(192 days)
No
The device description details a standard immunoassay technology and does not mention any AI/ML components. The analysis of performance is based on statistical measures and comparisons to a predicate device, not on the output of an AI/ML algorithm.
No
This device is an in vitro diagnostic immunoassay that determines PCT levels in patient samples, which aids in risk assessment and decision-making for antibiotic therapy. It does not directly treat or prevent a disease or condition.
Yes
The device is an immunoassay for the quantitative determination of PCT, which is used to aid in risk assessment for critically ill patients, assess mortality risk in severe sepsis, and aid in decision-making on antibiotic therapy and discontinuation. These functions clearly indicate its role in diagnosing and managing patient conditions.
No
The device description clearly outlines a physical immunoassay kit and its use on specific hardware analyzers (Elecsys and cobas e), involving chemical reactions, microparticles, and detection systems. This is not a software-only device.
Yes, this device is an IVD (In Vitro Diagnostic).
The "Intended Use / Indications for Use" section explicitly states: "Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma..."
This clearly indicates that the device is intended for use outside of the body to examine specimens (serum and plasma) for diagnostic purposes.
N/A
Intended Use / Indications for Use
Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2 –EDTA, K3-EDTA and Li-Heparin).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Used in conjunction with other laboratory findings and clinical assessments, Elecsys B.R.A.H.M.S.PCT is intended for use as follows:
· to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
· to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
· to aid in decision making on antibiotic therapy, for inpatients in the emergency department with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),
· to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
Product codes (comma separated list FDA assigned to the subject device)
PMT, PRI, NTM
Device Description
The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles and an electrochemiluminescence detection system. PCT in the sample reacts with these labeled antibodies to form a sandwich complex. This complex binds to streptavidin coated magnetic microparticles, which are magnetically captured onto an electrode. Application of voltage to the electrode induces chemiluminescence which is measured by a photomultiplier tube. Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode. An optional Procalcitonin CalCheck product is also available.
The reagent working solutions include:
Rackpack (kit placed on analyzer)
- M: Streptavidin-coated microparticles, .
- R1: Anti-PCT-Ab~biotin ●
- R2: Anti-PCT Ab~Ru(bpy) == ●
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
Adult patients (i.e. >18 years of age)
Intended User / Care Setting
Laboratory / ICU, Emergency Department, other medical wards, out of hospital
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
The Elecsys® B•R•A•H•M•S PCT clinical performance study was conducted by retrospective multicenter testing of PCT from available frozen samples of adult patients (i.e. >18 years of age) diagnosed with severe sepsis or septic shock who were enrolled in the BRAHMS MOSES study from the Intensive Care Unit or the emergency department, other wards or directly from out of hospital and subsequently admitted to the ICU.
Sample size (N) = 2617.
Data source: BRAHMS MOSES study.
Annotation protocol: Not explicitly stated, but clinical concordance analysis was performed with all available valid test results.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Precision Study:
- Study Type: Repeatability and intermediate precision study according to CLSI guideline EP5-A3, "Evaluation of Precision Performance of Quantitative Measurement Methods".
- Sample Size: Sixteen (16) human serum samples and two (2) QC samples.
- Key Results: Varied depending on PCT concentration, with repeatability CV% ranging from 1.4% to 16.7% and intermediate precision CV% ranging from 2.2% to 24.3%. %Total Error ranged from 5.36% to 57.02%.
Interference Study:
- Study Type: Assessment of endogenous and exogenous (drugs) interferences.
- Key Results: Endogenous substances (Hemoglobin, Biotin, Intralipid, Bilirubin, and Rheumatoid Factor) and 38 pharmaceutical compounds were found not to significantly affect test performance at clinically relevant concentrations, with recovery within ± 15% (endogenous) and ± 10% (drugs) of the initial value, except for biotin at concentrations greater than 30 ng/mL, which showed higher negative bias.
Clinical Performance Evaluation - Method Comparison to Predicate:
- Study Type: Retrospective multicenter study comparing Elecsys BRAHMS PCT to the predicate device (B.R.A.H.M.S. PCT sensitive KRYPTOR®).
- Sample Size: 2617 samples.
- Key Results:
- Clinical concordance: More than 97% total agreement between the Elecsys B.R.A.H.M.S PCT and the B.R.A.H.M.S PCT sensitive Kryptor® at medical decision points 0.1, 0.25, 0.5 and 2.0 ng/mL.
- Regression slopes (Passing-Bablok and Weighted Deming) are within +/- 10% of identity.
- Passing Bablok Slope: 0.959 (95% CI: 0.947; 0.972), Intercept: -0.023 (95% CI: -0.028; -0.018), Pearson Correlation Coefficient: 0.989.
- Weighted Deming Slope: 0.949 (95% CI: 0.937; 0.961), Intercept: -0.008 (95% CI: -0.013; -0.004), Pearson Correlation Coefficient: 0.989.
- Total Agreement at cutoffs: 0.10 ng/mL (97.8%), 0.25 ng/mL (97.5%), 0.50 ng/mL (97.4%), 2.00 ng/mL (97.4%).
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
- Total Agreement:
- At 0.10 ng/mL cutoff: 97.8% (Positive Agreement: 93.3% (86.6 - 97.3), Negative Agreement: 98.0% (97.4 - 97.3))
- At 0.25 ng/mL cutoff: 97.5% (Positive Agreement: 95.6% (93.1 - 97.4), Negative Agreement: 97.9% (97.2 - 98.4))
- At 0.50 ng/mL cutoff: 97.4% (Positive Agreement: 97.4% (95.9 - 98.4), Negative Agreement: 97.4% (96.6 - 98.1))
- At 2.00 ng/mL cutoff: 97.4% (Positive Agreement: 98.9% (98.2 - 99.4), Negative Agreement: 95.9% (94.8 - 96.9))
- Cohen's Kappa:
- At 0.10 ng/mL cutoff: 0.762
- At 0.25 ng/mL cutoff: 0.908
- At 0.50 ng/mL cutoff: 0.934
- At 2.00 ng/mL cutoff: 0.947
- Limits:
- Measuring Range: 0.02 - 100ng/mL
- LoB: 0.015 ng/mL
- LoD: 0.02 ng/mL
- LoQ: 0.06 ng/mL
- Lower Detection Limit: 0.015 ng/mL
- Hook Effect: No hook effect up to 1000ng/mL
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
B.R.A.H.M.S. PCT sensitive KRYPTOR® cleared under K171338.
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Not Found
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Not Found
§ 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.
0
Image /page/0/Picture/0 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, with the letters "FDA" in a blue box, followed by the words "U.S. FOOD & DRUG" in blue, and then the word "ADMINISTRATION" in a smaller font size below that.
July 6, 2018
Roche Diagnostics Wes Gerbig Regulatory Affairs Principal 9115 Hague Road Indianapolis, Indiana 46250
Re: K173927
Trade/Device Name: Elecsys BRAHMS PCT Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microbial analyte(s) in human clinical specimens to aid in assessment of patients with suspected sepsis Regulatory Class: Class II Product Code: PMT Dated: December 22, 2017 Received: December 26, 2017
Dear Wes Gerbig:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR
1
803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803). please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.
For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Steven R. Gitterman -S for
Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
2
Indications for Use
510(k) Number (if known) K173927
Device Name Elecsys BRAHMS PCT
Indications for Use (Describe) Elecsys BRAHMS PCT
Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2 –EDTA, K3-EDTA and Li-Heparin).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Used in conjunction with other laboratory findings and clinical assessments, Elecsys B.R.A.H.M.S.PCT is intended for use as follows:
· to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock,
· to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission,
· to aid in decision making on antibiotic therapy, for inpatients in the emergency department with suspected or confirmed lower respiratory tract infections (LRT) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD),
· to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| Prescription Use (Part 21 CER 801 Subpart D) | Over-The-Counter Use (21 CER 801 Subpart C) |
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3
Elecsys BRAHMS PCT 510(k) Summary
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of 21 CFR 807.92.
In accordance with 21 CFR 807.87, Roche Diagnostics hereby submits official notification as required by Section 510(k) of the Federal Food, Drug and Cosmetics Act of our intention to market the device described in this Premarket Notification 510(k).
The purpose of this Traditional 510(k) Premarket Notification is to obtain FDA review and clearance for the Elecsys BRAHMS PCT Test System.
4
| Submitter Name | Roche Diagnostics |
|---|---|
| Address | 9115 Hague Road |
| P.O. Box 50416 | |
| Indianapolis, IN 46250-0457 | |
| Contact | Wes Gerbig |
| Phone: (317) 521-3743 | |
| FAX: (317) 521-2324 | |
| Email: wes.gerbig@roche.com | |
| Secondary Contact Name | |
| Michael Leuther | |
| Phone: (317) 521-3930 | |
| FAX: (317) 521-2324 | |
| Email: michael.leuther@roche.com | |
| Date Prepared | December 22, 2017 |
| Proprietary Name | Elecsys BRAHMS PCT |
| Common Name | Procalcitonin |
| Classification Name | Device to detect and measure non-microbial analyte(s) in human clinical |
| specimens to aid in assessment of patients with suspected sepsis | |
| Product Codes, | |
| Regulation Numbers | PRI, PMT, NTM, 866.3215 |
| Predicate Devices | B.R.A.H.M.S. PCT sensitive KRYPTOR® cleared under K171338. |
| Establishment Registration | For the Elecsys BRAHMS PCT Test System the establishment registration |
| number for Roche Diagnostics GmbH in Mannheim, Germany is 9610126, and | |
| for Penzberg, Germany, 9610529. The establishment registration number for | |
| Roche Diagnostics in the United States is 1823260. |
5
1. DEVICE DESCRIPTION
The Elecsys BRAHMS PCT assay is a two-step sandwich immunoassay with streptavidin microparticles and an electrochemiluminescence detection system. PCT in the sample reacts with these labeled antibodies to form a sandwich complex. This complex binds to streptavidin coated magnetic microparticles, which are magnetically captured onto an electrode. Application of voltage to the electrode induces chemiluminescence which is measured by a photomultiplier tube. Results are determined via a calibration curve which is instrument-specifically generated by 2-point calibration and a master curve provided via the reagent barcode. An optional Procalcitonin CalCheck product is also available.
1.1. Reagents
The reagent working solutions include:
Rackpack (kit placed on analyzer)
- M: Streptavidin-coated microparticles, .
- R1: Anti-PCT-Ab~biotin ●
- R2: Anti-PCT Ab~Ru(bpy) == ●
2. INDICATIONS FOR USE
Immunoassay for the in vitro quantitative determination of PCT (procalcitonin) in human serum and plasma (K2 –EDTA, K3-EDTA and Li-Heparin).
The electrochemiluminescence immunoassay "ECLIA" is intended for use on Elecsys and cobas e immunoassay analyzers.
Used in conjunction with other laboratory findings and clinical assessments, Elecsys B·R·A·H·M·S PCT is intended for use as follows:
- to aid in the risk assessment of critically ill patients on their first day of ICU admission . for progression to severe sepsis and septic shock,
6
- 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.
7
TECHNOLOGICAL CHARACTERISTICS 3.
Table 1: Assay Comparison
| Feature | Candidate Device: Elecsys BRAHMS
PCT | Predicate Device: B.R.A.H.M.S.
PCT sensitive KRYPTOR®
(K171338). |
|--------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use/
Indications for Use | Immunoassay for the in vitro quantitative
determination of PCT (procalcitonin) in
human serum and plasma (K2 –EDTA,
K3-EDTA and Li-Heparin).
The electrochemiluminescence
immunoassay "ECLIA" is intended for use
on Elecsys and cobas e immunoassay
analyzers.
Used in conjunction with other laboratory
findings and clinical assessments, Elecsys
B·R·A·H·M·S PCT is intended for use as
follows:
• to aid in the risk assessment of
critically ill patients on their first day
of ICU admission for progression to
severe sepsis and septic shock,
• 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. | 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, |
| Intended Use/ | | • to aid in decision making on
antibiotic therapy, for |
| Feature | Candidate Device: Elecsys BRAHMS
PCT | Predicate Device: B.R.A.H.M.S.
PCT sensitive KRYPTOR®
(K171338). |
| Indications for Use Continued | | 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. |
| Assay Protocol | The Elecsys BRAHMS PCT assay is a
two-step sandwich immunoassay with
streptavidin microparticles and an
electrochemiluminescence detection
system. The test system reagents contain
a biotinylated monoclonal PCT-specific
antibody and a ruthenium labeled
monoclonal PCT-specific antibody. | The BRAHMS PCT sensitive
KRYPTOR® assay is a
homogeneous sandwich
immunoassay for detection of PCT
in human serum or plasma. The
measuring principle is based on
Time-Resolved Amplified Cryptate
Emission (TRACE®) technology,
which measures the signal that is
emitted from an immunocomplex
with time delay. |
| Detection Protocol | Electrochemiluminescent Assay | Time-Resolved Amplified Cryptate
Emission (TRACE®) |
| Applications | 18-minute application | 19-minute incubation |
| Instrument Platform | cobas e 411 analyzer | BRAHMS KRYPTOR® analyzer |
| Sample Volume | 30 μL | 50 μL |
| Sample Type | Human serum and plasma (Li-Heparin,
K2/K3 EDTA) | Human serum and plasma (EDTA,
heparin) |
| Feature | Candidate Device: Elecsys BRAHMS
PCT | Predicate Device: B.R.A.H.M.S.
PCT sensitive KRYPTOR®
(K171338). |
| Reagents | M: Streptavidin-coated microparticles:
Steptavidin-coated microparticles;
preservative
R1: Anti-PCT-Abbiotin:Ru(bpy) 2/3+ a
Biotinylated monoclonal anti-PCT antibody
(mouse), phosphate buffer, preservative
R2: Anti-PCT – Ab
monoclonal anti-PCT antibody (mouse)
labeled with reuthenium complex,
phosphate buffer, preservative | Cryptate conjugate, cryptate
labeled, anti-PCT antibody
(polyclonal, sheep), 3.2mL after
reconstitution with KRYPTOR®
Solution 2
XL665 conjugate, XL665 labeled,
anti-PCT antipody (monoclonal,
mouse), 3.95 mL after
reconstitution with KRYPTOR®
Solution 1 and KRYPTOR® Solution
2
Defibrinated human plasma, for
diluting samples above 50µg/L,
ready for use |
| Calibrator | Elecsys PCT CalSet | BRAHMS PCT sensitive
KRYPTOR® Calibrator |
| Calibration Interval | Calibration must be performed once per
reagent lot using fresh reagent (i.e. not
more than 24 hours since the reagent kit
was registered on the analyzer). Renewed
calibration is recommended as follows:
• after 8 weeks when using the same
reagent lot
• after 7 days (when using the same
reagent kit on the analyzer) as
required: e.g. quality control findings
outside the specified limits | Before first use of each new
BRAHMS PCT sensitive
KRYPTOR® lot, then repeated on a
regular basis automatically
managed by the BRAHMS PCT
sensitive KRYPTOR®. |
| Controls | Precicontrol PCT | BRAHMS PCT sensitive
KRYPTOR® Controls |
| Traceability/ Standardization | This method has been standardized
against the BRAHMS PCT LIA assay. | Not Provided |
| Reagent Stability | Store at 2-8 °C. Do not freeze. Store the
Elecsys reagent kit upright in order to
ensure complete availability of the
microparticles during automatic mixing
prior to use.
Stability:
• unopened at 2-8 °C: up to the stated
expiration date
• after opening at 2-8 °C: 12 weeks
• on the analyzers: 4 weeks | In original shipping containers
unopened at 2-8 °C: up to the
stated expiration date
after opening, onboard at 2-8 °C:
29 days |
| Measuring Range | 0.02 - 100ng/mL | 0.02-50µg/L |
| LoB | 0.015 ng/mL | N/P |
| LoD | 0.02 ng/mL | N/P |
| Feature | Candidate Device: Elecsys BRAHMS
PCT | Predicate Device: B.R.A.H.M.S.
PCT sensitive KRYPTOR®
(K171338). |
| LoQ | 0.06 ng/mL | 0.075 µg/L |
| Lower Detection Limit | 0.015 ng/mL | N/P |
| Hook Effect | No hook effect up to 1000ng/mL | N/A |
| Limitations | For diagnostic purposes, the results
should always be assessed in conjunction
with the patient's medical history, clinical
examination and other findings.
Increased PCT levels may not always be
related to systemic infection. These
include, but are not limited to: Patients
experiencing major trauma and/or recent
surgical procedure including
extracorporeal circulation or burns.
Patients undergoing treatment with OKT3
antibodies, OK-432, interleukins, TNF-
alpha and other drugs that stimulate the
release of pro-inflammatory cytokines or
result in anaphylaxis.
Patients diagnosed with active medullary
C-cell carcinoma, small cell lung
carcinoma, or bronchial carcinoid.
Patients with acute or chronic viral
hepatitis and/or decompensated severe
liver cirrhosis (Child-Pugh Class C).
Patients with prolonged or severe
cardiogenic shock, prolonged severe
organ perfusion anomalies, or after
resuscitation from cardiac arrest.
Patients receiving peritoneal dialysis or
hemodialysis treatment. Patients with
biliary pancreatitis, chemical pneumonitis
or heat stroke.
Patients with invasive fungal infections
(e.g., candidiasis, aspergillosis) or acute
attacks of plasmodium falciparum malaria.
Neonates during the first 2 days of life.
The results of the Elecsys BRAHMS PCT
assay should be evaluated in the context
of all laboratory findings and the total
clinical status of the patient. In cases
where laboratory results do not agree with
the clinical picture or history, additional
tests should be performed. | 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. In
cases where the
laboratory results do not agree with
the clinical picture or history,
additional tests should be
performed
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.
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 performed. |
| Feature | Candidate Device: Elecsys BRAHMS
PCT | Predicate Device: B.R.A.H.M.S.
PCT sensitive KRYPTOR®
(K171338). |
| Limitations Continued | | PCT levels may not be elevated in
patients infected by certain atypical
pathogens, such as Chlamydophila
pneumoniae and Mycoplasma
pneumoniae.1
Severity of renal failure or
insufficiency, may influence
procalcitonin values and should be
considered as potentially
confounding clinical factors when
interpreting PCT values.2
Increased PCT levels may not
always be related to systemic
infection 2-5. These conditions
include, but are not limited to:
Patients experiencing major trauma
and/or recent surgical procedure
including extracorporeal circulation
or burns; |
| | | • Patients under treatment
with OKT3 antibodies, OK-
432, interleukins, TNF-alpha
and other drugs stimulating
the release of pro-
inflammatory cytokines or
resulting in anaphylaxis; |
| | | • Patients diagnosed with
active medullary C-cell
carcinoma, small cell lung
carcinoma, or bronchial
carcinoid; |
| | | • Patients with acute or
chronic viral hepatitis and/or
decompensated severe liver
cirrhosis (Child-Pugh Class
C); |
| | • Patients with prolonged or
severe cardiogenic shock,
prolonged severe organ
perfusion anomalies or after
resuscitation from cardiac
arrest; | |
| | • Patients receiving peritoneal
dialysis or hemodialysis
treatment; | |
| | • Patients with biliary
pancreatitis, chemical
pneumonitis or heat stroke; | |
| Feature | Candidate Device: Elecsys BRAHMS PCT | Predicate Device: B.R.A.H.M.S. PCT sensitive KRYPTOR® (K171338). |
| Limitations Continued | | Patients with invasive fungal infections (e.g. candidiasis, aspergillosis ) or acute attacks of plasmodium falciparum malaria; and Neonates during the first 2 days of life. |
| Method Comparison | 2617 samples were run on the cobas e 411 and the predicate device (BRAHMS PCT sensitive KRYPTOR®). Passing Bablok Slope: 0.959 (95% CI: 0.947; 0.972) Intercept: -0.023 (95% CI: -0.028; -0.018) Coefficient: 0.989 (95% CI: 0.988; 0.990) | |
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9
10
11
12
PERFORMANCE EVALUATION 4.
The following data was requested by the FDA in Q171237 to support the updated Indications for Use statement and is listed below:
- Precision according to CLSI EP5-A3 .
- Interferences Endogenous .
- Interferences Exogenous (Drugs) •
- Clinical Performance Evaluation Method Comparison to Predicate .
The remaining data required to support the updated Indications for Use was supplied in the previous submission K160729:
- Analytical Sensitivity: LoB, LoD and LoQ according to CLSI EP17-A2 .
- Linearity according to CLSI EP6-A .
- High Dose Hook Affect .
- Human Anti-Mouse Antibodies (HAMA) .
13
- Analytical Specificity .
- Serum/Plasma Comparison .
- Sample Stability .
- Reagent Stability .
4.1. Precision
The repeatability and intermediate precision of the Elecsys BRAHMS PCT assay was conducted using the cobas e 411 analyzer. Studies were performed in accordance with CLSI guideline EP5-A3, "Evaluation of Precision Performance of Quantitative Measurement Methods". One reagent lot was evaluated. The precision study was conducted using the study design of 21 days x 2 runs per day x 2 replicates per sample. One (1) instrument was used for the study and calibration was performed according to the Instructions for Use. Aliquots of sixteen (16) human serum samples and two (2) QC samples (PC PCT 1 and PC PCT 2) distributed over the measuring range were assayed in duplicate and randomized order on the cobas e 411 analyzer using one lot of reagent. Data is acceptable and is summarized below. An analysis was also performed to calculate % Total Error across the measuring range.
14
| Mean (ng/mL) | Repeatability (CV%) | Intermediate Precision (CV%) | %Total Error |
|---|---|---|---|
| 0.037 | 16.7 | 24.3 | 57.02 |
| 0.085 | 6.4 | 9.2 | 22.49 |
| 0.121 | 4.2 | 6.2 | 14.95 |
| 0.183 | 3.1 | 4.2 | 10.18 |
| 0.242 | 2.2 | 3.6 | 8.67 |
| 0.300 | 2.1 | 2.8 | 6.75 |
| 0.400 | 2.0 | 3.2 | 7.68 |
| 0.415 | 1.9 | 2.3 | 5.56 |
| 1.52 | 1.6 | 2.2 | 5.36 |
| 2.12 | 1.5 | 2.2 | 5.38 |
| 2.93 | 1.4 | 2.4 | 5.76 |
| 26.1 | 1.5 | 2.8 | 6.81 |
| 44.6 | 1.6 | 2.8 | 6.69 |
| 64.5 | 1.9 | 3.0 | 7.33 |
| 97.6 | 1.7 | 2.4 | 5.79 |
Table 2: Summary of Precision Results – Elecsys BRAHMS PCT Repeatability and Intermediate Precision
Endogenous Interferences 4.2.
The effect on quantitation of PCT in the presence of five endogenous interfering substances (Hemoglobin, Biotin, Intralipid, Bilirubin, and Rheumatoid Factor) was tested using one cobas e 411 analyzer. Spiked serum pools were used for testing. The substances were found not to affect test performance at clinically relevant concentrations. Recovery was within ± 15 % of the initial value. See K160729 for additional interference data.
| Table 3: Potentially Interfering Endogenous Substances and Test Concentrations | ||||||
|---|---|---|---|---|---|---|
| -- | -- | -- | -- | -------------------------------------------------------------------------------- | -- | -- |
| Potential Interferent | Maximum Value With No Interference Observed |
|---|---|
| Intralipid | 2000 mg/dL |
| Bilirubin | 66 mg/dL |
| Hemoglobin | 1000 mg/dL |
| Rheumatic Factor | 1500 IU/mL |
15
| % Bias for samples containing various concentrations of biotin | |||||
|---|---|---|---|---|---|
| Samples PCT concentrations | |||||
| (ng/mL) | Biotin concentration (ng/mL) | ||||
| (ng/mL) | 9.6 | 20.4 | 30.0 | 39.6 | 80.4 |
| 0.04 | 2.3 | 2.8 | 0.2 | -17.0 | * |
| 0.10 | 4.5 | -2.8 | -6.6 | -13.2 | -26.8 |
| 0.13 | 0.5 | -2.8 | -3.1 | -4.8 | -25.1 |
| 0.20 | 1.5 | 0.3 | -8.6 | -11.5 | -38.4 |
| 0.48 | 0.9 | 0.5 | -0.03 | -0.5 | -9.1 |
| 1.96 | 3.9 | 3.6 | 1.4 | 0.5 | -8.0 |
Table 4: Biotin Interference
- = value below measurable range
** Specimens with biotin concentrations up to 30 ng/mL demonstrated ≤ 13 % bias in results. Biotin concentrations greater than 30 ng/mL can lead to higher negative bias for PCT results. The recommended daily intake for biotin is 30 µg. Higher doses of biotin (> 10 mg per day) may be taken as a dietary supplement aimed at reducing hair loss or improving nail or skin condition.13
Some pharmacokinetic studies have shown that serum concentrations of biotin can reach 355 ng/mL for subjects taking supplements containing at least 20 mg of biotin14 or 1160 ng/mL
16
for subjects taking doses of biotin up to 300 mg.13 These studies were performed in healthy subjects, and some patients may be taking supplements with biotin at levels greater than 20 mg per day. Clearance of biotin could be different in patients tested with this device, which may lead to higher than expected concentrations of biotin in serum.
4.3. Exogenous Interferences – Drugs
The effect on quantitation of analyte in the presence of drugs was determined by comparing values obtained from samples spiked with 38 pharmaceutical compounds into two human serum samples at differing analyte concentrations and tested on the cobas e 411 analyzer. The substances were found not to affect test performance at clinically relevant concentrations. Recovery was within ± 10 % of the reference value. See K160729 for additional interference data.
| Potential Interferent | Drug Level Tested (mg/L) |
|---|---|
| Cromolyn | 24 |
| Acetylsalicylic acid | 652 |
| Acetaminophen | 200 |
| Alcohol | 4000 |
| Azithromycin | 11.5 |
| Cetirizine HCL | 3.6 |
| Dextromethorphan | 1.4 |
| Ibuprofen | 500 |
| Imipenem | 1180 |
| Levofloxacin | 17.5 |
| Loratadine | 0.3 |
| Nicotine | 1 |
| Oxymetazoline HCL | 0.09 |
| Phenylephrine | 0.18 |
| Tiotropium | 0.0216 |
Potentially Interfering Drugs and Test Concentrations Table 5:
17
Clinical Performance Evaluation - Method Comparison to Predicate 4.4.
The Elecsys® B•R•A•H•M•S PCT clinical performance study was conducted by retrospective multicenter testing of PCT from available frozen samples of adult patients (i.e. >18 years of age) diagnosed with severe sepsis or septic shock who were enrolled in the BRAHMS MOSES study from the Intensive Care Unit or the emergency department, other wards or directly from out of hospital and subsequently admitted to the ICU.
The clinical concordance analysis in this report was performed with all available valid test results obtained in the Elecsys® B·R·A·H·M·S PCT clinical performance study. The clinical line data of the BRAHMS MOSES study is available via MAF2386 (Amendment 9 - Clinical Line Data). The line listings of the Elecsys B·R·A·H·M·S PCT clinical performance study was included in K160729.
The clinical concordance analysis of the Elecsys B.R.A.H.M.S PCT clinical performance study shows more than 97% total agreement between the Elecsys B.R.A.H.M.S.PCT and the B.R.A.H.M.S PCT sensitive Kryptor® (predicate device) at the medical decision points 0.1, 0.25, 0.5 and 2.0 ng/mL. The regression slopes are within +/- 10% of identity in Passing-Bablok and Weighted Deming Analysis. This demonstrates equivalence to the predicate device to include all currently cleared claims of the predicate device in the labeling of the candidate device.
| Elecsys BRAHMS PCT on
| cobas e 411 | B•R•A•H•M•S PCT sensitive Kryptor® | Total | |
|---|---|---|---|
| ≤ 0.5 ng/mL | > 0.5 ng/mL | ||
| ≤ 0.5 ng/mL | 667 | 50 | 717 |
| > 0.5 ng/mL | 18 | 1882 | 1900 |
| Total | 685 | 1932 | 2617 |
Table 6: Elecsys BRAHMS PCT vs Predicate at 0.5 ng/mL
Table 7: Elecsys BRAHMS PCT vs Predicate at 2.0 ng/mL
| Elecsys BRAHMS PCT on
| cobas e 411 | B•R•A•H•M•S PCT sensitive Kryptor® | Total | |
|---|---|---|---|
| ≤ 2.0 ng/mL | > 2.0 ng/mL | ||
| ≤ 2.0 ng/mL | 1223 | 56 | 1279 |
| > 2.0 ng/mL | 13 | 1325 | 1338 |
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| Elecsys BRAHMS PCT on
| cobas e 411 | B•R•A•H•M•S PCT sensitive Kryptor® | Total | |
|---|---|---|---|
| Total | ≤ 2.0 ng/mL | > 2.0 ng/mL | 2617 |
| 1236 | 1381 |
Table 8: 3 x 3 Table Elecsys BRAHMS PCT vs Predicate
| B•R•A•H•M•S PCT sensitive Kryptor® | ||||
|---|---|---|---|---|
| Elecsys BRAHMS PCT on cobas e | ||||
| 411 | ≤ 0.5 ng/mL | 0.5 ng/mL 2.0 ng/mL | Total | |
| ≤ 0.5 ng/mL | 667 | 48 | 2 | 717 |
| 0.5 ng/mL 2.0 ng/mL | 0 | 13 | 1325 | 1338 |
| Total | 685 | 551 | 1381 | 2617 |
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| B•R•A•H•M•S PCT sensitive Kryptor® | ||||||
|---|---|---|---|---|---|---|
| Elecsys | ||||||
| BRAHMS PCT on | ||||||
| cobas e 411 | ≤ 0.1 ng/mL | 0.1 ng/mL 2.0 ng/mL | Total | |||
| ≤0.1 ng/mL | 97 | 47 | 1 | 1 | 1 | 147 |
| 0.1 ng/mL 2.0 ng/mL | 0 | 0 | 0 | 13 | 1325 | 1338 |
| Total | 104 | 304 | 277 | 551 | 1381 | 2617 |
Table 9: 5 x 5 Table Elecsys BRAHMS PCT vs Predicate
Table 10: Comparison Elecsys BRAHMS PCT vs Predicate
N = 2617 (104 ≤ 0.1 ng/mL, 408 ≤ 0.25 ng/mL; 685 ≤ 0.5 ng/mL; 1236 ≤ 2.0 ng/mL)
| Cutoff (> vs. ≤) | Positive Agreement
(95% CI) | Negative Agreement
(95% CI) | Total Agreement | Cohen's Kappa |
|------------------|--------------------------------|--------------------------------|-----------------|---------------|
| 0.10 ng/mL | 93.3%
(86.6 - 97.3) | 98.0%
(97.4 - 97.3) | 97.8% | 0.762 |
| 0.25 ng/mL | 95.6%
(93.1 - 97.4) | 97.9%
(97.2 - 98.4) | 97.5% | 0.908 |
| 0.50 ng/mL | 97.4%
(95.9 - 98.4) | 97.4%
(96.6 - 98.1) | 97.4% | 0.934 |
| 2.00 ng/mL | 98.9%
(98.2 - 99.4) | 95.9%
(94.8 - 96.9) | 97.4% | 0.947 |
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| Parameter | Passing Bablok Regression | Weighted Deming (λ=1) Regression
Analysis |
|----------------------------------|---------------------------|----------------------------------------------|
| n | 2617 | 2617 |
| Slope | 0.959 | 0.949 |
| 95% CI | [0.947; 0.972] | [0.937; 0.961] |
| Intercept | -0.023 | -0.008 |
| 95% CI | [-0.028; -0.018] | [-0.013; -0.004] |
| Pearson Correlation Coefficient | 0.989 | 0.989 |
| Spearman Correlation Coefficient | 0.990 | 0.990 |
| Sample Range | [0.02; 662.86] | [0.02; 662.86] |
Table 11: Weighted Deming and Passing Bablok Regression Analysis
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Figure 1: Weighted Deming Regression plots of Elecsys BRAHMS PCT versus Predicate
Weighted Deming Regression e411 vs Kryptor
Image /page/21/Figure/1 description: The image is a scatter plot that shows the correlation between two different measurement methods, Roche e411 and Kryptor, for a specific scenario. The x-axis represents the Kryptor measurements, while the y-axis represents the Roche e411 measurements. The plot includes a regression line with the equation y = -0.008 + 0.949*x, indicating a strong positive correlation between the two methods. The data points are clustered around the regression line, with some scatter, and the sample size is n=2617.
B·R·A·H·M·S PCT sensitive Kryptor (ng/ml) The 0.95-confidence bounds are calculated with the bootstrap(quantile) method.
22
Image /page/22/Figure/0 description: The image is a scatter plot showing Passing Bablok Regression e411 vs Kryptor. The scenario is Roche e411 vs Kryptor, cutoff 0.1 ng/ml, Roche & Kryptor measurements valid (n=2617). The x-axis is labeled 'B-R-A-H-M-S PCT sensitive Kryptor (ng/ml)' and the y-axis is labeled 'B-R-A-H-M-S PCT Elecsys Cobas e411 (ng/ml)'. A regression line is plotted with the equation y = -0.023 + 0.959*x.
Figure 2: Passing Bablok Regression plots of Elecsys BRAHMS PCT versus Predicate
The 0.95-confidence bounds are calculated with the bootstrap(quantile) method.
5. ADDITIONAL INFORMATION
The calibration materials PCT Cal1 and PCT Cal2 as well as the control material PreciControl PCT1 and PreciControl PCT2 are in the Elecsys BRAHMS PCT kit and are not changed as a result of the new claims. The Elecsys BRAHMS PCT CalCheck 5 is also not changed as a result of the change. See K160729 for additional information.
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6. CONCLUSIONS
The information provided in this 510(k) Premarket Notification will support a determination of substantial equivalence for the Elecsys BRAHMS PCT test system. The data supports a safe, effective device which performs as well as or better than the predicate device.