Elecsys BRAHMS PCT

K192815 · Roche Diagnostics · PRI · Mar 9, 2020 · Microbiology

Device Facts

• Record ID: K192815
• Device Name: Elecsys BRAHMS PCT
• Applicant: Roche Diagnostics
• Product Code: PRI · Microbiology
• Decision Date: Mar 9, 2020
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.3215
• Device Class: Class 2

Indications for Use

Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2-EDTA, K3-EDTA and Li-Heparin). The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers. Used in conjunction with other laboratory findings and clinical assessments, Elecsys BRAHMS PCT is intended for use as follows: - to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock, - to 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.

Device Story

Two-step sandwich immunoassay; utilizes streptavidin-coated magnetic microparticles, biotinylated anti-PCT antibody, and ruthenium-labeled anti-PCT antibody. Input: human serum/plasma samples. Process: PCT binds to labeled antibodies; complex captured on electrode via magnetic microparticles; voltage application induces electrochemiluminescence measured by photomultiplier tube. Output: quantitative PCT concentration (ng/mL) determined via master curve/calibration. Used in clinical laboratories on cobas e immunoassay analyzers; operated by trained laboratory personnel. Biotin interference mitigated by added biotin-binding antibody. Results aid clinicians in sepsis risk stratification, mortality assessment, and antibiotic stewardship (initiation/discontinuation). Benefits include improved clinical decision-making for sepsis management and respiratory infections.

Clinical Evidence

Bench testing only. No new clinical trials were performed. Analytical performance was validated using precision studies (CLSI EP5-A3), specificity/interference testing, and method comparison against the predicate device (n=496 clinical samples). Concordance analysis showed >96% agreement at medical decision points (0.1, 0.25, 0.5, 2.0 ng/mL). Regression analysis (Passing-Bablok and Weighted Deming) confirmed equivalence (slope 0.990 and 0.969 respectively).

Technological Characteristics

Two-step sandwich immunoassay; electrochemiluminescence detection. Reagents: streptavidin-coated magnetic microparticles, biotinylated monoclonal anti-PCT antibody, ruthenium-labeled monoclonal anti-PCT antibody, and biotin-binding scavenger antibody. Energy source: electrical voltage applied to electrode. Platform: cobas e 601 analyzer. Sample volume: 30 µL. Measuring range: 0.02–100 ng/mL. Calibration: 2-point, master curve via barcode.

Indications for Use

Indicated for critically ill patients (ICU admission) to assess risk of progression to severe sepsis/septic shock; patients with severe sepsis/septic shock to assess 28-day all-cause mortality risk; inpatients/emergency department patients with suspected/confirmed LRTI (CAP, acute bronchitis, AECOPD) to guide antibiotic therapy; and patients with suspected/confirmed sepsis to guide antibiotic discontinuation. Not for use in patients <17 years, pregnant women, or immunocompromised individuals.

Regulatory Classification

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.

Special Controls

A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis must comply with the following special controls:

*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 820.10(c) design and development, 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.

Predicate Devices

• Elecsys BRAHMS PCT (K173927)

Submission Summary (Full Text)

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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

ASSAY ONLY

## I Background Information:

The Elecsys BRAHMS PCT assay has been reformulated to address a 2017 FDA Safety Communication¹ alerting the public, health care providers, lab personnel, and lab test developers that biotin can significantly interfere with certain lab tests and cause incorrect test results which may go undetected.

A 510(k) Number

K192815

B Applicant

Roche Diagnostics

C Proprietary and Established Names

Elecsys BRAHMS PCT

D Regulatory Information

| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| PRI | Class II | 21 CFR 866.3215 - Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis | MI - Microbiology |

## II Submission/Device Overview:

A Purpose for Submission:

The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA clearance for new reagents which have been added to the Elecsys BRAHMS PCT Test System. Additional reagents intended to minimize potentially interfering effects of biotin in a patient specimen have been added to the previously cleared product.

B Measurand:

¹ https://www.fda.gov/medical-devices/safety-communications/fda-warns-biotin-may-interfere-lab-tests-fda-safety-communication

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Procalcitonin (PCT)

## C Type of Test:
Quantitative, Electrochemiluminescence Immunoassay

## III Intended Use/Indications for Use:

### A Intended Use(s):
See Indications for Use below.

### B Indication(s) for Use:
Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2-EDTA, K3-EDTA and Li-Heparin).

The electrochemiluminescence immunoassay "ECLIA" is intended for use on cobas e immunoassay analyzers.

Used in conjunction with other laboratory findings and clinical assessments, Elecsys BRAHMS PCT is intended for use as follows:

- to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
- to 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.

## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only

Warnings and Precautions

The Elecsys BRAHMS PCT 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. In cases where the laboratory results do not agree with the clinical picture or history, additional tests should be

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performed. Changes in PCT should always be interpreted in the context of the clinical status of the patient and other laboratory results. Decisions regarding antibiotic therapy should NOT be based solely on procalcitonin concentrations.

There is no uniformly recognized interpretation of the change in PCT concentration levels for the prediction of mortality, and overall mortality is 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, SOFA score) are also significant predictors of 28 day cumulative mortality risk. Validation of the Elecsys BRAHMS PCT test as an aid in predicting mortality was performed in a study population with an overall 28 day mortality of 22 %.

Certain patient characteristics, such as severity of renal failure or insufficiency, may influence procalcitonin values and should be considered as potentially confounding clinical factors when interpreting PCT values. Increased PCT levels may be observed in severe illness such as polytrauma, burns, major surgery, prolonged or cardiogenic shock. PCT levels may not be elevated in patients infected by certain atypical pathogens, such as Chlamydia pneumoniae and Mycoplasma pneumoniae. The safety and performance of PCT-guided therapy for individuals younger than age 17 years, pregnant women, immunocompromised individuals or those on immunomodulatory agents, was not formally analyzed in the supportive clinical trials.

## D Special Instrument Requirements:

The submission demonstrates performance on the cobas e 601 immunoassay analyzer.

## IV Device/System Characteristics:

### A Device Description:

The Elecsys BRAHMS PCT assay is intended for use with the cobas e immunoassay analyzers, PCT Cal1 and Cal2 reagents, and the PreciControl PCT1 and PCT2 as part of the Elecsys BRAHMS PCT Kit. An optional Procalcitonin CalCheck product is also available.

### B Principle of Operation:

The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles, biotinylated antibody and antibody labeled with ruthenium as well as an electrochemiluminescence detection system. Procalcitonin (PCT) in the sample reacts with these labeled antibodies to form a sandwich complex. This complex binds to streptavidin coated magnetic microparticles, which are magnetically captured onto an electrode. Application of voltage to the electrode induces chemiluminescence which is measured by a photomultiplier tube. Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode.

Total duration of assay: 18 minutes.

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- 1st incubation: Antigen in the sample (30 µL), a biotinylated monoclonal PCT-specific antibody, and a monoclonal PCT-specific antibody labeled with a ruthenium complex*) react to form a sandwich complex.
- 2nd incubation: After addition of streptavidin-coated microparticles, the complex becomes bound to the solid phase via interaction of biotin and streptavidin.
- The reaction mixture is aspirated into the measuring cell where the microparticles are magnetically captured onto the surface of the electrode. Unbound substances are then removed with ProCell M. Application of a voltage to the electrode then induces chemiluminescent emission which is measured by a photomultiplier.
- Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode.

(*):Tris(2,2'-bipyridyl)ruthenium(II)-complex (Ru(bpy)₃²⁺)

## C Reagents

The reagent working solutions include:

Rackpack (kit placed on analyzer)

- M: Streptavidin-coated microparticles,
- R1: Anti-PCT-Ab~biotin
- R2: Anti-PCT-Ab~Ru(bpy)₃²⁺

The following change is proposed to block the interference of biotin with the Elecsys BRAHMS PCT assay: Roche is taking a one-step approach by adding an antibody to bind free biotin in the sample. For the neutralization of free biotin in serum and plasma, Roche developed an antibody which binds to free biotin. The antibodies are specific for free biotin and do not bind to, or interact with, the biotin-linker conjugates.

## V Substantial Equivalence Information:

### A Predicate Device Name(s):

Elecsys BRAHMS PCT

### B Predicate 510(k) Number(s):

K173927

### C Comparison with Predicate(s):

| Device & Predicate Device(s): | K192815 | K173927 |
| --- | --- | --- |
| Device Trade Name | Elecsys BRAHMS PCT | Same |

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| Device & Predicate Device(s): | K192815 | K173927 |
| --- | --- | --- |
| General Device Characteristic Similarities | | |
| Intended Use/Indications for Use | Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2 –EDTA, K3-EDTA and Li-Heparin).
The electrochemiluminescence immunoassay “ECLIA” is intended for use on Elecsys and cobas e immunoassay analyzers.
Used in conjunction with other laboratory findings and clinical assessments, Elecsys BRAHMS PCT is intended for use as follows:
• to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
• to 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. | Same with the exception of intended analyzers, Elecsys BRAHMS PCT with biotin update is only intended for use on cobas e immunoassay analyzers. |

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| Device & Predicate Device(s): | K192815 | K173927 |
| --- | --- | --- |
| Assay Protocol | The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles and an electrochemiluminescence detection system. The test system reagents contain a biotinylated monoclonal PCT-specific antibody and a ruthenium labeled monoclonal PCT-specific antibody. | Same |
| Detection Protocol | Electrochemiluminescent immunoassay | Same |
| Applications | 18-minute application | Same |
| Sample Volume | 30 μL | Same |
| Sample Type | Human serum and plasma (Li-Heparin, K2/K3 EDTA) | Same |
| Calibrator | PCT Cal1 and PCT Cal2 | Same |
| Calibration Interval | Calibration must be performed once per reagent lot using PCT Cal1, PCT Cal2 and fresh reagent (i.e. not more than 24 hours since the reagent kit was registered on the analyzer). Renewed calibration is recommended as follows:
• after 8 weeks when using the same reagent lot
• after 7 days (when using the same reagent kit on the analyzer)
• as required: e.g. quality control findings outside the specified limits | Same |
| Controls | PC PCT1 and PC PCT2 | Same |
| Traceability/Standardization | This method has been standardized against the BRAHMS PCT LIA assay. | Same |

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| Device & Predicate Device(s): | K192815 | K173927 |
| --- | --- | --- |
| Reagent Stability | Store at 2-8 °C. Do not freeze. Store the Elecsys reagent kit upright in order to ensure complete availability of the microparticles during automatic mixing prior to use.
Stability:
• unopened at 2-8 °C: up to the stated expiration date
• after opening at 2-8 °C: 12 weeks on the analyzers: 4 weeks | Same |
| Measuring Range | 0.02 – 100 ng/mL | Same |
| LoB | 0.015 ng/mL | Same |
| LoD | 0.02 ng/mL | Same |
| LoQ | 0.06 ng/mL | Same |
| Hook Effect | No hook effect up to 1000 ng/mL | Same |
| General Device Characteristic Differences | | |
| Biotin Limitations | Specimens with biotin concentrations up to 1200 ng/mL did not demonstrate bias in measured PCT values.
Specimens with biotin concentrations > 1200 ng/mL and ≤ 2600 ng/mL demonstrated ≤ 10 % negative bias in measured PCT levels.
Pharmacokinetic studies have shown that serum concentrations of biotin can reach up to 355 ng/mL within the first hour after biotin ingestion for subjects consuming supplements of 20 mg biotin per day and up to 1160 ng/mL for subjects after a single dose of 300 mg biotin. | Biotin interference can produce either falsely high or low results. Though the risk of misclassifying a test result due to biotin interference is lower than the risks from average assay imprecision, biological variability, or other known interference, patient biotin intake and the resulting % bias should be taken into account when interpreting PCT assay values. (See Interference study below).
Do not test samples from patients who have indicated or whose clinical status or history would indicate they are currently taking high doses of biotin (> 10 mg per day). If biotin interference is suspected, follow your established internal procedures to investigate the interference per CLIA and GLP recommendations.
Serial draws are indicated for procalcitonin measurements. Biotin will metabolize and clear, serum levels will reduce over time. |

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| Device & Predicate Device(s): | K192815 | K173927 |
| --- | --- | --- |
| Reagents | M: Streptavidin-coated microparticles: Steptavidin-coated microparticles; preservative
R1: Anti-PCT-Ab~biotin: Biotinylated monoclonal anti-PCT antibody (mouse), phosphate buffer, preservative
R2: Anti-PCT - Ab~Ru(bpy)3+ a monoclonal anti-PCT antibody (mouse) labeled with ruthenium complex, Biotin Scavenger Anti-body, phosphate buffer, preservative
Roche is taking a one-step approach by adding an antibody to bind free biotin in the sample. For the neutralization of free biotin in serum and plasma, Roche developed an antibody which binds to free biotin. The antibodies are specific for free biotin and do not bind to, or interact with, the biotin-linker conjugates. | M: Streptavidin-coated microparticles: Steptavidin-coated microparticles; preservative
R1: Anti-PCT-Ab~biotin: Biotinylated monoclonal anti-PCT antibody (mouse), phosphate buffer, preservative
R2: Anti-PCT - Ab~Ru(bpy)3+ a monoclonal anti-PCT antibody (mouse) labeled with ruthenium complex, phosphate buffer, preservative |
| Instrument Platform | cobas e 601 analyzer | cobas e 411 analyzer |

VI Standards/Guidance Documents Referenced:

1) CLSI EP05-A3; Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline

VII Performance Characteristics (if/when applicable):

A Analytical Performance:

1. Precision/Reproducibility:

The repeatability and intermediate precision of the Elecsys BRAHMS PCT assay was conducted using the cobas e 601 analyzer. Studies were performed in accordance with CLSI guideline EP5-A3, "Evaluation of Precision Performance of Quantitative Measurement Methods". One reagent lot was evaluated. The precision study was conducted using the study design of 21 days x 2 runs per day x 2 replicates per sample. One (1) instrument was used for the study and calibration was performed according to the Instructions for Use. Aliquots of seven (7) human serum samples and two (2) QC samples (PC PCT 1 and PC PCT 2) distributed over the measuring range were assayed in duplicate and randomized order on the cobas e 601 analyzer using one lot of reagent. Data is summarized in Table 1 below. An analysis was also performed to calculate % Total Error across the measuring range. The total error was calculated using the one-sided Westgard-Model as:

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TE = 1.65* CV + %bias

The %CV used corresponds to the intermediate precision.

Table 1: Summary of Elecsys BRAHMS PCT Repeatability and Intermediate Precision

| Sample | Mean (ng/mL) | Repeatability (CV%) | | Intermediate Precision (CV%) | | % Total Error |
| --- | --- | --- | --- | --- | --- | --- |
| | | Within Run | | Within Lab | | |
| | | SD (ng/mL) | CV% | SD (ng/mL) | CV% | |
| Control1 | 0.478 | 0.012 | 2.5 | 0.020 | 4.2 | 10.6 |
| Control2 | 10.0 | 0.119 | 1.2 | 0.306 | 3.1 | 7.44 |
| Sample1 | 0.045 | 0.006 | 13.2 | 0.007 | 16.1 | 39.9 |
| Sample2 | 0.112 | 0.007 | 6.3 | 0.010 | 8.6 | 21.3 |
| Sample3 | 0.249 | 0.008 | 3.0 | 0.011 | 4.3 | 10.4 |
| Sample4 | 0.495 | 0.013 | 2.7 | 0.021 | 4.2 | 10.3 |
| Sample5 | 1.71 | 0.031 | 1.8 | 0.058 | 3.4 | 8.09 |
| Sample6 | 31.4 | 0.326 | 1.0 | 0.985 | 3.1 | 7.38 |
| Sample7 | 93.0 | 1.52 | 1.6 | 3.40 | 3.7 | 8.71 |

2. Linearity:

Please refer to previously FDA-cleared 510(k) K160729 and K173927 for Linearity performance. No additional testing was conducted.

3. Analytical Specificity/Interference:

Analytical Specificity

The specificity of the Elecsys BRAHMS PCT was determined using native human serum samples spiked with potential cross-reactant compounds. The samples were tested on a cobas e 601 Immunoassay Analyzer. Recovery within ± 15 % of initial value at PCT concentrations of ~0.5 ng/mL and ~2 ng/mL were verified for the following cross-reactant concentrations:

Table 2: Analytical Specificity/Cross-Reactivity Data

| Cross Reactant | Serum Sample | | | |
| --- | --- | --- | --- | --- |
| | | Measured PCT (ng/mL) | | Recovery % |
| Type | Conc (ng/mL) | Reference | Spiked | |
| Human Katacalcin | 30 | 0.051 | 0.049 | 96% |
| | 30 | 0.188 | 0.176 | 94% |
| | 30 | 0.372 | 0.357 | 96% |
| | 30 | 1.39 | 1.31 | 94% |

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| Cross Reactant | Serum Sample | | | |
| --- | --- | --- | --- | --- |
| | | Measured PCT (ng/mL) | | Recovery % |
| Type | Conc (ng/mL) | Reference | Spiked | |
| Human Calcitonin | 10 | 0.049 | 0.050 | 102% |
| | 10 | 0.182 | 0.191 | 105% |
| | 10 | 0.396 | 0.409 | 103% |
| | 10 | 1.31 | 1.38 | 105% |
| Human alpha CGRP1 | 10000 | 0.055 | 0.053 | 96% |
| | 10000 | 0.189 | 0.178 | 94% |
| | 10000 | 0.393 | 0.385 | 98% |
| | 10000 | 1.41 | 1.41 | 100% |
| Human beta CGRP | 10000 | 0.048 | 0.052 | 108% |
| | 10000 | 0.187 | 0.189 | 101% |
| | 10000 | 0.389 | 0.379 | 97% |
| | 10000 | 1.38 | 1.40 | 101% |
| Calcitonin Salmon | 30000 | 0.082 | 0.081 | 99% |
| | 30000 | 0.216 | 0.218 | 101% |
| | 30000 | 0.390 | 0.392 | 101% |
| | 30000 | 1.98 | 2.01 | 102% |
| Calcitonin Eel | 30000 | 0.084 | 0.082 | 98% |
| | 30000 | 0.223 | 0.222 | 100% |
| | 30000 | 0.394 | 0.394 | 100% |
| | 30000 | 1.74 | 1.84 | 106% |

## Endogenous Interferences

The effect on quantitation of PCT in the presence of five endogenous interfering substances (Hemoglobin, Biotin, Intralipid, Bilirubin, and Rheumatoid Factor) was tested using one cobas e 601 analyzer at clinically relevant concentrations. One aliquot of each serum sample was spiked with the interfering substance, another aliquot was spiked with the same volume of the respective solvent (dilution pool). The interfering pool was then incrementally diluted into the dilution pool. The recovery for each sample was calculated by comparison to the analyte concentration of the respective dilution pools.

The following substances evaluated with the Elecsys BRAHMS PCT assay were found not to affect the test performance at concentrations reasonably and consistently found in clinical situations.

Table 3:Endogenous Substances

| Potential Interferent | Claimed level where no interference was observed | Maximum Value with No Interference Observed |
| --- | --- | --- |
| Intralipid | 1500 mg/dL | 2000 mg/dL |
| Biotin | 1200 ng/mL | 2600 ng/mL |
| Bilirubin | 25 mg/dL | 66 mg/dL |
| Hemoglobin | 900 mg/dL | 1287 mg/dL |
| Rheumatic Factor | 1500 IU/mL | 1500 IU/mL |

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# Exogenous Interference

Thirty-four pharmaceutical compounds were spiked into human serum sample pools at clinically relevant PCT concentrations (0.10 ng/mL, 0.25 ng/mL, 0.5 ng/mL and 2.0 ng/mL) and tested with the Elecsys BRAHMS PCT assay on the cobas e 604 analyzer.

The following substances evaluated with the Elecsys BRAHMS PCT assay were found not to affect the test performance at concentrations reasonably and consistently found in clinical situations.

Table 4: Exogenous Interference

| Potential Interferent | Drug Level Tested (mg/L) |
| --- | --- |
| Acetylcysteine | 150 |
| Ampicillin | 75 |
| Ascorbic acid | 52.5 |
| Cyclosporine | 1.8 |
| Cefoxitin | 750 |
| Heparin | 3300 U/L |
| Levodopa | 7.5 |
| Methyldopa | 22.5 |
| Metronidazole | 123 |
| Phenylbutazone | 321 |
| Doxycycline | 18 |
| Acetylsalicylic acid | 30 |
| Rifampicin | 48 |
| Acetaminophen | 156 |
| Ibuprofen | 219 |
| Theophylline | 60 |
| Imipenem | 1180 |
| Cefotaxime | 900 |
| Vancomycin | 3500 |
| Dopamine | 130 |
| Noradrenaline | 2 |
| Dobutamine | 11.2 |
| Furosemide | 20 |
| Cromolyn | 24 |
| Alcohol | 4000 |
| Azithromycin | 11.5 |
| Cetirizine HCl | 3.6 |
| Dextromethorphan | 1.4 |
| Levofloxacin | 17.5 |
| Loratadine | 0.3 |
| Nicotine | 1 |

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| Potential Interferent | Drug Level Tested (mg/L) |
| --- | --- |
| Oxymetazoline HCl | 0.09 |
| Phenylephrine | 0.18 |
| Tiotropium | 0.0216 |

## Hama Effect

Please refer to previously FDA-cleared 510(k) K160729 and K173927 for Hama Effect performance. No additional testing was conducted.

4. **High-Dose Hook Effect:**

Please refer to previously FDA-cleared 510(k) K160729 and K173927 for High Dose Hook Effect performance. No additional testing was conducted.

5. **Assay Reportable Range:**

Please refer to previously FDA-cleared 510(k) K160729 and K173927 for Assay Reportable Range/Linearity performance. No additional testing was conducted.

6. **Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):**

### Sample Stability

Please refer to previously FDA-cleared 510(k) K160729 and K173927 for Sample Stability Effect performance. No additional testing was conducted.

### Reagent On-Board Stability

A fresh Elecsys BRAHMS PCT test kit was placed on the cobas e 601 analyzer and calibrated. Reference values for the samples tested were determined (day 0). After 8, 15, 22 and 29 days (1, 2, 3 and 4 weeks) the same samples were measured with the same reagent kit kept under on- board condition. Re-calibration was performed at every measuring time point.

Samples tested include eight (8) human serum (HS) sample pools. Each sample was tested in two-fold determination. Samples were targeted with values near medical decision levels of 0.1 ng/mL, 0.25 ng/mL, 0.5 ng/mL and 2.0 ng/mL as one sample range, along with sample ranges at low, medium and high PCT concentration ranges relative to the measuring range. Mean recovery values for each sample range were calculated. Elecsys BRAHMS PCT reagent kits can be kept on board of the instruments for up to 4 weeks (28 days). A new calibration of the kit kept on board is recommended every 7 days.

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# Calibration Stability

The Elecsys BRAHMS PCT assay was calibrated with a fresh reagent kit on Day 0 using one cobas e 601 analyzer. After 3, 6, and 9 weeks a new reagent kit of the same lot was used with recovery of samples being determined using the calibration curve established on Day 0 for that reagent kit lot. Fourteen (14) human serum samples were tested in duplicate. Recovery compared to the reference value was calculated as absolute deviation in ng/mL or relative deviation in %. Samples were targeted with values near medical decision levels of 0.1 ng/mL, 0.25 ng/mL, 0.5 ng/mL and 2.0 ng/mL along with samples spread across the measuring range. Mean recovery values for each sample range were calculated. The resulting data support the package-insert claim of 8 weeks lot calibration stability when using the same reagent kit lot.

# 7. Detection Limit:

## Limit of Detection

Please refer to previously FDA-cleared 510(k) K160729 and K173927 for Limit of Detection performance. No additional testing was conducted.

## Limit of Quantitation

The Limit of Quantitation (LoQ) of the Elecsys BRAHMS PCT assay was determined according to CLSI EP17-A2. The LoQ represents the lowest amount of analyte that can be quantitatively determined with stated accuracy, precision, and experimental conditions. The LoQ was calculated based on intermediate precision according to CLSI EP17-A2. The LoQ was determined as the lowest concentration of analyte that can be quantified with an intermediate precision of no more than 20%.

A five-day LoQ experiment was carried out with one reagent lot on one cobas e 601 analyzer. Samples tested included seven native human serum (HS) samples and were measured in five-fold determination for each run. A total of 150 measuring points were collected.

The mean values and the intermediate precision (coefficient of variation and standard deviation) for each LoQ sample were calculated. To determine the LoQ, samples were sorted according to the concentration of their measured mean value. The LoQ is defined as the mean value of the sample that is first to fulfill the specification for intermediate precision, and for which there is no lower-concentration sample that exceeds the specification. The LoQ data are represented in the table below.

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Table 5. LoQ Data – cobas e 601 analyzer

| Sample Type | Day | | | | | Mean (ng/mL) | SD (ng/mL) | CV (%) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | 1 | 2 | 3 | 4 | 5 | | | |
| HS 1 | 0.032 | 0.029 | 0.026 | 0.021 | 0.021 | 0.025 | 0.004 | 18.0 |
| | 0.030 | 0.021 | 0.031 | 0.028 | 0.028 | | | |
| | 0.022 | 0.023 | 0.022 | 0.021 | 0.020 | | | |
| | 0.033 | 0.020 | 0.032 | 0.023 | 0.024 | | | |
| | 0.029 | 0.024 | 0.025 | 0.022 | 0.018 | | | |
| HS 2 | 0.042 | 0.041 | 0.043 | 0.041 | 0.045 | 0.043 | 0.003 | 7.7 |
| | 0.046 | 0.044 | 0.037 | 0.041 | 0.041 | | | |
| | 0.050 | 0.039 | 0.043 | 0.043 | 0.044 | | | |
| | 0.038 | 0.047 | 0.037 | 0.040 | 0.045 | | | |
| | 0.048 | 0.045 | 0.044 | 0.043 | 0.045 | | | |
| HS 3 | 0.056 | 0.057 | 0.052 | 0.052 | 0.057 | 0.049 | 0.004 | 9.0 |
| | 0.050 | 0.046 | 0.048 | 0.040 | 0.046 | | | |
| | 0.051 | 0.048 | 0.048 | 0.044 | 0.052 | | | |
| | 0.047 | 0.043 | 0.045 | 0.045 | 0.049 | | | |
| | 0.053 | 0.054 | 0.050 | 0.046 | 0.050 | | | |
| HS 4 | 0.066 | 0.063 | 0.067 | 0.059 | 0.062 | 0.066 | 0.004 | 5.8 |
| | 0.068 | 0.058 | 0.070 | 0.064 | 0.064 | | | |
| | 0.067 | 0.068 | 0.064 | 0.073 | 0.062 | | | |
| | 0.069 | 0.065 | 0.071 | 0.073 | 0.067 | | | |
| | 0.068 | 0.064 | 0.065 | 0.062 | 0.061 | | | |
| HS 5 | 0.069 | 0.062 | 0.068 | 0.067 | 0.068 | 0.066 | 0.004 | 6.8 |
| | 0.068 | 0.067 | 0.058 | 0.058 | 0.056 | | | |
| | 0.072 | 0.063 | 0.073 | 0.066 | 0.068 | | | |
| | 0.072 | 0.065 | 0.063 | 0.064 | 0.062 | | | |
| | 0.072 | 0.065 | 0.069 | 0.064 | 0.067 | | | |
| HS 6 | 0.088 | 0.090 | 0.088 | 0.083 | 0.089 | 0.089 | 0.004 | 4.4 |
| | 0.091 | 0.092 | 0.089 | 0.093 | 0.089 | | | |
| | 0.092 | 0.091 | 0.090 | 0.084 | 0.084 | | | |
| | 0.095 | 0.085 | 0.094 | 0.091 | 0.097 | | | |
| | 0.090 | 0.095 | 0.086 | 0.083 | 0.085 | | | |
| Overall Device LoQ: 0.025 ng/mL | | | | | | | | |

HS: human serum

The LoQ was determined to be 0.025 ng/mL. The LoQ claim for the Elecsys BRAHMS PCT assay is 0.06 ng/mL.

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Based on LoQ testing the following total error values were calculated.

Table 6: Total Error
| Expected value (ng/ml) | Elecsys BRAHMS PCT | | |
| --- | --- | --- | --- |
| | %CV | %Bias | %TE |
| 2.00 | 0.19 | 0.12 | 0.43 |
| 0.50 | 0.77 | 0.54 | 1.81 |
| 0.30 | 1.30 | 0.94 | 3.08 |
| 0.25 | 1.56 | 1.15 | 3.72 |
| 0.15 | 2.64 | 2.00 | 6.34 |
| 0.10 | 3.99 | 3.10 | 9.69 |
| 0.05 | 8.12 | 6.56 | 19.97 |

## Limit of Blank

Please refer to previously FDA-cleared 510(k) K160729 and K173927 for Limit of Blank performance. No additional testing was conducted.

## 8. Assay Cut-Off:

### 28-day mortality:

- $\Delta \mathrm{PCT} \leq 80\%$

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

- $\Delta \mathrm{PCT} &gt; 80\%$

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

NOTE: The combination of the first PCT level ($\leq 2.0 \, \mathrm{ng/mL}$ or $&gt; 2.0 \, \mathrm{ng/mL}$) at initial diagnosis of severe sepsis or septic shock with the patient's clinical course and the change in PCT level over time until Day 4 provides important additional information about the mortality risk.

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Progression Risk:

- PCT &gt; 2 µg/L

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

- PCT &lt; 0.5 µg/L

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

LRTI Antibiotic Decision Making:

- PCT &lt; 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 &gt;0.50 ng/mL

Antibiotic therapy strongly encouraged.

Sepsis Antibiotic Discontinuation:

- ΔPCT &gt; 80%

Antibiotic therapy may be discontinued

- PCT ≤ 0.50 ng/mL

Antibiotic therapy may be discontinued

Recommendations for Laboratory Reports for Initiation and Discontinuation:

The Change in Procalcitonin Calculator is available at http://www.brahms-pct-calculator.com. The Change in Procalcitonin Calculator can be used to determine ΔPCT results. It is suggested to report the numerical PCT values (individual or paired). For paired PCT values the report should also indicate if the ΔPCT(%) was ≤ 80% or &gt; 80%. The laboratory report should include a reference or a link to the package insert for a guided interpretation of the test results.

B Comparison Studies:

1. Method Comparison with Predicate Device:

A method comparison of the Elecsys BRAHMS PCT assay and the predicate was performed using 496 native serum human clinical samples. A concordance analysis was performed with the predicate device. Only samples in which the result from the candidate and the predicate device were within the measuring range were included in the concordance analysis. The clinical concordance analysis of the Elecsys BRAHMS PCT clinical performance study shows more than 96% total agreement between the Elecsys BRAHMS PCT and the predicate device at the medical decision points 0.1, 0.25, 0.5 and 2.0

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ng/mL. The regression slopes are within +/- 10% of identity in Passing-Bablok and Weighted Deming Analysis. This demonstrates equivalence to the predicate device to include all currently cleared claims of the predicate device in the labeling of the candidate device.

Further clinical performance study data can be found referenced in K173927 and K160729.

Table 7: PCT Agreement between Elecsys BRAHMS PCT and Predicate at 0.1 ng/mL

| Elecsys BRAHMS PCT on cobas e 601 | Predicate | | Total |
| --- | --- | --- | --- |
| | > 0.1 ng/mL | ≤ 0.1 ng/mL | |
| > 0.1 ng/mL | 354 | 1 | 355 |
| ≤ 0.1 ng/mL | 7 | 134 | 141 |
| Total | 361 | 135 | 496 |

Table 8: PCT Agreement between Elecsys BRAHMS PCT and Predicate at 0.25 ng/mL

| Elecsys BRAHMS PCT on cobas e 601 | Predicate | | Total |
| --- | --- | --- | --- |
| | > 0.25 ng/mL | ≤ 0.25 ng/mL | |
| > 0.25 ng/mL | 278 | 1 | 279 |
| ≤ 0.25 ng/mL | 6 | 211 | 217 |
| Total | 284 | 212 | 496 |

Table 9: PCT Agreement between Elecsys BRAHMS PCT and Predicate at 0.5 ng/mL

| Elecsys BRAHMS PCT on cobas e 601 | Predicate | | Total |
| --- | --- | --- | --- |
| | > 0.5 ng/mL | ≤ 0.5 ng/mL | |
| > 0.5 ng/mL | 220 | 0 | 220 |
| ≤ 0.5 ng/mL | 4 | 272 | 276 |
| Total | 224 | 272 | 496 |

Table 10:PCT Agreement between Elecsys BRAHMS PCT and Predicate at 2.0 ng/mL

| Elecsys BRAHMS PCT on cobas e 601 | Predicate | | Total |
| --- | --- | --- | --- |
| | > 2.0 ng/mL | ≤ 2.0 ng/mL | |
| > 2.0 ng/mL | 141 | 2 | 143 |
| ≤ 2.0 ng/mL | 3 | 350 | 353 |
| Total | 144 | 352 | 496 |

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Table 11: Comparison Elecsys BRAHMS PCT vs Predicate

| Cutoff (> vs. ≤) | Positive Agreement (95% CI) | Negative Agreement (95% CI) | Total Agreement | Cohen's Kappa |
| --- | --- | --- | --- | --- |
| 0.10 ng/mL | 98.1% | 99.3% | 98.4% | 0.960 |
| | (96.1 – 99.1) | (95.9 – 99.9) | | |
| 0.25 ng/mL | 97.9% | 99.5% | 98.6% | 0.971 |
| | (95.5 – 99.0) | (97.4 – 99.9) | | |
| 0.50 ng/mL | 98.2% | 100.0% | 99.2% | 0.984 |
| | (95.5 – 99.3) | (98.6 -100.0) | | |
| 2.00 ng/mL | 97.9% | 99.4% | 99.0% | 0.975 |
| | (94.1 - 99.3) | (98.0 – 99.8) | | |

Table 12: Weighted Deming and Passing Bablok Regression Analysis

| Parameter | Passing Bablok Regression | Weighted Deming (λ=1) Regression Analysis |
| --- | --- | --- |
| n | 474 | 474 |
| Slope | 0.990 | 0.969 |
| 95% CI | [0.984; 0.994] | [0.963; 0.975] |
| Intercept | -0.003 | 0.004 |
| 95% CI | [-0.004; -0.001] | [0.002; 0.005] |
| Pearson Correlation Coefficient (R) | 1.000 | 1.000 |
| Sample Range | [0.02; 85.69] | [0.02; 85.69] |

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Figure 1: Weighted Deming Regression plots of Elecsys BRAHMS PCT versus Predicate

Figure 2: Passing Bablok Regression plots of Elecsys BRAHMS PCT versus Predicate

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2. **Matrix Comparison:**

The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys BRAHMS PCT immunoassay was determined by comparing values obtained from samples (native human serum samples, single donors as well as pools) drawn into serum and Li-Heparin, K2-EDTA, K3-EDTA plasma tubes. A minimum of 40 serum/plasma pairs per sample material were tested in singleton with one reagent lot on one cobas e 601 analyzer. Data were evaluated using a regression analysis according to Passing/Bablok.

The results are acceptable and supports the following package-insert claim:

- SST is an acceptable sample type for use with the Elecsys PCT assay
- Li-Heparin plasma is an acceptable sample type for use with the Elecsys BRAHMS PCT assay
- K2-EDTA plasma is an acceptable sample type for use with the Elecsys BRAHMS PCT assay.
- K3-EDTA plasma is an acceptable sample type for use with the Elecsys BRAHMS PCT assay.

**C Clinical Studies:**

Not Applicable

**VIII Proposed Labeling:**

The labeling supports the finding of substantial equivalence for this device.

**IX Conclusion:**

The submitted information in this premarket notification is complete and supports a substantial equivalence decision.