The AlphaID™ At Home Genetic Health Risk Service uses qualitative genotyping to detect clinically relevant genetic variants associated with alpha-1 antitrypsin deficiency (AATD) in genomic DNA isolated from human saliva collected from individuals ≥ 18 years with ORAcollect Dx OCD-100.014 for the purpose of reporting and interpreting Genetic Health Risks (GHR).

This Service is indicated for reporting 14 genetic variants in the SERPINA1 gene: PIS; PIM procida; PIM malton; PIS iiyama; PIQ0 granite falls; PIQ0 west; PIQ0 bellingham; PIF; PIQ0 mattawa; PIQ0 clayton, and PI*M heerlen. The report describes if a person is at an increased risk of developing either liver disease linked to AATD. The report does not describe a person's overall risk of developing lung and/or liver disease. AATD is more common in persons of European descent.

Device Description

The AlphaID™ At Home Genetic Health Risk Service (AlphaID At Home) uses qualitative genotyping to detect clinically relevant genetic variants associated with alphal-antitrypsin deficiency (AATD) and provides a report describing if a person is at risk of developing either lung and/or liver disease linked to AATD. This Service is direct-to-consumer and intended for an Over-the Counter (OTC) use.

The AlphaID™ At Home Genetic Health Risk Service is composed by AlphaID™ At Home Saliva Collection kit for human saliva sample collection (ORAcollect®·Dx OCD-100.014), A1AT Genotyping Test for the genetic analysis and detection of genetic variants associated with alpha-1 antitrypsin deficiency (AATD), and AlphaID™ At Home Genetic Health Risk Service website and result portal software to provide the contents and the procedure to order and use the over the counter (OTC) Service.

A consumer's saliva is self-collected using custom version ORAcollect Dx (model OCD-100.014) device manufactured by DNA Genotek, Inc (See K212745) which consists of collection tube containing a stabilizing buffer solution. Once the sample is collected, it is shipped to Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory for processing.

Human DNA from the saliva sample is isolated and processed with the A1AT Genotyping Test device (K211115) that provides results on 14 genetic variants in the SERPINA / gene: PIS; PIZ; PIM procida; PIM malton; PIS iiyama; PIO0 granite falls: PIO0 west: PIO0 bellingham: PIF; PIP lowell; PIO0 mattawa; PIQ0 clayton, and PI*M heerlen.

Briefly, genomic DNA extracted from human saliva is amplified and biotinylated by multiplex PCR and PCR products are denatured and hybridized to oligonucleotide probes coupled to color-coded beads. Hybridized DNA is labeled with a fluorescent conjugate and the resulting signal is detected with a Luminex® 200™ system. Raw fluorescence data is processed with the A1AT Genotyping Test ANALYSIS SOFTWARE to provide allelic variant genotypes, which are subsequently converted into associated alleles, based on current scientific evidence. Additionally, the software application also provides the type of Genetic Health Risk Report associated with the identified alleles, which is subsequently used as the basis for the generation of personalized reports by the AlphaID™ At Home Genetic Health Risk Service website and result portal.

Depending on the specific variant combination detected, the AlphaID™ At Home Genetic Health Risk Service provides the individuals' genetic health risk for developing lung and liver disease linked to AATD. Personalized reports, in an easy-to-understand format are generated for each consumer that provide results of the testing performed.

AI/ML Overview

Here's a breakdown of the acceptance criteria and study information for the AlphaID™ At Home Genetic Health Risk Service, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

Performance Metric	Acceptance Criteria (Explicit or Implied)	Reported Device Performance
Analytical Performance
Reproducibility/Precision (CLIA Lab)	Concordance ≥ 99%, "Invalid Tests" ≤ 2% (between Progenika and Matrix Clinical Labs for OTC samples)	Concordance between A1AT Genotyping Test results obtained in Matrix Clinical Labs and Progenika was 100% per reported variant and overall. No "Invalid Tests" results were observed at Matrix Clinical Labs.
Method Comparison with Predicate	Overall agreement with Bi-Directional-Sequencing (BDS) for all variants and samples. Implicitly, high agreement is desired for substantial equivalence.	Overall agreement for 14 variants was 100% (227/227) with bi-directional sequencing, with a 95% confidence interval of 98.3% to 100%. The percentage of overall "Invalid Tests" was 0% (0/227) with a 95% confidence interval of 0% to 1.7%.
Analytical Sensitivity (LoD)	Minimum DNA concentration for performance. (Predicate: 15-50 ng/µl)	Minimum of 0.0215 ng/µl DNA. (The document notes this as a difference from the predicate, but it is the device's stated performance requirement).
Interfering Substances	No impact on test performance.	Endogenous (salivary a-amylase, hemoglobin, IgA, total protein) and exogenous (eating food without beef, eating food with beef, drinking, smoking, chewing gum, mouth washing, brushing teeth) interfering substances had no impact on test performance (at 30-minute timepoint for exogenous). Microbial (S. epidermis, S. mutans, L. casei, A. viscosus, C. albicans) had no impact.
Clinical Performance
Clinical Performance (Risk Categories)	Risk categorization for lung and liver disease linked to AATD based on reported clinical cases: - Increased risk: >80% development. - Slightly at Increased risk: 20-80% development. - Not likely at increased risk: <20% development. - Unknown risk: due to lack of data. (These are the defined categories the device uses to interpret and report results.)	The device uses these four categories to define risk for developing lung and liver disease linked to AATD based on the specific variant combination detected. The categories themselves are the interpretation framework. The clinical performance is supported by existing published data/references for each genetic result, rather than a de novo clinical study generating these percentages.
User Comprehension	Minimum of 90.1% comprehension score in the first step and 94.0% in the second step, across all reports and comprehension domains.	Achieved 90.1% or higher in the first step and 94.0% or higher in the second step across all reports. Overall comprehension scores were 92.7% (first step) and 96.8% (second step).
Sample Processability	Probability of lab being unable to process a sample up to 0.5%.	The study did not directly measure this, but the stated probability is a special condition for use. The reproducibility study had 0% invalid results, which implies good processability for the tested samples.

2. Sample Size Used for the Test Set and Data Provenance

Analytical Performance (Method Comparison with Bi-Directional Sequencing):
- Sample Size: 227 samples
- Data Provenance: Saliva samples collected in ORAcollect·Dx OCD-100.014. The document does not explicitly state the country of origin or if they were retrospectively collected or prospectively collected. However, the study "assessed the accuracy of A1AT Genotyping Test to correctly detect the genetic variants," suggesting these were samples with known or established variant status used for validation.
Analytical Performance (CLIA-Certified Laboratory Verification Study):
- Sample Size: 110 samples
- Data Provenance: Saliva samples collected with AlphaID™ At Home Saliva Collection kit in an over-the-counter (OTC) environment. The document implies these were collected for the purpose of this study. No country of origin is explicitly stated.
User Comprehension Study:
- Sample Size: 525 participants (after exclusion)
- Data Provenance: A demographically diverse US population of naïve users. These were prospectively recruited for the study.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

Analytical Performance (Method Comparison):
- Ground Truth Method: Bi-Directional-Sequencing (BDS) was used as the reference method. This is a molecular gold standard technique.
- Experts: The document does not specify the number or qualifications of experts involved in performing or interpreting the Bi-Directional-Sequencing. This method is typically performed by trained laboratory personnel.
Clinical Performance (Risk Categorization):
- Ground Truth Method: The risk categorization is based on "reported clinical cases (published references) for each genetic result."
- Experts: No specific number or qualifications of experts are cited for establishing the ground truth directly for this study. Instead, the study relies on the collective scientific and medical consensus embedded in published literature.

4. Adjudication Method for the Test Set

Not applicable as there is no mention of human adjudication in the context of establishing ground truth for the analytical and clinical performance studies described. The analytical studies primarily compared the device's results to a technical gold standard (Bi-Directional Sequencing).

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was Done

No, an MRMC comparative effectiveness study was not done. The performance studies focused on the accuracy of the device itself and user comprehension of its reports, not on how human readers' performance improves with or without AI assistance. The device is a direct-to-consumer genetic health risk service, not an AI-assisted diagnostic tool for medical professionals.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was Done

Yes, performance studies were conducted in a standalone manner for the device's genotyping capabilities.
- The "Method Comparison with Predicate" study directly compares the device's genetic variant detection to Bi-Directional Sequencing.
- The "CLIA-Certified Laboratory Verification Study" confirms the analytical procedure's performance by the designated lab using the A1AT Genotyping Test.
- The "A1AT Genotyping Test ANALYSIS SOFTWARE" processes raw data to provide allelic variant genotypes and associated GHR, indicating an algorithmic, standalone component.
- The service as a whole includes human components (sample collection, lab processing), but the core genetic analysis and risk interpretation by the software/algorithm is evaluated independently against established methods.

7. The Type of Ground Truth Used

Analytical Ground Truth: Bi-Directional-Sequencing (BDS) was used as the reference method for confirming genetic variants. This is a scientific gold standard for DNA sequencing.
Clinical Ground Truth: "Reported clinical cases (published references)" were used to establish the risk categorization associated with various genetic results. This represents expert consensus and outcomes data derived from scientific literature.

8. The Sample Size for the Training Set

The document does not provide information on the sample size used for the training set. Given that the device performs qualitative genotyping for known genetic variants, it is likely that the "training" (or development/optimization) process would have involved samples with known genotypes for these specific variants, but no specific dataset or size is listed. The analytical performance studies serve as a validation of the device against a reference method rather than demonstrating the learning process of an AI model on a training set.

9. How the Ground Truth for the Training Set Was Established

This information is not provided in the document. For genetic variant detection, ground truth for development/training samples would typically be established using established molecular methods such as Sanger sequencing (Bi-Directional Sequencing, as used in the validation) or other validated genotyping techniques at the time of the assay's development.

Summary

{0}------------------------------------------------

Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

October 27, 2022

Progenika Biopharma S.A., a Grifols company Diego Tejedor Technical Director Ibaizabal bidea, Edificio 504, Parque Tecnológico de Bizkaia Derio. Bizkaia 48160 Spain

Re: K221420

Trade/Device Name: AlphaID At Home Genetic Health Risk Service Regulation Number: 21 CFR 866.5950 Regulation Name: Genetic health risk assessment system Regulatory Class: Class II Product Code: PTA Dated: September 30, 2022 Received: October 6, 2022

Dear Diego Tejedor:

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

{1}------------------------------------------------

statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the 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 medical devices and radiation-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,

Ying Mao, Ph.D. Chief Division of Immunology and Hematology Devices OHT7: Office of In Vitro Diagnostics Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

{2}------------------------------------------------

Indications for Use

510(k) Number (if known) K221420

Device Name

AlphaID™ At Home Genetic Health Risk Service

Indications for Use (Describe)

This Service is indicated for reporting 14 genetic variants in the SERPINA1 gene: PIS; PIM procida; PIM malton; PIS iyama; PIQ0 granite falls; PIQ0 west; PIQ0 bellingham; PIF; PIQ0 mattawa; PIQ0 clayton, and PI*M heerlen. The report describes if a person is at an increased risk of developing either liver disease linked to AATD. The report does not describe a person's overall risk of developing lung and/or liver disease. AATD is more common in persons of European descent.

Special conditions for use statements:

a. For over-the-counter (OTC) use.

b. The test is intended for users ≥18 years old.

c. The test is not a substitute for an appointment with a healthcare professional. It is recommended that the user consults with a healthcare professional if the user has any questions or concerns about his/her results.

d. The test does not diagnose a disease or condition, determine medical intervention, or tell the user anything about their current state of healthcare professional can diagnose a disease or condition. e. Any diagnostic or treatment decisions must be based on confirmatory prescription testing and/or other information that a healthcare professional determines to be appropriate for the patient, such as additional clinical testing and other risk factors that may affect individual risk and health care.

f. The test detects 14 variants in the SERPINA1 gene linked to AATD. These 14 variants explain 95% of AATD cases. The absence of a variant tested does not rule out the genetic variants that may be disease-related.

g. The test does not describe a person's overall risk of developing AATD. In addition, other genetic and all non-genetic factors should be considered

h. The laboratory may be unable to process every user's sample. The probability that the laboratory cannot process a sample can be up to 0.5%. If this happens. the user will receive an email notification. The user will also receive another AlphaIDTM At Home Saliva Collection Kit to provide a new sample to the laboratory.

i. The user's race, ethnicity, age and sex may affect how the genetic results are interpreted.

i. Subject to meeting limitations contained in the special controls under the regulation 21 CFR 866.5950.

Type of Use (Select one or both, as applicable)

Prescription Use (Part 21 CFR 801 Subpart D)

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

CONTINUE ON A SEPARATE PAGE IF NEEDED.

{3}------------------------------------------------

This section applies only to requirements of the Paperwork Reduction Act of 1995.

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

The burden time for this collection of information is estimated to average 79 hours per response, including the time to review instructions, search existing data sources, gather and maintain the data needed and complete and review the collection of information. Send comments regarding this burden estimate or any other aspect of this information collection, including suggestions for reducing this burden, to:

Department of Health and Human Services Food and Drug Administration Office of Chief Information Officer Paperwork Reduction Act (PRA) Staff PRAStaff@fda.hhs.gov

"An agency may not conduct or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB number."

{4}------------------------------------------------

Progenika Biopharma, S.A

510(K) SUMMARY

A. GENERAL INFORMATION

Submission Date: May 6, 2022 Submitter Information: Submitted By: Progenika Biopharma S.A. Parque Tecnológico de Bizkaia Ibaizabal bidea, Edificio 504 C.P. 48160, Derio - Bizkaia (Spain) Telephone number: +34 94 406 45 25 Fax number: +34 94 406 45 26 Contact Person:

Diego Tejedor Technical Director, Progenika Biopharma S.A. diego.tejedor@grifols.com

B. PURPOSE FOR SUBMISSION

To obtain a substantial equivalence determination for AlphaID™ At Home Genetic Health Risk Service

C. MEASURAND

14 genetic variants in the SERPINA1 gene: PIS; PII; PII; PIM procida; PIM malton; PIS iiyama; PIQ0 granite falls; PIQ0 bellingham; PIF; PIP lowell; PIQ0 mattawa; PIQ0 clayton, and PI*M heerlen.

D. TYPE OF TEST

Qualitative in vitro molecular diagnostic system.

E. APPLICANT

Progenika Biopharma S.A.

{5}------------------------------------------------

Progenika Biopharma, S.A.

Ibaizabal bidea, Edificio 504
Parque Tecnológico de Bizkaia
48160 Derio - Bizkaia - SPAIN
Phone: +34 94 406 45 25
Fax: +34 94 406 45 26
CIF: ESA95091799
www.progenika.com - www.grifols.com

F. PROPRIETARY AND ESTABLISHED NAMES

AlphaID™ At Home Genetic Health Risk Service.

G. REGULATORY INFORMATION

Trade Name:	AlphaIDTM At Home Genetic Health Risk Service
Classification:	Class II (Special Controls)
Regulation:	21 CFR 866.5950
Regulation Name:	Genetic Health Risk Assessment System
Product Code:	PTA
Panel:	Immunology

H. INTENDED USE

See Indications for Use below.

I. INDICATIONS FOR USE

1. Indications for Use:

The AlphaID™ At Home Genetic Health Risk Service uses qualitative genotyping to detect clinically relevant genetic variants associated with alpha-1 antitrypsin deficiency (AATD) in genomic DNA isolated from human saliva collected from individuals ≥ 18 years with ORAcollect·Dx OCD-100.014 for the purpose of reporting and interpreting Genetic Health Risks (GHR).

This Service is indicated for reporting 14 genetic variants in the SERPINA1 gene: PIS; PIZ; PII; PIM procida; PIM malton; PIS iiyama; PIQ0 granite falls; PIQ0 west; PIQ0 bellingham; PIF; PIP lowell; PIQ0 mattawa; PIQ0 clayton, and PIM heerlen. The report describes if a person is at an increased risk of developing either lung and/or liver disease linked to AATD. The report does not describe a person's overall risk of developing lung and/or liver disease. AATD is more common in persons of European descent.

2. Special Conditions for Use Statements:

a. For over-the-counter (OTC) use.
b. The test is intended for users >18 years old.
c. The test is not a substitute for an appointment with a healthcare professional. It is recommended that the user consults with a healthcare professional if the user has any questions or concerns about his/her results.
d. The test does not diagnose a disease or condition, determine medical

{6}------------------------------------------------

treatment or other medical intervention, or tell the user anything about their current state of health. Only a healthcare professional can diagnose a disease or condition.

e. Any diagnostic or treatment decisions must be based on confirmatory prescription testing and/or other information that a healthcare professional determines to be appropriate for the patient, such as additional clinical testing and other risk factors that may affect individual risk and health care.
f. The test detects 14 variants in the SERPINA1 gene linked to AATD. These 14 variants explain 95% of AATD cases. The absence of a variant tested does not rule out the presence of other genetic variants that may be disease-related.
g. The test does not describe a person's overall risk of developing AATD. In addition, other genetic and all non-genetic factors should be considered
h. The laboratory may be unable to process every user's sample. The probability that the laboratory cannot process a sample can be up to 0.5%. If this happens, the user will receive an email notification. The user will also receive another AlphaID™ At Home Saliva Collection Kit to provide a new sample to the laboratory.
i. The user's race, ethnicity, age and sex may affect how the genetic results are interpreted.
j. Subject to meeting limitations contained in the special controls under the regulation 21 CFR 866.5950

3. Special Instrument Requirements:

The A1AT Genotyping Test Kit used for detection and identification of 14 allelic variants and their associated alleles found in the A1AT codifying gene SERPINAl is to be used with the Luminex 200TM instrument (with xPONENT® software).

Raw data from the Luminex System (csv. files containing the MFI value for each bead type) is processed with the A1AT Genotyping Test ANALYSIS SOFTWARE to provide allelic variant genotypes, which are subsequently converted into associated alleles, based on current scientific evidence. Additionally, the software application also provides the type of Genetic Health Risk Report associated with the identified alleles, which is subsequently used as the basis for the generation of personalized reports by the AlphaID™ At Home Genetic Health Risk Service website and result portal (AlphaID System).

{7}------------------------------------------------

Progenika Biopharma, S.A. Ibaizabal bidea. Edificio 504 60 Derio - Bizkaia - SPAIN w.progenika.com - www.grifols.com

J. DEVICE DESCRIPTION

Depending on the specific variant combination detected, the AlphaID™ At Home

{8}------------------------------------------------

Progenika Biopharma, S.A. abal bidea. Edificio 504 www.progenika.com - www.grifols.com

Genetic Health Risk Service provides the individuals' genetic health risk for developing lung and liver disease linked to AATD. Personalized reports, in an easy-to-understand format are generated for each consumer that provide results of the testing performed.

K. SUBSTANTIAL EQUIVALENCE INFORMATION

1. Predicate device name(s): 23andMe Personal Genome Service (PGS) Genetic Health Risk Test (Alpha-1 Antitrypsin Deficiency)
1. Predicate 510(k) number(s): DEN160026

{9}------------------------------------------------

Progenika Biopharma, S.A.

lbaizabal bidea, Edificio 504
Parque Tecnológico de Bizkaia
481600 Derio Bico de Bizkaia
Farque Derio Bickore de Bizkaia
Fax: 334 994 941 406 48 25 25 25 25
Bilb Frans 94 406 CIF: ESA95091799 www.progenika.com - www.grifols.com

3. Comparison with predicate:

Table 1: Predicate Device Comparison

Item	Predicate Device:23andMe Personal Genome Service (PGS) for A1AT(DEN160026/DEN140044)	Candidate Device:AlphaID At Home Genetic Health Risk Service
SIMILARITIES
Intended use	The 23andMe Personal Genome Service (PGS) Test usesqualitative genotyping to detect the following clinically relevantvariants in genomic DNA isolated from human saliva collected fromindividuals ≥18 years with the Oragene Dx model OGD-500.001 forthe purpose of reporting and interpreting Genetic Health Risks(GHR):The 23andMe PGS Genetic Health Risk Report for Alpha-1Antitrypsin Deficiency is indicated for reporting of the PIZ and PISvariants in the SERPINA1 gene. This report describes if a personhas variants associated with AAT deficiency and a higher risk forlung or liver disease, but it does not describe a person's overall riskof developing lung or liver disease. This test is most relevant forpeople of European descent.	The AlphaID™ At Home Genetic Health Risk Service usesqualitative genotyping to detect clinically relevant genetic variantsassociated with alpha-1 antitrypsin deficiency (AATD) in genomicDNA isolated from human saliva collected from individuals ≥ 18years with ORAcollect·Dx OCD-100.014 for the purpose of reportingand interpreting Genetic Health Risks (GHR).This Service is indicated for reporting 14 genetic variants in theSERPINA1 gene: PIS; PIZ; PII; PIM procida; PIM malton; PISiiyama; PIQ0 granite falls; PIQ0 west; PIQ0 bellingham; PIF;PIP lowell; PIQ0 mattawa; PIQ0 clayton, and PIM heerlen. Thereport describes if a person is at an increased risk of developingeither lung and/or liver disease linked to AATD. The Service doesnot describe a person's overall risk of developing lung and/or liverdisease. AATD is more common in persons of European descent.
Item	Predicate Device:23andMe Personal Genome Service (PGS) for A1AT(DEN160026/DEN140044)	Candidate Device:AlphaID At Home Genetic Health Risk Service
Special Conditions for UseStatements	a. For over-the-counter (OTC) use.b. This test is not a substitute for visits to a healthcare provider. It isrecommended that you consult with a healthcare provider if youhave any questions or concerns about your results.c. The 23andMe PGS Genetic Health Risk Tests for HereditaryThrombophilia, Alpha-1 Antitrypsin Deficiency, Alzheimer's disease,Parkinson's disease, Gaucher Disease,Factor XI Deficiency, Celiac disease, and Glucose-6-Phosphate-Dehydrogenase Deficiency, Early-Onset Primary Dystonia andHereditary Hemochromatosis do not detect all genetic variantsassociated with the aforementioned diseases. The absence of avariant tested does not rule out the presence of other geneticvariants that may be disease-related.d. The test is intended for users ≥ 18 years old.e. The test does not diagnose any specific health conditions.Results should not be used to make medical decisions.f. The laboratory may not be able to process a user's sample. Theprobability that the laboratory cannot process a sample can be up to7.6%.g. A user's race, ethnicity, age, and sex may affect how the genetictest results are interpreted.h. Subject to meeting the limitations contained in the specialcontrols under regulation 21 CFR 866.5950.	a. For over-the-counter (OTC) use.b. The test is intended for users ≥18 years old.c. The test is not a substitute for an appointment with ahealthcare professional. It is recommended that the userconsults with a healthcare professional if the user has anyquestions or concerns about his/her results.d. The test does not diagnose a disease or condition,determine medical treatment or other medical intervention, ortell the user anything about their current state of health. Only ahealthcare professional can diagnose a disease or condition.e. Any diagnostic or treatment decisions must be based onconfirmatory prescription testing and/or other information that ahealthcare professional determines to be appropriate for thepatient, such as additional clinical testing and other risk factorsthat may affect individual risk and health care.f. The test detects 14 variants in the SERPINA1 gene linkedto AATD. These 14 variants explain 95% of AATD cases. Theabsence of a variant tested does not rule out the presence ofother genetic variants that may be disease-related.g. The test does not describe a person's overall risk ofdeveloping AATD. In addition, other genetic and all non-genetic factors should be consideredh. The laboratory may be unable to process every user'ssample. The probability that the laboratory cannot process asample can be up to 0.5%. If this happens, the user willreceive an email notification. The user will also receive anotherAlphaID™ At Home Saliva Collection Kit to provide a newsample to the laboratory.i. The user's race, ethnicity, age and sex may affect how thegenetic results are interpreted.j. Subject to meeting limitations contained in the specialcontrols under the regulation 21 CFR 866.5950.
ltem	Predicate Device:23andMe Personal Genome Service (PGS) for A1AT(DEN160026/DEN140044)	Candidate Device:AlphalD At Home Genetic Health Risk Service
Indications for use	This report describes if a person has variants associated with A1ATdeficiency and a higher risk for lung or liver disease, but it does notdescribe a person's overall risk of developing lung or liver disease	Same
Intended use population	Any individual ≥18 years	Same
Classification	Class II	Same
Type of Test	Qualitative in vitro molecular diagnostic system	Same
Measurand	Detection and identification of PIZ (rs28929474) and PIS(rs17580) variants in the SERPINA1 gene.	Same but 12 additional allelic variants in the SERPINA1 gene (PII;PIM procida; PIM malton; PIS iiyama; PIQ0 granite falls; PIQ0west; PIQ0 bellingham; PIF; PIP lowell; PIQ0 mattawa; PIQ0clayton, PIM heerlen).
Specimen Type	Genomic DNA extracted from human saliva samples	Same
Sample Preparation Method	DNA extraction	Same
Comparison with Sanger Bi-directional Sequencing	Overall agreement was 100% (PZ:207/207; PS: 202/202) with bi-directional sequencing.	Same. Overall agreement for 14 variants was 100%(227/227) with bi-directional sequencing.
Reproducibility/Precision	Reproducibility for CLIA-labs (included in DEN140044 PGS test forBloom syndrome): two labs, 105 saliva samples (collected using theOGD-500.001), QC failure rates:First run: site 1: 1/105 (1%); site 2: 18/105 (17.1%)).First run retested: site 1: 0/105 (0%); site 2: 8/105 (7.6%).	Reproducibility for CLIA-lab: one lab (Matrix Clinical Labs) andmanufacturer, 110 saliva samples (collected using the OCD-100.014), Failure rate: site 1: 0/110 (0%); site 2: 0/110 (0%).
Item	Predicate Device:23andMe Personal Genome Service (PGS) for A1AT(DEN160026/DEN140044)	Candidate Device:AlphalD At Home Genetic Health Risk Service
User Comprehension Study	User Comprehension Study: 104 participants (for A1AT arm, afterexclusion), 1 report (2 variants detected; notat risk),comprehension concepts (Results, Purpose, Meaning of Results,Limitations, Inheritance, Follow-up), comprehension rate perdomain (89.4 – 94.2%).	User Comprehension Study: 525 participants (after exclusion), 5reports (covering the concepts of number of variants (0, 1, 2 andvariant not determined) and the 4 risk categories), at least 100participants per report type, comprehension concepts (Results,Purpose, Limitations, Ethnicity, Other factors, NextSteps),comprehension rate per domain (94% - 99.5%).
Endogenous InterferingSubstances	From 23andMe Personal Genome Service Carrier Screening Testfor Bloom Syndrome (DEN140044): N = 4 endogenous agents weretested in saliva: salivary a-amylase, hemoglobin, IgA, and totalprotein. There was no impact on test performance with allinterferents tested.	N=4 endogenous agents were tested in saliva: salivary a-amylase,hemoglobin; IgA and total protein. There was no impact on testperformance with all interferents tested.
Exogenous InterferingSubstances	From 23andMe Personal Genome Service Carrier Screening Testfor Bloom Syndrome (DEN140044): N = 6 exogenous agents weretested in saliva samples collected after performing the followingactions: eating food containing beef, eating food not containingbeef, drinking alcohol, chewing gum, using mouthwash, andsmoking.There was no impact on test performance at the 30 minutetimepoint with all interferents tested.	N=7 exogenous agents were tested in saliva samples collected afterperforming the following actions: eating food without beef, eatingfood with beef, drinking, smoking, chewing gum, mouth washing andbrushing teeth.There was no impact on test performance at the 30 minute timepointwith all interferents tested.
Microbial InterferingSubstances	From 23andMe Personal Genome Service Carrier Screening Testfor Bloom Syndrome (DEN140044): N = 5 microbial agents weretested in saliva: Staphylococcus epidermis, Streptococcus mutans,Lactobacillus casei, A., and Candida albicans. There was no impacton performance with all interferents tested	N=5 microbial agents were tested in saliva: Staphylococcusepidermis, Streptococcus mutans, Lactobacillus casei, Actinomycesviscosus and Candida albicans. There was no impact onperformance with all interferents tested.
Clinical Studies	Clinical performance was assessed using published data.	Same
DIFFERENCES
Sample collection device	Oragene Dx model OGD-500.001 (FDA-cleared for OTC)	ORAcollect Dx (custom version OCD-100.014) (currently in theprocess of getting FDA clearance for OTC, refer to K212745)
Item	Predicate Device:23andMe Personal Genome Service (PGS) for A1AT(DEN160026/DEN140044)	Candidate Device:AlphalD At Home Genetic Health Risk Service
Test principle	Qualitative genotyping. Multiplex assay using a customizedgenotyping chip (BeadChip v4 assay) and instrumentationmanufactured by Illumina, for single nucleotide polymorphismdetection. The raw data is generated using Illumina GenomeStudiosoftware.	Qualitative genotyping. Polymerase chain reaction (PCR) andhybridization-based in vitro diagnostic test for single nucleotidepolymorphism detection to be used with the Luminex 200TMinstrument (with xPONENT® software) and A1AT Genotyping TestAnalysis Software.
Analytical Sensitivity	The performance requirement for the PGS has been set at aminimum of 15 ng/µl DNA and maximum of 50 ng/µl DNA.	The performance requirement for the A1AT Genotyping Test hasbeen set at a minimum of 0.0215 ng/µl DNA.
Special InstrumentRequirements	The 23andMe PGS Genetic Health Risk Tests for HereditaryThrombophilia, Alpha-1 Antitrypsin Deficiency, Alzheimer's disease,Parkinson's disease, Gaucher Disease Type I, Factor XI Deficiency,Celiac Disease, and Glucose-6-Phosphate-DehydrogenaseDeficiency, Early-Onset Primary Dystonia and HereditaryHemochromatosis are to be performed using the Tecan Evo andIllumina iScan instruments.GenomeStudio is a modular software application that is used toview and analyze genotypic data obtained from the iScan. Coregensoftware conducts a variety of control checks on the file, resulting ina final genotype profile for each sample. These data are used togenerate test reports on a user's genotype and associated risk ofdisease.	The extraction of DNA (saliva samples) and PCR reaction usingA1AT Genotyping Test kit are performed with Biomek instrument.The A1AT Genotyping Test Kit used for detection and identificationof 14 allelic variants and their associated alleles found in the A1ATcodifying gene SERPINA1 is to be used with the Luminex 200TMinstrument (with xPONENT® software).Raw data from the Luminex System (csv. files containing the MFIvalue for each bead type) is processed with the A1AT GenotypingTest ANALYSIS SOFTWARE to provide allelic variant genotypes,which are subsequently converted into associated alleles, based oncurrent scientific evidence. Additionally, the software application alsoprovides the type of Genetic Health Risk Report associated with theidentified alleles, which is subsequently used as the basis for thegeneration of personalized reports by the AlphaID™ At HomeGenetic Health Risk Service website and result portal.Depending on the specific variant combination detected, theAlphaID™ At Home Genetic Health Risk Service provides theindividuals' genetic health risk for developing lung and liver diseaselinked to AATD.
Item	Predicate Device:23andMe Personal Genome Service (PGS) for A1AT(DEN160026/DEN140044)	Candidate Device:AlphaID At Home Genetic Health Risk Service
Lung Risk Categorization(Common variants)	PIM/PIM: Not Likely at riskPIM/PIS: Not Likely at increased riskPIM/PIZ: Non-smokers: Not likely at increased risk/ Smokers:increased riskPIS/PIS: Not likely at increased riskPIS/PIZ: Non-smokers: Not likely at increased risk/20-50%Smokers will develop signs of emphysema during their lifetimePIZ/PIZ: Increased risk	PIM/PIM: SamePIM/PIS: SamePIM/PIZ: Non-smokers: Same. Smokers: Slightly at increased risk(supported by clinical cases)PIS/PIS: SamePIS/PIZ: Slightly at increased risk (supported by clinical cases)PIZ/PIZ: Same
Liver Risk Categorization(Common variants)	PIM/PIM: Not Likely at riskPIM/PIS: Not Likely at increased riskPIM/PIZ: Not likely at increased risk.PIS/PIS: Not likely at increased riskPIS/PIZ: Not likely at increased risk.PIZ/PIZ: Increased risk	PIM/PIM: SamePIM/PIS: SamePIM/PIZ: Slightly at increased risk (supported by clinical cases)PIS/PIS: SamePIS/PIZ: Slightly at increased risk (supported by clinical cases)PIZ/PIZ: Slightly at increased risk (supported by clinical cases)
Interfering Mutations	Interfering Mutations for Alph-1 Antitrypsin Deficiency: Ninepotentially interfering mutations were identified for PIZ SERPINA1and six potentially interfering mutation in PIS SERPINA1. Thepotentially interfering mutations include: rs148362959.,rs533419579, rs551595739, rs201774333, rs143370956,rs1131139, rs200945035, rs373630097 and rs9630 for PIZ variantand rs538675821, rs550592374, rs141095970, rs149537225,rs1049800 and rs2230075 for PIS variant. Interference due tothese mutations was not tested.	The performance of this test may be affected by the presence of rarevariants, such as rs149537225 for PIS (rs17580); rs143370956,rs201774333, rs551595739, and rs372571769 for PIZ(rs28929474); rs199422213 for PII (rs28931570), PIM procida(rs28931569), PIM malton (rs775982338) and PIS iiyama(rs55819880); rs544632177 and rs577164283 for PIF(rs28929470); rs1049800 for PIP lowell (rs121912714); rs61761869and rs372571769 for PIM heerlen (rs199422209); rs148207011 forPIQ0 granite falls (rs267606950) and PIQ0 west (rs751235320);rs200634040 and rs72552401 for PIQ0 bellingham (rs199422211);rs148362959 and rs372571769 for PIQ0 mattawa (rs763023697),and rs143329723, rs121912712 and rs372571769 for PIQ0 clayton(rs764325655).

{10}------------------------------------------------

Progenika Biopharma, S.A.

{11}------------------------------------------------

Progenika Biopharma, S.A.

{12}------------------------------------------------

Progenika Biopharma, S.A.

{13}------------------------------------------------

Progenika Biopharma, S.A.

{14}------------------------------------------------

Progenika Biopharma, S.A.

{15}------------------------------------------------

Progenika Biopharma, S.A. Ibaizabal bidea. Edificio 504 160 Derio - Bizkaia - SPAIN ww.progenika.com - www.grifols.com

L. TEST PRINCIPLE

The AlphaID™ At Home Genetic Health Risk Service is performed by CLIAcertified laboratory using Alpha-1 antitrypsin (A1AT) Genotyping Test (K211115). A1AT Genotyping Test utilizes Luminex xMAP technology. Genomic DNA is extracted from from human saliva samples collected as buccal swabs using ORAcollect:Dx OCD-100.014. Extracted DNA is amplified and biotinylated by multiplex PCR and PCR products are denatured and hybridized to oligonucleotide probes coupled to color-coded beads. Hybridized DNA is labeled with a fluorescent conjugate and the resulting signal is detected with a Luminex® 200 system (with xPONENT® software). Raw data obtained is processed with the A1AT Genotyping Test ANALYSIS SOFTWARE. The A1AT Genotyping Test ANALYSIS SOFTWARE algorithm converts the allelic variant genotypes into associated alleles, based on the current literature. Additionally, this software application also provides an associated template number for each sample, this is, a code that defines the type of Genetic Health Risk Report that will be generated for each individual, depending on its combination of variants or Sample Result. This template number will be subsequently used as the basis for the generation of personalized reports by the AlphaID™ System.

M. PERFORMANCE CHARACTERISTICS

The analytical and clinical studies conducted to support the intended use and substantial equivalence claim to the predicate device are summarized below.

Analytical Performance 1.

a. Reproducibility/Precision

Lot-to-lot repeatability: See K211115. External Reproducibility: See K171868.

CLIA-Certified Laboratory Verification Study:

A total of 110 samples collected with AlphaID™ At Home Saliva Collection kit in an over the counter (OTC) environment were processed with the A1AT Genotyping Test at Progenika following the Package Insert and afterwards at Matrix Clinical Clinical Labs following the internal Standard Operational Procedure (SOP) that will be used afterwards during routine testing of the AlphaIDTM At Home Genetic Health Risk Service. The acceptance criteria for the study were fulfilled (concordance ≥99% and "Invalid Tests" ≤2%). The concordance between A1AT Genotyping Test results obtained in Matrix Clinical Labs and Progenika was 100% per reported variant and overall, among all tested samples. No "Invalid Tests" results were observed at Matrix

{16}------------------------------------------------

Clinical Labs. In conclusion, this study verifies that the CLIA laboratory designated to provide the AlphaID™ At Home Genetic Health Risk Service, Matrix Clinical Labs, is able to perform the analytical procedure with A1AT Genotyping Test correctly, using human saliva samples collected with the AlphaID™ At Home Saliva Collection kit (ORAcollect®·Dx OCD-100.014) in an OTC-like setting

b. Reagent Stability

See K171868 for initial Real-Time and Open-Vial Stabilities information and study designs and K192858 for final claimed stabilities of 24 months reagent stability when stored at 2-8℃ and up to 9 months reagent stability after the vials were first opened.

c. Specimen Stability

See K152464 and K192858 for saliva samples stability collected in ORAcollect Dx OCD-100.014 (customized version of ORAcollect-Dx OCD-100).

d. Shipping Stability

Saliva samples for testing are shipped in the AlphaID™ At Home Saliva Collection kit. See K152464 for sample shipping stability information.

e. Lower Limit of Detection (LoD)

See K211115 for Lower Limit of Detection (LoD) information.

f. DNA Extraction Variability

See K192858 for DNA Extraction Variability in saliva samples collected in ORAcollect Dx OCD-100.014 (customized version of ORAcollect-Dx OCD-100).

Cross-reactivity and Cross-contamination g.

See K171868 for Cross-reactivity and Cross-contamination information.

h. Interfering Substances

See K192858 for Interfering Substances information in Saliva samples collected in ORAcollect·Dx model OCD-100 and equivalent ORAcollect·Dx

{17}------------------------------------------------

Progenika Biopharma, S.A.

OCD-100.014.

i. Interfering variants

See K192858 for information about potentially interfering variants.

2. Comparison Studies

Method Comparison with the Predicate a.

Method Comparison study in saliva samples collected in ORAcollect. Dx OCD-100.014 (customized version of ORAcollect·Dx OCD-100):

A method comparison study was performed to assess the accuracy of A1AT Genotyping Test to correctly detect the genetic variants. A total of 227 samples representing all genetic variants interrogated by the assay were analyzed and compared with Bi-Directional-Sequencing (BDS) (reference method). Percent Agreement (PA) between the two methods for the overall variants and samples (14 variants and 227 samples) was 100% (227/227) with a 95% confidence interval 98.3% to 100%. The percentage of overall "Invalid Tests" was 0% (0/227) with 95% confidence interval 0% to 1.7%.

3. Clinical Studies

a. Clinical Performance

The AlphaID™ At Home Genetic Health Risk Service has been developed for the detection of 14 variants in the SERPINA1 gene associated with alphalantitrypsin deficiency (AATD), including the most common ones. Depending on the specific variant combination detected, the AlphaID™ At Home Genetic Health Risk Service provides the individuals' genetic health risk for developing lung and liver disease linked to alphal-antitrypsin deficiency (AATD).The risk categorization is based on the reported clinical cases (published references) for each genetic result.

The AlphaID™ At Home Genetic Health Risk Service uses four (4) categories to define risk:

Increased risk: There is an increased risk of developing lung or liver disease linked to AATD compared to the general population*. The chance of developing lung or liver disease linked to AATD is higher than that of the

{18}------------------------------------------------

general population. Above 80% of people with this genetic result develop lung or liver disease during their lifetime.

Slightly at Increased risk: There is a slightly increased risk of developing lung or liver disease linked to AATD compared to the general population*. The chance of developing lung or liver disease linked to AATD is slightly higher than that of the general population. 20-80% of people with this genetic result develop lung or liver disease during their lifetime.
Not likely at increased risk: There is average risk of developing lung or liver disease linked to AATD compared to the general population*. The chance of developing lung or liver disease linked to AATD is similar to that of the general population. Below 20% of people with this genetic result develop lung or liver disease during their lifetime.
Unknown risk: The risk of developing lung or liver disease linked to AATD is not known due to the lack of reported clinical cases or inconclusive data. The chance of developing lung or liver disease linked to AATD is unknown. More clinical studies are needed to determine the risk level.

*General population is defined as all adults who reside in the United States.

When "No Variants" are detected by the Service, the result will show "Not Likely at Risk for AATD".

b. User Comprehension Studies

AlphaID™ At Home Genetic Health Risk Service report user comprehension study:

The user comprehension study for the AlphaID™ At Home Genetic Health Risk Service showed that a demographically diverse US population of naïve users (525 participants) of the Service reports had excellent comprehension of the service's purpose, limitations, results, relevance of ethnicity, other factors that may impact test results, and appropriate next steps. Comprehension was tested through a two-step process. First, participants' comprehension was tested prior to viewing the educational module and Service reports. Second, participants were shown the educational module and the Service reports. Participants completed a survey after the first and second step. As a result, each comprehension domain achieved a minimum of 90.1% or higher user comprehension score in the first step, and 94.0% or higher user comprehension score in the second step, across all reports. The overall comprehension scores were of 92.7% and 96.8% across all comprehension domains and reports, for the first and second step respectively.

AlphaID™ At Home Saliva Collection kit user study:

{19}------------------------------------------------

Progenika Biopharma, S.A. Ibaizabal bidea, Edificio 504 w.progenika.com - www.grifols.com

See K212745.

N. INSTRUMENT NAME

Luminex 200TM instrument with xPONENT® software.

SYSTEM DESCRIPTION 0.

1. Modes of Operation:

The Luminex 200TM System is a flexible analyzer based on the principles of flow cytometry that enables you to multiplex up to 100 analytes in a single microplate well, using very small samples.

2. Software:

FDA has reviewed applicant's Hazard Analysis and software development processes for this line of product types:

Yes X

Level of Concern: Moderate

Software Description:

A1AT Genotyping Test ANALYSIS SOFTWARE: this software application is provided as part of the A1AT Genotyping Test device and it is used by the laboratory to process raw fluorescence data (csv. file) obtained from Luminex 200™ instrument with xPONENT software to obtain the genotyping results and associated health risk report template number.

AlphaID Genetic Health Risk Service Website and Results Portal (AlphaID System): this software application is a website in charge of controlling and managing the whole service, since a consumer is ordering a Saliva Collection Kit until a final report is generated based on template number and provided.

Revision Level History:

A software revision history record for the A1AT Genotyping Test ANALYSIS SOFTWARE and AlphaID™ At Home System were acceptable.

{20}------------------------------------------------

Progenika Biopharma, S.A.

Ibaizabal bidea, Edificio 504
Parque Tecnológico de Bizkaia
48160 Derio - Bizkaia - SPAIN
Phone: +34 94 406 45 25
Fax: +34 94 406 45 26
CIF: ESA95091799
www.progenika.com - www.grifols.com

Unresolved Anomalies:

There are no known unresolved anomalies associated with the system softwares.

EMC Testing: Not applicable.

3. Specimen Identification

Consumers must register their saliva collection kit, linking their saliva sample to a secure online account through a unique barcode, in order to access to their results report. The unique barcode is matched to records card of kits shipped to consumers to ensure it is a valid kit. A timestamp of the consumer completing the entries to register the kit is recorded. The saliva sample is processed and result reported by the laboratory using a traceable kit barcode.

4. Specimen Sampling and Handling

Saliva samples should be collected using the AlphaID™ At Home Saliva Collection kit (ORAcollect·Dx OCD-100.014 from DNA Genotek) collection kit.

Using the provided instructions for use, the consumer uses the integrated sponge on the device to collect a saliva sample from the mouth. After saliva is collected, the cap is removed from the tube, inverted to place the sponge into the collection tube with the stabilizing liquid, and re-capped with the sponge remaining inside the tube. Upon contacting saliva cells, the stabilizing liquid lyses cellular and nuclear membranes to release and stabilize nucleic acids (DNA). Samples can be immediately processed, transported or stored for future use. Device and sample integrity are preserved during typical ambient transport and storage conditions.

1. Calibration
  Calibration and verification procedures are established to demonstrate continued accuracy of the test systems.
1. Quality Control
  The AlphaID™ At Home Genetic Health Risk Service uses one (1) negative control (NTC) and one (1) positive control (synthetic plasmids) included with each run. The control material is genotyped using A1AT Genotyping Test performed on Luminex 2001M instrument according to routine SOPs at the laboratory.

{21}------------------------------------------------

com - www.grifols.com

P. PROPOSED LABELING

The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and 809 as applicable, and the special controls for this device type.

CONCLUSION Q.

The Intended use, technological and performance characteristics can be considered equivalent between the candidate and the predicate device. Therefore, the 23andMe Personal Genome Service (PGS) Genetic Health Risk Test for Alpha-1 Antitrypsin Deficiency is an appropriate predicate device for the AlphaID At Home Genetic Health Risk Service.

The labeling is sufficient and it satisfies the requirements of 21 CFR Parts 801 and 809 as applicable, and the special controls for this device type.

Regulation Number and Section

§ 866.5950 Genetic health risk assessment system.

(a)
Identification. A genetic health risk assessment system is a qualitative in vitro molecular diagnostic system used for detecting variants in genomic deoxyribonucleic acid (DNA) isolated from human specimens that will provide information to users about their genetic risk of developing a disease to inform lifestyle choices and/or conversations with a health care professional. This assessment system is for over-the-counter use. This device does not determine the person's overall risk of developing a disease.(b)
Classification. Class II (special controls). The genetic health risk assessment system device, when it has previously received a first-time FDA marketing authorization (e.g., 510(k) clearance) for the genetic health risk assessment system (a “one-time FDA reviewed genetic health risk assessment system”), is exempt from the premarket notification procedures in part 807, subpart E, of this chapter subject to the limitations in § 866.9. The device must comply with the following special controls:(1) The 21 CFR 809.10 compliant labeling and any prepurchase page and test report generated, unless otherwise specified, must include:
(i) A section addressed to users with the following information:
(A) The limiting statement explaining that this test provides genetic risk information based on assessment of specific genetic variants but does not report on a user's entire genetic profile. This test [does not/may not, as appropriate] detect all genetic variants related to a given disease, and the absence of a variant tested does not rule out the presence of other genetic variants that may be related to the disease.
(B) The limiting statement explaining that other companies offering a genetic risk test may be detecting different genetic variants for the same disease, so the user may get different results using a test from a different company.
(C) The limiting statement explaining that other factors such as environmental and lifestyle risk factors may affect the risk of developing a given disease.
(D) The limiting statement explaining that some people may feel anxious about getting genetic test health results. This is normal. If the potential user feels very anxious, such user should speak to his or her doctor or other health care professional prior to collection of a sample for testing. This test is not a substitute for visits to a doctor or other health care professional. Users should consult with their doctor or other health care professional if they have any questions or concerns about the results of their test or their current state of health.
(E) Information about how to obtain access to a genetic counselor, board-certified clinical molecular geneticist, or equivalent health care professional about the results of a user's test.
(F) The limiting statement explaining that this test is not intended to diagnose a disease, tell you anything about your current state of health, or be used to make medical decisions, including whether or not you should take a medication or how much of a medication you should take.
(G) A limiting statement explaining that the laboratory may not be able to process a sample, and a description of the next steps to be taken by the manufacturer and/or the customer, as applicable.
(ii) A section in your 21 CFR 809.10 labeling and any test report generated that is for health care professionals who may receive the test results from their patients with the following information:
(A) The limiting statement explaining that this test is not intended to diagnose a disease, determine medical treatment, or tell the user anything about their current state of health.
(B) The limiting statement explaining that this test is intended to provide users with their genetic information to inform lifestyle decisions and conversations with their doctor or other health care professional.
(C) The limiting statement explaining that any diagnostic or treatment decisions should be based on testing and/or other information that you determine to be appropriate for your patient.
(2) The genetic test must use a sample collection device that is FDA-cleared, -approved, or -classified as 510(k) exempt, with an indication for in vitro diagnostic use in over-the-counter DNA testing.
(3) The device's labeling must include a hyperlink to the manufacturer's public Web site where the manufacturer shall make the information identified in paragraph (b)(3) of this section publicly available. The manufacturer's home page, as well as the primary part of the manufacturer's Web site that discusses the device, must provide a hyperlink to the Web page containing this information and must allow unrestricted viewing access. If the device can be purchased from the Web site or testing using the device can be ordered from the Web site, the same information must be found on the Web page for ordering the device or provided in a publicly accessible hyperlink on the Web page for ordering the device. Any changes to the device that could significantly affect safety or effectiveness would require new data or information in support of such changes, which would also have to be posted on the manufacturer's Web site. The information must include:
(i) An index of the material being provided to meet the requirements in paragraph (b)(3) of this section and its location.
(ii) A section that highlights summary information that allows the user to understand how the test works and how to interpret the results of the test. This section must, at a minimum, be written in plain language understandable to a lay user and include:
(A) Consistent explanations of the risk of disease associated with all variants included in the test. If there are different categories of risk, the manufacturer must provide literature references that support the different risk categories. If there will be multiple test reports and multiple variants, the risk categories must be defined similarly among them. For example, “increased risk” must be defined similarly between different test reports and different variant combinations.
(B) Clear context for the user to understand the context in which the cited clinical performance data support the risk reported. This includes, but is not limited to, any risks that are influenced by ethnicity, age, gender, environment, and lifestyle choices.
(C) Materials that explain the main concepts and terminology used in the test that include:
(
1 )Definitions: Scientific terms that are used in the test reports.(
2 )Prepurchase page: This page must contain information that informs the user about what information the test will provide. This includes, but is not limited to, variant information, the condition or disease associated with the variant(s), professional guideline recommendations for general genetic risk testing, the limitations associated with the test (e.g., test does not detect all variants related to the disease) and any precautionary information about the test the user should be aware of before purchase. When the test reports the risk of a life-threatening or irreversibly debilitating disease or condition for which there are few or no options to prevent, treat, or cure the disease, a user opt-in section must be provided. This opt-in page must be provided for each disease that falls into this category and must provide specific information relevant to each test result. The opt-in page must include:(
i ) An option to accept or decline to receive this specific test result;(
ii ) Specification of the risk involved if the user is found to have the specific genetic test result;(
iii ) Professional guidelines that recommend when genetic testing for the associated target condition is or is not recommended; and(
iv ) A recommendation to speak with a health care professional, genetic counselor, or equivalent professional before getting the results of the test.(
3 )Frequently asked questions (FAQ) page: This page must provide information that is specific for each variant/disease pair that is reported. Information provided in this section must be scientifically valid and supported by corresponding publications. The FAQ page must explain the health condition/disease being tested, the purpose of the test, the information the test will and will not provide, the relevance of race and ethnicity to the test results, information about the population to which the variants in the test is most applicable, the meaning of the result(s), other risk factors that contribute to disease, appropriate followup procedures, how the results of the test may affect the user's family, including children, and links to resources that provide additional information.(iii) A technical information section containing the following information:
(A) Gene(s) and variant(s) the test detects using standardized nomenclature, Human Genome Organization nomenclature and coordinates as well as Single Nucleotide Polymorphism Database (dbSNP) reference SNP numbers (rs#).
(B) Scientifically established disease-risk association of each variant detected and reported by the test. This risk association information must include:
(
1 ) Genotype-phenotype information for the reported variants.(
2 ) Table of expected frequency and risks of developing the disease in relevant ethnic populations and the general population.(
3 ) A statement about the current professional guidelines for testing these specific gene(s) and variant(s).(
i ) If professional guidelines are available, provide the recommendations in the professional guideline for the gene, variant, and disease, for when genetic testing should or should not be performed, and cautionary information that should be communicated when a particular gene and variant is detected.(
ii ) If professional guidelines are not available, provide a statement that the professional guidelines are not available for these specific gene(s) and variant(s).(C) The specimen type (
e.g., saliva, capillary whole blood).(D) Assay steps and technology used.
(E) Specification of required ancillary reagents, instrumentation, and equipment.
(F) Specification of the specimen collection, processing, storage, and preparation methods.
(G) Specification of risk mitigation elements and description of all additional procedures, methods, and practices incorporated into the directions for use that mitigate risks associated with testing.
(H) Information pertaining to the probability of test failure (
i.e., percentage of tests that failed quality control) based on data from clinical samples, a description of scenarios in which a test can fail (i.e., low sample volume, low DNA concentration, etc.), how users will be notified of a test failure, and the nature of followup actions on a failed test to be taken by the user and the manufacturer.(I) Specification of the criteria for test result interpretation and reporting.
(J) Information that demonstrates the performance characteristics of the test, including:
(
1 ) Accuracy of study results for each claimed specimen type.(
i ) Accuracy of the test shall be evaluated with fresh clinical specimens collected and processed in a manner consistent with the test's instructions for use. If this is impractical, fresh clinical samples may be substituted or supplemented with archived clinical samples. Archived samples shall have been collected previously in accordance with the instructions for use, stored appropriately, and randomly selected. In some limited circumstances, use of contrived samples or human cell line samples may also be appropriate and used as an acceptable alternative. The contrived or human cell line samples shall mimic clinical specimens as much as is feasible and provide an unbiased evaluation of the device accuracy.(
ii ) Accuracy must be evaluated by comparison to bidirectional Sanger sequencing or other methods identified as appropriate by FDA. Performance criteria for both the comparator method and the device must be predefined and appropriate to the device's intended use. Detailed study protocols must be provided.(
iii ) Test specimens must include all genotypes that will be included in the tests and reports. The number of samples tested in the accuracy study for each variant reported must be based on the variant frequency using either the minimum numbers of samples identified in this paragraph or, when determined appropriate and identified by FDA, a minimum number of samples determined using an alternative method. When appropriate, the same samples may be used in testing to demonstrate the accuracy of testing for multiple genotypes by generating sequence information at multiple relevant genetic locations. At least 20 unique samples representing the wild-type genotype must be tested. To test samples that are heterozygous for the reported variant(s), common variants (>0.1 percent variant frequency in the relevant population) must be tested with at least 20 unique samples. Rare variants (≤0.1 percent variant frequency in the relevant population) must be tested with at least three unique samples. To test samples that are homozygous for the reported variant(s), variants with ≥2 percent variant frequency in a relevant population must be tested with at least 20 unique samples. Variants with a frequency in the relevant population