Predicate Devices

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Reference Devices

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AI/ML (Artificial Intelligence / Machine Learning)

No
The device is an immunoassay that measures PCT levels and calculates the percent change over time. The risk assessment is based on predefined thresholds and calculations, not on an AI/ML algorithm learning from data.

Therapeutic

No.
This device is an immunoassay for the quantitative determination of PCT levels, which is used as an aid in risk assessment for patients with severe sepsis or septic shock. It provides diagnostic information but does not actively treat or directly prevent any disease or condition.

Diagnostic

Yes

Explanation: The device is an immunoassay that measures PCT levels to aid in assessing the 28-day risk of all-cause mortality for patients with severe sepsis or septic shock. This risk assessment directly contributes to diagnosis, prognosis, and treatment decisions, which is a key function of a diagnostic device.

SaMD (Software as a Medical Device)

No

The device is an immunoassay that utilizes physical components (microparticles, antibodies, electrodes, photomultiplier tube) and chemical reactions to measure PCT levels. It is not solely software.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

The "Intended Use / Indications for Use" section explicitly states: "Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma..."

This clearly indicates that the device is intended for use outside of the body to analyze biological samples (serum and plasma) to provide diagnostic information. The subsequent description of its use as an aid in assessing mortality risk in patients with severe sepsis or septic shock further supports its classification as an IVD.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

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

The Elecsys BRAHMS PCT assay is intended for use to determine the change of PCT 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 Intensive Care Unit (ICU) or when obtained in the emergency department or other medical wards prior to ICU admission. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids 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. The percent change in PCT level over time aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.

A PCT level that declines 80 %.

The combination of the first PCT level ( 2.0 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.

The PCT level on Day 1 (the day after severe septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

Product codes (comma separated list FDA assigned to the subject device)

PMT, JJX

Device Description

The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles and an electrochemiluminescence detection system. 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. An optional Procalcitonin CalCheck product is also available.

Mentions image processing

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Mentions AI, DNN, or ML

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Input Imaging Modality

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Anatomical Site

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Indicated Patient Age Range

The prognostic value of PCT in the setting of sepsis has not been validated in US patients younger than 18.

Intended User / Care Setting

Intensive Care Unit (ICU) or when obtained in the emergency department or other medical wards prior to ICU admission.

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

858 adult patients diagnosed with severe sepsis or septic shock admitted to ICU care, across 13 investigational sites in the US.
The per protocol analysis population (598 subjects) was comprised of 44 % female and 56 % male patients with a mean age of 64 years. About half of the patients had severe sepsis (51 %) versus septic shock (49 %). Infections were mainly community acquired (91%).

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Precision (Human Sera)

Study Type: Non-clinical performance evaluation, evaluated on one cobas e 411 analyzer according to CLSI EP5-A3 guideline.
Sample Size: Two replicates of each control (PC PCT 1 and PC PCT 2) and six human serum samples per run, two runs per day for 21 days.
Key Results: Repeatability and Intermediate precision were calculated according to CLSI EP5-A3.
- cobas e 411 Repeatability:
  - HS1: 5.03% CV @ 0.079 ng/mL
  - HS2: 1.71% CV @ 0.442 ng/mL
  - HS3: 2.35% CV @ 1.49 ng/mL
  - HS4: 1.38% CV @ 27.5 ng/mL
  - HS5: 2.23% CV @ 71.4 ng/mL
  - HS6: 1.35% CV @ 88.1 ng/mL
  - PC1: 1.91% CV @ 0.456 ng/mL
  - PC2: 1.83% CV @ 9.07 ng/mL
- cobas e 411 Intermediate Precision:
  - HS1: 6.44% CV @ 0.079 ng/mL
  - HS2: 3.14% CV @ 0.442 ng/mL
  - HS3: 3.40% CV @ 1.49 ng/mL
  - HS4: 3.24% CV @ 27.5 ng/mL
  - HS5: 3.66% CV @ 71.4 ng/mL
  - HS6: 3.18% CV @ 88.1 ng/mL
  - PC1: 3.21% CV @ 0.456 ng/mL
  - PC2: 3.35% CV @ 9.07 ng/mL

Limit of Blank (LoB)

Study Type: Analytical sensitivity study according to CLSI EP17-A2.
Sample Size: 60 measuring points (five analyte-free serum samples measured in two-fold determination for each run, over three days for six runs total).
Key Results: LoB was determined as the 95th percentile of blank-sample measurements. LoB = 0.015 ng/mL.

Limit of Detection (LoD)

Study Type: Analytical sensitivity study according to CLSI EP17-A2.
Sample Size: 60 measuring points (five low-level human serum samples measured in two-fold determination for each run, over three days for six runs total).
Key Results: LoD was determined as the smallest amount of analyte that can be detected with 95% probability. LoD = 0.02 ng/mL.

Limit of Quantitation (LoQ)

Study Type: Determination according to CLSI EP17-A2, based on intermediate precision.
Sample Size: 125 measuring points (five human serum (HS) samples measured in five-fold determination for each run over a five-day precision experiment).
Key Results: LoQ was determined as the lowest concentration of analyte that can be quantified with an intermediate precision of no more than 20%. LoQ = 0.06 ng/mL.

Linearity

Study Type: Linearity study.
Sample Size: Three spiked human plasma samples and three spiked human serum samples diluted into six dilution series (at least 14 dilutions each). Samples assayed in threefold determination within a single run.
Key Results: Linearity data analyzed with linear, quadratic, and cubic polynomials, according to CLSI EP6-A. Linear regression first, then higher order models.

Dilution Study

Study Type: Dilution study.
Sample Size: Three different dilutions (with dilution factors between 1:1 and 1:5) prepared from three serum samples and one plasma sample spiked with PCT.
Key Results: Recovery investigated on the cobas e 411.

Analytical Specificity

Study Type: Specificity study.
Sample Size: Native human serum samples spiked with potential cross-reacting compounds (two human serum sample pools at four different concentrations each). Samples measured in duplicate.
Key Results: Specificity determined, cross-reactivity results reported in method sheet.

Endogenous Interferences

Study Type: Interference study.
Sample Size: Three human serum samples (low, mid, and high PCT concentrations) for each of five endogenous interfering substances (Hemoglobin, Biotin, Intralipid, Bilirubin, and Rheumatoid Factor).
Key Results: Effect on quantitation of PCT assessed.

HAMA Effect

Study Type: HAMA (human anti-mouse antibodies) effect assessment.
Sample Size: A suitable HAMA serum spiked with PCT analyte at multiple concentrations, and a control human serum sample spiked at same levels. Both series (11 dilutions) measured in duplicate.
Key Results: Recovery calculated by comparison to reference (no HAMA) sample. No interference was detected.

High-Dose Hook Effect

Study Type: High-dose hook effect assessment.
Sample Size: Human serum pools spiked with analyte up to 2,500 ng/mL, then diluted with negative human serum.
Key Results: Hook concentration determined. No hook effect up to 1000ng/mL.

Exogenous Interferences - Drugs

Study Type: Drug interference study.
Sample Size: Two human serum samples at differing analyte concentrations spiked with 27 pharmaceutical compounds. Tested in two-fold determination.
Key Results: Compared to reference aliquot. No interference with the assay was found.

Serum/Plasma Comparison

Study Type: Comparison of PCT quantitation across different sample types with anticoagulants.
Sample Size: Ten human serum samples tested in duplicate at three time points for SST. Minimum of 50 serum/plasma pairs tested for remaining comparison studies.
Key Results: Potential effects assessed by Passing/Bablok regression analysis. Method comparison on cobas e 601 vs. cobas e 411 (137 human serum samples).

Reagent Stability

Study Type: Reagent Stability.
Study 1. Reagent Stability (On Board): A fresh reagent Rack Pack calibrated and samples tested on Day 7 and Day 28 using the calibration curve of Day 0 and Day 21 respectively. Samples (five human serum and two controls) tested in duplicate.
Study 2. Reagent Stability (After Opening): A fresh reagent Rack Pack calibrated, stored at 2-8 C for 12 weeks after initial measurement, then re-tested. Samples (five human serum and two controls) tested.
Study 3. Reagent Stability (Real-Time Shelf Life): Reagent stored at 2-8 C and tested at time point 0 (manufacture) and specified intervals over shelf life. Samples (human serum from three reagent lots and two controls) tested in duplicate.

Sample Stability

Study Type: Includes four studies.
Study 1. Sample Stability (Freeze/Thaw Cycles): Ten samples of human serum and plasma aliquoted, measured fresh, and after one freeze/thaw cycle. Measurements in three-fold determination.
Study 2. Sample Stability (at -20°C): Ten samples of human serum and plasma aliquoted, measured fresh, and after storage for up to 13 months at -20°C. Measurements in three-fold determination.
Study 3. Sample Stability (at 2-8°C): Ten samples of human serum and plasma aliquoted, measured fresh, and after storage for up to 72 hours at 2-8°C. Measurements in three-fold determination.
Study 4. Sample Stability (at 15-25°C): Ten samples of human serum and plasma aliquoted, measured fresh, and after storage for up to 48 hours at 15-25°C. Measurements in three-fold determination.

Calibration Stability

Study Type: Includes two studies.
Study 1. Calibration (Lot) Stability: Elecsys BRAHMS PCT assay calibrated with fresh reagent kit on Day 0. New reagent kit of same lot used after 4, 8, and 12 weeks, with recovery determined using Day 0 curve. Five human serum samples and two controls tested in duplicate.
Study 2. Calibration (On Board) Stability: Fresh test kit placed on analyzer and calibrated. Five native human serum sample pools and two control samples tested (2-fold determination). Same samples re-tested on Day 7 and Day 28 with same reagent kit using Day 0 and Day 21 calibration curve respectively.

Calibrator Stability

Study Type: Includes three studies; also includes Calibrator Value Assignment.
Calibrator Value Assignment: Calibrators run in duplicate on at least six cobas e 411 and three cobas e 601/cobas e 602/MODULAR ANALYTICS E170 analyzers with available reagent lots. Assigned value defined as mean value over at least six runs on at least three analyzers. PreciControl PCT acceptance criteria must be met.
Study 1. Calibrator Stability (Post Reconstitution at -20°C): Reconstituted calibrators stored for 3 months at -20°C. Measured versus freshly reconstituted calibrators in one run.
Study 2. Calibrator Stability (Post Reconstitution at 20-25°C): Reconstituted calibrators stored for 5 hours at 20-25°C. Measured Versus freshly reconstituted calibrators in one run.
Study 3. Calibrator Stability (Real-Time Shelf Life part of Assay Testing): PCT CalSet stored at 2-8°C. Tested at time point 0 and specified intervals over shelf life (up to planned shelf life plus one month).

PreciControl PCT

Study Type: Includes three studies; also includes PreciControl Value Assignment.
PreciControl Value Assignment: Assigned values determined with Elecsys BRAHMS PCT assay using a Master Calibrators panel. Controls run in duplicate on at least six analyzers of master platform. Assigned value is median of at least six determinations.
Study 1. PreciControl Stability (Post Reconstitution at -20°C): Reconstituted calibrators stored for 3 months at -20°C. Measured versus freshly reconstituted calibrators in one run.
Study 2. PreciControl Stability (Post Reconstitution at 20-25°C): Reconstituted controls stored for 5 hours at 20-25°C. Measured versus freshly reconstituted controls in one run.
Study 3. PreciControl Stability (Real-Time Shelf Life part of Assay Testing): PCT samples tested at time point 0 and specified intervals over shelf life.

PCT CalCheck 5 Stability

Study Type: Includes three studies; also includes PCT CalCheck 5 Value Assignment.
PCT CalCheck 5 Value Assignment: Value assignment tested and passed pre-defined acceptance criteria. Each CalCheck run in duplicate on at least six analyzers of master platform. Assigned value is mean over at least six determinations. Assigned range calculated as +/-30% of assigned value for levels 2-5.
Study 1. PCT CalCheck 5 Accelerated and Open Vial Stability: One lot evaluated in duplicate. Stored for 3 weeks at 35°C, then reconstituted and stored for 3 hours at 25°C (open vial). Reference material was freshly reconstituted CalCheck 5.
Study 2. PCT CalCheck 5 Stability (Real-Time Shelf Life): Ongoing study. Stored at 2-8°C, tested at time point 0 and specified intervals. Five CalCheck levels tested in duplicate.
Study 3. PCT CalCheck 5* Stability (Real-Time Shelf Life): One lot stored at 2-8°C for up to 37 months. Tested at time point 0 and specified intervals. Five CalCheck levels tested in duplicate.

Clinical Performance

Study Type: Prospective clinical trial.
Sample Size: 858 adult patients (per protocol analysis population of 598 subjects)
- 44% female, 56% male; mean age 64 years.
- 51% severe sepsis, 49% septic shock.
- 91% community acquired infections.
Key Results:
- Binary test result (ΔPCT > 80 % or ≤ 80 %) significantly associated with 28-day cumulative mortality (Fisher's Exact Test p-value = 0.002).
- Adjusted for ICU vs. non-ICU patient subgroups: association remained significant (Cochran-Mantel-Haenszel Test p-value = 0.020).
- Kaplan Meier survival curves: patients with positive ΔPCT result (≤ 80 %) had clearly lower survival probability from Day 4.
- Univariate hazard ratio for binary ΔPCT4.0 is 1.80 (p = 0.011) for Per-Protocol population (1.81; p = 0.008 for Intention to Diagnose group), meaning 1.8-fold increased death risk with positive ΔPCT test result.
- ΔPCT from Day 0 (or Day 1) to Day 4 remains a prognostic parameter for 28-day all-cause mortality risk even when adjusted for other mortality predictors.
- Hazard ratios for ΔPCT:
  - ΔPCT 4.0 (univariate): 1.80 [1.15-2.82]; p=0.0106
  - ΔPCT 4.0 with binary APACHE + covariates: 1.94 [1.14-3.31]; p=0.0140
  - ΔPCT 4.0 with numeric APACHE + covariates: 1.72 [1.00-2.95]; p=0.0487
  - ΔPCT 4.0 with binary SOFA + covariates: 1.76 [1.05-2.96]; p=0.0320
  - ΔPCT 4.0 with numeric SOFA + covariates: 1.46 [0.86-2.48]; p=0.1595
  - ΔPCT 4.1 (univariate): 1.61 [1.04-2.49]; p=0.0345
  - ΔPCT 4.1 with binary APACHE + covariates: 1.68 [1.03-2.76]; p=0.0392
  - ΔPCT 4.1 with numeric APACHE + covariates: 1.61 [0.98-2.65]; p=0.0625
  - ΔPCT 4.1 with binary SOFA + covariates: 1.64 [1.00-2.69]; p=0.0483
  - ΔPCT 4.1 with numeric SOFA + covariates: 1.47 [0.89-2.42]; p=0.1300

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Prognostic accuracy for 28-day mortality risk in ICU subgroup

ΔРСТ 0-4
- Sensitivity: 73.4 (62.9-83.8)
- Specificity: 35.0 (28.2-41.8)
ΔРСТ 1-4
- Sensitivity: 71.6 (60.8-82.3)
- Specificity: 38.7 (31.7-45.7)

Prognostic accuracy for 28-day mortality risk in Non-ICU subgroup

ΔРСТ 0-4
- Sensitivity: 72.3 (55.9-88.6)
- Specificity: 44.4 (38.4-50.3)
ΔРСТ 1-4
- Sensitivity: 65.4 (48.0-82.7)
- Specificity: 43.3 (37.3-49.2)

Prognostic accuracy for 28-day mortality risk stratified by patient location on Day 4, absolute PCT value on Day 0 (ΔPCT 0-4)

ICU, PCT 2.0 μg/L

Sensitivity: 65.1 (51.8-78.3)
Specificity: 46.3 (37.5-55.0)

Non-ICU, PCT 2.0 μg/L

Sensitivity: 58.6 (35.1-82.1)
Specificity: 71.4 (64.1-78.8)

Prognostic accuracy for 28-day mortality risk stratified by patient location on Day 4, absolute PCT value on Day 1 (ΔPCT 1-4)

ICU, PCT 2.0 μg/L

Sensitivity: 62.9 (49.4-76.5)
Specificity: 51.3 (42.4-59.7)

Non-ICU, PCT 2.0 μg/L

Sensitivity: 47.2 (24.6-69.7)
Specificity: 69.4 (61.6-77.2)

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

BRAHMS PCT sensitive KRYPTOR® test system, Elecsys Progesterone III CalSet, Elecsys Progesterone III CalCheck 5, BRAHMS PCT sensitive KRYPTOR® QC Kit

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

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.

Summary

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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized image of an eagle with three human profiles incorporated into its design. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" are arranged in a circular pattern around the eagle.

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

August 3, 2016

Roche Diagnostics Mr. Adam Clark Regulatory Affairs Consultant 9115 Hague Road Indianapolis, IN 46250

Re: K160729

Trade/Device Name: Elecys BRAHMS PCT, Elecys BRAHMS PCT CalCheck 5 Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis Regulatory Class: II Product Code: PMT, JJX Dated: March 15, 2016 Received: March 16, 2016

Dear Mr. Clark:

This letter corrects our substantially equivalent letter of June 13, 2016.

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

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

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21

1

CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

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

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

Sincerely yours,

Kristian M.Roth -S

For : Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K160729

Device Name Elecsys BRAHMS PCT

Indications for Use (Describe)

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

The Elecsys BRAHMS PCT assay is intended for use to determine the change of PCT 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 Intensive Care Unit (ICU) or when obtained in the emergency department or other medical wards prior to ICU admission. The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.

Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids 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. The percent change in PCT level over time aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.

A PCT level that declines $[ \le ]$ 80 % from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28-day risk of all-cause mortality than a decline > 80 %.

The combination of the first PCT level ($[ \le ]$ 2.0 ng/mL or > 2.0 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.

The PCT level on Day 1 (the day after severe septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

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)
----------------------------------------------	---------------------------------------------

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

3

Indications for Use

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

510(k) Number (if known) K160729

Device Name Elecsys BRAHMS PCT CalCheck 5

Indications for Use (Describe)

The Elecsys BRAHMS PCT Calcheck 5 is an assayed control for use in calibration verification and for use in verification of the assay range established for the Elecsys BRAHMS PCT assay on the Elecsys and cobas e analyzers,

| CARACHER COLUMN COLLEGION
and the many of the county of the county of the county of

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

Prescription Use (Part 21 CFR 801 Subpart D)

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

CONTINUE ON A SEPARATE PAGE IF NEEDED.

This section applies only to requirements of the Paperwork Reduction Act of 1995.

DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff(@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

4

510(k) Summary

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.

Submitter Name	Roche Diagnostics
Address	9115 Hague Road
Indianapolis, IN 46250
Contact	Adam Clark
Phone: (317) 521-4371
FAX: (317) 521-2324
Email: adam.clark@roche.com
Date Prepared	March 15, 2016
Proprietary Name	1) Elecsys BRAHMS PCT

Elecsys BRAHMS PCT CalCheck 5 |
| Common Name | 1) PCT Test System (test system contains both controls and calibrators)
PCT CalCheck 5 |
| Classification Name | 1) Device to detect and measure non-microbial analyte(s) in human clinical
specimens to aid in assessment of patients with suspected sepsis
Secondary, calibrator
Multi-Analyte Control, All Kinds (Assayed)
Single (specified) analyte Controls (assayed and unassayed) |
| Product Codes | 1) PMT; 866.3215
JIT; 862.1150
JJY; 862.1660
JJX; 862.1660 |
| Predicate Devices | 1) BRAHMS PCT sensitive KRYPTOR® test system
Elecsys Progesterone III CalSet
Elecsys Progesterone III CalCheck 5
BRAHMS PCT sensitive KRYPTOR® QC Kit |
| Establishment Registration | Roche Diagnostics GmbH in Mannheim, Germany: 9610126
Roche Diagnostics GmbH in Penzberg, Germany: 9610529
Roche Diagnostics in the United States: 1823260 |

5

1. DEVICE DESCRIPTION

The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles and an electrochemiluminescence detection system. 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. An optional Procalcitonin CalCheck product is also available.

Reagents 1.1.

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)$\overline{2}$

1.2. Calibrator

PCT CalSet is a 2-level PCT calibrator consisting of lyophilized recombinant PCT in a human serum matrix. The CalSet includes:

PCT Call: approximately 0.10 ng/mL, 1 bottle, containing 4 mL ●
. PCT Cal2: approximately 54 ng/mL, 1 bottle, containing 4 mL

1.3. Control

PreciControl PCT is a single analyte control that is used for quality control of the Elecsys BRAHMS PCT assay. The PreciControl PCT includes:

PC PCT 1: approximately 0.5 ng/mL, 2 bottles each for 4 mL
PC PCT 2: approximately 10 ng/mL, 2 bottles each for 4 mL ●

6

1.4. CalCheck

PCT CalCheck 5 is a lyophilized Human serum matrix with added PCT in five concentration ranges. The CalCheck includes:

PCT CalCheck 1: approximately 80 %.

The combination of the first PCT level ($[ \le ]$ 2.0 ng/mL or > 2.0 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.

The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.

DISCUSSION OF ANALYZER PLATFORMS 3.

The following summary of the Elecsys platforms is provided.

The cobas e 411 analyzer is an updated version of the Elecsys 2010 analyzer. Roche Diagnostics pursued a conservative course and submitted a 510(k) for the analyzer under K062279. The submission was closed out under 'exempt' since the submission was only for the analyzer and the 'Joint Risk Assessment' performed internally identified no potential impact on reagent performance. However, to be on the conservative side. Roche Diagnostics conducted recovery and reproducibility testing with representative Elecsys assays, and those data are documented

7

internally. The modifications did not alter the measurement components of the analyzer or the means by which results are calculated. The systems are analytically identical. The majority of the hardware changes, outside of the obvious name change, were cosmetic (e.g., change to color scheme, an external PC versus an internal PC) or related to safety (e.g., protective shields added over moving parts), or were made to improve customer satisfaction (e.g., a larger external waste container, flash drive replacement of floppy drive). The user-interface changes were made for aesthetics, customer satisfaction, or to bring the 'old' 2010 analyzer up to parity with those features already designed into the cobas 6000 series system.

The cobas e 601 analyzer is an updated version of the MODULAR ANALYTICS E170 analyzer. The MODULAR ANALYTICS E170 analyzer was acknowledged by FDA under Addto-File K961481/A003 on May 23, 2001. The cobas e 601 analyzer was reviewed and cleared as a component of the cobas 6000 series system submission K060373. The submission was required to introduce the other component of the cobas 6000 series system: the cobas c 501 analyzer, a new clinical-chemistry analyzer.

The cobas e 602 analyzer, part of the cobas 8000 analyzer series, was cleared via Internal Documentation, in keeping with the Reagent Replacement and Instrument Family Policy, as a new member of the Roche/Elecsys family of analyzers. The cobas e 602 is analytically identical to the cobas e 601 analyzer, part of the cobas 6000 analyzer series cleared in K060373.

8

TECHNOLOGICAL CHARACTERISTICS 4.

| Feature | Candidate Device: Elecsys
BRAHMS PCT (K160729) | Predicate Device: BRAHMS PCT sensitive
KRYPTOR®(DEN150009) |
|--------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use/
Indications for Use | Immunoassay for the in vitro
quantitative determination of PCT
(procalcitonin) in human serum and
plasma.
The Elecsys BRAHMS PCT assay is
intended for use to determine the
change of PCT 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 Intensive Care
Unit (ICU) or when obtained in the
emergency department or other
medical wards prior to ICU
admission.
The electrochemiluminescence
immunoassay "ECLIA" is intended
for use on Elecsys and cobas e
immunoassay analyzers.
A PCT level that declines ≤ 80%
from the day that severe sepsis or
septic shock was clinically
diagnosed (Day 0) to four days after
clinical diagnosis (Day 4) is
associated with higher cumulative
28-day risk of all-cause mortality
than a decline > 80%.
The combination of the first PCT
level (≤ 2.0 ng/mL or > 2.0 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.
The PCT level on Day 1 (the day
after severe sepsis or septic shock
is first clinically diagnosed) can be
used to calculate the percent
change in PCT level at Day 4 if the
Day 0 measurement is unavailable. | The BRAHMS PCT sensitive KRYPTOR® is intended for
use in conjunction with other laboratory findings and
clinical assessments 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.
The BRAHMS PCT sensitive KRYPTOR® test is also
intended for use to determine the change of PCT 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 Intensive Care Unit (ICU)
or when obtained in the emergency department or other
medical wards prior to the ICU admission. |
| 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. | The BRAHMS PCT sensitive KRYPTOR® assay is a
homogeneous sandwich immunoassay for detection of
PCT in human serum or plasma. The measuring
principle is based on Time-Resolved Amplified Cryptate
Emission (TRACE®) technology, which measures the
signal that is emitted from an immunocomplex with time
delay. |
| Detection Protocol | Electrochemiluminescent Assay | Time-Resolved Amplified Cryptate Emission (TRACE®) |
| Applications | 18-minute application | 19-minute incubation |
| Feature | Candidate Device: Elecsys
BRAHMS PCT (K160729) | Predicate Device: BRAHMS PCT sensitive
KRYPTOR®(DEN150009) |
| Instrument
Platform | cobas e 411 analyzer | BRAHMS KRYPTOR® analyzer |
| Sample Volume | 30 μL | 50 μL |
| Sample Type | Human serum and plasma (Li-
Heparin, K2/K3 EDTA) | Human serum and plasma (EDTA, heparin) |
| Reagents | M: Streptavidin-coated
microparticles: Steptavidin-coated
microparticles; preservative
R1: Anti-PCT-Abbiotin: Biotinylated
monoclonal anti-PCT antibody
(mouse), phosphate buffer,
preservative
R2: Anti-PCT – AbRu(bpy) 2/3+ a
monoclonal anti-PCT antibody
(mouse) labeled with ruthenium
complex, phosphate buffer,
preservative | Cryptate conjugate, cryptate labeled, anti-PCT
antibody (polyclonal, sheep), 3.2mL after
reconstitution with KRYPTOR® Solution 2
XL665 conjugate, XL665 labeled, anti-PCT
antibody (monoclonal, mouse), 3.95 mL after
reconstitution with KRYPTOR® Solution 1 and
KRYPTOR® Solution 2
Defibrinated human plasma, for diluting samples
above 50µg/L, ready for use |
| Calibrator | Elecsys PCT CalSet | BRAHMS PCT sensitive KRYPTOR® Calibrator |
| Calibration Interval | Calibration must be performed once
per reagent lot using 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 | Before first use of each new BRAHMS PCT sensitive
KRYPTOR® assay lot, then repeated on a regular basis
automatically managed by the BRAHMS PCT sensitive
KRYPTOR®. |
| Controls | Elecsys Precicontrol PCT | BRAHMS PCT sensitive KRYPTOR® Controls |
| Traceability/
Standardization | This method has been standardized
against the BRAHMS PCT LIA
assay. | N/P |
| 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 | In original shipping containers unopened at 2-8 °C:
up to the stated expiration date
after opening, onboard at 2-8 °C: 29 days |
| Feature | Candidate Device: Elecsys
BRAHMS PCT (K160729) | Predicate Device: BRAHMS PCT sensitive
KRYPTOR®(DEN150009) |
| Measuring Range | 0.02 – 100ng/mL | 0.02-50000µg/L |
| Precision | cobas e 411
Repeatability
HS1: 5.03% CV @ 0.079 ng/mL
HS2: 1.71% CV @ 0.442 ng/mL
HS3: 2.35% CV @ 1.49 ng/mL
HS4: 1.38% CV @ 27.5 ng/mL
HS5: 2.23% CV @ 71.4 ng/mL
HS6: 1.35% CV @ 88.1 ng/mL
PC1: 1.91% CV @ 0.456 ng/mL
PC2: 1.83% CV @ 9.07 ng/mL
Intermediate Precision
HS1: 6.44% CV @ 0.079 ng/mL
HS2: 3.14% CV @ 0.442 ng/mL
HS3: 3.40% CV @ 1.49 ng/mL
HS4: 3.24% CV @ 27.5 ng/mL
HS5: 3.66% CV @ 71.4 ng/mL
HS6: 3.18% CV @ 88.1 ng/mL
PC1: 3.21% CV @ 0.456 ng/mL
PC2: 3.35% CV @ 9.07 ng/mL | Not Provided (N/P) |
| LoB | 0.015 ng/mL | N/P |
| LoD | 0.02 ng/mL | N/P |
| LoQ | 0.06 ng/mL | 0.075 µg/L |
| Lower Detection
Limit | 0.015 ng/mL | N/P |
| Hook Effect | No hook effect up to 1000ng/mL | N/A |
| Feature | Candidate Device: Elecsys
BRAHMS PCT (K160729) | Predicate Device: BRAHMS PCT sensitive
KRYPTOR®(DEN150009) |
| Limitations | The assay is unaffected by icterus
(bilirubin 5 mg/day) until at
least 8 hours following the last biotin
administration.
No interference was observed from
rheumatoid factors up to a
concentration of 1500 IU/mL.
In vitro tests were performed on 27
pharmaceuticals compounds. No
interference with the assay was
found.
Human Anti Mouse Antibody (HAMA)
interference testing was completed
with three PCT analyte
concentrations using a high HAMA
human serum pool. No interference
was detected.
Samples from patients routinely
exposed to animals or animal serum
products may contain heterophilic
antibodies causing an atypical result.
This assay has been formulated to
mitigate the risk of this type of
interference. However, potential
interactions between rare sera and
test components can occur.
In rare cases, interference due to
extremely high titers of antibodies to
analyte specific antibodies,
streptavidin or ruthenium can occur.
These effects are minimized by
suitable test design.
For diagnostic purposes, the results
should always be assessed in
conjunction with the patient's medical
history, clinical examination and
other findings. | Citrate plasma tubes should not be used as PCT
concentrations are underestimated.
• The prognostic value of PCT in the setting of sepsis
has not been validated in US patients younger than 18.
• Carefully follow the manufacturer's instructions.
Improper handling of the reagents may falsify the test
results.
• Increased PCT levels may not always be related to
systemic infection4, 11, 12, 13. These conditions include,
but are not limited to:
• Patients experiencing major trauma and/or recent
surgical procedure including extracorporeal circulation or
burns;
• Patients under treatment with OKT3 antibodies, OK-
432, interleukins, TNF-alpha and 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 bronchial
carcinoid;
• Patients with acute or chronic viral hepatitis and/or
decompensated severe liver cirrhosis (Child-Pugh Class
C);
• Patients with prolonged or severe cardiogenic shock,
prolonged severe organ perfusion anomalies or after
resuscitation from cardiac arrest;
• Patients receiving peritoneal dialysis or hemodialysis
treatment;
• Patients with biliary pancreatitis, chemical pneumonitis
or heat stroke;
• Patients with invasive fungal infections (e.g.
candidiasis, aspergillosis ) or acute attacks of
plasmodium falciparum malaria; and
• Neonates during the first 2 days of life.
The results of the B-R-A-H-M-S PCT sensitive
KRYPTOR® should be evaluated in context of all
laboratory findings and the total clinical status of the
patient. In cases where the laboratory results do not
agree with the clinical picture or history, additional tests
should be performed. |
| Feature | Candidate Device: Elecsys
BRAHMS PCT (K160729) | Predicate Device: BRAHMS PCT sensitive
KRYPTOR® (DEN150009) |
| Limitations
Continued | Increased PCT levels may not
always be related to systemic
infection. These include, but are not
limited to:
•Patients experiencing major trauma
and/or recent surgical procedure
including extracorporeal circulation
or burns.
•Patients undergoing treatment with
OKT3 antibodies, OK 432,
interleukins, TNF alpha and other
drugs that stimulate the release of
pro inflammatory cytokines or result
in anaphylaxis.
•Patients diagnosed with active
medullary C cell carcinoma, small
cell lung carcinoma, or bronchial
carcinoid.
•Patients with acute or chronic viral
hepatitis and/or decompensated
severe liver cirrhosis (Child Pugh
Class C).
•Patients with prolonged or severe
cardiogenic shock, prolonged severe
organ perfusion anomalies, or after
resuscitation from cardiac arrest.
•Patients receiving peritoneal dialysis
or hemodialysis treatment.
•Patients with biliary pancreatitis,
chemical pneumonitis, or heat
stroke.
•Patients with invasive fungal
infections (e.g. candidiasis,
aspergillosis) or acute attacks of
plasmodium falciparum malaria.
•Neonates during the first 2 days of
life.
The results of the Elecsys BRAHMS
PCT assay should be evaluated in
the context of all laboratory findings
and the total clinical status of the
patient. In cases where laboratory
results do not agree with the clinical
picture or history, additional tests
should be performed. | |
| Method
Comparison | 2617 samples were run on the Cobas e411 and the predicate device (BRAHMS PCT
sensitive KRYPTOR®).
Passing Bablok
Slope: 0.959 (95% CI: 0.947; 0.972)
Intercept: -0.023 (95% CI: -0.028; -0.018)
Coefficient: 0.989 (95% CI: 0.988; 0.990) | |

Table 1: Assay Comparison

9

10

11

12

13

	Table 2. CalSet Comparison

| Characteristic | Candidate Device: PCT CalSet
(K160729) | CalSet Predicate Device:
Progesterone III CalSet (K152526) |
|----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | PCT CalSet is used for calibrating
the quantitative Elecsys BRAHMS
PCT assay on the Elecsys and
cobas e analyzers. | The Progesterone III CalSet is used
for calibrating the quantitative
Elecsys Progesterone III assay on
the Elecsys and cobas e
immunoassay
analyzers. |
| Analyte | Recombinant PCT | Progesterone (plant-derived) |
| Matrix | Human serum matrix | Human serum matrix |
| Levels | Two | Two |
| Target Ranges | PCT Cal 1: 0.10 ng/mL
PCT Cal 2: 54 ng/mL | Cal 1: 0.80 ng/mL
Cal 2: 53 ng/mL |
| Format | Lyophilized | Lyophilized |
| Handling | Carefully dissolve the contents of
one bottle by adding exactly 4 mL of
distilled or deionized water and
allow to stand closed for 15 minutes
to reconstitute. Mix carefully,
avoiding the foam formation.
Transfer aliquots of the
reconstituted calibrators into
empty labeled snap-cap bottles
(CalSet Vials). Attach the
supplied labels to the additional
bottles. Store the aliquots
immediately at .15 to -25°C.
Perform only one calibration
procedure per aliquot. | Carefully dissolve the contents of
one bottle by adding exactly 1.0mL
of distilled or deionized water and
allow to stand closed for 15 minutes
to reconstitute. Mix carefully,
avoiding the foam formation.
Transfer aliquots of the
reconstituted calibrators into
empty labeled snap-cap bottles
(CalSet Vials). Attach the
supplied labels to the additional
bottles. Store the aliquots
immediately at -20°C.
Perform only one calibration
procedure per aliquot. |

14

Table 3. Control Comparison

| Characteristic | Candidate Device: PreciControl
PCT (K160729) | Predicate Device: BRAHMS PCT
sensitive KRYPTOR® QC Kit
(DEN150009) |
|----------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use | PreciControl PCT is a single analyte
control that is used for quality
control of the Elecsys BRAHMS
PCT assay. | The B-R-A-H-M-S PCT sensitive
KRYPTOR® QC is designed for
quality control on board the
B-R-A-H-M-S KRYPTOR® analyzer
for the B-R・A・H・M・S PCT sensitive
KRYPTOR® assay. |
| Analyte | Recombinant PCT | Recombinant PCT |
| Matrix | Human plasma | Human plasma |
| Levels | Two | Two |
| Target Ranges | PC1: 0.5 ng/mL
PC2: 10 ng/mL | PC1: 0.2-0.4 µg/L
PC2: 8-12 µg/L |
| Format | Lyophilized | Lyophilized |
| Handling | Carefully dissolve the contents of
one bottle by adding exactly 4 mL of
distilled or deionized water and
allow to stand closed for 15 minutes
to reconstitute. Mix carefully,
avoiding foam formation.
Transfer the reconstituted controls
into the empty labeled snap cap
bottles supplied or into additional
snapcap bottles (ControlSet Vials).
Attach the supplied labels to these
additional bottles. Aliquots intended
for storage at 15 to -25°C should
be frozen immediately.
Perform only one control procedure
per aliquot. | Reconstitute a vial with de-ionized
water (2.0mL) as indicated on the
vial label. Use de-ionized water with
conductivity of less than 50 µS/cm.
☐
dissolution of the lyophilisate.
☐ the control sample
using a Vortex.
☐ tubes.
☐ immediate measurements. Freeze
the other tubes immediately at 10% above the upper limit of the measuring range

5.11. Exogenous Interferences - Drugs

The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 27 pharmaceutical compounds into two human serum samples at differing analyte concentrations and tested on the Elecsys 2010 analyzer.

The PCT concentration of the spiked aliquots was tested in two-fold determination and compared to the PCT concentration for the reference aliquot (also tested in two-fold determination).

5.12. Serum/Plasma Comparison

The effect on quantitation of analyte in the presence of anticoagulants with the Elecsys BRAHMS PCT assay was determined by comparing values obtained from samples drawn into Serum Separator Tubes (SST), Serum, Li-Heparin Plasma, K2-, K3-EDTA and Plasma primary tubes and Plasma Separation Tubes (PST). Ten human serum samples were tested in duplicate on one Elecsys 2010 analyzer at three time points for SST. For remaining Serum/Plasma comparison studies, a minimum of 50 serum/plasma pairs were tested with one reagent lot on one cobas e 411 analyzer. Potential effects were assessed by Passing/Bablok regression analysis.

5.13. Method Comparison

A method comparison study was performed to compare the Elecsys BRAHMS PCT assay on the cobas e 601 analyzer with the Elecsys BRAHMS PCT assay on the cobas e 411 analyzer. A total of 137 human serum samples with PCT values from 0.0681 ng/mL to 99.1 ng/mL were measured.

The results were calculated using Passing/Bablok and Linear Regression analyses.

19

5.14. Reagent Stability

To test reagent stability, three studies were executed.

5.14.1. Study 1. Reagent Stability (On Board)

Reagent on-board stability for the Elecsys BRAHMS PCT assay was tested on one Elecsys 2010 analyzer.

A fresh reagent Rack Pack was placed on the analyzer and calibrated. Reference values for the samples tested were determined. On day 7 and day 28 the same samples were determined with the same reagent kit (kept on board the instrument) using the calibration curve of day 0 and day 21 respectively.

Samples tested in duplicate include five human serum samples and two controls.

5.14.2. Study 2. Reagent Stability (After Opening)

Reagent stability after first opening for the Elecsys BRAHMS PCt assay was tested on one Elecsys 2010 analyzer.

A fresh reagent Rack Pack was placed on the analyzer and calibrated. Reference values for the samples tested were determined. After measurement, the kit was removed from the analyzer and stored at 2-8°C for 12 weeks. The kit was again placed on the analyzer, calibrated, and the samples were tested.

Samples tested included five human serum samples and two controls.

5.14.3. Study 3. Reagent Stability (Real-Time Shelf Life)

In the real-time, shelf-life stability study, the Elecsys BRAHMS PCT assay reagent was stored at 2-8°C. The stored reagent was tested at time point 0 (at manufacture), then again at specified intervals over the shelf life of the device (up to the planned shelf life plus one month).

Samples tested in duplicate include human serum samples from three reagent lots and two controls.

5.15. Sample Stability

To test reagent stability, four studies were executed.

5.15.1. Study 1. Sample Stability (Freeze/Thaw Cycles)

Ten samples of each human serum and plasma types were aliquoted and measured fresh (reference value) and after one freeze/thaw cycle with the Elecsys BRAHMS PCT assay.

Measurements were performed in three-fold determination on one cobas e 601 analyzer, and recovery was calculated as percent of the reference value or as deviation in ne/mL.

20

5.15.2. Study 2. Sample Stability (at -20°C)

Ten samples of each human serum and plasma types were aliquoted and measured fresh (reference value) and after storage for up to 13 months at -20°C with the Elecsys BRAHMS PCT assay.

Measurement were performed in three-fold determination on one cobas e 601 analyzer, and recovery was calculated as percent of the reference value or as deviation in ng/mL.

5.15.3. Study 3. Sample Stability (at 2-8°C)

Ten samples of each human serum and plasma types were aliquoted and measured fresh (reference value) and after storage for up to 72 hours at 2-8°C with the Elecsys BRAHMS PCT assav.

Measurement were performed in three-fold determination on one cobas e 601 analyzer, and recovery was calculated as percent of the reference value or as a deviation in ng/mL.

5.15.4. Study 4. Sample Stability (at 15-25°C)

Ten samples of each human serum and plasma types were aliquoted and measured fresh (reference value) and after storage for up to 48 hours at 15-25℃ with the Elecsys BRAHMS PCT assay.

Measurement were performed in three-fold determination on one cobas e 601 analyzer, and recovery was calculated as percent of the reference value or as a deviation in ne/mL.

5.16. Calibration Stability

To test calibration stability, two studies were executed.

5.16.1. Study 1. Calibration (Lot) Stability

Calibration of an Elecsys BRAHMS PCT reagent lot is recommended every 4 weeks. During that time period, fresh reagent kits of the same lot can be used in conjunction with the calibration curve established at Day 0 for that reagent kit lot.

The Elecsys BRAHMS PCT assay was calibrated with a fresh reagent kit on Day 0 using one Elecsys 2010 analyzer. After 4, 8, and 12 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.

Five human serum (HS) samples and two controls were tested in duplicate. Recovery compared to the reference value was calculated as either deviation (in ng/mL).

5.16.2. Study 2. Calibration (On Board) Stability

A fresh Elecsys BRAHMS PCT test kit was placed on an Elecsys 2010 analyzer and calibrated. Five native human serum (HS) sample pools and two control samples were tested with the fresh reagent kit; each sample was tested with 2-fold determination. On day 7 and day 28 the same samples were determined with the same reagent kit (kept on board of the instruments) using the

21

calibration curve of day 0 and day 21 respectively. Each sample was tested with 2-fold determination.

5.16. Calibrator Stability

The PCT CalSet was evaluated for value assignment and stability; three studies were executed.

5.17.1. Calibrator Value Assignment

Value assignment tested was conducted and passed pre-defined acceptance criteria. The target values for the two levels of the PCT Calset are chosen to obtain the best fit with the Master Calibration Curve, together with the Rodbard curve parameters encoded in the reagent barcode. For each Elecsys PCT CalSet lot manufactured, the calibrators are run in duplicate on at least six cobas e 411 analyzers and least three cobas e 601/cobas e 602/MODULAR ANALYTICS E170 analyzers with all Elecsys BRAHMS PCT reagent lots available. The assigned value of each calibrator is defined as the mean value obtained over at least six runs on at least three analyzers of the respective calibrator.

Measurement values for PreciControl PCT (Levels 1 and 2), a single-analyte control recommended for use to monitor accuracy and precision of the PCT analyte, are read from the calibration curves generated. The pre-defined acceptance criteria for PreciControl PCT have to be met to release the Assigned Values for the PCT CalSet.

5.17.2. Study 1. Calibrator Stability (Post Reconstitution at −20°C)

Reconstituted calibrators were stored for 3 months at -20°C.

The freshly reconstituted calibrators, and the reconstituted calibrators stored for 3 months at -20℃, were measured in one run on one Elecsys 2010 analyzer.

Recoveries of the stressed calibrators versus the freshly reconstituted calibrators were calculated.

5.17.3. Study 2. Calibrator Stability (Post Reconstitution at 20-25°C)

Reconstituted calibrators were stored for 5 hours at 20-25°C.

The freshly reconstituted calibrators, and the reconstituted calibrators stored for 5 hours at 20-25°C, were measured in one run on one Elecsys 2010.

Recoveries of the stressed calibrators versus the freshly reconstituted calibrators were calculated.

5.17.4. Study 3. Calibrator Stability (Real-Time Shelf Life part of Assay Testing)

In the real-time, shelf-life stability study, the PCT CalSet was stored at 2-8°C. The stored calibrator was tested at time point 0 (at manufacture), then again at specified intervals over the shelf life of the device (up to the planned shelf life plus one month).

22

5.18. PreciControl PCT

PreciControl PCT was evaluated for value assignment and stability; three studies were executed.

5.18.1. PreciControl Value Assignment

The PreciControl PCT assigned values are determined with the Elecsys BRAHMS PCT assay. A human serum sample panel (Master Calibrators) covering the entire measuring range is available, which is traceable to the PCT.

The assigned values for PreciControl PCT are read from the master calibration curve. Values are assigned for each lot of PreciControl PCT in combination with each Elecsys PCT assay reagent lot available. The controls are run in duplicate on at least six analyzers of the master analyzer platform. The assigned value of each control level is defined as the median value obtained over at least six determinations of the respective control level. For additional analyzer platforms, the same value assignment procedure is performed. The assigned values obtained on the additional analyzer are compared to those obtained on the master platform.

5.18.2. Study 1. PreciControl Stability (Post Reconstitution at -20°C)

Reconstituted calibrators were stored for 3 months at -20°C.

The freshly reconstituted calibrators, and the reconstituted calibrators stored for 3 months at -20°C, were measured in one run on one Elecsys 2010 analyzer. Recovery of the stressed PreciControl PCT compared to the freshly reconstituted PreciControl PCT was calculated.

5.18.3. Study 2. PreciControl Stability (Post Reconstitution at 20-25°C)

Reconstituted controls were stored for 5 hours at 20-25°C.

The freshly reconstituted controls, and the reconstituted controls stored for 5 hours at 20-25°C, were measured in one run on one Elecsys 2010.

Recoveries of the stressed controls versus the freshly reconstituted controls.

5.18.4. Study 3. PreciControl Stability (Real-Time Shelf Life part of Assay Testing)

In the real-time, shelf-PCT samples were tested at time point 0 (at manufacture), then again at specified intervals over the shelf life of the device (up to the planned shelf life plus one month).

5.19. PCT CalCheck 5 Stability

PCT CalCheck 5 was evaluated for value assignment and stability; two studies were executed.

5.19.1. PCT CalCheck 5 Value Assignment

Value assignment testing was conducted and passed pre-defined acceptance criteria. For each Elecsys BRAHMS PCT CalCheck 5 lot manufactured, each CalCheck is run in duplicate on at

23

least six analyzers of the master analyzer platform. The assigned yalued of each CalCheck level is defined as the mean value obtained over at least six determinations (duplicate runs on at least three analyzers) of the respective CalCheck level.

The CalCheck assigned range is calculated as ±30% of the assigned value for levels two through five. The label states that each laboratory should establish appropriate acceptance criteria when using this product for its intended use.

The same value assignment procedure is performed on the cobas e 601 analyzer. The assigned values obtained are compared to those obtained on the cobas e 411 analyzer. The mean value obtained on the additional analyzer must be within 10% of the master platform assigned value. After this acceptance criterion is met, the assigned values from the master platform are deemed valid for the Elecsys 2010. MODULAR ANALYTICS E170, cobas e 411, cobas e 601, and cobas e 602 analyzers.

5.19.2. Study 1. PCT CalCheck 5 Accelerated and Open Vial Stability

One PCT CalCheck 5 lot was evaluated, in duplicate, on one cobas e 411 analyzer. A set of PCT CalCheck 5 was stored for 3 weeks at 35℃. After the three week period the test material was reconstituted and stored for 3 hours at 25℃ (in an open vial).

The reference material used was a freshly reconstituted set of PCT CalCheck 5. Recovery of the stressed PCT CalCheck 5 compared to the freshly reconstituted PCT CalCheck 5 was calculated.

5.19.3. Study 2. PCT CalCheck 5 Stability (Real-Time Shelf Life)

In the real-time shelf-life stability study (which is ongoing), the PCT CalCheck 5 will be stored at 2-8°C. The stored PCT CalCheck 5 will be tested at time point 0 (at manufacture), then again at specified intervals over the shelf life of the device (up to the planned shelf life plus one month).

Samples tested in duplicate include five CalCheck levels.

5.19.4. Study 3. PCT CalCheck 5* Stability (Real-Time Shelf Life)

In another real-time shelf-life stability study, a PCT CalCheck 5 lot (*with slightly different level 2 and 3 concentrations) was stored at 2-8°C for up to 37 months. The stored PCT CalCheck 5 was tested at time point 0 (at manufacture), then again at specified internals up to 37 months.

Samples tested in duplicate include five CalCheck levels.

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CLINICAL PERFORMANCE EVALUATION 6.

6.1 Reference Range

In a population of 282 self-reported healthy individuals, the 95th percentile, upper reference range limit was calculated at 0.08 ng/mL.

			assay
			PCT study
			unit
			ng/mL
			ResultStudyUnit
		NMiss	N	Min	Median	P95	Mean	StdDev	CV	Max
total (all)		0	282	0.02	0.02	0.08	0.03	0.03	100.25	0.39
gender		0	139	0.02	0.02	0.04	0.03	0.01	46.86	0.12
female	total (all)
male	total (all)	0	143	0.02	0.03	0.11	0.04	0.04	105.30	0.39
smoking		0	210	0.02	0.02	0.08	0.03	0.03	99.49	0.39
	no total (all)
yes	total (all)	0	40	0.02	0.02	0.11	0.04	0.05	122.89	0.29
unknown	total (all)	0	32	0.02	0.03	0.08	0.04	0.02	67.85	0.13
race		0	101	0.02	0.02	0.09	0.03	0.02	81.44	0.16
	African/black total (all)
Alaska Native/American Indian	total (all)	0	1	0.03	0.03	0.03	0.03	.		0.03
Asian	total (all)	0	4	0.02	0.03	0.15	0.06	0.06	99.45	0.15
Caucasian/white	total (all)	0	169	0.02	0.03	0.07	0.04	0.04	108.24	0.39
other	total (all)	0	7	0.02	0.02	0.05	0.03	0.01	42.75	0.05
age class		0	113	0.02	0.02	0.09	0.04	0.05	129.22	0.39
	20- 80 % or ≤ 80 %) was significantly associated with 28-day cumulative mortality (vital status on day 28) (Two-sided Fisher's Exact Test p-value = 0.002). Adjusted for ICU vs. non-ICU patient subgroups (based on hospital location at day 4 after initial diagnosis), the association remained significant (Cochran-Mantel-Haenszel Test p-value = 0.020). In each binary △PCT subgroup, the 28-day cumulative mortality rate was stratified by need to continue ICU care on day 4 and/or the selection of Day 1 as the baseline measurement day for the △PCT calculation. The data are as follows:

| 28-day mortality risk stratified by patient location on Day 4: ΔРСТ > 80 % = Test Negative;

ΔРCT ≤ 80 % = Test Positive per-protocol population
Day 4
patient
location	Measurement
interval	28-day mortality risk (%)	Prognostic accuracyb)
		ΔРСТ > 80 %	ΔРCT ≤ 80 %	Sensitivity	Specificity
ICU	ΔРСТ 0-4	22.1 (13.3-31.0)	29.6 (22.9-36.4)	73.4 (62.9-83.8)	35.0 (28.2-41.8)
	ΔРСТ 1-4	21.5 (13.0-29.9)	30.4 (23.4-37.3)	71.6 (60.8-82.3)	38.7 (31.7-45.7)
Non-ICU	ΔРСТ 0-4	5.6 (1.8-9.4)	11.0 (6.6-15.5)	72.3 (55.9-88.6)	44.4 (38.4-50.3)
	ΔРСТ 1-4	7.1 (2.8-11.3)	9.9 (5.7-14.2)	65.4 (48.0-82.7)	43.3 (37.3-49.2)

Prediction performances of binary ΔPCT stratified by ICU care on Day 4

b) Prognostic accuracy refers to how accurate the ΔΡCT (> 80 %) can predict mortality risk using 28-day mortality as the clinical reference.

Kaplan Meier survival curves show that patients with a positive ΔPCT result (≤ 80 %) had a clearly lower survival probability from study Day 4 till the end of follow up time compared to ΔΡCT negative (> 80 %) patients.

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Image /page/26/Figure/0 description: The image is a survival plot comparing two groups of patients based on their delta PCT values. The y-axis represents the proportion of patients surviving, ranging from 0% to 100%. The x-axis represents time in days, ranging from 0 to 28. The green line represents patients with a negative delta PCT (n=229, deaths=27), while the red line represents patients with a positive delta PCT (n=369, deaths=74).

Image /page/26/Figure/1 description: The image shows the text "Time (days)". The text is in a sans-serif font and is black. The background is white.

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

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

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| 28-day mortality risk stratified by patient location on Day 4, absolute PCT value on Day 0:

ΔPCT > 80 % = Test Negative; ΔPCT ≤ 80 % = Test Positive
Per-Protocol Population: ΔPCT 0-4 stratified PCT at Day 0
Day 4
patient
location	Measurement
interval	28-day mortality risk (%)		Prognostic accuracy*
		ΔPCT Day 0-4

80 % | ΔPCT Day 0-4
≤ 80 % | Sensitivity (%) | Specificity (%) |
| ICU | ≤ 2.0 μg/L | 10.4 (0.0-29.7) | 24.9 (15.2-34.6) | 94.9 (85.2-100) | 13.3 (4.9-21.8) |
| | > 2.0 μg/L | 23.6 (14.0-33.2) | 33.2 (24.0-42.4) | 65.1 (51.8-78.3) | 46.3 (37.5-55.0) |
| Non-ICU | ≤ 2.0 μg/L | 5.6 (0.0-16.3) | 8.3 (3.6-12.9) | 91.7 (76.0-100) | 12.3 (6.2-18.4) |
| | > 2.0 μg/L | 5.6 (1.6-9.7) | 17.5 (7.5-27.5) | 58.6 (35.1-82.1) | 71.4 (64.1-78.8) |

| 28-day mortality risk stratified by patient location on Day 4, absolute PCT value on Day 1:

$\Delta$ PCT > 80 % = Test Negative; $\Delta$ PCT ≤ 80 % = Test Positive
Per-Protocol Population: $\Delta$ PCT 1-4 stratified PCT at Day 1
Day 4 patient location	Measurement interval	28-day mortality risk (%)		Prognostic accuracy*
		$\Delta$ PCT Day 1-4 > 80 %	$\Delta$ PCT Day 1-4 ≤ 80 %
ICU	≤ 2.0 μg/L	11.8 (0.0-33.6)	25.5 (15.4-35.6)	94.7 (84.6-100.0)	12.7 (3.8-21.7)
	> 2.0 μg/L	22.5 (13.5-31.5)	34.0 (24.4-43.5)	62.9 (49.4-76.5)	51.3 (42.4-59.7)
Non-ICU	≤ 2.0 μg/L	0.0 (0.0-17.6%)c	7.5 (3.0-12.0)	100.0 (69.2-100.0)c	13.4 (7.3-19.5)
	> 2.0 μg/L	8.2 (3.3-13.1)	15.3 (6.0-24.7)	47.2 (24.6-69.7)	69.4 (61.6-77.2)

c) Normality approximation of within-imputation variance not valid, therefore the estimate corresponds to within-imputation variation based on exact confidence intervals [Clopper & Pearson, 1934]

Prognostic accuracy refers to how accurate the ΔΡCT (≤ 80%) can predict mortality risk.

Kaplan-Meier Plots are depicted below to illustrate the time-to-event structure in the extended patient subgroups according to hospital location on Day 4 and initial PCT level.

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Image /page/28/Figure/0 description: This image is a survival plot showing the proportion of patients surviving over time, up to 28 days. The plot compares two groups: those with negative ΔPCT (n=10, deaths=1) and those with positive ΔPCT (n=76, deaths=19). The survival rate is higher for the ΔPCT negative group compared to the ΔPCT positive group. The study includes patients with PCT ≤ 2.0 µg/L at Day 0, ICU Day 4 (n=86).

Image /page/28/Figure/1 description: This image shows a survival analysis until day 28 for patients with PCT > 2.0 ug/L at Day 0 and ICU Day 4 (n=179). The y-axis shows the proportion of patients surviving, and the x-axis shows the time in days. There are two lines on the graph, one for delta PCT negative (n=77, deaths=18) and one for delta PCT positive (n=102, deaths=34).

Image /page/28/Figure/2 description: This image is a survival curve comparing patients with negative and positive delta PCT values. The y-axis represents the proportion of patients surviving, ranging from 0% to 100%. The x-axis represents time in days, up to 28 days. The survival rate is higher for patients with negative delta PCT values, with 18 patients and 1 death, compared to patients with positive delta PCT values, with 133 patients and 11 deaths.

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Image /page/29/Figure/0 description: This image is a survival curve that shows the survival rate of patients until day 28. The title indicates that the patients had PCT > 2.0 µg/L at Day 0, non-ICU Day 4 (n=182). The green line represents patients with negative ΔPCT, where n=125 and deaths=7, while the red line represents patients with positive ΔPCT, where n=57 and deaths=10.

Time-to-event analysis evidently reveals that patients in the ICU or with an initial PCT value > 2.0 µg/L had a lower survival probability from study Day 4 until the end of follow up time (28 days) when the ΔΡCT test result was positive compared to ΔΡCT negative patients as illustrated by the Kaplan-Meier curves above (patient subgroups according to hospital location on Day 4 and initial PCT level).

A generally lower mortality rate was observed in the non-ICU subgroup. The mortality rates for △PCT positive vs. ΔPCT negative patient subgroups were:

Patients with PCT ≤ 2.0 µg/L at Day 0 receiving ICU care on Day 4	10.4 % vs. 24.9 %
Patients with PCT > 2.0 µg/L at Day 0 receiving ICU care on Day 4	23.6 % vs. 33.2 %
Patients with PCT ≤ 2.0 µg/L at Day 0 without ICU care on Day 4	5.6 % vs. 8.3 %
Patients with PCT > 2.0 µg/L at Day 0 without ICU care on Day 4	5.6 % vs. 17.5 %

Based on relative mortality ratios a decrease by more than 80 % from Day 0 (or Day 4 constitutes a lower risk for mortality within 28 days compared to smaller declines in each subgroup. For the prediction of absolute mortality risks ICU disposition at Day 4 and initial PCT concentrations should be considered:

1. An initial PCT level 2.0 µg/L (23.6 %). Regardless of the initial PCT level, patients in the ICU on Day 4 that do not decline by more than 80 % in PCT plasma concentration from Day 0 to Day 4 have an even higher mortality risk of 24.9-33.2 %.
1. An initial PCT level > 2.0 ug/L that does not decline by more than 80 % until Day 4 signals that such patients remain at high mortality risk (17.5 %) even when they are no longer receiving ICU care on Day 4. Mortality was otherwise observed between 5.6 to 8.3 % for patients discharged from the ICU by Day 4.

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In conclusion, hazard ratios for binary APCT for both subgroups enrolled show an increase in mortality with △PCT. The mortality risk stratification using ΔPCT is valid when calculated from the day severe sepsis or septic shock is first diagnosed (Day 0) or the day thereafter (Day 1) and compared to the fourth day (Day 4) after diagnosis. The APCT at Day 4 combined with the patient's clinical course provides important information for the 28-day all-cause mortality risk prediction after a diagnosis of severe sepsis or septic shock.

The prognostic value of APCT was quantified by pooled p values of Wald statistics (Rubin's rule). The hazard ratio of binary ΔPCT4.0 in the univariate model is 1.80 (p = 0.011) for patients of the Per-Protocol population and similarly of the Intention to diagnose group (1.81; p = 0.008). That means the risk of death is increased 1.8-fold if an individual has a positive test result for APCT.

Univariate hazard ratios for 28-day all-cause mortality of ΔPCT and clinical covariates
Factor	Comparison	Hazard ratio	p-Value
ΔPCT4.0	≤ 80 % vs. > 80 %	1.80 (1.15-2.82)	0.011
ΔPCT4.1	≤ 80 % vs. > 80 %	1.61 (1.04-2.49)	0.034
APACHE	Difference of 5 units	1.36 (1.22-1.53)	2 µg/L vs. ≤ 2 µg/L
Age	Difference of 5 years	1.16 (1.08-1.24)	1.80 [1.15-2.82]; p=0.0106
ΔPCT 4.0 with binary APACHE + covariatesd)	1.94 [1.14-3.31]; p=0.0140
ΔPCT 4.0 with numeric APACHE + covariatesc)	1.72 [1.00-2.95]; p=0.0487
ΔPCT 4.0 with binary SOFA + covariatesc)	1.76 [1.05-2.96]; p=0.0320
ΔPCT 4.0 with numeric SOFA + covariatesc)	1.46 [0.86-2.48]; p=0.1595
ΔPCT 4.1 (univariate)	1.61 [1.04-2.49]; p=0.0345
ΔPCT 4.1 with binary APACHE + covariatesc)	1.68 [1.03-2.76]; p=0.0392
ΔPCT 4.1 with numeric APACHE + covariatesc)	1.61 [0.98-2.65]; p=0.0625
ΔPCT 4.1 with binary SOFA + covariatesc)	1.64 [1.00-2.69]; p=0.0483
ΔPCT 4.1 with numeric SOFA + covariatesc)	1.47 [0.89-2.42]; p=0.1300

d) Antibiotic adequacy, Sepsis severity, ICU Care on Day 4, Biological infection type, Positive blood culture, PCT on Day 0, Age, Gender

Hazard ratios for ΔPCT and selected predictors from multivariate Cox Regression Models
Model		Hazard ratio (95 % confidence interval)
		Binary predictorse)
ΔPCT interval	Score + Covariatesf)	ΔPCT
(≤ 80 % vs > 80 %)	Day 4 patient location
(ICU vs. no ICU)
Day 0 until
Day 4	APACHE	1.72 (1.00-2.95)	2.61 (1.63-4.19)
	max SOFA	1.46 (0.86-2.48)	1.71 (1.04-2.81)
Day 1 until
Day 4	APACHE	1.61 (0.98-2.65)	2.63 (1.64-4.21)
	max SOFA	1.47 (0.89-2.42)	1.73 (1.06-2.84)

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e) In the analysis, missing values for predictors were multiple imputed assuming they were Missing at Random (MAR), with the multiple imputations combined according to Rubin D.B.,Wiley New York 1987; Multiple Imputation for Nonresponse in Surveys). f) The models also included the following predictors (HR results not shown): Antibiotic adequacy, Sepsis severity, Biological infection type, Clinical infection type, Positive blood culture, PCT on Day 0, Gender.

Hazard ratios for ΔPCT and selected predictors from multivariate Cox Regression Models
Model	Hazard ratio (95 % confidence interval)
	Continuous predictorsg) (HR per 1 SD)
ΔPCT interval	Score + Covariatesh)	APACHE (1 SD=8.13)	max SOFA (1 SD=3.98)	Age (1 SD=16.18)
Day 0 until Day 4	APACHE	1.25 (0.99-1.57)	----	1.59 (1.27-1.99)
	max SOFA	----	1.97 (1.53-2.53)	1.69 (1.35-2.10)
Day 1 until Day 4	APACHE	1.29 (1.04-1.62)	----	1.57 (1.25-1.96)
	max SOFA	----	2.00 (1.56-2.56)	1.67 (1.33-2.08)

g) In the analysis, missing values for predictors were multiple imputed assuming they were Missing at Random (MAR), with the multiple imputations combined according to Rubin D.B.,Wiley New York 1987; Multiple Imputation for Nonresponse in Surveys).

h) The models also included the following predictors (HR results not shown): Antibiotic adequacy, Sepsis severty, Biological infection type, Clinical infection type, Positive blood culture, PCT on Day 0, Gender.

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

$$PCT_{ratio} = \frac{PCT_{Day\ 4}}{PCT_{Day\ 0\ (or\ Day\ 1)}}$$

A decline of ΔPCT = 80 % translates into a PCT ratio of 0.2. The PCT ratio has values larger than 0.2 when the APCT decline is below 80 % which is associated with a higher risk for cumulative 28day all-cause mortality in patients diagnosed with severe sepsis or septic shock. Likewise, a PCT ratio below 0.2 indicates a lower risk for mortality within 28 days. On a continuous scale, the relative mortality risk for patients diagnosed with severe sepsis or septic shock is higher the larger the PCT ratio. The following tables list the hazard ratios for an increase by the factor 2 in PCT ratio, i.e. the relative increase in mortality risk for a patient with any given PCT ratio compared to a patient with a 2-fold lower PCT ratio. For comparison, selected predictors are indicated with corresponding equivalents in standard deviation. For the patient location at Day 4, the risk estimate compares the hazards for patients with vs. without ICU care on Day 4.

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Hazard ratios for ΔPCT and selected predictors from multivariate Cox Regression Models
ΔPCT interval	Model	Hazard ratio (95 % confidence interval)
	Score + Covariatesj	Binary predictorsj
Day 4 patient location (ICU vs. no ICU)
Day 0 until Day 4	APACHE	2.57 (1.59-4.13)
	Max SOFA	1.70 (1.03-2.80)
Day 1 until Day 4	APACHE	2.57 (1.60-4.11)
	Max SOFA	1.74 (1.06-2.86)

i) In the analysis, missing values for predictors were multiple imputed assuming they were Missing at the multiple imputations combined according to Rubin D.B.,Wiley New York 1987; Multiple Imputation for Norresponse in Surveys).

j) The models also included the following predictors (HR results not shown): Antibiotic adequacy, Sepsis severity, Biological infection type, Clinical infection type, Positive blood culture, PCT on Day 0, Gender.

Hazard ratios for ΔPCT and selected predictors from multivariate Cox Regression Models
		Hazard ratio (95 % confidence interval)
Model
Continuous predictorsk)
(HR per 2-fold increase in PCT ratio or per equivalent in SD)
ΔPCT
interval	Score +
Covarl,m)	PCT ratio
(2-fold
increase)	APACHE
(SD equivn),o))	Max SOFA
(SD equivi),j))	Age
(SD equivi),j))
Day 0 until
Day 4	APACHE	1.26 (1.12-1.42)	1.08 (0.96-1.22)	----	1.29 (1.15-1.45)
Day 0 until
Day 4	max SOFA	1.20 (1.07-1.35)	----	1.37 (1.20-1.57)	1.32 (1.18-1.49)
Day 1 until
Day 4	APACHE	1.29 (1.11-1.49)	1.19 (1.02-1.39)	----	1.37 (1.18-1.60)
Day 1 until
Day 4	max SOFA	1.23 (1.06-1.44)	----	1.58 (1.33-1.87)	1.43 (1.23-1.67)

k) In the analysis, missing values for predictors were multiple imputed assuming they were Missing at Random (MAR), with the multiple imputations combined according to Rubin D.B.,Wiley New York 1987; Multiple Imputation for Nonresponse in Surveys).

I) Covar = Covariates

m) The models also included the following predictors (HR results not shown): Antibiotic adequacy, Sepsis severity, Biological infection type, Clinical infection type, Positive blood culture, PCT on Day 0, Gender.

n) Equiv = Equivalent

o) A unit change of ΔPCT on log 2-scale corresponded to 0.52 SD of ΔPCT from Day 0 until Day 4 (0.69 SD for ΔPCT from Day 1 until Day 4). Accordingly, the reported ΔPCT hazard ratios refer to an increase of ΔPCT by a factor of 2. For comparability, hazard ratios of the other continuous predictors were estimated for the same fractional SDs, i.e. 0.52 or 0.69, respectively.

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		Per-protocol population (N=598)
Variable	Class	All N	Dead N	Alive N	Mortality %
Gender	Female	264	46	218	17.4
	Male	334	55	279	16.5
	30, 45, 55, 65, 75	166	41	125	24.7
	African-American	202	32	170	15.8
	Asian	7	0	7	0.0
Ethnicity	Caucasian	362	64	298	17.72
	Hispanic	23	5	18	21.7
	Other	4	0	4	0.0
	0.5, 2.0	353	69	284	19.5
	Missing	16	0	16	0.0

Cumulative 28-day all-cause mortality did not differ significantly for male vs. female patients (χ2 p-value = 0.84). Demographics with outcome information are shown below :

35

7. CONCLUSIONS

The information provided in this 510(k) Premarket Notification will support a determination of substantial equivalence for the Elecsys BRAHMS PCT test system. The data supports a safe, effective device which performs as well as or better than the predicate device.