(72 days)
The CEDIA Digoxin II homogeneous enzyme immunoassay is for the quantitation of digoxin in human serum or plasma using automated clinical chemistry analyzers. Measurements are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure proper therapy.
The CEDIA® Digoxin II Assay is based on the bacterial enzyme ßgalactosidase, which has been genetically engineered into two inactive fragments. These fragments spontaneously reassociate to form fully active enzyme that, in the assay format, cleaves a substrate, generating a color change that can be measured spectrophotometrically. In the assay, digoxin in the sample competes with analyte conjugated to one inactive fragment of B-galactosidase for antibody binding site. If analyte is present in the sample, it binds to antibody, leaving the inactive enzyme fragments free to form active enzyme. If analyte is not present in the sample, antibody binds to analyte conjugated on the inactive fragment, inhibiting the reassociation of inactive ß-galactosidase fragments, and no active enzyme is formed.
The presented document is a 510(k) Summary for the CEDIA® Digoxin II Assay. It describes the device, its intended use, and compares its performance characteristics to a predicate device, the Abbott TDx® Digoxin II Assay.
Here's an analysis of the acceptance criteria and study information based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are not explicitly stated as distinct acceptance thresholds (i.e., "the device must achieve X performance"). Instead, the performance of the CEDIA® Digoxin II Assay is compared directly to the predicate device, the Abbott TDx® Digoxin II Assay, implying that substantial equivalence to the predicate's performance is the overarching acceptance criterion.
| Feature | Acceptance Criteria (Implied by Predicate Performance) | Reported Device Performance (CEDIA® Digoxin II) |
|---|---|---|
| Precision | Modified NCCLS (ng/mL): | |
| Level 1 | Within run %CV: 5.75, Total %CV: 7.67 | Within run %CV: 4.25, Total %CV: 5.44 |
| Level 2 | Within run %CV: 3.15, Total %CV: 3.98 | Within run %CV: 2.22, Total %CV: 3.58 |
| Level 3 | Within run %CV: 1.87, Total %CV: 1.91 | Within run %CV: 1.56, Total %CV: 2.34 |
| Lower Detection Limit | 0.2 ng/mL | 0.15 ng/mL |
| Linearity Range | 0.0 - 4.0 ng/mL | 0.15 - 4 ng/mL |
| Method Comparison | ||
| vs Abbott TDx Digoxin | (Implied high correlation) | y = 0.94x + 0.08, r = 0.962 (N=200) |
| vs Baxter Dade Stratus | (Implied high correlation) | y = 0.98x - 0.12, r = 0.955 (N=99) |
| Deming's: y = 1.02x - 0.17, r = 0.955 (N=99) | ||
| Interfering Substances | No interference at (within ±10% of baseline): | |
| Bilirubin | 20 mg/dL | 66 mg/dL |
| Hemoglobin | 1000 mg/dL | 1000 mg/dL |
| Triglyceride Lipemia | 2500 mg/dL | 100 mg/dL |
| Total Protein | N/A (not provided for predicate) | 10 g/dL |
| Rheumatoid Factor | N/A (not provided for predicate) | 100 IU/mL |
| Specificity (% Cross-reactivity) | ||
| Digoxigenin | up to 200 | 60.5 |
| β-Acetyldigoxin | not tested | 77.0 |
| α-Acetyldigoxin | not tested | 75.3 |
| Gitalin | not tested | 2.1 |
| Digoxingenin-Mono-Digitoxiside | up to 200 | 102.5 |
| Digitoxin-Bis-Digitoxiside | up to 200 | 86.3 |
| Digitoxin | up to 200 | 1.5 |
| β-Methyldigoxin | 4.8 | 76.3 |
| 3-Epe-Digoxigenin | not tested | 37.6 |
| 3-Dehydrodigoxigenin | not tested | 82.6 |
| Epi-Digoxigenin-Glucuronide | not tested | 42.9 |
2. Sample Sizes Used for the Test Set and Data Provenance
- Precision Test Set N: 120 for each of 3 levels (Level 1, Level 2, Level 3). (Total 360 individual measurements for precision, but N refers to the number of individual tests run for each level.)
- Method Comparison Test Set N:
- Vs Abbott TDx Digoxin: N=200
- Vs Baxter Dade Stratus: N=99
- Data Provenance: Not explicitly stated (e.g., country of origin, retrospective or prospective). The samples are referred to as "human serum and plasma."
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
There is no mention of experts being used to establish ground truth for this diagnostic assay. The "ground truth" for quantitative assays like this is typically established by comparative analysis against established, often reference, methods or instruments.
4. Adjudication Method for the Test Set
Not applicable. As this is an in vitro diagnostic (IVD) assay for quantitative determination, there is no mention of adjudication by human readers/experts for the test results. The device's output is a quantitative value, not subject to interpretation needing adjudication.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No. This document describes an in vitro diagnostic (IVD) assay, not an imaging device or AI algorithm intended for human-in-the-loop interpretation that would typically involve an MRMC study.
6. Standalone Performance (Algorithm Only Without Human-in-the-Loop Performance)
Yes, the performance characteristics presented (precision, linearity, detection limit, method comparison, interfering substances, specificity) represent the standalone performance of the CEDIA® Digoxin II Assay. There is no human-in-the-loop component mentioned in its operation for these performance metrics.
7. Type of Ground Truth Used
The "ground truth" for the performance studies appears to be based on:
- Reference Methods/Predicate Devices: For method comparison, the results of the CEDIA® assay were compared against the Abbott TDx® Digoxin II Assay and the Baxter Dade Stratus, which serve as reference or predicate methods.
- Standard Spiked Samples: For parameters like precision, linearity, and detection limit, it is implied that samples with known concentrations of digoxin were used, or that the "levels" described were standardized reference materials.
- Known Concentrations of Interfering Substances: For interference and specificity studies, substances were tested at known concentrations.
8. Sample Size for the Training Set
The document does not specify a separate "training set" or its size. This is common for traditional in vitro diagnostic assays that are developed using biochemical principles rather than machine learning algorithms requiring explicit training data. The development and optimization process itself serves a similar function to "training," but it doesn't involve a distinct, quantifiable training set in the machine learning sense.
9. How the Ground Truth for the Training Set Was Established
As there is no explicit "training set" mentioned in the context of machine learning, this question is not directly applicable. The device's underlying principles are based on enzyme immunoassay chemistry, where performance is optimized through reagent formulation and assay design, not by training on a labeled dataset.
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K970883
MAY 21, 1997
510(k) Summary
| Introduction | According to the requirements of 21 CFR 807.92, the following information provides sufficient detail to understand the basis for a determination of substantial equivalence. | |
|---|---|---|
| 1.Submitter name, address, contact | Boehringer Mannheim Corporation2400 Bisso LaneP.O. Box 4117Concord, CA 94524-4117(510) 674 - 0690, extension 8240Fax: (510) 687-1850Contact Person: Yvette LloydDate Prepared: March 6, 1997 | |
| 2.Device name | Proprietary name: CEDIA® Digoxin II AssayCommon name: Homogeneous enzyme immunoassay for the determination of Digoxin.Classification name: Enzyme immunoassay, Digoxin | |
| 3.Predicate device | The Boehringer Mannheim CEDIA® Digoxin II is substantially equivalent to other products in commercial distribution intended for similar use. Most notably it is substantially equivalent to the currently marketed Abbott TDx® Digoxin II Assay (K882233). |
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Image /page/1/Picture/1 description: The image shows the logo for Boehringer Mannheim Corporation. The text is stacked in three lines, with "BOEHRINGER" on the top line, "MANNHEIM" on the second line, and "CORPORATION" on the third line. The text is in a bold, sans-serif font and is black.
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Device Description The CEDIA® Digoxin II Assay is based on the bacterial enzyme ßgalactosidase, which has been genetically engineered into two inactive fragments. These fragments spontaneously reassociate to form fully active enzyme that, in the assay format, cleaves a substrate, generating a color change that can be measured spectrophotometrically. In the assay, digoxin in the sample competes with analyte conjugated to one inactive fragment of B-galactosidase for antibody binding site. If analyte is present in the sample, it binds to antibody, leaving the inactive enzyme fragments free to form active enzyme. If analyte is not present in the sample, antibody binds to analyte conjugated on the inactive fragment, inhibiting the reassociation of inactive ß-galactosidase fragments, and no active enzyme is formed.
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510(k) Summary, Continued
BOEHRINGER MANNHEIM CORPORATION
| 5. Intended use | Immunoassay for the in vitro quantitative determination of Digoxin in human serum and plasma. |
|---|---|
| ----------------- | ----------------------------------------------------------------------------------------------- |
| 6. Comparison to predicate device | The Boehringer Mannheim CEDIA® Digoxin II Assay is substantially equivalent to other products in commercial distribution intended for similar use. Most notably it is substantially equivalent to the currently marketed Abbott TDx® Digoxin II Assay (K882233). |
|---|---|
| ----------------------------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ |
The following table compares the CEDIA® Digoxin II Assay with the predicate device, Abbott TDx® Digoxin II Assay. Specific data on the performance of the test have been incorporated into the draft labeling in attachment 5. Labeling for the predicate device is provided in attachment 6.
Similarities:
| •Intended Use: Immunoassay for the in vitro quantitative determination of Digoxin | |
|---|---|
| •Sample type: Serum and plasma | |
| •Assay range: 0.15 - 4 ng/mL |
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identificant province
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10(k) Summary, Continued ----Differences:
- Comparison
to predicate
device cont.
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| Feature | CEDIA®Digoxin II | TDxDigoxin II |
|---|---|---|
| Reaction testprinciple | Spectrophotometric570 nm | Fluorescence Polarization |
| Instrumentrequired | Hitachi 911 | Abbott TDx |
Performance Characteristics:
| Feature | CEDIA®Digoxin II | TDxDigoxin II | |||||
|---|---|---|---|---|---|---|---|
| Precision | Modified NCCLS (ng/mL): | NCCLS (ng/mL): | |||||
| Level | Level 1 | Level 2 | Level 3 | Low | Mid | High | |
| N | 120 | 120 | 120 | 50 | 50 | 50 | |
| Within run | 1.1 | 1.8 | 3.8 | 0.70 | 1.44 | 3.66 | |
| %CV | 4.25 | 2.22 | 1.56 | 5.75 | 3.15 | 1.87 | |
| Total | 1.1 | 1.8 | 3.8 | 0.70 | 1.44 | 3.66 | |
| %CV | 5.44 | 3.58 | 2.34 | 7.67 | 3.98 | 1.91 |
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510(k) Summary, Continued ____________________________________________________________________________________________________________________________________________________ BOEHRINGER ANNHEIM
Performance Characteristics:
RPORATION
11:00 11:00 11
- Comparison to predicate device, (cont.)
TDx CEDIA® Feature Digoxin II Digoxin II 0.2 ng/mL 0.15 ng/mL Lower Detection Limit 0.0 - 4.0 ng/mL 0.15 - 4 ng/mL Linearity Vs Abbott TDx Vs Baxter Dade Stratus Method Comparison Digoxin y =0.94x + 0.08 Least Squares r=0.962 y =0.98x - 0.12 N=200 r=0.955 N=99 Deming's: y=1.02x - 0.17 r=0.955 N=99
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| Feature | CEDIA®Digoxin II | TDxDigoxin II | |
|---|---|---|---|
| Interferingsubstances | No interference at:(within ±10% of baseline)15 | No interference at: | |
| BilirubinHemoglobinTriglyceride LipemiaTotal Protein | 66 mg/dL1000 mg/dL100 mg/dL10 g/dL | 20 mg/dL1000 mg/dL2500 mg/dLN/A | |
| Rheumatoid FactorSpecificity | 100 IU/mL% Cross-reactivity | N/A% Cross-reactivity | |
| Digoxigeninβ-Acetyldigoxinα-AcetyldigoxinGitalin | 60.577.075.32.1 | up to 200not testednot testednot tested | |
| Digoxingenin-Mono-DigitoxisideDigitoxin-Bis-Digitoxiside | 102.586.3 | up to 200 | |
| Digitoxinβ-Methyldigoxin3-Epe-Digoxigenin3- | 1.576.337.6 | up to 2004.8not tested | |
| DehydrodigoxigeninEpi-Digoxigenin- | 82.6 | not tested | |
| Glucuronide | 42.9 | not tested |
CC
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Image /page/6/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a circular seal with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" around the perimeter. Inside the circle is an abstract symbol that resembles an eagle or a stylized human figure with outstretched arms.
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
MAY 2 1 1997
Yvette R. Lloyd Regulatory Affairs Specialist Boehringer Mannheim Corporation 2400 Bisso Lane P.O. Box 4117 Concord, California 94524-4117
K970883 Re : CEDIA® Digoxin II Assay Regulatory Class: II Product Code: KXT Dated: April 18, 1997 Received: April 24, 1997
Dear Ms. Lloyd:
We have reviewed your Section 510(k) notification of intent to market the device referenced above and we have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to 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). "You may, therefore, market the device, subject to the general controls provisions The general controls provisions of the Act 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 (Premarket Approval), it may be subject to such additional controls. Existing major regulations affecting your device can be found in the Code of Federal Requlations, Title 21, Parts 800 to 895. ਜੋ substantially equivalent determination assumes compliance with the Good Manufacturing Practice for Medical Devices: General (GMP) requlation (21 CFR Part 820) and that, through periodic GMP inspections, the Food and Drug Administration (FDA) will verify such assumptions. Failure to comply with the GMP regulation may result in regulatory action. In addition, FDA may publish further announcements concerning your device in the Federal Reqister. Please note: this response to your premarket notification submission does not affect any obligation you might have under sections 531 through 542 of the Act for devices under the Electronic Product Radiation Control provisions, or other Federal laws or regulations.
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Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), this device may require a CLIA complexity categorization. To determine if it does, you should contact the Centers for Disease Control and Prevention (CDC) at (770) 488-7655 .
This letter will allow_you to begin marketing your device as = described in your 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 Part 801 and additionally 809.10 for in vitro diagnostic devices), please contact the Office of Compliance at (301) 594-4588. Additionally, for questions on the promotion and advertising of your device, please contact the Office of Compliance at (301) 594-4639. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). Other general information on your responsibilities under the Act may be obtained from the Division of Small Manufacturers Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its internet address "http://www.fda.gov/cdrh/dsmamain.html".
Sincerely yours,
Steven Gutman
Steven I. Gutman, M.D., M.B.A. Director Division of Clinical Laboratory Devices Office of Device Evaluation Center for Devices and Radiological Health
Enclosure
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510(k) Number (if known): N/A
Device Name: CEDIA® Digoxin II Assay
Indications For Use:
The CEDIA Digoxin II homogeneous enzyme immunoassay is for the quantitation of digoxin in human serum or plasma using automated clinical chemistry analyzers. Measurements are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure proper therapy .
Digoxin is widely prescribed for the treatment of congestive heart failure and various disturbances of cardiac rhythm. Therapeutic use of digoxin improves the strength of myocardial contraction and results in the beneficial effects of increased cardiac output, decreased heart size, decreased venous pressure and decreased blood volume. Digoxin therapy also results in stabilized and slowed ventricular pulse rate.
Although the availability of crystalline digoxin has permitted the standardization of drug dosage, therapeutic administration inadvertently, yet frequently, results in toxicity. Importantly, symptoms of digoxin toxicity often mimic the cardiac arrhythmias for which the drug was originally prescribed. Studies suggest that up to 25% of all hospitalized patients treated with digoxin experienced some degree of toxicity, and that the mortality rate among toxic patients was more than twice that of nontoxic patients. Digoxin concentrations of 0.9 to 2.0 ng/mL in serum or plasma are normally considered to be therapeutic. Symptoms of human toxicity generally only appear at concentrations above 2.0 ng/mL; however, concentrations as low as 1.4 ng/mL may be toxic for others.
Concurrence of CDRH, Office of Device Evaluation (ODE)
Prescription Use OR Over-The-Counter Use
(Per 21 CFR 801.109) the markdown is:
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INDICATIONS FOR USE, Continued:
Toxicity of digoxin may reflect several factors: a) The drug has a low therapeutic ratio (i.e., a very small difference exists between therapeutic and toxic tissue levels). b) Individuals vary in their response to digoxin. c) Absorption of various tablet forms of digoxin may vary over a two-fold range. d) Susceptibility to digitalis toxicity apparently increases with age.
In combination with other clinical data, monitoring serum or plasma levels may provide the physician with useful information to aid in adjusting patient dosage, and achieving optimal therapeutic effect, while avoiding both subtherapeutic and harmful toxic drug levels.
The CEDIA Digoxin II Assay performance has not been established with body fluids other than human serum and plasma (Na or Li heparin; Na EDTA).
Digoxin-like immunoreactive substances (DLIS) have been identified in blood from patients in renal failure, liver failure, and pregnant women in the third trimester. Studies have established that the presence of DLIS in a sample can result in a false elevation of digoxin when assayed by commercially available immunoassay.
Concurrence of CDRH, Office of Device Evaluation (ODE)
Prescription Use (Per 21 CFR 801.109) OR
Over-The-Counter Use
(Optional Format 1-2-96)
No
§ 862.3320 Digoxin test system.
(a)
Identification. A digoxin test system is a device intended to measure digoxin, a cardiovascular drug, in serum and plasma. Measurements obtained by this device are used in the diagnosis and treatment of digoxin overdose and in monitoring levels of digoxin to ensure appropriate therapy.(b)
Classification. Class II.