(148 days)
The 23andMe Personal Genome Service (PGS) is a qualitative genotyping assessment system applied to genomic DNA isolated from human saliva collected using the Oragene Dx OGD-500.001 to simultaneously detect, report, and interpret genetic variants in a broad multigene test. The assessment system is intended to enable users to access information about their genetics that could aid discussions with a healthcare professional. The 23andMe Personal Genome Service Pharmacogenetic Reports are indicated for reporting of the following variants:
| Gene | Variant(s) |
|---|---|
| CYP2C19 | *2, *3, *17 |
| CYP2C9 | *2, *3, *5, *6, rs7089580 |
| CYP3A5 | *3 |
| UGT1A1 | *6, *28 |
| DPYD | *2A, rs67376798 |
| TPMT | *2, *3C |
| SLCO1B1 | *5 |
| CYP2D6 | *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *15, *17, *20, *29, *35, |
| *40, *41 |
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 about metabolism of therapeutics. This report describes if a person has variants associated with metabolism of some therapeutics, but does not describe if a person will or will not respond to a particular therapeutic, and does not describe the association between detected variants and any specific therapeutic. The PGS Pharmacogenetic Reports are not a substitute for visits to a healthcare professional. The information provided by this report should not be used to start, stop, or change any course of treatment.
The 23andMe PGS is a non-invasive DNA testing service that uses qualitative genotyping. It is a direct-to-consumer, over-the-counter, DNA genetic test. 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. 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 by the scanning instrument's software, and then sent to 23andMe (the Manufacturer). The data are analyzed using the Manufacturer's proprietary 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 predicted metabolic function of the tested variants.
Personalized reports are generated for each user to provide 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 predicted metabolic function of the specific genetic variants. The genetic variants detected by the test are associated with the metabolism of some therapeutics. If no variant is detected, that information is also provided. If the association between the predicted metabolic function and the combination of detected variants has not been established, the report indicates that the results cannot be determined. The personalized reports are intended to present scientific concepts to users in an easy-to-understand format. The reports provide information about the association between the detected variant and the predicted metabolic function that has been associated with the metabolism of some drugs, further described below. The reports are designed to help users understand the meaning of their results and inform conversations with their doctor or other healthcare professional. The test reports do not provide any information on associations between the detected variants and any specific therapeutic and therefore, the test does not describe if a person will or will not respond to any specific therapeutic.
The 23andMe PGS Pharmacogenetic Reports detect 33 variants in 8 genes: CYP2C19, CYP2C9, CYP2D6, CYP3A5, CYP2D6, DPYD, TPMT, and UGT1A1. The 23andMe PGS Pharmacogenetic Reports provide information on the associated enzyme or protein function and the predicted metabolizer phenotype for variants in drug metabolizing enzymes: CYP2C19, CYP2C9, CYP2D6, CYP3A5, CYP2D6, DPYD, TPMT, and UGT1A1. The predicted metabolizer phenotype is identified according to the number and consequence of each allele where two no-function alleles are associated with being poor metabolizers, one no-function allele is associated with being an intermediate metabolizer, two functional alleles are associated with being normal metabolizers, one gain-of-function allele is associated with being a rapid metabolizer, and two gain-of-function alleles are associated with being an ultrarapid metabolizer. The predicted metabolizer phenotype or protein function is then used to provide information on the potential consequence on metabolism of some medications. For example, poor metabolizers may process some medications slower, internediate metabolizers may process some medications slightly slower than normal, normal metabolizers may process some medication at a normal rate. rapid metabolizers may process some medications slightly faster than normal, and ultrarapid metabolizers may process some medications faster than normal.
The 23andMe PGS Pharmacogenetic Report for SLCO1B1 will indicate that the detected variant is associated with a loss-of-function and slightly decreased transport of some medications.
Here's a breakdown of the acceptance criteria and the study details for the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports, based on the provided text:
Acceptance Criteria and Device Performance for 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports
1. Table of Acceptance Criteria and Reported Device Performance (Analytical Performance for CYP2C19)
The document primarily details the analytical performance for **CYP2C19 variants (*2, 3, 17) as the representative study for the broader pharmacogenetic reports. Protocols and acceptance criteria for other genes (CYP2C9, CYP2D6, CYP3A5, DPYD, TPMT, UGT1A1, and SLCO1B1) were reviewed and found acceptable, with the plan for the sponsor to perform testing and add them if validation data meet criteria.
Note: The provided text does not explicitly state numerical acceptance criteria for performance metrics like PPA/NPA. However, the reported results demonstrate 100% agreement with the reference method (Sanger sequencing), which can be inferred as meeting implicit high accuracy requirements. The special controls mention the need for "Data appropriate, as determined by FDA, to demonstrate the analytical (i) accuracy and reliability of the device."
| Performance Metric | Acceptance Criteria (Implied by study results meeting FDA approval) | Reported Device Performance (CYP2C19*2, *3, *17) |
|---|---|---|
| Reproducibility/Precision | ||
| Correct Call Percentage | The study design suggests an acceptance criterion of very high (ideally 100%) correctness in genotype calls across different sites, operators, reagents, and days, with minimal Failed Quality Controls (FQCs) and no incorrect calls. (Special Control 1(i)(A): "Data demonstrating appropriate, as determined by FDA, reproducibility for each genotype using each claimed sample type.") | 100% Correct Calls for all genotypes across both sites for CYP2C19*2, *3, and *17 (among valid calls). FQCs ranged from 0 to 22.2% per sample. Zero incorrect calls observed. |
| Limit of Detection (LoD) | ||
| Correct Call Percentage at Lowest DNA Concentration | Data demonstrating the minimum amount of input DNA that will consistently produce accurate results. (Special Control 1(i)(B)). Implies 100% correct calls at the established LoD. | 100% Correct Calls per genotype for all samples across all reagent lots, at all sample concentrations tested (5, 15, and 50 ng/uL). LoD set at 5 ng/uL. |
| Analytical Specificity (Interference) | ||
| Clinically Significant Interference | Data demonstrating no clinically significant effects from endogenous and exogenous interferers relevant to each intended use specimen type and assessment of potentially interfering genetic sequences (Special Control 1(i)(C)). Implies absence of incorrect calls due to common interferents. | Studies conducted (results referenced from DEN140044). Potentially interfering mutations for CYP2C19*2, *3, and *17 were identified and are listed in the labeling. No incorrect calls reported in the reproducibility/comparison studies. |
| Comparison to Reference Method (Accuracy) | ||
| Positive Percent Agreement (PPA) | The FDA's assessment for "analytical accuracy and reliability" (Special Control 1(i)) implies a high level of agreement with a recognized reference method. Given the nature of a De Novo classification, the reported 100% PPA for the studied variants aligns with this. | 100% PPA for all CYP2C19*2, *3, and *17 genotypes. 92.1-100% 95% CI. |
| Negative Percent Agreement (NPA) | The FDA's assessment for "analytical accuracy and reliability" (Special Control 1(i)) implies a high level of agreement with a recognized reference method. Given the nature of a De Novo classification, the reported 100% NPA for the studied variants aligns with this. | 100% NPA for all CYP2C19*2, *3, and *17 genotypes. 92.1-100% 95% CI. |
| User Comprehension | ||
| Comprehension Rate (various concepts) | "Results from an appropriate, as determined by FDA, user comprehension study that demonstrate the intended user can use the device safely." (Special Control 1(ii)). Implies high comprehension rates for critical concepts for safe use. | Overall comprehension rates: Purpose (89.9%), Result & meaning (89.9%), Limitations & variant coverage (93.1%), Limitations of medication coverage (94.8%), Appropriate actions (92.3%), Treatment adherence (97.0%), Other risk factors (95.0%). |
2. Sample Size and Data Provenance
-
Test Set (Analytical Studies - CYP2C19):
- Reproducibility/Precision:
- CYP2C19*2: 4 samples (GG, AG, AA) at Site 1; 4 samples (GG, AG, AA) at Site 2. Each sample replicated 81 times. (Total 81 replicates * 4 samples * 2 sites = 648 technical replicates, plus FQCs/no calls).
- CYP2C19*3: 4 samples (GG, AG, AA) at Site 1; 4 samples (GG, AG, AA) at Site 2. Each sample replicated 81 times. (Total 648 technical replicates, plus FQCs/no calls).
- CYP2C19*17: 5 samples (CC, CT, TT) at Site 1; 5 samples (CC, CT, TT) at Site 2. Each sample replicated 81 times. (Total 810 technical replicates, plus FQCs/no calls).
- Additional precision study: One sample of each genotype for each allele was genotyped in replicates of three at two sites.
- Data Provenance: DNA samples obtained from an "external vendor." Not explicitly stated, but typically these are commercially available, characterized genomic DNA samples. The study was retrospective in nature as samples were pre-selected.
- Limit of Detection (LoD): Not explicitly stated, but samples included homozygous common, heterozygous common, and homozygous rare genotypes for each allele (CYP2C19*2, *3, *17). Three replicates of each sample were diluted to three DNA concentrations.
- Data Provenance: Samples obtained from an "external vendor." Retrospective.
- Comparison with Sanger Bidirectional Sequencing (Accuracy):
- CYP2C19*2: 47 (Homozygous Common), 49 (Heterozygous), 48 (Homozygous Rare).
- CYP2C19*3: 48 (Homozygous Common), 45 (Heterozygous), 39 (Homozygous Rare).
- CYP2C19*17: 49 (Homozygous Common), 45 (Heterozygous), 47 (Homozygous Rare).
- Data Provenance: Saliva samples selected from the "23andMe customer biobank" based on predetermined genotypes. This implies a retrospective data provenance, and the potential for selection bias ("samples were chosen from a biobank based on the variants already detected by the candidate assay") is explicitly noted by the FDA. The country of origin of the biobank is not specified, but 23andMe is a US-based company, suggesting primarily US customers.
- Reproducibility/Precision:
-
Test Set (User Comprehension Study):
- Sample Size: 602 participants completed the study; 594 subjects included in primary analysis (after excluding 8 careless responders/previous users/technical issues). A second analysis excluded 63 participants who did not scroll/read the reports, resulting in 531 participants.
- Data Provenance: Participants were "demographically diverse (e.g., age, education) set of users naive to the study subject." The direct-to-consumer nature implies diverse backgrounds, likely from the US, but not explicitly stated. This would be considered a prospective study as participants were recruited specifically for this evaluation.
3. Number of Experts and Qualifications for Ground Truth
-
Analytical Studies (Reproducibility, LoD, Comparison with Sanger):
- Number of Experts: Not applicable in the traditional sense of clinical experts.
- Qualifications: The ground truth for the DNA samples used in analytical studies was established by bidirectional Sanger sequencing, which is considered a gold standard for genetic sequencing. The "external vendor" supplying samples would also have characterized them.
-
User Comprehension Study:
- Number of Experts: The study mentioned "moderators of the test" for identifying participants who did not scroll/read. Specific qualifications of these moderators are not provided. The "primary endpoint analysis" and "second analysis" indicate a statistical approach rather than expert consensus on individual comprehension.
4. Adjudication Method for the Test Set
-
Analytical Studies:
- Method: For reproducibility, LoD, and accuracy studies, the 23andMe PGS test results were compared to the results obtained from bidirectional Sanger sequencing. Discrepancies (incorrect calls) were counted. This is effectively a direct comparison to a gold standard, not a consensus-based adjudication among multiple interpretations of the same test.
- Specifics (e.g., 2+1): Not applicable, as it's a comparison to a single reference method.
-
User Comprehension Study:
- Method: Quantitative assessment of participant answers to comprehension questions. Not a traditional adjudication method.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- Was one done? No, a MRMC comparative effectiveness study involving human readers improving with AI vs. without AI assistance was not mentioned or conducted for this device.
- This device is a qualitative genotyping microarray intended for direct-to-consumer use, with results used to inform discussions with healthcare professionals. It does not involve a diagnostic image interpretation or similar task where human readers would typically "improve" with AI assistance in the way an MRMC study would measure.
- Effect Size: Not applicable.
6. Standalone Performance Study
- Was one done? Yes, the entire analytical performance section (Reproducibility/Precision, Limit of Detection, Analytical Specificity, Comparison with Sanger bidirectional Sequencing) represents a standalone (algorithm only, without human-in-the-loop performance) evaluation of the 23andMe PGS test's ability to accurately detect genetic variants. The user comprehension study assessed how well users understood the report generated by the algorithm, but the genotyping itself was assessed standalone.
7. Type of Ground Truth Used
-
Analytical Studies: Sanger bidirectional sequencing was used as the ground truth for confirming genotypes in the reproducibility, LoD, and comparison studies.
-
Clinical Studies (User Comprehension): The ground truth for the comprehension study was defined by pre-defined correct answers to questions about the information presented in the reports. This is a measure of objective understanding of the provided text, not directly related to a medical diagnosis or biological outcome.
8. Sample Size for the Training Set
- Training Set Sample Size: The document does not provide information regarding a specific "training set" sample size for the genotyping algorithm itself.
- Genotyping microarrays from companies like Illumina (which 23andMe uses/adapts) are developed and validated using extensive reference genomes and known variant databases during their initial design and manufacturing. 23andMe's proprietary software analyzes the raw data, and while such software might undergo internal validation and refinement, the specific training data for the core genotyping calls (determining AG, GG, etc.) is not detailed in this regulatory summary. The focus is on the analytical validation of the test performed by 23andMe using their specific chip and processes.
9. How the Ground Truth for the Training Set Was Established
- Ground Truth for Training Set: As no specific "training set" for the genotyping algorithm's core variant calling function is detailed, the method for establishing its ground truth is not provided in this document.
- However, for the specific pharmacogenetic associations and predicted metabolizer phenotypes (e.g., "poor metabolizer"), the document states: "The impact of protein or enzyme function for each allele and the predicted metabolizer phenotypes were identified from data in the literature for each allele for each gene." This is ground truth established through expert consensus and published literature.
§ 862.3364 Pharmacogenetic assessment system.
(a)
Identification. A pharmacogenetic assessment system is a qualitative in vitro molecular diagnostic system intended to detect nucleic acid variants isolated from human specimens for the purpose of assessing the presence of genetic variants that impact the metabolism, exposure, response, risk of adverse events, dosing, or mechanisms of prescription or over-the-counter medications. The intended use of the device must not include an indication for use in supporting or sustaining human life, being of substantial importance in preventing impairment of human health, or presenting a potential, unreasonable risk of illness or injury.(b)
Classification. Class II (special controls). A pharmacogenetic assessment system must comply with the following special controls:(1) Design verification and validation must include:
(i) Data appropriate, as determined by FDA, to demonstrate the analytical accuracy and reliability of the device in intended use specimens, including precision, reproducibility, accuracy, limits of detection, and interferences. This information must include:
(A) Data demonstrating appropriate, as determined by FDA, reproducibility for each genotype using each claimed sample type. Reproducibility data must be evaluated using specimens collected and processed in a manner consistent with the device's instructions for use, or, as determined by FDA, an appropriate alternative sample panel.
(B) Analytical data demonstrating the limits of detection, including the minimum amount of input deoxy-ribonucleic acid (DNA) that will consistently produce accurate results.
(C) Data demonstrating no clinically significant effects from endogenous and exogenous interferents relevant to each intended use specimen type. Interference data must also include an assessment of potentially interfering genetic sequences (
e.g., variants proximal to the variant of interest, pseudogenes).(D) Validation data appropriate, as determined by FDA, to support specimen collection and handling claims.
(E) Clinical data generated in intended use patient populations demonstrating the pharmacogenetic association between the genetic variant tested and any clinical claims or therapy-related recommendations associated with that genotype.
(ii) Results from an appropriate, as determined by FDA, user comprehension study that demonstrate the intended user can use the device safely. The user comprehension study must be designed to include the following:
(A) Study participants from a statistically sufficient sample size and a demographically diverse (
e.g., age, education level) population that is representative of the intended use population and naive to use of the device, and(B) An evaluation of all result comprehension concepts that are critical for safe use of the device.
(2) The labeling required under § 809.10 of this chapter must include:
(i) Clear information, written in language appropriate for the intended user, that describes instructions for how test results should be interpreted. These instructions must be supported by valid scientific evidence and include:
(A) Appropriate explanation of the claimed pharmacogenetic associations for all variants included in the test, any relevant variants not included in the test (
e.g., that may contribute to false negative results), and specific considerations by ethnicity, and(B) Appropriate explanation of non-genetic and non-tested genetic factors that may impact interpretation of the test results;
(ii) Detailed descriptions of analytical performance including, as applicable, precision, reproducibility, accuracy, limits of detection, and interferences as specified in paragraph (b)(1)(i) of this section, in language appropriate for the intended user;
(iii) A warning statement that the patient should not use the test results to stop or change any medication, and that medications should always be taken as prescribed by a healthcare professional;
(iv) A limiting statement explaining that this test is not intended to inform the patient about their current state of health, including whether the patient should or should not take a medication, or how much of a medication the patient should take, as appropriate;
(v) A warning statement that the test does not diagnose any health conditions and is not a substitute for visits to a doctor or other healthcare professional; and
(vi) A prominent and conspicuous limiting statement that the test provides only a preliminary test result that needs to be confirmed using an independent pharmacogenetic test without such a limitation prior to making any medical decisions. Alternatively, appropriate design verification and validation activities, including the generation of robust analytical data demonstrating appropriate analytical accuracy and reliability of test results for each genetic variant included in the test report, must be performed that demonstrate that the test can be used to make well-informed clinical decisions.
(3) The test report must include an appropriate description of how the test results should be used by healthcare providers who may receive the test results from their patients, as applicable.
(4) Publicly available pre-purchase labeling with unrestricted access that contains the following information must be provided:
(i) A clear description of the test and its technology, the genotypes detected, and relevant clinical claims associated with each genotype;
(ii) A clear description of what information the test will provide. This includes variant information, the limitations associated with the test, and any precautionary information about the test the user should be aware of before purchase; and
(iii) A discussion of answers to frequently asked questions that is sufficient to provide intended users with an appropriate understanding of information specific to each pharmacogenetic association that is claimed.
(5) The genetic test must use a sample collection device that is FDA-cleared or -approved, or classified as 510(k) exempt, with an indication for in vitro diagnostic use in DNA testing.
(6) The intended use of the device must not include an indication for use in supporting or sustaining human life, being of substantial importance in preventing impairment of human health, or presenting a potential, unreasonable risk of illness or injury.