(353 days)
The B·R·A·H·M·S PCT sensitive KRYPTOR is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma.
The B.R.A.H.M.S.PCT sensitive KRYPTOR is intended to be performed on the B·R·A·H·M·S KRYPTOR analyzer family.
The B R A H M S PCT sensitive KRYPTOR 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 Intensive Care Unit (ICU) admission for progression to severe sepsis and septic shock.
The B·R·A·M·S PCT sensitive KRYPTOR is also intended for use to determine the change in PCT level over time as an aid in assessing the cumulative 28-day risk of allcause 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 level on the first day of ICU admission above 2.0 µg/L is associated with a higher risk for progression to severe sepsis and/or septic shock than a PCT level below 0.5 ug/L.
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 PCT level (≤ 2.0 ug/L or > 2.0 µg/L) 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.
The B·R·A·H·M·S PCT sensitive KRYPTOR is an immunofluorescent assay using Time-Resolved Amplified Cryptate Emission (TRACE) technology to determine the concentration of PCT (procalcitonin) in human serum and EDTA or heparin plasma. It contains reagents including Cryptate Conjugate, XL665 Conjugate, and Diluent. Additional required materials include Calibrator, Controls, and KRYPTOR Consumables (Solutions 1, 2, 3, 4, BUFFER, Reaction plates, Dilution plates). The assay is a homogeneous sandwich immunoassay performed on the B·R·A·H·M·S KRYPTOR compact PLUS analyzer, a fully automated system. The measuring principle is based on Time-Resolved Amplified Cryptate Emission (TRACE®) technology, which measures the signal emitted from an immunocomplex with time delay. The system is a closed system and can only operate utilizing specially made reagent kits from B.R. A. H. M.S. The B.R.A.H-M-S KRYPTOR compact PLUS analyzer user interface displays the significant processes within the system to the user. An on-line 'Change in Procalcitonin Calculator' is also available as a web-based software application to aid in the interpretation of results.
B.R.A.H.M.S PCT sensitive KRYPTOR Device Performance Summary
This document describes the acceptance criteria and the supporting study for the B.R.A.H.M.S PCT sensitive KRYPTOR device, which aids in assessing the cumulative 28-day risk of all-cause mortality in patients with severe sepsis or septic shock.
1. Acceptance Criteria and Reported Device Performance
The device's performance regarding prognostic accuracy for 28-day all-cause mortality is evaluated based on the change in PCT levels over time. The primary acceptance criteria for the clinical claim are based on the association between the percent change in PCT level and 28-day all-cause mortality risk.
Table 1: Acceptance Criteria and Reported Device Performance for 28-Day Mortality Risk
| Acceptance Criteria (ΔPCT from Day 0/1 to Day 4) | Reported Device Performance (28-Day Mortality Risk) | P-value (Fisher's Exact Test) | Hazard Ratio (95% CI) (Cox Proportional Hazards Regression) |
|---|---|---|---|
| Non-significant decline in PCT (≤ 80%) associated with higher risk of 28-day all-cause mortality | Higher mortality risk observed for ΔPCT ≤ 80% | 0.002 | 2.02 (1.27-3.23) for ΔPCT (Day 0 to Day 4) |
| Significant decline in PCT (> 80%) associated with lower risk of 28-day all-cause mortality | Lower mortality risk observed for ΔPCT > 80% |
Note: The table above primarily focuses on the clinical claim of assessing 28-day mortality risk. Other analytical performance characteristics were evaluated against established CLSI guidelines, which implicitly define acceptance criteria for precision, linearity, stability, etc.
2. Sample Size and Data Provenance for the Test Set
The clinical study (MOSES study - ClinicalTrials.gov Identifier: NCT01523717) evaluated the device's performance.
- Test Set Sample Size: The analysis population for the clinical study consisted of 598 subjects.
- Data Provenance: The data was collected from a prospective clinical trial across 13 investigational sites in the US.
3. Number of Experts and Qualifications for Ground Truth Establishment (Test Set)
The ground truth for the clinical study was 28-day all-cause mortality. This is an objective outcome, and therefore, no human experts were required to establish the ground truth for the test set.
4. Adjudication Method (Test Set)
Given that the primary ground truth for the clinical study was 28-day all-cause mortality, which is a definitive clinical outcome, no adjudication method was necessary for the test set.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study was mentioned in the provided text. The device is an in vitro diagnostic assay, and the study focused on the performance of the assay itself in predicting mortality, rather than assessing human reader improvement with or without AI assistance.
6. Standalone (Algorithm Only) Performance
The clinical study evaluated the performance of the B.R.A.H.M.S PCT sensitive KRYPTOR assay in assessing 28-day mortality risk. This is inherently a standalone (algorithm only) performance evaluation, as it measures the quantitative change in PCT levels and correlates it with an outcome, without direct human intervention in the measurement interpretation for the purpose of the study's primary endpoint. The Change in Procalcitonin Calculator is a web-based tool provided as an aid for interpretation, but the assay results themselves are generated by the automated instrument.
7. Type of Ground Truth Used
The ground truth used for the clinical study was outcomes data, specifically cumulative 28-day all-cause mortality. This is a definitive patient outcome.
8. Sample Size for the Training Set
The provided document does not specify a separate training set sample size for the clinical study used to validate the mortality risk claim. The study (MOSES study) is described as a "prospective clinical trial... of 858 adult patients," with an "analysis population of 598 subjects." It is an observational study that evaluated the association between PCT change and mortality, rather than training an algorithm on a specific dataset. Therefore, the clinical claim was validated on the 598 subjects from the MOSES study, which may be considered the validation or test set rather than a training set for an AI model. For the analytical performance characteristics (precision, linearity, etc.), specific sample sizes were used for each analytical study, as detailed in section L.1.
9. How the Ground Truth for the Training Set Was Established
As mentioned in point 8, the document does not describe a separate training set for an algorithm that predicts mortality. The clinical study was an observational study that validated the prognostic utility of PCT changes. The ground truth for the outcomes measured in this study (28-day all-cause mortality) was established through patient follow-up and recorded vital status (i.e., objective outcomes data).
§ 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.