(603 days)
MammaPrint® is a gualitative in vitro diagnostic test service, performed in a single laboratory, using the gene expression profile of fresh breast cancer tissue samples to assess a patients' risk for distant metastasis (up to 10 years for patients less than 61 years old, up to 5 years for patients ≥ 61 years).
The test is performed for breast cancer patients with Stage I or Stage II disease, with a tumor size of ≤ 5.0 cm and lymph node negative. The MammaPrint 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 frozen tumor tissue sections, DNA'se treatment of isolated RNA, linear amplification and labeling of DNA'se treated RNA, cRNA purification, hybridization of the cRNA to the MammaPrint microarray, scanning the MammaPrint microarray and data acquisition (feature extraction), index calculation and determination of the risk of distant recurrence in breast cancer patients.
The MammaPrint analysis is designed to determine the gene activity of specific genes in a tissue sample compared to a reference standard. The result is an expression profile, or fingerprint, of the sample.
The correlation of the sample expression profile to a template (the mean expression profile of 44 tumors with a known good clinical outcome) is calculated and the molecular profile index of the sample is determined (Low Risk, High Risk).
Here's a breakdown of the acceptance criteria and the study information for the MammaPrint® device, based on the provided text:
MammaPrint® Acceptance Criteria and Study Information
1. Acceptance Criteria and Reported Device Performance
The provided document primarily focuses on analytical performance as internally validated and clinical performance as demonstrated through peer-reviewed studies. It doesn't explicitly state "acceptance criteria" in a typical pass/fail numerical sense for clinical performance, but rather presents the performance achieved by the device in various clinical settings.
| Acceptance Criteria Category | Specific Metric/Description | Reported Device Performance/Finding |
|---|---|---|
| Analytical Performance | Accuracy of measurement (based on repeated experiments of control samples) | 98.5% Analytical Accuracy of measurement |
| Accuracy of classifying a sample as High Risk or Low Risk | At least 98.9% (i.e., 1.1% false negative classification) | |
| Percentage of "Borderline Samples" | Less than 5% of analyzed samples are considered "Borderline Samples" | |
| Classification accuracy for "Borderline Samples" | Approximately 90% (i.e., 10% chance of false classification) | |
| Clinical Performance | Assessment of risk for distant metastasis (up to 10 years for patients < 61 years) (Nature Paper) | Within 5 year metastasis risk by profile multivariate OR 18 |
| Metastasis-free survival by profile at 10 years (low risk vs. high risk) (NEJM Paper) | Low risk profile 87%, high risk profile 44% (at 5 yrs: 93% and 56% respectively) | |
| Highly reproducible MammaPrint as diagnostic tool (MammaPrint Paper) | Highly reproducible (demonstrated by comparison to Nature and NEJM studies) | |
| Metastasis-free survival by profile at 10 years (low risk vs. high risk) (Transbig Paper - European validation) | Low risk profile 88%, high risk profile 71% (at 5 yrs: 96% and 83% respectively) | |
| Metastasis-free survival by profile at 5 years (low risk vs. high risk) in older age patients (55-87 yrs) ("Older Age" NKI/AVL series) | Low risk profile 94%, high risk profile 75% | |
| Overall Conclusion | "Equivalent performance in the age extended patient group up to 87 years old at 5 years metastasis free survival." | Achieved: "MammaPrint is a clinically and analytically accurate prognostic marker for providing a risk assessment of distant metastasis of breast cancer." |
| "MammaPrint analytical methodology is identical to the FDA cleared MammaPrint device with 510k number K070675." | Substantial equivalence shown for analytical performance; therefore, no need to show substantial equivalence for analytical performance for this submission (K081092) beyond confirming identity with the predicate device's methods. Validation studies listed above demonstrate clinical performance in specific populations and with extended age range compared to the predicate. |
2. Sample Sizes Used for the Test Set and Data Provenance
The document describes several clinical studies, which served as the basis for clinical performance validation. These studies effectively act as the "test set" for demonstrating clinical utility.
| Study | Sample Size (Test Set) | Data Provenance |
|---|---|---|
| Nature Paper (1) | 78 patients | Retrospective (implied by "Development of breast cancer prognosis 70-gene profile") |
| NEJM Paper (2) | 151 patients | Retrospective ("consecutive series of breast cancer patients") |
| MammaPrint Paper (3) | Not specified | Focused on reproducibility of prior studies on MammaPrint. |
| Transbig Paper (4) | 302 patients | Retrospective ("Independent European validation"). Implies multiple European countries by "European validation." |
| "Older Age" NKI/AVL series (5) | 177 patients | Retrospective ("consecutive series of breast cancer patients"). NKI/AVL is a Dutch cancer institute, implying Dutch data. |
| Analytical Performance Validation | More than 190 independent analyses (for accuracy) | Agendia (The Netherlands), and a three-way inter-laboratory comparison study between three independent laboratories in three different countries (Dutch, French and U.S.). |
| Analytical Performance Validation | 2500 samples / 5000 hybridizations (for QC cut-off) | Performed at Agendia (The Netherlands). |
3. Number of Experts Used to Establish Ground Truth for the Test Set and Qualifications
The MammaPrint test determines a "risk of distant recurrence." The "ground truth" in these studies is the actual clinical outcome, specifically distant metastasis-free survival. This type of ground truth is established through long-term follow-up of patients, typically overseen by clinical oncologists and other medical professionals, rather than a panel of experts reviewing images or other diagnostic outputs to establish a consensus. The studies are retrospective analyses of patient cohorts with known clinical outcomes.
Therefore, the concept of "number of experts used to establish ground truth" with specific qualifications in the traditional sense (e.g., radiologists for imaging) does not directly apply here. The "ground truth" is the observed patient outcome over time, documented by treating physicians and medical records.
4. Adjudication Method for the Test Set
Given that the ground truth is patient outcomes (distant metastasis-free survival) over many years, an adjudication method for a "test set" like 2+1 or 3+1 typically used for medical image review is not applicable. Clinical outcomes are factual events recorded over time.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No Multi-Reader Multi-Case (MRMC) comparative effectiveness study is mentioned in the provided text. MammaPrint is a gene expression profiling test, not an imaging device or a tool directly interpreted by human readers in the same way an MRI or X-ray would be. Its output is a risk classification (Low Risk, High Risk), which is directly provided to the physician for consideration alongside other clinical factors. The improvement in human reader performance with AI assistance is not a relevant metric for this type of device.
6. Standalone (Algorithm Only) Performance
Yes, the studies presented demonstrate the standalone performance of the MammaPrint algorithm. The clinical studies (Nature, NEJM, Transbig, Older Age NKI/AVL) evaluate the prognostic power of the MammaPrint profile (generated by the algorithm) in predicting distant metastasis-free survival. The reported metastasis-free survival rates for "low risk profile" and "high risk profile" directly reflect the algorithm's ability to stratify patients based solely on its gene expression analysis.
7. Type of Ground Truth Used
The type of ground truth used for the clinical studies is patient outcomes data, specifically distant metastasis-free survival. This is a robust and objective measure of a patient's disease progression.
8. Sample Size for the Training Set
The document states that the Nature Paper (1) describes the "Development of breast cancer prognosis 70-gene profile (LNO, <55)" using 78 patients. This study likely represents the initial cohort used to develop or train the 70-gene signature that underlies MammaPrint. While not explicitly called a "training set" in the modern machine learning sense, this cohort was instrumental in defining the profile.
The MammaPrint algorithm itself correlates a sample's expression profile to a template (the mean expression profile of 44 tumors with a known good clinical outcome). These 44 tumors could be considered part of the "training" or reference data for the algorithm's core functionality.
9. How the Ground Truth for the Training Set Was Established
For the "Nature Paper" (which describes the development of the 70-gene profile):
- The ground truth would have been established through long-term clinical follow-up and patient outcomes data, similar to the test sets. Patients in this development cohort would have had their distant metastasis status recorded over a period of years (e.g., 5-year metastasis risk).
- For the 44 tumors used to create the "template" for the MammaPrint Index calculation, their "known good clinical outcome" would have been established based on observed excellent patient prognosis/long-term metastasis-free survival from clinical records.
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KOH092
510k Summary
1. Assigned 510(k) number
The assigned 510(k) number is 081092
- Company
DEC 11 2009
Agendia BV
Sciencepark 406 1098XH Amsterdam
The Netherlands
Telephone : 31 20 462 1523
Facsimile : 31 20 462 1505
3. Contact
Guido Brink, Senior Director Regulatory Affairs and Quality Assurance
- Date Prepared
April 10th, 2008
5. Proprietary Name
MammaPrint®
6. Classification Name
Gene expression profiling test system, for breast cancer prognosis.
7. Common Name
Multivariate device for cancer prognosis
8. Classification
Class II, regulated under 21 CFR 866.6040, product code NYI
9. Predicate Device
Agendia BV's MammaPrint (K080252)
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10. Device Description
The MammaPrint service is a microarray based gene expression analysis of a tumor. The analysis is based on several processes: isolation of RNA from frozen tumor tissue sections, DNA'se treatment of isolated RNA, linear amplification and labeling of DNA'se treated RNA, cRNA purification, hybridization of the cRNA to the MammaPrint microarray, scanning the MammaPrint microarray and data acquisition (feature extraction), index calculation and determination of the risk of distant recurrence in breast cancer patients.
The MammaPrint analysis is designed to determine the gene activity of specific genes in a tissue sample compared to a reference standard. The result is an expression profile, or fingerprint, of the sample.
The correlation of the sample expression profile to a template (the mean expression profile of 44 tumors with a known good clinical outcome) is calculated and the molecular profile index of the sample is determined (Low Risk, High Risk).
11. Intended Use
MammaPrint is a qualitative in vitro diagnostic test service, performed in a single laboratory, using the gene expression profile of fresh breast cancer tissue samples to assess a patient's risk for distant metastasis.
The test is performed for breast cancer patients, with Stage I or Stage II disease, with tumor size <= 5.0 cm and who are lymph node negative. The MammaPrint result is indicated for use by physicians as a prognostic marker only, along with other clinicopathological factors.
12. Performance Data (non-clinical)
Analytical performance.
MammaPrint analytical (i.e., non-clinical) performance characteristics investigated comprise Precision, Reproducibility, Cutoff, Sensitivity, Specificity, Accuracy, Robustness and Ruggedness.
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The technical validity of MammaPrint is determined on multiple individual validation experiments; a comprehensive three-way inter-laboratory comparison study between three independent laboratories in three different countries (Dutch, French and U.S.); data of about 200 analyses of two reference samples over a period of 12 months, used to monitor experiment-to-experiment quality; and quality controls for which the cut-off for all QCs is based on over 5000 hybridizations (2500 samples) performed at Agendia.
Based on 12 month repeated experiments of a Low Risk and High Risk control sample (i.e., more than 190 independent analyses), the Analytical Accuracy of the measurement is 98,5%.
Classification performance
Based on the analytical performance of MammaPrint, the accuracy of classifying a sample as High Risk or Low Risk, is at least 98.9% (i.e., 1.1% false negative classification).
Borderline Sample
As a result of the technical inaccuracy, analytical measurements (i.e., MammaPrint Index) can fall within a pre-defined area around the classification cut-off between the High Risk and Low Risk profile (i.e., "Borderline Sample").
Based on the results of independent MammaPrint analyses over a time period of over 2 vears, it has been shown that less than 5% of the analyzed samples are considered to be "Borderline Samples".
"Borderline Samples" have approximately a 90% classification accuracy (i.e. 10% chance of false classification).
Conclusion
Analytical methodology used is identical to the FDA cleared MammaPrint device with 510k number K070675. Therefore substantially equivalence does not have to be shown for analytical performance.
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13. Clinical Data
Clinical performance testing is based on the following studies:
| Study | Purpose | Time Frame | Comments |
|---|---|---|---|
| Nature Paper (1) | Development ofbreast cancerprognosis 70-geneprofile (LNO, <55) | 2002, 78 patients,6.4% adjuvanttreatment | Within 5 yearmetastasis risk byprofile multivariateOR 18 |
| NEJM Paper (2) | Validation of the70-gene profile inconsecutive seriesof breast cancerpatients (LNO,<53) | 2002, 151 patients,5.2% adjuvanttreatment | Metastasis-freesurvival by profile at10 yrs: low riskprofile 87%, highrisk profile 44%(at 5 yrs: 93% and56% respectively) |
| MammaPrint Paper(3) | Development ofMammaPrint | 2006, reproducibilityof (1) and (2) onMammaPrint | Highly reproducibleMammaPrint asdiagnostic tool |
| Transbig Paper (4) | IndependentEuropeanvalidation of 70-gene signature(LNO, <61) | 2006, 302 patients,no adjuvanttreatment | Metastasis-freesurvival by profile at10 yrs: low riskprofile 88%, highrisk profile 71%(at 5 yrs: 96% and83% respectively) |
| "Older Age"NKI/AVL series (5) | Validation of the70-gene profile inconsecutive seriesof breast cancerpatients (55-87 yrs) | 2008/2009, 177patients, noadjuvant treatment | Metastasis-freesurvival by profile at5 yrs: low riskprofile 94%, highrisk profile 75% |
14. Conclusion
Clinical validation data contained in this submission demonstrate equivalent performance of MammaPrint in the age extended patient group up to 87 years old at 5 years metastasis free survival.
MammaPrint is a clinically and analytically accurate prognostic marker for providing a risk assessment of distant metastasis of breast cancer.
- (1) Gene expression profiling predicts clinical outcome of breast cancer;
- Laura J. Van 't Veer et al; Nature (2002) 415, p530-536.
- (2) A Gene-Expression Signature as a Predictor of Survival in Breast Cancer;
- Marc J. Van de Vijver et al;. New Engl J Med (2002) 347, p1999-2009.
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(3) Converting a breast cancer microarray signature into a high-throughput diagnostic test; Annuska M. Glas et al; BMC Genomics (2006) accepted.
(4) Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer; Marc Buyse et al; J Natl Cancer Inst (2006), 98, p1183-1192.
(5) Clinical Validation report of MammaPrint Service usage in Breast Cancer Patients of "All ages" – VR-CR-099
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Food and Drug Administration 10903 New Hampshire Avenue Building 66 Silver Spring, MD 20993
Agendia BV c/o Mr. Guido Brink Senior Director Regulatory Affairs and Quality Assurance Kruislaan 406 1098 SM Amsterdam The Netherlands
DEC 1 1 2009
Re: K081092
Trade/Device Name: MammaPrint® Regulation Number: 21 CFR §866.6040 Regulation Name: Gene expression profiling test system for breast cancer prognosis Regulatory Class: Class II Product Code: NYI Dated: June 17, 2009 Received: June 23, 2009
Dear Mr. Brink:
We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval (PMA). You may. therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration.
If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.
Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting (reporting of medical
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Page 2 - Mr. Guido Brink
device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please go to http://www.fda.gov/Aboutl7DA/CentersOffices/CDRH/CDRHOffices/ucm115809.htm for the Center for Devices and Radiological Health's (CDRH's) Office of Compliance. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to
http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/Resourcesfor You/Industry/default.htm.
Sincerely yours.
Maria M Chan
Maria M. Chan, Ph.D. Director Division of Immunology and Hematology Devices Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known): K081092
Device Name: MammaPrint®
Indications for Use:
MammaPrint® is a gualitative in vitro diagnostic test service, performed in a single laboratory, using the gene expression profile of fresh breast cancer tissue samples to assess a patients' risk for distant metastasis (up to 10 years for patients less than 61 years old, up to 5 years for patients ≥ 61 years).
The test is performed for breast cancer patients with Stage I or Stage II disease, with a tumor size of ≤ 5.0 cm and lymph node negative. The MammaPrint result is indicated for use by physicians as a prognostic marker only, along with other clinicopathological factors.
Prescription Use XX (Part 21 CFR 801 Subpart D)
AND/OR
Over-The-Counter Use (21 CFR 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE OF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)
Beena Philip
Division Sign-Off
Office of In Vitro Diagnostic Device Evaluation and Safety
510(k) K081092
§ 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.