K Number

Device Name

INTROL CF PANEL I CONTROL

Manufacturer

MAINE MOLECULAR QUALITY CONTROLS, INC.

Date Cleared

2006-10-12

(59 days)

Product Code

NZB QUA

Regulation Number

866.5910

Intended Use

INTROL™ CF Panel I Control is intended for in vitro diagnostic use as a quality control to monitor analytical performance of the extraction, amplification and detection steps of diagnostic assays used in the detection of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations and variants. This product is intended to be extracted and analyzed routinely with each CFTR assay run. The INTROL™ CF Panel I Control is designed to monitor the detection of 38 CFTR mutations associated with cystic fibrosis, including the 23 mutations recommended for testing by American College of Medical Genetics (ACMG) and American College of Obstetricians and Gynecologists (ACOG). The INTROLTM CF Panel I Control also monitors 3 polymorphisms (1506V, 1507V, F508C) and the 5/7/9T variants.

Device Description

INTROL™ CF Panel I Control consists of synthetic CFTR DNA suspended in a matrix of synthetic DNA targets, carrier DNA of a non-human species, preservatives, dye, and stabilizers. The synthetic DNA contains all 27 CFTR gene exons plus intronic borders, and contains specific mutations and polymorphisms which are divided among 5 bottles (bottles a, b, c, d, and e). The 5 bottles exist in two versions: Version G106ac includes bottles (a), (b), and (c), while Version G106de includes bottles (a), (b), (d), and (e). The specific mutations present in each bottle are listed below in Table 1; all other CFTR sequence is wild type. CFTR mutations that are not listed cannot be detected in the INTROL™ CF Panel I Control. Control sequences include the mutations, wild type alleles, and polymorphisms recommended for testing by the American College of Medical Genetics (ACMG) and American College of Obstetricians and Gynecologists (ACOG). CFTR mutations that are not listed cannot be detected in the INTROL™ CF Panel I Control. CFTR DNA is stabilized in the matrix and released when processed through common extraction methods as if it were a whole blood specimen. Following extraction, the released DNA can be used in common amplification based molecular assays techniques. Because INTROL™ CF Panel I Control is designed to mimic the whole blood sample, the resulting copy number of the artificial CFTR segment, after extraction, will be similar to that found in a processed human whole blood sample (v/v).

More Information

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Type

Center

Panel

Date Received

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Subsequent Product Codes

Applicant Name (Manufacturer)

Device Name

Decision

Street 1

Street 2

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ZIP

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Class Advise Committee

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Third Party Reviewed

Expedited Review

Predicate Devices

Not applicable.

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The device is a quality control material for genetic testing, not a diagnostic or analytical device that would typically incorporate AI/ML for interpretation or analysis. The description focuses on the composition and performance of the control material itself.

Therapeutic

No.
This device is an in vitro diagnostic quality control for monitoring diagnostic assays, not for treating a condition.

Diagnostic

This device is a quality control to monitor the performance of diagnostic assays, not a diagnostic device itself.

SaMD (Software as a Medical Device)

The device is a physical control material consisting of synthetic DNA suspended in a matrix, intended for use in laboratory assays. It is not software.

IVD (In Vitro Diagnostic)

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

Here's why:

Intended Use: The "Intended Use / Indications for Use" section explicitly states that the product is "intended for in vitro diagnostic use as a quality control to monitor analytical performance of the extraction, amplification and detection steps of diagnostic assays used in the detection of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations and variants." This clearly indicates its use in a laboratory setting to evaluate the performance of diagnostic tests.
Device Description: The description details the composition of the control material, which is designed to mimic a human sample for use in laboratory testing procedures (extraction, amplification, detection).
Intended User / Care Setting: The intended users are clinical laboratories, which are the typical setting for in vitro diagnostic testing.
Performance Studies: The document describes analytical performance studies conducted to evaluate the device's reproducibility, performance with different extraction methods, and stability. These types of studies are standard for demonstrating the performance of IVD devices.

The device is a quality control material used with diagnostic assays, but its intended use is specifically within the context of in vitro diagnostic testing to ensure the reliability of those assays.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

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

NZB

Device Description

Control sequences include the mutations, wild type alleles, and polymorphisms recommended for testing by the American College of Medical Genetics (ACMG) and American College of Obstetricians and Gynecologists (ACOG). CFTR mutations that are not listed cannot be detected in the INTROL™ CF Panel I Control.

CFTR DNA is stabilized in the matrix and released when processed through common extraction methods as if it were a whole blood specimen. Following extraction, the released DNA can be used in common amplification based molecular assays techniques. Because INTROL™ CF Panel I Control is designed to mimic the whole blood sample, the resulting copy number of the artificial CFTR segment, after extraction, will be similar to that found in a processed human whole blood sample (v/v).

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

Not Found

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)

Analytical Performance: All INTROL™ CF Panel I Control products are tested by an FDA-cleared CFTR mutation detection method before being released for market distribution. Any mutations not tested by the FDA-cleared method are sequenced bidirectionally before product is released. All mutations must be detected.

Precision/Reproducibility: The clinical study performed at the external sites evaluated reproducibility of INTROL™ CF Panel I quality control material with respect to within run, between run, between sites, between lots, and between methods. A total of 21 extraction methods were evaluated across 134 laboratories, with 129 successful laboratory extractions (96%). INTROL™ CF Panel I quality control material was tested using CFTR assays at 10 external sites, 8 of which were clinical laboratories representing intended users. Samples from 11 different manufacturing lots were tested at minimally 3 external sites in at least 3 separate runs. The total calls across all methods and sites was 1133, with 100% correct calls observed.

Stability:
Real time stability study: Results support a shelf-life of 12 months. Stability was tested using 4 different methods, including cleared Tag-It™ Cystic Fibrosis (CF) Kit from Tm Bioscience, and bidirectional sequencing. Testing was performed at 1, 2, 3, 4, and 12 months. In addition, real time testing was performed with 5 different lots of quality control material. At 12 months, all mutations and variants were tested using either the FDA cleared assay or bidirectional sequencing, showing 100% correct calls at all time points.

Stress testing:
Elevated Temperature Studies: Demonstrated product stability during prolonged shipping without refrigeration. No loss of signal after incubation at 60°C for 21-24 days.
Freeze/Thaw Studies: No loss of signal was detectable after one cycle of freeze/thaw at -20℃ for 48 hours.
Open Vial Stability: Two studies demonstrated no loss of signal when used in CFTR assay at the end of the test period after 49 days storage at 2-8℃ (briefly opened) and 35 days (opened with pipette simulation six times).

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Not Found

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

Not applicable.

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

Not Found

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

Regulation Number and Section

§ 866.5910 Quality control material for cystic fibrosis nucleic acid assays.

(a)
Identification. Quality control material for cystic fibrosis nucleic acid assays. A quality control material for cystic fibrosis nucleic acid assays is a device intended to help monitor reliability of a test system by detecting analytical deviations such as those that may arise from reagent or instrument variation in genetic testing. This type of device includes recombinant, synthetic, and cell line-based DNA controls.(b)
Classification. Class II (special controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 866.9. The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Quality Control Material for Cystic Fibrosis Nucleic Acid Assays.” See § 866.1(e) for the availability of this guidance document.

Summary

510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY

A. 510(k) Number: K060070
B. Purpose for Submission: New device
C. Measurand:

Controls for assays detecting Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations and variants

D. Type of Test: Assayed quality control material
E. Applicant: Maine Molecular Quality Controls, Inc. (MMQCI)
F. Proprietary and Established Names: INTROL™ CF Panel I Control
G. Regulatory Information:
- 1. Regulation section: 866.5910 DNA quality control material for genetic testing
- 1. Classification: De novo, Class II
- 1. Product code: NZB, Quality control material, genetics, DNA
- 1. Panel: Immunology (82)

H. Intended Use:

1. Intended use(s):
  INTROL™ CF Panel I Control is intended for in vitro diagnostic use as a quality control to monitor analytical performance of the extraction, amplification and detection steps of diagnostic assays used in the detection of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations and variants. This product is intended to be extracted and analyzed routinely with each CFTR assay run.
1. Indication(s) for use:
  INTROL™ CF Panel I Control is intended for in vitro diagnostic use as a quality control to monitor analytical performance of the extraction, amplification and detection steps of diagnostic assays used in the detection of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene mutations and variants. This product is intended to be extracted and analyzed routinely with each CFTR assay run.

The INTROL™ CF Panel I Control is designed to monitor the detection of 38 CFTR mutations associated with cystic fibrosis, including the 23 mutations recommended for testing by American College of Medical Genetics (ACMG) and American College of Obstetricians and Gynecologists (ACOG). The INTROLTM CF Panel I Control also monitors 3 polymorphisms (1506V, 1507V, F508C) and

the 5/7/9T variants.

1. Special conditions for use statement(s): For prescription use only.
  The INTROL™ CF Panel I Control is designed to monitor the presence of 38 CFTR mutations associated with cystic fibrosis, including the 23 mutations recommended for testing by American College of Medical Genetics (ACMG) and American College of Obstetricians and Gynecologists (ACOG). The INTROLTM CF Panel I Control also monitors 3 polymorphisms (1506V, 1507V, F508C) and the 5/7/9T variants.
1. Special instrument requirements: Not applicable.

I. Device Description:

Table 1. Composition of INTROLTM CF Panel I Control includes following combinations of CFTR mutations and polymorphisms (plus wild type sequence covering 27 CFTR exons).

Allele	Genotype	Allele	Genotype
	Bottle a (both versions)		Bottle b (both versions)
7T*	7T / 7T	E60X	Homozygous mutant
(I507V)*	I507V / WT	G85E*	Homozygous mutant
(F508C)*	F508C / WT	I148T	Homozygous mutant
S549N/ S549R	Heterozygous	621+1G>T*	Homozygous mutant
S1251N	Heterozygous	711+1G>T*	Homozygous mutant
		1078delT	Homozygous mutant
	Bottle c (Version ac only)	R334W*	Homozygous mutant
394delTT	Heterozygous	R347P*	Homozygous mutant
R117H*	Heterozygous	9T*	9T / 9T
R347H	Heterozygous	A455E*	Homozygous mutant
5T* / 7T*	Heterozygous	del F508*	Homozygous mutant
(I506V)*	I506V / WT	V520F	Homozygous mutant
del 1507*	Heterozygous	1717-1G>A*	Homozygous mutant
R553X*	Heterozygous	G542X*	Homozygous mutant
2183AA>G	Heterozygous	G551D*	Homozygous mutant
		R560T*	Homozygous mutant
	Bottle d (Version de only)	1898+1G>A*	Homozygous mutant
394delTT	Homozygous mutant	2143delT	Homozygous mutant
R117H*	Homozygous mutant	2184delA*	Homozygous mutant
R347H	Homozygous mutant	2789+5G>A*	Homozygous mutant
5T*	5T / 5T	3120+1G>A*	Homozygous mutant
del 1507*	Homozygous mutant	3199del6	Homozygous mutant
R553X*	Homozygous mutant	D1152H	Homozygous mutant
2183AA>G	Homozygous mutant	R1162X*	Homozygous mutant
		3659delC*	Homozygous mutant
	Bottle e (Version de only)		3849+10kbC>T*	Homozygous mutant
7T*	7T / 7T	3876delA	Homozygous mutant
(I506V)*	I506V / I506V	3905insT	Homozygous mutant
		W1282X*	Homozygous mutant
		N1303K*	Homozygous mutant

*ACMG / ACOG Panel

J. Substantial Equivalence Information:

1. Predicate device name(s): Not applicable.
1. Predicate 510(k) number(s): Not applicable.
1. Comparison with predicate: Not applicable

K. Standard/Guidance Document Referenced (if applicable): None referenced.

L. Test Principle:

Not applicable.

M. Performance Characteristics (if/when applicable):

1. Analytical performance:
  All INTROL™ CF Panel I Control products are tested by an FDA-cleared CFTR mutation detection method before being released for market distribution. Any mutations not tested by the FDA-cleared method are sequenced bidirectionally before product is released. All mutations must be detected.
a. Precision/Reproducibility:
The clinical study performed at the external sites evaluated reproducibility of INTROL™ CF Panel I quality control material with respect to within run, between run, between sites, between lots, and between methods. External site evaluations:

The clinical laboratory study performed at the external sites evaluated reproducibility of INTROL™ CF Panel I Control quality control material with respect to within run, between run, between sites, between lots, and between methods.

Evaluation using different extraction methods:

| # extraction
methods | #
laboratories | # successful laboratory
extractions | percent
successful |
|-------------------------|-------------------|----------------------------------------|-----------------------|
| 21 | 134 | 129 | 96% * |

Five laboratories didn't continue after DNA extraction because DNA quantitation method they used indicated that no DNA was extracted/isolated. Considering that the level of synthetic CFTR DNA present in the extracted control may not be detectable with certain quantitation methods, there is a possibility that extractions in these 5 laboratories may have been successful; however this could not be assessed because the assays were not performed.

INTROL™ CF Panel I quality control material has been tested using CFTR assays at 10 external sites. 8 of which were clinical laboratories representing intended user. Samples from 11 different manufacturing lots were tested at minimally 3 external sites in at least 3 separate runs. Results are summarized in the Table 2.

| Method | Site | # of
Lots1 | # of
Runs | Total
Calls | Percent
Correct
Calls |
|--------------------------------|------|---------------|--------------|----------------|-----------------------------|
| Tag-ItTM | 1 | 10 | 9 | 223 | 100% |
| Tag-ItTM | 2 | 3 | 9 | 138 | 100% |
| Tag-ItTM | 3 | 1 | 1 | 6 | 100% |
| Tag-ItTM | 4 | 1 | 1 | 7 | 100% |
| Tag-ItTM | 5 | 1 | 1 | 4 | 100% |
| eSensor | 6 | 5 | 1 | 30 | 100% |
| eSensor | 7 | 5 | 1 | 38 | 100% |
| Other Amplification
methods | 8 | 3 | 1 | 31 | 100% |
| Other Amplification
methods | 9 | 1 | 2 | 7 | 100% |
| Other Amplification
methods | 10 | 5 | 40 | 649 | 100% |
| 6 methods | | 11 Lots | 66
Runs | 1133
Calls | 100% |

Table 2. External site evaluations.

Each bottle is processed independently and has its own lot number.

b. Linearity/assay reportable range: Not applicable.
Traceability, Stability, Expected values (controls, calibrators, or methods): C. Bidirectional sequencing of INTROL™ CF Panel I DNA is used to validate the presence of mutant or wild type sequence.

Product acceptance criteria and testing: All INTROL™ CF Panel I Control products are tested by an FDA-cleared CFTR mutation detection method before being released for market distribution. Any mutations not tested by the FDA-cleared method are sequenced bidirectionally before product is released. All mutations must be detected.

Upon receipt and after opening, the material should be stored at 2° - 8°C. INTROL™ CF Panel I Control material is shipped with a "Do not freeze" warning in the device labeling.

Unopened INTROLTM CF Panel I Control material is stable through the expiration date printed on each bottle when stored refrigerated (2° - 8°C). Opened material returned to the refrigerator (2° - 8°C) shortly after use is stable for thirty (30) days from the date of opening.

Real time stability study:

Results of the real time studies are in the tables below. Stability was tested using 4 different methods, including cleared Tag-It™ Cystic Fibrosis (CF) Kit from Tm Bioscience, and bidirectional sequencing. Testing was performed at 1, 2, 3, 4, and 12 months. In addition, real time testing was performed with 5 different lots of quality control material. At 12 months, all mutations and variants were tested using either the FDA cleared assay or bidirectional sequencing. Data from this ongoing study currently supports a shelf-life of 12 months.

| Stability Testing | Number of
Lots | Percent
Correct Calls |
|---------------------|-------------------|--------------------------|
| Date of Manufacture | 5 | 100% |
| 1 month | 5 | 100% |
| 2 months | 3 | 100% |
| 3 months | 1 | 100% |
| 4 months | 2 | 100% |
| 12 months | 3 | 100% |

Stress testing:

Elevated Temperature Studies:

The study goal was to demonstrate product stability during prolonged shipping without refrigeration. A bottle of INTROLTM CF Panel I was removed from storage and mailed across the US and back without wet ice. Testing of the stressed product in the CFTR assay showed no loss of signal.

Two samples of INTROL™ CF Panel were compared after one was incubated at 60°C for 21-24 days, and the other incubated at 4°C, extracted and tested in duplicate in CFTR assay. There was no loss of signal after incubation at 60°C.

Freeze/Thaw Studies:

A bottle of INTROL™ CF Panel I was placed at -20℃ for 48 hours, thawed and tested in CFTR assay. No loss of signal was detectable after one cycle of freeze/ thaw.

Open Vial Stability:

Two open vial studies were performed. In the first study, a bottle of INTROLTM CF Panel I was mixed, opened briefly, then stored at 2-8℃ for 49 days. In the second study, a bottle of INTROL™ CF Panel I was mixed and opened with pipette simulation six times over 35 days. Both studies demonstrated no loss of signal when used in CFTR assay at the end of the test period.

Expected Results:

Expected results with the INTROLTM CF Panel I Control using two FDAcleared CFTR assays are presented in Table 3.

Method	Correctly Identified Alleles	No Call or other	Not Tested
Tag-It	All wt alleles
7T, I507V, F508C, S549R, G85E, I148T, 621+1G>T,
1078delT, R334W, R347P, 9T, A455E, delF508,
V520F, 1717+1G>A, G542X, G551D, R560T,
1898+1G>A, 2184delA, 3120+1G>A, R1162X,
3659delC, 3849+10kbC>T, 3876delA, 3905insT,
W1282X, N1303K, 394delTT, R117H, R347H, 5T/7T,
I506, dell507, R553X, 2183AA>G	S549N MUT1
711+1G>T No Call2
2789+5G>A No Call3	S1251N, E60X, 2143delT
3199del6, D1152H,
eSensor	All wt alleles
7T, I148T, 621+1G>T, 1078delT, R334W, R347P, 9T,
A455E, delF508, 1717+1G>A, G542X, G551D, R560T,
1898+1G>A, 2184delA, 2789+5G>A, 3120+1G>A,
R1162X, 3659delC, 3849+10kbC>T, W1282X,
N1303K, R117H, 5T/7T, dell507, R553X,	G85E No Amp3
711+1G>T No Amp4	I507V, F508C, S549N,
S549R, S1251N, E60X,
1078delT V520F,
2143delT, 3199del6,
D1152H, 3876delA,
3905insT, 394delTT,
R347H, I506V,
2183AA>G,

Table 3. Results with the INTROL™ CF Panel I using two FDA cleared CFTR assays.

' Detected as homozyqous mutant.

Insufficient control sequence for one of the 711+1G>T amplicon primers.

3 Insufficient control sequence for one of the 2789+5G>A amplicon primers.

4 Mutation E60X interferes with a G85E amplicon primer.

d. Detection limit: Not applicable
e. Analytical specificity: Not applicable.
f. Assay cut-off: Not applicable.

1. Comparison studies:
- Method comparison with predicate device: a. Not applicable.
- b. Matrix comparison: Not applicable.
1. Clinical studies:
- a. Clinical Sensitivity: Not applicable.
- Clinical specificity: b. Not applicable.
- c. Other clinical supportive data (when a. and b. are not applicable): Not applicable
1. Clinical cut-off: Not applicable
1. Expected values/Reference range: Not applicable

N. Proposed Labeling:

The labeling is sufficient and it satisfies the requirements of 21 CFR Part 809.10.

O. Conclusion:

The petition for Evaluation of Automatic Class III Designation for this device is accepted. The device is classified as Class II under regulation 21 CFR 866.5910 with special controls. The special control guidance document "Class II Special Controls Guidance Document: Quality Control Material for Cystic Fibrosis Nucleic Acid Assays" is available at http://www.fda.gov/cdrh/oivd/guidance/1614.html.