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510(k) Data Aggregation
(84 days)
PQW
The NeoLSD™ MSMS kit is intended for the quantitative measurement of the activity of the enzymes acid-9glucocerebrosidase (ABG), acid-sphingomyelinase (GAA), 8 galactocerebrosidase (GALC), agalactosidase A (GLA) and a-L-iduronidase (IDUA) in dried blood spots (DBS) from newborn babies. The analysis of the enzymatic activity is intended as an aid in screening newborns for the following lysosomal storage disorders (LSD) respectively; Gaucher Disease, Niemann-Pick A/B Disease, Krabbe Disease, Fabry Disease, and Mucopolyaccharidosis Type I (MPS I) Disease.
The NeoLSD MSMS test system uses mass spectrometry to quantitatively measure the activity of six lysosomal enzymes simultaneously from a dried blood spot sample. The NeoLSD MSMS test system is comprised of:
- NeoLSD MSMS kit, including substrates, internal standards, solutions and controls
- The QSight Instrument is comprised of:
QSight® 210 MD Mass Spectrometer O
QSight HC Autosampler MD Instrument Software O
QSight Binary Pump MD O
Simplicity Instrument control software: O
Simplicity Data Processing software (by sample): O
O PerkinElmer MSMS Workstation Data Processing Software
The NeoLSD MSMS kit evaluates enzyme activities by measuring the product generated when an enzyme reacts with a synthesized substrate to create a specific end product. The activities of the six lysosomal enzymes present in a 3.2 mm punch from a dried blood spot (DBS) are simultaneously measured by the NeoLSD MSMS kit. The punches are incubated with the assay reagent mixture which contains;
- six substrates, one corresponding to each lysosomal enzyme
- six stable-isotope mass-labeled internal standards (IS) each designed to chemically resemble each product generated
- . a buffer to maintain the reaction pH, and to carry inhibitors to limit activity from competing enzymes if present and additives to enhance the targeted enzyme reactions.
Here's a breakdown of the acceptance criteria and study information for the NeoLSD MSMS Kit, based on the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document doesn't explicitly state acceptance criteria in a dedicated table for screening performance per se, but it details the analytical performance and implies that meeting the predicate device's performance characteristics for screening, along with established analytical limits, constitutes acceptance. The "Comparison Chart" on page 6 includes some comparable metrics between the proposed and predicate device.
Below is a table summarizing the reported analytical performance, with implied acceptance criteria that the device's performance should be within acceptable clinical/analytical ranges and comparable to the predicate device.
| Performance Metric | Acceptance Criteria (Implied/General) | Reported Device Performance (QSight System) |
|---|---|---|
| Reportable Range (µmol/L/h) | Generally, a sufficiently broad and clinically relevant range. | IDUA: 0.19 – 22.3 |
| GAA: 0.31 – 25.3 | ||
| ABG: 0.79 – 20.0 | ||
| GLA: 0.80 – 20.4 | ||
| ASM: 0.16 – 13.8 | ||
| GALC: 0.20 – 7.75 | ||
| Lower Limits of Measure (LoB, LoD, LoQ) (µmol/L/h) | Limits should be clinically relevant and allow for detection of low enzyme activity associated with LSDs. Imprecision at LoQ within specified CV% limits (ABG, GLA, IDUA |
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(212 days)
PQW
The NeoLSD MSMS Kit is intended for the quantitative measurement of the activity of the enzymes acid-pglucocerebrosidase (ABG), acid-sphingomyelinase (ASM), acid-a-glucosidase (GAA), B-galactocerebrosidase (GALC), α-galactosidase A (GLA) and α-L-iduronidase (IDUA) in dried blood spots (DBS) from newborn babies. The analysis of the enzymatic activity is intended as an aid in screening newborns for the following lysosomal storage disorders (LSD) respectively; Gaucher Disease, Nieman-Pick A/B Disease, Pompe Disease, Fabry Disease, and MPS I Disease.
The NeoLSD MSMS test system uses mass spectrometry to quantitatively measure the activity of six lysosomal enzymes simultaneously from a dried blood spot sample. The NeoLSD MSMS test system is comprised of:
- NeoLSD MSMS kit, including substrates, internal standards, solutions and controls
- Waters TQD MSMS instrument comprised of,
a. Waters 1525 sample pump
b. Waters 2777c autosampler
c. Waters MassLynx v4.1 firmware C.
d. Power cables, tubing, syringes, connection cables - Waters NeoLynx v4.1 software and computer with monitor
- PerkinElmer MSMS Workstation Software
The NeoLSD MSMS kit evaluates enzyme activities by measuring the product generated when an enzyme reacts with a synthesized substrate to create a specific end product. The activities of the six lysosomal enzymes present in a 3.2 mm punch from a dried blood spot (DBS) are simultaneously measured by the NeoLSD MSMS kit. The punches are incubated with the assay reagent mixture which contains;
. six substrates, one corresponding to each lysosomal enzyme
. six stable-isotope mass-labeled internal standards (IS) each designed to chemically resemble each product generated
. a buffer to maintain the reaction pH, and to carry inhibitors to limit activity from competing enzymes if present and additives to enhance the targeted enzyme reactions.
The NeoLSD MSMS Kit is intended for the quantitative measurement of the activity of six lysosomal enzymes (acid-β-glucocerebrosidase (ABG), acid-sphingomyelinase (ASM), acid-α-glucosidase (GAA), β-galactocerebrosidase (GALC), α-galactosidase A (GLA), and α-L-iduronidase (IDUA)) in dried blood spots (DBS) from newborn babies. The analysis of enzymatic activity serves as an aid in screening newborns for Gaucher Disease, Niemann-Pick A/B Disease, Pompe Disease, Krabbe Disease, Fabry Disease, and MPS I Disease.
Here's an analysis of the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The acceptance criteria are generally implied by the performance metrics reported, such as linearity ranges, precision (reproducibility %CV), and LoQ values. The screening performance, particularly sensitivity and specificity, are key for a screening tool.
| Performance Characteristic | Acceptance Criteria (Implied) | Reported Device Performance (NeoLSD MSMS Kit) |
|---|---|---|
| Linear Range | Broad enough to cover physiological and pathological ranges | IDUA: 0.34 – 17.2 µmol/L/h |
| GAA: 0.44 – 24.2 µmol/L/h | ||
| ABG: 0.69 – 20.1 µmol/L/h | ||
| GLA: 0.97 – 20.9 µmol/L/h | ||
| ASM: 0.90 – 20.5 µmol/L/h | ||
| GALC: 0.63 – 6.3 µmol/L/h | ||
| Lower Limit of Quantitation (LoQ) | Low enough to detect deficient enzyme activity (within acceptable CV%) | IDUA: 0.44 µmol/L/h (CV% at LoQ: 18.2%) |
| GAA: 0.63 µmol/L/h (CV% at LoQ: 17.5%) | ||
| ABG: 0.69 µmol/L/h (CV% at LoQ: 21.7%) | ||
| GLA: 0.97 µmol/L/h (CV% at LoQ: 17.5%) | ||
| ASM: 0.90 µmol/L/h (CV% at LoQ: 20.0%) | ||
| GALC: 0.34 µmol/L/h (CV% at LoQ: 20.6%) | ||
| Reproducibility (%CV) | Within acceptable limits for a diagnostic assay (e.g., 90%) | 92.9% (76.5%-99.1%) (excluding invalid and lost-to-follow-up, including 2 Fabry females that were false negatives) |
| With female Fabry subjects excluded, the test system has no false negative results for any of the enzymes. | ||
| Specificity (overall) | High, to minimize false positives (e.g., >95%) | 99.4% (99.1%-99.6%) (excluding invalid and lost-to-follow-up) |
| False Positive Rate (overall) | Low, to minimize unnecessary follow-up (e.g., |
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(548 days)
PQW
The SEEKER System, including the SEEKER Instrument and the SEEKER LSD Reagent Kit-IDUA|GAA|GBA|GLA for use on the SEEKER Instrument, is intended for quantitative measurement of the activity of a-L-iduronidase, a-D-glucosidase, Bglucocerebrosidase and a-D-galactosidase A from newborn dried blood spot specimens as an aid in screening newborns for Mucopolysaccharidosis Type I, Pompe, Gaucher and Fabry diseases. Reduced activity of these enzymes may be indicative of these lysosomal storage diseases. The enzymes measured using the SEEKER LSD Reagent Kit-IDUA|GAA|GBA|GLA and their associated lysosomal storage diseases are listed below.
| Enzyme (abbreviation) | Disease |
|---|---|
| α-L-iduronidase (IDUA) | Mucopolysaccharidosis Type I (MPS I) |
| α-D-glucosidase (GAA) | Pompe |
| β-glucocerebrosidase (GBA) | Gaucher |
| α-D-galactosidase A (GLA) | Fabry |
The SEEKER System employs digital microfluidic technology to measure multiple lysosomal enzymatic activities quantitatively from newborn dried blood spot specimens. The following components are provided:
-
- SEEKER Instrument (including USB and power cables), Desktop PC with monitor, keyboard, mouse, and the Spot Logic software.
-
- SEEKER LSD Reagent Kit IDUA|GAA|GBA|GLA containing enzyme specific substrate reagents, dried blood spot extraction buffer, reaction stop buffer, 4 levels of calibrators and quality control dried blood spots containing 4 levels of quality control (OC) material. Each Reagent Kit contains sufficient consumables for 1440 tests. The contents of the kit are listed below:
| Component | Contents | Quantity |
|---|---|---|
| Quality control | ||
| dried blood spots | QC-Base Pool (QCBP) | 1x15 spots |
| QC-Low (QCL) | 1x15 spots | |
| QC-Medium (QCM) | 1x15 spots | |
| QC-High (QCH) | 1x15 spots | |
| Enzyme substrates | IDUA | 9x100 µL |
| GAA | 9x100 µL | |
| GBA | 9x100 µL | |
| GLA | 9x100 µL | |
| Calibrators | Calibrant A (CALA) | 9x50 µL |
| Calibrant B (CALB) | 9x50 µL | |
| Calibrant C (CALC) | 9x50 µL | |
| Calibrant D (CALD) | 9x50 µL |
Other components needed to run tests include the following:
| Component | Contents | Quantity |
|---|---|---|
| Other Reagents | Extraction Buffer (EXT) | 9 x 30 mL |
| Filler Fluid | 9 x 10 mL | |
| Cartridge | SEEKER cartridge | 1 x 36 |
The composition of the enzyme reagents and buffers are summarized below:
| Reagent (Description) | Composition |
|---|---|
| IDUA | |
| (α-L-iduronidase substrate) | 2 mM 4-MU-α-L-iduronide sodium salt |
| 3mM D-saccharolactone | |
| 0.04 M acetate buffer, pH 3.5 | |
| 20 mM methyl β-cyclodextrin | |
| 0.01% Tween20 | |
| GAA | |
| (α-D-glucosidase substrate) | 5 mM 4-MU-α-glucopyranoside |
| 12 µM acarbose | |
| 0.04 M acetate buffer, pH 3.8 | |
| 20 mM methyl β-cyclodextrin | |
| 0.01% Tween20 | |
| GBA | |
| (β-glucocerebrosidase substrate) | 16 mM 4-MU-β-glucopyranoside |
| 0.05 M/0.1M citrate phosphate buffer, pH 5.2 | |
| 0.01% Tween20 | |
| 1.5% sodium taurocholate | |
| GLA | |
| (α-D-galactosidase A substrate) | 10 mM 4-MU-α-galactopyranoside |
| 145 μM N-acetyl galactosamine | |
| 0.04 M acetate buffer, pH 4.6 | |
| 20 mM methyl β-cyclodextrin | |
| 0.01% Tween20 | |
| Stop Buffer STB | |
| (reaction stopping buffer) | 0.6 M NaHCO3, pH 11.0 in 0.04% Tween 20 |
| Extraction Buffer EXT | |
| (dried blood spot extraction buffer) | 0.1% Tween 20 in water |
| Filler Fluid | |
| (medium for droplet movement) | 0.1% Triton X-15 in 5cSt silicone oil |
The Seeker Calibrators are supplied as part of the SEEKER LSD Reagent Kit -IDUA|GAA|GBA|GLA. The calibrators consist of 4 levels of aqueous preparation of 4methylumbelliferone sodium salt (4-MU) in 0.6M sodium bicarbonate buffer, pH 11.0 with 0.01% Tween 20. The concentration of 4-MU in each of the 4 calibrators is indicated in the table below:
| Calibrator Level | Concentration of 4-MU |
|---|---|
| Calibrant A (CAL A) | 0.0375 µM |
| Calibrant B (CAL B) | 0.0750 µM |
| Calibrant C (CAL C) | 0.1500 µM |
| Calibrant D (CAL D) | 0.3000 µM |
The quality control dried blood spots include 4 levels of control material: OC Low (QCL), QC Medium (QCM) and QC High (QCH). The composition of the 4 quality control dried blood spot (DBS) is summarized below. QCBP is used to fill empty wells on a cartridge.
| Quality Control Level | Composition |
|---|---|
| QCBP | Heat inactivated human serum, adjusted to ~50% hematocrit |
| using human red blood cells | |
| QCL | 5% cord blood and 95% heat inactivated serum, adjusted to |
| ~50% hematocrit using human red blood cells | |
| QCM | 50% cord blood and 50% heat inactivated serum adjusted to |
| ~50% hematocrit using human red blood cells | |
| QCH | Human umbilical cord blood, adjusted to ~50% hematocrit |
| using human red blood cells |
The enzymatic activity values for the quality control DBS measured by the manufacturer are given on the lot specific quality control certificate included in each assay kit for all levels except QCBP. Each laboratory should establish its own mean and acceptable ranges for the quality control materials.
3. SEEKER Cartridges
-
- Finnipipette Novus 8-channel automatic pipette 1-10 uL
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- Finnipipette Novus 1-channel automatic pipette 10-100 uL
The SEEKER System is a device designed for quantitative measurement of the activity of α-L-iduronidase (IDUA), α-D-glucosidase (GAA), β-glucocerebrosidase (GBA), and α-D-galactosidase A (GLA) from newborn dried blood spot specimens. This serves as an aid in screening newborns for Mucopolysaccharidosis Type I (MPS I), Pompe, Gaucher, and Fabry diseases.
Here's an analysis of the acceptance criteria and the study that proves the device meets those criteria:
1. Acceptance Criteria and Reported Device Performance
The acceptance criteria for the SEEKER System are implicitly defined by the analytical and clinical performance standards required for its De Novo classification as a Class II device with special controls. These controls mandate thorough demonstration of performance characteristics, including clinical validity, reference intervals, carry-over, detection limits, and imprecision. The clinical validity is primarily demonstrated by the false positive and false negative rates observed in the pivotal clinical study.
Table: Acceptance Criteria (Implied by Regulatory Requirements) and Reported Device Performance
| Performance Characteristic | Acceptance Criteria (Implied) | Reported Device Performance (Pivotal Phase Study) | Notes |
|---|---|---|---|
| Clinical Validity (False Positive Rate) | Acceptable false positive rates to minimize unnecessary confirmatory testing and emotional burden. | IDUA: 0.035% | |
| GAA: 0.092% | |||
| GBA: 0.047% | |||
| GLA: 0.097% | These rates are considered acceptable, particularly given the benefits of early detection and the fact that newborns with "presumed normal" results after risk assessment were not followed up, potentially leading to an overestimation of the false positive rate. | ||
| Clinical Validity (False Negative Rate) | Acceptable false negative rates to ensure affected newborns are detected and receive timely therapy. | IDUA: 0% | |
| GAA: 0% | |||
| GBA: 0% | |||
| GLA: 0% (Note: 2 newborns that would have been FN at 7.0µmol/L/hr cutoff were TP at 8.0µmol/L/hr cutoff. Labeling specifies known limitations for female Fabry and late-onset Pompe). | The reported 0% false negative rate for IDUA, GAA, and GBA is based on active surveillance and the assumption that early-onset cases would be reported. However, some limitations are disclosed in the labeling, acknowledging potential false negatives due to clinical variability (e.g., late-onset Pompe, female Fabry patients). The adjustment of cutoffs over time also indicates complexities in achieving a perfect 0% FN rate. The note about GLA false negatives suggests that the 0% reported might be dependent on the specific cutoff used at the time. | ||
| Imprecision (Reproducibility) | Reproducibility across different instruments, reagent lots, and days, within acceptable limits. | ||
| (No explicit %CV target stated, but general medical device standards suggest low CVs for reliable quantitative assays). | IDUA: 14.2% - 28.5% CV (depending on concentration) | ||
| GAA: 12.0% - 17.0% CV | |||
| GBA: 15.7% - 38.0% CV | |||
| GLA: 9.4% - 16.3% CV | These CVs are generally considered acceptable for screening assays, especially at lower concentrations where biological variability or technical limitations might be higher. The CLSI EP5-A3 guideline was followed. | ||
| Linearity/Reportable Range | Linear response over the intended measurement range, covering normal and disease-associated values. | IDUA: 2.77 to 50.75 µmol/L/h | |
| GAA: 2.18 to 94.66 µmol/L/h | |||
| GBA: 2.14 to 73.24 µmol/L/h | |||
| GLA: 4.88 to 153.74 µmol/L/h. Max deviation from linearity 88 mg/mL and hematocrit at 66% caused significant negative bias; heparin increased imprecision. | Generally good, but specific interferences identified for IDUA (high protein, high hematocrit, heparin) are crucial for laboratories to consider. These are included in the package insert. | ||
| Carry-over | Demonstrate minimal or no significant impact from carry-over. | Most assays showed minimal bias ( |
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