51560 Federal Register / Vol. 82, No. 214 / Tuesday, November 7, 2017 / Rules and Regulations 

the performance of the device. The 

study must be conducted using samples 

collected from apparently healthy male 

and female adults at least 21 years of age 

and older from at least 3 distinct 

climatic regions within the United 

States in different weather seasons. The 

ethnic, racial, and gender background of 

this study population must be 

representative of the U.S. population 

demographics. 

(4) The results of the device as 

provided in the 21 CFR 809.10(b) 

compliant labeling and any test report 

generated must be reported as only total 

25-hydroxyvitamin D. 

Dated: October 31, 2017. 

Lauren Silvis, 

Chief of Staff. 

[FR Doc. 2017–24161 Filed 11–6–17; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 866 

[Docket No. FDA–2017–N–4341] 

Medical Devices; Immunology and 

Microbiology Devices; Classification of 

the Genetic Health Risk Assessment 

System 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final order. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is classifying the genetic health risk 

assessment system into class II (special 

controls). The special controls that 

apply to the device type are identified 

in this order and will be part of the 

codified language for the genetic health 

risk assessment system’s classification. 

We are taking this action because we 

have determined that classifying the 

device into class II (special controls) 

will provide a reasonable assurance of 

safety and effectiveness of the device. 

We believe this action will also enhance 

patients’ access to beneficial innovative 

devices, in part by reducing regulatory 

burdens. 

DATES: This order is effective November 

7, 2017. The classification was 

applicable on April 6, 2017. 

FOR FURTHER INFORMATION CONTACT: 

Steven Tjoe, Center for Devices and 

Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 66, Rm. 4550, Silver Spring, 

MD 20993–0002, 301–796–5866, 

steven.tjoe@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

Upon request, FDA has classified the 

genetic health risk assessment system as 

class II (special controls), which we 

have determined will provide a 

reasonable assurance of safety and 

effectiveness. In addition, we believe 

this action will enhance patients’ access 

to beneficial innovation, in part by 

reducing regulatory burdens by placing 

the device into a lower device class than 

the automatic class III assignment. 

The automatic assignment of class III 

occurs by operation of law and without 

any action by FDA, regardless of the 

level of risk posed by the new device. 

Any device that was not in commercial 

distribution before May 28, 1976, is 

automatically classified as, and remains 

within, class III and requires premarket 

approval unless and until FDA takes an 

action to classify or reclassify the device 

(see section 513(f)(1) of the Federal 

Food, Drug, and Cosmetic Act (the 

FD&C Act) (21 U.S.C. 360c(f)(1))). We 

refer to these devices as 

‘‘postamendments devices’’ because 

they were not in commercial 

distribution prior to the date of 

enactment of the Medical Device 

Amendments of 1976, which amended 

the FD&C Act. 

FDA may take a variety of actions in 

appropriate circumstances to classify or 

reclassify a device into class I or II. We 

may issue an order finding a new device 

to be substantially equivalent under 

section 513(i) of the FD&C Act to a 

predicate device that does not require 

premarket approval. We determine 

whether a new device is substantially 

equivalent to a predicate by means of 

the procedures for premarket 

notification under section 510(k) of the 

FD&C Act and part 807 (21 U.S.C. 360(k) 

and 21 CFR part 807, respectively). 

FDA may also classify a device 

through ‘‘De Novo’’ classification, a 

common name for the process 

authorized under section 513(f)(2) of the 

FD&C Act. Section 207 of the Food and 

Drug Administration Modernization Act 

of 1997 established the first procedure 

for De Novo classification (Pub. L. 105– 

115). Section 607 of the Food and Drug 

Administration Safety and Innovation 

Act modified the De Novo application 

process by adding a second procedure 

(Pub. L. 112–144). A device sponsor 

may utilize either procedure for De 

Novo classification. 

Under the first procedure, the person 

submits a 510(k) for a device that has 

not previously been classified. After 

receiving an order from FDA classifying 

the device into class III under section 

513(f)(1) of the FD&C Act, the person 

then requests a classification under 

section 513(f)(2). 

Under the second procedure, rather 

than first submitting a 510(k) and then 

a request for classification, if the person 

determines that there is no legally 

marketed device upon which to base a 

determination of substantial 

equivalence, that person requests a 

classification under section 513(f)(2) of 

the FD&C Act. 

Under either procedure for De Novo 

classification, FDA is required to 

classify the device by written order 

within 120 days. The classification will 

be according to the criteria under 

section 513(a)(1) of the FD&C Act. 

Although the device was automatically 

within class III, the De Novo 

classification is considered to be the 

initial classification of the device. 

We believe this De Novo classification 

will enhance patients’ access to 

beneficial innovation, in part by 

reducing regulatory burdens. When FDA 

classifies a device into class I or II via 

the De Novo process, the device can 

serve as a predicate for future devices of 

that type, including for 510(k)s (see 21 

U.S.C. 360c(f)(2)(B)(i)). As a result, other 

device sponsors do not have to submit 

a De Novo request or PMA in order to 

market a substantially equivalent device 

(see 21 U.S.C. 360c(i), defining 

‘‘substantial equivalence’’). Instead, 

sponsors can use the less-burdensome 

510(k) process, when necessary, to 

market their device. 

II. De Novo Classification 

On June 28, 2016, 23andMe, Inc. 

submitted a request for De Novo 

classification of the 23andMe Personal 

Genome Service (PGS) Test. FDA 

reviewed the request in order to classify 

the device under the criteria for 

classification set forth in section 

513(a)(1) of the FD&C Act. 

We classify devices into class II if 

general controls by themselves are 

insufficient to provide reasonable 

assurance of safety and effectiveness, 

but there is sufficient information to 

establish special controls that, in 

combination with the general controls, 

provide reasonable assurance of the 

safety and effectiveness of the device for 

its intended use (see 21 U.S.C. 

360c(a)(1)(B)). After review of the 

information submitted in the request, 

we determined that the device can be 

classified into class II with the 

establishment of special controls. FDA 

has determined that these special 

controls, in addition to the general 

controls, will provide reasonable 

assurance of the safety and effectiveness 

of the device. 


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Therefore, on April 6, 2017, FDA 

issued an order to the requester 

classifying the device into class II. FDA 

is codifying the classification of the 

device by adding 21 CFR 866.5950. We 

have named the generic type of device 

genetic health risk assessment system, 

and it is identified as 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. 

FDA has identified the following risks 

to health associated specifically with 

this type of device and the measures 

required to mitigate these risks in table 

1. 

TABLE 1—GENETIC HEALTH RISK ASSESSMENT SYSTEM RISKS AND MITIGATION MEASURES

Identified risk Mitigation measures 

Incorrect understanding of the device and test system ........................... General controls, Special control (1) (21 CFR 866.5950(b)(1)), Special 

control (3) (21 CFR 866.5950(b)(3)), and Special control (4) (21 CFR 

866.5950 (b)(4)). 

Incorrect test results (false positives, false negatives) ............................ General controls, Special control (2) (21 CFR 866.5950(b)(2)), and 

Special control (3) (21 CFR 866.5950(b)(3)). 

Incorrect interpretation of test results ....................................................... General controls, Special control (1) (21 CFR 866.5950(b)(1)), Special 

control (3) (21 CFR 866.5950(b)(3)), and Special control (4) (21 CFR 

866.5950(b)(4)). 

FDA has determined that special 

controls, in combination with the 

general controls, address these risks to 

health and provide reasonable assurance 

of safety and effectiveness. In order for 

a device to fall within this classification, 

and thus avoid automatic classification 

in class III, it would have to comply 

with the special controls named in this 

final order. The necessary special 

controls appear in the regulation 

codified by this order. This device is 

subject to premarket notification 

requirements under section 510(k) of the 

FD&C Act. 

Section 510(m)(2) of the FD&C Act 

provides that FDA may exempt a class 

II device from the premarket notification 

requirements under section 510(k) if, 

after notice of our intent to exempt and 

consideration of comments, we 

determine by order that premarket 

notification is not necessary to provide 

reasonable assurance of safety and 

effectiveness of the device. We believe 

this may be such a device. The notice 

of intent to exempt the device from 

premarket notification requirements is 

published elsewhere in this issue of the 

Federal Register. 

III. Analysis of Environmental Impact 

The Agency has determined under 21 

CFR 25.34(b) that this action is of a type 

that does not individually or 

cumulatively have a significant effect on 

the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

IV. Paperwork Reduction Act of 1995 

This final order establishes special 

controls that refer to previously 

approved collections of information 

found in other FDA regulations. These 

collections of information are subject to 

review by the Office of Management and 

Budget (OMB) under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501– 

3520). The collections of information in 

part 807, subpart E, regarding premarket 

notification submissions have been 

approved under OMB control number 

0910–0120, and the collections of 

information in 21 CFR parts 801 and 

809, regarding labeling have been 

approved under OMB control number 

0910–0485. 

List of Subjects in 21 CFR Part 866 

Biologics, Laboratories, Medical 

devices. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, 21 CFR part 866 is 

amended as follows: 

PART 866—IMMUNOLOGY AND 

MICROBIOLOGY DEVICES 

■ 1. The authority citation for part 866 

continues to read as follows: 

Authority: 21 U.S.C. 351, 360, 360c, 360e, 

360j, 360l, 371. 

■ 2. Add § 866.5950 to subpart F to read 

as follows: 

§ 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 special controls for this 

device are: 

(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 


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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, boardcertified 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 diseaserisk 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). 


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(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 <2 

percent and ≥0.5 percent must be tested 

with at least 10 unique samples. 

Variants with a frequency in the 

relevant population <0.5 percent must 

be tested with at least three unique 

samples. If variants with a frequency of 

<0.5 percent are not found within the 

relevant population and homozygous 

samples are not tested, then the test 

results for this homozygous rare variant 

must not be reported to the user. 

(iv) Information about the accuracy 

study shall include the number and type 

of samples that were compared to 

bidirectional Sanger sequencing or other 

methods identified as appropriate by 

FDA. This information must either be 

reported in tabular format and arranged 

by clinically relevant variants or 

reported using another method 

identified as appropriate by FDA. As an 

example, for samples with different 

genotypes DD, Dd, and dd, the following 

table represents data from the accuracy 

study presented in tabular format: 


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(v) The accuracy represents the 

degrees of agreement between the 

device results and the comparator 

results. The accuracy must be evaluated 

by measuring different percent 

agreements (PA) of device results with 

the comparator results and percent of 

‘no calls’ or ‘invalid calls.’ Calculate the 

rate of ‘no calls’ and ‘invalid calls’ for 

each comparator output as %Inv(DD) = 

A4/NDD, %Inv(Dd) = B4/NDd, %Inv(dd) = 

C4/Ndd. If ‘no calls’ or ‘invalid calls’ are 

required to be retested according to the 

device instructions for use, the percent 

of final ‘no calls’ or ‘invalid calls’ must 

be provided. In the table presenting the 

results of the accuracy study, use only 

the final results (i.e., after retesting the 

initial ‘no calls’ or ‘invalid calls’, if 

required according to the instructions 

for use). Samples that resulted in a ‘no 

call’ or ‘invalid call’ after retesting must 

not be included in the final calculations 

of agreement. If the percentages of ‘no 

calls’ or ‘invalid calls’ for each 

comparator output are similar, combine 

these estimates as (A4 + B4 + C4)/(NDD

+ NDd + Ndd) and provide a 95 percent 

two-sided confidence interval. The 

percent of final ‘no calls’ or ‘invalid 

calls’ must be clinically acceptable. 

(vi) Point estimates of percent 

agreement for each genotype must be 

calculated as the number of correct calls 

for that genotype divided by the number 

of samples known to contain that 

genotype excluding ‘no calls’ or ‘invalid 

calls’. The calculations must be 

performed as follows: 


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(vii) For percent agreements for DD, 

Dd and dd (PA(DD|DD), PA(Dd|Dd) and 

PA(dd|dd)) as described in paragraph 

(b)(3)(iii)(J)(1)(vi) of this section, the 95 

percent two-sided confidence intervals 

must be provided. The accuracy point 

estimates for percent agreements for DD, 

Dd and dd must be ≥99 percent per 

reported variant and overall. Any 

variants that have a point estimate for 

either PA(DD|DD), PA(Dd|Dd), or 

PA(dd|dd) of <99 percent compared to 

bidirectional sequencing or other 

methods identified as appropriate by 

FDA must not be incorporated into test 

claims and reports. Accuracy results 

generated from clinical specimens 

versus contrived samples or cell lines 

must be presented separately. Results 

must be summarized and presented in 

tabular format by sample type and by 

genotype or must be reported using 

another method identified as 

appropriate by FDA (see paragraph 

(b)(3)(iii)(J)(1)(iv) of this section). 

(viii) Information must be reported on 

the Technical Positive Predictive Value 

(TPPV) related to the analytical 

(technical) performance of the device for 

genotypes in each relevant 

subpopulation (e.g., ethnicity, gender, 

age, geographical location, etc.). TPPV is 

the percentage of individuals with the 

genotype truly present among 

individuals whose test reports indicate 

that this genotype is present. The TPPV 

depends on the accuracy measures of 

percent agreements and on the 

frequency of the genotypes in the 

subpopulation being studied. The f(DD) 

is the frequency of DD and f(Dd) is the 

frequency of Dd in the subpopulation 

being studied; TPPV must be calculated 

as described in paragraphs 

(b)(3)(iii)(J)(1)(ix) through (xi) of this 

section. 

(ix) For variants where the point 

estimates of PA(DD|DD), PA(Dd|Dd) and 

PA(dd|dd) are less than 100 percent, use 

these point estimates in TPPV 

calculations. 

(x) Point estimates of 100 percent in 

the accuracy study may have high 

uncertainty about performance of the 

test in the population. If these variants 

are measured using highly multiplexed 

technology, calculate the random error 

rate for the overall device. The accuracy 

study described in paragraph 

(b)(3)(iii)(J) of this section in those cases 

is more to determine that there is no 

systematic error in such devices. In 

those cases, incorporate that rate in the 

estimation of the percent agreements as 

calculated in paragraph 

(b)(3)(iii)(J)(1)(vi) of this section and 

include it in TPPV calculations. 

(xi) The TPPV for subpopulations 

with genotype frequencies of f(dd), f(Dd) 

and f(DD) = 1¥f(dd)¥f(Dd) in the 

subpopulation is calculated as: 

(2) Precision and reproducibility data 

must be provided using multiple 

instruments and multiple operators, on 

multiple non-consecutive days, and 

using multiple reagent lots. The sample 

panel must either include specimens 

from the claimed sample type (e.g., 

saliva) representing all genotypes for 

each variant (e.g., wild type, 

heterozygous, and homozygous) or, if an 

alternative panel composition of 

specimens is identified by FDA as 

appropriate, a panel composed of those 

specimens FDA identified as 

appropriate. A detailed study protocol 

must be created in advance of the study 

and must include predetermined 

acceptance criteria for performance 

results. The percentage of samples that 

failed quality control must be indicated 

(i.e., the total number of sample 

replicates for which a sequence variant 

cannot be called (no calls) or that fail 

sequencing quality control criteria 

divided by the total number of 

replicates tested). It must be clearly 

documented whether results were 

generated from clinical specimens, 

contrived samples, or cell lines. The 

study results shall report the variants 

tested in the study and the number of 

replicates for each variant, and what 

conditions were tested (i.e., number of 

runs, days, instruments, reagent lots, 

operators, specimens/type, etc.). Results 

must be evaluated and presented in 

tabular format and stratified by study 

parameter (e.g., by site, instrument(s), 

reagent lot, operator, and sample 

variant). The study must include all 

extraction steps from the claimed 

specimen type or matrix, unless a 

separate extraction reproducibility 

study for the claimed sample type is 

performed. If the device is to be used at 

more than one laboratory, different 

laboratories must be included in the 

reproducibility study and 

reproducibility across sites must be 

evaluated. Any no calls or invalid calls 

in the study must be listed as a part of 

the precision and reproducibility study 

results. 

(3) Analytical specificity data: Data 

must be provided that evaluates the 

effect of potential endogenous and 

exogenous interferents on test 

performance, including specimen 

extraction and variant detection. 

Interferents tested must include those 

reasonably likely to be potentially 

relevant to the sample type used for the 

device. 

(4) Interfering variant data: 

Nucleotide mutations that can interfere 

with the technology must be cited and 

evaluated. Data must be provided to 

demonstrate the effect of the interfering 

variant(s) on the performance of the 

correct calls. Alternatively, for each 

suspected interfering mutation for 

which data is not provided 

demonstrating the effect of the 

interfering variant, the manufacturer 

must identify the suspected interfering 


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variants in the labeling and indicate that 

the impact that the interfering variants 

may have on the assay’s performance 

has not been studied by providing a 

statement that reads ‘‘It is possible that 

the presence of [insert clearly 

identifying information for the 

suspected interfering variant] in a 

sample may interfere with the 

performance of this test. However, its 

effect on the performance of this test has 

not been studied.’’ 

(5) Analytical sensitivity data: Data 

must be provided demonstrating the 

minimum amount of DNA that will 

enable the test to perform correctly in 95 

percent of runs. 

(6) Reagent stability: The 

manufacturer must evaluate reagent 

stability using wild-type, heterozygous, 

and homozygous samples. Reagent 

stability data must demonstrate that the 

reagents maintain the claimed accuracy 

and reproducibility. Data supporting 

such claims must be provided. 

(7) Specimen type and matrix 

comparison data: Specimen type and 

matrix comparison data must be 

generated if more than one specimen 

type can be tested with this device, 

including failure rates for the different 

specimens. 

(K) Clinical performance summary. 

(1) Information to support the clinical 

performance of each variant reported by 

the test must be provided. 

(2) Manufacturers must organize 

information by the specific variant 

combination as appropriate (e.g., wild 

type, heterozygous, homozygous, 

compound heterozygous, hemizygous 

genotypes). For each variant 

combination, information must be 

provided in the clinical performance 

section to support clinical performance 

for the risk category (e.g., not at risk, 

increased risk). For each variant 

combination, a summary of key results 

must be provided in tabular format or 

using another method identified as 

appropriate by FDA to include the 

appropriate information regarding 

variant type, data source, definition of 

the target condition (e.g., disease), 

clinical criteria for determining whether 

the target disease is present or absent, 

description of subjects with the target 

disease present and target disease absent 

(exclusion or inclusion criteria), and 

technical method for genotyping. When 

available, information on the effect of 

the variant on risk must be provided as 

the risk of a disease (lifetime risk or 

lifetime incidences) for an individual 

compared with the general population 

risk. 

(i) If odds ratios are available, using 

information about the genotype 

distribution either among individuals 

with the target disease absent, or in the 

general population, or information 

about the risk variant frequency and 

odds ratios, the likelihood ratios for the 

corresponding device results along with 

95 percent confidence intervals must be 

calculated. Using information about 

pretest risk (p), an estimate of likelihood 

ratio (LR), and a relationship between 

post-test risk R as R/(1¥R) = LR·p/ 

(1¥p), the post-test risk R must be 

calculated. 

(ii) When available, likelihood ratios 

(LR) for different test results must be 

presented in a tabular format along with 

references to the source data or using 

another method identified as 

appropriate by FDA as stated in 

paragraph (b)(3)(iii)(K)(2) of this section. 

When these values are not directly 

available in published literature, 

likelihood ratios can be separately 

calculated along with the 95 percent 

confidence interval with references to 

the source data. Note that a minimum 

requirement for the presence of the 

variant’s effect on the risk is that a 

corresponding LR is statistically higher 

than 1 (a lower bound of 95 percent 

two-sided confidence interval is larger 

than 1). It means that the post-test risk 

is statistically higher than the pretest 

risk (an observed value of the difference 

between the post-test and pretest risks). 

(L) Materials that explain the main 

concepts and terminology used in the 

test that includes, but is not limited to: 

(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 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 on the test results, information 

about the population to which the 

variants in the test is most applicable, 

the meaning of the result(s), other risks 

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. 

(M) User comprehension study: 

Information on a study that assesses 

comprehension of the test process and 

results by potential users of the test 

must be provided. 

(1) The test manufacturer must 

provide a genetic risk education module 

to naı ̈ve user comprehension study 

participants prior to their participation 

in the user comprehension study. The 

module must define terms that are used 

in the test reports and explain the 

significance of genetic risk reports. 

(2) The test manufacturer must 

perform pre- and post-test user 

comprehension studies. The 

comprehension test questions must 

include directly evaluating a 

representative sample of the material 

being presented to the user as described 

in paragraph (b)(3)(ii) of this section. 

(3) The manufacturer must provide a 

justification from a physician and/or 

genetic counselor that identifies the 

appropriate general and variant-specific 

concepts contained within the material 

being tested in the user comprehension 

study to ensure that all relevant 

concepts are incorporated in the study. 

(4) The user study must meet the 

following criteria: 

(i) The study participants must 

comprise a statistically sufficient 

sample size and demographically 

diverse population (determined using 

methods such as quota-based sampling) 

that is representative of the intended 

user population. Furthermore, the study 

participants must comprise a diverse 


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range of age and educational levels and 

have no prior experience with the test 

or its manufacturer. These factors shall 

be well defined in the inclusion and 

exclusion criteria. 

(ii) All sources of bias must be 

predefined and accounted for in the 

study results with regard to both 

responders and non-responders. 

(iii) The testing must follow a format 

where users have limited time to 

complete the studies (such as an onsite 

survey format and a one-time visit with 

a cap on the maximum amount of time 

that a participant has to complete the 

tests). 

(iv) Users must be randomly assigned 

to study arms. Test reports in the user 

comprehension study given to users 

must define the target condition being 

tested and related symptoms, explain 

the intended use and limitations of the 

test, explain the relevant ethnicities in 

regard to the variant tested, explain 

genetic health risks and relevance to the 

user’s ethnicity, and assess participants’ 

ability to understand the following 

comprehension concepts: The test’s 

limitations, purpose, appropriate action, 

test results, and other factors that may 

have an impact on the test results. 

(v) Study participants must be 

untrained, be naı ̈ve to the test subject of 

the study, and be provided the labeling 

prior to the start of the user 

comprehension study. 

(vi) The user comprehension study 

must meet the predefined primary 

endpoint criteria, including a minimum 

of a 90 percent or greater overall 

comprehension rate (i.e., selection of the 

correct answer) for each comprehension 

concept. Other acceptance criteria may 

be acceptable depending on the concept 

being tested. Meeting or exceeding this 

overall comprehension rate 

demonstrates that the materials 

presented to the user are adequate for 

over-the-counter use. 

(vii) The analysis of the user 

comprehension results must include 

results regarding reports that are 

provided for each gene/variant/ethnicity 

tested, statistical methods used to 

analyze all data sets, and completion 

rate, non-responder rate, and reasons for 

nonresponse/data exclusion. A 

summary table of comprehension rates 

regarding comprehension concepts (e.g., 

purpose of test, test results, test 

limitations, ethnicity relevance for the 

test results, etc.) for each study report 

must be included. 

(4) The intended use of the device 

must not include the following 

indications for use: 

(i) Prenatal testing; 

(ii) Determining predisposition for 

cancer where the result of the test may 

lead to prophylactic screening, 

confirmatory procedures, or treatments 

that may incur morbidity or mortality to 

the patient; 

(iii) 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; or 

(iv) Assessing the presence of 

deterministic autosomal dominant 

variants. 

Dated: November 1, 2017. 

Lauren Silvis, 

Chief of Staff. 

[FR Doc. 2017–24159 Filed 11–6–17; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 866 

[Docket No. FDA–2015–N–3455] 

Medical Devices; Exemption From 

Premarket Notification; Class II 

Devices; Autosomal Recessive Carrier 

Screening Gene Mutation Detection 

System 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final order. 

SUMMARY: The Food and Drug 

Administration (FDA or Agency) is 

publishing an order to exempt 

autosomal recessive carrier screening 

gene mutation detection systems from 

the premarket notification requirements, 

subject to certain limitations. This 

exemption from 510(k), subject to 

certain limitations, is immediately in 

effect for autosomal recessive carrier 

screening gene mutation detection 

systems. This exemption will decrease 

regulatory burdens on the medical 

device industry and will eliminate 

private costs and expenditures required 

to comply with certain Federal 

regulations. FDA is also amending the 

codified language for the autosomal 

recessive carrier screening gene 

mutation detection system devices 

classification regulation to reflect this 

final determination. 

DATES: This order is effective November 

7, 2017. 

FOR FURTHER INFORMATION CONTACT: 

Steven Tjoe, Center for Devices and 

Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 66, Rm. 4550, Silver Spring, 

MD 20993–0002, 301–796–5866. 

SUPPLEMENTARY INFORMATION: 

I. Statutory Background 

Section 510(k) of the Federal Food, 

Drug, and Cosmetic Act (the FD&C Act) 

(21 U.S.C. 360(k)) and the implementing 

regulations, 21 CFR part 807 subpart E, 

require persons who intend to market a 

device to submit and obtain FDA 

clearance of a premarket notification 

(510(k)) containing information that 

allows FDA to determine whether the 

new device is ‘‘substantially equivalent’’ 

within the meaning of section 513(i) of 

the FD&C Act (21 U.S.C. 360c(i)) to a 

legally marketed device that does not 

require premarket approval. 

On December 13, 2016, the 21st 

Century Cures Act (Pub. L. 114–255) 

(Cures Act) was signed into law. Section 

3054 of the Cures Act amended section 

510(m) of the FD&C Act. As amended, 

section 510(m)(2) provides that, 1 

calendar day after the date of 

publication of the final list under 

paragraph (1)(B), FDA may exempt a 

class II device from the requirement to 

submit a report under section 510(k) of 

the FD&C Act, upon its own initiative or 

a petition of an interested person, if 

FDA determines that a 510(k) is not 

necessary to provide reasonable 

assurance of the safety and effectiveness 

of the device. This section requires FDA 

to publish in the Federal Register a 

notice of intent to exempt a device, or 

of the petition, and to provide a 60- 

calendar-day comment period. Within 

120 days of publication of such notice, 

FDA must publish an order in the 

Federal Register that sets forth its final 

determination regarding the exemption 

of the device that was the subject of the 

notice. If FDA fails to respond to a 

petition under this section within 180 

days of receiving it, the petition shall be 

deemed granted. 

II. Criteria for Exemption 

There are a number of factors FDA 

may consider to determine whether a 

510(k) is necessary to provide 

reasonable assurance of the safety and 

effectiveness of a class II device. These 

factors are discussed in the January 21, 

1998, Federal Register notice (63 FR 

3142) and subsequently in the guidance 

the Agency issued on February 19, 1998, 

entitled ‘‘Procedures for Class II Device 

Exemptions from Premarket 

Notification, Guidance for Industry and 

CDRH Staff’’ (referred to herein as the 

Class II 510(k) Exemption Guidance) 

(Ref. 1). 

III. Device Description 

On February 19, 2015, FDA 

completed its review of a De Novo 

request for classification of the 23andMe 


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