(244 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 Pharmacogenetic Reports are indicated for reporting of the following variants:
Gene: CYP2C19 Variant(s): *2, *3, *17
Gene: CYP2C9 Variant(s): *2, *3, *5, *6, rs7089580
Gene: CYP3A5 Variant(s): *3
Gene: UGT1A1 Variant(s): *6, *28
Gene: DPYD Variant(s):*2A, rs67376798
Gene: TPMT Variant(s): *2, *3C
Gene: SLC01B1 Variant(s): *5
Gene: CYP2D6 Variant(s): *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.
The 23andMe Personal Genome Service pharmacogenetic reports for CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, SLC01B1 and CYP2D6 describe 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.
23andMe Personal Genome Service pharmacogenetic reports for CYP2C19 describes if a person has variants associated with metabolism of some therapeutics and provides interpretive drug information regarding the potential effect of the identified metabolizer phenotype on citalopram and clopidogrel therapy.
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 Personal Genome Service (PGS) is an over-the-counter (direct-to-consumer), DNA testing service that provides information and tools for consumers to learn about and explore their DNA.
The PGS is a currently marketed, non-invasive genetic information 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.
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 (K141410, DEN140044, DEN160026, DEN170046, DEN180028, and K182784), which consists of a sealable collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory 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 device simultaneously tests for more than 600,000 variants, including those reported under the previously authorized PGS test indications.
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 variant(s) has/have been detected in their sample and provide information on metabolizer or transporter profile 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 metabolizer or transporter phenotype associated with the presence of a particular variant, or a combination of variants. In the pharmacogenetic report for CYP2C19, information regarding interpretive drug information to certain medications will be provided to the user in a medication "mini report", which is accessed via a link in the pharmacogenetic report for CYP2C19. 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.
The novel components in this traditional 510(k) submission are to provide interpretive drug information to two specific medications (citalopram and clopidogrel), and to remove the limitation language requiring confirmatory testing in the 23andMe pharmacogenetic report for CYP2C19. Pharmacogenetic reports for the other genes authorized in DEN180028 will not be modified to include interpretive drug information, or remove the confirmatory testing limitation.
Here's an analysis of the acceptance criteria and the supporting study for the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports, specifically focusing on the CYP2C19 gene, as described in the provided document:
1. Table of Acceptance Criteria and Reported Device Performance
The document focuses on the analytic performance of the genotyping assay for CYP2C19 variants (*2, *3, *17). The primary acceptance criteria provided relate to accuracy (method comparison) and precision (reproducibility).
| Acceptance Criteria Category | Specific Acceptance Criteria | Reported Device Performance (CYP2C19 variants: *2, *3, *17) |
|---|---|---|
| Method Comparison (Accuracy) | >99% agreement with the source of truth (PPA and NPA both >99%) | 100% overall agreement for all genotypes of each of the three variants, with Sanger sequencing as the source of truth. |
| 100% concordance to comparator source of truth for blinded studies (Coriell samples and East Asian saliva samples), achieving >99% PPA and >99% NPA. | ||
| Precision (Reproducibility) | ≥ 99% correct calls | >99% correct genotype calls for all samples across multiple days, operator teams, instruments, and reagent lots at two independent laboratory sites (initial study). |
| 100% correct genotype calls for all samples across multiple days, operator teams, instruments, and reagent lots at two independent laboratory sites (supplemental saliva study). | ||
| 100% reproducibility and 100% repeatability for intended use (saliva) samples. | ||
| Minimum DNA Input (MDI) | ≥ 95% of samples yielded the correct call at the lowest DNA concentration | 100% concordant test results/correct genotype calls for all samples and all reagent lots tested at sample DNA concentrations of 5, 15, and 50 ng/μL. |
| Passed acceptance criteria at a sample DNA concentration of 5 ng/μL for both initial and supplemental studies. |
2. Sample Sizes and Data Provenance for the Test Set
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Method Comparison (Accuracy) & Precision (Reproducibility) Test Sets:
- "Blinded Study 1" (single lab site, single day): Five 96-well plates of "incoming saliva samples." A specific numerical count of samples is not given, but 5 plates x 96 wells/plate = 480 samples.
- Coriell Reference Samples: Genomic DNA for the three CYP2C19 variants of interest (*2, *3, *17) was obtained from the Coriell Institute for Medical Research. The exact number of Coriell samples used is not specified.
- "Blinded Study 2" (East Asian ancestry): Intended use (saliva) samples "randomly selected in an unbiased manner from the 23andMe biobank based on their East Asian genetic ancestry." Numbers not specifically given. The purpose was to increase the likelihood of rare *3 allele combinations.
- Supplemental Precision Study (saliva): Intended use (saliva) samples selected from the 23andMe customer biobank based on their "putative genotype." Numbers not specifically given but tested over 3 days, with 3 lots of reagents, by unique operator teams, using 3 different serial numbers of each of 2 instruments (Tecan and iScan), at each of 2 laboratory sites.
- Minimum DNA Input (MDI) Test Set:
- DNA samples obtained from Coriell and the 23andMe biobank. Exact numbers not specified, but tested at 3 different DNA concentrations with 3 reagent lots.
- Supplemental MDI Study (saliva): Intended use (saliva) samples selected from the 23andMe customer database based on their "putative genotype." Numbers not specified, but each sample was diluted to 3 different DNA concentrations and genotyped with 3 reagent lots.
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Data Provenance:
- Retrospective: Samples from the 23andMe biobank and customer database are retrospective, representing previously collected data.
- Prospective (Implicit): "Incoming saliva samples" in the first blinded study could imply prospective collection for that specific study's initiation if they were fresh samples received for routine processing on that day.
- External Reference: Coriell Institute for Medical Research samples are an external, well-characterized source.
- Country of Origin: Not explicitly stated for all samples, but the 23andMe customer base is likely predominantly from the US and other countries where they operate.
3. Number of Experts and Qualifications for Ground Truth Establishment (Test Set)
This device is a genotyping system, and the ground truth for its analytical performance is established through genomic sequencing, not expert interpretation of phenotypic data or images.
- No human experts were used to establish the ground truth in the traditional sense of clinical interpretation.
- The "experts" in this context are the robust and established methods of bi-directional Sanger sequencing and Coriell Institute's characterization of their reference materials. These methods are considered the "source of truth" for genetic sequences and genotypes.
4. Adjudication Method for the Test Set
- No human adjudication method (like 2+1, 3+1) was used as the ground truth is based on objective genetic sequencing data.
- The comparison involved directly comparing the device's genotyping results against the known sequences/genotypes derived from Sanger sequencing or Coriell's reference data. Discrepancies would likely lead to re-sequencing or further investigation to ascertain the true genotype.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done.
- This device is an automated genotyping system, not one that involves human "readers" interpreting output in a diagnostic setting in the way an imaging AI might. Its primary function is to accurately identify genetic variants. The "interpretive drug information" is a downstream output of the accurate genotyping, not something itself interpreted by multiple human readers in a study of this type.
6. Standalone Performance Study (Algorithm Only)
- Yes, the performance studies described (Method Comparison, Precision, Minimum DNA Input) are all standalone performance studies of the genotyping algorithm and associated laboratory process.
- The studies evaluate the accuracy and reliability of the device itself (the genotyping platform, reagents, and analysis software) in determining genetic variants, separate from how a human might interpret the final report.
7. Type of Ground Truth Used
- Expert Consensus (Genomic): The ground truth for the analytical performance studies was established using:
- Bi-directional Sanger Sequencing: A gold standard method for DNA sequencing, considered highly accurate for confirming specific genetic variants.
- Reference Samples from Coriell Institute for Medical Research: These are well-characterized genomic DNA samples with established and verified genotypes, essentially an expert-characterized reference.
8. Sample Size for the Training Set
- The document does not explicitly state a separate "training set" for the genotyping algorithm. Genetic genotyping algorithms often rely on established biochemical principles and mapping to known reference genomes rather than machine learning on a large, labeled training dataset of raw signals to call genotypes.
- However, the "23andMe database" is mentioned, with variant and allele frequencies from "8,004,302 customers" and "16,008,604 alleles." This massive dataset, along with public databases like gnomAD, would likely be used in the development and refinement of allele frequency estimation and potentially for algorithm fine-tuning or quality control, but not as a distinct "training set" in the typical AI sense for classifying novel inputs.
9. How the Ground Truth for the Training Set was Established
- Given that a distinct "training set" as understood in machine learning is not explicitly detailed, the ground truth establishment for algorithm development would implicitly rely on the same principles as the test set: established genetic sequencing methodologies (like Sanger sequencing) and comprehensive genetic reference databases (like the human reference genome and population-specific variant databases). These resources allow for the accurate mapping and identification of genetic variants within the raw genotyping data.
§ 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.