(182 days)
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 PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) is indicated for reporting of the 185delAG and 5382insC variants in the BRCA1 gene and the 6174delT variant in the BRCA2 gene. The report describes if a woman is at increased risk of developing breast and ovarian cancer, and if a man is at increased risk of developing breast cancer or may be at increased risk of developing prostate cancer. The three variants included in this report are most common in people of Ashkenazi Jewish descent and do not represent the majority of the BRCA1/BRCA2 variants in the general population. 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 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.
The 23andMe PGS is a non-invasive DNA testing service that combines qualitative genotyping data covering genetic ancestry, traits, and certain heritable health conditions from a single multiplex assay with descriptive information derived from peer reviewed, published genetic research studies. It is a direct-to-consumer, over-the-counter, DNA genetic test intended to provide information and tools for individual users.
A user's saliva is self-collected using the Oragene Dx device manufactured by DNA Genotek. Inc. (previously cleared 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 multiplex assay simultaneously tests for more than 500,000 variants, including those for the previously authorized indications, as well as for the indication proposed herein.
The raw data is generated using Illumina GenomeStudio software, and then sent to 23andMe (the Manufacturer). The data are analyzed using the Manufacturer's proprietary Coregen software, and a genotype is determined for each tested variant. The results for certain of these variants, as noted in the indications for use, are used to generate personalized reports for users that provide information about the diseases associated with tested variants.
Personalized reports are generated for each user that provides results of the testing performed. These reports tell the user which variant(s) has/have been detected in their sample and provide information on the risk of 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 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 inform conversations with their doctor or other healthcare professional. The 23andMe PGS Genetic Health Risk Report for BRCA1/BRCA2 (Selected Variants) reports on three specific variants including the 185de1AG and 5382insC variants in the BRCA1 gene and the 6174delT variant in the BRCA2 gene. The variants included in this report are most common in people of Ashkenazi Jewish descent and do not represent the majority of BRCA2 variants in the general population. Therefore the absence of a variant tested does not rule out the presence of other genetic variants that may be disease-related.
Here's a breakdown of the acceptance criteria and the study that proves the device meets them, based on the provided text:
1. A table of acceptance criteria and the reported device performance
The document specifies acceptance criteria for analytical performance studies, particularly for accuracy.
| Study Type | Acceptance Criteria | Reported Device Performance |
|---|---|---|
| Precision/Reproducibility | Not explicitly stated as numerical criteria, but implied to be "100% correct genotype calls with a valid call" and acceptable FQC rates. | BRCA1 185delAG (i400377): |
- Site 1: 0.41% FQC for Homozygous Common, 2.53% FQC for Heterozygous.
- Site 2: 3.85% FQC for Homozygous Common, 8.00% FQC for Heterozygous.
BRCA1 5382insC (i400378): - Site 1: 0.41% FQC for Homozygous Common, 1.25% FQC for Heterozygous.
- Site 2: 3.85% FQC for Homozygous Common, 3.18% FQC for Heterozygous.
BRCA2 6174delT (i400379): - Site 1: 0.41% FQC for Homozygous Common, 0% FQC for Heterozygous.
- Site 2: 3.84% FQC for Homozygous Common, 2.53% FQC for Heterozygous.
All valid calls were 100% correct across all conditions. |
| Detection Limit (LoD) | At least 95% correct calls at the lowest concentration tested (5 ng/uL). | 100% correct calls per genotype for all samples across all reagent lots, at all sample concentrations tested (including 5 ng/uL). |
| Accuracy (Comparison with Sanger Bidirectional Sequencing) | Minimum of 99% positive percent agreement (PPA) and negative percent agreement (NPA) for each genotype. Uncertainty of the point estimate within an acceptable range, presented using 95% confidence interval. | BRCA1 185delAG: - Homozygous Common: 100% PPA, 100% NPA (95% CI: 96.6 - 100)
- Heterozygous: 100% PPA, 100% NPA (95% CI: 93.8 - 100)
BRCA1 5382insC (referring to the first instance of this variant in Table 4 for combined entries): - Homozygous Common: 100% PPA, 100% NPA (95% CI: 94.0 - 100)
- Heterozygous: 100% PPA, 100% NPA (95% CI: 83.9 - 100)
BRCA2 6174delT (referring to the combined entries for this variant in Table 4): - Homozygous Common: 100% PPA, 100% NPA (95% CI: 93.9 - 100)
- Heterozygous: 100% PPA, 100% NPA (95% CI: 92.1 - 100)
All reported agreements are 100% for correct calls, with some samples failing QC ("No Call" or "FQC") which are accounted for separately. The CIs met the acceptance criteria. |
| User Comprehension | Minimum of a 90% or greater overall comprehension rate for each comprehension concept, with justification from physician/genetic counselor identifying relevant concepts. | Specific user comprehension studies were not performed for this specific BRCA1/BRCA2 report. Instead, the document refers to studies from DEN160026. The general acceptance criteria for user comprehension studies from the special controls are listed (90% comprehension rate). |
2. Sample sizes used for the test set and the data provenance
-
Accuracy Study (Test Set):
- Sample Size:
- BRCA1 185delAG Homozygous Common: 109 samples
- BRCA1 185delAG Heterozygous: 58 samples
- BRCA1 5382insC Homozygous Common: 60 samples
- BRCA1 5382insC Heterozygous: 22 samples
- BRCA2 6174delT Homozygous Common (presumably the combined 59 samples from the table as the 6174delT is mistakenly written as 5382insC for its second entry in Table 4): 60 samples (including 1 FQC)
- BRCA2 6174delT Heterozygous (presumably the combined 45 samples from the table as the 6174delT is mistakenly written as 5382insC for its second entry in Table 4): 46 samples (including 1 FQC)
- Data Provenance: Saliva samples were selected from the 23andMe customer biobank. The document doesn't explicitly state the country of origin, but "customer biobank" implies they are from their existing customer base, likely primarily US. The study appears to be retrospective as samples were "selected... based on predetermined genotypes."
- Sample Size:
-
Precision/Reproducibility Study:
- Sample Size:
- BRCA1 185delAG: 2 wildtype samples, 1 heterozygous sample. Each replicated multiple times (e.g., 242-321 replicates per site for specific genotypes, across multiple runs).
- BRCA1 5382insC: 2 wildtype samples, 1 heterozygous sample. Each replicated multiple times (e.g., 321-402 replicates per site for specific genotypes).
- BRCA2 6174delT: 2 wildtype samples, 1 heterozygous sample. Each replicated multiple times (e.g., 313-323 replicates per site for specific genotypes).
- Data Provenance: DNA samples were procured and genotyped. No specific country of origin mentioned, likely internal to 23andMe's operations or commercial vendors.
- Sample Size:
3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts
The ground truth for the analytical validation (accuracy study) was established by Sanger bidirectional sequencing performed at an independent laboratory site. There is no mention of human experts defining the ground truth for the analytical studies. The "experts" in the context of user comprehension studies (which were not specifically performed for this report but referenced generally) would be physicians and genetic counselors to determine relevant concepts, but not for establishing a genetic variant ground truth.
4. Adjudication method (e.g. 2+1, 3+1, none) for the test set
No adjudication method for the genetic variant determination is mentioned. The ground truth was established directly by Sanger bidirectional sequencing. This is a direct comparison study, not a human reader study requiring adjudication.
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
No such MRMC comparative effectiveness study was done. This device is a qualitative genetic test for detecting specific SNPs, not an imaging AI diagnostic aid for human readers.
6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
Yes, the analytical performance studies (precision, LoD, and accuracy against Sanger sequencing) represent the standalone performance of the 23andMe PGS test, which is an algorithm interpreting genotyping data. The human element is in the initial sample acquisition and laboratory processing, but the "device" itself (the genotyping and data analysis system) operates in a standalone manner for assigning genotypes.
7. The type of ground truth used (expert consensus, pathology, outcomes data, etc)
The primary ground truth for validating the device's accuracy in identifying genetic variants was Sanger bidirectional sequencing. For analytical studies, this is considered a highly reliable and established gold standard for DNA sequencing.
8. The sample size for the training set
The document describes performance studies on a "test set" (accuracy, precision, LoD), but does not provide details on the training set size for the underlying genotyping and analysis algorithms (e.g., Illumina's GenomeStudio or 23andMe's Coregen software). Genetic tests like this rely on established biochemical and computational methods for genotype calling, which are developed and validated using extensive, but typically not detailed in regulatory submissions in terms of a specific "training set" size in the same way an AI model's training set would be. The focus is on the analytical validation of the test system's performance for the specific variants.
9. How the ground truth for the training set was established
As there's no explicit mention of a "training set" in the context of a machine learning model, the concept of ground truth establishment for it isn't directly addressed. For the underlying genotyping technology and software, ground truth is typically based on known genetic sequences, synthetic constructs, or samples previously characterized by highly accurate sequencing methods like Sanger.
§ 866.6090 Cancer predisposition risk assessment system.
(a)
Identification. 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.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The labeling required under § 809.10 of this chapter and any pre-purchase page and test report generated, unless otherwise specified, must include:
(i) An intended use that specifies in the indications for use the genetic variants detected by the test. The specific variants must be appropriately validated as described in paragraphs (b)(4)(xii) and (b)(4)(xiii) of this section.
(ii) A section addressed to users with the following information:
(A) A warning statement accurately disclosing the genetic coverage of the test in lay terms, including information on variants not queried by the test, and the proportion of pathogenic variants in the genes that the assay detects in a specific population as identified in paragraph (b)(1)(i) of this section. The warning statement must indicate that the test [does not/may not, as appropriate] detect all genetic variants related to the genetic disease, and that the absence of a variant tested does not rule out the presence of other genetic variants that may impact cancer risk. The warning statement must also include the relevant population for which the variants reported by the test are most relevant.
(B) A limiting statement explaining that some people may feel anxious about getting genetic test health results. This is normal. If the potential user feels very anxious, such user should speak to his or her doctor or other healthcare professional prior to collection of a sample for testing. This test is not a substitute for visits to a doctor or other healthcare professional. Users should consult with their doctor or other healthcare professional if they have any questions or concerns about the results of their test or their current state of health.
(C) A limiting statement that a user's ethnicity may affect whether the test is relevant for them and may also affect how their genetic health results are interpreted.
(D) A warning statement that the test is not a substitute for visits to a healthcare professional for recommended screenings, and should not be used to determine any treatments or medical interventions.
(E) A warning statement that the test does not diagnose cancer or any other health conditions and should not be used to make medical decisions. The warning statement must indicate that the results should be confirmed in a clinical setting before taking any medical action.
(F) A limiting statement explaining that other companies offering a genetic risk test may be detecting different genetic variants for the same disease, so the user may get different results using a test from a different company.
(G) If applicable, a limiting statement that states the test does not test for variants in other genes linked to hereditary cancer.
(H) A limiting statement explaining that this test does not account for non-genetic factors and that other factors such as environmental and lifestyle risk factors may affect the risk of developing a given disease.
(I) Information to a potential purchaser or actual test report recipient about how to obtain access to a board-certified clinical molecular geneticist or equivalent to assist in pre- and post-test counseling.
(J) A limiting statement explaining that this test is not intended to tell you anything about your current state of health, or be used to make medical decisions, including whether or not you should take a medication or how much of a medication you should take.
(K) A limiting statement explaining that the laboratory may not be able to process a sample, and a description of the next steps to be taken by the manufacturer and/or the customer, as applicable.
(iii) A section in the labeling required under § 809.10 of this chapter and any test report generated that is for healthcare professionals who may receive the test results from their patients with the following information:
(A) A limiting statement explaining that 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.
(B) A limiting statement explaining that this test is intended to provide users with their genetic information to inform health-related lifestyle decisions and conversations with their doctor or other healthcare professional.
(C) A limiting statement explaining that any diagnostic or treatment decisions should be based on confirmatory prescription testing and/or other information that is determined to be appropriate for the patient (
e.g., additional clinical testing and other risk factors that may affect individual risk and health care).(2) The genetic test must use a sample collection device that is FDA-cleared, -approved, or -classified as 510(k) exempt, with an indication for in vitro diagnostic use in over-the-counter DNA testing.
(3) The device's labeling must include a hyperlink to the manufacturer's public website where the manufacturer must make the information identified in paragraph (b)(3) of this section publicly available. The manufacturer's home page, as well as the primary part of the manufacturer's website that discusses the device, must provide a hyperlink to the web page containing this information and must allow unrestricted viewing access. If the device can be purchased from the website or testing using the device can be ordered from the website, the same information must be found on the web page for ordering the device or provided in a publicly accessible hyperlink on the web page for ordering the device. Any changes to the device that could significantly affect safety or effectiveness would require new data or information in support of such changes, which must also be posted on the manufacturer's website. The information must include:
(i) An index of the material being provided to meet the requirements in paragraph (b)(3) of this section and its location.
(ii) Technical information about the device, as specified in paragraph (b)(4) of this section.
(iii) A section that highlights summary information that allows the user to understand how the test works and how to interpret the results of the test. This section must, at a minimum, be written in plain language understandable to a lay user and include:
(A) Consistent explanations of the risk of disease associated with all variants included in the test, variants not included in the test, and specific considerations by ethnicity. If there are different categories of risk, the manufacturer must provide literature references and/or data that support the different risk categories. If there will be multiple test reports and multiple variants, the risk categories must be defined similarly among them. For example, “increased risk” must be defined similarly between different test reports and different variant combinations.
(B) Clear context for the user to understand the context in which the cited clinical performance data support the risk reported. This includes any risks that are influenced by ethnicity, age, gender, environment, and lifestyle choices.
(C) Materials that explain the main concepts and terminology used in the test that include:
(
1 ) Definitions: scientific terms that are used in the test reports.(
2 ) Pre-purchase page: this page must contain information that informs the user about what information the test will provide. This includes variant information, the condition(s) or disease(s) associated with the variant(s), professional guideline recommendations for general genetic risk testing, the limitations associated with the test (e.g., test does not detect all variants related to the disease), relevance of race/ethnicity, and any precautionary information about the test the user should be aware of before purchase. When the test reports the risk of a life-threatening or irreversibly debilitating disease or condition for which there are few or no options to prevent, treat, or cure the disease, a user opt-in page must be provided. This opt-in page must be provided for each disease type that falls into this category and must provide specific information relevant to each test result. The opt-in page must include:(
i ) An option to accept or decline to receive this specific test result;(
ii ) Specification of the risk involved if the user is found to have the specific genetic test result;(
iii ) Summary of professional guidelines that recommend when genetic testing for the associated target condition is or is not recommended;(
iv ) A recommendation to speak with a healthcare professional, genetic counselor, or equivalent professional before getting the results of the test;(
v ) The implications of receiving a no variants detected result; and(
vi ) The statement that the test does not diagnose cancer or any other health conditions and should not be used to make medical decisions. Results should be confirmed in a clinical setting before taking any medical action. Users should consult with a healthcare professional before taking any medical action.(
3 ) Frequently asked questions (FAQ) page: This page must provide information that is specific for each variant/disease pair that is reported. Information provided in this section must be scientifically valid and supported by corresponding peer-reviewed publications. The FAQ page must explain the health condition/disease being tested, the purpose of the test, the information the test will and will not provide, the relevance of race and ethnicity to the test results, information about the population to which the variants in the test is most applicable, the meaning of the result(s), other risk factors that contribute to disease, appropriate follow-up procedures, how the results of the test may affect the user's family, including children, and links to resources that provide additional information.(4) The device labeling must include a technical information section containing the following information:
(i) Gene(s) and variant(s) the test detects using standardized nomenclature, Human Genome Organization (HUGO) nomenclature and coordinates, as well as Single Nucleotide Polymorphism Database (dbSNP) reference SNP numbers (rs#).
(ii) A statement indicating that more than 1,000 variants in the BRCA1 and BRCA2 genes are known to increase cancer risk, as applicable.
(iii) Scientifically established disease-risk association of each variant detected and reported by the test. This risk association information must include:
(A) Genotype-phenotype information for the reported variants.
(B) When available, a table of expected frequency in the general population and different ethnicities, and risks of developing the disease in relevant ethnic populations and the general population.
(C) Information such as peer-reviewed published literature and/or professional guidelines used to determine what types and levels of evidence will distinguish whether the selected variants are reported as “are associated with increased risk” versus “may be associated with increased risk” of developing other cancers. All selected variants must be appropriately validated as required under paragraph (b)(1)(i) of this section. For selected variants reported as “are associated with increased risk,” the clinical evidence must be demonstrated with sufficient information (
e.g., professional guidelines and consistent associations in peer-reviewed published literature). For the selected variants reported as “may be associated with increased risk,” the clinical evidence must be reported in professional guidelines, but peer-reviewed published literature may not be consistent.(D) A statement about the current professional guidelines for testing these specific gene(s) and variant(s) for the specified disease(s).
(
1 ) If professional guidelines are available, provide the recommendations in the professional guideline(s) for the gene, variant, and disease for when genetic testing should or should not be performed, and cautionary information that should be communicated when a particular gene and variant is detected.(
2 ) If professional guidelines are not available, provide a statement that the professional guidelines are not available for these specific gene(s) and variant(s).(iv) The specimen type (
e.g., saliva, whole blood).(v) Assay steps and technology used.
(vi) Specification of required ancillary reagents, instrumentation, and equipment.
(vii) Specification of the specimen collection, processing, storage, and preparation methods.
(viii) Specification of risk mitigation elements and description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.
(ix) Information pertaining to the probability of test failure (
e.g., percentage of tests that failed quality control) based on data from clinical samples, a description of scenarios in which a test can fail (e.g., low sample volume, low DNA concentration), how users will be notified of a test failure, and the nature of follow-up actions on a failed test to be taken by the user and the manufacturer.(x) When available, information specifying the probability of a false negative and false positive analytical result and any additional considerations by ethnicity.
(xi) Specification of the criteria for test result interpretation and reporting, including any distinctions between risk categories (
i.e., increased risk and greatly increased risk; are associated and may be associated).(xii) Information that demonstrates the performance characteristics of the test including:
(A) Accuracy of study results for each claimed specimen type.
(
1 ) Accuracy of the test must be evaluated with fresh clinical specimens collected and processed in a manner consistent with the test's instructions for use. If this is impractical, fresh clinical samples may be substituted or supplemented with archived clinical samples. Archived samples must have been collected previously in accordance with the instructions for use, stored appropriately, and randomly selected. In some limited circumstances, use of contrived samples or human cell line samples may also be appropriate and used as an acceptable alternative. The contrived or human cell line samples must mimic clinical specimens as much as is feasible and provide an unbiased evaluation of the test's accuracy.(
2 ) Accuracy must be evaluated by comparison to bidirectional Sanger sequencing or other methods identified as appropriate by FDA. Performance criteria for both the comparator method and the test must be pre-defined and appropriate to the test's intended use. Detailed study protocols must be provided.(
3 ) Information provided must include the number and type of specimens, broken down by clinically relevant variants for each indicated report that were compared to bidirectional sequencing or other methods identified as appropriate by FDA. The accuracy as positive percent agreement (PPA) and negative percent agreement (NPA) must be measured, and accuracy point estimates must be >99 percent (both per reported variant and overall). Uncertainty of the point estimate must be within an acceptable range, as identified by FDA, and must be presented using the 95 percent confidence interval.(
4 ) Sufficient specimens must be tested per genotype and must include all genotypes that will be included in the tests and reports. The number of samples tested in the accuracy study for each variant reported must be based on the variant frequency.(
5 ) Any no calls (i.e., absence of a result) or invalid calls (e.g., failed quality control) in the study must be included in accuracy study results and reported separately. The percent of final 'no calls' or 'invalid calls' must be clinically acceptable. Variants that have a point estimate for PPA or NPA of