(26 days)
For in-vitro diagnostic use only.
For the quantitative measurement of procalcitonin (PCT) in human serum and plasma (lithium heparin and EDTA) using the VITROS 3600 Immunodiagnostic System.
Used in conjunction with other laboratory findings and clinical assessments, the VITROS B R A PA - M S PCT test 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 VITROS B·R·A·H·M·S PCT test is performed using the VITROS B·R·A·H·M·S PCT Reagent Pack and the VITROS B·R·A·H·M·S PCT Calibrators on the VITROS Systems.
Reagent Pack Contents
1 reagent pack containing:
- 100 coated wells (rat monoclonal anti-procalcitonin antibody, 1.0 µg/mL) ●
- 10.20 mL assay reagent (buffer containing bovine gamma globulin, bovine serum ● albumin and antimicrobial agent)
- . 13.10 mL conjugate reagent (HRP-conjugated mouse monoclonal procalcitonin antibody. 1.65 ug/mL in buffer with bovine serum albumin and antimicrobial agent)
Calibrator Contents
- . 3 sets of VITROS B•R•A•H•M•S PCT Calibrators 1 and 2, 1.0 mL, procalcitonin in buffer with antimicrobial agent, nominal values 0.080 and 75.0 ng/mL (ug/L)
- . Lot calibration card
- Protocol card ●
- 16 calibrator bar code labels (8 for each calibrator) ●
The provided text is a 510(k) Summary for the VITROS B·R·A·H·M·S PCT Reagent Pack and Calibrators, intended for quantitative measurement of procalcitonin (PCT). This document describes the device's performance characteristics and clinical studies to establish substantial equivalence to a predicate device.
Here's an analysis of the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
Since this is a 510(k) summary for an in vitro diagnostic device, the "acceptance criteria" are implied by the comparison to the predicate device and established analytical performance metrics. The key criterion is demonstrating substantial equivalence to the predicate device, B·R·A·H·M·S PCT sensitive KRYPTOR (K171338), especially at critical clinical decision points.
| Feature / Acceptance Criteria Category | Specific Criteria (Implied/Stated) | Reported Device Performance (VITROS B·R·A·H·M·S PCT) | Supporting Study / Section |
|---|---|---|---|
| Predicate Device Comparison (Substantial Equivalence) | Correlation with predicate (B·R·A·H·M·S PCT sensitive KRYPTOR) | Correlation Coefficient (r): 0.995 (all samples), 0.994 (within measuring range) | Method Comparison with Predicate Device |
| Mean Percent Bias | 1.31% (all samples), 1.88% (within measuring range) | Method Comparison with Predicate Device | |
| Passing & Bablok Slope (95% CI) | 1.001 (0.9773 to 1.027) (all samples), 1.025 (1.002 to 1.054) (within measuring range) | Method Comparison with Predicate Device | |
| Passing & Bablok Intercept (95% CI) | 0.01041 (0.001562 to 0.03272) (all samples), 0.004237 (-0.004908 to 0.01905) (within measuring range) | Method Comparison with Predicate Device | |
| Weighted Deming Slope (95% CI) | 1.046 (1.025 to 1.066) (all samples), 1.057 (1.035 to 1.078) (within measuring range) | Method Comparison with Predicate Device | |
| Weighted Deming Intercept (95% CI) | -0.009264 (-0.01498 to -0.003549) (all samples), -0.009994 (-0.01585 to -0.004140) (within measuring range) | Method Comparison with Predicate Device | |
| Clinical Agreement at Decision Points | Total clinical agreement > 97% at 0.100, 0.250, 0.500, 2.00 ng/mL | 98.5% (0.100 ng/mL), 98.0% (0.250 ng/mL), 97.4% (0.500 ng/mL), 97.8% (2.00 ng/mL) | Clinical Concordance |
| Cohen's Kappa for agreement | 0.772 (0.100 ng/mL), >0.910 (0.250, 0.500, 2.00 ng/mL) | Clinical Concordance | |
| Precision (Within-lab %CV) | Acceptable precision specified by CLSI EP05-A3 | Ranges from 3.1% to 6.4% across various concentrations (VITROS 3600) | Precision/Reproducibility |
| Multi-Site Precision (Reproducibility %CV) | Acceptable precision across sites | Ranges from 4.6% to 15.9% across various concentrations (VITROS 3600) | Multi-Site Precision |
| Accuracy (Linearity) | Linear over the measuring range | Linear from 0.030 to 100 ng/mL; Bias criteria of ±10% met | Linearity/Assay Measuring Range |
| Limit of Detection (LoD) | Determined consistent with CLSI EP17-A2 | 0.007 ng/mL | Detection Limits |
| Limit of Quantitation (LoQ) | Determined consistent with CLSI EP17-A2 | 0.030 ng/mL (at 20% CV) | Detection Limits |
| Analytical Specificity (Interference) | No bias >10% at specified concentrations for various compounds | None of tested compounds caused >10% bias | Analytical Specificity |
| Matrix Equivalence | Less than 10% bias from serum (slope 0.90-1.10) for plasma | Passing & Bablok Slope: 0.980 (Lithium Heparin), 0.992 (EDTA) | Matrix Comparison |
| High Dose Hook | No hook effect up to 5,000 ng/mL | No evidence of high dose hook up to 5,000 ng/mL | High Dose Hook |
2. Sample Sizes and Data Provenance
-
Test Set (Method Comparison with Predicate):
- Sample Size: 266 patient samples were used for the regression analysis comparing the VITROS B·R·A·H·M·S PCT test to the B·R·A·H·M·S PCT sensitive KRYPTOR assay. 246 samples were within the measuring range.
- Data Provenance: Not explicitly stated for analytical studies, but for the clinical performance study, samples were "retrospective samples from a study of 858 adult patients diagnosed with severe sepsis or septic shock recruited across 13 investigational sites in the United States." The original MOSES Study (DEN150009) collected samples from patients admitted to ICU from emergency departments, other wards, or directly from out of the hospital. EDTA samples were used.
-
Test Set (Clinical Concordance):
- Sample Size: 2168 samples (evaluating concordance at various PCT decision points).
- Data Provenance: "serial sample sets obtained from the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study collection, a well-characterized sample collection in 13 sites across the United States." This indicates a prospective collection used retrospectively for this specific device's evaluation.
-
Test Set (28-Day Mortality Prediction):
- Sample Size: 858 adult patients in the study, with an analysis population of 598 subjects.
- Data Provenance: Retrospective samples from the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study collection in 13 sites across the United States.
3. Number of Experts and Qualifications for Ground Truth
- For an in vitro diagnostic device measuring an analyte (procalcitonin), the "ground truth" for analytical studies is typically established by reference methods or gravimetric preparation with known concentrations. Experts are not typically involved in establishing ground truth for analytical performance like precision, linearity, LoD/LoQ, and interference.
- For clinical studies (concordance and mortality prediction), the primary "ground truth" for the device's performance against clinical decision points is the predicate device's measurement (B.R.A.H.M.S PCT sensitive KRYPTOR assay). Physician discretion and clinical assessments were used for patient diagnosis and mortality outcomes in the MOSES study, which provided the samples. While physicians made clinical diagnoses, they were not experts establishing a "ground truth score" for the device; rather, clinical outcomes (mortality, diagnosis of sepsis/septic shock) were endpoints. No individual "experts" were formally used to establish a ground truth for the test set, but rather the clinical outcomes and the predicate device's results served as the reference.
4. Adjudication Method
- Not applicable in the context of this 510(k) summary for an in vitro diagnostic device assessing an analyte level. Adjudication methods like 2+1 or 3+1 are typically used for subjective evaluations (e.g., imaging interpretation) where expert consensus is needed to determine the correct ground truth for a given case. Here, the ground truth for analytical performance is quantitative, and for clinical performance, it is the predicate device's measurement and observed clinical outcomes (e.g., 28-day mortality).
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, an MRMC comparative effectiveness study was not performed. This device is an in vitro diagnostic assay, not an AI-assisted diagnostic tool for human readers. Therefore, the concept of "how much human readers improve with AI vs without AI assistance" does not apply.
6. Standalone Performance Study
- Yes, the performance described is a standalone performance study of the VITROS B·R·A·H·M·S PCT Reagent Pack and Calibrators. The "algorithm only" in this context refers to the assay's ability to quantitatively measure PCT levels. All analytical performance studies (precision, linearity, detection limits, analytical specificity, matrix comparison, high-dose hook, sample auto-dilution, carry-over) were conducted to demonstrate the standalone performance of the VITROS B·R·A·H·M·S PCT test. The clinical concordance with the predicate device also serves as a standalone performance benchmark.
7. Type of Ground Truth Used
- Analytical Ground Truth: For analytical performance studies (precision, linearity, LoD/LoQ, interference, matrix equivalence, high dose hook, carry over), the ground truth was established by:
- Reference calibrators: Traceable to in-house reference calibrators, which were value-assigned to correlate to B·R·A·H·M·S PCT sensitive KRYPTOR.
- Known concentrations: Prepared by gravimetric spiking with recombinant PCT.
- Validated analytical methods: Following CLSI guidelines (e.g., EP05-A3 for precision, EP17-A2 for detection limits, EP06-A for linearity, EP07-A3 for interference).
- Clinical Ground Truth:
- Predicate device results: For clinical concordance, the measurements from the B·R·A·H·M·S PCT sensitive KRYPTOR assay were considered the reference for comparison.
- Outcomes data: For the 28-day mortality prediction claim, the vital status (mortality) of patients at Day 28 was the ground truth. This outcome data was collected during the original MOSES study.
8. Sample Size for the Training Set
- This 510(k) document describes a traditional in vitro diagnostic device clearance, not an AI/ML software submission that often explicitly details "training sets."
- However, the device's calibration is "traceable to in-house reference calibrators, which have been value-assigned to correlate to B·R·A·H·M·S PCT sensitive KRYPTOR." The development of these in-house reference calibrators and the assay itself would have involved some form of "training" or optimization using an internal dataset, but its size and specific characteristics are not provided in this regulatory summary.
- The clinical study samples from the MOSES study were used for validation (evaluation) of the device's clinical performance, not as a training set for the assay's underlying methodology.
9. How the Ground Truth for the Training Set Was Established
- As noted above, a formal "training set" in the AI/ML sense is not described. The ground truth for the development of the assay (e.g., for calibrator assignment) would have been established through a combination of:
- Reference materials: Highly characterized procalcitonin standards.
- Defined analytical methods: Using established laboratory practices and potentially comparing to existing, well-regarded PCT assays during the R&D phase to create the "in-house reference calibrators."
- Value assignment: A process where the concentration of an analyte in a calibrator is accurately determined. This often involves multiple measurements using reference methods or by gravimetric preparation.
§ 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.