(223 days)
The GBI TSH Neonatal Screening Kit is designed for the quantitative determination of Thyroid Stimulating Hormone (TSH) concentrations in neonatal blood samples that have been collected onto Whatman 903 specimen collection paper. The results are used to screen newborns for congenital hypothyroidism.
The GBI TSH Neonatal Screening Kit is an enzyme immunoassay. A highly specific polyclonal goat antihTSH (human) antibody has been immobilized onto each well of the 96-well microplates provided. To begin the assay, sample discs punched from dried whole blood spot standards, controls and neonate specimens are added to the coated wells. An elution buffer is also added. The plate is incubated to elute TSH from the sample disc and to allow capture of the eluted TSH by the antibody immobilized onto the microplate wells. Following incubation the plates are washed to remove the sample discs as well as the eluate. A second antibody, a D-specific anti-hTSH monoclonal that has been conjugated to the enzyme horseradishperoxidase (HRP), is then added to the wells and incubated. The eluted TSH of the sample already captured by the microplate-bound antibody is now also bound by the enzyme-conjugated monoclonal antibody added. An antibody-TSH-antibody bridge, or "sandwich", forms that is bound to the surface of the microplate wells. Any unbound complexes are removed with subsequent plate washings. The final stage of the assay is the detection of the microwell-bound complexes by the addition of a color developing reagent. The enzyme (HRP) portion of the bound "sandwich" reacts with the color developer, 3, 3', 5, 5'-Tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2). The TMB/ H2O2 liquid is converted from colorless to blue. The degree of color change is directly proportional to the amount of TSH antigen that is bound in the well. The color development is terminated with the addition of a color stopper that converts the blue to yellow. The results are measured with a microplate reader at a wavelength of 450 mm. The absorbance measured is directly proportional to the concentration of TSH in the sample. A standard curve is generated by plotting the light absorbance of each standard versus its known TSH concentrations of TSH in the unknown samples are determined by interpolation from this standard curve.
Here's an analysis of the acceptance criteria and study proving the device meets them, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Metric | Acceptance Criteria (Predicate Device) | Reported Device Performance (GBI TSH Neonatal Screening Kit) |
|---|---|---|
| Analytical Sensitivity | 2.9 uIU/ml | 2.4 uIU/ml |
| Precision (Within-Run) | NA (Specific values for predicate not provided in the same format) | 15 uIU/ml: Sr = 0.9 uIU/ml (cv= 6.2%) 30 uIU/ml: Sr = 1.3 uIU/ml (cv= 4.6%) 25+ uIU/ml: Sr = 2.6 uIU/ml (cv= 8.5%) 40+ uIU/ml: Sr = 4.2 uIU/ml (cv= 9.1%) 80+ uIU/ml: Sr = 6.5 uIU/ml (cv=7.5%) |
| Precision (Between-Day) | NA (Specific values for predicate not provided in the same format) | 15 uIU/ml: Sdd = 1.0 uIU/ml (cv= 6.8%) 30 uIU/ml: Sdd = 2.3 uIU/ml (cv= 8.1%) 25+ uIU/ml: Sdd = 2.6 uIU/ml (cv= 8.5%) 40+ uIU/ml: Sdd = 1.2 uIU/ml (cv= 2.6%) 80+ uIU/ml: Sdd = 10.3 uIU/ml (cv= 11.9%) |
| Precision (Within-Device) | NA (Not published for predicate) | 15 uIU/ml: ST = 1.2 uIU/ml (cv= 8.2%) 30 uIU/ml: ST = 2.5 uIU/ml (cv= 8.8%) 25+ uIU/ml: ST = 3.7 uIU/ml (cv= 12.1%) 40+ uIU/ml: ST = 4.4 uIU/ml (cv= 9.5%) 80+ uIU/ml: ST = 12.2 uIU/ml (cv= 14.1%) |
| Interfering Substances | No interference at highest concentrations tested: Bilirubin (up to 60 mg/dl), Lipids (up to 1000 mg/dl), Hemoglobin (up to 78 g/dl) | No interference with expected values of clinical significance: - Bilirubin: no interference up to 20 mg/dl (Note: lower than predicate's stated limit, but the study shows no interference at this level) - Lipids: no interference up to 1350 mg/dl - Hemoglobin: no interference up to 80 g/dl - Specific test results show observed values within +/- 1 SD of control values for lipid, bilirubin (conj/un), and hemoglobin (at various concentrations, including higher ones in an additional study). |
| Cross Reacting Substances | No interference at highest concentrations tested: FSH (up to 500 mIU/ml), LH (up to 500 mIU/ml), HCG (up to 100,000 mIU/ml) | No interference found at highest concentrations tested (values were below the limit of detection for the assay, < 2.4 ulU/ml): - FSH (up to 500 mIU/ml) - LH (up to 500 mIU/ml) - HCG (up to 100,000 mIU/ml) |
| Method Comparison (Overall) | Normal = 97.9%, Borderline = 0.6%, Positive = 1.5% (N=995) | Normal = 97.4%, Borderline = 1.1%, Positive = 1.5% (N=995) |
| Method Comparison (Regression) | N=832: Mean = 8.1 uIU/ml; Range = 2.9 to 104 uIU/ml | N=832: Mean = 8.9 uIU/ml; Range = 2.4 to 114 uIU/ml. y (GBI TSH EIA) = 1.0695x (Predicate) + 0.2671, R² = 0.9185 |
Study Description and Details
The provided document describes a 510(k) premarket notification for the GBI TSH Neonatal Screening Kit, comparing it to a legally marketed predicate device (Accuwell Thyroid Stimulating Hormone (TSH) ELISA). The studies performed demonstrate the analytical performance of the GBI TSH EIA kit.
2. Sample Size Used for the Test Set and Data Provenance
- Precision Study:
- Sample Size: 40 replicates (2 aliquots per run, 1 run per day, over 20 days) for five different sample IDs (C1-C5).
- Data Provenance: "in-house" testing, implying controlled laboratory conditions. The specific country of origin is not explicitly stated for the samples themselves beyond "human whole blood" used for standards. The study was conducted by Golden Bridge International, Inc. (Mukilteo, WA, USA). This appears to be a prospective study designed for this submission.
- Analytical Sensitivity Study:
- Sample Size: 20 measurements of the zero standard within a single assay.
- Data Provenance: "in-house" testing, likely from the manufacturer's lab.
- Linearity, Recovery and Assay Measurable Range Study:
- Sample Size: 19 different TSH concentrations (expected values), with two 1/8 inch punches from each concentration tested in two runs (total of n=4 results per concentration level).
- Data Provenance: Prepared dried whole blood spot samples for the study, likely in-house.
- Specificity (Cross-Reactivity) Study:
- Sample Size: Not explicitly stated as a count of individual samples, but various concentrations of FSH, LH, and HCG were tested in TSH-free whole blood.
- Data Provenance: Likely in-house prepared samples.
- Interfering Substances Study:
- Sample Size: Not explicitly stated as a count of individual samples, but various concentrations of lipid, conjugated bilirubin, unconjugated bilirubin, and hemoglobin were tested. The main interference study involved "fresh whole blood" specimens at desired concentrations, and an "additional study" challenged the assay with higher hemoglobin concentrations using CDC TSH control samples C1-C4, with 6 measurements per condition ("Mean; n=6").
- Data Provenance: Likely in-house prepared or spiked samples for the main study. For the additional hemoglobin study, CDC TSH control samples were used.
- Method Comparison Study:
- Sample Size: 995 neonatal blood spot specimens (980 from a presumed normal population and 15 from patients confirmed as positive for hypothyroidism). A subset of N=832 samples was used for statistical analysis after excluding non-numeric results.
- Data Provenance: "in-house" analysis using neonatal blood spot specimens. The origin of these specimens (e.g., specific country, retrospective/prospective collection) is not explicitly detailed beyond being "from a presumed normal population" and "from patients confirmed as positive for hypothyroidism." It is common for such samples to be retrospectively collected or part of a sample bank.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
- No specific experts are mentioned for establishing ground truth for the test set samples.
- For the Method Comparison study, 15 samples were "from patients confirmed as positive for hypothyroidism." This implies a clinical diagnosis served as a ground truth, but the number and qualifications of the clinicians/experts making these diagnoses are not specified.
- For the Interfering Substances study, CDC TSH control samples were used, implying the CDC's established values serve as a reference, but no specific "experts" were consulted to establish the ground truth for the study samples.
- The "Expected Value" for linearity was a technical target, not an expert-derived ground truth from patient samples.
- The standards (calibrators) and controls are referenced against WHO 3rd IRP of human TSH 81/565, which is an international standard, not an expert consensus from individual case review.
4. Adjudication Method for the Test Set
- There is no mention of an adjudication method (like 2+1, 3+1, none) typically used for subjective endpoints or diagnostic imaging.
- For quantitative assays like this TSH EIA, the comparison is typically against a reference method (the predicate device) or known established values (e.g., CDC controls, spiked samples). Discrepancies are analyzed statistically rather than by expert adjudication.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Readers Improve with AI vs without AI Assistance
- No, this is not applicable. The GBI TSH Neonatal Screening Kit is an in-vitro diagnostic (IVD) device, specifically an enzyme immunoassay (EIA). It's a laboratory-based test that provides a quantitative numerical result for TSH concentration. It does not involve human "readers" interpreting images or other subjective data, nor does it involve AI assistance in that context. Therefore, a multi-reader multi-case (MRMC) study or assessment of AI's effect on human reader improvement is not relevant to this type of device.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
- Yes, this is effectively a standalone performance study. The GBI TSH Neonatal Screening Kit itself is the "algorithm" (the immunoassay process and signal detection). The performance metrics (analytical sensitivity, precision, linearity, specificity, interference, method comparison) are all measures of the device's intrinsic analytical capabilities without human intervention influencing the result generation, other than standard laboratory procedures for running the assay. The intent is for the device to quantitatively determine TSH levels.
7. The Type of Ground Truth Used
The ground truth for the various studies primarily relies on:
- Known concentrations: For precision, analytical sensitivity, linearity, cross-reactivity, and interference, the "ground truth" refers to the known concentrations of TSH (or lack thereof for specificity) in spiked samples, control materials (like CDC controls), or standards.
- Reference method comparison: For the method comparison study, the results from the predicate device (Accuwell TSH ELISA) served as the primary reference or "ground truth" to which the new device's results were compared.
- Clinical Diagnosis: For the 15 positive samples in the method comparison, they were "from patients confirmed as positive for hypothyroidism," implying a clinical diagnosis as ground truth.
8. The Sample Size for the Training Set
- The document does not explicitly describe a "training set" in the context of machine learning. This is an IVD device, not an AI/ML device that undergoes training.
- However, the standards (calibrators) used to generate the standard curve that unknowns are interpolated from can be considered analogous to training data for the assay itself. The kit includes "TSH Dried Blood Standards and Controls" described as 6 standards (zero, 7.5, 15.0, 30.0, 60.0, and 120.0 ulU/ml serum equivalent) and 3 controls (15, 30, and 80 µIU/m1 serum equivalent). These are used in every run to establish the curve and validate the assay, which is more akin to continuous calibration and quality control rather than a one-time training set for an algorithm.
9. How the Ground Truth for the Training Set Was Established
- As noted above, for an EIA kit, the "training set" is effectively the calibrators (standards).
- The ground truth for these standards is established by:
- Preparation from human whole blood adjusted to 55% hematocrit and spotted onto Whatman 903 paper.
- Addition of known concentrations of TSH analyte.
- Referenced against WHO 3rd IRP of human TSH 81/565. This indicates traceability to an internationally accepted reference standard, ensuring the accuracy of the assigned TSH concentrations.
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Golden Bridge International, Inc. Mukilteo, WA 98275 USA
APR 1 0 2008
| 1) | Submitter Name: | Golden Bridge International, Inc. |
|---|---|---|
| Address: | 9700 Harbour Place, Suite 129Mukilteo, WA 98725 USA | |
| Telephone Number: | 425-493-1801 | |
| Contact Person: | Xiaoping Zhang, Vice President | |
| Date Prepared: | 03/27/08 | |
| 2) | Device Trade orProprietary Name: | GBI TSH Neonatal Screening Kit |
| Device Common orUsual Name: | Thyroid stimulating hormone (TSH) neonatal screening enzymeimmunoassay (EIA) | |
| Device Classification Name: | Radioimmunoassay, Thyroid Stimulating Hormone | |
| Product Code: | JLW | |
| 3) | Legally MarketedPredicate Device: | Accuwell Thyroid Stimulating Hormone (TSH) ELISA |
GBI Thyroid Stimulating Hormone (TSH) EIA 510(k) Summary
4) Device Description:
Summary and Explanation of the Test
Congenital hypothyroidism (CH) is one of the most common metabolic disorders resulting in permanent mental retardation if undetected or left untreated soon after birth. Newborns that have been identified and treated for CH within two weeks of birth can be expected to have normal cognitive development.
Screening programs for the disorder were developed early in 1974 and have now been established in Western Europe, North America, Japan and parts of Eastern Europe, Asia, South and Central American Academy of Pediatrics first published recommendations for CH in 1993. Advances in screening methods and expanded knowledge of the physiology of thyroid hormones has lead to new recommendations by the Academy in 2006.2 In North America more than five million newborns are screened annually with over 1400 hypothyroid cases detected each year. The incidence of hypothyroidism varies among different populations and ranges from 1 in 3000 to 1 in 4000. The incidence of CH is higher in Hispanics and lower in black individuals. Females have a 2:1 greater incidence of CH than males. A higher frequency of the CH disorder has been observed in individuals with Downs Syndrome.
Thyroid stimulating hormone (TSH) is a pituitary-derived glycoprotein with a molecular weight of approximately 28 kDa. TSH is produced by the anterior lobe of the pituitary gland under the control of thyrotropin releasing hormone (TRH) which is secreted by the hypothalamus. TSH acts on the thyroid gland to release the thyroid hormones triiodothyronine (T)) and thyroxine (T). Under normal thyroid function, the level of the thyroid hormones T3 and T4 is inversely related to the concentrations of TSH and TRH in the bloodstream via a negative feedback mechanism. As a result of this negative feedback mechanism between the thyroid gland and the pituitary, TSH is always elevated in cases of primary hypothyroidism and often to very high levels. It is
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for this reason that the measurement of TSH concentration is a valuable diagnostic tool for the detection of hypothyroidism.
Thyroid hormone (TH) levels of the fetus are low during the first half of pregnancy. Maternal status of TH hormones is entirely responsible for the regulation of fetal TH, transmitted through the placenta. The fetal hypothalamic-pituitary-thyroid axis develops during the second half of gestation and is mature at time of birth. A surge of TSH concentration occurs at birth and then declines rapidly within the first few days of life, and continues to decrease more slowly to adult levels. It is recommended to perform screening for CH ideally within the 2nd to 4th days after birth or at time of discharge.
Blood samples collected before 24 hours of age, from low birth weight or ill infants can lead to elevated TSH and thus false positive results. Hypothyroid infants may be partially protected by maternal TH levels and so most infants will appear normal at birth. There have also been reported cases of transient hypothyroidism due to maternal hypothyroidism and other maternal abnormalities. Hypothyroidism can develop after birth, and in such cases will yield a normal newborn screening result.
Since the incidence of hypothyroidism and the concentrations of TSH have been shown to a variety of factors (e.g., demographics, ethnicity, the sex and age of the infant, low birth weights and premature births) it is important that each newborn screening laboratory examine its test population and determine its own normal range and cut-off values with these factors taken into consideration.
Screening algorithms vary among centers from initial TSH with confirmation via T4 initial screen with confirmation via TSH measurements, to both tests (174 and TSH) being performed simultaneously. Regardless of method, repeated positive results on a neonate should be cause for referral for additional confirmation testing.
Principle of the Assay
The GBI TSH Neonatal Screening Kit is an enzyme immunoassay. A highly specific polyclonal goat antihTSH (human) antibody has been immobilized onto each well of the 96-well microplates provided. To begin the assay, sample discs punched from dried whole blood spot standards, controls and neonate specimens are added to the coated wells. An elution buffer is also added. The plate is incubated to elute TSH from the sample disc and to allow capture of the eluted TSH by the antibody immobilized onto the microplate wells. Following incubation the plates are washed to remove the sample discs as well as the eluate.
A second antibody, a D-specific anti-hTSH monoclonal that has been conjugated to the enzyme horseradishperoxidase (HRP), is then added to the wells and incubated. The eluted TSH of the sample already captured by the microplate-bound antibody is now also bound by the enzyme-conjugated monoclonal antibody added. An antibody-TSH-antibody bridge, or "sandwich", forms that is bound to the surface of the microplate wells. Any unbound complexes are removed with subsequent plate washings.
The final stage of the assay is the detection of the microwell-bound complexes by the addition of a color developing reagent. The enzyme (HRP) portion of the bound "sandwich" reacts with the color developer, 3, 3', 5, 5'-Tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2). The TMB/ H2O2 liquid is converted from colorless to blue. The degree of color change is directly proportional to the amount of TSH antigen that is bound in the well. The color development is terminated with the addition of a color stopper that converts the blue to yellow.
The results are measured with a microplate reader at a wavelength of 450 mm. The absorbance measured is directly proportional to the concentration of TSH in the sample. A standard curve is generated by plotting the light absorbance of each standard versus its known TSH concentrations of TSH in the unknown samples are determined by interpolation from this standard curve.
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Kit Contents
Materials Supplied
| Quantity per Kit | |
|---|---|
| Total Tests: | 576 |
| TSH Capture Microplate | 6 X 96 wells |
| TSH Elution Buffer | 1 x 70 ml |
| Anti-TSH PO Conjugate | 1 x 1.4 ml |
| TSH Diluent Buffer | 1 x 70 ml |
| PO Wash Buffer (20X) | 1 x 100 ml |
| PO Color Reagent* | 1 x 70 ml |
| PO Color Stopper | 1 x 70 ml |
| TSH Dried Blood Standards and Controls | 1 Set |
* This reagent is light sensitive. Avoid prolonged exposure to light.
NOTE: Do NOT use reagents that are cloudy or discolored as these conditions indicate deterioration. Reagents should be stored in their original containers with the exception of the diluted wash buffer.
Do NOT exchange reagents from one kit with those of another kit.
Reagent Descriptions
TSH Capture Microplate
Goat polyclonal anti-alpha hTSH antibody coated 96-well microplates. The microplates are packaged in zipper-lock bags containing a desiccant. Store the unused microplates in zipper-lock bags with desiccant. Storage: Dry at 2-25° C.
Expiration: Refer to the expiration date printed on the label
TSH Elution Buffer
A borate buffer containing bovine albumin, surfactant and preservatives. This buffer contains sodium azide as a preservative.
Storage: 2-8° C Refer to the expiration date printed on the label. Expiration:
Anti-TSH PO Conjugate
A mouse monoclonal p-specific antibody conjugated to horseradish peroxidase (HRP) in borate buffer containing bovine albumin, surfactant, and preservatives. This buffer contains thimerosal as a preservative; refer to "Warnings and Precautions", below. Store in the original brown container. This conjugate is concentrated and must be diluted before use.
Storage: 2-8° C
Refer to the expiration date printed on the label. Expiration:
TSH Diluent Buffer
A borate buffer containing bovine albumin, surfactant, and preservatives. This buffer contains thimerosal as a preservative.
2-8° C Storage:
Refer to the expiration date printed on the label. Expiration:
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PO Wash Buffer (20X)
A concentrated solution of phosphate buffered saline containing a surfactant and preservatives. Wash Buffer Concentrate must be diluted with deionized or distilled water before use. Storage: 2-25° C
Expiration:
Concentrate: Refer to the expiration date printed on the label. Diluted wash buffer is stable for 1 month when stored at 2-25° C.
PO Color Reagent*
hydrogen coloriess solution of 3,3', 5,5'-Tetramethylbenzidine (TMB) and peroxide. A *This reagent is light sensitive. Store in the original brown container. Do not pour any of the unused Color Developer back into the original container. This reagent should remain colorless. If it has discolored, discard it.
2-8° C Protected from light. Storage:
Refer to the expiration date printed on the label. Expiration:
PQ Color Stopper
、
A solution containing < 1% hydrochloric acid. Storage: 2-8° C. Refer to the expiration date printed on the label. Expiration:
TSH Dried Blood Standards and Controls
Prepared from human whole blood, adjusted to a hematocrit of 55% and spotted onto Whatman 903% specimen collection paper. The six Standards contain concentrations of added TSH at approximately zero, 7.5, 15.0, 30.0, 60.0, and 120.0 ulU/ml serum equivalent. The three Controls contain approximate TSH concentrations of 15, 30 and 80 µIU/m1 serum equivalent. Refer to the labels for the exact concentrations of the Standards and acceptable ranges for the Controls. Store in a zipper-lock bag containing a desiccant. Standards are referenced against WHO 3rd IRP of human TSH 81/565.
Storage: Dry at 2-8° C or below.
Refer to the expiration date printed on the label. Expiration:
Materials Required But Not Supplied
- 1/8 inch (3 mm) diameter hole punch (sample prep) 1.
- Forceps or fine tweezers to pick up the punched sample discs 2.
- Plastic, disposable tube and screw-cap; ≥ 15 ml volume (conjugate prep) ి.
- Serological pipette to dispense 10 ml volumes (wash buffer prep) 4.
- Precision pipettes to accurately dispense 100 ul volumes (reagent adds) 5.
- Multi-channel pipettes to dispense 350 ul volumes or an automated plate washer (plate washes) 6.
- Microplate reader capable of reading at a wavelength of 450 nm 7.
- Plate rotator (sample & test reagent mixing) 8.
- Clear, adhesive sealing tape or plate sealers; solid plastic, reusable microplate covers 9.
-
- Graduated cylinders
-
- Deionized or distilled water
-
- Intended Use:
The GBI TSH Neonatal Screening Kit is designed for the quantitative determination of Thyroid Stimulating Hormone (TSH) concentrations in neonatal blood samples that have been collected onto Whatman 903 % specimen collection paper. The results are used to screen newborns for congenital hypothyroidism.
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6) Summary of Technological Characteristics:
| Item#: | Characteristic: | Predicate¹²: | New Device: |
|---|---|---|---|
| 1 | Intended User | Clinical Laboratory Professionals | Clinical Laboratory Professionals |
| 2 | Target Population | Neonates only | Neonates only |
| 3 | Intended Use | The quantitative determination of ThyroidStimulating Hormone (TSH) concentrationsin neonatal blood samples that have beencollected onto Whatman 903® specimencollection paper. | The quantitative determination of ThyroidStimulating Hormone (TSH) concentrationsin neonatal blood samples that have beencollected onto Whatman 903® specimencollection paper. |
| 4 | Indications for Use | The screening of newborns for elevated TSHsuggestive of congenital hypothyroidism. | The screening of newborns for elevated TSHsuggestive of congenital hypothyroidism. |
| 5 | Assay Type | Enzyme-Linked Immunosorbent assay(ELISA) | Enzyme Immunoassay (EIA) |
| 6 | Assay ProcessingMethod | Manual | Manual |
| 7 | Chemical Principle | Polyclonal goat anti-hTSH that is bound tothe microplate captures eluted specimenTSH; after washing away free TSH,conjugated monoclonal-horseradishperoxidase is added and binds to the capturedTSH thus forming an immobilizedantibody+TSH+antibody-enzyme"sandwich". After washing away freeenzyme, immobilized peroxidase reacts withadded color developer containing hydrogenperoxide and 3,3',5,5'-Tetramethylbenzidine(TMB). The TMB is converted fromcolorless to blue. The color development isterminated by the addition of a stoppingreagent.The light absorbance of the reaction endpoint | Polyclonal goat anti-hTSH that is bound tothe microplate captures eluted specimenTSH; after washing away free TSH,conjugated monoclonal-horseradishperoxidase is added and binds to the capturedTSH thus forming an immobilizedantibody+TSH+antibody-enzyme"sandwich". After washing away freeenzyme, immobilized peroxidase reacts withadded color developer containing hydrogenperoxide and 3,3',5,5'-Tetramethylbenzidine(TMB). The TMB is converted fromcolorless to blue. The color development isterminated by the addition of a stoppingreagent that also converts the blue to yellow.The light absorbance of the reaction endpoint |
| 8 | Detection Method | is measured spectrophotometrically at awavelength of 650nm. The degree of colordevelopment is directly proportional to theamount of TSH antigen that has been"sandwiched" onto the microwell. | is measured spectrophotometrically at awavelength of 450nm. The degree of colordevelopment is directly proportional to theamount of TSH antigen that has been"sandwiched" onto the microwell. |
| 9 | Special InstrumentationRequired | Microplate Spectrophotometer (at 650 nm) | Microplate Spectrophotometer (at 450 nm) |
| 10 | Specimen Type | Neonatal whole blood collected ontoWhatman 903® filter paper and dried | Neonatal whole blood collected ontoWhatman 903 filter paper and dried |
| 11 | Specimen VolumeRequirement | 1/8 inch punch (from dried blood spotsample) | 1/8 inch punch (from dried blood spotsample) |
| 12 | Calibrator (Standard)Configuration | Stripped serum, lysed cells and purified TSHanalyte combined, spotted onto Whatman903® filter paper and dried | Stripped serum, lysed cells and purified TSHanalyte combined, spotted onto Whatman903 filter paper and dried |
| 13 | Calibrator (Standard)Range of Values | 0 - 160 uIU/ml serum equivalents | 0 - 120 ulU/ml serum equivalents |
| 14 | Internal ControlConfiguration | Stripped serum, lysed cells and purified TSHanalyte combined, spotted onto Whatman903 filter paper and dried | Stripped serum, lysed cells and purified TSHanalyte combined, spotted onto Whatman903® filter paper and dried |
| 15 | Internal Control Levels | Low at ≈ 20 uIU/mlMid at ≈ 40 uIU/mlHigh at ≈ 80 uIU/ml | Low at ≈ 15 ulU/mlMid at ≈ 30 uIU/mlHigh at ≈ 80 uIU/ml |
| 16 | RecommendedReference Ranges | From American Academy of Pediatrics:Normal < 20 ulU/ml serum equivalentBorderline 20-40 ulU/ml serum equivalentHypothyroid > 40 uIU/ml serum equivalent | From American Academy of Pediatrics:Normal < 20 ulU/ml serum equivalentBorderline 20-40 ulU/ml serum equivalentHypothyroid > 40 uIU/ml serum equivalent |
| 17 | Expected Values -Normal NeonatePopulation | N=1040:Mean = 9.9 ulU/mlS.D. = 5.8 uIU/ml | N=902:Mean = 8.1 uIU/mlS.D. = 4.0 uIU/ml |
| 18 | Analytical Sensitivity | 2.9 uIU/ml | 2.4 uIU/ml |
| 19 | Precision³ | Within Run Precision:NANA24.0 uIU/ml cv = 10.0 %51.1 uIU/ml cv = 7.8 %159.2 uIU/ml cv = 4.3 %Between Run Precision:NANA27.3 uIU/ml cv = 6.1 %40.8 uIU/ml cv = 8.4 %78.5 uIU/ml cv = 6.5 %Over-All (Within-Device) Precision:NA - Not published | Within-Run Standard Deviation (Sr):15 uIU/ml Sr = 0.9 ulU/ml cv= 6.2%30 uIU/ml Sr = 1.3 " cv= 4.6%25+uIU/ml Sr = 2.6 " cv= 8.5%40+ ulU/ml Sr = 4.2 " cv= 9.1%80+ ulU/ml Sr = 6.5 " cv=7.5%Between-Day Standard Deviation (Sdd):15 uIU/ml Sdd = 1.0 ulU/ml cv= 6.8%30 uIU/ml Sdd = 2.3 " cv= 8.1%25+uIU/ml Sdd = 2.6 " cv= 8.5%40+uIU/ml Sdd = 1.2 " cv= 2.6%80+uIU/ml Sdd = 10.3 " cv= 11.9%Within-Device Standard Deviation (ST):15 ulU/ml ST = 1.2 ulU/ml cv= 8.2%30 ulU/ml ST = 2.5 " cv= 8.8%25+ ulU/ml ST = 3.7 " cv= 12.1%40+uIU/ml ST = 4.4 " cv= 9.5%80+uIU/ml ST = 12.2 " cv= 14.1% |
| 20 | Interfering Substances | No Interference observed at the highestconcentration tested*:Bilirubin - no interference up to 60 mg/dl*Lipids - no interference up to 1000 mg/dl*Hemoglobin - no interference up to 78 g/dl* | No Interference observed at the highestconcentration tested*:Bilirubin - no interference up to 20 mg/dl*Lipids - no interference up to 1350 mg/dl*Hemoglobin - no interference up to 80 g/dl* |
| 21 | Cross ReactingSubstances | No interference found at the highestconcentration tested:FSH- no interference up to 500 mIU/mlLH- no interference up to 500 mIU/mlHCG- no interference up to 100,000 mIU/ml | No interference found at the highestconcentration tested:FSH- no interference up to 500 mIU/mlLH- no interference up to 500 mIU/mlHCG- no interference up to 100,000 mIU/ml |
| 22 | Method Comparison | For N=995:Normal = 974/995 (97.9%)Borderline = 6/995 (0.6%)Positive = 15/995 (1.5%)For (subset) N=832:Mean = 8.1 uIU/ml;Range = 2.9 to 104 uIU/ml. | For N=995:Normal = 969/995 (97.4%)Borderline = 11/995 (1.1%)Positive = 15/995 (1.5%)For (subset) N=832:Mean = 8.9 ulU/ml;Range = 2.4 to 114 uIU/mly (GBI TSH EIA) = 1.0695x (Predicate) +0.2671. R² = 0.9185 |
| CDC Controls(Enrichment Values inserum equivalents) | N = 294intercept = 0.1505slope = 1.0231 | N = 405intercept = 5.2083slope = 1.0208 | |
| 23 | CDC Lot 611 –25 uIU/ml | 26.0 uIU/ml serum equivalent | 30.6 uIU/ml serum equivalent |
| CDC Lot 612 –40 uIU/ml | 40.7 uIU/ml serum equivalent | 46.3 uIU/ml serum equivalent | |
| CDC Lot 613 –80 uIU/ml | 82.1 uIU/ml serum equivalent | 86.8 uIU/ml serum equivalent |
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Golden Bridge International, Inc. Mukilteo, WA 98275 USA
l
Predicate data and descriptive text were obtained from the Accuwell TSH ELISA Directions For Use (DFU) unless otherwise indicated.
2 The predicate DFU declares the use of "Schleicher & Schuell (S&S) 903™" filter paper as the sample substrate. S&S has since been purchased by Whatman and the name of the 903 filter paper has been changed to "Whatman 903". For this reason, table references throughout use the Whatman 903" designation only, even though the predicate DFU actually refers to the paper as S&S 903™
3 Precision data were not generated in the same way nor reported in precisely the same terms for the predicate vs the new device. The new (GBI TSH) device precision was established and reported according to NCCLS EP5-A2, "Evaluation of Precision Performance of Quantitative Measurement Methods"; Approved Guideline-Second Edition.
4 Predicate values were obtained from the CDC's Newborn Screening Quality Assurance Program (NSQAP) 2006 Annual Summary Report; Volume 24, January 2007.
5 GBI values were obtained from the same data sct that was used to establish assay precision values.
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7) Clinical and Non-Clinical Data:
Precision
Precision studies were conducted in accordance with NCCLS EP5-A2: Evaluation of Precision Performance of Quantitative Measurement Methods; Approved Guideline-Second Edition.
Testing included two sample aliquots per run, one run per day, performed on 20 different days using the GBI published assay procedure. The resulting data were used to estimate repeatability, between-day and withindevice precision as described by the standard. Refer to the table below.
Sources of variability included the use of different: operators, days and reagent lot numbers.
| Summary Results and Estimates of Precision for GBP TSH EIA Kit | ||||||
|---|---|---|---|---|---|---|
| Sample ID: | C1 | C2 | C3 | C4 | C5 | |
| Precision Parameter | Count | 40 | 40 | 40 | 40 | 40 |
| Mean | 14.6 | 28.3 | 30.6 | 46.3 | 86.8 | |
| SD | 1.2 | 2.5 | 3.7 | 4.4 | 12.1 | |
| %CV | 7.9 | 8.7 | 11.9 | 9.4 | 13.9 | |
| Min | 12.5 | 23.5 | 23.3 | 37.5 | 71.4 | |
| Max | 18.0 | 34.0 | 40.4 | 59.1 | 122.5 | |
| Within-Run Standard Deviation: | Sr = | 0.9 | 1.3 | 2.6 | 4.2 | 6.5 |
| Between-Day Standard Deviation: | Sdd = | 1.0 | 2.3 | 2.6 | 1.2 | 10.3 |
| Within Device Standard Deviation: | ST = | 1.2 | 2.5 | 3.7 | 4.4 | 12.2 |
Summary Results and Estimates of Precision for GBI TSH EIA Kit
Analytical Sensitivity
The Analytical Limit at Low Levels (limit of sensitivity) for the GBI TSH EIA Kit was determined by testing the zero standard multiple times (N=20) within a single assay. The resulting data were used to calculate the analytical limit at low levels. Refer to the table below.
The analytical sensitivity is defined as the calculated concentration that corresponds to the mean of the absorbance values of the zero standard (N=20) plus two times the standard deviation derived from those same (N=20) absorbance values.
These data are provided for example only. Each laboratory should establish appropriate working limits based upon their own patient population and/or data.
| Summary Results and Analytical Limits at Low Levels for GBI TSH EL | |
|---|---|
| GBI TSH | |
| Count | 20 |
| Mean ABS | 0.0354 |
| SD | 0.0063 |
| %CV | 18 |
| Min | 0.0289 |
| Max | 0.0570 |
| Mean + (2 *S.D.) ABS: | 0.0480 |
| Analytical Limit (uIU/ml) | 2.4 |
Posults and Analytical Limits of Low Levels for CBI TSH FIA ﮯ
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Linearity, Recovery and Assay Measurable (Reportable) Range
The GBI TSH EIA Kit linear range was assessed according to the NCCLS Guideline EP6-A: Evaluation of the Linearity of Quantitative Analytical Methods, 2003.
A series of dried whole blood spot samples was prepared to provide the desired range of TSH concentrations for the study (N=19; see table column "Expected Value", below).
Two one-eighth inch punches from each concentration level were tested in each of two runs. The mean of the total number of results for a level (n=4) was compared to the expected value. Results are described in the table below.
| Linear Regression Analysis | $y = 0.8997x + 0.6036, R^2 = 0.999$ | ||
|---|---|---|---|
| Linearity Sample # | Expected Value(uIU/ml) | GBI Assay Result(Mean uIU/ml; N=4) | Recovery (%) |
| 1 | 1.5 | 1.6 | 107 |
| 2 | 2.7 | 3.1 | 114 |
| 3 | 3.9 | 4.1 | 105 |
| 4 | 6.2 | 6.0 | 96.8 |
| 5 | 8.6 | 8.1 | 93.6 |
| 6 | 10.0 | 10.6 | 106 |
| 7 | 10.9 | 9.8 | 89.4 |
| 8 | 13.3 | 12.4 | 93.0 |
| 9 | 15.6 | 14.9 | 95.4 |
| 10 | 18.0 | 16.1 | 89.2 |
| 11 | 20.3 | 17.9 | 88.1 |
| 12 | 22.7 | 20.1 | 88.3 |
| 13 | 24.5 | 21.9 | 89.4 |
| 14 | 25.0 | 22.8 | 91.1 |
| 15 | 39.0 | 37.2 | 95.3 |
| 16 | 68.0 | 65.4 | 96.2 |
| 17 | 97.0 | 89.5 | 92.3 |
| 18 | 126.0 | 113.5 | 90.1 |
| 19 | 155.0 | 138.0 | 89.0 |
| Average Recovery-Overall % | 95.2 | ||
| Minimum % | 88.1 | ||
| Maximum % | 114 |
Results of Assay Linearity and % Recovery Study for GBI TSH ELA Kit
The GBI TSH EIA Kit reportable range is approximately 2.4 uIU/ml. The lower limit is the concentration calculated from the analytical sensitivity study (above) and the upper limit is the concentration of the highest standard of the calibration curve.
Assay results obtained outside the measuring (reportable) range should be reported as either "less than" or "greater than" the established low or high limit, respectively, as applicable to the individual result.
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Specificity
Cross Reactivity
The following compounds were tested for cross-reactivity. Each compound was added at several concentrations to TSH-free whole blood which had been adjusted to a hematocrit of 55%. The samples were spotted onto Whatman 903 specimen collection paper, air-dried and assayed. Refer to the table below.
| Results of a Cross-Reactivity Study of the GBI TSH EIA Screening Assay | ||
|---|---|---|
| Peptide Hormone | Cross-ReactantConcentration Added(µIU/ml) | TSH ConcentrationMeasured(µIU/ml) |
| FSH(WHO 2nd IRP HMG) | 125 | None Detected* |
| 250 | None Detected* | |
| 500 | None Detected* | |
| LH(WHO 1st IRP 68/40) | 125 | None Detected* |
| 250 | None Detected* | |
| 500 | None Detected* | |
| HCG(WHO 2nd I.S. 61/6) | 10,000 | None Detected* |
| 50,000 | None Detected* | |
| 100,000 | None Detected* |
- "None Detected" represents values obtained that were below the limit of detection for the assay (i.e., < 2.4 ulU/ml.)
Interfering Substances
Assay interference due to the presence of hemoglobin, conjugated bilirubin, and lipids was studied using methods described in NCCLS EP7A: Interference Testing in Clinical Chemistry as guidance.
Testing was performed to evaluate the effects of interfering substances at the medical decision(s) concentrations using fresh whole blood. The interferents (i.e., hemoglobin, conjugated and unconjugated bilirubin, and lipids) were present in the whole blood specimens at the desired ("worst case") concentrations before specimens were spotted onto filter paper and dried. As such, the sample elution procedure was captured in the subsequent testing process. These prepared dried blood spot specimens were then assayed using the GBI TSH Kit as prescribed herein. (Results are presented below.)
An additional study was conducted that challenged the assay at a much higher hemoglobin concentration. During the initial sample elution step of the assay procedure, three different concentrations (physiologic low, mid, high) of hemoglobin were added separately to microplate wells that also separately contained the three different concentrations (physiologic low, mid, high) of a CDC TSH control sample series. The remainder of the GBI TSH assay was performed as prescribed herein. (Results are presented below.)
Interference was defined as a test value obtained that was greater than +/- 1 S.D. (within-run) of the matching control value obtained in the same assay; AND, the difference of the test value obtained from the matching control value is clinically significant at that level.
No interference with expected values of any clinical significance was observed from any substance tested, at any concentration tested.
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.
| DBSSampleID# | Interferent | InterferentConcentration | TSH uIU/ml -ExpectedValue | TSH uIU/ml -Observed(Mean; n=4) | AcceptanceCriteria(+/- 1 SD ofControl Value) |
|---|---|---|---|---|---|
| 25 | Lipid-Control | 0 mg/dL | na | 16.2 | 16.2 +/- 0.9 |
| 19 | Lipid | 1350 mg/dL | 16.2 | 18.0 | 15.3 - 17.1 |
| 26 | Lipid-Control | 0 mg/dL | na | 46.1 | 46.1 +/- 4.2 |
| 20 | Lipid | 1350 mg/dL | 46.1 | 44.2 | 41.9 - 50.3 |
| 27 | Lipid-Control | 0 mg/dL | -- | 85.6 | 85.6 +/- 6.5 |
| 21 | Lipid | 1350 mg/dL | 85.6 | 83.5 | 79.1 - 92.1 |
| 36 | Bili-Control | 0 mg/dL | na | 13.6 | 13.6 +/- 0.9 |
| 31 | Conj-Bilirubin | 20 mg/dL | 13.6 | 14.6 | 12.7 - 14.5 |
| 28 | Un-Bilirubin | 20 mg/dL | 13.6 | 14.9 | |
| 41 | Bili-Control | 0 mg/dL | na | 27.1 | 27.1 +/- 1.3 |
| 32 | Conj-Bilirubin | 20 mg/dL | 27.1 | 27.4 | 25.8 - 28.4 |
| 29 | Un-Bilirubin | 20 mg/dL | 27.1 | 28.1 | |
| 46 | Bili-Control | 0 mg/dL | na | 68.2 | 68.2 +/- 5.4 |
| 33 | Conj-Bilirubin | 20 mg/dL | 68.2 | 68.4 | 62.8 - 73.6 |
| 30 | Un-Bilirubin | 20 mg/dL | 68.2 | 67.6 | |
| 36 | Hb-Control | 17.0 gm/dL | 13.6 | 13.6 | +/- 0.9 |
| 37 | Hb | 18.7 gm/dL | 12.1 | 13.1 | 12.7 - 14.5 |
| 41 | Hb-Control | 17.0 gm/dL | 27.1 | 27.1 | +/- 1.3 |
| 42 | Hb | 18.7 gm/dL | 24.0 | 25.4 | 25.8 - 28.4 |
| 46 | Hb-Control | 17.0 gm/dL | 68.2 | 68.2 | +/- 5.4 |
| 47 | Hb | 18.7 gm/dL | 60.6 | 63.6 | 62.8 - 73.6 |
| Results of Interference Testing of the GBI TSH EIA Screening Assay | ||||
|---|---|---|---|---|
| -------------------------------------------------------------------- | -- | -- | -- | -- |
Results of Additional Hemoglobin Interference Testing of the GB1 TSH EIA Screening Assay
| DBS Sample ID# | HemoglobinConcentration -(gm/dL) | TSH uIU/ml -ExpectedValue | TSH uIU/ml -Observed(Mean; n=6) | AcceptanceCriteria(+/- 1 SD ofControl Value) |
|---|---|---|---|---|
| C1+ Saline Ctrl | 17 | na | 14.8 | 14.8 +/- 0.9 |
| C1+ Lysate (Hb) | 40 | 14.8 | 14.3 | (13.9 - 15.7) |
| C1+ Lysate (Hb) | 80 | 14.8 | 15.2 | |
| C2 + Saline Ctrl | 17 | na | 33.7 | 33.7 +/- 1.3 |
| C2 + Lysate (Hb) | 40 | 33.7 | 32.3 | (32.4 - 35.0) |
| C2 + Lysate (Hb) | 80 | 33.7 | 31.5 | |
| C3 + Saline Ctrl | 17 | na | 53.4 | 53.4 +/- 4.2 |
| C3 + Lysate (Hb) | 40 | 53.4 | 50.5 | (49.2 - 57.6) |
| C3 + Lysate (Hb) | 80 | 53.4 | 51.9 | |
| C4+ Saline Ctrl | 17 | na | 92.1 | 92.1 +/- 6.5 |
| C4+ Lysate (Hb) | 40 | 92.1 | 89.9 | (85.6 - 98.6) |
| C4+ Lysate (Hb) | 80 | 92.1 | 90.7 |
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Method Comparison
A total of 995 neonatal blood spot specimens, 980 randomly selected from a presumed normal population and 15 from patients confirmed as positive for hypothyroidism, were analyzed in-house with the GBI TSH EIA. Results were compared to those obtained using a commercially available neonatal TSH assay (Predicate). Refer to the Table below.
Comparison of Result Interpretations Obtained by the GBI TSH EIA versus a Predicate TSH EIA
| Population N=995 | GBI Results | |||||
|---|---|---|---|---|---|---|
| Published Cut-off Ranges | Normal | Borderline | Positive | |||
| < 20 | 20 - 40 | > 40 | (Row) Totals: | |||
| Predicate Results | Normal | (<20) N=974 | 967 | 7 | 0 | 974 |
| Borderline | (20-40) N=6 | 2 | 4 | 0 | 6 | |
| Positive | (>40) N=15 | 0 | 0 | 15 | 15 | |
| (Column) Totals: | 969 | 11 | 15 | 995 |
Of the 995 total blood spot samples tested, 163 results produced non-numeric values (either "less than the limit of sensitivity", n=153; or "greater than the highest standard", n=10) for one or both assays. These samples could not therefore be included in statistical analysis presented below and account for the observed difference in method comparison population "N" (995 - 163 = 832),
The method comparison results for the N=832 population were:
GBI TSH Mean = 8.9 uIU/ml, with a range of 2.4 to 114 uIU/ml, Predicate TSH Mean = 8.1 uTU/ml, with a range of 2.9 to 104 uIU/ml.
The results of linear regression analysis were:
y (GBI TSH EIA) = 1.0695x (Predicate) + 0.2671, R2 = 0.9185
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Image /page/12/Picture/1 description: The image shows the seal of the Department of Health & Human Services - USA. The seal features a stylized eagle-like symbol with flowing lines, representing the department's mission. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the symbol. The seal is presented in black and white.
Public Health Service
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Golden Bridge International, Inc. c/o Dr. Xiaoping Zhang 9700 Harbour Place, Suite 129 Mukilteo, WA 98275
APR 1 0 2008
Re: K072458
Trade/Device Name: GBI TSH Neonatal Screening Kit Regulation Number: 21 CFR 862.1690 Regulation Name: Thyroid Stimulating Hormone Test System Regulatory Class: II Product Code: JLW Dated: March 10, 2008 Received: March 12, 2008
Dear Dr. Zhang:
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 (240) 276-0490. 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 (240) 276-3150 or at its Internet address at http://www.fda.gov/cdrh/industry/support/index.html.
Sincerely yours.
Jean M. Cooper, M.S., D.V.M.
Yean M. Cooper, M.S., D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{14}------------------------------------------------
Indication for Use
510(k) Number (if known): K072458
Device Name: GBI TSH Neonatal Screening Kit
Indication For Use:
The GBI TSH Neonatal Screening Kit is designed for the quantitative determination of Thyroid Stimulating Hormone (TSH) concentrations in neonatal blood samples that have been collected onto Whatman 903 specimen collection paper. The results are used to screen newborns for congenital hypothyroidism.
Prescription Use X (21 CFR Part 801 Subpart D) And/Or
Over the Counter Use (21 CFR Part 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE; CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OVD)
Signature Off.
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K072458 = ==
§ 862.1690 Thyroid stimulating hormone test system.
(a)
Identification. A thyroid stimulating hormone test system is a device intended to measure thyroid stimulating hormone, also known as thyrotrophin and thyrotrophic hormone, in serum and plasma. Measurements of thyroid stimulating hormone produced by the anterior pituitary are used in the diagnosis of thyroid or pituitary disorders.(b)
Classification. Class II.