(170 days)
VIDAS® BRAHMS PCT is an automated test for use on the VIDAS instruments for the determination of human procalcitonin in human serum or plasma (lithium heparin) using the ELFA (Enzyme-Linked Fluorescent Assay) technique. The VIDAS BRAHMS PCT assay is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission, for progression to severe sepsis and septic shock.
The VIDAS BRAHMS PCT Assay is an enzyme-linked fluorescent immunoassay (ELFA) performed in an automated VIDAS® instrument. 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 for the assay. 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-procalcitorin 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-Methylumbellifery| 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 revelation steps and stored in memory, and then printed out.
The provided document describes the VIDAS® B-R.A.H.M.S PCT Assay, an enzyme-linked fluorescent immunoassay (ELFA) for determining human procalcitonin in serum or plasma. It is intended for critically ill patients on their first day of ICU admission to aid in the risk assessment for progression to severe sepsis and septic shock.
The study presented focuses on establishing substantial equivalence to a predicate device, the BRAHMS PCT LIA Assay, rather than proving the device meets specific acceptance criteria via a standalone study with pre-defined metrics. Therefore, a table of acceptance criteria and reported device performance as typically understood for a novel device demonstrating efficacy against disease outcomes is not explicitly provided. Instead, the document compares analytical and clinical performance between the new device and the predicate.
Here's an analysis based on the provided information, framed to address your questions as much as possible, interpreting "acceptance criteria" as meeting or exceeding the performance of the predicate device.
1. Table of "Acceptance Criteria" and Reported Device Performance
As mentioned, explicit "acceptance criteria" for clinical performance are not stated in terms of specific sensitivity, specificity, PPV, or NPV targets for predicting severe sepsis/septic shock against a definitive ground truth. Instead, the comparison is against the predicate device's performance. The analytical performance comparisons can be seen as meeting "acceptance criteria" if they are comparable to or better than the predicate's.
| Metric (Implied Acceptance Criteria: Comparable to or Better than Predicate) | VIDAS BRAHMS PCT (Device) Performance | BRAHMS PCT LIA (Predicate) Performance |
|---|---|---|
| Analytical Performance | ||
| Matrix Comparison | Serum similar to Plasma | Same |
| Precision (Total CV) | 6.17 - 15.31% CV | 5.3 - 16.6% CV |
| Precision (Intra-run CV) | 1.93 - 4.61% CV | 2.4 - 10% CV |
| Precision (Inter-run CV) | 3.57 - 7.04% CV | Not explicitly separated |
| Precision (Inter-site CV) | 4.21 - 11.40% CV | Not explicitly separated |
| Analytical Detection Limit | <0.05 ng/ml | 1.0 ng/ml |
| Functional Detection Limit | 0.09 ng/ml | 0.3 ng/ml |
| Interfering Substances (Bilirubin) | 574 µmol/l (no significant interf.) | 40 mg/dl (no significant interf.) |
| Interfering Substances (Hemoglobin) | 347 µmol/l (no significant interf.) | 500 mg/dl (no significant interf.) |
| Interfering Substances (Triglycerides) | 30 g/l (no significant interf.) | 634 mg/dl (no significant interf.) |
| Analytical Specificity (Protein) | 4 g/dl (no significant interf.) | 1 g/dl (no significant interf.) |
| Analytical Specificity (Human calcitonin) | 60 ng/ml (no significant interf.) | 8 ng/ml (no significant interf.) |
| Hook Effect | No hook effect up to 2600 ng/ml | No hook effect up to 4000 µg/L |
| Measurement Range | 0.05 to 200 ng/ml | 0.3 - 500 ng/ml |
| Clinical Performance (Comparison to Predicate, not absolute criteria) | ||
| Cut-off for high risk | >2 ng/ml | Same |
| Cut-off for low risk | <0.5 ng/ml | Same |
| Clinical Sensitivity/Specificity Studies | ||
| Patients with PCT ≤0.5 ng/ml, with severe sepsis or septic shock | 18 out of 92 patients | 0 out of 44 patients |
| Patients with severe sepsis or septic shock, with low PCT | 37 out of 104 patients (low PCT) | 1 out of 77 patients (low PCT) |
| Clinical Specificity Study on Healthy Subjects | ||
| 95th percentile Healthy Subjects | <0.05 ng/ml | Not directly comparable |
| 99th percentile Healthy Subjects | 0.09 ng/ml | 143/144 healthy subjects <0.3 ng/ml |
2. Sample Size Used for the Test Set and Data Provenance
- Clinical Sensitivity/Specificity Study:
- Device (VIDAS BRAHMS PCT): 232 patients (US and Europe, likely retrospective or mixed, not explicitly stated but common for such studies).
- Predicate (BRAHMS PCT LIA): 179 patients (Europe).
- Clinical Specificity Study on Healthy Subjects:
- Device (VIDAS BRAHMS PCT): 200 healthy subjects (US).
- Predicate (BRAHMS PCT LIA): 144 healthy subjects (US).
- Non-clinical (Analytical) Precision Study: 6 samples over 20 days for the device, 14 samples over 20 days for the predicate (no specific provenance mentioned for these samples, but assumed to be laboratory-prepared or pooled clinical samples).
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
The document does not specify the number of experts or their qualifications used to establish the ground truth for "severe sepsis or septic shock." The studies are comparing the PCT assay results between the device and the predicate, and how those results correlate with the clinical diagnosis of severe sepsis or septic shock. The diagnostic criteria for severe sepsis/septic shock are assumed to be standard clinical practice at the study sites.
4. Adjudication Method for the Test Set
No multi-reader adjudication method (e.g., 2+1, 3+1) is described for establishing the clinical ground truth. It is implied that the clinical diagnoses of severe sepsis or septic shock were based on standard clinical assessments by treating physicians at the study sites.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No MRMC comparative effectiveness study involving human readers and AI assistance is described. This device is an in-vitro diagnostic (IVD) assay, not an AI-powered diagnostic imaging or decision support system that would typically involve human-in-the-loop performance evaluation.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the performance data presented (analytical and clinical comparison) reflects the standalone performance of the VIDAS® B-R.A.H.M.S PCT Assay in determining procalcitonin levels. The assay itself is the algorithm/device being evaluated. Its intended use is "in conjunction with other laboratory findings and clinical assessments," meaning it's a tool for clinicians, not a complete standalone diagnostic for severe sepsis/septic shock.
7. The Type of Ground Truth Used
The ground truth for the clinical studies appears to be the clinical diagnosis of "severe sepsis or septic shock" in critically ill patients, and the classification of subjects as "healthy." For the healthy subjects, the ground truth is simply their healthy status. For the critically ill patients, the ground truth is the outcome or diagnosis of severe sepsis/septic shock, which would be based on established medical criteria (e.g., Sepsis-3 definitions, though the document is from 2007 so older criteria like SIRS/Sepsis/Severe Sepsis/Septic Shock definitions would apply).
8. The Sample Size for the Training Set
The document does not explicitly mention a separate "training set" for the device, as it is an immunoassay, not a machine learning algorithm that typically requires a large training dataset. The development and optimization of the assay would have involved various internal studies, but these are not specified as a "training set" in the context of clinical validation data.
9. How the Ground Truth for the Training Set Was Established
Given that this is an immunoassay, the concept of "ground truth for a training set" as it applies to machine learning is not directly applicable. Assay development would involve optimizing parameters against known concentration controls and spiked samples, and eventually validating against clinical samples with known diagnoses (as described in the clinical studies).
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J 1 2007
510(k) SUMMARY
VIDAS® B-R.A.H.M.S PCT Assay
| A. Submitter Information | |
|---|---|
| Submitter's Name: | bioMérieux, Inc. |
| Address: | 595 Anglum RoadHazelwood, MO 63042 |
| Contact Person: | Nikita S. Mapp |
| Phone Number: | 314-731-7474 |
| Fax Number: | 314-731-8689 |
| Date of Preparation: | March 1, 2007 |
| B. Device Name | |
| Trade Name: | VIDAS® BRAHMS PCT |
| Common Name: | Endotoxin Assay |
| Classification Name: | 21 CFR 866.3210, Product Code NTMAntigen, Inflammatory Response Marker, Seps |
| C. Predicate Device Name | |
| Trade Name: | BRAHMS PCT LIA Assay |
D. Device Description
The VIDAS BRAHMS PCT Assay is an enzyme-linked fluorescent immunoassay (ELFA) performed in an automated VIDAS® instrument.
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 for the assay. 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-procalcitorin 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-Methylumbellifery| phosphate) is cycled in and out of the SPR. The conjugate enzyme catalyzes the
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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 revelation steps and stored in memory, and then printed out.
E. Intended Use
VIDAS BRAHMS PCT is an automated test for use on the VIDAS instruments for the determination of human procalcitonin in human serum or plasma (lithium heparin) using the ELFA (Enzyme-Linked Fluorescent Assay). VIDAS BRAHMS PCT is intended for use in conjunction with othe laboratory findings and clinical assessments 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.
F. Technological Characteristics Summary
A comparison of the similarities and differences of the assays is presented in the table below.
| IDAS BRAHMS PCT | BRAHMS POWER | |
|---|---|---|
| Intended Use | Determination of human procalcitonin inhuman serum or plasma (lithium heparin) | Same |
| Indications for Use | For use in conjunction with other laboratoryfindings and clinical assessments to aid inthe risk assessment of critically ill patientson their first day of ICU admission, forprogression to severe sepsis and septicshock | Same |
| Specimen | Human serum or plasma (lithium heparin) | Same |
| Analyte | Measures procalcitonin concentration | Same |
| Antibody | Anti-PCT antibody (monoclonal mouse) | Same |
| Assay Principle | Immunoassay based on sandwich principle | Immunoluminometric assay basedon sandwich principle |
| Automated | Automated assay | Non-automated assay |
| Final Detection of PCTantigen | Fluorescence (ELFA) of 4-methyl-umbelliferyl measured at 450 nm | Luminescence signalmeasurement via luminometer |
| Assay Technique | Enzyme-Linked Fluorescent Assay(ELFA) | Immunoluminometric assay (ILMA) |
| Special instrumentrequirements | None | Luminometer required |
| Sample Volume | 200 µl | 20 pl |
| Assay Time | ~20 minutes | ~90 minutes |
| Measurement range | 0.05 to 200 ng/ml | 0.3 - 500 ng/ml |
| Device[VIDAS BRAHMS PCT] | Predicate[BRAHMS PCT LIA] | |
| Non-clinical (Analytical) Comparison | ||
| Matrix Comparison | Serum similar to PlasmaFor a given patient, the same type ofsample tube must be performed for eachpatient | Same |
| Precision/Reproducibility | 6 samples tested in duplicate over 20 daystotal precision: 6.17 - 15.31% CVintra-run precision: 1.93 - 4.61% CVinter-run precision: 3.57 - 7.04% CVinter-site precision: 4.21 - 11.40% CV | 14 samples tested in duplicateover 20 daystotal precision: 5.3 - 16.6% CVwithin run precision: 2.4-10% CV |
| Analytical DetectionLimit | <0.05 ng/ml | 1.0 ng/ml |
| Functional DetectionLimit | 0.09 ng/ml | 0.3 ng/ml |
| Interfering Substances | No significant interference | No significant interference |
| Bilirubin | 574 µmol/l | 40 mg/dl |
| Hemoglobin | 347 µmol/l | 500 mg/dl |
| Triglycerides | 30 g/l | 634 mg/dl |
| Analytical Specificity | No significant interference | No significant interference |
| Protein (albumin) | 4 g/dl | 1 g/dl |
| Human calcitonin | 60 ng/ml | 8 ng/ml |
| Human katacalcin | 10 ng/ml | 30 ng/ml |
| Human alpha-CGRP | 10 µg/ml | 30 ng/ml |
| Human beta-CGRP | 10 µg/ml | 30 ng/ml |
| Drug Interference | No significant interference | No significant interference |
| Imipenem | 0.5 mg/ml | 1.18 mg/ml |
| Cefotaxime | 180 mg/dl | 90 mg/dl |
| Vancomycin | 3 mg/ml | 3.5 mg/ml |
| Dopamine | 26 mg/dl | 13 mg/dl |
| Noradrenalin | 4 µg/ml | 2 µg/ml |
| Dobutamine | 22.4 µg/ml | 11.2 µg/ml |
| Heparin | 16,000 U/L | 8000 U/I |
| Furosemide | 4 mg/dl | 2 mg/dl |
| Hook Effect | No hook effect found up to concentrationsof 2600 ng/ml | No hook effect found up toconcentrations of 4000 µg/L |
| Clinical Comparison | ||
| Cut-off | >2 ng/ml = high risk of severe sepsisand/or septic shock<0.5 ng/ml = low risk of severe sepsisand/or septic shock | Same |
| Clinical Sensitivity/Specificity Studies | ||
| Number of patients | 232 patients | 179 patients |
| Study Site(s) | US and Europe | Europe |
| Results | → In 92 patients with PCT level ≤0.5ng/ml, 18 patients had severe sepsis orseptic shock→ In 104 patients with severe sepsis orseptic shock, 37 patients had PCT | → In 44 patients with PCT<0.5 ng/ml, no patient hadsevere sepsis or septic shock→ In 77 patients with severesepsis or septic shock, one |
| Test | Device[VIDAS BRAHMS PCT] | Predicate[BRAHMS PCT LIA] |
| ng/ml | ||
| Clinical Specificity Study on U.S. Healthy Subjects (normal values) | ||
| Number of patients | 200 healthy subjects | 144 healthy subjects |
| Study Site(s) | US | US |
| Results | 200 healthy subjects;95th percentile: <0.05 ng/ml cut-off99th percentile: 0.09 ng/ml | 143 out of 144 healthy subjectshad PCT values of <0.3 ng/ml |
G. Performance Data
A summary of the non-clinical and clinical test results is presented in the table below.
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H. Conclusion
The VIDAS® BRAHMS PCT Assay is substantially equivalent to the BRAHMS PCT LIA Assay.
The 510(k) summary includes only information that is also covered in the body of the 510(k). The summary does not contain any puffery or unsubstantiated labeling claims. The summary does not contain any raw data, i.e., contains only summary data. The summary does not contain any trade secret or confidential commercial information. The summary does not contain any patient identification information.
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Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle or bird-like symbol with three curved lines representing its body and wings. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" is arranged in a circular fashion around the bird symbol. The text is in all capital letters and is evenly spaced around the circle.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Ms. Nikita S. Mapp Senior Regulatory Affairs Specialist bioMérieux, Inc. 595 Anglum Road Hazelwood, MO 63042
OCT 1 1 2007
Re: K071146
Trade/Device Name: VIDAS® BRAHMS PCT Regulation Number: 21 CFR 866.3210 Regulation Name: Endotoxin Assay Regulatory Class: Class II Product Code: NTM Dated: August 30, 2007 Received: September 4, 2007
Dear Ms. Mapp:
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.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at 240-276-0450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at 240-276-3474. For questions regarding the reporting of device adverse events (Medical Device Reporting (MDR)), please contact the Division of Surveillance Systems at 240-276-3464. You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (240) 276-3150 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours.
Sally attym
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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VIDAS® B.R.A.H.M.S PCT Assay Traditional 510(k) Submission
INDICATIONS FOR USE
510(k) Number (if known): K071146
Device Name: VIDAS BRAHMS PCT Assay
Indications for Use: VIDAS® BRAHMS PCT is an automated test for use on the VIDAS instruments for the determination of human procalcitonin in human serum or plasma (lithium heparin) using the ELFA (Enzyme-Linked Fluorescent Assay) technique. The VIDAS BRAHMS PCT assay is intended for use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission, for progression to severe sepsis and septic shock.
Prescription Use_ × (Part 21 CFR 801 Subpart D)
AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH. Office of Device Evaluation (ODE)
Kudith te Poole
Division Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Safety
§ 866.3210 Endotoxin assay.
(a)
Identification. An endotoxin assay is a device that uses serological techniques in whole blood. The device is intended for use in conjunction with other laboratory findings and clinical assessment of the patient to aid in the risk assessment of critically ill patients for progression to severe sepsis.(b)
Classification. Class II (special controls). The special control for this device is the FDA guidance entitled “Class II Special Controls Guidance Document: Endotoxin Assay.” See § 866.1(e) for the availability of this guidance document.