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The MONOLISA™ Anti-HAV EIA is an in vitro enzyme immunoassay kit intended for use in the qualitative detection of total antibodies (IgG and IgM) to hepatitis A virus (anti-HAV) in human (adult and pediatric) serum or plasma (EDTA, Heparin, Citrate, ACD). This kit can be used as an aid in the diagnosis of acute or past hepatitis A virus (HAV) infection or as an aid in the identification of HAV-susceptible individuals for vaccination. However, any diagnosis should take into consideration the patient's clinical history and symptoms, as well as serological data. The MONOLISA™ Anti-HAV EIA is intended for manual use and with the EVOLIS™ Automated Microplate System in the detection of total 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 EIA is an enzyme immunoassay (competitive assay format) for the detection of total antibodies to hepatitis A virus. In the assay procedure, patient specimens, a Calibrator and controls are incubated with HAV antigen in microwells that have been coated with mouse monoclonal anti-hepatitis A antibodies to HAV present in a specimen or control will complex with the HAV antigen reagent and with antibodies coated on the microwells. Excess sample and HAV Viral Antigen reagent are removed by a wash step. The Conjugate (containing horseradish peroxidase-labeled mouse monoclonal antibody to HAV) is subsequently added to the microwells and incubated. The Coniugate binds to the HAV antigen bound to the microwell, in the absence of antibodies to HAV from the specimen. Excess Conjuqate is removed by a wash step, and a TMB Chromogen/Substrate solution is added to the microwells and allowed to incubate. If a sample does not contain anti-HAV antibodies, the bound enzyme (HRP) causes the colorless tetramethylbenzidine (TMB) in the Chromogen solution to change to blue. The blue color turns vellow after the addition of a Stopping Solution. If a sample contains anti-HAV antibodies, 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 determined by the mean of the Calibrator absorbance values.

The performance of the MONOLISA™ Anti-HAV 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 summary of the acceptance criteria and study details based on the provided text, focusing on the performance of the MONOLISA™ Anti-HAV EIA when used with the EVOLIS™ Automated Microplate System.

Acceptance Criteria and Device Performance

The acceptance criteria for the MONOLISA™ Anti-HAV EIA with the EVOLIS™ Automated Microplate System are demonstrated by its substantial equivalence to the manual method (K063318). This equivalence is primarily shown through high percent agreement in comparative studies and acceptable precision and reproducibility.

Study Details

1. Sample sizes used for the test set and the data provenance:

   • Main Correlation/Method Comparison: 688 retrospective samples. The country of origin is not specified.
   • Combination Plate Testing: 315 samples. The provenance (retrospective/prospective, country) is not specified, but they are compared to the "same samples tested manually."

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • The ground truth for the test set was established by the "manual method" of the MONOLISA™ Anti-HAV EIA (K063318). This is a previously cleared assay and not a consensus from human experts. Therefore, the concept of "number of experts" or their "qualifications" is not directly applicable here in the context of human interpretation of a diagnostic outcome. The "ground truth" is the result from the established and cleared manual assay.

3. Adjudication method for the test set:

   • Not applicable as the ground truth is derived from a reference assay's output, not from human interpretation requiring adjudication. For borderline results in the main correlation study, specimens borderline with the reference assay and negative with EVOLIS™ were considered false negative for EVOLIS™, and specimens borderline with the reference assay and reactive with EVOLIS™ were considered false positive for EVOLIS™. This effectively defines how discrepancies were treated for agreement calculations.

4. 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 MRMC comparative effectiveness study was performed. This device is an automated analyzer for an immunoassay, not an AI-assisted diagnostic tool that aids human readers in interpreting complex images or clinical data. The comparison is between an automated system and a manual laboratory method.

5. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:

   • Yes, the performance data presented (correlation, precision, reproducibility) represents the standalone performance of the MONOLISA™ Anti-HAV EIA when run on the EVOLIS™ Automated Microplate System. The system performs all functions including reagent dispensing, incubation, washing, and photometric measurement, and results evaluation (based on optical density readings and cutoff values). The human operator's role is loading samples/reagents and initiating processing, not interpreting the primary assay output or forming a diagnosis from it directly.

6. The type of ground truth used:

   • The ground truth (or reference method) was the MONOLISA™ Anti-HAV EIA tested manually, which is a previously FDA-cleared laboratory assay. This is a form of reference standard comparison against an established assay.

7. The sample size for the training set:

   • The document does not specify a separate "training set" for the EVOLIS™ Automated Microplate System. Automated systems like this typically undergo a development and validation process during which algorithms (e.g., for robotic movements, optical density reading, cutoff calculations) are built and refined. The data presented here are for the performance validation of the final product. It's an assay system, not a machine learning model that requires a discrete "training set" in the conventional sense.

8. How the ground truth for the training set was established:

   • Not applicable, as a distinct training set (in the machine learning sense) and its ground truth are not detailed in this submission. The ground truth for the performance validation was the previously cleared manual assay.

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The MONOLISA™ Anti-HAV EIA is an in vitro enzyme immunoassay kit intended for use in the qualitative detection of total antibodies (IgG and IgM) to Hepatitis A Virus (anti-HAV) in human (adult and pediatric) serum or plasma (EDTA, Heparin, Citrate, ACD). This kit can be used as an aid in the diagnosis of acute or past Hepatitis A Virus (HAV) infection or as an aid in the identification of HAVsusceptible individuals for vaccination. However, any diagnosis should take into consideration the patient's clinical history and symptoms, as well as serological data.

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 EIA is an enzyme immunoassay (competitive assay format) for the detection of total antibodies to Hepatitis A virus. In the assay procedure, patient specimens, a calibrator and controls are incubated with HAV antigen in microwells that have been coated with mouse monoclonal anti-Hepatitis A antibodies to HAV present in a specimen or control will complex with the HAV antigen reagent and with antibodies coated on the microwells. Excess sample and HAV Viral antigen reagent are removed by a wash step. The conjugate (containing horseradish peroxidase-labeled mouse monoclonal antibody to HAV) is subsequently added to the microwells and incubated. The conjuqate binds to the HAV antigen bound to the microwell in the absence of antibodies to HAV from the specimen. Excess conjugate is removed by a wash step, and a TMB Chromogen / Substrate solution is added to the microwells and allowed to incubate. If a sample does not contain anti-HAV antibodies, 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 contains anti-HAV antibodies, 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 determined by the mean of the Calibrator absorbance values.

Here's a breakdown of the acceptance criteria and study information for the MONOLISA™ Anti-HAV EIA, based on the provided document:

Acceptance Criteria and Reported Device Performance

Study Information

1. Sample Size and Data Provenance (Test Set):

   • Overall Test Set: 1327 samples (404 US, 928 European) for clinical performance, plus additional samples for acute HAV infection (84), pediatrics (60 additional to acute HAV), vaccinated subjects (62 pre/post-vaccination from 38 individuals, plus 14 purchased post-vaccination), seroconversion panels (6 panels), and cross-reactivity (255 specimens).
   • Clinical Performance (US): 404 specimens (174 with signs/symptoms of Hepatitis, 230 high-risk).
     • Country of Origin: US (Los Angeles, Santa Ana, CA, and Miami, FL).
     • Retrospective/Prospective: Both prospective and retrospective.
   • Clinical Performance (Europe): 928 specimens (252 signs/symptoms of Hepatitis, 62 high-risk, 345 asymptomatic hospitalized, 34 healthcare workers, 151 recovered HAV infection).
     • Country of Origin: Europe (France and Italy).
     • Retrospective/Prospective: Both prospective and retrospective.
   • Acute HAV Infection: 84 retrospective samples (European population, adult and pediatric).
   • Pediatric Subjects: 60 samples from US and Europe (in addition to the 39 from acute HAV infection).
   • High Risk Individuals (Expected Values):
     • US: 230 subjects (Los Angeles, CA; Santa Ana, CA; Miami, FL).
     • Europe: 62 subjects.
   • Healthy Individuals (Expected Values):
     • Mid-west US: 280 subjects (St. Louis, Missouri).
     • Western US: 245 subjects (California and Washington).
     • Europe: 285 subjects (Parma, Italy).
   • Vaccinated Subjects: 62 pre- and post-vaccination samples from 38 individuals (US and Europe), plus 14 purchased post-vaccination samples (US).
   • Seroconversion Panels: 6 commercially available panels.
   • Cross-Reactivity Study: 255 specimens from 16 clinical conditions.

2. Number of Experts and Qualifications for Ground Truth (Test Set):

   • The document mentions comparison against a "comparative assay" (predicate device, DiaSorin ETI-AB-HAVK PLUS, PMA Number: P890019) and "FDA approved methods" to confirm disease state for cross-reactivity.
   • It does not explicitly state the number of experts or their qualifications for establishing the ground truth for the test set. For clinical assays like this, it is common for the ground truth to be established by the results of a previously approved, well-established method (the comparative assay) or by a composite reference standard that might involve expert clinical diagnosis and other laboratory tests, but this detail is not provided.

3. Adjudication Method (Test Set):

   • The primary method was comparison against a "comparative assay" (predicate device).
   • For instances where the MONOLISA™ Anti-HAV EIA produced a borderline result or where the comparative assay produced a borderline result, specific rules were applied for agreement calculations (e.g., a borderline comparative assay result reactive with MONOLISA™ was considered a false positive for MONOLISA™).
   • There is no mention of a traditional expert adjudication panel (e.g., 2+1, 3+1).

4. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

   • No, a MRMC comparative effectiveness study was not done. This is an automated in vitro diagnostic device, not an imaging device that would typically involve human readers. The comparison is between the new device and a predicate device.

5. Standalone Performance Study:

   • Yes, Standalone performance was done. The entire clinical and analytical performance evaluation describes the algorithm's (device's) performance in isolation against a ground truth (the comparative assay/FDA approved methods), without human interpretation in the loop other than performing the assay and reading the spectrophotometric results.

6. Type of Ground Truth Used:

   • For clinical performance studies, the ground truth was predominantly established by the results of a "comparative assay" (the legally marketed equivalent device, DiaSorin ETI-AB-HAVK PLUS).
   • For the cross-reactivity study, "FDA approved methods" were used to confirm the disease state of each specimen.
   • For acute HAV infection, samples were "from subjects with a medical history and laboratory results indicative of acute Hepatitis A."
   • For vaccinated subjects, the ground truth was pre/post-vaccination status as determined by clinical trial enrollment and/or other laboratory methods in addition to the comparative assay.

7. Sample Size for the Training Set:

   • The document describes performance studies (validation). It does not explicitly mention a separate "training set" sample size for machine learning or AI models. Given that it's an enzyme immunoassay kit, it's a biochemical assay rather than a predictive algorithm that undergoes a training phase in the typical AI sense. The development of such a kit would involve internal optimization and calibration (which could be considered analogous to training) but not usually with a distinctly defined 'training set' of patient samples as seen in AI/ML validation studies.

8. How Ground Truth for the Training Set Was Established:

   • As noted above, a distinct "training set" for an AI/ML model isn't described. For the biochemical assay, internal controls, calibrators, and development batches would have been used during the product development phase. The "ground truth" for these would be based on known concentrations or presence/absence of analytes, established through established laboratory methods and reference materials, but these details are not provided in the 510(k) summary (which focuses on validation).

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