Predicate Devices

Reference Devices

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a standard immunoassay and analyzer system based on established TRACE technology. There is no mention of AI or ML in the device description, intended use, or performance studies. The clinical studies are meta-analyses of RCTs, not studies of an AI/ML algorithm's performance.

Therapeutic

No
Explanation: This device is an in vitro diagnostic (IVD) device used to measure PCT levels to aid in risk assessment and decision-making regarding antibiotic therapy. It does not provide therapy or treatment itself.

Diagnostic

Yes

Explanation: The "Intended Use / Indications for Use" section explicitly states that the device is "intended for use as follows:" to "aid in the risk assessment of critically ill patients," "determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality," and "aid in decision making on antibiotic therapy" and "antibiotic discontinuation." These uses clearly indicate its role in diagnosis, risk assessment, and guiding clinical decisions.

SaMD (Software as a Medical Device)

No

The device is an immunofluorescent assay performed on a specific analyzer family (B·R·A·H·M·S KRYPTOR® analyzer family), which are hardware components. The description explicitly mentions the "B·R·A·H·M·S KRYPTOR® compact PLUS analyzer" as a fully automated system.

IVD (In Vitro Diagnostic)

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

Here's why:

Intended Use: The intended use explicitly states that the device is an "immunofluorescent assay... to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma." This is a classic description of an in vitro diagnostic test, as it analyzes a sample taken from the human body (serum or plasma) outside of the body to provide diagnostic information.
Device Description: The device description further clarifies that it's a "homogeneous sandwich immunoassay for detection of PCT in human serum or plasma," reinforcing its function as a test performed on biological samples.
Care Setting: The intended user/care setting section implies use in a laboratory setting, which is typical for IVD devices that analyze biological samples.
Performance Studies: The document details analytical and clinical performance studies, which are required for regulatory approval of IVD devices to demonstrate their accuracy and clinical utility.
Predicate Devices: The mention of predicate devices (DEN150009 and K162827) which are also IVD devices, further supports the classification of this device as an IVD.

The device performs a test on a biological sample (serum or plasma) to provide information about a patient's health status (PCT levels), which is the core function of an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for 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.

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

PRI, PMT, NTM

Device Description

The B.R.A.H.M.S.PCT sensitive KRYPTOR® contains sufficient reagents for 50 determinations.
Materials Provided:
Cryptate Conjugate: 1 bottle lyophilized, containing cryptate conjugate, cryptate labeled, anti-PCT antibody (polyclonal, sheep), 3.2 mL after reconstitution with KRYPTOR Solution 1 and KRYPTOR Solution 2.
XL665 Conjugate: 1 bottle lyophilized, containing XL665 conjugate, XL665 labeled, anti-PCT antibody (monoclonal, mouse), 3.95 mL after reconstitution with KRYPTOR Solution 1 and KRYPTOR Solution 2.
Diluent: 1 bottle, containing defibrinated human plasma, for diluting samples above 50 μg/L, ready for use.

Additional materials required but not provided:
B·R·A·H·M·S PCT sensitive KRYPTOR® Calibrator: Lyophilized recombinant PCT in defibrinated human plasma, reconstitute with 0.75 mL de-ionized water with conductivity of less than 50 µS/cm [range: 22.5 – 27.5 µg/L].
B·R·A·H·M·S PCT sensitive KRYPTOR® Controls:
Control 1: PCT control 1, lyophilized recombinant PCT in defibrinated 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 in defibrinated human plasma, reconstitute with 2 mL de-ionized water with conductivity of less than 50 µS/cm [range: 8 - 12 µg/L].

KRYPTOR® Consumables:
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®

The B·R·A·H·M·S PCT sensitive KRYPTOR® is a homogeneous sandwich immunoassay for detection of PCT in human serum or plasma. It uses Time-Resolved Amplified Cryptate Emission (TRACE®) technology to measure the fluorescent signal emitted from an immunocomplex. The B.R.A.H.M.S.KRYPTOR® compact PLUS software controls the instrument operation, collects and analyzes data, and automatically generates a test report.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

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 supportive clinical trials.

Intended User / Care Setting

Used in conjunction with other laboratory findings and clinical assessments.
ICU admission, emergency department or other medical wards.
For prescription use only.

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

Not Found

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

Not Found

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

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

b. Linearity/Assay Reportable Range:
See DEN150009:

Direct measuring range 0.02 µg/L -50 µg/L
Measuring range with automatic dilution 0.02µg/mL 5000 µg/L

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 80% defines a lower risk for 28-day all-cause mortality.

Progression Risk: (Unchanged from K070310)
- PCT > 2 µg/L on first day of ICU admission is associated with a high risk for progression to severe sepsis and/or septic shock.
- PCT 0.50 µg/L: Antibiotic therapy strongly encouraged.
- Discontinuation:
  - ∆PCT > 80%: Antibiotic therapy may be discontinued.
  - PCT 80%: Antibiotic therapy may be discontinued.
- PCT

Regulation Number and Section

§ 866.3215 Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis.

(a)
Identification. A device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis is identified as an in vitro device intended for the detection and qualitative and/or quantitative measurement of one or more non-microbial analytes in human clinical specimens to aid in the assessment of patients with suspected sepsis when used in conjunction with clinical signs and symptoms and other clinical and laboratory findings.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the device's detailed Indications for Use statement describing what the device detects and measures, the results provided to the user, whether the measure is qualitative and/or quantitative, the clinical indications for which the test is to be used, and the specific population(s) for which the device use is intended.
(2) Premarket notification submissions must include detailed documentation of the device description, including (as applicable), all device components, software, ancillary reagents required but not provided, explanation of the device principle and methodology, and for molecular devices include detailed documentation of the primer/probe sequence, design, and rationale for sequence selection.
(3) Premarket notification submissions must include detailed documentation of applicable analytical studies, such as, analytical sensitivity (Limit of Detection, Limit of Blank, and Limit of Quantitation), precision, reproducibility, analytical measuring range, interference, cross-reactivity, and specimen stability.
(4) Premarket notification submissions must include detailed documentation of a prospective clinical study or, if appropriate, results from an equivalent sample set. This detailed documentation must include the following information:
(i) Results must demonstrate adequate device performance relative to a well-accepted comparator.
(ii) Clinical sample results must demonstrate consistency of device output throughout the device measuring range likely to be encountered in the Intended Use population.
(iii) Clinical study documentation must include the original study protocol (including predefined statistical analysis plan), study report documenting support for the Indications for Use(s), and results of all statistical analyses.
(5) Premarket notification submissions must include evaluation of the level of the non-microbial analyte in asymptomatic patients with demographic characteristics (
e.g., age, racial, ethnic, and gender distribution) similar to the Intended Use population.(6) As part of the risk management activities performed under 21 CFR 820.30 design controls, you must document an appropriate end user device training program that will be offered as part of your efforts to mitigate the risk of failure to correctly operate the instrument.
(7) A detailed explanation of the interpretation of results and acceptance criteria must be included in the device's 21 CFR 809.10(b)(9) compliant labeling, and a detailed explanation of the interpretation of the limitations of the samples (
e.g., collected on day of diagnosis) must be included in the device's 21 CFR 809.10(b)(10) compliant labeling.

Summary

0

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

1

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

2

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)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

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

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

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

Department of Health and Human Services
Food and Drug Administration
Office of Chief Information Officer
Paperwork Reduction Act (PRA) Staff
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"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB number."

FORM FDA 3881 (8/14)
Page 1 of 1
PSC Publishing Services (301) -443-6740
EF

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5.0 510(K) SUMMARY

4

510K SUMMARY

GENERAL INFORMATION

Submission Date:	May 2, 2017
Submitter Information:
Submitted By:	B·R·A·H·M·S GmbH
Neuendorfstr. 25
16761 Hennigsdorf, Germany
Contact Person:	Sascha Johannes, PhD
Global Medical Affairs Manager
Clinical Diagnostics
Thermo Fisher Scientific
Neuendorfstr. 25
16761 Hennigsdorf, Germany
Tel: +49 3302 883-729
Fax: +49 3302 883-728
Email: 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®

5

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

6

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

7

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), 3.2
mL after reconstitution with KRYPTOR
Solution 1 and KRYPTOR Solution 2
XL665 Conjugate	1 bottle lyophilized	XL665 conjugate, XL665 labeled, anti-
PCT antibody (monoclonal, mouse), 3.95
mL after reconstitution with KRYPTOR
Solution 1 and KRYPTOR Solution 2
Diluent	1 bottle	Defibrinated human plasma, for diluting
samples above 50 μg/L, ready for use

8

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 human
plasma, reconstitute with 0.75 mL de-ionized water
with 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 in
defibrinated 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 in
defibrinated 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

9

3. Comparison with predicate:

| Item | Subject Device:
B·R·A·H·M·S PCT
sensitive KRYPTOR® | Predicate Device:
DEN150009
B·R·A·H·M·S PCT
sensitive KRYPTOR® | Predicate Device:
K162827
VIDAS B·R·A·H·M·S
PCT (PCT) |
|-----------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use
and
Indications
for 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 | 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.
The B•R•A•H•M•S PCT
sensitive KRYPTOR® is
intended for use in
conjunction with other
laboratory findings and
clinical assessments to aid
in the risk assessment of
critically ill patients on
their first day of Intensive
Care Unit (ICU) admission
for progression to severe
sepsis and septic shock.
The B•R•A•H•M•S PCT
sensitive KRYPTOR® is
also intended for use to
determine the change in
PCT level over time as an
aid in assessing the
cumulative 28-day risk of
all-cause mortality in
conjunction with other
laboratory findings and
clinical assessments for | VIDAS B·R·A·H·M·S PCT
(PCT) is an automated test
for use on the instruments
of the VIDAS family for
the determination of human
procalcitonin in human
serum or plasma (lithium
heparinate) using the ELFA
(Enzyme-Linked
Fluorescent Assay)
technique.
Used in conjunction with
other laboratory findings
and clinical assessments,
VIDAS B•R•A•H•M•S
PCT (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 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,
using a change in PCT
level over time,
• to aid in decision
making on antibiotic
therapy for inpatients
with suspected or |
| Item | Subject Device:
B·R·A·H·M·S PCT
sensitive KRYPTOR® | Predicate Device:
DEN150009
B·R·A·H·M·S PCT
sensitive KRYPTOR® | Predicate Device:
K162827
VIDAS B·R·A·H·M·S
PCT (PCT) |
| | • 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. | 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.
Procalcitonin (PCT) is a
biomarker associated with
the inflammatory response
to bacterial infection that
aids in the risk assessment
of critically ill patients on
their first day of Intensive
Care Unit (ICU) admission
for progression to severe
sepsis and septic shock.
The percent change in
PCT level over time also
aids in the prediction of
cumulative 28-day
mortality in patients with
severe sepsis and septic
shock.
PCT level on the first day
of ICU admission above
2.0 $μ$ g/L is associated with
a higher risk for
progression to severe
sepsis and/or septic shock
than a PCT level below 0.5
$μ$ g/L.
A PCT level that declines
≤ 80% from the day that
severe sepsis or septic
shock was clinically
diagnosed (Day 0) to four
days after clinical
diagnosis (Day 4) is
associated with higher
cumulative 28-day risk of
all-cause mortality than a
decline > 80%. | respiratory tract
infections (LRTI)
defined as community-
acquired pneumonia
(CAP), acute bronchitis,
and acute exacerbation
of Chronic Obstructive
Pulmonary Disease
(AECOPD) – in an
inpatient setting or an
emergency department;
• to aid in decision
making on antibiotic
discontinuation for
patients with suspected
or confirmed sepsis. |
| Item | Subject Device:
B·R·A·H·M·S PCT
sensitive KRYPTOR® | Predicate Device:
DEN150009
B·R·A·H·M·S PCT
sensitive KRYPTOR® | Predicate Device:
K162827
VIDAS B·R·A·H·M·S
PCT (PCT) |
| Specimen | Human serum and
plasma (EDTA,
heparin) | Same | Human serum or plasma
(lithium heparinate). |
| Analyte | Procalcitonin (PCT) | Same | Procalcitonin (PCT) |
| Automated | Automated assay | Same | Automated assay |
| Assay
Technique | TRACE® technology | Same | ELFA (Enzyme-Linked
Fluorescent Assay)
technique. |
| Assay
principle | Two antibody
"sandwich" binding of
Procalcitonin. | Same | Immunoassay based on
sandwich principle |
| Detection
method | Time-Resolved
Amplified Cryptate
Emission (TRACE®) | Same | Fluorescence (ELFA) of 4-
methyl-umbelliferyl
measured at 450 nm |
| Assay
duration | 19 minutes | Same | Approximately 20 minutes |
| Combination
devices | B·R·A·H·M·S
KRYPTOR® analyzer
family | Same | Instruments of the VIDAS
family: VIDAS,
miniVIDAS or VIDAS 2 |
| Item | Subject Device:
B·R·A·H·M·S PCT
sensitive KRYPTOR® | Predicate Device:
DEN150009
B·R·A·H·M·S PCT
sensitive KRYPTOR® | Predicate Device:
K162827
VIDAS B·R·A·H·M·S
PCT (PCT) |
| Antibodies | Cryptate conjugate,
cryptate labeled,
anti-PCT antibody
(polyclonal, sheep) XL665 conjugate,
XL665 labeled,
anti-PCTantibody
(monoclonal,
mouse) | Same | Conjugate: Alkaline
phosphatase-labeled
mouse monoclonal
anti-human
procalcitonin
immunoglobulins Solid phase: Mouse
monoclonal anti-
procalcitonin
immunoglobulins
coated on interior of
the SPR |
| Sample
volume | 50μl | Same | 200 μL |

10

11

12

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)]

13

L. Test Principle:

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.

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.

14

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.

16

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 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
Beclomethasone
dipropionate	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

18

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
0.1 and
≤0.25 µg/L	15	19	2	0	0	36
	>0.25 and
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.

23

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 0.50 µg/L ● Antibiotic therapy strongly encouraged.

Discontinuation:

APCT > 80% Antibiotic therapy may be discontinued
PCT 80% Antibiotic therapy may be discontinued
- . PCT 60 years | 55 | 0 | 1 | 54 | 0 | 0 |

24

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:

25

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.