(678 days)
For in vitro diagnostic use. For use on the Biocartis Idylla™ System only.
The Idylla™ MSI Test, for use on the Idylla™ System, uses formalin-fixed, paraffin-embedded (FFPE) tissue sections of human CRC tumor, from which nucleic acids are liberated, then analyzed using PCR amplification of seven monomorphic biomarkers (ACVR2A, BTBD7, DID01, MRE11, RYR3, SEC31A and SULF2) and subsequent melt-curve analysis. The Idylla™MSI Test reports results as either microsatellite stable (MSS), or microsatellite instability high (MSI-H) or invalid.
Idylla™ MSI Test is indicated for use by healthcare professionals for the qualitative identification of microsatellite instability (MSI) in colorectal cancer (CRC) tumors, indicative of mismatch repair deficiency, as an and in the identification of potential Lynch syndrome to help identify patients that would benefit from additional genetic testing to diagnose Lynch syndrome.
The results from the Idylla™ MSI Test should be interpreted by healthcare professionals in conjunction with other clinical findings, family history, and other laboratory data. The Idyla™ MSI Test should not be used for diagnosis of CRC. The clinical performance of this device to guide treatment decision for MSI high patients has not been established.
The Biocartis Idylla™ System covers the entire process from sample to result with fully integrated sample preparation followed by PCR amplification and high-resolution melting detection of the targeted sequences. The Idylla™ System consists of the Idylla™ Console connected to one or more Idylla™ Instruments (up to eight instruments). Idylla™ Cartridges, designed for specific applications, can be processed by the Idylla System using test specific software (Test Type Package, MSI TTP). The Idylla™ MSI Test procedure and data analysis are validated for FFPE tissue sections.
The Idylla™ MSI Test detects a novel panel of seven monomorphic biomarkers.
The Idylla™ MSI Test Cartridges are ready-for-use and contain the necessary reagents to perform sample preparation, PCR amplification and high-resolution detection, starting from insertion of FFPE tissue sections. The MSI TTP directs the processing of the sample within the cartridge.
The process steps in the Idylla™ MSI Test are:
- FFPE liquefaction and cell lysis: After insertion of the FFPE tissue section into the cartridge, a combination of chemical reagents, enzymes, heat, and High Frequency Ultrasound (HIFU) induces deparaffinization, disruption of the tissue and lysis of the cells. The nucleic acids are liberated for subsequent PCR amplification.
- PCR using biomarker-specific primers: All necessary PCR reagents are present in a stable formulation and are used to amplify seven biomarkers indicative for MSI status.
- Detection and analysis: Detection of these specific targets is performed using fluorescently labeled molecular beacons after PCR amplification. These beacons differentially melt from the wild type or mutated amplicons with increasing temperature. The fluorescence differences at melting temperatures are further analyzed by the MSI TTP and translated into genetic calls on biomarker level and MSI status on sample level.
- Reporting: At the end of the run, the result, reporting the MSI status, the number of mutated biomarkers, and an MSI score range in the analyzed sample is displayed on the console screen.
Here's a breakdown of the acceptance criteria and study details for the Idylla™ MSI Test based on the provided FDA 510(k) summary:
1. Table of Acceptance Criteria & Reported Device Performance
The document doesn't explicitly state "acceptance criteria" as a separate section with numerical targets. Instead, it demonstrates performance through various analytical and clinical studies, showing high concordance and hit rates. Below is a summary of the performance metrics reported, which implicitly serve as the evidence for meeting acceptance for substantial equivalence.
| Metric (Implicit Acceptance Criteria) | Reported Device Performance |
|---|---|
| Analytical Performance | |
| Analytical Specificity (LoB) | Correctly generated 'Invalid' when no sample. Correctly generated 'MSS' for wild-type samples. No cross-reactivity between mutant/wild-type targets or interference from known mutations. |
| Analytical Sensitivity (LoD) - Contrived | Estimated LoD was 30% allelic frequency. Correct MSI status calls with estimated allelic frequency LoD using contrived specimens, ranging from 15 to 30% for low input background in individual biomarkers. (91.7% at 10% AF for low input, 100% at 10% AF for high input, and 100% at 15% AF or higher for both inputs). |
| Analytical Sensitivity (LoD) - Clinical | 100% correct calls for 7 clinical samples (MSI-H and MSS) tested at ~33% neoplastic cell content and lowest sample input size (25 mm² per 10 µm section). This confirms LoD at 33% neoplastic cell content. |
| Reproducibility (Across sites, lots, days) | 100% identical and correct MSI status calls across three sites for all seven clinical samples tested (252 valid runs). No relevant effects of inter-instrument, inter-lot, or inter-day variability. Biomarker reproducibility >85% for most markers, with some exceptions noted for specific samples (e.g., Sample 2 BTBD7 at 77.78%, Sample 4 BTBD7 at 66.67%, Sample 7 ACVR2A at 88.89% - these are noted to be discordant from the clinical sample characterization). |
| Non-Interfering Substances | Hemoglobin (2 mg/mL), Triglycerides (37 mmol/L), and Paraffin (1 additional 10 µm section) showed 100% concordance with control results, indicating no impact on Idylla™ MSI Test. |
| Mucinous Content Interference | Samples with mucinous cell content up to 60% generated correct MSI status calls (96.5% of runs, 55/57), indicating no negative impact. |
| Necrotic Content Interference | Necrosis content up to 73% had no impact on the Idylla™ MSI Test, generating correct MSI status calls. |
| Clinical Performance (Vs. Predicate) | |
| PPA (Idylla vs. OncoMate) | 96.88% (95% CI: 83.78 - 99.92) across all samples (sequential + enrichment). For sequential cohort, 100% (78.2 - 100%). For enrichment cohort, 94.12% (71.31 - 99.85). |
| NPA (Idylla vs. OncoMate) | 99.07% (95% CI: 94.95 - 99.98) across all samples (sequential + enrichment). For sequential cohort, 99.07% (94.95 - 99.98%). For enrichment cohort, N/A (all were MSI-H). |
| OPA (Idylla vs. OncoMate) | 98.57% (95% CI: 94.93 – 99.83) across all samples. For sequential cohort, 99.19% (95.55 - 99.98). For enrichment cohort, 94.12% (71.31 - 99.85). |
| Clinical Performance (Vs. Germline NGS) | |
| PPA (Idylla vs. Germline NGS) | 92.00% (95% CI: 73.97 – 99.02) across all samples for identifying Lynch cases. For sequential cohort, 80% (28.36 - 99.49). For enrichment cohort, 95% (75.13 – 99.87). |
| NPA (Idylla vs. Germline NGS) | 89.81% (95% CI: 82.50 – 94.80) across all samples. For sequential cohort, 89.81% (82.51 - 94.80). For enrichment cohort, N/A. (Note: less informative as Lynch negative samples by NGS can still be MSI-H due to sporadic dMMR). |
| OPA (Idylla vs. Germline NGS) | 90.22% (95% CI: 83.99 – 94.20) across all samples. For sequential cohort, 89.38% (82.18 - 94.39). For enrichment cohort, N/A. |
2. Sample Size Used for the Test Set and Data Provenance
-
Analytical Studies (LoD, Reproducibility, Interference):
- LoD Estimation (Contrived): 24 replicates per allelic frequency level (Table 3), various levels (50%, 30%, 20%, 15%, 10%, 5%) for both high and low sample input.
- LoD Estimation (Clinical): 4 FFPE samples (titration experiments), with 6 replicates per concentration level.
- LoD Confirmation (Clinical): 7 FFPE clinical samples (MSI-H, MSS, borderline) tested in 10 replicates per lot (n=20) over 5 days on multiple instruments (total n=140 from all seven samples).
- Reproducibility: 7 individual FFPE clinical specimens (MSI-H and MSS) tested at 3 laboratory sites, with 12 replicates per sample per site (total 36 tests/sample, 252 valid runs across all sites).
- Interference (Hemoglobin, Triglycerides, Paraffin): 7 FFPE colorectal cancer clinical samples, tested in 5 replicates with each interfering substance.
- Interference (Mucin): 19 FFPE clinical samples (MSI-H and MSS) with varying mucinous content, tested in 3 replicates each (total 57 runs, 55 valid).
- Interference (Necrosis): 4 FFPE clinical samples with various necrosis levels, tested in triplicate with and without necrosis.
- Data Provenance: The document states "clinical samples" and "hospital biobanks", indicating human sample origin. The reference to "Colorectal Cancer Family Registry" for the enrichment cohort suggests these are existing, well-characterized clinical samples. It is retrospective in nature, using archived FFPE tissue sections. Origin country is not explicitly stated but implies multicenter (multiple sites for reproducibility) data.
-
Clinical Performance Study:
- Total samples: 143 samples.
- Sequential cohort: 123 samples (sequentially selected from two hospital biobanks).
- Enrichment cohort: 20 confirmed Lynch cases (obtained from the Colorectal Cancer Family Registry).
- Data Provenance: Retrospective, FFPE tissue sections of human CRC tumor.
3. Number of Experts Used to Establish Ground Truth for the Test Set and Their Qualifications
The document does not explicitly state the number of experts or their specific qualifications for establishing the ground truth for the test set as per a typical adjudication process for imaging or pathology.
The ground truth reference methods are:
- OncoMate™ MSI Dx Analysis System (Predicate Device): This is a legally marketed predicate device, implying its results are accepted as a reference standard.
- Germline NGS for MMR Genes: This is a molecular diagnostic method, considered a gold standard for identifying Lynch syndrome.
- Sample Characterization: For analytical studies, samples were characterized as MSI-H or MSS based on known properties (e.g., cell lines, clinical samples).
Therefore, the "experts" here are essentially the established and validated methods of the predicate device and germline NGS, rather than human expert readers adjudicating images.
4. Adjudication Method for the Test Set
No explicit adjudication method (like 2+1, 3+1) is mentioned or implied for the clinical performance study. The comparison is made directly against established reference methods: the OncoMate™ MSI Dx Analysis System and Germline NGS for MMR genes. These are direct comparisons between the device's output and the reference method's output.
5. If a Multi Reader Multi Case (MRMC) Comparative Effectiveness Study Was Done, and Effect Size of Human Readers Improvement with AI vs. Without AI Assistance
This device, the Idylla™ MSI Test, is an in vitro diagnostic (IVD) test that automatically reports results (MSS, MSI-H, or invalid) based on molecular analysis of tissue samples. It is not an AI-assisted diagnostic imaging device or a software that assists human readers in interpreting clinical data. Therefore, an MRMC comparative effectiveness study involving human readers with and without AI assistance is not applicable to this device. There is no human-in-the-loop component for result generation, so there's no "effect size of how much human readers improve with AI vs without AI assistance" to report.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done
Yes, the studies performed are inherently standalone performance of the Idylla™ MSI Test. The device provides an automated result (MSS, MSI-H, or Invalid) directly from the FFPE tissue sample without intermediate human intervention for interpretation of the molecular signals. The performance metrics (PPA, NPA, etc.) represent the algorithm's standalone accuracy against reference methods.
7. The Type of Ground Truth Used
The ground truth used for the clinical performance study was:
- Predicate Device Output: The results from the OncoMate™ MSI Dx Analysis System.
- Molecular Gold Standard: Germline Next Generation Sequencing (NGS) for DNA mismatch repair (MMR) genes, particularly for identifying Lynch cases.
For analytical studies, the ground truth was also based on well-characterized samples (e.g., cell lines with known allelic frequencies, clinical samples previously characterized as MSI-H or MSS).
8. The Sample Size for the Training Set
The document does not provide information about a separate "training set" or its sample size. This is typical for IVD submissions which validate a fixed algorithm or assay rather than continuously learning AI models. The development and optimization of such a test would involve internal R&D, but the submission focuses on the validation of the finalized product.
9. How the Ground Truth for the Training Set Was Established
As no specific training set is mentioned in the context of an AI/ML model, this question is not directly applicable. For the development of the Idylla™ MSI Test, the "ground truth" for optimizing the assay (e.g., primer design, melt curve analysis parameters) would have been established through a combination of scientific literature, internal studies using characterized cell lines, and reference clinical samples with known MSI status (likely determined by established methods like IHC or other PCR-based MSI tests).
§ 864.1866 Lynch syndrome test systems.
(a)
Identification. Lynch syndrome test systems are in vitro diagnostic tests for use with tumor tissue to identify previously diagnosed cancer patients at risk for having Lynch syndrome.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the following information, as appropriate:
(i) A detailed description of all test components, including all provided reagents, and required but not provided, ancillary reagents.
(ii) A detailed description of instrumentation and equipment, including illustrations or photographs of non-standard equipment or manuals.
(iii) Detailed documentation of the device software, including, but not limited to, standalone software applications and hardware-based devices that incorporate software.
(iv) A detailed description of quality controls including appropriate positive and negative controls that are recommended or provided.
(v) Detailed specifications for sample collection, processing, and storage.
(vi) A detailed description of methodology and assay procedure.
(vii) A description of the assay cut-off (
i.e., the medical decision point between positive and negative results) or other relevant criteria that distinguishes positive and negative results, or ordinal classes of marker expression, including the rationale for the chosen cut-off or other relevant criteria and results supporting validation of the cut-off.(viii) Detailed specification of the criteria for test result interpretation and reporting.
(ix) Detailed information demonstrating the performance characteristics of the device, including:
(A) Data from an appropriate study demonstrating clinical accuracy using well-characterized clinical specimens representative of the intended use population (
i.e., concordance to Deoxyribonucleic Acid (DNA) sequencing results of the Lynch syndrome associated genes or method comparison to the predicate device using samples with known alterations in genes representative of Lynch syndrome). Pre-specified acceptance criteria must be provided and followed.(B) Appropriate device reproducibility data investigating all sources of variance (
e.g., for distributed tests, data generated using a minimum of three sites, of which at least two sites must be external sites). Each site must perform testing over a minimum of 5 nonconsecutive days evaluating a sample panel that spans the claimed measuring range, and includes the clinical threshold. Pre-specified acceptance criteria must be provided and followed.(C) Data demonstrating reader reproducibility, both within-reader and between-reader, assessed by three readers over 3 nonconsecutive days at each site, including a 2 week washout period between reads, as appropriate.
(D) Device precision data using clinical samples spanning the measuring range and controls to evaluate the within-lot, between-lot, within-run, between run, and total variation.
(E) Analytical specificity studies including as appropriate, western blots, peptide inhibition, testing in normal tissues and neoplastic tissues, interference by endogenous and exogenous substances, and cross-reactivity and cross contamination testing.
(F) Device analytical sensitivity data generated by testing an adequate number of samples from individuals with the target condition such that prevalence of the biomarker in the target population is established.
(G) Device stability data, including real-time stability and in-use stability, and stability evaluating various storage times, temperatures, and freeze-thaw conditions, as appropriate.
(H) The staining performance criteria assessed must include overall staining acceptability, background staining acceptability, and morphology acceptability, as appropriate.
(I) Appropriate training requirements for users, including interpretation manual, as applicable.
(J) Identification of risk mitigation elements used by the device, including a description of all additional procedures, methods, and practices incorporated into the instructions for use that mitigate risks associated with testing.
(2) The device's § 809.10(b) of this chapter compliant labeling must include a detailed description of the protocol, including the information described in paragraphs (b)(1)(i) through (viii) of this section, as appropriate, and a detailed description of the performance studies performed and the summary of the results, including those that relate to paragraph (b)(1)(ix) of this section, as appropriate.