(162 days)
An enzyme immunoassay for the quantitative in vitro diagnostic measurement of active free cortisol (hydrocortisone and hydroxycorticosterone) in saliva. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.
The DRG Salivary Cortisol ELISA KIT is based on the competition principle and the microplate separation. An unknown amount of Cortisol present in the sample and a fixed amount of Cortisol coniugated with horseradish peroxidase compete for the binding sites of mouse polyclonal Cortisol-antiserum coated onto the wells. After one hour incubation the microplate is washed to stop the competition reaction. After addition of the TMB substrate solution the concentration of Cortisol is inversely proportional to the optical density measured.
Here's an analysis of the provided text regarding the DRG Salivary Cortisol ELISA, focusing on acceptance criteria and study details:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are implied through the performance data presented, as explicit criteria (e.g., "must achieve X correlation") are not stated. The performance is reported against other commercially available methods or standard analytical techniques.
| Performance Metric | Implied Acceptance Criteria (Based on context) | Reported Device Performance |
|---|---|---|
| Method Comparison (vs. LIA) | High correlation (e.g., >0.85) | 0.872 (Study 1, n=114) |
| High correlation (e.g., >0.95) for expanded study | 0.9795 (Expanded Study 1, n=40) | |
| Method Comparison (vs. EIA) | High correlation (e.g., >0.90) | 0.936 (Study 2, n=72) |
| High correlation (e.g., >0.95) for expanded study | 0.9920 (Expanded Study 2, n=40) | |
| Method Comparison (vs. LC-MS) | High correlation (e.g., >0.85) | 0.89056 (Study 3, n=28) |
| Sensitivity (Lowest Detectable Limit) | As low as reasonably achievable for clinical utility (no specific numerical criterion given) | 0.537 ng/mL or 0.0537 ug/dl at 95% confidence limit |
| Specificity (Cross-Reactivity) | Low cross-reactivity with structurally similar compounds | Cortisol: 100%, Corticosterone: 29.00%, Cortisone: 3.00%, most others <1% or <0.5% |
| Intra-Assay Reproducibility (CV) | Low CV (typically <10-15%) | Data missing for this section in the provided text. |
| Inter-Assay Reproducibility (CV) | Low CV (typically <15-20%) | 7.47% (24.29 ng/mL mean), 5.82% (40.85 ng/mL mean) |
| Inter-Lot Reproducibility (CV) | Low CV (typically <15-20%) | Data missing for this section in the provided text. |
| Recovery | % Recovery within a generally accepted range (e.g., 80-120%) | Range of 90.1% to 108.8% across various spiked samples and concentrations. |
| Linearity (% Recovery) | % Recovery within a generally accepted range (e.g., 80-120%) | Average % Recovery: Sample 1: 107.0%, Sample 2: 99.1%, Sample 3: 97.5%. Range of % Recovery: Sample 1: 101.1-114.0%, Sample 2: 97.8-99.6%, Sample 3: 92.4-104.4% |
2. Sample Size Used for the Test Set and Data Provenance
The "test set" in this context refers to the samples used for method comparison and performance evaluation.
- Normal Range Study: 109 saliva samples. Adult male and female apparently healthy subjects, ages 20 to 80 years. Morning collection. (Provenance not specified, but likely domestic to DRG International, Inc. in NJ, USA, or related clinical sites). Prospective in nature.
- Method Comparison (Study 1 vs. LIA): 114 saliva samples. Subjects ages 40 to 70 years. (Provenance not specified). Retrospective implied as samples were "run".
- Method Comparison (Study 2 vs. EIA): 72 saliva samples. Men ages 40 to 70 years. (Provenance not specified). Retrospective implied.
- Method Comparison (Study 3 vs. LC-MS): 28 saliva samples. (Provenance not specified). Retrospective implied.
- Expanded Method Comparison (Study 1 vs. LIA): 40 saliva samples. Subjects ages 25-65 years. (Provenance not specified). Retrospective implied.
- Expanded Method Comparison (Study 2 vs. EIA): 40 saliva samples. Men and women ages 25-65 years. (Provenance not specified). Retrospective implied.
- Sensitivity: This is typically an in-vitro measurement using dilutions of known concentrations, not patient samples.
- Specificity: In-vitro evaluation of various steroid compounds.
- Reproducibility (Intra- and Inter-Assay): 4 saliva samples for intra-assay; commercial control samples for inter-assay.
- Reproducibility (Inter-Lot): 5 saliva samples.
- Recovery: 3 saliva samples with endogenous cortisol spiked with known amounts.
- Linearity: 3 saliva samples serially diluted.
The provenance regarding country of origin is not explicitly stated for any of the patient samples, but given the manufacturer's location, US-based samples are a reasonable assumption for a US regulatory submission. All studies appear to be retrospective analyses of collected samples.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts
This type of diagnostic device (ELISA kit for cortisol) doesn't typically rely on human expert interpretation of images or complex data for "ground truth" in the way an AI imaging device would. Instead, the ground truth for method comparison studies is established by:
- Reference method: Commercial LIA, EIA, and LC-MS methods. These methods are themselves established, and their results are treated as the "ground truth" for comparison.
- Known concentrations: For sensitivity, specificity, recovery, and linearity studies, known concentrations of cortisol or interfering substances are used.
Therefore, the concept of "experts establishing ground truth for the test set" is not directly applicable in the same way as for subjective diagnostic tasks. The performance is compared against existing, validated analytical methods.
4. Adjudication Method for the Test Set
Not applicable. As explained above, the "ground truth" for this type of device is established through comparison with recognized analytical methods or known sample concentrations, not through expert adjudication of subjective findings.
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 ELISA kit, a laboratory diagnostic test measuring a biochemical marker. It does not involve human "readers" or "AI assistance" in the interpretation of complex data (like medical images) where MRMC studies are relevant.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) was Done
This is an in vitro diagnostic (IVD) kit. Its performance is inherently standalone, in that it provides a quantitative result based on the chemical reaction. There's no "human-in-the-loop" component in the interpretation of the raw assay signal (optical density) to derive the cortisol concentration once the assay is run and the standard curve is established. The device itself is the "algorithm only" (chemical reaction and measurement) to produce the result.
7. The Type of Ground Truth Used
The ground truth for the performance studies was primarily established by:
- Reference analytical methods: Commercially available LIA (Luminescence Immunoassay) and EIA (Enzyme Immunoassay) methods, and a reference LC-MS (Liquid Chromatography-Mass Spectrometry) method.
- Known concentrations: For sensitivity, specificity (known cross-reactants), recovery (spiked samples with known added cortisol), and linearity (serum samples with known dilutions).
8. The Sample Size for the Training Set
This document describes a premarket notification (510(k)) for a traditional IVD device. The language "training set" is typically associated with machine learning or AI algorithm development. For an ELISA kit, there isn't a "training set" in that sense. The kit's reagents, protocols, and standard curve parameters are developed through R&D experiments and optimization processes, but this is not typically referred to as a "training set" for an algorithm. The reported studies (method comparison, reproducibility, etc.) are essentially validation studies for the finalized product.
9. How the Ground Truth for the Training Set Was Established
As there isn't a "training set" for an algorithm in the AI sense, this question is not directly applicable. The "ground truth" for the development and optimization of the ELISA kit would involve established biochemical principles and highly controlled experiments using known concentrations of cortisol and other substances, likely following established laboratory practices for assay development.
{0}------------------------------------------------
DEC 7 2005
SUMMARY OF SAFETY AND EFFECTIVENESS FOR DRG SALIVARY CORTISOL ELISA
| Manufacturer: | DRG International, Inc.1167 U.S. Highway 22Mountainside, NJ 07092 |
|---|---|
| Contact Information: | Lehnus & AssociatesGary Lehnus150 Cherry Lane Rd.East Stroudsburg, PA 18301Tel: (570) 620-0198 |
Device Name / Classification:
The device trade name is the DRG SLV Cortisol ELISA having FDA assigned name: Cortisol test system, 21 CFR, 862.1205, categorized as Class II medical devices for the Clinical Chemistry and Clinical Toxicology Panel, as Product Code NHG.
Test Principle
The DRG Salivary Cortisol ELISA KIT is based on the competition principle and the microplate separation. An unknown amount of Cortisol present in the sample and a fixed amount of Cortisol coniugated with horseradish peroxidase compete for the binding sites of mouse polyclonal Cortisol-antiserum coated onto the wells. After one hour incubation the microplate is washed to stop the competition reaction. After addition of the TMB substrate solution the concentration of Cortisol is inversely proportional to the optical density measured.
Device Intended Use:
An enzyme immunoassay for the quantitative in vitro diagnostic measurement of active free cortisol (hydrocortisone and hydroxycorticosterone) in saliva. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.
Device Performance
Normal Range Study
In order to determine the normal range of SLV cortisol, 109 saliva samples from adult male and female apparently healthy subjects, ages 20 to 80 years, were collected in the morning and analyzed using the DRG SLV Cortisol ELISA kit. The following range was calculated from this study.
0.12 - 1.47 µg/dL or 1.2 - 14.7 ng/mL (AM collection) Adults:
Method comparison
Studies were performed to compare the DRG SLV Cortisol test to commercially available tests. One study evaluated saliva samples from 114 subjects ages 40 to 70 years. The samples were run in duplicate on the DRG test and another commercially available LIA method to determine the concentration of Cortisol in the samples. A correlation of 0.872 was obtained versus this method.
A second study was performed using saliva samples from seventy-two (72) saliva samples collected from 40 - 70 year old men and run in duplicate on DRG
{1}------------------------------------------------
and another commercially available EIA test. A correlation of 0.936 was observed compared to another EIA method.
Another study was performed comparing 28 saliva samples to a reference LC-MS method. A correlation of r = 0.89056 with a formula of y = 1.0144x + 1.7762 was obtained to this method.
To further demonstrate substantial equivalence of the DRG SLV test, additional expanded comparison studies were requested. One expanded study evaluated saliva samples from 40 subjects ages 25 - 65 years. The samples were run in duplicate on the DRG test and another commercially available LIA method to determine the concentration of Cortisol in the samples. An overall correlation of 0.9795 and a regression formula of y = 0.9588x - 0.0338 was obtained versus this method.
A second expanded study was performed using 40 saliva samples collected from men and women ages 25 - 65 years and run in duplicate on DRG and another commercially available EJA test. A correlation of 0.9920 with a regression formula of y = 1.0722x + 0.1482 was observed compared to another EIA method.
The DRG Cortisol ELISA test demonstrated equivalent performance to commercially available ELISA and LIA methods for detection of Cortisol in saliva.
Sensitivity
The lowest detectable level of Cortisol that can be distinguished from the Zero Standard is 0.537 ng/mL or 0.0537 ug/dl at the 95 % confidence limit.
Specificity
The following materials have been evaluated for cross reactivity. The percentage indicates cross reactivity at 50% displacement compared to Cortisol.
| Steroid | % Crossreaction |
|---|---|
| Cortisol | 100% |
| Corticosterone | 29.00% |
| Cortisone | 3.00% |
| 11-Deoxycortisol | < 1,00% |
| 17-OH Progesterrone | < 0,50% |
| Prednisone | <0,10% |
| Progesterone | < 0,10% |
| Dexamethazone | < 0,10% |
| Desoxycorticosterone | < 0,10% |
| Dehydroepiandrosteronesulfate | < 0,10% |
| Estradiol | < 0,10% |
| Estriol | < 0,10% |
| Estrone | < 0,10% |
| Testosterone | < 0,10% |
Reproducibility
Intra-Assay
The intra-assay variation was determined by replicate measurements of 4 saliva samples using DRG ELISA kit. The within assay variability is shown below:
{2}------------------------------------------------
| Mean | 1 M | |||
|---|---|---|---|---|
| ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | 1 | |||
| A . A . A- | and announce and subscribed144 | A 16 | C |
Inter-Assay
The inter-assay (between-run) variation was determined by quadruplicate measurements of commercial control samples in three different days runs.
| Mean | 24.29 ng/mL | 40.85 ng/mL |
|---|---|---|
| SD | 1.81 ng/mL | 2.38 ng/mL |
| CV (%) | 7.47 | 5.82 |
| n= | 12 | 12 |
Inter-Lot
The Inter-Lot (between-lot) variation was determined by duplicate measurements of five saliva samples in three different kit lots. The between run variability is shown below.
| A ST REAL PROPERTY STATUS STATES------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | 100 000 | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | THE COLLECTION COLLEGIONAL | ||
|---|---|---|---|---|---|
| and and a chambre a program and services and services and services and services and any and | A BREAK TO CONTRACT TO | and and consisted and second and contrôleand comes and come a many as a many a | Parties - Station - Station - Station - Station - Station - Station - Station - Province - Province - Province - Province - Province - Province - Province - Province - Provin | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | |
| 4.0 | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | THE T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------of Cattle. The labor of the | ||
| Compress Top of Cat and States and | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------A 16 September 2011 September 2011 | THE THE PERSONAL CONNECT CALL CONTRACT COLLEGION | State Standard States And States |
Recovery
Recovery of the DRG ELISA was determined by adding increasing amounts of the analyte to three different saliva samples containing different amounts of endogenous analyte. Each sample (non-spiked and spiked) was assayed and analyte concentrations of the samples were calculated from the standard curve. The percentage recoveries were determined by comparing expected and measured values of the samples
| Sample | Endogenouscortisolng/ml | Addedcortisolng/ml | Measured ODmean of duplicate(450 nm) | Measured Conc.SLV cortisolng/ml | Expectedconcng/ml | Recovery(%) |
|---|---|---|---|---|---|---|
| 1 | 0.90 | 0.00 | 1.284 | 0.90 | ||
| 40.00 | 0.175 | 38.74 | 40.90 | 94.7 | ||
| 20.00 | 0.262 | 22.45 | 20.90 | 107.4 | ||
| 10.00 | 0.421 | 11.50 | 10.90 | 105.5 | ||
| 5.00 | 0.608 | 6.42 | 5.90 | 108.8 | ||
| 2 | 8.37 | 0.00 | 0.518 | 8.37 | ||
| 40.00 | 0.160 | 43.57 | 48.37 | 90.1 | ||
| 20.00 | 0.225 | 27.59 | 28.37 | 97.3 | ||
| 10.00 | 0.321 | 17.00 | 18.37 | 92.5 | ||
| 5.00 | 0.367 | 14.07 | 13.37 | 105.2 | ||
| 3 | 14.60 | 0.00 | 0.357 | 14.61 | ||
| 40.00 | 0.144 | 50.31 | 54.61 | 92.1 | ||
| 20.00 | 0.187 | 35.55 | 34.60 | 102.7 | ||
| 10.00 | 0.246 | 24.52 | 24.60 | 99.7 | ||
| 5.00 | 0.279 | 20.60 | 19.60 | 105.1 |
{3}------------------------------------------------
Linearity
Three samples (saliva) containing different amounts of analyte were serially diluted to 1:64 with zero standard and assayed with the DRG ELISA. The percentage recovery was calculated by comparing the expected and measured values for SLV cortisol. An assay linearity of 0.537 - 77 ng/mL has been identified as the usable range. Samples above this range must be diluted and re-run.
| Sample 1 | Sample 2 | Sample 3 | ||
|---|---|---|---|---|
| Concentr. | ng/ml | 33.13 | 80.00 | 23.23 |
| Average % Recovery | 107.0 | 99.1 | 97.5 | |
| Range of | from | 101.1 | 97.8 | 92.4 |
| % Recovery | to | 114.0 | 99.6 | 104.4 |
{4}------------------------------------------------
Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three stripes forming its wing and tail feathers. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the eagle.
Public Health Service
Food and Drug Administration 2098 Gaither Road Rockville MD 20850
DEC 7 2005
DRG International, Inc. c/o Mr. Gary Lehnus Lehnus & Associates 150 Cherry Lane Rd. East Stroudsburg, PA 18301
Re: K051733
Trade/Device Name: DRG Salivary Cortisol ELISA test Regulation Number: 21 CFR 864.1205 Regulation Name: Cortisol (hydrocortisone and hydroxycorticosterone) test system Regulatory Class: Class II Product Code: NHG Dated: November 16, 2005 Received: November 21, 2005
Dear Mr. Lehnus:
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).
{5}------------------------------------------------
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 promated 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) 276-0484. 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/industry/support/index.html.
Sincerely yours,
Alberto Guts
Alberto Gutierrez, Ph.D. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{6}------------------------------------------------
Indications for Use
510(k) Number (if known):
Device Name: _________________________________________________________________________________________________________________________________________________________________
Indications For Use:
An enzyme immunoassay for the quantitative in vitro diagnostic measurement of active free All Che Immanoused Trenvroxycorticosterone) in saliva. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.
Prescription Use X (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use _________________________________________________________________________________________________________________________________________________________ (21 CFR 801 Subpart C)
(Please DO NOT WRITE BELOW THIS LINE - CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of Device Evaluation (OIVD)
Division Sign-Off
Division Sign-Off
Office of In Vitro Diagnostic Ice Evaluation and Safety
510(k) K051733
Page 1 of _1
§ 862.1205 Cortisol (hydrocortisone and hydroxycorticosterone) test system.
(a)
Identification. A cortisol (hydrocortisone and hydroxycorticosterone) test system is a device intended to measure the cortisol hormones secreted by the adrenal gland in plasma and urine. Measurements of cortisol are used in the diagnosis and treatment of disorders of the adrenal gland.(b)
Classification. Class II.