(427 days)
Not Found
No
The description details a standard immunoassay kit and instrument for measuring a specific biomarker. There is no mention of AI or ML in the device description, intended use, or performance studies. The analysis is based on a direct measurement, not an interpretation or prediction using AI/ML algorithms.
No.
The device is an in vitro diagnostic (IVD) test kit used to aid in the screening of newborns for Duchenne Muscular Dystrophy (DMD) by measuring the concentration of creatine kinase MM-isoform. It does not provide treatment or therapy.
Yes
The device is intended to aid in screening newborns for Duchenne Muscular Dystrophy (DMD) by quantitatively determining creatine kinase MM-isoform concentration, which directly relates to diagnosis.
No
The device description clearly lists multiple physical components (calibrators, controls, buffers, strips, barcodes) which are part of a chemical assay kit, not a software-only device.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states "in vitro determination of creatine kinase MM-isoform (CK-MM) concentration in blood specimens dried on filter paper". "In vitro" means "in glass" or "outside the body," which is a key characteristic of IVDs.
- Specimen Type: The device analyzes "blood specimens dried on filter paper," which are biological samples taken from the human body.
- Purpose: The purpose is to "aid in screening newborns for Duchenne Muscular Dystrophy (DMD)". This is a diagnostic purpose, even though it's a screening test.
- Device Description: The description details a "solid phase, two-site fluoroimmunometric assay," which is a laboratory test method used to analyze biological samples. The components listed are typical reagents and materials used in IVD assays.
All of these points align with the definition of an In Vitro Diagnostic device, which is a medical device intended for use in the examination of specimens derived from the human body to provide information for diagnostic, monitoring, or compatibility purposes.
N/A
Intended Use / Indications for Use
The GSP Neonatal Creatine Kinase-MM kit, is intended for the quantitative in vitro determination of creatine kinase MM-isoform (CK-MM) concentration in blood specimens dried on filter paper as an aid in screening newborns for Duchenne Muscular Dystrophy (DMD) using the GSP instrument.
Product codes
QJE
Device Description
The GSP Neonatal Creatine Kinase-MM assay is a solid phase, two-site fluoroimmunometric assay based on the direct sandwich technique and utilizes standard PerkinElmer DELFIA chemistry with the GSP instrument. The kit contains:
- . The CK-MM Calibrators (containing 0, 30, 120, 500, 2000 and 8000 ng/mL of creatine kinase) consisting of 7 cassettes each containing 1 set of dried blood spots.
- The CK-MM Controls (containing 130, 500 and 2000 ng/mL of creatine kinase) consisting of 5 cassettes each containing 2 set of dried blood spots.
- Anti-CK-MM-Eu Tracer ●
- CK-MM Assay Buffer ●
- Anti-CK-MM Microtitration strips ●
- Extra barcodes for the plates ●
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Blood specimens
Indicated Patient Age Range
Newborns
Intended User / Care Setting
Not Found
Description of the training set, sample size, data source, and annotation protocol
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Description of the test set, sample size, data source, and annotation protocol
The screening performance of the creatine kinase-MM kit was determined in a prospective clinical study of routine newborn screening samples and retrospectively confirmed positive DMD samples from newborns. Three thousand forty-one routine newborn samples and 30 clinically confirmed DMD positive newborn samples were tested. Most routine samples (97.3%) tested were from newborns ≤72 hours old. Routine samples were stored for (b) (4) days prior to testing and confirmed DMD positive samples ranged from 1 to 12 years of storage.
Clinical diagnosis of the 30 DMD confirmed retrospective positive samples was known. All confirmed DMD positive samples were screen positive.
Using next generation sequencing, four routine samples that were screen positive were determined to be DMD positive based on the genetic variant detected. Genetic variants of unknown significance were detected in three routine samples that were screen negative.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical studies:
The screening performance of the creatine kinase-MM kit was determined in a prospective clinical study of routine newborn screening samples and retrospectively confirmed positive DMD samples from newborns. Three thousand forty-one routine newborn samples and 30 clinically confirmed DMD positive newborn samples were tested. Most routine samples (97.3%) tested were from newborns ≤72 hours old. Routine samples were stored for (b) (4) days prior to testing and confirmed DMD positive samples ranged from 1 to 12 years of storage.
Screening algorithm:
Samples were initially tested in singlicate. If the CK-MM concentration was greater than the cut-off, new dried blood spot punches were re-tested in duplicate to confirm the high concentration results. For the specimens that were re-tested, final screening categorization was based on the mean value of the replicate retest results.
A cut-off value was applied to all specimens to classify samples into screen positives and screen negatives to estimate the false positive and false negative screening rates of the test. The outcome of all routine samples with CK-MM concentrations above 1250 ng/mL when initially tested (prior to duplicate re-test) was evaluated using next generation sequencing of the DMD gene. To estimate the false negative rate of the test, the outcome of samples with CK-MM concentrations between 984 and 1210 ng/mL when initially tested were also evaluated using next generation sequencing of the DMD gene. During the review of this submission. FDA consulted with experts in the field of DMD diagnosis who confirmed that sequencing of the DMD gene is a widely accepted method of diagnosing DMD.
Outcome for routine samples only (cut-off 1250 ng/mL):
- Screened samples: 3041
- Above initial cutoff: 86
- Below initial cutoff: 2955
- Retest rate: (b) (4)
- Screen Positive (above cut-off after repeat testing): 73*
- Screen Negative (below cut-off after repeat testing): 2968**
- False positive rate: 2.26%
Outcome for routine samples only (cut-off 2040 ng/mL):
- Screened samples: 3041
- Above initial cutoff: 21
- Below initial cutoff: 3020
- Screen Positive (above cut-off after repeat testing): 20*
- Screen Negative (below cut-off after repeat testing): 3021**
- False positive rate: 0.53%
Outcome for routine samples and DMD confirmed positives (cut-off 1250 ng/mL):
- Screened samples: 3071
- Above initial cutoff: (b) (4)
- Screen Positive (above cut-off after repeat testing): (b) (4)
- Screen Negative (above cut-off after repeat testing): (b) (4)
Outcome for routine samples and DMD confirmed positives (cut-off 2040 ng/mL):
- Screened samples: 3071
- Above initial cutoff: (b) (4)
- Screen Positive (above cut-off after repeat testing): (b) (4)
- Screen Negative (above cut-off after repeat testing): (b) (4)
Screening Performance (Cut-off: 1250 ng/mL):
- Creatine Kinase MM kit Positive: 34* (DMD positive), 0 (Indeterminate), 69 (Presumed DMD negative), 0 (Not determined), Total: 103
- Creatine Kinase MM kit Negative: 0 (DMD positive), 3** (Indeterminate), 97 (Presumed DMD negative), 2868 (Not determined), Total: 2968
- Total: 34 (DMD positive), 3** (Indeterminate), 166 (Presumed DMD negative), 2868 (Not determined), Total: 3071
Screening Performance (Cut-off: 2040 ng/mL):
- Creatine Kinase MM kit Positive: 34* (DMD positive), 0 (Indeterminate), 16 (Presumed DMD negative), 0 (Not determined), Total: 50
- Creatine Kinase MM kit Negative: 0 (DMD positive), 3** (Indeterminate), 150 (Presumed DMD negative), 2868 (Not determined), Total: 3021
- Total: 34 (DMD positive), 3** (Indeterminate), 166 (Presumed DMD negative), 2868 (Not determined), Total: 3071
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
False positive rate (cut-off 1250 ng/mL): 2.26% (routine samples only)
False positive rate (cut-off 2040 ng/mL): 0.53% (routine samples only)
The sponsor included the following statement in the labeling regarding future lots:
At the 99.5th percentile the false negative screen rate of future lots could range from 0% to 0.48% (based on the upper 95% confidence interval) and the false positive screen rate of future lots could range from 0.4 to 0.7%. At the 97.5th percentile the false negative screen rate of future lots could range from 0% to 0.05% (based on the upper 95% confidence interval) and the false positive screen rate of future lots could range from 2.0 to 3.7%.
Predicate Device(s)
Not Found
Reference Device(s)
Predetermined Change Control Plan (PCCP) - All Relevant Information
Not Found
§ 862.1506 Muscular dystrophy newborn screening test.
(a)
Identification. A muscular dystrophy newborn screening test is an in vitro diagnostic device intended to measure creatine kinase levels obtained from dried blood spot specimens on filter paper from newborns as an aid in screening newborns for muscular dystrophy.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Design verification and validation must include a clinical validation study that includes the following:
(i) Results that demonstrate that the analyte being measured identifies a population of newborns who should be subject to follow up diagnostic testing for the condition being screened.
(ii) Predictive value of the device demonstrated using either well characterized prospectively or retrospectively obtained clinical specimens from the intended use population.
(iii) Testing performed by device users who are representative of the types of operators intended to use the test.
(iv) A design that assesses the effects of sample collection and processing steps on test performance.
(v) Tested confirmed positive specimens must have associated diagnostic outcome information based on confirmatory diagnostic methods, or clinically meaningful information regarding the status of the subject must be obtained.
(vi) Data, provided or referenced, generated in samples from the intended use population, that demonstrates the upper reference interval(s), including sufficient samples to calculate the 97.5th and 99.5th percentile information, for the analyte or analytes measured by the device.
(2) The labeling required under § 809.10(b) of this chapter must include:
(i) A warning which states that test results are not intended to diagnose muscular dystrophies.
(ii) A warning which states that test results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods, and clinical evaluation as appropriate.
(iii) Detailed information on device performance, including the false positive screen rate and the false negative screen rate observed in the clinical study, and any limitations to the data generated in the clinical study (
e.g., necessity for testing at a specific age).(iv) Information on device performance in relevant subgroups (
e.g., age of newborn at time of sample collection, birth weight, sex, gestational age) observed in the clinical study.
0
EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR GSP Neonatal Creatine Kinase-MM kit
DECISION SUMMARY
A. DEN Number:
B. Purpose for Submission:
De Novo request for evaluation of automatic class III designation for the GSP Neonatal Creatine Kinase-MM kit
C. Measurand:
Creatine Kinase MM-isoform
D. Type of Test:
Quantitative, fluoroimmunometric assay
E. Applicant:
PerkinElmer, Inc.
F. Proprietary and Established Names:
GSP Neonatal Creatine Kinase-MM kit
G. Regulatory Information:
| Regulation | Name | Product
Code | Panel |
|-----------------|----------------------------------------------|-----------------|----------------|
| 21 CFR 862.1506 | Muscular dystrophy newborn
screening test | QJE | Chemistry (75) |
H. Indications for Use:
-
- Indications for Use:
The GSP Neonatal Creatine Kinase-MM kit, is intended for the quantitative in vitro determination of creatine kinase MM-isoform (CK-MM) concentration in blood specimens dried on filter paper as an aid in screening newborns for Duchenne Muscular Dystrophy (DMD) using the GSP instrument.
- Indications for Use:
1
2. Special conditions for use statement(s)
-
For prescription use only ●
-
This kit is not intended for use as a diagnostic test for DMD or for screening of other ● forms of muscular dystrophies
-
Due to the complexity of the DMD carrier phenotype, there is a possibility that asymptomatic female carriers may have a false positive screening result and that symptomatic/manifesting female carriers may have a false negative screening result.
-
. Test results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods, and clinical evaluation as appropriate.
-
. Storage of samples in an environment with elevated temperatures (37℃) and humidity (80%) increases the risk of false negative screening results.
-
. CK-MM may not be elevated in all DMD infants immediately after birth as it is a marker of skeletal muscle damage and therefore an indirect marker of DMD. In cases such as extremely preterm birth or very low birth weight, the muscle damage sustained by the newborn due to DMD may be limited, and thus false negative DMD screening results may be obtained. While no newborns with DMD were missed in the clinical validity study, in another study a known DMD positive, extremely preterm (50,000 ng/mL.
-
c. Traceability, Stability, Expected values:
In the absence of an international reference preparation or a reference method for CK-MM concentration, the calibration is anchored to an in-house CK-MM reference preparation. The traceability scheme was reviewed and found acceptable.
The sponsor included the following statement in the labeling:
As a result of possible variability and systematic bias among lots, at the 99.5th percentile the false negative screen rate of future lots could range from 0% to 0.48% (based on the upper 95% confidence interval) and the false positive screen rate of future lots could range from 0.4 to 0.7%. At the 97.5th percentile the false negative screen rate of future lots could range from 0% to 0.05% (based on the upper 95% confidence interval) and the false positive screen rate of future lots could range from 2.0 to 3.7%.
Detection limit:
The Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantitation (LoQ) for the test system was determined. The analysis of the LoB, LoD, and LoQ were performed following the recommendations in the CLSI EP17-A2 guideline.
To determine the LoB, five blank samples were prepared from a(b) (4) human red blood cells (RBCs) (b) (4) . Each sample was prepared from a different lot of RBCs. Hematocrit (P) (4) (b) (4) The samples were assayed in(D) (4) The LoB was determined for each lot using the non-parametric approach described in CLSI EP17-A2. The LoB for the worse performing lot is reported in the package insert.
To determine LoD, (b) (4)
Each
sample was prepared from a different lot of RBCs. Hematocrit (b) (4) The samples were assayed (b) (4)
LoD was determined for each lot using the precision profile approach described in CLSI EP17-A2. The LoD for the worse performing lot is reported in the package insert.
LoO was estimated by first fitting a linear model with SD as the response variable and then determining the point where the fitted variation model reaches the LoQ study acceptance limit ((b) % CV). (4)
The LoB, LoD, and LoQ are summarized in the table below:
7
| LoB | LoD | LoQ |
|---|---|---|
| 0.7 ng/mL | 2.2 ng/mL | 6.8 ng/mL |
d. Analytical specificity:
Analytical specificity studies were performed following the recommendations in the CLSI EP07-A2 guideline. Potential interferents tested included unconjugated bilirubin, conjugated bilirubin, triglycerides (intralipid), free hemoglobin, albumin, acetaminophen, calcifediol, chlorhexidine, glucose, and galactose. Three blood pools with different CK-MM concentration levels (approximately 200 ng/mL, 500 ng/mL and 1500 ng/mL) were prepared by spiking human whole blood with purified human CK-MM. The hematocrit values of the blood pools used in the sample preparation were (b) (4) %. The test pools were prepared by (b) (4) Control pools were prepared by (b) (4) Test and were prepared by were (b) (4)
(b) = E Samples were assayed in replicates of For the hematocrit interference studies, pools were prepared by (b) (4)
% for the control pool, and hematocrit targets of (b)
for the test pools. The limit for significant interference was defined as (b) (4) The following substances at the listed concentrations did not interfere with the performance of the test:
| Potential Interferent | Highest Concentration of interferent
tested that did not show significant
interference (Endogenous + added
concentration of tested substance in
whole blood) |
|------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Unconjugated bilirubin | 20 mg/dL (20 mg/dL) |
| Conjugated bilirubin | 33 mg/dL (33 mg/dL) |
| Triglycerides | 1500 mg/dL (1590mg/dL) |
| Albumin | 30 g/L (47 g/L) |
| Acetaminophen | 5.5 mg/dL |
| Ascorbic acid | 1.5 mg/dL |
| Ampicillin | 18 mg/L |
| Calcifediol | 250 nmol/L (283 nmol/L) |
| Gamma Globulin | 30 g/L (36 g/L) |
| Folate | 3 mg/L |
| EDTA | 9 mg/mL |
| Glucose | 500 mg/dL |
| Galactose | 7.5 mg/dL |
| Hemoglobin | 3.75 g/dL (20 g/dL) |
The following is included in the package insert:
8
Chlorhexidine digluconate was found to result in significant interference to the device at a concentration of 0.04%. This interference resulted in an increased CK-MM level. which could result in false positive screen results from the test. This information is included in the test labeling, with instructions that when chlorhexidine digluconate is used for cleaning of the skin prior to specimen collection, the skin is allowed to thoroughly air dry before puncture to avoid contamination of the sample with the disinfectant.
The effect of hematocrit was tested by adjusting the amount of red blood cells with plasma on three whole blood DBS samples with different CK-MM concentrations (159, 514, and 1870 ng/mL) and testing the blood samples with the GSP Neonatal Creatine Kinase-MM kit for hematocrit interference according to CLSI document EP07-A2. The labeling includes a notation that the device is subject to interference in samples with low hematocrit (35-45%) with the lowest CK-MM concentration tested (159 ng/mL). The other tested CK-MM concentration results were equivalent within the tested range of hematocrit (35-65%).
Cross-reactivity
To assess cross reactivity of CK-BB, three blood pools with different CK-MM concentration levels (b) (4) were prepared by spiking human whole blood with purified human CK-MM. An additional blood pool with CK-MM was prepared from a suspension of red blood cells (b) (4) The hematocrit values of the blood pools used in the sample preparation (b) (4) The test pools were prepared by (b) (4) Control pools were prepared by (b) (4) (b) (4) Cross-reaction percentages
were calculated by determining the (D) (4)
The limit for significant cross-Samples were assaved in replicates of(b) reactivity was defined as
| CK-BB
level
(ng/mL)
(b) (4) | CK-MM
(ng/mL) | Cross
reactivity
(%) |
|--------------------------------------|------------------|----------------------------|
| | | |
| | | |
| | | |
In a separate study, clinically relevant levels of CK-MB were assessed for crossreactivity. Three blood pools with different CK-MM concentration level (approximately 200 ng/mL, 500 ng/mL and 1500 ng/mL) were prepared by (b) (4) The hematocrit values of the
9
| blood pools used in the sample preparation (b) (4) | (b) (4) | |
|---|---|---|
| . The results are summarized below | ||
| CK-MM | ||
| level | ||
| (ng/mL) | CK-MB | |
| (ng/mL) | Cross | |
| reactivity | ||
| (%) | ||
| (b) (4) |
-
e. Assay Cut-off:
Not applicable. -
f. Specimen Stability
The sponsor provided information to support the following information regarding DBS sample stability in their labeling: -
CK-MM is stable for up to 200 days at +4°C in dry conditions .
-
CK-MM may have moderate loss of concentration (up to 27%) after 6 days at . +4℃ in ambient conditions
-
CK-MM is stable for up to 25 days at -20℃ in ambient conditions .
-
CK-MM is stable for up to 20 days at +21°C in dry conditions .
-
CK-MM may have moderate loss of concentration (up to 30%) after 2 days at . +21℃ in ambient conditions
-
CK-MM is unstable in humid (RH 80%) conditions at +21 ℃ and +35℃ (