(139 days)
VIDAS® B+R+A+H+M+S PCT™ (PCT) is an automated test for use on the instruments of the VIDAS® family for the determination of human procalcitonin in human serum or plasma (lithium heparinate) using the ELFA (Enzyme-Linked Fluorescent Assay) technique.
Used in conjunction with other laboratory findings and clinical assessments, VIDAS® B•R•A•H•M•S PCT™ is intended for use as follows:
· to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
· to aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.
· to aid in decision making on antibiotic therapy for 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,
· to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
The assay principle combines a one-step immunoassay sandwich method with a final fluorescent detection (ELFA).
The Solid Phase Receptacle (SPR®), serves as the solid phase as well as the pipetting device. Reagents for the assay are ready-to-use and pre-dispensed in the sealed reagent strips.
All of the assay steps are performed automatically by the instrument. The sample is transferred into the wells containing anti-procalcitonin antibodies labeled with alkaline phosphatase (conjugate). The sample/conjugate mixture is cycled in and out of the SPR® several times. This operation enables the antigen to bind with the immunoglobulins fixed to the interior wall of the SPR® and the conjugate to form a sandwich. Unbound compounds are eliminated during washing steps.
Two detection steps are performed successively. During each step, the substrate (4-Methylumbelliferyl phosphate) is cycled in and out of the SPR®. The conjugate enzyme catalyzes the hydrolysis of this substrate into a fluorescent product (4-Methyl-umbelliferone) the fluorescence of which is measured at 450 nm. The intensity of the fluorescence is proportional to the concentration of antigen present in the sample.
At the end of the assay, results are automatically calculated by the instrument in relation to two calibration curves corresponding to the two detection steps. A fluorescence threshold value determines the calibration curve to be used for each sample. The results are then printed out.
The provided text describes the non-clinical and clinical studies conducted for the clearance of the VIDAS® B·R·A·H·M·S PCT™ device.
1. Table of Acceptance Criteria and Reported Device Performance
The document provides analytical performance (non-clinical) results rather than specific acceptance criteria thresholds the device must meet in a table. However, it reports the performance of the device against common analytical metrics. For clinical performance, it summarizes the findings of meta-analyses.
Analytical Performance (Non-Clinical)
| Performance Metric | Reported Device Performance (VIDAS®) | Reported Device Performance (VIDAS® 3) | Acceptance Criteria (Implicit from CLSI® recommendations for determining the limits) |
|---|---|---|---|
| Limits of Detection & Quantitation | |||
| Limit of Blank (LoB) | 0.01 ng/mL | 0.01 ng/mL | Determined per CLSI® EEP17-A recommendations |
| Limit of Detection (LoD) | 0.03 ng/mL | 0.03 ng/mL | Determined per CLSI® EEP17-A recommendations |
| Limit of Quantitation (LoQ) | 0.05 ng/mL | 0.05 ng/mL | 0.05 ng/mL (with bias ≤ 10%, %CV ≤ 20%, Total Error ≤ 50%) |
| Precision | |||
| Repeatability CV (%) (Range) | 1.3% - 14.6% | 2.0% - 9.7% | Determined per CLSI® EP5-A3 recommendations |
| Between-Day Precision CV (%) (Range) | 3.0% - 15.9% | 3.5% - 10.9% | Determined per CLSI® EP5-A3 recommendations |
| Within-Lab Precision CV (%) (Range) | 3.9% - 20.2% | 3.9% - 18.2% | Determined per CLSI® EP5-A3 recommendations |
| Reproducibility/Total Precision CV (%) (Range) | 3.9% - 20.2% | 4.3% - 18.2% | Determined per CLSI® EP5-A3 recommendations |
| Interference | |||
| Drugs & Potentially Interfering Substances | No interference observed at tested concentrations | No interference observed at tested concentrations | No interference observed at tested concentrations (relative to CLSI® EP7-A2 recommendations) |
Clinical Performance (Summary of Meta-Analyses Findings)
The clinical studies involved meta-analyses of existing Randomized Control Trials (RCTs) rather than new primary clinical trials with specific acceptance criteria in the format of sensitivity/specificity/accuracy for the device itself. Instead, the meta-analyses aimed to demonstrate the clinical utility of PCT-guided therapy.
For Decision Making on Antibiotic Therapy for LRTI:
- Antibiotic initiation: 19.2% reduction in relative antibiotic initiation for all patients.
- Overall antibiotic exposure: 38% reduction for inpatients, 51% reduction for ER patients.
- Antibiotic duration: 2.9 days reduction (patient-level meta-analysis), 1.25 days reduction (study-level meta-analysis).
- Total antibiotic exposure: 3.6 days reduction (patient-level meta-analysis), 2.79 days reduction (study-level meta-analysis).
- Negative effects (mortality, complications, length of stay): No negative effects observed.
- Ranked patient outcomes: Statistically significant improvement in PCT-guided management vs. standard management.
For Decision Making on Antibiotic Discontinuation for Septic Patients:
- Antibiotic duration: 1.5 days reduction.
- Total antibiotic exposure: 3.2 days reduction.
- Overall antibiotic exposure: 23% reduction.
- Negative effects (mortality, hospital/ICU length of stay): No negative effects observed.
2. Sample Size Used for the Test Set and Data Provenance
-
Analytical (Non-Clinical) Test Set:
- Limits of Detection & Quantitation: The sample size is not explicitly stated as a number of individual samples, but rather as determinations on the VIDAS® and VIDAS®3 instruments.
- Precision Study: Panel of 11 human samples. Each sample was tested in duplicate in 2 runs per day over 20 days using 3 VIDAS® and 3 VIDAS®3 instruments (N=240 values for each sample) at 3 sites. Two reagent lots were used (10 days of tests, 6 calibrations per lot).
- Interference Study: Not specified how many samples, but multiple drugs and substances were tested at specified concentrations.
- Data Provenance: Not explicitly stated, but generally, such analytical studies are conducted in a laboratory setting, likely within the manufacturer's R&D or a contract research organization.
-
Clinical Test Set:
- Decision making on antibiotic therapy for LRTI:
- Study-level meta-analysis: 11 Randomized Control Trials (RCTs), 4090 patients.
- Patient-level meta-analysis: 13 RCTs, 3142 patients.
- Decision making on antibiotic discontinuation for septic patients:
- Study-level meta-analysis: 10 RCTs, 3489 patients.
- Patient-level meta-analysis: 5 RCTs, 598 patients.
- Data Provenance for Clinical Studies: The data comes from retrospective meta-analyses of previously published Randomized Control Trials (RCTs). The countries of origin for these RCTs are not specified in the provided text.
- Decision making on antibiotic therapy for LRTI:
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
- Analytical (Non-Clinical) Test Set: Ground truth for analytical performance (LoB, LoD, LoQ, precision, interference) is established through standardized laboratory reference methods and certified control materials, following CLSI guidelines. This typically does not involve human experts establishing ground truth in the same way clinical ground truth is established.
- Clinical Test Set (Meta-Analyses): The "ground truth" in these meta-analyses refers to the patient outcomes (e.g., antibiotic exposure, mortality, complications, length of stay) as reported in the original RCTs. These outcomes would have been objectively measured or determined by the clinicians and researchers involved in those original studies, based on their clinical assessments, laboratory findings, and established diagnostic criteria. No specific number or qualification of experts for "establishing ground truth" for the meta-analysis itself is mentioned, as the meta-analysis aggregates existing validated data.
4. Adjudication Method for the Test Set
- Analytical (Non-Clinical) Test Set: Adjudication is not typically applicable for these types of analytical tests as they rely on quantitative measurements against reference standards and statistical analysis.
- Clinical Test Set (Meta-Analyses): The meta-analyses involve combining and contrasting data from multiple sources. Each original RCT would have had its own methods for clinical assessment and outcome determination, which might have included adjudication by a panel of clinicians. However, the provided document does not describe an adjudication method for the meta-analysis itself beyond the systematic review and pooling of data.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed. The device is an in vitro diagnostic (IVD) test that measures procalcitonin levels, not an imaging device or AI-driven diagnostic that would involve human readers interpreting cases with and without AI assistance. The clinical studies performed were meta-analyses of PCT-guided therapy vs. standard care, focusing on patient outcomes and antibiotic usage, not on human reader performance.
6. Standalone Performance Study
Yes, the analytical (non-clinical) tests demonstrate the standalone performance of the algorithm/device. The "Limits of detection and quantitation," "Precision," and "Study of drugs and other potentially interfering substances" sections describe the device's inherent performance characteristics independent of human interpretation or intervention beyond performing the assay itself. This is the algorithm only without human-in-the-loop performance for an IVD device.
7. Type of Ground Truth Used
- Analytical (Non-Clinical) Studies: The ground truth is based on:
- Established analytical methods and reference materials for measuring procalcitonin concentration.
- Statistical methods (e.g., CLSI guidelines) for determining LoB, LoD, LoQ, and precision.
- Controlled interference studies with known concentrations of drugs and substances.
- Clinical Studies (Meta-Analyses): The ground truth is based on:
- Outcomes Data from previously published Randomized Control Trials (RCTs), including antibiotic administration duration, total antibiotic exposure, mortality, hospital length of stay, and ICU length of stay.
- Clinical assessments and diagnoses made in the original RCTs for patient admission with suspected sepsis/LRTI and severe sepsis/septic shock.
8. Sample Size for the Training Set
The document describes premarket notification for a diagnostic test, not a machine learning or AI algorithm in the typical sense that requires a training set for model development. The VIDAS® B·R·A·H·M·S PCT™ is an ELFA (Enzyme-Linked Fluorescent Assay) technique. Therefore, the concept of a "training set" for a machine learning model is not applicable here. The assay relies on a biochemical reaction and fluorescent detection.
9. How the Ground Truth for the Training Set Was Established
As explained in point 8, the concept of a "training set" for model development is not relevant to this type of diagnostic assay. The ground truth for calibrating the assay and establishing its analytical performance relies on established laboratory standards, controls, and reference methods as part of its development and validation process.
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Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
May 22, 2017
bioMérieux, Inc. John Albright Regulatory Affairs Manager 595 Anglum Rd., Hazelwood, MO 63042 US
Re: K162827 Trade/Device Name: VIDAS B.R.A.H.M.S. PCT (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: PRI, PMT, NTM Dated: January 25, 2017 Received: January 25, 2017
Dear Mr. Albright:
This letter corrects our substantially equivalent letter of February 23, 2017.
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
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CFR Part 807); labeling 21 CFR Parts 801 and 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 Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulation 21 CFR Parts 801 and 809, please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely.
Steven R. Gitterman -S for
Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiological Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Form Approved: OMB No. 0910-0120
Expiration Date: January 31, 2017
See PRA Statement below.
DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration
Indications for Use
510(k) Number (if known) K162827
Device Name
VIDAS B.R.A.H.M.S PCT (PCT)
Indications for Use (Describe)
VIDAS® B+R+A+H+M+S PCT™ (PCT) is an automated test for use on the instruments of the VIDAS® family for the determination of human procalcitonin in human serum or plasma (lithium heparinate) using the ELFA (Enzyme-Linked Fluorescent Assay) technique.
Used in conjunction with other laboratory findings and clinical assessments, VIDAS® B•R•A•H•M•S PCT™ is intended for use as follows:
· to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
· to aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.
· to aid in decision making on antibiotic therapy for 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,
· 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 CFR 801 Subpart D)
| Over-The-Counter Use (21 CFR 801 Subpart C)
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Image /page/3/Picture/0 description: The image shows the logo for bioMérieux. The logo features the company name in gray, block letters. Above the name is a blue and white globe-like design with a green curved line extending upwards from it. Below the name is a horizontal bar that transitions from yellow to green.
510(K) SUMMARY
This 510(k) summary of safety and effectiveness information is being submitted in accordance with the requirement of Safe Medical Devices Act of 1990 and 21 CFR 807.92.
VIDAS® B-R-A-H-M-S PCT™
A. Submitter Information
| Submitter's Name: | bioMérieux, Inc. |
|---|---|
| Address: | 595 Anglum RoadHazelwood, MO 63042 |
| Contact Person: | John Albright |
| Phone Number: | 314-731-8546 |
| Fax Number: | 314-731-8689 |
| Date of Preparation: | October 6, 2016 |
B. Device Name
| Trade Name: | VIDAS® B·R·A·H·M·S PCT™ (PCT) |
|---|---|
| Common Name: | Endotoxin Assay |
| Classification Names: | Device to detect and measure procalcitonin (pct) in human clinicalspecimens (21 CFR 866.3215, Product Code PMT)Procalcitonin assay (21 CFR 866.3215, Product Code PRI) |
C. Predicate Devices
VIDAS® B·R·A·H·M·S PCT™ (K160911)
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D. Device Description
The assay principle combines a one-step immunoassay sandwich method with a final fluorescent detection (ELFA).
The Solid Phase Receptacle (SPR®), serves as the solid phase as well as the pipetting device. Reagents for the assay are ready-to-use and pre-dispensed in the sealed reagent strips.
All of the assay steps are performed automatically by the instrument. The sample is transferred into the wells containing anti-procalcitonin antibodies labeled with alkaline phosphatase (conjugate). The sample/conjugate mixture is cycled in and out of the SPR® several times. This operation enables the antigen to bind with the immunoglobulins fixed to the interior wall of the SPR® and the conjugate to form a sandwich. Unbound compounds are eliminated during washing steps.
Two detection steps are performed successively. During each step, the substrate (4-Methylumbelliferyl phosphate) is cycled in and out of the SPR®. The conjugate enzyme catalyzes the hydrolysis of this substrate into a fluorescent product (4-Methyl-umbelliferone) the fluorescence of which is measured at 450 nm. The intensity of the fluorescence is proportional to the concentration of antigen present in the sample.
At the end of the assay, results are automatically calculated by the instrument in relation to two calibration curves corresponding to the two detection steps. A fluorescence threshold value determines the calibration curve to be used for each sample. The results are then printed out.
E. Intended Use
VIDAS® B·R·A·H·M·S PCT™ (PCT) is an automated test for use on the instruments of the VIDAS® family for the determination of human procalcitonin in human serum or plasma (lithium heparinate) using the ELFA (Enzyme-Linked Fluorescent Assay) technique.
Used in conjunction with other laboratory findings and clinical assessments, VIDAS® B+R+A+H+M+S PCT™ is intended for use as follows:
- to aid in the risk assessment of critically ill patients on their first day of ICU admission for . progression to severe sepsis and septic shock,
- . to aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission. using a change in PCT level over time.
- . to aid in decision making on antibiotic therapy for 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,
- . to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
F. Technological Characteristics Summary
A general comparison of the similarities and differences of the assay with the predicates is presented in the following table.
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| Item | Proposed Device:VIDAS® B-R-A-H-M-STM PCT | Predicate device:VIDAS® B-R-A-H-M-S PCTTM (K160911) |
|---|---|---|
| IntendedUse andindicationsfor use | VIDAS® B-R-A-H-M-S PCTTM (PCT) is anautomated test for use on the instruments of theVIDAS® family for the determination of humanprocalcitonin in human serum or plasma (lithiumheparinate) using the ELFA (Enzyme-LinkedFluorescent Assay) technique.Used in conjunction with other laboratoryfindings and clinical assessments, VIDAS®B·R·A·H·M·S PCTTM is intended for use asfollows:to aid in the risk assessment of critically illpatients on their first day of ICU admissionfor progression to severe sepsis andseptic shock, to aid in assessing the cumulative 28-dayrisk of all-cause mortality for patientsdiagnosed with severe sepsis or septicshock in the ICU or when obtained in theemergency department or other medicalwards prior to ICU admission, using achange in PCT level over time, to aid in decision making on antibiotictherapy for patients with suspected orconfirmed lower respiratory tract infections(LRTI) - defined as community-acquiredpneumonia (CAP), acute bronchitis, andacute exacerbation of chronic obstructivepulmonary disease (AECOPD) – in aninpatient setting or an emergencydepartment, to aid in decision making on antibioticdiscontinuation for patients with suspectedor confirmed sepsis. | VIDAS® B-R-A-H-M-S PCTTM (PCT) is anautomated test for use on the instruments of theVIDAS® family for the determination of humanprocalcitonin in human serum or plasma (lithiumheparinate) using the ELFA (Enzyme-LinkedFluorescent Assay) technique.VIDAS® B-R-A-H-M-S PCTTM (PCT) is intended foruse in conjunction with other laboratory findingsand clinical assessments to aid in the riskassessment of critically ill patients on their first dayof ICU admission for progression to severe sepsisand septic shock.VIDAS® B-R-A-H-M-S PCTTM (PCT) is alsointended for use to determine the change in PCTlevel over time as an aid in assessing thecumulative 28-day risk of all-cause mortality inconjunction with other laboratory findings andclinical assessments for patients diagnosed withsevere sepsis or septic shock in the ICU or whenobtained in the emergency department or othermedical wards prior to ICU admission.Procalcitonin (PCT) is a biomarker associated withthe inflammatory response to bacterial infection thataids in the risk assessment of critically ill patientson their first day of Intensive Care Unit (ICU)admission for progression to severe sepsis andseptic shock. The percent change in PCT level overtime also aids in the prediction of cumulative 28-daymortality in patients with severe sepsis and septicshock.PCT levels on the first day of ICU admission above2.0 ng/mL are associated with a higher risk forprogression to severe sepsis and/or septic shockthan PCT levels below 0.5 ng/mL.A PCT level that declines ≤ 80% from the day thatsevere sepsis or septic shock was clinicallydiagnosed (Day 0) to four days after clinicaldiagnosis (Day 4) is associated with highercumulative 28-day risk of all-cause mortality than adecline > 80%.The combination of the first PCT level (≤ 2.0 ng/mLor > 2.0 ng/mL) at initial diagnosis of severe sepsisor septic shock with the patient's clinical course andthe change in PCT level over time until Day 4provides important additional information about themortality risk.The PCT level on Day 1 (the day after severesepsis or septic shock is first clinically diagnosed)can be used to calculate the percent change in PCTlevel at Day 4 if the Day 0 measurement isunavailable. |
| Specimen | Human serum or plasma (lithium heparinate). | Same as the proposed device |
| Analyte | Procalcitonin (PCT) | Same as the proposed device |
| Item | Proposed Device:VIDAS® B-R-A-H-M-S™ PCT | Predicate device:VIDAS® B-R-A-H-M-S PCT™ (K160911) |
| Automated | Automated assay | Same as the proposed device |
| AssayTechnique | ELFA (Enzyme-Linked Fluorescent Assay)technique. | Same as the proposed device |
| Assayprinciple | Immunoassay based on sandwich principle | Same as the proposed device |
| Detectionmethod | Fluorescence (ELFA) of 4-methyl-umbelliferylmeasured at 450 nm | Same as the proposed device |
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G. Nonclinical Tests
A summary of the non-clinical (analytical) results is presented below.
Limits of detection and quantitation
The Limit of Blank (LoB), the Limit of Detection (LoD) and the Limit of Quantitation (LoQ) were
determined on the VIDAS® and VIDAS® instruments according to the CLSI® EEP17-A recommendations. The limits reported below apply for all the instruments of the VIDAS family:
| Limit of Blank (LoB) | 0.01 ng/mL |
|---|---|
| Limit of Detection (LoD) | 0.03 ng/mL |
| Limit of Quantitation (LoQ) | 0.05 ng/mL |
The LoQ was determined to be 0.05 ng/mL (with bias ≤ 10%, %CV ≤ 20% and Total Error ≤ 50%.)
Precision
The study was performed according to the recommendations of CLSI® document EP5-A3. A panel of 11 human samples covering the measuring range were tested in duplicate in 2 runs per day, over 20 days using 3 VIDAS® and 3 VIDAS® 3 instruments (N=240 values for each sample) at 3 sites (one instrument per site). Two reagent lots were used: 10 days of tests and 6 calibrations were performed for each lot. The repeatability, between-day precision, within-laboratory precision and reproducibility/total precision (between-laboratory precision) were estimated for each sample and are reported in the following tables:
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| VIDAS® | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Sample | N | Meanconcentration(ng/mL) | Repeatability | Between-Dayprecision | Within-Laboratoryprecision | Reproducibility /Total precision | ||||
| StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | |||
| PP12 | 240 | 0.08 | 0.011 | 14.6% | 0.012 | 15.9% | 0.015 | 20.2% | 0.015 | 20.2% |
| PP16 | 240 | 0.10 | 0.009 | 9.0% | 0.011 | 10.4% | 0.016 | 15.9% | 0.016 | 15.9% |
| PS01 | 240 | 0.12 | 0.011 | 8.9% | 0.013 | 10.8% | 0.017 | 14.2% | 0.017 | 14.2% |
| PS02 | 240 | 0.15 | 0.010 | 6.5% | 0.014 | 8.9% | 0.019 | 12.3% | 0.019 | 12.3% |
| PP14 | 240 | 0.23 | 0.009 | 4.0% | 0.011 | 4.9% | 0.016 | 7.1% | 0.016 | 7.1% |
| PS04 | 240 | 0.53 | 0.013 | 2.4% | 0.021 | 4.0% | 0.023 | 4.2% | 0.023 | 4.2% |
| PS05 | 240 | 2.14 | 0.027 | 1.3% | 0.063 | 3.0% | 0.083 | 3.9% | 0.083 | 3.9% |
| PS06 | 240 | 23.12 | 0.504 | 2.2% | 0.882 | 3.8% | 1.020 | 4.4% | 1.020 | 4.4% |
| PS07 | 240 | 92.30 | 3.113 | 3.4% | 5.972 | 6.5% | 6.423 | 7.0% | 6.423 | 7.0% |
| PS08 | 240 | 128.56 | 5.275 | 4.1% | 9.562 | 7.4% | 11.087 | 8.6% | 11.087 | 8.6% |
| PS11 | 240 | 162.99 | 7.308 | 4.5% | 11.377 | 7.0% | 16.082 | 9.9% | 16.082 | 9.9% |
VIDAS® 3
| Sample | N | Meanconcentration(ng/mL) | Repeatability | Between-Dayprecision | Within-Laboratoryprecision | Reproducibility /Total precision | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | |||
| PP13 | 240 | 0.08 | 0.008 | 9.4% | 0.009 | 10.4% | 0.015 | 18.2% | 0.015 | 18.2% |
| PP16 | 240 | 0.10 | 0.009 | 9.7% | 0.010 | 10.9% | 0.015 | 15.9% | 0.015 | 15.9% |
| PS01 | 240 | 0.12 | 0.010 | 8.7% | 0.011 | 9.4% | 0.015 | 12.5% | 0.015 | 12.5% |
| PS02 | 239 | 0.15 | 0.013 | 8.3% | 0.014 | 9.3% | 0.017 | 11.2% | 0.017 | 11.2% |
| PP14 | 240 | 0.22 | 0.010 | 4.3% | 0.011 | 4.9% | 0.015 | 6.8% | 0.015 | 6.8% |
| PS04 | 239 | 0.52 | 0.020 | 3.8% | 0.024 | 4.6% | 0.026 | 5.0% | 0.032 | 6.1% |
| PS05 | 240 | 2.06 | 0.041 | 2.0% | 0.073 | 3.5% | 0.098 | 4.8% | 0.102 | 5.0% |
| PS06 | 240 | 21.85 | 0.583 | 2.7% | 0.814 | 3.7% | 0.860 | 3.9% | 0.946 | 4.3% |
| PS07 | 240 | 83.60 | 3.372 | 4.0% | 4.445 | 5.3% | 4.895 | 5.9% | 5.785 | 6.9% |
| PS08 | 240 | 110.83 | 5.495 | 5.0% | 7.091 | 6.4% | 7.927 | 7.2% | 8.525 | 7.7% |
| PS11 | 240 | 140.34 | 6.450 | 4.6% | 10.611 | 7.6% | 11.253 | 8.0% | 12.596 | 9.0% |
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Study of drugs and other potentially interfering substances
Following the recommendations of CLSI® document EP7-A2, the potential interferences with the following drugs and potentially interfering substances were studied. No interference was observed at the concentration tested.
| Tested drug | Tested concentration |
|---|---|
| Acetominophen | 20 mg/dL |
| Acetylsalicylic Acid | 65.2 mg/dL |
| Alcohol | 400 mg/dL |
| Amoxicillin | 7.53 mg/dL |
| Ampicillin | 5.31 mg/dL |
| Azithromycin | 1.15 mg/dL |
| Beclometasone dipropionate | 0.1 mg/dL |
| Caffeine | 5.98 mg/dL |
| Cefotaxime | 32.13 mg/dL |
| Ceftriaxone | 93.7 mg/dL |
| Celecoxib | 24 mg/dL |
| Cetirizine HCI | 0.36 mg/dL |
| Cromolyn | 2.4 mg/dL |
| Dextromethorphan | 0.14 mg/dL |
| Dobutamine | 0.15 mg/dL |
| Dopamine | 0.11 mg/dL |
| Epinephrine (adrenaline) | 0.18 mg/dL |
| Fluticasone | 0.03 mg/dL |
| Tested drug | Tested concentration |
| Formoterol | 0.0029 mg/dL |
| Furosemide | 5.98 mg/dL |
| Heparin sodium | 3000 UI/L |
| Ibuprofen | 50 mg/dL |
| Imipenem | 18 mg/dL |
| Levoflaxacin | 1.75 mg/dL |
| Linezolid | 48 mg/dL |
| Loratadine | 0.03 mg/dL |
| Naproxen | 50 mg/dL |
| Nicotine | 0.1 mg/dL |
| Noradrenaline | 0.00021 mg/dL |
| Oxymetazoline HCl | 0.009 mg/dL |
| Phenylephrine | 0.018 mg/dL |
| Prednisolone | 0.3 mg/dL |
| Salmeterol | 0.006 mg/dL |
| Theophylline | 4 mg/dL |
| Tiotropium | 0.0022 mg/dL |
| Vancomycin | 10.25 mg/dL |
| Tested Substances | Tested concentrations |
|---|---|
| Protein (albumin) | 6.5 g/dL |
| Hemoglobin | 600 mg/dL |
| Triglycerides | 3000 mg/dL |
| Bilirubin | 33 mg/dL |
{9}------------------------------------------------
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H. Clinical performance data
A summary of the clinical performance data is presented below.
Decision making on antibiotic therapy for patients with suspected or confirmed LRTI
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 encompassed 11 randomized control trials (RCTs) which were published between 2004-2016, and included 4090 patient-level meta-analysis encompassed 13 RCTs which were published between 2004-2011, and included 3142 patients.
These meta-analyses concluded that PCT quided antibiotic therapy resulted in:
- 19.2% reduction in relative antibiotic initiation for all patients
- 38% reduction in overall antibiotic exposure (i.e. total days of antibiotic therapy) for inpatients
- . 51% reduction in overall antibiotic exposure (i.e. total days of antibiotic therapy) for patients in emergency departments*
- 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.
*Patients who presented to the Emergency Department and other associated clinics, but were not admitted.
Additionally, a modified DOOR/RADAR analysis, in which patient outcomes were ranked by clinical severity, was conducted on the patient level data, and found that PCT-guided management had a statistically significant improvement in ranked patient outcomes compared to standard management.
Decision making on antibiotic discontinuation for 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 encompassed 10 RCTs which were published between 2008-2016, and included 3489 patients. The patient-level meta-analysis encompassed 5 RCTs which were published between 2008-2010, and included 598 patients.
These meta-analyses concluded that PCT guided antibiotic therapy resulted in:
- . 1.5 day reduction in antibiotic duration
- 3.2 day reduction in total antibiotic exposure ●
- 23% reduction in overall antibiotic exposure (i.e. total days of antibiotic therapy) ●
- No negative effects in reqards to mortality, hospital length of stay, or ICU length of stay.
. Conclusion
The results from the non-clinical performance data submitted in this premarket notification are complete and demonstrate that the VIDAS® B·R·A·H·M·S PCT assay is substantially equivalent to the predicate device.
§ 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.