(45 days)
Capture-CMV® is an in vitro qualitative solid phase red cell adherence test system for the detection of antibodies (IgG plus IgM) to cytomegalovirus (CMV) in human serum or plasma. Capture-CMV is intended to be used in screening of blood and plasma donors or patients for serological evidence of previous infection by CMV.
Capture-CMV is a solid phase red cell adherence antibody detection system based on procedures of Plapp et al. This procedure is a modification of the mixed agglutination tests for antigen and antibody detection of Coombs et al. and Hogman employing anti-IgG and IgM-coated red cells as the indicator system. Serum or plasma samples are added to the viral-coated wells. The samples are incubated for five minutes; during which antibodies specific for CMV proteins bind to immobilized viral proteins. Unbound immunoglobulins are washed from the wells and replaced with a suspension of anti-IgG plus anti-IgM-coated indicator red cells. Centrifugation brings the indicator red cells in contact with antibodies bound to the immobilized viral proteins. In the case of a positive test, the migration of the indicator cells to the bottom of the well is impeded as the anti-IgG and anti-IgM bridges are formed between the indicator red cells and the viral-bound antibodies. As a consequence, the indicator red cells adhere over the surface of the test well. In contrast, in the absence of viral antigen-antibody interactions (i.e. a negative test) the indicator red cells are not impeded during their migration, and pellet to the bottom of the well as a packed, well-defined cell button. CMV antigen from cytomegalovirus strain AS 169 grown in human foreskin fibroblast cells is inactivated and coated onto microtitration wells and dried.
Here's an analysis of the provided text to fulfill your request regarding acceptance criteria and the study proving the device meets them:
Device: Capture-CMV®
Intended Use: An in vitro qualitative solid phase red cell adherence test system for the detection of antibodies (IgG plus IgM) to cytomegalovirus (CMV) in human serum or plasma. Intended for use in screening of blood and plasma donors or patients for serological evidence of previous infection by CMV.
The document describes the performance of the Capture-CMV assay specifically when run on the NEO Iris instrument, comparing it to the predicate device (Capture-CMV on Galileo Neo). The "acceptance criteria" here are implied by the clinical performance targets for sensitivity and specificity necessary to demonstrate substantial equivalence to the predicate device and suitability for its intended use.
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" in a separate table with quantified thresholds before presenting the results. Instead, it presents the results of clinical performance studies (sensitivity and specificity) and reproducibility, which implicitly demonstrate that the device meets the required performance for its intended use and substantial equivalence to the predicate. The performance of the predicate device (Galileo Neo) serves as the de facto benchmark.
Based on the "CMV Resolved Results" and "Concordance by Site" tables, the performance targets appear to be very high agreement with the predicate and high sensitivity/specificity.
| Performance Metric | Implicit Acceptance Criteria (based on provided data demonstrating performance) | Reported Device Performance (Capture-CMV on NEO Iris) |
|---|---|---|
| Sensitivity | High, approaching 100% (to ensure detection of CMV antibodies) | 100.0% (98.7%, 95% 2-sided LCI) |
| Specificity | High, approaching 100% (to minimize false positives) | 97.8% (95.0%, 95% 2-sided LCI) |
| Reproducibility (Positive Samples) | 100% concordance across sites and runs | 100.0% (98.5% LCI) |
| Reproducibility (Negative Samples) | High concordance across sites and runs (minimal false positives) | 99.8% (99.2% LCI) |
2. Sample Size Used for the Test Set and Data Provenance
- Test Set Sample Size: N=501 patient samples were used for the method comparison study (sensitivity and specificity analysis). For reproducibility, 10 coded samples (5 positive, 5 negative) were tested for 400 total tests per site across 3 sites, totaling 1200 tests.
- Data Provenance: The studies were conducted at three clinical sites: two external sites and internally at Immucor, Inc. The document does not specify the country of origin but implies a US context given the FDA submission. The study appears to be retrospective as it uses existing patient samples and compares the new device to a predicate device and a commercial particle agglutination assay.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
The document does not explicitly state the number or qualifications of experts used to establish the ground truth.
However, the ground truth for discordant results was established by further testing with a commercially available particle agglutination assay for total antibody (IgG+IgM) to CMV. This implies that the accepted "gold standard" or reference method for CMV antibody detection served as the arbiter, rather than human experts reviewing raw data. For reproducibility, "Expected Positive" and "Expected Negative" values were used for the coded samples, implying a pre-established ground truth for these control samples.
4. Adjudication Method for the Test Set
- For the sensitivity and specificity comparison: Discordant results between the NEO Iris and Galileo Neo were adjudicated using a commercially available particle agglutination assay for total antibody (IgG+IgM) to CMV. This acts as an objective, third-party reference method for reconciliation.
- For reproducibility: The reproducibility study used "coded samples" with "Expected Positive" and "Expected Negative" results, implying that these samples had a predetermined ground truth. No further adjudication method is described beyond comparing the device's output to these expected results.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done
No, an MRMC comparative effectiveness study was not done. This device is an in vitro diagnostic (IVD) assay that produces a qualitative (positive/negative) result, not an imaging device requiring human interpretation. Therefore, a multi-reader study is not applicable. The comparison here is between different automated analyzer platforms run by presumably trained lab technicians.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done
Yes, the performance presented is inherently standalone (algorithm/device only). The Capture-CMV assay on the NEO Iris instrument is an automated system that produces a result (positive/negative for CMV antibodies). The performance metrics (sensitivity, specificity, reproducibility) reflect the device's ability to correctly classify samples based on its internal processes, without direct human intervention in the result determination beyond loading samples and running the assay.
7. The Type of Ground Truth Used
- For the method comparison (sensitivity/specificity): The initial ground truth seems to be established by the predicate device (Capture-CMV on Galileo Neo), and discordant results were then resolved using an alternative commercial reference assay (particle agglutination assay). This is a form of reference standard test result.
- For reproducibility: The ground truth was based on pre-defined "expected" results for coded positive and negative control samples.
8. The Sample Size for the Training Set
The document does not mention a training set sample size. This is typical for a traditional IVD device like this, which is validated through performance studies rather than developed using machine learning with distinct training and test sets in the same way an AI/ML algorithm would be. The "training" in this context would likely refer to the iterative development and optimization of the assay's biochemical components and the instrument's operational parameters, which is not usually quantified as a "training set" in regulatory submissions for non-AI devices.
9. How the Ground Truth for the Training Set was Established
As noted above, a distinct "training set" in the AI/ML sense is not described. The device's performance is validated against clinical samples and known control materials. Any "ground truth" during the development phase would have been established through a combination of well-characterized clinical samples, reference laboratory methods, and known concentrations of analytes, analogous to how IVD assays are traditionally developed and optimized.
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February 4, 2019
Immucor, Inc. Howard Yorek Senior Director, Regulatory Affairs 3130 Gateway Drive Norcross, Georgia 30071
Re: K183571
Trade/Device Name: Capture-CMV Regulation Number: 21 CFR 866.3175 Regulation Name: Cytomegalovirus serological reagents Regulatory Class: Class II Product Code: LJO Dated: December 14, 2018 Received: January 8, 2019
Dear Howard Yorek:
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. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. 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 Part
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801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.htm); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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 comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn
(http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Steven R. Gitterman -S for
Uwe Scherf, Ph.D. Director Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K183571
Device Name Capture-CMV®
Indications for Use (Describe)
Capture-CMV® is an in vitro qualitative solid phase red cell adherence test system for the detection of antibodies (IgG plus IgM) to cytomegalovirus (CMV) in human serum or plasma. Capture-CMV is intended to be used in screening of blood and plasma donors or patients for serological evidence of previous infection by CMV.
| Type of Use (Select one or both, as applicable) | |
|---|---|
| Prescription Use (Part 21 CFR 801 Subpart D) | ☑ |
| Over-The-Counter Use (21 CFR 801 Subpart C) | ☐ |
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Applicant Information
510(k) Owner: Immucor, Inc. Address: 3130 Gateway Drive Norcross, GA 30071 Telephone: 770-441-2051 Fax: 770-441-3081 Contact: Howard Yorek Date Prepared: December 14, 2018 Device Information
Device Trade Name: Device Common Name: Device Classification Name: Device Classification: Classification Product Code: Regulation Number: Predicate Device: 510(k) Number:
Capture-CMV® CMV Antibody Screen Cytomegalovirus serological reagents Class II LJO 21 CFR 866.3175 Capture-CMV (K910003) K183571
Device Description and Intended Use
Summary of the Test
Cytomegalovirus (CMV) is a common human viral pathogen which belongs to the family of herpes viruses. The presence of CMV antibodies in an individual indicates prior infection by the virus. The possibility exists that viral reactivation can occur in such individuals. CMV infection is usually asymptomatic, and can persist as a latent or chronic infection. Viral transmission may occur through transfusion of blood or transplantation of organs from seropositive donors.
Immunocompromised patients, such as premature neonates, organ transplant patients, and oncology patients, are at greater risk of developing more severe manifestations of CMV infections which can be a major direct or indirect cause of mortality in such patients. Congenitally infected newborns are especially prone to developing severe cytomegalic inclusion disease (CID). The severe form of CID may be fatal or may cause permanent neurological sequelae, such as mental retardation, deafness, microcephaly, and motor dysfunction. A CMV mononucleosis-type syndrome can result from the transfusion of CMV-infected blood products or the transplantation of CMV-infected donor organs in a seronegative immunocompromised patient. Low birth weight neonates are also at high risk to CMV mononucleosis through transfusion of CMV-infected blood products.
One method of preventing or reducing CMV infection in seronegative immunocompromised patients is to select CMV seronegative blood donors or organ donors that have been tested by serological screening test for antibodies to CMV. Capture-CMV is a solid phase red cell
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adherence antibody detection system based on procedures of Plapp et al. This procedure is a modification of the mixed agglutination tests for antigen and antibody detection of Coombs et al. and Hogman employing anti-IgG and IgM-coated red cells as the indicator system.
Intended Use
Capture-CMV® is an in vitro qualitative solid phase red cell adherence test system for the detection of antibodies (IgG plus IgM) to cytomegalovirus (CMV) in human serum or plasma. Capture-CMV is intended to be used in screening of blood and plasma donors or patients for serological evidence of previous infection by CMV.
| TechnologicalCharacteristics | Predicate Device | Proposed Device | Comparison |
|---|---|---|---|
| Intended Use | Capture-CMV® is an in vitroqualitative solid phase red celladherence test system for thedetection of antibodies (IgG plusIgM) to cytomegalovirus (CMV)in human serum or plasma.Capture-CMV is intended to beused in screening of blood andplasma donors or patients forserological evidence of previousinfection by CMV. | Capture-CMV® is an in vitroqualitative solid phase red celladherence test system for thedetection of antibodies (IgG plusIgM) to cytomegalovirus (CMV)in human serum or plasma.Capture-CMV is intended to beused in screening of blood andplasma donors or patients forserological evidence of previousinfection by CMV. | Equivalent -Indications for useadd NEO Iris fordiagnosticscreening |
| Test Principle | Serum or plasma samples areadded to the viral-coated wells.The samples are incubated for fiveminutes; during which antibodiesspecific for CMV proteins bind toimmobilized viral proteins.Unbound immunoglobulins arewashed from the wells andreplaced with a suspension of anti-IgG plus anti-IgM-coated indicatorred cells. Centrifugation brings theindicator red cells in contact withantibodies bound to theimmobilized viral proteins. In thecase of a positive test, themigration of the indicator cells tothe bottom of the well is impededas the anti-IgG and anti-IgMbridges are formed between theindicator red cells and the viral-bound antibodies. As aconsequence, the indicator redcells adhere over the surface of thetest well. In contrast, in theabsence of viral antigen-antibodyinteractions (i.e. a negative test)the indicator red cells are not | Serum or plasma samples areadded to the viral-coated wells.The samples are incubated for fiveminutes; during which antibodiesspecific for CMV proteins bind toimmobilized viral proteins.Unbound immunoglobulins arewashed from the wells andreplaced with a suspension of anti-IgG plus anti-IgM-coated indicatorred cells. Centrifugation brings theindicator red cells in contact withantibodies bound to theimmobilized viral proteins. In thecase of a positive test, themigration of the indicator cells tothe bottom of the well is impededas the anti-IgG and anti-IgMbridges are formed between theindicator red cells and the viral-bound antibodies. As aconsequence, the indicator redcells adhere over the surface of thetest well. In contrast, in theabsence of viral antigen-antibodyinteractions (i.e. a negative test)the indicator red cells are not | Identical |
| Test Wells | impeded during their migration, and pellet to the bottom of the well as a packed, well-defined cell button.CMV antigen from cytomegalovirus strain AS 169 grown in human foreskin fibroblast cells is inactivated and coated onto microtitration wells and dried. | IdenticalCMV antigen from cytomegalovirus strain AS 169 grown in human foreskin fibroblast cells is inactivated and coated onto microtitration wells and dried. | |
| Capture-CMVPositive ControlSerum (Weak) | Human serum containing IgG antibodies to CMV viral proteins. Capture-CMV Positive Control Serum (Weak) is manufactured to represent the reactivity obtained by weak CMV antibody donors. Weak CMV antibody positive donors have a titration endpoint of 1:2 or less. Sodium azide (0.1%) has been added as a preservative. | IdenticalHuman serum containing IgG antibodies to CMV viral proteins. Capture-CMV Positive Control Serum (Weak) is manufactured to represent the reactivity obtained by weak CMV antibody donors. Weak CMV antibody positive donors have a titration endpoint of 1:2 or less. Sodium azide (0.1%) has been added as a preservative. | |
| Capture-CMVNegative ControlSerum | Human serum containing no antibodies to CMV viral proteins. Sodium azide (0.1%) has been added as a preservative. | IdenticalHuman serum containing no antibodies to CMV viral proteins. Sodium azide (0.1%) has been added as a preservative. | |
| Capture-CMVIndicator RedCells | A suspension of human red blood cells coated with rabbit anti-human IgG plus goat anti-human IgM antibodies. The red blood cells are suspended in a buffered solution to which chloramphenicol (0.25 mg/mL), neomycin sulfate (0.1 mg/mL), and gentamycin sulfate (0.05 mg/mL) have been added as preservatives. | IdenticalA suspension of human red blood cells coated with rabbit anti-human IgG plus goat anti-human IgM antibodies. The red blood cells are suspended in a buffered solution to which chloramphenicol (0.25 mg/mL), neomycin sulfate (0.1 mg/mL), and gentamycin sulfate (0.05 mg/mL) have been added as preservatives. | |
| Capture LISS | A low-ionic strength solution containing glycine, bromocresol purple dye and the preservative sodium azide (0.1%). | IdenticalA low-ionic strength solution containing glycine, bromocresol purple dye and the preservative sodium azide (0.1%). | |
| Shelf Life | Test wells – 6 monthsControls – 15 monthsCapture LISS – 12 monthsIndicator Red Cells – 60 days | IdenticalTest wells - 6 monthsControls - 15 monthsCapture LISS – 12 monthsIndicator Red Cells – 60 days | |
| Specimen | Serum or plasma | IdenticalSerum or plasma | |
| Test Methods | Manual/Semi-automated diagnostic screening (K910003)Manual/Semi-automated donor screening (BK950029)Galileo® donor and diagnostic screening (BK050050)Galileo Neo® donor and diagnostic screening (BK100033)NEO Iris™ donor screening | Equivalent –Indications for use add NEO Iris for diagnostic screeningManual/Semi-automated diagnostic screening (K910003)Manual/Semi-automated donor screening (BK950029)Galileo® donor and diagnostic screening (BK050050)Galileo Neo® donor and diagnostic screening (BK100033)NEO Iris™ donor screening |
Substantial Equivalence and Comparison to the Predicate Device
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Performance Testing - Non-Clinical
Design verification studies and other studies were performed to demonstrate design inputs for the Capture-CMV assay on the NEO Iris were met and to demonstrate equivalence in performance between the predicate device, Capture-CMV testing on the Galileo Neo" and the proposed device, Capture-CMV testing on the NEO Iris™.
Performance Testing - Clinical
Method comparison studies were performed at three clinical sites, two external sites and internally at Immucor, Inc. Specimens were tested on NEO Iris and Galileo Neo. Test results were evaluated for agreement between analyzers. Specimens with discordant results were further tested with a commercially available particle agglutination assay for total antibody (IgG+IgM) to CMV.
| Galileo Neo | |||
|---|---|---|---|
| CMV Initial ResultsPatient SamplesN=501 | Positive | Negative | |
| NEO Iris | Positive | 272 | 5 |
| Negative | 0 | 224 | |
| Galileo Neo /Anti-CMV PA | |||
| CMV Resolved Results | Positive | Negative | |
| NEO Iris | Positive | 272 | 5 |
| Negative | 0 | 224 | |
| Sensitivity 100.0% (98.7%, 95% 2-sided LCI) | |||
| Specificity 97.8% (95.0%, 95% 2-sided LCI) |
The reproducibility of the Capture-CMV assay on NEO Iris was determined using a panel of ten (10) coded samples, five (5) CMV antibody positive and five (5) CMV antibody negative, at three (3) test sites, two external sites and internally at Immucor, Inc. The samples were tested by two operators, in duplicated on two (2) runs per day for five (5) nonconsecutive days. The summary of reproducibility results by site are presented in the following table:
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| Concordance by Site | |||||||
|---|---|---|---|---|---|---|---|
| Site | TotalTests | ExpectedPositive | ObservedPositive | %Concordance(95% LCI) | ExpectedNegative | ObservedNegative | %Concordance(95% LCI) |
| 1 | 400 | 200 | 200 | 100.0%(98.5%) | 200 | 200 | 100.0%(98.5%) |
| 2 | 400 | 200 | 200 | 100.0%(98.5%) | 200 | 200 | 100.0%(98.5%) |
| 3 | 400 | 200 | 200 | 100.0%(98.5%) | 200 | 199 | 99.5%(97.7%) |
| Total | 1200 | 600 | 600 | 100.0%(98.5%) | 600 | 599 | 99.8%(99.2%) |
Conclusion
The clinical and non-clinical performance data demonstrate substantial equivalence of the NEO Iris Capture-CMV assay in terms of safety, design, performance and reproducibility compared to the predicate device.
§ 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).