The B-R-A-H-M-S PCT sensitive KRYPTOR® is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma.
The B-R-A-H-M-S PCT sensitive KRYPTOR® is intended to be performed on the B·R·A·H·M·S KRYPTOR® analyzer family.
Used in conjunction with other laboratory findings and clinical assessments, B·R·A·H·M·S PCT sensitive KRYPTOR® is intended for use as follows:

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

Device Description

The B·R·A·H·M·S KRYPTOR® compact PLUS analyzer is a fully automated system. The B-R-A-H-M-S KRYPTOR® compact PLUS analyzer is a closed system and can only operate utilizing special reagents provided by B.R.A.H.M.S GmbH.
The B·R·A·H·M·S PCT sensitive KRYPTOR® 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.

AI/ML Overview

The provided text describes a 510(k) premarket notification for the B·R·A·H·M·S PCT sensitive KRYPTOR® device, which measures procalcitonin levels. The submission seeks clearance for expanded indications for use based on comparisons to predicate devices and meta-analyses of clinical studies.

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided document:

1. Table of Acceptance Criteria and Reported Device Performance

The document doesn't explicitly state "acceptance criteria" in a tabular format with corresponding performance results for each expanded indication in a single place. Instead, it details various analytical and clinical performance characteristics from previous submissions (DEN150009 and K070310) and new meta-analyses to support the expanded claims.

However, we can infer acceptance criteria from the context of a 510(k) submission, which generally requires demonstrating substantial equivalence to a legally marketed predicate device. This often involves showing comparable analytical performance and equivalent safety and effectiveness for the intended use. For the expanded indications, the performance is demonstrated through meta-analyses of existing clinical trial data.

Inferred "Acceptance Criteria" (based on regulatory expectations for an IVD and expanded claims) and Reported Device Performance:

Acceptance Criteria (Inferred)	Reported Device Performance (from sections M.1 and M.2)
Analytical Performance (from previous clearances, largely not re-evaluated for this submission)
Precision (Reproducibility)	Internal Precision (from DEN150009) shown in table on Page 15:- %CV values for repeatability ranged from 0.58% to 12.31%.- Total Reproducibility %CV ranged from 2.57% to 14.88%. (The table provides detailed SD and %CV for various components like repeatability, between-operator, between-day, between-calibration, between-run, and between-lot for 12 different samples (P10-P16, QC1, QC2, HG1-HG3) with N=56 for most samples and N=54 for HG3.)
Linearity/Assay Reportable Range	From DEN150009 (Page 16):- Direct measuring range: 0.02 µg/L - 50 µg/L- Measuring range with automatic dilution: 0.02 µg/mL - 5000 µg/L
Detection Limit (LoB, LoD, LoQ)	From DEN150009 (Page 17):- LoB and LoD determined (same as predicate).- LOQ (lowest reported concentration level with bias ≤ 5%, % CV ≤ 15%, TE ≤ 30%) = 0.075 µg/L.- TE ≤ 20% at 0.25 µg/L (bias ≤ 5%, precision CV ≤ 10%)- TE ≤ 30% at 0.10 µg/L (bias ≤ 5%, precision CV ≤ 15%)Performance at key cutoffs (table on Page 17):- 0.10 µg/L: %CV 10.33, %BIAS 2.07, %TE 19.11- 0.23 µg/L: %CV 5.04, %BIAS 1.85, %TE 10.17- 0.27 µg/L: %CV 6.71, %BIAS 0.76, %TE 11.83
Analytical Specificity/Interference	From DEN150009; supplementary interference studies performed for lower cut-offs (Page 17-18):- No interference up to specified concentrations for numerous endogenous substances (e.g., Hemoglobin 500 mg/dL, Triglycerides 22.5 mg/mL, Bilirubin 20mg/dL), cross-reacting substances (e.g., Human calcitonin 3.9 ng/mL), and drugs (e.g., Cefotaxim 90 mg/dL, Heparin 8000 IU/L, common asthma/COPD drugs like Budesonide, Albuterol, etc.).
Method Comparison (vs. Predicate)	Qualitative Agreement with VIDAS B·R·A·H·M·S PCT (PCT) on 203 samples (Page 19):- At 0.10 µg/L: Positive Agreement 86.5%, Negative Agreement 86.8%, Overall Agreement 86.7%, Kappa 0.7309.- At 0.25 µg/L: Positive Agreement 96.4%, Negative Agreement 98.0%, Overall Agreement 97.5%, Kappa 0.9380.- At 0.50 µg/L: Positive Agreement 95.6%, Negative Agreement 100.0%, Overall Agreement 99.0%, Kappa 0.9710.- At 2.00 µg/L: Positive Agreement 79.2%, Negative Agreement 100.0%, Overall Agreement 97.5%, Kappa 0.8702.
Clinical Performance (supporting expanded claims via Meta-analyses)
Aid in decision-making on antibiotic therapy for LRTI (reduce antibiotic use without negative outcomes)	Patient-level meta-analysis (13 RCTs, N=3142 total patients) for LRTI (Page 21):- 19.2% reduction in relative antibiotic initiation.- 38% reduction in overall antibiotic exposure (inpatients).- 51% reduction in overall antibiotic exposure (ED/outpatients).- 2.9 day reduction in antibiotic duration.- 3.6 day reduction in total antibiotic exposure.- No negative effects in regards to mortality, complications, or length of stay.Summary table (Page 21):- Antibiotic initiation: 88.4% (standard) vs. 71.4% (PCT guided)- Duration of antibiotics: 10 days (standard) vs. 7 days (PCT guided)- Total exposure of antibiotics: 9 days (standard) vs. 5 days (PCT guided)- 30-day mortality: 7.4% (standard) vs. 6.7% (PCT guided)- Complications: 21.1% (standard) vs. 18.0% (PCT guided)
Aid in decision-making on antibiotic discontinuation for sepsis (reduce antibiotic use without negative outcomes)	Patient-level meta-analysis for Sepsis (5 RCTs, N=598 sepsis patients) (Page 22):- 1.5 day reduction in antibiotic duration.- 3.2 day reduction in total antibiotic exposure.- 23% reduction in overall antibiotic exposure.- No negative effects in regards to mortality, hospital length of stay, or ICU length of stay.Summary table (Page 22):- Total exposure of antibiotics: 12 days (standard) vs. 8 days (PCT guided)- 30-day mortality: 23.8% (standard) vs. 19.9% (PCT guided)

2. Sample Size Used for the Test Set and Data Provenance

Analytical Performance Test Set (Method Comparison):
- Sample Size: 203 frozen banked samples.
- Data Provenance: Retrospective. Samples were from the "ProRESP trial bank of consecutive patients with clinically suspected COPD, acute bronchitis and CAP," analyzed for concordance with a predicate device.
- Country of Origin: Not explicitly stated but the publication referenced, "Schuetz P, et al. Clin Biochem. 2010," suggests European origin (Switzerland is common for Müller and Schuetz research groups).
Clinical Performance Test Set (Meta-analyses for expanded indications):
- LRTI Antibiotic Decision Making:
  - Study-level Meta-analysis: 11 Randomized Controlled Trials (RCTs), 4090 patients.
  - Patient-level Meta-analysis: 13 RCTs, 3142 patients.
  - Data Provenance: Retrospective, aggregated from previously published RCTs.
  - Country of Origin: Not specified, but given the list of publications, these would be multi-national clinical trials.
- Sepsis Antibiotic Discontinuation:
  - Study-level Meta-analysis: 10 RCTs, 3489 patients.
  - Patient-level Meta-analysis: 5 RCTs, 598 patients (after excluding non-sepsis patients).
  - Data Provenance: Retrospective, aggregated from previously published RCTs.
  - Country of Origin: Not specified, but likely multi-national.

3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications

Analytical Performance (Method Comparison): The "ground truth" here is the measurement by the predicate device (VIDAS B·R·A·H·M·S PCT). No human experts were involved in establishing the ground truth for this direct measurement comparison.
Clinical Performance (Meta-analyses): For PCT-guided therapy trials, the ground truth for patient outcomes (e.g., diagnosis of LRTI, sepsis, mortality, complications, length of stay, antibiotic duration) would have been established by the clinical teams and investigators involved in each of the original RCTs. The document does not specify the number or qualifications of these individual experts for the initial studies, as it relies on published, peer-reviewed clinical trial data as its basis. The meta-analyses themselves are statistical syntheses of these existing ground truths.

4. Adjudication Method for the Test Set

Analytical Performance: Not applicable for a quantitative assay method comparison. Results are compared directly between two devices.
Clinical Performance: For the individual RCTs that form the basis of the meta-analyses, adjudication methods for clinical endpoints would have been defined in their original protocols. The meta-analyses themselves don't involve a separate adjudication process beyond the data synthesis. The text states "Each meta-analysis used random-effects models and calculated point estimates, differences, odds ratios (OR), interquartile ranges (IQRs) and 95% confidence intervals as appropriate," which describes the statistical method, not human adjudication.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

This is an In Vitro Diagnostic (IVD) device (a blood test for procalcitonin), not an imaging AI device. Therefore, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study, which is typically relevant for evaluating medical imaging interpretation (human readers with/without AI assistance), was not conducted. The "comparative effectiveness" demonstrated here is about the utility of the PCT biomarker (measured by the device) in guiding clinical decisions (like antibiotic therapy) when compared to standard care, based on clinical trial outcomes.

6. Standalone Performance

The device is an in vitro diagnostic (IVD) that provides a quantitative measurement of PCT. Its "standalone performance" is implicitly covered by the analytical performance studies (precision, linearity, detection limit, interference). It's not an "algorithm only" device in the sense of an AI interpreting medical images; it's a lab instrument that measures an analyte. Its performance is the accurate measurement of PCT levels.

The "standalone" statement regarding its clinical use (Page 6) is a warning/precaution: "B·R·A·H·M·S PCT sensitive KRYPTOR® 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." This clarifies that the clinical decision-making should not solely rely on PCT even if the device itself accurately measures PCT.

7. Type of Ground Truth Used

Analytical Performance: The ground truth for the method comparison was the quantitative result provided by a legally marketed predicate device (VIDAS B·R·A·H·M·S PCT).
Clinical Performance: The ground truth for the expanded indications was based on outcomes data and clinical diagnoses established in prospective, randomized controlled trials. These outcomes include antibiotic initiation and duration, total antibiotic exposure, 30-day mortality, complications, and length of hospital/ICU stay.

8. Sample Size for the Training Set

The document does not directly mention a "training set" in the context of machine learning or AI algorithm development, as this is an IVD device measuring a biomarker. The analytical performance data (precision, linearity, detection limits, interference) are part of its fundamental characterization, not typically referred to as a "training set."

For the meta-analyses, the "training" analogous to that for an AI would be the collective body of clinical evidence from the published RCTs. The data from various studies (Ns provided in point 2) are "pooled" or combined within the meta-analysis framework. It's not a single "training set" for a new algorithm, but rather a synthesis of existing clinical evidence to support a new clinical claim for an established diagnostic test.

9. How the Ground Truth for the Training Set Was Established

Since there isn't a "training set" for a machine-learning algorithm in this context, the question translates to: How were the original clinical trial data (which underpin the meta-analyses) established?

The clinical data used in the meta-analyses (serving as the "evidence base" for the expanded indications) were derived from multi-center, prospective, randomized controlled clinical trials (RCTs). In these trials, patient outcomes (e.g., diagnosis, mortality, antibiotic use) were carefully collected and documented by the individual study investigators according to their original study protocols. This type of data from well-designed RCTs is considered high-quality evidence in medical research. The meta-analyses then systematically combined and statistically analyzed the results from these individual studies, effectively using their established "ground truths."

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 features a stylized depiction of an eagle or bird in flight, composed of three curved lines that suggest feathers or wings. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the bird symbol.

May 31, 2017

Food and Drug Administration

Public Health Service

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

B.R.A.H.M.S GMBH Bernhard Ciommer, Ph.D. Director Global RA / QA Compliance Neuendorfstrasse. 25 D-16761 Hennigsdorf Germany

Re: K171338 Trade/Device Name: B R A H M S PCT Sensitive Kryptor 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: PRI, PMT, NTM Dated: May 2, 2017 Received: May 8, 2017

Dear Dr. Ciommer:

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 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

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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/Resourcesfor You/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,

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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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
Indications for Use
Form Approved: OMB No. 0910-0120
Expiration Date: January 31, 2017
See PRA Statement below.
510(k) Number (if known)
Device Name	B-R-A-H-M-S PCT sensitive KRYPTOR®
Indications for Use (Describe)
1. Intended Use:
	The B-R-A-H-M-S PCT sensitive KRYPTOR® is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma.
	The B-R-A-H-M-S PCT sensitive KRYPTOR® is intended to be performed on the B·R·A·H·M·S KRYPTOR® analyzer family.
	Used in conjunction with other laboratory findings and clinical assessments, B·R·A·H·M·S PCT sensitive KRYPTOR® is intended for use as follows: to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,to aid in decision making on antibiotic therapy, for inpatients or patients in the emergency department with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
2. Indications for use:
	Same as Intended Use.
Type of Use (Select one or both, as applicable)
	Prescription Use (Part 21 CFR 801 Subpart D) Over-The-Counter Use (21 CFR 801 Subpart C)

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5.0 510(K) SUMMARY

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510K SUMMARY

GENERAL INFORMATION

Submission Date:	May 2, 2017
Submitter Information:
Submitted By:	B·R·A·H·M·S GmbHNeuendorfstr. 2516761 Hennigsdorf, Germany
Contact Person:	Sascha Johannes, PhDGlobal Medical Affairs ManagerClinical DiagnosticsThermo Fisher ScientificNeuendorfstr. 2516761 Hennigsdorf, GermanyTel: +49 3302 883-729Fax: +49 3302 883-728Email: sascha.johannes@thermofisher.com

A. 510(k) Number:

K171338

B. Purpose for Submission:

To obtain clearance for expanded indications for use(s) for the B.R.A.H. M.S PCT sensitive KRYPTOR®

C. Measurand:

Procalcitonin

D. Type of Test:

Immunofluorescent assay

E. Applicant:

B·R·A·H·M·S GmbH, part of Thermo Fisher Scientific

F. Proprietary and Established Names:

B·R·A·H·M·S PCT sensitive KRYPTOR®

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G. Regulatory Information:

1. Regulation section:
  21 CFR 866.3215; Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis
1. Classification:
  Class II (Special Controls)
1. Product codes:
  PRI, PMT, NTM
1. Panel:
  83 - (Microbiology)

H. Intended Use:

1. Intended Use:
  The B.R.A.H.M.S.PCT sensitive KRYPTOR® is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma.

The B·R·A·H·M·S PCT sensitive KRYPTOR® is intended to be performed on the B·R·A·H·M·S KRYPTOR® analyzer family.

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

. to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
. to aid in decision making on antibiotic therapy, for inpatients or

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patients in the emergency department with suspected or confirmed lower respiratory tract infections (LRTI) - defined as communityacquired 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.
1. Indications for use:

Same as Intended Use.

1. Special conditions for use statement(s):
  For prescription use only

Warnings and Precautions:

B·R·A·H·M·S PCT sensitive KRYPTOR® 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 procalcitonin 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 (e.g., ● age and SOFA score) are also significant predictors of 28-day cumulative mortality risk.
Certain patient characteristics, such as severity of renal failure or ● insufficiency, may influence procalcitonin values and should be considered as potentially confounding clinical factors when interpreting PCT values.
Increased PCT levels may be observed in severe illness such as polytrauma, burns, major surgery, prolonged or cardiogenic shock.
PCT levels may not be elevated in patients infected by certain atypical pathogens, such as Chlamydophila pneumoniae and Mycoplasma pneumoniae.
The safety and performance of PCT-guided therapy for individuals . younger than age 18 years, pregnant women, immunocompromised individuals or those on immunomodulatory agents, was not formally analyzed in the

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supportive clinical trials.

4. Special instrument requirements:

B·R·A·H·M·S KRYPTOR® analyzer family

I. Device Description: Reagents

Materials provided in B·R·A·H·M·S PCT sensitive KRYPTOR®

The B.R.A.H.M.S.PCT sensitive KRYPTOR® contains sufficient reagents for 50 determinations.

Materials Provided: Reagent	Quantity for 50 determinations	Content
Cryptate Conjugate	1 bottle lyophilized	Cryptate conjugate,cryptate labeled, anti-PCT antibody (polyclonal, sheep), 3.2mL after reconstitution with KRYPTORSolution 1 and KRYPTOR Solution 2
XL665 Conjugate	1 bottle lyophilized	XL665 conjugate, XL665 labeled, anti-PCT antibody (monoclonal, mouse), 3.95mL after reconstitution with KRYPTORSolution 1 and KRYPTOR Solution 2
Diluent	1 bottle	Defibrinated human plasma, for dilutingsamples above 50 μg/L, ready for use

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Additional materials required but not provided with the B·R·A·H·M·S PCT sensitive KRYPTOR:

B·R·A·H·M·S PCT sensitive KRYPTOR® Calibrator

Content
Calibrator	Lyophilized recombinant PCT in defibrinated humanplasma, reconstitute with 0.75 mL de-ionized waterwith conductivity of less than 50 μS/cm [range: 22.5 –27.5 μg/L]

B·R·A·H·M·S PCT sensitive KRYPTOR® Controls

Content
Control 1	PCT control 1, lyophilized recombinant PCT indefibrinated human plasma, reconstitute with 2 mL de-ionized water with conductivity of less than 50 µS/cm[range: 0.2 – 0.4 µg/L]
Control 2	PCT control 2, lyophilized recombinant PCT indefibrinated human plasma, reconstitute with 2 mL de-ionized water with conductivity of less than 50 µS/cm[range: 8 - 12 µg/L]

KRYPTOR® Consumables

Content
KRYPTOR Solution 1	ProClin 150 Solution
KRYPTOR Solution 2	Potassium fluoride solution
KRYPTOR Solution 3	Active chlorine and sodium hydroxide solution
KRYPTOR Solution 4	Sodium hydroxide solution
KRYPTOR BUFFER	Phosphate Buffer Saline (PBS) buffer, not reconstituted, 5 liters after reconstitution

Reaction plates KRYPTOR® ●
Dilution plates KRYPTOR® ●

J. Substantial Equivalence Information:

1. Predicate device name(s):
  B·R·A·H·M·S PCT sensitive KRYPTOR®

VIDAS B·R·A·H·M·S PCT (PCT)

1. Predicate 510(k) number(s):
  DEN150009 K162827

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3. Comparison with predicate:

Item	Subject Device:B·R·A·H·M·S PCTsensitive KRYPTOR®	Predicate Device:DEN150009B·R·A·H·M·S PCTsensitive KRYPTOR®	Predicate Device:K162827VIDAS B·R·A·H·M·SPCT (PCT)
Intended UseandIndicationsfor Use	The B·R·A·H·M·SPCT sensitiveKRYPTOR® is animmunofluorescentassay using Time-Resolved AmplifiedCryptate Emission(TRACE) technologyto determine theconcentration of PCT(procalcitonin) inhuman serum andEDTA or heparinplasma.The B·R·A·H·M·SPCT sensitiveKRYPTOR® isintended to beperformed on theB·R·A·H·M·SKRYPTOR® analyzerfamily.Used in conjunctionwith other laboratoryfindings and clinicalassessments,B·R·A·H·M·S PCTsensitive KRYPTOR®is intended for use asfollows:• to aid in the riskassessment ofcritically ill patientson their first day ofICU admission forprogression to severesepsis and septicshock,• to determine thechange in PCT level	The B•R•A•H•M•S PCTsensitive KRYPTOR® isan immunofluorescentassay using Time-Resolved AmplifiedCryptate Emission(TRACE) technology todetermine theconcentration of PCT(procalcitonin) in humanserum and EDTA orheparin plasma.The B•R•A•H•M•S PCTsensitive KRYPTOR® isintended to be performedon the B·R·A·H·M·SKRYPTOR® analyzerfamily.The B•R•A•H•M•S PCTsensitive KRYPTOR® isintended for use inconjunction with otherlaboratory findings andclinical assessments to aidin the risk assessment ofcritically ill patients ontheir first day of IntensiveCare Unit (ICU) admissionfor progression to severesepsis and septic shock.The B•R•A•H•M•S PCTsensitive KRYPTOR® isalso intended for use todetermine the change inPCT level over time as anaid in assessing thecumulative 28-day risk ofall-cause mortality inconjunction with otherlaboratory findings andclinical assessments for	VIDAS B·R·A·H·M·S PCT(PCT) is an automated testfor use on the instrumentsof the VIDAS family forthe determination of humanprocalcitonin in humanserum or plasma (lithiumheparinate) using the ELFA(Enzyme-LinkedFluorescent Assay)technique.Used in conjunction withother laboratory findingsand clinical assessments,VIDAS B•R•A•H•M•SPCT (PCT) is intended foruse as follows:• to aid in the riskassessment of criticallyill patients on their firstday of ICU admissionfor progression tosevere sepsis and septicshock,• to aid in assessing thecumulative 28-day riskof all-cause mortalityfor patients diagnosedwith severe sepsis orseptic shock in the ICUor when obtained in theemergency departmentor other medical wardsprior to ICU admission,using a change in PCTlevel over time,• to aid in decisionmaking on antibiotictherapy for inpatientswith suspected or
Item	Subject Device:B·R·A·H·M·S PCTsensitive KRYPTOR®	Predicate Device:DEN150009B·R·A·H·M·S PCTsensitive KRYPTOR®	Predicate Device:K162827VIDAS B·R·A·H·M·SPCT (PCT)
	• in assessing thecumulative 28-dayrisk of all-causemortality for patientsdiagnosed withsevere sepsis orseptic shock in theICU or whenobtained in theemergencydepartment or othermedical wards priorto ICU admission,• to aid in decisionmaking on antibiotictherapy, forinpatients or patientsin the emergencydepartment withsuspected orconfirmed lowerrespiratory tractinfections (LRTI) –defined ascommunity-acquiredpneumonia (CAP),acute bronchitis, andacute exacerbationof chronicobstructivepulmonary disease(AECOPD),• to aid in decisionmaking on antibioticdiscontinuation forpatients withsuspected orconfirmed sepsis.	patients diagnosed withsevere sepsis or septicshock in the ICU or whenobtained in the emergencydepartment or othermedical wards prior toICU admission.Procalcitonin (PCT) is abiomarker associated withthe inflammatory responseto bacterial infection thataids in the risk assessmentof critically ill patients ontheir first day of IntensiveCare Unit (ICU) admissionfor progression to severesepsis and septic shock.The percent change inPCT level over time alsoaids in the prediction ofcumulative 28-daymortality in patients withsevere sepsis and septicshock.PCT level on the first dayof ICU admission above2.0 $μ$ g/L is associated witha higher risk forprogression to severesepsis and/or septic shockthan a PCT level below 0.5$μ$ g/L.A PCT level that declines≤ 80% from the day thatsevere sepsis or septicshock was clinicallydiagnosed (Day 0) to fourdays after clinicaldiagnosis (Day 4) isassociated with highercumulative 28-day risk ofall-cause mortality than adecline > 80%.	respiratory tractinfections (LRTI)defined as community-acquired pneumonia(CAP), acute bronchitis,and acute exacerbationof Chronic ObstructivePulmonary Disease(AECOPD) – in aninpatient setting or anemergency department;• to aid in decisionmaking on antibioticdiscontinuation forpatients with suspectedor confirmed sepsis.
Item	Subject Device:B·R·A·H·M·S PCTsensitive KRYPTOR®	Predicate Device:DEN150009B·R·A·H·M·S PCTsensitive KRYPTOR®	Predicate Device:K162827VIDAS B·R·A·H·M·SPCT (PCT)
Specimen	Human serum andplasma (EDTA,heparin)	Same	Human serum or plasma(lithium heparinate).
Analyte	Procalcitonin (PCT)	Same	Procalcitonin (PCT)
Automated	Automated assay	Same	Automated assay
AssayTechnique	TRACE® technology	Same	ELFA (Enzyme-LinkedFluorescent Assay)technique.
Assayprinciple	Two antibody"sandwich" binding ofProcalcitonin.	Same	Immunoassay based onsandwich principle
Detectionmethod	Time-ResolvedAmplified CryptateEmission (TRACE®)	Same	Fluorescence (ELFA) of 4-methyl-umbelliferylmeasured at 450 nm
Assayduration	19 minutes	Same	Approximately 20 minutes
Combinationdevices	B·R·A·H·M·SKRYPTOR® analyzerfamily	Same	Instruments of the VIDASfamily: VIDAS,miniVIDAS or VIDAS 2
Item	Subject Device:B·R·A·H·M·S PCTsensitive KRYPTOR®	Predicate Device:DEN150009B·R·A·H·M·S PCTsensitive KRYPTOR®	Predicate Device:K162827VIDAS B·R·A·H·M·SPCT (PCT)
Antibodies	Cryptate conjugate,cryptate labeled,anti-PCT antibody(polyclonal, sheep) XL665 conjugate,XL665 labeled,anti-PCTantibody(monoclonal,mouse)	Same	Conjugate: Alkalinephosphatase-labeledmouse monoclonalanti-humanprocalcitoninimmunoglobulins Solid phase: Mousemonoclonal anti-procalcitoninimmunoglobulinscoated on interior ofthe SPR
Samplevolume	50μl	Same	200 μL

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{11}------------------------------------------------

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K. Standard/Guidance Document Referenced (if applicable):

CLSI Guideline EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; ● Approved Guideline - Third Edition.
CLSI Guideline EP06-A, Evaluation of the Linearity of Quantitative Measurement ● Procedures: A Statistical Approach; Approved Guideline.
CLSI Guideline EP07-A2, Interference Testing in Clinical Chemistry; Approved Guideline -Second Edition.
CLSI Guideline EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline - Second Edition.
CLSI Guideline EP25-A, Evaluation of Stability of In Vitro Diagnostic Reagents; Approved ● Guideline - First Edition.
CLSI Guideline EP21-Ed2: Evaluation of Total Analytical Error for Quantitative Medical Laboratory Measurement Procedures; Approved Guideline - Second Edition.
EN ISO 14971: Medical devices - Application of risk management to medical devices, Second edition 2007-03-01 (General I (QS/RM)).
EN ISO 15223-1: 2012, Medical Devices, Symbols to be Used with Medical Device Labels, Labelling and Information to be supplied (Part 1: General Requirements).
AAMI/ANSI/IEC 62304:2006, Medical Device Software - Software Life Cycle Processes (Software/Informatics).
IEC 61010-1: 2011, Safety Requirements for Electrical Equipment for Measurement, Control, and Laboratory Use - Third Edition (Part 1: General Requirement) [including: Corrigendum 1 (2011)]

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L. Test Principle:

The B·R·A·H·M·S PCT sensitive KRYPTOR® 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.

Measuring Principle

The basis of the TRACE® technology is a non-radiative energy transfer from a donor [a cagelike structure with a europium ion in the center (cryptate)] to an acceptor (XL 665). The proximity of donor (cryptate) and acceptor (XL 665) in a formed immunocomplex and the spectral overlap between donor emission and acceptor absorption spectra on the one hand intensifies the fluorescent signal and on the other hand extends the life span of the acceptor signal, allowing for the measurement of temporally delayed fluorescence.

After the sample to be measured has been excited with a nitrogen laser at 337 nm, the donor (cryptate) emits a long-life fluorescent signal in the millisecond range at 620 mm, while the acceptor (XL 665) generates a short-life signal in the range of nanoseconds at 665 nm. When both components are bound in an immunocomplex, both the signal amplification and the prolonged life span of the acceptor signal occur at 665 nm, and the life is in the microsecond range. This delayed acceptor signal is proportional to the concentration of the analyte to be measured.

The specific fluorescence which is proportional to the antigen concentration is obtained through a double selection: spectral (separation depending on wave-length) and temporal (time resolved measurement). This enables an exclusive measurement of the signal emitted by the immunological complex and the ratio between the two wave-lengths (665/620) allows a real-time correction of the variations in optic transmission from the medium.

The B·R·A·H·M·S PCT sensitive KRYPTOR® is homogenous, and does not require separation or washing steps. It is thus possible to obtain data without interrupting the immunological reaction. High concentration samples (> 50 µg/L) are detected in the first few seconds of incubation and may be diluted by the appropriate dilution factor, then re-assayed automatically.

The molecules of PCT present in the assay samples are sandwiched between the antibodies; thus, the intensity of the signal is proportional to the amount of PCT.

The B.R.A.H.M.S.KRYPTOR® compact PLUS software controls the operation of the instrument, collects and analyzes data and automatically generates a test report at the end of the run.

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M. Performance Characteristics:

1. Analytical performance

Most analytical performance metrics of the B·R·A·H·M·S PCT sensitive KRYPTOR® assay were previously established in K070310 and DEN150009, and are not affected by the additional claims. Supplementary interference studies were performed at the lower analytical cut-offs to support the new claims. These include:

. Precision
Interference Testing ●
. Method Comparison.
a. Reproducibility/Precision:

External and internal precision was determined in DEN150009.

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

SampleID	Mean	N	Repeatability		Between-Operator		Between-Day
			SD	%CV	SD	%CV	SD	%CV
P10	0.098	56	0.012	12.31	0.000	0.43	0.002	1.70
P11	0.226	56	0.010	4.40	0.000	0.00	0.000	0.00
QC1	0.267	56	0.010	3.77	0.000	0.00	0.000	0.00
P12	0.529	56	0.013	2.51	0.002	0.32	0.006	1.05
P13	1.362	56	0.023	1.66	0.000	0.00	0.019	1.40
P14	2.956	56	0.026	0.87	0.004	0.14	0.022	0.75
QC2	10.434	56	0.060	0.58	0.012	0.11	0.198	1.90
P15	14.277	56	0.133	0.93	0.067	0.47	0.134	0.94
P16	18.374	56	0.125	0.68	0.025	0.14	0.231	1.26
HG1	63.909	56	0.832	1.30	0.115	0.18	0.657	1.03
HG2	617.999	56	8.464	1.37	1.406	0.23	8.772	1.42
HG3	6013.488	54	88.403	1.47	20.725	0.34	133.125	2.21
SampleID	Mean	N	Between Calibration		Between-Run		Between-Lot
			SD	%CV	SD	%CV	SD	%CV
P10	0.098	56	0.000	0.00	0.000	0.00	0.008	8.18
P11	0.226	56	0.000	0.16	0.002	0.71	0.005	2.17
QC1	0.267	56	0.003	0.94	0.006	2.36	0.004	1.49
P12	0.529	56	0.004	0.71	0.016	3.09	0.005	0.86
P13	1.362	56	0.009	0.66	0.034	2.47	0.000	0.00
P14	2.956	56	0.019	0.65	0.073	2.46	0.000	0.00
QC2	10.434	56	0.075	0.72	0.214	2.05	0.000	0.00
P15	14.277	56	0.080	0.56	0.493	3.45	0.307	2.15
P16	18.374	56	0.058	0.32	0.398	2.17	0.000	0.00
HG1	63.909	56	0.282	0.44	0.912	1.43	0.800	1.25
HG2	617.999	56	1.852	0.30	6.654	1.08	12.792	2.07
HG3	6013.488	54	18.187	0.30	61.064	1.02	107.862	1.79
SampleID	Mean	N	Reproducibility (Total)
			SD	%CV
P10	0.098	56	0.015	14.88
P11	0.226	56	0.011	4.96
QC1	0.267	56	0.013	4.78
P12	0.529	56	0.023	4.28
P13	1.362	56	0.046	3.36
P14	2.956	56	0.083	2.80
QC2	10.434	56	0.307	2.95
P15	14.277	56	0.619	4.34
P16	18.374	56	0.481	2.62
HG1	63.909	56	1.640	2.57
HG2	617.999	56	19.024	3.08
HG3	6013.488	54	204.109	3.39

A summary table of the internal precision study results are given below:

Please note that Reproducibility corresponds to Within-Laboratory precision with all listed variance components.

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b. Linearity/Assay Reportable Range:

See DEN150009:

Direct measuring range 0.02 ug/L -50 ug/L O
Measuring range with automatic dilution 0.02ug/mL 5000 ug/L O
c. Traceability, Stability, Expected Values (controls, calibrators, or methods):

Reagent Stability: Real-Time Shelf Life

See DEN150009. Same as predicate: Testing demonstrated that the BRAHMS PCT sensitive KRYPTOR reagents are stable for 29 days after reconstitution with solutions 1 and 2 when stored on board the B-R.A.H-M.S KRYPTOR compact PLUS analyzer.

Control (Post-Reconstitution) Stability:

See DEN150009. Same as predicate: Data demonstrated that the B.R.A.H.M.S.PCT sensitive KRYPTOR controls are stable for up to 24 hours at 2-8°C, 4 hours on board, and up to one month at <-16°C

Calibrators (Post-Reconstitution) Stability:

See DEN150009. Same as predicate: Data demonstrated that the B·R·A·H·M·S PCT sensitive KRYPTOR calibrator is stable for up to 4 hours at room temperature (18 -25°C).

Expected Values for Controls and Calibrators:

See DEN150009.

The B.R.A.H.M.S.PCT sensitive KRYPTOR contains 2 two levels of antigen concentration, a bar code card, bar code stick-on labels. Each vial contains lyophilized recombinant PCT in defibrinated human plasma.

B·R·A·H·M·S PCT sensitive KRYPTOR Control 1 (level 1): 0.2 0.4 µg/L ●
B.R.A.H.M.S.PCT sensitive KRYPTOR - Control 2 (level 2): 8 - 12 µg/L

The bar code card contains information related to the control batch (i.e., the target concentrations), the standard deviations, and the concentration acceptance ranges.

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d. Detection Limit:

LoB and LoD determination - See DEN150009: Same as predicate.

Limit of Quantitation:

The LOQ determined as the lowest reported concentration level with bias ≤ 5%, % CV ≤ 15% and total error (TE) ≤ 30% was determined at 0.075 µg/L.

The Total Error (TE) at the two proposed additional cut-offs is:

TE ≤ 20% at 0.25 µg/L (with a bias ≤ 5% and a precision CV ≤ 10%) ●
. TE ≤ 30% at 0.10 µg/L (with a bias ≤ 5% and a precision CV ≤ 15%)

Target Value (µg/L)	%CV	%BIAS	%TE
0.05	23.48	3.46	42.20
0.10	10.33	2.07	19.11
0.23	5.04	1.85	10.17
0.27	6.71	0.76	11.83
0.53	4.16	1.19	8.06

TE was calculated according to Westgard-Model as 1.65x %CV + %BIAS

e. Matrix Equivalency Study:
See DEN150009.
f. Analytical Specificity/ Cross-Reactivity:
See DEN150009.
g. Interfering Substances:

Interfering Substance	Maximum Concentration Tested	Results
Endogenous Substances
Hæmoglobin	500 mg/dL	No interference up to 500 mg/dL
Triglycerides	22.5 mg/mL	No interference up to 22.5 mg/mL
Unconjugated Bilirubin	40 mg/dL	No interference up to 20 mg/dL
Albumin	1 g/dL	No interference up to 1 g/dL
Potential Cross-Reacting Substances
Human calcitonin	3.9 ng/mL	No interference up to 3.9 ng/mL
Human katacalcin	25.6 ng/mL	No interference up to 25.6 ng/mL
α-CGRP	30 ng/mL	No interference up to 30 ng/mL
β-CGRP	30 ng/mL	No interference up to 30 ng/mL
Salmon calcitonin	13.2 µg/mL	No interference up to 13.2 µg/mL
Eel calcitonin	7.5 µg/mL	No interference up to 7.5µg/mL
Drugs:
Cefotaxim	90 mg/dL	No interference up to 90 mg/dL
Vancomycin	3 mg/mL	No interference up to 2.6 mg/mL
Dopamine	13 mg/dL	No interference up to 13 mg/dL
Noradrenaline	2 µg/mL	No interference up to 2 µg/mL
Dobutamine	11.2 µg/mL	No interference up to 11.2 µg/mL
Heparin	8000 IU/L	No interference up to 8000 IU/L
Furosemide	2 mg/dL	No interference up to 2 mg/dL
Beclomethasonedipropionate	1 µg/mL	No interference up to 1 µg/mL
Budesonide	0.72 µg/mL	No interference up to 0.72 µg/mL
Flunisonide	2.4 µg/mL	No interference up to 2.4 µg/mL
Fluticasone	0.3 µg/mL	No interference up to 0.3 µg/mL
Triamcinolone	2.4 µg/mL	No interference up to 2.4 µg/mL
Methylsprednisolone	72 µg/mL	No interference up to 72 µg/mL
Prednisolone	8.31 µmol/L	No interference up to 8.31 µmol/L
Prednisone	0.84 µmol/L	No interference up to 0.84 µmol/L
Nedocromil	8.4 µg/mL	No interference up to 8.4 µg/mL
Albuterol	1.67 µmol/L	No interference up to 1.67 µmol/L
Salmeterol	60 ng/mL	No interference up to 60 ng/mL
Theophylline	222 µmol/L	No interference up to 222 µmol/L
Montelukast	6 µg/mL	No interference up to 6 µg/mL
Epinephrine	1.8 µg/mL	No interference up to 1.8 µg/mL
Terbutaline	0.9µg/mL	No interference up to 0.9µg/mL
Ipratropium bromide	0.9 µg/mL	No interference up to 0.9 µg/mL
Formoterol	28.8 ng/mL	No interference up to 28.8 ng/mL
Cromolyn	24 µg/mL	No interference up to 24 µg/mL
Acetaminophen	20 mg/dL	No interference up to 20 mg/dL
Acetylsalicylic acid	65.2 mg/dL	No interference up to 65.2 mg/dL
Alcohol	400 mg/dL	No interference up to 400 mg/dL
Azithromycin	1.15 mg/dL	No interference up to 1.15 mg/dL
Cetirizine HCl	0.36 mg/dL	No interference up to 0.36 mg/dL
Dextromethorphan	0.14 mg/dL	No interference up to 0.14 mg/dL
Ibuprofen	50 mg/dL	No interference up to 50 mg/dL
Imipenem	1.18 mg/mL	No interference up to 1.18 mg/mL
Levofloxacin	1.75 mg/dL	No interference up to 1.75 mg/dL
Loratadine	0.03 mg/dL	No interference up to 0.03 mg/dL
Nicotine	0.1 mg/dL	No interference up to 0.1 mg/dL
Oxymetazoline HCl	0.009 mg/dL	No interference up to 0.009 mg/dL
Phenylephrine	0.018 mg/dL	No interference up to 0.018 mg/dL

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

h. High-dose Hook Effect:
See DEN150009.
i. Diluent Study:
See DEN150009.
j. Method Comparison:
The B.R.A.H.M.S PCT sensitive KRYPTOR® and the VIDAS B.R.A.H.M.S PCT (PCT) assays were compared in terms of qualitative agreement at clinical decision points (0.10, 0.25, 0.50, and 2.00 µg/L). 203 frozen banked samples from the ProRESP trial bank of consecutive patients with clinically suspected COPD, acute bronchitis and CAP were analyzed for concordance in "Schuetz P, Christ-Crain M, Huber AR, Müller B. Long-term stability of procalcitonin in frozen samples and comparison of Kryptor and VIDAS automated immunoassays. Clin Biochem. 2010;43(3):341-344".

PCT cutoff	Positive Agreement (95% CI)	Negative Agreement (95% CI)	Overall Agreement (95% CI)	Kappa
0.10 µg/L	86.5% (77.6 - 92.8)	86.8% (79.2 - 92.4)	86.7% (81.2 - 91.0)	0.7309
0.25 µg/L	96.4% (87.5 - 99.6)	98.0% (94.2 - 99.6)	97.5% (94.3 - 99.2)	0.9380
0.50 µg/L	95.6% (84.9 - 99.5)	100.0% (97.7 - 100.0)	99.0% (96.5 - 99.9)	0.9710
2.00 µg/L	79.2% (57.8 - 92.9)	100.0% (98.0 - 100.0)	97.5% (94.3 - 99.3)	0.8702

		VIDAS B·R·A·H·M·S PCT
		≤0.1 µg/L	>0.1 and≤0.25 µg/L	>0.25 and<0.50 µg/L	≥0.50 and<2.00 µg/L	≥2.00 µg/L	TOTAL
B·R·A·H·M·S PCT sensitiveKRYPTOR®	≤0.1 µg/L	99	12	0	0	0	111
	>0.1 and≤0.25 µg/L	15	19	2	0	0	36
	>0.25 and<0.50 µg/L	0	3	8	2	0	13
	≥0.50 and<2.00 µg/L	0	0	0	19	5	24
	≥2.00 µg/L	0	0	0	0	19	19
	TOTAL	114	34	10	21	24	203

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

2. Clinical Studies

Decision making on antibiotic therapy for patients with suspected or confirmed LRTI

Two systematic literature reviews were performed to produce both study and patient-level meta-analyses, which are studies that combine and contrast data from multiple sources to identify patterns among study results (FDA public docket FDA-2016-N-2880). The studylevel meta-analysis used aggregate descriptive information extracted from publications, and the patient-level meta-analysis used aggregate patient-level data from the raw dataset of each study. Each meta-analysis used random-effects models and calculated point estimates, differences, odds ratios (OR), interquartile ranges (IQRs) and 95% confidence intervals as appropriate. The endpoints evaluated were: proportion of subjects initiating antibiotics, duration of antibiotic therapy, exposure to antibiotics, length of hospital stay, mortality, and complications (patient level only).

The study-level meta-analysis encompassed 11 randomized control trials (RCTs) 6.13.15-18.30-34 which were published between 2004-2016, and included 4090 patients The patient-level meta-analysis encompassed 13 RCTs 6.13-18,21-23, 30, 31,35 which were published between 2004-2011, and included 3142 patients as listed below.

Publication	N patients	PCT device
Bouadma, 2010	630	B·R·A·H·M·S PCT sensitive Kryptor®
Briel, 2008	300	B·R·A·H·M·S PCT sensitive Kryptor®
Burkhardt, 2010	550	B·R·A·H·M·S PCT sensitive Kryptor®
Christ-Crain, 2004	243	B·R·A·H·M·S PCT sensitive Kryptor®
Christ-Crain, 2006	302	B·R·A·H·M·S PCT sensitive Kryptor®
Hochreiter, 2009	110	B·R·A·H·M·S PCT LIA®
Kristoffersen, 2009	223	B·R·A·H·M·S PCT sensitive Kryptor®
Long, 2011	172	B·R·A·H·M·S PCT sensitive Kryptor®
Long, 2009	127	B·R·A·H·M·S PCT LIA®
Nobre, 2008	79	B·R·A·H·M·S PCT sensitive Kryptor®
Schroeder, 2009	27	B·R·A·H·M·S PCT LIA®
Schuetz, 2009	1381	B·R·A·H·M·S PCT sensitive Kryptor®
Stolz, 2007	226	B·R·A·H·M·S PCT sensitive Kryptor®

These meta-analyses concluded that PCT guided antibiotic therapy resulted in:

· 19.2% reduction in relative antibiotic initiation for all patients
· 38% reduction in overall antibiotic exposure (i.e. total days of antibiotic therapy) for inpatients
· 51% reduction in overall antibiotic exposure (i.e. total days of antibiotic therapy) for patients who presented to the Emergency Department and other associated clinics, but were not admitted
· 2.9 day reduction in antibiotic duration [1.25 day reduction in study-level]

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

· 3.6 day reduction in total antibiotic exposure [2.79 day reduction in study-level]
· No negative effects in regards to mortality, complications, or length of stay

Parameter	Standard Care Therapy		PCT Guided Therapy
	N included	N (%) or Days, median (IQR)	N included	N (%) or Days, median (IQR)
Initiation of antibiotics	1606	1420 (88.4%)	1536	1096 (71,4%)
Duration of antibiotics	1420	10 (7, 12)	1096	7 (4, 10)
Total exposure of antibiotics	1606	9 (8, 12)	1536	5 (0, 8)
30 day mortality	1606	119 (7.4%)	1536	103 (6.7%)
Complications	1606	339 (21.1%)	1536	276 (18.0%)
Hospital length of stay	1583	6 (0, 13)	1508	7 (0, 12)

Overview of the patient-level meta-analysis:

Decision making on antibiotic discontinuation for suspected or confirmed septic patients

Two systematic literature reviews were performed along with study and patient-level metaanalyses, which are studies that combine and contrast data from multiple sources to identify patterns among study results. The study-level meta-analysis used aggregate descriptive information extracted from publications, and the patient-level meta-analysis used aggregate patient-level data from the raw dataset of each study. Each meta-analysis used randomeffects models and calculated point estimates, differences, odds ratios (OR), interquartile ranges (IQRs) and 95% confidence intervals as appropriate (see tables below). The endpoints evaluated were: duration of antibiotic therapy (study level only), exposure to antibiotics (patient level only), length of ICU stay, length of hospital stay (patient level only), and mortality. The study-level meta-analysis encompassed 10 RCTs 14,21-24,36-40 which were published between 2008-2016, and included 3489 patients. See FDA public docket FDA-2016-N-2880.

The above patient-level meta-analysis encompassed 5 RCTs 1421,22,37,41 which were published between 2008-2010, and included 598 patients as listed below.

Publication	N patients*	PCT device
Bouadma, 2010	630	B·R·A·H·M·S PCT sensitive Kryptor®
Hochreiter, 2009	110	B·R·A·H·M·S PCT LIA®
Nobre, 2008	79	B·R·A·H·M·S PCT sensitive Kryptor®
Schroeder, 2009	27	B·R·A·H·M·S PCT LIA®
Stolz, 2009	101	B·R·A·H·M·S PCT sensitive Kryptor®

*Patients that did not classify as sepsis were removed prior to analysis (185 for PCT group and 164 for control group), leaving 598 patients

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

Using this subset of meta-analyses it was concluded that PCT guided antibiotic therapy resulted in:

· 1.5 day reduction in antibiotic duration
· 3.2 day reduction in total antibiotic exposure
· 23% reduction in overall antibiotic exposure (i.e. total days of antibiotic therapy)
· No negative effects in regards to mortality, hospital length of stay, or ICU length of stay.

Parameter	Standard Care Therapy		PCT Guided Therapy
	N included	N (%) or Days, median (IQR)	N included	N (%) or Days, median (IQR)
Total exposure of antibiotics	311	12 (8, 18)	287	8 (5, 15)
30 day mortality	311	74 (23.8%)	287	57 (19.9%)
Hospital length of stay	288	23 (13, 38)	259	21 (11, 37)
ICU length of stay	311	12 (6, 22)	287	12 (6, 23)

Overview of the patient-level meta-analysis:

3. Clinical Cut-offs:

28-day mortality: (Unchanged from DEN150009). a.
- APCT ≤ 80%

A decrease in the PCT levels below or equal to 80% defines a positive APCT test result representing a higher risk for 28-day allcause mortality of patients diagnosed with severe sepsis or septic shock.

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

NOTE:

The combination of the first PCT level (≤ 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.

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b. Progression Risk :(Unchanged from K070310)
- PCT > 2 µg/L .

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

PCT < 0.5 µg/L .
A PCT level below 0.5 µg/L on the first day of ICU admission is associated with a low risk for progression to severe sepsis and/or septic shock.
c. LRTI Antibiotic Decision Making: (K162827)

Initiation:

. PCT < 0.10 ug/L Antibiotic therapy strongly discouraged.
. PCT 0.10-0.25 ug/L Antibiotic therapy discouraged.
PCT 0.26-0.50 ug/L ● Antibiotic therapy encouraged.
PCT >0.50 µg/L ● Antibiotic therapy strongly encouraged.

Discontinuation:

APCT > 80% Antibiotic therapy may be discontinued
PCT < 0.25 ug/L Antibiotic therapy may be discontinued
d. Sepsis Antibiotic Discontinuation: (K162827)
- . APCT > 80% Antibiotic therapy may be discontinued
- . PCT < 0.50 µg/L Antibiotic therapy may be discontinued
1. Expected Values/Reference Range:

See DEN150009. In non-infected subjects, PCT concentrations are usually <0.1 ug/L. In a population of 132 self-reported healthy individuals, 128 tested <0.1 µl/L and the top end 95th percentile was calculated at 0.0895 µg/L

Age Range	N	PCT (range)
		AfricanAmerican	Asian	Caucasian	Hispanic	Other
<60 years	77	15	5	56	1	0
>60 years	55	0	1	54	0	0

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N. Instrument Names:

B·R·A·H·M·S KRYPTOR® analyzer family

O. System Descriptions:

1. Modes of Operation:
  See Device Description (Section I) above

2. Software

See DEN150009.

1. Specimen Identification:
  Specimens are identified by unique bar codes.

4. Specimen Sampling and Handling:

a. Specimen type and collection
See DEN150009. Human serum or plasma (EDTA or heparin plasma heparinate).
b. Sample preparation
See DEN150009.
c. Sample stability
See DEN150009.
d. Sample-related interferences
See DEN150009.
1. Calibration:
  See DEN150009.
1. Quality Control:
  See "Traceability, Stability, Expected Values (controls, calibrators, or methods)" in section M.1.c above.

P. Other Supportive Instrument Performance Characteristics Data Not Covered In the "Performance Characteristics" Section above:

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See DEN150009.

Q. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and 809 and the specials controls for this device type.

R. Conclusion:

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

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.