(91 days)
No
The device description and performance studies focus on a standard immunoassay technology and statistical analysis of results, with no mention of AI or ML algorithms.
No.
The device is an in vitro diagnostic (IVD) assay designed for quantitative determination of procalcitonin (PCT) levels, intended to aid in risk assessment and decision-making regarding antibiotic therapy. It does not directly treat or prevent a disease, which is characteristic of a therapeutic device.
Yes
Explanation: The "Intended Use / Indications for Use" section explicitly states that the assay "is for in vitro diagnostic use." It also describes its use "as an aid in" risk assessment and decision-making for antibiotic therapy, which are diagnostic purposes.
No
The device is an in vitro diagnostic assay that uses chemical reagents and an analyzer (Atellica IM Analyzer) to measure procalcitonin levels in biological samples. This involves physical components and chemical reactions, not solely software.
Yes, this device is an IVD (In Vitro Diagnostic).
The "Intended Use / Indications for Use" section explicitly states: "The Atellica® IM BRAHMS Procalcitonin (PCT) assay is for in vitro diagnostic use in the quantitative determination of procalcitonin in human serum and plasma..."
This statement directly identifies the device as being intended for in vitro diagnostic purposes.
N/A
Intended Use / Indications for Use
The Atellica® IM BRAHMS Procalcitonin (PCT) assay is for in vitro diagnostic use in the quantitative determination of procalcitonin in human serum and plasma (EDTA, lithium heparin, and sodium heparin) using the Atellica® IM Analyzer.
The Atellica IM BRAHMS PCT assay is intended for use, in conjunction with other laboratory findings and clinical assessments, as an aid in:
· The risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
• Assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using percent change in PCT level over time.
· Decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) – defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.
- · Decision-making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
Product codes (comma separated list FDA assigned to the subject device)
PRI, PMT, PTF
Device Description
The Atellica IM BRAHMS PCT assay is comprised of the following reagents:
| Component | Volume | Ingredients |
|---|---|---|
| Atellica IM BRAHMS PCT Primary Reagent ReadyPack (assay kit) | ||
| PCT Lite Reagent | 5.0 mL/pack | Mouse monoclonal anti-PCT antibody (~0.5 μg/mL) labeled with acridinium ester in protein buffer; bovine serum albumin; surfactant; preservatives |
| PCT Solid Phase Reagent | 10.0 mL/pack | Mouse monoclonal anti-fluorescein antibody coated paramagnetic particles (~0.15 mg/mL) in buffer; surfactant; preservatives |
| PCT Ancillary Reagent | 4.5 mL/pack | Mouse monoclonal anti-PCT antibody (~13.3 μg/mL) labeled with fluorescein in protein buffer; bovine serum albumin; surfactant; preservatives |
| PCT Calibrator (Kitted-included in assay kit) | ||
| PCT Low and High Calibrators | 2.0 mL/vial | Lyophilized; after reconstitution, recombinant PCT; equine serum; preservatives |
| Atellica IM BRAHMS PCT Quality Control (sold separately) | ||
| PCT Low and High Quality Controls | 2.0 mL/vial | Lyophilized; after reconstitution recombinant PCT; equine serum; preservatives |
| Atellica IM BRAHMS PCT Master Curve Material (sold separately) | ||
| PCT MCM1-5 | 1.0 mL/vial | Lyophilized; after reconstitution, various levels of recombinant PCT; equine serum; preservatives |
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 18 years of age, pregnant women, immunocompromised individuals, or those on immunomodulatory agents, was not formally analyzed in the supportive clinical trials.
The analysis population (598 subjects) comprised 44% female and 56% male patients with a mean age of 64 years.
Intended User / Care Setting
ICU, emergency department or other medical wards, inpatient setting.
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
Clinical Studies: The Atellica IM BRAHMS PCT clinical performance study was conducted with banked specimens that were collected from subjects(>18 years of age) diagnosed with severe sepsis or septic shock, admitted to the ICU and included as part of the intention-todiagnose population from the BRAHMS MOSES study (DEN150009). The analysis population (598 subjects) comprised 44% female and 56% male patients with a mean age of 64 years. About half of the patients had severe sepsis (51%) vs. septic shock (49%). Infections were mainly community-acquired (91%).
Method Comparison with Predicate Device: A total of 623 native human serum samples with assigned BRAHMS Kryptor does values (0-1000 ng/mL) were tested with the Atellica IM BRAHMS PCT assay. Samples > 50.00 ng/mL were auto-diluted (1:20) by the Atellica IM Analyzer.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Precision:
A single site study was conducted with a panel of five (5) contrived human serum samples, calibrators, and controls were tested. Each sample was assayed in two (2) replicates per run, with two (2) runs per day separated by at least 2 hours, for 20 days yielding a total of 40 runs, and 80 replicates per sample. The %Total Error was calculated as 1.65*(%CV) + (%Bias).
| Sample | No. of replicates | Mean (ng/mL) | Repeatability (Within-Run) SD | Repeatability (Within-Run) %CV | Within-Lab (Total Precision) SD | Within-Lab (Total Precision) %CV |
|---|---|---|---|---|---|---|
| Serum 1 | 80 | 0.05 | 0.00 | 9.7 | 0.01 | 12.1 |
| Serum 2 | 80 | 0.27 | 0.00 | 1.8 | 0.01 | 2.8 |
| Serum 3 | 80 | 0.75 | 0.01 | 1.2 | 0.02 | 2.1 |
| Serum 4 | 80 | 1.52 | 0.02 | 1.4 | 0.04 | 2.6 |
| Serum 5 | 80 | 19.14 | 0.29 | 1.5 | 0.43 | 2.2 |
| Control 1 | 80 | 0.23 | 0.01 | 3.4 | 0.01 | 5.6 |
| Control 2 | 80 | 7.85 | 0.11 | 1.4 | 0.60 | 7.7 |
| PCT Level (ng/mL) | Bias (%) | CV (%) | Total Error (%) |
|---|---|---|---|
| 0.10 | 22% | 6.1 | 32% |
| 0.25 | 6% | 2.6 | 11% |
| 0.5 | 2% | 1.4 | 4% |
| 2.0 | -1% | 0.4 | 1% |
Linearity/Assay Measuring Range: Linearity was confirmed in the range of 0.03 – 63.24 ng/mL. The measuring range claim for the Atellica IM BRAHMS PCT assay is 0.04 – 50.00 ng/mL. For PCT concentrations greater than 50.00 ng/mL, the measurement range can be extended up to 1000 ng/mL by 1:20 dilution of the sample.
Dilution Recovery: Recoveries ranged from 96% to 102% with a mean of 99% for manual dilution, and from 92% to 107% for auto-dilution.
Hook Effect: Patient samples with procalcitonin concentrations as high as 2000 ng/mL will report > 50.00 ng/mL.
Detection Limits: The LoB of the Atellica IM BRAHMS PCT assay is 0.00 ng/mL. The LoD for the Atellica IM BRAHMS PCT assay is 0.03 ng/mL. The LoQ of the Atellica IM BRAHMS PCT assay is 0.04 ng/mL.
Interference: No interference observed from Bilirubin (Conjugated and Unconjugated), Cholesterol, Hemoglobin, Triglycerides, Fluorescein, Human Immunoglobulin, Total Protein, HAMA, RF, and all tested therapeutic drugs.
Cross Reactivity: No interference observed from Calcitonin-human, Calcitonin salmon, Calcitonin eel, α-CGRP, β-CGRP, Katacalcin, Cefotaxim, Dobutamine, Dopamine, Furosemide, Heparin, Imipenem, Noradrenaline, and Vancomycin at indicated concentrations.
Method Comparison with Predicate Device: N=623 native human serum samples (522 samples in range 0.06-49.20 ng/mL).
- Weighted Deming Regression for N=522: Slope 1.02 (95% CI 0.99 to 1.05), Intercept -0.02 (95% CI -0.03 to -0.01), Correlation coefficient (r) 0.98.
- Passing & Bablok Regression for N=522: Slope 1.06 (95% CI 1.04 to 1.09), Intercept -0.04 (95% CI -0.06 to -0.03), Correlation coefficient (r) 0.98.
Matrix Comparison: N=51 matched specimen sets (Serum, EDTA plasma, Lithium Heparin Plasma, Sodium Heparin Plasma). Regression analysis demonstrated no significant matrix effect.
- Serum vs. EDTA: y = 1.04x + 0.03 ng/mL, r = 1.00
- Serum vs. Li Heparin: y = 1.05x + 0.02 ng/mL, r = 1.00
- Serum vs. Na Heparin: y = 1.03x + 0.02 ng/mL, r = 1.00
Expected Values/ Reference Interval: 99th percentile PCT value was 80%): HR 1.82 (1.14-2.89), p-value 0.012
- ΔPCT4.1 (≤ 80% vs. > 80%): HR 1.72 (1.08-2.75), p-value 0.023
- APACHE (Difference of 5 Units): HR 1.36 (1.22-1.53), p-value 2.0 ng/mL vs. ≤ 2.0 ng/mL): HR 1.62 (1.04-2.50), p-value 0.031
- Age (Difference of 5 Years): HR 1.16 (1.08-1.24), p-value 80%):**
- ICU Day 4 (ΔPCT4.0): Sensitivity 75.8% (65.7-85.9%), Specificity 33.8% (26.9-40.7%)
- ICU Day 4 (ΔPCT4.1): Sensitivity 77.3% (67.1-87.5%), Specificity 36.1% (29.1-43.1%)
- Non-ICU Day 4 (ΔPCT4.0): Sensitivity 73.7% (57.1-90.3%), Specificity 41.3% (35.5-47.2%)
- Non-ICU Day 4 (ΔPCT4.1): Sensitivity 67.9% (50.6-85.2%), Specificity 38.5% (32.7-44.3%)
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.
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, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
July 16, 2018
Siemens Healthcare Diagnostics Inc. Fatima Pacheco Regulatory Affairs Clinical Specialist 511 Benedict Ave Tarrytown, New York 10591-5097
Re: K181002
Trade/Device Name: Atellica IM BRAHMS Procalcitonin (PCT) Regulation Number: 21 CFR 866.3215 Regulation Name: Device to detect and measure non-microial analytes in human clinical specimens to aid in assessment of patients with suspected sepsis. Regulatory Class: Class II Product Code: PRI, PMT, PTF Dated: April 13, 2018 Received: April 16, 2018
Dear Fatima Pacheco:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR
1
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) K181002
Device Name
Atellica IM B.R.A.H.M.S Procalcitonin (PCT)
Indications for Use (Describe)
The Atellica® IM BRAHMS Procalcitonin (PCT) assay is for in the quantitative determination of procalcitonin in human serum and plasma (EDTA, lithium heparin) using the Atellica® IM Analyzer. The Atellica IM BRAHMS PCT assay is intended for use, in conjunction with other laboratory findings and clinical assessments, as an aid in:
· The risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
• Assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using percent change in PCT level over time.
· Decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive
pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.
· Decision-making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
Type of Use (Select one or both, as applicable)
| X Prescription Use (Part 21 CFR 801 Subpart D) | Over-The-Counter Use (21 CFR 801 Subpart C) |
|---|---|
| ------------------------------------------------------------------------------------------------ | --------------------------------------------- |
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3
510K SUMMARY
Atellica® IM B.R.A.H.M.S Procalcitonin (PCT)
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
1. 510(k) Number: K181002
2. Purpose for Submission:
To obtain a substantial equivalence determination for the Atellica® IM B.R.A.H.M.S Procalcitonin (PCT) assay.
3. Applicant:
Contact: Fatima Pacheco Regulatory Clinical Affairs Specialist Address: Siemens Healthcare Diagnostics Inc. 511 Benedict Ave. Tarrytown, NY 10591 Phone: (914) 374-3770
Email: fatima.pacheco@siemens-healthineers.com
Date: June 04, 2018
4. Proprietary and Established Names: Atellica® IM B.R.A.H.M.S Procalcitonin (PCT)
-
- Measurand
Procalcitonin
- Measurand
6. Regulatory Information:
Regulatory Information for Atellica® IM B.R.A.H.M.S Procalcitonin (PCT)
| Trade Name | Atellica® IM B.R.A.H.M.S Procalcitonin (PCT) |
|---|---|
| Common Name | Immunoassay, Procalcitonin |
| Classification Name | Device to detect and measure non-microbial |
| analyte(s) in human clinical specimens to aid in | |
| assessment of patients with suspected sepsis. | |
| FDA Classification | Class II |
| Review Panel | Microbiology (83) |
| Product Code | PMT |
| Regulation Number | 21 CFR 866.3215 |
4
Regulatory Information for Atellica® IM B.R.A.H.M.S Procalcitonin Calibrator (Included in assay kit)
| Trade Name | Atellica® IM B.R.A.H.M.S Procalcitonin Calibrator |
|---|---|
| Common Name | Single (specified) analyte calibrators (assayed and |
| unassayed) | |
| Classification Name | Calibrator (assayed and unassayed) |
| FDA Classification | Class II (Exempt) |
| Review Panel | Clinical Chemistry (75) |
| Product Code | JIT |
| Regulation Number | 21 CFR 862.1150 |
Regulatory Information for Atellica® IM B.R.A.H.M.S Procalcitonin QC & MCM (Sold Separately)
| Trade Name | Atellica® IM B.R.A.H.M.S Procalcitonin Quality
Control (QC)
Atellica® IM B.R.A.H.M.S Procalcitonin Master Curve
Material (QC) |
|---------------------|----------------------------------------------------------------------------------------------------------------------------------------|
| Common Name | Single (specified) analyte calibrators (assayed and
unassayed) |
| Classification Name | Calibrator (assayed and unassayed) |
| FDA Classification | Class II (Exempt) |
| Review Panel | Clinical Chemistry (75) |
| Product Code | JIT |
| Regulation Number | 21 CFR 862.1150 |
7. Predicate Devices:
Device Name: B.R.A.H.M.S PCT sensitive KRYPTOR 510(k) Number: DEN150009; K171338 Manufacturer: B.R.A.H.M.S GmbH (Thermo Fisher Scientific)
8. Intended Use:
Same as Indications for Use
9. Indications for Use:
The Atellica® IM BRAHMS Procalcitonin (PCT) assay is for in vitro diagnostic use in the quantitative determination of procalcitonin in human serum and plasma (EDTA, lithium heparin, and sodium heparin) using the Atellica® IM Analyzer.
The Atellica IM BRAHMS PCT assay is intended for use, in conjunction with other laboratory findings and clinical assessments, as an aid in:
· The risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
5
• Assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using percent change in PCT level over time.
· Decision-making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) – defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department.
- · Decision-making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
10. Special Conditions for use statement(s):
For Prescription Use Only
11. Warnings and Precautions for Test Interpretation:
The Atellica® IM BRAHMS Procalcitonin (PCT) assay is not indicated to be used as a stand-alone diagnostic assay and should be used in conjunction with clinical signs and symptoms of infection and other diagnostic evidence.
Decisions regarding antibiotic therapy should NOT be based solely on PCT concentrations.
PCT results should always be interpreted in the context of the clinical status of the patient and other laboratory results. Changes in PCT levels for the prediction of mortality, and overall mortality, are strongly dependent on many factors, including pre-existing patient risk factors and clinical course.
The need to continue ICU care at Day 4 and other covariates, such as age and Sequential Organ Failure Assessment (SOFA) score, are also significant predictors of 28-day cumulative mortality risk.
PCT levels may not be elevated in patients infected by certain atypical pathogens, such as Chlamydophila pneumoniae and Mycoplasma pneumoniae.
Certain patient characteristics, such as severity of renal failure or insufficiency, may influence PCT values and should be considered as potentially confounding clinical factors when interpreting PCT values.
The safety and performance of PCT-quided therapy for individuals younger than 18 years of age, pregnant women, immunocompromised individuals, or those on immunomodulatory agents, was not formally analyzed in the supportive clinical trials.
Increased PCT levels may not always be related to systemic infection. These conditions include, but are not limited to:
- · Patients experiencing major trauma and/or recent surgical procedure, including extracorporeal circulation or burns:
- · Patients under treatment with OKT3 antibodies, OK-432, interleukins, TNF-alpha, and other drugs stimulating the release of pro-inflammatory cytokines or resulting in anaphylaxis:
- · Patients diagnosed with active medullary C-cell carcinoma, small cell lunq carcinoma, or bronchial carcinoid:
6
- · Patients with acute or chronic viral hepatitis and/or decompensated severe liver cirrhosis (Child-Pugh Class C);
- Patients with prolonged or severe cardiogenic shock, prolonged severe organ perfusion anomalies, or after resuscitation from cardiac arrest;
- · Patients receiving peritoneal dialysis or hemodialysis treatment;
- · Patients with biliary pancreatitis, chemical pneumonitis, or heat stroke;
- · Patients with invasive fungal infections (such as candidiasis and aspergillosis) or acute attacks of plasmodium falciparum malaria; and
- Neonates during the first 2 days of life.
12. Special Instrument Requirement:
For use on the Atellica® IM Analyzer
13. Device Description:
The Atellica IM BRAHMS PCT assay is comprised of the following reagents:
| Component | Volume | Ingredients |
|---|---|---|
| Atellica IM BRAHMS PCT Primary Reagent ReadyPack (assay kit) | ||
| PCT Lite Reagent | 5.0 mL/pack | Mouse monoclonal anti-PCT antibody (~0.5 μg/mL) labeled with acridinium ester in protein buffer; bovine serum albumin; surfactant; preservatives |
| PCT Solid Phase Reagent | 10.0 mL/pack | Mouse monoclonal anti-fluorescein antibody coated paramagnetic particles (~0.15 mg/mL) in buffer; surfactant; preservatives |
| PCT Ancillary Reagent | 4.5 mL/pack | Mouse monoclonal anti-PCT antibody (~13.3 μg/mL) labeled with fluorescein in protein buffer; bovine serum albumin; surfactant; preservatives |
| PCT Calibrator (Kitted-included in assay kit) | ||
| PCT Low and High Calibrators | 2.0 mL/vial | Lyophilized; after reconstitution, recombinant PCT; equine serum; preservatives |
| Atellica IM BRAHMS PCT Quality Control (sold separately) | ||
| PCT Low and High Quality Controls | 2.0 mL/vial | Lyophilized; after reconstitution recombinant PCT; equine serum; preservatives |
| Atellica IM BRAHMS PCT Master Curve Material (sold separately) | ||
| PCT MCM1-5 | 1.0 mL/vial | Lyophilized; after reconstitution, various levels of recombinant PCT; equine serum; preservatives |
7
14. Substantial Equivalence Information
The following table describes the similarities and differences between the Atellica IM BRAHMS PCT (Candidate Device) and the B.R.A.H.M.S PCT sensitive KRYPTOR® (Predicate Device).
| Trade Name | Candidate Device | Predicate Device |
|---|---|---|
| Atellica® IM B.R.A.H.M.S | ||
| Procalcitonin (PCT) | B.R.A.H.M.S PCT sensitive | |
| KRYPTOR® | ||
| Intended Use | The Atellica® IM BRAHMS | |
| Procalcitonin (PCT) assay is for | ||
| in vitro diagnostic use in the | ||
| quantitative determination of | ||
| procalcitonin in human serum | ||
| and plasma (EDTA, lithium | ||
| heparin, and sodium heparin) | ||
| using the Atellica® IM Analyzer. |
The Atellica IM BRAHMS
PCT is intended for use, in
conjunction with other
laboratory findings and clinical
assessments as an aid in:
The risk assessment of
critically ill patients on their
first day of intensive care unit
(ICU) admission for
progression to severe sepsis
and septic shock.
Assessing the cumulative 28-
day risk of all-cause mortality
for patients diagnosed with
severe sepsis or septic shock
in the ICU or when obtained
in the emergency department
or other medical wards prior
to ICU admission, using
percent change in PCT level
over time.
Decision making on antibiotic
therapy for patients with
suspected or confirmed lower
respiratory tract infections
(LRTI) - defined as
community-acquired
pneumonia (CAP), acute
bronchitis, and acute
exacerbation of chronic
obstructive pulmonary
disease (AECOPD) – in an
inpatient setting or an | 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 |
| | emergency department.
Decision making on antibiotic
discontinuation for patients with
suspected or confirmed sepsis. | exacerbation of chronic
obstructive pulmonary disease
(AECOPD),
to aid in decision making on
antibiotic discontinuation for
patients with suspected or
confirmed sepsis. |
| Analyte | Procalcitonin (PCT) | Same |
| Automated | Automated assay | Same |
| Measurement | Quantitative | Same |
| Sample Type | Human Serum, Plasma (EDTA,
Lithium, Heparin, Sodium
Heparin) | Human Serum, Plasma ( EDTA
and Heparin) |
| Assay Measuring
Interval | 0.04 - 50.00 ng/mL | 0.02 - 50 µg/L |
| Operating Principle | Sandwich | Sandwich |
| Technology | Direct Chemiluminescent
technology | Immunofluorescence TRACE®
technology |
| Instrument | Atellica IM Analyzer | KRYPTOR® Test System |
| Sample Volume | 100 µL | 50 µL |
| Calibrators | Atellica IM B.R.A.H.M.S PCT
Calibrators (lyophilized)
2 levels (Low and High); After
reconstitution, recombinant PCT;
equine serum; preservatives | B.R.A.H.M.S PCT sensitive
KRYPTOR® Calibrator:
1 vial of lyophilized
recombinant PCT in
defibrinated human plasma
(range 22.50-27.50µg/L) |
| Controls | Atellica IM B.R.A.H.M.S PCT
Quality Control (lyophilized)
2 levels (Low and High); After
reconstitution, recombinant PCT;
equine serum; preservatives | B.R.A.H.M.S PCT sensitive
KRYPTOR® QC Kit:
6 vials (3 of each control):
Control 1 (0.20-0.40µg/L)
Control 2 (8.00-12.00µg/L) |
8
9
Standard/Guidance Document Referenced 15.
The following recognized standards from Clinical Laboratory Standards Institute (CLSI) were used as a basis of the study procedures described in this submission:
- 트 Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline -Third Edition (CLSI EP05-A3, 2014; Recognition Number 7-251)
- Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical . Approach; Approved Guideline (CLSI EP06-A, 2003; Recognition Number 7-193)
- . Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition (CLSI EP07-A2, 2005; Recognition Number 7-127)
- . Measurement Procedure Comparison And Bias Estimation Using Patient Samples --Third Edition (CLSI EP09-A3, 2013; Recognition Number 7-245)
- . Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline -- Second Edition (CLSI EP17-A2, 2012; Recognition Number 7-233)
- Defining, Establishing and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition (CLSI EP28-A3c - formerly C28-A3c, 2010; Recognition Number 7-224)
- . Medical devices – Application of risk manaqement to medical devices (ANSI/AAMI/ISO 14971:2007/(R)2010; Recognition Number 5-70)
16. Test Principle
The Atellica IM BRAHMS PCT assay is a 2-site sandwich immunoassay using direct chemiluminescent technology that uses 3 mouse monoclonal antibodies specific for PCT. The first antibody, in the Lite Reagent, is a mouse monoclonal anti-PCT antibody labeled with acridinium ester. The second and third antibodies, in the ancillary reagent, are mouse monoclonal anti-PCT antibodies labeled with fluorescein. The immunocomplex formed with PCT is captured with mouse monoclonal anti-fluorescein antibody coupled to paramagnetic particles in the Solid Phase.
A direct relationship exists between the amount of PCT present in the patient sample and the amount of relative light units (RLUs) detected by the system.
10
17. Performance Characteristics
1. Analytical Performance
A. Precision
The precision of the Atellica IM B.R.A.H.M.S PCT assay precision study was performed in accordance with CLSI EP05-A3 - Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline—Third Edition. Wayne, PA: Clinical and Laboratory Standards Institute; 2014.
A single site study was conducted with a panel of five (5) contrived human serum samples, calibrators, and controls were tested. The panel of human samples was prepared by spiking normal serum samples with recombinant PCT spiking material. Samples were frozen in aliquots prior to the study. Each sample was assayed in two (2) replicates per run, with two (2) runs per day separated by at least 2 hours, for 20 days yielding a total of 40 runs, and 80 replicates per sample. For each analyte concentration level, the mean value with variance components (standard deviation and %CV) was determined. The following results were obtained:
| Sample | No. of
replicates | Mean
(ng/mL) | Repeatability
(Within-Run) | | Within-Lab
(Total Precision) | |
|-----------|----------------------|-----------------|-------------------------------|-----|---------------------------------|------|
| | | | SD | %CV | SD | %CV |
| Serum 1 | 80 | 0.05 | 0.00 | 9.7 | 0.01 | 12.1 |
| Serum 2 | 80 | 0.27 | 0.00 | 1.8 | 0.01 | 2.8 |
| Serum 3 | 80 | 0.75 | 0.01 | 1.2 | 0.02 | 2.1 |
| Serum 4 | 80 | 1.52 | 0.02 | 1.4 | 0.04 | 2.6 |
| Serum 5 | 80 | 19.14 | 0.29 | 1.5 | 0.43 | 2.2 |
| Control 1 | 80 | 0.23 | 0.01 | 3.4 | 0.01 | 5.6 |
| Control 2 | 80 | 7.85 | 0.11 | 1.4 | 0.60 | 7.7 |
A modeling analysis was conducted to estimate the %Bias, %CV, and % Total Error at each medical decision point. %Bias was calculated relative to reference values derived using the slope and the intercept derived experimentally from the method comparison study between Atellica IM BRAHMS PCT and BRAHMS sensitive KRYPTOR. The %CV measurement was derived using the precision profile: the %Total Error was calculated as 1.65*(%CV) + (%Bias). The results from each of three regressions (%Bias, %CV, and %TE) are summarized in the table below.
| PCT Level
(ng/mL) | Bias
(%) | CV
(%) | Total Error
(%) |
|----------------------|-------------|-----------|--------------------|
| 0.10 | 22% | 6.1 | 32% |
| 0.25 | 6% | 2.6 | 11% |
| 0.5 | 2% | 1.4 | 4% |
| 2.0 | -1% | 0.4 | 1% |
11
B. Linearity/Assay Measuring Range
Linearity of the Atellica IM B.R.A.H.M.S PCT assay was performed according to CLSI EP06-A - Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach: Approved Guideline. The study was performed using 9 samples spanning the assay range, prepared using high and low human serum pools. Testing was performed on one (1) Atellica IM Analyzer with 2 PCT reagent lots, 3 replicates per level. The mean dose value of each sample was used in data analysis. The results were analyzed by % Deviation from Linear Fit.
Regression analysis using the first, second, and third order models were conducted to assess the linearity of the assay. Regression statistics (i.e., deviation from linearity for non-linear pools) at all levels tested demonstrated a ≤10% deviation from linear fit.
Linearity was confirmed in the range of 0.03 – 63.24 ng/mL. The measuring range claim for the Atellica IM BRAHMS PCT assay is 0.04 – 50.00 ng/mL. For PCT concentrations greater than 50.00 ng/mL, the measurement range can be extended up to 1000 ng/mL by 1:20 dilution of the sample.
C. Dilution Recovery
To evaluate the degree of bias introduced when the instrument auto-dilution is used on samples within the assay measuring range or above.
Five (5) human serum samples spiked with recombinant PCT stock. The samples were diluted to 1:20 with Atellica IM Multi-Diluent 1 both manually and automatically onboard the system. Recoveries ranged from 96% to 102% with a mean of 99%.
The samples were diluted (1:20) with Atellica IM Multi-Diluent 1 using the auto-dilution protocol. Recoveries ranged from 92% to 107%.
D. Hook Effect
A study was performed to evaluate the hook effect. In this assay, patient samples with procalcitonin concentrations as high as 2000 ng/mL will report > 50.00 ng/mL.
E. Detection Limits
Detection capability was determined in accordance with CLSI Document EP17-A2. The assay is designed to have a limit of blank (LoB) 50.00 ng/mL were auto-diluted (1:20) by the Atellica IM Analyzer.
Two separate data analysis for this was performed, one with analysis of all samples with BRAHMS PCT sensitive KRYPTOR assay with sample range 0.06-49.20 ng/mL (N=522) and one with an extended analysis including all samples tested (N=623). Weighted Deming and Passing & Bablok regression analyses including slope and intercept with 95% Cl were calculated for N=522 samples. Regression analysis comparing the Atellica IM BRAHMS PCT assay results to the predicate assay results are summarized in table below and illustrated in Figures below.
| Parameter | Weighted Deming
Regression | Passing & Bablok
Regression |
|-------------------------------|-------------------------------|--------------------------------|
| N | 522 | 522 |
| Slope | 1.02 | 1.06 |
| 95% CI two sided | 0.99 to 1.05 | 1.04 to 1.09 |
| Intercept | -0.02 | -0.04 |
| 95% Cl two sided | -0.03 to -0.01 | -0.06 to -0.03 |
| Correlation coefficient ( r ) | 0.98 | 0.98 |
| Sample Range (ng/mL) | 0.06-49.20 | 0.06-49.20 |
15
Image /page/15/Figure/0 description: The image is a scatter plot comparing two sets of data, labeled as 'Rep 1 of atellica im' on the y-axis and 'Rep 1 of brahms kryptor' on the x-axis, both ranging from 0 to 60. The plot includes individual data points represented by triangles, along with two trend lines: an 'Identity Line' shown as a dashed line and a 'Weighted Deming Fit' shown as a solid line. The data points generally cluster around the trend lines, indicating a positive correlation between the two sets of data.
Figure 1: Weighted Deming Regression Analysis Atellica IM BRAHMS PCT vs. Predicate
Figure 2: Passing & Bablock Regression Analysis Atellica IM BRAHMS PCT vs. Predicate
Image /page/15/Figure/3 description: The image is a scatter plot comparing "Rep 1 of atellica im" on the y-axis and "Rep 1 of brahms kryptor" on the x-axis. The plot includes data points represented by triangles, along with two lines: an "Identity Line" and a "Passing & Bablok Fit" line. The data points are clustered along the lines, indicating a positive correlation between the two variables. The axes range from 0 to 60.
16
Data was further analyzed for concordance at the 0.1, 0.25, 0.5, and 2.0 ng/mL clinical cutoffs. From the total N=623 samples tested, the percent agreement between the Atellica IM BRAHMS PCT and the predicate BRAHMS sensitive KRYPTOR PCT at the cutoffs obtained are presented in Tables below.
| Atellica IM BRAHMS PCT | BRAHMS sensitive KRYPTOR | Total | |
|---|---|---|---|
| > 0.1 ng/mL | ≤ 0.1 ng/mL | ||
| > 0.1 ng/mL | 539 | 4 | 543 |
| ≤ 0.1 ng/mL | 4 | 76 | 80 |
| Total | 543 | 80 | 623 |
Atellica IM BRAHMS PCT vs Predicate at 0.1 ng/mL cutoff
Positive percent agreement (PPA) = 539/543 (99.3%); 95% two sided Cl 98.1%-99.7% Negative percent agreement (NPA) = 76/80 (95.0%); 95% two sided Cl 87.8%-98.0% Overall percent agreement = 98.7%; 95% Confidence Interval: 97.5%-99.4%
Atellica IM BRAHMS PCT vs Predicate at 0.25 ng/mL cutoff
| BRAHMS sensitive KRYPTOR | |||
|---|---|---|---|
| Atellica IM BRAHMS PCT | > 0.25 ng/mL | ≤ 0.25 ng/mL | Total |
| > 0.25 ng/mL | 488 | 7 | 495 |
| ≤ 0.25 ng/mL | 5 | 123 | 128 |
| Total | 493 | 130 | 623 |
Positive percent agreement (PPA) = 488/493 (99.0%); 95% two sided Cl 97.7%-99.6% Negative percent agreement (NPA) = 123/130 (94.6%); 95% two sided Cl 89.3%-97.4% Overall percent agreement = 98.1%; 95% Confidence Interval: 96.7%-98.9%
Atellica IM BRAHMS PCT vs Predicate at 0.50 ng/mL cutoff
| Atellica IM BRAHMS PCT | BRAHMS sensitive KRYPTOR | Total | |
|---|---|---|---|
| > 0.50 ng/mL | ≤ 0.50 ng/mL | ||
| > 0.50 ng/mL | 414 | 5 | 419 |
| ≤ 0.50 ng/mL | 14 | 190 | 204 |
| Total | 428 | 195 | 623 |
Positive percent agreement (PPA) = 414/428 (96.7%); 95% two sided Cl% 94.6-98.0% Negative percent agreement (NPA) =190/195 (97.4%); 95% two sided Cl 94.1%-98.8% Overall percent agreement = 97.0%; 95% Confidence Interval: 95.3%-98.0%
Atellica IM BRAHMS PCT vs Predicate at 2.0 ng/mL cutoff
| Atellica IM BRAHMS PCT | BRAHMS sensitive KRYPTOR | Total | |
|---|---|---|---|
| > 2.0 ng/mL | ≤ 2.0 ng/mL | ||
| > 2.0 ng/mL | 279 | 8 | 287 |
| ≤ 2.0 ng/mL | 8 | 328 | 336 |
| Total | 287 | 336 | 623 |
Positive percent agreement (PPA) =279/287 (97.2%); 95% two sided Cl 94.6%-98.6% Negative percent agreement (NPA) = 328/336 (97.6%); 95% two sided Cl 95.4%-98.8% Overall percent agreement = 97.4%: 95% Confidence Interval: 95.9%-98.4%
17
| Atellica IM
BRAHMS PCT
| (ng/mL) | ≤ 0.10 | > 0.10 - ≤ 0.25 | > 0.25 - ≤ 0.50 | > 0.50 - ≤ 2.0 | > 2.0 | Total |
|---|---|---|---|---|---|---|
| ≤ 0.10 | 76 | 4 | 0 | 0 | 0 | 80 |
| > 0.10 - ≤ 0.25 | 4 | 39 | 7 | 0 | 0 | 50 |
| > 0.25 - ≤ 0.50 | 0 | 5 | 55 | 5 | 0 | 65 |
| > 0.50 - ≤ 2.0 | 0 | 0 | 14 | 119 | 8 | 141 |
| > 2.0 | 0 | 0 | 0 | 8 | 279 | 287 |
| Total | 80 | 48 | 76 | 132 | 287 | 623 |
Cross Tabulation of all Samples (n=623) Atellica IM BRAHMS PCT vs Predicate
K. Matrix Comparison
Specimen equivalency was determined using the Passing-Bablok regression model in accordance with CLSI Document EP09-A3. Fifty-one (51) matched specimen sets in 4 tube types (Serum, EDTA plasma, Lithium Heparin Plasma, Sodium Heparin Plasma) were obtained from a vendor and spiked with equal amounts of recombinant PCT stock. Each sample as tested in singlicate per sample matrix and compared to the serum tube. Regression analysis demonstrated that no significant matrix effect between Serum, EDTA plasma, Lithium Heparin Plasma, Sodium Heparin Plasma tubes. The following results were obtained.
| Specimen
Type
(x) | Comparison
Sample Type
(y) | N | Sample Range
(ng/mL) | Regression Equation | Correlation
Coefficient |
|-------------------------|----------------------------------|----|-------------------------|------------------------|----------------------------|
| Serum | EDTA | 51 | 0.05—44.72 | y = 1.04x + 0.03 ng/mL | 1.00 |
| Serum | Li Heparin | 51 | 0.05—44.72 | y = 1.05x + 0.02 ng/mL | 1.00 |
| Serum | Na Heparin | 51 | 0.05—44.72 | y = 1.03x + 0.02 ng/mL | 1.00 |
L. Expected Values/ Reference Interval
To establish the reference interval of a normal population, one-hundred and forty-four (144) serum samples from normal subjects were tested using the Atellica IM BRAHMS PCT assay on the Atellica IM Analyzer according to the CLSI Guideline EP28-A3c. In a population of N=144 self-reported healthy subjects, the PCT value corresponding to the 99t0 percentile was 18 years of age) diagnosed with severe sepsis or septic shock, admitted to the ICU and included as part of the intention-todiagnose population from the BRAHMS MOSES study (DEN150009).
Cumulative 28-day mortality in patients with Severe Sepsis and Septic Shock a. · APCT ≤ 80%
A decrease in the PCT levels below or equal to 80% defines a positive ΔPCT test result representing a higher risk for 28-day all-cause mortality of patients diagnosed with severe sepsis or septic shock.
ΔΡCT > 80% .
A decrease in the PCT levels of more than 80% defines a negative ΔPCT test result representing a lower risk for 28-day all-cause mortality of patients diagnosed with severe sepsis or septic shock.
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.
b. Risk Assessment for progression to Severe Sepsis and Septic Shock
- PCT > 2.0 ng/mL: A PCT level above 2.0 ng/mL on the first day of ICU . admission is associated with a high risk for progression to severe sepsis and/or septic shock.
- . PCT 80% or ≤ 80%) was significantly associated with 28-day cumulative mortality (vital status on day 28) (Two-sided Fisher's Exact Test p-value = 0.009). Adjusted for ICU vs. non-ICU patient subgroups (based on hospital location at Day 4 after initial diagnosis), the association remained significant (Cochran-Mantel-Haenszel Test p-value = 0.044). In each binary ΔPCT subgroup, the 28-day cumulative mortality rate was stratified by need to continue ICU care on Day 4 and/or the selection of Day 0 vs. Day 1 as the baseline measurement day for the ΔΡCT calculation as follows:
19
Prediction performance of binary ΔPCT stratified by ICU care on Day 4.
28-Day Mortality Risk Stratified by Patient Location on Day 4 ΔΡCT > 80% = Test Negative
| ΔPCT ≤ 80% = Test Positive | |||||
|---|---|---|---|---|---|
| 28-Day Mortality Risk | Prognostic Accuracya | ||||
| Day 4 Patient | |||||
| Location | PCT | ||||
| Interval | ΔPCT > 80% | ||||
| (95% CI)b | ΔPCT ≤ 80% | ||||
| (95% CI) | Sensitivity (%) | ||||
| (95% CI) | Specificity (%) | ||||
| (95% CI) | |||||
| ICU | ΔPCT4.0 | 21.1 | 29.9 | 75.8 | 33.8 |
| (12.2-30.0) | (23.2-36.6) | (65.7-85.9) | (26.9-40.7) | ||
| ΔPCT4.1 | 19.0 | 31.1 | 77.3 | 36.1 | |
| (10.4-27.6) | (24.2-37.9) | (67.1-87.5) | (29.1-43.1) | ||
| Non-ICU | ΔPCT4.0 | 5.7 | 10.7 | 73.7 | 41.3 |
| (1.7-9.8) | (6.4-15.0) | (57.1-90.3) | (35.5-47.2) | ||
| ΔPCT4.1 | 7.4 | 9.5 | 67.9 | 38.5 | |
| (2.7-12.0) | (5.5-13.6) | (50.6-85.2) | (32.7-44.3) |
a Prognostic accuracy refers to how accurate the ΔΡCT (≤ 80% vs. > 80%) can predict mortality risk.
b Confidence interval.
Additional stratification of patients based on absolute initial PCT levels (> or ≤ 2.0 ng/mL) at Day 0 (ΔΡCT4.0) or Day 1 (ΔΡCT4.1) revealed subgroups with particularly reduced or elevated mortality risk considering their hospital disposition on Day 4. Mortality risk and prognostic performance are given for the following subgroups in the tables below:
- Patients with PCT > 2.0 ng/mL at Day 0 (or Day 1) receiving ICU care on Day 4. 1.
- Patients with PCT ≤ 2.0 ng/mL at Day 0 (or Day 1) receiving ICU care on Day 4. 2.
- Patients with PCT > 2.0 ng/mL at Day 0 (or Day 1) without ICU care on Day 4. 3.
- Patients with PCT ≤ 2.0 ng/mL at Day 0 (or Day 1) without ICU care on Day 4. ব
28-Day Mortality Risk Stratified by Patient Location on Day 4
Absolute PCT Value on Day 0
ΔΡCT > 80% = Test Negative
ΔΡCT ≤80% = Test Positive
| Day 4 Patient
Location | PCT at Day
0 | ΔPCT > 80%
(95% CI)b | ΔPCT ≤ 80%
(95% CI) | Sensitivity (%)
(95% CI) | Specificity (%)
(95% CI) |
|---------------------------|-----------------|-------------------------|------------------------|-----------------------------|-----------------------------|
| ICU | ≤ 2.0 ng/mL | 12.8
(0.0-36.7) | 23.2
(13.9-32.5) | 94.8
(84.9-100.0) | 10.3
(2.4-18.2) |
| | > 2.0 ng/mL | 22.0
(12.5-31.6) | 35.2
(25.8-44.6) | 68.6
(55.7-81.5) | 46.9
(37.8-55.9) |
| Non-ICU | ≤ 2.0 ng/mL | 0.0
(0.0-21.8) | 8.1
(3.5-12.7) | 100.0
(71.5-100.0) | 10.5
(4.9-16.2) |
| | > 2.0 ng/mL | 6.4
(1.9-11.0) | 16.1
(6.8-25.3) | 57.6
(33.7-81.4) | 67.2
(59.5-74.9) |
ര Prognostic accuracy refers to how accurate the ΔΡCT (≤ 80% vs. > 80%) can predict mortality risk.
b Confidence interval.
20
28-Day Mortality Risk Stratified by Patient Location on Day 4
Absolute PCT Value on Day 1 ΔΡCT > 80% = Test Negative
| ΔPCT ≤ 80% = Test Positive | |||||
|---|---|---|---|---|---|
| Day 4 Patient | |||||
| Location | PCT at Day 1 | 28-Day Mortality Risk | Prognostic Accuracya | ||
| ΔPCT > 80% | |||||
| (95% CI)b | ΔPCT ≤ 80% | ||||
| (95% CI) | Sensitivity (%) | ||||
| (95% CI) | Specificity (%) | ||||
| (95% CI) | |||||
| ICU | ≤ 2.0 ng/mL | 20.2 | |||
| (0.0-57.2) | 26 | ||||
| (16.2-35.8) | 95.2 | ||||
| (86.0-100.0) | 6.9 | ||||
| (0.0-14.3) | |||||
| > 2.0 ng/mL | 19.0 | ||||
| (10.1-27.9) | 35.0 | ||||
| (25.5-44.5) | 69.8 | ||||
| (56.4-83.1) | 49.9 | ||||
| (41.1-58.6) | |||||
| Non-ICU | ≤ 2.0 ng/mL | 0.1 | |||
| (0.0-26.5) | 6.4 | ||||
| (2.3-10.4) | 99.9 | ||||
| (66.4-100.0) | 8.5 | ||||
| (3.2-13.7) | |||||
| > 2.0 ng/mL | 8.2 | ||||
| (3.1-13.3) | 16.4 | ||||
| (7.2-25.5) | 53.4 | ||||
| (31.1-75.8) | 65.7 | ||||
| (57.7-73.7) |
a Prognostic accuracy refers to how accurate the ΔΡCT (≤ 80% vs. > 80%) can predict mortality risk.
b Confidence interval.
Image /page/20/Figure/5 description: The image shows the text "Survival until Day 28, PCT >2.0 ng/mL at Day 0, ICU Day 4 (n=176)". The text describes survival until day 28 with a procalcitonin (PCT) level greater than 2.0 ng/mL. The data was collected at day 0, and the intensive care unit (ICU) stay was day 4. The sample size is 176.
Image /page/20/Figure/6 description: This image is a survival plot showing the proportion of patients surviving over a period of 28 days. The x-axis represents time in days, ranging from 0 to 28. The y-axis represents the proportion of patients surviving, ranging from 0% to 100%. Two survival curves are plotted: one for patients who tested negative (ΔPCT > 80%) and another for patients who tested positive (ΔPCT ≤ 80%). The survival rate is higher for patients who tested negative.
21
Image /page/21/Figure/0 description: This image is a survival plot showing the proportion of patients surviving over time. The x-axis represents time in days, ranging from 0 to 28. There are two survival curves, one for patients who tested negative (ΔPCT > 80%) and another for patients who tested positive (ΔPCT ≤ 80%). The survival rate is higher for patients who tested negative compared to those who tested positive.
Survival until Day 28, PCT >2.0 ng/mL at Day 0, non-ICU Day 4 (n=183)
Time (days)
Survival until Day 28, PCT ≤ 2.0 ng/mL at Day 0, ICU Day 4 (n=89)
Image /page/21/Figure/4 description: This image is a survival plot showing the proportion of patients surviving over time in days. The x-axis represents time in days, ranging from 0 to 28, and the y-axis represents the proportion of patients surviving, ranging from 0% to 100%. There are two lines on the plot, one representing patients who tested negative (ΔPCT > 80%) and the other representing patients who tested positive (ΔPCT ≤ 80%). The survival rate is higher for patients who tested negative.
22
Image /page/22/Figure/0 description: This image is a survival plot showing the proportion of patients surviving over a period of 28 days. The x-axis represents the number of days, ranging from 0 to 28. The y-axis represents the proportion of patients surviving, ranging from 0% to 100%. There are two lines on the plot, one green and one red, representing two different test groups: test negative (ΔPCT > 80%) and test positive (ΔPCT ≤ 80%).
Survival until Day 28, PCT ≤ 2.0 ng/mL at Day 0, non-ICU Day 4 (n=150)
Time (days)
Time-to-event analysis illustrated by the Kaplan-Meier curves above shows that patients in the ICU, or with an initial PCT value > 2.0 ng/mL, had a lower survival probability (higher cumulative mortality risk) from study Day 4 until the end of follow-up time (28 days) when the APCT test result was positive compared to when the APCT result was negative (patient subgroups according to hospital location on Day 4 and initial PCT level). A generally lower mortality rate was observed in the non-ICU subgroup.
The mortality ratios for ΔΡCT positive vs. ΔΡCT negative patient subgroups were:
- 1.92 for patients with PCT > 2.0 ng/mL at Day 0 receiving ICU care on Day 4 .
- . 2.11 for patients with PCT ≤ 2.0 ng/mL at Day 0 receiving ICU care on Day 4
- . 2.78 for patients with PCT > 2.0 ng/mL at Day 0 without ICU care on Day 4
- . ---* for patients with PCT ≤ 2.0 ng/mL at Day 0 without ICU care on Day 4
*Mortality ratio cannot be calculated due to 0 fatalities in the APCT negative group. Mathematically, it tends towards infinite
Based on relative mortality ratios, a decrease by more than 80% from Day 0 (or Day 1) to Day 4 constitutes a lower risk for mortality within 28 days compared to smaller declines in each subgroup. For the prediction of absolute mortality risks, ICU disposition at Day 4 and initial PCT concentrations should be considered:
. An initial PCT level ≤ 2.0 ng/mL on Day 0 followed by a PCT decline of more than 80% until Day 4 indicates an almost 2-fold lower cumulative 28-day mortality risk (12.8%) for patients with severe sepsis or septic shock who are still in the ICU by Day 4 compared to those patients with an initial PCT level > 2.0 ng/mL (22.0%). Regardless of the initial PCT level, patients in the ICU on Day 4 that do not decline by more than 80% in PCT plasma concentration from Day 0 to Day 4 have an even higher mortality risk of 23.2-35.2%.
23
. An initial PCT level > 2.0 ng/mL that does not decline by more than 80% until Day 4 signals that such patients remain at a high mortality risk (16.1%) even when they are no longer receiving ICU care on Day 4. Mortality was otherwise observed between 0.0-8.1% for patients discharged from the ICU by Day 4.
Performance of ΔPCT from Day 0 to Day 4 (≤ 80% vs. > 80%) as a prognostic for 28-day cumulative risk of mortality was quantified by Cox proportional hazards regression analysis with a hazard ratio of 1.82 (95% Cl: 1.14-2.89; p-value = 0.012). That is, the relative risk of cumulative 28-day mortality is about 1.8-fold higher if an individual tests positive for ΔΡCT (≤ 80%) than if an individual tests neqative (> 80%). As a comparison, the table below lists the univariate hazard ratios for other clinical factors evaluated as separate predictors of mortality in the study population.
| Hazard | p-Value | ||
|---|---|---|---|
| Factor | Comparison | Ratio Per-Protocol | Per-Protocol |
| ΔPCT4.0 | ≤ 80% vs. > 80% | 1.82 (1.14-2.89) | 0.012 |
| ΔPCT4.1 | ≤ 80% vs. > 80% | 1.72 (1.08-2.75) | 0.023 |
| APACHE | Difference of 5 Units | 1.36 (1.22-1.53) | 2.0 ng/mL vs. ≤ 2.0 ng/mL |
| Age | Difference of 5 Years | 1.16 (1.08-1.24) | 80%) |
| Location | |||
| (ICU vs. Non-ICU) | APACHE | ||
| (1SD = | |||
| 8.13) | max | ||
| SOFA | |||
| (1SD = | |||
| 3.98) | Age | ||
| (1SD = 16.18) | |||
| Day 0 | |||
| until | |||
| Day 4 | APACHE | 1.91 | |
| (1.09–3.35) | 2.65 | ||
| (1.65–4.24) | 1.23 | ||
| (0.98–1.55) | – | 1.59 | |
| (1.27–1.98) | |||
| max SOFA | 1.75 | ||
| (1.01–3.02) | 1.69 | ||
| (1.02–2.78) | – | 1.96 | |
| (1.53–2.52) | 1.69 | ||
| (1.35–2.10) | |||
| Day 1 | |||
| until | |||
| Day 4 | APACHE | 1.91 | |
| (1.12–3.28) | 2.64 | ||
| (1.65–4.22) | 1.27 | ||
| (1.02–1.59) | – | 1.58 | |
| (1.26–1.97) | |||
| max SOFA | 1.73 | ||
| (1.02–2.95) | 1.74 | ||
| (1.06–2.84) | – | 1.95 | |
| (1.52–2.50) | 1.67 | ||
| (1.34–2.09) |
Hazard Ratios for APCT and Selected Predictors from Multivariate Cox Regression Models
The models also included the following predictors (HR results not shown): Antibiotic Adequacy, Sepsis Severity,
Biological Infection Type, Clinical Infection Type, Positive B analysis, missing values for predictors were multiple imputed assuming they were Missing at Random (MAR) with the multiple imputations combined according to Rubin's rules.
The change of PCT over time can also be described by the ratio of PCT values from Day 4 and Day 0 (or Day 1):
PCT ratio = PCT Day 4/PCT Day 0 (or Day 1)
A decline of ΔΡCT = 80% translates into a PCT ratio of 0.2. The PCT ratio has values larger than 0.2 when the ΔΡCT decline is 30, ≤ 45 | 45 | 4 | 41 | 8.9 |
| | > 45, ≤ 55 | 74 | 8 | 66 | 10.8 |
| | > 55, ≤ 65 | 149 | 26 | 123 | 17.4 |
| | > 65, ≤ 75 | 125 | 21 | 104 | 16.8 |
26
| Variable | Class | All
Na | Dead
N | Alive
N | % Dead
% |
|------------------------------------|------------------|-----------|-----------|------------|-------------|
| Ethnicity | > 75 | 166 | 41 | 125 | 24.7 |
| Ethnicity | African-American | 202 | 32 | 170 | 15.8 |
| Ethnicity | Asian | 7 | 0 | 7 | 0.0 |
| Ethnicity | Caucasian | 362 | 64 | 298 | 17.7 |
| Ethnicity | Hispanic | 23 | 5 | 18 | 21.7 |
| Ethnicity | Other | 4 | 0 | 4 | 0.0 |
| Sepsis Classification on Admission | Septic Shock | 291 | 53 | 238 | 18.2 |
| Sepsis Classification on Admission | Severe Sepsis | 307 | 48 | 259 | 15.6 |
| Baseline PCT, ng/mL | 2.0 | 338 | 66 | 272 | 19.5 |
| Baseline PCT, ng/mL | Missing | 32 | 7 | 25 | 21.9 |
a Number of patients.
- c. Decision-making on antibiotic therapy for patients with suspected or confirmed LRTI
- PCT 0.50 ng/mL
Antibiotic therapy strongly encouraged.
- PCT 0.50 ng/mL
d. Sepsis Antibiotic Discontinuation:
- . ДРСТ > 80% Antibiotic therapy may be discontinued
- . PCT ≤ 0.50 ng/mL Antibiotic therapy may be discontinued
Two systematic literature reviews were performed to produce both study- and patientlevel meta-analyses, which are studies that combine and contrast data from multiple sources to identify patterns among study results (FDA public docket FDA-2016-N-2880).
The study-level meta-analysis used aggregate descriptive information extracted from publications, and the patient-level meta-analysis used aggregate patient-level data from
27
the raw dataset of each study. Each meta-analysis used random-effects models and calculated point estimates, differences, odds ratios (OR), interquartile ranges (IQRs), and 95% confidence intervals as appropriate. The endpoints evaluated were: proportion of subjects initiating antibiotics, duration of antibiotic therapy, exposure to antibiotics, length of hospital stay, mortality, and complications (patient-level only).
The study-level meta-analysis encompassed 11 randomized control trials (RCTs), which were published between 2004–2016, and included 4090 patients.
The patient-level meta-analysis encompassed 13 RCTs, which were published between 2004-2011 and included 3142 patients as listed below.
| Publication | Na | PCT Device |
|---|---|---|
| Bouadma, 2010 | 630 | B·R·A·H·M·S PCT sensitive KRYPTOR® |
| Briel, 2008 | 300 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Burkhardt, 2010 | 550 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Christ-Crain, 2004 | 243 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Christ-Crain, 2006 | 302 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Hochreiter, 2009 | 110 | B·R·A·H·M·S PCT LIA® |
| Kristoffersen, 2009 | 223 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Long, 2011 | 172 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Long, 2009 | 127 | B·R·A·H·M·S PCT LIA |
| Nobre, 2008 | 79 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Schroeder, 2009 | 27 | B·R·A·H·M·S PCT LIA |
| Schuetz, 2009 | 1381 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Stolz, 2007 | 226 | B·R·A·H·M·S PCT sensitive KRYPTOR |
a Number of patients.
These meta-analyses concluded that PCT-guided antibiotic therapy resulted in:
- 19.2% reduction in relative antibiotic initiation for all patients. ●
- 38% reduction in overall antibiotic exposure (that is, total days of antibiotic therapy) for inpatients.
- . 51% reduction in overall antibiotic exposure (that is, total days of antibiotic therapy) for patients who presented to the emergency department and other associated clinics, but were not admitted.
- . 2.9-day reduction in antibiotic duration [1.25-day reduction in study-level].
- 3.6-day reduction in total antibiotic exposure [2.79-day reduction in study-level].
- . No negative effects in regards to mortality, complications, or length of stay.
28
| Parameter | Standard Care Therapy | PCT-Guided Therapy | ||
|---|---|---|---|---|
| Na | N (%) or Days, median (IQR) | N | N (%) or Days, median (IQR) | |
| Initiation of antibiotics | 1606 | 1420 (88.4%) | 1536 | 1096 (71.4%) |
| Duration of antibiotics | 1420 | 10 (7, 12) | 1096 | 7 (4, 10) |
| Total exposure of antibiotics | 1606 | 9 (8, 12) | 1536 | 5 (0, 8) |
| 30-day mortality | 1606 | 119 (7.4%) | 1536 | 103 (6.7%) |
| Complications | 1606 | 339 (21.1%) | 1536 | 276 (18.0%) |
| Hospital length of stay | 1583 | 6 (0, 13) | 1508 | 7 (0, 12) |
Overview of the Patient-Level Meta-Analysis
a Number of patients included.
Decision-Making on Antibiotic Discontinuation for Suspected or Confirmed Septic Patients
Two systematic literature reviews were performed along with study- and patient-level meta-analyses, which are studies that combine and contrast data from multiple sources to identify patterns among study results. The study-level meta-analysis used aggregate descriptive information extracted from publications, and the patient-level meta-analysis used aggregate patient-level data from the raw dataset of each study. Each metaanalysis used random-effects models and calculated point estimates, differences, odds ratios (OR), interquartile ranges (IQRs), and 95% confidence intervals as appropriate (see tables below). The endpoints evaluated were: duration of antibiotic therapy (study level only), exposure to antibiotics (patient-level only), length of ICU stay, length of hospital stay (patient-level only), and mortality.
The study-level meta-analysis encompassed 10 RCTs, which were published between 2008-2016 and included 3489 patients. (See FDA public docket FDA-2016-N-2880).
| Publication | Na, b | PCT Device |
|---|---|---|
| Bouadma, 2010 | 630 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Hochreiter, 2009 | 110 | B·R·A·H·M·S PCT LIA |
| Nobre, 2008 | 79 | B·R·A·H·M·S PCT sensitive KRYPTOR |
| Schroeder, 2009 | 27 | B·R·A·H·M·S PCT LIA |
| Stolz, 2007 | 101 | B·R·A·H·M·S PCT sensitive KRYPTOR |
The above patient-level meta-analysis encompassed 5 RCTs, which were published between 2008-2010 and included 598 patients as listed below.
a Number of patients.
b Patients that did not classify as sepsis were removed prior to analysis (185 for PCT group and 164 for control group), leaving 598 patients.
29
Using this subset of meta-analyses, it was concluded that PCT-guided antibiotic therapy resulted in:
- 1.5-day reduction in antibiotic duration. ●
- . 3.2-day reduction in total antibiotic exposure.
- 23% reduction in overall antibiotic exposure (that is, total days of antibiotic therapy) for patients who presented to the emergency department and other associated clinics, but were not admitted.
- . No negative effects in regards to mortality, hospital length of stay, or ICU length of stay.
| Parameter | Na | Standard Care Therapy
N (%) or Days, median (IQR) | PCT-Guided Therapy
N (%) or Days, median (IQR) |
|-------------------------------|-----|------------------------------------------------------|---------------------------------------------------|
| Total exposure of antibiotics | 311 | 12 (8, 18) | 287 8 (5, 15) |
| 30-day mortality | 311 | 74 (23.8%) | 287 57 (19.9%) |
| Hospital length of stay | 288 | 23 (13, 38) | 259 21 (11, 37) |
| ICU length of stay | 311 | 12 (6, 22) | 287 12 (6, 23) |
Overview of the Patient-Level Meta-Analysis
a Number of patients included.
Recommendations for Laboratory Reports for Initiation and Discontinuation:
Procalcitonin Calculator is available at www.BRAHMS-PCT-The Change in Calculator.com.
It is suggested to report the absolute PCT values (single or serial). For serial PCT values, the report should also indicate if the ΔΡCT (%) was ≤ 80% or > 80%. The laboratory report should include a reference or a link to the Atellica IM BRAHMS PCT package insert for a guided interpretation of the test results.
3. Traceability and Value Assignment
The Atellica IM BRAHMS PCT assay is standardized using a reference preparation antigen as master standard. Assay standardization is verified through regression analysis of a PCT-positive patient population. Assigned values for calibrators and controls are traceable to this standardization.
4. Stability
Reagent Stability - Shelf-life
To establish the shelf-life claims for the Atellica IM BRAHMS PCT reagents and Calibrator (kit), the readents and calibrators stored at 2-8°C and were tested with various samples at multiple time points. Sets of calibrators were also stored at or below -40°C and were tested at the same time points.
Testing demonstrated that the Atellica IM BRAHMS PCT reagents are stable up to 12 months when properly stored at 2-8°C. Unopened Atellica IM BRAHMS PCT reagents and calibrators are stable at 2-8°C until expiration date printed on the product packaging.
Reagent Stability - On-Board
30
The onboard stability of the Atellica IM BRAHMS PCT reagents is 60 days onboard, pack calibration interval of 35 days, and lot calibration interval of 82 days.
Calibrator Stability- Shelf-life
Testing demonstrated that the Atellica IM BRAHMS PCT reagents are stable up to 12 months when properly stored at 2-8°C. Lyophilized calibrators are stable until the expiration date on the product when stored at 2-8°C.
Calibrator Stability- Reconstituted In use (2-8°C/OBS)
Reconstituted calibrators are stable for 24 hours at 2-8°C or for 8 hours at room temperature (package insert claims).
Specimen Stability
-
a. Room temperature
Studies demonstrated that serum samples specimens are stable for 8 hours at room temperature. -
b. Refrigerated (2-8°C)
Studies demonstrated that serum samples are stable for 24 hours at 2-8°C. -
c. Freeze/Thaw cycles (≤ -20°C)
The recommended specimen handling are provided below. -
Do not use samples that have been stored at room temperature for longer than 8 hours.
-
Tightly cap and refrigerate specimens at 2-8°C if the assay is not completed within 8 hours.
-
Freeze samples at ≤ -20°C if the sample is not assayed within 48 hours.
-
· Freeze samples up to 5 times, and mix thoroughly after thawing.
Additional sample stability studies were performed on the MOSES clinical samples as described in DEN150009.
18. Proposed Labeling
The labeling is sufficient and it meets the requirements of 21 CFR Parts 801 and 809, as applicable and the special controls for this device under 21 CFR 866.3215.
19. Conclusion
The submitted information in this premarket notification is complete and supports a substantial equivalence determination.