(86 days)
IMMULITE® 2000 CMV IgM is for in vitro diagnostic use with IMMULITE® 2000 Systems analyzers for the qualitative detection of IgM antibodies to cytomegalovirus (CMV) in human serum or plasma (EDTA or heparinized), as an aid in the diagnosis of current and recent CMV infection in individuals with signs and symptoms of CMV infection or clinical suspicion of CMV infection. This assay is not FDA cleared or approved for use in testing (screening) blood or plasma donors, neonatal screening, or for use at point-of-care facilities.
Performance characteristics for this assay have not been established in immunocompromised, immunosuppressed or organ transplant individuals.
CMV IgM Controls are assayed, bi-level controls intended for use with the IMMULITE 2000 CMV IgM assay. They are intended as an aid in monitoring day-today assay performance.
IMMULITE 2000 CMV IgM is a solid-phase, enzyme labeled chemiluminescent three-step immunoassay. The solid phase (bead) is coated with inactivated, purified CMV antigen (strain AD-169 from infected cell lysates). The liquid phase consists of two reagents: 1) polyclonal goat anti-human IgG antibody in buffer, and 2) alkaline phosphatase (bovine calf intestine) conjugated to polyclonal goat anti-human IgM antibody in buffer.
In the first cycle, the patient sample and polyclonal goat anti-human IgG antibody are incubated together without the bead for 30 minutes. During this time, anti-IgG antibodies block IgG present in the patient's sample.
In the second cycle, the pretreated sample and polyclonal goat anti-human IgG antibody are transferred to the second reaction tube. Anti-IgG antibodies block the remaining IgG from the patient's sample from binding to the CMV antigen on the bead. During this time, CMV IgM in the patient sample binds to CMV antigen on the bead. Unbound sample and reagent are then removed by centrifugal washes.
In the third cycle, the enzyme conjugated polyclonal goat anti-human IgM antibody is added to the second reaction tube. The enzyme conjugate binds to immobilized IgM to form the antibody sandwich complex. The unbound enzyme conjugate is removed by centrifugal washes. Finally, chemiluminescent substrate is added to the reaction tube and the signal is generated in proportion to the bound enzyme.
Here's an analysis of the provided text, focusing on the acceptance criteria and study details for the IMMULITE® 2000 CMV IgM device:
Acceptance Criteria and Reported Device Performance
The document does not explicitly state pre-defined acceptance criteria in terms of specific percentages for "Positive Agreement" and "Negative Agreement." Instead, it presents the results of a comparison study against a predicate device (Kit A, which is the bioMerieux Vitek VIDAS CMV IgM assay). The "acceptance criteria" are implied by the demonstration of substantial equivalence to the predicate device. The performance is reported as "Positive Agreement" and "Negative Agreement" with the predicate device.
Table 1: Acceptance Criteria (Implied) and Reported Device Performance
| Performance Metric | Implied Acceptance Criteria (Substantial Equivalence) | Reported Device Performance (IMMULITE® 2000 CMV IgM vs. Kit A) |
|---|---|---|
| Prospective Subjects | Achieve substantial equivalence to predicate device | Positive Agreement: 47.1% (95% CI: 23.0% - 72.2%) |
| Negative Agreement: 97.2% (95% CI: 95.4% - 98.5%) | ||
| Retrospective Subjects | Achieve substantial equivalence to predicate device | Positive Agreement: 97.8% (95% CI: 92.4% - 99.7%) |
| Negative Agreement: 56.3% (95% CI: 29.9% - 80.2%) | ||
| Precision | Comparable to predicate device (4.0% to 6.5% CV) | Total CV ranged from 5.1% to 21.4% |
Note on "Acceptance Criteria": The document's primary goal is to demonstrate "substantial equivalence" to a legally marketed predicate device (VIDAS® CMV IgM). This regulatory pathway often relies on showing comparable performance rather than meeting strict pre-defined numerical thresholds for a new device's absolute performance. The provided "Positive Agreement" and "Negative Agreement" with the predicate device are key metrics used to support this claim of equivalence.
Study Details
-
Sample Size used for the test set and the data provenance:
- Total Samples: 636 serum samples.
- Prospective Samples: 527 samples from "target enrollment groups" collected prospectively.
- Retrospective Samples: 109 samples where the CMV IgM+ status was known.
- Data Provenance: Samples were collected at four U.S. sites and three commercial suppliers. The testing was performed at three U.S. sites. It is a multi-site, mixed retrospective and prospective study conducted within the U.S.
-
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
The document does not specify the number of experts or their qualifications for establishing ground truth. The "ground truth" for comparison is primarily defined by the results of a "commercially available CMV IgM assay (Kit A)" which is identified as the VIDAS® CMV IgM assay. For the 109 retrospective samples, it states "where the CMV IgM + status was known," implying a prior determination, but details on how that status was established are not provided. -
Adjudication method for the test set:
The document does not describe any adjudication method. The results are directly compared between the IMMULITE® 2000 CMV IgM assay and the predicate device (Kit A). -
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, this is not an MRMC comparative effectiveness study involving human readers and AI. This is a study comparing the performance of two in vitro diagnostic assays (IMMULITE® 2000 CMV IgM vs. VIDAS® CMV IgM). AI assistance for human readers is not relevant to this type of device and study. -
If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
Yes, this is a standalone performance study of an in vitro diagnostic assay. There is no human-in-the-loop component described for the interpretation or operation of the device during the performance evaluation, beyond routine laboratory procedures. The output of the device is a qualitative result (Reactive, Indeterminate, Nonreactive). -
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
The primary "ground truth" or reference standard used for comparison is the result obtained from a commercially available, legally marketed predicate device (VIDAS® CMV IgM assay). For the retrospective samples, "CMV IgM + status was known," implying prior clinical or laboratory determination. It is not expert consensus, pathology, or outcomes data, but rather a comparison to an established diagnostic test. -
The sample size for the training set:
The document does not provide information on a specific "training set" sample size. This is likely because the document describes a regulatory submission for device performance evaluation and equivalence demonstration, not the development process of a novel algorithm that typically involves distinct training, validation, and test sets. For an immunoassay like this, the 'training' would typically refer to the assay's development and optimization process, not a dedicated data set in the same way as machine learning models. -
How the ground truth for the training set was established:
As no explicit "training set" is mentioned in the context of ground truth establishment for an algorithm, this information is not applicable/not provided in the document. The focus is on the performance evaluation against a predicate device.
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510(k) Summary as Required by 21 CFR 807.92
| Submitter: | Siemens Healthcare Diagnostics Inc.5210 Pacific Concourse DriveLos Angeles, CA 90045-6900 |
|---|---|
| Contact Person: | Robert C. EusebioDirector Regulatory Affairs1584 Enterprise BlvdWest Sacramento, CA 95691(916) 374-3183 |
| Date Prepared: | May 10, 2010 |
| Device Trade Name: | IMMULITE® 2000 CMV IgM |
| Common Name: | Cytomegalovirus serological reagents21 CFR 866.3175 |
| SubstantialEquivalence: | K933549VIDAS® CMV IgM assay |
| Device Description: | IMMULITE 2000 CMV IgM is a solid-phase, enzymelabeled chemiluminescent three-step immunoassay. Thesolid phase (bead) is coated with inactivated, purifiedCMV antigen (strain AD-169 from infected cell lysates).The liquid phase consists of two reagents: 1) polyclonalgoat anti-human IgG antibody in buffer, and 2) alkalinephosphatase (bovine calf intestine) conjugated topolyclonal goat anti-human IgM antibody in buffer. |
MAY 13 2010
In the first cycle, the patient sample and polyclonal goat
anti-human IgG antibody are incubated together without
the bead for 30 minutes. During this time, anti-IgG
antibodies block IgG present in the patient's sample.
In the second cycle, the pretreated sample and polyclonal
goat anti-human IgG antibody are transferred to the second
reaction tube. Anti-IgG antibodies block the remaining IgG
from the patient's sample from binding to the CMV
antigen on the bead. During this time, CMV IgM in the
patient sample binds to CMV antigen on the bead.
Unbound sample and reagent are then removed by
centrifugal washes.
In the third cycle, the enzyme conjugated polyclonal goat
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| anti-human IgM antibody is added to the second reaction tube. The enzyme conjugate binds to immobilized IgM to form the antibody sandwich complex. The unbound enzyme conjugate is removed by centrifugal washes. Finally, chemiluminescent substrate is added to the reaction tube and the signal is generated in proportion to the bound enzyme. | |
|---|---|
| Intended Use: | IMMULITE® 2000 CMV IgM is for in vitro diagnostic use with IMMULITE® 2000 Systems analyzers for the qualitative detection of IgM antibodies to cytomegalovirus (CMV) in human serum or plasma (EDTA or heparinized), as an aid in the diagnosis of current and recent CMV infection in individuals with signs and symptoms of CMV infection or clinical suspicion of CMV infection. This assay is not FDA cleared or approved for use in testing (screening) blood or plasma donors, neonatal screening, or for use at point-of-care facilities. |
| Performance characteristics for this assay have not been established in immunocompromised, immunosuppressed or organ transplant individuals. | |
| Technological Aspects: | A comparison of the device features, intended use, laboratory data and other information demonstrate that the IMMULITE® 2000 CMV IgM assay is substantially equivalent to the currently marketed bioMerieux Vitek VIDAS CMV IgM assay, as summarized in the following tables. |
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. . . . .
. . .
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| IMMULITE 2000 | VIDAS | |
|---|---|---|
| Intended Use | For in vitro diagnostic use withIMMULITE® 2000 Systemsanalyzers — for the qualitativedetection of IgM antibodies tocytomegalovirus (CMV) inhuman serum or plasma(EDTA or heparinized), as anaid in the diagnosis of currentand recent CMV infection inindividuals with signs andsymptoms of CMV infection orclinical suspicion of CMVinfection. This assay is notFDA cleared or approved foruse in testing (screening)blood or plasma donors,neonatal screening, or for useat point-of-care facilities.Performance characteristicsfor this assay have not beenestablished inimmunocompromised,immunosuppressed or organtransplant individuals. | For in vitro diagnostic usewith a VIDAS instrument asan automated enzyme-linkedfluorescent immunoassay(ELFA) for the qualitativedetection of anti-CMV IgMantibodies in human serum. Itis intended to be used as anaid in the diagnosis ofcytomegalovirus infection. Itis not intended for use intesting (screening) blood orplasma donors. |
| Assay Type | Chemiluminescent enzymeIgM antibody μ-captureimmunoassay | Enzyme-linked fluorescentimmunoassay (ELFA) |
| Capture/DetectionAntigen/Antibody | The solid phase is a beadcoated with inactivated,purified CMV antigen (strainAD-169 from infected celllysates). The conjugate ispolyclonal goat anti-humanIgM antibody conjugated toalkaline phosphatase. | The Solid Phase Receptacle iscoated with CMV antigen(strain AD169). Theconjugate is comprised ofmouse monoclonal anti-human IgM antibodiesconjugated to alkalinephosphatase. |
| Type of Assay | Qualitative Assay | Qualitative Assay |
| IMMULITE 2000 | VIDAS | |
| Cut-Offs | Test value = ratio of signalfrom sample to that of signalof adjustor curve parameterP1. | Test Value Threshold = ratioof signal from sample to set ofthresholds stored in thecomputer |
| ≥1.1 Reactive | ≥0.90 Positive | |
| 0.9 to < 1.1 Indeterminate | ≥0.70 to < 0.90 Equivocal | |
| <0.9 Non-reactive | <0.70 Negative | |
| Sample Volume | 10 µL | 100 µL |
| Sample Type | Serum or plasma(EDTA or heparinized) | Serum |
| Cross-Reactivity | Of 197 samples tested forpotential crossreactivity onerheumatoid factor (RF) sampletested reactive and one RFsample tested indeterminate. | Of 62 samples tested forpotential crossreactivity, 6yielded positive results. |
| Interference | Not effected by hemolysis,lipemia or icterus at testlevels. | Potential hemolysis, icterusand lipemia interferencesunknown as testing is notreported in package insert. |
Table 1: Comparison of IMMULITE® with VIDAS® Assay
.
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As part of the clinical study, samples from various patient populations were tested with both the IMMULITE® 2000 CMV IgM assay and the VIDAS® CMV IgM assay. A total of 636 serum samples were collected at four U.S. sites and three commercial suppliers and were tested at three U.S. sites. There were 109 retrospective samples tested where the CMV IgM + status was known. The remaining 527 samples from target enrollment groups were collected prospectively. Each sample was tested with the IMMULITE 2000 CMV IgM assay and with a commercially available CMV IgM assay (Kit A).
Comparison for Prospective Subjects*
| Kit A | IMMULITE 2000CMV IgM | ||
|---|---|---|---|
| Reactive | Indeterminate | Nonreactive | |
| Positive | 8 | 0 | 2 |
| Equivocal | 2 | 1 | 7 |
| Negative | 6 | 6 | 495 |
Positive Agreement: 47.1% (8/17, 95% CI: 23.0% - 72.2%) Negative Agreement: 97.2 % (495/509, 95% CI: 95.4% - 98.5%
- Note: The terms "reactive", "nonreactive" and "indeterminate" (Ind) used for IMMULITE 2000 results correspond to "positive", "negative" and "equivocal" as used by other manufacturers in this context.
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Comparison for Retrospective Subjects
| IMMULITE 2000CMV IgM | |||
|---|---|---|---|
| Kit A | Reactive | Indeterminate | Nonreactive |
| Positive | 90 | 0 | 1 |
| Equivocal | 5 | 1 | 1 |
| Negative | 2 | 0 | 9 |
Positive Agreement: 97.8% (90/92, 95% CI: 92.4% - 99.7%) Negative Agreement: 56.3% (9/16, 95% CI: 29.9% - 80.2%
Precision information in the product insert for the predicate CMV IgM assay shows interassay coefficients of variation (CV) ranging from 4.0% to 6.5% for the two controls reported. The precision of the IMMULITE 2000 CMV assay as measured by total CV ranged from 5.1% to 21.4% for the 8 samples tested.
A comparison of the device features, intended use, laboratory data and other information demonstrates that the IMMULITE® 2000 CMV IgM is substantially equivalent to the currently marketed bioMerieux Vitek VIDAS CMV IgM assay.
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three stripes forming its body and wings. The eagle is facing to the right. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the eagle.
Public Health Service
Siemens Healthcare Diagnostics c/o Mr. Robert C. Eusebio Director Regulatory Affairs 1584 Enterprise Blvd. West Sacramento, CA 95691
Food & Drug Administration 10903 New Hampshire Avenue Building 66 Silver Spring, MD 20993
Image /page/5/Picture/5 description: The image shows the date "MAY 13 2001". The text is in bold and appears to be from a document. The date is likely a reference to a specific event or record within the document.
Rc: K100433
Trade/Device Name: IMMULITE® 2000 CMV IgM Regulation Number: 21 CFR 866.3175 Regulation Name: Cytomegalovirus serological reagents. Regulatory Class: Class II Product Code: LKQ, JIT, JJX Dated: February 09, 2010 Received: February 16, 2010
Dear Mr. Eusebio:
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 class II (Special Controls), 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); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
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Page 2 -
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 advice for your device on our labeling regulation (21 CFR Parts 801 and 809), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours,
Sally A. Hojvat, M.Sc., Ph.D. Director Division of Microbiology Devices Office of In Vitro Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Indications for Use Form
510(k) Number (if known): K100433
Device Name: 1MMULITE® 2000 CMV IgM
Indications for Use:
IMMULITE® 2000 CMV IgM is for in vitro diagnostic use with IMMULITE® 2000 Systems analyzers for the qualitative detection of IgM antibodies to cytomegalovirus (CMV) in human serum or plasma (EDTA or heparinized), as an aid in the diagnosis of current and recent CMV infection in individuals with signs and symptoms of CMV infection or clinical suspicion of CMV infection. This assay is not FDA cleared or approved for use in testing (screening) blood or plasma donors, neonatal screening, or for use at point-of-care facilities.
Performance characteristics for this assay have not been established in immunocompromised, immunosuppressed or organ transplant individuals.
CMV IgM Controls are assayed, bi-level controls intended for use with the IMMULITE 2000 CMV IgM assay. They are intended as an aid in monitoring day-today assay performance.
Prescription Use X (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE OF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Division Sign-Off Office of In Vitro Diagnostic
| Device Evaluation and Safety | |
|---|---|
| 510(k) | The Scif |
Division Sign-Off
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Office of In Vitro Diagnostic Device
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| 510(k) | K100433 |
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§ 866.3175 Cytomegalovirus serological reagents.
(a)
Identification. Cytomegalovirus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to cytomegalovirus in serum. The identification aids in the diagnosis of diseases caused by cytomegaloviruses (principally cytomegalic inclusion disease) and provides epidemiological information on these diseases. Cytomegalic inclusion disease is a generalized infection of infants and is caused by intrauterine or early postnatal infection with the virus. The disease may cause severe congenital abnormalities, such as microcephaly (abnormal smallness of the head), motor disability, and mental retardation. Cytomegalovirus infection has also been associated with acquired hemolytic anemia, acute and chronic hepatitis, and an infectious mononucleosis-like syndrome.(b)
Classification. Class II (performance standards).