(120 days)
MammaPrint® FFPE is a qualitative in vitro diagnostic test, performed in a central laboratory, using the gene expression profile obtained from formalin-fixed paraffin embedded (FFPE) breast cancer tissue samples to assess a patient's risk for distant metastasis within 5 years.
The test is performed for breast cancer patients, with Stage I disease, with tumor size ≤ 5.0 cm and lymph node negative. The MammaPrint FFPE result is indicated for use by physicians as a prognostic marker only, along with other clinicopathological factors.
The MammaPrint service is a microarray-based gene expression analysis of a tumor. The analysis is based on several processes: isolation of RNA from formalin-fixed paraffin embedded (FFPE) tumor tissue sections, DNase treatment of isolated RNA, amplification DNase treated RNA resulting in cDNA, labeling and purification of amplified cDNA, hybridization of the diagnostic microarray, scanning the MammaPrint microarray and data acquisition (Feature Extraction), calculation and determination of the risk of recurrence in breast cancer patients.
The MammaPrint analysis is designed to determine the gene activity of specific genes in a FFPE tissue sample. The result is an expression profile, or fingerprint, of the sample.
The molecular profile of the sample is determined (Low Risk) by calculating the MammaPrint index (MPI) by determining the correlation of the sample expression profile to the mean expression profiles of risk templates of tumors with a known good and poor outcome.
The provided text describes the acceptance criteria and study for the MammaPrint FFPE device, focusing on the analytical performance related to a change in microarray scanner.
Here's the breakdown of the information requested:
1. A table of acceptance criteria and the reported device performance
| Acceptance Criteria Category | Specific Criteria | Reported Device Performance |
|---|---|---|
| Technical Equivalence (Concordance between Scanners) | Passing and Bablok regression for MammaPrint indices between C-scanners (Agilent G2505) and D-scanners (Agilent SureScan Dx G5761AA) must meet pre-defined acceptance criteria (specific values for slope and intercept not explicitly stated, but implied to be near 1 and 0, respectively). | Scanner SG18309119 vs. C-scanners: y=0.00 +1.00 x (95%Cl – slope: 1.000 – 1.002, 95%Cl intercept: -0.0002 to 0.000). Scanner SG18449122 vs. C-scanners: y=0.0010 +1.00 x (95%Cl – slope: 1.000 – 1.0021, 95%Cl intercept: 0.0014 to 0.001). Both results are stated to be "within the pre-defined acceptance criteria." |
| Overall concordance, Negative Percent Agreement (NPA), and Positive Percent Agreement (PPA) for MammaPrint categorical results (High/Low Risk) between C-scanners and D-scanners must be within pre-defined acceptance criteria. | Scanner SG18309119 vs. C-scanners: Overall concordance: 99.7%. NPA: 100% (95%Cl: 98.1-100). PPA: 99.3% (95%Cl: 96.0 – 99.9). Scanner SG18449122 vs. C-scanners: Overall concordance: 100%. NPA: 100% (95%Cl: 97.1 – 100). PPA: 100% (95%Cl: 97.5 - 100). All reported values are stated to be "within the predefined acceptance criteria." | |
| Precision Assessment | F-test p-values for variability of repeated measurements of control samples between C-scanners and D-scanners should not show a significant difference (i.e., p-value > 0.05). | F-test p-values for all four control samples were "all well below the significance level of 0.05, indicating there is no significant difference in precision between C and D-scanners." (This wording is a bit confusing; "well below 0.05" would typically indicate a significant difference. However, given the context of demonstrating no significant difference, it likely implies that the null hypothesis of equal variance could not be rejected, which means the p-value was above 0.05. Re-reading, "indicating there is no significant difference" following "well below the significance level of 0.05" is a logical contradiction. Assuming the intent was to show no significant difference in precision, the p-values should have been above 0.05. This might be a typo in the FDA document, or the interpretation of the F-test result is inversely stated. Given the conclusion that "there is no significant difference," the F-test result must have been non-significant, meaning p > 0.05. Let's assume the intent was to show non-significant difference.) |
| Clinical Correlation | MammaPrint index should correlate with clinical outcome (distant recurrence risk). | Result distribution: In the RASTER study, Bin 1 (MPI 0.36 to +1) had 0% observed 5-yr DR risk (N=37). Bin 4 (MPI -1 to -0.57) had 13.6% observed 5-yr DR risk (N=66). Cox regression analysis: With each increase in MammaPrint index unit, there is a 0.224 (4.5 folds) decrease in recurrence risk at 5 years (p=0.001; 95% Cl: 0.092-0.543). This demonstrates correlation. |
2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)
- Sample Size for Technical Equivalence (Concordance): 92 8-pack arrays (likely representing 92 individual samples, or potentially 92 unique arrays, each containing multiple spots/analyses).
- Sample Size for Precision Assessment: Four diagnostic control samples (PLEP3, PHHE2, PHTR2, PBCL2), measured repeatedly. The number of repeated measurements is not specified.
- Sample Size for Clinical Correlation (RASTER study): 345 patients.
- Data Provenance: Not explicitly stated for analytical performance (concordance and precision). For the clinical correlation, it references the RASTER study, which was "previously submitted in K141142," but country of origin and retrospective/prospective nature are not detailed here.
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)
- For Analytical Performance: Ground truth is established by the MammaPrint index and categorical results from the FDA-cleared C-scanners (Agilent G2505), acting as the reference. No human experts are involved in establishing this specific ground truth.
- For Clinical Correlation (RASTER study): The clinical outcome (distant recurrence risk) is the ground truth. While not detailed in this excerpt, clinical outcomes studies typically rely on physician diagnoses, follow-up, and potentially pathology reports, rather than a panel of experts specifically adjudicating "ground truth" for the test results.
4. Adjudication method (e.g., 2+1, 3+1, none) for the test set
- For Analytical Performance: None. The ground truth is the output from the predicate device's scanner (Agilent G2505).
- For Clinical Correlation: Not specified in this document. Clinical outcome data collection methods vary, but typically don't involve an adjudication panel for the outcome itself, but rather established clinical trial protocols and follow-up.
5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance
- This is not an MRMC study. The MammaPrint device is a gene expression profiling test, not an AI imaging or diagnostic assistance tool for human readers. It provides a prognostic marker directly from tissue analysis.
6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done
- Yes, this is a standalone device. The MammaPrint FFPE test generates a result (MammaPrint Index and High/Low Risk classification) directly from the gene expression profile of the tumor tissue. The "algorithm only" performance is what is being evaluated and validated. The "human-in-the-loop" component mentioned is the physician's use of the result "along with other clinicopathological factors" for prognostic assessment.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
- For Analytical Performance (concordance and precision): The ground truth is the MammaPrint index and categorical result generated by the previously FDA-cleared C-scanners (Agilent G2505).
- For Clinical Correlation: The ground truth is 5-year distant recurrence (DR) risk, which is a form of outcomes data.
8. The sample size for the training set
- Not explicitly mentioned for the current submission. The MammaPrint assay itself was developed and validated earlier, and the current submission is for a modification (scanner change) to an already cleared predicate device (K141142). The original training set for the MammaPrint algorithm would have been part of the earlier submissions but is not detailed here.
9. How the ground truth for the training set was established
- Not explicitly mentioned in this document. For the original MammaPrint development, the ground truth for training would have involved gene expression profiles correlated with long-term clinical outcomes (e.g., distant metastasis-free survival) from large cohorts of breast cancer patients, likely using robust clinical data and follow-up.
§ 866.6040 Gene expression profiling test system for breast cancer prognosis.
(a)
Identification. A gene expression profiling test system for breast cancer prognosis is a device that measures the ribonucleic acid (RNA) expression level of multiple genes and combines this information to yield a signature (pattern or classifier or index) to aid in prognosis of previously diagnosed breast cancer.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Gene Expression Profiling Test System for Breast Cancer Prognosis.” See § 866.1(e) for the availability of this guidance document.