(244 days)
The Neobase Non-derivatized MSMS reagent kit (for use on the PerkinElmer TQD MSMS Screening System) is intended for the measurement and evaluation of amino acids, succinylacetone, free carnitine, and acylcarnitine concentrations from newborn heel prick blood samples dried on filter paper. Quantitative analysis of these analytes (Table 1) and their relationship with each other is intended to provide analyte concentration profiles that may aid in screening newborns for metabolic disorders.
The measurement of amino acids, succinylacetone, free carnitine, and acylcarnitines with the NeoBase assay involves extraction of dried blood spots from newborns with a solution containing stable-isotope labeled internal standards and analysis using a tandem mass spectrometry (MSMS) system. The each analyte relative to their response of internal stable-isotope labeled corresponding standard is proportional to analyte concentration.
The device being described is the NeoBase Non-derivatized MSMS Kit, intended for the measurement and evaluation of amino acid, succinylacetone, free carnitine, and acylcarnitine concentrations from newborn heel prick blood samples dried on filter paper. This quantitative analysis aids in screening newborns for metabolic disorders.
The study presented is a non-clinical study comparing the performance of the NeoBase Non-derivatized MSMS kit on the PerkinElmer TQD Triple Quadrupole Mass Spectrometer System (PerkinElmer TQD platform) against its predicate devices, the MS2 and PerkinElmer Quattro Micro platforms (QMicro). The goal was to demonstrate substantial equivalence.
Here's the breakdown of the acceptance criteria and study information:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" as a set of predefined thresholds. Instead, it demonstrates equivalence to predicate devices by showing comparable performance characteristics. The key performance metrics evaluated were:
- Precision (Imprecision Percent Coefficient of Variation - %CV): Lower %CV indicates higher precision.
- Recovery (Mean % Recovery and 95% Confidence Interval): Indicates the accuracy of analyte measurement.
- Measurable Ranges: The range over which the device can accurately quantify analytes, ensuring coverage of clinically significant levels.
- Method Correlation (Ratio of Measured Concentration): Comparing the TQD platform with predicate devices (MS2 and QMicro). A ratio of 1.0 indicates equivalent concentration measurements.
- Clinical Correlation (Percent Agreement in clinical determinations): How well the TQD platform agrees with predicate platforms in classifying samples above or below clinical cutoffs.
- Detection of True Positive Samples: The ability of the device to correctly identify known positive cases.
Here's a summary of the reported device performance, focusing on the TQD platform's comparison to predicate devices:
| Performance Characteristic | Acceptance Criteria (Implied: Comparable to Predicate) | NeoBase Non-derivatized MSMS Kit (TQD Platform) Performance (as compared to MS2/QMicro) |
|---|---|---|
| Precision (Average Total Imprecision %CV) | Should be comparable to or better than predicate devices. | Amino Acids: Generally around 10-18% for TQD, similar to or slightly better than MS2/QMicro (e.g., ALA 10, ARG 10, MET 18, TYR 8, VAL 12). Carnitines/Acylcarnitines: Not explicitly provided for all, but overall implied to be adequate based on predicate comparison. |
| Recovery (Mean % Recovery) | Should be comparable to predicate devices. | Amino Acids: Ranges from 57% (SA) to 104% (C0) for TQD, generally comparable to MS2/QMicro. 95% CI also presented. |
| Measurable Ranges | Should cover all clinically significant ranges. | For all analytes, the TQD range (µM) includes or extends beyond the "Cutoff Range (µM)", demonstrating sufficiency for clinical use. |
| Method Correlation (Mean Ratio of Measured Concentration) | Ratios close to 1.0 (indicating statistical equivalence). | MS2/TQD: Ratios ranged from 0.89 to 1.09, with small variation, indicating statistical equivalence. QMicro/TQD: Ratios ranged from 0.92 to 1.08, with small variation, indicating statistical equivalence. |
| Clinical Correlation (% Agreement) | High percentage agreement with predicate devices. | All Analytes: Ranged from 99.2% to 100.0% agreement between TQD and MS2/Sciex platforms in clinical determinations. |
| Detection of True Positive Samples | 100% agreement with predicate devices in detection. | 100% agreement for all 17 true positive samples (representing 14 disorders) between TQD and MS platforms. |
2. Sample Size Used for the Test Set and Data Provenance
- Non-clinical (Analytical) Test Set:
- Precision and Recovery: The tables provided (5.3, 5.4, 5.5) show averaged data, but the explicit number of samples/replicates isn't detailed for each specific test. However, the method correlation section states that "enriched samples (five levels) was analyzed (as singlicates of each level) for 16 runs to provide a total of 80 individual measurements" for each analyte on each platform.
- Method Correlation: Data from "dried blood spots enriched with the analytes of interest," specifically "5 levels times 5 runs per analyte" resulted in 25 means per platform for each analyte (80 individual measurements total, as above).
- Clinical Test Set:
- Clinical Correlation (Percent Agreement): 2499 random newborn screening specimens (presumptive negative data set) and 17 specimens with true positive diagnoses. Some analytes specify 2598 total observations (2499 + 80 individual measurements from enriched samples for other tests?), while others specify 2518* (2499 presumptive negatives + 19 true positives, including newly acquired NKH and H-ALA samples mentioned in footnote).
- True Positive Samples: 17 samples with true positive diagnoses representing 14 disorders.
- Data Provenance: The document does not specify the country of origin for the samples. It mentions "newborn heel prick blood samples dried on filter paper," which is a standard collection method. The data is retrospective in the sense that these were pre-existing biological samples used for evaluation. It's not a prospective collection of new patients for this specific study.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications
This study focuses on diagnostic device performance (quantitative measurements of analytes) rather than interpretive tasks that would typically require human expert adjudication of images or complex clinical scenarios.
- Analytical Performance (Precision, Recovery, Measurable Ranges, Method Correlation): Ground truth is established by the known concentrations of analytes in the spiked/enriched samples, and the quantitative measurements determined by specialized laboratory equipment (Mass Spectrometers). No human experts are involved in establishing this type of ground truth.
- Clinical Correlation and True Positive Samples: The "ground truth" for the 17 true positive samples is referred to as "true positive diagnoses." The document does not specify how these diagnoses were established (e.g., whether by pathology, genetic testing, or clinical consensus) nor does it mention the number or qualifications of experts involved in these initial diagnoses.
4. Adjudication Method for the Test Set
Not applicable. This is an analytical/quantitative device performance study rather than an interpretive study requiring human adjudication. The "agreement" for clinical correlation refers to the concordance between the numerical results of the TQD platform and the predicate platforms against established clinical cutoffs, not human expert consensus on a diagnosis.
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study was done
No, an MRMC comparative effectiveness study was not done. This study is evaluating the analytical performance and clinical correlation of a laboratory diagnostic assay, not a device that requires human interpretation of outputs.
6. If a Standalone Study (algorithm only without human-in-the-loop performance) was done
Yes, this is essentially a standalone (algorithm only) study. The "device" is a reagent kit used on an automated mass spectrometry system. The study compares the quantitative results generated by the TQD platform (with the NeoBase kit) directly to the predicate MS2 and QMicro platforms (also using the NeoBase kit) without a human-in-the-loop interpretation step being evaluated as part of the primary outcome for device clearance. The output is a numerical concentration.
7. The Type of Ground Truth Used
- Analytical Performance: Ground truth is based on known concentrations in control and enriched samples. These are prepared by spiking analytes into a matrix (dried blood spots) at specific, verifiable concentrations.
- Clinical Correlation and True Positive Samples:
- For the 2499 random newborn screening specimens, the "ground truth" for clinical "agreement" is whether the analyte concentrations fall above or below their respective clinical cutoffs (as determined by the predicate device).
- For the 17 true positive samples, the ground truth is established clinical diagnoses of metabolic disorders ("true positive diagnoses").
8. The Sample Size for the Training Set
The document describes evaluation of the device performance, not the training of an AI algorithm requiring a specific "training set." This device is a reagent kit for a mass spectrometry system, not an AI/ML software device in the typical sense. Therefore, there is no explicit "training set" in the context of an AI model.
Historically, the predicate devices (MS2 and QMicro) and their associated kits would have undergone extensive validation and optimization (which could be conceptually analogous to a training phase, but for analytical chemistry rather than AI). The current study is demonstrating the equivalence of the NeoBase kit on a new platform (TQD) to these previously validated systems.
9. How the Ground Truth for the Training Set was Established
As there is no distinct "training set" for an AI algorithm in this context, this question is not applicable. The methods used in developing and validating the NeoBase kit and its use on mass spectrometry platforms would involve many iterations of experiments to establish linearity, accuracy, precision, and other analytical specifications. This process relies on robust analytical chemistry principles and reference materials with known concentrations, rather than a "ground truth" established by human experts for AI training.
{0}------------------------------------------------
AUG 2 3 2010
510(k) SUMMARY
This summary of 510(k) safety and effectiveness information is supplied in accordance with the requirements of the SMDA of 1990 and 21 CFR 807.92
The assigned 510(k) number is K093916
Date: August 18, 2010
Submitted by:
Wallac Oy a subsidiary of PerkinElmer Mustionkatu 6 20750 Turku, Finland
Contact person:
Primary:
Kay A. Taylor Tele: 317-418-1735 Fax: 317-536-3064
Secondary:
Susan Hamann Tele: 781-633-5872 781-633-5983 Fax:
Trade Name:
NeoBase Non-derivatized MSMS Kit
NeoBase kit or Non-derivatized kit Common Name:
Newborn screening test system for amino acids, free Classification Name: carnitine, and acylcarnitines using tandem mass spectrometry (21 CFR § 862.1055 /Product code NQL)
NeoBase Non-derivatized MSMS Kit, K083130 Predicate device(s):
The measurement of amino acids, succinylacetone, Device description: free carnitine, and acylcarnitines with the NeoBase assay involves extraction of dried blood spots from newborns with a solution containing stable-isotope labeled internal standards and analysis using a tandem mass spectrometry (MSMS) system. The each analyte relative to their response of internal stable-isotope labeled corresponding standard is proportional to analyte concentration
1
{1}------------------------------------------------
Intended Use: Indications for Use
The Neobase Non-derivatized MSMS reagent kit (for use on the PerkinElmer TQD MSMS Screening System) is intended for the measurement and evaluation of amino acids, succinylacetone, free carnitine, and acylcarnitine concentrations from newborn heel prick blood samples dried on filter paper.
Quantitative analysis of these analytes (Table 1) and their relationship with each other is intended to provide analyte concentration profiles that may aid in screening newborns for metabolic disorders.
Instruments: - PerkinElmer MS2 Tandem Mass Spectrometer System (MS2) - PerkinElmer MSMS Quattro Micro (Qmicro) Newborn Screening System
- PerkinElmer MSMS TQD Newborn Screening System
| ANALYTE NAME | ABBREVIATION |
|---|---|
| Amino acids | |
| Alanine | Ala |
| Arginine | Arg |
| Citrulline | Cit |
| Glycine | Gly |
| Leucine/Isoleucine/Hydroxyproline* | Leu/Ile/Pro-OH |
| Methionine | Met |
| Ornithine | Orn |
| Phenylalanine | Phe |
| Proline | Pro |
| Tyrosine | Tyr |
| Valine | Val |
| Carnitines | |
| Free carnitine | C0 |
| Acetylcarnitine | C2 |
| Propionylcarnitine | C3 |
| Malonylcarnitine / 3-Hydroxy-butyrylcarnitine* | C3DC/C4OH |
| Butyrylcarnitine | C4 |
| Methylmalonyl / 3-Hydroxy-isovalerylcarnitine* | C4DC/C5OH |
| Isovalerylcarnitine | C5 |
| Tiglylcarnitine | C5:1 |
| Glutarylcarnitine / 3-Hydroxy-hexanoylcarnitine* | C5DC/C6OH |
| Hexanoylcarnitine | C6 |
| Adipylcarnitine | C6DC |
| Octanoylcarnitine | C8 |
Table 1. Analytes measured by the NeoBase Non-derivatized MSMS Kit
{2}------------------------------------------------
| Octenoylcarnitine | C8:1 |
|---|---|
| Decanoylcarnitine | C10 |
| Decenoylcarnitine | C10:1 |
| Decadienoylcarnitine | C10:2 |
| Dodecanoylcarnitine | C12 |
| ANALYTE NAME | ABBREVIATION |
| Carnitines | |
| Dodecenoylcarnitine | C12:1 |
| Tetradecanoylcarnitine (Myristoylcarnitine) | C14 |
| Tetradecenoylcarnitine | C14:1 |
| Tetradecadienoylcarnitine | C14:2 |
| 3-Hydroxy-tetradecanoylcarnitine | C14OH |
| Hexadecanoylcarnitine (palmitoylcarnitine) | C16 |
| Hexadecenoylcarnitine | C16:1 |
| 3-Hydroxy-hexadecanoylcarnitine | C16OH |
| 3-Hydroxy-hexadecenoylcarnitine | C16:1OH |
| Octadecanoylcarnitine (Stearoylcarnitine) | C18 |
| Octadecenoylcarnitine (Oleylcarnitine) | C18:1 |
| Octadecadienoylcarnitine (Linoleylcarnitine) | C18:2 |
| 3-Hydroxy-octadecanoylcarnitine | C18OH |
| 3-Hydroxy-octadecenoylcarnitine | C18:1OH |
| Ketones | |
| Succinylacetone | SA |
*Analytes in these rows are either isomers or isobars and cannot be distinguished in the tandem mass spectrometry experiment.
Device Comparison:
Table 5.1: Comparison of the modified device (NeoBase Non-derivatized MSMS Assay on the TQD Platform_ and predicate device.
| GENERAL CHARACTERISTICS | ||
|---|---|---|
| Parameter | Modified Device | Predicate Device |
| Intended Use | The NeoBase Non-derivatized MSMSreagent kit is intended for the measurementand evaluation of amino acids,succinylacetone, free carnitine, andacylcarnitine concentrations from newbornheel prick blood samples dried on filterpaper. Quantitative analysis of theseanalytes (Table 1) and their relationshipwith each other is intended to provideanalyte concentration profiles that may aidin screening newborns for metabolicdisorders.(intended use employs a table to identifyeach analyte detected) | Same |
| Instrumentation | PerkinElmer MS2 Tandem MassSpectrometer System (MS2)PerkinElmer MSMS Quattro Micro (Qmicro) | - PerkinElmer MS2 TandemMass Spectrometer System- PerkinElmer MS/MS Qmicro |
{3}------------------------------------------------
| Newborn Screening SystemPerkinElmer MSMS TQD NewbornScreening System | Screening System |
|---|---|
| ------------------------------------------------------------------------------ | ------------------ |
·
| GENERAL CHARACTERISTICS | ||
|---|---|---|
| Parameter | Modified Device | Predicate Device |
| Disorders Screened | Amino-, organic-, and fatty acid metabolicdisorders | Same |
| Analytes Measured | Amino acids, free carnitine, acylcarnitines,and succinylacetone | Same |
| Methodology | Microplate based tandem massspectrometric assay | Same |
| Test Principle | Amino acids and carnitines in sample aremeasured by tandem mass spectrometrythrough analyte-specific mass transitionsappropriate for each type of analyte. Theextracted analytes are measured for settime periods and compared to the signalintensities produced by the correspondingisotope-labeled internal standards. Theconcentrations are determined bycomparing the signal intensities of theknown standards to the measured analytes. | Same |
| Quantitative Nature | Quantitative by internal standardization | Same |
| Sample Requirements | Newborn blood collected on Schleicher andSchuell 903 filter paper per NCCLSstandards | Same |
| Throughput | Ninety-six tests per microtiter plate. Multipleplates can be analyzed | Same |
| Analysis Time | 2 to 2.5 hours per plate. | Same |
| Controls | Controls are blood spots from processedhuman blood enriched with several aminoacids, carnitines and succinylacetone. | Same |
| Calibrators | Internal calibration using several isotopicallylabeled standards, included as driedmaterial in vials. Internal standards must bereconstituted with extraction solution prior totheir use. | Same |
| Assay format | Non-derivatized (analytes measured in theirnative forms) | Same |
Analytes measured by the device
:
| ANALYTE NAME | ABBREVIATION |
|---|---|
| Amino acids | |
| Alanine | Ala |
| Arginine | Arg |
| Citrulline | Cit |
| Glycine | Gly |
| Leucine/Isoleucine/Hydroxyproline* | Leu/Ile/Pro-OH |
| Methionine | Met |
{4}------------------------------------------------
| Ornithine | Orn |
|---|---|
| Phenylalanine | Phe |
| Proline | Pro |
| Tyrosine | Tyr |
| Valine | Val |
| Carnitines | |
| Free carnitine | CO |
| Acetylcarnitine | C2 |
| Propionylcarnitine | C3 |
| Malonylcarnitine / 3-Hydroxy-butyrylcarnitine* | C3DC/C4OH |
| Butyrylcarnitine | C4 |
| Methylmalonyl / 3-Hydroxy-isovalerylcarnitine* | C4DC/C5OH |
| Isovalerylcarnitine | C5 |
| Tiglylcarnitine | C5:1 |
| Glutarylcarnitine / 3-Hydroxy-hexanoylcarnitine* | C5DC/C6OH |
| Hexanoylcarnitine | C6 |
| Adipylcarnitine | C6DC |
| Octanoylcarnitine | C8 |
| Octenoylcarnitine | C8:1 |
| Decanoylcarnitine | C10 |
| Decenoylcarnitine | C10:1 |
| Decadienoylcarnitine | C10:2 |
| Dodecanoylcarnitine | C12 |
| Dodecenoylcarnitine | C12:1 |
| Tetradecanoylcarnitine (Myristoylcarnitine) | C14 |
| Tetradecenoylcarnitine | C14:1 |
| Tetradecadienoylcarnitine | C14:2 |
| 3-Hydroxy-tetradecanoylcarnitine | C14OH |
| Hexadecanoylcarnitine (palmitoylcarnitine) | C16 |
| Hexadecenoylcarnitine | C16:1 |
| 3-Hydroxy-hexadecanoylcarnitine | C16OH |
| 3-Hydroxy-hexadecenoylcarnitine | C16:1OH |
| Octadecanoylcarnitine (Stearoylcarnitine) | C18 |
| Octadecenoylcarnitine (Oleylcarnitine) | C18:1 |
| Octadecadienoylcarnitine (Linoleylcarnitine) | C18:2 |
| 3-Hydroxy-octadecanoylcarnitine | C18OH |
| 3-Hydroxy-octadecenoylcarnitine | C18:1OH |
| Ketones | |
| Succinylacetone | SA or SUAC |
*Analytes in these rows are either isomers or isobars and cannot be distinguished in the tandem mass spectrometry experiment.
Substantial equivalency:
(1) Non-clinical
The performance of the NeoBase Non-derivatized MSMS kit on the PerkinElmer TQD Triple Quadrupole Mass Spectrometer System (PerkinElmer TQD platform) was compared to the predicate MS2 and PerkinElmer Quattro Micro platforms performance, K031878. All of these are tandem mass spectrometry platforms capable of measuring the NeoBase panel of amino acids and acylcarnitines from neonatal dried blood spots. The panel of analytes measured by all three platforms is the same. Analytically, all devices are identical regarding sample
{5}------------------------------------------------
requirements, sample processing, analysis time and assay format (Tables 5.1 and 5.2).
The performance of the NeoBase kit on the PerkinElmer TQD platform was compared against the corresponding characteristics reported in the predicate device product insert. A summary of the performance characteristics is presented in Tables 5.3 to 5.6. The NeoBase kit provides equivalent precision, recoveries and measurable ranges that cover all clinically significant ranges on all platforms tested. Therefore, the NeoBase kit provides performance levels that are adequate for its intended use on the MS2, PerkinElmer Quattro Micro and PerkinElmer TQD platforms
Precision
Table 5.3: Averaged Total imprecision for amino acids. Data shown are average Total imprecision coefficients of variation (%CV) for each platform.
| Assav | ALA | ARG | CIT ' | GLY | LEU | MET | ORN | PHE | SA | TYR | VAL |
|---|---|---|---|---|---|---|---|---|---|---|---|
| QM | 10 | 8 | 13 | 10 | |||||||
| MS2 | 14 | 10 | 15 | 10 | 13 | 8 | |||||
| TQD | 10 | 10 | 10 | The Children Children Children Children Children Children Children Station Children Children Station of Children Station of Children Station of Children Station of Children | 10 | 18 | 12 |
Table 5.4: Averaged Total imprecision for carnitine and acylcarnitines. Data shown are average Total imprecision coefficients of variation (%CV) for each platform.
| on the first and the collection and the consisted to the consisted to the continues | -------------------------------------------------------------------- | ------------------------ | стание в приводство в с с с с в полниками своемника в можно в | C16 | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| -------------------------------------------------- | . | ------------------------------------ | A mond anno a month and contract and collection and all development to | ------------------------------------ | |||||||
| ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | And 11 the American Andrew of American Andrew of | . | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | STATIS A . A . A . C | |||||||
| ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------1 | ------------------ |
Recovery
Table 5.5: Averaged analyte percent recovery and recovery ranges for all platforms
| Mean % Recovery | Recovery SD, % | 95% Confidence interval | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Analyte | TQD | QMicro | MS2 | TQD | QMicro | MS2 | TQD | QMicro | MS2 |
| ALA | 100 | 92 | 83 | 7 | 12 | 10 | 85-115 | 69-116 | 63-104 |
| ARG | 86 | 87 | 87 | 7 | 8 | 7 | 72-100 | 72-102 | 73-100 |
| CIT | 93 | 96 | 95 | 6 | 7 | 11 | 82-104 | 83-109 | 73-116 |
| GLY | 90 | 93 | 86 | 19 | 12 | 17 | 51-128 | 69-117 | 51-120 |
| LEU | 101 | 93 | 88 | 14 | 10 | 8 | 73-128 | 72-113 | 72-103 |
| MET | 97 | 88 | 86 | 6 | 6 | 6 | 85-110 | 75-101 | 73-98 |
| ORN | 98 | 91 | 91 | 10 | 8 | 6 | 78-117 | 75-108 | 78-103 |
| PHE | 94 | 95 | 89 | 8 | 7 | 6 | 78-109 | 81-109 | 76-101 |
| PRO | 97 | 93 | 84 | 6 | 8 | 8 | 84-110 | 78-108 | 68-100 |
| SA | 57 | 64 | 62 | 6 | 6 | 7 | 44-70 | 52-77 | 48-76 |
| TYR | 84 | 96 | 102 | 6 | 9 | 10 | 72-95 | 79-114 | 81-122 |
| VAL | 90 | 88 | 78 | 9 | 9 | 10 | 72-109 | 69-106 | 58-97 |
| C0 | 104 | 91 | 107 | 5 | 11 | 14 | 95-114 | 70-112 | 80-134 |
{6}------------------------------------------------
| C2 | 95 | 93 | 97 | 7 | 7 | 8 | 82-108 | 79-108 | 80-113 |
|---|---|---|---|---|---|---|---|---|---|
| C3 | 93 | 94 | 95 | 4 | 8 | 10 | 85-102 | 78-110 | 76-115 |
| C4 | 93 | 91 | 92 | 4 | 9 | 14 | 85-101 | 72-109 | 64-121 |
| C5 | 86 | 91 | 94 | 5 | 7 | 10 | 75-97 | 78-105 | 74-114 |
| C5DC | 99 | 99 | 104 | 4 | 8 | 8 | 90-107 | 83-115 | 87-121 |
| C6 | 91 | 91 | 83 | 6 | 5 | 10 | 80-103 | 82-101 | 63-103 |
| C8 | 100 | 90 | 96 | 8 | 11 | 13 | 84-117 | 68-113 | 70-121 |
| C10 | 92 | 97 | 95 | 3 | 5 | 9 | 85-99 | 86-108 | 78-112 |
| C12 | 102 | 93 | 103 | 5 | 9 | 14 | 93-111 | 75-112 | 75-130 |
| C14 | 92 | 92 | 94 | 6 | 5 | 6 | 81-104 | 82-102 | 81-107 |
| C16 | 92 | 93 | 84 | 5 | 13 | 15 | 83-101 | 68-118 | 55-114 |
| C18 | 89 | 91 | 94 | 10 | 7 | 13 | 70-109 | 77-105 | 69-119 |
Measurable Ranges
Table 5.6: Measurable ranges for both assays and corresponding clinically significant ranges (all in
μML).
| Analyte | TQD Range (µM) | QMicro Range (µM) | MS² Range (µM) | Cutoff Range (µM) | |||
|---|---|---|---|---|---|---|---|
| Lower | Upper | Lower | Upper | Lower | Upper | ||
| Ala | 452 | 4841 | 387 | 4090 | 444 | 4203 | 975-1625 |
| Arg | 27 | 4140 | 25 | 3721 | 27 | 3806 | 180-300 |
| Cit | 28 | 1716 | 27 | 1683 | 26 | 1655 | 113-188 |
| Gly | 309 | 4350 | 334 | 4487 | 365 | 4504 | 975-1625 |
| Leu | 266 | 2992 | 218 | 2545 | 219 | 2463 | 263-438 |
| Met | 31 | 1252 | 30 | 1185 | 28 | 1100 | 120-200 |
| Orn | 110 | 3914 | 115 | 3771 | 110 | 3645 | 360-600 |
| Phe | 79 | 2607 | 71 | 2341 | 73 | 2169 | 225-375 |
| Pro | 248 | 3735 | 251 | 3659 | 238 | 3327 | 450-750 |
| SA | 0.6 | 164.9 | 0.4 | 158.1 | 0.4 | 155.0 | 4-7.0 |
| Tyr | 75 | 2980 | 72 | 2816 | 75 | 2857 | 578-963 |
| Val | 197 | 2300 | 205 | 2358 | 176 | 1902 | 300-500 |
| C0 | 51 | 2930 | 42 | 2274 | 43 | 2386 | 90-150 |
| C2 | 35 | 743 | 35 | 735 | 37 | 745 | 128-213 |
| C3 | 3.3 | 96 | 3.1 | 88 | 3.2 | 94 | 9.75-16.25 |
| C4 | 0.20 | 70.8 | 0.14 | 59.8 | 0.13 | 57 | 2.25-3.75 |
| C5 | 0.20 | 62.9 | 0.18 | 59.1 | 0.17 | 59.9 | 1.88-3.13 |
| C5DC | 0.18 | 32.6 | 0.13 | 28.9 | 0.10 | 29.2 | 0.6-1 |
| C6 | 0.03 | 67.6 | 0.03 | 61.5 | 0.03 | 66.6 | 0.98-1.63 |
| C8 | 0.05 | 39.8 | 0.04 | 35.2 | 0.04 | 35.8 | 1.2-2 |
| C10 | 0.07 | 29.8 | 0.07 | 28.9 | 0.06 | 27.9 | 1.35-2.25 |
| C12 | 0.05 | 50.8 | 0.05 | 42.7 | 0.05 | 41.7 | 1.88-3.13 |
| C14 | 0.1 | 42.7 | 0.1 | 41.8 | 0.1 | 42.3 | 1.5-2.5 |
| C16 | 2.3 | 90.5 | 2.8 | 107.3 | 2.9 | 106.7 | 11.25-18.75 |
7
{7}------------------------------------------------
| ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------LAND AND LAND LAND | 1State of the American1 | |||||||
|---|---|---|---|---|---|---|---|---|
| -- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | -- | -- | -- | -- | -- | --------------------------------- | -- |
Method Correlation
An additional measure of the equivalency in the results obtained when the assay is executed using three platforms is the comparison of the actual measured concentrations for each of the analytes included in dried blood spots enriched with the analytes of interest. The raw data was matched per run per level for two comparisons: 1) MS2 to PerkinElmer TQD; and 2) PerkinElmer Q Micro to TQD. Means were calculated per run per analyte per spiked level, to result in 25 means per platform for each analyte (5 levels times 5 runs per analyte). The results were averaged over the five spiked levels and the ratios of the means (per analyte) were then determined for the two comparisons (MS2/TQD and Q Micro/TQD). If the two platforms being compared give equivalent concentration measurements, then the ratio will be 1.0. The mean ratio (averaged over five levels) of each analyte is presented in Tables 5.7 and 5.8 for the MS2/TQD and Q Micro/TQD comparisons, respectively.
| ALA | ARG | CIT | GLY | LEU | MET | ORN | PHE | ||
|---|---|---|---|---|---|---|---|---|---|
| Mean | 1.09 | 1.01 | 0.93 | 1.04 | 0.98 | 0.98 | 0.99 | 0.89 | |
| SD | 0.07 | 0.02 | 0.03 | 0.07 | 0.03 | 0.03 | 0.02 | 0.03 | |
| % CV | 6 | 2 | 3 | 7 | 3 | 3 | 2 | 3 | |
| LCL | 0.96 | 0.96 | 0.86 | 0.90 | 0.92 | 0.92 | 0.94 | 0.83 | |
| UCL | 1.22 | 1.05 | 0.99 | 1.17 | 1.04 | 1.05 | 1.04 | 0.95 | |
| PRO | SA | TYR | VAL | C0 | C2 | C3 | C4 | ||
| Mean | 0.94 | 1.08 | 1.01 | 1.08 | 0.98 | 0.99 | 1.04 | 0.92 | |
| SD | 0.03 | 0.05 | 0.03 | 0.06 | 0.03 | 0.03 | 0.03 | 0.03 | |
| % CV | 3 | 5 | 3 | 6 | 3 | 3 | 3 | 3 | |
| LCL | 0.87 | 0.98 | 0.95 | 0.96 | 0.92 | 0.92 | 0.98 | 0.86 | |
| UCL | 1.00 | 1.17 | 1.06 | 1.19 | 1.05 | 1.05 | 1.10 | 0.98 | |
| C5 | C5DC | C6 | C8 | C10 | C12 | C14 | C16 | C18 | |
| Mean | 0.92 | 0.97 | 0.89 | 0.97 | 0.94 | 0.98 | 1.01 | 0.99 | 0.99 |
| SD | 0.03 | 0.04 | 0.03 | 0.04 | 0.03 | 0.04 | 0.04 | 0.03 | 0.04 |
| % CV | 3 | 4 | 4 | 4 | 3 | 4 | 4 | 3 | 4 |
| LCL | 0.85 | 0.88 | 0.82 | 0.90 | 0.87 | 0.89 | 0.94 | 0.93 | 0.92 |
| UCL | 0.99 | 1.06 | 0.96 | 1.04 | 1.00 | 1.06 | 1.09 | 1.06 | 1.06 |
Table 5.7: Mean ratio of measured concentration for MS2TTQD comparison. Mean ratios of 25 measurements shown along with corresponding SD, %CV, and upper and lower 95% confidence limits.
Table 5.8: Mean ratio of measured concentration for Q Micro/TQD comparison. Mean ratios of 25 measurements shown along with corresponding SD, %CV, and upper and lower 95% confidence limits.
| ALA | ARG | CIT | GLY | LEU | MET | ORN | PHE | ||
|---|---|---|---|---|---|---|---|---|---|
| Micr01/0 | Mean | 0.92 | 1.00 | 1.00 | 0.98 | 1.01 | 1.08 | 1.06 | 0.97 |
| SD | 0.04 | 0.05 | 0.06 | 0.05 | 0.06 | 0.04 | 0.04 | 0.06 |
{8}------------------------------------------------
| % CV | 4 | 5 | 6 | 5 | 6 | 4 | 4 | 6 | |
|---|---|---|---|---|---|---|---|---|---|
| LCL | 0.84 | 0.90 | 0.87 | 0.88 | 0.90 | 1.00 | 0.98 | 0.84 | |
| UCL | 0.99 | 1.11 | 1.13 | 1.07 | 1.12 | 1.16 | 1.14 | 1.09 | |
| PRO | SA | TYR | VAL | C0 | C2 | C3 | C4 | ||
| Mean | 1.02 | 1.04 | 1.00 | 1.08 | 0.99 | 0.94 | 0.95 | 1.03 | |
| SD | 0.03 | 0.04 | 0.05 | 0.07 | 0.03 | 0.04 | 0.04 | 0.04 | |
| % CV | 3 | 4 | 5 | 7 | 3 | 4 | 4 | 4 | |
| LCL | 0.95 | 0.96 | 0.91 | 0.95 | 0.93 | 0.86 | 0.87 | 0.96 | |
| UCL | 1.09 | 1.13 | 1.10 | 1.21 | 1.05 | 1.02 | 1.04 | 1.10 | |
| C5 | C5DC | C6 | C8 | C10 | C12 | C14 | C16 | C18 | |
| Mean | 0.97 | 0.97 | 1.00 | 1.00 | 0.98 | 1.02 | 1.00 | 1.00 | 1.02 |
| SD | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | 0.03 | 0.04 | 0.04 | 0.04 |
| % CV | 3 | 3 | 3 | 3 | 3 | 3 | 4 | 4 | 4 |
| LCL | 0.91 | 0.91 | 0.93 | 0.94 | 0.92 | 0.96 | 0.93 | 0.93 | 0.95 |
| UCL | 1.03 | 1.03 | 1.07 | 1.07 | 1.05 | 1.09 | 1.07 | 1.08 | 1.10 |
The ratios range from 0.89 to 1.09 for the MS2/TQD comparison. Taking into account the small variation, the results indicate these two platforms give statistically equivalent results. Likewise, the ratios range from 0.92 to 1.08 for the Q Micro/TQD comparison and noting the small variation in the mean ratios, the results indicate these two platforms give statistically equivalent results.
(2) Clinical
CLINICAL CORRELATION STUDIES
The clinical correlation studies involved the analysis of 2499 random newborn screening specimens and 17 specimens with true positive diagnoses. In addition, a set of enriched samples (five levels) was analyzed (as singlicates of each level) for 16 runs to provide a total of 80 individual measurements. All samples were evaluated in parallel on the TQD and the predicate MS- platforms using the NeoBase kit. Clinical correlation was established by assessing whether or not the platforms were concordant in determining the paired samples to have analyte concentration values above or below their corresponding cutoffs. Examination on the number of concordant pairs for each analyte (cases in which both methods agreed) provided the percent agreements shown in Table 5.9.
| Analyte | Total # ofobservations | %agreement | Analyte | Total # ofobservations | %agreement |
|---|---|---|---|---|---|
| ALA | 2598 | 99.6% | C14 | 2598 | 99.9% |
| ARG | 2598 | 99.9% | C16 | 2598 | 99.6% |
| CIT | 2598 | 99.8% | C18 | 2598 | 99.9% |
| GLY | 2598 | 99.5% | C4OH/C3DC | 2518* | 99.9% |
| LEU | 2598 | 99.6% | C5OH/C4DC | 2518* | 99.9% |
| MET | 2598 | 100.0% | C5:1 | 2518* | 99.4% |
Table 5.9: Percent agreement in clinical determinations between the TQD and MS2 platforms.
{9}------------------------------------------------
| ORN | 2598 | 99.6% | C6DC | 2518* | 99.8% |
|---|---|---|---|---|---|
| PHE | 2598 | 99.9% | C8:1 | 2518* | 99.9% |
| PRO | 2598 | 99.8% | C10:1 | 2518* | 100.0% |
| SA | 2598 | 99.5% | C10:2 | 2518* | 99.7% |
| TYR | 2598 | 99.2% | C12:1 | 2518* | 100.0% |
| VAL | 2598 | 99.7% | C14-OH | 2518* | 99.7% |
| C0 | 2598 | 100.0% | C14:1 | 2518* | 99.8% |
| C2 | 2598 | 99.9% | C14:2 | 2518* | 99.8% |
| C3 | 2598 | 100.0% | C16-OH | 2518* | 99.8% |
| C4 | 2598 | 99.9% | C16:1 | 2518* | 99.9% |
| C5 | 2598 | 99.9% | C16:1-OH | 2518* | 99.8% |
| C5DC | 2598 | 99.7% | C18-OH | 2518* | 99.6% |
| C6 | 2598 | 99.7% | C18:1 | 2518* | 99.9% |
| C8 | 2598 | 99.8% | C18:1-OH | 2518* | 99.2% |
| C10 | 2598 | 99.9% | C18:2 | 2518* | 100.0% |
| C12 | 2598 | 99.8% |
ً For these analytes, newborn screening samples (presumptive negative data set, n=2499) and true positives (n=19, include the newly acquired NKH and H-ALA samples) were used.
COMPARISON OF TRUE POSITIVE SAMPLE RESULTS BETWEEN PLATFORM
The correlation between the test and predicate platforms included 17 samples with true positive diagnoses representing 14 disorders (Table 5.10). All of these cases were successfully detected by both platforms for 100% agreement in the clinical determination (Table 5.10).
| Table 5.10: Summary of the analysis of true Positive samples by the NeoBase assay when performed | ||
|---|---|---|
| on the MS and TQD platformsAnd American American Participant Production Comprehensive Children Comments of Children Comments of Children Comments of Children | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ |
| Sample | Disorder | Cases Detected | Elevated Analytes Detected by each Platform | ||
|---|---|---|---|---|---|
| TQD | Sciex | TQD | Sciex | ||
| 1 | TYR I | yes | yes | SA, TYR | SA, TYR |
| 2 | CPT II | yes | yes | C12, C14, C16, C16:1, C16:1 OH, C16-OH, C18, C18:1, C18:1-OH | C14, C14:OH, C16, C16:1, C16:1 OH, C16-OH, C18, C18:1, C18:1-OH, C18-OH |
| 3 | MMA | yes | yes | C3, C6, | C3 |
| 4 | HMG | yes | yes | C5OH/C4DC, C6DC | C5OH/C4DC |
| 5 | VLCAD | yes | yes | C14:1 | C14:1 |
| 6 | IVA | yes | yes | C5 | C5 |
| 7 | MCC | yes | yes | C5OH/C4DC | C5OH/C4DC |
| 8 | BTK | yes | yes | C0, C4, C5:1, C6, C8 | C0, C4, C5:1, |
{10}------------------------------------------------
| 9 | MSUD | yes | yes | LEU | LEU |
|---|---|---|---|---|---|
| 10 | MCAD | yes | yes | C6, C8, C10:1 | C0 low, C8, C10:1 |
| 11 | PPA | yes | yes | C3, C16:1 OH | C3, C16:1 OH |
| 12 | PKU | yes | yes | PHE | PHE |
| 13 | CIT | yes | yes | CIT | CIT |
| 14 | PKU | yes | yes | PHE | PHE |
| 15 | MCAD | yes | yes | C6, C6DC, C8, C10,C10:1, C12:1 | C6, C6DC, C8, C10,C10:1 |
| 16 | GAI | yes | yes | C5DC | C5DC |
| 17 | PKU | yes | yes | PHE | PHE |
Finally, the established performance characteristics and method comparison at the analytical and clinical levels show that using the Neo Base Non-derivatized MSMS kit on the PerkinElmer TQD platform provides performance that is equivalent to the performance of the kit when used on the predicate platforms.
the country of the
1
{11}------------------------------------------------
DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/11/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized eagle or bird-like figure with outstretched wings. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the bird.
Public Health Service
Building 66
Food & Drug Administration
Silver Spring, MD 20993
10903 New Hampshire Avenue
PerkinElmer c/o Kay Taylor Director, Regulatory and Clinical Affairs 8275 Carloway Road Indiannapolis, IN 46236
AUG 2 3 2010
Re: K093916
Trade Name: NeoBase Non-derivatized MSMS reagent kit Regulation Number: 21 CFR 862.1055
Regulation Name: Newborn screening test system for amino acids, free carnitine, and acylcarnitines using tandem mass spectrometry
Regulatory Class: Class II Product Codes: NQL Dated: August 10, 2010 Received: August 11, 2010
Dear Ms. Taylor:
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); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).
{12}------------------------------------------------
Page 2
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 796-5450. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding postmarket surveillance, please contact CDRH's Office of Surveillance and Biometric's (OSB's) Division of Postmarket Surveillance at (301) 796-5760. 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.
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 ) 796-5680 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.
Sincerely yours,
CA
Courtney C. Harper, Ph.D. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
{13}------------------------------------------------
Indications for Use Form
510(k) Number (if known): K093916
Device Name: NeoBase Non-derivatized MSMS Kit
Indications for Use:
The Neobase Non-derivatized MSMS reagent kit (for use on the PerkinElmer TQD MSMS Screening System) is intended for the measurement and evaluation of amino acids, succinylacetone, free carnitine, and acylcarnitine concentrations from newborn heel prick blood samples dried on filter paper.
Quantitative analysis of these analytes (Table 1) and their relationship with each other is intended to provide analyte concentration profiles that may aid in screening newborns for metabolic disorders.
| ANALYTE NAME | ABBREVIATION |
|---|---|
| Amino acids | |
| Alanine | Ala |
| Arginine | Arg |
| Citrulline | Cit |
| Glycine | Gly |
| Leucine/Isoleucine/Hydroxyproline* | Leu/Ile/Pro-OH |
| Methionine | Met |
| Ornithine | Orn |
| Phenylalanine | Phe |
| Proline | Pro |
| Tyrosine | Tyr |
| Valine | Val |
Table 1. Analytes measured by the NeoBase™ Non-derivatized MSMS Kit.
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
Carol C. Benson
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
KO939112 510(k)
Page 1 of 3
{14}------------------------------------------------
| ANALYTE NAME (continued) | ABBREVIATION |
|---|---|
| Carnitines | |
| Free carnitine | C0 |
| Acetylcarnitine | C2 |
| Propionylcarnitine | C3 |
| Malonylcarnitine / 3-Hydroxy-butyrylcarnitine* | C3DC/C4OH |
| Butyrylcarnitine | C4 |
| Methylmalonyl / 3-Hydroxy-isovalerylcarnitine* | C4DC/C5OH |
| Isovalerylcarnitine | C5 |
| Tiglylcarnitine | C5:1 |
| Glutarylcarnitine / 3-Hydroxy-hexanoylcarnitine* | C5DC/C6OH |
| Hexanoylcarnitine | C6 |
| Adipylcarnitine | C6DC |
| Octanoylcarnitine | C8 |
| Octenoylcarnitine | C8:1 |
| Decanoylcarnitine | C10 |
| Decenoylcarnitine | C10:1 |
| Decadienoylcarnitine | C10:2 |
| Dodecanoylcarnitine | C12 |
| Dodecenoylcarnitine | C12:1 |
| Tetradecanoylcarnitine (Myristoylcarnitine) | C14 |
| Tetradecenoylcarnitine | C14:1 |
| Tetradecadienoylcarnitine | C14:2 |
| 3-Hydroxy-tetradecanoylcarnitine | C14OH |
| Hexadecanoylcarnitine (Palmitoylcarnitine) | C16 |
| Hexadecenoylcarnitine | C16:1 |
| 3-Hydroxy-hexadecanoylcarnitine | C16OH |
| 3-Hydroxy-hexadecenoylcarnitine | C16:1OH |
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
Carol C. Benson
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K093916
Page 2 of 3
{15}------------------------------------------------
| ANALYTE NAME (continued) | ABBREVIATION |
|---|---|
| Octadecanoylcarnitine (Stearoylcarnitine) | C18 |
| Octadecenoylcarnitine (Oleylcarnitine) | C18:1 |
| Octadecadienoylcarnitine (Linoleylcarnitine) | C18:2 |
| 3-Hydroxy-octadecanoylcarnitine | C18OH |
| 3-Hydroxy-octadecenoylcarnitine | C18:1OH |
| Ketones | |
| Succinylacetone | SA |
- Analytes in these rows are either isomers or isobars and cannot be distinguished in the tandem mass spectrometry experiment.
Prescription Use XXXX (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 OF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD)
Carol C. Benson
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K693916
Page 3 of 3
§ 862.1055 Newborn screening test system for amino acids, free carnitine, and acylcarnitines using tandem mass spectrometry.
(a)
Identification. A newborn screening test system for amino acids, free carnitine, and acylcarnitines using tandem mass spectrometry is a device that consists of stable isotope internal standards, control materials, extraction solutions, flow solvents, instrumentation, software packages, and other reagents and materials. The device is intended for the measurement and evaluation of amino acids, free carnitine, and acylcarnitine concentrations from newborn whole blood filter paper samples. The quantitative analysis of amino acids, free carnitine, and acylcarnitines and their relationship with each other provides analyte concentration profiles that may aid in screening newborns for one or more inborn errors of amino acid, free carnitine, and acyl-carnitine metabolism.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Newborn Screening Test Systems for Amino Acids, Free Carnitine, and Acylcarnitines Using Tandem Mass Spectrometry.” See § 862.1(d) for the availability of this guidance document.