(110 days)
The 1,25-Dihydroxyvitamin D 1251 RIA is a competitive equilibrium radioimmunoassay intended for the quantitative determination of 1,25 dihydroxyvitamin D (1,25-(OH)2-D) in human serum or EDTA plasma to be used to assess 1,25-(OH)2-D deficiency associated with renal disease. Assay results should be used in conjunction with other clinical and laboratory data to assist the clinician in making individual patient management decisions in adult populations.
The 1,25-Dihydroxyvitamin D 1251 RIA is a competitive radioimmunoassay intended for the quantitative determination of 1,25 Dihydroxyvitamin D (1,25-(OH)2-D) in human serum or EDTA plasma. The assay consists of a two-step procedure. Serum or plasma patient samples as well as standards and kit controls are first extracted with acetonitrile to free the 1,25-(OH)2 vitamin D2 and D3 from their vitamin D binding protein, and remove lipids that might interfere with the assay. The metabolites are then extracted by column chromatography on C18OH silica cartridges using a series of organic solvent washes. Following the extraction, the treated samples are assayed using a competitive radioimmunassay procedure. The primary antibody (rabbit anti-1,25-(OH)2 vitamin D) is highly specific for both 1,25(OH)2 vitamin D3 and 1,25(OH)2.vitamin D2. Vitamin D) is inghty specific for both 1,25(011)2 (011)2 vitamin D tracer Daring the binding sites on the primary antibody. Separation of bound and unbound vitamin D2 or D3 is accomplished using a goat anti-rabbit (GAR) polyethylene glycol precipitating complex. After an incubation and centrifugation, sample precipitates are proofitaing complex. The amount of radioactivity in the precipitate is inversely proportional to the concentration of 1,25-(OH)2 vitamin D in the sample. Values are proportional to the coma standard curve of known calibrators and expressed as pg/ml.
Here's an analysis of the provided text regarding the acceptance criteria and study for the 1,25-Dihydroxyvitamin D 1251 RIA Kit.
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state "acceptance criteria" in a typical quantitative pass/fail format. Instead, it presents performance characteristics (reproducibility and distinct reference ranges) that effectively serve as evidence of the device's suitability for its intended use. For this exercise, I will infer the implied acceptance criteria from the reported performance.
| Performance Metric | Inferred Acceptance Criteria (Implicit) | Reported Device Performance |
|---|---|---|
| Reference Ranges | Distinct 1,25-(OH)2-D values for healthy normals and End-Stage Renal Disease (ESRD) patients. | Normals (n=123): Mean 43.9 pg/mL, Range 19.8-68.0 pg/mL (2 SD of 24.1) ESRDs (n=87): Range 1.6-17.3 pg/mL Conclusion: Reference ranges are "fully distinct," indicating effective discrimination. |
| Sample Equivalency (Frozen vs. Fresh) | No statistically significant difference (p > 0.05) between frozen and fresh samples. | Normals (Frozen n=72, Fresh n=51): Mean Frozen 43.2, Mean Fresh 44.8, ANOVA p=0.49 ESRDs (Frozen n=70, Fresh n=17): Mean Frozen 6.1, Mean Fresh 5.3, ANOVA p=0.29 Conclusion: No significant difference. |
| Reproducibility (DiaSorin Lab) | Acceptable Within-run, Between Day, and Total %CVs for low, mid, and high concentration samples. | Low (25.8 pg/mL): Within-run %CV 6.8, Between Day %CV 14.6, Total %CV 15.3 Mid (41.3 pg/mL): Within-run %CV 7.7, Between Day %CV 11.1, Total %CV 12.3 High (105.2 pg/mL): Within-run %CV 11.3, Between Day %CV 11.2, Total %CV 13.7 |
| Reproducibility (Clinical Trial - Human Serum Samples) | Acceptable %CVs for low, mid, and high concentration human serum-based samples across multiple sites. | Low (24.2 pg/mL): %CV 16.2 Mid (41.0 pg/mL): %CV 14.1 High (97.7 pg/mL): %CV 11.6 |
| Reproducibility (Clinical Trial - Kit Controls) | Acceptable %CVs for Kit Control 1 and Kit Control 2 across multiple sites. | Kit Control 1 (25.6 pg/mL): %CV 13.7 (total across 3 sites) Kit Control 2 (65.2 pg/mL): %CV 12.4 (total across 3 sites) |
2. Sample Sizes Used for the Test Set and Data Provenance
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Reference Ranges Study (Implicit Test Set):
- Normals: 123
- ESRDs: 87
- Data Provenance: Clinical trial conducted at "three independent clinical laboratories." The country of origin is not specified, but the submission is to the FDA, suggesting it's likely US-based or at least compliant with US regulatory standards. The data is prospective, collected during the clinical trial for the purpose of demonstrating the device's performance.
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Sample Equivalency Study (Frozen vs. Fresh):
- Normals: 72 (Frozen) + 51 (Fresh) = 123
- ESRDs: 70 (Frozen) + 17 (Fresh) = 87
- Data Provenance: Same as above, presumed prospective from the clinical trial.
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Reproducibility Studies (Test Sets for Precision):
- DiaSorin Lab: 25 per sample type (Low, Mid, High)
- Clinical Trial (Human Serum Samples): 16 per sample type (Low, Mid, High)
- Clinical Trial (Kit Controls): 19 for Control 1, 18 for Control 2 (across three sites).
- Data Provenance: DiaSorin Inc. laboratory (in-house) and three independent clinical laboratories (clinical trial). All are prospective data generation.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
This type of in-vitro diagnostic (IVD) device, which quantitatively measures a biomarker, does not typically rely on "experts" to establish ground truth in the same way an imaging AI might. Instead, the "ground truth" for quantitative assays is the assigned concentration of the analyte in calibrators and controls, and the known clinical status (healthy vs. ESRD) of the patient samples.
- Number of 'Experts': Not applicable in the sense of human interpretation.
- Qualifications of Experts: Not applicable. The "ground truth" is derived from the established methods of preparing and characterizing assay standards and controls, and clinical diagnosis of the patient populations.
4. Adjudication Method for the Test Set
Not applicable. As a quantitative immunoassay, there is no subjective adjudication of results. The results are numerical values. The clinical status of patients (normality vs. ESRD) is presumably based on standard diagnostic criteria, not an adjudication process specified here for the device's output.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance
Not applicable. This is an in-vitro diagnostic assay (RIA kit) for measuring a biomarker, not an imaging or interpretive AI device that assists human readers.
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 device (RIA kit) produces quantitative results (pg/mL of 1,25-(OH)2-D) directly. The performance studies (reference ranges, equivalency, reproducibility) demonstrate the accuracy and precision of these direct measurements. While clinicians use these results for patient management, the device itself operates "standalone" in providing the measurement.
7. The Type of Ground Truth Used
The ground truth for this device's performance assessment relies on:
- Assigned Concentrations: For calibrators and controls, the "ground truth" is the known, pre-defined concentration of 1,25-(OH)2-D in these materials.
- Clinical Diagnosis: For the reference range studies, the "ground truth" for patient populations is their established clinical status (e.g., "apparently healthy normal donors" vs. "patients with end-stage renal disease (ESRD)"). This clinical diagnosis serves as the label for demonstrating the device's ability to discriminate between these groups.
8. The Sample Size for the Training Set
The document does not explicitly mention a "training set" in the context of machine learning or AI. This is a traditional IVD device, not an AI/ML product. The assay's parameters (e.g., antibody specificity, incubation times, standard curve generation) are developed and optimized through assay development rather than through a formal "training set" as understood in AI. The standard curve itself, derived from five levels of human serum-based standards, could be considered analogous to a small training set for calibrating each run, but it's not a general training set for an algorithm.
9. How the Ground Truth for the Training Set Was Established
Not applicable in the AI/ML context. For the instrument's calibration (which is similar to training its measurement curve), the ground truth for the five serum-based standards is established by precisely formulating them with known concentrations of 1,25-(OH)2-D or through comparison to a reference method, although the latter is not detailed here.
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APPENDIX E
As required by 21 CFR 807.3, a summary of the 510(k) safety and effectiveness information contained in this submission is provided as Appendix E.
510(k) SUMMARY
SUBMITTED BY:
Diana Clive DiaSorin, Inc. 1951 Northwestern Ave. P.O. Box 285 Stillwater, MN 55082-0285 (651) 351-5582 voice (651) 351-5669 fax November 30, 2001
This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.
NAME OF DEVICE: Trade Name:
1,25-Dihydroxyvitamin D 1251 RIA
Common Names/Descriptions:
the the Immunoassay for quantitative determination of 1,25 dihydroxyvitamin D (1,25-(OH)2-D)
Classification Name:
Vitamin D test system
PREDICATE DEVICE:
DiaSorin 25-Hydroxyvitamin D 1251 RIA
The 1,25-Dihydroxyvitamin D 1251 RIA assay is a competitive INTENDED USE: equilibrium radioimmunoassay intended for the quantitative determination of 1,25 dihydroxyvitamin D (1,25-(OH)2-D) in human serum or EDTA plasma to be used to assess 1,25-(OH)2-D deficiency associated with renal disease. Assay results should be used in conjunction with other clinical and laboratory data to assist the clinician in making individual patient management decisions in adult populations.
DEVICE DESCRIPTION: The 1,25-Dihydroxyvitamin D 1251 RIA is a competitive radioimmunoassay intended for the quantitative determination of 1,25 Dihydroxyvitamin D (1,25-(OH)2-D) in human serum or EDTA plasma. The assay consists of a two-step procedure. Serum or plasma patient samples as well as standards and kit controls are first extracted with acetonitrile to free the 1,25-(OH)2 vitamin D2 and D3 from their vitamin D binding protein, and remove lipids that might interfere with the assay. The metabolites are then extracted by column chromatography on C18OH silica cartridges using a series of organic solvent washes. Following the extraction, the treated samples are assayed using a
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competitive radioimmunassay procedure. The primary antibody (rabbit anti-1,25-(OH)2 vitamin D) is highly specific for both 1,25(OH)2 vitamin D3 and 1,25(OH)2.vitamin D2. Vitamin D) is inghty specific for both 1,25(011)2 (011)2 vitamin D tracer Daring the binding sites on the primary antibody. Separation of bound and unbound vitamin D2 or D3 is accomplished using a goat anti-rabbit (GAR) polyethylene glycol precipitating complex. After an incubation and centrifugation, sample precipitates are proofitaing complex. The amount of radioactivity in the precipitate is inversely proportional to the concentration of 1,25-(OH)2 vitamin D in the sample. Values are proportional to the coma standard curve of known calibrators and expressed as pg/ml.
| Feature | 25-OH-D | 1,25-(OH)2-D |
|---|---|---|
| Intended Use | FOR IN VITRO DIAGNOSTIC USE.This kit is intended for the quantitativedetermination of 25-hydroxyvitamin D(25-OH-D) and other hydroxylatedvitamin D metabolites in human serumor plasma to be used in the assessmentof vitamin D sufficiency. Assayresults should be used in conjunctionwith other clinical and laboratory datato assist the clinician in makingindividual patient managementdecisions in an adult population. | FOR IN VITRO DIAGNOSTIC USE.This kit is intended for the quantitativedetermination of 1,25-dihydroxy-vitamin D (1,25-(OH)2-D) in humanserum or EDTA plasma to be used toassess 1,25-(OH)2-D deficiencyassociated with renal disease. Assayresults should be used in conjunctionwith other clinical and laboratory datato assist the clinician in makingindividual patient managementdecisions in adult populations. |
| Assay Type | RIA | RIA |
| AcetonitrileExtraction | For isolation of 25-(OH)-D | For isolation of 1,25-(OH)2-D |
| Antiserum | Polyclonal specific for 25-(OH)-D2/D3 | Polyclonal specific for 1,25-(OH)2-D2/D3 |
| Tracer | 125I radiolabeled 25-(OH)-D analog | 125I radiolabeled 1,25-(OH)2-D3 analog |
| PrecipitatingComplex | 20 minute incubation at 20-25° C withsecond antibody precipitating complex | 20 minute incubation at 20-25° C withsecond antibody precipitating complex |
| Kit Controls | Two levels, human serum based,extracted identical to standards andpatient samples. | Two levels, human serum based,extracted identical to standards andpatient samples. |
| Standards | Five levels, human serum based,extracted identical to controls andpatient samples. | Five levels, human serum based,extracted identical to controls andpatient samples. |
TECHNOLOGICAL COMPARISON TO PREDICATE:
PERFORMANCE DATA: A clinical trial was conducted at three independent clinical laboratories. Serum values for 1,25(OH)2-vitamin D were collected from two distinct populations: apparently healthy normal donors, and patients with end-stage renal disease (ESRD). Reference ranges established in the trial are summarized below.
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| All Sites | 1,25(OH)2D (pg/mL) | |||
|---|---|---|---|---|
| Population | n | Mean | 2 SD | Range |
| Normals | 123 | 43.9 | 24.1 | 19.8-68.0 |
| ESRD's | 87 | 1.6-17.3 |
The equivalency of assay samples as either fresh serum or serum that has been frozen and The equivalely of about bangles mory table with 95% ANOVA determined P-values is presented below.
| Normals | ESRD's | |||
|---|---|---|---|---|
| Frozen | Fresh | Frozen | Fresh | |
| N | 72 | 51 | 70 | 17 |
| Mean | 43.2 | 44.8 | 6.1 | 5.3 |
| ANOVA | 0.49 | 0.29 |
Reproducibility was established both at DiaSorin and during the clinical trial. Three human serum-based samples with 1,25-(OH)2-D concentrations distributed across the numan berain based calliples with 5 assay days at DiaSorin, spanning more than 60 Multiple technicians, as well as multiple lot numbers for all operating days. operaing were included. The combined results were evaluated by analysis of variance (ANOVA) and are summarized in the following table.
| Within-run | Between Day | Total | ||||||
|---|---|---|---|---|---|---|---|---|
| Sample | n | Mean(pg/mL) | S.D. | %C.V. | S.D. | %C.V. | S.D. | %C.V. |
| Low | 25 | 25.8 | 1.76 | 6.8 | 3.8 | 14.6 | 4.0 | 15.3 |
| Mid | 25 | 41.3 | 3.16 | 7.7 | 4.6 | 11.1 | 5.1 | 12.3 |
| High | 25 | 105.2 | 11.86 | 11.3 | 11.8 | 11.2 | 14.4 | 13.7 |
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These identical human serum-based controls were assayed during a clinical trial conducted at three different laboratories, over 16 different assays, spanning more than 110 days. The combined results from all three sites are summarized below.
| Sample | n | Mean(pg/mL) | S.D. | %CV |
|---|---|---|---|---|
| Low | 16 | 24.2 | 3.9 | 16.2 |
| Mid | 16 | 41.0 | 5.8 | 14.1 |
| High | 16 | 97.7 | 11.3 | 11.6 |
Similarly, kit controls included with each kit were included in each of the 16 assays The following table above, as prescribed in the package insert instructions. summarizes the precision of the controls over the course of the clinical trial.
| Site A | Site B | Site C | Total | ||
|---|---|---|---|---|---|
| Kit Control 1 | n | 7 | 4 | 8 | 19 |
| Mean | 24.7 | 27.2 | 25.5 | 25.6 | |
| SD | 3.1 | 3.3 | 4.0 | 3.5 | |
| %CV | 12.5 | 12.2 | 15.8 | 13.7 | |
| Kit Control 2 | n | 7 | 4 | 7 | 18 |
| Mean | 66.2 | 59.9 | 67.2 | 65.2 | |
| SD | 5.1 | 4.2 | 11.1 | 8.1 | |
| %CV | 7.8 | 7.1 | 16.6 | 12.4 |
The data collected during the clinical trial described above fully CONCLUSION: substantiates the intended use of the 1,25-Dihydroxyvitamin D 1251 RIA. Reference ranges established for both a healthy population and one with end stage renal disease are fully distinct. This indicates that the DiaSorin 1,25-Dihydroxvitamin D 131 RIA can effectively discriminate between the two populations based on 1,25-(OH)2-D serum values. Assay results can be used to assess 1,25-(OH)2-D deficiency associated with renal disease.
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Image /page/4/Picture/2 description: The image shows the logo for the Department of Health & Human Services. The logo consists of a circular border with the text "DEPARTMENT OF HEALTH & HUMAN SERVICES USA" arranged around the perimeter. Inside the circle is a stylized symbol featuring three abstract shapes that resemble a person or a bird in flight. The shapes are layered on top of each other, creating a sense of movement and depth.
MAR 2 6 2002
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
Mr. David M. Ikeda Manager, Regulatory Affairs and Quality Systems DiaSorin Inc. 1990 Industrial Blvd. P.O. Box 285 Stillwater, MN 55082-0285
Re: K014030
Trade/Device Name: 1,25-Dihydroxyvitamin D 1251 RIA Kit Regulation Number: 21 CFR 862.1825 Regulation Name: Vitamin D test system Regulatory Class: Class II Product Code: MRG Dated: February 18, 2002 Received: February 20, 2002
Dear Mr. Ikeda:
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 the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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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 1 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" (21CFR 807.97). Other general information on your responsibilities under the Act may be obtained 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 Butman
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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INDICATIONS FOR USE
510(k) Number (if known):
Device Name:
1,25-Dihydroxyvitamin D 1251 RIA Kit
Indications For Use:
The 1,25-Dihydroxyvitamin D 1251 RIA is a competitive equilibrium radioimmunoassay intended for the quantitative determination of 1,25-dihydroxyvitamin D (1,25-(OH)2-D) in human serum or EDTA plasma to be used to assess 1,25-(OH)2-D deficiency associated with renal disease. Since hydroxylation of circulating 25-hydroxyvitamin D to the biologically active form 1,25-(OH)2-D occurs in the kidney, renal disease may result in reduced levels of 1,25-(OH)2-D and compromised calcium metabolic homeostasis. Assay results should be used in conjunction with other clinical and laboratory data to assist the clinician in making individual patient management decisions in adult populations.
(PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (ODE)
Division Sign-Off
Carol C. Benson for Jean Cooper
vision of Clinical Laboratory D 510fki Number Prescription Use: the-Counter Use: (Per 21 CFR 801.109)
§ 862.1825 Vitamin D test system.
(a)
Identification. A vitamin D test system is a device intended for use in clinical laboratories for the quantitative determination of 25-hydroxyvitamin D (25-OH-D) and other hydroxylated metabolites of vitamin D in serum or plasma to be used in the assessment of vitamin D sufficiency.(b)
Classification. Class II (special controls). Vitamin D test systems must comply with the following special controls:(1) Labeling in conformance with 21 CFR 809.10 and
(2) Compliance with existing standards of the National Committee on Clinical Laboratory Standards.