The ARCHITECT B R A H M S PCT assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA) on the ARCHITECT iSystem.

Used in conjunction with other laboratory findings and clinical assessments, the ARCHITECT BR A-H-M-S PCT assay is intended for use as an:

· Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock.

· 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.

· 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.

· Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

The ARCHITECT B R A H M S PCT Calibrators are for the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.

The ARCHITECT B-R-A-H-M-S PCT Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.

Device Description

The ARCHITECT B.R.A.H.M.S PCT assay reagents are available in 100 or 500 test kits. The kit components include PCT Microparticles coated with Rat monoclonal anti-PCT and PCT Conjugate with Mouse monoclonal anti-PCT acridinium-labeled conjugate. Both contain Bovine serum albumin and preservatives. The ARCHITECT B.R.A.H.M.S PCT Calibrators kit consists of 6 bottles, with Calibrator A containing normal human plasma and Calibrators B-F containing recombinant human PCT in phosphate buffer. The ARCHITECT B.R.A.H.M.S PCT Controls kit consists of 2 x 3 bottles at three target concentrations of recombinant PCT in phosphate buffer. The assay is a two-step immunoassay using chemiluminescent microparticle immunoassay (CMIA) technology.

AI/ML Overview

The ARCHITECT B.R.A.H.M.S PCT assay is a chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA) on the ARCHITECT iSystem. It is intended to aid in the risk assessment of critically ill patients for progression to severe sepsis and septic shock, aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock, and aid in decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) or sepsis.

Here's an analysis of the acceptance criteria and study proving the device meets these criteria:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" in a tabulated format for all performance characteristics. Instead, it describes validated performance characteristics. I will compile a table based on the provided performance summaries and their implied acceptance as suitable for the intended use.

Performance Characteristic	Acceptance Criteria (Implied)	Reported Device Performance
Reproducibility/Precision	Meets CLSI EP05-A3 guidelines for internal precision.	Internal Precision: Within-laboratory (total) %CVs: - Low control: 2.5% to 2.8% - Medium control: 2.1% to 2.5% - High control: 3.5% to 3.8% - Panel 1: 2.5% - Panel 3: 2.1% - Panel 5: 2.2% to 2.3%
	Meets CLSI EP15-A3 guidelines for multi-site precision.	Multi-Site Precision: - Within-laboratory %CVs (individual sites): 1.5% to 4.0% for concentrations > 0.1 ng/mL; SD ≤ 0.005 ng/mL for concentrations ≤ 0.1 ng/mL. - Total precision %CVs (pooled data): 2.3% to 4.0% for concentrations > 0.1 ng/mL; SD ≤ 0.005 ng/mL for concentrations ≤ 0.1 ng/mL.
Linearity/Assay Reportable Range	Meets CLSI EP06-A for linearity across the intended range. Bias acceptance criteria met for auto-dilution.	Linearity: Linear in the range of 0.01 to 106.80 ng/mL. Dilution Tests: 1:10 auto-dilution protocol meets 10% bias acceptance criteria from 20.5 ng/mL to 1000 ng/mL. Analytical Measuring Range: 0.02 to 100.00 ng/mL. Extended Measuring Range (with auto-dilution): Up to 1000.00 ng/mL.
Reagent Stability	Sufficient shelf-life for intended use.	Reagent Shelf Life: 9 months for intended storage (2-8°C). Transport Stability: Can be shipped at ambient or refrigerated conditions.
Calibrator Stability	Sufficient shelf-life for intended use.	Calibrator Shelf Life: 9 months for frozen conditions (-10°C or colder), including 3 freeze/thaw cycles.
Control Stability	Sufficient shelf-life for intended use.	Control Shelf Life: 9 months for frozen conditions (-10°C or colder). In Use Storage: 30 days post-thaw at 2-8°C.
Detection Limit	Meets CLSI EP17-A2 for detection capabilities.	LoB: 0.0004 ng/mL LoD: 0.0018 ng/mL LoQ: 0.0077 ng/mL
Analytical Specificity/Cross Reactivity	No significant interference from tested substances.	No interference seen with up to: - 10 ng/mL Human Katacalcin - 2 ng/mL Human Calcitonin - 10 µg/mL Human α-CGRP - 10 µg/mL Human β-CGRP
Interfering Substances (Endogenous)	Less than 5% interference from tested endogenous substances.	Interferent levels not affecting test performance: - Hemoglobin: ≤ 500 mg/dL (1.9% interference) - Triglycerides: ≤ 3000 mg/dL (0.9% interference) - Unconjugated Bilirubin: ≤ 20 mg/dL (2.8% interference) - Conjugated Bilirubin: ≤ 30 mg/dL (3.9% interference) - Total Protein: ≤ 12 g/dL (4.8% interference)
Interfering Substances (Exogenous)	No significant interference from tested substances.	No interference seen with up to listed concentrations for: Imipenem, Cefotaxime, Vancomycin, Dopamine, Noradrenaline, Dobutamine, Heparin, Furosemide. HAMA Effect: No interference seen with up to 3600 ng/mL. RF Effect: No interference seen with up to 2000 IU/mL.
High Dose Hook Effect	No hook effect within the tested range.	Free of hook effects up to 10,000 ng/mL PCT.
Specimen Stability	Samples remain stable for specified storage conditions and times.	On Board Stability: Stable for up to 3 hours. Room Temperature (15-30°C): Stable for up to 24 hours (plasma/serum harvested); ≤ 8 hours (on cells/clot/separator gel); ≤ 24 hours (off cells/clot/separator gel). Refrigerated (2-8°C): Stable for up to 48 hours. Freeze-Thaw Cycles: Up to 3 cycles (EDTA plasma, no-additive serum, SST serum); 1 cycle (lithium heparin plasma). Frozen Short Term (-10°C or colder): Up to 15 days. Frozen Long Term (-70°C): 18 months.
Matrix Comparison	Different matrix types are equivalent within defined bias.	Minimal bias between K2EDTA plasma (base tube) and other types: - Lithium heparin plasma: +2% bias - Serum: -4% bias - SST: -6% bias All four tube types considered equivalent.
Method Comparison	Strong correlation with the predicate device.	Correlation coefficient (r): 0.99 (between ARCHITECT B.R.A.H.M.S PCT and B.R.A.H.M.S PCT sensitive KRYPTOR®). Slope: 1.00; Intercept: -0.02.
Clinical Performance (28-day mortality)	Significant association between ΔPCT and 28-day mortality. Prognostic accuracy demonstrated. Ability to differentiate risk groups.	MOSES Study: - Binary test result (ΔPCT > 80% or ≤ 80%) significantly associated with 28-day cumulative mortality (p=0.001). - Adjusted for ICU vs. non-ICU: p=0.017. - Relative mortality ratios (ΔPCT positive vs. negative) ranged from 1.49 to 3.38 across subgroups. - Kaplan-Meier curves showed lower survival probability for ΔPCT positive. - Hazard ratio for ΔPCT ≤ 80% vs. > 80% was 1.99 (p=0.002) for Day 0 to Day 4 change, indicating a ~2-fold higher mortality risk. - ΔPCT remains a prognostic parameter even when adjusted for other mortality predictors in Cox multi-regression models. - Clinical Concordance: >96% total agreement with predicate at 0.5 µg/L and 2.0 µg/L decision points.

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

Analytical Performance Studies (Precision, Linearity, Detection Limit, Specificity, Interference, Hook Effect, Reagent/Calibrator/Control Stability):
- Precision (Internal): 320 replicates (80 per sample-reagent-calibrator lot combination) for controls and plasma panels.
- Precision (Multi-Site): 25 replicates per sample per site over 5 days.
- Linearity: 3 unique EDTA plasma High pools, each diluted to 10 levels.
- Dilution Tests: 5 specimens evaluated by three methods (neat, manual, auto-dilution) in replicates of five for concentrations between Cal E and Cal F; 5 specimens evaluated by manual and auto-dilution in replicates of five for concentrations between Cal F and 1000 ng/mL.
- Detection Limit (LoB): 288 replicates (4 blank plasma lots, 6 replicates each, on 2 instruments with 2 reagent lots per instrument for 3 days).
- Detection Limit (LoD): 400 replicates (1 blank plasma lot spiked to 4 levels, 5 replicates each, for 5 days on 2 instruments with 3 reagent lots and 2 calibrator lots).
- Detection Limit (LoQ): 1000 replicates (2 blank plasma lots spiked to 5 levels, 5 replicates each, for 5 days on 2 instruments with 3 reagent lots and 2 calibrator lots).
- Analytical Specificity/Cross Reactivity: Samples tested in replicates of seven in a single run.
- Interfering Substances (Endogenous): 3 plasma-based panels, each tested in replicates of eight across three runs.
- Interfering Substances (Exogenous): 8 potential drug interferents, spiked into 3 plasma panels, run in replicates of eight. HAMA stock solutions spiked into 3 plasma panels, run in replicates of eight. RF stock solution spiked into 3 plasma panels, run in replicates of eight.
- High Dose Hook Effect: 7 spiked samples and Cal F tested in 18 replicates each.
- Specimen Stability: Fresh samples from 53 patients for 4 tube types.
- Matrix Comparison: Matched set specimens from patients (number not specified but assumed to be sufficient per CLSI EP09-A3).
- Method Comparison: 142 human K2EDTA plasma specimens.
- Reference Range Study: n=446 normal healthy donor K2EDTA plasma individuals.
- Data Provenance: Primarily conducted at the Thermo Fisher internal laboratory. Multi-site precision involved two external CLIA certified laboratories and the Thermo Fisher internal laboratory. Clinical samples for linearity were from multiple donors; for specimen stability and matrix comparison, samples were prospectively collected from two hospital sites in Switzerland. The clinical study (MOSES) involved 13 investigational sites in the United States. The method comparison study used human K2EDTA plasma specimens. All samples appear to be retrospective clinical samples or laboratory-prepared panels.
Clinical Studies (MOSES Study):
- Sample Size: 858 adult patients initially, analyzed population of 598 subjects.
- Data Provenance: Prospective clinical trial conducted across 13 investigational sites in the United States.

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

This device is an in-vitro diagnostic (IVD) assay that measures a biomarker (PCT) quantitatively. The "ground truth" for analytical performance tests is typically established through reference methods, certified standards, and rigorous statistical analysis according to CLSI guidelines, rather than expert interpretation of images or clinical cases. For the clinical study, the ground truth for mortality was the outcome data (28-day all-cause mortality). No information is provided about experts establishing ground truth for the test set in the traditional sense of consensus reading for subjective data.

4. Adjudication Method for the Test Set:

Not applicable in the typical sense for quantitative biomarker assays. The clinical ground truth (28-day mortality) is an objective outcome, not requiring adjudication. Analytical studies rely on quantitative measurements against defined standards and statistical methods.

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:

Not applicable. This is a standalone quantitative diagnostic assay for a biomarker (PCT), not a device that assists human readers in interpreting medical images or clinical cases.

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

Yes, the device is explicitly a standalone assay. It quantitatively determines PCT levels. Although the indications for use state "Used in conjunction with other laboratory findings and clinical assessments," the performance data presented is for the assay's output itself, not for human-in-the-loop interpretation of the assay's results. The hazard ratios and mortality predictions are based solely on the PCT values generated by the device.

7. The Type of Ground Truth Used:

Analytical Performance: Various types of ground truth relevant to analytical testing were used:
- Reference standards/gravimetric dilutions: For linearity, detection limits, and calibrator/control value assignment.
- Known concentrations: For spike-recovery and interference studies.
- Predicate device results: For method comparison (B.R.A.H.M.S PCT sensitive KRYPTOR®).
Clinical Performance (MOSES Study):
- Outcomes Data: 28-day all-cause mortality was the primary outcome for the clinical study. This is objective, hard outcome data.

8. The Sample Size for the Training Set:

The document describes performance studies, not a machine learning model that requires a distinct "training set." The analytical studies and clinical validation study (MOSES study) collectively serve as the evidence base demonstrating the device's performance and suitability for its intended use. The samples used in these studies, as detailed in point 2, were used for validation and verification, not for training a model in the AI/ML sense.

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

Not applicable, as there isn't a "training set" in the context of an AI/ML model for this device. The ground truth for the various performance evaluation samples was established through established laboratory methods, reference standards, and objective clinical outcomes as described in point 7.

Summary

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

June 1, 2017

FISHER DIAGNOSTICS c/o KENNON DANIELS, PH.D. SENIOR CONSULTANT, IVD REGULATORY AFFAIRS 2 BETHESDA METRO CENTER, SUITE 850 BETHESDA MD 20814

Re: K170652

Trade/Device Name: ARCHITECT B.R.A.H.M.S PCT, ARCHITECT B.R.A.H.M.S PCT Calibrators, ARCHITECT B.R.A.H.M.S PCT Controls 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: PRI, PMT, PTF, JIT, JJX Dated: March 1, 2017 Received: March 3, 2017

Dear Dr. Daniels:

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,

Kristian M. Roth-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) K170652

Device Name

ARCHITECT B·R·A·H·M·S PCT ARCHITECT B·R·A·H·M·S PCT Calibrators ARCHITECT B·R·A·H·M·S PCT Controls

Indications for Use (Describe)

Used in conjunction with other laboratory findings and clinical assessments, the ARCHITECT BR A-H-M-S PCT assay is intended for use as an:

· Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock.

· 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)
Over-The-Counter Use (21 CFR 801 Subpart C)

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510K SUMMARY

A. GENERAL INFORMATION

Submission Date:	March 1, 2017
------------------	---------------

Submitter Information:

Submitted By:	Fisher DiagnosticsA Div. of Fisher Scientific Company, LLCA Part of Thermo Fisher Scientific, Inc.8365 Valley PikeMiddletown, VA 22645
Contact Person:	Connie Yang, MSPHRegulatory Affairs SpecialistClinical Diagnostics OEM & Contract ManufacturingThermo Fisher ScientificTel: (540) 868-3603Fax: (540) 869-8117Email: connie.yang@thermofisher.com

B. PURPOSE FOR SUBMISSION

To obtain a substantial equivalence determination for the ARCHITECT B.R.A.H.M.S PCT, ARCHITECT B.R.A.H.M.S PCT Calibrators, and ARCHITECT B.R.A.H.M.S PCT Controls.

C. MEASURAND

Procalcitonin

D. TYPE OF TEST

Quantitative, chemiluminescent microparticle immunoassay (CMIA)

E. APPLICANT

Fisher Diagnostics

F. PROPRIETARY AND ESTABLISHED NAMES

ARCHITECT B.R.A.H.M.S PCT ARCHITECT B.R.A.H.M.S PCT Calibrators ARCHITECT B.R.A.H.M.S PCT Controls

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G. REGULATORY INFORMATION

Assay
Trade Name:	ARCHITECT B.R.A.H.M.S PCT
Classification:	Class II
Regulation:	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
Product Code:	PRI, PMT, PTF
Panel:	83 - (Microbiology)
Calibrators
Trade Name:	ARCHITECT B.R.A.H.M.S PCT Calibrators
Classification:	Class II
Regulation:	21 CFR 862.1150
Classification Name:	Calibrator, Secondary
Product Code:	JIT
Controls
Trade Name:	ARCHITECT B.R.A.H.M.S PCT Controls
Classification:	Class I
Regulation:	21 CFR 862.1660

Regulation: Classification Name: Product Code:

21 CFR 862.1660 Quality Control Material (assayed and unassayed) JJX

H. INTENDED USE / INDICATIONS FOR USE

1. Intended Use

Used in conjunction with other laboratory findings and clinical assessments, the ARCHITECT B.R.A.H.M.S PCT assay is intended for use as an:

Aid in the risk assessment of critically ill patients on their first day of intensive care . unit (ICU) admission for progression to severe sepsis and septic shock.
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.
. 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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. Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
The ARCHITECT B.R.A.H.M.S PCT Calibrators are for the calibration of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.

The ARCHITECT B.R.A.H.M.S PCT Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.

1. Special conditions for use statement(s):
  For prescription use only

Warnings and Precautions for the Assay:

The ARCHITECT B.R.A.H.M.S PCT assay is not indicated to be used as a stand-. alone diagnostic assay and should be used in conjunction with clinical signs and symptoms of infection and other diagnostic evidence.
Decisions regarding antibiotic therapy should NOT be based solely on PCT . concentrations.
. PCT results should always be interpreted in the context of the clinical status of the patient and other laboratory results. Changes in PCT levels for the prediction of mortality, and overall mortality, are strongly dependent on many factors, including pre-existing patient risk factors and clinical course.
. The need to continue ICU care at Day 4 and other covariates (e.g., age and SOFA score) are also significant predictors of 28-day cumulative mortality risk.
. Certain patient characteristics, such as severity of renal failure or insufficiency, may influence PCT values and should be considered as potentially confounding clinical factors when interpreting PCT values.
PCT levels may not be elevated in patients infected by certain atypical pathogens, . such as Chlamydophila pneumoniae and Mycoplasma pneumoniae.
. Low PCT levels do not always indicate absence of bacterial infection. Falsely low PCT levels in the presence of bacterial infection may occur during the early course of infections, in localized infections, and in subacute infectious endocarditis.
. Increased PCT levels may not always be related to systemic bacterial infection. There are a few situations where PCT levels may be elevated by non-bacterial causes. These include, but are not limited to, the following:
- Neonates at < 48 hours of life (physiological elevation). ।
- Severe illness such as polytrauma, burns, major surgery, and prolonged or । cardiogenic shock,
- । Treatment with OKT3 (muromonab-CD3) antibodies and other drugs stimulating the release of pro-inflammatory cytokines,
- Patients with invasive fungal infections. -
- -Patients with acute attacks of Plasmodium falciparum malaria,

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Patients receiving peritoneal dialysis or hemodialysis treatment, —
। Patients with biliary pancreatitis, chemical pneumonitis, or heat stroke,
Patients with small cell lung cancer, severe liver cirrhosis and acute or chronic viral hepatitis, or medullary C-cell carcinoma of the thyroid.
The safety and performance of PCT-guided therapy for individuals younger than age . 18 years, pregnant women, immunocompromised individuals or those on immunomodulatory agents, was not formally analyzed in the supportive clinical trials.
. ARCHITECT B.R.A.H.M.S PCT results should not be used interchangeably with other methods for PCT determinations for monitoring patients.
. If the PCT results are inconsistent with clinical evidence, additional testing is recommended.
1. Special instrument requirements:

ARCHITECT iSystem

I. INDICATIONS FOR USE

Same as Intended Use.

J. DEVICE DESCRIPTION

Reagents

The ARCHITECT B.R.A.H.M.S PCT assay reagents are available in 100 or 500 test kits.

Kit Components and Chemical Composition

Reagent KitComponents	Reactive Ingredients	Materials(human / animal origin)	Main Buffer Component
PCTMicroparticles(1 bottle)	Rat monoclonal anti-PCT(CALC 01R 03-1C2)coated microparticles	• Bovine serum albumin• Rat IgG	• Tris based buffer• Preservatives:Sodium Azide .08%and ProClin 950
PCTConjugate(1 bottle)	Mouse monoclonal anti-PCT (23-101) acridinium-labeled conjugate	• Bovine serum albumin	• Sodium phosphate buffer• Preservatives:Sodium Azide .08%and ProClin 950

Calibrators

The ARCHITECT B.R.A.H.M.S PCT Calibrators kit consists of 6 bottles (2.0 mL each). Calibrator A contains normal human plasma. Calibrators B-F contain different concentrations of recombinant human PCT in phosphate buffer with PCT concentrations that range from 0.10-100.00 ng/mL. All of the calibrators contain the preservatives ProClin 950 and sodium azide.

Controls

The ARCHITECT B.R.A.H.M.S PCT Controls kit consists of 2 x 3 bottles (3.0 mL each). The Low Control, Medium Control, and High Contain recombinant PCT prepared in

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phosphate buffer at 3 target concentrations: Low (0.20 ng/mL), Medium (2.00 ng/mL), and High (70.00 ng/mL). All of the controls contain the preservatives ProClin 950 and sodium azide. The control ranges are as follows: Low (0.14-0.26 ng/mL), Medium (1.38-2.62 ng/mL), and High (42.00-98.00 ng/mL).

Materials required but not provided:

ARCHITECT B.R.A.H.M.S PCT Assay file obtained from the ARCHITECT iSystem e-. Assay CD-ROM found on www.abbottdiagnostics.com
. ARCHITECT B.R.A.H.M.S PCT Calibrators
ARCHITECT B.R.A.H.M.S PCT Controls or other control material
י ARCHITECT Pre-Trigger Solution
" ARCHITECT Trigger Solution
י ARCHITECT Wash Buffer
" ARCHITECT Reaction Vessels
. ARCHITECT Sample Cups
. ARCHITECT Septum
. ARCHITECT Replacement Caps
Pipettes or pipette tips

K. SUBSTANTIAL EQUIVALENCE INFORMATION

1. Predicate device name(s):
  B.R.A.H.M.S PCT sensitive KRYPTOR®
1. Predicate 510(k) number(s):
  K171338
1. Comparison with predicate:

	ARCHITECT B.R.A.H.M.S PCT	B.R.A.H.M.S PCT sensitive KRYPTOR®(Predicate Device)
K Number	Subject of submission	K171338
	SIMILARITIES
AssayIntended Use	The ARCHITECT B.R.A.H.M.S PCT is achemiluminescent microparticle immunoassay(CMIA) for the quantitative determination ofprocalcitonin (PCT) in human serum and plasma(lithium heparin and K2EDTA).	The B.R.A.H.M.S PCT sensitiveKRYPTOR® is an immunofluorescent assayusing Time-Resolved Amplified CryptateEmission (TRACE®) technology to determinethe concentration of PCT (procalcitonin) inhuman serum and EDTA or heparin plasma.The B.R.A.H.M.S PCT sensitiveKRYPTOR® is intended to be performed onthe B.R.A.H.M.S KRYPTOR® analyzerfamily.
	Used in conjunction with other laboratoryfindings and clinical assessments, theARCHITECT B.R.A.H.M.S PCT assay isintended for use as an:• Aid in the risk assessment of critically illpatients on their first day of intensive care unit	Used in conjunction with other laboratoryfindings and clinical assessments, theB.R.A.H.M.S PCT sensitive KRYPTOR® isintended for use as follows:• to aid in the risk assessment of critically illpatients on their first day of ICU admission
	ARCHITECT B.R.A.H.M.S PCT	B.R.A.H.M.S PCT sensitive KRYPTOR®(Predicate Device)
	(ICU) admission for progression to severe sepsis and septic shock. 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. 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. Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis. The ARCHITECT B.R.A.H.M.S PCT Calibrators are for the calibration of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.The ARCHITECT B.R.A.H.M.S PCT Controls are for the estimation of test precision and the detection of systematic analytical deviations of the ARCHITECT iSystem when used for the quantitative determination of procalcitonin (PCT) in human serum and plasma (lithium heparin and K2EDTA). For in vitro diagnostic use only.	for progression to severe sepsis and septic shock, to determine the change in PCT level over time as an 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, to aid in decision making on antibiotic therapy for inpatients or patients in the emergency department 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), to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
Classification	Class II	Same
Product Code	PRI, PMT, PTF	PRI, PMT, NTM
Regulation	21 CFR 866.3215	Same
DIFFERENCES
Mode ofMeasurement	Chemiluminescence	Immunofluorescence (TRACE)
DetectionMethod	Chemiluminescent MicroparticleImmunoassay (CMIA), where a direct relationship exists between the amount of PCT in the sample and the light detected by the instrument system.	Measuring principle based on Time-Resolved Amplified Cryptate Emission(TRACE) technology which measures the signal emitted from an immunocomplex with time delay and where a direct relationship exists between the amount of PCT in the sample and the fluorescence detected.
Instrument	ARCHITECT iSystem	KRYPTOR® Test System
Application	29 minutes	19-minute incubation
SampleVolume	100 μL	50 μL
	ARCHITECT B.R.A.H.M.S PCT	B.R.A.H.M.S PCT sensitive KRYPTOR®(Predicate Device)
Sample Type	Human serum and plasma (Lithium Heparin andK2EDTA)	Human serum and plasma (EDTA andHeparin)
Linearity /MeasuringRange	0.02-100.00 ng/mL	0.02 µg/L-50.00 µg/L
Auto DilutionMeasuringRange	20.50-1000.00 ng/mL	50.00-5000.00 µg/L
Reagents	2 vials:• Anti-PCT antibody (monoclonal mouse)acridinium-labeled conjugate• Anti-PCT antibody (monoclonal rat) coatedmicroparticle	3 vials:Cryptate conjugate (cryptate conjugate,cryptate labeled, anti-PCT antibody(polyclonal, sheep))• XL665 conjugate• (XL665 conjugate, XL665 labeled, anti-PCT antibody (monoclonal, mouse))• Diluent (defibrinated human plasma)
Calibrators	ARCHITECT B.R.A.H.M.S PCT Calibrators:6 level set (1 bottle/level):• Calibrator A: Normal defibrinated humanplasma• Calibrator B-F: Recombinant human PCT inphosphate buffer (range 0.10-100.00 ng/mL)	B.R.A.H.M.S PCT sensitive KRYPTOR®Calibrator:1 vial of lyophilized recombinant PCT indefibrinated human plasma (range 22.50-27.50 µg/L)
Controls	ARCHITECT B.R.A.H.M.S PCT Controls:6 bottles (2 of each control):• Low (0.14-0.26 ng/mL)• Medium (1.38-2.62 ng/mL)• High (42.00-98.00 ng/mL)	B.R.A.H.M.S PCT sensitive KRYPTOR®QC Kit:6 vials (3 of each control):• Control 1 (0.20-0.40 µg/L)• Control 2 (8.00-12.00 µg/L)

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L. STANDARDS/GUIDANCE DOCUMENTS REFERENCED

CLSI Guideline EP05-A3, Evaluation of Precision of Quantitative Measurements . Procedures; Approved Guideline; Third Edition.
CLSI Guideline EP06-A, Evaluation of the Linearity of Quantitative Measurement ● Procedures: A Statistical Approach; Approved Guideline.
CLSI Guideline EP07-A2, Interference Testing in Clinical Chemistry; Approved ● Guideline - Second Edition.
. CLSI Guideline EP09-A3. Measurement Procedure Comparison and Bias Estimation Using Patient Samples; Approved Guideline; Third Edition
CLSI Guideline EP15-A3, User Verification of Precision and Estimation of Bias-Third ● Edition
CLSI Guideline EP17-A2, Evaluation of Detection Capability for Clinical Laboratory ● Measurement Procedures; Approved Guideline-Second Edition.
. CLSI Guideline EP25-A, Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline.
CLSI Guideline EP28-A3c, Defining, Establishing, and Verifying. Reference Intervals in . the Clinical Laboratory; Approved Guideline-Third Edition.

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M. TEST PRINICIPLE

The ARCHITECT B.R.A.H.M.S PCT is a two-step immunoassay to determine the presence of PCT in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology.

In the first step, paramagnetic microparticles coated with a monoclonal anti-PCT antibody are combined with the patient's sample. PCT present in the sample binds to the anti-PCT antibodies coated onto the microparticles. After incubation and washing, acridinium-labeled anti-PCT antibody conjugate is added in the second step. Following another incubation and wash step, pre-trigger and trigger solutions are added to the reaction mixture. The resulting chemiluminescent reaction is measured in terms of relative light units (RLUs). A direct relationship exists between the amount of PCT in the sample and the number of RLUs detected by the ARCHITECT iSystem optics. The concentration of PCT is read relative to a standard curve established with calibrators of known PCT concentrations.

N. PERFORMANCE CHARACTERISTICS

1. Analytical Performance

a. Reproducibility/Precision

Internal Precision

The single site precision study was conducted using the ARCHITECT B.R.A.H.M.S PCT assay at the internal laboratory according to CLSI EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures. Three PCT level controls (low, medium, and high) and three PCT plasma panels (1, 3, and 5) were evaluated in duplicate with two runs per day over 20 testing days. Two reagent lots, two calibrator lots, one control lot, and one panel lot was used for 320 replicates (80 per samplereagent-calibrator lot). Testing was performed using two ARCHITECT i2000SR instruments and one instrument operator. Control concentrations were selected to cover the measuring range of the assay, and panel concentrations were selected to cover physiologically low, medium, and high concentrations found in plasma.

Analysis of the internal precision study data for the ARCHITECT B.R.A.H.M.S PCT assay demonstrated within-laboratory precision (total) of 2.5% to 2.8% for Low control. 2.1% to 2.5% for Medium control. 3.5% to 3.8% for High control. 2.5% for Panel 1, 2.1% for Panel 3, and 2.2 to 2.3% for Panel 5 concentrations.

Sample	Instrument/Reagent Lot	CalibratorLot	n	Mean(ng/mL)	Within-Run		Within-Laboratory(Total)a
Low Control	1	1	80	0.19	0.0052	2.7	0.0054	2.8
		2	80	0.20	0.0053	2.7	0.0055	2.8
	2	1	80	0.20	0.0046	2.4	0.0049	2.5
		2	80	0.20	0.0045	2.3	0.0049	2.5

Summary of Internal Precision Data

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	Instrument/Reagent Lot	CalibratorLot	n	Mean(ng/mL)	Within-Run		Within-Laboratory(Total)a
Sample					SD	%CV	SD	%CV
MediumControl	1	1	80	1.94	0.0437	2.2	0.0480	2.5
	1	2	80	1.97	0.0439	2.2	0.0482	2.5
	2	1	80	1.92	0.0320	1.7	0.0412	2.1
	2	2	80	1.94	0.0324	1.7	0.0418	2.2
High Control	1	1	80	68.60	1.8407	2.7	2.4899	3.6
	1	2	80	70.41	1.9577	2.8	2.6485	3.8
	2	1	80	67.33	1.6972	2.5	2.4172	3.6
	2	2	80	67.73	1.6146	2.4	2.3667	3.5
Panel 1	1	1	80	0.06	0.0015	2.4	0.0016	2.5
	1	2	80	0.07	0.0016	2.4	0.0016	2.5
	2	1	80	0.06	0.0013	2.1	0.0016	2.5
	2	2	80	0.06	0.0013	2.1	0.0016	2.5
Panel 3	1	1	80	1.33	0.0235	1.8	0.0286	2.1
	1	2	80	1.35	0.0237	1.8	0.0288	2.1
	2	1	80	1.31	0.0207	1.6	0.0279	2.1
	2	2	80	1.32	0.0209	1.6	0.0283	2.1
Panel 5	1	1	80	13.24	0.2505	1.9	0.2943	2.2
	1	2	80	13.30	0.2516	1.9	0.2957	2.2
	2	1	80	12.62	0.1936	1.5	0.2917	2.3
	2	2	80	12.85	0.1979	1.5	0.2989	2.3

4 Includes within-run, between-run, and between-day variability.

Multi-Site Precision

The multi-site assay repeatability and reproducibility study was performed at two external CLIA certified laboratories and at the Thermo Fisher internal laboratory according to CLSI EP15-A3, User Verification of Precision and Estimation of Bias. The study used one reagent lot, one calibrator lot, one control lot, and one ARCHITECT i2000sr instrument per site over 5 days. For each sample, the sites tested five replicates per sample with one run per day over the 5 days for a total of 25 replicates per sample per site. Control concentrations were selected to cover the measuring range of the assay and panel concentrations were selected to cover physiologically low, medium, and high concentrations found in plasma. Specifically, the samples comprised three-level PCT Controls (Low, Medium, and High) and threelevel plasma panels (Panel 1, 3, and 5).

Analysis of the external precision study data for the ARCHITECT B.R.A.H.M.S PCT assay demonstrated precision of the method with within-laboratory % CVs ranging from 1.5% to 4.0% for each site evaluated individually where sample concentrations

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greater than 0.1 ng/mL and with a SD of ≤ 0.005 ng/mL where sample concentrations are less than 0.1 ng/mL. Pooling data from all sites, a total precision percentage CVs ranging from 2.3% to 4.0% obtained where sample concentrations > 0.1 ng/mL and with a SD of ≤ 0.005 ng/mL where sample concentrations ≤ 0.1 ng/mL.

Sample	LowControl	MediumControl	HighControl	Panel 1	Panel 3	Panel 5
3 Sites
Between-Site %CV	2.8%	0.0%	0.4%	5.5%	2.1%	1.2%
Between-Day %CV	1.4%	2.0%	2.0%	0.0%	0.9%	0.0%
Between-Rep %CV	2.6%	2.0%	2.7%	5.4%	1.9%	2.0%
Total Precision %CV	4.0%	2.7%	3.4%	7.7%	3.0%	2.3%
Total Precision SD	N/A	N/A	N/A	0.005ng/mL	N/A	N/A
Site 1
Between-Day %CV	0.0%	0.0%	1.9%	0.0%	1.1%	0.0%
Between-Rep %CV	2.0%	1.5%	2.8%	8.1%	2.4%	2.1%
Within-Lab %CV	2.0%	1.5%	3.4%	8.1%	2.6%	2.1%
Within-Lab SD	N/A	N/A	N/A	0.005ng/mL	N/A	N/A
Site 2
Between-Day %CV	1.2%	1.4%	1.8%	0.0%	1.0%	0.8%
Between-Rep %CV	2.1%	1.6%	2.2%	2.8%	1.4%	1.5%
Within-Lab %CV	2.4%	2.6%	2.9%	2.8%	1.8%	1.7%
Within-Lab SD	N/A	N/A	N/A	0.002ng/mL	N/A	N/A
Site 3
Between-Day %CV	2.2%	2.3%	2.2%	1.6%	0.2%	0.0%
Between-Rep %CV	3.3%	2.6%	3.1%	4.6%	1.9%	2.3%
Within-Lab %CV	4.0%	4.0%	3.8%	4.9%	2.0%	2.3%
Within-Lab SD	N/A	N/A	N/A	0.003ng/mL	N/A	N/A

Summary of Multi-Site Precision Data

b. Linearity/Assay Reportable Range

Linearity

Assay linearity studies were performed at the Thermo Fisher internal laboratory according to CLSI Guideline EP06-A. Evaluation of the Linearity of Quantitative Measurement Procedures. The linearity data was obtained in two independent studies. For both studies, three unique EDTA plasma High pools were produced by pooling multiple clinical samples from multiple donors. From each "High" pool, ten sample levels in addition to the High sample were created by diluting each High pool gravimetrically with Calibrator Diluent. The targeted concentration range for the eleven sample levels was 0.01 ng/mL to ~110.00 ng/mL for each of the clinical sample sets. The PCT concentration of each clinical sample pool was unknown prior to executing

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the study. The data from the studies demonstrate that the assay is linear in the range of 0.01 to 106.80 ng/mL.

Dilution Tests

The auto-dilution study was conducted at the Thermo Fisher internal laboratory using one lot of ARCHITECT B.R.A.H.M.S PCT assay reagents, calibrators, and controls on one ARCHITECT i2000sr instrument. The study utilized disease state plasma panels (≥0.5 ng/mL) spiked with recombinant PCT to the desired levels. The panels were evaluated using the 1:10 auto-dilution protocol, neat without dilution, and by manual dilution. Five specimens between Cal E and Cal F (>20.50 to ≤100.00 ng/mL) were evaluated by three methods (neat, manual dilution, and auto-dilution) in replicates of five. In addition, five specimens between Cal F and the auto-dilution limit of 1000.00 ng/mL were evaluated by manual dilution and auto-dilution in replicates of five. The study was completed on one day within two runs. The study demonstrates that the 1:10 auto-dilution protocol meets the 10% bias acceptance criteria from 20.5 ng/mL to the auto-dilution limit of 1000 ng/mL.

The studies support an analytical measuring range of 0.02 to 100.00 ng/mL and an extended measuring range with automatic dilution up to 1000.00 ng/mL.

c. Traceability, Stability, Expected Values (controls, calibrators, or methods) Reagent Stability

The reagent stability data was obtained in two independent studies with three lots of the ARCHITECT B.R.A.H.M.S PCT assay reagents per study for a total of six reagent lots. Both studies were run on one ARCHITECT i2000sr instrument at Thermo Fisher Scientific. Testing data support a shelf life of 9 months for Intended Storage in refrigerated conditions at 2-8°C. The Transport Stability data indicated the reagents can be shipped at ambient or refrigerated conditions.

Calibrator Stability

The calibrator shelf life data was obtained in two independent studies with three lots of the ARCHITECT B.R.A.H.M.S PCT Calibrators per study for a total of six calibrator lots. Both studies were run on one ARCHITECT i2000sR instrument at Thermo Fisher Scientific. Testing data for Intended Storage and In Use/Freeze/Thaw including 3 freeze/thaw cycles support stability at frozen conditions (-10°C or colder) for 9 months.

Controls Stability

The controls shelf life data was obtained in two independent studies with three lots of the ARCHITECT B.R.A.H.M.S PCT Controls per study for a total of six control lots. Both studies were run on one ARCHITECT i2000sr instrument at Thermo Fisher Scientific. Three ARCHITECT B.R.A.H.M.S PCT Controls were tested at each time point: low, medium and high. The ARCHITECT B.R.A.H.M.S PCT Controls were stable at the Intended Storage under frozen conditions (-10°C or colder) for 9 months. In addition, testing data to date support In Use Storage of 30 days post-thaw at 2-8°C for Controls aged for 6 months at the intended storage conditions (-10°C or colder).

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Expected Values

The ARCHITECT B.R.A.H.M.S PCT Calibrators contain six levels with one bottle per level. Calibrator A contains normal human plasma with native PCT removed (0.00 ng/mL). Calibrators B (0.10 ng/mL), C (0.50 ng/mL), D (12.10 ng/mL), E (20.50 ng/mL), and F (100.00 ng/mL) contain recombinant human PCT in phosphate buffer with protein (bovine) stabilizer.

The ARCHITECT B.R.A.H.M.S PCT Controls contain three levels including Low (0.20 ng/mL), Medium (2.00 ng/mL), and High (70.00 ng/mL) with two bottles per level. All controls comprise recombinant human PCT in phosphate buffer with protein (bovine) stabilizer.

d. Detection Limit

Per the CLSI Guideline EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures, the following studies were conducted at the Thermo Fisher internal laboratory to evaluate the detection limits of the ARCHITECT B.R.A.H.M.S PCT assay.

LoB:

The Limit of Blank (LoB) Study used four blank plasma lots run in replicates of six on each of the two i2000sr instruments and two reagent lots per instrument with one run per day for three days using three reagent lots and two calibrator lots. A total of 288 replicates were tested (n=72 replicates per reagent lot per instrument).

LoD:

The Limit of Detection (LoD) used one blank plasma lot spiked to four levels (~0.004, 0.005, 0.006, and 0.007 ng/mL, respectively). Each level was run in replicates of five with one run per day for five days on each of the two i2000sr instruments with three reagent lots and two calibrator lots. A total of 400 replicates were tested (n=100 replicates per reagent lot per instrument).

LoQ:

The Limit of Quantitation (LoQ) study was conducted with two blank plasma lots, and each lot was spiked to five levels spanning a concentration range of 0.0016 ng/mL to 0.0500 ng/mL (estimated to include a concentration with 20% CV). The ten spiked panels were run in replicates of five with one run per day for five days on each of the two i2000sr instruments with three reagent lots and two calibrator lots. A total of 1000 replicates were tested (n=250 replicates per reagent lot per instrument).

The LoB, LoD, LoQ of the method are 0.0004 ng/mL, 0.0018 ng/mL, and 0.0077 ng/mL, respectively.

e. Analytical Specificity/Cross Reactivity

The cross reactivity study followed the guidance of CLSI Guideline EP7-A2, Interference Testing in Clinical Chemistry. Four potential cross-reactants were evaluated in PCT-free plasma and 2 medically relevant levels of PCT (0.5 and 2.0

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ng/mL). For each PCT level, two samples (a Test Sample and a Reference Sample) were tested in replicates of seven in a single run using one ARCHITECT i2000sR instrument and one reagent lot.

No interference was seen with up to 10 ng/mL Human Katacalcin, 2 ng/mL Human Calcitonin, 10 µg/mL Human a-CGRP, or 10 µg/mL Human ß-CGRP.

f. Interfering Substances

Endogenous

The endogenous interference study followed the guidance of CLSI Guideline EP7-A2, Interference Testing in Clinical Chemistry. Five potential endogenous interfering substances (Hemoglobin, conjugated Bilirubin, unconjugated Bilirubin, Total Protein and Triglycerides) were evaluated for their effect on the quantitation of PCT.

Three plasma-based panels (PCT-free, medium and high) were used for endogenous interference testing. For each interferent, a "reference sample" (endogenous level of interferent) and a "test sample" (elevated level of interferent) were tested in replicates of eight across three runs. The potentially interfering endogenous substances are listed below and were found not to affect the test performance up to the listed concentrations.

Endogenous Interferents	Interferent Level	% Interference
Hemoglobin	≤ 500 mg/dL	1.9%
Triglycerides	≤ 3000 mg/dL	0.9%
Unconjugated Bilirubin	≤ 20 mg/dL	2.8%
Conjugated Bilirubin	≤ 30 mg/dL	3.9%
Total Protein	≤ 12 g/dL	4.8%

Exogenous

The exogenous interference study followed the guidance CLSI Guideline EP7-A2: Interference Testing in Clinical Chemistry.

Drug Interferents

Stock drug solutions were prepared and spiked into plasma to form test samples at the approximate concentrations listed for the 8 potential drug interferents: Imipenem (1.18 mg/mL); Cefotaxime (90 mg/dL); Vancomycin (2.6 mg/mL); Dopamine (13 mg/dL); Noradrenaline (2 ug/mL): Dobutamine (11.2 ug/mL): Heparin (8000 U/L): Furosemide (2 mg/dL). Each drug was spiked into the three human PCT plasma panels (PCT-free plasma, medium and high) with varying amounts of PCT to form the Test Samples. Reference samples were also prepared in plasma by adding the same volume of solvent to the same volume of plasma for each of the samples. Test and reference samples were run in replicates of eight as a sample set in the same run. No interference was seen with up to the listed concentrations.

HAMA Effect

Human anti-mouse antibody (HAMA) stock solutions were spiked into the three PCT plasma panels (PCT-free plasma, medium, and high) at nominal concentrations of 4000, 6000, and 8000 ng/mL. Reference samples were prepared by performing the

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same percent dilution with blank diluent instead of HAMA stock solution. Test and reference samples were run in replicates of eight as a sample set in the same run. No interference was seen with up to 3600 ng/mL.

RF Effect

A Rheumatoid Factor (RF) stock solution of 47,287 IU/mL was spiked into the three PCT plasma panels (PCT-free plasma, medium, and high) at nominal concentrations of 2,000 IU/mL, 1,000 IU/mL, and 500 IU/mL which created nine Test Samples. Reference samples were produced for each of the nine samples by spiking blank diluent (saline) into the three plasma samples. Each RF Test sample and its respective reference sample were run as a sample set in the same run in replicates of eight. No interference was seen with up to 2000 IU/mL.

g. High Dose Hook Effect

The Prozone or Hook Effect was evaluated at the Thermo Fisher internal laboratory on EDTA disease state plasma samples spiked with recombinant PCT. The EDTA plasma pools were prepared within 10% of CAL F at approximately 90, 95, and 99 ng/mL and at extremely high concentrations far above CAL F at 500, 1,000, 5,000, and 10,000 ng/mL. The seven spiked samples and CAL F were tested in one run with 18 replicates per sample. The study shows that assay is free of hook effects up to 10,000 ng/mL PCT.

h. Assay Cut-off

28-Day Mortality:

ΔPCT ≤ 80%

A decrease in the PCT levels below or equal to 80% defines a positive APCT test result representing a higher risk for 28-day all-cause mortality of patients diagnosed with severe sepsis or septic shock.

ΔPCT > 80%

A decrease in the PCT levels of more than 80% defines a negative ΔPCT result representing a lower risk for 28-day all-cause mortality of patients diagnosed with severe sepsis or septic shock.

Progression Risk:

PCT > 2 ng/mL

A PCT level above 2.0 ng/mL on the first day of ICU admission is associated with a high risk for progression to severe sepsis and/or septic shock.

PCT < 0.5 ng/mL

A PCT level below 0.5 ng/mL on the first day of ICU admission is associated with a low risk for progression to severe sepsis and/or septic shock.

Note: A PCT level below 0.5 ng/mL does not exclude infection. If the PCT measurement is done very early after the systemic infection process has started (usually < 6 hours), these values may still be low. Various non-infectious conditions are known to induce changes in PCT level. PCT levels between 0.5 ng/mL and 2.0 ng/mL should

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be interpreted in the context of the specific clinical background and condition(s) of the individual patient. It is recommended to retest PCT as clinically indicated within 6-24 hours if any concentrations < 2 ng/mL are obtained.

LRTI Antibiotic Decision Making: PCT < 0.10 ng/mL Antibiotic therapy strongly discouraged.

PCT 0.10-0.25 ng/mL Antibiotic therapy discouraged.

PCT 0.26-0.50 ng/mL Antibiotic therapy encouraged.

PCT > 0.50 ng/mL Antibiotic therapy strongly encouraged.

Sepsis Antibiotic Discontinuation: ΔPCT > 80% Antibiotic therapy may be discontinued.

PCT ≤ 0.50 ng/mL

Antibiotic therapy may be discontinued.

i. Specimen Stability

The Specimen Stability Study was carried out using fresh samples collected from 53 patients across the range of 0.02 to 62.28 ng/mL in four tube types from subjects located in various hospital departments (e.g., Emergency Department, Critical Care Unit, or In-Patient Unit) from two hospital sites in Switzerland. However, not all donors entered into each storage condition. The study used plasma and serum collected in four tube types:

1. K2EDTA Plasma
1. Serum
1. Lithium Heparin Plasma
1. Serum Separator Tube

All samples were tested in duplicate at one clinical laboratory on one ARCHITECT i2000SR instrument. The following storage conditions were tested in the study (all storage conditions were off the cells or clot unless otherwise noted) and the results are as follows.

On Board Stability:

Plasma and serum specimens are stable when left on-board the instrument for up to 3 hours.

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Room Temperature:

Specimens are stable at room temperature (15-30°C) for up to 24 hours for plasma or serum harvested from all four tube types. Further, the study verifies specimen stability at room temperature (15-30°C) for plasma left on the cells and for serum left on the clot or separator for:

≤ 8 hours on the clot, red blood cells, or separator gel; and .
≤ 24 hours off the clot, red blood cells, or separator gel. .

Refrigerated:

Specimens are stable for up to 48 hours when stored refrigerated (2-8°C) for plasma and serum harvested from all four tube types (off the clot, red blood cells, or separator gel).

Freeze-Thaw Cycles:

The study verifies specimen stability for up to 3 freeze/thaw cycles for plasma harvested from an EDTA tube and for serum harvested from a no-additive serum tube or from a serum separator tube. In addition, specimens are stable for 1 freeze/thaw cycle for plasma harvested from a lithium heparin plasma draw tube.

Frozen Short Term:

The study verifies short term frozen (-10°C or colder) specimen stability for up to 15 days for all four tube types (off the clot, red blood cells, or separator gel).

Frozen Long Term:

Sample stability studies that support 18-month stability at -70°C were performed on the MOSES clinical samples in DEN150009. In addition, long-term frozen stability was evaluated with MOSES samples on the ARCHITECT assay (see summary in Section 2 below).

i. Matrix Comparison

The Anticoagulant Matrix Comparison Study followed the guidance of the CLSI Guideline EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples. Matched set specimens were prospectively collected from donors located in various departments (e.g., Emergency Department, Critical Care Unit, or In-Patient Unit) at two hospitals sites in Switzerland. Four tube types were collected from each donor:

1. K2 EDTA Plasma
1. Serum
1. Lithium Heparin Plasma
1. Serum Separator Tube (SST)

For each patient, each sample was tested in duplicate per sample matrix. Results from serum and lithium heparin plasma were compared to the K2EDTA base tube. The data verify that the bias for Lithium heparin plasma, Serum, and SST with respect to the K2EDTA draw tube is +2%, -4%, and -6%, respectively. Therefore, these four tube types are considered equivalent.

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k. Method Comparison

The Method Comparison Study followed the guidance of CLSI Document EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples. A correlation study using human K2EDTA plasma specimens (n = 142) was performed. The specimens were tested with the ARCHITECT B.R.A.H.M.S PCT assay and compared to values obtained with the B.R.A.H.M.S PCT sensitive KRYPTOR assay. Each donor sample was thawed and run on both instruments on the same day. The results were evaluated using a weighted Deming regression method. The data demonstrates that the comparison of the ARCHITECT B.R.A.H.M.S PCT results to the predicate B.R.A.H.M.S PCT sensitive KRYPTOR® results yielded a slope of 1.00, and a correlation coefficient of 0.99. The data are summarized in the following table and figure.

Concentration Range (ng/mL)
ARCHITECTB.R.A.H.M.S PCT assay	B.R.A.H.M.S PCT sensitiveKRYPTOR assay	CorrelationCoefficient	Slope	Intercept
0.01 - 91.03	0.03 - 82.39	0.99	1.00	-0.02

Image /page/19/Figure/3 description: This image is a scatter plot that compares the ARCHITECT Mean to the Kryptor Mean, both measured in ng/mL. The plot includes a best fit line, represented by the equation ARCHITECT Mean = -0.02 + 1.00 * Kryptor Mean. The correlation coefficient (r) is 0.99, based on a sample size of n = 142, indicating a strong positive correlation between the two variables. The plot also displays the 95% confidence interval of the fit.

2. Clinical Studies

The ARCHITECT B.R.A.H.M.S PCT assay was evaluated for the prediction of cumulative 28-day all-cause mortality in a prospective clinical trial (MOSES study -Procalcitonin Monitoring Sepsis Study; ClinicalTrials.gov Identifier: NCT01523717) of 858 adult patients diagnosed with severe sepsis or septic shock admitted to ICU care. PCT levels were measured on Days 0, 1, and 4 across the 13 investigational sites in the

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United States. The analysis population (598 subjects) included 44% female and 56% male patients with a mean age of 64 years. About half of the patients had severe sepsis (51%) versus (vs.) septic shock (49%). Infections were mainly community acquired (91%). Testing was performed at 2 external sites and one internal site. Validation of the ARCHITECT B.R.A.H.M.S PCT assay as an aid in predicting mortality was performed in a study population with an overall 28-day mortality of 22%.

The binary test result (ΔPCT > 80% or ≤ 80%) was significantly associated with 28-day cumulative mortality (i.e., vital status on Day 28). The 2-sided Fisher's exact test p-value was 0.001. Adjusted for ICU vs. non-ICU patient subgroups (based on patient location at Day 4 after initial diagnosis), the association remained significant (Cochran-Mantel-Haenszel test p-value = 0.017). In each binary ΔPCT subgroup, the 28-day cumulative mortality rate was stratified by need to continue ICU care on Day 4 and the selection of Day 0 vs. Day 1 as the baseline measurement day for the ΔPCT calculation:

28-Day Mortality Risk Stratified by Patient Location on Day 4:ΔΡCT > 80% = Test Negative; ΔΡCT ≤ 80% = Test Positive
		Mortality (%)		Prognostic Accuracya
APCT Interval	Day 4 PatientLocation	ΔPCT > 80%(95% CI)	ΔPCT ≤ 80%(95% CI)	Sensitivity (%)(95% CI)	Specificity (%)(95% CI)
Day 0 to Day 4	ICU	20.7(12.4-29.0)	30.6(23.7-37.5)	73.4(63.2-83.7)	38.0(31.0-45.0)
	Non-ICU	5.7(2.1-9.4)	11.4(6.7-16.2)	68.8(51.8-85.7)	49.1(43.1-55.1)
Day 1 to Day 4	ICU	20.2(12.1-28.3)	31.2(24.2-38.3)	72.6(62.0-83.1)	40.4(33.3-47.5)
	Non-ICU	5.3(1.7-8.9)	11.6(6.9-16.3)	71.9(55.3-88.5)	47.6(41.5-53.7)

a Prognostic accuracy refers to how accurate the ΔPCT (> 80% vs. ≤ 80%) can predict mortality risk.

Additional stratification of patients based on absolute initial PCT concentrations (> 2.0 ng/mL or < 2.0 ng/mL) at Day 0 (or Day 1) revealed subgroups with particularly reduced or elevated mortality risk considering their hospital disposition on Day 4. Mortality risk and prognostic performance are given for the following subgroups in the tables below:

1. Patients with PCT > 2.0 ng/mL at Day 0 (or Day 1) receiving ICU care on Day 4
1. Patients with PCT < 2.0 ng/mL at Day 0 (or Day 1) receiving ICU care on Day 4
1. Patients with PCT > 2.0 ng/mL at Day 0 (or Day 1) without ICU care on Day 4
1. Patients with PCT ≤ 2.0 ng/mL at Day 0 (or Day 1) without ICU care on Day 4

28-Day Mortality Risk Stratified by Patient Location on Day 4:ΔPCT > 80% = Test Negative; ΔPCT ≤ 80% = Test Positive
ΔPCTInterval	Day 4 PatientLocation	Initial PCTConcentration(Day 0 or Day 1)	Mortality (%)		Prognostic Accuracya
			ΔPCT > 80%(95% CI)	ΔPCT ≤ 80%(95% CI)	Sensitivity (%)(95% CI)	Specificity (%)(95% CI)

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28-Day Mortality Risk Stratified by Patient Location on Day 4:ΔΡСТ > 80% = Test Negative; ΔΡCT ≤ 80% = Test Positive
		Initial PCTConcentration(Day 0 or Day 1)	Mortality (%)		Prognostic Accuracya
APCTInterval	Day 4 PatientLocation		ΔΡCT > 80%(95% CI)	ΔΡCT ≤ 80%(95% CI)	Sensitivity (%) Specificity (%)(95% CI)	(95% CI)
Day 0 toDay 4	ICU	≤ 2.0 ng/mL	7.3(0.0-21.1)	24.7(14.5-34.9)	94.1(82.8-100.0)	20.7(10.6-30.8)
		> 2.0 ng/mL	23.2(13.8-32.6)	34.5(25.4-43.7)	66.5(53.9-79.2)	46.8(38.0-55.6)
	Non-ICU	≤ 2.0 ng/mL	3.3(0.0-9.8)	8.6(3.5-13.7)	90.9(73.9-100.0)	21.6(14.0-29.1)
		> 2.0 ng/mL	6.3(2.1-10.5)	17.0(7.2-26.7)	55.2(32.1-78.3)	71.1(63.7-78.6)
Day 1 toDay 4	ICU	≤ 2.0 ng/mL	12.4(0.0-32.3)	25.7(15.1-36.2)	91.7(77.7-100.0)	17.9(8.0-27.7)
		> 2.0 ng/mL	21.3(12.5-30.1)	35.0(25.6-44.5)	65.7(52.8-78.7)	50.9(42.2-59.7)
	Non-ICU	≤ 2.0 ng/mL	0.0(0.0-12.3)b	8.5(3.5-13.5)	100.0(69.2-100.0)b	19.8(12.5-27.1)
		> 2.0 ng/mL	6.5(2.1-10.9)	18.2(7.9-28.5)	56.1(33.1-79.0)	71.4(63.7-79.1)

a Prognostic accuracy refers to how accurate the ΔPCT (> 80% vs.≤ 80%) can predict mortality risk. b Normality approximation of within-imputation variance not valid, therefore the estimate corresponds to withinimputation variation based on exact confidence intervals.

The relative mortality ratios for ΔPCT positive (< 80%) vs. ΔPCT negative (> 80%) patient subgroups were:

1.49 for patients with PCT > 2.0 ng/mL at Day 0 receiving ICU care on Day 4 .
3.38 for patients with PCT ≤ 2.0 ng/mL at Day 0 receiving ICU care on Day 4 .
2.70 for patients with PCT > 2.0 ng/mL at Day 0 without ICU care on Day 4 .
2.61 for patients with PCT < 2.0 ng/mL at Day 0 without ICU care on Day 4 .

Based on relative mortality ratios, a decrease in PCT concentration by < 80% from Day 0 (or Day 1) to Day 4 constitutes a higher risk for mortality within 28 days compared to > 80% decreases in each subgroup.

Time-to-event analyses, illustrated by the Kaplan-Meier curves below, demonstrate that patients had a lower survival probability (higher cumulative mortality risk) from Day 4 until the end of follow-up time (Day 28) when the APCT test result was positive compared to when the ΔPCT result was negative in all patient subgroups according to patient location on Day 4 and initial PCT concentration.

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Image /page/22/Figure/0 description: This image is a survival curve comparing two groups of patients. The x-axis represents time in days, ranging from 0 to 28, and the y-axis represents the proportion of patients surviving, ranging from 0% to 100%. The dashed line represents patients with negative delta PCT (n=78, deaths=18), while the solid line represents patients with positive delta PCT (n=104, deaths=36). The survival rate is higher for patients with negative delta PCT compared to those with positive delta PCT.

Survival until Day 28, PCT > 2.0 ng/mL at Day 0, ICU Day 4 (n=182)

Survival until Day 28, PCT > 2.0 ng/mL at Day 0, Non-ICU Day 4 (n=187)

Image /page/22/Figure/3 description: This image is a survival analysis plot comparing two groups of patients based on their delta procalcitonin (ΔPCT) levels. The x-axis represents time in days, ranging from 0 to 28, while the y-axis represents the proportion of patients surviving, ranging from 0% to 100%. The dashed line represents patients with negative ΔPCT (n=128, deaths=8), and the solid line represents patients with positive ΔPCT (n=59, deaths=10). The survival rate is higher for patients with negative ΔPCT compared to those with positive ΔPCT over the 28-day period.

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Image /page/23/Figure/0 description: This image is a survival plot comparing two groups of patients, one with negative ΔPCT and the other with positive ΔPCT. The x-axis represents time in days, ranging from 0 to 28, while the y-axis represents the proportion of patients surviving. The plot shows that patients with negative ΔPCT have a higher survival rate compared to those with positive ΔPCT. Specifically, the negative ΔPCT group had 14 patients with 1 death, while the positive ΔPCT group had 69 patients with 17 deaths.

Survival until Day 28, PCT ≤ 2.0 ng/mL at Day 0, ICU Day 4 (n=84)

Survival until Day 28, PCT ≤ 2.0 ng/mL at Day 0, Non-ICU Day 4 (n=147)

Image /page/23/Figure/3 description: The image is a survival plot showing the proportion of patients surviving over time in days. The x-axis represents time in days from 0 to 28, and the y-axis represents the proportion of patients surviving from 0% to 100%. There are two survival curves, one for patients with negative delta PCT (n=30, deaths=1) and one for patients with positive delta PCT (n=116, deaths=10). The survival rate is higher for patients with negative delta PCT compared to those with positive delta PCT.

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For the prediction of absolute mortality risks, patient location on Day 4 and initial PCT concentration should be considered:

An initial PCT concentration ≤ 2.0 ng/mL on Day 0 followed by a PCT concentration . decrease of more than 80% by Day 4 indicates approximately a one-third lower cumulative 28-day mortality risk (7.3%) for patients with severe sepsis or septic shock who are still in the ICU by Day 4 compared to those patients with an initial PCT concentration > 2.0 ng/mL (23.2%). Regardless of the initial PCT concentration, patients in the ICU on Day 4 that do not have a PCT concentration decrease of more than 80% in PCT plasma concentration from Day 0 to Day 4 have even higher mortality risks of 24.7% and 34.5%.
An initial PCT concentration > 2.0 ng/mL that does not decrease by more than 80% ● by Day 4 signals that such patients remain at high mortality risk (17.0%) even when they are no longer receiving ICU care on Day 4. Mortality was otherwise observed between 3.3% to 8.6% for patients discharged from the ICU by Day 4. ΔPCT from Day 0 to Day 4 (≤ 80% vs. > 80%) as a prognostic for 28-day cumulative risk of mortality was quantified by Cox proportional hazards regression analysis with a hazard ratio of 1.99 (95% CI of 1.28–3.09, p-value = 0.0021). The relative risk of cumulative 28-day mortality is about 2-fold higher if an individual tests positive for ΔPCT (≤ 80%) than if an individual tests negative (> 80%).

Predictors	Comparison	Hazard Ratio	95% CI	p-Value
ΔPCT (Day 0 to Day4)	≤ 80% vs. > 80%	1.99	1.28-3.09	0.002
ΔPCT (Day 1 to Day4)	≤ 80% vs. > 80%	2.03	1.30-3.18	0.002
APACHEa	Difference of 5 Units	1.36	1.22-1.53	< 0.001
Maximum SOFA	Difference of 3 Units	1.73	1.50-2.00	< 0.001
Antibiotic Adequacy	No vs. Yes	1.59	1.00-2.53	0.051
Sepsis Severity	Septic Shock vs.Severe Sepsis	1.19	0.80-1.76	0.386
Biological InfectionType	Gram Positive vs.Gram Negative	0.83	0.48-1.45	0.522
	Other vs. GramNegative	0.99	0.63-1.54	0.960
	Fungal vs. GramNegative	2.44	0.87-6.84	0.090
Clinical Infection Type	Nosocomial vs.Community	0.76	0.35-1.64	0.481
Positive Blood Culture	Yes vs. No	1.05	0.69-1.58	0.834

As a comparison, the table below lists the univariate hazard ratios for other clinical factors evaluated as separate predictors of mortality in the study population.

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Predictors	Comparison	Hazard Ratio	95% CI	p-Value
PCT on Day 0	> 2 ng/mL vs. ≤ 2ng/mL	1.59	1.04-2.45	0.034
Age	Difference of 5 Years	1.16	1.08-1.24	< 0.001
Gender	Male vs. Female	0.95	0.64-1.40	0.782
ICU Care on Day 4	Yes vs. No	3.45	2.24-5.31	< 0.001

a Acute Physiology and Chronic Health Evaluation

ΔPCT from Day 0 (or Day 1) to Day 4 remains a prognostic parameter for the risk of cumulative 28-day mortality in patients diagnosed with severe sepsis or septic shock even when the hazard ratio is adjusted for other mortality predictors in Cox multiple regression models. The relative mortality risk estimates for APCT and selected predictors are presented below with 95% confidence intervals. For continuous predictors, the hazard ratio was calculated for one SD change in the predictor. For binary predictors, the risk estimate compares the hazards for the two binary results.

		Hazard Ratio (HR)(95% CI)
Model		Binary Predictors			Continuous Predictors (HR per 1 SD)
ΔPCT Interval	Score +Covariatesa	ΔPCT (≤ 80%vs. > 80%)	Day 4 PatientLocation (ICUvs. Non-ICU)	APACHE(1 SD = 8.13)	MaximumSOFA(1 SD = 3.98)	Age(1 SD = 16.18)
Day 0 to Day 4	APACHE	1.89(1.14-3.14)	2.59(1.61-4.15)	1.22(0.98-1.53)	N/A	1.60(1.28-2.00)
	MaximumSOFA	1.55(0.94-2.57)	1.70(1.03-2.80)	N/A	1.93(1.49-2.49)	1.69(1.35-2.11)
Day 1 to Day 4	APACHE	1.96(1.20-3.22)	2.61(1.63-4.18)	1.26(1.01-1.58)	N/A	1.56(1.24-1.95)
	MaximumSOFA	1.74(1.06-2.86)	1.72(1.05-2.83)	N/A	1.94(1.51-2.50)	1.65(1.32-2.06)

The change of PCT over time can also be described by the ratio of PCT concentrations from Day 4 and Day 0 (or Day 1):

$$\mathsf{PCT}{\mathsf{ratio}} = \frac{\mathsf{PCT}{\mathsf{Day},4}}{\mathsf{PCT}_{\mathsf{Day}} \bullet (\mathsf{or} \ \mathsf{copy} \ t)}$$

A decline of ΔPCT = 80% translates into a PCT ratio of 0.2. The PCT ratio has values larger than 0.2 when the ΔPCT decrease is less than 80%, which is associated with a higher risk for cumulative 28-day all-cause mortality in patients diagnosed with severe sepsis or septic shock. Likewise, a PCT ratio below 0.2 indicates a lower risk for mortality within 28 days. On a continuous scale, the relative mortality risk for such

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patients is higher the larger the PCT ratio. The following table lists the hazard ratios for an increase by the factor 2 in PCT ratio (i.e., the relative increase in mortality risk for a patient with any given PCT ratio compared to a patient with a 2-fold lower PCT ratio). For comparison, selected predictors are indicated with corresponding equivalents in standard deviation (0.53 SD for Day 0 until Day 4 and 0.72 SD for Day 1 until Day 4). For the patient location at Day 4, the risk estimate compares the hazards for patients with vs. without ICU care on Day 4.

		Hazard Ratio (95% CI)
Model		Continuous Predictors(HR per 2-fold increase in PCT ratio or per equivalent in SD)			BinaryPredictor
ΔPCTInterval	Score +Covariatesa	PCT Ratio (2-Fold Increase)	APACHE (SDEquivalent)b	MaximumSOFA (SDEquivalent)b	Age (SDEquivalent)b	Day 4 PatientLocationICU vs.Non-ICU
Day 0 toDay 4	APACHE	1.28(1.14-1.44)	1.07(0.95-1.21)	N/A	1.29(1.15-1.45)	2.50(1.55-4.02)
	MaximumSOFA	1.21(1.07-1.36)	N/A	1.36(1.19-1.55)	1.32(1.18-1.48)	1.69(1.02-2.78)
Day 1 toDay 4	APACHE	1.35(1.17-1.57)	1.18(1.01-1.38)	N/A	1.38(1.18-1.61)	2.54(1.58-4.06)
	MaximumSOFA	1.29(1.10-1.50)	N/A	1.55(1.31-1.84)	1.44(1.23-1.67)	1.74(1.06-2.86)

a The models also included the following predictors (hazard ratio results not shown): antibiotic adequacy, sepsis severity, biological infection type, clinical infection type, positive blood culture, PCT concentration on Day 0, and gender. b A unit change of ΔPCT on log-2-scale corresponded to 0.52 SD of ΔPCT from Day 0 until Day 4 (0.69 SD for ΔPCT from Day 1 until Day 4). Accordingly, the reported APCT hazard ratios refer to an increase of ΔPCT by a factor of 2. For comparability, hazard ratios of the other continuous predictors were estimated for the same fractional SD (i.e., 0.52 or 0.69, respectively).

Cumulative 28-day all-cause mortality did not differ significantly for male vs. female patients ($\chi^{2}$ p-value = 0.84). Demographics with outcome information are presented below:

Variable	Class	All Patients(n = 598)	Dead (n)	Alive (n)	Mortality (%)
Gender	Female	264	46	218	17.4%
	Male	334	55	279	16.5%
Age (Years)	≤ 30	39	1	38	2.6%
	> 30 to 45	45	4	41	8.9%
	> 45 to 55	74	8	66	10.8%
	> 55 to 65	149	26	123	17.4%
	> 65 to 75	125	21	104	16.8%
	> 75	166	41	125	24.7%
Ethnicity	African-American	202	32	170	15.8%
	Asian	7	0	7	0.0%
	Caucasian	362	64	298	17.7%

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Variable	Class	All Patients(n = 598)	Dead (n)	Alive (n)	Mortality (%)
	Hispanic	23	5	18	21.7%
	Other	4	0	4	0.0%
PCT on Day 0(ng/mL)	< 0.5	127	19	108	15.0%
(ng/mL)	0.5 to 2.0	96	10	86	10.4%
	> 2.0	360	72	288	20.0%
	Missing	15	0	15	0.0%

The clinical concordance analysis of the ARCHITECT B.R.A.H.M.S PCT clinical performance study showed more than 96% total agreement between the ARCHITECT B.R.A.H.M.S PCT and the B.R.A.H.M.S PCT sensitive Kryptor® (predicate device) at the medical decision points 0.5 µg/L and 2.0 µg/L.

3. Clinical Cut-Off

See Section N.1.h., Assay Cut-Off.

4. Expected Values/Reference Range

The Reference Range study was performed using the ARCHITECT B.R.A.H.M.S PCT Assay on normal healthy donor K2EDTA plasma collected from n=446 individuals, males (n=217) and females (n=229). The reference limits at the 2.5" and 97.5" percentiles were determined to be 0.006 ng/mL and 0.065 ng/mL, respectively.

AGE	N	Ethnicity
		African American	Asian	Caucasian	Hispanic	Other
< 60 years	407	292	28	55	27	5
≥ 60 years	39	13	1	18	7	0

O. INSTRUMENT NAME

ARCHITECT i2000sr Analyzer (K983212)

P. SYSTEM DESCRIPTION

1. Modes of Operation

The assay is an automated quantitative two-step chemiluminescent immunoassay run on the ARCHITECT iSystem.

2. Software

ARCHITECT iSystem Software version 9.00 was 510(k) cleared on April 28, 2016 (K151502).

3. Specimen Identification

Sample IDs can be entered manually or by barcode reader.

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4. Calibration

The ARCHITECT B.R.A.H.M.S PCT Calibrators kit consists of one vial of defibrinated human plasma free of PCT and five vials of liquid recombinant PCT (rPCT) in a Bovine Serum Albumin and phosphate solution. The calibration range is 0.00 - 100.00 ng/mL (0.00 - 100.00 ug/L).

Once an ARCHITECT B.R.A.H.M.S PCT calibration is accepted and stored, all subsequent samples may be tested without further calibration unless:

A reagent kit with a new lot number is used. .
Daily quality control results are outside of statistically based quality control limits . used to monitor and control system performance.
- If statistically based quality control limits are not available then the calibration । should not exceed a 30-day limit for recalibration frequency.

The ARCHITECT B.R.A.H.M.S PCT assay may also need to be recalibrated after specified service procedures have been performed or maintenance to critical part or subsystems that might influence the performance of the assay.

5. Quality Control

The recommended control requirement for the ARCHITECT B.R.A.H.M.S PCT assay is that a single sample of each control level be tested:

Once every 24 hours each day of use; .
After performing calibration; and ●
After instrument service procedures or maintenance that may affect assay . performance have been performed.

If the quality control procedures in the laboratory require more frequent use of controls to demonstrate test results, follow the laboratory-specific procedures. Additional controls may be tested in accordance with local, state, and/or federal regulations or accreditation requirements and the laboratory's quality control policy. Each laboratory should establish control ranges to monitor the acceptable performance of the assay. If a control is out of its specified range, the associated sample results are invalid and the samples must be retested. Recalibration may be indicated.

O. PROPOSED LABELING

The labeling satisfies the requirements of 21 CFR Parts 801 and 809 as well as the special controls for a PCT assay (21 CFR 866.3215).

R. CONCLUSION

The results of the analytical studies submitted in this 510(k) premarket notification are complete and demonstrate that the ARCHITECT B.R.A.H.M.S PCT, ARCHITECT B.R.A.H.M.S PCT Calibrators, and ARCHITECT B.R.A.H.M.S PCT Controls meet the established specifications necessary for consistent performance during the intended clinical use for the quantitative detection of procalcitonin (PCT) in human serum and plasma

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samples. The results support a decision that the ARCHITECT B.R.A.H.M.S PCT, Calibrators, and Controls are substantially equivalent to the predicate.

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.