(262 days)
The Alere NT-proBNP for Alinity i assay is a chemiluminescent microparticle immunoassay (CMIA) used for the in vitro quantitative determination of N-terminal pro B-type natriuretic peptide (NT-proBNP) in human serum and plasma on the Alinity i system.
In the emergency department, measurements of NT-proBNP are used as an aid in the diagnosis of heart failure (HF) in patients with clinical suspicion of new onset or worsening HF.
The Alere NT-proBNP for Alinity i assay is an automated, two-step immunoassay for the in vitro quantitative determination of NT-proBNP in human serum and plasma using chemiluminescent microparticle immunoassay (CMIA) technology. Sample and anti-NT-proBNP coated paramagnetic microparticles are combined and incubated. The NT-proBNP present in the sample binds to the anti-NT-proBNP coated microparticles. The mixture is washed. Anti-NT-proBNP acridinium-labeled conjugate is added to create a reaction mixture and incubated. Following a wash cycle, Pre-Trigger and Trigger Solutions are added. The resulting chemiluminescent reaction is measured as a relative light unit (RLU). There is a direct relationship between the amount of NT-proBNP in the sample and the RLU detected by the system optics.
Despite the request for acceptance criteria and study proving the device meets said criteria, the provided document is a 510(k) summary for a diagnostic test (Alere NT-proBNP for Alinity i Reagent Kit). This type of document focuses on demonstrating substantial equivalence to a predicate device, and thus does not explicitly list "acceptance criteria" for performance in the same way one might find for a new medical device claiming superiority or non-inferiority.
Instead, the document details various performance characteristics of the device, comparing them to relevant standards (CLSI guidelines) and providing statistical data. It aims to show that the new device performs acceptably and similarly to a previously cleared device.
Therefore, I cannot extract a table of "acceptance criteria" as such a table is not explicitly presented. However, I can infer the implied acceptance criteria from the reported performance, specifically from the "No Significant Interference" and "within acceptable performance" statements in the nonclinical performance section, and the effectiveness of the cutoffs for diagnosis in the clinical performance. The "reported device performance" will be the actual numbers provided in the document.
Here's a summary of the available information, structured to address your points as much as possible given the document type:
Implied Acceptance Criteria and Reported Device Performance
As this is a 510(k) submission, explicit quantitative acceptance criteria are not stated in a dedicated table format. Instead, the device's performance characteristics are presented as evidence of substantial equivalence to a predicate device and adherence to recognized standards. The implied acceptance criteria are that the device demonstrates acceptable accuracy, precision, and clinical utility for its stated indications for use.
Here's a table summarizing key performance indicators that would implicitly serve as acceptance criteria given standard diagnostic device requirements:
| Performance Characteristic | Implied Acceptance Criterion | Reported Device Performance |
|---|---|---|
| Analytical Measuring Interval (AMI) | The range over which results can be reliably quantified. | 15.8 to 35,000.0 pg/mL (1.9 to 4130.0 pmol/L). Extended Measuring Interval (EMI) up to 350,000 pg/mL (41,300.0 pmol/L) for diluted samples. |
| Linearity | Device should demonstrate linear response across AMI. | Linear across the AMI of 15.8 to 35,000.0 pg/mL. |
| Within-Laboratory Precision (Overall CV) | Low variability; specific CV targets for different concentration levels. | Low Control: 6.2% CV |
| Medium Control: 4.1% CV | ||
| High Control: 4.0% CV | ||
| Panels A-F: 3.6% - 10.0% CV | ||
| Panel G: 4.0% CV | ||
| Panel H (Supplemented): 7.7% CV | ||
| Reproducibility (Overall CV) | Low variability across sites, days, and lots. | Low Control: 4.7% CV |
| Medium Control: 4.8% CV | ||
| High Control: 6.7% CV | ||
| Panel 1: 18.9% CV | ||
| Panels 2-6: 4.3% - 6.0% CV | ||
| Panel 7 (Supplemented): 6.6% CV | ||
| Panel 8 (Supplemented): 7.2% CV | ||
| Lower Limits of Measurement (LoQ) | Detect and quantify analyte at low concentrations with acceptable precision. | LoQ: 15.8 pg/mL (1.9 pmol/L) (defined as lowest concentration at which 20% CV was met). |
| LoB: 0.1 pg/mL | ||
| LoD: 3.6 pg/mL (0.4 pmol/L) | ||
| Analytical Specificity (Interference) | Interference within ±10.0% for listed substances/drugs. | No significant interference (within ±10.0%): Bilirubin, Biotin, Cholesterol, HAMA, Hemoglobin, IgG, Intralipid, RF (up to 600 IU/mL), Total Protein (up to 12.6 g/dL), and a comprehensive list of 50+ drugs at specified concentrations. |
| Interference beyond ±10.0% observed for: RF at 1520 IU/mL (-8.9% to -11.4%), Total Protein at 15.2 g/dL (-12.7%). | ||
| Cross-Reactivity | % recovery within 100% ± 10% for listed cross-reactants. | All evaluated cross-reactants (e.g., Adrenomedullin, Aldosterone, Angiotensin I/II/III, ANP, BNP, CNP, Endothelin, NT-proANP, Renin, Urodilatin) showed % recovery within 100% ± 10%. |
| High Dose Hook | No hook effect up to a specified high concentration. | No hook effect observed up to 372,620 pg/mL. |
| Clinical Performance (Posttest Probability for HF) | Positive test result to show high posttest probability of HF; Negative test result to show high posttest probability of Non-HF. | All Subjects (Positive): 75.2% (708/942) posttest probability of HF. |
| All Subjects (Negative): 94.0% (794/845) posttest probability of Non-HF. | ||
| Grayzone: 35.6% posttest probability of HF. | ||
| Similar detailed results provided for various age groups, sexes, eGFR, BMI, and comorbidity subgroups. | ||
| Clinical Performance (Likelihood Ratios for HF) | High LR (Positive), Low LR (Negative). | All Subjects (Positive): 4.29 (3.80, 4.83) |
| All Subjects (Negative): 0.09 (0.07, 0.12) | ||
| Grayzone: 0.78 (0.64, 0.96) | ||
| Similar detailed results provided for various age groups, sexes, eGFR, BMI, and comorbidity subgroups. |
Study Details:
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Sample sizes used for the test set and the data provenance:
- Clinical Performance Study (test set): 2127 Emergency Department (ED) subjects.
- Provenance: Multi-center prospective study across 17 collection sites in the US.
- Demographics: 1030 (48.4%) female, 1097 (51.6%) male, age 19-97 years. Predominantly White (53.1%) and Black/African American (39.5%). 90.9% non-Hispanic/Latino.
- Nonclinical Performance (examples):
- Within-Laboratory Precision: 240 replicates (controls/panels).
- Reproducibility: 360 replicates (controls/panels) per assay (across 3 sites).
- Lower Limits of Measurement: n ≥ 60 replicates for LoB, LoD, LoQ.
- Analytical Specificity/Interference: Each substance tested at 2 analyte levels (approximately 125 pg/mL and 2000 pg/mL).
- Clinical Performance Study (test set): 2127 Emergency Department (ED) subjects.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- The ground truth for the clinical study was an "adjudicated diagnosis" determined by a panel of board-certified cardiologists. The exact number of cardiologists on the panel is not specified in the provided text.
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Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- The document states "An adjudicated diagnosis was determined by a panel of board-certified cardiologists." It does not specify the exact adjudication method (e.g., majority vote, sequential review, etc.).
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If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- No, this document describes the validation of a quantitative in vitro diagnostic (IVD) reagent kit for measuring NT-proBNP levels using an automated chemiluminescent immunoassay (CMIA) system. It is not an AI-assisted diagnostic imaging device, so an MRMC study is not relevant to this submission. The "readers" are the automated analyzers and laboratory personnel interpreting numerical results.
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If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
- This device is a standalone diagnostic test in the sense that it provides a quantitative NT-proBNP result. The assay itself is a fully automated process on the Alinity i system. The performance data presented (precision, linearity, limits, specificity, clinical performance tables) represent the performance of the device "standalone" in generating these quantitative results, which are then used by clinicians as an "aid in diagnosis." There isn't a "human-in-the-loop" component to the measurement itself, though medical professionals interpret the results in a clinical context.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- For the clinical performance study, the ground truth for Heart Failure (HF) diagnosis was established by expert consensus (adjudicated diagnosis by a panel of board-certified cardiologists).
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The sample size for the training set:
- This document describes a 510(k) submission for an in vitro diagnostic reagent kit. Unlike AI/ML software, such devices typically undergo analytical and clinical validation studies with defined test sets but do not have a "training set" in the sense of machine learning algorithms. The development and optimization of the assay would have involved various internal samples and experiments, but these are not explicitly termed "training sets" and their size is not reported in this context.
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How the ground truth for the training set was established:
- As explained above, the concept of a "training set" with established ground truth, as typically applied to machine learning or AI models, does not directly apply to the regulatory submission type for this diagnostic reagent kit. The assay is based on chemical and biological principles (CMIA) rather than learned algorithms from large datasets.
§ 862.1117 B-type natriuretic peptide test system.
(a)
Identification. The B-type natriuretic peptide (BNP) test system is an in vitro diagnostic device intended to measure BNP in whole blood and plasma. Measurements of BNP are used as an aid in the diagnosis of patients with congestive heart failure.(b)
Classification. Class II (special controls). The special control is “Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications; Final Guidance for Industry and FDA Reviewers.”