The Synermed Enzyme Immunoassay is intended for the qualitative and semi-quantitative determination of opiates in human urine at a cutoff value of 300 ng/mL when calibrated against morphine. The assay is designed for professional use with a number of automated clinical chemistry analyzers. This assay is for prescription use only. The semi-quantitative mode is for purposes of enabling laboratories to determine an appropriate dilution of the specimen for confirmatory method such as GCMS or permitting laboratories to establish quality control procedures.

The assay provides only a preliminary analytical result. A more specific alternative analytical chemistry method must be used in order to obtain a confirmed analytical result. Gas or Liquid Chromatography/Mass Spectrometry (GC/MS or LC/ MS) are the preferred confirmatory methods. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary test result is positive.

Device Description

The Synermed Opiate Enzyme Immunoassay is ready to use. The composition of the Synermed Opiate Enzyme Immunoassay Reagent is as follows:

Antibody/Substrate Reagent (R1): Contains mouse monoclonal anti-morphine antibody, opiate-6-phosphate (G6P), nicotinamide adenine dinucleotide (NAD), stabilizers, and sodium azide (0.09 %) as a preservative.

Enzyme-drug Conjugate Reagent (R2): Contains morphine-labeled opiate-6-phosphate dehydrogenase (G6PDH) in buffer with sodium azide (0.09 %) as a preservative.

AI/ML Overview

Acceptance Criteria and Study for Synermed Opiate Enzyme Immunoassay

This response describes the acceptance criteria and the study conducted for the Synermed Opiate Enzyme Immunoassay, based on the provided FDA 510(k) summary.

1. Table of Acceptance Criteria and Reported Device Performance

The core of the performance evaluation for this device is the demonstration of substantial equivalence to a predicate device (Lin-Zhi Opiate Immunoassay) and the validation of its performance characteristics on a new analyzer (Synermed IR-500) compared to an existing one (Hitachi 717). The primary analytical performance aspects evaluated are precision, linearity, analytical specificity, and method comparison.

Note: The document does not explicitly state numerical acceptance criteria in the typical "pass if X" format. Instead, it presents results and implies that these results meet the required performance for substantial equivalence. For the comparative data, the percentage agreement with LC/MS serves as a key performance indicator.

Acceptance Criterion (Implied)	Reported Device Performance
Precision (Qualitative and Semi-Quantitative) - Demonstrate consistent results across multiple runs and within a run for various opiate concentrations.	Qualitative Precision (Table 4): All tested concentrations (0-1000 ng/mL) showed consistent "Negative" or "Positive" results for both within-run and run-to-run, matching the expected result. Semi-Quantitative Precision (Table 3): Consistently matched "Expected Results Pos/Neg" for all tested concentrations (0-1000 ng/mL) for both within-run and run-to-run. Specific CV% and standard deviation data are mentioned as being determined but not explicitly reported in the summary tables.
Linearity/Reportable Range - Demonstrate a consistent relationship between expected and observed opiate concentrations across the measuring range.	Analytical Recovery (Table 3): Recovery values ranged from 62.0% (at 25 ng/mL) to 90.0% (at 150 ng/mL) across various concentrations (25 ng/mL to 1250 ng/mL), indicating a generally good linear response, although the exact acceptance range for recovery is not specified.
Analytical Specificity - Demonstrate no significant interference from common endogenous compounds.	Compounds tested (Acetone, Ascorbic Acid, Creatinine, Ethanol, Glucose, Hemoglobin, Human Serum Albumin, Riboflavin, Sodium Chloride, Urea) at specified concentrations showed no interference (results remained Negative for -25% Cutoff samples and Positive for +25% Cutoff samples).
Method Comparison (IR-500 vs. LC/MS) - Demonstrate high agreement with a gold standard confirmatory method (LC/MS) at and around the cutoff.	Percent Agreement with LC/MS: 91% for Positive results and 100% for Negative results.

2. Sample Size and Data Provenance for the Test Set

Precision/Reproducibility:
- Sample Size: Eleven concentrations of pooled human urine were used for opiate. Each aliquot was run in duplicate twice a day for twenty days, totaling 80 measurements at each concentration.
- Data Provenance: The data provenance is not explicitly stated beyond "pooled human urine." It is implicitly retrospective or manufactured for testing purposes, as it's a controlled laboratory study to assess device performance rather than patient data. The country of origin is not specified but is presumably the US given the FDA submission.
Linearity/Reportable Range:
- Sample Size: Ten concentrations were obtained by intermixing a high urine pool with a low urine pool. Each concentration was tested with four replicates.
- Data Provenance: Similar to precision, it's "pooled human urine," suggesting retrospective or manufactured data for a controlled study.
Analytical Specificity:
- Sample Size: A unspecified number of urine samples spiked with morphine to +/- 25% of cutoff were used, containing specific endogenous compounds.
- Data Provenance: This involves controlled laboratory spiking experiments, indicating manufactured test samples.
Comparison Studies (Method Comparison):
- Sample Size: 100 samples for opiate were tested.
- Data Provenance: "Pooled human urine" is mentioned. Given it's a comparison against LC-MSMS, these are likely retrospective samples from a laboratory setting. The country of origin is not specified but is presumably the US.

3. Number of Experts and their Qualifications for Ground Truth

The concept of "experts" as human readers/interpreters does not directly apply to this type of in-vitro diagnostic device. The ground truth is established through:

Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry (UHPLC-MSMS or LC-MSMS): This is considered the analytical "gold standard" for confirming drug concentrations in urine.
The document does not mention any human experts establishing ground truth for the test set.

4. Adjudication Method for the Test Set

Adjudication methods like 2+1 or 3+1 are typically used in imaging or pathology studies where human interpretation is involved. For this immunoassay device, the ground truth is established by a more specific alternative analytical chemistry method (LC-MSMS). There is no mention of human adjudication.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a multi-reader multi-case (MRMC) comparative effectiveness study was not conducted. This type of study is relevant for evaluating the impact of AI on human reader performance, typically in diagnostic imaging. The Synermed Opiate Enzyme Immunoassay is an in-vitro diagnostic test, not an AI-assisted diagnostic tool for human readers.

6. Standalone (Algorithm Only) Performance Study

Yes, the studies described are essentially standalone performance studies for the Synermed Opiate Enzyme Immunoassay. The device (reagents on the Synermed IR-500 analyzer) directly performs the analysis and provides a result. Its performance is evaluated independently against a gold standard (LC-MSMS) and compared to a predicate device, without direct human-in-the-loop interaction for the primary diagnostic output.

7. Type of Ground Truth Used

The ground truth used for the test set was:

Analytical Chemistry (LC-MSMS): Specifically, Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry (UHPLC-MSMS or LC-MSMS) was used to confirm target concentrations for precision, linearity, and as the comparative gold standard in the method comparison studies.

8. Sample Size for the Training Set

The document does not mention a "training set" in the context of machine learning or AI. This device is an immunoassay, which functions based on a biochemical reaction, not a machine learning algorithm that requires a training set. The various studies described (precision, linearity, specificity, comparison) serve as validation studies for the device's analytical performance.

9. How the Ground Truth for the Training Set was Established

Since there is no "training set" in the AI/ML sense, this question is not applicable. The device's operational parameters and calibration are established through standard laboratory practices and quality control using known standards and calibrators, which would have their concentrations confirmed by analytical reference methods.

Summary

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April 19, 2018

Infrared Laboratory Systems, LLC (dba Synermed) Julie Paschal Regulatory Affairs Specialist 17408 Tiller Court, Suite 1900 Westfield, IN 40674

Re: K172416

Trade/Device Name: Synermed Opiate Enzyme Immunoassay Regulation Number: 21 CFR 862.3650 Regulation Name: Opiate test system Regulatory Class: Class II Product Code: DJG Dated: February 28, 2018 Received: March 5, 2018

Dear Julie Paschal:

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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to 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 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

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803); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

Kellie B. Kelm -S

for Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K172416

Device Name Synermed Opiate Enzyme Immunoassay

Indications for Use (Describe)

Type of Use (Select one or both, as applicable)
× Prescription Use (Part 21 CFR 801 Subpart D)	Over-The-Counter Use (21 CFR 801 Subpart C)

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K172416 510(k) Summary

1. Company Information

Infrared Laboratory Systems, LLC 17408 Tiller Court Suite 1900 Westfield, Indiana 46074 Telephone; (317) 896-1565 FAX: (317) 896-1566

2. Contact Information

Julie Paschal Regulatory Affairs Specialist Telephone: 336-269-5069 Email: jpaschal@slplabs.com

1. Date Prepared: August 3rd 2017
1. Device Trade Name: Synermed Opiate Enzyme Immunoassay
1. Common Name: Opiate Enzyme Immunoassay
1. Classification Name: Enzyme Immunoassay, Opiate
1. Classification Regulation: 21CFR862.3650
1. Classification Product Code: DJG
1. Panel: Toxicology (91)

10. Reagent Device Classification:

Pro Code	Classification Regulation	Classification Name	Device Class	Panel
DJG	862.3650	Enzyme Immunoassay, Opiate	Class II	91

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11. Identification of Predicates:

K-number	Manufacturer	Product	Method
K110298	Lin-ZhiInternational	EnzymeImmunoassay,Opiate	EnzymeImmunoassay

12. Device Description

Synermed Opiate Enzyme Immunoassay

The Synermed Opiate Enzyme Immunoassay is ready to use. The composition of the Synermed Opiate Enzyme Immunoassay Reagent is as follows:

Enzyme-drug Conjugate Reagent (R2): Contains morphine-labeled opiate-6-phosphate dehydrogenase (G6PDH) in buffer with sodium azide (0.09 %) as a preservative.

Intended Use

Synermed Opiate Enzyme Immunoassay

The assay provides only a preliminary analytical result. A more specific alternative analytical chemistry method must be used in order to obtain a confirmed analytical result. Gas or Liguid Chromatography/Mass Spectrometry (GC/MS or LC/MS) are the preferred confirmatory methods. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary test result is positive.

13. Comparison of Technological Characteristics with the Predicate Device

The new device is substantially equivalent to the predicate because it has the same intended use and has the same or similar technological characteristics including safety and effectiveness. The same specimen type can be analyzed to detect the amount of absorbance which is proportional to the concentration of the analyte in the specimen.

Items
	Candidate Device: Synermed IR-500 Opiate Enzyme Immunoassay
	Predicate Device: Lin-Zhi Opiate Immunoassay

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Similarity/Difference
Intended Use	The Synermed Opiate Enzyme Immunoassay TheOpiate Enzyme Immunoassay fromImmunoassay, when used in conjunction withSynermed IR series analyzers is intended fordetermination of morphine in humanurine at a cutoff value of 300 ng/mL in urine.The assay is designed for professional use.	Same
Analyte	Morphine	Same
Specimen	Urine	Same
Cutoff	300 ng/mL	Same
Matrix	Urine	Same
Storage	2-8°C until expiration date	Same
Calibration/QC	Programmable Cal/OC	Same

15. Summary of Performance Testing

The purpose of the performance studies was to validate that the previously cleared reagents have the same performance characteristics on the proposed new analyzer (Synermed IR-500) as compared to the previously cleared Hitachi 717. The sponsor has chosen the representative analyte Opiate using urine as the representative sample matrix.

Analytical Performance

a. Precision/Reproducibility

Verification of semi-quantitative precision on the Synermed IR-500 was accomplished by implementing the study protocol laid out in NCCLS document EP05-A3, Chapter 3. Qualitative verification was accomplished by implementing the study protocol laid out in CLSI EP12-A, Chapter 7. Eleven concentrations of pooled human urine were run for opiate. Each aliquot was run in duplicate twice a day for twenty days for a total of 80 measurements at each concentration. The mean, standard deviation and coefficient of variation were determined for opiate at each concentration. For qualitative analysis, the results were compared to the expected result (negative expected results should yield negative results in the precision study). Each level of pooled human urine was confirmed by Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry, for verification chromatography refer to Appendix A: UHPLC-MSMS Raw Data.

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Table 3 – Semi-Quantitative Opiate Precision Comparison to Lin-Zhi Results (per Package Insert)

Opiate TestedConcentrations	IR-500Within-RunExpected	ResultsPos/Neg	IR-500Run-To-RunExpected	ResultsPos/Neg
0 ng/mL	-	-	-	-
75 ng/mL	-	-	-	-
150 ng/mL	-	-	-	-
225 ng/mL	-	-	-	-
300 ng/mL	+	+	+	+
375 ng/mL	+	+	+	+
450 ng/mL	+	+	+	+
525 ng/mL	+	+	+	+
600 ng/mL	+	+	+	+
800 ng/mL	+	+	+	+
1000 ng/mL	+	+	+	+

Table 4 – Qualitative Opiate Precision Comparison to Lin-Zhi Results (per Package Insert)

Opiate TestedConcentrations	Within-RunResultsPos/Neg	Run-to-RunResultsPos/Neg	ExpectedResult(Pos/Neg)
0 ng/mL	-	-	-
75 ng/mL	-	-	-
150 ng/mL	-	-	-
225 ng/mL	-	-	-
300 ng/mL	+	+	+
375 ng/mL	+	+	+
450 ng/mL	+	+	+
525 ng/mL	+	+	+
600 ng/mL	+	+	+
800 ng/mL	+	+	+
1000 ng/mL	+	+	+

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b. Linearity/Reportable Range

Linearity studies were designed using NCCLS EP06-A. Samples were prepared by intermixing a high urine pool with a low urine pool to obtain ten concentrations across the measuring range with four replicates at each concentration. The observed values were compared to the expected values and are summarized below. Each level of pooled human urine was confirmed by Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry.

"Expected" Value(ng/mL)	Mean Observed Value(ng/mL)	Recovery(%)
1250	1032.5	82.6
1100	907.3	82.5
1000	875.0	87.5
800	662.0	82.8
600	513.8	85.6
450	369.5	82.1
300	240.5	80.2
225	192.3	85.4
150	135.0	90.0
75	67.3	89.7
25	15.5	62.0
0	11.0	#DIV/0!

Table 3 - Opiate Analytical Recovery

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c. Analytical Specificity

The following endogenous compounds were spiked into urine spiked with morphine to +/- 25% of cutoff (225 and 375 ng/mL). The spiked solutions were evaluated on the IR-500. The substances listed in the following table were determined not to interfere at the concentrations tested.

Compound	Concentrationng/mL	-25% Cutoff		+25% Cutoff
		Qual	Semi-Quant	Qual	Semi-Quant
Acetone	1000	Negative	Negative	Positive	Positive
Ascorbic Acid	1500	Negative	Negative	Positive	Positive
Creatinine	500	Negative	Negative	Positive	Positive
Ethanol	1000	Negative	Negative	Positive	Positive
Glucose	3000	Negative	Negative	Positive	Positive
Hemoglobin	300	Negative	Negative	Positive	Positive
Human SerumAlbumin	500	Negative	Negative	Positive	Positive
Riboflavin	0.3	Negative	Negative	Positive	Positive
SodiumChloride	6000	Negative	Negative	Positive	Positive
Urea	6000	Negative	Negative	Positive	Positive

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d. Comparison Studies

Method comparison was performed according to CLSI EP09-A3, 100 samples for opiate were tested on the IR-500, Hitachi 717 chemistry analyzers, and Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry (LC-MSMS). The study results are summarized in the table below. Each level of pooled human urine was confirmed by Ultra High-Pressure Liquid Chromatography Tandem Mass Spectrometry, for verification chromatography refer to Appendix A: UHPLC-MSMS Raw Data.

Table 2 - IR-500 Summary of Semi-Quantitative Comparison Data vs LCMS

CandidateDeviceResults	Negative	LowNegative(< 50% of thecutoff byLC/MS)	Near CutoffNegative(50% belowthe cutoff tothe cutoff byLC/MS)	Near CutoffPositive(50% abovethe cutoff tothe cutoff byLC/MS)	PercentAgreementwith LC/MS
Positive	0	0	0	11	91%
Negative	5	19	30	4	100%

DiscrepantSample #	Drug/Metabolite LC/MS value based oncross reactivity profile	POS/NEGResult	POS/NEGResult
50	321.82 ng/mL (Morphine)	Positive	Negative
53	306.20 ng/mL (Morphine)	Positive	Negative
57	314.80 ng/mL (Morphine)	Positive	Negative
58	327.67 ng/mL (Morphine)	Positive	Negative

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16. Conclusions

The new device is substantially equivalent to the predicate because it has the same intended use and has the same or similar technological characteristics that do not raise new types of questions of safety and effectiveness.

Regulation Number and Section

§ 862.3650 Opiate test system.

(a)
Identification. An opiate test system is a device intended to measure any of the addictive narcotic pain-relieving opiate drugs in blood, serum, urine, gastric contents, and saliva. An opiate is any natural or synthetic drug that has morphine-like pharmocological actions. The opiates include drugs such as morphine, morphine glucoronide, heroin, codeine, nalorphine, and meperedine. Measurements obtained by this device are used in the diagnosis and treatment of opiate use or overdose and in monitoring the levels of opiate administration to ensure appropriate therapy.(b)
Classification. Class II (special controls). An opiate test system is not exempt if it is intended for any use other than employment or insurance testing or is intended for Federal drug testing programs. The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9, provided the test system is intended for employment and insurance testing and includes a statement in the labeling that the device is intended solely for use in employment and insurance testing, and does not include devices intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military).