthma questionnaires).
- Internal Consistency: For the Clinical Precision studies, the "ground truth" was essentially the device's own measurement output, and the studies focused on the consistency and variability of these measurements across different operators and occasions.

8. The Sample Size for the Training Set

The document does not explicitly describe a "training set" in the context of an machine learning model that would require separate training data. The device appears to be a physical sensor-based measurement system rather than a machine learning algorithm that learns from a dataset.

The listed studies refer to:

Non-clinical testing: Performed on a limited number of devices (e.g., 2 devices for accuracy, 5 for precision) against controlled gas mixtures. This is instrument verification/validation, not AI model training.
Clinical studies: These are validation studies on human subjects to demonstrate performance characteristics like precision and concordance with established clinical measures, after the device's design is largely finalized. They do not constitute a "training set" for an AI algorithm.

Therefore, the concept of a "training set sample size" as typically understood for AI/ML devices is not applicable here.

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

As explained in point 8, a "training set" for an AI/ML model is not applicable to this device description. The device's fundamental measurement principle relies on solid-state electrochemical sensor technology, calibrated using reference standards in a laboratory setting, rather than being "trained" on a large dataset of patient results.

Summary

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February 13, 2019

Spirosure, Inc. % Erika Ammirati, President Ammirati Regulatory Consulting 575 Shirlynn Court Los Altos, CA 94022

Re: K182874

Trade/Device Name: Fenom ProTM Nitric Oxide Test Regulation Number: 21 CFR 862.3080 Regulation Name: Breath nitric oxide test system Regulatory Class: Class II Product Code: MXA Dated: January 11, 2019 Received: January 15, 2019

Dear Erika Ammirati:

We have reviewed vour 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 Mav 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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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

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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 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.html; good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; 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 comprehensive regulatory information about mediation-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,

Kellie B. Kelm -S

for 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) K182874

Device Name Fenom Pro™ Nitric Oxide Test

Indications for Use (Describe)

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

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92. The assigned 510(k) number is K182874. This document was

807.92 (a)(1): Name:Address:	Spirosure, Inc.7020 Koll Center Parkway, Suite 110Pleasanton, CA 94566
Phone:Email:Contact:	(925) 264-7720ryan@spirosure.comMr. Ryan Leard

Date of Preparation: October 11, 2018

807.92 (a)(2): Device name- trade name and common name, and classification

Trade name: Fenom Pro™ Nitric Oxide Test

Common Name: Breath nitric oxide test system

Classification: 21 CFR Part 862.3080

807.92 (a)(3): Identification of the legally marketed predicate devices NIOX MINO (Aerocrine AB, Morrisville, NC), K072816

807.92 (a)(4): Device Description

Fenom Pro is comprised of four major components. The main unit contains a touch screen interface for the use as well as houses the nitric oxide sensor and pneumatics needed to sample the

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patient's breath. The patient interfaces with Fenom though the mouthpiece which is attached to the handpiece. The handpiece is connected to the main unit via a breath tube. The handpiece contains a breath conditioning cartridge which prepares the breath sample from the patient for proper analysis in the main unit. Both the mouthpiece and the breath conditioning cartridge are consumables.

807.92 (a)(5): Intended Use

Fenom Pro™ Nitric Oxide Test is a portable, non-invasive device to measure fractional exhaled nitric oxide (FeNO) in human breath. FeNO is increased in some airway inflammatory processes, such as asthma, and often decreases in response to anti-inflammatory treatment of FeNO by Fenom Pro™ is a 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 therapeutic effect in patients with elevated FeNO measurements are to be used as an adjunct to established clinical assessments. Fenom Pro™ is suitable for children, approximately 7-17 years, and adults 18 years and older.

807.92 (a)(6): Technological Similarities and Differences to the Predicate

The following chart describes similarities and differences between Fenom Pro™ and the predicate.

Comparison	Subject DeviceFenom Pro™ Nitric Oxide Test	Predicate DeviceNIOX MINO(K072816)
Intended Use	Fenom Pro™ Nitric Oxide Test is aportable, non-invasive device to measurefractional exhaled nitric oxide (FeNO) inhuman breath. FeNO is increased insome airway inflammatory processes,such as asthma, and often decreases inresponse to anti-inflammatory treatment.Measurement of FeNO by Fenom Pro™is a method to measure the decrease inFeNO concentration in asthma patientsthat often occurs after treatment withanti-inflammatory pharmacologicaltherapy as an indication of therapeuticeffect in patients with elevated FeNOlevels. FeNO measurements are to beused as an adjunct to established clinicalassessments. Fenom Pro™ is suitablefor children, approximately 7-17 years,and adults 18 years and older.	NIOX MINO® measures Nitric Oxide(NO) in human breath. Nitric Oxide isfrequently increased in someinflammatory processes such asasthma. The fractional NOconcentration in expired breath(FeNO), can be measured by NIOXMINO according to guidelines for NOmeasurement established by theAmerican Thoracic Society.Measurement of FeNO by NIOXMINO is a quantitative, non-invasive,simple and safe method to measure thedecrease in FeNO concentration inasthma patients that often occurs aftertreatment with anti-inflammatorypharmacological therapy, as anindication of the therapeutic effect inpatients with elevated FeNO levels.NIOX MINO is suitable for children.

	Testing using the Fenom Pro™ shouldonly be done in a point-of-carehealthcare setting under professionalsupervision. Fenom Pro™ should not beused in critical care, emergency care orin anesthesiology.	approximately 7 - 17 years, and adults18 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 NIOXMINO is intended for prescription useand should only be used as directed inthe NIOX MINO User Manual bytrained healthcare professionals. NIOXMINO cannot be used with infants orby children approximately under theage of 7, as measurement requirespatient cooperation. NIOX MINOshould not be used in critical care,emergency care or in anesthesiology.
Class	Class II	Same
Regulation Number	21 CFR 862.3080	Same
Product Code	MXA	Same
FDA Branch	Toxicology/Chemistry (75)	Same
Result Type	Quantitative	Same
Test Locale	Point-of-Care, Professional	Same
Sample Type	Exhaled human breath	Same
Test Principle	Electrochemical sensor technology	Same
Sensor Calibration	Factory Calibrated	Same
Measurement Range	10-200ppb NO	5-300ppb NO
Detection Level	10ppb	5ppb
Analysis Time	approximately 30 seconds	approximately one minute
Power Supply	100-240V, ~50-60Hz	100-240V, ~47-63Hz

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807.92 (b)(1): Brief Description of Nonclinical Data

Accuracy and Environmental Testing

Two devices were tested over three concentrations with five replicates each at 5 different environmental conditions for a total of 150 tests. The five different conditions tested are summarized in the table below .

Tested Conditions
Test Case	Test Case Description	Temperature (°C)	Relative Humidity (%RH)
1	Ambient Temp / Ambient Humidity	22°	37%
2	Low Temp / Low Humidity	15°	20%
3	High Temp / Low Humidity	30°	20%
4	Low Temp / High Humidity	15°	80%
5	High Temp / High Humidity	30°	80%

For each concentration, nitric oxide was mixed in a balance gas of simulated breath. Each concentration sample was measured using a chemiluminescence device calibrated against a NIST traceable NO tank. This measurement was used to calculate the device error for each replicate. The data are shown below.

Test Case	Target Conc.(ppb)	Device	ActualConcentration(ppb)	Mean Score(ppb)	Std Dev Score(ppb)	Upper 95%Error Limit(ppb/%)	Lower 95% ErrorLimit (ppb/%)	AccuracyAcceptanceCriterion	Pass/Fail
Ambient T/ Ambient RH	15	GP18	14.5	13.6	0.548	0.17ppb	-1.97ppb	+/-5ppb	Pass
Ambient T/ Ambient RH	15	GP35	14.5	12.8	1.095	0.44ppb	-3.84ppb	+/-5ppb	Pass
Ambient T/ Ambient RH	75	GP18	70.1	70	0.707	1.83%	-2.12%	+/-10%	Pass
Ambient T/ Ambient RH	75	GP35	70.1	70.2	0.837	2.48%	-2.20%	+/-10%	Pass
Ambient T/ Ambient RH	200	GP18	187.5	185	0.707	-0.59%	-2.07%	+/-10%	Pass
Ambient T/ Ambient RH	200	GP35	187.5	184.6	1.517	0.04%	-3.13%	+/-10%	Pass
High T/ High RH	15	GP18	14.5	16	1.225	3.90ppb	-0.90ppb	+/-5ppb	Pass
High T/ High RH	15	GP35	14.5	15.2	0.837	2.33ppb	-0.93ppb	+/-5ppb	Pass
High T/ High RH	75	GP18	70.1	68.8	1.643	2.74%	-6.45%	+/-10%	Pass
High T/ High RH	75	GP35	70.1	68.8	1.483	2.29%	-6.00%	+/-10%	Pass
High T/ High RH	200	GP18	187.5	182.8	2.683	0.30%	-5.31%	+/-10%	Pass
High T/ High RH	200	GP35	187.5	182	1.581	-1.28%	-4.59%	+/-10%	Pass
High T/ Low RH	15	GP18	14.5	15	1.000	2.46ppb	-1.46ppb	+/-5ppb	Pass
High T/ Low RH	15	GP35	14.5	14.6	0.894	1.85ppb	-1.65ppb	+/-5ppb	Pass
High T/ Low RH	75	GP18	70.1	68.8	0.837	0.48%	-4.19%	+/-10%	Pass
High T/ Low RH	75	GP35	70.1	69	0.707	0.41%	-3.55%	+/-10%	Pass
High T/ Low RH	200	GP18	187.5	183	1.414	-0.92%	-3.88%	+/-10%	Pass
High T/ Low RH	200	GP35	187.5	182.8	0.837	-1.63%	-3.38%	+/-10%	Pass
Low T/ High RH	15	GP18	14.5	14.8	1.304	2.85ppb	-2.25ppb	+/-5ppb	Pass
Low T/ High RH	15	GP35	14.5	14.8	0.447	1.17ppb	-0.57ppb	+/-5ppb	Pass
Low T/ High RH	75	GP18	70.1	70.8	1.304	4.64%	-2.65%	+/-10%	Pass
Low T/ High RH	75	GP35	70.1	69.4	0.894	1.50%	-3.50%	+/-10%	Pass
Low T/ High RH	200	GP18	187.5	184.6	1.342	-0.14%	-2.95%	+/-10%	Pass
Low T/ High RH	200	GP35	187.5	183.4	0.548	-1.61%	-2.76%	+/-10%	Pass
Low T/ Low RH	15	GP18	14.5	14	0.000	-0.5ppb	-0.5ppb	+/-5ppb	Pass
Low T/ Low RH	15	GP35	14.5	13.8	0.447	0.17ppb	-1.57ppb	+/-5ppb	Pass
Low T/ Low RH	75	GP18	70.1	68.2	1.095	0.35%	-5.77%	+/-10%	Pass
Low T/ Low RH	75	GP35	70.1	68.8	0.447	-0.60%	-3.10%	+/-10%	Pass
Low T/ Low RH	200	GP18	187.5	174.4	2.702	-4.16%	-9.81%	+/-10%	Pass
Low T/ Low RH	200	GP35	187.5	176.8	1.304	-4.34%	-7.07%	+/-10%	Pass

Accuracy Study Summary

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Precision

The precision study was based on CLSI EP05-A3 (80 replicates per sample per device). Nitric oxide was mixed in a balance gas of simulated breath. Samples were measured using a chemiluminescence device calibrated against a NIST traceable NO tank. Data were collected from 5 devices over 5 operating days, 2 sessions per day, 4 runs per session with 2 replicates for each concentration, using the concentrations 10, 25, 75 and 200 ppb, by multiple operators. The data are shown below.

	Repeatability
	SD(ppb)	SD(ppb)	%CV	%CV
Bag ID	10 ppb	25 ppb	75 ppb	200 ppb
GammaPrime02	1.6	1.8	3.7%	3.9%
GammaPrime04	1.6	1.4	5.3%	4.9%
GammaPrime05	1.2	1.5	4.0%	3.0%
GammaPrime06	1.1	1.2	3.2%	3.1%
GammaPrime07	1.9	2.3	7.1%	7.3%

Analytical Precision Summary

	Within-Device Precision
	SD(ppb)	SD(ppb)	%CV	%CV
Bag ID	10 ppb	25 ppb	75 ppb	200 ppb
GammaPrime02	1.5	2.3	5.9%	6.8%
GammaPrime04	1.5	1.7	6.2%	6.2%
GammaPrime05	1.2	1.6	4.3%	3.4%
GammaPrime06	1.2	1.2	4.0%	4.5%
GammaPrime07	2.3	3.3	7.5%	8.5%

Linearity

Nitric oxide was mixed in a balance gas of simulated breath to obtain 8 NO concentration levels (5, 10, 15, 30, 50, 100, 150, 200 ppb). Samples were measured using a chemiluminescence device calibrated against a NIST traceable NO tank. Each concentration was tested in five replicates. Linearity was assessed across two devices. The linear regression of the device as compared to a reference measurement shall have a slope between 0.95 and 1.05 and 1.05 and 1.05 and 1.0 998.

	Linearity
Device	Slope	Intercept	R
GammaPrime42	1.03	2.32	0.999
GammaPrime49	1.02	0.231	0.999
Combined	1.02	1.27	0.998

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Limit of Detection

The limit of detection study was based on CLSI-EP17-A2. Two devices were tested at 0 ppb (60 replicates), 5 ppb (30 replicates) and 10 ppb (30 replicates) over three days. Using the parametric option in CLSI-EP17-A2, the Limit of Detection (LoD) was calculated. The results are shown below.

Device	Limit of Detection (ppb)	Spec Requirement (ppb)	Pass/Fail
Device #1	1.8	<10	Pass
Device #2	4.6	<10	Pass

I imit of Detection Study

Interference Testing- other gasses

Sensor interference levels were tested in a laboratory setting. The applicable concentration of each substance was generated, the gas stream was fed to the sensor by a gas mixing system, and the sensor signal was measured. In the cases were test concentrations were higher than the minimum test concentrations, the sensor signals were scaled appropriately. Test gases were flowed at 100 ccm, and were exposed to the sensors for 25 seconds. The target was that the change in response to the interference gases at specified minimum or higher concentrations shall be equal to or less than the response of 4 ppb NO.

Substance	Concentration Tested	Concentration Expected inExhaled Breath	Sensor Interference,Equivalent to ppb NO
Acetaldehyde	150 ppb	100 ppb	0.8 ppb
Acetone	5 ppm	10 ppb	3.7 ppb
Acetonitrile	150 ppb	100 ppb	120.8 ppb
Ammonia	1 ppm	0.5 ppb	1.9 ppb
Carbon Dioxide	8% vol	8% vol	2.6 ppb
Carbon Monoxide	50 ppm	50 ppm	1.5 ppb
Ethanol	165 ppm	165 ppm	-0.2 ppb
Hydrogen	50 ppm	50 ppm	0.5 ppb
Hydrogen Sulfide	5 ppm	1 ppm	-2.0 ppb
Isoprene	1.5 ppm	1 ppm	2.3 ppb
Hydrogen Peroxide	500 ppm, balance air	1 ppm	4.0 ppb
Oxygen	21%	16%	-1.4 ppb

There were no observed interferences causing a response larger than a 4 ppb NO equivalent response for any of the substances except acetomitrile is only present in exhaled breath when someone has recently smoked 1-2. The ATS recommends that FeNO testing not be performed after smoking, and Fenom Pro is labeled in this manner.

1 Analysis of exhaled breath from smokers and non-smokers by solid phase microextraction gas chromatography/mass spectrometry. Buszewski B, Ulanowska A, Ligor T, Denderz N, Amann A. Biomatogr. 2009 May23(5):51-6. doi: 10.1002/bmc.1141.

2 Quantification of acetonitrile in exhaled breath and urings selected ion flow tube mass spectrometry. Abbott S.M., Elder J.B., Spanel P., Smith D. International Journal of Mass Spectrometry, Vol. 228, Issues 2-3, 2003 August 15, Pages 655-665.

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Interference Testing- Exogenous Substances

A study was performed with seven commonly used oral substances (see below). A minimum of 10 volunteers per substance determined their baseline Fenom Pro levels, ingested or used the substance, and then repeated their Fenom Pro measurements 10 minutes and 60 minutes after the exposure. The 10-mintue data were for interest, only. For non-interference to be validated, the mean differences between 60 minutes and baseline values needed to be within 5 ppb. Further, the lower and upper 95% confidence intervals around the means needed to pass through zero.

#	Exogenous Compound
1	Alcohol Free Mouthwash
2	Caffeinated Soda
3	Caffeine Free Soda
4	Menthol Lozenge
5	Mouthwash with Alcohol
6	Non-Menthol Lozenge
7	Toothpaste

The data indicated that Fenom Pro was not impacted by any of the substances at 60 minutes.

Exposure	Testdescription	Meandifference	Meandifference<5ppb	Lower95%	Upper95%	95% CI includes zero
Alcohol FreeMouthwash	PRE	0.0
	60 Min	-0.8	PASS	-3.5	1.9	PASS
Caffeinated Soda	PRE	0.0
	60 Min	-3.0	PASS	-6.2	0.2	PASS
Caffeine Free Soda	PRE	0.0
	60 Min	-1.7	PASS	-6.9	3.5	PASS
Menthol Lozenge	PRE	0.0
	60 Min	0.9	PASS	-1.0	2.8	PASS
Mouthwash withAlcohol	PRE	0.0
	60 Min	-1.2	PASS	-7.4	5.0	PASS
Non-MentholLozenge	PRE	0.0
	60 Min	0.8	PASS	-1.9	3.5	PASS
Toothpaste	PRE	0.0
	60 Min	-1.8	PASS	-4.0	0.5	PASS

Summary Data Pre and Post Exogenous Exposure

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807.92 (b)(2): Brief Description of Clinical Data

In one study, the clinical precision, as it relates to user bias of Fenom Pro, was evaluated in a mixed study population of 127 subjects- including 44 pediatric subjects (ages 5-17 years) and 83 adults. Subjects were asked to obtain two Fenom Pro measurements with the assistance of three health care professionals (HCPs), for a total of six Fenom Pro evaluations per subject. Both subjects and HCPs completed ease-of-use questionnaires after the testing.

The objective of the evaluation was to confirm there is no user bias for Fenom Pro. The maximum mean bias observed was only 1.2 ppb between pairs of HCPs. Very high quantitative agreement was demonstrated between HCPs by Deming regression, correlation, and all bias analyses as shown in the table below.

	Slope	Y-Intercept	Pearson R
HCP 1 v HCP 2	0.9775	0.4455	0.9937
	95% CI: 0.9473 to 1.008	95% CI: -0.53 to 1.42	95% CI: 0.9910 to 0.9955
HCP 2 vs HCP 3	0.9815	0.6193	0.9945
	95% CI: 0.9467 to 1.0160	95% CI: -0.080 to 2.04	95% CI: 0.9923 to 0.9962
HCP 1 v HCP 3	0.9584	1.098	0.9873
	95% CI: 0.9169 to 0.9999	95% CI: -0.36 to 2.55	95% CI: 0.9819 to 0.9910

The within subject precision was also assessed from this study population and is presented below in three tables: the first for the whole study population (n=127), second the pediation (n=44), and third those aged =>18 (n=83).

Summary of Clinical Precision for FeNO measurements. Age group = ALL (n=127)

Median Concentrations	N	Within Subject Mean SD	95% CI for SD	Within Subject Mean CV (%)	95% CI for CV
0 to <10	0	-	-	-	-
10 to <20	13	2.19	1.57, 3.61	14.23%	10.21%, 23.49%
20 to <30	30	2.44	1.94, 3.28	10.11%	8.05%, 13.59%
30 to <40	29	2.71	2.15, 3.66	8.11%	6.44%, 10.97%
40 to <50	11	4.74	3.31, 8.31	10.98%	7.67%, 19.27%
>=50	44	5.57	4.60, 7.05	5.94%	4.91%, 7.52%

Median Concentrations	N	Within SubjectMean SD	95% CI for SD	Within SubjectMean CV (%)	95% CI for CV
0 to <10	0	-	-	-	-
10 to <20	6	2.51	1.57, 6.16	14.70%	9.18%, 36.06%
20 to <30	8	2.60	1.72, 5.29	10.84%	7.17%, 22.07%
30 to <40	6	2.55	1.59, 6.25	7.25%	4.52%, 17.77%
40 to <50	4	6.38	3.62, 23.78	13.89%	7.87%, 51.77%
>=50	20	5.74	4.36, 8.38	6.27%	4.77%, 9.16%

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Median Concentrations	N	Within SubjectMean SD	95% CI for SD	Within SubjectMean CV (%)	95% CI for CV
0 to <10	0	-	-	-	-
10 to <20	7	1.91	1.23, 4.21	13.83%	8.91%, 30.46%
20 to <30	22	2.38	1.83, 3.40	9.85%	7.57%, 14.07%
30 to <40	23	2.75	2.13, 3.89	8.34%	6.45%, 11.80%
40 to <50	7	3.80	2.45, 8.36	9.32%	6.00%, 20.52%
>=50	24	5.43	4.22, 7.61	5.66%	4.40%, 7.94%

							Summary of Clinical Precision for FeNO measurements. Age group >= 18yrs (n=83)
--	--	--	--	--	--	--	--------------------------------------------------------------------------------	--	--	--	--	--	--

HCPs and subjects generally indicated favorable responses for the features of the device via their questionnaires. For the subject group, favorable impressions of the system were recorded approximately 93% of time; for the HCP group, favorable impressions of the system were recorded approximately 96% of time.

Clinical Precision was also assessed from a study that closely embodies the clinical use condition, where each subject provided replicate (n = 2) FeNO measurements at Visit 1 (baseline) and Visit 2 (after approximately two weeks of high dose corticosteroid therapy). The data were analyzed by median FeNO scores within FeNO concentration subgroups across the reporting range for the device. The table below presents the whole study population (n=82), but data were also subgrouped by age range: 5 to 17 years (n=37), and ≥ 18 years (n=45). The clinical imprecision was less than 5ppb by mean standard deviation for FeNO values below 50ppb, and %CVs for FeNO values greater than 50ppb were maintained at less than 10%, unless the sample size was small, across all subgroups.

Age Group	Visit	Median Concentrations	N	Within SubjectMean SD	95% CI for SD	Within SubjectMean CV (%)	95% CI for CV
All	Visit 1 (Baseline)	0 to <10	0	-	-	-	-
		10 to <20	6	1.28	0.80, 3.14	7.09%	4.43%, 17.40%
		20 to <30	5	4.97	2.98, 14.30	20.78%	12.45%, 59.75%
		30 to <40	5	2.04	1.22, 5.86	5.76%	3.45%, 16.55%
		40 to <50	13	3.03	2.18, 5.01	6.76%	4.85%, 11.16%
		50 to <75	23	3.69	2.86, 5.23	6.23%	4.82%, 8.82%
		75 to <100	12	6.39	4.53, 10.85	7.35%	5.20%, 12.47%
		>=100	18	4.37	3.28, 6.54	3.09%	2.32%, 4.63%
	Visit 2	0 to <10	2	0.29	0.13, 9.38	3.48%	1.55%, 111.03%
		10 to <20	12	1.18	0.83, 2.00	7.71%	5.46%, 13.08%
		20 to <30	20	1.88	1.43, 2.75	7.48%	5.69%, 10.93%
		30 to <40	18	1.81	1.36, 2.71	5.23%	3.93%, 7.85%
		40 to <50	11	2.23	1.56, 3.92	5.21%	3.64%, 9.15%
		50 to <75	15	2.93	2.15, 4.63	4.87%	3.56%, 7.68%
		75 to <100	3	5.22	2.72, 32.79	6.40%	3.33%, 40.25%
		>=100	1	2.41		1.69%

Summary of Clinical Precision of FeNO Measurements by Visit

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Age Group	Visit	Median Concentrations	N	Within SubjectMean SD	95% CI for SD	Within SubjectMean CV (%)	95% CI for CV
5 to 17	Visit 1 (Baseline)	0 to <10	0
		10 to <20	2	0.27	0.12, 8.67	1.63%	0.73%, 51.98%
		20 to <30	4	5.54	3.14, 20.66	23.45%	13.29%, 87.40%
		30 to <40	2	2.82	1.26, 89.96	7.34%	3.27%, 234.17%
		40 to <50	5	4.52	2.71, 13.00	10.23%	6.13%, 29.42%
		50 to <75	11	4.13	2.88, 7.24	7.04%	4.92%, 12.36%
		75 to <100	3	16.31	8.49, 102.54	18.73%	9.75%, 117.75%
		>=100	10	4.57	3.14, 8.34	3.31%	2.28%, 6.05%
	Visit 2	0 to <10	1	0.20		2.78%
		10 to <20	7	1.33	0.86, 2.93	8.28%	5.33%, 18.23%
		20 to <30	11	1.48	1.04, 2.60	5.88%	4.11%, 10.32%
		30 to <40	7	1.43	0.92, 3.15	4.00%	2.58%, 8.81%
		40 to <50	1	1.59		3.19%
		50 to <75	8	2.83	1.87, 5.76	4.71%	3.12%, 9.59%
		75 to <100	1	3.50		3.97%
		>=100	1	2.41		1.69%
>=18	Visit 1 (Baseline)	0 to <10	0
		10 to <20	4	1.78	1.01, 6.65	9.83%	5.57%, 36.62%
		20 to <30	1	2.70		10.11%
		30 to <40	3	1.52	0.79, 9.54	4.70%	2.45%, 29.55%
		40 to <50	8	2.11	1.39, 4.29	4.59%	3.04%, 9.35%
		50 to <75	12	3.30	2.33, 5.59	5.49%	3.89%, 9.33%
		75 to <100	9	3.09	2.08, 5.91	3.55%	2.40%, 6.80%
		>=100	8	4.12	2.72, 8.38	2.80%	1.85%, 5.70%
	Visit 2	0 to <10	1	0.39		4.18%
		10 to <20	5	0.96	0.57, 2.75	6.91%	4.14%, 19.86%
		20 to <30	9	2.36	1.60, 4.53	9.44%	6.37%, 18.08%
		30 to <40	11	2.05	1.43, 3.60	6.02%	4.21%, 10.56%
		40 to <50	10	2.30	1.58, 4.19	5.42%	3.73%, 9.89%
		50 to <75	7	3.05	1.97, 6.73	5.05%	3.25%, 11.12%
		75 to <100	2	6.07	2.71, 193.82	7.62%	3.40%, 243.16%
		>=100	0

In a third study, Fenom Pro was evaluated to show clinical efficacy; the study was designed to demonstrate that the device can be used successfully to monitor changes in fractional exhaled nitric oxide in uncontrolled asthma patients when therapeutic agents are administered. Specifically, the intent was to show that there is a significant concordance between Fenom Pro and other established asthma-related outcome measures.

A total of 82 subjects (37 five to 17 years of age and 45 aged 18 and older) with uncontrolled asthma participated in a longitudinal study where measurements for FeNO, spirometry, and asthma questionnaires were completed at baseline (Visit 1) and two weeks later (Visit 2) after therapeutic agents were administered. The data demonstrated that significant differences between the two visits were achieved for all three modalities, and therefore concordance between Fenom Pro and the established asthma-related outcome measures.

The results of Passing-Bablok regressions are summarized in the table below for the key asthma condition assessments of FEV1 and ACQ/pACQ that show concordance. Note that two subject records did not have asthma symptom scores available thus study population for the correlations dropped to n=80.

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Parameter	FeNO vs. FEV1	FeNO vs. ACQ/pACQ
N in comparison	80	80
Slope point estimate	-0.0017	0.0089
Slope 95% CI	-0.0032 to 0.0000	0.0014 - 0.0148
Y-intercept point estimate	0.0956	-0.5018
Y-intercept 95% CI	0.0091 - 0.1250	-0.7432 to -0.1848
Kendall's Tau point estimate	-0.1599	0.1931
Kendall's Tau 95% CI	-0.3003 to -0.0126	0.0468 - 0.3312
Kendall's Tau p-value	0.0370	0.0125

807.92 (b)(3): Conclusions from Nonclinical and Clinical Data

The conclusions drawn from the analytical and clinical data demonstrate that the device is safe and effective for its intended use.

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.