(210 days)
The DiaSorin LIAISON® MeMed BV® is an automated in vitro diagnostic semi-quantitative assay that uses chemiluminescent immunoassay (CLIA) technology to measure three non-microbial (host) proteins (TRAIL, IP-10, and CRP) in adult and pediatric serum samples and is intended for use in conjunction with clinical assessments and other laboratory findings as an aid to differentiate bacterial from viral infection. The LIAISON® MeMed BV® assay is indicated for use in patients presenting to the emergency department or urgent care center and with samples collected at hospital admission from patients with suspected acute bacterial or viral infection, who have had symptoms for seven days or less. The LIAISON® MeMed BV® assay generates a numeric score that falls within discrete interpretation ranges based on the increasing likelihood of bacterial infection. The assay has to be performed on the automated LIAISON® XL Analyzer.
The DiaSorin LIAISON® MeMed BV® Control Set is intended for use as assayed quality control to monitor the performance of the DiaSorin LIAISON® MeMed BV® assay. The performance characteristics of the LIAISON® controls have not been established for any other assays or instrument platforms different from the automated LIAISON® XL Analyzer. The control set is intended for in vitro diagnostic use in a professional laboratory only.
The LIAISON MeMed BV assay consists of three individual chemiluminescence immunoassay (CLIA) for quantitative determination of TRAIL, IP-10, and CRP. The LIAISON MeMed BV test result is a score between 0 and 100 derived from computational integration of the measurements of the three proteins TRAIL, IP-10, and CRP, where low scores are indicative of viral infection and high score of bacterial infection. All three reagent packs must be the same lot and present at the same time on the same instrument used for sample testing. All three reagent packs are individually calibrated and quality controlled. Specimens are to be assigned to the MMBV assay protocol where all three reagent packs will be utilized to provide combined results and a final score.
The TRAIL reagent pack uses a monoclonal antibody for capture of TRAIL and a polyclonal antibody for the detection of TRAIL. The assay incubates sample, calibrator or control with assay buffer and paramagnetic particles coated with a monoclonal antibody that specifically recognizes the TRAL. Following the incubation, an isoluminol conjugated polyconal antibody that recognizes TRAIL is then added to the reaction and incubated. The unbound conjugate is removed with a wash step. Starter reagents are then added and a flash chemiluminescent reaction is initiated. The light signal is measured by a photomultiplier as relative light units (RLU) and is proportional to the concentration of TRAL present in the calibrators, controls or samples. The result of the TRAIL reagent pack is only used to calculate a final LIAISON MeMed BV Score and should not be used individually for diagnosis.
The IP-10 reagent pack uses a monoclonal antibody for the capture of IP-10 and a polyclonal antibody for the detection of IP-10. The assay incubates sample, calibrator or control with assay buffer and paramagnetic particles coated with a monoclonal antibody that specifically recognizes the IP-10. Following the incubation, an isoluminol conjugated polyclonal antibody that recognizes IP-10 is then added to the reaction and incubated. The unbound conjugate is removed with a wash step. Starter reagents are then added and a flash chemiluminescent reaction is initiated. The light signal is measured by a photomultiplier as relative light units (RLU) and is proportional to the concentration of IP-10 present in the calibrators, controls or samples. The result of the IP-10 reagent pack is only used to calculate a final LIAISON MeMed BV Score and should not be used individually for diagnosis.
The CRP reagent pack uses monoclonal antibodies for capture and detection of CRP. First the patient serum sample is pre-diluted 1:196 with assay buffer. The assay incubates the pre-diluted sample, calibrator or control with assay buffer and paramagnetic particles coated with a monoclonal antibody that specifically recognizes the CRP. Following the incubation, an isoluminol conjugated monoclonal antibody that recognizes CRP is then added to the reaction and incubated. The unbound conjugate is removed with a wash step. Starter reagents are then added and a flash chemiluminescent reaction is initiated. The light signal is measured by a photomultiplier as relative light units (RLU) and is proportional to the concentration of CRP present in the calibrators, controls or samples. The result of the CRP reagent pack is only used to calculate a final LIAISON MeMed BV Score and should not be used individually for diagnosis.
The provided document describes the FDA clearance (K213936) for the DiaSorin LIAISON® MeMed BV® assay, which aids in differentiating bacterial from viral infections. Here's a breakdown of the acceptance criteria and study details:
1. Table of Acceptance Criteria and Reported Device Performance
The document primarily focuses on demonstrating substantial equivalence to a predicate device rather than explicitly listing predefined acceptance criteria with numerical targets. However, the performance data presented implies a set of internal acceptance criteria related to statistical significance, agreement with expert adjudication, and reproducibility.
Given the information provided, here's a table summarizing the reported device performance, with implicit acceptance criteria derived from the study's conclusions:
| Performance Metric | Implicit Acceptance Criteria (based on stated conclusions) | Reported Device Performance (LIAISON MeMed BV) |
|---|---|---|
| Clinical Agreement (Primary Endpoint) | Significant trend between SCORE and likelihood of bacterial infection; high percentage of patients in outer bins. | Significant trend demonstrated between LIAISON MeMed BV SCORE and increasing likelihood of bacterial infections across SCORE bins. High percentage of patients found in outer bins (Bin 1 and 5). |
| Likelihood Ratio for Bacterial Basis (Bin 5: High Bacterial) | High Likelihood Ratio indicating strong association with bacterial infection. | 13.00 (7.09-25.83) |
| Likelihood Ratio for Bacterial Basis (Bin 1: Viral) | Low Likelihood Ratio indicating strong association with viral/non-infection. | 0.043 (0.002-0.180) |
| Clinical Agreement (Secondary Endpoint) | Significant trend between SCORE and likelihood of bacterial infection; high percentage of patients in outer bins. | Significant trend demonstrated between LIAISON MeMed BV SCORE and increasing likelihood of bacterial infections across SCORE bins. High percentage of patients found in outer bins (Bin 1 and 5). |
| Likelihood Ratio for Bacterial Basis (Bin 5: High Bacterial) | High Likelihood Ratio. | 52.97 (19.90-214.87) |
| Likelihood Ratio for Bacterial Basis (Bin 1: Viral) | Low Likelihood Ratio. | 0.051 (0.003-0.214) |
| Method Correlation (Primary Endpoint) | High overall agreement and high agreement in outer bins with predicate device. | Overall Agreement: 79.3% (95% CI: 74.2% - 83.6%). Bin 1: 91.8%; Bin 5: 96.7%. |
| Method Correlation (Secondary Endpoint) | High overall agreement and high agreement in outer bins with predicate device. | Overall Agreement: 79.0% (95% CI: 73.6% - 83.5%). Bin 1: 92.2%; Bin 5: 100%. |
| Reproducibility (SCORE) | Acceptable coefficient of variation (CV) across laboratories and within-laboratory. | Reproducibility CV for Score: KC1 (2.24): 0.688 (N/A); KC2 (98.3): 0.491 (N/A); MMBV-PREC3 (55.0): 2.765 (N/A); MMBV-PREC4 (7.84): 1.072 (N/A). |
| Matrix Equivalence (Fresh vs. Frozen Serum) | Strong correlation (slope ~1, intercept ~0, high R-squared) between fresh and frozen samples. | SCORE: Slope 1.00, Intercept 0.00, R-squared 0.9843, R 0.992. |
| Limit of Blank (LoB) | Quantifiable low limit. | CRP: 0.024 mg/L; IP-10: 0.578 pg/mL; TRAIL: 5.33 pg/mL. |
| Limit of Detection (LoD) | Quantifiable low limit. | CRP: 0.067 mg/L; IP-10: 4.31 pg/mL; TRAIL: 7.03 pg/mL. |
| Limit of Quantitation (LoQ) | Quantifiable low limit. | CRP: 1.0 mg/L; IP-10: 100 pg/mL; TRAIL: 15.0 pg/mL. |
| Cross-Reactivity | No significant cross-reactivity with specified substances. | Testing performed; implies no significant cross-reactivity observed (conclusion not explicitly stated but implied by study inclusion). |
| Interfering Substances | No interference observed for specified substances. | "No interference was observed for substances." |
2. Sample Sizes Used for the Test Set and Data Provenance
- Clinical Agreement Test Set: 285 serum samples.
- Provenance: Collected at hospital admission, Emergency Department, and Urgent Care Centers. Patients ranged in age from 5 months to 92 years. The origin country is not explicitly stated, but the mention of "21 international experts" suggests a multi-national or at least internationally adjudicated dataset. The study is retrospective in the sense that samples were likely collected before the adjudication process and testing with the device.
- Method Correlation Test Set:
- Primary Endpoint analysis: 285 clinical samples (the same as the clinical agreement test set).
- Secondary Endpoint analysis: 257 clinical samples (28 of the 285 were excluded).
- Expected Values Test Set: 150 serum samples from apparently healthy asymptomatic adults.
- Provenance: Collected in the Southwestern U.S.
- Reproducibility Study Test Set: 4 serum samples (1 normal, 1 viral, 1 bacterial, 1 equivocal) plus kit controls.
- Cross-Reactivity Study Test Set: Two (2) serum samples (one low, one high SCORE) for each cross-reactant being tested.
- Interfering Substances Study Test Set: Two (2) serum samples (one low, one high SCORE) for each interfering substance being tested.
- Matrix Equivalence Study Test Set: 43 fresh serum samples from individual patients, with 20 spiked for range coverage.
- Limit of Blank, Detection, Quantitation Test Set: Varied based on particular limit, ranging from 4-8 serum/spiked matrix samples for LoD/LoQ studies and 5 calibrator matrix samples for LoB.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
- Number of Experts: A pool of 21 international experts.
- Qualifications of Experts: Clinicians with at least 7 years of relevant clinical experience. Each panel comprised at least three experts.
4. Adjudication Method for the Test Set
- Method: Expert adjudication.
- Process: Panelists for each subject adjudication were drawn from the pool of 21 international experts. Each panel comprised at least three experts who independently adjudicated the etiologic label for each patient. The etiologic label was determined as bacterial, viral, or non-infectious. The adjudication was based on anonymized patient data. Critically, the adjudicators were blinded to the MeMed BV result (for the primary endpoint) and to CRT and PCT results (for the primary endpoint). For the secondary endpoint, adjudicators were un-blinded to PCT and CRP results.
5. 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
- This document describes the analytical and clinical performance of an in vitro diagnostic assay (a laboratory test that measures protein levels and computes a score), not an AI-assisted diagnostic tool that human readers interpret. Therefore, an MRMC comparative effectiveness study involving human readers assisting with AI is not applicable and was not performed. The device itself is the "AI" (computational algorithm) that processes biomarker data.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was done
- Yes, the performance presented for the "LIAISON MeMed BV" assay is a standalone performance of the device (assay and its integrated computational scoring). The "SCORE" is generated by the device's algorithm based on the measured protein levels (TRAIL, IP-10, and CRP), without a human in the loop for the scoring itself. The clinical utility is then evaluated by comparing this score to expert adjudication.
7. The Type of Ground Truth Used
- Type of Ground Truth: Expert consensus (physician expert adjudication). Specifically, physicians were forced to make a bacterial, viral, or non-infectious diagnosis.
8. The Sample Size for the Training Set
- The document does not specify the sample size used for training the algorithm (the "SCORE" computation). This document focuses on the validation of the device for FDA clearance. Typically, details of the training dataset are considered proprietary or part of the algorithm development process prior to clinical validation.
9. How the Ground Truth for the Training Set was Established
- Since the training set size and details are not provided, information on how its ground truth was established is also not available in this document. It is typical for such algorithms to be trained on large, well-characterized datasets, often with similar expert-adjudicated ground truth, but these details are not part of the premarket notification summary.
§ 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.