(440 days)
The Genomadix Cube CYP2C19 System is a qualitative in vitro diagnostic test for the identification of a patient's CYP2C19 *2, *3, and *17 genotypes determined from genomic DNA obtained from a buccal swab sample.
The Genomadix Cube CYP2C19 System can be used to aid clinicians in determining therapeutic strategy for therapeutics that are metabolized by the cytochrome P450 2C19 gene product, specifically *2, *3, and *17 alleles. This test is not intended to be used to predict drug response or non-response.
The Genomadix Cube CYP2C19 Test Kit is indicated for use with the Genomadix Cube CYP2C19 Platform.
The Genomadix Cube CYP2C19 System is a sample-to-result DNA testing system with integrated DNA extraction and amplification. Genotypes are determined using Polymerase Chain Reaction (PCR) and fluorescent probe detection. The Genomadix Cube CYP2C19 System is comprised of the Genomadix Cube CYP2C19 Platform (Genomadix Cube, computer, and barcode scanner) and the Genomadix Cube CYP2C19 Test Kit (swabs and cartridges). The test is run on the Genomadix Cube CYP2C19 Platform.
The Genomadix Cube is a thermal cycling instrument that automatically integrates extraction of DNA from the buccal sample, PCR amplification, fluorescence-based detection of CYP2C19 alleles, and genotype calling.
Acceptance Criteria and Study Details for Genomadix Cube CYP2C19 System
The Genomadix Cube CYP2C19 System is a qualitative in vitro diagnostic test for the identification of a patient's CYP2C19 *2, *3, and *17 genotypes from genomic DNA obtained from a buccal swab sample.
The acceptance criteria for the device performance are not explicitly stated as distinct pass/fail thresholds in the provided text. However, the study results demonstrate the device's accuracy and reproducibility, implying that the reported performance metrics serve as the de facto acceptance criteria. The primary performance metric appears to be the "correct call rate."
1. Table of Acceptance Criteria and Reported Device Performance
| Performance Metric | Acceptance Criteria (Implied) | Reported Device Performance | Study Type |
|---|---|---|---|
| Reproducibility (First Pass) | High correct call rate | 99.1% (95% LCL of 98.2%) | Site-to-Site Reproducibility |
| Reproducibility (Second Pass) | Very high correct call rate | 99.7% (95% LCL of 99.1%) | Site-to-Site Reproducibility |
| Lot-to-Lot Reproducibility | High correct call rate | Lot A: 99.7%, Lot B: 99.4%, Lot C: 100% | Site-to-Site Reproducibility (using 3 lots) |
| Interference (First Pass) | High correct call rate | 100% correct calls after retest (4 inconclusive from first pass) | Analytical Specificity/Interference |
| Lower Limit of Detection (LLoD) - Cheek Touch (First Pass) | High correct call rate | 99.5% (after second pass) | Detection Limit |
| LLoD and ULoD (Expected DNA) (First Pass) | High correct call rate | 100% correct calls (after second pass for 1 inconclusive) | Detection Limit |
| Carry-Over | 100% concordance | 100% concordant results (122/122) after second pass | Carry-Over |
| Method Comparison (First Pass) | High correct call rate | 96% | Method Comparison |
| Method Comparison (Second Pass) | Very high correct call rate | 99% (95% LCL of 98%) | Method Comparison |
2. Sample Sizes and Data Provenance
Reproducibility Study:
- Test Set Sample Size: 8 individuals (buccal samples) across 3 sites. A total of 960 tests were performed across the 3 sites (8 subjects x 2 operators x 2 sessions x 2 replicates x 5 days).
- Data Provenance: Not explicitly stated, but the study was conducted at 3 sites, implying a multi-center study likely within the country of the applicant (Genomadix Inc.). The study involved prospective sample collection from individuals for the purpose of the study.
Analytical Specificity/Interference Study:
- Test Set Sample Size: 16 samples for each of the 14 potential interfering substances, totaling 224 samples. These were buccal swab samples from individuals with specific genotypes (4 replicates of each genotype tested).
- Data Provenance: Not explicitly stated, but likely prospective collection for the study.
Detection Limit Study:
- Test Set Sample Size:
- Swabbing conditions (LLoD, IFU, ULoD): A total of 208 tests in the first pass across various swabbing conditions.
- Expected DNA concentration: 140 samples for low concentration (20 replicates from 7 individuals) and 21 samples for high concentration (3 replicates from 7 individuals).
- Data Provenance: Not explicitly stated, but likely prospective collection for the study.
Carry-Over Study:
- Test Set Sample Size: 122 samples (61 *1/*1 genotypes alternated with 61 non-*1/*1 genotypes).
- Data Provenance: Not explicitly stated.
Method Comparison Study:
- Test Set Sample Size: 444 unique patient samples initially collected. 11 samples were excluded for low quality, resulting in 433 samples included in the final analysis.
- Data Provenance: Not explicitly stated, but samples were collected from unique patients for this study, implying prospective collection. The multi-site nature (3 sites) suggests a broader data collection if applicable.
3. Number of Experts for Ground Truth and Qualifications
For Reproducibility, Analytical Specificity/Interference, Detection Limit, and Method Comparison Studies:
- Number of Experts: Not explicitly stated in terms of "experts establishing ground truth."
- Qualifications of Experts: The ground truth for these studies was established by bi-directional sequencing. This is a highly accurate molecular method and itself serves as the "gold standard" for genotype confirmation. The performance of the sequencing would be overseen by qualified laboratory personnel, though details on their specific qualifications (e.g., molecular geneticists, clinical laboratory directors) are not provided.
4. Adjudication Method for the Test Set
The adjudication method used throughout the performance studies (reproducibility, interference, detection limit, method comparison) involved a "second pass" testing for inconclusive results:
- "If an inconclusive result was obtained on the first set of samples, the second set of samples from the same patient were used for a second pass test."
- This indicates a repeat testing adjudication for inconclusive results. There is no mention of a formal expert consensus (e.g., 2+1, 3+1) for resolving discrepancies between the device and the ground truth. The ground truth (bi-directional sequencing) is considered definitive.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not explicitly described or performed. The device is an automated genotyping system, so the concept of human readers "improving with AI vs. without AI assistance" does not directly apply in the traditional sense of image interpretation or complex diagnostic decision-making. The study focuses on the device's accuracy against a molecular gold standard.
6. Standalone Performance Study
Yes, the studies described (Reproducibility, Analytical Specificity/Interference, Detection Limit, Carry-Over, and Method Comparison) represent standalone performance of the algorithm/device. The device processes samples and generates genotype calls without direct human intervention in the interpretation of raw signal data. The "correct call rate" is a measure of the algorithm's performance alone against the established ground truth.
7. Type of Ground Truth Used
The primary type of ground truth used across all reported studies (reproducibility, interference, detection limit, and method comparison) was bi-directional sequencing. This is a gold standard molecular technique for confirming DNA sequences and, consequently, genotypes.
8. Sample Size for the Training Set
The document does not provide details on the sample size used for the training set. This is common for this type of medical device submission, as the focus is on the analytical validation of the finished device. The underlying algorithms for PCR-based fluorescent probe detection are based on well-established biochemical principles rather than statistical machine learning models that require explicit training sets.
9. How the Ground Truth for the Training Set Was Established
As no explicit "training set" and associated ground truth establishment is described for a machine learning model, this information is not applicable in the context of the provided document. The device's operation relies on established principles of molecular diagnostics (PCR, fluorescent probe detection) and programmed thresholds for signal analysis, rather than an trained artificial intelligence model in the contemporary sense.
§ 862.3360 Drug metabolizing enzyme genotyping system.
(a)
Identification. A drug metabolizing enzyme genotyping system is a device intended for use in testing deoxyribonucleic acid (DNA) extracted from clinical samples to identify the presence or absence of human genotypic markers encoding a drug metabolizing enzyme. This device is used as an aid in determining treatment choice and individualizing treatment dose for therapeutics that are metabolized primarily by the specific enzyme about which the system provides genotypic information.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Drug Metabolizing Enzyme Genotyping Test System.” See § 862.1(d) for the availability of this guidance document.