(182 days)
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
| Criteria | Acceptance Criteria (Implied by reported performance vs. comparative assay) | Reported Device Performance (MONOLISA™ Anti-HAV EIA) |
|---|---|---|
| Overall Positive Percent Agreement (PPA) with comparative assay | Not explicitly stated, but generally expected to be very high (e.g., >95%) | 99.5% (931/936) with 95% CI (98.8% - 99.8%) |
| Overall Negative Percent Agreement (NPA) with comparative assay | Not explicitly stated, but generally expected to be very high (e.g., >95%) | 96.2% (378/393) with 95% CI (93.8% - 97.9%) |
| PPA for US population | Not explicitly stated | 98.8% (237/240) with 95% CI (96.4% - 99.7%) |
| NPA for US population | Not explicitly stated | 92.6% (151/163) with 95% CI (87.5% - 96.1%) |
| PPA for European population | Not explicitly stated | 99.7% (610/612) with 95% CI (98.8% - 99.9%) |
| NPA for European population | Not explicitly stated | 98.7% (227/230) with 95% CI (96.2% - 99.7%) |
| PPA for Acute HAV Infection | Not explicitly stated | 100% (84/84) with 95% CI (96.5% - 100%) |
| PPA for Pediatric Subjects | Not explicitly stated | 100% (29/29) with 95% CI (90.2% - 100%) |
| NPA for Pediatric Subjects | Not explicitly stated | 96.8% (30/31) with 95% CI (83.3% - 99.9%) |
| Seroconversion Panel Sensitivity (compared to comparative assay) | Equivalent or more sensitive | Equivalent to or more sensitive in 6/6 panels. |
| Device Precision (Within-run, Between-run, Between-day CV) | CVs typically expected to be low (e.g., <15-20%) | Refer to tables 17, 18, 19, 20 for detailed CVs. Generally: <12% for most individual categories, some total CVs up to 28% for certain panel members at specific sites in reproducibility studies. |
| Device Reproducibility (Across sites, lots, operators CV) | CVs typically expected to be low (e.g., <15-20%) | Refer to tables 18, 19, 20 for detailed CVs. Generally: <15% for most individual categories for controls/low reactive samples, but some total CVs as high as ~24% for higher reactive panel members. |
| Cross-Reactivity | Low to no clinically significant cross-reactivity with common interfering conditions/viruses. | 7 samples were discrepant (4 reactive with MONOLISA™ Anti-HAV EIA but non-reactive with comparative assay; 3 non-reactive with MONOLISA™ Anti-HAV EIA but reactive with comparative assay) out of 255 tested across 16 clinical conditions. Specific rates per condition are listed in Table 16. |
Study Information
-
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.
-
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.
-
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).
-
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.
-
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.
-
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.
-
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.
-
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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MONOLISA™ Anti-HAV EIA 510(k) SUMMARY
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
| 510(k) Number: | K 063318 |
|---|---|
| 510(k) Summary Report Date: | April, 2007 |
| MANUFACTURER INFORMATION | |
| MANUFACTURER ADDRESS: | Bio-Rad3, Boulevard Raymond Poincaré92430 Marnes-la-Coquette, France |
| TELEPHONE : | 00 33 1 47 95 60 00 |
| ESTABLISHMENT REG. NUMBER : | 8023060 |
| OWNER/OPERATOR : | Bio-Rad3, Boulevard Raymond Poincaré92430 Marnes-la-Coquette, France |
| OWNER/ OPERATOR NUMBER : | 8023061 |
| OFFICIAL CORRESPONDENTADDRESS : | Bio-Rad3, Boulevard Raymond Poincaré92430 Marnes-la-Coquette, France |
| TELEPHONE: | 00 33 1 47 95 60 00 |
| OFFICIAL CORRESPONDENT : | Mrs. Sylvie Confida |
| TELEPHONE :FAX : | 00 33 1 47 95 61 3800 33 1 47 95 62 42 |
| CLASSIFICATION INFORMATION |
| COMMON NAME: | Total Antibody to Hepatitis A Virus |
|---|---|
| PRODUCT TRADE NAME: | MONOLISA™ Anti-HAV EIA |
| DEVICE CLASS: | Class II LOL |
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CLASSIFICATION PANEL :
Immunology and Microbiology Devices
REGULATION NUMBER : 21 CFR 866.3310
LEGALLY MARKETED EQUIVALENT (SE) DEVICE
DiaSorin ETI-AB-HAVK PLUS PMA Number : P890019 Decision Date : 12/12/2005
DEVICE DESCRIPTION
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.
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KIT COMPONENTS
| Component | Description |
|---|---|
| R1 Microwell Strip Plates | Two (2) x 12 strips of 8 wells coated with monoclonal anti-HAVantibodies. |
| R2 Wash SolutionConcentrate (30x) | One (1) 120 mL bottle, Tris-buffer containing NaCl and Tween 20. |
| C0 Negative Control | One (1) 1.5 mL vial, containing human serum, negative for total anti-HAV antibodies, HBs antigen, anti-HCV antibodies and anti-HIV-1/HIV-2 antibodies. Preservatives : Sodium azide (< 0.1%) and Proclin™300 (0.25%). |
| C1 Positive Control | One (1) 1.5 mL vial, containing human serum, positive for anti-HAVantibodies and negative for HBs antigen, anti-HCV antibodies andanti-HIV-1/HIV-2 antibodies, diluted in human serum pool negative foranti-HAV antibodies. Preservatives : Sodium azide (< 0.1%) andProclin™ 300 (0.25%). |
| C2 Calibrator | Two (2) x 1.5 mL vials, containing human serum, positive for anti-HAVantibodies, and negative for HBs Antigen, anti-HCV antibodies andanti-HIV-1/HIV-2 antibodies, diluted in human serum pool negative foranti-HAV antibodies. Preservatives : Sodium azide (< 0.1%) andProclin™ 300 (0.25%). |
| R6 HAV Viral Antigen | Two (2) x 14 mL bottles, inactivated HAV virus in Tris buffer containingproteins and sample indicator dye. Preservative : Proclin™ 300 (0.1%). |
| R7 Conjugate | Two (2) x 14 mL bottles, conjugate (Peroxidase labeled mousemonoclonal antibody to HAV) in Tris buffer containing proteins,detergent and sample indicator dye. Preservative : Proclin™ 300(0.1%). |
| R8 Substrate Buffer | One (1) 120 mL bottle, containing Hydogen Peroxide, citric acid /sodium acetate buffer and Dimethylsulfoxide (DMSO). |
| R9 Chromogen (11x) | One (1) 12 mL bottle, containing Tetramethylbenzidine (TMB). |
| R10 Stopping Solution | One (1) 120 mL bottle, containing 1 N H2SO4. |
| Plate sealers | Eight (8) clear plastic sealers. |
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INTENDED USE
The MONOLISA™ anti-HAV EIA is an in vitro enzyme immunoassay kit intended for use in the qualitative detection of total antibodies (anti-HAV IgG and IgM) to Hepatitis A virus (anti-HAV) in human (adult and pediatric) serum or plasma (EDTA, Heparin, Citrate, ACD.
This assay is not intended for screening blood or solid or soft tissue donors.
INDICATIONS FOR USE
The MONOLISA™ anti-HAV EIA is indicated for use 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.
Assay performance characteristics have not been established for immunocompromised or immunosuppressed patients, and core blood or neonatal specimens.
TECHNOLOGICAL CHARACTERISTICS
The following tables summarize similarities and differences between the MONOLISA™ Anti-HAV EIA kit and the predicate device ETI-AB-HAVK PLUS.
| Similarities in | MONOLISAT™ Anti-HAV | ETI-AB-HAVK PLUS |
|---|---|---|
| Components / Materials | EIA | Catalog# P001926 |
| Catalog# 72496 | ||
| Solid Phase | Microplate wells coated withmouse Monoclonal anti-HAVantibodies. | Microplate wells coated withmouse Monoclonal anti-HAVantibodies. |
| Conjugate | Peroxidase-labeled mousemonoclonal antibody to HAV. | Peroxidase-labeled mousemonoclonal antibody to HAV. |
| Negative Control | Human serum, negative fortotal anti-HAV antibodies. | Human serum/plasma,negative for total anti-HAVantibodies. |
| Calibrator | Human serum, positive foranti-HAV antibodies, dilutedin human serum poolnegative for anti-HAVantibodies. | Human serum/plasma,containing anti-HAVantibodies. |
| Positive Control | Human serum, positive foranti-HAV antibodies, dilutedin human serum poolnegative for anti-HAVantibodies. | Human serum/plasma,reactive for anti-HAVantibodies. |
| Chromogen | Tetramethylbenzidine (TMB) | Tetramethylbenzidine (TMB) |
Table 1: Similarities between kit components and materials
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| Substrate | Hydrogen Peroxide | Hydrogen Peroxide |
|---|---|---|
| Washing Solution | Concentrated bufferedsolution with Tween 20. | Concentrated bufferedsolution with detergents. |
Table 2: Differences between kit components and materials
| Differences inComponents / Materials | MONOLISA™ Anti-HAVEIACatalog# 72496 | ETI-AB-HAVK PLUSCatalog# P001926 |
|---|---|---|
| Conjugate | Ready-to-use. | To be diluted. |
| Incubation buffer | NA | Buffer, containing proteinstabilizers and an inert bluedye. |
| Viral Antigen / NeutralizingSolution | Tris-buffer, containinginactivated HAV-virus,proteins and sampleindicator dye. | Buffer, containing HAV,human serum/plasma andprotein stabilizers. |
| Stopping Solution | $1N H_2SO_4$ . | $0.4N H_2SO_4$ . |
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| Similarities in Functionand Use | MONOLISA™ Anti-HAVEIACatalog# 72496 | ETI-AB-HAVK PLUSCatalog# P001926 |
|---|---|---|
| Test Method | EIA (competitive assay format) | EIA (competitive test) |
| Format | 96-well microplate | 96-well microplate |
| Intended Use | Assay for the qualitativedetection of total anti-HAVantibodies in human serum orplasma. | Assay for the qualitativedetection of total anti-HAVantibodies in human serum orplasma. |
| Required sample volume | 50 μl | 50 μl |
| Specimen StorageRequirements | Samples may be stored at2-8 °C for up to 24 hours. | Samples may be stored at2-8 °C for up to 24 hours. |
| Calibrator | Referenced to WHO Anti-Hepatitis A Immunoglobulin2nd International Standard. | Referenced to WHO Anti-Hepatitis A Immunoglobulin2nd International Standard. |
| Wavelength | Dual wavelength reading at450 nm and 615/630 nm. | Dual wavelength reading at450 nm and 630 nm. |
| Interpretation of results | Obtained absorbance valuereadings for patientspecimens are compared tothe cut-off value determinedby the mean of the calibrator | Obtained absorbancereadings for patientspecimens are compared to acut-off value determined fromthe mean of the calibrator |
Table 3: Similarities between kits with regard to function and use
Table 4: Differences between kits with regard to function and use
| Differences in Functionand Use | MONOLISAT™ anti-HAV EIACatalog# 72496 | ETI-AB-HAVK PLUSCatalog# P001926 |
|---|---|---|
| SpectrophotometricVerification of Sample andReagent Pipetting | Possible (but optional) | NA |
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EXPECTED VALUES
Healthy individuals
The expected results of the MONOLISA™ Anti-HAV EIA assay were determined in presumably healthy individuals from the Mid-west US (St Louis, Missouri), the Western US (California and Washington) and from Europe (Parma, Italy).
In the Mid-west, the population was 55% female and 45% male, with ages ranging from 1 to 96 years. 48% (134) were pediatric specimens.
The majority of the subjects were White/Caucasian (64%), and 32% were black or African American; for 4% data were not available.
In this study, 41 % were found reactive for Anti-HAV total antibodies, and 57% were found nonreactive.
In the Western US, 73% were from California, 27% were from Washington. The population was 56% female and 44% male, and their ages ranged from 15 to 90 years.
In this population, 38% were found reactive for Anti-HAV total antibodies, and 62% were found nonreactive.
In Europe, the population was 50% female and 50% male, with ages ranging from 18 to 87 years. In this group, 69% were found reactive for Anti-HAV total antibodies and 31% were found nonreactive.
The expected results for the US and for presumably healthy individuals living in Europe are presented below (Tables 5, 6 and 7).
Table 5: Expected Results for MONOLISA™ Anti-HAV EIA in subjects from the Midwest US (N= 280)
| MONOLISA™ Anti-HAV EIA | ||||||||
|---|---|---|---|---|---|---|---|---|
| Age Range | Gender | Reactive | Borderline | Nonreactive | Total | |||
| N | % | N | % | N | % | |||
| < 10 | Female | 10 | 28.6% | 0 | N/A | 25 | 71.4% | 35 |
| Male | 7 | 18.4% | 2 | 5.3% | 29 | 76.3% | 38 | |
| 10-19 | Female | 14 | 36.8% | 2 | 5.3% | 22 | 57.9% | 38 |
| Male | 9 | 39.1% | 0 | N/A | 14 | 60.9% | 23 | |
| 20-29 | Female | 3 | 60.0% | 0 | N/A | 2 | 40.0% | 5 |
| Male | 3 | 100.0% | 0 | N/A | 0 | N/A | 3 | |
| 30-39 | Female | 5 | 50.0% | 0 | N/A | 5 | 50.0% | 10 |
| Male | 3 | 33.3% | 0 | N/A | 6 | 66.7% | 9 | |
| 40-49 | Female | 3 | 23.1% | 0 | N/A | 10 | 76.9% | 13 |
| Male | 4 | 50.0% | 0 | N/A | 4 | 50.0% | 8 | |
| 50-59 | Female | 10 | 55.6% | 0 | N/A | 8 | 44.4% | 18 |
| Male | 8 | 47.1% | 0 | N/A | 9 | 52.9% | 17 | |
| 60-69 | Female | 8 | 57.1% | 0 | N/A | 6 | 42.9% | 14 |
| Male | 4 | 30.8% | 0 | N/A | 9 | 69.2% | 13 | |
| 70-79 | Female | 6 | 66.7% | 1 | 11.1% | 2 | 22.2% | 9 |
| Male | 5 | 83.3% | 0 | N/A | 1 | 16.7% | 6 | |
| 80-89 | Female | 9 | 69.2% | 0 | N/A | 4 | 30.8% | 13 |
| Male | 3 | 50.0% | 0 | N/A | 3 | 50.0% | 6 | |
| >=90 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 1 | 50.0% | 0 | N/A | 1 | 50.0% | 2 | |
| Total | 115 | 41.1% | 5 | 1.8% | 160 | 57.1% | 280 |
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| MONOLISAT™ Anti-HAV EIA | ||||||||
|---|---|---|---|---|---|---|---|---|
| Gender | Reactive | Borderline | Nonreactive | |||||
| Age Range | N | % | N | % | N | % | Total | |
| <19 | Female | 3 | 60.0% | 0 | N/A | 2 | 40.0% | 5 |
| Male | 1 | 20.0% | 0 | N/A | 4 | 80.0% | 5 | |
| 20-29 | Female | 11 | 42.3% | 0 | N/A | 15 | 57.7% | 26 |
| Male | 5 | 20.8% | 0 | N/A | 19 | 79.2% | 24 | |
| 30-39 | Female | 10 | 50.0% | 0 | N/A | 10 | 50.0% | 20 |
| Male | 5 | 27.8% | 0 | N/A | 13 | 72.2% | 18 | |
| 40-49 | Female | 6 | 33.3% | 0 | N/A | 12 | 66.7% | 18 |
| Male | 10 | 45.5% | 0 | N/A | 12 | 54.5% | 22 | |
| 50-59 | Female | 15 | 38.5% | 1 | 2.6% | 23 | 59.0% | 39 |
| Male | 5 | 23.8% | 0 | N/A | 16 | 76.2% | 21 | |
| 60-69 | Female | 6 | 50.0% | 0 | N/A | 6 | 50.0% | 12 |
| Male | 4 | 33.3% | 0 | N/A | 8 | 66.7% | 12 | |
| 70-79 | Female | 1 | 11.1% | 0 | N/A | 8 | 88.9% | 9 |
| Male | 1 | 50.0% | 0 | N/A | 1 | 50.0% | 2 | |
| 80-89 | Female | 6 | 100% | 0 | N/A | 0 | N/A | 6 |
| Male | 3 | 75.0% | 0 | N/A | 1 | 25.0% | 4 | |
| >=90 | Female | 0 | N/A | 0 | N/A | 1 | 100.0% | 1 |
| Male | 0 | N/A | 0 | N/A | 0 | N/A | 0 | |
| Unknown | Female | 0 | N/A | 0 | N/A | 1 | 100.0% | 1 |
| Total | 92 | 37.6% | 1 | 0.4% | 152 | 62.0% | 245 |
Table 6: Expected Results for MONOLISA™ Anti-HAV EIA in subjects from the Western US (N= 245)
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| MONOLISAT™ Anti-HAV EIA | ||||||||
|---|---|---|---|---|---|---|---|---|
| Age Range | Gender | Reactive | Borderline | Nonreactive | Total | |||
| N | % | N | % | N | % | |||
| < 19 | Female | 0 | N/A | 0 | N/A | 1 | 100.0% | 1 |
| Male | 0 | N/A | 0 | N/A | 1 | 100.0% | 1 | |
| 20-29 | Female | 1 | 33.3% | 0 | N/A | 2 | 66.7% | 3 |
| Male | 0 | N/A | 0 | N/A | 2 | 100.0% | 2 | |
| 30-39 | Female | 1 | 14.3% | 0 | N/A | 6 | 85.7% | 7 |
| Male | 2 | 28.6% | 0 | N/A | 5 | 71.4% | 7 | |
| 40-49 | Female | 7 | 33.3% | 0 | N/A | 14 | 66.7% | 21 |
| Male | 3 | 15.8% | 0 | N/A | 16 | 84.2% | 19 | |
| 50-59 | Female | 10 | 45.5% | 0 | N/A | 12 | 54.5% | 22 |
| Male | 14 | 51.9% | 0 | N/A | 13 | 48.1% | 27 | |
| 60-69 | Female | 37 | 86.0% | 0 | N/A | 6 | 14.0% | 43 |
| Male | 23 | 85.2% | 0 | N/A | 4 | 14.8% | 27 | |
| 70-79 | Female | 31 | 96.9% | 0 | N/A | 1 | 3.1% | 32 |
| Male | 32 | 86.5% | 0 | N/A | 5 | 13.5% | 37 | |
| 80-89 | Female | 13 | 100.0% | 0 | N/A | 0 | N/A | 13 |
| Male | 23 | 100.0% | 0 | N/A | 0 | N/A | 23 | |
| Total | 197 | 69.1% | 0 | N/A | 88 | 30.9% | 285 |
:
Table 7: Expected Results for MONOLISA™ Anti-HAV EIA in subjects from Italy, Europe (N= 285)
:
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Adult Subjects At High Risk For Viral Hepatitis:
Expected results of asymptomatic prospective high-risk subjects, determined from a multi-center study in the US and in Europe, are reported in the following tables.
A total of 230 US subjects were at high risk for viral hepatitis including intravenous drug users (N= 55), homosexual males (N=15), sex workers (N=39), prison history (N= 92), high-risk sex partners (N=25), and high-risk occupation/health care workers (N=4). Many had more than 1 high-risk behavior or risk factor. Subjects were from Los Angeles, CA, (86.5%), Santa Ana, CA (4.3%), or Miami, FL (9.1%). The group was Caucasian (7.4%), Black or African American (74.3%), Hispanic or Latino (15.2%), Asian (0.4%), Native Hawaiian or other Pacific Islander (0.4%), and American Indian or Alaska native (0.9%), with the remaining (1.3%) represented by multiple ethnic groups.
Of these subjects, 81% were male and 19% were female, and they ranged in age from 18 to 70 years (mean age of 45). The data are reported in Table 8.
The percent of Anti-HAV reactive results with MONOLISA™ Anti-HAV EIA in this high-risk asymptomatic population was 53%.
The European group (N= 62) was 87% male and 13% female, and ranged in age from 21 to 75 years (mean age of 40). It consisted of intravenous drug users (30), subjects who had clotting factor disorders (7) and MSM patients (25). The data are reported in Table 9.
The percent of Anti-HAV reactive results with MONOLISA™ Anti-HAV EIA in this high-risk asymptomatic population was 45%.
| MONOLISAT™ Anti-HAV EIA | ||||||||
|---|---|---|---|---|---|---|---|---|
| Age | Gender | Reactive | Borderline | Nonreactive | ||||
| Range | N | % | N | % | N | % | Total | |
| < 19 | Female | 1 | 100.0% | 0 | N/A | 0 | N/A | 1 |
| Male | 1 | 100.0% | 0 | N/A | 0 | N/A | 1 | |
| 20-29 | Female | 1 | 33.3% | 0 | N/A | 2 | 66.7% | 3 |
| Male | 1 | 50.0% | 0 | N/A | 1 | 50.0% | 2 | |
| 30-39 | Female | 4 | 57.1% | 0 | N/A | 3 | 42.9% | 7 |
| Male | 12 | 33.3% | 0 | N/A | 24 | 66.7% | 36 | |
| 40-49 | Female | 15 | 62.5% | 0 | N/A | 9 | 37.5% | 24 |
| Male | 37 | 43.5% | 1 | 1.2% | 47 | 55.3% | 85 | |
| 50-59 | Female | 6 | 85.7% | 0 | N/A | 1 | 14.3% | 7 |
| Male | 31 | 60.8% | 1 | 2.0% | 19 | 37.3% | 51 | |
| 60-69 | Female | 1 | 100.0% | 0 | N/A | 0 | N/A | 1 |
| Male | 9 | 90.0% | 0 | N/A | 1 | 10.0% | 10 | |
| 70-79 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 2 | 100.0% | 0 | N/A | 0 | N/A | 2 | |
| Total | 121 | 52.6% | 2 | 0.9% | 107 | 46.5% | 230 |
Table 8: Expected results for MONOLISA™ Anti-HAV EIA in the US High Risk Group for Viral Hepatitis A (N=230)
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Table 9: Expected results for MONOLISA™ Anti-HAV EIA in the European High Risk Group for Viral Hepatitis A (N=62)
| AgeRange | Gender | Reactive | Borderline | Nonreactive | Total | |||
|---|---|---|---|---|---|---|---|---|
| N | % | N | % | N | % | |||
| < 19 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 0 | N/A | 0 | N/A | 0 | N/A | 0 | |
| 20-29 | Female | 0 | N/A | 0 | N/A | 5 | 100.0% | 5 |
| Male | 0 | N/A | 0 | N/A | 11 | 100.0% | 11 | |
| 30-39 | Female | 1 | 50.0% | 0 | N/A | 1 | 50.0% | 2 |
| Male | 5 | 35.7% | 0 | N/A | 9 | 64.3% | 14 | |
| 40-49 | Female | 1 | 100.0% | 0 | N/A | 0 | N/A | 1 |
| Male | 9 | 64.3% | 0 | N/A | 5 | 35.7% | 14 | |
| 50-59 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 9 | 81.8% | 0 | N/A | 2 | 18.2% | 11 | |
| 60-69 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 1 | 50.0% | 0 | N/A | 1 | 50.0% | 2 | |
| 70-79 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 2 | 100.0% | 0 | N/A | 0 | N/A | 2 | |
| >80 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 0 | N/A | 0 | N/A | 0 | N/A | 0 | |
| Total | 28 | 45.2% | 0 | N/A | 34 | 54.8% | 62 |
.
.
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PERFORMANCE CHARACTERISTICS
Clinical performance
A multi-center prospective and retrospective study was conducted to evaluate the clinical performance of the MONOLISA™ Anti-HAV EIA assay among individuals with signs or symptoms and those at high risk of Hepatitis infection. Specimens were collected in 3 different geographical areas: 404 specimens were collected in the US and 928 were collected in Europe (France and Italy).
The US population consisted of 174 subjects with signs and symptoms of Hepatitis.
Of these, 60% were male and 40% were female, and they ranged in age from 17 to 72 years (mean age of 38). The group was Caucasian (13.2%), Black or African American (4.6%), Hispanic or Latino (2.9%), and Asian (41.9%), with 1.1% represented by multiple ethnic groups. The remaining 36.8% were unknown. Among these 174 subjects, 23 (13.2%) were pediatric samples.
The 230 subjects from the high-risk group for Hepatitis A include intravenous drug users (N= 55), homosexual males (N=15), sex workers (N=39), prison history (N= 92), high-risk sex partners (N=25), and high-risk occupation/health care workers (N=4). Many had more than 1 high-risk behavior or risk factor. The group was Caucasian (7.4%), Black or African American (74.3%), Hispanic or Latino (15.2%), Asian (0.4%), Native Hawaiian or other Pacific Islander (0.4%), and American Indian or Alaska native (0.9%), with the remaining (1.3%) represented by multiple ethnic groups. Of these, 81% were male and 19% were female, and they ranged in age from 18 to 70 years (mean age of 45). Among these 230 subjects, 2 (0,9%) were pediatric samples.
The European population consisted of 252 specimens collected from patients with signs and symptoms of Hepatitis. Of these, 51% were male and 49% were female, and they ranged in age from 1 to 105 years (mean age of 53).
Sixty-two (62) specimens were collected from a population at high risk for hepatitis composed of intravenous drug users (30), subjects who had clotting factor disorders (7) and MSM patients (25). The group was 87% male and 13% female, and ranged in age from 21 to 75 years (mean age of 40).
Three hundred and forty five (345) specimens were from an asymptomatic hospitalized population. Of these, 51% were male and 49% were female, and they ranged in age from 18 to 87 years (mean age of 59).
Thirfty four (34) specimens were from healthcare workers (for HAV pre-vaccination screening). One hundred and fifty one (151) patients had recovered HAV infection.
Among these 844 european samples, 35 (4.1%) were from pediatric subjects.
Vaccinated subjects:
Sixty-two (62) pre- and post-vaccination samples from 38 individuals were tested. Fourteen (14) individuals were enrolled in a vaccination program. They received the TWINRIX® vaccine, a combined Hepatitis A and Hepatitis B vaccine from GlaxoSmithKline. A pre-vaccination sample was collected the day of the first vaccination dose. A second sample was collected before the second vaccination dose was injected (one month after the first dose). A third dose of vaccine was scheduled 6 months after the first injection. The sample after the third vaccination dose was not available.
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Twenty (20) samples were collected from 10 subjects, aged 24 to 45 years, who had received the HAVRIX® vaccine. These subjects received HAVRIX® 1440, an inactivated Hepatitis A vaccine from GlaxoSmithKline, in a two-dose schedule (at 0 and 6 to 12 months). For each subject, a preand a post-vaccination specimen was obtained. All post-vaccination samples were obtained 4 weeks after vaccination.
Fourteen (14) purchased post-vaccination samples were from individuals vaccinated with HAVRIX® and 6 were from individuals vaccinated with VAQTA® from Merck &Co.
Percent Agreement
The results obtained with MONOLISA™ Anti-HAV EIA were compared with the results obtained using the comparative assay.
The positive and negative percent agreements and the 95% exact confidence between MONOLISA™ Anti-HAV EIA and the comparative assay were calculated.
To determine the percent agreement on borderline results the following criteria were used:
-
Specimens that were borderline with the comparative assay and reactive with MONOLISA™ Anti-HAV EIA were considered as false positives for MONOLISA™ Anti-HAV EIA assay.
-
Specimens that were borderline with the comparative assay and nonreactive with MONOLISA™ Anti-HAV EIA were considered as false negatives for MONOLISA™ Anti-HAV EIA.
The results obtained with the US specimens and with the European specimens are presented in the following tables.
| Table 10: MONOLISA™ Anti-HAV EIA versus the comparative assay Results in the US | |||
|---|---|---|---|
| Population (N=404)would and the country of the contract and the contrôleant with and |
| Subject category | Comparative assay:PositiveMONOLISA™ Anti-HAV EIA | Comparative assay:BorderlineMONOLISA™ Anti-HAVEIA | Comparative assay:NegativeMONOLISA™ Anti-HAV EIA | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R | BRD | NR | R | BRD | NR | R | BRD | NR | ||
| Subjects with signsand symptoms | 123 | 0 | 2 | 1 | 0 | 0 | 1 | 3 | 44 | 174 |
| Subjects with highrisk for Hepatitis | 114 | 0 | 0 | 2 | 1 | 1 | 4 | 1 | 107 | 230 |
| Total | 237 | 0 | 2 | 3b | 1d | 1c | 5 | 4a | 151 | 404 |
| Positive percentagreement | 95% ExactConfidence interval | Negative percentagreement | 95% ExactConfidence interval | |
|---|---|---|---|---|
| Total | 98,8%(237/240) | 96.4 - 99.7 | 92.6%(151/163) | 87.5 - 96.1 |
R : Reactive, NR : Nonreactive, BRD : Borderline
8 : the Borderline results with MONOLISA™ Anti-HAV EIA were considered as false positives.
b: the specimens that were Borderline with the comparative assay and reactive with MONOLISA'™ Anti-HAV EIA were considered as false positives with MONOLISA™ Anti-HAV EIA.
4: the results that were borderline with both the MONOLISA™ Anti-HAV EIA and with the comparative assay were not included in the negative agreement or the positive agreement calculations.
ci the specimens that were Borderline with the comparative with MONOLISA™ Anti-HAV EIA were considered as false negative with MONOLISA™ Anti-HAV EIA.
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| Table 11: Comparison of Results for MONOLISA™ Anti-HAV EIA versus the | |||||
|---|---|---|---|---|---|
| comparative assay in the European Population (N= 844) |
| Subjectcategory | Comparative assay:PositiveMONOLISA™ Anti-HAV EIA | Comparative assay:BorderlineMONOLISA™ Anti-HAV EIA | Comparative assay:NegativeMONOLISA™ Anti-HAV EIA | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R | BRD | NR | R | BRD | NR | R | BRD | NR | ||
| Generalhospitalizedpopulation | 236 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 108 | 345 |
| Sign /Symptoms ofHepatitis | 190 | 0 | 0 | 0 | 2 | 1 | 1 | 1 | 57 | 252 |
| Subjectswith highrisk forHepatitis | 28 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 34 | 62 |
| Healthcareworkers | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 28 | 34 |
| Infected/recoveredHAV | 150 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 151 |
| Total | 610 | 0 | 1 | 1b | 2d | 1c | 1 | 1a | 227 | 844 |
| Positive percentagreement | 95% ExactConfidence interval | Negative percentagreement | 95% ExactConfidence interval | |
|---|---|---|---|---|
| Total | 99.7%(610/612) | 98.8 – 99.9 | 98.7%(227/230) | 96.2 – 99.7 |
R : Reactive, NR : Nonreactive, BRD : Borderline
a : the Borderline result with MONOLISA™ Anti-HAV EIA was considered as false positive
b the specimen that was Borderline with the comparative assay and reactive with MONOLISA™ Anti-HAV EIA was considered as false positive with MONOLISA™ Anti-HAV EIA.
^ the specimen that was Borderline with the comparative assay and nonreactive with MONOLISA™ Anti-HAV EIA was considered as false negative with MONOLISA™ Anti-HAV EIA.
d :the 2 borderline results with both MONOLISA™ Anti-HAV EIA and with the comparative assay were not included in the calculation of the negative agreement or the positive agreement.
Acute HAV Infection:
Among the retrospective samples, 84 were from subjects with a medical history and laboratory results indicative of acute Hepatitis A. The subjects included 56% male, 37% female; the gender was not available for 7%. The mean age was 21, and subjects ranged from 1 to 55 years. Among them 39 were pediatric subjects.
The results are presented in the following table:
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Table 12: Comparison of Results for MONOLISA™ Anti-HAV EIA versus the comparative assay on Acute HAV infection in the adult and pediatric European Population (N= 84) :
| Comparative assay:PositiveMONOLISA™ Anti-HAV EIA | Comparative assay:BorderlineMONOLISA™ Anti-HAV EIA | Comparative assay:NegativeMONOLISA™ Anti-HAV EIA | Total | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R | BRD | NR | R | BRD | NR | R | BRD | NR | ||
| Adults | 45 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 45 |
| Pediatrics | 39 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 39 |
| Total | 84 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 84 |
R: Reactive, NR: Nonreactive, BRD : Borderline
The positive agreement was 100% (84/84) with a 95% exact confidence interval of 96.5% to 100%.
Performance of MONOLISA™ Anti-HAV EIA in pediatric subjects:
Sixty (60) pediatric samples were tested during the US and European clinical studies in addition to the 39 pediatric samples from acute HAV infection.
Among the US population, 23 had signs and symptoms of hepatitis and 2 were from the high risk group. In the European population, 3 belonged to the general hospitalized population, 22 had signs and symptoms of hepatitis, 2 were from the high risk group, 3 were healthcare workers, 5 had recovered from Hepatitis A infection. The results from these pediatric samples are summarized in the following table.
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| Table 13 : Comparison of Results for MONOLISA™ Anti-HAV EIA versus the | |||||
|---|---|---|---|---|---|
| comparative assay in the Pediatric European and US Population (N= 60) |
| Subjectcategory | Comparative assay:Positive | Comparative assay:Borderline | Comparative assay:Negative | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R | BRD | NR | R | BRD | NR | R | BRD | NR | ||
| EuropeanPediatrics | 16 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 19 | 35 |
| USPediatrics | 13 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 11 | 25 |
| Total | 29 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 30 | 60 |
| Positive percentagreement | 95% ExactConfidence interval | Negative percentagreement | 95% ExactConfidence interval | |
|---|---|---|---|---|
| Total | 100%(29/29) | 90.2 - 100 | 96.8%(30/31) | 83.3 - 99.9 |
R: Reactive, NR: Nonreactive, BRD: Borderline
Including the combined US and European Sites, the positive percent agreement of the MONOLISA™ Anti-HAV EIA with the comparative anti-HAV assay was 99.5% (931/936) with a 95% exact confidence interval of 98.8% to 99.8%. The negative percent agreement of the MONOLISA™ Anti-HAV EIA with the comparative anti-HAV assay was 96.2% (378/393) with a 95% exact confidence interval of 93.8% to 97.9%.
Study On Vaccinated Subjects:
The HAV antibody response to vaccination was evaluated with 3 different vaccines that are currently licensed in the US: VAQTA® from Merck & Co, HAVRIX® 1440 from Glaxo SmithKline and TWINRIX® from Glaxo SmithKline.
For VAQTA® vaccine, 6 post-vaccination samples from US subjects were available.
For HAVRIX® vaccine, 10 matched sets of pre- and post-vaccination samples from European subjects and 8 post-vaccination samples from US subjects were available.
For TWINRIX® vaccine, 14 matched sets of pre-vaccination and post first dose samples from European individuals were available.
The following results were obtained:
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| Comparative assay:PositiveMONOLISA™ Anti-HAV EIA | Comparative assay:BorderlineMONOLISA™ Anti- HAV EIA | Comparative assay:NegativeMONOLISA™ Anti-HAV EIA | Total | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| R | BRD | NR | R | BRD | NR | R | BRD | NR | ||||
| VAQTA | Post-vaccination | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 6 | |
| HAVRIX | Pre-vaccination | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 10 | 10 | |
| HAVRIX | Post-vaccination | 18 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 18 | |
| TWINRIX | Pre-vaccination | 1 | 0 | 0 | 0 | 0 | 0 | 1* | 0 | 12 | 14 | |
| TWINRIX | Post 1st injection | 9 | 1 | 0 | 0 | 0 | 2 | 0 | 0 | 2 | 14 |
Table 14: MONOLISA™ Anti-HAV EIA Results on Vaccinated Subjects versus the comparative assay - All testing sites
R : reactive, NR : Nonreactive , BRD : Borderline
- Result close to the cutoff value (CO/S=1.2)
In pre-vaccination samples, MONOLISA™ Anti-HAV EIA was in overall agreement with the comparative assay for 21/22 (95.5%) of samples tested.
For TWINRIX® vaccine on post first dose vaccination, MONOLISA™ Anti-HAV EIA demonstrated reactivity in 9/14 (64.3%) samples. The reference method demonstrated reactivity in 10/14 (71.4%) samples.
For HAVRIX® post-vaccination samples, MONOLISA™ Anti-HAV EIA demonstrated reactivity in 18/18 (100%) samples. The reference method demonstrated reactivity in 18/18 (100%) samples.
For VAQTA® post-vaccination samples, MONOLISA™ Anti-HAV EIA demonstrated reactivity in 6/6 (100%) samples. The reference method demonstrated reactivity in 6/6 (100%) samples.
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Seroconversion Panels
Six commercially available HAV seroconversion panels were tested using MONOLISA™ Anti-HAV EIA and the FDA approved comparative assay to determine the sensitivity of the assay. The results are summarized in the following table:
| Panel ID | MONOLISA™ Anti-HAV EIA | Comparative assay | |
|---|---|---|---|
| Post bleed day of firstreactive result | Post bleed day of firstreactive result | Difference in Days toReactive result | |
| 07467A | 0 | 0 | 0 |
| 60160K | 0 | 0 | 0 |
| HAV01 | 0 | 0 | 0 |
| RP-004 | 0 | 6 | - 6 |
| RP-013 | 8 | 8 | 0 |
| PHT902 | 16 | 16 | 0 |
Table 15: MONOLISA™Anti-HAV EIA Seroconversion Panels Results :
The sensitivity of the MONOLISA™ Anti-HAV EIA was equivalent to or more sensitive than the comparative assay in the six seroconversion panels tested.
Cross Reactivity Study
The potential for cross reactivity to other disease states, or viruses was evaluated for the MONOLISA™ Anti-HAV EIA Assay and the comparative assay.
In addition, samples containing rheumatoid factors, auto-antibodies, anti-mouse antibodies were tested.
In total, 255 specimens (including both serum and plasma) from 16 groups of potential crossreactivity were tested. FDA approved methods were used to confirm the disease state of each specimen.
The results are summarized in the following table.
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Table 16: Potential cross reactivity study
| Clinical Condition | Comparative assay PositiveMONOLISA™ Anti-HAV EIA | Comparative assay BRDMONOLISA™ Anti-HAV EIA | Comparative assay NegativeMONOLISA™ Anti-HAV EIA | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R | BRD | NR | R | BRD | NR | R | BRD | NR | ||
| Hepatitis C (HCV) | 7 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 7 | 15 |
| Hepatitis B (HBV) HBs Ag | 9 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 6 | 15 |
| Hepatitis B (HBV) anti HBc | 10 | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 1 | 15 |
| Human Immunodeficiency Virus (HIV) | 6 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 7 | 15 |
| Epstein Barr Virus (EBV) IgG | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 13 | 15 |
| Epstein Barr Virus (EBV) IgM | 15 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 15 |
| Cytomegalovirus (CMV) IgG | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 9 | 15 |
| Cytomegalovirus (CMV) IgM | 7 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 8 | 15 |
| Rubella IgG | 5 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 9 | 15 |
| Toxoplasmosis IgG | 10 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 15 |
| Toxoplasmosis IgM | 8 | 2 | 0 | 0 | 0 | 1 | 0 | 0 | 4 | 15 |
| Mumps IgG | 3 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 11 | 15 |
| Varicella Zoster Virus(VZV) IgG | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 14 | 15 |
| Varicella Zoster Virus(VZV) IgM | 6 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 7 | 15 |
| Anti Nuclear Antibody (ANA) | 7 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 7 | 15 |
| Human Anti Mouse Antibody (HAMA) | 2 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 12 | 15 |
| Rheumatoid Arthritis | 12 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 15 |
| Total | 115 | 2 | 3 | 3 | 0 | 4 | 4 | 1 | 123 | 255 |
7 samples were discrepant: 4 reactive on MONOLISA™ Anti-HAV EIA, nonreactive on comparative assay and 3 were
nonreactive on MONOLISA™ Anti-HAV EIA and reactive on comparative
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Precision Study
Within-Laboratory Precision Study :
A 21-member panel was tested: serum samples with the 6 corresponding plasma samples (EDTA K2, EDTA K3, Sodium Citrate, Sodium Heparin, Lithium heparin, ACD) at 3 different levels (1 negative, 1 negative near the cutoff, 1 low positive near the cutoff) were tested on 1 lot, in duplicate, in 2 different runs per day (am and pm), by the same operator for a period of 20 days. The data were analyzed following the CLSI guidance EP5A2. The mean ratio, the Standard Deviation (SD) and percent coefficient of variation (%CV) were calculated for each panel member.
The data summary is shown in the following tables.
| Panel Member | N | MeanCO/S | Within run¹ | Between Run ² | Between Day ³ | Total ⁴ | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | |||
| Negative Control C0 | 40 | 0.282 | NA | NA | 0.02 | 6.4% | 0.01 | 5.0% | 0.02 | 8.1% |
| Positive Control C1 | 40 | 4.093 | NA | NA | 0.54 | 13.5% | 0.00 | 0.0% | 0.49 | 12.3% |
| Serum 1 | 80 | 0.395 | 0.02 | 4.1% | 0.03 | 6.3% | 0.01 | 1.9% | 0.03 | 7.7% |
| EDTA K2 1 | 80 | 0.379 | 0.02 | 5.0% | 0.03 | 6.8% | 0.01 | 1.4% | 0.03 | 8.6% |
| EDTA K3 1 | 80 | 0.376 | 0.01 | 3.4% | 0.04 | 9.3% | 0.00 | 0.0% | 0.04 | 9.9% |
| Sodium Citrate 1 | 80 | 0.387 | 0.04 | 10.1% | 0.01 | 3.3% | 0.02 | 5.1% | 0.05 | 11.8% |
| Sodium Heparin 1 | 80 | 0.363 | 0.01 | 3.4% | 0.03 | 7.6% | 0.00 | 0.0% | 0.03 | 8.3% |
| Lithium Heparin 1 | 80 | 0.364 | 0.01 | 3.4% | 0.03 | 7.0% | 0.01 | 3.5% | 0.03 | 8.5% |
| ACD 1 | 80 | 0.402 | 0.02 | 4.3% | 0.04 | 10.4% | 0.00 | 0.0% | 0.05 | 11.3% |
| Serum 2 | 80 | 0.691 | 0.03 | 4.9% | 0.06 | 9.6% | 0.01 | 2.3% | 0.06 | 11.0% |
| EDTA K2 2 | 80 | 0.657 | 0.02 | 3.2% | 0.05 | 6.6% | 0.01 | 1.8% | 0.05 | 7.5% |
| EDTA K3 2 | 80 | 0.686 | 0.03 | 4.9% | 0.06 | 8.2% | 0.00 | 0.0% | 0.07 | 9.5% |
| Sodium Citrate 2 | 80 | 0.636 | 0.03 | 3.7% | 0.05 | 7.0% | 0.03 | 4.8% | 0.06 | 9.2% |
| Sodium Heparin 2 | 80 | 0.628 | 0.02 | 3.1% | 0.04 | 6.0% | 0.03 | 4.2% | 0.06 | 7.9% |
| Lithium Heparin 2 | 80 | 0.685 | 0.05 | 6.6% | 0.06 | 8.6% | 0.00 | 0.0% | 0.08 | 10.8% |
| ACD 2 | 80 | 0.746 | 0.04 | 5.6% | 0.05 | 6.4% | 0.03 | 4.7% | 0.07 | 9.7% |
| Serum 3 | 80 | 1.506 | 0.06 | 4.2% | 0.14 | 9.4% | 0.00 | 0.4% | 0.15 | 10.3% |
| EDTA K2 3 | 80 | 1.261 | 0.07 | 4.7% | 0.11 | 7.0% | 0.07 | 4.8% | 0.15 | 9.7% |
| EDTA K3 3 | 80 | 1.257 | 0.04 | 2.4% | 0.09 | 6.0% | 0.05 | 3.6% | 0.11 | 7.4% |
| Sodium Citrate 3 | 80 | 1.462 | 0.08 | 5.1% | 0.13 | 8.7% | 0.07 | 4.9% | 0.17 | 11.2% |
| Sodium Heparin 3 | 80 | 1.380 | 0.11 | 7.5% | 0.12 | 8.0% | 0.05 | 3.4% | 0.17 | 11.4% |
| Lithium Heparin 3 | 80 | 1.346 | 0.08 | 5.6% | 0.11 | 7.1% | 0.03 | 1.8% | 0.14 | 9.2% |
| ACD 3 | 80 | 1.344 | 0.05 | 3.4% | 0.08 | 5.6% | 0.09 | 6.0% | 0.13 | 8.9% |
Table 17: MONOLISA™ Anti-HAV EIA Precision Results by Panel Member Cutoff to Signal (CO/S)
NA : Not Applicable
1 Within Run: variability of the assay performance from replicate to replicate
2Between Run: variability of the assay performance from Run to Run
3 Between Day: variability of the assay performance from Day to Day
*Total :total variability of the assay performance includes within run, between run and between day.
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Reproducibility Study:
A 6 member panel consisting of diluted plasma specimens (negative and different levels of positive) was tested in triplicate, once a day for 3 days on 3 lots* of MONOLISA™ Anti-HAV EIA at 3 separate clinical trial sites. Each panel was coded with a different number on each day tested in order to blind the operator to the expected value of the sample.
*:3 different lots were used at the Bio-Rad site and 2 lots were used on each of the external sites.
The data from all reagent lots and sites were combined to obtain Standard Deviation (SD) and percent coefficient of variation (CV) for within run, between lot, between lot, between site and total variance. The data were analyzed according to the principles described in the Clinical Laboratory Standards Institute guidance EP5-A2, revised November 2004 and ISO/TR 22971:2005. The PROC GLM procedure in SAS® was used to estimate the variance components of the model. The model was y = site + lot (site) + day (lot site) + error.
The summaries are shown in the following tables.
Table 18: MONOLISA™ Anti-HAV EIA Reproducibility Results by Panel Member Cutoff to Signal (CO/S)
| Testsite | PanelMember | N | MeanCO/S | Within Run¹ | Between Day² | Between Lot³ | Total⁴ | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||||
| Site#1 | P1 | 18 | 0.33 | 0.01 | 3.03 | 0.09 | 28.1 | 0⁵ | 0 | 0.09 | 28.3 |
| P2 | 18 | 0.68 | 0.03 | 4.9 | 0.07 | 10.0 | 0⁵ | 0 | 0.07 | 11.1 | |
| P3 | 18 | 1.02 | 0.05 | 5.0 | 0.05 | 5.2 | 0⁵ | 4.1 | 0.08 | 8.3 | |
| P4 | 18 | 1.98 | 0.09 | 4.7 | 0.32 | 16.0 | 0⁵ | 0 | 0.33 | 16.7 | |
| P5 | 18 | 2.48 | 0.18 | 7.4 | 0.36 | 14.8 | 0⁵ | 0 | 0.41 | 16.5 | |
| P6 | 18 | 3.66 | 0.23 | 6.2 | 0.20 | 5.5 | 0⁵ | 0 | 0.3 | 8.3 | |
| Site#2 | P1 | 18 | 0.35 | 0.01 | 1.6 | 0.02 | 4.7 | 0.01 | 1.2 | 0.02 | 5.1 |
| P2 | 18 | 0.92 | 0.03 | 3.0 | 0.07 | 8.0 | 0⁵ | 0 | 0.08 | 8.5 | |
| P3 | 18 | 1.28 | 0.04 | 3.5 | 0.00 | 0.0 | 0.01 | 0.62 | 0.05 | 3.6 | |
| P4 | 18 | 2.32 | 0.08 | 3.6 | 0.20 | 8.5 | 0.02 | 0.95 | 0.21 | 9.3 | |
| P5 | 18 | 3.10 | 0.13 | 4.1 | 0.20 | 6.4 | 0⁵ | 0 | 0.23 | 7.5 | |
| P6 | 18 | 4.16 | 0.13 | 3.2 | 0.36 | 8.7 | 0⁵ | 0 | 0.39 | 9.3 | |
| Site#3 | P1 | 27 | 0.36 | 0.01 | 4.0 | 0.02 | 5.4 | 0.02 | 6.6 | 0.03 | 9.4 |
| P2 | 27 | 0.81 | 0.03 | 3.4 | 0.03 | 3.9 | 0.06 | 7.2 | 0.07 | 8.8 | |
| P3 | 27 | 1.27 | 0.08 | 6.6 | 0.04 | 3.6 | 0.14 | 11.2 | 0.17 | 13.5 | |
| P4 | 27 | 2.16 | 0.11 | 5.0 | 0.05 | 2.2 | 0.34 | 15.7 | 0.36 | 16.6 | |
| P5 | 27 | 3.09 | 0.11 | 3.7 | 0.15 | 4.9 | 0.49 | 15.7 | 0.52 | 16.9 | |
| P6 | 27 | 4.47 | 0.11 | 2.5 | 0.33 | 7.3 | 1.01 | 22.5 | 1.06 | 23.8 |
1 Within Run: variability of the assay performance from replicate to replicate
2Between Day: variability of the assay performance from Day to Day
3 Between Lot: variability of the assay performance from Lot to Lot
"Total : total variability of the assay performance includes within run, between day and between lot.
ً Negative variances were rounded to zero, per statistical convention.
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Table 19: MONOLISA™ Anti-HAV Reproducibility Summary by Panel Member Cutoff to Signal (CO/S)
| Panel Member | N | Mean | Within Run1 | Between Day2 | Between Lot3 | Between Site5 | Total4 | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| P1 | 63 | 0.35 | 0.01 | 3.2 | 0.05 | 14.8 | 05 | 0 | 0.01 | 2.9 | 0.05 | 15.5 |
| P2 | 63 | 0.80 | 0.03 | 3.7 | 0.06 | 7.12 | 0.03 | 3.7 | 0.11 | 13.4 | 0.13 | 16.0 |
| P3 | 63 | 1.20 | 0.07 | 5.5 | 0.04 | 3.3 | 0.10 | 8.6 | 0.12 | 10.3 | 0.18 | 14.9 |
| P4 | 63 | 2.15 | 0.10 | 4.5 | 0.20 | 9.5 | 0.22 | 10.0 | 0.00 | 0.0 | 0.31 | 14.5 |
| P5 | 63 | 2.92 | 0.14 | 4.8 | 0.24 | 8.3 | 0.32 | 11.0 | 0.25 | 8.7 | 0.50 | 17.0 |
| P6 | 63 | 4.15 | 0.16 | 3.8 | 0.31 | 7.4 | 0.70 | 16.9 | 05 | 0 | 0.78 | 18.9 |
1 Within Run: variability of the assay performance from replicate to replicate
2Between Day: variability of the assay performance from Day to Day
3Between Lot: variability of the assay performance from Lot to Lot
*Between site: variability of the assay performance from Site to Site
"Total : total variability of the assay performance includes within run, between lot and between site.
Trotal . total variablity of the assuy performance includes within full,
5 Negative variances were rounded to zero, per statistical convention.
Reproducibility study on Negative and Positive Controls:
The negative and positive controls were tested in triplicate, once a day by 3 different operators for 3 days. The data were analyzed according to the principles described in the Clinical Laboratory Standards Institute guidance EP5-A2, revised November 2004 and ISO/TR 22971:2005.
Table 20: MONOLISA™ Anti-HAV EIA Control Reproducibility summary by Operator (CO/S)
| Samples | N | Mean | Within Run1 | Between Day2 | BetweenOperator 3 | Total4 | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| Negative Control | 27 | 0.30 | 0.01 | 2.6 | 0.02 | 8.3 | 05 | 0 | 0.03 | 8.7 |
| Positive Control | 27 | 4.74 | 0.16 | 3.5 | 0.48 | 10.1 | 0.07 | 1.5 | 0.51 | 10.8 |
1 Within Run: variability of the assay performance from replicate to replicate
2Between Day: variability of the assay performance from Day to Day
3 Between operator: variability of the assay performance from Operator to Operator
*Total :total variability of the assay performance includes within run, between day and between Operator.
5 Negative variances were rounded to zero, per statistical convention.
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Image /page/22/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features the department's name in a circular arrangement around a stylized eagle emblem. The eagle is depicted with three wavy lines forming its body and wings, symbolizing the department's mission to protect and promote the health and well-being of Americans.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Manuela Kaul RA-Manager Bio-Rad France 3, Boulevard Raymond Poincaré 92430 Marnes-la-Coquette, France
MAY - 3 2007
Re: K063318
Trade/Device Name: MONOLISA™ Anti-HAV EIA Regulation Number: 21 CFR 866.3310 Regulation Name: Hepatitis A Virus (HAV) Serological Reagents Regulatory Class: Class II Product Code: LOL Dated: March 21, 2007 Received: April 3, 2007
Dear Ms. Kaul:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food. Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration. Ilsting of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820).
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This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.
If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled. "Misbranding by reference to premarket notification" (21CFR Part 807.97), Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.
Sincerely yours,
Kaily att
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostic Devices Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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INDICATIONS FOR USE STATEMENT
510(k) Number : K 063318
MONOLISA™ Anti-HAV EIA Device Name:
Indications for Use:
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.
Prescription Use: ___ X (Per 21 CFR 801.109) AND/OR
Over-The-Counter Use: (Optional Format 1-2-96)
(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Faisano
Division Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Safety
51000 K063318
§ 866.3310 Hepatitis A virus (HAV) serological assays.
(a)
Identification. HAV serological assays are devices that consist of antigens and antisera for the detection of hepatitis A virus-specific IgM, IgG, or total antibodies (IgM and IgG), in human serum or plasma. These devices are used for testing specimens from individuals who have signs and symptoms consistent with acute hepatitis to determine if an individual has been previously infected with HAV, or as an aid to identify HAV-susceptible individuals. The detection of these antibodies aids in the clinical laboratory diagnosis of an acute or past infection by HAV in conjunction with other clinical laboratory findings. These devices are not intended for screening blood or solid or soft tissue donors.(b)
Classification. Class II (special controls). The special control is “Guidance for Industry and FDA Staff: Class II Special Controls Guidance Document: Hepatitis A Virus Serological Assays.” See § 866.1(e) for the availability of this guidance document.