(182 days)
The Copalis™ TORC, Toxo, Rubella, and CMV Total Antibody Assays use Coupled Particle Light Scattering (Copalis) technology in microparticle agglutination-based immunoassays for the qualitative detection of total antibodies (IgG and IgM) to Toxoplasma gondii, rubella and/or cytomegalovirus (CMV) in human serum using the Copalis™ I Immunoassay System. The presence of antibodies is indicative of current or prior infection with the suspected organism. The results of these assays on a single serum specimen are used to determine the patient's immune status for rubella and to determine the patient's immunological experience for Toxoplasma gondii and CMV. When evaluating properly paired sera, the results of these assays are used to demonstrate seroconversion as evidence of recent infection. Both specimens should be tested simultaneously (see Interpretation of Results).
These assays has not been FDA cleared or approved for the screening of blood or plasma donors.
The assay will also be offered as separate microparticle immunoassays for the qualitative detection of total antibodies (IgG and IgM) to Toxoplasma gondii, rubella and cytomegalovirus (CMV) in human serum using the Copalis™ One Immunoassay System. The intended use of the individual assays will be specific to the individual antibodies detected but, other than that, will remain the same as the combination assay.
Coupled Particle Light Scattering (Copalis) technology provides a rapid method for the measurement of antibodies to specific viral or protozoal pathogens.
The Copalis™ TORC, Toxo, Rubella, and CMV Total Antibody Assays are based on the principle of antibody-dependent particle aggregation as detected by measurement of changes in light scattering. Due to the unique measuring system, a sample can be tested for antibodies to Toxoplasma gondii, rubella and CMV using a single TORC reagent and obtain results for the individual antibodies. Sized latex microparticles coated with inactivated Toxoplasma gondii, rubella and CMV antigens aggregate in the presence of antibodies to these infectious agents. After 10 minutes of agitation, the levels of aggregation are determined by discrimination of particle sizes (for the TORC assay) and measurement of the number of reacted and unreacted particles as they flow past a detector. Reactivity is assessed by the level of aggregation per particle size relative to a cutoff value. The Copalis TORC and individual Total Antibody Assays detect the presence of both IgM and IgG antibodies. Two levels of controls are used to monitor system performance.
Here's a breakdown of the acceptance criteria and study information for the Copalis TORC Total Antibody Assay, based on the provided text:
1. Acceptance Criteria and Reported Device Performance
The acceptance criteria are implied by the results presented in the clinical trials, specifically the "Relative Sensitivity" and "Relative Specificity" (which are effectively measures of accuracy against comparator devices). The reproducibility data also indicates levels of acceptable variation.
| Metric | Acceptance Criteria (Implied) | Reported Device Performance (Copalis TORC Total Antibody Assay) |
|---|---|---|
| Relative Sensitivity (Toxoplasma gondii Antibody) | High (demonstrated by comparison to predicate) | 95.4% (92.0 - 97.6% CI) |
| Relative Specificity (Toxoplasma gondii Antibody) | High (demonstrated by comparison to predicate) | 93.9% (91.5 - 95.8% CI) |
| Relative Sensitivity (Rubella Antibody) | High (demonstrated by comparison to predicate) | 95.0% (92.9 - 96.5% CI) |
| Relative Specificity (Rubella Antibody) | High (demonstrated by comparison to predicate) | 91.7% (87.6 - 94.8% CI) |
| Relative Sensitivity (CMV Antibody) | High (demonstrated by comparison to predicate) | 93.0% (90.3 - 95.2% CI) |
| Relative Specificity (CMV Antibody) | High (demonstrated by comparison to predicate) | 97.1% (94.6 - 98.6% CI) |
| Initial Agreement (Toxoplasma gondii Antibody) | High (demonstrated by comparison to predicate) | 94.3% |
| Agreement Following Resolution of Discordants (Toxoplasma gondii Antibody) | Very High (demonstrated by comparison to predicate) | 97.9% |
| Initial Agreement (Rubella Antibody) | High (demonstrated by comparison to predicate) | 93.9% |
| Agreement Following Resolution of Discordants (Rubella Antibody) | Very High (demonstrated by comparison to predicate) | 97.8% |
| Initial Agreement (CMV Antibody) | High (demonstrated by comparison to predicate) | 94.7% |
| Agreement Following Resolution of Discordants (CMV Antibody) | Very High (demonstrated by comparison to predicate) | 99.7% |
| Reproducibility (Within-Run %CV) | Low (specific target not stated, but results are low) | 1.8% - 4.8% (for various samples and antibodies) |
| Reproducibility (Total %CV) | Low (specific target not stated, but results are low) | 2.0% - 7.7% (for various samples and antibodies) |
| Controls Total Precision (%CV) | Low (specific target not stated, but results are low) | 2.6% - 4.5% |
| Lot-to-Lot Reproducibility (%CV) | Low (specific target not stated, but results are low) | 1.3% - 7.6% |
| Agreement with CDC Serum Panels (Rubella) | 100% agreement expected | 100% |
| Agreement with CDC Serum Panels (CMV) | 100% agreement expected | 100% |
| Quantitative Sensitivity & Reproducibility at Cutoffs (WHO/CDC Standards %CV) | Low (specific target not stated, but results are low) | 0.9% - 2.1% |
2. Sample Size Used for the Test Set and Data Provenance
- Test Set Sample Size: A total of 769 serum samples were tested.
- Data Provenance: The samples were collected as part of clinical trials conducted at 3 sites (2 clinical laboratories and Sienna Biotech laboratory). The text states "20% of which were fresh samples," implying the remaining 80% were retrospective or banked samples. The country of origin is not explicitly stated, but given "Sienna Biotech, Inc." in Columbia, MD, it is likely the US. The nature of the samples being "patient specimens" suggests they were from individual patients.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The ground truth was established by comparison to predicate devices: the BioWhittaker ToxoStat, Becton Dickinson And Co. Rubascan, and CMVscan assays. Therefore, the "experts" were the established predicate assays themselves, which are assumed to have undergone prior rigorous validation. The qualifications of a human expert are not relevant here, as the comparison is device-to-device.
4. Adjudication Method for the Test Set
The adjudication method is described as "Agreement Following Resolution of Discordants." This indicates that samples where the Copalis assay results disagreed with the predicate assay results were further investigated or adjudicated to determine the true status, likely using a "tie-breaker" or a more definitive method. The exact method of resolution is not detailed (e.g., if a third, more definitive test was used, or if human review was involved).
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done
No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This study is an in vitro diagnostic (IVD) device, and its performance is evaluated objectively against established methods (predicate devices) on biological samples. There is no human reader "improving with AI vs. without AI assistance" in this context.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
Yes, the performance reported is inherently standalone. The Copalis™ Immunoassay System is described as using "Coupled Particle Light Scattering (Copalis) technology" and "measurement of changes in light scattering" to detect aggregation and discrimination of particle sizes. The results are "assessed by the level of aggregation per particle size relative to a cutoff value." This indicates an automated system producing qualitative (positive/negative) results directly, without human interpretation of raw data for diagnosis.
7. The Type of Ground Truth Used
The primary type of ground truth used was the results from established, commercially available predicate devices (BioWhittaker ToxoStat, Becton Dickinson And Co. Rubascan, CMVscan assays). For the CDC serum panels, the ground truth was the known, characterized status of the samples as determined by the CDC. For reproducibility and reference standard testing, the ground truth was related to expected values and consistency, rather than a diagnostic 'truth' for patient samples.
8. The Sample Size for the Training Set
The text does not provide information on a specific training set size. As an immunoassay system, it likely relies on a pre-defined algorithm and cutoff values established during previous assay development and validation, rather than a "training set" in the machine learning sense. The clinical trials described here are for validation and performance assessment rather than training.
9. How the Ground Truth for the Training Set Was Established
Since there is no explicit mention of a "training set" in the context of machine learning, the question of how its ground truth was established is not directly applicable. For a traditional immunoassay, the "training" (or development) phase involves establishing optimal reagent concentrations, reaction conditions, and cutoff values using a characterized set of positive and negative samples, which would have their true status determined by well-established diagnostic methods (e.g., other validated assays, clinical diagnosis, or a combination).
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SUMMARY OF SAFETY AND EFFECTIVENESS
SUBMITTED BY:
Judith J. Smith Sienna Biotech, Inc. 9115 Guilford Rd. Suite 180 Columbia, MD 21046
Image /page/0/Picture/5 description: The image shows the date October 31, 1996. The text is written in a bold, sans-serif font. The letters and numbers are all black, and the background is white. The date is written in the format month, day, year.
NAME OF DEVICES:
Trade Name:
Copalis One Immunoassay System; Copalis TORC Total Antibody Assay; Copalis Toxoplasma gondii Total Antibody Assay; Copalis Rubella Total Antibody Assay Copalis CMV Total Antibody Assay
Common Names/Descriptions:
Immunoassay Analyzer; Immunoassay for the Detection of Total Antibodies to Toxoplasma gondii, Rubella and Cytomegalovirus
Classification Names:
Nephelometer for clinical use; Toxoplasma gondii serological reagents; Rubella virus serological reagents; Cytomegalovirus serological reagents
PREDICATE DEVICES:
BioWhittaker Toxostat; Becton Dickinson And Co. Rubascan and CMVscan; Abbott IMx
DEVICE DESCRIPTION:
INTENDED USE: The Copalis™ TORC, Toxo, Rubella, and CMV Total Antibody Assays use Coupled Particle Light Scattering (Copalis) technology in microparticle agglutination-based immunoassays for the qualitative detection of total antibodies (IgG and IgM) to Toxoplasma gondii, rubella and/or cytomegalovirus (CMV) in human serum using the Copalis™ I Immunoassay System. The presence of antibodies is indicative of current or prior infection with the suspected organism. The results of these assays on a single serum specimen are used to determine the patient's immune status for rubella and to determine the patient's immunological experience for Toxoplasma gondii and CMV. When evaluating properly paired sera, the results of these assays are used to demonstrate seroconversion as evidence of recent infection. Both specimens should be tested simultaneously (see Interpretation of Results).
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These assays has not been FDA cleared or approved for the screening of blood or plasma donors.
The assay will also be offered as separate microparticle immunoassays for the qualitative detection of total antibodies (IgG and IgM) to Toxoplasma gondii, rubella and cytomegalovirus (CMV) in human serum using the Copalis™ One Immunoassay System. The intended use of the individual assays will be specific to the individual antibodies detected but, other than that, will remain the same as the combination assay.
KIT DESCRIPTION: Coupled Particle Light Scattering (Copalis) technology provides a rapid method for the measurement of antibodies to specific viral or protozoal pathogens.
The Copalis™ TORC, Toxo, Rubella, and CMV Total Antibody Assays are based on the principle of antibody-dependent particle aggregation as detected by measurement of changes in light scattering. Due to the unique measuring system, a sample can be tested for antibodies to Toxoplasma gondii, rubella and CMV using a single TORC reagent and obtain results for the individual antibodies. Sized latex microparticles coated with inactivated Toxoplasma gondii, rubella and CMV antigens aggregate in the presence of antibodies to these infectious agents. After 10 minutes of agitation, the levels of aggregation are determined by discrimination of particle sizes (for the TORC assay) and measurement of the number of reacted and unreacted particles as they flow past a detector. Reactivity is assessed by the level of aggregation per particle size relative to a cutoff value. The Copalis TORC and individual Total Antibody Assays detect the presence of both IgM and IgG antibodies. Two levels of controls are used to monitor system performance.
PERFORMANCE DATA:
Comparison: A comparison study was performed of patient specimens and controls using the Copalis TORC Total Antibody Assay and the Copalis individual assays. Analyses of the data by One Way Analysis of Variance showed that the differences in mean values between the component of the TORC assay and the corresponding individual assay are not great enough to exclude the possibility that the difference is due to random sampling variability: there is not a statistically significant difference (p = 0.849).
In addition, a reproducibility study was conducted to compare the components of the Copalis TORC Total Antibody Assay and the Copalis individual assays. The difference in mean CTRs and %CVs of the component of the TORC assay and the individual assay were not clinically significant. Therefore, it can be concluded that the clinical performance of the TORC and individual assays are equivalent.
Clinical trials were conducted at 3 sites (2 clinical laboratories and Sienna Biotech laboratory) to evaluate the performance of the Copalis TORC, Toxo,
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Rubella, and CMV Total Antibody Assays in detecting antibodies to Toxoplasma gondii, rubella and CMV on the modified Copalis One Immunoassay System. The assay performance was compared to the BioWhittaker ToxoStat (ToxoStat) and the Becton Dickinson and Co. Rubascan (Rubascan) and CMVscan (CMVscan) assays.
A total of 769 serum samples were tested, 20% of which were fresh samples. Combined site testing results for each component of the assay are presented in Table A.
Table A Comparison of the Copalis™ TORC Total Antibody Assay with Commercially Available Assays -Combined Site Results
| Toxoplasma gondii Antibody | Rubella Antibody | CMV Antibody | |
|---|---|---|---|
| Relative Sensitivity(95% Confidence Interval) | 95.4% | 95.0% | 93.0% |
| (92.0 - 97.6%) | (92.9 - 96.5%) | (90.3 - 95.2%) | |
| Relative Specificity(95% Confidence Interval) | 93.9% | 91.7% | 97.1% |
| (91.5 - 95.8%) | (87.6 - 94.8%) | (94.6 - 98.6%) | |
| Initial Agreement | 94.3% | 93.9% | 94.7% |
| Agreement FollowingResolution of Discordants | 97.9% | 97.8% | 99.7% |
Reproducibility:
Reproducibility studies were performed at the 3 sites using one lot of TORC tests. Assay component reproducibility was determined by testing 4 samples - 1 negative, 1 low positive (near the components' cutoffs) and 2 high positive (near the upper limit of the components' ranges). Samples were tested in triplicate twice a day for 5 days. The results are summarized in Table B.
Table B Reproducibility Results For Copalis Torc Total Antibody Assay - Combined Sites
| SAMPLE | ANTIBODY TO TOXOPLASMAGONDII | ANTIBODY TO RUBELLA | ANTIBODY TO CMV | ||||||
|---|---|---|---|---|---|---|---|---|---|
| MEANCTR | WITHINRUN%CV | TOTAL%CV | MEANCTR | WITHINRUN%CV | TOTAL%CV | MEANCTR | WITHINRUN%CV | TOTAL%CV | |
| RP1(n = 89) | 103 | 1.8 | 2.0 | 105 | 1.9 | 2.0 | 102 | 2.1 | 2.8 |
| RP2(n = 86) | 129 | 3.0 | 4.4 | 116 | 2.1 | 2.7 | 132 | 3.9 | 4.6 |
| RP3(n = 86) | 157 | 4.1 | 5.9 | 128 | 3.0 | 5.2 | 166 | 4.5 | 5.8 |
| RP4(n = 85) | 177 | 4.7 | 7.3 | 150 | 3.6 | 7.3 | 207 | 4.8 | 7.7 |
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During the clinical trials, the Negative and Low Positive Controls were assayed each day of use at each site for the length of the trial. Results are summarized in Table C.
| Component | ||||
|---|---|---|---|---|
| Control | Toxoplasma gondii | Rubella | CMV | |
| Negative | Mean | 102 | 102 | 101 |
| % CV | 2.6 | 3.1 | 2.8 | |
| n | રૂદ | રૂદ | રૂડ્યુ | |
| Low Positive | Mean | 124 | 120 | 124 |
| % CV | 4.5 | 4.5 | 4.1 | |
| n | તે રેણ | તે રેણવાડી તેમ જ દૂધની ડેરી જેવી સવલતો પ્રાપ્ય થયેલી છે. આ ગામનાં લોકોનો મુખ્ય વ્યવસાય ખેતી, ખેતમજૂરી તેમ જ પશુપાલન છે. આ ગામનાં મુખ્યત્વે ખેત-ઉત્પત્તમજૂરી તેમ જ દૂધની ડેરી | વેરૂ |
Table C Controls Total Precision
Lot-to-lot reproducibility was established using 3 test cup lots of Copalis Rubella Total Antibody Assay. A summary of the data is presented in Table D.
| Level | Lot #1 | Lot #2 | Lot #3 | |
|---|---|---|---|---|
| Negative | Mean | 100 | 100 | 102 |
| % CV | 1.3 | 3.0 | 1.5 | |
| Low Positive | Mean | 131 | 125 | 128 |
| % CV | 4.7 | 2.9 | 2.4 | |
| Mid Positive | Mean | 162 | 150 | 156 |
| % CV | 7.6 | 6.7 | 4.8 | |
| High Positive | Mean | 204 | 187 | 197 |
| % CV | 5.1 | 2.9 | 7.1 |
Table D Lot-to-Lot Reproducibility - Antibody to Rubella
CDC SERUM PANELS: The following information is from Rubella and CMV Serum Panels obtained from the CDC and tested by Sienna Biotech, Inc. The results are presented as a means to convey further information of the performance of this assay with masked, characterized serum panels. This does not imply an endorsement of the assay by the CDC.
The Rubella Serum Panel consists of 82% positive and 18% negative samples. The Copalis TORC Total Antibody Assay demonstrated 100% total agreement with the CDC rubella antibody results.
The CMV Serum Panel consists of 66% positive and 34% negative samples. The Copalis TORC Total Antibody Assay demonstrated 100% total agreement with the CDC CMV antibody results.
WHO AND CDC REFERENCE STANDARD TESTING: The WHO 30 International Standards for Toxoplasma gondii (1000 IU/mL) and rubella (1700 IU/mL) and the CDC Rubella Standard (21 IU/mL) were tested on the Copalis TORC Total Antibody Assay. Each was diluted and tested in replicates of 5 to
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establish the quantitative sensitivity of the assay components' cutoffs and the reproducibility at those cutoffs. Results are summarized in Table E.
| WHO and CDC Reference Standard Testing Results | |||
|---|---|---|---|
| WHO 3rd I.S. Toxoplasmagondii (1000 IU/mL)25 IU/mL Dilution | WHO 3rd I.S. Rubella(1700 IU/mL)10 IU/mL Dilution | CDC Rubella(21 IU/mL)10 IU/mL Dilution | |
| Mean (CTR) | 116 | 117 | 116 |
| %CV | 0.9% | 2.1% | 1.3% |
| Range (CTR) | 115 - 118 | 114 - 120 | 115 - 118 |
Table E WHO and CDC Refer d Tostina Posulta
§ 866.3510 Rubella virus serological reagents.
(a)
Identification. Rubella virus serological reagents are devices that consist of antigens and antisera used in serological tests to identify antibodies to rubella virus in serum. The identification aids in the diagnosis of rubella (German measles) or confirmation of a person's immune status from past infections or immunizations and provides epidemiological information on German measles. Newborns infected in the uterus with rubella virus may be born with multiple congenital defects (rubella syndrome).(b)
Classification. Class II. The special controls for this device are:(1) National Committee for Clinical Laboratory Standards':
(i) 1/LA6 “Detection and Quantitation of Rubella IgG Antibody: Evaluation and Performance Criteria for Multiple Component Test Products, Speciment Handling, and Use of the Test Products in the Clinical Laboratory, October 1997,”
(ii) 1/LA18 “Specifications for Immunological Testing for Infectious Diseases, December 1994,”
(iii) D13 “Agglutination Characteristics, Methodology, Limitations, and Clinical Validation, October 1993,”
(iv) EP5 “Evaluation of Precision Performance of Clinical Chemistry Devices, February 1999,” and
(v) EP10 “Preliminary Evaluation of the Linearity of Quantitive Clinical Laboratory Methods, May 1998,”
(2) Centers for Disease Control's:
(i) Low Titer Rubella Standard,
(ii) Reference Panel of Well Characterized Rubella Sera, and
(3) World Health Organization's International Rubella Standard.