The LIAISON® B.R.A.H.M.S PCT® II GEN assay uses chemiluminescence immunoassay (CLIA) technology for the in vitro quantitative determination of Procalcitonin in human serum and lithium heparin plasma specimens. Used in conjunction with other laboratory findings and clinical assessments, LIAISON® B.R.A.H.M.S.PCT® II GEN is intended for use as follows:

to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
to aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time,
to aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRT) defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department,
to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The LIAISON® Control B.R.A.H.M.S PCT® II GEN (level 1 and level 2) are intended for use as assayed quality control samples to monitor the performance and reliability of the LIAISON® BRAHMS PCT® II GEN assay. The performance characteristics of LIAISON® BRAHMS PCT® II GEN controls have not been established with any other assay or instrument platform different from the LIAISON® Analyzer.

The LIAISON® B.R.A.H.M.S PCT® II GEN Verifiers (four levels) are assayed quality control materials intended in the quantitative verification of calibration and reportable range of the LIAISON® BRAHMS PCT® II GEN assay. The performance characteristics of LIAISON® BRAHMS PCT® II GEN calibration verifiers have not been established in connection with any other assay or instrument platforms different from the LIAISON® Analyzer.

Device Description

The method for the quantitative determination of PCT is a sandwich chemiluminescence immunoassav. A specific monoclonal antibody is coated on the magnetic particles (solid phase); another monoclonal antibody (specific for a different epitope of the procalcitonin molecule) is linked to an isoluminol derivative (isoluminol-antibody conjugate).

During the first incubation, PCT present in calibrators, samples or controls binds to the antibody conjugate. Then the solid phase is added to the reaction. A sandwich is formed only in the presence of PCT molecules that bridge both antibodies. After the second incubation, the unbound material is removed with a wash cycle.

Subsequently, the starter reagents are added and a flash chemiluminescence reaction is thus induced. The light signal, and hence the amount of isoluminolantibody conjugate, is measured by a photomultiplier as relative light units (RLU) and is indicative of PCT concentration present in calibrators, samples or controls.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study details for the LIAISON® BRAHMS PCT® II GEN assay, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Specific Metric (Criteria not explicitly stated as numerical targets, but implied by methodology and comparison to predicate)	Reported Device Performance
Analytical Performance	Limit of Blank (LoB)	0.01 ng/mL
	Limit of Detection (LoD)	0.02 ng/mL
	Limit of Quantitation (LoQ) (Bias < 5%, CV < 15%, Total Error < 30%)	0.05 ng/mL (at 0.05 ng/mL: CV% 14.0%, Bias% 2.7%, Total Error% 25.8%)
	Total Error (at various PCT levels)	0.05 ng/mL: 25.8%; 0.10 ng/mL: 25.1%; 0.25 ng/mL: 22.9%; 0.50 ng/mL: 19.9%; 2.0 ng/mL: 15.3%
Method Comparison	Quantitative Agreement (vs. predicate device, Deming Regression: y = 1.07x + 0.03 range)	Slope 1.07 (95% CI: 1.03 to 1.11), Intercept 0.03 ng/mL (95% CI: 0.02 to 0.05 ng/mL)
	Bias at Decision Points (0.5 ng/mL and 2.0 ng/mL)	0.5 ng/mL: 0.06481 (13%); 2.0 ng/mL: 0.16588 (8%)
	Qualitative Agreement at Clinical Decision Points (agreement table against predicate)	Presented in Table 6, showing high agreement across various cut-off points. For example, for ≤0.10 ng/mL, 108/125 samples agreed, and for ≥2.0 ng/mL, 100/100 samples agreed.
Precision	Internal 20-day Precision (CV% for kit controls, verifiers, and patient samples)	Kit Control 1 Total CV%: 6.5%; Kit Control 2 Total CV%: 6.1%; CV A: 8.7%; CV B: 7.0%; CV C: 5.5%; CV D: 6.2%; Patient samples (P001-P010) Total CV% ranged from 5.5% to 17.1%.
	Multi-Site Precision (Total CV% for kit controls, verifiers, and patient samples)	Kit Control 1 (Lot 1) Total CV%: 7.1%; Kit Control 2 (Lot 1) Total CV%: 7.7%; Kit Control 1 (Lot 2) Total CV%: 7.3%; Kit Control 2 (Lot 2) Total CV%: 5.9%; CV A (Lot 1): 8.6%; CV B (Lot 1): 8.1%; CV C (Lot 1): 7.0%; CV D (Lot 1): 4.9%; CV A (Lot 2): 9.1%; CV B (Lot 2): 5.7%; CV C (Lot 2): 8.8%; CV D (Lot 2): 5.2%; Patient samples (P001-P010) Total CV% ranged from 4.8% to 16.8%.
Stability	Reagent Stability (Calibration Curve, On-board Analyzer, Refrigerator, Freeze/Thaw)	Calibration Curve: 8 weeks; Open Use On-board: 12 weeks; Open Use Refrigerator: 12 weeks; Calibrator Freeze/Thaw: 3 cycles
	Control Stability (Open Use -20°C, Freeze/Thaw, Diluent 2-8°C)	Open Use -20°C: 8 weeks; Control Freeze/Thaw: 7 cycles; Diluent 2-8°C: 3 months
	Verifier Stability (Open Use -20°C, Freeze/Thaw)	Open Use -20°C: 8 weeks; Cal Verifier Freeze/Thaw: 7 cycles
	Sample Stability (Room Temp, Refrigerated, Frozen, Freeze/Thaw)	Room Temp (20-25°C): 24 hours; Refrigerated (2-8°C): 24 hours; Frozen (-20°C): 3 months; Freeze/Thaw Cycles: 5 cycles
Sample Equivalence	Serum and Lithium Heparin Plasma Equivalence (Passing & Bablok, Weighted Deming regression)	Passing & Bablok: Slope 1.019 (95% CI: 1.012-1.031), Intercept 0.003 (95% CI: -0.003-0.006); Weighted Deming: Slope 0.9998 (95% CI: 0.9712-1.028), Intercept 0.005 (95% CI: 0.0015-0.0079). Conclusion: Serum and Lithium Heparin Plasma are acceptable.

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

Quantitative Analysis/Method Comparison: 369 samples (349 serum samples and 20 lithium heparin plasma samples).
- 104 samples were excluded because they read <0.05 ng/mL (below reading range).
- 1 sample was excluded because it read >100 ng/mL.
- The origin of these samples (e.g., country) and whether they were retrospective or prospective is not explicitly stated in the provided text.
Precision (Internal 20-day): 10 frozen serum panel samples, 2 levels of kit controls, and 4 levels of verifiers.
- The origin of the serum samples is not explicitly stated, but they were prepared by DiaSorin S.p.A.
Precision (Multi-Site): 10 frozen serum panel samples, 2 lots of kit controls (2 levels each), and 2 lots of verifiers (4 levels each).
- The origin of the serum samples is not explicitly stated, but they were prepared by DiaSorin S.p.A.
Sample Equivalence: 40 matched patient samples (serum and lithium heparin collection tubes). These were "spiked or diluted" to span the assay range.
- The origin of these samples is not explicitly stated.

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

This device is an in vitro diagnostic (IVD) assay that measures a specific analyte (Procalcitonin) quantitatively. For such devices, "ground truth" is typically established by comparing the device's measurements against a recognized reference method or by using samples with known, carefully characterized concentrations of the analyte.

The document states:

Method Comparison: "A quantitative method comparison study was performed... following CLSI EP09-A2." This implies comparison against a predicate device (VIDAS® B-R-A-H·M·S PCT™ (K162827)), which serves as the reference method.
Analytical Performance (LoB, LoD, LoQ): "Following the method from CLSI EP17-A2." This refers to standard statistical methods for determining these analytical characteristics, not expert consensus on individual case diagnoses.
Precision: Standard statistical methods for assessing reproducibility.

Therefore, for this type of device, the "ground truth" is established by:

Reference measurement methods: The predicate device itself acts as the comparative reference.
Analytical standards/spiked samples: For LoB, LoD, LoQ, and precision, samples with known or precisely defined analyte concentrations (e.g., purified calibrators, spiked samples, control materials) are used.

Thus, this document does not indicate the use of human "experts" to establish a diagnostic ground truth for individual cases in the way one might for an imaging AI device (e.g., radiologists reviewing images). The ground truth here is analytical and comparative to a well-established predicate.

4. Adjudication Method for the Test Set

Not applicable in the context of an IVD assay measuring an analyte. The comparative method is against an established reference method (the predicate device) or analytical standards, not through human adjudication of diagnostic interpretations.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

No, an MRMC study was not done. This is an in vitro diagnostic device, not an imaging AI device that would assist human readers in interpretation. Its performance is measured analytically and comparatively against a predicate device.

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

Yes, the studies presented are all standalone. The LIAISON® BRAHMS PCT® II GEN assay is an automated chemiluminescence immunoassay device. The results presented (LoB, LoD, LoQ, method comparison, precision, stability) reflect the direct output of the assay system without human interpretation or intervention in the measurement process itself. The indication for use states it is "Used in conjunction with other laboratory findings and clinical assessments," implying that clinicians will interpret the results, but the performance data presented is for the device operating independently.

7. The Type of Ground Truth Used

The ground truth used in the studies is primarily:

Reference Method Comparison: The measurements obtained from the FDA-cleared predicate device (VIDAS® B-R-A-H·M·S PCT™) for the method comparison studies.
Known Concentrations/Analytical Standards: For LoB, LoD, LoQ, accuracy, and precision, samples with known, manufactured, or precisely characterized concentrations of Procalcitonin (e.g., calibrators, controls, characterized panel samples) are used.

It is not pathology, outcomes data, or expert diagnostic consensus on patient cases for the performance studies presented here.

8. The Sample Size for the Training Set

The provided document describes performance verification studies for a medical device (an IVD assay). It does not pertain to an AI/Machine Learning device that undergoes "training." Therefore, there is no training set in the context of AI models. The device operates based on established chemical and immunological principles, not learned patterns from data.

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

As there is no training set for this type of device, this question is not applicable.

Summary

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

February 27, 2018

DiaSorin Inc. Carol A DePouw Regulatory Affairs Specialist 1951 Northwestern Ave. Stillwater, MN 55082-0285 US

Re: K173683

Trade/Device Name: LIAISON BRAHMS PCT II GEN assay, LIAISON Control BRAHMS PCT II GEN and LIAISON BRAHMS PCT II GEN Verifiers 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: PMT, NTM, JJX Dated: November 30, 2017 Received: December 1, 2017

Dear Ms. DePouw:

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 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

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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/Resourcesfor You/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.

Sincerely yours,

Steven R. Gitterman -S for

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)

Device Name

LIAISON® B.R.A.H.M.S PCT® II Gen LIAISON® Control B.R.A.H.M.S PCT® II Gen LIAISON® B.R.A.H.M.S PCT® II Gen Verifiers

Indications for Use (Describe)

to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
to aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time,
to aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRT) defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department,
to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

Type of Use (Select one or both, as applicable)

☑ Prescription Use (Part 21 CFR 801 Subpart D)
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☐ Over-The-Counter Use (21 CFR 801 Subpart C)
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CONTINUE ON A SEPARATE PAGE IF NEEDED.

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5.0 510(k) SUMMARY

SUBMITTED BY:	Carol A. DePouwRegulatory Affairs SpecialistDiaSorin Inc.1951 Northwestern AvenueStillwater, MN 55082-0285Phone (651) 351-5850Fax (651) 351-5669Email: carol.depouw@diasorin.com
NAME OF DEVICE:
Trade Name:	LIAISON® BRAHMS PCT® II GEN,LIAISON® Control BRAHMS PCT® II GENLIAISON® BRAHMS PCT® II GEN Verifiers
Common Names/Descriptions:	Procalcitonin Assay
Classification Names:	Device to detect and measure non microbialanalyte(s) in human clinical specimens to aid inassessment of patients with suspected sepsis21 CFR 866.3215 (PMT)Procalcitonin Assay 21 CFR 866.3215(PRI)
Product Code:	PRI, PMT, NTM, JJX
PREDICATE DEVICES:	VIDAS® B-R-A-H·M·S PCT™ (K162827)

DEVICE DESCRIPTION:

INTENDED USE:

LIAISON® BRAHMS PCT® II GEN assay uses chemiluminescence immunoassay (CLIA) technology for the in vitro quantitative determination of Procalcitonin in human serum and lithium heparin plasma specimens. Used in conjunction with other laboratory findings and clinical assessments, LIAISON® BRAHMS PCT® II GEN is intended for use as follows:

to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
to aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.
to aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department,

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to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The LIAISON® Control BRAHMS PCT® (level 1 and level 2) are intended for use as assayed quality control samples to monitor the performance and reliability of the LIAISON® BRAHMS PCT® II GEN assay. The performance characteristics of LIAISON® BRAHMS PCT® II GEN controls have not been established with any other assay or instrument platform different from the LIAISON® Analyzer.

The LIAISON® BRAHMS PCT® II GEN calibration verifiers (four levels) are assayed quality control materials intended in the quantitative verification of calibration and reportable range of the LIAISON® BRAHMS PCT® II GEN assay. The performance characteristics of LIAISON® BRAHMS PCT® II GEN calibration verifiers have not been established in connection with any other assay or instrument platforms different from the LIAISON® Analyzer.

KIT DESCRIPTION:

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Sample Matrix	Serum and Lithium Heparin	Serum and Lithium Heparin
Calibrators	Two	Two
Controls	Two (Low and High)	Two (Low and High)
Reagent Storage	2-8°C, Refrigerator	2-8°C onboard or in Refrigerator

Table 2:	Table of Differences
Characteristic	Predicate Device:VIDAS® BRAHMS PCT™(K162827)	Candidate Device:LIAISON® BRAHMS PCT® II GEN(K173683)
Type of Assay	Enzyme Immunoassay	Chemiluminescent Immunoassay
Detection	ELFA - Enzyme-LinkedFluorescent Assay	CLIA - ChemiluminescenceImmunoassay
SampleHandling/processing	Manual	Automated
Detector	Alkaline phosphatase-labeledmouse monoclonal anti-humanprocalcitonin immunoglobulins	Anti-calcitonin antibody, labelledwith isoluminol, monoclonal(mouse)
Capture Reagent	Microwells coated with mousemonoclonal anti-humanprocalcitonin immunoglobulins	Magnetic particles coated withanti-katacalcin antibody,monoclonal (mouse)
Sample Volume	200 µL	225 µL specimen(75 µL specimen + 150 µL deadvolume)
MeasurementSystem	Spectrophotometer(EIA Microtiter plate reader)	Photomultiplier(flash chemiluminescence reader)
Total incubation	20 minutes	40 minutes

Table 3: Control Similarities and Differences
Characteristics	Predicate Device:VIDAS® BRAHMS(K162827)	Candidate Device:LIAISON® Controls BRAHMSPCT® II GEN (K173683)
Intended Use	Intended for use as assayed quality control samples to monitor the performance of the LIAISON® BRAHMS PCT II GEN assay	Same
Matrix	Recombinant human PCT	Recombinant Antigen Procalcitonin
Storage	2-8°C	Same
Quantity andVolume	2 x 2 mL (lyophilized)	2 x 1.1 mL (lyophilized)

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Table 4: Calibration Verifiers Similarities and Differences
Characteristic	Predicate Device(K141463) - LIAISON® XL1,25 Dihydroxyvitamin DCalibration Verifiers	Candidate DeviceLIAISON® BRAHMS PCT®II GEN Verifiers (K173683)
Intended Use	Assayed quality control materialsintended for the quantitativeverification of calibration andreportable range of the LIAISON®XL 1,25 Dihydroxyvitamin D	Assayed quality controlmaterials intended in thequantitative verification ofcalibration and reportablerange of the LIAISON®BRAHMS PCT® II GEN assay.
Product Storage	2 to 8°C until ready to use	Same
Levels	4 levels; lyophilized	Same
Volume	2.0 mLs	1.1 mLs

PERFORMANCE DATA:

Limit of Blank (LoB)*

Following the method from CLSI EP17-A2, the limit of blank for the LIAISON® BRAHMS PCT® II GEN assay is 0.01 ng/mL.

*Limit of Blank, or the highest value likely to be observed with a sample containing no analyte, replaces the term "analytical sensitivity".

Limit of Detection (LoD)

Following the method from CLSI EP17-A2, the limit of detection for the LIAISON® BRAHMS PCT® II GEN assay is 0.02 ng/mL.

Limit of Quantification (LoQ)

Following the method from CLSI EP17-A2, the limit of quantitation for the LIAISON® BRAHMS PCT® II GEN assay is 0.05 ng/mL ( %Bias < 5%, %CV < 15% and %Total error <30%).

A modeling analysis was conducted to evaluate the LOQ and each medical decision point. The Total Error (TE) % was calculated as 1.65*(CV%) + (Bias%). The results from each of three regression (Bias, CV and TE%) are summarized in the table below and were based on fitting the Bias, CV and TE% from 320 data points for each medical decision point (0.10, 0.25, 0.50 and 2 ng/mL) generated from Precision studies and from 60 data points around 0.05 ng/mL (ranging from 0.036 to 0.069 ng/mL) generated from LOQ study.

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DiaSorin LIAISON® BRAHMS PCT® II GEN Premarket Notification

PCT level(ng/mL)	CV%	Bias%	TotalError%
0.05	14.0%	2.7%	25.8%
0.10	15.0%	0.3%	25.1%
0.25	13.0%	1.4%	22.9%
0.50	10.3%	3.0%	19.9%
2.0	6.8%	4.0%	15.3%

LOQ and Medical Decision Point

COMPARATIVE STUDIES/METHOD COMPARISON:

Quantitative Analysis Study Design

A quantitative method comparison study was performed on 349 serum samples and 20 lithium heparin plasma samples for a total of 369 samples following CLSI EP09-A2.

Of the 369 samples, one hundred four (104) samples were not included in the analysis because they read <0.05 ng/mL which is below the reading range of either or both assays and one (1) sample read > 100 ng/mL on the LIAISON® BRAHMS PCT® II GEN assay and therefore was also removed from the analysis.

The PCT sample results ranged from 0.05 ng/mL to 131 ng/mL.

Weighted Deming analysis was applied to the results across the range of the LIAISON® BRAHMS PCT® II GEN assay yielding agreement of y = 1.07x + 0.03. The 95% confidence intervals for the slope were 1.03 to 1.11 and the 95% confidence intervals for the intercept 0.02 to 0.05 ng/mL.

Table 5: Bias calculated at two medical decision points 0.50 and 2.0 ng mL with 95% Cl

Decision level	Bias	95% CI	Bias Calculation
0.5	0.06481	0.05021 to 0.07941	13%
2	0.16588	0.09894 to 0.23283	8%

Qualitative Analysis Study Design - Agreement at Clinical Decision Points

A qualitative method comparison study was also performed on the 369 samples. Results for the LIAISON® BRAHMS PCT® II GEN assay are provided in an agreement table and confidence intervals for each level within a comparison table for the following cut-offs:

a.) ≤ 0.10;	b.) > 0.10 and ≤ 0.25;	c.) > 0.25 and < 0.5;	d.) ≥ 0.5 and < 2.0;	e.) ≥ 2.0;
-------------	------------------------	-----------------------	----------------------	------------

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	Reference Method
LIAISON® BRAHMSPCT® II GEN	≤0.10 ng/mL	>0.10 and ≤ 0.25 ng/mL	>0.25 and < 0.50 ng/mL	≥0.50 and < 2.0 ng/mL	≥2.0 ng/mL	TOTAL
≤0.10 ng/mL	108	2	0	0	0	110
>0.10 and ≤ 0.25 ng/mL	17	31	3	0	0	51
>0.25 and < 0.50 ng/mL	0	15	27	1	0	43
≥0.50 and < 2.0 ng/mL	0	2	10	50	0	62
≥2.0 ng/mL	0	0	0	3	100	103
TOTAL	125	50	40	54	100	369

Table 6: Qualitative Agreement at Clinical Decision points

REPRODUCIBILITY/PRECISION:

Internal 20-day Precision

A twenty day reproducibility/precision study was performed internally at DiaSorin Inc.

A coded panel comprised of 10 frozen serum samples spanning the assay range was prepared by DiaSorin S.p.A. One lot of LIAISON® Control BRAHMS PCT® II GEN (2 levels) and one lot of LIAISON® BRAHMS PCT® II GEN verifiers (4 levels) were also tested in the study. The CLSI document EP05-A3 was consulted in the preparation of the testing protocol.

The precision panel samples, kit controls and verifiers were tested on two lots of LIAISON® BRAHMS PCT® II GEN in two replicates per run, 2 runs per day for 20 operating days on 1 LIAISON® Analyzer with multiple operators performing the testing The testing spanned at least two calibration cycles.

The 20 day results are summarized in Table 7 for the combined reagent lot numbers as sample mean PCT concentration in ng/mL, computed SDs and %CVs for between lot and Total across lots for each of the tested specimens, kit controls and verifiers.

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		Mean
		PCT	Between-Lot		Total (Across Lots)
Sample ID	n	(ng/mL)	SD	%CV	SD	%CV
Kit Control 1	160	1.36	0.03	2.0%	0.09	6.5%
Kit Control 2	160	45.8	0.25	0.6%	2.82	6.1%
CV A	160	0.47	0.02	3.7%	0.04	8.7%
CV B	160	1.78	0.04	2.1%	0.13	7.0%
CV C	160	6.33	0.10	1.7%	0.35	5.5%
CV D	160	43.6	0.58	1.3%	2.69	6.2%
P001	158*	0.12	0.00	3.1%	0.02	16.6%
P002	158*	0.11	0.01	6.2%	0.02	17.1%
P003	160	0.29	0.01	3.7%	0.03	11.8%
P004	160	0.28	0.00	0.6%	0.03	12.3%
P005	160	0.59	0.01	2.0%	0.05	8.9%
P006	160	0.59	0.00	0.7%	0.06	10.3%
P007	160	2.21	0.03	1.4%	0.22	10.0%
P008	160	2.24	0.04	1.9%	0.15	6.6%
P009	160	24.4	0.17	0.7%	1.84	7.5%
P010	160	67.8	1.06	1.6%	3.74	5.5%

Multi-Site Precision

A five day precision/reproducibility study was performed at two external laboratories and internally at DiaSorin Inc. to verify the precision of the LIAISON® BRAHMS PCT® II GEN assay.

A coded panel comprised of 10 frozen serum samples spanning the assay range was prepared by DiaSorin S.p.A. Two lots of LIAISON® Control BRAHMS PCT® II GEN (2 levels) and two lots of LIAISON® BRAHMS PCT® II GEN verifiers (4 levels) were also tested in the study. The CLSI document EP15-A3 was consulted in the preparation of the testing protocol.

The precision panel samples, kit controls, and verifiers were tested on one lot of LIAISON® BRAHMS PCT® II GEN in three replicates per run, 2 runs per day for 5 operating days on 3 LIAISON® Analyzers with multiple operators performing the testing

Results

The 5 day study results are summarized in table 8 for the 3 sites combined. The 3 sites combined data includes sample mean, SD and % CV for With-in run, Between day, Site to Site, and Total.

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Sample ID	MeanPCT(ng/mL)	Within Run		Between Day		Site to Site		Total
		SD	%CV	SD	%CV	SD	%CV	SD	%CV
Kit Control 1Lot 1	1.4	0.05	3.2%	0.05	3.8%	0.07	5.2%	0.10	7.1%
Kit Control 2Lot 1	42.92	1.08	2.5%	2.15	5.0%	2.34	5.4%	3.32	7.7%
Kit Control 1Lot 2	1.39	0.04	3.1%	0.05	3.6%	0.08	5.6%	0.10	7.3%
Kit Control 2Lot 2	46.25	1.77	3.8%	1.82	3.9%	1.27	2.7%	2.75	5.9%
CV A Lot 1	0.48	0.03	5.8%	0.03	5.3%	0.02	4.4%	0.04	8.6%
CV B Lot 1	1.83	0.07	3.6%	0.06	3.4%	0.12	6.6%	0.15	8.1%
CV C Lot 1	6.45	0.19	2.9%	0.21	3.2%	0.36	5.6%	0.45	7.0%
CV D Lot 1	44.31	1.13	2.6%	1.03	2.3%	1.62	3.7%	2.18	4.9%
CV A Lot 2	0.385	0.02	5.8%	0.02	4.6%	0.02	5.8%	0.04	9.1%
CV B Lot 2	1.75	0.05	3.0%	0.05	3.0%	0.07	4.0%	0.10	5.7%
CV C Lot 2	8.48	0.31	3.6%	0.45	5.2%	0.53	6.3%	0.75	8.8%
CV D Lot 2	43.14	0.92	2.1%	1.28	3.0%	1.63	3.8%	2.23	5.2%
P001	0.135	0.01	10.7%	0.01	9.3%	0.01	4.0%	0.02	14.0%
P002	0.129	0.02	12.3%	0.01	6.9%	0.01	10.4%	0.02	16.8%
P003	0.321	0.01	3.6%	0.01	4.0%	0.02	5.5%	0.02	7.6%
P004	0.312	0.03	8.6%	0.02	6.6%	0.02	7.1%	0.04	12.5%
P005	0.651	0.03	3.8%	0.03	4.3%	0.04	5.3%	0.05	7.7%
P006	0.65	0.03	3.9%	0.04	5.4%	0.04	5.9%	0.06	8.8%
P007	2.39	0.06	2.5%	0.08	3.3%	0.14	5.7%	0.17	7.0%
P008	2.43	0.07	2.7%	0.13	5.2%	0.14	5.7%	0.20	8.0%
P009	26.37	0.80	3.0%	1.01	3.8%	0.62	2.3%	1.39	5.3%
P010	70.9	2.76	3.9%	1.90	2.7%	1.28	1.8%	3.40	4.8%

Table 8: 5 day Combined Site Precision

Table 9: STABILITY STUDIES: REAGENTS

Study	Stability
Calibration Curve	8 weeks
Open Use storage On-board Analyzer	12 weeks
Open Use storage at 2-8°C	12 weeks
Calibrator Freeze/Thaw cycles	3 cycles

LIAISON® Control BRAHMS PCT® II GEN
Study	Stability
Open Use storage at -20°C	8 weeks
Control Freeze/Thaw cycles	7 cycles
Diluent provided with Controls
Open Use storage at 2-8°C	3 months

{13}------------------------------------------------

LIAISON® BRAHMS PCT® II GEN Verifiers
Study	Stability
Open Use storage at -20°C	8 weeks
Cal Verifier Freeze/Thaw cycles	7 cycles

SAMPLE EQUIVALENCY AND STABILITY STUDIES:

Equivalence testing was performed with 40 matched patient samples consisting of serum and lithium heparin collection tubes. Samples spanned the full assay measuring range. Spiked or diluted samples were used in order to span the assay range.

Paired samples were tested in triplicate in the same run using 1 reagent lot and 1 analyzer in order to exclude the effects of other variables on the results.

The (mean) result of each sample type under examination (y) is reported versus the mean result obtained with the reference sample type (x).

Results of the serum and lithium heparin plasma samples were compared by Passing and Bablok and Weighted Deming regression. Human serum and Lithium Heparin Plasma are acceptable sample types for use in the LIAISON® BRAHMS PCT® II GEN assav. A summary of the results are in Table 10 below.

Passing & Bablok
Slope	1.019	95% CI	1.012 - 1.031
Intercept	0.003	95% CI	-0.003 - 0.006
Weighted Deming
Slope	0.9998	95% CI	0.9712 - 1.028
Intercept	0.005	95% CI	0.0015 - 0.0079

Table 10: Summary of Sample Equivalence Regression analysis

SAMPLE STABILITY:

Studies were performed to evaluate the stability of samples at different sample storage conditions. The results are provided in the table below.

Table 11: Sample Stability

Specimen
Study	Stability
Room Temperature (20-25°C)	24 hours
Refrigerated (2-8°C)	24 hours
Frozen (-20°C)	3 months
Freeze/Thaw Cycles	5 cycles

CONCLUSION:

The material submitted in this premarket notification is complete and supports a substantial equivalence decision. The labeling is sufficient and it satisfies the requirements of 21CFR 809.10.

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.