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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)

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.

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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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%.

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:

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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