Idylla MSI Test
Device Facts
| Record ID | K211181 |
|---|---|
| Device Name | Idylla MSI Test |
| Applicant | Biocartis NV |
| Product Code | PZJ · Immunology |
| Decision Date | Feb 27, 2023 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 864.1866 |
| Device Class | Class 2 |
Indications for Use
The Idylla MSI Test, for use on the Idylla System, uses formalin-fixed, paraffin-embedded (FFPE) tissue sections of human colorectal cancer (CRC) tumor, from which nucleic acids are liberated, then analyzed using PCR amplification of seven monomorphic biomarkers (ACVR2A, BTBD7, DIDO1, 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 CRC tumors, indicative of mismatch repair deficiency, as an aid 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 Idylla 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.
Device Story
Device processes FFPE human CRC tumor tissue sections; utilizes fully integrated sample preparation, PCR amplification, and high-resolution melting detection. Input: FFPE tissue sections. Process: Chemical/enzymatic/HIFU-induced deparaffinization and cell lysis; PCR amplification of seven monomorphic biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2); fluorescently labeled molecular beacon detection. Output: MSI status (MSS, MSI-H, or invalid), number of mutated biomarkers, and MSI score range. Used in clinical laboratory settings; operated by trained laboratory personnel. Output interpreted by healthcare professionals alongside clinical/family history to identify potential Lynch syndrome patients for further genetic testing. Benefits: Streamlined, automated workflow for MSI detection in CRC tumors.
Clinical Evidence
Method comparison study (n=143) compared Idylla™ MSI Test against OncoMate™ MSI Dx Analysis System and germline NGS. Combined cohort PPA 96.88% (95% CI: 83.78-99.92) and NPA 99.07% (95% CI: 94.95-99.98) vs. OncoMate™. PPA vs. germline NGS was 92% (95% CI: 73.97-99.02). Analytical studies confirmed LoD at ~33% neoplastic cell content. Reproducibility study (n=252 runs) showed 100% concordance across sites, operators, and cartridge lots.
Technological Characteristics
Fully integrated system (console + instruments) using single-use cartridges. Employs High Frequency Ultrasound (HIFU) for deparaffinization/lysis. PCR-based amplification of 7 monomorphic biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) with fluorescent molecular beacon detection and melt-curve analysis. Standalone system; no external connectivity mentioned. Software: MSI Test Type Package (TTP).
Indications for Use
Indicated for healthcare professionals to qualitatively identify microsatellite instability (MSI) in colorectal cancer (CRC) tumors, indicative of mismatch repair deficiency, as an aid in identifying potential Lynch syndrome in patients diagnosed with CRC.
Regulatory Classification
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.
Special Controls
*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.
Predicate Devices
- OncoMate™ MSI Dx Analysis System (K200129)
Related Devices
- P250005 — Idylla CDx MSI Test · Biocartis Us, Inc. · Aug 15, 2025
- K200129 — OncoMate MSI Dx Analysis System · Promega Corporation · Jul 26, 2021
- K213348 — BOND MMR Antibody Panel · Leica Biosystems Newcastle, Ltd. · Feb 21, 2023
Submission Summary (Full Text)
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# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
## I. Background Information:
A. 510(k) Number:
K211181
B. Applicant
Biocartis NV
C. Proprietary and Established Names
Idylla™ MSI Test
D. Regulatory Information
| Product Code | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| PZJ | Class II | 21 CFR 864.1866 - Lynch Syndrome Test Systems | 88 Pathology |
## II. Submission/Device Overview:
A. Purpose for Submission:
New Device
B. Measurand:
Seven microsatellite alleles (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A and SULF2) in DNA in formalin fixed, paraffin-embedded (FFPE) colorectal tissue sections.
C. Type of Test:
Polymerase chain reaction (PCR)-based nucleic acid amplification and subsequent melt-curve analysis
## III. Intended Use/Indications for Use:
A. Intended Use
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Idylla™ MSI Test K211181
Biocartis NV
The Idylla MSI Test, for use on the Idylla System, uses formalin-fixed, paraffin-embedded (FFPE) tissue sections of human colorectal cancer (CRC) tumor, from which nucleic acids are liberated, then analyzed using PCR amplification of seven monomorphic biomarkers (ACVR2A, BTBD7, DIDO1, 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 CRC tumors, indicative of mismatch repair deficiency, as an aid 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 Idylla 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.
B. Special conditions for use statement(s)
Rx – For prescription use
For in vitro diagnostic use
C. Special instrument requirements
Biocartis Idylla System with Idylla MSI Test TTP.
## IV. Device Description
### 1. Principle of Operation
The Idylla MSI Test is an automated test on the Idylla System. The Biocartis Idylla System covers the entire process from sample to result with fully integrated sample preparation followed by real time polymerase chain reaction (PCR) amplification and fluorescence detection of the targeted sequences. The Idylla System consists of the Idylla Console connected to up to eight Idylla Instruments. Idylla Cartridges, designed for specific applications, are processed by the Idylla System using test specific software. The test specific software, referred to as Test Type Package (TTP), is available for download to the Idylla Console. The Test procedure and data analysis are validated for FFPE tissue sections.
The Idylla MSI Test detects a novel panel of seven monomorphic biomarkers which are listed in the Table 1 below.
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
Table 1. Seven biomarkers in the Idylla MSI Test
| Biomarkers |
| --- |
| ACVR2A |
| BTBD7 |
| DIDO1 |
| MRE11 |
| RYR3 |
| SEC31A |
| SULF2 |
The process steps in the Idylla MSI Test are:
- Sample Processing (FFPE liquefaction and cell lysis): After insertion of the FFPE tissue section into the cartridge, a combination of chemical reagents, enzymes, heat, and high intensity focused ultrasound (HIFU) induces deparaffinization, disruption of the tissue and lysis of the cells. The nucleic acids are liberated for subsequent PCR amplification. There is no DNA extraction step in the procedure.
- Amplification, Detection and Analysis: All necessary PCR reagents are present in a stable formulation and are used to amplify seven biomarkers. After amplification of the specific regions of the seven (7) biomarkers, the molecular beacons bind to the target regions. Contact quenching no longer takes place and the beacons will produce a fluorescence signal. These mutant-specific 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, a result report outlining the MSI status along with the number of positive MSI biomarkers detected in the analyzed sample is displayed on the console screen. The MSI status of the sample can be determined if at least five valid marker-specific fluorescence profiles could be fully analyzed (otherwise the MSI status is called 'Invalid'). The presence of at least two mutant markers results in an 'MSI-H' call (Microsatellite Instability-High), otherwise the status is reported as 'MSS' (Microsatellite Stable).
2. Specimen Handling/Requirement
Standard formalin-fixation and paraffin-embedding procedures should be followed. Tissue samples should be fixed as quickly as possible and fixation times limited to preferably less than 72 hours to reduce the risk of severe DNA fragmentation. 4 µm to 10 µm FFPE tissue
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
sections can be used as specimen in the Idylla MSI Test. Specimens should be macrodissected if less than 33% of the section is tumor.
# 3. Interpretation of Results
The Idylla System automatically interprets the test results and makes them available for viewing on the Console. The Idylla MSI Test reports a result for the MSI status of the sample, the MSI Score Range of the sample, the number of positive biomarkers and an overall quality status. A sample is called Microsatellite Instability-High or MSI-H if the sample has ≥2 mutant biomarkers and an MSI Score Range ≥ 0.15. A sample is called Microsatellite Stable or MSS if the sample has <2 mutant biomarkers and an MSI Score Range <0.15 (Table 2).
Table 2. Result Interpretation
| Number of Positive Biomarkers | MSI Score Range | MSI Status |
| --- | --- | --- |
| <2 | <0.15 | MSS |
| ≥2 | ≥0.15 | MSI-H |
An 'Invalid' call for a biomarker is observed when no PCR product was formed in a particular sample and therefore no characteristic fluorescent profile could be analyzed. This may occur when using poor quality samples. A Cartridge is considered valid if ≥ 5 out of 7 MSI biomarkers show a valid marker result for the sample. An invalid Cartridge will report the MSI status being 'Invalid'. An 'Invalid' result is reported if >2 out of 7 MSI biomarkers show an invalid biomarker result for a particular sample (Table 3).
Table 3. Invalid Reporting
| Number of Invalid Biomarkers | THE QUALITY STATUS SHOWN ON THE RESULT REPORT IS... |
| --- | --- |
| 0 Invalid biomarkers | 7 MSI biomarkers have been properly amplified and therefore the Test result is VALID |
| 1 Invalid biomarkers | 6 of the 7 MSI biomarkers have been properly amplified and therefore the Test result is VALID |
| 2 Invalid biomarkers | 5 of the 7 MSI biomarkers have been properly amplified and therefore the Test result is VALID |
| 3 or more Invalid biomarkers | Less than 5 MSI biomarkers have been properly amplified and therefore the Test result is INVALID |
# 4. Materials Provided
The following materials are provided when purchasing the Idylla MSI Test:
- Idylla MSI Test Cartridges
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
Each Cartridge contains the following:
- Liquefaction buffer: 1.7 mL
- Dilution buffer: 2.2 mL
- Enzymes, Primers and Probes (dried)
Electronic Components required to perform an Idylla MSI Test
- MSI Test Type Package (TTP): MSI_IVD/2.0
- Idylla MSI Test Instructions
- Idylla Operator Manual
# 5. Materials Required But Not Provided
The following materials are not provided, but are required to perform an Idylla MSI Test:
Table 4. Materials required but not provided .
| ITEM | SPECIFICATION |
| --- | --- |
| Idylla Instrument | Cat. No. P0010 |
| Idylla Console | Cat. No. P1010 |
| Idylla MSI FFPE Reference Set | SENSID-GMBH |
| Nuclease-free water | |
# V. Quality Control
Blank or No Template Controls are not included in the design of the Idylla MSI Test.
Idylla MSI FFPE Reference Set, manufactured by SensID GmbH, is intended as qualitative control material for MSI markers in FFPE format based on human cell lines. It consists of MSI FFPE MSI-H control with all MSI markers at a frequency of 1x LOD and MSI FFPE MSS control with 0% frequency for all MSI markers. This Reference set should be used as the external controls to demonstrate that the reagents and the assay procedure perform properly. The quality control results should pass before testing patient samples. If the controls do not perform as expected, the test must be repeated and/or contact Biocartis technical support before testing patient samples. Controls should be tested:
- At the beginning of the study before the first specimen test.
- Before each new lot of Biocartis Idylla MSI Test (IUO) cartridges were placed into use.
- After every 24 tests per Idylla™ console.
- After each major service of the instrument and/or critical instrument part replacement.
- At the end of testing.
- As required by laboratory’s standard quality control procedures.
- As required by federal, state and local guidelines.
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
# VI. Substantial Equivalence Information
A. Predicate Device Name:
OncoMate MSI Dx Analysis System
B. Predicate 510(k) Number:
K200129
C. Comparison with Predicate:
| Item | Subject Device: Idylla MSI Test K211181 | Predicate Device: OncoMate MSI Dx Analysis System K200129 |
| --- | --- | --- |
| Similarities | | |
| Intended Use | 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, DIDO1, 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 aid 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 | The OncoMate MSI Dx Analysis System is a qualitative multiplex polymerase chain reaction (PCR) test intended to detect the deletion of mononucleotides in 5 microsatellite loci (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) using matched tumor and normal DNA obtained from formalin fixed, paraffin-embedded (FFPE) colorectal tissue sections.
The OncoMate MSI Dx Analysis System is for use with the Applied Biosystems® 3500Dx Genetic Analyzer and OncoMate MSI Dx Interpretive Software.
The OncoMate MSI Dx Analysis System is indicated in patients diagnosed with colorectal cancer (CRC) to detect microsatellite instability (MSI) as an aid in the identification of probable Lynch syndrome to help identify patients that would benefit from additional genetic testing to diagnose Lynch syndrome.
Results from the OncoMate MSI Dx Analysis System should be interpreted by healthcare |
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
| Item | Subject Device: Idylla MSI Test K211181 | Predicate Device: OncoMate MSI Dx Analysis System K200129 |
| --- | --- | --- |
| | healthcare professionals in conjunction with other clinical findings, family history, and other laboratory data. The Idylla 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. | professionals in conjunction with other clinical findings, family history, and other laboratory data.
The clinical performance of this device to guide treatment decision for MSI high patients has not been established. |
| Special Conditions for Use Statements | Rx- For prescription use.
For In Vitro Diagnostic use. | Same |
| Specimen | FFPE Tumor Tissue | Same |
| Results | MSS or MSI-H | Same |
| Target Population | Patients diagnosed with CRC | Same |
| Differences | | |
| Technology | PCR followed by melting point analysis | PCR followed by capillary electrophoresis |
| Software | MSI TTP | OncoMate MSI Dx Interpretive Software |
| Targets | ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, and SULF2 | 5 Mononucleotide tracts BAT25, BAT26, MONO27, NR21 and NR24 |
| External Controls | 2 cell line-based FFPE sections designed to represent MSS and MSI-H | DNA extracted from MSS human cell line |
| Internal Control | The melt analysis result of the sample processing control in each of the PCR reactions is used to check for adequate execution of the complete process from sample to result. | None |
| Instrument | Idylla System | Applied BioSystems 3500 Dx Genetic Analyzer |
## VII. Standards/Guidance Documents Referenced:
Table 5. Consulted Standards
| STANDARD ORG. | STANDARD DESIGNATION NUMBER | TITLE OF STANDARD |
| --- | --- | --- |
| CLSI | EP05-A3 | Evaluation of Precision of Quantitative Measurement Procedures, 3rd Edition |
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
| STANDARD ORG. | STANDARD DESIGNATION NUMBER | TITLE OF STANDARD |
| --- | --- | --- |
| CLSI | EP07-A2 | Interference Testing in Clinical Chemistry; Approved Guideline - Second Edition |
| CLSI | EP17-A2 | Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline -- Second Edition |
| CLSI | EP25-A | Evaluation of Stability of In Vitro Diagnostic Reagents; Approved Guideline |
| CLSI | EP14-A3 | Evaluation of Commutability of Processed Samples; Approved Guideline --Third Edition |
| CLSI | EP12-A2 | User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline - Second Edition. |
| CLSI | MM13-A | Collection Transport Preparation and Storage of Specimens for Molecular Methods; Approved Guideline |
| AAMI ANSI IEC | 62304:2006/Amd 1:2015 | Medical device software - Software life cycle processes |
| IEC | TR 80002-1 Edition 1.0 2009-09 | Medical Device Software – Part 1: Guidance on the Application of ISO 14971 to Medical Device Software |
| AAMI | TIR-45:2012 | Guidance on the Use of AGILE Practices in the Development of Medical Device Software |
| ISO | 15223-1 Fourth Edition 2021-07 | Medical devices - Symbols to be used with information to be supplied by the manufacturer - Part 1: General requirements |
| IEC | 61326-2-6 Edition 3.0 2020-10 | Electrical equipment for measurement, control and laboratory use - EMC requirements - Part 2-6: Particular requirements - In vitro diagnostic (IVD) medical equipment |
| ANSI AAMI IEC | 62366-1:2015 | Medical devices - Part 1: Application of usability engineering to medical devices |
| ANSI UL | 61010-1 3rd Ed, dated May 12, 2012 with revision through July 19, 2019 | Standard for Safety for Electrical Equipment For Measurement, Control and Laboratory Use; Part 1: General Requirements |
| ISO | 14971 Third Edition 2019-12 | Medical devices - Application of risk management to medical devices |
Applicable FDA Guidance Documents:
- Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests
- Guidance for the Content of Premarket Submission for Software Contained in Medical Devices - Guidance for Industry and FDA Staff, May 2005
- General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 2002
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
- Content of Premarket Submissions for Management of Cybersecurity in Medical Devices- Guidance for Industry and Food and Drug Administration Staff (2014)
- Postmarket Management of Cybersecurity in Medical Devices- Guidance for Industry and Food and Drug Administration Staff (2016)
## VIII. Performance Characteristics
## A. Analytical Performance:
### 1. Precision/Reproducibility
The inter-lab reproducibility study was conducted at three laboratory sites. Seven individual clinical specimens [MSI-H and MSS FFPE colorectal (CRC) tissue sections] were tested at all three sites with three lots of Idylla MSI Test Cartridges, on the Idylla Platform. Samples were selected to cover a range of repeats, size, and biomarker status as shown in Table 6.
Table 6. Details of FFPE clinical samples used in the inter-lab reproducibility study
| SAMPLE ID (IN SLIMS) | SECTI ON ON SIZE (μm) | PER PATHOLOGY REPORT | | Idylla MSI 2.0 FINAL CALL AND INDIVIDUAL MARKER STATUS (MUT or WT) | | | | | | | | PROME GA RESULTS |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | TISSUE SIZE (mm²) | %NEO PLASTIC CELLS IN TISSUE | MSI Status | BTB D7 | RYR 3 | SEC3 1A | ACV R2A | DIO1 | MRE 11 | SUL F2 | |
| Sample 1 | 10 μm | 75 | 30 - 40 | MSI-H | MUT | WT | WT | MUT | MUT | MUT | MUT | MSI |
| Sample 2 | 10 μm | 30 | 50 - 60 | MSI-H | WT | WT | WT | MUT | MUT | MUT | WT | MSI |
| Sample 3 | 4 μm | 160 | 30 - 40 | MSI-H | MUT | MUT | MUT | MUT | MUT | MUT | MUT | MSI |
| Sample 4 | 10 μm | 125 | 40 | MSI-H | MUT | MUT | MUT | MUT | MUT | MUT | WT | MSI |
| Sample 5 | 10 μm | 37 | 35 | MSS | WT | WT | WT | WT | WT | WT | WT | MSS |
| Sample 6 | 10 μm | 35 | 50 | MSS | WT | WT | WT | WT | WT | WT | WT | MSS |
| Sample 7 | 4 μm | 110 | 40 | MSS | WT | WT | WT | MUT | WT | WT | WT | MSS |
Note: MUT = Positive for MSI marker; WT (wild type) = Negative for MSI marker
This study was designed to evaluate lot-to-lot, instrument/operator, inter-day and inter-lab variability on the Idylla MSI Test. At each site, each sample was tested by one operator on four instruments with one replicate per instrument per day, for three non-consecutive days using three lots of Idylla MSI Test Cartridges, resulting in a total of twelve replicates per sample per site. Overall, this study produced 36 results (tests) in total per sample from all three sites. All 252 valid runs from the three sites were used for data analysis.
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
Table 7. Reproducibility study results
| CLINICAL SAMPLE | NUMBER OF REPLICATES TESTED | REPRODUCIBILITY RESULTS | |
| --- | --- | --- | --- |
| | | NUMBER OF CORRECT MSI STATUS CALLS | CONCORDANCE RATE (%) |
| Sample 1 (MSI-H) | 36 | 36/36 | 100% |
| Sample 2 (MSI-H) | 36 | 36/36 | 100% |
| Sample 3 (MSI-H) | 36 | 36/36 | 100% |
| Sample 4 (MSI-H) | 36 | 36/36 | 100% |
| Sample 5 (MSS) | 36 | 36/36 | 100% |
| Sample 6 (MSS) | 36 | 36/36 | 100% |
| Sample 7 (MSS) | 36 | 36/36 | 100% |
| WITHIN SITE | | | |
| Site 1 | 84 | 84/84 | 100% |
| Site 2 | 84 | 84/84 | 100% |
| Site 3 | 84 | 84/84 | 100% |
| All Sites | 252 | 252 / 252 | 100% |
Table 8. Summary of PPA (MUT) and NPA (WT) and 95% CI for MSI status and individual biomarkers in FFPE clinical samples
| SAMPLE | REFERENCE MSI STATUS | AGREEMENT TO REFERENCE STATUS % PPA (MUT) AND NPA (WT) (HIT RATE), 95% CI | INDIVIDUAL BIOMARKER RESULTS (POINT ESTIMATE (HIT RATE*), 95% CI) | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | BTBD7 | RYR3 | SEC31A | ACVR2A | DIDO1 | MRE11 | SULF2 |
| Sample 1 | MSI-H | 100% (36/36) | 100% (36/36 MUT) | 100% ** (36/36 MUT) | 100% (36/36 WT) | 100% (36/36 MUT) | 100% (36/36 MUT) | 100% (36/36 MUT) | 100% (36/36 MUT) |
| | | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% |
| Sample 2 | MSI-H | 100% (36/36) | 77.78% (28/36 WT) | 97.22% ** (35/36 WT) | 100% (36/36 WT) | 100% (36/36 MUT) | 100% (36/36 MUT) | 100% (36/36 MUT) | 86.11% (31/36 WT) |
| | | 90.36-100% | 61.92-88.28% | 85.83-99.51% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 71.34-93.92% |
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
| SAMPLE | REFERENCE MSI STATUS | AGREEMENT TO REFERENCE STATUS % PPA (MUT) AND NPA (WT) (HIT RATE), 95% CI | INDIVIDUAL BIOMARKER RESULTS (POINT ESTIMATE (HIT RATE*), 95% CI) | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | BTBD7 | RYR3 | SEC31A | ACVR2A | DIDO1 | MRE11 | SULF2 |
| Sample 3 | MSI-H | 100% (36/36) | 80.56% (29/36 MUT) | 97.22% (35/36 MUT) | 97.22% (35/36 MUT) | 100% (36/36 MUT) | 100% (36/36 MUT) | 94.44% (34/36 MUT) | 97.22% (35/36 MUT) |
| | | 90.36-100% | 64.97-90.25% | 85.83-99.51% | 85.83-99.51% | 90.36-100% | 90.36-100% | 81.86-98.46% | 85.83-99.51% |
| Sample 4 | MSI-H | 100% (36/36) | 100% (36/36 MUT) | 66.67% (24/36 MUT) | 100% (36/36 MUT) | 100% (36/36 MUT) | 100% (36/36 MUT) | 86.11% (31/36 MUT) | 97.22% (35/36 WT) |
| | | 90.36-100% | 90.36-100% | 50.33-79.79% | 90.36-100% | 90.36-100% | 90.36-100% | 71.34-93.92% | 85.83-99.51% |
| Sample 5 | MSS | 100% (36/36) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) |
| | | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% |
| Sample 6 | MSS | 100% (36/36) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) |
| | | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% |
| Sample 7* | MSS | 100% (36/36) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) | 88.89% ** (32/36 MUT) | 100% (36/36 WT) | 100% (36/36 WT) | 100% (36/36 WT) |
| | | 90.36-100% | 90.36-100% | 90.36-100% | 90.36-100% | 74.69 - 95.59 | 90.36-100% | 90.36-100% | 90.36-100% |
* Borderline samples per Idylla Test v2.0 initial screening results
** While reproducibility for this marker across 36 replicates is > 85%, the biomarker call observed is discordant to the biomarker status of the clinical sample that was obtained during sample characterization.
All three sites generated correct MSI status calls across the sites for all seven clinical samples tested (Table 7). The reproducibility across 36 replicates for each biomarker per sample is between 77.8 and 100%, for some occasions a biomarker call is observed that is discordant to the initial biomarker status of the clinical sample (** indicated in Table 8).
## 2. MSS and MSI-H FFPE Control Reproducibility
The reproducibility of the external controls was evaluated at three laboratory sites. The test panel consisted of 2 types of contrived reference sample types (MSI-H and MSS),
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manufactured in 3 different sample lots by supplier SenslD. At the individual sites, each sample was tested on a set of 4 instruments, by 2 operators and with samples originating from 3 lots during 6 non-consecutive days with 2 replicates. It was observed that the call rate per sample lot was at least 35/36 (97%) and overall call rate on for all replicates was 216/216 (100%) in this study. A call rate of at least 105/108 was observed with a point estimate of 97% for individual biomarkers (Tables 9 and 10).
Table 9. Overview of primary analysis
| DESCRIPTION CRITERION | HIT RATE | POINT ESTIMATE | CI |
| --- | --- | --- | --- |
| Within sample lot | 36/36 | 100% | [90.36% -100.00%] |
| Within day | 36/36 | 100% | [90.36% - 100.00%] |
| Within site | 72/72 | 100% | [94.93% -100.00%] |
| Within operator | 108/108 | 100% | [96.57% -100.00%] |
| Within study | 216/216 | 100% | [98.25% - 100.00%] |
Table 10. The correct call rates at marker level per sample type and corresponding 95% confidence interval
| SAMPLE TYPE | TARGET | CORRECT CALL | TOTAL | CALL RATE | POINT ESTIMATE | LOWER LIMIT | UPPER LIMIT |
| --- | --- | --- | --- | --- | --- | --- | --- |
| MSI-H | ACVR2A | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | BTBD7 | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | DIDO1 | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | MREII | 105 | 108 | 105/108 | 0.97 | 0.9215 | 0.9905 |
| | RYR3 | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | SEC31A | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | SULF2 | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| MSS | ACVR2A | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | BTBD7 | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | DIDO1 | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | MREII | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | RYR3 | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | SEC31A | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
| | SULF2 | 108 | 108 | 108/108 | 1 | 0.9657 | 1 |
## 3. Linearity
Not Applicable
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# 4. Analytical Sensitivity
## 4.1 Limit of Blank
The limit of blank (LoB) study was conducted to evaluate the non-specific amplification and cross-reactivity between the mutant and wild type targets and consisted of two parts.
Part 1: The no template control (NTC) study wherein the level of contamination with human DNA was determined in MSI cartridges produced in the manufacturing facilities.
Part 2: Wild Type (WT) study wherein the background signals caused by potential cross-reactivity of the MSI mutation amplicons with MSI WT DNA were evaluated.
For the NTC study, 60 cartridges from three lots were tested to examine the contamination in the investigational use only (IUO) MSI Test cartridges. The results obtained from NTC study were calculated for the proportion of invalid calls (# of invalid/60). For the WT study, 20 FFPE MSS clinical samples were tested in duplicate using three different lots of IUO MSI Test cartridges to evaluate the analytical specificity of the test.
The LoB study results demonstrate that the Idylla MSI Test can correctly generate an 'Invalid' MSI status call when there is no sample in the Cartridge and the MSI status 'MSS' when a wild type sample is tested with the Idylla MSI Test.
## 4.2 Limit of Detection
The Limit of Detection (LoD) is defined as the lowest average mutant/total allele ratio (of weighted combined MSI biomarkers based on prevalence) generating a positive MSI status in 95% of cases (at a 95% confidence level).
Estimation of LoD with reference samples: The LoD estimation study was performed using reference cell lines (0% and 100% allelic frequency (AF) samples), by a titration experiment using varying levels of MSI-H allelic frequency (5% - 50%) at two different sample input levels (high and low input) representative for clinical samples. This study result showed the estimated LoD was 30% allelic frequency, at which the Idylla MSI Test generated correct MSI status calls for all the biomarkers (Table 11 and 12).
Table 11. Estimation of LoD results using reference (contrived) samples.
| ALLELIC FREQUENCY (% MSI-H) | NUMBER OF REPLICATES TESTED | LOD ESTIMATION RESULTS | |
| --- | --- | --- | --- |
| | | LOW SAMPLE INPUT | HIGH SAMPLE INPUT |
| | | NUMBER OF CORRECT CALLS (%) | NUMBER OF CORRECT CALLS (%) |
| 50% | 24 | 24/24 (100%) | 24/24 (100%) |
| 30% | 24 | 24/24 (100%) | 24/24 (100%) |
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| ALLELIC FREQUENCY (% MSI-H) | NUMBER OF REPLICATES TESTED | LOD ESTIMATION RESULTS | |
| --- | --- | --- | --- |
| | | LOW SAMPLE INPUT | HIGH SAMPLE INPUT |
| | | NUMBER OF CORRECT CALLS (%) | NUMBER OF CORRECT CALLS (%) |
| 20% | 24 | 24/24 (100%) | 24/24 (100%) |
| 15% | 24 | 24/24 (100%) | 24/24 (100%) |
| 10% | 24 | 22/24 (91.7%) | 24/24 (100%) |
| 5% | 24 | 4/24 (16.7%) | 0/24 (0%) |
Table 12: LoD estimation hit rates* and 95% confidence interval per biomarker and per sample in high and low input (contrived samples)
| SAMPLE DILUTION SERIES (AF%) | INDIVIDUAL BIOMARKER RESULTS (POINT ESTIMATE OR HIT RATE), 95% CI) |
| --- | --- |
| BTBD7 | RYR3 | SEC31A | ACVR2A | DIDO1 | MRE11 | SULF2 |
| high input background | 5% MSI-H | 4% (1/24) | 0% (0/24) | 0% (0/24) | 0% (0/24) | 0% (0/24) | 0% (0/24) | 0% (0/24) |
| 0.74-20.24% | 0.00-13.80% | 0.00-13.80% | 0.00-13.80% | 0.00-13.80% | 0.00-13.80% | 0.00-13.80% |
| 10% MSI-H | 100% (24/24) | 88% (21/24) | 100% (24/24) | 100% (24/24) | 75% (18/24) | 12% (3/24) | 83% (20/24) |
| 86.20-100% | 69.00-95.66% | 86.20-100% | 86.20-100% | 55.10-88.00% | 4.34-31.00% | 64.15-93.32% |
| 15% MSI-H | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 92% (22/24) | 42% (10/24) | 100% (24/24) |
| 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 74.15-97.68% | 24.47-61.17% | 86.20-100% |
| 20% MSI-H | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 92% (22/24) | 100% (24/24) |
| 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 74.15-97.68% | 86.20-100% |
| 30% MSI-H | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) |
| 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% |
| 50% MSI-H | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) |
| 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% |
| low input background | 5% MSI-H | 17% (4/24) | 8% (2/24) | 4% (1/24) | 17% (4/24) | 4% (1/24) | 0% (0/24) | 8% (2/24) |
| 6.68-35.85% | 2.32-25.85% | 0.74-20.24% | 6.68-35.85% | 0.74-20.24% | 0.00-13.80% | 2.32-25.85% |
| 10% MSI-H | 83% (20/24) | 50% (12/24) | 88% (21/24) | 75% (18/24) | 88% (21/24) | 17% (4/24) | 75% (18/24) |
| 64.15-93.32% | 31.43-68.57% | 69.00-95.66% | 55.10-88.00% | 69.00-95.66% | 6.68-35.85% | 55.10-88.00% |
| | 88% (21/24) | 88% (21/24) | 100% (24/24) | 96% (23/24) | 92% (22/24) | 33% (8/24) | 83% (20/24) |
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| SAMPLE DILUTION SERIES (AF%) | INDIVIDUAL BIOMARKER RESULTS (POINT ESTIMATE OR HIT RATE), 95% CI) | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | BTBD7 | RYR3 | SEC31A | ACVR2A | DIDO1 | MRE11 | SULF2 |
| | 15% MSI-H | 69.00-95.66% | 69.00-95.66% | 86.20-100% | 79.76-99.26% | 74.15-97.68% | 17.97-53.29% | 64.15-93.32% |
| | 20% MSI-H | 100% (24/24) | 96% (23/24) | 100% (24/24) | 100% (24/24) | 96% (23/24) | 58% (14/24) | 92% (22/24) |
| | | 86.20-100% | 79.76-99.26% | 86.20-100% | 86.20-100% | 79.76-99.26% | 38.83-75.53% | 74.15-97.68% |
| | 30% MSI-H | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 96% (23/24) | 100% (24/24) |
| | | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 79.76-99.26% | 86.20-100% |
| | 50% MSI-H | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) | 100% (24/24) |
| | | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% | 86.20-100% |
Clinical LoD estimation: The LoD using clinical samples was estimated using four FFPE samples by a titration experiment using varying levels of MSI-H neoplastic cell content (5-50%). The call rates for sample 4 were variable: this sample had a droplet digital PCR (ddPCR) measurement which was well below the validated linear range of the ddPCR method before dilutions were made. This sample was also originally characterized as a challenging sample with only 2 positive markers. Therefore, the call rate for this sample could also be indicative for the performance of challenging samples (Table 13).
Table 13. Estimation of LoD results using clinical samples
| %NEOPLATIC CELL CONTENT | CORRECT MSI-H CALL (HIT RATE) | | | | RESULTS (CORRECT CALLS) |
| --- | --- | --- | --- | --- | --- |
| | SAMPLE 1 | SAMPLE 2 | SAMPLE 3 | SAMPLE 4 | |
| 50% | 6/6 | 6/6 | 6/6 | 6/6 | 24/24 |
| 40% | 6/6 | 6/6 | 6/6 | 6/6 | 24/24 |
| 30% | 6/6 | 6/6 | 6/6 | 4/6 | 22/24 |
| 20% | 6/6 | 6/6 | 6/6 | 5/6 | 23/24 |
| 10% | 6/6 | 6/6 | 6/6 | 5/6 | 23/24 |
| 5% | 0/6 | 3/6 | 6/6 | 1/6 | 10/24 |
Clinical LOD confirmation: The LOD was confirmed using seven FFPE clinical samples (MSI-H and MSS including challenging samples) at approximately $33\%$ neoplastic cell content, and the minimum required tissue level $(25\mathrm{mm}^2$ per $10~{\mu\mathrm{m}}$ section). The samples were tested across two Cartridge lots in ten replicates per lot $(n = 20)$ over five days on multiple Instruments (total $n = 140$ from all seven samples). As
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presented in Table 14 below, the results revealed that all seven (7) samples tested (three (3) MSS and four (4) MSI-H) generated 100 % correct MSI status calls. This study confirms the clinical analytical sensitivity (LoD) of the Idylla MSI Test at ≤33% neoplastic cell content in clinical samples at the lowest sample input size (25 mm² per 10 μm section).
Table 14. Clinical LoD confirmation study results (clinical samples tested at approximately 33 % neoplastic cell content and the lowest sample input)
| SAMPLE ID | CARTRIDGE LOT | TOTAL RUNS | MSI STATUS (IDYLLA RESULTS) | CONCORDANT (CORRECT) CALL % |
| --- | --- | --- | --- | --- |
| Sample 1 (MSI-H) | Lot 1 | 40 | MSI-H | 100% (80/80) |
| Sample 2 (MSI-H) | | | | |
| Sample 3 (MSI-H) | | | | |
| Sample 4 (MSI-H) | Lot 2 | 40 | | |
| Sample 5 (MSS) | Lot 1 | 30 | MSS | 100% (60/60) |
| Sample 6 (MSS) | | | | |
| Sample 7 (MSS) | Lot 2 | 30 | | |
Table 15. LOD confirmation study: Point estimate and 95% CI presented per biomarker and per sample for MSI-H samples (clinical specimens)
| SAMPLE | INDIVIDUAL BIOMARKER RESULTS (POINT ESTIMATE OR HIT RATE*) 95% CI AT 33% NEOPLASTIC CELL CONTENT | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | BTBD7 | RYR3 | SEC31A | ACVR2A | DIDO1 | MRE11 | SULF2 |
| Sample 1 (MSI-H) | 100% (20/20 mut) | 95.00% (19/20 wt) | 100% (20/20 mut) | 100% (20/20 mut) | 70% (14/20 mut) | 95.00% (19/20 wt) | 100% (20/20 mut) |
| | 83.89-100% | 76.39-99.11% | 83.89-100% | 83.89-100% | 48.1-85.45% | 76.39-99.11% | 83.89-100% |
| Sample 2 (MSI-H) | 100% (20/20 mut) | 100% (20/20 mut) | 100% (20/20 mut) | 100% (20/20 mut) | 100% (20/20 mut) | 95.00% (19/20 mut) | 65% (13/20 mut) |
| | 83.89-100% | 83.89-100% | 83.89-100% | 83.89-100% | 83.89-100% | 76.39-99.11% | 43.29-81.88% |
| Sample 3 (MSI-H) | 100% (20/20 mut) | 100% (20/20 mut) | 85% (17/20 wt) | 100% (20/20 wt) | 100% (20/20 mut) | 100% (20/20 wt) | 100% (20/20 wt) |
| | 83.89-100% | 83.89-100% | 63.96-94.76% | 83.89-100% | 83.89-100% | 83.89-100% | 83.89-100% |
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| SAMPLE | INDIVIDUAL BIOMARKER RESULTS (POINT ESTIMATE OR HIT RATE*) 95% CI AT 33% NEOPLASTIC CELL CONTENT | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | BTBD7 | RYR3 | SEC31A | ACVR2A | DIDO1 | MRE11 | SULF2 |
| Sample 4 (MSI-H) | 100% (20/20 mut) | 100% (20/20 wt) | 35% (7/20 wt) | 100% (20/20 mut) | 100% (20/20 mut) | 100% (20/20 mut) | 100% (20/20 mut) |
| | 83.89-100% | 83.89-100% | 18.12-57.00% | 83.89-100% | 83.89-100% | 83.89-100% | 83.89-100% |
Table 16. LOD confirmation study: mutant hit rates and 95% CI presented per biomarker and per sample for MSS samples
| SAMPLE | INDIVIDUAL BIOMARKER RESULTS (POINT ESTIMATE OR HIT RATE*) 95% CI AT 33% NEOPLASTIC CELL CONTENT | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | BTBD7 | RYR3 | SEC31A | ACVR2A | DIDO1 | MRE11 | SULF2 |
| Sample 5 (MSS) | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% |
| Sample 6 (MSS) | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% |
| Sample 7 (MSS) | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% | 100% (20/20 wt)
83.89-100% |
*Hit rates are provided as fraction of calls observed (n/N: ratio of calls) with as reference the call observed in the initial screening
**MSI-H borderline sample per Idylla MSI Test v2.0 initial screening results
Note: 'mut' refers to a mutant biomarker and 'wt' refers to a wild type biomarker
For MSS samples, individual biomarkers score consistently wild type (Table 16). For clinical MSI-H samples, a concordance of ≥ 95%-point estimate can be observed for 4 biomarkers (BTBD7, RYR3, ACVR2A and MRE11) across all 4 MSI-H samples. The remaining biomarkers showed concordance below 95% for some samples. For SEC31A, two samples had hit rates below 95%, Sample 3 at 85% and Sample 4 at 35%. DIDO1 demonstrated a 70% hit rate in sample 1, and SULF2 demonstrated a hit rate of 65% with sample 2 (Table 15).
## 5. Analytical Specificity/Interference
Interference testing was performed using seven FFPE colorectal cancer clinical samples (MSI-H and MSS), including commonly encountered interfering substances such as
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hemoglobin, triglycerides, and paraffin. For hemoglobin and triglycerides, interference was tested at the highest possible concentration levels (2 mg/mL and 37 mmol/L, respectively). To assess the paraffin interference, one additional 10 µm paraffin blank section was added to the cartridge along with the sample. Each sample was tested with an interfering substance in five replicates using a single lot of Idylla MSI Cartridges. Additionally, the samples were tested without an interfering substance as a control. The results obtained for each interfering substance were checked for a correct MSI status call and compared with the control results (runs without interfering substance) for the proportion (%) of concordance with control results.
Table 17. Interference results for hemoglobin, triglycerides and paraffin
| INTERFERENCE SUBSTANCE | TOTAL RUN* WITH EACH INTERFERENCE SUBSTANCE | INTERFERENCE TEST RESULTS | |
| --- | --- | --- | --- |
| | | CORRECT MSI STATUS CALLS (%) | CONCORDANCE WITH CONTROL RESULTS (%) |
| Control (No Interferent) | 35 | 35 / 35 (100%) | - |
| Hemoglobin (2 mg / mL) | 35 | 35 / 35 (100%) | 100% |
| Triglycerides (37 mM) | 35 | 35 / 35 (100%) | 100% |
| Paraffin (1 x 10 µm section) | 35 | 35 / 35 (100%) | 100% |
* Total runs from all seven clinical samples tested (at five runs per sample)
All seven samples tested with interference substances i.e., hemoglobin, triglycerides and excess paraffin generated correct MSI status calls, showed 100% concordance with control results (Table 17).
Mucin (i.e., % mucinous cells in FFPE sample) impact on the Idylla MSI Test was evaluated using nineteen individual FFPE clinical samples with various levels of mucinous cell content (0% - 60%). These samples included both MSI-H and MSS samples that met sample requirement criteria for the test. Each mucinous sample was tested in three replicates using one lot of Idylla MSI Test Cartridges. All nineteen mucinous samples results showed correct MSI calls for approximately 96.5% runs (55 of 57 runs) performed, except one sample which generated 'Invalid' results for 2 out of 3 runs performed. This study indicated that samples with mucinous cell content up to 60% have no impact on the performance of the Idylla MSI Test, and can still generate correct MSI status calls.
The impact of necrosis content >50% on the Idylla MSI Test was evaluated using four FFPE clinical samples with various levels of necrosis content (66-73%). The samples included both MSI-H and MSS samples. Each sample was tested in triplicate with and without necrosis content. All four samples generated a correct MSI status call for testing with and without necrosis. Therefore, necrosis content up to 73% has no impact on the Idylla MSI Test.
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## 6. Assay Reportable Range
Seven samples consisting of four MSI-H and three MSS clinical FFPE samples (including one each of MSI-H and MSS borderline samples) were used for this study. In this study, borderline samples refer to MSI mutant samples with one positive marker (MSS borderline, negative) or 2/3 positive markers (MSI-H borderline, positive). The minimum and maximum tissue requirement was determined by a titration experiment using six different levels of input material (12.5 mm² – 300 mm²) per sample using 10 μm FFPE clinical specimens containing the minimum required tumor content (i.e., ≥ 33%) per the product requirements. Sufficient FFPE MSI-H/MSS sections from each sample were liquefied using MSI Test split protocol Part 1, and these liquefactions were diluted with buffer to prepare the desired six level tissue input samples (300, 200, 100, 50, 25 and 12.5 mm²). Each dilution sample was tested in six replicates using three different MSI Test cartridge lots. The results obtained were analyzed for proportion of correct calls and checked against the acceptance criteria specified in the protocol.
Data analysis showed that overall, the results met the acceptance criteria of ≥95% concordance (correct MSI status calls) for tissue input levels (mm²) 300, 200, 100, 50, and 25. However, input level 12.5 mm² did not meet the acceptance criteria with an 85.7% (36/42) concordance (correct MSI status calls).
The results demonstrated that the Idylla MSI Test can achieve valid and correct MSI status calls with tissue input levels from minimum of 25 mm² to maximum of 300 mm² for 10 μm sections, equivalent for 4 μm sections from minimum of 62.5 mm² to maximum 750 mm² tissue input.
## 7. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods)
### 7.1 Shelf Life
Four verification lots and one validation lot were tested in support of the Idylla MSI Test shelf life. The product lots were stored at temperatures of 5±3°C and 30±2°C representing the worst-case scenarios. A limited number of cartridges were stored at temperature of 25±2°C to be tested if the instability trend is observed at 30±2°C (fallback scenario). One product lot (#3505) was subjected to the mixed thermal program prior to the real time stability testing as described in the Shipping Stability section.
The real time stability testing results support the current claimed shelf life and the unopened Idylla MSI Test is stable up to 18 months (Table 18).
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Table 18. Stability testing plan
| LOT # | STUDY | CONDITIONS | TIME POINTS (MONTHS) | | | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | | T0 | T0' | 3 | 7 | 10 | 12 | 13 | 16 | 19 |
| 3505 | Thermocycling followed by long term | 5±3°C | x | x | - | x | - | x | x | - | x |
| | | 25±2°C | | | fallback scenario for 30 °C storage | | | | | | |
| | | 30±2°C | | | x | x | x | x | x | x | x |
| 3507 | long term | 5±3°C | x | - | - | x | - | x | x | - | x |
| | | 25±2°C | | | fallback scenario for 30 °C storage | | | | | | |
| | | 30±2°C | | | x | x | x | x | x | x | x |
| 3509 | long term | 5±3°C | x | - | - | x | - | x | x | - | x |
| | | 25±2°C | | | fallback scenario for 30 °C storage | | | | | | |
| | | 30±2°C | | | x | x | x | x | x | x | x |
| 3504 | long term | 5±3°C | x | - | - | x | - | x | x | - | x |
| | | 25±2°C | | | fallback scenario for 30 °C storage | | | | | | |
| | | 30±2°C | | | x | x | x | x | x | x | x |
| 3794 | long term | 5±3°C | x | - | - | x | - | x | x | - | x |
| | | 25±2°C | | | fallback scenario for 30 °C storage | | | | | | |
| | | 30±2°C | | | x | x | x | x | x | x | x |
## 7.2 Shipping Stability
Cartridges underwent temperature cycling between -20°C for 72 hours and +25°C for 24 hours across a total of two cycles. The third winter cycle of 48 hours at -20°C and 24 hours at +25°C hours followed immediately. After completion of winter cycling, the cartridges were exposed to the temperature of 40°C for 72 hours.
Immediately after temperature cycles, 9 MSI cartridges were tested with 6 FFPE MSI slices and 3 FFPE MSS slices to generate the time point 0' data. The reference baseline for data analysis was time point 0 data (QC release). The cartridges exposed to the thermal cycling have been stored at 30 ± 2 °C and further tested according to the real time stability study protocol.
The results show that exposing the Idylla MSI Test to high (up to 40°C) and low temperatures (to -20°C) for a limited time up to 72 hours does not impact the product performance.
## 7.3 In Use Stability
For this study, 84 MSI cartridges were removed from the pouch and kept in the incubator at 30 ± 2 °C and 75 % RH for 6 days. First 12 cartridges were removed from the incubator
510(k) Summary Original 510(k) Application
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Idylla™ MSI Test K211181
Biocartis NV
after two hours (= day 0) and tested with 6 MSI-H samples and 6 MSS samples. The remaining cartridges were run on day 1 to 6 (six cartridges per day). In-use stability study (without pouch, without specimen) is verified at the beginning (within 3 months after T0) and at the end of shelf life.
For in-use study 1, MSI cartridges were removed from their pouches and placed in an incubator (at 30 ± 2 °C and 75 ± 5 %RH) for up to 6 days. The first cartridges were tested with MSS and MSI FFPE slices after 2 hours (= day 0) in the incubator, and the remaining cartridges were tested at the 5 subsequent time points, i.e., day 2 to day 6. Six cartridges were tested per time point: 3 cartridges with FFPE MSS slices and 3 cartridges with FFPE MSI slices.
For In-use study 2, MSI cartridges were removed from their pouches, loaded with a MSS FFPE slice or MSI slice. Six cartridges loaded with the two input sample types were run on Idylla immediately after the sample was loaded (hour 0). The other loaded cartridges were placed in an incubator (at 30 ± 2 °C and 75 ± 5 %RH) for 3 and 9 hours before running them on Idylla. Six cartridges were tested per time point: 3 cartridges with FFPE MSS slices and 3 cartridges with FFPE MSI slices.
The in-use stability data obtained at beginning and end of shelf life support that MSI cartridges can be used up to:
- 5 days after removed from the pouch and stored on the bench (at laboratory ambient conditions) without sample
- 8 hours after removed from pouch, loaded with a sample and stored at laboratory ambient conditions.
# 8. Assay Cut-Off
Seven novel individual MSI markers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A and SULF2) will be tested.
- A sample is called Microsatellite Instability-High or MSI-H if the sample has ≥2 mutant biomarkers and an MSI Score Range ≥ 0.15.
- A sample is called Microsatellite Stable or MSS if the sample has <2 mutant biomarkers and an MSI Score Range <0.15.
# 9. Cartridge Accuracy for Minimal Number of Expansions
The test panel to assess cartridge accuracy consisted of synthetic targets (ST), representing all seven MSI biomarkers, containing the repeat sequence with one additional nucleotide (+1) or one deleted nucleotide (-1). Both reference sample and spiked MSS samples were tested in triplicate in cartridges resulting from one cartridge lot (Table 19).
Table 19. Overview analytical accuracy testing results
| PANEL | MSI STATUS | CALL RATE |
| --- | --- | --- |
| MSS | MSS | 3/3 |
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{21}
Idylla™ MSI Test K211181
Biocartis NV
| PANEL | MSI STATUS | CALL RATE |
| --- | --- | --- |
| MSS + ST cocktail 1 (-1) | MSI-H | 3/3 |
| MSS + ST cocktail 2 (+1) | MSS | 3/3 |
Table 20. Overview individual calls on marker level
| | MSI BIOMARKERS – CURVE CALL | | | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| PANEL | ACVR2A | BTBD7 | DIDO1 | MRE11 | RYR3 | SEC31A | SULF2 |
| MSS | 0/3 | 0/3 | 0/3 | 0/3 | 0/3 | 0/3 | 0/3 |
| MSS + ST cocktail 1 (-1) | 3/3 | 3/3 | 3/3 | 3/3 | 3/3 | 3/3 | 3/3 |
| MSS + ST cocktail 2 (+1) | 0/3 | 0/3 | 0/3 | 0/3 | 0/3 | 0/3 | 0/3 |
All nine Idylla runs resulted in valid test results. Three cartridges tested with the control panel, MSS contrived sample, resulted in an MSS call. Three cartridges tested with MSS sample spiked with ST cocktail 1 (-1 nucleotide) resulted in an MSI-H call. Cartridges tested with MSS sample spiked with ST cocktail 2 (+1 nucleotide) resulted in three MSS calls (Table 20).
## 10. Carry-Over
The Idylla MSI Test is a unitized cartridge test system. Therefore, this study is not applicable.
## 11. Curls versus Slides of FFPE Specimens
Ten paired (curls and slides) FFPE MSS and ten paired (curls and slides) FFPE MSI-H samples from CRC patients that fulfilled the sample requirements per Idylla MSI Test Instructions For Use were tested. A total of 40 samples (20 curls and 20 slides) were tested. The agreement of the final MSI status (genetic) call results between curls and slides for each sample tested (10 MSS and 10 MSI-H) were compared.
The data analysis revealed that of the 20 samples tested (10 MSS and 10 MSI-H), one MSI-H sample had discordant results between curl and slide, and the remaining 19 samples showed agreement for results between curls and slides.
## B. Comparison Studies:
A method comparison study was conducted to clinically validate the accuracy of the Idylla MSI Test against a predicate device, the OncoMate MSI Dx Analysis System for the detection of MSI status. A comparison of the Idylla MSI Test result to results of a germline Next Generation Sequencing (NGS) for DNA mismatch repair genes (MMR) was performed for identification of Lynch syndrome (LS) cases.
510(k) Summary Original 510(k) Application
{22}
Idylla™ MSI Test K211181
Biocartis NV
The study was conducted by testing 123 sequentially enrolled colorectal samples representative of the intended use population. The sequential sample set was supplemented with 20 confirmed Lynch cases (enrichment cohort) obtained from the Colorectal Cancer Family Registry (CCFR). The study used retrospective FFPE tissue samples collected from CRC patients in the US representative of the intended use population. All stages of CRC (stages I – IV), and tumors from different sites of the colorectal area were represented.
Of the total 143 samples included in the study (123 sequential and 20 confirmed Lynch), valid test results were obtained for all 143 with Idylla MSI Test, for 140 with the predicate and 133 with germline NGS of MMR genes.
The agreement parameters PPA, NPA and OPA were calculated between Idylla MSI Test and the predicate for MSI status calls and between Idylla MSI Test and germline NGS of MMR genes for Lynch identification.
# 1. Idylla MSI Test vs Predicate
The concordance and agreement analysis between Idylla MSI Test and the predicate for the 143 samples is presented in Table 21 and Table 22, respectively. A total of 32 samples were detected as MSI-H by the predicate out of which 31 were also detected as MSI-H by the Idylla MSI Test. Of the total 108 samples detected as MSS by the predicate, 107 were also MSS by Idylla MSI Test. The PPA was 96.88% and the NPA was 99.07% with OPA of 98.57% between the two methods.
Table 21. Concordance for MSI status between Idylla MSI Test and the predicate for all samples.
| IDYLLA MSI TEST | ONCOMATE MSI | | | | |
| --- | --- | --- | --- | --- | --- |
| | MSI-H | MSS | INVALID | NO CALL | TOTAL |
| MSI-H | 31 | 1** | 0 | 3 | 35 |
| MSS | 1* | 107 | 0 | 0 | 108 |
| Invalid | 0 | 0 | 0 | 0 | 0 |
| Total | 32 | 108 | 0 | 3 | 143 |
*: One (1) sample that tested MSS by Idylla MSI Test and MSI-H by the OncoMate MSI Dx Analysis System is a confirmed Lynch case by NGS.
**: One (1) sample that tested MSI-H by Idylla MSI Test and MSS by the OncoMate MSI Dx Analysis System is a confirmed Lynch case by NGS.
Table 22. Percent agreement for Idylla MSI test and the predicate for all samples.
| MEASURE | RATE | POINT ESTIMATE (%) | 95% CI |
| --- | --- | --- | --- |
| PPA | 31/32 | 96.88 | 83.78 – 99.92 |
| NPA | 107/108 | 99.07 | 94.95 – 99.98 |
| OPA | 138/140 | 98.57 | 94.93 – 99.83 |
510(k) Summary Original 510(k) Application
{23}
Idylla™ MSI Test K211181
Biocartis NV
Concordance and agreement analysis categorized by sequential and enrichment cohorts are provided in Table 23 - Table 26.
Table 23. Concordance for MSI status between Idylla MSI Test and the predicate for sequential cohort.
| IDYLLA MSI TEST | ONCOMATE MSI | | | | |
| --- | --- | --- | --- | --- | --- |
| | MSI-H | MSS | INVALID | NO CALL | TOTAL |
| MSI-H | 15 | 1 | 0 | 0 | 16 |
| MSS | 0 | 107 | 0 | 0 | 107 |
| Invalid | 0 | 0 | 0 | 0 | 0 |
| Total | 15 | 108 | 0 | 0 | 123 |
Table 24. Concordance for MSI status between Idylla MSI Test and the predicate for sequential cohort.
| MEASURE | RATE | POINT ESTIMATE (%) | 95% CI |
| --- | --- | --- | --- |
| PPA | 15/15 | 100 | 78.2 – 100.00 |
| NPA | 107/108 | 99.07 | 94.95 – 99.98 |
| OPA | 122/123 | 99.19 | 95.55 – 99.98 |
Table 25. Concordance for MSI status between Idylla MSI Test and the predicate for enrichment cohort.
| IDYLLA MSI TEST | ONCOMATE MSI | | | | |
| --- | --- | --- | --- | --- | --- |
| | MSI-H | MSS | INVALID | NO CALL | TOTAL |
| MSI-H | 16 | 0 | 0 | 3 | 19 |
| MSS | 1 | 0 | 0 | 0 | 1 |
| Invalid | 0 | 0 | 0 | 0 | 0 |
| Total | 17 | 0 | 0 | 3 | 20 |
Table 26. Concordance for MSI status between Idylla MSI Test and the predicate for enrichment cohort.
| MEASURE | RATE | POINT ESTIMATE (%) | 95% CI |
| --- | --- | --- | --- |
| PPA | 16/17 | 94.12 | 71.31 – 99.85 |
| NPA* | 0/0 | N/A | N/A |
| OPA | 16/17 | 94.12 | 71.31 – 99.85 |
*: All samples in the enrichment cohort are confirmed Lynch cases expected to be MSI-H.
510(k) Summary Original 510(k) Application
{24}
Idylla™ MSI Test K211181
Biocartis NV
The analysis demonstrated the agreement of the Idylla MSI Test with the predicate device, the predicate to detect MSI status from samples collected from CRC patients representative of the intended use population.
## 2. Idylla MSI Test Vs Germline NGS for MMR Genes
Based on the detection of germline pathogenic mutations by NGS in the MMR genes (MLH1, MSH2, MSH6 or PMS2), a total of 25 samples were Lynch syndrome positive. Table 27 and Table 28 present concordance and agreement results, respectively, between the Idylla MSI Test and germline NGS of MMR genes for all samples. Of the total 25 confirmed Lynch cases by germline NGS, the Idylla MSI Test correctly identified 23 samples as MSI-H. Two (2) samples typed as MSS were confirmed by NGS to have pathogenic mutations in the MSH2 gene.
The PPA between Idylla MSI Test and NGS for identification of Lynch syndrome was 92%. The NPA is less informative since Lynch syndrome negative samples by germline NGS can still exhibit MSI-H due to sporadic somatic mutations in one or more of the MMR genes (sporadic dMMR).
Table 27. Concordance for MSI status between Idylla MSI Test and germline NGS for MMR genes for all samples.
| IDYLLA MSI TEST | GERMLINE NGS RESULTS | | | |
| --- | --- | --- | --- | --- |
| | LYNCH POSITIVE | LYNCH NEGATIVE | INVALID | TOTAL |
| MSI-H | 23 | 11 | 1 | 35 |
| MSS | 2 | 97 | 9 | 108 |
| Invalid | 0 | 0 | 0 | 0 |
| Total | 25 | 108 | 10 | 143 |
Table 28. Agreement for MSI status between Idylla MSI Test and germline NGS for MMR genes for all samples.
| MEASURE | RATE | POINT ESTIMATE (%) | 95% CI |
| --- | --- | --- | --- |
| PPA | 23/25 | 92% | 73.97 – 99.02 |
| NPA | 97/108 | 89.81% | 82.50 – 94.80 |
| OPA | 120/133 | 90.22% | 83.99 – 94.20 |
The concordance and agreement result between the Idylla™ MSI Test and germline NGS of MMR genes categorized by sequential cohort and enrichment cohort is presented in Table 29 - Table 32 below. The PPA for identification of Lynch syndrome cases was 80% and 95% with sequential and enrichment cohorts, respectively.
510(k) Summary Original 510(k) Application
{25}
Idylla™ MSI Test K211181
Biocartis NV
Table 29. Concordance for MSI status between Idylla MSI Test and germline NGS for MMR genes for sequential cohort.
| IDYLLA MSI TEST | GERMLINE NGS RESULTS | | | |
| --- | --- | --- | --- | --- |
| | LYNCH POSITIVE | LYNCH NEGATIVE | INVALID | TOTAL |
| MSI-H | 4 | 11 | 1 | 16 |
| MSS | 1 | 97 | 9 | 107 |
| Invalid | 0 | 0 | 0 | 0 |
| Total | 5 | 108 | 10 | 123 |
Table 30. Agreement for MSI status between Idylla MSI Test and germline NGS for MMR genes for sequential cohort.
| MEASURE | RATE | POINT ESTIMATE (%) | 95% CI |
| --- | --- | --- | --- |
| PPA | 4/5 | 80% | 28.36 – 99.49 |
| NPA | 97/108 | 89.81% | 82.51 – 94.80 |
| OPA | 101/113 | 89.38% | 82.18 – 94.39 |
Table 31. Concordance for MSI status between Idylla MSI Test and germline NGS for MMR genes for enrichment cohort.
| IDYLLA MSI TEST | GERMLINE NGS RESULTS | | | |
| --- | --- | --- | --- | --- |
| | LYNCH NEGATIVE | LYNCH NEGATIVE* | INVALID | TOTAL |
| MSI-H | 19 | N/A | 0 | 19 |
| MSS | 1 | N/A | 0 | 1 |
| Invalid | 0 | N/A | 0 | 0 |
| Total | 20 | N/A | 0 | 20 |
Table 32. Agreement for MSI status between Idylla MSI Test and germline NGS for MMR genes for enrichment cohort.
| MEASURE | RATE | POINT ESTIMATE (%) | 95% CI |
| --- | --- | --- | --- |
| PPA | 19/20 | 95% | 75.13 – 99.87 |
| NPA | N/A | N/A | N/A |
| OPA | N/A | N/A | N/A |
IX. Instrument Name
Biocartis Idylla System
510(k) Summary Original 510(k) Application
{26}
Idylla™ MSI Test K211181
Biocartis NV
# X. System Description:
1. Modes of Operation:
Does the applicant’s device contain the ability to transmit data to a computer, webserver, or mobile device?
Yes ☐ X ☐ or No ☐
Does the applicant’s device transmit data to a computer, webserver, or mobile device using wireless transmission?
Yes ☐ or No ☐ X ☐
2. Software:
FDA has reviewed applicant’s Hazard Analysis and software development processes for this line of product types:
Yes ☐ X ☐ or No ☐
3. Level of Concern:
Moderate
4. Specimen Handling:
Please refer to Device Description section above.
5. Calibration and Quality controls:
In contrast to standard PCR equipment, the Idylla System is calibrated at the time of manufacturing. No user performed system calibration is needed. The instrument automatically initiates a self-test before a cartridge is processed. This test checks individual instrument modules. If the self-test fails, a fatal error is reported and the instrument is disabled. On a monthly basis, the system requires a self-diagnostic test to check for potential hardware issues. The system notifies the user of the test need by displaying a warning icon on the console. Self-diagnostic test failure leads to a fatal error and requires the intervention of authorized service personnel.
# XI. Other Supportive Instrument Performance Characteristics Data Not Covered In The "Performance Characteristics" Section above:
Not Applicable
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{27}
Idylla™ MSI Test K211181
Biocartis NV
XII. Proposed labeling:
The labeling is sufficient, and it satisfies the requirements of 21 CFR Parts 801 and 809, as applicable, and the special controls for this device type.
XIII. Patient Perspectives:
This submission did not include specific information on patient perspectives for this device.
XIV. Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
510(k) Summary Original 510(k) Application
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