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: 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: SLCO1B1 Variant(s): c.521T>C (rs4149056)
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 inform discussions with a healthcare professional about metabolism of therapeutics.

The 23andMe Personal Genome Service pharmacogenetic reports for CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT 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 pharmacogenetics report 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.

23andMe Personal Genome Service pharmacogenetics report for SLCO1B1 describes if a person has variants associated with the processing of some therapeutics and provides interpretive drug information regarding the potential effect of the identified transport function phenotype on simvastatin 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.

Device Description

The 23andMe Personal Genome Service (PGS) is a direct-to-consumer/over-the-counter, 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. K182784. K193492. and K211499), 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 the metabolizer or transporter profile associated with the 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 transport function phenotype associated with the presence of a particular variant, or a combination of variants.

In the pharmacogenetic report for SLCO1B1. 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 SLCO1B1. 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.

As noted in Table 5.2, the PGS assay components for the SLCO1B1 Drug Transport report such as the custom beadchip, reagents, and instrumentation are the same as the predicate devices. No new reagents were needed and the beadchip was unchanged to test for the c.521T>C (rs4149056) variant. The probes to detect c.521T>C (rs4149056) already existed on the beadchip.

The novel components in this Traditional 510(k) submission are to provide interpretive drug information to one specific medication (simvastatin), and to remove the limitation language requiring confirmatory testing in the 23andMe pharmacogenetics report for SLCO1B1. Pharmacogenetic reports for other genes authorized in DEN180028 will not be modified to remove the confirmatory testing limitation, include interpretive drug information, or add a prescription indication.

Engineering drawings, schematics, etc. of the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports are not applicable to this device.

AI/ML Overview

The provided document, a 510(k) Summary for the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports (K221885), focuses on the modifications to the SLCO1B1 pharmacogenetic report. The primary changes are the addition of interpretive drug information for simvastatin and the removal of the confirmatory testing requirement for SLCO1B1. The summary details analytical performance studies conducted to support these changes.

Here's a breakdown of the requested information based on the provided document:

1. Table of acceptance criteria and the reported device performance

The document specifies acceptance criteria for analytical performance studies. These are primarily related to accuracy (method comparison) and precision (reproducibility) for the c.521T>C (rs4149056) variant in the SLCO1B1 gene.

Study Type	Acceptance Criteria	Reported Device Performance
Method Comparison (Accuracy)	>99% overall agreement (PPA and NPA both >99%) compared to bidirectional Sanger sequencing.	100% overall agreement for all genotypes of the c.521T>C (rs4149056) variant. PPA and NPA both >99% (specifically reported as 100% concordance).
Precision (Reproducibility)	Minimum of 99% correct genotype calls at each of two laboratory sites.	100% correct genotype calls for all samples across multiple days, operator teams, instruments, and reagent lots at 2 independent laboratory sites. The study also had >99% reproducibility and >99% repeatability.
Minimum DNA Input (MDI)	Passed acceptance criteria at a sample DNA concentration of 5 ng/µL.	100% concordant test results and correct genotype calls for all samples and all 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.

2. Sample size used for the test set and the data provenance

Test Set Sample Size: The document does not explicitly state a total numerical sample size for the method comparison and precision studies. It mentions that for the method comparison, samples were selected from 23andMe's database to enrich for prevalent variants in specific ethnicities, and allele and diplotype frequencies were used to inform the number of samples selected. For the precision study and MDI, "intended use (saliva) samples were selected from the 23andMe customer biobank based on their putative genotype" and "obtained for each of the c.521C>T genotype combinations." While specific numbers aren't given, the language suggests a controlled selection of samples representing relevant genotype combinations.
Data Provenance: The samples for performance testing were obtained from the "23andMe customer biobank." This suggests that the data is from real-world customer samples. The document does not specify the country of origin of these customers, but 23andMe is a US-based company, implying a significant US customer base. The data would be considered retrospective as it's from pre-existing biobank samples.

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 performance studies (method comparison, precision, MDI) was established using bidirectional Sanger sequencing, which is a widely accepted laboratory gold standard for genetic variant confirmation.
The document does not mention the use of human experts (like radiologists or genetic counselors) to establish the ground truth for these analytical performance tests, as the ground truth is a direct genetic sequencing result, not an interpretation of an image or a clinical diagnosis.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

Since the ground truth for the analytical performance studies was established by bidirectional Sanger sequencing, there was no human adjudication method employed for these specific tests. The comparison was directly between the device's genotyping result and the sequencing result.

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 MRMC comparative effectiveness study was performed or is relevant for this type of device. The 23andMe Personal Genome Service is a direct-to-consumer genetic testing product that provides raw genetic data and interpretive reports; it is not an AI-assisted diagnostic imaging tool or a system where human readers interpret data with or without AI assistance. The "human readers" in this context are the end-users (consumers) who read the reports, and their "improvement" is not measured in the traditional MRMC sense.
The document does mention "robust user comprehension testing, previously reviewed and authorized under DEN180028 and K193492," indicating that the readability and understanding of the reports by users were assessed. However, this is distinct from an MRMC study and the specific results of this comprehension testing (e.g., effect size) are not detailed in this 510(k) summary, only referenced as having been sufficient for prior clearances.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

Yes, standalone performance was evaluated. The method comparison, precision, and minimum DNA input studies directly assess the accuracy and reliability of the 23andMe BeadChip assay and its associated software (Genome Studio, Coregen) in determining genotypes, without direct human intervention or interpretation during the genotyping process itself. The reported performance (e.g., 100% agreement with Sanger sequencing) is the standalone performance of the genotyping system.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth used for the analytical performance studies (method comparison, precision, MDI) was bidirectional Sanger sequencing, which is a highly accurate and widely accepted method for determining the true genetic sequence/variant status.

8. The sample size for the training set

The document does not explicitly state the sample size for the training set for the device's algorithms. As the device involves a genotyping array and software for data analysis (Coregen), it's likely that a substantial amount of genetic data was used in the development and initial training/optimization of these systems. However, this 510(k) summary focuses on the validation of modifications to a previously cleared device rather than the initial development of the core genotyping platform.

9. How the ground truth for the training set was established

The document does not detail how the ground truth for the training set (if any specific to training was used for this modification) was established. For a genotyping platform like this, the "training" (or more accurately, the development and verification) would typically involve using samples with known genetic variations confirmed by gold-standard methods like Sanger sequencing or whole-genome sequencing. The 510(k) focuses on the validation of the current device's performance against a gold standard (Sanger sequencing).

Summary

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Image /page/0/Picture/0 description: The image shows the logo for the U.S. Food & Drug Administration (FDA). The logo consists of two parts: the Department of Health & Human Services seal on the left and the FDA acronym followed by the full name of the agency on the right. The FDA part of the logo is in blue, with the acronym in a solid blue square and the agency name in a lighter blue. The text reads "FDA U.S. FOOD & DRUG ADMINISTRATION".

October 26, 2022

23andMe, Inc. Marianna Frendo Manager Regulatory Affairs 349 Oyster Point Blvd South San Francisco, CA 94080

Re: K221885

Trade/Device Name: 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports Regulation Number: 21 CFR 862.3364 Regulation Name: Pharmacogenetic Assessment System Regulatory Class: Class II Product Code: QDJ Dated: June 27, 2022 Received: June 29, 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.

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

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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 quality systems (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-regulatoryassistance/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,

Paula Caposino, Ph.D. Acting Deputy Director Division of Chemistry and Toxicology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Ouality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K221885

Device Name

23andMe Personal Genome Service (PGS) Pharmacogenetic Reports

Indications for Use (Describe)

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: SLCO1B1 Variant(s): c.521T>C (rs4149056) 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 inform discussions with a healthcare professional about metabolism of therapeutics.

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Prescription Use (Part 21 CFR 801 Subpart D)

X Over-The-Counter Use (21 CFR 801 Subpart C)

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DO NOT SEND YOUR COMPLETED FORM TO THE PRA STAFF EMAIL ADDRESS BELOW.

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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: K221885

Submitter/Primary Contact

Marianna Frendo, Manager Regulatory Affairs 23andMe, Inc. 349 Oyster Point Blvd SSF, CA 94080 650-686-9288 mfrendo@23andme.com Establishment Registration Number: 3007699459 Owner Operator Number: 10029404

Alternative Contact

Nikki Arora, Sr. Manager, Regulatory Affairs 23andMe, Inc. 349 Oyster Point Blvd SSF, CA 94080 650-504-2406 nikkia@23andme.com

Date Prepared

26 October 2022

5.1. REGULATORY INFORMATION

Table 5.1 Proposed New Device

Type of Submission:	Traditional 510(k)
Common/Usual Name:	Pharmacogenetic reports for CYP2C19, CYP2C9, CYP3A5,UGT1A1, DPYD, TPMT, SLCO1B1, CYP2D6
Trade/proprietary Name:	23andMe Personal Genome Service (PGS) PharmacogeneticReports

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Regulation Description:	A pharmacogenetic assessment system is a qualitative in vitromolecular diagnostic system intended to detect nucleic acidvariants isolated from human specimens for the purpose ofassessing the presence of genetic variants that impact themetabolism, exposure, response, risk of adverse events,dosing, or mechanisms of prescription or over-the-countermedications. The intended use of the device must not includean indication for use in supporting or sustaining human life,being of substantial importance in preventing impairment ofhuman health, or presenting a potential, unreasonable risk ofillness or injury.
Regulation Number:	21 CFR 862.3364
Product Code:	QDJ
Class:	Class II
Predicate Device:	23andMe Pharmacogenetic Reports cleared on August 17,2020 under K193492

5.2. INTENDED USE

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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	c.521T>C (rs4149056)
CYP2D6	2, 3, 4, 5, 6, 7, 8, 9, 10,11, 15, 17, 20, 29, 35, 40,*41

5.3. INDICATIONS FOR USE

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 PGS Pharmacogenetic Reports are not a substitute for visits to a healthcare professional.

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The information provided by this report should not be used to start, stop, or change any course of treatment.

5.4. SUBSTANTIALLY EQUIVALENT PREDICATE DEVICE

The components of the PGS are unchanged from the 510(k) clearance for the predicate device, the PGS Pharmacogenetics Assessment System (K193492). 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) Pharmacogenetic Reports as follows: (1) Provide interpretive drug information for simvastatin, accessible through the pharmacogenetic report for SLCO1B1, and (2) Remove the requirement for confirmatory testing in the pharmacogenetic report for SLCO1B1.

Interpretive drug information will be provided to users in the pharmacogenetic report for SLCO1B1, and will be accessed through medication specific links in the pharmacogenetic report for SLCO1B1. Additionally, the pharmacogenetic report for SLCO1B1 will be modified to include a medication list containing drugs processed in part by the SLCO1B1 protein, including drugs listed in FDA's Table of Pharmacogenetic Associations for SLCO1B1. There will be no changes to the Pharmacogenetic reports for the other genes authorized in DEN180028 (CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, CYP2D6). These reports will not be modified to include interpretive drug information, a prescription indication will not be added, nor will the confirmatory testing limitation statement be removed.

The pharmacogenetic report for SLCO1B1 is intended for over-the-counter (OTC), direct-to consumer (DTC) use without prescription or physician order. In both the predicate device(s) and the proposed modified device, all customers are advised to share their results with their healthcare provider regardless of their results. Customers with altered function of the SLCO1B1 protein are strongly advised to share their results with their healthcare provider. The proposed revised labeling of the modified device includes certain healthcare provider limitations, as required. The Package Insert has been revised to incorporate information pursuant to agreements specific to this submission. Modifications proposed are to remove the confirmatory testing requirement for SLCO1B1, and to address the inclusion of the pharmacogenetic association information for SLCO1B1, consistent with the product classification under 21 CFR 862.3364. The proposed modifications are based on the additional test system performance data submitted in this Traditional 510(k).

Warnings, precautions, and limitations for CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, CYP2D6

Do not use your results to start, stop or change any course of treatment. .
. Results from this test should not be used to make medical decisions. Results should be confirmed by an independent genetic test prescribed by your

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own healthcare provider before taking any medical action.

This test does not provide information on associations between specific DNA variants and any specific therapeutic.
. This test does not diagnose any health conditions, predict drug response, provide medical advice, or determine whether a medication is indicated for the user.
This test does not determine if a person will or will not respond to a particular therapeutic.
This test does not detect all genetic variants related to drug metabolism. The absence of a variant tested does not rule out the presence of other genetic variants that may be related to drug metabolism.
This test is not a substitute for visits to a healthcare professional. You should consult ● with a healthcare professional if you have any questions or concerns about your results.
This test may not be able to determine a result for all variants analyzed.
. Different companies offering genetic testing may be measuring different genetic variants for drug metabolism, so you may get different results from a different test.
. As with every test the possibility for an incorrect result exists. Speak to your personal healthcare professional or a genetic counselor if your results are unexpected.

Warning, precautions, and limitations specific for CYP2C19 and SLCO1B1

Do not use your results to start, stop or change any course of treatment. ●
This test does not diagnose any health conditions, provide medical advice, or determine whether a medication is indicated for the user.
. This test provides interpretive drug information on citalopram and clopidogrel (CYP2C19) and simvastatin (SLCO1B1).
This test does not determine if a person will or will not respond to a particular therapeutic.
. This test does not detect all genetic variants related to drug metabolism. The absence of a variant tested does not rule out the presence of other genetic variants that may be related to drug metabolism.
This test is not a substitute for visits to a healthcare professional. You should consult with a healthcare professional if you have any questions or concerns about your results.
This test may not be able to determine a result for all variants analyzed.
. For CYP2C19 only: This test does not provide interpretive drug information for the CYP2C19 *3/*17 genotype or other CYP2C19 genotype combinations where the predicted metabolizer profile cannot be interpreted. In addition, results for these genotypes should be confirmed by an independent genetic test prescribed by your own healthcare provider before taking any medical action.
. Different companies offering genetic testing may be measuring different genetic variants for drug metabolism, so you may get different results from a different test.
. As with every test the possibility for an incorrect result exists. Speak to your personal healthcare professional or a genetic counselor if your results are unexpected.

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This submission proposes an intended use for the pharmacogenetics report for SLCO1B1 that does not introduce new concerns of safety and effectiveness and is supported by performance data collected for this purpose, or similar. As such, the modified 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports is substantially equivalent to the predicate device cleared under K193492.

5.5. DEVICE DESCRIPTION

The 23andMe Personal Genome Service (PGS) is a direct-to-consumer/over-the-counter, DNA testing service that provides information and tools for consumers to learn about and explore their DNA.

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Engineering drawings, schematics, etc. of the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports are not applicable to this device.

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: CYP2C19, CYP2C9, CYP3A5, UGT1A1, DPYD, TPMT, SLCO1B1, CYP2D6

Variants: *2, *3, *17 variants in the CYP2C19 gene, *2, *3, *6, rs7089580 in the CYP2C9 gene, *3 in the CYP3A5 gene, *6, *28 in the UGT1A1 gene, *2A, rs67376798 in the DPYD gene, *2, *3C in the TPMT gene, c.521T>C in the SLCO1B1 gene, *2, *3, *4, *5, *6, *7, *8, *9, *10, *11, *15, *17, *20, *29, *35, *40, *41 in the CYP2D6 gene

SNP: c.521T>C (rs4149056)

Genotyping principle: The DNA is fragmented and captured on a bead array by hybridization to immobilized SNP-specific primers, followed by extension with hapten-labeled nucleotides. The primers hybridize adiacent 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, and then integrated into predefined report templates specific for each condition associated with each genotype.

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Table 5.2 Substantial Equivalence

	PredicatePharmacogenetic ReportsK193492	Proposed modifiedindication for thepharmacogenetic reportfor SLCO1B1	SimilaritiesandDifferences
IntendedUse	The 23andMe PersonalGenome Service (PGS) is aqualitative genotypingassessment system appliedto genomic DNA isolatedfrom human saliva collectedusing the Oragene Dx OGD-500.001 to simultaneouslydetect, report, and interpretgenetic variants in a broadmultigene test. Theassessment system isintended to enable users toaccess information abouttheir genetics that could aiddiscussions with ahealthcare professional. The23andMe Personal GenomeService (PGS)Pharmacogenetic Reportsare indicated for thereporting of the followingvariants:Gene: CYP2C19Variant(s): 2, 3, 17Gene: CYP2C9Variant(s): 2, 3, 5, 6,rs7089580Gene: CYP3A5Variant(s): 3Gene: UGT1A1Variant(s): 6, 28Gene: DPYDVariant(s):*2A, rs67376798Gene: TPMT	The 23andMe PersonalGenome Service (PGS) is aqualitative genotypingassessment system appliedto genomic DNA isolatedfrom human saliva collectedusing the Oragene Dx OGD-500.001 to simultaneouslydetect, report, and interpretgenetic variants in a broadmultigene test. Theassessment system isintended to enable users toaccess information abouttheir genetics that could aiddiscussions with ahealthcare professional. The23andMe Personal GenomeService (PGS)Pharmacogenetic Reportsare indicated for thereporting of the followingvariants:Gene: CYP2C19Variant(s): 2, 3, 17Gene: CYP2C9Variant(s): 2, 3, 5, 6,rs7089580Gene: CYP3A5Variant(s): 3Gene: UGT1A1Variant(s): 6, 28Gene: DPYDVariant(s):*2A, rs67376798Gene: TPMT	No change tothe intendeduse.
	Variant(s): 2, 3CGene: SLCO1B1Variant(s): 5Gene: CYP2D6Variant(s): 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 15, 17,20, 29, 35, 40, 41	Variant(s): 2, 3CGene: SLCO1B1Variant(s): c.521T>C(rs4149056)Gene: CYP2D6Variant(s): 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 15, 17,20, 29, 35, 40, *41
Indicationsfor Use	The 23andMe PersonalGenome Servicepharmacogenetic reports forCYP2C9, CYP3A5,UGT1A1, DPYD, TPMT andCYP2D6 describe if aperson has variantsassociatedwith metabolism of sometherapeutics, but does notdescribe if a person will orwill not respond to aparticular therapeutic, anddoes not describe theassociation betweendetected variants and anyspecific therapeutic.23andMe Personal GenomeService pharmacogeneticsreport for CYP2C19describes if a person hasvariants associated withmetabolism of sometherapeutics and providesinterpretive drug informationregarding the potential effectof the identified metabolizerphenotype on citalopramand clopidogrel therapy.The 23andMe PGSPharmacogenetic Reportsare not a substitute for visitsto a healthcare professional.	The 23andMe PersonalGenome Servicepharmacogenetic reports forCYP2C9, CYP3A5,UGT1A1, DPYD, TPMT andCYP2D6 describe if aperson has variantsassociatedwith metabolism of sometherapeutics, but does notdescribe if a person will orwill not respond to aparticular therapeutic, anddoes not describe theassociation betweendetected variants and anyspecific therapeutic.23andMe Personal GenomeService pharmacogeneticsreport for CYP2C19describes if a person hasvariants associated withmetabolism of sometherapeutics and providesinterpretive drug informationregarding the potential effectof the identified metabolizerphenotype on citalopramand clopidogrel therapy.23andMe Personal GenomeService pharmacogeneticsreport for SLCO1B1describes if a person has	Addition of anew indicationforinterpretivedruginformationfor onespecificmedication(simvastatin)and removalof therequirementforconfirmatorytesting.New claimsare limited tothe SLCO1B1variant.
	The information provided bythis report should not beused to start, stop, orchange any course oftreatment.	variants associated with theprocessing of sometherapeutics and providesinterpretive drug informationregarding the potential effectof the identified transportfunction phenotype onsimvastatin therapy.The 23andMe PGSPharmacogenetic Reportsare not a substitute for visitsto a healthcare professional.The information provided bythis report should not beused to start, stop, orchange any course oftreatment.
CollectionKit	Oragene Dx® salivacollection device (OGD-500.001)K141410	Oragene.Dx® salivacollection device (OGD-500.001)K141410	Same
Reagents	Illumina Infinium HTS AssayReagents	Illumina Infinium HTS ExtraAssay Reagents	Same.
BeadChip	Illumina Global ScreeningArray customized for thePGS. The chip is designedto detect specific singlenucleotide polymorphisms(SNPs) as well as othergenetic variants; all markersrefer to specific positions inthe National Center forBiotechnology Information(NCBI) reference humangenome.	Illumina Global ScreeningArray customized for thePGS. The chip is designedto detect specific singlenucleotide polymorphisms(SNPs) as well as othergenetic variants; all markersrefer to specific positions inthe National Center forBiotechnology Information(NCBI) reference humangenome.	Same.
Beadpool	Customized for 23andMe	Customized for 23andMe	Same
Instruments	Tecan Evo	Tecan Evo	Same
	Illumina iScan	Illumina iScan
Software	Genome StudioCoregen	Genome StudioCoregen	Same
SampleMatrix	Saliva	Saliva	Same
MethodComparison	>99% PPA and NPA for allgenotypes	>99% PPA and NPA for allgenotypes	Same

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5.7. PERFORMANCE TESTING SUMMARY

The purpose of this submission is to modify the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports as follows:

1. Provide interpretive drug information for simvastatin, accessible through the pharmacogenetic report for SLCO1B1
1. Remove the requirement for confirmatory testing in the pharmacogenetic report for SLCO1B1

In addition to the analytical requirements outlined in DEN180028, the Company generated additional data (K193492), and performed an additional blinded method comparison study to assess the performance of the 23andMe Personal Genome Service (PGS) pharmacogenetic report for SLCO1B1, in support of the removal of the confirmatory testing requirement and 510(k) clearance.

5.7.1 Method Comparison (Accuracy)

23andMe performed a method comparison study using bidirectional Sanger sequencing as the comparator to assess the accuracy of the assay. Results of the test were compared with sequencing results for samples with known c.521T>C (rs4149056) variant status. The method comparison study yielded 100% overall agreement for all genotypes of the c.521T>C (rs4149056) variant in the SLCO1B1 gene for all samples compared to Sanger sequencing. Therefore, the study passed the acceptance criteria of >99% agreement, with PPA and NPA both >99%. The method comparison study showed that the assay is comparable to bidirectional Sanger sequencing for the c.521T>C (rs4149056) variant in the SLCO1B1 gene.

To mitigate the risk for false positive/negative results potentially influenced by selecting samples with genotypes previously determined by the PGS, a study was performed utilizing a blinded sampling selection from 23andMe's database. For variants prevalent in specific ethnicities, samples consisting of those genetic ancestries were randomly selected from the database to

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enrich the sample selection pool. Allele and diplotype frequencies for each genotype were used to inform the number of samples selected for this study.

Upon completion of genotyping, results were compared to sequencing results to calculate positive percent agreement (PPA) and negative percent agreement (NPA), with the bidirectional Sanger sequencing results considered as the source of truth.

The genotyping data demonstrated 100% concordance to the comparator source of truth, achieving the pre-defined acceptance criteria of greater than 99% PPA and greater than 90% NPA for each sample.

5.7.2 Precision (Reproducibility)

23andMe performed a precision study to evaluate the following precision parameters of the assay: intra-assay, operator-to-operator, instrument-to-instrument, and reagent lot-to-lot for the c.521T>C (rs4149056) variant in the SLCO1B1 gene. In order to ensure that the assay accurately reflected the reproducibility of intended use (saliva) samples, intended use (saliva) samples were selected from the 23andMe customer biobank based on their putative genotype. Per the Agency's recommendation intended use (saliva) samples were obtained for each of the c.521C>T genotype combinations used to report results used to make clinical interpretations. These samples were genotyped by the 23andMe BeadChip assay in a blinded fashion over 3 days, with 3 lots of reagents, by a unique operator team per day, using 3 different serial numbers of each of 2 instruments (Tecan and iScan), at each of 2 laboratory sites. To confirm the BeadChip genotype, each sample was also sequenced by bi-directional Sanger sequencing. BeadChip genotypes were compared with sequenced genotypes to determine the rates of correct BeadChip genotype calls. The acceptance criteria is 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 determine the lowest concentration of DNA that is necessary for successful assignment of the correct genotypes for the c.521T>C (rs4149056) variant in the SLCO1B1 gene. In order to ensure that the assay accurately reflected the performance of intended use (saliva) samples, intended use (saliva) samples were selected from the 23andMe customer biobank based on their putative genotype. Per the Agency's recommendation intended use (saliva) samples were obtained for each of the c.521C>T genotype combinations used to report results used to make clinical interpretations. These DNA samples

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were diluted to 3 different DNA concentrations using 3 lots of reagents. Results of this MDI study yielded 100% concordant test results, and correct genotype calls for all samples and all 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.

5.7.4 Shelf life

The PGS uses the same FDA-cleared collection device and reagents that have been previously reviewed and authorized in K141410 and DEN140044.

Table 5.3 Clinical Performance

Allele frequencies from 23andMe database and Genome Aggregation Database (gnomAD)

Allele frequencies from gnomAD database were obtained from https://gnomad.broadinstitute.org/ on 24May2022.

	c.521T>C (rs4149056:C)
AncestryGroup	Percent of 23andMecustomers withvarianta(n = 8,005,896customers)	Allele frequenciesamong 23andMecustomersa(n = 16,011,792alleles)	Allele frequencies fromgnomADb(n = 282,308 alleles)
European	29.39%	15.99%	15.89%(European, non-Finnish)
AfricanAmerican	10.06%	5.21%	2.98%
AshkenaziJewish	33.33%	18.37%	17.97%
East Asian	23.56%	12.59%	12.54%
Hispanic /Latino	25.29%	13.61%	11.21%
South Asian	9.66%	5.00%	5.05%

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Middle Eastern	32.10%	17.75%	not included
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ªSmall changes to observed allele and variant frequencies are expected to occur as the database grows. Frequencies are truncated at a minimum frequency if the number of carriers is fewer than 5.

5.8. DISCUSSION

This Traditional 510(k) submission is to modify the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports as follows: (1) Provide interpretive drug information for simvastatin, accessible through the pharmacogenetic report for SLCO1B1. and (2) Remove the confirmatory testing requirement in the pharmacogenetic report for SLCO1B1. The analytical and clinical data demonstrates that 23andMe's BeadChip assay generates accurate results specific to the SLCO1B1 variant reported in its results. The 23andMe Personal Genome Service (PGS) Pharmacogenetic reports, pharmacogenetic report for SLCO1B1 is not technologically different nor does it introduce any new concerns of safety or effectiveness when compared to the previously authorized predicate device (K193492).

It was shown through robust user comprehension testing, previously reviewed and authorized under DEN180028 and K193492, that the user can adequately interpret the results for the c.521T>C (rs4149056) variant, as well as understand interpretive drug information as presented in the pharmacogenetic report for SLCO1B1.

5.9. CONCLUSION

The modifications to the 23andMe Personal Genome Service (PGS) Pharmacogenetic Reports are substantially equivalent to the predicate device (K193492). As presented, the modified pharmacogenetic report for SLCO1B1, without the confirmatory testing requirement, is a safe and effective consumer product that can safely and effectively assist customers with certain SLCO1B1 genotypes in understanding how their body may respond to certain medications and encourage informed conversations with their healthcare provider.

Regulation Number and Section

§ 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.