Predicate Devices

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a reagent kit and a standard laboratory analysis method (tandem mass spectrometry) for measuring analyte concentrations. There is no mention of AI or ML being used for data analysis, interpretation, or decision-making. The performance studies focus on agreement with a predicate device based on established cutoffs, not on the performance of an AI/ML algorithm.

Therapeutic

No
This device is an in vitro diagnostic (IVD) kit used for screening newborns for metabolic disorders by measuring specific analytes in blood samples. It does not directly treat or prevent a disease, which is the definition of a therapeutic device.

Diagnostic

Yes

Explanation: The "Intended Use / Indications for Use" section explicitly states that the device is intended to "provide analyte concentration profiles that may aid in screening newborns for metabolic disorders," which is a diagnostic purpose. The device measures specific analytes to screen for medical conditions.

SaMD (Software as a Medical Device)

No

The device description clearly states it is a "reagent kit" and involves "extraction of dried blood spots" and "analysis using a tandem mass spectrometry (MSMS) system," indicating it is a hardware-based diagnostic assay, not software only.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Intended Use: The intended use explicitly states that the kit is for the "measurement and evaluation of amino acids, succinylacetone, free carnitine, and acylcarnitine concentrations from newborn heel prick blood samples dried on filter paper." This involves testing a sample taken from the human body (blood) in vitro (outside the body).
Purpose: The purpose is to "provide analyte concentration profiles that may aid in screening newborns for metabolic disorders." This is a diagnostic purpose, even though it's for screening rather than definitive diagnosis.
Device Description: The description details a process of extracting analytes from blood samples and analyzing them using a laboratory technique (tandem mass spectrometry). This is characteristic of an in vitro diagnostic test.
Anatomical Site: The sample is taken from a human anatomical site (newborn heel prick blood).
Intended User / Care Setting: The intended users are "Newborn screening laboratories," which are settings where in vitro diagnostic testing is performed.

All of these factors align with the definition of an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / 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 (Tabel 1) and their relationship with each other is intended to provide analyte concentration profiles that may aid in screening newborns for metabolic disorders.

Product codes (comma separated list FDA assigned to the subject device)

NQL

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 corresponding stable-isotope labeled internal standard is proportional to analyte concentration.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

Newborns

Intended User / Care Setting

Not Found

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Precision:
Table 5.3: Averaged Total imprecision for amino acids. Data shown are average Total imprecision coefficients of variation (%CV) for both assays.
Table 5.4: Averaged Total Imprecision for carnitine and acylcarnitines. Data shown are average Total imprecision coefficients of variation (%CV) for both assays.

Recovery:
Table 5.5: Averaged analyte percent recovery for both assays and associated %CV

Measurable Ranges:
Table 5.6: Measurable ranges for both assays and corresponding clinically significant ranges (all in μM/L).

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.

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 concordant pairs for each analyte (cases in which both methods agreed) provided the percent agreements shown in Table 5.11.

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. 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.

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 (

Regulation Number and Section

§ 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.

Summary

0

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 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.
[intended use employs a table to
identify each analyte detected]	The NeoGram Amino Acids and
Acylcarnitines Tandem Mass
Spectrometry kit is intended for the
measurement and evaluation of
amino acids, free carnitine, and
acylcarnitine concentrations from
newborn heel prick blood samples
dried on filter paper. Table 1 details
the analytes measured by the kit
Quantitative analysis of amino
acids, free carnitine, and
acylcarnitine and their relationship
with each other is intended to
provide analyte concentration
profiles that may aid in screening
newborns for one or more of
several metabolic disorders. This
kit is to be used for in vitro

3

| Disorders Screened | Amino-, organic-, and fatty acid
metabolic disorders | Same |
|---------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|
| Analytes Measured | Amino acids, free carnitine,
acylcarnitines, and succinylacetone | Amino acids, free carnitine, and
acylcarnitines |
| Methodology | Microplate based tandem mass
spectrometric assay | Same |
| Test Principle | Amino acids and carnitines in sample
are measured by tandem mass
spectrometry through analyte-specific
mass transitions appropriate for each
type of analyte. The extracted analytes
are measured for set time periods and
compared to the signal intensities
produced by the corresponding isotope-
labeled internal standards. The
concentrations are determined by
comparing the signal intensities of the
known standards to the measured
analytes. | Same |
| Quantitative Nature | Quantitative by internal standardization | Same |
| Sample Requirements | Newborn blood collected on Schleicher
and Schuell 903 filter paper per NCCLS
standards | 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 from
processed human blood enriched with
several amino acids, carnitines and
succinylacetone. | Controls are blood spots from
processed human blood enriched
with several amino acids and
carnitines. |
| Calibrators | Internal calibration using several
isotopically labeled standards, included
as dried material in vials. Internal
standards must be reconstituted with
extraction solution prior to their use. | Same |
| Assay format | Non-derivatized (analytes measured in
their native forms) | Derivatized (analytes converted to
butyl esters prior to being
measured) |

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

6

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.
-----------------------------------------------------------------------------------------	--	--	--	--	--

| Bell C. La branderson
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Table 5.8: Method comparison: Correlation coefficient R and the R for free carnitine and acylcarnitines.

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STATUS STORE PASSES PARCOM PUSAN ASSOCIATION PRODUCTION PRODUCTION PRODUCTION PARTICLES PARTICLE PARTICLE PARTICLE PARTICLE PARTICLE PARTICLE PARTICLE PARTICLE PARTICLE PARTE
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Table 5.9: Method comparison: Slopes and Intercepts for all amino acids.

| CON OF ANTIQUE ALL A LE A LE A LE A LE R LE R LE R LE R LE R LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE B LE
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Table 5.10: Method comparison: Slopes and Intercepts for free carnitine and acvicarnitines.

| CALIFORNIA COLORIES LE LE COLORIES CONSULACIO C LECCRECARI CARAL PURCLES POLECTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CON
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Callery of Children Company of Children Comments of Children Comments of Children Comments of Children Comments of Children Comments of Children Comments of Children Comments
****************************************************************************************************************************************************************************** | product any for aller. The first and alle | ****************************************************************************************************************************************************************************** | | PATION Co is Chan (an a can the first (first ) | 1 1 4 8 4 6 7 6 7 8 6 7 6 6 7 8 7 8 7 8 7 8 7 4 7 4 7 4 7 4 7 4 7 4 7 4 7 4 7 4 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 |
A CATAY CATATATA CONTROL CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSULTION CONSUL
19 2 2 2 4 2 4 2 4 2 4 2 6 9 4 2 6 2 4 7 6 2 6 2 6 2 6 2 6 2 6 2 6 2 6 2 6 6 2 6 6 2 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 | |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--|------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--|
| --------------------------------

(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

| Disorder
Abbreviation | Disorder Full name | Number Analyzed | Detected by
NeoBase Study
Cutoffs | Detected by
Predicate Study
Cutoffs |
|--------------------------|---------------------------------------------|-----------------|-----------------------------------------|-------------------------------------------|
| 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 | Assay
Marker | NeoBase | | Predicate |
|-----------|---------------------------|------------|------------|------------|
| Patient 1 | Sample1 (25 hours of age) | SA
4.42 | Tyr
66 | Tyr
NA |
| Patient 1 | Sample2 (15 days of age) | SA
5.73 | Tyr
232 | Tyr
NA |
| Patient 2 | Sample1 | SA
4.19 | Tyr
144 | Tyr
135 |
| Patient 3 | Sample2 | SA
4.46 | Tyr
227 | Tyr
247 |

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 ( 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