(272 days)
No
The description focuses on qualitative genotyping and analysis using proprietary software, without mentioning AI or ML techniques for interpretation or reporting.
No.
The 23andMe Personal Genome Service provides genetic health risk information and is explicitly stated as "not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments," which means it does not diagnose, treat, mitigate, or prevent disease.
Yes
Explanation: The "Intended Use / Indications for Use" section explicitly states that the device "uses qualitative genotyping to detect select clinically relevant variants in genomic DNA" for "reporting and interpreting genetic health risks," and "The report describes if a person's genetic result is associated with an increased risk of developing breast cancer and ovarian cancer and may be associated with an increased risk for prostate cancer, and potentially other cancers." This falls under the definition of a diagnostic device as it aims to identify specific biological markers associated with a disease risk.
No
The device description explicitly states the use of a physical saliva collection device (Oragene-Dx® Device), DNA isolation, genotyping beadchip, reagents, and instrumentation (Illumina). While software is used for analysis and reporting, the device relies on significant hardware components and laboratory processes.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Intended Use: The intended use explicitly states that the device is used for "qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva... for the purpose of reporting and interpreting genetic health risks". This involves testing a sample taken from the human body (saliva) to provide information about a person's health status or risk of developing a condition (genetic health risks related to BRCA1/BRCA2 variants).
- Sample Source: The device uses human saliva, which is a biological specimen.
- Purpose: The purpose is to provide information about genetic health risks, which is a diagnostic purpose.
- Regulatory Context: The document mentions FDA clearance (K141410 for the saliva collection device and DEN170046 as the predicate device), which is a regulatory pathway for medical devices, including IVDs. The mention of CLIA certified laboratories also indicates a clinical testing context.
Therefore, based on the definition of an IVD (a device intended for use in vitro for the examination of specimens derived from the human body to provide information for diagnostic, monitoring, or compatibility purposes), the 23andMe Personal Genome Service (PGS) as described here fits the criteria of an IVD.
Yes.
The document explicitly states: "This submission included a predetermined change control plan (PCCP) that was reviewed and authorized by FDA for adding additional validated BRCA1 and BRCA2 variants and associated cancer risk information to the 23andMe PGS® Cancer Predisposition Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) without additional pre-market review." It further details the scope, validation criteria, and specific protocols of this PCCP.
Intended Use / Indications for Use
The 23andMe Personal Genome Service (PGS) uses qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva collected from individuals >=18 years with the Oragene Dx model OGD500.001 for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants).
The 23andMe Personal Genome Service (PGS) Risk Report for BRCA1/BRCA2 (Selected Variants) is indicated for the reporting of the following 44 variants in the BRCA1 and BRCA2 genes.
BRCA1: c.68 69del, c.213-11T>G, c.427G>T, c.815 824dup, c.1556del, c.1687C>T, c.1961del, c.2681 2682del, c.2864C>A, c.3481 3491del, c.3598C>T, c.3627dup, c.3756 3759del, c.3770 3771del, c.4035del, c.4065 4068del.c.4327C>T.c.4357+1G>A.c.4964 4982del.c.4986+6T>G.c.5123C>A.c.5177 5180del.c.5266dup
BRCA2: c.658 659del, c.771 775del, c.2808 2811del, c.2957 2958insG, c.3170 3174del, c.3264dup, c.3545 3546del, c.3847 3848del, c.4471 4474del, c.5542del, c.5576 5579del, c.5682C>G, c.5946del, c.6037A>T, c.6275 6276del, c.7024C>T, c.7480C>T, c.7934del, c.8904del
The report describes if a person's genetic result is associated with an increased risk of developing breast cancer and ovarian cancer and may be associated with an increased risk for prostate cancer, and potentially other cancers. The variants included in this report do not represent the majority of the BRCA1/BRCA2 variants in people of most ethnicities. The test report does not describe a person's overall risk of developing any type of cancer, and the absence of a variant tested does not rule out the presence of other variants that may be cancer-related. This report is for over-the-counter use by adults over the age of 18, and provides genetic information to inform discussions with a healthcare professional. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.
Product codes
OAZ
Device Description
Customer saliva specimens are self-collected using the Oragene-Dx® Device manufactured by DNA Genotek, Inc. cleared by FDA for use with the PGS device under K141410, which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to one of two Clinical Laboratory Improvement Amendments (CLIA) certified laboratories for testing.
DNA is isolated from the saliva and tested in a multiplex assay using a customized genotyping beadchip, reagents and instrumentation manufactured by Illumina.
The raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe for analysis and interpretation. The raw data received is analyzed using 23andMe's proprietary Coregen software, where a genotype is determined for each tested SNP. The results for certain of these SNPs are used to generate personalized reports for the customer that provide information about the detected genotype.
Personalized reports are generated for each user that provide results of the testing performed. These reports tell the user which genetic health risk variant(s) have been detected in their sample and provide information about the disease associated with the variant(s). If no variant was detected, that information is also provided. The personalized reports are designed to present scientific concepts to users in an easy-to-understand format. The reports provide scientifically and clinically valid information about the risks associated with the presence of a particular variant. The reports are designed to help users understand the meaning of their results and any appropriate actions that may be taken based on their results.
Engineering drawings, schematics, etc. of the 23andMe Personal Genome Service (PGS) BRCA1/BRCA2 (Selected Variants) report are not applicable to this device.
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Not Found
Indicated Patient Age Range
individuals >=18 years
Intended User / Care Setting
Over-The-Counter Use
Description of the training set, sample size, data source, and annotation protocol
Not Found
Description of the test set, sample size, data source, and annotation protocol
Method Comparison Study (Accuracy):
- Samples were randomly selected from the 23andMe customer database based on their putative genotype.
- Genotyping of these samples was performed at a CLIA certified contract laboratory.
- All chosen samples were then tested using bidirectional Sanger sequencing.
- Genotyping results were compared between the 23andMe PGS assay and sequencing to calculate positive percent agreement (PPA) and negative percent agreement (NPA), with the sequencing results considered to be "truth".
- The passing criteria were greater than 99% PPA and greater than 99% NPA for each SNP.
Precision (Reproducibility) Study:
- Samples were identified from the 23andMe customer database based on their putative genotype.
- Samples were genotyped by the assay in a blinded fashion, with 3 lots of reagents, by multiple operator teams per day, using 3 different serial numbers of each of 2 instruments, over 3 days, at each of 2 laboratory sites.
- Genotype results were confirmed using bidirectional Sanger sequencing.
- The passing criteria were a minimum of 99% correct genotype calls at each of two laboratory sites.
Minimum DNA Input (MDI) Study:
- Samples were identified from the 23andMe customer database based on their putative genotype.
- Each sample was diluted to 3 different concentrations and genotyped by the assay in a blinded fashion using 3 lots of reagents.
- Genotype results were confirmed using bidirectional Sanger sequencing.
- The minimum DNA requirement was defined as the lowest concentration at which at least 95% of samples yield the correct call.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Method Comparison (Accuracy):
- Study Type: Method Comparison Study
- Sample Size: All 41 variants were included in this study. (Specific number of samples not provided)
- Key Results: The study yielded greater than 99% agreement, passing the acceptance criteria of greater than 99% PPA and greater than 99% NPA. This showed that the 23andMe assay is comparable to bidirectional Sanger sequencing.
Precision (Reproducibility):
- Study Type: Precision Study
- Sample Size: All 41 variants were included in this study. (Specific number of samples not provided)
- Key Results: The study yielded 100% correct genotype calls for all samples across multiple days, operator teams, instruments, and reagent lots at 2 independent laboratory sites. The study passed the acceptance criteria of at least 99% correct calls, and had greater than 99% reproducibility and greater than 99% repeatability.
Minimum DNA Input (MDI):
- Study Type: Sensitivity Study
- Sample Size: All 41 variants were included in this study. (Specific number of samples not provided)
- Key Results: The study yielded 100% correct genotype calls for all samples and reagent lots tested at sample DNA concentrations of 5, 15, and 50 ng/uL. The study passed the acceptance criteria at a sample DNA concentration of 5 ng/uL. The study demonstrated that the 23andMe assay is valid for samples with a DNA concentration range of 5 ng/uL to 50 ng/uL.
Shelf life:
- Study Type: Not specified (brief mention)
- Key Results: The PGS requires the use of the same FDA-cleared collection device and reagents that have been previously reviewed and authorized in K141410 and DEN140044.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
Accuracy: positive percent agreement (PPA) and negative percent agreement (NPA) of greater than 99%.
Precision: 99% correct genotype calls, greater than 99% reproducibility, and greater than 99% repeatability.
Minimum DNA Input: 100% correct genotype calls for all samples and reagent lots tested at sample DNA concentrations of 5, 15, and 50 ng/uL. Performance requirement conservatively set at a minimum of 15 ng/uL and a maximum of 50 ng/uL.
Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.
23andMe PGS Risk Report for BRCA1/BRCA2 (Selected Variants), DEN170046, authorized on March 6, 2018
Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.
Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).
Establish a Pre-Determined Change Control Plan (PCCP) for reporting additional BRCA1 and BRCA2 variants and associated cancer risk information to the report.
This submission included a predetermined change control plan (PCCP) that was reviewed and authorized by FDA for adding additional validated BRCA1 and BRCA2 variants and associated cancer risk information to the 23andMe PGS® Cancer Predisposition Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) without additional pre-market review. The PCCP outlined the specific protocols and acceptance criteria that 23andMe intends to use to clinically and analytically validate eligible BRCA1/BRCA2 variants.
The PCCP is limited to the addition of single nucleotide variants and small insertions and deletions (=99% positive percent agreement (PPA) and negative percent agreement (NPA), established by comparing the results of the 23andMe to bidirectional Sanger sequencing
-
=99% correct genotype calls assigned at each of two laboratory sites
-
=95% of samples yielding the correct genotype call at the minimum DNA input tested
Additionally, software verification and validation activities are detailed in the PCCP and all must be completed successfully to modify the report to add the new BRCA1/2 variants. The plan specifies change control for genotype calling definitions and labeling updates to ensure the device remains as safe and effective as the predicate device.
N/A
0
September 22, 2023
Image /page/0/Picture/1 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.
23andMe, Inc. Marianna Frendo Manager Regulatory Affairs 349 Oyster Point Blvd South San Francisco, California 94080
Re: K223597
Trade/Device Name: 23andMe® Personal Genome Service® (PGS®) Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) Regulation Number: 21 CFR 866.6090 Regulation Name: Cancer Predisposition Risk Assessment System Regulatory Class: Class II Product Code: OAZ
Dear Marianna Frendo:
The Food and Drug Administration (FDA) is sending this letter to notify you of an administrative change related to your previous substantial equivalence (SE) determination letter dated August 31, 2023. Specifically, FDA is updating this SE Letter to correct an error in the device trade name from 23andMe Personal Genome Service® (PGS®) Cancer Predisposition Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) to 23andMe® Personal Genome Service® (PGS®) Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) as an administrative correction.
Please note that the 510(k) submission was not re-reviewed. For questions regarding this letter please contact Shyam Kalavar, OHT7: Office of In Vitro Diagnostics, at 301-796-6807 or at Shyam.Kalavar(@fda.hhs.gov.
Sincerely.
Shyam Kalavar -S
Shyam Kalavar Deputy Branch Chief Molecular Pathology and Cytology Branch Division of Molecular Genetics and Pathology OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
1
Image /page/1/Picture/0 description: The image contains the logos of the Department of Health & Human Services and the Food and Drug Administration (FDA). The Department of Health & Human Services logo is on the left, and the FDA logo is on the right. The FDA logo is a blue square with the letters "FDA" in white, followed by the words "U.S. Food & Drug Administration" in blue.
August 31, 2023
23andMe, Inc. Marianna Frendo Manager Regulatory Affairs 349 Ovster Point Blvd South San Francisco, California 94080
Re: K223597
Trade/Device Name: 23andMe® Personal Genome Service® (PGS®) Cancer Predisposition Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) Regulation Number: 21 CFR 866.6090 Regulation Name: Cancer Predisposition Risk Assessment System Regulatory Class: Class II Product Code: OAZ Dated: November 29, 2022 Received: December 2, 2022
Dear Marianna Frendo:
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 application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. 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. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.
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.
FDA's substantial equivalence determination also included the review and clearance of your Predetermined Change Control Plan (PCCP). Under section 515C(b)(1) of the Act, a new premarket notification is not
2
required for a change to a device cleared under section 510(k) of the Act, if such change is consistent with an established PCCP granted pursuant to section 515C(b)(2) of the Act. Under 21 CFR 807.81(a)(3), a new premarket notification is required if there is a major change or modification in the intended use of a device, or if there is a change or modification in a device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemical composition, energy source, or manufacturing process. Accordingly, if deviations from the established PCCP result in a major change or modification in the intended use of the device, or result in a change or modification in the device that could significantly affect the safety or effectiveness of the a new premarket notification would be required consistent with section 515C(b)(1) of the Act and 21 CFR 807.81(a)(3). Failure to submit such a premarket submission would constitute adulteration and misbranding under sections 501(f)(1)(B) and 502(o) of the Act, respectively. Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).
Your device is also subject to, among other requirements, the Quality System (OS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).
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 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the QS regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act): 21 CFR 1000-1050.
Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.
For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatory
3
assistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).
Sincerely,
Shyam Kalayar -S
Shyam Kalavar Deputy Branch Chief Molecular Pathology and Cytology Branch Division of Molecular Genetics and Pathology OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known) K223597
Device Name
23andMe Personal Genome Service (PGS) Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants)
Indications for Use (Describe)
The 23andMe Personal Genome Service (PGS) uses qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with the Oragene Dx model OGD500.001 for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Risk Report for BRCA1/BRCA2 (Selected Variants).
The 23andMe Personal Genome Service (PGS) Risk Report for BRCA1/BRCA2 (Selected Variants) is indicated for the reporting of the following 44 variants in the BRCA1 and BRCA2 genes.
BRCA1: c.68 69del, c.213-11T>G, c.427G>T, c.815 824dup, c.1556del, c.1687C>T, c.1961del, c.2681 2682del, c.2864C>A, c.3481 3491del, c.3598C>T, c.3627dup, c.3756 3759del, c.3770 3771del, c.4035del, c.4065 4068del.c.4327C>T.c.4357+1G>A.c.4964 4982del.c.4986+6T>G.c.5123C>A.c.5177 5180del.c.5266dup
BRCA2: c.658 659del, c.771 775del, c.2808 2811del, c.2957 2958insG, c.3170 3174del, c.3264dup, c.3545 3546del, c.3847 3848del, c.4471 4474del, c.5542del, c.5576 5579del, c.5682C>G, c.5946del, c.6037A>T, c.6275 6276del, c.7024C>T, c.7480C>T, c.7934del, c.8904del
The report describes if a person's genetic result is associated with an increased risk of developing breast cancer and ovarian cancer and may be associated with an increased risk for prostate cancer, and potentially other cancers. The variants included in this report do not represent the majority of the BRCA1/BRCA2 variants in people of most ethnicities. The test report does not describe a person's overall risk of developing any type of cancer, and the absence of a variant tested does not rule out the presence of other variants that may be cancer-related. This report is for over-the-counter use by adults over the age of 18, and provides genetic information to inform discussions with a healthcare professional. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.
Type of Use (Select one or both, as applicable)
Prescription Use (Part 21 CFR 801 Subpart D)
X Over-The-Counter Use (21 CFR 801 Subpart C)
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Traditional 510(k) Summary
This summary of Traditional 510(k) safety and effectiveness information is being submitted in accordance with the requirements of Safe Medical Devices Act of 1990 and 21 CFR 807.92
The assigned Traditional 510(k) number is: K223597
Submitter/Primary Contact
Marianna Frendo, Manager, Requlatory Affairs 23andMe. Inc. 349 Oyster Point Blvd. SSF, CA 94080 (650) 938-6300 mfrendo@23andme.com Establishment Registration Number: 3007699459 Owner Operator Number: 10029404
Alternative Contact
Kathy Hibbs, Chief Administrative Officer 23andMe, Inc. 349 Oyster Point Blvd. SSF, CA 94080 (650) 938-6300 khibbs@23andme.com
Date Prepared
29 August 2023
5.0 PURPOSE OF SUBMISSION
In this Traditional 510(k) submission 23andMe seeks the following:
-
- Clearance for an additional 41 BRCA1 and BRCA2 variants to be added to the existing authorized BRCA1/BRCA2 (Selected Variants) report, (DEN170046);
-
- Establish a Pre-Determined Change Control Plan (PCCP) for reporting additional BRCA1 and BRCA2 variants and associated cancer risk information to the report.
This 510(k) summary describes the submission content supporting pre-market review for the proposed 41 additional variants to be added to the existing BRCA1/BRCA2 (Selected Variants) report, (DEN170046). This submission included a predetermined change control plan (PCCP) that was reviewed and authorized by FDA for adding additional
6
validated BRCA1 and BRCA2 variants and associated cancer risk information to the 23andMe PGS® Cancer Predisposition Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) without additional pre-market review. The PCCP outlined the specific protocols and acceptance criteria that 23andMe intends to use to clinically and analytically validate eligible BRCA1/BRCA2 variants.
5.1. REGULATORY INFORMATION
Table 1. Proposed New Device
| Type of Submission: | Traditional 510(k) |
|---|---|
| Common/Usual Name: | BRCA1/BRCA2 (Selected Variants) |
| Trade/proprietary Name: | 23andMe Personal Genome Service (PGS) Genetic |
| Health Risk Report for BRCA1/BRCA2 (Selected Variants) | |
| Regulation Description: | A Cancer Predisposition Risk Assessment System is a |
| qualitative in vitro molecular diagnostic system used for | |
| determining predisposition for cancer where the result of | |
| the test may lead to prophylactic screening, confirmatory | |
| procedures, or treatments that may incur morbidity or | |
| mortality to the patient. The test could help to inform | |
| conversations with a healthcare professional. This | |
| assessment system is for over-the-counter use. This | |
| device does not determine the person's overall risk of | |
| developing any types of cancer. This test is not a | |
| substitute for visits to a healthcare provider for | |
| recommended screenings or appropriate follow-up and | |
| should not be used to determine any treatments. | |
| Regulation Number: | 21 CFR §866.6090 |
| Product Code: | QAZ |
| Class | Class II |
| Predicate Device: | 23andMe PGS Risk Report for BRCA1/BRCA2 (Selected |
| Variants), DEN170046, authorized on March 6, 2018 |
5.2. INTENDED USE
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The 23andMe Personal Genome Service (PGS) uses qualitative genotyping to detect select clinically relevant variants in genomic DNA isolated from human saliva collected from individuals ≥18 years with the Oragene Dx model OGD500.001 for the purpose of reporting and interpreting genetic health risks, including the 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants).
5.3. INDICATIONS FOR USE
The 23andMe Personal Genome Service (PGS) Risk Report for BRCA1/BRCA2 (Selected Variants) is indicated for the reporting of the following 44 variants in the BRCA1 and BRCA2 genes.
| Gene | Variant(s) |
|---|---|
| BRCA1 | c.68_69del, c.213-11T>G, c.427G>T, c.815_824dup, c.1556del, c.1687C>T, c.1960A>T, c.1961del, c.2681_2682del, c.2864C>A, c.3481_3491del, c.3598C>T, c.3627dup, c.3756_3759del, c.3770_3771del, c.4035del, c.4065_4068del, c.4327C>T, c.4357+1G>A, c.4964_4982del, c.4986+6T>G, c.5123C>A, c.5177_5180del, c.5266dup |
| BRCA2 | c.658_659del, c.771_775del, c.1929del, c.2808_2811del, c.2957_2958insG, c.3170_3174del, c.3264dup, c.3545_3546del, c.3847_3848del, c.4471_4474del, c.5542del, c.5576_5579del, c.5682C>G, c.5946del, c.6037A>T, c.6275_6276del, c.7024C>T, c.7480C>T, c.7934del, c.8904del |
The report describes if a person's genetic result is associated with an increased risk of developing breast cancer and ovarian cancer and may be associated with an increased risk for prostate cancer, pancreatic cancer, and potentially other cancers. The variants included in this report do not represent the majority of the BRCA1/BRCA2 variants in people of most ethnicities. The test report does not describe a person's overall risk of developing any type of cancer, and the absence of a variant tested does not rule out the presence of other variants that may be cancer-related. This report is for over-thecounter use by adults over the age of 18, and provides genetic information to inform discussions with a healthcare professional. This test is not a substitute for visits to a healthcare provider for recommended screenings or appropriate follow-up and should not be used to determine any treatments.
5.4. SUBSTANTIALLY EQUIVALENT PREDICATE DEVICE
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The components of the PGS are unchanged from the De Novo authorization for the predicate device, the PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) (DEN170046). These components include the saliva collection kit, reagents, beadchip, instrumentation, software, test processes and procedures.
The purpose of this Traditional 510(k) submission is to modify the 23andMe Personal Genome Service (PGS) Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) to include 41 additional BRCA1 and BRCA2 variants to the existing authorized BRCA1/BRCA2 (Selected Variants) report (DEN170046) and to establish a Pre-Determined Change Control Plan (PCCP) for adding additional BRCA1 and BRCA2 variants and associated cancer risk information to the report.
The 23andMe Personal Genome Service (PGS) Risk Report for BRCA1/BRCA2 (Selected Variants) is similar to the predicate, having similar indications for use, the same intended use, and the same technological characteristics as its predicate device, with the exception of the implementation of a Predetermined Change Control Plan (PCCP) that specifies the protocols and acceptance criteria for making modifications to the reportable BRCA1/BRCA2 variants in a controlled manner such that the device is as safe and effective as the predicate.
Specific test methods for clinical and analytical validation are specified in the PCCP to establish substantial equivalence relative to DEN170046, and include sample size determination, analysis methods, and acceptance criteria. The Sponsor will perform testing of the additional BRCA1/2 variants according to the specified protocols, and if the validation data meet the specified acceptance criteria, they may add those variants to the BRCA1/2 report without additional premarket review.
The PCCP is limited to the addition of single nucleotide variants and small insertions and deletions (≤20 bp) in the BRCA1 and BRCA2 genes. The plan describes the specific clinical validation criteria that must be met to demonstrate that the new BRCA1/2 variants are high-risk, highly penetrant BRCA1/2 variants (i.e., those that are demonstrated to be linked to hereditary breast and ovarian cancer (HBOC) syndrome). Specific analytical validation protocols and acceptance criteria are also detailed in the plan to ensure that the device maintains the following performance characteristics for each new BRCA1/2 variant:
- Accuracy point estimates of ≥99% positive percent agreement (PPA) and negative . percent agreement (NPA), established by comparing the results of the 23andMe to bidirectional Sanger sequencing
- . ≥99% correct genotype calls assigned at each of two laboratory sites
- . ≥95% of samples vielding the correct genotype call at the minimum DNA input tested
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Additionally, software verification and validation activities are detailed in the PCCP and all must be completed successfully to modify the report to add the new BRCA1/2 variants. The plan specifies change control for genotype calling definitions and labeling updates to ensure the device remains as safe and effective as the predicate device.
Customers who previously opted-in to receive their BRCA1/2 report will receive an email notification informing them that the report has been updated. Customers will have access to their updated report unless they exercise their option to opt-out.
The PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) report is intended for over-the-counter, direct-to consumer use without prescription or physician order. As with the predicate device, the proposed modifications to the labeling of the BRCA1/BRCA2 (Selected Variants) report conform to submission requirements, and special controls of the original authorization (DEN170046). Before viewing the proposed modified labeling, customers must view an updated version of the BRCA1/BRCA2 (Selected Variants) education module that reflects the additional 41 variants, and customers with positive results are strongly advised to share their results with their healthcare provider. As instructed in the predicate device authorization DEN170046, the same healthcare provider limitations are included in the package insert:
- . This test is not intended to diagnose a disease, determine medical treatment or other medical intervention, or tell the user anything about their current state of health.
- This test is intended to provide users with their genetic information, which may inform health-related lifestyle decisions and conversations with their doctor or other healthcare professional.
- · Any diagnostic or treatment decisions must be based on confirmatory prescription testing and/or other information that you determine to be appropriate for your patient, such as additional clinical testing and other risk factors that may affect individual risk and health care.
The Package Insert has been revised to incorporate information pursuant to the special controls agreed upon during DEN170046 - in particular, the addition of clinical and analytical validation information in support of the proposed additional 41 BRCA1/BRCA2 variants introduced in the modified BRCA1/BRCA2 (Selected Variants) report. Additionally, the Package Insert has been revised to provide a link to consumers to find a genetic counselor in the area in which they live. These revisions are consistent with the product classification under 21 CFR §866.6090. The proposed modifications are based on the additional test system performance data, developed according to the well
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established study protocols and acceptance criteria for 23andMe PGS cancer predisposition risk reports and submitted in this Traditional 510(k).
This submission proposes the same intended use for the Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants), does not introduce new risks to safety and effectiveness, and is supported by performance data collected for this purpose. As such, the proposed modifications to the labeling of the 23andMe Personal Genome Service Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) are substantially equivalent to the predicate device authorized under DEN170046.
5.5. DEVICE DESCRIPTION
Customer saliva specimens are self-collected using the Oragene-Dx® Device manufactured by DNA Genotek, Inc. cleared by FDA for use with the PGS device under K141410, which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to one of two Clinical Laboratory Improvement Amendments (CLIA) certified laboratories for testing.
DNA is isolated from the saliva and tested in a multiplex assay using a customized genotyping beadchip, reagents and instrumentation manufactured by Illumina.
The raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe for analysis and interpretation. The raw data received is analyzed using 23andMe's proprietary Coregen software, where a genotype is determined for each tested SNP. The results for certain of these SNPs are used to generate personalized reports for the customer that provide information about the detected genotype.
Personalized reports are generated for each user that provide results of the testing performed. These reports tell the user which genetic health risk variant(s) have been detected in their sample and provide information about the disease associated with the variant(s). If no variant was detected, that information is also provided. The personalized reports are designed to present scientific concepts to users in an easy-to-understand format. The reports provide scientifically and clinically valid information about the risks associated with the presence of a particular variant. The reports are designed to help users understand the meaning of their results and any appropriate actions that may be taken based on their results.
Engineering drawings, schematics, etc. of the 23andMe Personal Genome Service (PGS) BRCA1/BRCA2 (Selected Variants) report are not applicable to this device.
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5.6. TECHNOLOGICAL CHARACTERISTICS
Test Type: Qualitative genetic test for single nucleotide polymorphism detection. Sample Type: Genomic DNA obtained from a human saliva sample. Target of detection: Single-nucleotide polymorphism. DNA extraction: Automated and manual methods. Gene(s): BRCA1, BRCA2 Variants: BRCA1 gene variants: c.68 69del, c.213-11T>G, c.427G>T, c.815 824dup, c.1556del, c.1687C>T. c.1960A>T. c.1961del, c.2681 2682del, c.2864C>A. c.3481 3491del, c.3598C>T, c.3627dup, c.3756 3759del, c.3770 3771del, c.4035del, c.4065 4068del, c.4327C>T, c.4357+1G>A, c.4964 4982del, c.4986+6T>G, c.5123C>A, c.5177 5180del, c.5266dup
BRCA2 gene variants: c.658 659del, c.771 775del, c.1929del, c.2808 2811del, c.2957 2958insG, c.3170 3174del, c.3264dup, c.3545 3546del, c.3847 3848del, c.4471 4474del, c.5542del, c.5576 5579del, c.5682C>G, c.5946del, c.6037A>T, c.6275 6276del, c.7024C>T, c.7480C>T, c.7934del, c.8904del
Genotyping principle: The DNA is fragmented and captured on a bead array by hybridization to immobilized SNP-specific primers, followed by extension with haptenlabeled nucleotides. The primers hybridize adjacent to the SNPs and are extended with a single nucleotide corresponding to the SNP allele. The incorporated hapten-modified nucleotides are detected by adding fluorescently labeled antibodies in several steps to amplify the signals. Data analysis is performed using scatter plots.
Instrument: Illumina iScan and GenomeStudio system.
Assay results: The genotype content is separated, analyzed, and then integrated into pre-defined report templates specific for each condition associated with each genotype.
Table 2. Substantial Equivalence
| Predicate
BRCA1/BRCA2
(Selected Variants)
Report
DEN170046 | Proposed modified
BRCA1/BRCA2
(Selected Variants)
Report
K223597 | |
|------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|
| General Device Characterisitic Similarities | | |
| Intended
Use | The 23andMe Personal
Genome Service (PGS) | Same |
| | Predicate
BRCA1/BRCA2
(Selected Variants)
Report
DEN170046 | Proposed modified
BRCA1/BRCA2
(Selected Variants)
Report
K223597 |
| | uses qualitative
genotyping to detect
select clinically relevant
variants in genomic DNA
isolated from human
saliva collected from
individuals ≥18 years with
the Oragene Dx model
OGD500.001 for the
purpose of reporting and
interpreting genetic
health risks, including the
23andMe PGS Genetic
Health Risk Report for
BRCA1/BRCA2 (Selected
Variants). | |
| Collection
Kit | Oragene·Dx® saliva
collection device (OGD-
500.001)
K141410 | Same |
| BeadChip | Illumina Global Screening
Array customized for the
PGS. The chip is
designed to detect
specific single nucleotide
polymorphisms (SNPs)
as well as other genetic
variants; all markers refer
to specific positions in the
National Center for
Biotechnology
Information (NCBI) | Same |
| Predicate
BRCA1/BRCA2
(Selected Variants)
Report
DEN170046 | Proposed modified
BRCA1/BRCA2
(Selected Variants)
Report
K223597 | |
| reference human
genome. | | |
| Beadpool | Customized for 23andMe | |
| Instruments | Tecan Evo
Illumina iScan | |
| Software | Genome Studio
Coregen | |
| Specimen
Type | Saliva | |
| Differences | | |
| Measurand | 3 variants | |
| Reagents | Illumina Infinium HTS
Assay Reagents | |
| | Same | |
| | Same | |
| | Same | |
| | Same | |
| | 44 variants | |
| | Illumina Infinium HTS
Extra Assay Reagents | |
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5.7. PERFORMANCE TESTING SUMMARY
5.7.1 Method Comparison (Accuracy)
23andMe performed a method comparison study to assess the accuracy of the 23andMe Personal Genome Service (PGS) test for the additional 41 variants to be added to the existing BRCA1/BRCA2 (Selected Variants) report. All 41 variants were included in this study.
The purpose of the study was to show equivalent genotype assignment between the 23andMe PGS assay and bidirectional Sanger sequencing. Samples were randomly selected from the 23andMe customer database based on their putative genotype. Genotyping of these samples was performed at a CLIA certified contract laboratory. All chosen samples were then tested using bidirectional Sanger sequencing. Genotyping results were compared between the 23andMe PGS assay and sequencing to calculate
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positive percent agreement (PPA) and negative percent agreement (NPA), with the sequencing results considered to be "truth". The passing criteria were greater than 99% PPA and greater than 99% NPA for each SNP.
This method comparison study vielded greater than 99% agreement. Therefore, the study passed the acceptance criteria of greater than 99% PPA and greater than 99% NPA. The method comparison study showed that the 23andMe assay is comparable to bidirectional Sanger sequencing.
5.7.2 Precision (Reproducibility)
23andMe performed a precision study to assess the repeatability and reproducibility of the 23andMe Personal Genome Service (PGS) test for the additional 41 variants to be added to the existing BRCA1/BRCA2 (Selected Variants) report. All 41 variants were included in this study.
This study evaluated intra-assay, inter-lot, inter-instrument, inter-operator, inter-day, and inter-lab precision. Samples were identified from the 23andMe customer database based on their putative genotype and genotyped by the assay in a blinded fashion, with 3 lots of reagents, by multiple operator teams per day, using 3 different serial numbers of each of 2 instruments, over 3 days, at each of 2 laboratory sites. Genotype results were confirmed using bidirectional Sanger sequencing. The passing criteria were a minimum of 99% correct genotype calls at each of two laboratory sites.
This precision study yielded 100% correct genotype calls for all samples across multiple days, operator teams, instruments, and reagent lots at 2 independent laboratory sites. Therefore, the study passed the acceptance criteria of at least 99% correct calls. In addition, the study had greater than 99% reproducibility and greater than 99% repeatability.
5.7.3 Minimum DNA Input (MDI)
23andMe performed a minimum DNA input study to assess the sensitivity of the 23andMe Personal Genome Service (PGS) test for the additional 41 variants to be added to the existing BRCA1/BRCA2 (Selected Variants) report. All 41 variants were included in this study.
Samples were identified from the 23andMe customer database based on their putative genotype. Each sample was diluted to 3 different concentrations and genotyped by the assay in a blinded fashion using 3 lots of reagents. Genotype results were confirmed using bidirectional Sanger sequencing. The minimum DNA requirement was defined as the lowest concentration at which at least 95% of samples yield the correct call.
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This minimum DNA input study yielded 100% correct genotype calls for all samples and reagent lots tested at sample DNA concentrations of 5, 15, and 50 ng/μL. Therefore, the study passed the acceptance criteria at a sample DNA concentration of 5 ng/μL. The performance requirement, specified by contract laboratory SOPs, is conservatively set at a minimum of 15 ng/μL and a maximum of 50 ng/μL. This minimum DNA input study demonstrated that the 23andMe assay is valid for samples with a DNA concentration range of 5 ng/μL to 50 nq/μL.
5.7.4 Shelf life
The PGS requires the use of the same FDA-cleared collection device and reagents that have been previously reviewed and authorized in K141410 and DEN140044.
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5.8. CLINICAL PERFORMANCE
The variants included in the modified BRCA1/BRCA2 (Selected Variants) report account for more than 90% of cancer-related BRCA1 and BRCA2 variants among people of Ashkenazi Jewish descent; about 30-40% among African Americans, people of European descent, and people of Hispanic or Latino descent; about 5-25% among people of East Asian Descent; and up to 35% among people of South Asian descent1. The pathogenicity of each variant is supported by multiple peer-reviewed studies and, in many cases, by the classification determination of an expert panel (ENIGMA²). In addition, most pathogenic BRCA1/2 variants are truncating; for those that are not, we rely on strong functional evidence demonstrating an impact on protein function.
Table 3. Allele frequencies from 23andMe database and Genome Aggregation Database (gnomAD)
| Variant # | Gene | Variant name | rsID | Population | Allele frequencies
from 23andMe
(%)* | Allele
frequencies
from gnomAD
(%)** |
|--------------------|---------|---------------------|--------------|--------------------|--------------------------------------------|-----------------------------------------------|
| 1 | BRCA1 | c.68_69del | rs386833395 | European | 0.012% | 0.009% |
| | | | | African American | 0.004% | 0.000% |
| | | | | Ashkenazi Jewish | 0.445% | 0.405% |
| | | | | East Asian | 0.000% | 0.000% |
| | | | | Hispanic or Latino | 0.017% | 0.003% |
| | | | | South Asian | 0.025% | 0.013% |
| | | | | Middle Eastern | 0.007% | not available |
| 2 | BRCA1 | c.213-11T>G | rs80358061 | European | 0.003% | 0.003% |
| | | | | African American | T | rs80356991 | European | 0.001% | not observed in
gnomAD |
| | | | | African American | T | rs80356898 | European | 0.002% | 0.006% |
| | | | | African American | 0.000% | 0.000% |
| | | | | Ashkenazi Jewish | 0.000% | 0.000% |
| | | | | East Asian | 0.000% | 0.000% |
| | | | | Hispanic or Latino | 0.001% | 0.000% |
| | | | | South Asian | 0.000% | 0.000% |
| | | | | Middle Eastern | 0.000% | not available |
| 7 | BRCA1 | c.1960A>T | rs80357355 | European | A | rs80357295 | European | T | rs62625307 | European | T | rs41293455 | European | 0.002% | 0.004% |
| | | | | African American | A | rs80358027 | European | G | rs80358086 | European | A | rs28897696 | European | 0.000% | 0.003% |
| | | | | African American | G | rs41293497 | European | 0.002% | 0.001% |
| | | | | African American | 0.002% | 0.000% |
| | | | | Ashkenazi Jewish | 0.000% | 0.000% |
| | | | | East Asian | T | rs80358840 | European | 0.001% | not observed in
gnomAD |
| | | | | African American | 0.000% | |
| | | | | Ashkenazi Jewish | 0.000% | |
| | | | | East Asian | 0.000% | |
| Variant # | Gene | Variant name | rsID | Population | Allele frequencies
from 23andMe
(%)* | Allele
frequencies
from gnomAD
(%)** |
| | | | | Hispanic or Latino | T | rs80358928 | European | 0.000% | 0.000% |
| | | | | African American | T | rs80358972 | European |