Atellica IM BRAHMS Procalcitonin (PCT)

K181002 · Siemens Healthcare Diagnostics, Inc. · PMT · Jul 16, 2018 · Microbiology

Device Facts

• Record ID: K181002
• Device Name: Atellica IM BRAHMS Procalcitonin (PCT)
• Applicant: Siemens Healthcare Diagnostics, Inc.
• Product Code: PMT · Microbiology
• Decision Date: Jul 16, 2018
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 866.3215
• Device Class: Class 2

Intended Use

The Atellica® IM BRAHMS Procalcitonin (PCT) assay is for in vitro diagnostic use in the quantitative determination of procalcitonin in human serum and plasma (EDTA, lithium heparin, and sodium heparin) using the Atellica® IM Analyzer. The Atellica IM BRAHMS PCT assay is intended for use, in conjunction with other laboratory findings and clinical assessments, as an aid in: · The risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock. · Assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using percent change in PCT level over time. · Decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department. · Decision-making on antibiotic discontinuation for patients with suspected or confirmed sepsis.

Device Story

Atellica IM BRAHMS PCT is a quantitative chemiluminescent immunoassay for procalcitonin in human serum/plasma. It uses three mouse monoclonal antibodies: one labeled with acridinium ester (Lite Reagent) and two labeled with fluorescein (Ancillary Reagent). The immunocomplex is captured by anti-fluorescein antibody-coated paramagnetic particles (Solid Phase). The system measures relative light units (RLUs) proportional to PCT concentration. Used in clinical laboratories on the Atellica IM Analyzer; operated by trained laboratory personnel. Results aid clinicians in assessing sepsis progression, 28-day mortality risk, and antibiotic therapy management (initiation/discontinuation) for LRTI and sepsis. The device provides quantitative data to support clinical decision-making, potentially improving patient management in ICU and emergency settings.

Clinical Evidence

Clinical performance validated via retrospective multicenter study of 2,285 adult patients diagnosed with severe sepsis or septic shock. Concordance with predicate device evaluated at clinical cutoffs (0.1, 0.25, 0.5, 2.0 μg/L). Total agreement >96% at all decision points. Weighted Deming regression slope 0.979 (95% CI: 0.965-0.996), intercept -0.014. Passing-Bablok slope 0.941, intercept 0.017. Pearson R²=0.979. Study confirms clinical agreement with predicate.

Technological Characteristics

Two-site sandwich chemiluminescent immunoassay (CMIA). Reagents: mouse monoclonal anti-PCT antibodies (acridinium ester-labeled, fluorescein-labeled) and anti-fluorescein antibody-coated paramagnetic particles. Measuring range: 0.04–50.00 ng/mL (extendable to 1000 ng/mL via 1:20 auto-dilution). Energy source: Atellica IM Analyzer. Connectivity: Integrated system. Software: Automated processing and calibration. Traceability: ISO 17511:2003.

Indications for Use

Indicated for critically ill patients (≥18 years) at ICU admission for sepsis/septic shock risk assessment; patients with severe sepsis/septic shock for 28-day mortality risk assessment; patients with suspected/confirmed LRTI (CAP, acute bronchitis, AECOPD) for antibiotic therapy decisions; and patients with suspected/confirmed sepsis for antibiotic discontinuation. Not for stand-alone diagnosis. Contraindicated/confounded by: atypical pathogens (Chlamydophila/Mycoplasma pneumoniae), renal failure, major trauma/burns, certain drug treatments (OKT3, interleukins), medullary C-cell carcinoma, small cell lung carcinoma, severe liver cirrhosis, cardiogenic shock, dialysis, pancreatitis, fungal infections, malaria, and neonates <2 days old. Safety/performance not established for <18 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

• B.R.A.H.M.S PCT sensitive KRYPTOR assay (K171338)

Submission Summary (Full Text)

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Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

July 16, 2018

Siemens Healthcare Diagnostics Inc. Fatima Pacheco Regulatory Affairs Clinical Specialist 511 Benedict Ave Tarrytown, New York 10591-5097

Re: K181002

Trade/Device Name: Atellica IM BRAHMS Procalcitonin (PCT) Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microial analytes in human clinical specimens to aid in assessment of patients with suspected sepsis. Regulatory Class: Class II Product Code: PRI, PMT, PTF Dated: April 13, 2018 Received: April 16, 2018

Dear Fatima Pacheco:

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

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

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device 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

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Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely.

Steven R. Gitterman -S

for

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

Enclosure

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## Indications for Use

510(k) Number (if known) K181002

Device Name

Atellica IM B.R.A.H.M.S Procalcitonin (PCT)

Indications for Use (Describe)

The Atellica® IM BRAHMS Procalcitonin (PCT) assay is for in the quantitative determination of procalcitonin in human serum and plasma (EDTA, lithium heparin) using the Atellica® IM Analyzer. The Atellica IM BRAHMS PCT assay is intended for use, in conjunction with other laboratory findings and clinical assessments, as an aid in:

· The risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

• Assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using percent change in PCT level over time.

· Decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive

pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.

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

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

| <span style="text-decoration: overline;">X</span> Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
|------------------------------------------------------------------------------------------------|---------------------------------------------|
|------------------------------------------------------------------------------------------------|---------------------------------------------|

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# 510K SUMMARY

# Atellica® IM B.R.A.H.M.S Procalcitonin (PCT)

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

#### 1. 510(k) Number: k181002

## 2. Purpose for Submission:

To obtain a substantial equivalence determination for the Atellica® IM B.R.A.H.M.S Procalcitonin (PCT) assay.

## 3. Applicant:

Contact: Fatima Pacheco Regulatory Clinical Affairs Specialist Address: Siemens Healthcare Diagnostics Inc. 511 Benedict Ave. Tarrytown, NY 10591 Phone: [phone]

Email: [e-mail]

#### Date: June 04, 2018

## 4. Proprietary and Established Names: Atellica® IM B.R.A.H.M.S Procalcitonin (PCT)

- 5. Measurand
Procalcitonin

## 6. Regulatory Information:

## Regulatory Information for Atellica® IM B.R.A.H.M.S Procalcitonin (PCT)

| Trade Name | Atellica® IM B.R.A.H.M.S Procalcitonin (PCT) |
|---------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|
| Common Name | Immunoassay, Procalcitonin |
| Classification Name | Device to detect and measure non-microbial<br>analyte(s) in human clinical specimens to aid in<br>assessment of patients with suspected sepsis. |
| FDA Classification | Class II |
| Review Panel | Microbiology (83) |
| Product Code | PMT |
| Regulation Number | 21 CFR 866.3215 |

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## Regulatory Information for Atellica® IM B.R.A.H.M.S Procalcitonin Calibrator (Included in assay kit)

| Trade Name | Atellica® IM B.R.A.H.M.S Procalcitonin Calibrator |
|---------------------|-------------------------------------------------------------------|
| Common Name | Single (specified) analyte calibrators (assayed and<br>unassayed) |
| Classification Name | Calibrator (assayed and unassayed) |
| FDA Classification | Class II (Exempt) |
| Review Panel | Clinical Chemistry (75) |
| Product Code | JIT |
| Regulation Number | 21 CFR 862.1150 |

## Regulatory Information for Atellica® IM B.R.A.H.M.S Procalcitonin QC & MCM (Sold Separately)

| Trade Name | Atellica® IM B.R.A.H.M.S Procalcitonin Quality<br>Control (QC)<br>Atellica® IM B.R.A.H.M.S Procalcitonin Master Curve<br>Material (QC) |
|---------------------|----------------------------------------------------------------------------------------------------------------------------------------|
| Common Name | Single (specified) analyte calibrators (assayed and<br>unassayed) |
| Classification Name | Calibrator (assayed and unassayed) |
| FDA Classification | Class II (Exempt) |
| Review Panel | Clinical Chemistry (75) |
| Product Code | JIT |
| Regulation Number | 21 CFR 862.1150 |

## 7. Predicate Devices:

Device Name: B.R.A.H.M.S PCT sensitive KRYPTOR 510(k) Number: DEN150009; k171338 Manufacturer: B.R.A.H.M.S GmbH (Thermo Fisher Scientific)

## 8. Intended Use:

Same as Indications for Use

## 9. Indications for Use:

The Atellica® IM BRAHMS Procalcitonin (PCT) assay is for in vitro diagnostic use in the quantitative determination of procalcitonin in human serum and plasma (EDTA, lithium heparin, and sodium heparin) using the Atellica® IM Analyzer.

The Atellica IM BRAHMS PCT assay is intended for use, in conjunction with other laboratory findings and clinical assessments, as an aid in:

· The risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.

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• Assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using percent change in PCT level over time.

· Decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) – defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.

- · Decision-making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
#### 10. Special Conditions for use statement(s):

For Prescription Use Only

#### 11. Warnings and Precautions for Test Interpretation:

The Atellica® IM BRAHMS Procalcitonin (PCT) assay is not indicated to be used as a stand-alone diagnostic assay and should be used in conjunction with clinical signs and symptoms of infection and other diagnostic evidence.

Decisions regarding antibiotic therapy should NOT be based solely on PCT concentrations.

PCT results should always be interpreted in the context of the clinical status of the patient and other laboratory results. Changes in PCT levels for the prediction of mortality, and overall mortality, are strongly dependent on many factors, including pre-existing patient risk factors and clinical course.

The need to continue ICU care at Day 4 and other covariates, such as age and Sequential Organ Failure Assessment (SOFA) score, are also significant predictors of 28-day cumulative mortality risk.

PCT levels may not be elevated in patients infected by certain atypical pathogens, such as Chlamydophila pneumoniae and Mycoplasma pneumoniae.

Certain patient characteristics, such as severity of renal failure or insufficiency, may influence PCT values and should be considered as potentially confounding clinical factors when interpreting PCT values.

The safety and performance of PCT-quided therapy for individuals younger than 18 years of age, pregnant women, immunocompromised individuals, or those on immunomodulatory agents, was not formally analyzed in the supportive clinical trials.

Increased PCT levels may not always be related to systemic infection. These conditions include, but are not limited to:

- · 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 lunq carcinoma, or bronchial carcinoid:

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- · 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 (such as candidiasis and aspergillosis) or acute attacks of plasmodium falciparum malaria; and
- Neonates during the first 2 days of life.

#### 12. Special Instrument Requirement:

For use on the Atellica® IM Analyzer

#### 13. Device Description:

The Atellica IM BRAHMS PCT assay is comprised of the following reagents:

| Component | Volume | Ingredients |
|----------------------------------------------------------------|--------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| Atellica IM BRAHMS PCT Primary Reagent ReadyPack (assay kit) | | |
| PCT Lite Reagent | 5.0 mL/pack | Mouse monoclonal anti-PCT antibody (~0.5 μg/mL) labeled with acridinium ester in protein buffer; bovine serum albumin; surfactant; preservatives |
| PCT Solid Phase Reagent | 10.0 mL/pack | Mouse monoclonal anti-fluorescein antibody coated paramagnetic particles (~0.15 mg/mL) in buffer; surfactant; preservatives |
| PCT Ancillary Reagent | 4.5 mL/pack | Mouse monoclonal anti-PCT antibody (~13.3 μg/mL) labeled with fluorescein in protein buffer; bovine serum albumin; surfactant; preservatives |
| PCT Calibrator (Kitted-included in assay kit) | | |
| PCT Low and High Calibrators | 2.0 mL/vial | Lyophilized; after reconstitution, recombinant PCT; equine serum; preservatives |
| Atellica IM BRAHMS PCT Quality Control (sold separately) | | |
| PCT Low and High Quality Controls | 2.0 mL/vial | Lyophilized; after reconstitution recombinant PCT; equine serum; preservatives |
| Atellica IM BRAHMS PCT Master Curve Material (sold separately) | | |
| PCT MCM1-5 | 1.0 mL/vial | Lyophilized; after reconstitution, various levels of recombinant PCT; equine serum; preservatives |

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#### 14. Substantial Equivalence Information

The following table describes the similarities and differences between the Atellica IM BRAHMS PCT (Candidate Device) and the B.R.A.H.M.S PCT sensitive KRYPTOR® (Predicate Device).

| Trade Name | Candidate Device | Predicate Device |
|-----------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| | Atellica® IM B.R.A.H.M.S<br>Procalcitonin (PCT) | B.R.A.H.M.S PCT sensitive<br>KRYPTOR® |
| Intended Use | The Atellica® IM BRAHMS<br>Procalcitonin (PCT) assay is for<br><i>in vitro</i> diagnostic use in the<br>quantitative determination of<br>procalcitonin in human serum<br>and plasma (EDTA, lithium<br>heparin, and sodium heparin)<br>using the Atellica® IM Analyzer.<br><br>The Atellica IM BRAHMS<br>PCT is intended for use, in<br>conjunction with other<br>laboratory findings and clinical<br>assessments as an aid in:<br><br>The risk assessment of<br>critically ill patients on their<br>first day of intensive care unit<br>(ICU) admission for<br>progression to severe sepsis<br>and septic shock.<br><br>Assessing the cumulative 28-<br>day risk of all-cause mortality<br>for patients diagnosed with<br>severe sepsis or septic shock<br>in the ICU or when obtained<br>in the emergency department<br>or other medical wards prior<br>to ICU admission, using<br>percent change in PCT level<br>over time.<br><br>Decision making on antibiotic<br>therapy for patients with<br>suspected or confirmed lower<br>respiratory tract infections<br>(LRTI) - defined as<br>community-acquired<br>pneumonia (CAP), acute<br>bronchitis, and acute<br>exacerbation of chronic<br>obstructive pulmonary<br>disease (AECOPD) – in an<br>inpatient setting or an | The B·R·A·H·M·S PCT<br>sensitive KRYPTOR® is an<br>immunofluorescent assay using<br>Time-Resolved Amplified<br>Cryptate Emission (TRACE®)<br>technology to determine the<br>concentration of PCT<br>(procalcitonin) in human serum<br>and EDTA or heparin plasma.<br>The B·R·A·H·M·S PCT<br>sensitive KRYPTOR® is<br>intended to be performed on<br>the B·R·A·H·M·S KRYPTOR®<br>analyzer family.<br>Used in conjunction with other<br>laboratory findings and clinical<br>assessments, B·R·A·H·M·S<br>PCT sensitive KRYPTOR® is<br>intended for use as follows:<br>to aid in the risk assessment of<br>critically ill patients on their first<br>day of ICU admission for<br>progression to severe sepsis<br>and septic shock,<br>to determine the change in PCT<br>level over time as an aid in<br>assessing the cumulative 28-<br>day risk of all-cause mortality<br>for patients diagnosed with<br>severe sepsis or septic shock in<br>the ICU or when obtained in the<br>emergency department or other<br>medical wards prior to ICU<br>admission,<br>to aid in decision making on<br>antibiotic therapy, for inpatients<br>or patients in the emergency<br>department with suspected or<br>confirmed lower respiratory<br>tract infections (LRTI) – defined<br>as community-acquired<br>pneumonia (CAP), acute<br>bronchitis and acute |
| | emergency department.<br>Decision making on antibiotic<br>discontinuation for patients with<br>suspected or confirmed sepsis. | exacerbation of chronic<br>obstructive pulmonary disease<br>(AECOPD),<br>to aid in decision making on<br>antibiotic discontinuation for<br>patients with suspected or<br>confirmed sepsis. |
| Analyte | Procalcitonin (PCT) | Same |
| Automated | Automated assay | Same |
| Measurement | Quantitative | Same |
| Sample Type | Human Serum, Plasma (EDTA,<br>Lithium, Heparin, Sodium<br>Heparin) | Human Serum, Plasma ( EDTA<br>and Heparin) |
| Assay Measuring<br>Interval | 0.04 - 50.00 ng/mL | 0.02 - 50 µg/L |
| Operating Principle | Sandwich | Sandwich |
| Technology | Direct Chemiluminescent<br>technology | Immunofluorescence TRACE®<br>technology |
| Instrument | Atellica IM Analyzer | KRYPTOR® Test System |
| Sample Volume | 100 µL | 50 µL |
| Calibrators | Atellica IM B.R.A.H.M.S PCT<br>Calibrators (lyophilized)<br>2 levels (Low and High); After<br>reconstitution, recombinant PCT;<br>equine serum; preservatives | B.R.A.H.M.S PCT sensitive<br>KRYPTOR® Calibrator:<br>1 vial of lyophilized<br>recombinant PCT in<br>defibrinated human plasma<br>(range 22.50-27.50µg/L) |
| Controls | Atellica IM B.R.A.H.M.S PCT<br>Quality Control (lyophilized)<br>2 levels (Low and High); After<br>reconstitution, recombinant PCT;<br>equine serum; preservatives | B.R.A.H.M.S PCT sensitive<br>KRYPTOR® QC Kit:<br>6 vials (3 of each control):<br>Control 1 (0.20-0.40µg/L)<br>Control 2 (8.00-12.00µg/L) |

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#### Standard/Guidance Document Referenced 15.

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

- 트 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline -Third Edition (CLSI EP05-A3, 2014; Recognition Number 7-251)
- Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical . Approach; Approved Guideline (CLSI EP06-A, 2003; Recognition Number 7-193)
- . Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition (CLSI EP07-A2, 2005; Recognition Number 7-127)
- . Measurement Procedure Comparison And Bias Estimation Using Patient Samples --Third Edition (CLSI EP09-A3, 2013; Recognition Number 7-245)
- . Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline -- Second Edition (CLSI EP17-A2, 2012; Recognition Number 7-233)
- Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition (CLSI EP28-A3c - formerly C28-A3c, 2010; Recognition Number 7-224)
- . Medical devices – Application of risk manaqement to medical devices (ANSI/AAMI/ISO 14971:2007/(R)2010; Recognition Number 5-70)

#### 16. Test Principle

The Atellica IM BRAHMS PCT assay is a 2-site sandwich immunoassay using direct chemiluminescent technology that uses 3 mouse monoclonal antibodies specific for PCT. The first antibody, in the Lite Reagent, is a mouse monoclonal anti-PCT antibody labeled with acridinium ester. The second and third antibodies, in the ancillary reagent, are mouse monoclonal anti-PCT antibodies labeled with fluorescein. The immunocomplex formed with PCT is captured with mouse monoclonal anti-fluorescein antibody coupled to paramagnetic particles in the Solid Phase.

A direct relationship exists between the amount of PCT present in the patient sample and the amount of relative light units (RLUs) detected by the system.

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#### 17. Performance Characteristics

## 1. Analytical Performance

## A. Precision

The precision of the Atellica IM B.R.A.H.M.S PCT assay precision study was performed in accordance with CLSI EP05-A3 - Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline—Third Edition. Wayne, PA: Clinical and Laboratory Standards Institute; 2014.

A single site study was conducted with a panel of five (5) contrived human serum samples, calibrators, and controls were tested. The panel of human samples was prepared by spiking normal serum samples with recombinant PCT spiking material. Samples were frozen in aliquots prior to the study. Each sample was assayed in two (2) replicates per run, with two (2) runs per day separated by at least 2 hours, for 20 days yielding a total of 40 runs, and 80 replicates per sample. For each analyte concentration level, the mean value with variance components (standard deviation and %CV) was determined. The following results were obtained:

| Sample | No. of<br>replicates | Mean<br>(ng/mL) | Repeatability<br>(Within-Run) | | Within-Lab<br>(Total Precision) | |
|-----------|----------------------|-----------------|-------------------------------|-----|---------------------------------|------|
| | | | SD | %CV | SD | %CV |
| Serum 1 | 80 | 0.05 | 0.00 | 9.7 | 0.01 | 12.1 |
| Serum 2 | 80 | 0.27 | 0.00 | 1.8 | 0.01 | 2.8 |
| Serum 3 | 80 | 0.75 | 0.01 | 1.2 | 0.02 | 2.1 |
| Serum 4 | 80 | 1.52 | 0.02 | 1.4 | 0.04 | 2.6 |
| Serum 5 | 80 | 19.14 | 0.29 | 1.5 | 0.43 | 2.2 |
| Control 1 | 80 | 0.23 | 0.01 | 3.4 | 0.01 | 5.6 |
| Control 2 | 80 | 7.85 | 0.11 | 1.4 | 0.60 | 7.7 |

A modeling analysis was conducted to estimate the %Bias, %CV, and % Total Error at each medical decision point. %Bias was calculated relative to reference values derived using the slope and the intercept derived experimentally from the method comparison study between Atellica IM BRAHMS PCT and BRAHMS sensitive KRYPTOR. The %CV measurement was derived using the precision profile: the %Total Error was calculated as 1.65*(%CV) + (%Bias). The results from each of three regressions (%Bias, %CV, and %TE) are summarized in the table below.

| PCT Level<br>(ng/mL) | Bias<br>(%) | CV<br>(%) | Total Error<br>(%) |
|----------------------|-------------|-----------|--------------------|
| 0.10 | 22% | 6.1 | 32% |
| 0.25 | 6% | 2.6 | 11% |
| 0.5 | 2% | 1.4 | 4% |
| 2.0 | -1% | 0.4 | 1% |

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## B. Linearity/Assay Measuring Range

Linearity of the Atellica IM B.R.A.H.M.S PCT assay was performed according to CLSI EP06-A - Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach: Approved Guideline. The study was performed using 9 samples spanning the assay range, prepared using high and low human serum pools. Testing was performed on one (1) Atellica IM Analyzer with 2 PCT reagent lots, 3 replicates per level. The mean dose value of each sample was used in data analysis. The results were analyzed by % Deviation from Linear Fit.

Regression analysis using the first, second, and third order models were conducted to assess the linearity of the assay. Regression statistics (i.e., deviation from linearity for non-linear pools) at all levels tested demonstrated a ≤10% deviation from linear fit.

Linearity was confirmed in the range of 0.03 – 63.24 ng/mL. The measuring range claim for the Atellica IM BRAHMS PCT assay is 0.04 – 50.00 ng/mL. For PCT concentrations greater than 50.00 ng/mL, the measurement range can be extended up to 1000 ng/mL by 1:20 dilution of the sample.

## C. Dilution Recovery

To evaluate the degree of bias introduced when the instrument auto-dilution is used on samples within the assay measuring range or above.

Five (5) human serum samples spiked with recombinant PCT stock. The samples were diluted to 1:20 with Atellica IM Multi-Diluent 1 both manually and automatically onboard the system. Recoveries ranged from 96% to 102% with a mean of 99%.

The samples were diluted (1:20) with Atellica IM Multi-Diluent 1 using the auto-dilution protocol. Recoveries ranged from 92% to 107%.

## D. Hook Effect

A study was performed to evaluate the hook effect. In this assay, patient samples with procalcitonin concentrations as high as 2000 ng/mL will report > 50.00 ng/mL.

## E. Detection Limits

Detection capability was determined in accordance with CLSI Document EP17-A2. The assay is designed to have a limit of blank (LoB) < 0.03 ng/mL, a limit of detection (LoD) < 0.04 ng/mL, and a limit of quantitation (LoQ) ≤ 0.06 ng/mL. Representative detection capability data are presented below.

The LoB corresponds to the highest measurement result that is likely to be observed for a blank sample. The LoB of the Atellica IM BRAHMS PCT assay is 0.00 ng/mL.

The LoD corresponds to the lowest concentration of procalcitonin that can be detected with a probability of 95%. The LoD for the Atellica IM BRAHMS PCT assay is 0.03 ng/mL and was determined using 360 determinations, with 160 blank and 200 low-level replicates, and LoB of 0.00 ng/mL.

The LoQ corresponds to the lowest amount of procalcitonin in a sample at which the within-lab CV is ≤ 20%. The LoQ of the Atellica IM BRAHMS PCT assay is 0.04 ng/mL, and was determined using multiple patient samples in the interval 0.01-0.05 ng/mL. All samples were assayed in duplicate in each of 2 runs per day using 2 reagent lots, over a period of 20 days.

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## F. Endogenous Interference

Endogenous interference studies were performed according to CLSI EP07-A2. The assay was designed to have ≤ 10% interference from the following substances. Interference (bias) is the difference in the results between the control sample (does not contain the interferent) and the test sample (contains the interferent) expressed in percent. Potential interference from the following substances was tested by adding these substances to serum pools containing PCT ranging from 0.32-2.59 ng/mL.

The interference with biotin was not evaluated since Atellica IM BRAHMS PCT reagents architecture does not use biotin:streptavidin. Therefore interference with biotin is not possible.

| Endogenous Substance | Concentration Tested<br>(mg/dL) | Results |
|----------------------------|---------------------------------|--------------------------|
| Bilirubin (Conjugated) | 40 mg/dL | No interference observed |
| Bilirubin (Unconjugated) | 40 mg/dL | No interference observed |
| Cholesterol | 400 mg/dL | No interference observed |
| Hemoglobin | 500 mg/dL | No interference observed |
| Triglycerides | 1000 mg/dL | No interference observed |
| Fluorescein | 0.1 µg/mL | No interference observed |
| Human Immunoglobulin | 3.6 g/dL | No interference observed |
| Total Protein (as low as ) | 3.5 g/dL | No interference observed |
| Total Protein (as high as) | up to 12.0 g/dL | No interference observed |

## G. Heterophile Interference

Testing was performed to determine whether the presence of HAMA (Human anti-mouse antibody) may interfere with Atellica IM BRAHMS PCT assay results.

HAMA and RF positive patient samples were divided in half and spiked with PCT to a "Level 1" (0.4-0.7 ng/mL) and a "Level 2" (1.5-2.0 ng/mL) concentrations. A control sample negative for HAMA and RF ("serum control" and "plasma control") was spiked with equal amounts of PCT. Acceptance criteria were met for the HAMA spiking study. The presence of HAMA in the samples did not influence the performance of the Atellica IM BRAHMS PCT assay. No HAMA/RF interference was observed for PCT analyte with the presence of HAMA at the concentrations tested.

## H. Therapeutic Drug Interference

Therapeutic drug interference studies were performed according to CLSI EP07-A2. The assay was designed to have ≤ 10% interference from the following substances. Interference (bias) is the difference in the results between the control sample (does not

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contain the interferent) and the test sample (contains the interferent) expressed in percent. Potential interference from the following substances was tested by adding these substances to serum pools containing PCT ranging from 0.42-1.99 ng/mL. All the therapeutic drugs evaluated did not affect the test performance at concentrations evaluated.

| Drug | Concentration Tested<br>(mg/dL) | Results |
|----------------------|---------------------------------|--------------------------|
| Acetaminophen | 20 | No interference observed |
| Acetylsalicylic Acid | 100 | No interference observed |
| Alcohol | 405 | No interference observed |
| Azithromycin | 1.17 | No interference observed |
| Caffeine | 6 | No interference observed |
| Celecoxib | 24 | No interference observed |
| Cetirizine HCl | 0.36 | No interference observed |
| Dextramethorphan | 0.14 | No interference observed |
| Doxycycline | 5 | No interference observed |
| Epinephrine | 1.79 | No interference observed |
| Fentanyl | 1 | No interference observed |
| lbuprofen | 50 | No interference observed |
| Levofloxacin | 1.75 | No interference observed |
| Loratadine | 0.03 | No interference observed |
| Nicotine | 0.1 | No interference observed |
| Oxymetazoline HCl | 0.01 | No interference observed |
| Phenylephrine | 0.02 | No interference observed |
| Prednisolone | 0.3 | No interference observed |
| Salmeterol | 0.006 | No interference observed |
| Tiotropium | 0.0022 | No interference observed |

#### l. Cross Reactivity

Potential cross-reactivity of drugs and metabolites were evaluated in accordance with CLSI document EP07-A2. The following substances were evaluated for cross-reactivity and do not interfere with the Atellica IM BRAHMS PCT assay when present in serum and plasma at the concentrations indicated. Testing was performed with serum, EDTA plasma, sodium heparin, and lithium heparin plasma matrices. The results are presented in the table below:

| Substance | Concentration Tested<br>(mg/dL) | Results |
|-------------------|---------------------------------|--------------------------|
| Calcitonin-human | 8 | No interference observed |
| Calcitonin salmon | 30 | No interference observed |
| Calcitonin eel | 30 | No interference observed |
| α-CGRP | 30 | No interference observed |
| β-CGRP | 30 | No interference observed |
| Katacalcin | 30 | No interference observed |
| Cefotaxim | 900,000 | No interference observed |
| Dobutamine | 11,200 | No interference observed |

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| Substance | Concentration Tested<br>(mg/dL) | Results |
|---------------|---------------------------------|--------------------------|
| Dopamine | 130,000 | No interference observed |
| Furosemide | 20,000 | No interference observed |
| Heparin | 40,000 | No interference observed |
| Imipenem | 1,180,000 | No interference observed |
| Noradrenaline | 2000 | No interference observed |
| Vancomycin | 3,500,000 | No interference observed |

## J. Method Comparison with Predicate Device

The method comparison study was performed according to the quidance of CLSI Guideline EP09-A3, Measurement Procedure Comparison and Bias Estimation Using Patient Samples.

A total of 623 native human serum samples with assigned BRAHMS Kryptor does values (0-1000 ng/mL) were tested with the Atellica IM BRAHMS PCT assay. Samples > 50.00 ng/mL were auto-diluted (1:20) by the Atellica IM Analyzer.

Two separate data analysis for this was performed, one with analysis of all samples with BRAHMS PCT sensitive KRYPTOR assay with sample range 0.06-49.20 ng/mL (N=522) and one with an extended analysis including all samples tested (N=623). Weighted Deming and Passing & Bablok regression analyses including slope and intercept with 95% Cl were calculated for N=522 samples. Regression analysis comparing the Atellica IM BRAHMS PCT assay results to the predicate assay results are summarized in table below and illustrated in Figures below.

| Parameter | Weighted Deming<br>Regression | Passing & Bablok<br>Regression |
|-------------------------------|-------------------------------|--------------------------------|
| N | 522 | 522 |
| Slope | 1.02 | 1.06 |
| 95% CI two sided | 0.99 to 1.05 | 1.04 to 1.09 |
| Intercept | -0.02 | -0.04 |
| 95% Cl two sided | -0.03 to -0.01 | -0.06 to -0.03 |
| Correlation coefficient ( r ) | 0.98 | 0.98 |
| Sample Range (ng/mL) | 0.06-49.20 | 0.06-49.20 |

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Image /page/15/Figure/0 description: The image is a scatter plot comparing two sets of data, labeled as 'Rep 1 of atellica im' on the y-axis and 'Rep 1 of brahms kryptor' on the x-axis, both ranging from 0 to 60. The plot includes individual data points represented by triangles, along with two trend lines: an 'Identity Line' shown as a dashed line and a 'Weighted Deming Fit' shown as a solid line. The data points generally cluster around the trend lines, indicating a positive correlation between the two sets of data.

Figure 1: Weighted Deming Regression Analysis Atellica IM BRAHMS PCT vs. Predicate

Figure 2: Passing & Bablock Regression Analysis Atellica IM BRAHMS PCT vs. Predicate

Image /page/15/Figure/3 description: The image is a scatter plot comparing "Rep 1 of atellica im" on the y-axis and "Rep 1 of brahms kryptor" on the x-axis. The plot includes data points represented by triangles, along with two lines: an "Identity Line" and a "Passing & Bablok Fit" line. The data points are clustered along the lines, indicating a positive correlation between the two variables. The axes range from 0 to 60.

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Data was further analyzed for concordance at the 0.1, 0.25, 0.5, and 2.0 ng/mL clinical cutoffs. From the total N=623 samples tested, the percent agreement between the Atellica IM BRAHMS PCT and the predicate BRAHMS sensitive KRYPTOR PCT at the cutoffs obtained are presented in Tables below.

| Atellica IM BRAHMS PCT | BRAHMS sensitive KRYPTOR | | Total |
|------------------------|--------------------------|-------------|-------|
| | > 0.1 ng/mL | ≤ 0.1 ng/mL | |
| > 0.1 ng/mL | 539 | 4 | 543 |
| ≤ 0.1 ng/mL | 4 | 76 | 80 |
| Total | 543 | 80 | 623 |

Atellica IM BRAHMS PCT vs Predicate at 0.1 ng/mL cutoff

Positive percent agreement (PPA) = 539/543 (99.3%); 95% two sided Cl 98.1%-99.7% Negative percent agreement (NPA) = 76/80 (95.0%); 95% two sided Cl 87.8%-98.0% Overall percent agreement = 98.7%; 95% Confidence Interval: 97.5%-99.4%

### Atellica IM BRAHMS PCT vs Predicate at 0.25 ng/mL cutoff

| | BRAHMS sensitive KRYPTOR | | |
|------------------------|--------------------------|--------------|-------|
| Atellica IM BRAHMS PCT | > 0.25 ng/mL | ≤ 0.25 ng/mL | Total |
| > 0.25 ng/m…