SeptiCyte™ LAB is a gene expression assay using reverse transcription polymerase chain reaction to quantify the relative expression levels of host response genes isolated from whole blood collected in the PAXgene™ Blood RNA Tube. SeptiCyte™ LAB is used in conjunction with clinical assessments and other laboratory findings as an aid to differentiate infection-positive (sepsis) from infection-negative systemic in patients suspected of sepsis on their first day of ICU admission. The test generates a score (SeptiSCORE™) that falls within one of four discrete Interpretation Bands based on the increasing likelihood of infection-positive systemic inflammation. SeptiCyte™ LAB is in-vitro diagnostic use.

Device Description

SeptiCyte™ LAB is an in vitro diagnostic test to be used when prescribed by a clinician in professional settings such as central hospital laboratories. SeptiCyte™ LAB is a reverse transcription quantitative polymerase chain reaction (RT-gPCR)-based laboratory test that quantifies the relative expression levels of four host response genes (CEACAM4, LAMP1, PLA2G7, PLAC8) using RNA extracted from the whole blood of critically ill patients suspected of sepsis. It is a kit developed specifically for the Applied Biosystems® 7500 Fast Dx Real-Time PCR System. SeptiCyte™ LAB serves as an indicator of the host response to infection in systemically inflamed patients by measuring the expression of specific genes with roles in immune function, and infection. More specifically it aids in differentiating infection-positive systemic inflammation (IPSI) from infection-negative systemic inflammation (INSI).

SeptiCyte™ LAB measures the relative expression levels of the four genes by threshold cycle (Ct) in RT-qPCR. Ct values are linearly combined in a SeptiSCORE™ ranging from 0 to 10 by SeptiCyte™ Analysis software. The higher the SeptiSCORE™ value, the greater the likelihood of IPSI; the lower the SeptiSCORE™, the less likely the condition is caused by infection (INSI).

AI/ML Overview

The provided text describes the SeptiCyte™ LAB device, an in vitro diagnostic test for aiding in the differentiation of infection-positive (sepsis) from infection-negative systemic inflammation in patients suspected of sepsis.

Here's the breakdown of the acceptance criteria and study details:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly state "acceptance criteria" with specific numerical thresholds for performance metrics. Instead, it describes "Primary Endpoint" and "Secondary Endpoint" which the clinical study "met." I will use these endpoints as the de facto acceptance criteria.

Acceptance Criteria (Endpoint)	Reported Device Performance
Primary Endpoint: Demonstration that SeptiSCORE™ correlates with probability of sepsis across each SeptiSCORE™ Interpretation Band. Non-adjacent SeptiSCORE™ Interpretation Bands should display non-overlapping 80% confidence intervals (Cls) with respect to sepsis probability.	The clinical data exhibited a direct relationship between SeptiSCORE™ and the probability of sepsis across each SeptiSCORE™ Interpretation Band. Non-adjacent SeptiSCORE™ Interpretation Bands displayed non-overlapping 80% confidence intervals (Cls) with respect to sepsis probability. (The study met this endpoint.)
Secondary Endpoint: Demonstration that SeptiSCORE™ is a significant component of a logistic regression model of sepsis diagnosis, providing diagnostic clinical utility beyond that provided by combinations of other clinical variables and laboratory assessments.	The SeptiSCORE™ was always a significant component of the logistic regression models built to classify infection-positive (sepsis) and infection-negative (SIRS/INSI) patients, regardless of whether PCT was available as a variable. SeptiSCORE™ was also the top-ranked variable in all sepsis diagnosis backward-elimination models. (The study met this endpoint.)

2. Sample size used for the test set and the data provenance

Sample Size: 447 adult patients
Data Provenance: Observational, prospective clinical trials conducted across eight clinical sites in the US and Europe.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts

Number of Experts: Three medical experts.
Qualifications of Experts: Assumed to be medical professionals with expertise in critically ill patients and sepsis diagnosis, as they were referred to as an "RPD panel" and "medical experts" providing "independent clinical case review." Specific experience duration (e.g., "10 years experience") is not provided.

4. Adjudication method for the test set

The adjudication method involved a "majority opinion of three medical experts."

Consensus RPD: Subjects were stratified by diagnosis (SIRS, Sepsis, or Indeterminate) according to the majority opinion. Indeterminate cases (n=37) were excluded from the analysis.
Forced RPD: Subjects were stratified by diagnosis (SIRS or Sepsis) according to the majority opinion, with no Indeterminate category allowed, forcing all patients into either SIRS or sepsis categories.

This closely resembles a 3+1 or simply majority consensus method, where at least two out of three experts had to agree for a definitive diagnosis.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, a multi-reader multi-case (MRMC) comparative effectiveness study focusing on human readers' improvement with AI assistance was not done. The study evaluated the standalone performance of the SeptiCyte™ LAB device in relation to a retrospective physician diagnosis, and its contribution to logistic regression models alongside other clinical variables. There is no mention of human readers interpreting images or data with and without AI assistance.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, the primary and secondary endpoints evaluate the performance of the SeptiSCORE™ (generated by the device's algorithm) as a standalone diagnostic aid. The SeptiSCORE™ was compared against a ground truth established by medical experts (RPD). The logistic regression models also assessed the SeptiSCORE's contribution amongst other variables, indicating its standalone diagnostic utility.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth used was expert consensus (Retrospective Physician Diagnosis or RPD), established by a panel of three medical experts. This diagnosis was made after the patient was discharged from the hospital and after all clinical information was available at discharge, and the experts were blinded to the SeptiCyte™ LAB test results.

8. The sample size for the training set

The document does not specify the sample size for a training set. The clinical study described involved 447 patients, which served as the evaluation (test) set for the device's performance. Information about a separate training set used to develop the SeptiSCORE™ algorithm is not provided in this document.

9. How the ground truth for the training set was established

Since the document does not mention a specific training set or its sample size, it does not describe how ground truth for a training set was established.

Summary

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Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

IMMUNEXPRESS, INC. VICTORIA ROTHWELL REGUALTORY AND SCIENTIFIC SPECIALIST 425 PONTIUS AVE. NORTH SEATTLE WA 98109

April 6, 2017

Re: K163260 Trade/Device Name: SeptiCyte™ LAB Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis. Regulatory Class: II Product Code: PRE Dated: November 17, 2016 Received: November 21, 2016

Dear Dr. Rothwell.

This letter corrects our substantially equivalent letter of February 17, 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

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comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. 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.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely,

Uwe Scherf -S

Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiology 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) K163260

Device Name SeptiCyte™ LAB

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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the signature diagnostics for sepsis

510(k) Summary - SeptiCyte™ LAB

1. OWNER:

Immunexpress, Inc. 425 Pontius Ave. North Seattle, WA 98109 Telephone: 206-858-6436

Contact Person: Victoria Rothwell, Ph.D. Email: victoria.r@Immunexpress.com Telephone: 206-858-6436

February 16, 2017

2. DEVICE

Name of Device: SeptiCyte™ LAB Common or Usual Name: Infection Biomarker Classification Name: Non-microbial human analyte(s) which are meant to aid in the assessment of patients with suspected sepsis (21 CFR 866.3215). Regulatory Class: II

3. PREDICATE DEVICE

B.R.A.H.M.S.PCT sensitive KRYPTOR® (DEN150009)

4. DEVICE DESCRIPTION

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patients by measuring the expression of specific genes with roles in immune function, and infection. More specifically it aids in differentiating infection-positive systemic inflammation (IPSI) from infection-negative systemic inflammation (INSI).

Description	Volume(12 Determinations)	Storage Temperature
SeptiCyte™ LAB ReagentsKit Box 1 of 2
Diluent	1000 μL	-15 to -30 °C
RT Buffer	250 μL	-15 to -30 °C
RT Enzyme Mix	115 μL	-15 to -30 °C
qPCR Buffer	1500 μL	-15 to -30 °C
Primer/Probe Mix A	3 x75 μL	-15 to -30 °C
Primer/Probe Mix B	3 x 75 μL	-15 to -30 °C
qPCR Enzyme Mix	85 μL	-15 to -30 °C
SeptiCyte™ Lab Control SetKit Box 2 of 2
High Positive Control	3 x 55 μL	-15 to -30 °C
Low Positive Control	3 x 55 μL	-15 to -30 °C
Negative Control	3 x 55 μL	-15 to -30 °C

Contents of SeptiCyte™ LAB Test Kits

Performing SeptiCyte™ LAB includes:

a) Isolation of total (unfractionated) RNA from whole blood collected from peripheral venous blood (using PAXgene™ Blood RNA System, K042613, manual or QlAcube® automated procedure)
b) Reverse transcription of RNA to cDNA
c) Amplification of specific regions of cDNAs corresponding to CEACAM4, LAMP1, PLA2G7, PLAC8 mRNAs, with acquisition of real time gene expression detected by fluorescent quantification using Applied Biosystems® 7500 Fast Dx Real-Time PCR Instrument (K082562), and
d) Incorporation of information from the raw RT-qPCR gene expression data into the calculation of a single numerical SeptiSCORE™ by the SeptiCyte™ Analysis software.

All steps within the SeptiCyte™ LAB protocol are performed in a 96-well plate based assay format according to the Instructions for Use. Each SeptiCyte™ LAB kit includes reagents sufficient for up to 12 patient samples. Up to three patient samples can be run together on the same plate.

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Components including master-mixes and individual reagents (i.e., oligonucleotide primers, probe sets, reverse transcriptase (RT), random hexamers, polymerase, and controls) are added to the assay according to the Instructions for Use.

5. INDICATIONS FOR USE

SeptiCyte™ LAB is a gene expression assay using RT-qPCR to quantify relative expression levels of four host response genes isolated from whole blood collected in the PAXgene™ Blood RNA Tube. SeptiCyte™ LAB is used in conjunction with clinical assessments and other laboratory findings as an aid to differentiate infection-positive (sepsis) from infection-negative systemic inflammation in patients suspected of sepsis on their first day of ICU admission. The test generates a score (SeptiSCORE™) that falls within one of four discrete Interpretation Bands based on the increasing likelihood of infection-positive systemic inflammation. SeptiCyte™ LAB is intended for invitro diagnostic use.

SeptiCyte™ LAB is a test for non-microbial human analyte(s) with the general purpose of aiding in the assessment of critically ill patients suspected of sepsic. SeptiCyte™ LAB is intended for prescription use, to be performed only by a trained professional, and used in conjunction with clinical assessments and other laboratory findings to aid in managing patients with, and suspected of, sepsis.

The BRAHMS PCT Sensitive KRYPTOR® predicate device aids in the risk assessment of progression from severe sepsis to septic shock. In addition, PCT aids in the prediction of 28-dav mortality in sepsis patients. Unlike PCT, SeptiCyte™ LAB does not aid in risk assessment or prediction, but aids in differentiating infection-positive (sepsis) from infection-negative systemic inflammation in patients suspected of sepsis on their first day of ICU admission.

6. COMPARISON OF TECHNOLOGICAL CHARACTERISTICS WITH THE PREDICATE DEVICE

The predicate device B.R.A.H.M.S PCT Sensitive KRYPTOR® is a homogeneous sandwich immunoassay for detection and quantitation of the circulating protein Procalcitonin (PCT) in human serum or plasma. The measuring principle is based on Time-Resolved Amplified Cryptate Emission (TRACE®) technology, which measures the signal emitted from an immuno-complex with time delay. SeptiCvte™ LAB is a whole blood quantitative gene expression assay for four genes (CEACAM4, LAMP1, PLA2G7, PLAC8) with roles in immune function, inflammation, and infection. The assay is based on real-time generation of fluorescence from hydrolysis of dye-quencher hydrolysis probes during cycles of PCR amplification of nucleic acid templates using the Applied Biosystems® 7500 Fast Dx Real-Time PCR System (Applied Biosystems®, Foster City, CA, catalogue number 440685; K082562). Relative expression levels of the four genes, as represented by Ct values in RT-qPCR, are processed by an algorithm and a SeptiSCORE™ ranging from 1 to 10 is generated as the report output.

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7. PERFORMANCE DATA

A. Bench Studies

Precision and Reproducibility:

Intermediate Precision was assessed at Ct level. The standard deviation (SD) was < 1.3 cycles and the coefficient of variation (CV) < 7%. SD for SeptiSCORE™ was ≤ 0.37 score units, and the CV ≤ 10%. Ct reproducibility was SD < 1.4 cycles and CV < 8%. SD for SeptiSCORE™ was ≤ 0.5 score units, and the CV ≤ 10%. Limits of Detection and Quantitation for SeptiCyte™ LAB were 0.27 X 100 WBC/mL blood. Patients with a White Blood Cell (WBC) concentration below this limit should not be evaluated with SeptiCyte™ LAB. The linear response range of SeptiCyte™ LAB is 20 ng to 500 ng of RNA input per RT reaction. RNA samples above this range should be diluted, and below this range not evaluated with SeptiCyte™ LAB.

Interfering Substances:

Based on the CLSI Guidance EP07-A2, "Interference Testing in Clinical Chemistry", SeptiCyte™ LAB was evaluated in the presence of potentially interfering substances. No interference was found for any of the substances in the following table, at the listed concentrations.

Interferent	Concentration in PAXgene™ Blood RNA Tube(pre- RNA extraction)
Rheumatoid Factor	45 IU/mL
Heparin	3000 U/L
Imipenem	1.18 mg/mL
Bilirubin	20 mg/dL
Triglycerides	500 mg/dL
Vancomycin	69 µmol/L
Cefotaxime	673 µmol/L
Dopamine	5.87 µmol/L
C-reactive Protein	4 mg/dL
Noradrenaline or Norepinephrine	700 pg/mL
Dobutamine	11.2 µg/mL
Hemoglobin	20 g/dL
Albumin	5 g/dL
Furosemide	181 µmol/L
Soluble CD14	5 µg/mL
IL-6	15 pg/mL
Lipopolysaccharide Binding Protein	45 µg/mL

Interference Testing Levels:

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Additional Potential Sources of Interference:

A signal is generated for PLAC8 in the presence of genomic DNA and absence of reverse transcriptase enzyme. The PLAC8 signal from genomic DNA should not be detected when using SeptiCyte™ LAB following the recommended assay procedure.

B. Software Verification and Validation Testing:

Software verification and validation testing were conducted and documented as recommended by the FDA Guidance for Industry and FDA Staff, "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices." - Verification and validation testing was performed as recommended for "moderate" level of concern. Software risks have been mitigated to an acceptable level.

C. Clinical Study:

Clinical performance was evaluated in observational, prospective clinical trials conducted across eight clinical sites in the US and Europe. The evaluation recruited 447 adult patients admitted to the ICU with two or more signs of systemic inflammation (≥ 2 SIRS criteria). The SeptiSCORE™ was compared to a non-reference method (termed Retrospective Physician Diagnosis or RPD) based on independent clinical case review by a panel of three medical experts after the patient was discharged from the hospital and other information available at discharge. The medical experts remained blinded to SeptiCyte™ LAB test results. The medical experts based their diagnosis on data and had no direct contact with patients.

Two Diagnostic Methods were followed:

1. Consensus RPD: Subiects were stratified by diagnosis SIRS. Sepsis or Indeterminate according to the majority opinion of three medical experts (RPD panel). Indeterminate cases (n=37) were those for which a definitive diagnosis could not be reached by expert review and were not included in the analysis.
1. Forced RPD: Subjects were stratified by diagnosis SIRS or sepsis according to the majority opinion of three expert reviewers. The Indeterminate category was not allowed, so all patients were forced into either the SIRS or sepsis categories, with no exclusions.

The clinical study met both the Primary and Secondary Endpoints, using either the Consensus or the Forced RPD method.

Primary Endpoint: Demonstration that SeptiSCORE™ correlates with probability of sepsis:

The clinical data exhibited a direct relationship between SeptiSCORE™ and the probability of sepsis across each SeptiSCORE™ Interpretation Band. Non-adjacent SeptiSCORE™ Interpretation Bands displayed non-overlapping 80% confidence intervals (Cls) with respect to sepsis probability.

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Secondary Endpoint: Demonstration that SeptiSCORE™ is a significant component of a logistic regression model of sepsis diagnosis:

The SeptiSCORE™ was evaluated to determine if it provides diagnostic clinical utility beyond that provided by combinations of other clinical variables and laboratory assessments available within the first ~24 hours of the suspicion of sepsis in a patient with ≥ 2 SIRS criteria.

Models were constructed including or excluding PCT using a backwards-elimination variable selection procedure combined with a logistic regression rule. The backwards-elimination was used to determine which clinical variables best discriminate IPSI (sepsis) from INSI (SIRS). Area Under Receiver Operating Characteristic Curve (AUC) was used as the metric for assessing model performance for each analysis. Regardless of whether PCT was available as a variable, the SeptiSCORE™ was always a significant component of the logistic regression models built to classify IPSI (sepsis) and INSI (SIRS) patients. SeptiSCORE™ was also the top-ranked variable in all sepsis diagnosis backward-elimination models indicating it contained the most clinical value irrespective of what other clinical variables were used during modeling.

No adverse events were reported during the Clinical Study.

8. CONCLUSIONS

Based on the nonclinical and clinical testing, SeptiCyte™ LAB is substantially equivalent to the predicate device B·R·A·H·M·S PCT sensitive KRYPTOR® (DEN150009) detect non-microbial human analyte(s) to aid in the assessment of suspected sepsis patients.

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Regulation Number and Section

§ 866.3215 Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis.

(a)
Identification. A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended.
(2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection.
(3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability.
(4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information:
(i) Results must demonstrate adequate device performance relative to a well-accepted comparator.
(ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population.
(iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses.
(5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (
e.g., age, racial, ethnic, and gender distribution) similar to the Intended Use population.(6) As part of the risk management activities performed under 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.
(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples (
e.g., collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.