(58 days)
The Trinity Biotech Captia™ Borrelia burgdorferi IgM ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for the qualitative presumptive detection of IgM antibodies to Borrelia burgdorferi in human serum. This ELISA should be used for patients with signs and symptoms that are consistent with Lyme disease. Equivocal or positive results must be supplemented by testing with a standardized Western blot procedure. Positive supplemental results are supportive evidence of exposure to B. burgdorferi and can be used to support a clinical diagnosis of Lyme disease.
The Borrelia burgdorferi IgM ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for the qualitative presumptive detection of IgM antibodies to Borrelia burgdorferi in human serum. This ELISA should only be used for patients with signs and symptoms that are consistent with Lyme disease. Equivocal or positive results must be supplemented by testing with a standardized Western blot procedure. Positive supplemental results are supportive evidence of exposure to B. burgendorferi and can be used to support a clinical diagnosis of Lyme disease.
The Borrelia burgdorferi IgM ELISA test is an enzyme linked immunosorbent assay to detect IgM antibodies to Borrelia burgdorferi. Purified Borrelia burgdorferi antigen is attached to a solid phase microtiter well. Pretreated test sera is added to each well. If the antibodies are present that recognize the antigen, they will bind to the antigen in the well. After incubation, the wells are washed to remove unbound antibody. An enzyme labeled anti-human IgM is added to each well. If antibody is present it will bind to the antibody attached to the antigen on the well. After incubation, the wells are washed to remove unbound conjugate. A substrate solution is added to each well. If enzyme is present the substrate will undergo a color change. After an incubation period, the reaction is stopped and the color intensity is measured photometrically, producing an indirect measurement of specific antibody in the patient specimen.
The provided document describes the Trinity Biotech Borrelia burgdorferi IgM ELISA Test Kit, an immunoassay for the qualitative detection of IgM antibodies to Borrelia burgdorferi (the causative agent of Lyme disease) in human serum.
Here's an analysis of the acceptance criteria and the studies performed:
1. Table of Acceptance Criteria and Reported Device Performance:
The document does not explicitly state pre-defined acceptance criteria (e.g., "The device must achieve X sensitivity and Y specificity"). Instead, it presents performance characteristics from comparative studies against clinical diagnosis and a predicate device (BioWhittaker's Lyme M STAT test) combined with Western Blot confirmation.
Implicit Acceptance Criteria (inferred from context and comparison to predicate):
| Performance Characteristic | Acceptance Criteria (Implicit/Benchmark) | Reported Device Performance (Trinity Biotech) |
|---|---|---|
| Agreement with Clinical Diagnosis (CDC Panel) | Expected to show reasonable agreement, particularly for early disease. No explicit threshold is given. | 47.6% (20/42) agreement with clinical diagnosis of Lyme disease (considering equivocal as 1-step positive). |
| Agreement with Predicate (ELISA 1-step Pos. or Eq.) | Comparable percentage of positive/equivocal results to predicate device. | 10.8% (19/176) (95% CI: 6.1-15.5%) |
| Agreement with Predicate (2-step Pos.) | Comparable percentage of 2-step positive results to predicate device. | 3.41% (6/176) (95% CI: 0.7-6.1%) |
| 2-step Pos. among 1-step Pos. or Eq. | Comparable percentage of Western Blot confirmed positives among ELISA positive/equivocal results to predicate device. | 31.6% (6/19) (95% CI: 10.3-52.9%) |
| Inter-Assay Precision (CV) | Positive samples, Calibrators, and Positive Controls should have <20% CV. | Serum #1: 8.96%, Serum #2: 9.64%, Serum #3: 11.2%, Serum #5: 15.82%, Serum #6: 13.96%, Serum #7: 17.18%. HPC: 7.04%, Cal: 4.70%, LPC: 5.11%. (Serum #4 and NC were high at 68.0% and 64.0% respectively, likely due to low signal close to baseline). All other reported values meet the <20% CV. |
| Cross-Reactivity | No positive results with known cross-reactive samples. | 0 positives reported for all tested cross-reactive samples (Lipemic, Bilirubinemic, RPR+, RF+, EBV+, CMV+, RMS+, CRP+, Elevated ESR, dsDNA+). |
2. Sample Size Used for the Test Set and Data Provenance:
- Study 1 (CDC Lyme Disease Serum Panel):
- Sample Size: 47 serum samples (5 normals, 5 <1 month, 10 1-2 months, 19 3-12 months, 8 >1 year post-onset).
- Data Provenance: From the CDC (Centers for Disease Control and Prevention). This suggests the data is likely retrospective, as it's a "panel obtained from the CDC." The country of origin is the USA.
- Study 2 (Comparative Effectiveness with Predicate):
- Sample Size: 176 sera.
- Data Provenance: From patients submitted to a large clinical lab for B. burgdorferi antibody testing. This suggests the data is retrospective, collected from existing patient samples. The country of origin is not explicitly stated but implied to be the USA given the context of the submission.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:
- Study 1 (CDC Lyme Disease Serum Panel): The ground truth is described as "clinical diagnosis" and the panel samples were "masked, characterized serum panel." While the document doesn't specify the exact number or qualifications of experts involved in establishing the clinical diagnosis for this CDC panel, CDC panels are typically established by expert consensus of clinicians and specialists in infectious diseases, based on a comprehensive review of clinical, epidemiological, and laboratory data.
- Study 2 (Comparative Effectiveness with Predicate): The ground truth for this study was established by Mardx Diagnostics Western Blot for both IgG and IgM for any serum found positive or equivocal by either ELISA. This is a laboratory-based gold standard, not directly established by medical experts in this context.
4. Adjudication Method for the Test Set:
- Study 1 (CDC Lyme Disease Serum Panel): "Because the equivocals would have been tested by immunoblotting in a 2-step test system, they were considered 1-step positive for purposes of calculating % agreement." This indicates a specific rule for handling equivocal results in the calculation, rather than a multi-reader/multi-expert adjudication.
- Study 2 (Comparative Effectiveness with Predicate): Equivocal or positive ELISA results were further tested by Western Blot. There's no mention of adjudication between multiple readers for the Western Blot results; the Western Blot itself served as the confirmatory method.
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 explicitly stated or described. The studies focus on device performance (ELISA) against a clinical diagnosis panel or a predicate device and Western Blot, not on the impact of the device on human reader performance.
6. If a Standalone Study (Algorithm Only Without Human-in-the-Loop Performance) was Done:
Yes, the studies presented are primarily standalone performance evaluations of the ELISA kit. The ELISA kit generates a quantitative result which is then interpreted qualitatively (positive, equivocal, negative). This process does not involve human interpretation within a diagnostic workflow that the device is assisting, but rather the device itself provides the result.
7. The Type of Ground Truth Used:
- Study 1: Clinical Diagnosis (from the CDC panel).
- Study 2: Western Blot (laboratory-based gold standard).
8. The Sample Size for the Training Set:
The document does not provide information regarding a "training set" or its size. This is typical for traditional in vitro diagnostic (IVD) device submissions (like an ELISA kit), where the device development process might involve internal optimization and validation, but not a formally separate "training set" and "test set" in the same way as machine learning or AI algorithm development. The studies presented are "test set" or "validation set" studies for the final device.
9. How the Ground Truth for the Training Set Was Established:
As no training set is described, this question is not applicable to the provided information.
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NOV 26 2003
Summary of Safety and Effectiveness Information Borrelia burgdorferi IgM ELISA Test Kit
I. Trinity Biotech 2823 Girts Road Jamestown, NY 14701 Contact person: Bonnie B. DeJoy Telephone: 716-483-3851 Date of preparation: Nov. 20, 2003
II. Description of Device
The Borrelia burgdorferi IgM ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for the qualitative presumptive detection of IgM antibodies to Borrelia burgdorferi in human serum. This ELISA should only be used for patients with signs and symptoms that are consistent with Lyme disease. Equivocal or positive results must be supplemented by testing with a standardized Western blot procedure. Positive supplemental results are supportive evidence of exposure to B. burgdorferi and can be used to support a clinical diagnosis of Lyme disease.
The Borrelia burgdorferi IgM ELISA test is an enzyme linked immunosorbent assay to detect IgM antibodies to Borrelia burgdorferi. Purified Borrelia burgdorferi antigen is attached to a solid phase microtiter well. Pretreated test sera is added to each well. If the antibodies are present that recognize the antigen, they will bind to the antigen in the well. After incubation, the wells are washed to remove unbound antibody. An enzyme labeled anti-human IgM is added to each well. If antibody is present it will bind to the antibody attached to the antigen on the well. After incubation, the wells are washed to remove unbound conjugate. A substrate solution is added to each well. If enzyme is present the substrate will undergo a color change. After an incubation period, the reaction is stopped and the color intensity is measured photometrically, producing an indirect measurement of specific antibody in the patient specimen.
III. Predicate Device
The Borrelia burgdorferi IgM ELISA test is substantially equivalent to Bio Whittaker's Lyme M STAT test. Equivalence is demonstrated by the following comparative results:
Performance Characteristics
The CDC Lyme Disease Serum Panel Stratified by Time After OnsetThe following information is from a serum panel obtained from the CDC and tested by Trinity Biotech. The results are presented as a means to convey further information on the performance of this assay with a masked, characterized serum panel. This does not imply an endorsement of the assay by the CDC.
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| Time FromOnset | positive | equivocal | negative | Total | %Agreementwith ClinicalDiagnosis |
|---|---|---|---|---|---|
| normals | 0 | 0 | 5 | 5 | 100.0% |
| < 1 month | 3 | 1 | 1 | 5 | 80.0% |
| 1-2 months | 6 | 0 | 4 | 10 | 60.0% |
| 3-12 months | 7 | 2 | 10 | 19 | 47.4% |
| > 1 year | 1 | 0 | 7 | 8 | 12.5% |
| Total | 17 | 3 | 27 | 47 |
Table 1 Trinity Biotech B. burgdorferi IgM ELISA Results
Because the equivocals would have been tested by immunoblotting in a 2-step test system, they were considered 1-step positive for purposes of calculating % agreement. The Trinity Biotech B. burgdorferi IgM ELISA demonstrated 47.6% (20/42) agreement with clinical diagnosis of Lyme disease.
Study 2
One hundred seventy-six sera from patients of various ages and genders that were submitted to a large clinical lab for B. burgdorferi antibody testing were tested on the Trinity Biotech B. burgdorferi IgM ELISA and BioWhittaker LYME STAT. Any serum found positive or equivocal was tested by Mardx Diagnostics Western Blot on both IgG and IgM. The results are illustrated in Table 2.
Table 2
| Western Blot | ||||||
|---|---|---|---|---|---|---|
| + | + | - | ||||
| Trinity Biotech | + | 6 | 10 | |||
| B. burgdorferi eq.IgM | 0 | 3 | ||||
| LYME STAT | + | 6 | 9 | |||
| eq. | 0 | 3 | ||||
| Type of Result | Trinity | (95%CI) | LYME STAT | (95%CI) | ||
| 1-step (ELISA) Pos. or Eq. | 10.8%(19/176) | (6.1-15.5%) | 10.2%(18/176) | (5.7-14.8%) | ||
| 1-step Pos. or Eq. &2-step (WB) pos. | 3.41%(6/176) | (0.7-6.1%) | 3.41%(6/176) | (0.7-6.1%) | ||
| 2-step Pos. among1-step Pos. or Eq. | 31.6%(6/19) | (10.3-52.9%) | 33.3%(6/18) | (11.1-55.6%) | ||
| CI = Confidence Interval |
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Precision
Seven sera were assayed ten times each on three different assays at two different sites. The intersite precision is shown in Table 3. With appropriate technique the user should obtain precision of <20% CV for positive samples, Calibrators and Positive Controls.
Table 3 Trinity Biotech Borrelia burgdorferi IgM ELISA Inter-Assay Precision Between Sites
Inter-Assay (n=60)
| Serum # | X | SD | CV |
|---|---|---|---|
| 1 | 3.74 | 0.335 | 8.96% |
| 2 | 1.95 | 0.188 | 9.64% |
| 3 | 0.94 | 0.105 | 11.2% |
| 4 | 0.05 | 0.034 | 68.0% |
| 5 | 0.98 | 0.155 | 15.82% |
| 6 | 1.34 | 0.187 | 13.96% |
| 7 | 1.24 | 0.213 | 17.18% |
| HPC * | 4.07 | 0.287 | 7.04% |
| Cal ** | 2.22 | 0.104 | 4.70% |
| LPC * | 2.21 | 0.113 | 5.11% |
| NC * | 0.05 | 0.031 | 64.0% |
$$\text{* For HPC, LPC, and NC } \text{ n} = 12.$$
** For Cal n = 36
A total of four hundred ninety-two determinations were made at the two sites. In all of the determinations there was not one case of a positive result for a negative serum or a negative result for a positive serum.
Equivocal sample #3 was negative 23 times and positive 19 times. Equivocal sample #5 was negative 19 times and positive 3 times. X=Mean ISR SD=Standard Deviation CV=Coefficient of Variation = $SD/X$ x 100
The methods in NCCLS EPS were utililized for precision parameters.
Cross-Reactivity
The following potentially cross-reactive sera were run on the Trinity Biotech Borrelia burgdorferi IgM ELISA assay to assess cross-reactivity with the assay: lipemic, bilirubinemic, RPR +, dsDNA +, RF +, EBV +, CMV +, RMS +, elevated ESR, and CRP. The data in Table 4 illustrate the amount of reactivity with the sera.
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Table 4 Cross-Reactivity
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| Laboratory Result (Titer) | # of samples | # of positives |
|---|---|---|
| Lipemic (+++) | 5 | 0 |
| Bilirubinemic (1.9-16.9) | 5 | 0 |
| RPR + (1:2-1:64) | 10 | 0 |
| Rheumatoid Factor + (1:40-1:320) | 8 | 0 |
| Epstein Barr Virus Antibody +(1:40-1:2560) | 7 | 0 |
| Cytomegalovirus Antibody + (O.D. 0.718-2.308) | 6 | 0 |
| Rocky Mt Spotted Fever Antibody + (1:256-1:16,384) | 4 | 0 |
| CRP + (2.79-8.61 mg/dL) | 5 | 0 |
| Elevated ESR (40-115) | 10 | 0 |
| dsDNA + (52.3-1072 IU) | 16 | 0 |
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Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle with three lines forming its body and head. The words "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" are arranged in a circular pattern around the eagle.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
NOV 26 2003
Ms. Bonnie B. DeJoy Director, Quality Systems Trinity Biotech USA P.O. Box 1059 Jamestown, NY 14702-1059
Re: K033070 Trade/Device Name: Captia Borrelia burgdorferi IgM ELISA Regulation Number: 21 CFR 866.3830 Regulation Name: Treponema pallidum treponemal test reagents Regulatory Class: Class II Product Code: LSR Dated: September 17, 2003 Received: September 29, 2003
Dear Ms. DeJoy:
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 (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 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). 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) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.
Sincerely yours,
Steven Putman
Steven I. Gutman, M.D., M.B.A. Director Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Page 1 of 1
510(k) Number: K033070
Device Name: Trinity Biotech Captia™ Borrelia burgdorferi IgM ELISA
Indications For Use: The Trinity Biotech Captia™ Borrelia burgdorferi IgM ELISA kit is an Enzyme-Linked Immunosorbent Assay (ELISA) for the qualitative presumptive detection of IgM antibodies to Borrelia burgdorferi in human serum. This ELISA should be used for patients with signs and symptoms that are consistent with Lyme disease. Equivocal or positive results must be supplemented by testing with a standardized Western blot procedure. Positive supplemental results are supportive evidence of exposure to B. burgdorferi and can be used to support a clinical diagnosis of Lyme disease.
PLEASE DO NOT WRITE BELOW THIS LINE – CONTINUE ON ANOTHER PAGE IF NEEDED
Concurrence of CDRH, Office of Device Evaluation (ODE)
| Prescription Use(Per 21 XFR 801.109) | OR | Over-The-Counter Use(Optional Format 1-2-96) |
|---|---|---|
| ------------------------------------------ | ---- | -------------------------------------------------- |
| Division Sign-Off |
|---|
Office of In Vitro Diagnostic DeviceOmoo tion and Safety
510(k) Ro33070
§ 866.3830
Treponema pallidum treponemal test reagents.(a)
Identification. Treponema pallidum treponemal test reagents are devices that consist of the antigens, antisera and all control reagents (standardized reagents with which test results are compared) which are derived from treponemal sources and that are used in the fluorescent treponemal antibody absorption test (FTA-ABS), theTreponema pallidum immobilization test (T.P.I.), and other treponemal tests used to identify antibodies toTreponema pallidum directly from infecting treponemal organisms in serum. The identification aids in the diagnosis of syphilis caused by bacteria belonging to the genusTreponema and provides epidemiological information on syphilis.(b)
Classification. Class II (performance standards).