Elecsys BRAHMS PCT

• K Number: K173927
• Device Name: Elecsys BRAHMS PCT
• Manufacturer: Roche Diagnostics
• Date Cleared: 2018-07-06 ( 192 days)
• Product Code: PRI , NTM , PMT
• Regulation Number: 866.3215
• Type: Traditional
• Panel: Microbiology
• Reference & Predicate Devices: K171338
• Predicate For: K192815

Intended Use

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

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

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

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

· to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,

· to aid in decision making on antibiotic therapy, for inpatients in the emergency department with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),

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

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.

AI/ML Overview

This document describes the Elecsys BRAHMS PCT assay, an in vitro diagnostic immunoassay for the quantitative determination of Procalcitonin (PCT) in human serum and plasma. The K173927 510(k) submission seeks substantial equivalence to the B.R.A.H.M.S. PCT sensitive KRYPTOR® (K171338) for updated Indications for Use.

Acceptance Criteria and Reported Device Performance

Criteria	Acceptance Criteria	Reported Device Performance and Study Findings
Clinical Concordance	Total agreement between the candidate device and the predicate device at medical decision points of 0.1, 0.25, 0.5, and 2.0 ng/mL should demonstrate equivalence for all cleared claims. Regression slopes within +/- 10% of identity in Passing-Bablok and Weighted Deming Analysis.	Total Agreement: - 0.10 ng/mL: 97.8% (95% CI: 97.4 - 97.3) - 0.25 ng/mL: 97.5% (95% CI: 97.2 - 98.4) - 0.50 ng/mL: 97.4% (95% CI: 96.6 - 98.1) - 2.00 ng/mL: 97.4% (95% CI: 94.8 - 96.9) Passing Bablok Regression: Slope = 0.959 (95% CI: 0.947; 0.972), Intercept = -0.023 (95% CI: -0.028; -0.018) Weighted Deming Regression: Slope = 0.949 (95% CI: 0.937; 0.961), Intercept = -0.008 (95% CI: -0.013; -0.004) All regression slopes are within ±10% of identity (i.e., between 0.90 and 1.10) and intercepts are close to zero.
Precision	Not explicitly stated in the provided text as an acceptance criterion for substantial equivalence, but internal studies were conducted according to CLSI guideline EP5-A3.	A precision study was conducted per CLSI EP5-A3. - Repeatability (CV%) ranged from 1.4% to 16.7%. - Intermediate Precision (CV%) ranged from 2.2% to 24.3%. - %Total Error ranged from 5.36% to 57.02%. (The acceptable range for these values is not provided for comparison).
Endogenous Interference	Recovery within ± 15% of the initial value.	No effect observed at clinically relevant concentrations for Hemoglobin (1000 mg/dL), Biotin (up to 30 ng/mL, with caution for >30 ng/mL), Intralipid (2000 mg/dL), Bilirubin (66 mg/dL), and Rheumatoid Factor (1500 IU/mL). Biotin concentrations > 30 ng/mL can lead to higher negative bias.
Exogenous Interference (Drugs)	Recovery within ± 10% of the reference value.	No effect observed at clinically relevant concentrations for 38 pharmaceutical compounds, including those listed in the table (e.g., Cromolyn, Acetylsalicylic acid, Acetaminophen, Alcohol, etc.).

Study Information:

1. Sample Size used for the test set and data provenance:

   • Sample Size: 2617 samples were used for the clinical performance evaluation (method comparison to predicate).
   • Data Provenance: Retrospective multicenter testing of PCT from available frozen samples of adult patients (>18 years of age) diagnosed with severe sepsis or septic shock. These patients were enrolled in the BRAHMS MOSES study from the Intensive Care Unit (ICU) or the emergency department, other wards, or directly from out of hospital and subsequently admitted to the ICU.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable. The ground truth for the comparative study was based on measurements obtained from the predicate device (B.R.A.H.M.S. PCT sensitive KRYPTOR®). Clinical diagnoses (severe sepsis or septic shock) were based on patient enrollment criteria for the BRAHMS MOSES study, which likely involved clinicians, but specific details on expert involvement in establishing ground truth for the test set's PCT values are not provided.

3. Adjudication method (e.g., 2+1, 3+1, none) for the test set: Not applicable. The study compares the candidate device's analytical results directly against the predicate device's analytical results. There is no mention of a human adjudication process for resolving discrepancies.

4. If a multi reader multi case (MRMC) comparative effectiveness study was done, if so, what was the effect size of how much human readers improve with AI vs without AI assistance: Not applicable. This is an analytical performance study comparing an immunoassay device to a predicate immunoassay device, not a human reader or AI-assisted diagnostic study.

5. If a standalone (i.e. algorithm only without human-in-the loop performance) was done: Yes, the entire performance evaluation described is a standalone evaluation of the Elecsys BRAHMS PCT assay, an automated immunoassay device, without human-in-the-loop performance influencing the assay results themselves. The results are intended to be used in conjunction with other laboratory findings and clinical assessments.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.): The "ground truth" for the method comparison study was the results obtained from the legally marketed predicate device, the B.R.A.H.M.S. PCT sensitive KRYPTOR®. For the clinical context, patients were diagnosed with severe sepsis or septic shock based on the BRAHMS MOSES study criteria, implying clinical and outcomes data were involved in the original classification of these patients.

7. The sample size for the training set: Not applicable. This is an in vitro diagnostic immunoassay, not a machine learning algorithm that typically requires a discrete training set for model development. The assay itself is a chemical and electrochemiluminescence process.

8. How the ground truth for the training set was established: Not applicable, as there is no specific "training set" in the context of an immunoassay for which ground truth would be established in the same way as for a machine learning model. The assay's analytical characteristics and calibration are established through standard laboratory and calibration procedures, which involve reference materials and calibrators. The assay is standardized against the BRAHMS PCT LIA assay.

Summary

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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, with the letters "FDA" in a blue box, followed by the words "U.S. FOOD & DRUG" in blue, and then the word "ADMINISTRATION" in a smaller font size below that.

July 6, 2018

Roche Diagnostics Wes Gerbig Regulatory Affairs Principal 9115 Hague Road Indianapolis, Indiana 46250

Re: K173927

Trade/Device Name: Elecsys BRAHMS PCT Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis Regulatory Class: Class II Product Code: PMT Dated: December 22, 2017 Received: December 26, 2017

Dear Wes Gerbig:

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

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803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR 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) K173927

Device Name Elecsys BRAHMS PCT

Indications for Use (Describe) Elecsys BRAHMS PCT

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

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

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

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

· to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,

· to aid in decision making on antibiotic therapy, for inpatients in the emergency department with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),

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

Type of Use (Select one or both, as applicable)
Prescription Use (Part 21 CER 801 Subpart D)	Over-The-Counter Use (21 CER 801 Subpart C)

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Elecsys BRAHMS PCT 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.

In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).

The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the Elecsys BRAHMS PCT Test System.

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Submitter Name	Roche Diagnostics
Address	9115 Hague RoadP.O. Box 50416Indianapolis, IN 46250-0457
Contact	Wes GerbigPhone: [phone]FAX: [phone]Email: [e-mail]
	Secondary Contact NameMichael LeutherPhone: [phone]FAX: [phone]Email: [e-mail]
Date Prepared	December 22, 2017
Proprietary Name	Elecsys BRAHMS PCT
Common Name	Procalcitonin
Classification Name	Device to detect and measure non-microbial analyte(s) in human clinicalspecimens to aid in assessment of patients with suspected sepsis
Product Codes,Regulation Numbers	PRI, PMT, NTM, 866.3215
Predicate Devices	B.R.A.H.M.S. PCT sensitive KRYPTOR® cleared under K171338.
Establishment Registration	For the Elecsys BRAHMS PCT Test System the establishment registrationnumber for Roche Diagnostics GmbH in Mannheim, Germany is 9610126, andfor Penzberg, Germany, 9610529. The establishment registration number forRoche Diagnostics in the United States is 1823260.

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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.

1.1. Reagents

The reagent working solutions include:

Rackpack (kit placed on analyzer)

• M: Streptavidin-coated microparticles, .
• R1: Anti-PCT-Ab~biotin ●
• R2: Anti-PCT Ab~Ru(bpy) == ●

2. INDICATIONS FOR USE

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

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

Used in conjunction with other laboratory findings and clinical assessments, Elecsys B·R·A·H·M·S PCT is intended for use as follows:

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

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• to determine the change in PCT level over time as an aid in assessing the cumulative . 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
• to aid in decision making on antibiotic therapy, for inpatients or patients in the . emergency department with suspected or confirmed lower respiratory tract infections (LRTI) – defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),
• to aid in decision making on antibiotic discontinuation for patients with suspected or . confirmed sepsis.

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TECHNOLOGICAL CHARACTERISTICS 3.

Table 1: Assay Comparison

Feature	Candidate Device: Elecsys BRAHMSPCT	Predicate Device: B.R.A.H.M.S.PCT sensitive KRYPTOR®(K171338).
Intended Use/Indications for Use	Immunoassay for the in vitro quantitativedetermination of PCT (procalcitonin) inhuman serum and plasma (K2 –EDTA,K3-EDTA and Li-Heparin).The electrochemiluminescenceimmunoassay "ECLIA" is intended for useon Elecsys and cobas e immunoassayanalyzers.Used in conjunction with other laboratoryfindings and clinical assessments, ElecsysB·R·A·H·M·S PCT is intended for use asfollows:• to aid in the risk assessment ofcritically ill patients on their first dayof ICU admission for progression tosevere sepsis and septic shock,• to determine the change in PCTlevel over time as an aid inassessing the cumulative 28-dayrisk of all-cause mortality forpatients diagnosed with severesepsis or septic shock in the ICU orwhen obtained in the emergencydepartment or other medical wardsprior to ICU admission,• to aid in decision making onantibiotic therapy, for inpatients orpatients in the emergencydepartment with suspected orconfirmed lower respiratory tractinfections (LRTI) – defined ascommunity-acquired pneumonia(CAP), acute bronchitis, and acuteexacerbation of chronic obstructivepulmonary disease (AECOPD),• to aid in decision making onantibiotic discontinuation forpatients with suspected orconfirmed sepsis.	The B·R·A·H·M·S PCT sensitiveKRYPTOR® is animmunofluorescent assay usingTime-Resolved Amplified CryptateEmission (TRACE®) technology todetermine the concentration of PCT(procalcitonin) in human serum andEDTA orheparin plasma.The B·R·A·H·M·S PCT sensitiveKRYPTOR® is intended to beperformed on the B·R·A·H·M·SKRYPTOR® analyzerfamily.Used in conjunction with otherlaboratory findings and clinicalassessments, B·R·A·H·M·S PCTsensitive KRYPTOR®is intended for use as follows:• to aid in the risk assessmentof critically ill patients ontheir first day of ICUadmission for progression tosevere sepsis and septicshock,• to determine the change inPCT level over time as anaid in assessing thecumulative 28-day risk of all-cause mortality for patientsdiagnosed with severesepsis or septic shock in theICU or when obtained in theemergency department orother medical wards prior toICU admission,
Intended Use/		• to aid in decision making onantibiotic therapy, for
Feature	Candidate Device: Elecsys BRAHMSPCT	Predicate Device: B.R.A.H.M.S.PCT sensitive KRYPTOR®(K171338).
Indications for Use Continued		inpatients or patients in theemergency department withsuspected or confirmedlower respiratory tractinfections (LRTI) – definedas community-acquiredpneumonia (CAP), acutebronchitis, and acuteexacerbation of chronicobstructive pulmonarydisease (AECOPD),• to aid in decision making onantibiotic discontinuation forpatients with suspected orconfirmed sepsis.
Assay Protocol	The Elecsys BRAHMS PCT assay is atwo-step sandwich immunoassay withstreptavidin microparticles and anelectrochemiluminescence detectionsystem. The test system reagents containa biotinylated monoclonal PCT-specificantibody and a ruthenium labeledmonoclonal PCT-specific antibody.	The BRAHMS PCT sensitiveKRYPTOR® assay is ahomogeneous sandwichimmunoassay for detection of PCTin human serum or plasma. Themeasuring principle is based onTime-Resolved Amplified CryptateEmission (TRACE®) technology,which measures the signal that isemitted from an immunocomplexwith time delay.
Detection Protocol	Electrochemiluminescent Assay	Time-Resolved Amplified CryptateEmission (TRACE®)
Applications	18-minute application	19-minute incubation
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)
Feature	Candidate Device: Elecsys BRAHMSPCT	Predicate Device: B.R.A.H.M.S.PCT sensitive KRYPTOR®(K171338).
Reagents	M: Streptavidin-coated microparticles:Steptavidin-coated microparticles;preservativeR1: Anti-PCT-Abbiotin:Biotinylated monoclonal anti-PCT antibody(mouse), phosphate buffer, preservativeR2: Anti-PCT – AbRu(bpy) 2/3+ amonoclonal anti-PCT antibody (mouse)labeled with reuthenium complex,phosphate buffer, preservative	Cryptate conjugate, cryptatelabeled, anti-PCT antibody(polyclonal, sheep), 3.2mL afterreconstitution with KRYPTOR®Solution 2XL665 conjugate, XL665 labeled,anti-PCT antipody (monoclonal,mouse), 3.95 mL afterreconstitution with KRYPTOR®Solution 1 and KRYPTOR® Solution2Defibrinated human plasma, fordiluting samples above 50µg/L,ready for use
Calibrator	Elecsys PCT CalSet	BRAHMS PCT sensitiveKRYPTOR® Calibrator
Calibration Interval	Calibration must be performed once perreagent lot using fresh reagent (i.e. notmore than 24 hours since the reagent kitwas registered on the analyzer). Renewedcalibration is recommended as follows:• after 8 weeks when using the samereagent lot• after 7 days (when using the samereagent kit on the analyzer) asrequired: e.g. quality control findingsoutside the specified limits	Before first use of each newBRAHMS PCT sensitiveKRYPTOR® lot, then repeated on aregular basis automaticallymanaged by the BRAHMS PCTsensitive KRYPTOR®.
Controls	Precicontrol PCT	BRAHMS PCT sensitiveKRYPTOR® Controls
Traceability/ Standardization	This method has been standardizedagainst the BRAHMS PCT LIA assay.	Not Provided
Reagent Stability	Store at 2-8 °C. Do not freeze. Store theElecsys reagent kit upright in order toensure complete availability of themicroparticles during automatic mixingprior to use.Stability:• unopened at 2-8 °C: up to the statedexpiration date• after opening at 2-8 °C: 12 weeks• on the analyzers: 4 weeks	In original shipping containersunopened at 2-8 °C: up to thestated expiration dateafter opening, onboard at 2-8 °C:29 days
Measuring Range	0.02 - 100ng/mL	0.02-50µg/L
LoB	0.015 ng/mL	N/P
LoD	0.02 ng/mL	N/P
Feature	Candidate Device: Elecsys BRAHMSPCT	Predicate Device: B.R.A.H.M.S.PCT sensitive KRYPTOR®(K171338).
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
Limitations	For diagnostic purposes, the resultsshould always be assessed in conjunctionwith the patient's medical history, clinicalexamination and other findings.Increased PCT levels may not always berelated to systemic infection. Theseinclude, but are not limited to: Patientsexperiencing major trauma and/or recentsurgical procedure includingextracorporeal circulation or burns.Patients undergoing treatment with OKT3antibodies, OK-432, interleukins, TNF-alpha and other drugs that stimulate therelease of pro-inflammatory cytokines orresult in anaphylaxis.Patients diagnosed with active medullaryC-cell carcinoma, small cell lungcarcinoma, or bronchial carcinoid.Patients with acute or chronic viralhepatitis and/or decompensated severeliver cirrhosis (Child-Pugh Class C).Patients with prolonged or severecardiogenic shock, prolonged severeorgan perfusion anomalies, or afterresuscitation from cardiac arrest.Patients receiving peritoneal dialysis orhemodialysis treatment. Patients withbiliary pancreatitis, chemical pneumonitisor heat stroke.Patients with invasive fungal infections(e.g., candidiasis, aspergillosis) or acuteattacks of plasmodium falciparum malaria.Neonates during the first 2 days of life.The results of the Elecsys BRAHMS PCTassay should be evaluated in the contextof all laboratory findings and the totalclinical status of the patient. In caseswhere laboratory results do not agree withthe clinical picture or history, additionaltests should be performed.	B.R.A.H.M.S PCT sensitiveKRYPTOR® is not indicated to beused as a stand-alone diagnosticassay and should beused in conjunction with clinicalsigns and symptoms of infectionand other diagnostic evidence. Incases where thelaboratory results do not agree withthe clinical picture or history,additional tests should beperformedDecisions regarding antibiotictherapy should NOT be basedsolely on procalcitoninconcentrations.PCT results should always beinterpreted in the context of theclinical status of the patient andother laboratory results.Changes in PCT levels for theprediction of mortality, and overallmortality, are strongly dependenton many factors,including pre-existing patient riskfactors and clinical course.The need to continue ICU care atDay 4 and other covariates (e.g.,age and SOFA score) are alsosignificantpredictors of 28-day cumulativemortality risk.The safety and performance ofPCT-guided therapy for individualsyounger than age 18 years,pregnant women,immunocompromised individuals orthose on immunomodulatoryagents, was not formally analyzedin the supportiveclinical trials performed.
Feature	Candidate Device: Elecsys BRAHMSPCT	Predicate Device: B.R.A.H.M.S.PCT sensitive KRYPTOR®(K171338).
Limitations Continued		PCT levels may not be elevated inpatients infected by certain atypicalpathogens, such as Chlamydophilapneumoniae and Mycoplasmapneumoniae.1Severity of renal failure orinsufficiency, may influenceprocalcitonin values and should beconsidered as potentiallyconfounding clinical factors wheninterpreting PCT values.2Increased PCT levels may notalways be related to systemicinfection 2-5. These conditionsinclude, but are not limited to:Patients experiencing major traumaand/or recent surgical procedureincluding extracorporeal circulationor burns;
		• Patients under treatmentwith OKT3 antibodies, OK-432, interleukins, TNF-alphaand other drugs stimulatingthe release of pro-inflammatory cytokines orresulting in anaphylaxis;
		• Patients diagnosed withactive medullary C-cellcarcinoma, small cell lungcarcinoma, or bronchialcarcinoid;
		• Patients with acute orchronic viral hepatitis and/ordecompensated severe livercirrhosis (Child-Pugh ClassC);
	• Patients with prolonged orsevere cardiogenic shock,prolonged severe organperfusion anomalies or afterresuscitation from cardiacarrest;
	• Patients receiving peritonealdialysis or hemodialysistreatment;
	• Patients with biliarypancreatitis, chemicalpneumonitis or heat stroke;
Feature	Candidate Device: Elecsys BRAHMS PCT	Predicate Device: B.R.A.H.M.S. PCT sensitive KRYPTOR® (K171338).
Limitations Continued		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.
Method Comparison	2617 samples were run on the cobas e 411 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)

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PERFORMANCE EVALUATION 4.

The following data was requested by the FDA in Q171237 to support the updated Indications for Use statement and is listed below:

• Precision according to CLSI EP5-A3 .
• Interferences Endogenous .
• Interferences Exogenous (Drugs) •
• Clinical Performance Evaluation Method Comparison to Predicate .

The remaining data required to support the updated Indications for Use was supplied in the previous submission K160729:

• Analytical Sensitivity: LoB, LoD and LoQ according to CLSI EP17-A2 .
• Linearity according to CLSI EP6-A .
• High Dose Hook Affect .
• Human Anti-Mouse Antibodies (HAMA) .

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• Analytical Specificity .
• Serum/Plasma Comparison .
• Sample Stability .
• Reagent Stability .

4.1. Precision

The repeatability and intermediate precision of the Elecsys BRAHMS PCT assay was conducted using the cobas e 411 analyzer. Studies were performed in accordance with CLSI guideline EP5-A3, "Evaluation of Precision Performance of Quantitative Measurement Methods". One reagent lot was evaluated. The precision study was conducted using the study design of 21 days x 2 runs per day x 2 replicates per sample. One (1) instrument was used for the study and calibration was performed according to the Instructions for Use. Aliquots of sixteen (16) human serum samples and two (2) QC samples (PC PCT 1 and PC PCT 2) distributed over the measuring range were assayed in duplicate and randomized order on the cobas e 411 analyzer using one lot of reagent. Data is acceptable and is summarized below. An analysis was also performed to calculate % Total Error across the measuring range.

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Mean (ng/mL)	Repeatability (CV%)	Intermediate Precision (CV%)	%Total Error
0.037	16.7	24.3	57.02
0.085	6.4	9.2	22.49
0.121	4.2	6.2	14.95
0.183	3.1	4.2	10.18
0.242	2.2	3.6	8.67
0.300	2.1	2.8	6.75
0.400	2.0	3.2	7.68
0.415	1.9	2.3	5.56
1.52	1.6	2.2	5.36
2.12	1.5	2.2	5.38
2.93	1.4	2.4	5.76
26.1	1.5	2.8	6.81
44.6	1.6	2.8	6.69
64.5	1.9	3.0	7.33
97.6	1.7	2.4	5.79

Table 2: Summary of Precision Results – Elecsys BRAHMS PCT Repeatability and Intermediate Precision

Endogenous Interferences 4.2.

The effect on quantitation of PCT in the presence of five endogenous interfering substances (Hemoglobin, Biotin, Intralipid, Bilirubin, and Rheumatoid Factor) was tested using one cobas e 411 analyzer. Spiked serum pools were used for testing. The substances were found not to affect test performance at clinically relevant concentrations. Recovery was within ± 15 % of the initial value. See K160729 for additional interference data.

				Table 3: Potentially Interfering Endogenous Substances and Test Concentrations
--	--	--	--	--------------------------------------------------------------------------------	--	--

Potential Interferent	Maximum Value With No Interference Observed
Intralipid	2000 mg/dL
Bilirubin	66 mg/dL
Hemoglobin	1000 mg/dL
Rheumatic Factor	1500 IU/mL

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% Bias for samples containing various concentrations of biotin
Samples PCT concentrations(ng/mL)	Biotin concentration (ng/mL)
(ng/mL)	9.6	20.4	30.0	39.6	80.4
0.04	2.3	2.8	0.2	-17.0	*
0.10	4.5	-2.8	-6.6	-13.2	-26.8
0.13	0.5	-2.8	-3.1	-4.8	-25.1
0.20	1.5	0.3	-8.6	-11.5	-38.4
0.48	0.9	0.5	-0.03	-0.5	-9.1
1.96	3.9	3.6	1.4	0.5	-8.0

Table 4: Biotin Interference

• = value below measurable range

** Specimens with biotin concentrations up to 30 ng/mL demonstrated ≤ 13 % bias in results. Biotin concentrations greater than 30 ng/mL can lead to higher negative bias for PCT results. The recommended daily intake for biotin is 30 µg. Higher doses of biotin (> 10 mg per day) may be taken as a dietary supplement aimed at reducing hair loss or improving nail or skin condition.13

Some pharmacokinetic studies have shown that serum concentrations of biotin can reach 355 ng/mL for subjects taking supplements containing at least 20 mg of biotin14 or 1160 ng/mL

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for subjects taking doses of biotin up to 300 mg.13 These studies were performed in healthy subjects, and some patients may be taking supplements with biotin at levels greater than 20 mg per day. Clearance of biotin could be different in patients tested with this device, which may lead to higher than expected concentrations of biotin in serum.

4.3. Exogenous Interferences – Drugs

The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 38 pharmaceutical compounds into two human serum samples at differing analyte concentrations and tested on the cobas e 411 analyzer. The substances were found not to affect test performance at clinically relevant concentrations. Recovery was within ± 10 % of the reference value. See K160729 for additional interference data.

Potential Interferent	Drug Level Tested (mg/L)
Cromolyn	24
Acetylsalicylic acid	652
Acetaminophen	200
Alcohol	4000
Azithromycin	11.5
Cetirizine HCL	3.6
Dextromethorphan	1.4
Ibuprofen	500
Imipenem	1180
Levofloxacin	17.5
Loratadine	0.3
Nicotine	1
Oxymetazoline HCL	0.09
Phenylephrine	0.18
Tiotropium	0.0216

Potentially Interfering Drugs and Test Concentrations Table 5:

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Clinical Performance Evaluation - Method Comparison to Predicate 4.4.

The Elecsys® B•R•A•H•M•S PCT clinical performance study was conducted by retrospective multicenter testing of PCT from available frozen samples of adult patients (i.e. >18 years of age) diagnosed with severe sepsis or septic shock who were enrolled in the BRAHMS MOSES study from the Intensive Care Unit or the emergency department, other wards or directly from out of hospital and subsequently admitted to the ICU.

The clinical concordance analysis in this report was performed with all available valid test results obtained in the Elecsys® B·R·A·H·M·S PCT clinical performance study. The clinical line data of the BRAHMS MOSES study is available via MAF2386 (Amendment 9 - Clinical Line Data). The line listings of the Elecsys B·R·A·H·M·S PCT clinical performance study was included in K160729.

The clinical concordance analysis of the Elecsys B.R.A.H.M.S PCT clinical performance study shows more than 97% total agreement between the Elecsys B.R.A.H.M.S.PCT and the B.R.A.H.M.S PCT sensitive Kryptor® (predicate device) at the medical decision points 0.1, 0.25, 0.5 and 2.0 ng/mL. The regression slopes are within +/- 10% of identity in Passing-Bablok and Weighted Deming Analysis. This demonstrates equivalence to the predicate device to include all currently cleared claims of the predicate device in the labeling of the candidate device.

Elecsys BRAHMS PCT oncobas e 411	B•R•A•H•M•S PCT sensitive Kryptor®		Total
	≤ 0.5 ng/mL	> 0.5 ng/mL
≤ 0.5 ng/mL	667	50	717
> 0.5 ng/mL	18	1882	1900
Total	685	1932	2617

Table 6: Elecsys BRAHMS PCT vs Predicate at 0.5 ng/mL

Table 7: Elecsys BRAHMS PCT vs Predicate at 2.0 ng/mL

Elecsys BRAHMS PCT oncobas e 411	B•R•A•H•M•S PCT sensitive Kryptor®		Total
	≤ 2.0 ng/mL	> 2.0 ng/mL
≤ 2.0 ng/mL	1223	56	1279
> 2.0 ng/mL	13	1325	1338

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Elecsys BRAHMS PCT oncobas e 411	B•R•A•H•M•S PCT sensitive Kryptor®		Total
Total	≤ 2.0 ng/mL	> 2.0 ng/mL	2617
	1236	1381

Table 8: 3 x 3 Table Elecsys BRAHMS PCT vs Predicate

	B•R•A•H•M•S PCT sensitive Kryptor®
Elecsys BRAHMS PCT on cobas e411	≤ 0.5 ng/mL	0.5 ng/mL < PCT≤ 2.0 ng/mL	> 2.0 ng/mL	Total
≤ 0.5 ng/mL	667	48	2	717
0.5 ng/mL < PCT ≤ 2.0 ng/mL	18	490	54	562
> 2.0 ng/mL	0	13	1325	1338
Total	685	551	1381	2617

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	B•R•A•H•M•S PCT sensitive Kryptor®
ElecsysBRAHMS PCT oncobas e 411	≤ 0.1 ng/mL	0.1 ng/mL < PCT≤ 0.25 ng/mL	0.25 ng/mL < PCT≤ 0.5 ng/mL	0.5 ng/mL < PCT≤ 2.0 ng/mL	> 2.0 ng/mL	Total
≤0.1 ng/mL	97	47	1	1	1	147
0.1 ng/mL < PCT≤0.25 ng/mL	6	240	42	1	1	290
0.25 ng/mL < PCT≤0.5 ng/mL	0	16	218	46	0	280
0.5 ng/mL < PCT≤2.0 ng/mL	1	1	16	490	54	562
> 2.0 ng/mL	0	0	0	13	1325	1338
Total	104	304	277	551	1381	2617

Table 9: 5 x 5 Table Elecsys BRAHMS PCT vs Predicate

Table 10: Comparison Elecsys BRAHMS PCT vs Predicate

N = 2617 (104 ≤ 0.1 ng/mL, 408 ≤ 0.25 ng/mL; 685 ≤ 0.5 ng/mL; 1236 ≤ 2.0 ng/mL)

Cutoff (> vs. ≤)	Positive Agreement(95% CI)	Negative Agreement(95% CI)	Total Agreement	Cohen's Kappa
0.10 ng/mL	93.3%(86.6 - 97.3)	98.0%(97.4 - 97.3)	97.8%	0.762
0.25 ng/mL	95.6%(93.1 - 97.4)	97.9%(97.2 - 98.4)	97.5%	0.908
0.50 ng/mL	97.4%(95.9 - 98.4)	97.4%(96.6 - 98.1)	97.4%	0.934
2.00 ng/mL	98.9%(98.2 - 99.4)	95.9%(94.8 - 96.9)	97.4%	0.947

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Parameter	Passing Bablok Regression	Weighted Deming (λ=1) RegressionAnalysis
n	2617	2617
Slope	0.959	0.949
95% CI	[0.947; 0.972]	[0.937; 0.961]
Intercept	-0.023	-0.008
95% CI	[-0.028; -0.018]	[-0.013; -0.004]
Pearson Correlation Coefficient	0.989	0.989
Spearman Correlation Coefficient	0.990	0.990
Sample Range	[0.02; 662.86]	[0.02; 662.86]

Table 11: Weighted Deming and Passing Bablok Regression Analysis

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

Weighted Deming Regression e411 vs Kryptor

Image /page/21/Figure/1 description: The image is a scatter plot that shows the correlation between two different measurement methods, Roche e411 and Kryptor, for a specific scenario. The x-axis represents the Kryptor measurements, while the y-axis represents the Roche e411 measurements. The plot includes a regression line with the equation y = -0.008 + 0.949*x, indicating a strong positive correlation between the two methods. The data points are clustered around the regression line, with some scatter, and the sample size is n=2617.

B·R·A·H·M·S PCT sensitive Kryptor (ng/ml) The 0.95-confidence bounds are calculated with the bootstrap(quantile) method.

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Image /page/22/Figure/0 description: The image is a scatter plot showing Passing Bablok Regression e411 vs Kryptor. The scenario is Roche e411 vs Kryptor, cutoff 0.1 ng/ml, Roche & Kryptor measurements valid (n=2617). The x-axis is labeled 'B-R-A-H-M-S PCT sensitive Kryptor (ng/ml)' and the y-axis is labeled 'B-R-A-H-M-S PCT Elecsys Cobas e411 (ng/ml)'. A regression line is plotted with the equation y = -0.023 + 0.959*x.

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

The 0.95-confidence bounds are calculated with the bootstrap(quantile) method.

5. ADDITIONAL INFORMATION

The calibration materials PCT Cal1 and PCT Cal2 as well as the control material PreciControl PCT1 and PreciControl PCT2 are in the Elecsys BRAHMS PCT kit and are not changed as a result of the new claims. The Elecsys BRAHMS PCT CalCheck 5 is also not changed as a result of the change. See K160729 for additional information.

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6. 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.

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.