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510(k) Data Aggregation
(86 days)
The MONOLISA™ Anti-HAV IgM EIA is an in vitro enzyme immunoassay kit intended for use in the qualitative detection of IgM antibodies to hepatitis A virus (anti-HAV IgM) in human (adult and pediatric) serum or plasma (EDTA, Heparin, Citrate, ACD). This assay is indicated for testing specimens from individuals who have signs and symptoms consistent with acute hepatitis. Assay results, in conjunction with other serological or clinical information, may be used for the laboratory diagnosis of individuals with acute or recent hepatitis A. The MONOLISA™ Anti-HAV IgM EIA is intended for manual use and with the Evolis™ Automated Microplate System in the detection of IgM antibodies to hepatitis A virus.
Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients, and cord blood or neonatal specimens.
Warning: This assay is not intended for screening blood or solid or soft tissue donors.
The MONOLISA™ Anti-HAV IgM EIA is an enzyme immunoassay (IgM antibody capture format) for the detection of IgM antibodies to hepatitis A virus. In the assay procedure, patient specimens, a calibrator, and controls are incubated with antibodies coated on the microwells. If IgM antibodies to HAV are present in a specimen or control, they bind to the antibody. Excess sample is removed by a wash step. The HAV Viral Antigen and the Conjugate (containing horseradish peroxidase - labeled mouse monoclonal antibody to HAV) are successively added to the microwells and allowed to incubate. The presence of anti-HAV IgM in the sample enables the HAV Viral Antigen and the Conjugate to bind to the solid phase. Excess Conjugate and HAV Viral Antigen are removed by a wash step, and a TMB Chromogen /Substrate solution is added to the microwells and allowed to incubate. If a sample contains anti-HAV IgM, the bound enzyme (HRP) causes the colorless tetramethylbenzidine (TMB) in the Chromogen solution to change to blue. The blue color turns yellow after the addition of a Stopping Solution. If a sample does not contain anti-HAV IgM, the Chromogen/Substrate solution in the well remains colorless during the substrate incubation, and after the Stopping Solution. The color intensity is measured spectrophotometrically. Absorbance value readings for patient specimens are compared to the cutoff value.
The performance of the MONOLISA™ Anti-HAV IgM EIA was evaluated in conjunction with the EVOLIS™ Automated Microplate System. The EVOLIS™ Automated Microplate System is a fully automated microplate analyzer that performs all functions necessary for the complete processing of microplate assays. Functions include: barcode scanning, sample pre-dilutions, sample and reagent dispensing, plate incubations, plate wash cycles, photometric measurement of completed assay plates and results evaluation. The analyzer instrument is controlled via the EVOLIS™ software, a Windows® 2000 application running on a separate dedicated PC. An operator loads the appropriate microplates, assay reagents, and patient and control samples, then selects assay parameters, loads sample information, initiates instrument processing, and generates result reports.
Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided 510(k) summary:
1. Table of Acceptance Criteria and Reported Device Performance
| Acceptance Criteria Category | Specific Criteria (Implicitly Derived) | Reported Device Performance (MONOLISA™ Anti-HAV IgM EIA on EVOLIS™ vs. Manual) |
|---|---|---|
| Correlation/Method Comparison | Overall Agreement: High percentage agreement with the manual method. | Overall Percent Agreement: 99.7% (with 95% CI of 98.9 - 99.9%) |
| Positive Agreement: High percentage agreement for reactive samples. | Positive Percent Agreement: 100% (with 95% CI of 96.1 - 100%) | |
| Negative Agreement: High percentage agreement for nonreactive samples. | Negative Percent Agreement: 99.7% (with 95% CI of 98.8 - 99.9%) | |
| Reproducibility (Combination Plate) | Overall Agreement: High percentage agreement with the manual method (individual plate format). | Overall Percent Agreement: 99.4% (with 95% CI of 97.7 - 99.8%) |
| Positive Agreement: High percentage agreement for reactive samples (combination plate). | Positive Percent Agreement: 100% (with 95% CI of 92.7 - 100%) | |
| Negative Agreement: High percentage agreement for nonreactive samples (combination plate). | Negative Percent Agreement: 99.2% (with 95% CI of 97.3 - 99.8%) | |
| Precision | Low coefficients of variation (%CV) for within-run, between-run, between-day variability across different panel members (positive, high negative, negative, and controls), and different sample types (serum, various plasma types). | Within-run %CV: Ranged from 1.3% to 6.1% (Panel Set 1, 2, 3) |
| Between-Run %CV: Ranged from 3.5% to 14.9% | ||
| Between-Day %CV: Ranged from 4.4% to 14.7% | ||
| Total %CV: Ranged from 6.8% to 21.8% | ||
| Reproducibility (Multi-site) | Low coefficients of variation (%CV) for within-run, between-day, between-site, and total variance across different panel members. | Within-run %CV: Ranged from 2.3% to 20.5% (across all sites and panel members) |
| Between-Day %CV: Ranged from 0.4% to 19.4% | ||
| Between-Site %CV: Ranged from 0.0% to 2.9% (for P2 and P5 only, others 0.0%) | ||
| Total %CV: Ranged from 2.5% to 23.9% | ||
| Pipettor and Washer Carry-over | No significant carry-over between samples/wells. | Verified that disposable tip pipettes and washer do not carry residuals. |
| Pipetting Accuracy | Achieve a coefficient of variation (CV) of ≤7.7% across the microwell plate for sample and reagent dispensing. | Demonstrated pipetting accuracy with a CV of ≤7.7%. |
2. Sample Sizes and Data Provenance
- Test set for Correlation/Method Comparison:
- Study 1 (EVOLIS™ vs. Manual): 691 retrospective samples.
- Study 2 (EVOLIS™ Combination Plate vs. Manual): 313 samples.
- Data Provenance: The document does not explicitly state the country of origin. The samples were retrospective.
3. Number of Experts and Qualifications for Ground Truth
- The document does not mention the use of experts to establish ground truth for the test set.
- The "ground truth" for the comparison studies was the result of the MONOLISA™ Anti-HAV IgM EIA tested manually (the predicate device). The assumption is that the manual method itself, having received prior FDA clearance (K063319), represents the established truth for HAV IgM detection.
4. Adjudication Method
- The document does not describe a specific adjudication method using experts.
- For borderline results in the correlation studies, the following rule was applied: "specimens that were borderline with the reference assay and negative with EVOLIS™ were considered as false negative for the EVOLIS™." This represents a specific rule for handling discordant borderline results rather than an expert adjudication process.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done.
- This study pertains to the performance of an automated assay system compared to a manual assay method, not a comparison of human readers with and without AI assistance. Therefore, there is no effect size reported for human readers improving with AI.
6. Standalone Performance Study
- Yes, a standalone (algorithm only) performance study was effectively done. The performance studies (correlation/method comparison, precision, reproducibility, carry-over, pipetting accuracy) evaluate the MONOLISA™ Anti-HAV IgM EIA when used with the EVOLIS™ Automated Microplate System as a fully automated system, without direct human intervention in the result determination process itself (beyond loading, selecting parameters, and generating reports). The "algorithm" here refers to the automated system and its integrated processes compared to the manual method.
7. Type of Ground Truth Used
- The ground truth used for the performance comparison studies was the result from the predicate device (Manual MONOLISA™ Anti-HAV IgM EIA assay). This is a comparative ground truth established by another existing, cleared diagnostic method, rather than direct pathology, expert consensus on clinical findings, or outcomes data.
8. Sample Size for the Training Set
- The document does not specify a separate "training set" in the context of an algorithm or AI model development. This submittal is for an automated system running an existing assay, not a novel AI algorithm that requires training on a data set. Therefore, this information is not applicable or provided.
9. How Ground Truth for Training Set Was Established
- As noted above, there is no explicit "training set" for an AI algorithm mentioned. The performance characteristics of the assay itself (MONOLISA™ Anti-HAV IgM EIA) were established through its prior 510(k) clearance (K063319) when used manually. The current submission focuses on demonstrating that combining this assay with the EVOLIS™ Automated Microplate System yields equivalent performance.
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(182 days)
The MONOLISA™ Anti-HAV IgM EIA is an in vitro enzyme immunoassay kit intended for use in the qualitative detection of IgM antibodies to Hepatitis A virus (anti-HAV IgM) in human (adult and pediatric) serum or plasma (EDTA, Heparin, Citrate, ACD). This assay is indicated for testing specimens from individuals who have signs and symptoms consistent with acute Hepatitis. Assay results, in conjunction with other serological or clinical information, may be used for the laboratory diagnosis of individuals with acute or recent Hepatitis A.
Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients, and cord blood or neonatal specimens.
This assay is not intended for screening blood or solid or soft tissue donors.
The MONOLISA™ Anti-HAV IgM EIA is an enzyme immunoassay (IgM antibody capture format) for the detection of IgM antibodies to Hepatitis A Virus. In the assay procedure, patient specimens, a calibrator, and controls are incubated with anti-human IgM antibodies coated on the microwells. If IgM antibodies to HAV are present in a specimen or control, they bind to the antibody. Excess sample is removed by a wash step. The HAV Viral Antigen and the Containing horseradish peroxidase - labeled mouse monoclonal antibody to HAV) are successively added to the microwells and allowed to incubate. The presence of IgM anti-HAV in the sample enables the HAV Viral Antigen and the Conjugate to bind to the solid phase. Excess Conjugate and HAV Viral Antigen are removed by a wash step, and a TMB Chromogen / Substrate solution is added to the microwells and allowed to incubate. If a sample contains anti-HAV IgM, the bound enzyme (HRP) causes the colorless TMB in the Chromogen solution to change to blue. The blue color turns yellow after the addition of a Stopping Solution. If a sample does not contain anti-HAV IgM, the Chromogen / Substrate solution in the well remains colorless during the substrate incubation, and after the addition of the Stopping Solution. The color intensity is measured spectrophotometrically. Absorbance value readings for patient specimens are compared to the cutoff value.
Here's a breakdown of the acceptance criteria and the study details for the MONOLISA™ Anti-HAV IgM EIA device, based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are not explicitly stated as distinct numerical targets beyond simply evaluating "percent agreement" with a comparative assay. However, the study aims to show substantial equivalence based on high agreement rates and acceptable precision.
| Metric / Acceptance Criteria | Reported Device Performance (MONOLISA™ Anti-HAV IgM EIA) |
|---|---|
| Clinical Performance: | |
| Positive Percent Agreement with Comparative Assay (US) | 100% (1/1) - (Note: Very small sample size for positive cases in US) |
| Negative Percent Agreement with Comparative Assay (US) | 99.3% (400/403) with 95% Exact Confidence interval: 97.8-99.9% |
| Positive Percent Agreement with Comparative Assay (Europe) | 100% (1/1) - (Note: Very small sample size for positive cases in Europe) |
| Negative Percent Agreement with Comparative Assay (Europe) | 99.0% (836/844) with 95% Exact Confidence interval: 98.1-99.6% |
| Positive Agreement (Acute HAV Infection) | 100% (84/84) with 95% exact confidence interval: 96.5% to 100% |
| Negative Agreement (Pediatric Population, non-HAV) | 96.7% (59/61) with 95% Exact Confidence interval: 88.6-99.6% (Note: This is specifically for non-HAV IgM positive pediatric samples) |
| Overall Positive Percent Agreement (Combined US & Europe) | 100% (86/86) with 95% exact confidence interval: 96.6% to 100% |
| Overall Negative Percent Agreement (Combined US & Europe) | 99.1% (1233/1244) with 95% exact confidence interval: 98.4% to 99.6% |
| Seroconversion Panels: | |
| Detection of HAV IgM antibodies (first bleed) | Identical to comparative assay for all 8 panels. |
| Duration of IgM detection | Appears to detect IgM for a longer period than the comparator assay for qualitative determination of IgM antibody to Hepatitis A (e.g., HAV01 panel: +14 days difference for last reactive result). |
| Cross-Reactivity Study: | |
| Reactivity in presence of interfering substances | All 255 specimens (from 16 different clinical conditions/interfering substances: Hep C, Hep B, HIV, EBV, CMV, Rubella, Toxoplasmosis, Mumps, VZV, ANA, HAMA, Rheumatoid Arthritis) were nonreactive with MONOLISA™ Anti-HAV IgM and with the predicate assay, indicating no cross-reactivity. |
| Precision Study (Within-Laboratory): | |
| Coefficient of Variation (CV) for various sample types | Negative Control C0: Total CV 11.0% (Mean S/CO 0.08) |
| Positive Control C1: Total CV 4.8% (Mean S/CO 2.03) | |
| Serum (Neg/Low Pos/Pos): Total CV 15.3% to 17.7% (Negative), 6.5% to 9.2% (Near Cutoff), 7.2% to 10.5% (Low Positive) | |
| Similar ranges for plasma types (EDTA K2, EDTA K3, Sodium Citrate, Sodium Heparin, Lithium Heparin, ACD) | |
| Reproducibility Study (Multi-site, Multi-lot): | |
| Total CV for various panel members (across runs, days, lots, sites) | Panel Member P1 (low negative): Total CV 43.3% (Mean S/CO 0.05) |
| Panel Member P2 (medium negative/near cutoff): Total CV 11.1% (Mean S/CO 0.74) | |
| Panel Member P3 (low positive/near cutoff): Total CV 11.1% (Mean S/CO 1.16) | |
| Panel Member P4 (positive): Total CV 11.5% (Mean S/CO 1.82) | |
| Panel Member P5 (positive): Total CV 10.1% (Mean S/CO 3.41) | |
| Panel Member P6 (strong positive): Total CV 12.2% (Mean S/CO 4.25) | |
| Reproducibility of Controls (operator variability) | Negative Control: Total SD 0.02, N/A %CV (Mean 0.06) |
| Positive Control: Total SD 0.08, 4.17 %CV (Mean 1.91) |
2. Sample size used for the test set and the data provenance
- Clinical Performance Study (US & Europe Combined):
- Total Test Set Sample Size: 1308
- US population: 404 specimens (174 symptomatic, 230 high-risk)
- European population: 929 specimens (253 symptomatic, 62 high-risk, 345 asymptomatic hospitalized, 34 healthcare workers, 151 recovered HAV infection)
- Data Provenance: Multi-center, prospective and retrospective study.
- US data: Mid-west US (St Louis, Missouri), Western US (California and Washington), Los Angeles, CA, Santa Ana, CA, Miami, FL.
- European data: Parma, Italy, France.
- Total Test Set Sample Size: 1308
- Acute HAV Infection Sample Size: 84 (retrospective samples, European)
- Pediatric Sample Size (non-acute HAV): 61 (US and Europe combined)
- Seroconversion Panels: 8 commercially available HAV seroconversion panels.
- Cross Reactivity Study: 255 specimens (serum and plasma) from 16 groups of potential cross-reactivity.
- Precision Study: A 21-member panel (serum and 6 corresponding plasma types at 3 levels: negative, negative near cutoff, low positive near cutoff).
- Reproducibility Study: A 6-member panel (diluted plasma specimens: negative and different levels of positive).
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The information provided does not specify the number of experts used to establish the ground truth or their qualifications. The ground truth for the clinical studies appears to be based on a "comparative assay" and "medical history and laboratory results indicative of acute Hepatitis A" for the acute HAV infection group, as well as an "FDA approved method" to confirm disease state for the cross-reactivity study.
4. Adjudication method for the test set
The document states that the results obtained with the MONOLISA™ Anti-HAV IgM EIA were compared with the results obtained using a "comparative assay." In cases of borderline results with the comparative assay, specific criteria were used for classification:
- Specimens borderline with the comparative assay and reactive with MONOLISA™ were considered false positives for MONOLISA™.
- Specimens borderline with the comparative assay and non-reactive with MONOLISA™ were considered false negatives for MONOLISA™.
This implies a direct comparison rather than an adjudication involving multiple independent readers/experts to resolve discrepancies.
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
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not explicitly mentioned or performed. This device is an in-vitro diagnostic (IVD) assay (enzyme immunoassay), not an AI-assisted diagnostic tool that would typically involve human readers interpreting results with or without AI assistance.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the studies reported are for the standalone performance of the MONOLISA™ Anti-HAV IgM EIA assay itself. It's an automated or semi-automated lab test, and its performance is evaluated directly based on its output compared to a reference standard (the comparative assay or clinical/laboratory evidence). Human interpretation is involved in setting up the assay and reading the spectrophotometric values, but the performance metrics are for the device's output.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
The ground truth used was primarily a "comparative assay" (another existing, presumably cleared/approved Anti-HAV IgM assay) for the vast majority of the clinical performance data. For the "Acute HAV Infection" group, the ground truth was based on "medical history and laboratory results indicative of acute Hepatitis A." For the "Cross Reactivity Study," "FDA approved methods were used to confirm the disease state of each specimen."
8. The sample size for the training set
This document describes a performance evaluation of a medical device (an in-vitro diagnostic test), not a machine learning or AI algorithm in the traditional sense that requires a "training set" for model development. Therefore, there is no mention of a training set sample size. The clinical and analytical studies described are for validation and performance assessment.
9. How the ground truth for the training set was established
As there is no mention of a "training set" in the context of an AI/ML algorithm, this question is not applicable to the provided document.
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