(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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MONOLISA™ Anti-HAV IgM 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 063319 |
|---|---|
| 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 | |
| CLASSIFICATION NAME: | Hepatitis A Test (IgM Antibody) |
| COMMON NAME: | IgM Antibody to Hepatitis A Virus |
| PRODUCT TRADE NAME: | MONOLISA™ Anti-HAV IgM 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-HA-IGMK PLUS PMA Number : P890014 Decision Date : 12/14/2005
DEVICE DESCRIPTION
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,
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KIT COMPONENTS
| Component | Description |
|---|---|
| R1 Microwell Strip Plates | Two (2) x 12 strips of 8 wells coated with polyclonal anti-human IgMantibodies. |
| R2 Wash SolutionConcentrate (30x) | One (1) 120 mL bottle, Tris buffer containing NaCl and Tween 20. |
| C0 Negative Control | One (1) 1 mL vial, containing human plasma, negative for IgM anti-HAV antibodies, total anti-HAV antibodies, HBs antigen, anti-HCVantibodies and anti-HIV-1/HIV-2 antibodies. Preservatives: Sodiumazide (< 0.1%) and Proclin™ 300 (0.25%). |
| C1 Positive Control | One (1) 1 mL vial, containing human plasma, positive for IgM anti-HAVantibodies and negative for HBs antigen, anti-HCV antibodies and anti-HIV-1/HIV-2 antibodies, diluted in human plasma pool negative foranti-HAV antibodies. Preservatives: Sodium azide (<0.1%) andProclin™ 300 (0.25%). |
| C2 Calibrator | One (1) 1.6 mL vial, containing human plasma, positive for IgM anti-HAV antibodies and negative for HBs antigen, anti-HCV antibodies andanti anti-HIV-1/HIV-2 antibodies, diluted in colored synthetic base.Preservatives: Sodium azide (< 0.1%) and Proclin™ 300 (0.25%). |
| R6 Sample Diluent | Two (2) x 14 mL bottles, Tris buffer containing protein and sampleindicator dye. Preservative: Proclin™ 300 (0.1%). |
| R7a HAV Viral Antigen | One (1) 13 mL bottle, Inactivated HAV virus in Tris buffer containingproteins and sample indicator dye. Preservative: Proclin™ 300 (0.1%). |
| R7b Conjugate | One (1) 13 mL bottle, 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, Solution containing Tetramethylbenzidine (TMB). |
| R10 Stopping Solution | One (1) 120 mL bottle, 1 N H2SO4. |
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INTENDED USE
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 not intended for screening blood or solid or soft tissue donors.
INDICATIONS FOR USE
The MONOLISA™ Anti-HAV IgM EIA kit 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 core blood or neonatal specimens.
TECHNOLOGICAL CHARACTERISTICS
The following tables summarize similarities and differences between the MONOLISA™ Anti-HAV IgM EIA kit and the predicate device ETI-HA-IGMK PLUS.
| Similarities inComponents / Materials | MONOLISAT™ Anti-HAVIgM EIA | ETI-HA-IGMK PLUS |
|---|---|---|
| Catalog# 72495 | Catalog# P001925 | |
| Conjugate | Peroxidase-labeled mousemonoclonal antibody to HAV. | Peroxidase-labeled mousemonoclonal antibody to HAV. |
| Positive Control | Human plasma, positive forIgM anti-HAV antibodies,diluted in human plasmanegative for anti-HAVantibodies. | Human serum/plasmareactive for IgM anti-HAV,diluted with buffer. |
| Chromogen | Tetramethylbenzidine (TMB) | Tetramethylbenzidine (TMB) |
| Substrate | Hydrogen Peroxide | Hydrogen Peroxide |
| Washing Solution | Concentrated buffered solutionwith Tween 20. | Concentrated buffered solutionwith detergents. |
| Sample diluent | Buffered solution with proteinsand sample indicator dye. | Buffered solution withproteins and an inert bluedye. |
| Table 1: Similarities between kit components and materials | |
|---|---|
| -- | ------------------------------------------------------------ |
Table 2: Differences between kit components and materials
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| Differences inComponents / Materials | MONOLISA™ Anti-HAVIgM EIACatalog# 72495 | ETI-HA-IGMK PLUSCatalog# P001925 |
|---|---|---|
| Solid Phase | Microplate wells coated withpolyclonal anti-human IgMantibodies. | Microplate wells coated withmouse monoclonal antibodiesto human IgM. |
| Negative Control | Human plasma, negative forIgM anti-HAV antibodies andtotal anti-HAV antibodies. | Human serum/plasma non-reactive for IgM anti-HAV andreactive for IgG anti-HAV,diluted in buffer. |
| Calibrator | Human plasma, positive forIgM anti-HAV antibodiesdiluted in buffer. | Human serum/plasma non-reactive for IgM anti-HAV andreactive for IgG anti-HAVdiluted with buffer. |
| Conjugate | Ready-to-use | To be diluted. |
| Stopping Solution | 1N H2SO4. | 0.4N H2SO4. |
| Required sample volume | 20 μl | 10 μl |
.
Table 3: Similarities between kits with regard to function and use
| Similarities in Functionand Use | MONOLISA™ Anti-HAVIgM EIA | ETI-HA-IGMK PLUS |
|---|---|---|
| Catalog# 72495 | Catalog# P001925 | |
| Test Method | EIA (antibody capture) | EIA (antibody capture) |
| Specimen StorageRequirements | Samples may be stored at 2-8°C for up to 24 hours. | Samples may be stored at 2-8°C for up to 24 hours. |
| Format | 96-well microplate | 96-well microplate |
| Intended Use | Assay for the qualitativedetection of anti-HAV IgMantibodies in human serum orplasma. | Assay for the qualitativedetection of anti-HAV IgMantibodies in human serum orplasma. |
| Wavelength | Dual wavelength reading at450 nm and 615/630 nm. | Dual wavelength reading at450 nm and 630 nm. |
| Interpretation of results | Obtained absorbancereadings for patientspecimens compared to cut-off value determined by themean of the calibratorabsorbance values. | Obtained absorbancereadings for patient samplescompared to cut-off valuedetermined by the mean ofthe calibrator absorbancevalues. |
.
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Table 4: Differences between kits with regard to function and use
| Differences in Functionand Use | MONOLISA TM Anti-HAVIgM EIACatalog# 72495 | ETI-HA-IGMK PLUSCatalog# P001925 |
|---|---|---|
| SpectrophotometricVerification of Sample andReagent Pipeting | Possible (but optional) | NA |
| Cutoff calculation | Mean absorbance ofcalibrator values divided by 4 | Mean absorbance of thecalibrator values + 0.250 |
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EXPECTED VALUES Healthy individuals
The expected results of the MONOLISA™ Anti-HAV IgM 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 that ranged 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 the Western USA, 73% were from California and 27% were from Washington. The population was 56% female and 44% male, with ages that ranged from 15 to 90 years.
In Europe, the population was 50% female and 50% male, with ages that ranged from 18 to 87 years.
The expected results for presumably healthy individuals living in the United States and in Europe are presented below (Tables 5, 6 and 7).
The percent of Anti-HAV IgM reactive results with MONOLISA™ Anti-HAV IgM EIA were 0.4% for both Mid-west and Western US and 0.7% in Europe.
| MONOLISA™ Anti-HAV IgM EIA | ||||||||
|---|---|---|---|---|---|---|---|---|
| Age Range | Gender | Reactive | Borderline | Nonreactive | Total | |||
| N | % | N | % | N | % | |||
| < 10 | Female | 0 | N/A | 0 | N/A | 35 | 100.0% | 35 |
| Male | 0 | N/A | 0 | N/A | 38 | 100.0% | 38 | |
| 10-19 | Female | 0 | N/A | 0 | N/A | 38 | 100.0% | 38 |
| Male | 0 | N/A | 0 | N/A | 23 | 100.0% | 23 | |
| 20- 29 | Female | 0 | N/A | 0 | N/A | 5 | 100.0% | 5 |
| Male | 0 | N/A | 0 | N/A | 3 | 100.0% | 3 | |
| 30 -39 | Female | 0 | N/A | 0 | N/A | 10 | 100.0% | 10 |
| Male | 0 | N/A | 0 | N/A | 9 | 100.0% | 9 | |
| 40 -49 | Female | 0 | N/A | 0 | N/A | 13 | 100.0% | 13 |
| Male | 0 | N/A | 0 | N/A | 8 | 100.0% | 8 | |
| 50 -59 | Female | 1 | 5.6% | 1 | 5.6% | 16 | 88.9% | 18 |
| Male | 0 | N/A | 0 | N/A | 17 | 100.0% | 17 | |
| 60 -69 | Female | 0 | N/A | 0 | N/A | 14 | 100.0% | 14 |
| Male | 0 | N/A | 0 | N/A | 13 | 100.0% | 13 | |
| 70-79 | Female | 0 | N/A | 0 | N/A | 9 | 100.0% | 9 |
| Male | 0 | N/A | 0 | N/A | 6 | 100.0% | 6 | |
| 80-89 | Female | 0 | N/A | 0 | N/A | 13 | 100.0% | 13 |
| Male | 0 | N/A | 0 | N/A | 6 | 100.0% | 6 | |
| >=90 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 0 | N/A | 0 | N/A | 2 | 100.0% | 2 | |
| Total | 1* | 0.4% | 1** | 0.4% | 278 | 99.3% | 280 |
Table 5: Expected Results for MONOLISA™ Anti-HAV IqM EIA in subjects from the Mid-West US (N= 280)
*1 subject was reactive with a result of 2.25 (S/CO)
** 1 subject gave an initial borderline result of 1.04 (S/CO).
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| MONOLISA™ Anti-HAV IgM EIA | ||||||||
|---|---|---|---|---|---|---|---|---|
| Age Range | Gender | Reactive N | Reactive % | Borderline N | Borderline % | Nonreactive N | Nonreactive % | Total |
| <19 | Female | 0 | N/A | 0 | N/A | 5 | 100.0% | 5 |
| Male | 0 | N/A | 0 | N/A | 5 | 100.0% | 5 | |
| 20-29 | Female | 0 | N/A | 0 | N/A | 26 | 100.0% | 26 |
| Male | 0 | N/A | 0 | N/A | 24 | 100.0% | 24 | |
| 30-39 | Female | 0 | N/A | 0 | N/A | 20 | 100.0% | 20 |
| Male | 0 | N/A | 0 | N/A | 18 | 100.0% | 18 | |
| 40-49 | Female | 0 | N/A | 0 | N/A | 18 | 100.0% | 18 |
| Male | 0 | N/A | 0 | N/A | 22 | 100.0% | 22 | |
| 50-59 | Female | 1 | 2.6% | 0 | N/A | 38 | 97.4% | 39 |
| Male | 0 | N/A | 1 | 4.8% | 20 | 95.2% | 21 | |
| 60-69 | Female | 0 | N/A | 0 | N/A | 12 | 100.0% | 12 |
| Male | 0 | N/A | 0 | N/A | 12 | 100.0% | 12 | |
| 70-79 | Female | 0 | N/A | 0 | N/A | 9 | 100.0% | 9 |
| Male | 0 | N/A | 0 | N/A | 2 | 100.0% | 2 | |
| 80-89 | Female | 0 | N/A | 0 | N/A | 6 | 100.0% | 6 |
| Male | 0 | N/A | 0 | N/A | 4 | 100.0% | 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 | 1* | 0.4% | 1** | 0.4% | 243 | 99.2% | 245 |
・
Table 6: Expected Results for MONOLISA™ Anti-HAV IgM EIA in subjects from the Western US (N= 245)
*1 subject was reactive with a result of 1.34 (S/CO)
*1 subject was reactive with a result of 1.34 (S/CO)
** 1 subject gave an initial borderline result of 0.96 (S/CO).
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| MONOLISA™ Anti-HAV IgM EIA | ||||||||
|---|---|---|---|---|---|---|---|---|
| Gender | Reactive | Borderline | Nonreactive | |||||
| Age Range | N | % | N | % | N | % | Total | |
| < 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 | 0 | N/A | 0 | N/A | 3 | 100.0% | 3 |
| Male | 0 | N/A | 0 | N/A | 2 | 100.0% | 2 | |
| 30 -39 | Female | 0 | N/A | 0 | N/A | 7 | 100.0% | 7 |
| Male | 0 | N/A | 0 | N/A | 7 | 100.0% | 7 | |
| 40 -49 | Female | 0 | N/A | 0 | N/A | 21 | 100.0% | 21 |
| Male | 0 | N/A | 0 | N/A | 19 | 100.0% | 19 | |
| 50 -59 | Female | 0 | N/A | 0 | N/A | 22 | 100.0% | 22 |
| Male | 0 | N/A | 0 | N/A | 27 | 100.0% | 27 | |
| 60 -69 | Female | 1 | 2.5% | 1 | 2.5% | 41 | 95.0% | 43 |
| Male | 0 | N/A | 0 | N/A | 27 | 100.0% | 27 | |
| 70-79 | Female | 1 | 3.6% | 0 | N/A | 31 | 96.4% | 32 |
| Male | 0 | N/A | 0 | N/A | 37 | 100% | 37 | |
| 80-89 | Female | 0 | N/A | 0 | N/A | 13 | 100% | 13 |
| Male | 0 | N/A | 0 | N/A | 23 | 100% | 23 | |
| Total | 2* | 0.7% | 1** | 0.4% | 282 | 98.9% | 285 |
Table 7: Expected Results for MONOLISA™ Anti-HAV IgM EIA in subjects from Italy, Europe (N= 285)
*2 subjects gave reactive results of 3.4 and 1.2 (S/CO)
** 1 subject gave an initial borderline result of 1.07 (S/CO)
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), 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.
The subjects were 81% male and 19% female, and ranged in age from 18 to 70 years (mean age of 45). The data are reported in Table 8.
The percent of Anti-HAV IgM reactive results with MONOLISA™ Anti-HAV IgM EIA in this high-risk asymptomatic population was 0%.
The European group (N= 62) was 87% male 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 IgM reactive results with MONOLISA™ Anti-HAV IqM EIA in this high-risk asymptomatic population was 0%.
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| 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 | 0 | N/A | 0 | N/A | 3 | 100.0% | 3 |
| Male | 0 | N/A | 0 | N/A | 2 | 100.0% | 2 | |
| 30 -39 | Female | 0 | N/A | 0 | N/A | 7 | 100.0% | 7 |
| Male | 0 | N/A | 0 | N/A | 36 | 100.0% | 36 | |
| 40 -49 | Female | 0 | N/A | 0 | N/A | 24 | 100.0% | 24 |
| Male | 0 | N/A | 1 | 1.2 % | 84 | 98.8% | 85 | |
| 50 -59 | Female | 0 | N/A | 0 | N/A | 7 | 100.0% | 7 |
| Male | 0 | N/A | 0 | N/A | 51 | 100.0% | 51 | |
| 60 -69 | Female | 0 | N/A | 0 | N/A | 1 | 100.0% | 1 |
| Male | 0 | N/A | 0 | N/A | 10 | 100.0% | 10 | |
| 70-79 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 0 | N/A | 0 | N/A | 2 | 100.0% | 2 | |
| Total | 0 | N/A | 1 | 0.4% | 229 | 99.6% | 230 |
Table 8: Expected results for MONOLISA™ Anti-HAV IgM EIA in the US High risk Group for Viral Hepatitis A (N=230)
Table 9: Expected results for MONOLISA™ Anti-HAV IgM EIA in the European High risk group for Viral Hepatitis A (N=62)
| MONOLISA™ Anti-HAV IgM EIA | ||||||||
|---|---|---|---|---|---|---|---|---|
| Age Range | Gender | Reactive N | Reactive % | Borderline N | Borderline % | Non reactive N | Non reactive % | Total |
| < 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 | 0 | N/A | 0 | N/A | 2 | 100.0% | 2 |
| Male | 0 | N/A | 0 | N/A | 14 | 100.0% | 14 | |
| 40 -49 | Female | 0 | N/A | 0 | N/A | 1 | 100.0% | 1 |
| Male | 0 | N/A | 0 | N/A | 14 | 100.0% | 14 | |
| 50 -59 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 0 | N/A | 0 | N/A | 11 | 100.0% | 11 | |
| 60 -69 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 0 | N/A | 0 | N/A | 2 | 100.0% | 2 | |
| 70-79 | Female | 0 | N/A | 0 | N/A | 0 | N/A | 0 |
| Male | 0 | N/A | 0 | N/A | 2 | 100.0% | 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 | 0 | N/A | 0 | N/A | 62 | 100.0% | 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 IgM EIA assay among individuals with signs or symptoms and those at high risk for Hepatitis infection. Specimens were collected in 3 different geographical areas: 404 specimens were collected in the US and 929 were collected in Europe (France and Italy).
The US population consisted of 174 subjects with signs and symptoms of Hepatitis. In this group, 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 the remaining 1.1% represented by multiple ethnic groups. The ethnicity of 36.8% was unknown. Among these 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), 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. In this group, 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 253 specimens collected from patients with signs and symptoms of Hepatitis. In this group, 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).
There were 345 specimens from an asymptomatic hospitalized population and 34 were from healthcare workers (for HAV pre-vaccination screening),
One hundred and fifty one (151) patients had recovered HAV infection.
Among these 845 european samples, 36 (4.3%) were from pediatric subjects.
Percent Agreement
The results obtained with MONOLISA™ Anti-HAV IgM 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 IgM EIA and the comparative assay were calculated.
To determine the percent agreement on borderline results the following criteria were used:
- 프 Specimens that were borderline with the comparative assay and reactive with MONOLISA™ Anti-HAV IgM EIA were considered as false positives for MONOLISA™ Anti-HAV IgM EIA assay
- a Specimens that were borderline with the comparative assay and non reactive with MONOLISA™ Anti-HAV IgM EIA were considered as false negatives for MONOLISA™ Anti-HAV IgM EIA
The results obtained with the US specimens and with the European specimens are presented in the following tables:
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Table 10: MONOLISA™ Anti-HAV IgM EIA versus the comparative assay results in the US population (N=404)
| Subjectcategory | Comparative assay:PositiveMONOLISA™ Anti-HAV IgM EIA | Comparative assay :BorderlineMONOLISA™ Anti-HAV IgM EIA | Comparative assay:NegativeMONOLISA™ Anti-HAV IgM EIA | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R | BRD | NR | R | BRD | NR | R | BRD | NR | ||
| Subjects withsigns andsymptoms | 1 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 171 | 174 |
| Subjects withhigh risk forHepatitis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 229 | 230 |
| Total | 1 | 0 | 0 | 0 | 0 | 0 | 2b | 1a b | 400 | 404 |
R: Reactive, NR: Nonreactive, BRD : Borderline
³: the borderline sample with MONOLISA was considered as "false positive"
b: these samples were found HAV IgG reactive.
| Positive percentagreement | 95% ExactConfidence interval | Negative percentagreement | 95% ExactConfidence interval | |
|---|---|---|---|---|
| Total | 100%(1/1) | NA | 99.3%(400/403) | 97.8-99.9% |
Table 11: MONOLISA™ Anti-HAV IgM EIA versus the comparative assay results in the European population (N= 845)
| Comparativeassay: PositiveMONOLISA™Anti-HAV IgMEIA | Comparativeassay: BorderlineMONOLISA™Anti-HAV IgMEIA | Comparativeassay: NegativeMONOLISA™Anti-HAV IgMEIA | Total | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Subjectcategory | R | BRD | NR | R | BRD | NR | R | BRD | NR | |
| Generalhospitalizedpopulation | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 1b | 342 | 345 |
| Sign /Symptoms ofHepatitis | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | 250 | 253 |
| Subjects withhigh risk forHepatitis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 62 | 62 |
| Healthcareworkers | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 34 | 34 |
| Infected/recovered HAV | 0 | 0 | 0 | 2a | 0 | 0 | 1 | 0 | 148 | 151 |
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| Company of Children College1and the first of the first of the first of the first of the first of the first of the first for the first for the first and------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------THE LEASE | AND LABOR | THE LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LEAST LE | -----CCompany of the results of the results of the results of the first of the first of the first of the first of the first of the first the first the first the first the first the | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ***Access Accessful and | 11 16 100------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------1845A Property (4) 4 (4) 4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | ||
|---|---|---|---|---|---|---|---|---|---|---|
| -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ----------- | -- | -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ----------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | -- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- |
| Positive percentagreement | 95% ExactConfidence interval | Negative percentagreement | 95% ExactConfidence interval | |
|---|---|---|---|---|
| Total | 100%(1/1) | N/A | 99.0%(836/844) | 98.1-99.6 |
R: Reactive, NR: Nonreactive, BRD : Borderline
ª the 2 borderline samples with the comparative assay were considered "false positive" with MONOLISA
b: the borderline sample with MONOLISA was considered as "false positive"
°; these samples were found HAV IgG Reactive
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:
| Table 12 : Comparison of Results for MONOLISA™ Anti-HAV IgM EIA versus the | |||
|---|---|---|---|
| comparative assay on Acute HAV infection in the adult and pediatric European | |||
| Population (N= 84) : |
| Comparative assay: Positive | Comparative assay: Borderline | Comparative assay : Negative | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| MONOLISA™ Anti-HAV IgM EIA | MONOLISA™ Anti-HAV IgM EIA | MONOLISA™ Anti-HAV IgM 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-one (61) pediatric samples were tested during the US and European clinical studies in addition to the 39 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, 23 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 IgM EIA versus the comparative assay in the Pediatric European and US Population (N= 61)
| Subject category | Comparative assay: PositiveMONOLISATM Anti-HAV IgM EIA | Comparative assay: BorderlineMONOLISATM Anti-HAV IgM EIA | Comparative assay : NegativeMONOLISATM Anti-HAV IgM EIA | Total | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| R | BRD | NR | R | BRD | NR | R | BRD | NR | ||
| European pediatrics | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 35 | 36 |
| US pediatrics | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 24 | 25 |
| Total | 0 | 0 | 0 | 0 | 0 | 0 | 2a | 0 | 59 | 61 |
R: Reactive, NR: Nonreactive, BRD : Borderline
³: these samples were found HAV IgG Reactive
| Positive percentagreement | 95% ExactConfidence interval | Negative percentagreement | 95% ExactConfidence interval | |
|---|---|---|---|---|
| Total | 0 | N/A | 96.7%(59/61) | 88.6 - 99.6 |
Including the combined US and European Sites, the positive percent agreement of the MONOLISA™ Anti-HAV IgM EIA with the comparative assay was 100% (86/86), with a 95% exact confidence interval of 96.6% to 100%. The negative percent agreement of the MONOLISA™ Anti-HAV IgM EIA with the comparative assay was 99.1% (1233/1244) with a 95% exact confidence interval of 98.4% to 99.6%.
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Seroconversion Panels
Eight commercially available HAV seroconversion panels were tested using MONOLISA™ Anti-HAV IgM EIA and the comparative assay to determine the sensitivity of the assay. The results are summarized in the following table:
| Panel ID | MONOLISA™ Anti-HAV IgM EIA | Anti-HAV IgMComparative Assay | |
|---|---|---|---|
| Post bleed day of firstreactive result | Post bleed day of firstreactive result | Difference in Daysto Reactive result | |
| 07467A | 0 | 0 | 0 |
| 60160K | 0 | 0 | 0 |
| 60162K | 0 | 0 | 0 |
| HAV01 | 0 | 0 | 0 |
| RP-004 | 6 | 6 | 0 |
| RP-013 | 8 | 8 | 0 |
| PHT901 | 12 | 12 | 0 |
| PHT902 | 16 | 16 | 0 |
Table 14: MONOLISA™Anti-HAV IgM EIA Seroconversion panels Results
| Panel ID | MONOLISA™ Anti-HAVIgM EIA | Anti-HAV IgMComparative Assay | |
|---|---|---|---|
| Post bleed day of lastreactive result* | Post bleed day of lastreactive result* | Difference in Daysfrom last Reactiveresult | |
| HAV01 | 91a | 77 | +14 |
a: last bleed of the panel
For all seroconversion panels, both MONOLISA™ Anti-HAV IgM EIA and the comparative assay detected HAV IgM antibodies at the same first bleed. MONOLISA™ Anti-HAV IgM EIA appears to detect IgM for a longer period than the comparator assay for qualitative determination of IgM antibody to Hepatitis A.
Among seroconversion panels beginning with samples negative for antibodies and having subsequent samples to 5-6 months, one (PHT-902) becomes borderline after 5 months and one (PHT-901) gives a negative result after more than 20 months. Another seroconversion panel (RP-013) with samples collected through 6 months has a declining ratio but still remains positive. The other panels contain members collected through 2 to 3 months.
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Cross Reactivity Study
The potential for cross reactivity to other disease states, or viruses was evaluated for the MONOLISA™ Anti-HAV IgM EIA Assay. In addition, samples containing rheumatoid factors, autoantibodies, anti-mouse antibodies were tested.
In total, 255 specimens (including both serum and plasma) from 16 groups of potential cross reactivity were tested. FDA approved methods were used to confirm the disease state of each specimen. All the samples were found negative on another commercially Anti-HAV IgM assay. The results are summarized in the following table:
| Clinical condition | Numbertested | MONOLISA™Anti-HAV IgM EIAnonreactive |
|---|---|---|
| Hepatitis C (HCV) | 15 | 15 |
| Hepatitis B (HBV) HBs Ag | 15 | 15 |
| Hepatitis B (HBV) anti HBc | 15 | 15 |
| Human Immunodeficiency Virus (HIV) | 15 | 15 |
| Epstein Barr Virus (EBV) IgG | 15 | 15 |
| Epstein Barr Virus (EBV) IgM | 15 | 15 |
| Cytomegalovirus (CMV) IgG | 15 | 15 |
| Cytomegalovirus (CMV) IgM | 15 | 15 |
| Rubella IgG | 15 | 15 |
| Toxoplasmosis IgG | 15 | 15 |
| Toxoplasmosis IgM | 15 | 15 |
| Mumps IgG | 15 | 15 |
| Varicella Zoster Virus(VZV) IgG | 15 | 15 |
| Varicella Zoster Virus(VZV) IgM | 15 | 15 |
| Anti Nuclear Antibody (ANA) | 15 | 15 |
| Human Anti Mouse Antibody (HAMA) | 15 | 15 |
| Rheumatoid Arthritis | 15 | 15 |
| Total Samples tested | 255 | 255 |
Table 15: Potential cross reactivity study
All the 255 specimens were found nonreactive with HAV IgM with MONOLISA™ Anti-HAV IgM and with the predicate assay.
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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 table:
| Table 16: MONOLISA™ Anti-HAV IgM EIA Precision Results by Panel Member Signal to | |||
|---|---|---|---|
| Cutoff (S/CO) |
| Panel Member | N | Mean S/CO | Within run¹ | Between Run ² | Between Day ³ | Total ⁴ | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | CV (%) | SD | CV (%) | SD | CV (%) | SD | CV (%) | |||
| Negative Control C0 | 40 | 0.08 | NA | NA | 0.01 | 11.0% | 0.00 | 0.8% | 0.01 | 11.0% |
| Positive Control C1 | 40 | 2.03 | NA | NA | 0.08 | 4.2% | 0.05 | 2.5% | 0.10 | 4.8% |
| serum 1 | 80 | 0.05 | 0.00 | 5.5% | 0.01 | 14.1% | 0.00 | 7.7% | 0.01 | 17.0% |
| EDTA K2 1 | 80 | 0.05 | 0.00 | 6.3% | 0.01 | 13.4% | 0.00 | 6.4% | 0.01 | 16.1% |
| EDTA K3 1 | 80 | 0.05 | 0.00 | 6.3% | 0.01 | 15.2% | 0.00 | 4.6% | 0.01 | 17.1% |
| Sodium Citrate 1 | 80 | 0.05 | 0.00 | 6.7% | 0.01 | 14.0% | 0.00 | 0.0% | 0.01 | 15.5% |
| Sodium Heparin 1 | 80 | 0.05 | 0.00 | 6.7% | 0.01 | 12.6% | 0.00 | 5.6% | 0.01 | 15.4% |
| Lithium Heparin 1 | 80 | 0.05 | 0.00 | 6.7% | 0.01 | 14.5% | 0.00 | 7.6% | 0.01 | 17.7% |
| ACD A | 80 | 0.05 | 0.00 | 6.3% | 0.01 | 14.0% | 0.00 | 0.4% | 0.01 | 15.3% |
| Serum 2 | 80 | 0.55 | 0.02 | 3.7% | 0.02 | 4.0% | 0.02 | 3.6% | 0.04 | 6.5% |
| EDTA K2 2 | 80 | 0.66 | 0.02 | 3.5% | 0.03 | 4.9% | 0.03 | 5.3% | 0.05 | 8.0% |
| EDTA K3 2 | 80 | 0.65 | 0.02 | 3.3% | 0.04 | 6.1% | 0.03 | 4.7% | 0.05 | 8.3% |
| Sodium Citrate 2 | 80 | 0.65 | 0.03 | 5.0% | 0.03 | 5.0% | 0.02 | 3.8% | 0.05 | 8.0% |
| Sodium Heparin 2 | 80 | 0.57 | 0.01 | 2.5% | 0.02 | 3.7% | 0.03 | 4.8% | 0.04 | 6.6% |
| Lithium Heparin 2 | 80 | 0.57 | 0.02 | 2.7% | 0.04 | 6.1% | 0.02 | 4.0% | 0.05 | 7.8% |
| ACD 2 | 80 | 0.68 | 0.03 | 5.2% | 0.04 | 6.3% | 0.03 | 4.4% | 0.06 | 9.2% |
| Serum 3 | 80 | 1.33 | 0.03 | 2.1% | 0.06 | 4.8% | 0.06 | 5.2% | 0.09 | 7.4% |
| EDTA K2 3 | 80 | 1.44 | 0.03 | 2.5% | 0.06 | 4.8% | 0.06 | 4.7% | 0.09 | 7.2% |
| EDTA K3 3 | 80 | 1.35 | 0.07 | 6.2% | 0.07 | 5.4% | 0.05 | 4.5% | 0.11 | 9.4% |
| Sodium Citrate 3 | 80 | 1.44 | 0.04 | 3.1% | 0.05 | 4.2% | 0.06 | 5.2% | 0.09 | 7.4% |
| Sodium Heparin 3 | 80 | 1.36 | 0.02 | 2.1% | 0.06 | 5.1% | 0.06 | 4.7% | 0.09 | 7.2% |
| Lithium Heparin 3 | 80 | 1.35 | 0.05 | 4.1% | 0.07 | 5.8% | 0.05 | 4.3% | 0.10 | 8.3% |
| ACD 3 | 80 | 1.47 | 0.04 | 3.5% | 0.10 | 8.4% | 0.06 | 5.1% | 0.13 | 10.5% |
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
3Between Day: variability of the assay performance from Day to Day
"Total :total :total variability of the assay performance includes within run, 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 IgM 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 17: MONOLISA™ Anti-HAV IgM ETA Reproducibility Results by Panel Member Signal to Cutoff (S/CO)
| Testsite | PanelMember | N | MeanS/CO | Within Run1 | Between Day2 | Between Lot3 | Total4 | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | ||||||
| Site #1 | P1 | 18 | 0.05 | 0.03 | 74.6 | 05 | 0 | 05 | 0 | 0.03 | 74.6 | ||
| P2 | 18 | 0.69 | 0.03 | 4.7 | 0.06 | 8.1 | 05 | 0 | 0.06 | 9.4 | |||
| P3 | 18 | 1.10 | 0.04 | 3.6 | 0.07 | 6.7 | 05 | 0 | 0.08 | 7.6 | |||
| P4 | 18 | 1.69 | 0.05 | 2.7 | 0.13 | 7.6 | 05 | 0 | 0.14 | 8.1 | |||
| P5 | 18 | 3.26 | 0.07 | 2.2 | 0.03 | 1.1 | 05 | 0 | 0.08 | 2.4 | |||
| P6 | 18 | 4.19 | 0.19 | 4.6 | 0.00 | 0.0 | 0.05 | 1.1 | 0.20 | 4.7 | |||
| Site#2 | P1 | 18 | 0.06 | 0.00 | 6.4 | 0.01 | 12.2 | 0.00 | 6.7 | 0.01 | 15.4 | ||
| P2 | 18 | 0.82 | 0.02 | 2.8 | 0.06 | 7.0 | 05 | 0 | 0.06 | 7.5 | |||
| P3 | 18 | 1.27 | 0.05 | 3.8 | 0.08 | 6.6 | 0.11 | 8.6 | 0.15 | 11.5 | |||
| P4 | 18 | 2.01 | 0.12 | 5.7 | 0.14 | 7.0 | 05 | 0 | 0.18 | 9.1 | |||
| P5 | 18 | 3.8 | 0.15 | 4.0 | 0.20 | 5.2 | 05 | 0 | 0.25 | 6.6 | |||
| P6 | 18 | 4.8 | 0.14 | 2.8 | 0.38 | 7.9 | 05 | 0 | 0.40 | 8.3 | |||
| Site #3 | P1 | 27 | 0.04 | 0.00 | 6.7 | 0.01 | 13.0 | 0.00 | 11.7 | 0.01 | 18.7 | ||
| P2 | 27 | 0.71 | 0.02 | 3.3 | 0.03 | 4.0 | 0.04 | 6.1 | 0.06 | 8.0 | |||
| P3 | 27 | 1.12 | 0.05 | 4.3 | 0.02 | 2.1 | 0.09 | 7.7 | 0.10 | 9.1 | |||
| P4 | 27 | 1.77 | 0.06 | 3.4 | 0.08 | 4.3 | 0.10 | 5.8 | 0.14 | 8.0 | |||
| P5 | 27 | 3.26 | 0.09 | 2.8 | 0.10 | 3.1 | 0.13 | 4.0 | 0.19 | 5.8 | |||
| P6 | 27 | 3.93 | 0.10 | 2.6 | 0.10 | 2.5 | 0.20 | 5.1 | 0.25 | 6.3 |
1 Within Run: variability of the assay performance from replicate to replicate
4Between Day: variability of the assay performance from Day to Day
3Between 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.
5: Negative variances were rounded to zero, per statistical convention.
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Table 18: MONOLISA™ Anti-HAV IgM EIA Reproducibility summary by Panel Member Signal to Cutoff (S/CO).
| PanelMember | N | MeanS/CO | Within Run¹ | Between Day² | Between Lot³ | Between Site⁵ | Total⁴ | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| P1 | 63 | 0.05 | 0.02 | 37.8 | 0.00 | 0.0 | 0.00 | 8.1 | 0.01 | 19.6 | 0.02 | 43.3 |
| P2 | 63 | 0.74 | 0.03 | 3.6 | 0.05 | 6.4 | 0.02 | 2.6 | 0.06 | 8.0 | 0.08 | 11.1 |
| P3 | 63 | 1.16 | 0.05 | 3.9 | 0.06 | 5.3 | 0.08 | 6.8 | 0.07 | 5.8 | 0.13 | 11.1 |
| P4 | 63 | 1.82 | 0.08 | 4.2 | 0.11 | 6.3 | 0.05 | 3.0 | 0.15 | 8.1 | 0.21 | 11.5 |
| P5 | 63 | 3.41 | 0.11 | 3.0 | 0.13 | 3.7 | 0.09 | 2.5 | 0.29 | 8.5 | 0.35 | 10.1 |
| P6 | 63 | 4.25 | 0.14 | 3.3 | 0.21 | 5.0 | 0.14 | 3.2 | 0.43 | 10.1 | 0.52 | 12.2 |
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
් 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.
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 19 : MONOLISA™ Anti-HAV IgM EIA Control Reproducibility summary by Operator by Signal to Cutoff (S/CO).
| Samples | N | Mean | Within Run1 | Between Day2 | Between Operator3 | Total4 | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| SD | %CV | SD | %CV | SD | %CV | SD | %CV | |||
| Negative Control | 27 | 0.06 | 0.02 | 24.2 | 0.02 | 23.3 | 05 | 0 | 0.02 | N/A |
| Positive Control | 27 | 1.91 | 0.08 | 4.1 | 0.02 | 0.9 | 05 | 0 | 0.08 | 4.17 |
1 Within Run: variability of the assay performance from replicate to replicate
2 Between Day: variability of the assay performance from Day to Day
3 Between Operator: variability of the assay performance from Operator to Operator
4 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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Food and Drug Administration 2098 Gaither Road Rockville MD 20850
MAY - 3 2007
Manuela Kaul RA-Manager Bio-Rad France 3, Boulevard Raymond Poincaré 92430 Marnes-la-Coquette, France
Re: K063319 Trade/Device Name: MONOLISA™ Anti-HAV IgM 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, listing 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,
Salgang
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 063319
Device Name: MONOLISA™ Anti-HAV IgM EIA
Indications for Use:
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 Hearttis. 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
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)
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§ 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.