(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%.
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.
§ 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.