Dimension EXL LOCI BRAHMS Procalcitonin (PCT)

• K Number: K220262
• Device Name: Dimension EXL LOCI BRAHMS Procalcitonin (PCT)
• Manufacturer: Siemens Healthcare Diagnostics, Inc.
• Date Cleared: 2022-08-26 ( 207 days)
• Product Code: PRI , PMT
• Regulation Number: 866.3215
• Type: Traditional
• Panel: Microbiology
• Reference & Predicate Devices: N/A
• Predicate For: N/A

Intended Use

The Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay is an in vitro diagnostic test for the quantitative measurement of procalcitonin in human serum and plasma (lithium heparin, K2EDTA, and K3EDTA) using the Dimension® EXL™ integrated chemistry system with LOCI® Module.

The Dimension EXL LOCI® BRAHMS PCT assay is intended for use in conjunction with other laboratory findings and clinical assessments, 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.

• 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 percentage change in PCT levels over time.

· 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.

· Decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

Device Description

The Dimension EXL LOCI BRAHMS PCT assay is a homogeneous sandwich chemiluminescent immunoassay based on LOCI technology. The LOCI reagents include two synthetic bead reagents and one biotinylated anti-procalcitonin (anti-PCT) monoclonal antibody. The first bead reagent (Sensibeads) is coated with streptavidin and contains photosensitizer dye. The second bead reagent (Chemibeads) is coated with two anti-PCT monoclonal antibodies and contains chemiluminescent dye. Sample is incubated with biotinylated antibody and Chemibeads to form bead-PCT-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of the procalcitonin (PCT) concentration in the sample.

AI/ML Overview

The provided document describes the performance characteristics of the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay and its equivalence to a predicate device.

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

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Specific Criteria	Reported Device Performance
Precision	Within-lab %CV: ≤ 10.0% for QC1, QC2, QC3, Serum 2, 3, 4, 5; ≤ 15.0% for Plasma, Serum 1.	Lot FB1218: QC1 (4.3%), QC2 (2.2%), QC3 (2.5%), Plasma (4.0%), Serum 1 (4.0%), Serum 2 (2.7%), Serum 3 (2.0%), Serum 4 (1.5%), Serum 5 (2.7%). All Pass. Lot FC1218: QC1 (3.3%), QC2 (4.2%), QC3 (2.6%), Plasma (4.0%), Serum 1 (3.0%), Serum 2 (2.7%), Serum 3 (2.7%), Serum 4 (2.1%), Serum 5 (2.3%). All Pass.
	Total %CV: ≤ 10.0% for QC1, QC2, QC3, Serum 2, 3, 4, 5; ≤ 15.0% for Plasma, Serum 1.	Lot FB1218: QC1 (7.1%), QC2 (3.5%), QC3 (3.2%), Plasma (6.0%), Serum 1 (5.0%), Serum 2 (4.1%), Serum 3 (2.7%), Serum 4 (3.0%), Serum 5 (5.5%). All Pass. Lot FC1218: QC1 (6.2%), QC2 (4.5%), QC3 (3.2%), Plasma (6.0%), Serum 1 (6.0%), Serum 2 (3.6%), Serum 3 (3.2%), Serum 4 (3.1%), Serum 5 (5.8%). All Pass.
Reproducibility	Total Reproducibility (CV%) for various PCT levels. (No explicit criteria mentioned in the document, but results are provided indicating good reproducibility).	MDP1 (0.10 ng/mL): 7.0%, MDP2 (0.25 ng/mL): 4.4%, MDP3 (0.48 ng/mL): 3.8%, MDP4 (1.95 ng/mL): 3.8%, MDP5 (8.94 ng/mL): 4.2%, MDP6 (41.01 ng/mL): 9.3%.
Detection Capability	LoB < LoD, LoD ≤ 0.04 ng/mL, LoQ ≤ 0.05 ng/mL (using within-lab %CV of 20%).	LoB: 0.03 ng/mL, LoD: 0.04 ng/mL, LoQ: 0.05 ng/mL. All claims met.
Linearity	Regression statistics (deviation from linearity for non-linear pools) at all levels tested demonstrated a ≤20% deviation (≤ 0.04 ng/mL for the lowest sample) from the predicted linear fit.	The study demonstrated a linear range of 0.03 to 55.05 ng/mL, which supports a measuring interval of 0.05 to 50.00 ng/mL. Results met the acceptance criteria.
Dilution Recovery	Recoveries for all specimens ranged from 88 to 108%.	Ten native serum specimens diluted 1:20 with saline. Recoveries ranged from 88% to 108% (mean 98%). Pass. Manual dilution supports an extended measuring interval from 50.00 ng/mL to 1000.00 ng/mL.
Interference (HIL)	≤10% interference from hemoglobin, bilirubin, and lipemia.	Bilirubin (Conjugated/Unconjugated, 40 mg/dL): 0% or 1% bias. Hemoglobin (1000 mg/dL): -5% or -7% bias. Lipemia (2000 mg/dL): 0% or 3% bias. All met ≤10% criteria.
Non-Interfering Substances	Bias due to substances ≤10% at PCT analyte concentrations of 0.25 and 2.00 ng/mL.	Most substances tested (Acetaminophen, Acetylsalicylic acid, Amoxicillin, Azithromycin, Caffeine, Cefotaxime, Celecoxib, Cetirizine HCl, Cholesterol, Dextran 40, Dextromethorphan, Dobutamine, Dopamine, Doxycycline, EDTA, Epinephrine, Ethanol, Fentanyl, Fluorescein, Furosemide, HAMA (various concentrations, except high levels), Heparin, Human Immunoglobulin (IgG), Human serum albumin, Human serum gamma globulin, Ibuprofen, Imipenem, Levofloxacin, Loratadine, Nicotine, Noradrenaline, Oxymetazoline HCl, Phenylephrine, Prednisolone, Rheumatoid Factor, Salmeterol, Tiotropium, Triglycerides, Vancomycin) showed ≤10% bias.
Interfering Substances	Biotin >10% interference at >1200 ng/mL. HAMA >10% interference at 32.5 mg/mL (HAMA 1) and 65.0 mg/mL (HAMA 1 and 2), Total Protein >10% interference at 15.0 g/dL.	Biotin: >10% interference at 1500 ng/mL (-19% bias at 1.88 ng/mL PCT) and 3510 ng/mL (-26% to -29% bias). HAMA 1: -10% to -12% bias at 65.0 mg/mL and -11% to -12% bias at 32.5 mg/mL. HAMA 2: -14% to -13% bias at 65.0 mg/mL and -11% bias at 32.5 mg/mL (at 2.19 ng/mL PCT). Total Protein: -18% bias at 15.0 g/dL. These led to specific labeling cautions.
Cross-Reactivity	No explicit criterion provided, only results of testing.	No significant cross-reactivity observed with Calcitonin (Human, Eel, Salmon), Katacalcin (Human), α-CGRP, and β-CGRP. For example, Human Calcitonin at 8 ng/mL showed 0.00% to -0.50% cross-reactivity.
Hook Effect	No hook effect for PCT concentrations up to 2000.00 ng/mL.	For patient specimens with PCT concentrations between 50.00 ng/mL and 2000.00 ng/mL the assay will report results as "Above Assay Range" (> 50.00 ng/mL).
Sample Carryover	No sample carryover from high to low samples.	Calculated to be 0.00 ng/mL. No sample carryover observed.
Method Comparison	Strong correlation (r), passing Deming/Passing-Bablok regression, high percentage agreement at clinical cutoffs with predicate device.	Measuring Interval (0.05-50.00 ng/mL): Lot FB1218: r = 0.958, Slopes 1.07, Intercepts -0.01. Lot FC1218: r = 0.963, Slopes 1.04, Intercepts 0.00 to -0.01. Positive % agreement: 96.1-97.8%, Negative % agreement: 89.1-97.5%, Overall % agreement: 95.9-97.5% across various cut-offs (0.10, 0.25, 0.50, 2.00 ng/mL). Extended Measuring Interval (0.05-1000.00 ng/mL): Lot FB1218: r = 0.988, Slopes 1.08, Intercepts -0.01. Lot FC1218: r = 0.991, Slopes 1.05, Intercepts 0.00 to -0.01. Positive % agreement: 96.5-98.0%, Negative % agreement: 89.1-97.5%, Overall % agreement: 96.1-97.6% across various cut-offs. These results demonstrate substantial equivalence to the predicate device.
Matrix Comparison	No significant difference based on Passing-Bablok regression analysis between serum and plasma samples.	All specimen types (Serum (SST), Serum (RST), Lithium Heparin plasma, Sodium Heparin plasma, K2EDTA plasma, and K3EDTA plasma) showed high correlation coefficients (0.996-0.998) and regression equations close to y=x (slopes around 0.98-1.00, intercepts around 0.00-0.01 ng/mL) when compared to Serum (SST), indicating no significant difference.
Reference Interval Verification	Reference interval claim of <0.10 ng/mL verified.	The reference interval claim in the Instructions For Use is <0.10 ng/mL [<0.10 µg/L] verified using 33 apparently healthy individuals.
Reagent Stability	Real-time shelf life (12 months), Calibration interval (7 days), Unopened onboard stability (30 days), Opened onboard stability (3 days).	Shelf life: Two lots demonstrated 12 months of stability (ongoing). Calibration interval: Results support 7 days. Unopened onboard stability: Results support 30 days. Opened onboard stability: Results support 3 days.
Sample Stability	Storage and handling recommendations in IFU are supported (room temp 8h, refrig 24h, frozen -70C/90d -20C/90d, 6 freeze-thaw cycles, onboard 1h).	Studies supported all specified conditions for serum and plasma tube types (SST, RST, Li Hep, Na Hep, K2EDTA, K3EDTA) at various PCT levels, showing accurate results.

2. Sample sizes for the test set and data provenance:

• Precision Studies: 80 replicates for each sample (QC and serum/plasma pools) for each lot (total 2 lots tested).
• Reproducibility Study: 225 replicates per sample ID (5 replicates/day x 5 days x 3 instruments x 3 reagent lots).
• Detection Capability: No specific sample size mentioned, CLSI EP17-A2 was referenced.
• Linearity: 16 samples.
• Dilution Recovery: 10 native serum specimens.
• Interference and Cross-Reactivity: Human serum pools, specifically "approximately 0.25 ng/mL and 2.00 ng/mL PCT". The exact number of individual samples is not explicitly stated.
• Hook Effect: Testing for PCT concentrations up to 2000.00 ng/mL. Number of samples not explicitly stated.
• Sample Carryover: 11 separate runs, each testing a pattern of high and low samples (21 tests per run).
• Method Comparison: 595 native human serum samples within the concentration range of 0.05-1000.00 ng/mL.
• Matrix Comparison: 76 matched sets (Serum, Lithium Heparin plasma, Sodium Heparin plasma, K2EDTA plasma, and K3EDTA plasma - except RST with 75 matched sets).
• Reference Interval Verification: Serum and plasma specimens from 33 apparently healthy individuals.

Data Provenance: The studies used human serum and plasma samples, as indicated by terms like "native human serum samples" and "patient-sourced internal standards." The document does not specify the country of origin, but it mentions Siemens Healthcare Diagnostics, Inc. in Newark, Delaware, USA, as the applicant. The nature of the studies (e.g., method comparison, stability) suggests these are retrospective analyses of collected samples or controlled laboratory experiments. It does not explicitly state prospective or retrospective data collection for all studies, but method comparison using "native human serum samples" implies existing clinical samples from a test set.

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

This device is an in vitro diagnostic (IVD) test for quantitative measurement of procalcitonin (PCT). The "ground truth" here is not established by human readers/experts in the same way as, for example, a diagnostic imaging AI. Instead, the ground truth for this type of device is based on:

• Reference Method/Predicate Device: For method comparison, the predicate device (B·R·A·H·M·S PCT sensitive KRYPTOR) serves as the reference for comparison.
• Analytical Standards: For studies like linearity, detection capability, and precision, the "ground truth" or true value of PCT is established using known concentrations in control materials, calibrators, or by spiking samples with recombinant PCT. These are typically prepared and validated by qualified laboratory professionals following established analytical chemistry principles and CLSI guidelines.
• Defined Clinical Cut-offs: While the device aids in decision-making, the clinical cut-offs (e.g., 0.10 ng/mL, 0.25 ng/mL) are established within medical guidelines and clinical practice, not by individual experts for the purpose of validating this specific device's performance.

Therefore, the concept of "number of experts and their qualifications for establishing ground truth" as it applies to image interpretation AI is not directly applicable here. The "experts" would be the scientists and laboratorians who designed and executed the analytical validation studies according to CLSI guidelines and robust quality control practices.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

Adjudication methods like 2+1 or 3+1 are typically used in studies involving human readers interpreting diagnostic images or clinical cases where disagreement needs to be resolved by a tie-breaker. This is an in vitro diagnostic assay with quantitative results. Therefore, adjudication in that sense is not applicable or done. The performance is assessed against quantitative metrics, reference methods, or predicate devices.

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:

An MRMC comparative effectiveness study is not applicable for this device. This is a standalone in vitro diagnostic assay that provides a quantitative measurement of a biomarker (PCT) in clinical specimens. It does not involve human readers interpreting cases with or without AI assistance, nor does it involve improving human reader performance.

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

Yes, the studies presented are all standalone performance studies for the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay. The device measures PCT levels directly from patient samples, and its performance characteristics (precision, linearity, detection capability, interference, method comparison, etc.) are evaluated intrinsically without direct human interpretation influencing the measurement outcome. The role of the human is in operating the instrument, collecting samples, and interpreting the numerical results in a clinical context.

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

The ground truth used for this quantitative in vitro diagnostic device is primarily based on:

• Assigned Values of Calibrators and Control Materials: For accuracy, precision, and linearity studies, known concentrations of PCT in calibrators and quality control materials serve as the ground truth. These values are established through rigorous analytical methods and traceability chains.
• Reference Method/Predicate Device Results: In the method comparison study, the results from the legally marketed predicate device (B·R·A·H·M·S PCT sensitive KRYPTOR) are used as the reference against which the candidate device's performance is compared to establish substantial equivalence.
• Spiking with Recombinant Procalcitonin: For studies like dilution recovery, interference, and cross-reactivity, samples are often "spiked" with known concentrations of highly purified recombinant procalcitonin (or interfering substances) to create samples with a known "true" concentration of the analyte for testing the assay's behavior.

8. The sample size for the training set:

This document describes the validation of an in vitro diagnostic assay, not a machine learning or AI algorithm in the context of typical "training" and "test" sets. Therefore, there isn't a "training set" in the sense of data used to train a predictive model. The development of such assays involves extensive R&D and analytical optimization, but a specific "training set sample size" as asked in the context of AI is not applicable.

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

As mentioned above, there is no "training set" in the AI/ML context. The development and optimization of an IVD assay like this involve:

• Immunoassay Design: Selection of specific antibodies (monoclonal anti-PCT antibodies) that bind to the analyte.
• Reagent Formulation: Optimizing concentrations of reagents (sensibeads, chemibeads, biotinylated antibody, assay buffer) and reaction conditions to achieve desired sensitivity, specificity, and dynamic range.
• Analytical Verification Studies: These studies (like those described in the document, e.g., precision, linearity, detection capability) are used iteratively during development to ensure the assay performs as intended. The "ground truth" during this phase would be known concentrations of purified analyte, reference materials, and comparison to established methods or predicate devices.

The "ground truth" is thus established through fundamental analytical chemistry principles, quantitative measurements, and comparison to internationally recognized standards or well-characterized reference materials and methods.

Summary

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August 26, 2022

Siemens Healthcare Diagnostics, Inc. Amy Tyler Regulatory Affairs Professional 500 GBC Drive, P.O. Box 6101 Mail Stop 514 Newark, Delaware 19714

Re: K220262

Trade/Device Name: Dimension EXL LOCI BRAHMS Procalcitonin (PCT) 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: Class II Product Code: PRI, PMT Dated: January 26, 2022 Received: January 31, 2022

Dear Amy Tyler:

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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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

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Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely.

for

Noel Gerald Branch Chief Division of Microbiology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K220262

Device Name Dimension EXL LOCI BRAHMS Procalcitonin (PCT)

Indications for Use (Describe)

The Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay is an in vitro diagnostic test for the quantitative measurement of procalcitonin in human serum and plasma (lithium heparin, K2EDTA, and K3EDTA) using the Dimension® EXL™ integrated chemistry system with LOCI® Module.

The Dimension EXL LOCI® BRAHMS PCT assay is intended for use in conjunction with other laboratory findings and clinical assessments, 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.

• 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 percentage change in PCT levels over time.

· 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.

· 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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This 510(k) Summary of Safety and Effectiveness is being submitted in accordance with the requirements of 21 CFR 807.92 and the Safe Medical Device Act of 1990.

The assigned 510(k) Number is: K220262

1. Date Updated

August 24, 2022

2. Applicant Information

Contact:	Amy TylerRegulatory Affairs Professional
Address:	Siemens Healthcare Diagnostics, Inc.500 GBC Drive, P.O. Box 6101Mail Stop 514Newark, DE 19714, USA
Email:	[e-mail]

3. Regulatory Information

Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT)

Trade Name:	Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT)
Classification Name:	Procalcitonin Assay: Device to detect and measure non-microbialanalyte(s) in human clinical specimens to aid in assessment of patientswith suspected sepsis.
FDA Classification:	Class II
Review Panel:	Microbiology
Product Codes:	PRI, PMT
Regulation Numbers:	21 CFR 866.3215

4. Predicate Device Information

Device Name: B·R·A·H·M·S PCT sensitive KRYPTOR 510(k) Number: DEN150009/K171338 Manufacturer: B·R·A·H·M·S GmbH (Thermo Fisher Scientific)

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5. Intended Use / Indications For Use

The Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay is an in vitro diagnostic test for the quantitative measurement of procalcitonin in human serum and plasma (lithium heparin, sodium heparin, K2EDTA, and K3EDTA) using the Dimension® EXL™ integrated chemistry system with LOCI® Module.

The Dimension EXL LOCI® BRAHMS PCT assay is intended for use in conjunction with other laboratory findings and clinical assessments, 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.
• . 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 percentage change in PCT levels over time.
• . 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.
• Decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

6. Special Conditions for Use Statement

For Prescription Use Only

7. Warnings and Precautions for Test Interpretation

• The Dimension EXL LOCI BRAHMS 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, such as age and Sequential Organ Failure Assessment (SOFA) score, are also significant predictors of 28-day cumulative mortality risk.
• . PCT levels may not be elevated in patients infected by certain atypical pathogens, such as Chlamydophila pneumoniae and Mycoplasma pneumoniae.
• 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.
• . The safety and performance of PCT-guided therapy for individuals younger than 18 years of age, pregnant women, immunocompromised individuals, or those on immunomodulatory agents, was not formally analyzed in the supportive clinical trials.
• Increased PCT levels may not always be related to systemic infection. These conditions include, but are not limited to:

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• Patients experiencing major trauma and/or recent surgical procedure, including O extracorporeal circulation or burns;
• Patients under treatment with OKT3 antibodies, OK-432, interleukins, TNF-alpha, and O other drugs stimulating the release of pro-inflammatory cytokines or resulting in anaphylaxis;
• Patients diagnosed with active medullary C-cell carcinoma, small cell lung carcinoma, or O bronchial carcinoid;
• Patients with acute or chronic viral hepatitis and/or decompensated severe liver O cirrhosis (Child-Pugh Class C);
• Patients with prolonged or severe cardiogenic shock, prolonged severe organ perfusion O anomalies, or after resuscitation from cardiac arrest;
• O Patients receiving peritoneal dialysis or hemodialysis treatment;
• O Patients with biliary pancreatitis, chemical pneumonitis, or heat stroke;
• Patients with invasive fungal infections (such as candidiasis and aspergillosis) or acute O attacks of plasmodium falciparum malaria; and
• Neonates during the first 2 days of life. O

8. Special Instrument Requirement

For use on the Dimension® EXL™ integrated chemistry system with LOCI® Module.

9. Test Principle and Device Description

The Dimension EXL LOCI BRAHMS PCT assay is a homogeneous sandwich chemiluminescent immunoassay based on LOCI technology. The LOCI reagents include two synthetic bead reagents and one biotinylated anti-procalcitonin (anti-PCT) monoclonal antibody. The first bead reagent (Sensibeads) is coated with streptavidin and contains photosensitizer dye. The second bead reagent (Chemibeads) is coated with two anti-PCT monoclonal antibodies and contains chemiluminescent dye. Sample is incubated with biotinylated antibody and Chemibeads to form bead-PCT-biotinylated antibody sandwiches. Sensibeads are added and bind to the biotin to form bead-pair immunocomplexes. Illumination of the complex at 680 nm generates singlet oxygen from Sensibeads which diffuses into the Chemibeads, triggering a chemiluminescent reaction. The resulting signal is measured at 612 nm and is a direct function of the procalcitonin (PCT) concentration in the sample.

Component	Volume	Ingredients
Biotinylated AntibodyWell 1 (W1) and Well 2 (W2)Reagent 1 (R1)	1.0 mL	PCT Biotinylated Antibody-mouse monoclonal(3.5 µg/mL), bovine serum albumin, bovinegamma globulin, goat serum, mouse IgG, ratIgG, sodium azide (<0.1%), buffer,preservatives, and stabilizers
		ChemibeadWell 3 (W3) and Well 4 (W4)Reagent 2 (R2)	1.0 mL	PCT Chemibead reagent (40 µg/mL), bovineserum albumin, bovine gamma globulin, goatserum, sodium azide (<0.1%), buffer,preservatives, and stabilizers

The Dimension EXL LOCI BRAHMS PCT assay is comprised of the following reagents:

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Component	Volume	Ingredients
SensibeadWell 5 (W5) and Well 6 (W6)Reagent 3 (R3)	0.8 mL	PCT Sensibead reagent (1500 $ \mu $ g/mL), bovineserum albumin, buffer, preservatives, andstabilizers
	Assay bufferWell 7 (W7) and Well 8 (W8)Reagent 4 (R4)		3.0 mL (W7)2.6 mL (W8)	Assay buffer, bovine serum albumin, bovinegamma globulin, goat serum, mouse IgG,sodium azide (<0.1%), preservatives, andstabilizers

10. Purpose of Submission

The purpose of this submission is a premarket notification for a new device: Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT)

11. Comparison of Candidate Device and Predicate Device

The following table describes the similarities and differences between the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay (Candidate Device) and the B·R·A·H·M·S PCT sensitive KRYPTOR (Predicate Device).

	Candidate Device	Predicate Device
Attributes	Dimension® EXL™ LOCI®BRAHMS PCT	B·R·A·H·M·S PCT sensitiveKRYPTOR® (DEN150009 / K171338)
Intended Use (includingindications for use)	The Dimension® EXL™ LOCI®BRAHMS Procalcitonin (PCT)assay is an in vitro diagnostic testfor the quantitativemeasurement of procalcitonin inhuman serum and plasma(lithium heparin, sodium heparin,K2EDTA, and K3EDTA) using theDimension® EXL™ integratedchemistry system with LOCI®Module.The Dimension EXL LOCI®BRAHMS PCT assay is intendedfor use in conjunction with otherlaboratory findings and clinicalassessments, as an aid in:• The risk assessment ofcritically ill patients on theirfirst day of Intensive CareUnit (ICU) admission forprogression to severe sepsisand septic shock.	The B·R·A·H·M·S PCT sensitiveKRYPTOR® is animmunofluorescent assay usingTime-Resolved Amplified CryptateEmission (TRACE®) technology todetermine the concentration ofPCT (procalcitonin) in humanserum and EDTA or heparinplasma. The B·R·A·H·M·S PCTsensitive KRYPTOR® is intended tobe performed on the B·R·A·H·M·SKRYPTOR® analyzer family. Used inconjunction with other laboratoryfindings and clinical assessments,B·R·A·H·M·S PCT sensitiveKRYPTOR® is intended for use asfollows:• to aid in the risk assessment ofcritically ill patients on their firstday of ICU admission forprogression to severe sepsis andseptic shock,
Attributes	Candidate DeviceDimension® EXLTM LOCI®BRAHMS PCT	Predicate DeviceB-R-A-H-M-S PCT sensitiveKRYPTOR® (DEN150009 / K171338)
	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 percentage change in PCT levels over time. 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. Decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.	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
Analyte	Procalcitonin (PCT)	same
Automated	Automated assay	same
Measurement	Quantitative	same
Instrument	Dimension® EXLTM integratedchemistry system with LOCI®Module	KRYPTOR® Test System
Assay format	Sandwich immunoassay	Sandwich immunoassay
Technology	Chemiluminescent technology	Immunofluorescence TRACE®technologyTRACE: Time-Resolved AmplifiedCryptate Emission
Attributes	Candidate DeviceDimension® EXL™ LOCI®BRAHMS PCT	Predicate DeviceB·R·A·H·M·S PCT sensitiveKRYPTOR® (DEN150009 / K171338)
Specimen type	Serum, Plasma (lithium heparin,sodium heparin, K2EDTA, andK3EDTA)	Serum, Plasma (EDTA, lithiumheparin and sodium heparin)
Units of measure	Conventional units: ng/mLS.I. units: µg/L	µg/L
Assay Range / MeasuringInterval	0.05 to 50.00 ng/mLMeasuring range with manualdilution 0.05 to 1000.00 ng/mL	0.02 to 50 µg/LMeasuring range with automaticdilution 0.02 to 5000 µg/L
Sample volume	5µL	50µL
Calibration frequency	7 days	15 days
Calibrators	Dimension EXL LOCI BRAHMSProcalcitonin Calibrator (LOCI PCTCAL): 5-level frozen liquidproductLevel 1: bovine albumin-basedproduct with preservatives.Levels 2-5: serum-based productcontaining recombinant humanprocalcitonin and preservatives.	B·R·A·H·M·S PCT sensitiveKRYPTOR® Calibrator:Single level: 1 vial of lyophilizedrecombinant PCT in defibrinatedhuman plasma (range 22.50-27.50µg/L)

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12. Standard / Guidance Document References

The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:

• Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline-. Third Edition (CLSI EP05-A3; Recognition Number 7-251)
• Interference Testing in Clinical Chemistry (CLSI EP07-ED3; Recognition Number 7-275); for general use
• Measurement Procedure Comparison and Bias Estimation Using Patient Samples (CLSI EP09c-ED3; Recognition Number 7-296)
• Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline-Second Edition (EP17-A2; Recognition Number 7-233)
• . Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline (CLSI EP25-A; Recognition Number 7-235)
• . Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline – Third Edition (CLSI EP28-A3c; Recognition Number 7-224)
• . Establishing and Verifying an Extended Measuring Interval Through Specimen Dilution and Spiking (CLSI EP34-ED1; Recognition Number 7-290)
• Evaluation of Linearity of Quantitative Measurement Procedures (CLSI EP06-ED2; Recognition Number 7-306)

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13. Performance Characteristics for Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT)

13.1 Precision

The precision study was performed in accordance with CLSI EP05-A3. Samples were assayed on the Dimension® EXL™ 200 system in duplicate in two runs per day for 20 days. The following results were obtained:

Sample	Na	Meanng/mL(µg/L)	SDbng/mL(µg/L)	CVc(%)	SDng/mL(µg/L)	CV(%)	AcceptanceCriteria%CV	Result	AcceptanceCriteria%CV	Result
QC1	80	0.21(0.21)	0.009(0.009)	4.3	0.015(0.015)	7.1	≤ 10.0	PASS	≤ 15.0	PASS
QC2	80	0.98(0.98)	0.022(0.022)	2.2	0.034(0.034)	3.5	≤ 10.0	PASS	≤ 15.0	PASS
QC3	80	0.93(0.93)	0.023(0.023)	2.5	0.030(0.030)	3.2	≤ 10.0	PASS	≤ 15.0	PASS
Plasma	80	0.10(0.10)	0.004(0.004)	4.0	0.006(0.006)	6.0	≤ 15.0	PASS	≤ 20.0	PASS
Serum 1	80	0.10(0.10)	0.004(0.004)	4.0	0.005(0.005)	5.0	≤ 15.0	PASS	≤ 20.0	PASS
Serum 2	80	0.22(0.22)	0.006(0.006)	2.7	0.009(0.009)	4.1	≤ 10.0	PASS	≤ 15.0	PASS
Serum 3	80	0.44(0.44)	0.009(0.009)	2.0	0.012(0.012)	2.7	≤ 10.0	PASS	≤ 15.0	PASS
Serum 4	80	1.68(1.68)	0.026(0.026)	1.5	0.050(0.050)	3.0	≤ 10.0	PASS	≤ 15.0	PASS
Serum 5	80	8.56(8.56)	0.230(0.230)	2.7	0.472(0.472)	5.5	≤ 10.0	PASS	≤ 15.0	PASS

Precision data for Dimension EXL LOCI BRAHMS PCT lot FB1218

ª Number of replicates tested

b Standard deviation

° Coefficient of variation

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SpecimenType	Na	Meanng/mL(µg/L)	SDbng/mL(µg/L)	CVc(%)	SD(ng/mL)	CV(%)	AcceptanceCriteria%CV	Result	AcceptanceCriteria%CV	Result
QC1	80	0.21(0.21)	0.007(0.007)	3.3	0.013(0.013)	6.2	≤ 10.0	PASS	≤ 15.0	PASS
QC2	80	0.99(0.99)	0.042(0.042)	4.2	0.045(0.045)	4.5	≤ 10.0	PASS	≤ 15.0	PASS
QC3	80	0.94(0.94)	0.024(0.024)	2.6	0.030(0.030)	3.2	≤ 10.0	PASS	≤ 15.0	PASS
Plasma	80	0.10(0.10)	0.004(0.004)	4.0	0.006(0.006)	6.0	≤ 15.0	PASS	≤ 20.0	PASS
Serum 1	80	0.10(0.10)	0.003(0.003)	3.0	0.006(0.006)	6.0	≤ 15.0	PASS	≤ 20.0	PASS
Serum 2	80	0.22(0.22)	0.006(0.006)	2.7	0.008(0.008)	3.6	≤ 10.0	PASS	≤ 15.0	PASS
Serum 3	80	0.44(0.44)	0.012(0.012)	2.7	0.014(0.014)	3.2	≤ 10.0	PASS	≤ 15.0	PASS
Serum 4	80	1.69(1.69)	0.036(0.036)	2.1	0.053(0.053)	3.1	≤ 10.0	PASS	≤ 15.0	PASS
Serum 5	80	8.63(8.63)	0.199(0.199)	2.3	0.499(0.499)	5.8	≤ 10.0	PASS	≤ 15.0	PASS

Precision data for Dimension EXL LOCI BRAHMS PCT lot FC1218

ª Number of replicates tested

b Standard deviation

ک Coefficient of variation

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13.2 Reproducibility

The reproducibility study was performed in accordance with CLSI EP05-A3. Samples were assayed with (3) reagent lots on each of three (3) instruments over five (5) days with five (5) replicates per sample per day on each instrument with each reagent lot, yielding 75 results per reagent lot for each sample. Six (6) serum pools were included in this study. The following results were obtained:

SampleID	Na	Mean	Repeatability		Between-Day		Between-Lot		Between-Instrument		TotalReproducibility
			SDb	CVc	SD	CV	SD	CV	SD	CV	SD	CV
		ng/mL	ng/mL	%	ng/mL	%	ng/mL	%	ng/mL	%	ng/mL	%
MDP1	225	0.10	0.005	5.0	0.002	2.0	0.004	4.0	0.000	0.0	0.007	7.0
MDP2	225	0.25	0.008	3.2	0.005	2.0	0.005	2.0	0.000	0.0	0.011	4.4
MDP3	225	0.48	0.014	2.9	0.007	1.5	0.010	2.1	0.000	0.0	0.018	3.8
MDP4	225	1.95	0.046	2.4	0.039	2.0	0.045	2.3	0.000	0.0	0.075	3.8
MDP5	225	8.94	0.228	2.6	0.255	2.9	0.123	1.4	0.099	1.1	0.377	4.2
MDP6	225	41.01	2.538	6.2	2.289	5.6	1.073	2.6	1.350	3.3	3.828	9.3

	Reproducibility data summary for all reagent lots (reagent lots 1, 2, and 3)

ª Number of replicates tested

b Standard deviation

° Coefficient of variation

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13.3 Detection Capability

Detection capability was determined in accordance with CLSI EP17-A2.

Limit of Blank (LoB) is the highest value expected in a series of results on a human serum sample that contains no analyte. The assay is designed to have an LoB < Limit of Detection (LoD).

The Limit of Detection (LoD) corresponds to the lowest concentration of procalcitonin that can be detected with a probability of 95%. The assay is designed to have an LoD ≤ 0.04 ng/mL.

Limit of Quantitation (LoQ as functional sensitivity) is the lowest amount of procalcitonin in a material that can be quantitatively determined with stated accuracy. For this assay, the LoQ is defined as the concentration at which the CV is 20% in the precision profile. The assay is designed to have an LoQ ≤ 0.05 ng/mL (using within-lab %CV of 20%).

Attribute	Claim
LoB	0.03 ng/mL
LoD	0.04 ng/mL
LoQ	0.05 ng/mL
Lower Limit of AnalyticalMeasuring Range	0.05 ng/mL

The results are shown in the following table:

13.4 Linearity

Linearity was conducted according to CLSI EP06-ED2. The study was performed using 16 samples spanning the assay range, prepared using high and low human serum pools (11 levels were made using a high pool >50.00 ng/mL and 4 additional levels with concentrations near the lower medical decision levels were made with a second high pool targeted near 4.00 ng/mL).

Regression analysis using first, second, and third order models was conducted to determine the linearity of the assay. Regression statistics (i.e., deviation from linearity for non-linear pools) at all levels tested demonstrated a ≤20% deviation (≤ 0.04 ng/mL for the lowest sample) from the predicted linear fit.

The study demonstrated a linear range of 0.03 to 55.05 ng/mL, which supports a measuring interval of 0.05 to 50.00 ng/mL for the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay.

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13.5 Dilution Recovery

Dilution recovery (using manual dilution) was conducted according to CLSI EP34-ED1. Ten native serum specimens with concentrations determined to be greater than 50.00 ng/mL were diluted 1:20 with saline, which is the recommended diluent for this assay. Recoveries for all specimens ranged from 88 to 108% (mean % recovery was 98%). The following results were obtained:

Sample	Dilution	PCT Mean Results ng/mL (µg/L)		% Recovery
		Expected	Observed
1	1:20	411.3 (411.3)	390.60 (390.60)	95%
2	1:20	300.3 (300.3)	285.40 (285.40)	95%
3	1:20	394.4 (394.4)	413.60 (413.60)	105%
4	1:20	646.2 (646.2)	695.00 (695.00)	108%
5	1:20	203.2 (203.2)	178.80 (178.80)	88%
6	1:20	65.23 (65.23)	61.60 (61.60)	94%
7	1:20	72.43 (72.43)	73.40 (73.40)	101%
8	1:20	216.9 (216.9)	202.20 (202.20)	93%
9	1:20	124.1 (124.1)	118.80 (118.80)	96%
10	1:20	143.1 (143.1)	148.40 (148.40)	104%

Manual dilution of 1:20 increases the upper end of the analytical measuring interval which supports an extended measuring interval from 50.00 ng/mL (50.00 µg/L) to 1000.00 ng/mL (1000.00 µg/L).

13.6 Interference and Cross-Reactivity

Interference testing was conducted using EP07-ED3 for general guidance. Human serum pools at approximately 0.25 ng/mL and 2.00 ng/mL PCT were prepared by pooling native PCT. Each pool was divided into control and test pools were spiked with the potentially interfering substances and the control pools were spiked with an equivalent volume of diluent.

Percent interference (% bias) was calculated according to the following equation:

$$% \text{ Bias} = \frac{(\text{Observed Mean} - \text{Control Mean Concentration})}{\text{Control Mean concentration}} \times 100$$

Bias >10% is considered interference. Analyte results should not be corrected based on this bias.

The conversion factor from conventional units (ng/mL) to SI units (ug/L) is 1.00. Based on this, all results shown in ng/mL units would have the same values when displayed in µg/L units.

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Hemolysis, Icterus, and Lipemia (HIL)

The Dimension EXL LOCI BRAHMS PCT assay is designed to have ≤10% interference from hemoglobin, bilirubin, and lipemia. The following results were obtained:

Substance	Substance Concentration		PCT AnalyteConcentration(ng/mL)	% Bias
	Conventional Units	SI Units
Bilirubin, Conjugated	40 mg/dL	474 µmol/L	0.24	0
Bilirubin, Conjugated	40 mg/dL	474 µmol/L	2.02	0
Bilirubin, Unconjugated	40 mg/dL	684 µmol/L	0.22	0
Bilirubin, Unconjugated	40 mg/dL	684 µmol/L	1.75	1
Hemoglobin	1000 mg/dL	10 g/L	0.20	-5
Hemoglobin	1000 mg/dL	10 g/L	1.61	-7
Lipemia (from Intralipid®)	2000 mg/dL	20 g/L	0.21	0
Lipemia (from Intralipid®)	2000 mg/dL	20 g/L	1.69	3

Non-Interfering Substances

The following substances do not interfere with the Dimension EXL LOCI BRAHMS PCT assay when present in serum, lithium heparin plasma, sodium heparin plasma, K2EDTA plasma, or K3EDTA plasma. Bias due to these substances was ≤10% at PCT analyte concentrations of 0.25 and 2.00 ng/mL.

Substance	Substance Concentration		PCT AnalyteConcentrationng/mL	% Bias
	Conventional Units	SI Units
Acetaminophen	20 mg/dL	1324 µmol/L	0.25	-4
Acetaminophen	20 mg/dL	1324 µmol/L	2.02	1
Acetylsalicylic acid	3 mg/dL	166.5 µmol/L	0.24	4
Acetylsalicylic acid	3 mg/dL	166.5 µmol/L	2.04	0
Albumin	6 g/dL	60 g/L	0.21	-5
Albumin	6 g/dL	60 g/L	1.75	-9
Amoxicillin	5.4 mg/dL	147.96 µmol/L	0.22	5
Amoxicillin	5.4 mg/dL	147.96 µmol/L	1.81	2
Azithromycin	1.15 mg/dL	15.4 µmol/L	0.22	0
Substance	Substance Concentration		PCT AnalyteConcentrationng/mL	% Bias
	Conventional Units	SI Units
Azithromycin	1.15 mg/dL	15.4 µmol/L	1.78	-1
Caffeine	10.8 mg/dL	556.2 µmol/L	0.24	0
Caffeine	10.8 mg/dL	556.2 µmol/L	2.02	0
Cefotaxime	52.8 mg/dL	1161.6 µmol/L	0.25	0
Cefotaxime	52.8 mg/dL	1161.6 µmol/L	2.02	0
Celecoxib	0.88 mg/dL	23 µmol/L	0.22	0
Celecoxib	0.88 mg/dL	23 µmol/L	1.81	-1
Cetirizine HCl	0.43 mg/dL	11.1 µmol/L	0.22	0
Cetirizine HCl	0.43 mg/dL	11.1 µmol/L	1.81	-3
Cholesterol	400 mg/dL	10.4 mmol/L	0.22	-5
Cholesterol	400 mg/dL	10.4 mmol/L	1.73	-2
Dextran 40	4500 mg/dL	1125 µmol/L	0.26	-4
Dextran 40	4500 mg/dL	1125 µmol/L	2.12	-1
Dextromethorphan	0.00156 mg/dL	0.057 µmol/L	0.24	4
Dextromethorphan	0.00156 mg/dL	0.057 µmol/L	2.04	-5
Dobutamine	0.121 mg/dL	4 µmol/L	0.22	5
Dobutamine	0.121 mg/dL	4 µmol/L	1.81	-3
Dopamine	0.06 mg/dL	3.9 µmol/L	0.25	0
Dopamine	0.06 mg/dL	3.9 µmol/L	2.02	0
Doxycycline	1.8 mg/dL	40.5 µmol/L	0.22	0
Doxycycline	1.8 mg/dL	40.5 µmol/L	1.81	-4
EDTA	0.099 mg/dL	3.4 µmol/L	0.22	5
EDTA	0.099 mg/dL	3.4 µmol/L	1.75	3
Epinephrine	0.18 mg/dL	9.8 µmol/L	0.25	0
Epinephrine	0.18 mg/dL	9.8 µmol/L	2.02	1
Ethanol	400 mg/dL	86.8 mmol/L	0.24	0
Substance	Substance Concentration		PCT AnalyteConcentrationng/mL	% Bias
	Conventional Units	SI Units
Ethanol	400 mg/dL	86.8 mmol/L	2.02	-1
Fentanyl	0.03 mg/dL	0.89 µmol/L	0.24	0
Fentanyl	0.03 mg/dL	0.89 µmol/L	2.04	-1
Fluorescein	0.01 mg/dL	0.3 µmol/L	0.22	0
Fluorescein	0.01 mg/dL	0.3 µmol/L	1.75	0
Furosemide	2 mg/dL	60.4 µmol/L	0.24	-8
Furosemide	2 mg/dL	60.4 µmol/L	2.04	-1
HAMA	22.8 mg/mL	22.8 g/L	0.27	-7
HAMA	22.8 mg/mL	22.8 g/L	2.19	-9
Heparin	330 U/dL	3300 U/L	0.25	-4
Heparin	330 U/dL	3300 U/L	2.02	3
Human Immunoglobulin (IgG)	5 g/dL	50 g/L	0.23	-9
Human Immunoglobulin (IgG)	5 g/dL	50 g/L	1.80	-8
Human serum albumin	1 g/dL	10 g/L	0.22	5
Human serum albumin	1 g/dL	10 g/L	1.85	-1
Human serum gamma globulin	2.5 g/dL	25 g/L	0.26	-8
Human serum gamma globulin	2.5 g/dL	25 g/L	2.12	-7
Ibuprofen	21.9 mg/dL	1062.2 µmol/L	0.24	4
Ibuprofen	21.9 mg/dL	1062.2 µmol/L	2.04	-1
Imipenem	118 mg/dL	3941.2 µmol/L	0.22	5
Imipenem	118 mg/dL	3941.2 µmol/L	1.75	3
Levofloxacin	3.6 mg/dL	99.7 µmol/L	0.22	0
Levofloxacin	3.6 mg/dL	99.7 µmol/L	1.75	-1
Loratadine	0.0087 mg/dL	0.27 µmol/L	0.22	5
Loratadine	0.0087 mg/dL	0.27 µmol/L	1.81	-1
Nicotine	0.1 mg/dL	6.2 µmol/L	0.24	-4
Substance	Substance Concentration		PCT AnalyteConcentrationng/mL	% Bias
	Conventional Units	SI Units
Nicotine	0.1 mg/dL	6.2 µmol/L	2.04	-5
Noradrenaline	0.2 mg/dL	11.8 µmol/L	0.22	0
Noradrenaline	0.2 mg/dL	11.8 µmol/L	1.75	-2
Oxymetazoline HCl	9 µg/dL	0.3 µmol/L	0.25	0
Oxymetazoline HCl	9 µg/dL	0.3 µmol/L	2.02	2
Phenylephrine	0.003 mg/dL	0.179 µmol/L	0.25	0
Phenylephrine	0.003 mg/dL	0.179 µmol/L	2.02	1
Prednisolone	0.12 mg/dL	3.3 µmol/L	0.22	5
Prednisolone	0.12 mg/dL	3.3 µmol/L	1.81	-1
Rheumatoid Factor	500 IU/mL	500 IU/mL	0.21	-5
Rheumatoid Factor	500 IU/mL	500 IU/mL	1.64	1
Salmeterol	6 µg/dL	0.1 µmol/L	0.24	4
Salmeterol	6 µg/dL	0.1 µmol/L	2.04	-6
Tiotropium	2.16 mg/dL	45.8 µmol/L	0.24	0
Tiotropium	2.16 mg/dL	45.8 µmol/L	2.04	-3
Total Protein	10.6 g/dL	106 g/L	0.22	-9
Total Protein	10.6 g/dL	106 g/L	1.74	-9
Triglycerides	1500 mg/dL	16.9 mmol/L	0.22	-5
Triglycerides	1500 mg/dL	16.9 mmol/L	1.73	-2
Vancomycin	12 mg/dL	82.8 µmol/L	0.25	-4
Vancomycin	12 mg/dL	82.8 µmol/L	2.02	0
Substance	Substance Concentration		PCT AnalyteConcentration(ng/mL)	% Bias
	Conventional Units	SI Units
Biotin (mega dose)	3510 ng/mL	14.356 µmol/L	0.23	-26
Biotin (mega dose)	3510 ng/mL	14.356 µmol/L	1.88	-29
Biotin	1500 ng/mL	6.135 µmol/L	0.23	-4
Biotin	1500 ng/mL	6.135 µmol/L	1.88	-19
Biotin	1200 ng/mL	4.908 µmol/L	0.23	0
Biotin	1200 ng/mL	4.908 µmol/L	1.78	-2
Biotin	600 ng/mL	2.454 µmol/L	0.23	4
Biotin	600 ng/mL	2.454 µmol/L	1.88	1
Biotin	300 ng/mL	1.227 µmol/L	0.23	0
Biotin	300 ng/mL	1.227 µmol/L	1.88	-2
Biotin	150 ng/mL	0.614 µmol/L	0.23	0
Biotin	150 ng/mL	0.614 µmol/L	1.88	-3
Biotin	99.6 ng/mL	0.407 µmol/L	0.23	0
Biotin	99.6 ng/mL	0.407 µmol/L	1.88	-2
Biotin	80.4 ng/mL	0.329 µmol/L	0.23	0
Biotin	80.4 ng/mL	0.329 µmol/L	1.88	-1
Biotin	39.6 ng/mL	0.162 µmol/L	0.23	4
Biotin	39.6 ng/mL	0.162 µmol/L	1.88	-3
Biotin	30.0 ng/mL	0.123 µmol/L	0.23	4
Biotin	30.0 ng/mL	0.123 µmol/L	1.88	-1
Biotin	20.4 ng/mL	0.083 µmol/L	0.23	0
Biotin	20.4 ng/mL	0.083 µmol/L	1.88	-1
Biotin	9.6 ng/mL	0.039 µmol/L	0.23	4
Biotin	9.6 ng/mL	0.039 µmol/L	1.88	0
Substance	Substance Concentration		PCT Analyte	% Bias
	Conventional Units	SI Units	Concentration ng/mL
HAMA 1	65.0 mg/mL	65.0 g/L	0.21	-10
HAMA 1	65.0 mg/mL	65.0 g/L	1.64	-12
HAMA 2	65.0 mg/mL	65.0 g/L	0.21	-14
HAMA 2	65.0 mg/mL	65.0 g/L	1.64	-13
HAMA 1	32.5 mg/mL	32.5 g/L	0.27	-11
HAMA 1	32.5 mg/mL	32.5 g/L	2.19	-12
HAMA 2	32.5 mg/mL	32.5 g/L	0.27	-7
HAMA 2	32.5 mg/mL	32.5 g/L	2.19	-11
HAMA 1	22.8 mg/mL	22.8 g/L	0.27	-7
HAMA 1	22.8 mg/mL	22.8 g/L	2.19	-9
HAMA 2	22.8 mg/mL	22.8 g/L	0.27	-7
HAMA 2	22.8 mg/mL	22.8 g/L	2.19	-7
HAMA 1	16.3 mg/mL	16.3 g/L	0.27	-4
HAMA 1	16.3 mg/mL	16.3 g/L	2.19	-9
HAMA 2	16.3 mg/mL	16.3 g/L	0.27	-4
HAMA 2	16.3 mg/mL	16.3 g/L	2.19	-5
HAMA 1	0.001 mg/mL	0.001 g/L	0.21	0
HAMA 1	0.001 mg/mL	0.001 g/L	1.64	4
HAMA 2	0.001 mg/mL	0.001 g/L	0.21	-5
HAMA 2	0.001 mg/mL	0.001 g/L	1.64	2
Substance	Substance Concentration		PCT AnalyteConcentrationng/mL	% Bias
	Conventional Units	SI Units
Biotin	3510 ng/mL	14.356 $ \u03bcmol/L $	0.23	-26
Biotin	3510 ng/mL	14.356 $ \u03bcmol/L $	1.88	-29
HAMA 1	32.5 mg/mL	32.5 g/L	0.27	-11
HAMA 1	32.5 mg/mL	32.5 g/L	2.19	-12
HAMA 2	32.5 mg/mL	32.5 g/L	0.27	-7
HAMA 2	32.5 mg/mL	32.5 g/L	2.19	-11
Total Protein	15.0 g/dL	150 g/L	0.22	-18
Total Protein	15.0 g/dL	150 g/L	1.74	-18

{15}------------------------------------------------

{16}------------------------------------------------

{17}------------------------------------------------

Biotin Interference Testing

Biotin testing was performed by spiking a range of concentrations into serum pools with PCT analyte concentrations of 0.25 and 2.00 ng/mL. The results of this testing are shown in the following table.

{18}------------------------------------------------

{19}------------------------------------------------

HAMA Interference Testing

HAMA testing was performed at a range of concentrations to determine the level at which HAMA would cause >10% interference. Both HAMA 1 and HAMA 2 were tested in serum pools with PCT analyte concentrations of 0.25 and 2.00 ng/mL. The results of this testing are shown in the following table.

{20}------------------------------------------------

Interfering Substances

The following substances were observed to have >10% interference in serum pools with PCT analyte concentrations of 0.25 and 2.00 ng/mL. The Instructions For Use contains limitations statements for these substances at the concentrations listed in the following table.

Note: HAMA interference listed in the IFU does not differentiate between HAMA 1 and HAMA 2.

Cross-Reactivity

Potential cross-reactivity was evaluated using EP07-ED3 for general guidance. Human serum pools at approximately 0.25 ng/mL and 2.00 ng/mL PCT were prepared by pooling native PCT. Each pool was divided into control and test pools. The test pools were spiked with the potentially crossreacting substances and the control pools were spiked with an equivalent volume of diluent. Cross-reactivity was calculated using the following equation:

$$% \text{Cross} - \text{recativity} = 100 \frac{[\text{Test} - \text{Control}]}{[\text{Compound}]}$$

The results of this testing are shown in the following table.

Cross-Reactant	Cross-Reactant test concentration		PCT Analyte
	Conventional units	SI Units	Concentration ng/mL	% Cross-Reactivity
Calcitonin (Human)	8 ng/mL	8 µg/L	0.23	0.00%
Calcitonin (Human)	8 ng/mL	8 µg/L	1.79	-0.50%
Calcitonin (Eel)	30 ng/mL	30 µg/L	0.23	-0.03%
Calcitonin (Eel)	30 ng/mL	30 µg/L	1.79	-0.13%

{21}------------------------------------------------

	Cross-Reactant test concentration		PCT AnalyteConcentration ng/mL	% Cross-Reactivity
Cross-Reactant	Conventional units	SI Units
Calcitonin (Salmon)	30 ng/mL	30 µg/L	0.24	-0.03%
Calcitonin (Salmon)	30 ng/mL	30 µg/L	1.78	0.07%
Katacalcin (Human)	30 ng/mL	30 µg/L	0.23	-0.03%
Katacalcin (Human)	30 ng/mL	30 µg/L	1.79	-0.20%
α-CGRP	30 ng/mL	30 µg/L	0.23	0.00%
α-CGRP	30 ng/mL	30 µg/L	1.79	0.00%
B-CGRP	30 ng/mL	30 µg/L	0.23	0.00%
B-CGRP	30 ng/mL	30 µg/L	1.79	0.00%

13.7 Hook Effect

A study was performed to evaluate whether a hook effect occurs with the assay for PCT concentrations up to 2000.00 ng/mL. For patient specimens with PCT concentrations between 50.00 ng/mL and 2000.00 ng/mL the assay will report results as "Above Assay Range" (> 50.00 ng/mL).

13.8 Sample Carryover

Sample carryover was performed using eleven separate runs. Each run consisted of testing a pattern of high (1068.88 ng/mL PCT) and low (≤0.10 ng/mL PCT) analyte samples for a total of 21 tests per run. The high sample was prepared by spiking recombinant procalcitonin into a normal human serum sample and the low sample was a normal human serum sample containing ≤0.10 ng/ml PCT (no spiking or dilution occurred). The following test order was used for each run, with L corresponding to the low sample and H corresponding to the high sample: 11, L2, L3, H1, H2, L4, H3, H4, L5, L6, L7, L8, H5, H6, L9, H7, H8, L10, H9, H10, L11.

No sample carryover from high samples into low samples was observed when a pattern of high and low samples was tested (sample carryover was calculated to be 0.00 ng/mL).

{22}------------------------------------------------

13.9 Method Comparison

The method comparison study was designed in accordance with CLSI EP09c-ED3 to compare the performance of the Dimension EXL LOCI BRAHMS Procalcitonin (PCT) assay to that of the predicate device (B·R·A·H·M·S PCT sensitive KRYPTOR).

A total of 595 native human serum samples within the concentration range of 0.05-1000.00 ng/mL were tested with the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay and the predicate device (B·R·A·H·M·S PCT sensitive KRYPTOR). Samples recovering >50.00 ng/mL were diluted manually with saline using a 1:20 dilution and tested.

Data analysis for method comparison was completed for both the measuring interval (n=555) and the extended measuring interval (n=595) for each Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay lot. Weighted Deming and Passing and Bablok regression statistics were calculated. Data was further analyzed for concordance (percent agreement) between the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay and the predicate B·R·A·H·M·S PCT sensitive KRYPTOR at each Clinical cutoff / Medical Decision Level (MDL).

Method comparison statistics for weighted Deming regression and Passing and Bablok regression for the measuring interval (0.05-50.00 ng/mL (0.05-50.00 µg/L))

	Lot FB1218		Lot FC1218
Parameter	Weighted Deming Regression	Passing and Bablok Regression	Weighted Deming Regression	Passing and Bablok Regression
N	555	555	555	555
Slope	1.07	1.07	1.04	1.04
95% Confidence Interval	1.05 to 1.10	1.05 to 1.09	1.02 to 1.07	1.02 to 1.06
Intercept (ng/mL)	-0.01	-0.01	0.00	-0.01
95% Confidence Interval	-0.02 to 0.00	-0.02 to -0.01	-0.01 to 0.00	-0.01 to 0.00
Correlation coefficient (r)	0.958	0.958	0.963	0.963
Sample range (ng/mL)	0.02 to 49.03	0.02 to 49.03	0.02 to 49.03	0.02 to 49.03

{23}------------------------------------------------

Concordance data for Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) lot FB1218 (measuring interval, 0.05-50.00 ng/mL (0.05-50.00 µg/L)).

PCT Results at 0.10 ng/mL Cut-Off

B·R·A·H·M·S PCT sensitive KRYPTOR
Dimension EXL LOCI BRAHMS PCT		>0.10 ng/mL	≤0.10 ng/mL	Total
	>0.10 ng/mL	489	6	495
	≤0.10 ng/mL	11	49	60
	Total	500	55	555
Positive % Agreement	= 97.8 % ;	95% Confidence Interval:	96.5%	- 99.1%
Negative % Agreement	= 89.1 % ;	95% Confidence Interval:	80.9%	- 97.3%
Overall % Agreement	= 96.9 % ;	95% Confidence Interval:	95.5%	- 98.4%

PCT Results at 0.25 ng/mL Cut-Off

	B·R·A·H·M·S PCT sensitive KRYPTOR
Dimension EXL LOCI BRAHMS PCT	>0.25 ng/mL	≤0.25 ng/mL	Total
>0.25 ng/mL	401	11	412
≤0.25ng/mL	10	133	143
Total	411	144	555
Positive % Agreement	= 97.6% ;	95% Confidence Interval: 96.1% - 99.1%
Negative % Agreement	= 92.4% ;	95% Confidence Interval: 88.0% - 96.7%
Overall % Agreement	= 96.2% ;	95% Confidence Interval: 94.6% - 97.8%

PCT Results at 0.50 ng/mL Cut-Off

			B·R·A·H·M·S PCT sensitive KRYPTOR
Dimension EXL LOCI BRAHMS PCT			>0.50 ng/mL	≤0.50 ng/mL	Total
>0.50 ng/mL			294	11	305
≤0.50 ng/mL			12	238	250
Total			306	249	555
Positive % Agreement	=	96.1%;	95% Confidence Interval:	93.9%	98.3%
Negative % Agreement	=	95.6%;	95% Confidence Interval:	93.0%	98.1%
Overall % Agreement	=	95.9%;	95% Confidence Interval:	94.2%	97.5%

PCT Results at 2.00 ng/mL Cut-Off

		B·R·A·H·M·S PCT sensitive KRYPTOR
		>2.00 ng/mL	≤2.00 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT	>2.00 ng/mL	188	9	197
	≤2.00 ng/mL	5	353	358
	Total	193	362	555
Positive % Agreement	= 97.4 % ;	95% Confidence Interval:	95.2%	- 99.7%
Negative % Agreement	= 97.5 % ;	95% Confidence Interval:	95.9%	- 99.1%
Overall % Agreement	= 97.5 % ;	95% Confidence Interval:	96.2%	- 98.8%

{24}------------------------------------------------

Cross-Tabulation of concordance data for all samples (n=555) for Dimension ° EXL™ LOCI ° BRAHMS Procalcitonin versus Predicate for lot FB1218 (measuring interval)

Dimension EXL LOCIBRAHMS PCT(ng/mL)	≤0.10	>0.10 - ≤0.25	>0.25 - ≤0.50	>0.50 - ≤2.00	>2.00	Total
≤0.10	49	11	0	0	0	60
>0.10 - ≤0.25	6	67	10	0	0	83
>0.25 - ≤0.50	0	10	85	12	0	107
>0.50 - ≤2.00	0	1	10	92	5	108
>2.00	0	0	0	9	188	197
Total	55	89	105	113	193	555

{25}------------------------------------------------

Concordance data for Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) lot FC1218 (measuring interval, 0.05-50.00 ng/mL (0.05-50.00 μg/L))

PCT Results at 0.10 ng/mL Cut-Off

			B·R·A·H·M·S PCT sensitive KRYPTOR
			>0.10 ng/mL	≤0.10 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT	>0.10 ng/mL		486	6	492
	≤0.10 ng/mL		14	49	63
	Total		500	55	555
Positive % Agreement	= 97.2 %	; 95% Confidence Interval:	95.8%	-	98.6%
Negative % Agreement	= 89.1 %	; 95% Confidence Interval:	80.9%	-	97.3%
Overall % Agreement	= 96.4 %	; 95% Confidence Interval:	94.8%	-	97.9%

PCT Results at 0.25 ng/mL Cut-Off

			B·R·A·H·M·S PCT sensitive KRYPTOR
			>0.25 ng/mL	≤0.25 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT
>0.25 ng/mL			402	11	413
≤0.25ng/mL			9	133	142
Total			411	144	555
Positive % Agreement	=	97.8 % ;	95% Confidence Interval:	96.4 %	99.2 %
Negative % Agreement	=	92.4 % ;	95% Confidence Interval:	88.0 %	96.7 %
Overall % Agreement	=	96.4 % ;	95% Confidence Interval:	94.8 %	97.9 %

PCT Results at 0.50 ng/mL Cut-Off

		B·R·A·H·M·S PCT sensitive KRYPTOR
	Dimension EXL LOCI BRAHMS PCT	>0.50 ng/mL	≤0.50 ng/mL	Total
	>0.50 ng/mL	295	9	304
	≤0.50 ng/mL	11	240	251
	Total	306	249	555
Positive % Agreement	= 96.4 % ;	95% Confidence Interval:	94.3 %	98.5 %
Negative % Agreement	= 96.4 % ;	95% Confidence Interval:	94.1 %	98.7 %
Overall % Agreement	= 96.4 % ;	95% Confidence Interval:	94.8 %	97.9 %

PCT Results at 2.00 ng/mL Cut-Off

			B·R·A·H·M·S PCT sensitive KRYPTOR
			>2.00 ng/mL	≤2.00 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT			>2.00 ng/mL	189	10	199
			≤2.00 ng/mL	4	352	356
			Total	193	362	555
Positive % Agreement	=	97.9 % ;	95% Confidence Interval:	95.9%	-	99.9%
Negative % Agreement	=	97.2 % ;	95% Confidence Interval:	95.5%	-	98.9%
Overall % Agreement	=	97.5 % ;	95% Confidence Interval:	96.2%	-	98.8%

{26}------------------------------------------------

Cross-Tabulation of concordance data for all samples (n=555) for Dimension " EXL™ LOCI" BRAHMS Procalcitonin versus Predicate for lot FC1218 (measuring interval)

Dimension EXL LOCIBRAHMS PCT(ng/mL)	B·R·A·H·M·S PCT sensitive KRYPTOR (ng/mL)
	≤0.10	>0.10 - ≤0.25	>0.25 - ≤0.50	>0.50 - ≤2.00	>2.00	Total
≤0.10	49	14	0	0	0	63
>0.10 - ≤0.25	6	64	9	0	0	79
>0.25 - ≤0.50	0	10	88	11	0	109
>0.50 - ≤2.00	0	1	8	92	4	105
>2.00	0	0	0	10	189	199
Total	55	89	105	113	193	555

Method comparison statistics for weighted Deming regression and Passing and Bablok regression for the extended measuring interval (0.05-1000.00 ng/mL (0.05-1000.00 μg/L))

Parameter	Lot FB1218		Lot FC1218
	Weighted Deming Regression*	Passing and Bablok Regression*	Weighted Deming Regression	Passing and Bablok Regression
N	595	595	595	595
Slope	1.08	1.07	1.05	1.05
95% Confidence Interval	1.05 to 1.10	1.05 to 1.09	1.02 to 1.07	1.04 to 1.07
Intercept (ng/mL)	-0.01	-0.01	0.00	-0.01
95% Confidence Interval	-0.02 to 0.00	-0.02 to -0.01	-0.01 to 0.00	-0.02 to 0.00
Correlation coefficient (r)	0.988	0.988	0.991	0.991
Sample range (ng/mL)	0.02 to 691.00	0.02 to 691.00	0.02 to 691.00	0.02 to 691.00

*Data shown in IFU

{27}------------------------------------------------

Concordance data for Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) lot FB1218 (extended measuring interval, 0.05-1000.00 ng/mL (0.05-1000.00 μg/L))

PCT Results at 0.10 ng/mL Cut-Off

	B·R·A·H·M·S PCT sensitive KRYPTOR
		>0.10 ng/mL	≤0.10 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT	>0.10 ng/mL	529	6	535
	≤0.10 ng/mL	11	49	60
	Total	540	55	595
Positive % Agreement	= 98.0% ;	95% Confidence Interval:	96.8%	99.2%
Negative % Agreement	= 89.1% ;	95% Confidence Interval:	80.9%	97.3%
Overall % Agreement	= 97.1% ;	95% Confidence Interval:	95.8%	98.5%

PCT Results at 0.25 ng/mL Cut-Off

			B·R·A·H·M·S PCT sensitive KRYPTOR
			>0.25 ng/mL	≤0.25 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT		>0.25 ng/mL	441	11	452
		≤0.25ng/mL	10	133	143
		Total	451	144	595
Positive % Agreement	= 97.8%	;	95% Confidence Interval:	96.4%	99.1%
Negative % Agreement	= 92.4%	;	95% Confidence Interval:	88.0%	96.7%
Overall % Agreement	= 96.5%	;	95% Confidence Interval:	95.0%	98.0%

PCT Results at 0.50 ng/mL Cut-Off

			B·R·A·H·M·S PCT sensitive KRYPTOR
			>0.50 ng/mL	≤0.50 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT		>0.50 ng/mL	334	11	345
		≤0.50 ng/mL	12	238	250
			Total	346	249	595
Positive % Agreement	= 96.5%	;	95% Confidence Interval:	94.6%	-	98.5%
Negative % Agreement	= 95.6%	;	95% Confidence Interval:	93.0%	-	98.1%
Overall % Agreement	= 96.1%	;	95% Confidence Interval:	94.6%	-	97.7%

PCT Results at 2.00 ng/mL Cut-Off

B·R·A·H·M·S PCT sensitive KRYPTOR
					>2.00 ng/mL	≤2.00 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT				>2.00 ng/mL	228	9	237
				≤2.00 ng/mL	5	353	358
				Total	233	362	595
Positive % Agreement		= 97.9%	;	95% Confidence Interval:	96.0%	-	99.7%
Negative % Agreement		= 97.5%	;	95% Confidence Interval:	95.9%	-	99.1%
Overall % Agreement		= 97.6%	;	95% Confidence Interval:	96.4%	-	98.9%

{28}------------------------------------------------

Cross-Tabulation of concordance data for all samples (n=595) for Dimension® EXL™ LOCI® BRAHMS Procalcitonin versus Predicate for lot FB1218 (extended measuring interval)

Dimension EXL LOCIBRAHMS PCT(ng/mL)	B·R·A·H·M·S PCT sensitive KRYPTOR (ng/mL)
	≤0.10	>0.10 - ≤0.25	>0.25 - ≤0.50	>0.50 - ≤2.00	>2.00	Total
≤0.10	49	11	0	0	0	60
>0.10 - ≤0.25	6	67	10	0	0	83
>0.25 -≤0.50	0	10	85	12	0	107
>0.50 - ≤2.00	0	1	10	92	5	108
>2.00	0	0	0	9	228	237
Total	55	89	105	113	233	595

{29}------------------------------------------------

Concordance data for Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) lot FC1218 (extended measuring interval, 0.05-1000.00 ng/mL (0.05-1000.00 μg/L))

PCT Results at 0.10 ng/mL Cut-Off

		B·R·A·H·M·S PCT sensitive KRYPTOR
		>0.10 ng/mL	≤0.10 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT	>0.10 ng/mL	526	6	532
	≤0.10 ng/mL	14	49	63
	Total	540	55	595
Positive % Agreement	= 97.4% ;	95% Confidence Interval:	96.1%	98.7%
Negative % Agreement	= 89.1% ;	95% Confidence Interval:	80.9%	97.3%
Overall % Agreement	= 96.6% ;	95% Confidence Interval:	95.2%	98.1%

PCT Results at 0.25 ng/mL Cut-Off

			B·R·A·H·M·S PCT sensitive KRYPTOR
			>0.25 ng/mL	≤0.25 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT			>0.25 ng/mL	442	11	453
			≤0.25ng/mL	9	133	142
			Total	451	144	595
Positive % Agreement	=	98.0%	; 95% Confidence Interval:	96.7%	-	99.3%
Negative % Agreement	=	92.4%	; 95% Confidence Interval:	88.0%	-	96.7%
Overall % Agreement	=	96.6%	; 95% Confidence Interval:	95.2%	-	98.1%

PCT Results at 0.50 ng/mL Cut-Off

				B·R·A·H·M·S PCT sensitive KRYPTOR
				>0.50 ng/mL	≤0.50 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT		>0.50 ng/mL		335	9	344
		≤0.50 ng/mL		11	240	251
		Total		346	249	595
Positive % Agreement	= 96.8% ;		95% Confidence Interval:	95.0%	-	98.7%
Negative % Agreement	= 96.4% ;		95% Confidence Interval:	94.1%	-	98.7%
Overall % Agreement	= 96.6% ;		95% Confidence Interval:	95.2%	-	98.1%

PCT Results at 2.00 ng/mL Cut-Off

					B·R·A·H·M·S PCT sensitive KRYPTOR
					>2.00 ng/mL	≤2.00 ng/mL	Total
Dimension EXL LOCI BRAHMS PCT					>2.00 ng/mL	229	10	239
					≤2.00 ng/mL	4	352	356
					Total	233	362	595
Positive % Agreement		= 98.3% ;	95% Confidence Interval:	96.6%	-	100.0%
Negative % Agreement		= 97.2% ;	95% Confidence Interval:	95.5%	-	98.9%
Overall % Agreement		= 97.6% ;	95% Confidence Interval:	96.4%	-	98.9%

{30}------------------------------------------------

Cross-Tabulation of concordance data for all samples (n=595) for Dimension EXL™ LOCI BRAHMS Procalcitonin versus Predicate for lot FC1218 (extended measuring interval)

Dimension EXL LOCIBRAHMS PCT(ng/mL)	B-R-A-H-M-S PCT sensitive KRYPTOR (ng/mL)
	≤0.10	>0.10 - ≤0.25	>0.25 - ≤0.50	>0.50 - ≤2.00	>2.00	Total
≤0.10	49	14	0	0	0	63
>0.10 - ≤0.25	6	64	9	0	0	79
>0.25 - ≤0.50	0	10	88	11	0	109
>0.50 - ≤2.00	0	1	8	92	4	105
>2.00	0	0	0	10	229	239
Total	55	89	105	113	233	595

13.10 Matrix Comparison

The matrix comparison study was conducted in accordance with CLSI EP09C-ED3 to evaluate the comparison between serum and plasma samples. A total of 76 matched sets (Serum, Lithium Heparin plasma, Sodium Heparin plasma, K2EDTA plasma, and K3EDTA plasma) spanning the assay range were evaluated, except for RST (rapid serum tubes) where 75 matched sets were evaluated. SST (serum separator tube) and RST were both included in this study. The SST was used as the control tube for comparison with all other tubes. Matched samples were spiked with equal amounts of recombinant procalcitonin (PCT) in order to span the assay range. No significant difference was observed based on Passing-Bablok regression analysis. Results are shown in the following table.

SpecimenType (x)	ComparisonSpecimen Type(y)	N	Sample range(ng/mL)	Regression Equation	CorrelationCoefficient (r)
Serum (SST)	Serum (RST)	75	0.05-46.59	y = 1.00x + 0.00 ng/mL	0.998
Serum (SST)	LithiumHeparin	76	0.05-46.59	y = 0.99x + 0.00 ng/mL	0.997
Serum (SST)	SodiumHeparin	76	0.05-46.59	y = 0.98x + 0.01 ng/mL	0.998
Serum (SST)	K2EDTA	76	0.05-46.59	y = 0.99x + 0.00 ng/mL	0.996
Serum (SST)	K3EDTA	76	0.05-46.59	y = 1.00x + 0.01 ng/mL	0.996

{31}------------------------------------------------

14. Clinical Study

Not applicable

14.1 Reference Interval

The reference Interval for the B·R·A·H·M·S PCT sensitive KRYPTOR assay was verified for serum and plasma specimens from 33 apparently healthy individuals with the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay according to CLSI EP28-A3c. The reference interval claim in the Instructions For Use is <0.10 ng/mL [<0.10 µg/L].

15. Traceability and Value Assignment

An International Reference for PCT is not available. Values assigned to the Dimension EXL LOCI PCT CAL are traceable to a reference preparation of PCT. The standardization is maintained through patient-sourced internal standards verified using the B-R-A-H-M-S PCT sensitive KRYPTOR assay. Assigned values for calibrators are traceable to this standardization.

16. Clinical Cut-Off

Not applicable

17. Stability

Stability studies for Dimension® EXL™ LOCI® BRAHMS PCT reagents were conducted according to CLSI EP25-A.

17.1 Reagent Stability - Shelf Life

Real time shelf life stability studies are being conducted with three (3) Dimension® EXL™ LOCI® BRAHMS PCT reagent lots. Reagents are stored under normal storage conditions (refrigerated at 2-8°C) for the duration of the studies are ongoing. At this time, two (2) lots have demonstrated 12 months of stability when stored at 2-8°C.

17.2 Reagent Stability - Calibration Interval

The calibration interval was evaluated with three (3) reagent lots. The results from these studies support a claim of 7 days for the calibration interval.

17.3 Reagent Stability - Unopened Onboard Stability

Unopened onboard stability was evaluated with two (2) reagent lots. The results from these studies support a claim of 30 days for the unopened product when stored onboard the instrument.

17.4 Reagent Stability - Opened Onboard Stability

Opened onboard stability was evaluated with three (3) reagent lots. The results from these studies support a claim of 3 days for the opened onboard (open-well) product.

{32}------------------------------------------------

17.5 Sample Stability

Sample stability was evaluated at multiple storage conditions to support storage and handling recommendations in the Instructions For Use. Specimens from the following tube types were prepared and tested at each medical decision level as well as near the upper limit of the assay range: serum (Serum Separator Tube (SST) and Rapid Serum Tube (RST)) and plasma (lithium heparin (Li Hep), sodium heparin (Na Hep), K2EDTA, and K3EDTA). All samples were prepared by spiking freshly drawn serum or plasma specimens with native PCT at the desired concentration levels.

The results from the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay sample stability studies support that serum (SST and RST) and plasma (Li Hep, Na Hep, K2EDTA, and K3EDTA) samples can be subjected to the following conditions and still generate accurate results when tested using the Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT) assay:

• . Storage at room temperature (25°C) for up to 8 hours
• Storage at refrigerated temperature (2-8°C) for up to 24 hours ●
• Storage at frozen temperature (-70°C) for up to 90 days
• Storage at frozen temperature (-20°C) for up to 90 days ●
• Freeze-thawed up to 6 cycles ●
• On the instrument (sample wheel) for up to 1 hour before processing

18. Proposed Labeling

The labeling is sufficient and it meets the requirements of 21 CFR Parts 801 and 809, as applicable and the special controls for this device under 21 CFR 866.3215.

19. Conclusion

The results from the performance studies support that the Candidate Device, Dimension® EXL™ LOCI® BRAHMS Procalcitonin (PCT), is substantially equivalent to the Predicate Device, B-R-A-M-S PCT sensitive KRYPTOR (DEN150009 / K171338).

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.