(88 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.
VIDAS® B·R·A·H·M·S PCT™ (PCT) 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.
VIDAS® B·R·A·H·M·S PCT™ (PCT) is also intended for use to determine the change of PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality in conjunction with other laboratory findings and clinical assessments for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission.
Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids in the risk assessment of critically ill patients on their first day of Intension for progression to severe sepss and septic shock. The percent change in PCT level over time also aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.
PCT levels on the first day of ICU admission above 2.0 ng/mL are associated with a higher risk for progression to severe sepsis and/or septic shock than PCT levels below 0.5 ng/mL.
A PCT level that declines < 80% from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28-day risk of all-cause mortality than a decline > 80%.
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 adout the mortality risk.
The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.
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.
This document describes the VIDAS® B·R·A·H·M·S PCT™ (PCT), an automated test for determining human procalcitonin levels in serum or plasma, used to aid in the risk assessment of critically ill patients for progression to severe sepsis and septic shock, and to assess the cumulative 28-day risk of all-cause mortality in patients diagnosed with severe sepsis or septic shock.
Here's an analysis of the acceptance criteria and study proving device performance:
1. Table of Acceptance Criteria and Reported Device Performance:
The document doesn't explicitly define "acceptance criteria" for clinical performance in a comparative table with reported values. Instead, it provides clinical study results demonstrating the device's prognostic accuracy. Analytical performance is reported against established guidelines.
Here's a summary of the analytical performance:
| Acceptance Criterion (Implicit) | Reported Device Performance |
|---|---|
| Analytical Performance | |
| Limit of Blank (LoB) | 0.01 ng/mL |
| Limit of Detection (LoD) | 0.03 ng/mL |
| Limit of Quantitation (LoQ) (lowest conc. w/ CV ≤ 20%) | 0.05 ng/mL (Lowest PCT conc. measured with acceptable precision of 20% CV) |
| Precision (Within-Laboratory CV) | VIDAS®: 4.2% - 14.6% across 9 samples (mean range 0.12 - 164.85 ng/mL) VIDAS®3: 5.0% - 12.6% across 9 samples (mean range 0.12 - 140.35 ng/mL) |
| Linearity (over complete measurement range) | Confirmed to be linear over the complete measurement range for both VIDAS® and VIDAS®3. |
| Clinical Performance (Prognostic Accuracy for 28-Day Mortality) | |
| Association of ΔPCT ≤ 80% with higher mortality risk | Statistically significant association: Patients with ΔPCT ≤ 80% had a statistically significantly increased 28-day mortality compared to patients with ΔPCT > 80% (p-value 0.0003 and 0.002 for VIDAS®3 and VIDAS® respectively for ΔPCT based on Day 0). Mortality in the group with ΔPCT ≤ 80% was increased by a factor of 2.1 (Day 0) to 1.8 (Day 1) on VIDAS®3, and 2.05 (Day 0) to 1.6 (Day 1) on VIDAS®. Prognostic Accuracy (Sensitivity & Specificity) - Examples from table on page 11 (VIDAS®3, Day 0 to Day 4, ICU, All PCT levels): Sensitivity: 78.4% (95% CI: 68.7-88.1%), Specificity: 35.7% (95% CI: 28.7-42.7%) Hazard Ratios (ΔPCT ≤ 80% vs. > 80%): VIDAS®3: 2.27 (Day 0 to Day 4), 1.96 (Day 1 to Day 4) VIDAS®: 2.05 (Day 0 to Day 4), 1.74 (Day 1 to Day 4) |
2. Sample Size Used for the Test Set and Data Provenance:
- Sample Size (Clinical Study): 858 adult patients were recruited across 13 investigational sites. The "per protocol population" used for the analysis comprised 598 patients.
- Data Provenance: The study was conducted at 13 investigational sites in the US. The study is prospective, as patients were recruited and followed for 28 days to assess mortality.
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 used or their qualifications for establishing the ground truth related to patient diagnosis of severe sepsis or septic shock, or the 28-day all-cause mortality outcome. These are assumed to be standard clinical diagnoses and outcome tracking in a hospital setting.
4. Adjudication Method for the Test Set:
- The document does not specify an explicit adjudication method for clinical diagnoses or outcomes. It implies that diagnoses of severe sepsis/septic shock and 28-day mortality were determined based on standard clinical practice at the participating sites.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Improvement with AI vs. Without AI Assistance:
- No, this is not an MRMC study. This is a clinical study evaluating the prognostic utility of a biomarker (PCT) measured by an automated in-vitro diagnostic device. It does not involve human readers interpreting cases or AI assistance in interpretation. The device provides a quantitative measurement, which clinicians then use in conjunction with other findings.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done:
- Yes, in essence, the analytical performance studies are "standalone" algorithm-only performance. The device automatically measures procalcitonin levels. The clinical study then evaluates how these quantitative results, particularly the change in PCT levels (ΔPCT), correlate with patient outcomes (28-day mortality), independent of human interpretation of the PCT value itself, though still in the context of clinical assessment.
7. The Type of Ground Truth Used (Expert Consensus, Pathology, Outcomes Data, etc.):
- Outcomes Data and Clinical Diagnosis:
- Clinical Diagnosis of severe sepsis or septic shock: This served as the inclusion criteria for the patient cohort. While the method for establishing this initial diagnosis is not detailed, it would typically be based on established clinical criteria.
- Cumulative 28-day all-cause mortality: This was the primary outcome measured and served as the ground truth for evaluating the prognostic accuracy of the PCT values and ΔPCT.
8. The Sample Size for the Training Set:
- The document does not specify a separate training set size for the clinical performance evaluation. The 598 patients in the per-protocol population appear to be a single cohort used for the performance assessment. For analytical performance (e.g., LoB, LoD, LoQ, Precision), specific numbers of replicates and samples are provided (e.g., 240 values for each of 9 samples for precision).
9. How the Ground Truth for the Training Set Was Established:
- As a separate "training set" for clinical performance is not explicitly mentioned for this 510(k) submission, the method for establishing ground truth for a training set is not provided. For the clinical study that assessed prognostic accuracy, the ground truth was the 28-day all-cause mortality outcome, as observed and recorded for the enrolled patients. The diagnoses of severe sepsis or septic shock were clinical diagnoses used for patient enrollment.
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June 28, 2016
Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
BIOMERIEUX, INC. THI DANG REGULATORY AFFAIRS SPECIALIST 595 ANGLUM RD. HAZELWOOD, MO 63042
Re: K160911
Trade/Device Name: VIDAS® BRAHMS 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: II Product Code: PMT Dated: March 31, 2016 Received: April 1, 2016
Dear Ms. Dang:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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If you desire specific advice for your device on our labeling regulations (21 CFR Parts 801 and 809), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638 2041 or (301) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
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Sincerely yours,
Steven R. Gitterman -S
For Uwe Scherf, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K160911
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.
VIDAS® B·R·A·H·M·S PCT™ (PCT) 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.
VIDAS® B·R·A·H·M·S PCT™ (PCT) is also intended for use to determine the change of PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality in conjunction with other laboratory findings and clinical assessments for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission.
Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids in the risk assessment of critically ill patients on their first day of Intension for progression to severe sepss and septic shock. The percent change in PCT level over time also aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.
PCT levels on the first day of ICU admission above 2.0 ng/mL are associated with a higher risk for progression to severe sepsis and/or septic shock than PCT levels below 0.5 ng/mL.
A PCT level that declines < 80% from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28-day risk of all-cause mortality than a decline > 80%.
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 adout the mortality risk.
The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.
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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Image /page/3/Picture/0 description: The image shows the logo for bioMerieux. The logo consists of the company name in gray, stylized text, with a blue globe-like icon above it. A green curved line extends from the top of the globe down through the middle of the company name, and a green and yellow bar is located below the company name.
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: | Thi My Lan Dang |
| Phone Number: | 314-731-8799 |
| Fax Number: | 314-731-8689 |
| Date of Preparation: | March 31, 2016 |
B. Device Name
| Trade Name: | VIDAS® B·R·A·H·M·S PCT™ (PCT) |
|---|---|
| Common Name: | Endotoxin Assay |
| Classification Name: | Device to detect and measure non-microbial analyte(s) in humanclinical specimens to aid in assessment of patients with suspectedsepsis (21 CFR 866.3215, Product Code PMT) – Class II in vitroDiagnostic device |
C. Predicate Devices
Predicate device 1, trade name: B·R·A·H·M·S PCT Sensitive KRYPTOR® (DEN150009)
Predicate device 2, trade name: VIDAS® B·R·A·H·M·S PCT™ (K071146)
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Image /page/4/Picture/0 description: The image shows the logo for bioMérieux, a French multinational biotechnology company. The logo features a stylized globe with blue and white lines, with a green sprout emerging from the top. Below the globe is the company name, "BIOMÉRIEUX," in a bold, sans-serif font. The background transitions from green to yellow.
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. Indications for 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.
VIDAS® B+R+A+H+M+S PCT™ (PCT) 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.
VIDAS® B+R+A+H+M+S PCT™ (PCT) is also intended for use to determine the change of PCT level over time as an aid in assessing the cumulative 28-day risk of all-cause mortality in conjunction with other laboratory findings and clinical assessments for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission.
Procalcitonin (PCT) is a biomarker associated with the inflammatory response to bacterial infection that aids in the risk assessment of critically ill patients on their first day of Intensive Care Unit (ICU) admission for progression to severe sepsis and septic shock. The percent change in PCT level over time also aids in the prediction of cumulative 28-day mortality in patients with severe sepsis and septic shock.
PCT levels on the first day of ICU admission above 2.0 ng/mL are associated with a higher risk for progression to severe sepsis and/or septic shock than PCT levels below 0.5 ng/mL.
A PCT level that declines ≤ 80% from the day that severe sepsis or septic shock was clinically diagnosed (Day 0) to four days after clinical diagnosis (Day 4) is associated with higher cumulative 28day risk of all-cause mortality than a decline > 80%.
The combination of the first PCT level (≤ 2.0 ng/mL or > 2.0 ng/mL) at initial diagnosis of severe sepsis or septic shock with the patient's clinical course and the change in PCT level over time until Day 4 provides important additional information about the mortality risk.
The PCT level on Day 1 (the day after severe sepsis or septic shock is first clinically diagnosed) can be used to calculate the percent change in PCT level at Day 4 if the Day 0 measurement is unavailable.
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Image /page/5/Picture/0 description: The image shows the logo for bioMérieux, a French multinational biotechnology company. The logo features the company name in a sans-serif font, with the "BIO" portion in a darker, bolder font than the "MÉRIEUX" portion. Above the name is a stylized graphic consisting of a blue sphere with curved lines and a green curved line extending upwards from the sphere. The logo also has a green and yellow gradient bar at the bottom.
F. Technological Characteristics Summary
A general comparison of the similarities and differences of the assay with the predicates is presented in the following table.
| Item | Proposed Device:VIDAS® B-R-A-H-M-S™ PCT | Predicate device 1:B·R·A·H·M·S PCT SensitiveKRYPTOR® (DEN150009) | Predicate device 2:VIDAS® B-R-A-H-M-S PCT™(K071146) |
|---|---|---|---|
| Indicationsfor use | VIDAS® B·R·A·H·M·S PCT™(PCT) is an automated test foruse on the instruments of theVIDAS® family for thedetermination of humanprocalcitonin in human serum orplasma (lithium heparinate)using the ELFA (Enzyme-LinkedFluorescent Assay) technique.VIDAS® B·R·A·H·M·S PCT™(PCT) is intended for use inconjunction with other laboratoryfindings and clinicalassessments to aid in the riskassessment of critically illpatients on their first day of ICUadmission for progression tosevere sepsis and septic shock.VIDAS® B·R·A·H·M·S PCT™(PCT) is also intended for use todetermine the change of PCTlevel over time as an aid inassessing the cumulative 28-dayrisk of all-cause mortality inconjunction with other laboratoryfindings and clinicalassessments for patientsdiagnosed with severe sepsis orseptic shock in the ICU or whenobtained in the emergencydepartment or other medicalwards prior to ICU admission. | The B·R·A·H·M·S PCT sensitiveKRYPTOR® is animmunofluorescent assay usingTime-Resolved AmplifiedCryptate Emission (TRACE®)technology to determine theconcentration of PCT(procalcitonin) in human serumand EDTA or heparin plasma.The B·R·A·H·M·S PCT sensitiveKRYPTOR® is intended to beperformed on the B·R·A·H·M·SKRYPTOR® analyzer family.The B·R·A·H·M·S PCT sensitiveKRYPTOR® is intended for usein conjunction with otherlaboratory findings and clinicalassessments to aid in the riskassessment of critically illpatients on their first day ofIntensive Care Unit (ICU)admission for progression tosevere sepsis and septic shock.The B·R·A·H·M·S PCT sensitiveKRYPTOR® is also intended foruse to determine the change inPCT level over time as an aid inassessing the cumulative 28-dayrisk of all-cause mortality inconjunction with other laboratoryfindings and clinicalassessments for patientsdiagnosed with severe sepsis orseptic shock in the ICU or whenobtained in the emergencydepartment or other medicalwards prior to ICU admission.Procalcitonin (PCT) is abiomarker associated with theinflammatory response tobacterial infection that aids in therisk assessment of critically ill | VIDAS® B·R·A·H·M·S PCT™(PCT) is an automated test foruse on the instruments of theVIDAS® family for thedetermination of humanprocalcitonin in human serum orplasma (lithium heparinate)using the ELFA (Enzyme-LinkedFluorescent Assay) technique.VIDAS® B·R·A·H·M·SPCT™ (PCT) is intended for usein conjunction with otherlaboratory findings and clinicalassessments to aid in the riskassessment of critically illpatients on their first day of ICUadmission for progression tosevere sepsis and septic shock.Procalcitonin (PCT) is abiomarker associated with theinflammatory response tobacterial infection that aids in therisk assessment of critically illpatients on their first day ofIntensive Care Unit (ICU)admission for progression tosevere sepsis and septic shock.The percent change in PCT levelover time also aids in the |
| Item | Proposed Device:VIDAS® B-R-A-H-M-STM PCT | Predicate device 1:B-R-A-H-M-S PCT SensitiveKRYPTOR® (DEN150009) | Predicate device 2:VIDAS® B-R-A-H-M-S PCTTM(K071146) |
| are associated with a higher riskfor progression to severe sepsisand/or septic shock than PCTlevels below 0.5 ng/mL.A PCT level that declines ≤ 80%from the day that severe sepsisor septic shock was clinicallydiagnosed (Day 0) to four daysafter clinical diagnosis (Day 4) isassociated with highercumulative 28-day risk of all-cause mortality than a decline >80%.The combination of the first PCTlevel (≤ 2.0 ng/mL or > 2.0ng/mL) at initial diagnosis ofsevere sepsis or septic shockwith the patient's clinical courseand the change in PCT levelover time until Day 4 providesimportant additional informationabout the mortality risk.The PCT level on Day 1 (the dayafter severe sepsis or septicshock is first clinicallydiagnosed) can be used tocalculate the percent change inPCT level at Day 4 if the Day 0measurement is unavailable. | prediction of cumulative 28-daymortality in patients with severesepsis and septic shock.PCT levels on the first day ofICU admission above 2.0 µg/Lare associated with a higher riskfor progression to severe sepsisand/or septic shock than PCTlevels below 0.5 µg/L.A PCT level that declines ≤ 80%from the day that severe sepsisor septic shock was clinicallydiagnosed (Day 0) to four daysafter clinical diagnosis (Day 4) isassociated with highercumulative 28-day risk of all-cause mortality than a decline >80%.The combination of the first PCTlevel (≤ 2.0 µg/L or > 2.0 µg/L) atinitial diagnosis of severe sepsisor septic shock with the patient'sclinical course and the change inPCT level over time until Day 4provides important additionalinformation about the mortalityrisk.The PCT level on Day 1 (the dayafter severe sepsis or septicshock is first clinicallydiagnosed) can be used tocalculate the percent change inPCT level at Day 4 if the Day 0measurement is unavailable. | ||
| Specimen | Human serum or plasma (lithiumheparinate). | Human serum, plasma (EDTA,heparin) | Same as the proposed device |
| Analyte | Procalcitonin (PCT) | Same as the proposed device | Same as the proposed device |
| Automated | Automated assay | Same as the proposed device | Same as the proposed device |
| AssayTechnique | ELFA (Enzyme-LinkedFluorescent Assay) technique. | Immunofluorescent assay | Same as the proposed device |
| Assayprinciple | Immunoassay based onsandwich principle | Immunofluorescent assay basedon sandwich principle | Same as the proposed device |
| Detectionmethod | Fluorescence (ELFA) of 4-methyl-umbelliferyl measured at450 nm | Measuring principle based onTRACE® technology whichmeasures the signal emittedfrom an immunocomplex withtime delay | Same as the proposed device |
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Image /page/6/Picture/0 description: The image contains the logo for bioMérieux. The logo features the company name in a sans-serif font, with the "bio" portion in a darker shade. Above the name is a stylized graphic of a globe with curved lines, bisected by a curved green line, possibly representing growth or a biological element.
G. Nonclinical Test
A summary of the non-clinical (analytical) results is presented below.
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Dilution for sample volumes between 50 uL and 200 uL
A dilution study was performed on the VIDAS® according to a protocol based on the CLSI EPG-A guideline. Sample volumes between 50 µL and 200 µL can be tested after performing a manual dilution up to 1:4 (1 volume of test sample + 3 volume of diluent) before testing with the VIDAS® B·R·A·H·M·S PCT assay.
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®3 instruments according to the CLSI® EP17-A2 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 Limit of Quantitation (LoQ) is the lowest concentration of PCT measured with a level of acceptable precision of 20% CV.
Precision
The study was performed according to the recommendations of CLSI® document EP5-A3. A panel of 9 human samples covering the measuring range were tested 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:
VIDAS®
| Meanconcentration(ng/mL) | Repeatability | Between-Dayprecision | Within-Laboratoryprecision | Reproducibility /Total precision | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Sample | N | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | |
| Sample 1 | 240 | 0.12 | 0.011 | 9.0% | 0.013 | 10.9% | 0.018 | 14.6% | 0.018 | 14.6% |
| Sample 2 | 240 | 0.16 | 0.010 | 6.6% | 0.013 | 8.5% | 0.020 | 12.7% | 0.020 | 12.7% |
| Sample 3 | 240 | 0.20 | 0.011 | 5.4% | 0.013 | 6.1% | 0.017 | 8.2% | 0.017 | 8.2% |
| Sample 4 | 240 | 0.53 | 0.013 | 2.4% | 0.017 | 3.2% | 0.023 | 4.2% | 0.023 | 4.2% |
| Sample 5 | 240 | 2.14 | 0.027 | 1.3% | 0.048 | 2.3% | 0.081 | 3.8% | 0.081 | 3.8% |
| Sample 6 | 240 | 23.20 | 0.506 | 2.2% | 0.749 | 3.2% | 0.962 | 4.1% | 0.962 | 4.1% |
| Sample 7 | 240 | 93.01 | 3.136 | 3.4% | 5.343 | 5.7% | 6.962 | 7.5% | 6.962 | 7.5% |
| Sample 8 | 240 | 129.86 | 5.368 | 4.1% | 8.436 | 6.5% | 12.664 | 9.8% | 12.664 | 9.8% |
| Sample 9 | 240 | 164.85 | 7.364 | 4.5% | 10.613 | 6.4% | 18.445 | 11.2% | 18.445 | 11.2% |
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Image /page/8/Picture/0 description: The image shows the logo for bioMérieux. The logo features the company name in a sans-serif font, with the "bio" portion in a darker, bolder font than the "Mérieux" portion. Above the company name is a stylized graphic consisting of a blue globe-like shape with curved lines, bisected by a green, curved line that resembles a plant stem or leaf.
| N | Meanconcentration(ng/mL) | Repeatability | Between-Dayprecision | Within-Laboratoryprecision | Reproducibility /Total precision | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Sample | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | StandardDeviation(ng/mL) | CV(%) | ||
| Sample 1 | 240 | 0.12 | 0.010 | 8.6% | 0.010 | 8.6% | 0.015 | 12.6% | 0.015 | 12.6% |
| Sample 2 | 239 | 0.15 | 0.013 | 8.3% | 0.014 | 9.2% | 0.017 | 11.2% | 0.017 | 11.2% |
| Sample 3 | 239 | 0.20 | 0.012 | 6.2% | 0.013 | 6.6% | 0.016 | 8.2% | 0.017 | 8.5% |
| Sample 4 | 239 | 0.52 | 0.020 | 3.8% | 0.022 | 4.2% | 0.026 | 5.0% | 0.031 | 6.1% |
| Sample 5 | 240 | 2.06 | 0.042 | 2.0% | 0.061 | 3.0% | 0.095 | 4.6% | 0.100 | 4.9% |
| Sample 6 | 240 | 21.85 | 0.583 | 2.7% | 0.694 | 3.2% | 0.844 | 3.9% | 0.955 | 4.4% |
| Sample 7 | 240 | 83.60 | 3.365 | 4.0% | 3.520 | 4.2% | 4.791 | 5.7% | 5.815 | 7.0% |
| Sample 8 | 240 | 110.83 | 5.494 | 5.0% | 5.750 | 5.2% | 7.884 | 7.1% | 8.669 | 7.8% |
| Sample 9 | 240 | 140.35 | 6.470 | 4.6% | 7.329 | 5.2% | 11.301 | 8.1% | 13.026 | 9.3% |
Linearity
VIDAC® 2
The test linearity was studied on the VIDAS® and VIDAS® 3 instruments according to a procedure taken from the CLSI EP6-A guideline. The test is linear over the complete measurement range.
Clinical Testing H.
A study was conducted on a population of 858 adult patients recruited across 13 investigational sites in the US to assess the performance of VIDAS® BRANHIM SPCT™ (PCT) on VIDAS® and VIDAS for the prediction of cumulative 28-day all-cause mortality.
In the per protocol population (598 patients) was comprised of 44% female and 56% male patients with a mean age of 64 years, diagnosed either with severe sepsis (51%) or septic shock (49%), presenting mainly with community acquired infections (91%) and less frequently with nosocomial infections (9%). All patients were admitted into ICU at some point during their hospital stay, 44% were still located in ICU at Day 4 of the study ("ICU" group), where at Day 4 already transferred to a location outside of the ICU ("non-ICU" group).
Demographics with patients outcome and % mortality information are shown below:
| Variable | Class | N* | Dead | Alive | % Mortality |
|---|---|---|---|---|---|
| Gender | Female | 264 | 46 | 218 | 17.4% |
| Gender | Male | 334 | 55 | 279 | 16.5% |
| Age | ≤ 30 | 39 | 1 | 38 | 2.6% |
| (years) | 31-45 | 45 | 4 | 41 | 8.9% |
| 46-55 | 74 | 8 | 66 | 10.8% | |
| 56-65 | 149 | 26 | 123 | 17.4% | |
| 66-75 | 125 | 21 | 104 | 16.8% | |
| > 75 | 166 | 41 | 125 | 24.7% | |
| Ethnicity | African-American | 202 | 32 | 170 | 15.8% |
| Asian | 7 | 0 | 7 | 0.0% | |
| Caucasian | 362 | 64 | 298 | 17.7% | |
| Hispanic | 23 | 5 | 18 | 21.7% | |
| Other | 4 | 0 | 4 | 0.0% |
*per protocol population
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Cumulative 28-day all-cause mortality did not differ significantly for male vs. female patients ($χ$2 pvalue = 0.84).
| Variable | Class | VIDAS® 3 | VIDAS® | ||||||
|---|---|---|---|---|---|---|---|---|---|
| N | Dead | Alive | % Mortality | N | Dead | Alive | % Mortality | ||
| PCT on Day 0(ng/mL) | < 0.5 | 101 | 17 | 84 | 16.8% | 97 | 16 | 81 | 16.5% |
| 0.5-2.0 | 89 | 10 | 79 | 11.2% | 92 | 10 | 82 | 10.9% | |
| > 2.0 | 373 | 70 | 303 | 18.8% | 367 | 69 | 298 | 18.8% | |
| Unavailable* | 35 | 4 | 31 | 11.4% | 42 | 6 | 36 | 14.3% |
Initial PCT levels at Day 0 with patients outcome and % mortality were as follows:
- Unavailable patients results were either not available for testing (VIDAS 3 n = 24, VIDAS n = 29), or were below assay measuring range of 0.05 ng/mL (VIDAS 3 n = 11, VIDAS n = 13).
The study demonstrated that for patients diagnosed with severe sepsis or septic shock, the 28-Day mortality was statistically significantly increased for patients with ΔPCT ≤ 80% compared to patients with ΔPCT > 80%:
- Binary ΔPCT was significantly associated with 28-day cumulative mortality (Two-sided Fisher's ● Exact Test p-value 0.0003 and 0.002 for VIDAS®3 and VIDAS® respectively for ΔPCT based on Day 0 and p-value = 0.003 and 0.019 for VIDAS®3 and VIDAS® respectively for $\Delta$PCT based on Day 1) and this association remained significant in each patient location subgroup, ICU vs. non ICU at Day 4 (for VIDAS 3 and VIDAS® respectively Cochran-Mantel-Haenszel Test p-value =0.006 and 0.016 using $\Delta$PCT based on Day 0 and p-value = 0.023 and 0.073 using $\Delta$PCT based on Day 1). The mortality in the group with $\Delta$PCT $\leq$ 80 % was increased by a factor of 2.1 on on Day of the more and to the group with APCT > 80% using JPCT based on Day 0 (factor 1.8 on VIDAS 3 and 1.6 on VIDAS® using ΔPCT based on Day 1). The observed mortality risk was generally higher in the ICU subgroup than in the non-ICU group (5.4 to 11.4% vs. 18.4 to 31.6%). In each subgroup, the mortality was even higher for patients with a ΔΡCT ≤ 80% than for patients with a $\Delta$PCT > 80%.
- Supplementary classification of patients based on the patient location on Day 4 and initial PCT . level (< 2.0 vs. ≥ 2.0 ng/mL) at Day 0 (or Day 1) showed that in each patient location and initial PCT level subgroup, a PCT decrease ≤ 80% from Day 0 (or Day 1) to Day 4 constitutes a higher risk for mortality within 28 days compared to a higher PCT decline (> 80%). For the prediction of absolute mortality risks, ICU disposition at Day 4 and initial PCT level at Day 0 (or Day 1) should be considered in addition to binary $\Delta$PCT ($\leq$ 80% or > 80%).
Significantly reduced or increased mortality were observed by patient location and initial PCT level subgroups:
a) Patients still receiving ICU care on Day 4 or patients with initial PCT level > 2.0 ng/mL have a higher mortality risk from study Day 4 to the end of follow-up time (28 days) when the $\Delta$PCT is $\leq$ 80% compared to when the $\Delta$PCT is > 80%.
b) among patients who are still in the ICU on Day 4, patients with $\Delta$PCT > 80% and an initial PCT level of ≤ 2.0 ng/mL on Day 0 have a particularly lower cumulative 28-day mortality risk compared to patients with an initial PCT level at Day 0 of > 2.0 ng/mL (2.2% vs. 20.3% on VIDAS®3; 1.8% vs. 21.4% on VIDAS®). In addition, regardless of the initial PCT level, patients in the ICU on Day 4
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which have ΔΡCT ≤ 80% (Day 0 to Day 4) have an even higher mortality risk (26.4% to 34.1% on VIDAS3; 27.0% to 33.5% on VIDAS®).
c) even when they are no longer in the ICU on Day 4, patients with an initial PCT level > 2.0 ng/mL and with a ΔPCT ≤ 80% (Day 0 to Day 4) remain at high mortality risk (14.1% on VIDAS®3; 13.4% on VIDAS®). Overall, a lower mortality risk was observed for patients discharged from the ICU before or on Day 4 with an initial PCT level ≤ 2.0 ng/mL than for patients with an initial PCT level of > 2.0 ng/mL (3.7% to 9.5% vs. 5.8% to 14.1% on VIDAS3; 4.2% to 9.2% vs. 6.5% to 13.4% on VIDAS®).
The table below shows the 28-day cumulative mortality risk and prognostic accuracy by binary ΔPCT group (≤ 80% or > 80%), by the selection of either Day 0 or Day 1 for the ΔPCT calculation, by patient location at Day 4, and by initial PCT level.
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| Mortality Risk by binary ΔPCT group and Prognostic Accuracy* by Patient Location on Day 4 and by initial PCT level | ||||||||
|---|---|---|---|---|---|---|---|---|
| ΔPCTInterval | Day 4PatientLocation | InitialPCT level | 28 Day Mortality Risk | Prognostic Accuracy | ||||
| ΔPCT > 80%(95% CI) | ΔPCT ≤ 80%(95% CI) | Sensitivity(95% CI) | Specificity(95% CI) | |||||
| VIDAS®3 | Day 0 toDay 4 | ICU | All PCT levels | 18.4%(10.0-26.8%) | 31.3%(24.5-38.1%) | 78.4%(68.7-88.1%) | 35.7%(28.7-42.7%) | |
| ≤ 2.0 ng/mL | 2.2%(0.0-15.1%) | 26.4%(15.8-37.1%) | 98.8%(91.7-100.0%) | 14.9%(5.1-24.7%) | ||||
| > 2.0 ng/mL | 20.3%(11.1-29.5%) | 34.1%(25.3-42.9%) | 71.6%(59.4-83.8%) | 44.6%(36.0-53.3%) | ||||
| non ICU | All PCT levels | 5.4%(1.8-9.1%) | 11.4%(6.8-16.1%) | 71.7%(55.0-88.3%) | 47.0%(40.9-53.0%) | |||
| ≤ 2.0 ng/mL | 3.7%(0.0-11.0%) | 9.5%(3.9-15.1%) | 91.0%(74.2-100.0%) | 21.2%(13.2-29.1%) | ||||
| > 2.0 ng/mL | 5.8%(1.6-10.0%) | 14.1%(6.1-22.1%) | 59.6%(36.4-82.8%) | 64.3%(56.7-72.0%) | ||||
| ICU | All PCT levels | 18.4%(10.1-26.7%) | 31.6%(24.7-38.5%) | 77.2%(67.2-87.2%) | 37.7%(30.6-44.7%) | |||
| Day 1 toDay 4 | ≤ 2.0 ng/mL | 12.6%(0.0-34.0%) | 22.2%(11.6-32.7%) | 90.6%(74.1-100.0%) | 16.8%(6.4-27.2%) | |||
| > 2.0 ng/mL | 19.2%(10.3-28.1%) | 36.8%(27.8-45.7%) | 73.6%(61.9-85.3%) | 46.7%(38.0-55.3%) | ||||
| non ICU | All PCT levels | 7.0%(2.8-11.2%) | 10.1%(5.7-14.5%) | 63.8%(45.8-81.8%) | 45.8%(39.6-52.0%) | |||
| ≤ 2.0 ng/mL | 0.0%(0.0-13.2*%) | 8.1%(2.9-13.3%) | 100.0%(66.4-100.0*%) | 20.7%(12.9-28.4%) | ||||
| > 2.0 ng/mL | 8.5%(3.5-13.5%) | 13.0%(5.2-20.9%) | 48.1%(25.7-70.5%) | 63.5%(55.6-71.5%) | ||||
| VIDAS® | ICU | All PCT levels | 19.2%(10.7-27.6%) | 31.0%(24.2-37.8%) | 77.0%(67.1-87.0%) | 36.1%(29.1-43.1%) | ||
| Day 0 toDay 4 | ≤ 2.0 ng/mL | 1.8%(0.0-12.8%) | 27.0%(16.3-37.8%) | 98.9%(92.4-100.0%) | 16.4%(6.4-26.5%) | |||
| > 2.0 ng/mL | 21.4%(12.1-30.7%) | 33.5%(24.6-42.3%) | 69.5%(56.9-82.0%) | 44.8%(36.1-53.5%) | ||||
| non ICU | All PCT levels | 6.1%(2.2-10.0%) | 10.9%(6.3-15.4%) | 68.2%(51.0-85.4%) | 46.6%(40.6-52.7%) | |||
| ≤ 2.0 ng/mL | 4.2%(0.0-12.2%) | 9.2%(3.8-14.7%) | 91.0%(74.1-100.0%) | 19.0%(11.4-26.6%) | ||||
| > 2.0 ng/mL | 6.5%(2.1-10.8%) | 13.4%(5.3-21.5%) | 53.9%(30.3-77.6%) | 65.5%(57.9-73.2%) | ||||
| ICU | All PCT levels | 20.2%(11.7-28.6%) | 30.8%(23.9-37.7%) | 74.6%(64.3-85.0%) | 37.5%(30.4-44.5%) | |||
| Day 1 toDay 4 | ≤ 2.0 ng/mL | 2.2%(0.0-14.2%) | 22.2%(11.8-32.7%) | 98.2%(88.5-100.0%) | 17.7%(7.3-28.1%) | |||
| > 2.0 ng/mL | 22.5%(13.3-31.8%) | 35.6%(26.6-44.5%) | 68.9%(56.7-81.1%) | 46.2%(37.5-54.8%) | ||||
| non ICU | All PCT levels | 7.3%(2.9-11.6%) | 9.8%(5.5-14.2%) | 63.6%(45.5-81.7%) | 44.3%(38.2-50.4%) | |||
| ≤ 2.0 ng/mL | 0.2%(0.0-14.2%) | 6.9%(2.1-11.8%) | 99.5%(85.8-100.0%) | 19.0%(11.5-26.4%) | ||||
| > 2.0 ng/mL | 8.7%(3.5-13.8%) | 13.9%(6.0-21.8%) | 50.8%(28.9-72.6%) | 62.3%(54.3-70.2%) |
*Prognostic accuracy refers to how the binary ΔPCT can accurately predict mortality risk.
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Image /page/12/Picture/0 description: The image shows the logo for bioMérieux. The logo consists of the company name in a sans-serif font, with the "BIO" portion in a darker gray and the "MÉ RIEUX" portion in a lighter gray. Above the name is a blue globe-like design with a green curved line extending from the top of the globe down between the two parts of the company name. The background is white, with a green and yellow gradient bar at the bottom.
Time-to-event analysis is illustrated by the Kaplan-Meier survival probability curves below.
Image /page/12/Figure/3 description: The image contains four Kaplan-Meier survival curves, comparing the survival rates of patients based on their procalcitonin (PCT) levels and the change in PCT levels (ΔPCT). The top two graphs show data for VIDAS®3, while the bottom two show data for VIDAS®. The graphs on the left show patients with PCT levels less than or equal to 2.0 ng/mL at Day 0, with N=76 for VIDAS®3 and N=77 for VIDAS®. The graphs on the right show patients with PCT levels greater than 2.0 ng/mL at Day 0, with N=189 for VIDAS®3 and N=187 for VIDAS®. Each graph plots the proportion of patients surviving over time (in days) for both test-negative (ΔPCT > 80%) and test-positive (ΔPCT ≤ 80%) groups.
Survival probability until Day 28 for Patients still receiving ICU Care on Day 4
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Image /page/13/Picture/0 description: The image contains the logo for bioMérieux. The logo consists of the company name in a sans-serif font, with the "BIO" portion in a darker shade of gray and the "Mérieux" portion in a lighter shade. Above the name is a circular graphic that is half blue and half white with a green curved line extending upwards from the center. Below the name is a gradient bar that transitions from yellow to green.
Image /page/13/Figure/2 description: The image contains four Kaplan-Meier survival curves, comparing the survival rates of patients based on their procalcitonin (PCT) levels at Day 0 and the change in PCT levels (ΔPCT). The top two graphs show the survival curves for patients with PCT levels less than or equal to 2.0 ng/mL at Day 0 (left) and greater than 2.0 ng/mL at Day 0 (right) using VIDAS®3. The bottom two graphs show the survival curves for patients with PCT levels less than or equal to 2.0 ng/mL at Day 0 (left) and greater than 2.0 ng/mL at Day 0 (right) using VIDAS®. Each graph displays two curves: one for patients with a test negative (ΔPCT > 80%) and another for patients with a test positive (ΔPCT ≤ 80%), along with the number of patients in each group (N=134, N=200, N=134, N=198).
Survival probability until Day 28 for Patients without ICU Care on Day 4
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Performance of binary ΔPCT from Day 0 to Day 4 for the prognosis of 28-day cumulative mortality risk was quantified by Cox proportional hazards regression. Hazard ratio of 2.27 and 2.05 were observed for VIDAS®3 and VIDAS® respectively: patients with ΔPCT ≤ 80% have about a 2-fold higher 28day mortality risk than patients with ΔPCT > 80%.
In the table below, the relative mortality risk (univariate hazard ratios) are shown for binary ΔΡCT, and for other clinical factors evaluated as separate predictors of mortality, for indication.
| Predictors | Comparison | Hazard Ratio | 95% CI | p-Value | |
|---|---|---|---|---|---|
| VIDAS® 3 | ΔPCT (Day 0 to Day 4) | ≤ 80% vs. > 80% | 2.27 | 1.41 - 3.63 | 0.0007 |
| ΔPCT (Day 1 to Day 4) | ≤ 80% vs. > 80% | 1.96 | 1.24 - 3.11 | 0.004 | |
| PCT on Day 0 | >2 ng/mL vs. ≤ 2 ng/mL | 1.38 | 0.89 - 2.14 | 0.149 | |
| VIDAS® | ΔPCT (Day 0 to Day 4) | ≤ 80% vs. > 80% | 2.05 | 1.30 - 3.23 | 0.002 |
| ΔPCT (Day 1 to Day 4) | ≤ 80% vs. > 80% | 1.74 | 1.11 - 2.73 | 0.015 | |
| PCT on Day 0 | >2 ng/mL vs. ≤ 2 ng/mL | 1.39 | 0.89 - 2.15 | 0.145 | |
| APACHE on Day 1 | difference of 5 units | 1.36 | 1.22 - 1.53 | < 0.001 | |
| Max SOFA of Day 0-Day 4 | difference of 3 units | 1.73 | 1.50 - 2.00 | < 0.001 | |
| Antibiotic Adequacy | no vs. yes | 1.59 | 1.00 - 2.53 | 0.051 | |
| Sepsis Severity | septic shock vs. severe sepsis | 1.19 | 0.80 - 1.76 | 0.386 | |
| ICU Care on Day 4 | yes vs. no | 3.45 | 2.24 - 5.31 | < 0.001 | |
| Biological Infection Type | gram positive vs. gram negative | 0.83 | 0.48 - 1.45 | 0.522 | |
| Biological Infection Type | Fungal vs. gram negative | 2.44 | 0.87 - 6.84 | 0.09 | |
| Clinical Infection Type | Nosocomial vs. community acquired | 0.76 | 0.35 - 1.64 | 0.481 | |
| Positive Blood Culture | yes vs. no | 1.05 | 0.69 - 1.58 | 0.834 | |
| Age | difference of 5 years | 1.16 | 1.08 - 1.24 | < 0.001 | |
| Gender | male vs. female | 0.95 | 0.64 - 1.40 | 0.782 |
The binary ΔPCT was shown to have an added-value related to other mortality predictors in the prognosis of the risk of 28-day mortality in patients diagnosed with severe sepsis or septic shock. The relative mortality risk (Hazard ratio) for binary ΔΡCT and selected predictors (Patient location at Day 4, APACHE, max SOFA, Age) reported below were estimated with 95% confidence intervals using Cox multiple regression models adjusted for scores and other mortality predictors.
| Model | Hazard Ratio (95% Confidence Interval) | ||||||
|---|---|---|---|---|---|---|---|
| ΔPCT Interval | Score + covariates* | ΔPCT(≤80% vs. >80%) | Patient Location at Day 4(ICU vs. non ICU) | APACHE(1 SD = 8.13) | max SOFA(1 SD = 3.98) | Age(1 SD = 16.18) | |
| VIDAS® 3 | Day 0 to Day 4 | APACHE | 2.11 (1.24-3.59) | 2.59 (1.62-4.16) | 1.23 (0.98-1.54) | -- | 1.61 (1.28-2.01) |
| Day 0 to Day 4 | max SOFA | 1.81 (1.06-3.07) | 1.68 (1.02-2.77) | -- | 1.93 (1.50-2.49) | 1.69 (1.35-2.11) | |
| VIDAS® 3 | Day 1 to Day 4 | APACHE | 1.72 (1.05-2.82) | 2.60 (1.62-4.16) | 1.29 (1.03-1.61) | -- | 1.56 (1.25-1.95) |
| Day 1 to Day 4 | max SOFA | 1.60 (0.97-2.63) | 1.70 (1.04-2.79) | -- | 1.99 (1.55-2.55) | 1.65 (1.32-2.06) | |
| VIDAS® | Day 0 to Day 4 | APACHE | 1.82 (1.08-3.05) | 2.60 (1.62-4.17) | 1.24 (0.99-1.56) | -- | 1.59 (1.27-2.00) |
| Day 0 to Day 4 | max SOFA | 1.59 (0.95-2.67) | 1.68 (1.02-2.77) | -- | 1.96 (1.52-2.51) | 1.69 (1.35-2.11) | |
| VIDAS® | Day 1 to Day 4 | APACHE | 1.58 (0.97-2.57) | 2.61 (1.63-4.17) | 1.30 (1.04-1.63) | -- | 1.57 (1.25-1.96) |
| Day 1 to Day 4 | max SOFA | 1.42 (0.87-2.34) | 1.72 (1.05-2.82) | -- | 1.99 (1.56-2.56) | 1.67 (1.33-2.08) |
*The models also included the following predictors considered as covariates (hazard ratibiotic Adequacy, Sepsis Severity, Biological Infection Type, Positive Blood Culture, PCT on Day 0, Gender. In
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the 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.
Note: For binary predictors, the risk estimate compares the hazards for the two binary results. For continuous predictors, the hazard ratio (HR) was calculated for one standard deviation (SD) change in the predictor.
The change of PCT over time can also be described by the ratio of PCT values from Day 4 to Day 0 (or Day 1):
$$PCT_{_ratio} = \frac{PCT_{_Day_4}}{PCT_{_Day_0(\text{or } Day_1)}}$$
A ΔPCT of 80% corresponds to a PCT ratio of 0.2 (i.e. PCT level at Day 4 is 5 times less than PCT level at Day 0, or Day 1). When ΔPCT is ≤ 80%, the PCT ratio is ≥ 0.2, which is associated with a higher risk for cumulative 28-day all-cause mortality in patients diagnosed with severe sepsis or septic shock. Likewise, a PCT ratio < 0.2 indicates a lower risk for mortality within 28 days.
On a continuous scale, the larger the PCT ratio, the higher the relative mortality risk is.
In the following table, the relative increase in mortality risk (hazard ratio) are reported for a patient with any given PCT ratio compared to a patient with a 2-fold lower PCT ratio. For comparison, other selected predictors (APACHE, max SOFA, Age, Patient location at Day 4) are indicated with corresponding equivalents in standard deviation (0.50 SD on VIDAS3 and 0.51 SD on VIDAS for Day 0 to Day 4; 0.69 SD on VIDAS3 and 0.67 SD on VIDAS for Day 1 to Day 4).
| Model* | Hazard Ratio (95% Confidence Interval) | ||||||
|---|---|---|---|---|---|---|---|
| ΔPCT Interval | Score + covariates* | Continuous Predictors(HR per 2-fold increase in PCT ratio or per equivalent in SD) | Binary Predictor | ||||
| PCT ratio(2-fold increase) | APACHE(SD equivalent) | max SOFA(SD equivalent) | Age(SD equivalent) | Patient Location at Day 4(ICU vs. non ICU) | |||
| VIDAS®3 | Day 0 to Day 4 | APACHE | 1.28 (1.14-1.44) | 1.07 (0.95-1.20) | --- | 1.28 (1.14-1.43) | 2.50 (1.55-4.03) |
| max SOFA | 1.21 (1.08-1.36) | --- | 1.34 (1.18-1.52) | 1.31 (1.17-1.46) | 1.68 (1.02-2.77) | ||
| Day 1 to Day 4 | APACHE | 1.27 (1.09-1.48) | 1.19 (1.02-1.39) | --- | 1.37 (1.18-1.60) | 2.60 (1.62-4.17) | |
| max SOFA | 1.21 (1.03-1.42) | --- | 1.58 (1.33-1.87) | 1.43 (1.23-1.67) | 1.75 (1.06-2.87) | ||
| VIDAS® | Day 0 to Day 4 | APACHE | 1.29 (1.14-1.45) | 1.08 (0.96-1.21) | --- | 1.28 (1.14-1.44) | 2.49 (1.54-4.02) |
| max SOFA | 1.22 (1.08-1.37) | --- | 1.35 (1.19-1.54) | 1.31 (1.17-1.47) | 1.68 (1.02-2.76) | ||
| Day 1 to Day 4 | APACHE | 1.26 (1.08-1.46) | 1.18 (1.02-1.37) | --- | 1.36 (1.17-1.58) | 2.60 (1.62-4.17) | |
| max SOFA | 1.19 (1.02-1.39) | --- | 1.56 (1.32-1.84) | 1.42 (1.22-1.64) | 1.75 (1.06-2.86) |
*The models also included the following predictors considered as covariates (hazard ratio results not shown): Antibiotic Adequacy, Sepsis Severity, Biological Infection Type, Clinical Infection Type, Positive Blood Culture, PCT on Day 0, Gender. In the 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.
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l. Conclusion
The results from the non-clinical and clinical studies 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 devices.
§ 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.