(139 days)
VIDAS® B+R+A+H+M+S PCT™ (PCT) is an automated test for use on the instruments of the VIDAS® family for the determination of human procalcitonin in human serum or plasma (lithium heparinate) using the ELFA (Enzyme-Linked Fluorescent Assay) technique.
Used in conjunction with other laboratory findings and clinical assessments, VIDAS® B•R•A•H•M•S PCT™ is intended for use as follows:
· to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock.
· to aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time.
· to aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) - defined as community-acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) - in an inpatient setting or an emergency department,
· to aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis.
The assay principle combines a one-step immunoassay sandwich method with a final fluorescent detection (ELFA).
The Solid Phase Receptacle (SPR®), serves as the solid phase as well as the pipetting device. Reagents for the assay are ready-to-use and pre-dispensed in the sealed reagent strips.
All of the assay steps are performed automatically by the instrument. The sample is transferred into the wells containing anti-procalcitonin antibodies labeled with alkaline phosphatase (conjugate). The sample/conjugate mixture is cycled in and out of the SPR® several times. This operation enables the antigen to bind with the immunoglobulins fixed to the interior wall of the SPR® and the conjugate to form a sandwich. Unbound compounds are eliminated during washing steps.
Two detection steps are performed successively. During each step, the substrate (4-Methylumbelliferyl phosphate) is cycled in and out of the SPR®. The conjugate enzyme catalyzes the hydrolysis of this substrate into a fluorescent product (4-Methyl-umbelliferone) the fluorescence of which is measured at 450 nm. The intensity of the fluorescence is proportional to the concentration of antigen present in the sample.
At the end of the assay, results are automatically calculated by the instrument in relation to two calibration curves corresponding to the two detection steps. A fluorescence threshold value determines the calibration curve to be used for each sample. The results are then printed out.
The provided text describes the non-clinical and clinical studies conducted for the clearance of the VIDAS® B·R·A·H·M·S PCT™ device.
1. Table of Acceptance Criteria and Reported Device Performance
The document provides analytical performance (non-clinical) results rather than specific acceptance criteria thresholds the device must meet in a table. However, it reports the performance of the device against common analytical metrics. For clinical performance, it summarizes the findings of meta-analyses.
Analytical Performance (Non-Clinical)
| Performance Metric | Reported Device Performance (VIDAS®) | Reported Device Performance (VIDAS® 3) | Acceptance Criteria (Implicit from CLSI® recommendations for determining the limits) |
|---|---|---|---|
| Limits of Detection & Quantitation | |||
| Limit of Blank (LoB) | 0.01 ng/mL | 0.01 ng/mL | Determined per CLSI® EEP17-A recommendations |
| Limit of Detection (LoD) | 0.03 ng/mL | 0.03 ng/mL | Determined per CLSI® EEP17-A recommendations |
| Limit of Quantitation (LoQ) | 0.05 ng/mL | 0.05 ng/mL | 0.05 ng/mL (with bias ≤ 10%, %CV ≤ 20%, Total Error ≤ 50%) |
| Precision | |||
| Repeatability CV (%) (Range) | 1.3% - 14.6% | 2.0% - 9.7% | Determined per CLSI® EP5-A3 recommendations |
| Between-Day Precision CV (%) (Range) | 3.0% - 15.9% | 3.5% - 10.9% | Determined per CLSI® EP5-A3 recommendations |
| Within-Lab Precision CV (%) (Range) | 3.9% - 20.2% | 3.9% - 18.2% | Determined per CLSI® EP5-A3 recommendations |
| Reproducibility/Total Precision CV (%) (Range) | 3.9% - 20.2% | 4.3% - 18.2% | Determined per CLSI® EP5-A3 recommendations |
| Interference | |||
| Drugs & Potentially Interfering Substances | No interference observed at tested concentrations | No interference observed at tested concentrations | No interference observed at tested concentrations (relative to CLSI® EP7-A2 recommendations) |
Clinical Performance (Summary of Meta-Analyses Findings)
The clinical studies involved meta-analyses of existing Randomized Control Trials (RCTs) rather than new primary clinical trials with specific acceptance criteria in the format of sensitivity/specificity/accuracy for the device itself. Instead, the meta-analyses aimed to demonstrate the clinical utility of PCT-guided therapy.
For Decision Making on Antibiotic Therapy for LRTI:
- Antibiotic initiation: 19.2% reduction in relative antibiotic initiation for all patients.
- Overall antibiotic exposure: 38% reduction for inpatients, 51% reduction for ER patients.
- Antibiotic duration: 2.9 days reduction (patient-level meta-analysis), 1.25 days reduction (study-level meta-analysis).
- Total antibiotic exposure: 3.6 days reduction (patient-level meta-analysis), 2.79 days reduction (study-level meta-analysis).
- Negative effects (mortality, complications, length of stay): No negative effects observed.
- Ranked patient outcomes: Statistically significant improvement in PCT-guided management vs. standard management.
For Decision Making on Antibiotic Discontinuation for Septic Patients:
- Antibiotic duration: 1.5 days reduction.
- Total antibiotic exposure: 3.2 days reduction.
- Overall antibiotic exposure: 23% reduction.
- Negative effects (mortality, hospital/ICU length of stay): No negative effects observed.
2. Sample Size Used for the Test Set and Data Provenance
-
Analytical (Non-Clinical) Test Set:
- Limits of Detection & Quantitation: The sample size is not explicitly stated as a number of individual samples, but rather as determinations on the VIDAS® and VIDAS®3 instruments.
- Precision Study: Panel of 11 human samples. Each sample was tested in duplicate in 2 runs per day over 20 days using 3 VIDAS® and 3 VIDAS®3 instruments (N=240 values for each sample) at 3 sites. Two reagent lots were used (10 days of tests, 6 calibrations per lot).
- Interference Study: Not specified how many samples, but multiple drugs and substances were tested at specified concentrations.
- Data Provenance: Not explicitly stated, but generally, such analytical studies are conducted in a laboratory setting, likely within the manufacturer's R&D or a contract research organization.
-
Clinical Test Set:
- Decision making on antibiotic therapy for LRTI:
- Study-level meta-analysis: 11 Randomized Control Trials (RCTs), 4090 patients.
- Patient-level meta-analysis: 13 RCTs, 3142 patients.
- Decision making on antibiotic discontinuation for septic patients:
- Study-level meta-analysis: 10 RCTs, 3489 patients.
- Patient-level meta-analysis: 5 RCTs, 598 patients.
- Data Provenance for Clinical Studies: The data comes from retrospective meta-analyses of previously published Randomized Control Trials (RCTs). The countries of origin for these RCTs are not specified in the provided text.
- Decision making on antibiotic therapy for LRTI:
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
- Analytical (Non-Clinical) Test Set: Ground truth for analytical performance (LoB, LoD, LoQ, precision, interference) is established through standardized laboratory reference methods and certified control materials, following CLSI guidelines. This typically does not involve human experts establishing ground truth in the same way clinical ground truth is established.
- Clinical Test Set (Meta-Analyses): The "ground truth" in these meta-analyses refers to the patient outcomes (e.g., antibiotic exposure, mortality, complications, length of stay) as reported in the original RCTs. These outcomes would have been objectively measured or determined by the clinicians and researchers involved in those original studies, based on their clinical assessments, laboratory findings, and established diagnostic criteria. No specific number or qualification of experts for "establishing ground truth" for the meta-analysis itself is mentioned, as the meta-analysis aggregates existing validated data.
4. Adjudication Method for the Test Set
- Analytical (Non-Clinical) Test Set: Adjudication is not typically applicable for these types of analytical tests as they rely on quantitative measurements against reference standards and statistical analysis.
- Clinical Test Set (Meta-Analyses): The meta-analyses involve combining and contrasting data from multiple sources. Each original RCT would have had its own methods for clinical assessment and outcome determination, which might have included adjudication by a panel of clinicians. However, the provided document does not describe an adjudication method for the meta-analysis itself beyond the systematic review and pooling of data.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed. The device is an in vitro diagnostic (IVD) test that measures procalcitonin levels, not an imaging device or AI-driven diagnostic that would involve human readers interpreting cases with and without AI assistance. The clinical studies performed were meta-analyses of PCT-guided therapy vs. standard care, focusing on patient outcomes and antibiotic usage, not on human reader performance.
6. Standalone Performance Study
Yes, the analytical (non-clinical) tests demonstrate the standalone performance of the algorithm/device. The "Limits of detection and quantitation," "Precision," and "Study of drugs and other potentially interfering substances" sections describe the device's inherent performance characteristics independent of human interpretation or intervention beyond performing the assay itself. This is the algorithm only without human-in-the-loop performance for an IVD device.
7. Type of Ground Truth Used
- Analytical (Non-Clinical) Studies: The ground truth is based on:
- Established analytical methods and reference materials for measuring procalcitonin concentration.
- Statistical methods (e.g., CLSI guidelines) for determining LoB, LoD, LoQ, and precision.
- Controlled interference studies with known concentrations of drugs and substances.
- Clinical Studies (Meta-Analyses): The ground truth is based on:
- Outcomes Data from previously published Randomized Control Trials (RCTs), including antibiotic administration duration, total antibiotic exposure, mortality, hospital length of stay, and ICU length of stay.
- Clinical assessments and diagnoses made in the original RCTs for patient admission with suspected sepsis/LRTI and severe sepsis/septic shock.
8. Sample Size for the Training Set
The document describes premarket notification for a diagnostic test, not a machine learning or AI algorithm in the typical sense that requires a training set for model development. The VIDAS® B·R·A·H·M·S PCT™ is an ELFA (Enzyme-Linked Fluorescent Assay) technique. Therefore, the concept of a "training set" for a machine learning model is not applicable here. The assay relies on a biochemical reaction and fluorescent detection.
9. How the Ground Truth for the Training Set Was Established
As explained in point 8, the concept of a "training set" for model development is not relevant to this type of diagnostic assay. The ground truth for calibrating the assay and establishing its analytical performance relies on established laboratory standards, controls, and reference methods as part of its development and validation process.
§ 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.