(259 days)
The NeoBase Non-derivatized MSMS reagent kit 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 response of each analyte relative to their corresponding stable-isotope labeled internal standard is proportional to analyte concentration.
The provided 510(k) summary describes the NeoBase Non-derivatized MSMS Kit, intended for newborn screening of metabolic disorders by measuring amino acids, succinylacetone, free carnitine, and acylcarnitine concentrations from dried blood spots. The device's performance was compared to a legally marketed predicate device, the NeoGram Amino Acids and Acylcarnitines Tandem Mass Spectrometry Kit (K031878).
Here's a breakdown of the requested information based on the provided text:
1. Table of Acceptance Criteria and Reported Device Performance
The document does not explicitly state "acceptance criteria" as numerical thresholds for precision, recovery, or correlation that the device must meet. Instead, it presents the device's performance characteristics and compares them to those reported for the predicate device to demonstrate substantial equivalence. The implication is that performance comparable to the predicate device is considered acceptable.
| Performance Characteristic | Acceptance Criteria (Implicit) | NeoBase Non-derivatized MSMS Kit Performance (Reported) | Predicate Device (NeoGram) Performance (Reported) |
|---|---|---|---|
| Precision (Averaged Total Imprecision %CV for Amino Acids) | Comparable to predicate | < 10% (median across analytes, approximated from table) | < 20% (median across analytes, approximated from table) |
| Precision (Averaged Total Imprecision %CV for Carnitines & Acylcarnitines) | Comparable to predicate | < 10% (median across analytes, approximated from table) | < 20% (median across analytes, approximated from table) |
| Recovery (Average % for Amino Acids) | Comparable to predicate, ideally close to 100% | 89-101% | 68-96% |
| Recovery (Average % for Carnitines & Acylcarnitines) | Comparable to predicate, ideally close to 100% | 93-102% | 67-139% |
| Measurable Ranges | Must cover clinically significant ranges | All NeoBase analyte ranges cover or extend beyond "Normal" and "Cutoff" clinical ranges. | All Predicate analyte ranges cover or extend beyond "Normal" and "Cutoff" clinical ranges. |
| Method Correlation (R for Amino Acids) | "Correlated very well" with predicate (R-values close to 1) | Most R values ≥ 0.95 (approximated from Table 5.7) | Most R values ≥ 0.95 (approximated from Table 5.7) |
| Method Correlation (R for Carnitines & Acylcarnitines) | "Correlated very well" with predicate (R-values close to 1) | Most R values ≥ 0.95 (approximated from Table 5.8) | Most R values ≥ 0.95 (approximated from Table 5.8) |
| Clinical Agreement (% Agreement for all analytes) | High percentage agreement with predicate (implied close to 100%) | 97.2% to 100.0% | N/A (agreement between methods) |
| Detection of True Positive Samples (Disorders) | Comparable sensitivity to predicate for common disorders; ability to detect Tyrosinemia Type I | Detected 107/108 true positive samples (excluding 2 samples decayed due to storage) | Detected 103/108 true positive samples (excluding 2 samples decayed due to storage, and 4 Tyrosinemia Type I samples) |
| Detection of Tyrosinemia Type I specifically | Successful detection of Tyrosinemia Type I (using SA) | Detected 4/4 Tyrosinemia Type I samples via SA | Detected 0/4 Tyrosinemia Type I samples |
2. Sample Size Used for the Test Set and Data Provenance
- Non-clinical (Precision, Recovery, Measurable Ranges): The document doesn't specify a distinct "test set" for these parameters in terms of a separate sample size. The data for these characteristics is generated through laboratory experiments likely using controlled samples (e.g., spiked samples, internal controls) rather than clinical patient samples. The provenance is implied to be laboratory-generated.
- Method Correlation:
- Sample Size: 158 samples.
- Data Provenance: Not explicitly stated, but samples were "prepared in duplicates" and assayed using both devices. Implied to be laboratory-controlled or clinical samples processed for comparison, but specific origin (e.g., country) is not mentioned. Given the context of newborn screening, they would likely be dried blood spots.
- Clinical Correlation Studies:
- Sample Size:
- 9416 random neonatal samples
- 104 samples with true positive diagnoses
- 320 artificially enriched dried blood spots
- Data Provenance: From two different US newborn screening laboratories. The studies evaluated the NeoBase kit "in parallel to the predicate device (identical specimens were analyzed as paired samples by both methods)." This suggests a retrospective collection of these samples, as they are referred to as "random neonatal samples" and "samples with true positive diagnoses."
- True Positive Samples (Specific breakdown): 108 total true positive samples were analyzed (104 from screening sites + 4 Tyrosinemia Type I samples analyzed by PerkinElmer R&D). The two samples that weren't detected by either assay were CPT-2 and VLCAD cases which had degraded due to storage.
- Sample Size:
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications
The document does not specify the number of experts or their qualifications used to establish the ground truth for the clinical correlation studies or the true positive samples.
For the true positive samples, the text refers to them as "samples with true positive diagnoses" and later lists "Disorder Full name" for each, implying that the diagnoses were established clinically through standard diagnostic procedures. However, the exact method of ground truth confirmation or number of experts involved is not detailed.
4. Adjudication Method for the Test Set
The document does not describe an adjudication method for the test set.
For the "Clinical Correlation Studies," it states that "Clinical correlation was established by assessing whether or not the methods were concordant in determining the paired samples to have analyte concentration values above or below their corresponding cutoffs." This implies a direct comparison of the readings from the NeoBase and predicate device against predetermined clinical cutoffs, rather than an expert adjudication process determining the ultimate "true" status of each sample for the purpose of the study.
5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done.
This device is an in vitro diagnostic (IVD) kit for quantitative measurement of analytes using tandem mass spectrometry. Its performance evaluation focuses on analytical characteristics (precision, recovery, measurable range) and method correlation with a predicate device, as well as clinical correlation of quantitative measurements to established cutoffs. MRMC studies are typically used for imaging devices or other diagnostic tools where human readers interpret results, and the study would then compare human performance with and without AI assistance. This is not applicable here.
6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) Was Done
Yes, a standalone performance evaluation was done.
The entire study described in the 510(k) refers to the performance of the device kit (NeoBase Non-derivatized MSMS Kit) itself. This is an assay system that produces quantitative values. The precision, recovery, measurable ranges, and direct comparisons of analyte concentrations to clinical cutoffs are all measures of the kit's standalone analytical performance. Human involvement is limited to operating the instrument and following the assay protocol, not to interpreting ambiguous results in a way that would alter the quantitative output.
7. The Type of Ground Truth Used
- Non-clinical (Precision, Recovery, Measurable Ranges): The ground truth for these studies would be based on known concentrations of analytes in controlled, laboratory-prepared samples (e.g., spiked samples, calibrators).
- Method Correlation: The "ground truth" here is the measurement from the predicate device. The study compares the new device's measurements against those from the established predicate device.
- Clinical Correlation Studies:
- For the 9416 random neonatal samples, the ground truth was effectively the clinical cutoff values for each analyte. Samples were categorized as "above or below their corresponding cutoffs."
- For the 104 (plus 4 Tyrosinemia Type I) "true positive samples," the ground truth was the established clinical diagnosis of specific metabolic disorders (e.g., 3-Methylcrotonyl-CoA Carboxylase Deficiency, Phenylketonuria, Tyrosinemia Type I). This implies outcomes data or a strong clinical consensus for the natural diagnosis itself.
8. The Sample Size for the Training Set
The document does not explicitly mention a "training set" for the NeoBase Non-derivatized MSMS Kit. This is an in vitro diagnostic assay, not a machine learning algorithm that typically undergoes a distinct training phase on a large dataset. The development of such a kit involves analytical validation studies to optimize reagents and protocols, which is different from "training" an algorithm.
9. How the Ground Truth for the Training Set Was Established
As no training set is explicitly described in the context of an algorithm or machine learning, this question is not applicable based on the provided text. The "ground truth" in the development of an IVD kit is established through standard analytical chemistry principles, reference methods, and clinical validation.
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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 K083130.
Date: July 6, 2009
Submitted by:
Wallac Oy - PerkinElmer Inc. Mustionkatu 6 20750 Turku, Finland
Contact person:
Primary:
Kay A. Taylor Tele: 317-418-1735 Fax: 317-536-3064
Secondary:
Raija Koskivaara Tele: +358-2-2678 111 Fax: +358-2-2678 357
Trade Name:
NeoBase Non-derivatized MSMS Kit
Common Name: NeoBase kit or Non-derivatized kit
Classification Name: Newborn screening test system for amino acids, free carnitine, and acylcarnitines using tandem mass spectrometry (21 CFR § 862.1055 /Product code NQL)
NeoGram Amino Acids and Acylcarnitines Tandem Predicate device(s): Mass Spectrometry Kit, K031878
Device description: 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 response of each analyte relative to their
{1}------------------------------------------------
corresponding stable-isotope labeled internal standard is proportional to analyte concentration
The NeoBase Non-derivatized MSMS reagent kit is Intended Use: 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 (Tabel 1) and their relationship with each other is intended to provide analyte concentration profiles that may aid in screening newborns for metabolic disorders.
PerkinElmer MS2 Tandem Mass Spectrometer Instruments: . System and,
- PerkinElmer MS/MS Qmicro Screening System
| ANALYTE NAME | ABBREVIATION |
|---|---|
| Amino acids | |
| Alanine | Ala |
| Arginine | Arg |
| Citrulline | Cit |
| Glycine | Gly |
| Leucine/Isoleucine/Hydroxyproline* | Leu/lle/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 |
| Octenoylcarnitine | C8:1 |
- Alan de civation d MCMC Kit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
{2}------------------------------------------------
| 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 NeoBase Non-derivatized MSMS and predicate device.
.
| GENERAL CHARACTERISTICS | ||
|---|---|---|
| Parameter | NeoBase Non-derivatized MSMS kit | Predicate Device |
| Intended Use | The NeoBase Non-derivatized MSMSreagent kit is intended for themeasurement and evaluation of aminoacids, succinylacetone, free carnitine,and acylcarnitine concentrations fromnewborn heel prick blood samples driedon filter paper. Quantitative analysis ofthese analytes (Table 1) and theirrelationship with each other is intendedto provide analyte concentration profilesthat may aid in screening newborns formetabolic disorders.[intended use employs a table toidentify each analyte detected] | The NeoGram Amino Acids andAcylcarnitines Tandem MassSpectrometry kit is intended for themeasurement and evaluation ofamino acids, free carnitine, andacylcarnitine concentrations fromnewborn heel prick blood samplesdried on filter paper. Table 1 detailsthe analytes measured by the kitQuantitative analysis of aminoacids, free carnitine, andacylcarnitine and their relationshipwith each other is intended toprovide analyte concentrationprofiles that may aid in screeningnewborns for one or more ofseveral metabolic disorders. Thiskit is to be used for in vitro |
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| Disorders Screened | Amino-, organic-, and fatty acidmetabolic disorders | Same |
|---|---|---|
| Analytes Measured | Amino acids, free carnitine,acylcarnitines, and succinylacetone | Amino acids, free carnitine, andacylcarnitines |
| Methodology | Microplate based tandem massspectrometric assay | Same |
| Test Principle | Amino acids and carnitines in sampleare measured by tandem massspectrometry through analyte-specificmass transitions appropriate for eachtype of analyte. The extracted analytesare measured for set time periods andcompared to the signal intensitiesproduced by the corresponding isotope-labeled internal standards. Theconcentrations are determined bycomparing the signal intensities of theknown standards to the measuredanalytes. | Same |
| Quantitative Nature | Quantitative by internal standardization | Same |
| Sample Requirements | Newborn blood collected on Schleicherand Schuell 903 filter paper per NCCLSstandards | Same |
| Throughput | Ninety-six tests per microtiter plate.Multiple plates can be analyzed | Same |
| Analysis Time | 2 to 2.5 hours per plate. | Same |
| Controls | Controls are blood spots fromprocessed human blood enriched withseveral amino acids, carnitines andsuccinylacetone. | Controls are blood spots fromprocessed human blood enrichedwith several amino acids andcarnitines. |
| Calibrators | Internal calibration using severalisotopically labeled standards, includedas dried material in vials. Internalstandards must be reconstituted withextraction solution prior to their use. | Same |
| Assay format | Non-derivatized (analytes measured intheir native forms) | Derivatized (analytes converted tobutyl esters prior to beingmeasured) |
11 - 1 - 1 - 1
Analytes measured by the device
:
.
:
| Table 5.2: Analytes measured by the NeoBase kit and their most common abbreviated names | |
|---|---|
| ANALYTE NAME | ABBREVIATION |
| Amino acids | |
| Alanine | Ala |
| Arginine | Arg |
| Citrulline | Cit |
| Glycine | Gly |
:
1
·
{4}------------------------------------------------
| 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 |
| Octenoylcarnitine | C8:1 |
| Decanoylcarnitine | C10 |
| Decenoylcarnitine | C10:1 |
| Decadienoylcarnitine | C10:2 |
| Dodecanoylcarnitine | C12 |
| Dodecenoylcarnitine | C12:1 |
| Table 5.2: Analytes measured by the NeoBase kit and their most common abbreviated names (continued) | |
| 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 NeoBase Non-derivatized MSMS kit was compared to the predicate NeoGram Amino Acids and Acylcarnitines Tandem Mass Spectrometry Kit, K031878. Both devices utilize tandem mass spectrometry to measure a panel of
{5}------------------------------------------------
amino acids and acvicarnitines from neonatal dried blood spots. The panel of analytes measured by both devices is the same with the main exception that the NeoBase kit also includes the measurement of succinylacetone (the primary marker for the screening of Tyrosinemia Type I). Analytically, both devices are also very similar with the exception that the NeoBase kit does not require the derivatization of the sample prior to measurement (Tables 5.1 and 5.2).
The established performance characteristics of the NeoBase kit were 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. Both kits provide equivalent precision and recoveries and both devices have measurable ranges that cover all clinically significant ranges. Therefore, both kits provide performance levels that are adequate for their intended use.
Precision
Table 5.3: Averaged Total imprecision for amino acids. Data shown are average Total imprecision coefficients of variation (%CV) for both assays.
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Table 5.4: Averaged Total Imprecision for carnitine and acylcarnitines. Data shown are average Total imprecision coefficients of variation (%CV) for both assays.
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Recovery
Table 5.5: Averaged analyte percent recovery for both assays and associated %CV
| Analyte | NeoBase Recovery | Predicate Recovery | ||
|---|---|---|---|---|
| Average % | %CV | Average % | %CV | |
| ALA | 101 | 8 | 71 | 11 |
| ARG | 94 | 7 | 91 | 12 |
| CIT | 101 | 7 | 93 | 9 |
| GLY | 100 | 9 | 87 | 11 |
| LEU | 97 | 9 | 69 | 9 |
| MET | 89 | 6 | 89 | 18 |
| ORN | 91 | 7 | 72 | 14 |
| PHE | 99 | 7 | 96 | 22 |
| TYR | 101 | 6 | 81 | 11 |
| VAL | 90 | 10 | 68 | 16 |
| C0 | 93 | 7 | 139 | 12 |
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| C2 | 97 | 6 | 67 | 23 |
|---|---|---|---|---|
| C3 | 100 | 5 | 97 | 19 |
| C4 | 94 | 4 | 104 | 11 |
| C5 | 98 | 6 | 111 | 7 |
| C5DC | 102 | 4 | 102 | 14 |
| C6 | 95 | 4 | 89 | 10 |
| C8 | 97 | 5 | 105 | 21 |
| C10 | 101 | 5 | 83 | 10 |
| C12 | 97 | 5 | 106 | 33 |
| C14 | 95 | 5 | 95 | 18 |
| C16 | 93 | 5 | 98 | 15 |
| C18 | 94 | 6 | 89 | 18 |
Measurable Ranges
Table 5.6: Measurable ranges for both assays and corresponding clinically significant ranges (all in μM/L). and the comments of the comments of the comments of the comments of ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
| NeoBase Range | Predicate Range | Clinical Ranges | ||||
|---|---|---|---|---|---|---|
| Analyte | Lower | Upper | Lower | Upper | Normal | Cutoff |
| ALA | 4.5 | 4109 | 4.92 | 2868.0 | 67 - 492 | 975 - 1625 |
| ARG | 0.6 | 3754 | 0.31 | 5469.0 | 0 - 58 | 180 - 300 |
| CIT | 4.8 | 1711 | 0.53 | 2169.2 | 0 - 36 | 113 - 188 |
| GLY | 50.4 | 4794 | 9.81 | 4023.3 | 238 - 808 | 975 - 1625 |
| LEU | 1.3 | 2598 | 9.06 | 3078.0 | 26 - 239 | 263 - 438 |
Table 5.6: Measurable ranges for both assays and corresponding clinically significant ranges (all in μM/L). Continued.
| Analyte | NeoBase Range | Predicate Range | Clinical Ranges | |||
|---|---|---|---|---|---|---|
| Lower | Upper | Lower | Upper | Normal | Cutoff | |
| MET | 2.5 | 1192 | 8.03 | 1476.7 | 3 - 59 | 120 - 200 |
| ORN | 0.6 | 3825 | 1.60 | 4675.4 | 5 - 214 | 360 - 600 |
| PHE | 0.3 | 2395 | 0.75 | 2906.0 | 10 - 130 | 225 - 375 |
| TYR | 1.2 | 2867 | 1.42 | 2537.1 | 14 - 194 | 578 - 963 |
| VAL | 0.6 | 2388 | 114.80 | 2900.0 | 34 - 213 | 300 - 500 |
| C0 | 0.2 | 2298 | 2.13 | 4143.0 | 6.6 - 70.6 | 90 - 150 |
| C2 | 0.2 | 732 | 0.13 | 166.3 | 6.2 - 44.3 | 128 - 213 |
| C3 | 0.03 | 88 | 0.09 | 130.7 | 0 - 4.9 | 9.75 - 16.25 |
| C4 | 0.07 | 59.61 | 0.02 | 58.4 | 0 - 0.92 | 2.25 - 3.75 |
| C5 | 0.04 | 58.73 | 0.02 | 101.6 | 0 - 0.61 | 1.88 - 3.13 |
| C5DC | 0.08 | 28.88 | 0.16 | 30.9 | 0 - 0.22 | 0.6 - 1 |
| C6 | 0.08 | 61.50 | 0.01 | 38.0 | 0 - 0.33 | 0.98 - 1.63 |
| C8 | 0.02 | 35.42 | 0.02 | 48.0 | 0 - 0.46 | 1.2 - 2 |
| C10 | 0.04 | 28.69 | 0.01 | 46.6 | 0 - 0.32 | 1.35 - 2.25 |
| C12 | 0.04 | 42.99 | 0.04 | 76.4 | 0 - 0.74 | 1.88 - 3.13 |
| C14 | 0.02 | 41.88 | 0.01 | 32.1 | 0 - 0.55 | 1.5 - 2.5 |
| C16 | 0.10 | 107.40 | 0.04 | 76.4 | 0.08 - 5.78 | 11.25 - 18.75 |
| C18 | 0.04 | 32.19 | 0.01 | 55.9 | 0.1 - 1.69 | 3 - 5.0 |
...
.
7
:
:
{7}------------------------------------------------
Method Correlation
The method comparison study was executed based on the CLSI EP9-A2 quidelines. Samples were prepared in duplicates and assayed using both the NeoBase and NeoGram kits according to the corresponding kit inserts resulting in total of 158 samples acquired with each method. Each sample was tested twice within the same run within each method. Linear regression analysis provided correlation coefficients (R and R2) as well as slopes (Tables 5.7 to 5.9). The results from this study indicate that the test and predicate method correlated very well.
| Table 5.7: Method comparison: Correlation coefficient R and the Re for all amino acids. | |||||
|---|---|---|---|---|---|
| ----------------------------------------------------------------------------------------- | -- | -- | -- | -- | -- |
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Table 5.8: Method comparison: Correlation coefficient R and the R for free carnitine and acylcarnitines.
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Table 5.9: Method comparison: Slopes and Intercepts for all amino acids.
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Table 5.10: Method comparison: Slopes and Intercepts for free carnitine and acvicarnitines.
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|---|---|---|---|---|---|---|---|---|---|
| --------------------------------Controller College of the | |||||||||
| CAPANYMPACWOVAYAYAYAYAWAWWAWAAPHA. |
(2) Clinical
CLINICAL CORRELATION STUDIES
The clinical correlation studies took place at two different US newborn screening laboratories that evaluated the NeoBase kit in parallel to the predicate device (identical specimens were analyzed as paired samples by both methods). The sample set consisted of 9416 random neonatal samples, 104 samples from with true positive diagnoses, and 320 artificially enriched dried blood spots. Clinical correlation was established by assessing whether or not the methods were concordant in determining the paired samples to have analyte concentration values above or below their corresponding cutoffs. Examination on the number of
{8}------------------------------------------------
concordant pairs for each analyte (cases in which both methods agreed) provided the percent agreements shown in Table 5.11.
| Analyte | Total # of Observations | % Agreement | Analyte | Total # of Observations | % Agreement |
|---|---|---|---|---|---|
| ALA | 2559 | 99.7% | C14 | 9813 | 99.9% |
| ARG | 2564 | 100.0% | C16 | 9803 | 99.9% |
| CIT | 9805 | 99.8% | C18 | 9781 | 100.0% |
| GLY | 2474 | 99.8% | C4-OH/C3DC* | 2564 | 99.5% |
| LEU | 9771 | 99.6% | C5:1 | 9840 | 100.0% |
| MET | 9808 | 99.7% | C5-OH/C4DC* | 7276 | 98.4% |
| ORN | 2554 | 99.7% | C6DC | 9840 | 99.1% |
| PHE | 9749 | 99.8% | C10:1 | 9840 | 100.0% |
| TYR | 9803 | 99.9% | C12:1* | 2564 | 100.0% |
| VAL | 9745 | 99.5% | C14:1 | 9840 | 99.9% |
| C0 | 9461 | 99.9% | C14:2* | 2564 | 99.9% |
| C2 | 9808 | 100.0% | C14-OH* | 2564 | 99.9% |
| C3 | 9781 | 99.9% | C16:1* | 2564 | 100.0% |
| C4 | 2559 | 99.9% | C16:1-OH | 9840 | 100.0% |
| C5 | 9809 | 99.6% | C16-OH | 9840 | 100.0% |
| C5DC | 9840 | 97.2% | C18:1 | 9840 | 99.0% |
| C6 | 9840 | 100.0% | C18:1-OH | 9840 | 100.0% |
| C8 | 9840 | 100.0% | C18:2* | 2564 | 99.9% |
| C10 | 9840 | 99.9% | C18-OH | 9840 | 100.0% |
| C12 | 2559 | 99.9% |
Table 5.11: Percent agreement in clinical determinations by both methods (all samples)
*Only one of the two sites measured the indicated analytes.
*Several observations were associated with plate controls out of range. These observations were removed from the analysis and thus the lesser number of observations vs. the 9840 total.
COMPARISON OF TRUE POSITIVE SAMPLE RESULTS BETWEEN ASSAYS
In addition to the 104 true positive samples analyzed at the newborn screening sites, PerkinElmer R&D analyzed four Tyrosinemia Type I samples in parallel with both methods. Two of the 4 samples were acquired from the same subject approximately 14 days apart. The results for all true positive samples are summarized in Table 5.12
Table 5.12: Summary of the analysis of true Positive samples by the NeoBase and NeoGram assays. Disorders, along with number of corresponding true positive samples analyzed and detected are shown. N=108
| DisorderAbbreviation | Disorder Full name | Number Analyzed | Detected byNeoBase StudyCutoffs | Detected byPredicate StudyCutoffs |
|---|---|---|---|---|
| 3MCC | 3-Methylcrotonyl-CoA Carboxylase Deficiency | 9 | 9 | 9 |
| CUD | Carnitine Uptake Defect | 10 | 10 | 10 |
| CTD | Carnitine Transporter Defect | 1 | 1 | 1 |
| CPT-1 | Carnitine Palmitoyltransferase I Deficiency | 1 | 1 | 1 |
{9}------------------------------------------------
| Glutaric acidemia, type 1 | 9 | 9 | 9 | |
|---|---|---|---|---|
| HCY | Homocystinuria | 7 | 7 | 7 |
| IVA | Isovaleric acidemia | 9 | 9 | 9 |
| 2MBDD | 2-Methylbutyryl-CoA Dehydrogenase Deficiency | 1 | 1 | 1 |
| MCAD | Medium-Chain Acyl-CoA Dehydrogenase Deficiency | 16 | 16 | 16 |
| MCD | Multiple CoA Carboxylase Deficiency | 3 | 3 | 3 |
| MMA | Methylmalonic Aciduria | 2 | 2 | 2 |
| PPA | Propionic Acidemia | 3 | 3 | 3 |
| MSUD | Maple Syrup Urine Disease | 2 | 2 | 2 |
| SCAD | Short-Chain Acyl-CoA Dehydrogenase Deficiency | 1 | 1 | 1 |
| PKU | Phenylketonuria | 12 | 12 | 12 |
| CPT-2 | Carnitine Palmitoyltransferase II Deficiency | 1 | 0 | 0 |
| LCHAD | Long-Chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency | 5 | 5 | 5 |
| VLCAD | Very Long-Chain Acyl-CoA Dehydrogenase Deficiency | 11 | 10 | 10 |
| VLCHAD | Very Long-Chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency | 1 | 1 | 1 |
| TYR 1 | Tyrosinemia Type 1 | 4 | 4 | 0 |
The data presented in Table 5.12 indicate that with the exception of Tyrosinemia Type 1. the NeoBase assay is just as sensitive as the predicate NeoGram assay in detecting the true positive samples. The two samples that neither of the two assays were able to detect based on the study cutoffs were a CPT-2 and a VLCAD case. The CPT-2 sample had been in storage for over three years and the VLCAD sample had been stored at room temperature for over one year. As a result, it is very likely that the acylcarnitine analytes in these samples had experienced a significant degree of decay during that period of time and thus causing the corresponding analytes to be below the study cutoffs.
One significant difference between the NeoBase and the NeoGram assays is the fact that the NeoBase assay enables the measurement and detection of succinylacetone (SA), the primary marker for Tyrosinemia Type I. The results of the analysis of four Tyrosinemia Type I true positive samples are presented in Table 5.13.
| Table 5.13: SA and Tvr results for four true positives Tyrosinemia Type I samples. Results are shown | |||
|---|---|---|---|
| in uM quantities. | |||
| Site | AssayMarker | NeoBase | Predicate | |
|---|---|---|---|---|
| Patient 1 | Sample1 (25 hours of age) | SA4.42 | Tyr66 | TyrNA |
| Patient 1 | Sample2 (15 days of age) | SA5.73 | Tyr232 | TyrNA |
| Patient 2 | Sample1 | SA4.19 | Tyr144 | Tyr135 |
| Patient 3 | Sample2 | SA4.46 | Tyr227 | Tyr247 |
From the data presented in Table 5.13 it is evident that when patients are afflicted with Tyrosinemia Type I, their blood contains highly elevated levels of succinylacetone. However, elevated levels of Tyrosine are not always associated with this disorder. In the four cases presented in table 5.13, all four SA measurements are above the corresponding cutoff of >2uM. However, all available Tyrosine measurements are below cutoffs (<300uM). Such striking
{10}------------------------------------------------
results indicate that inclusion of succinylacetone in the panel provides improved specificity and sensitivity in the detection of Tyrosinemia type I.
Finally, the established performance characteristics and method comparison at the analytical and clinical levels show that the Neo Base Non-derivatized MSMS kit is substantial equivalent to the predicate device.
{11}------------------------------------------------
Image /page/11/Picture/0 description: The image shows the logo for the Department of Health & Human Services (HHS). The logo consists of a stylized depiction of an eagle or bird in flight, with three curved lines representing the wings. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the bird symbol. The logo is black and white.
Food and Drug Administration 10903 New Hampshire Avenue Building 66 Silver Spring, MD 20993
PerkinElmer Inc. c/o Ms. Kay A. Taylor Senior Manager Regulatory Affairs Wallac Oy 8275 Carloway Road Indianapolis, IN 46236
JUL - 9 2009
Re: K083130
Trade Name: NeoBase Non-Derivatized MSMS 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: NOL Dated: June 10, 2009 Received: June 11, 2009
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 vours.
G.C.H.
Courtney C. Harper, Ph.D. Acting 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
510(k) Number (if known): K083130
Device Name: NeoBase Non-derivatized MSMS kit
Indications For Use:
The NeoBase Non-derivatized MSMS reagent kit 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 |
asured by the NeoBase Non-derivatized MSMS Kit.
Prescription Use XX (Part 21 CFR 801 Subpart D) Over-The-Counter Use (21 CFR 807 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
AND/OR .
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Carol C. Benari
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K083130
Page 1 of 2
{14}------------------------------------------------
| ANALYTE NAME | ABBREVIATION |
|---|---|
| Carnitines | |
| 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 |
*Analytes in these rows are either isomers or isobars and cannot be distinguished in the tandem mass spectrometry experiment.
Prescription Use XX (Part 21 CFR 801 Subpart D) AND/OR
Over-The-Counter Use (21 CFR 807 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Carol C. Benson
Division Sign-Off Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K083130
Page 2 of 2
§ 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.