Document ID: FDA-2015-N-3455-0005
Agency: fda
Document Type: Rule
Title: Medical Devices: Exemption From Premarket Notification; Class II Devices; Autosomal Recessive Carrier Screening Gene Mutation Detection System
Posted Date: 2017-11-07T05:00Z

[Federal Register Volume 82, Number 214 (Tuesday, November 7, 2017)]
[Rules and Regulations]
[Pages 51567-51570]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-24162]

-----------------------------------------------------------------------

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

[[Page 51568]]

Personal Genome Service (PGS) Carrier Screening Test for Bloom 
syndrome. FDA classified the 23andMe PGS Carrier Screening Test for 
Bloom syndrome, and substantially equivalent devices of this generic 
type, into class II (special controls) under the generic name 
``Autosomal recessive carrier screening gene mutation detection 
system.'' This type of device is a qualitative in vitro molecular 
diagnostic system used for genotyping of clinically relevant variants 
in genomic DNA isolated from human specimens intended for prescription 
use or over-the-counter (OTC) use. The device is intended for autosomal 
recessive disease carrier screening in adults of reproductive age. The 
device is not intended for copy number variation, cytogenetic, or 
biochemical testing.
    FDA believes that 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 determining 
substantial equivalence for future devices within that type (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 a premarket approval application 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.
    In the Federal Register of October 27, 2015 (80 FR 65774), FDA 
published a notice (``October 2015 notice'') announcing its intent to 
exempt autosomal recessive carrier screening gene mutation detection 
system devices from premarket notification requirements, subject to 
certain limitations, and provided opportunity for interested persons to 
submit comments by November 27, 2015. After reviewing comments received 
(summarized in section IV), FDA is now providing its final 
determination for autosomal recessive carrier screening gene mutation 
detection system devices by exempting this type of device from 
premarket notification requirements, subject to certain limitations as 
identified in this notice. 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. Persons with pending 510(k) submissions for devices that 
are now exempt from premarket notification, subject to the limitations, 
should withdraw their submissions.

IV. Comments on the Proposed Exemption and FDA Response

    In response to the October 2015 notice announcing FDA's intent to 
exempt autosomal recessive carrier screening gene mutation detection 
system devices from premarket notification requirements, FDA received 
submissions from three commenters--a device industry manufacturer, a 
professional organization, and a health care organization--supporting 
an exemption from premarket notification for this type of device.
    To make it easier to identify comments and our responses, the word 
``Comment'' and a comment number appear in parentheses before each 
comment's description, and the word ``Response'' in parentheses 
precedes each response. Similar comments are grouped together under the 
same number. Specific issues raised by the comments and the Agency's 
responses follow.
    (Comment 1) Two commenters requested that FDA clarify that the list 
of autosomal recessive carrier diseases included in the October 2015 
notice is not exhaustive or expand the list of diseases and conditions 
covered by the exemption to include all diseases and conditions 
described in the scientific literature as inherited in an autosomal 
recessive manner. One commenter further requested that FDA clarify that 
the determination of the applicability of Sec.  866.5940 (21 CFR 
866.5940) should be based upon scientific and clinical literature as to 
the autosomal recessive nature of the disease or condition.
    (Response) The diseases and conditions listed in table 1 of the 
October 2015 notice were based upon a limited review of the scientific 
and clinical literature at that time. After consideration of the public 
comments, FDA agrees that the autosomal recessive diseases and 
conditions listed in that table should be treated as illustrative, and 
not an exhaustive list. Based on FDA's review of current scientific and 
clinical literature, FDA would not consider screening for autosomal 
recessive carrier status by detection of clinically relevant gene 
mutations associated with a large variety of diseases and conditions, 
in addition to those listed in table 1 of the October 2015 notice, to 
constitute a different intended use from that of a legally marketed 
device in the generic type under Sec.  866.5940 for purposes of Sec.  
866.9 (21 CFR 866.9). Because FDA agrees that the list of diseases and 
conditions provided in the October 2015 notice is not comprehensive, 
and that applicability of Sec.  866.5940 should be based upon 
scientific and clinical literature as to the autosomal recessive nature 
of a particular disease or condition, we are not providing a revised 
list in this final order.
    (Comment 2) One commenter requested clarification that Sec.  
866.5940 applies to OTC carrier detection devices for the determination 
of carrier status by detection of clinically relevant gene mutations 
associated with cystic fibrosis.
    (Response) In the October 2015 notice, FDA stated ``[a] gene 
mutation detection system indicated for the determination of carrier 
status by detection of clinically relevant gene mutations associated 
with Cystic Fibrosis is not 510(k)-exempt since it is a class II device 
subject to premarket notification and special controls under 21 CFR 
866.5900--Cystic fibrosis transmembrane conductance regulator (CFTR) 
gene mutation detection system.'' Similarly, in the final order 
announcing the classification of an autosomal recessive carrier 
screening gene mutation detection system into class II (80 FR 65626, 
October 27, 2015), FDA stated ``A gene mutation detection system 
indicated for the determination of carrier status by detection of 
clinically relevant gene mutations associated with cystic fibrosis is 
separately classified under 21 CFR 866.5900--Cystic fibrosis 
transmembrane conductance regulator (CFTR) gene mutation detection 
system (class II, special controls), and is thus not included in the de 
novo classification.''
    However, after considering the comments regarding this exemption 
action, and after reviewing the devices that are classified as CTFR 
gene mutation detection systems under Sec.  866.5900 (21 CFR 866.5900), 
FDA is now clarifying that an OTC gene mutation detection system 
indicated for the determination of autosomal recessive carrier status 
by detection of clinically relevant gene mutations associated with 
cystic fibrosis (``OTC Cystic Fibrosis carrier screening test'') is 
included within the scope of the classification regulation for an 
autosomal recessive carrier screening gene mutation detection system 
(Sec.  866.5940) and this exemption action.
    At the time FDA classified a CFTR gene mutation detection system 
under Sec.  866.5900, we were not aware of any OTC Cystic Fibrosis 
carrier screening tests, and it was not our intent at the time to 
classify this test for OTC use. We also note that, to date, the only 
Cystic Fibrosis carrier screening tests that have been cleared by FDA 
under Sec.  866.5900 are for prescription use only. Finally,

[[Page 51569]]

FDA does not believe that the special controls under Sec.  866.5900(b) 
would reasonably assure the safety and effectiveness of OTC Cystic 
Fibrosis carrier screening tests, as such special controls were 
developed to be applicable to prescription use only tests. For example, 
when classifying a CFTR gene mutation detection system into class II, 
FDA determined that the special controls under Sec.  866.5900(b), in 
conjunction with general controls, provided a reasonable assurance of 
the safety and effectiveness of the device. One risk to health that FDA 
identified was that ``errors in interpretation of results may lead to 
improper clinical recommendations and medical patient management.'' The 
special controls concerning generation of test results, interpretation 
of test results, and precautions for interpretation of the test results 
were developed only for prescription use only tests with health care 
providers in mind (see Section 6--Device Description; Test Results/
Reporting, Section 10--Labeling; Interpretation of Results, and Section 
10--Labeling; Precautions for interpretations of the ``Class II Special 
Controls Guidance Document: CFTR Gene Mutation Detection Systems'' 
(October 26, 2005) (Ref. 2).
    Therefore, FDA is clarifying that with regard to gene mutation 
detection systems indicated for the determination of carrier status by 
detection of clinically relevant gene mutations associated with cystic 
fibrosis, the classification regulation Sec.  866.5900 is only 
applicable to prescription use only tests. FDA is further clarifying 
that we would not consider a gene mutation detection system indicated 
for use as an OTC device for the determination of carrier status by 
detection of clinically relevant gene mutations associated with cystic 
fibrosis to constitute a different intended use from that of a legally 
marketed device in the generic type Sec.  866.5940 for purposes of 
Sec.  866.9(a). As such, OTC Cystic Fibrosis carrier screening tests 
are within the scope of the classification regulation for an autosomal 
recessive carrier screening gene mutation detection system (Sec.  
866.5940) and are included within the scope of this action.
    (Comment 3) One commenter requested that the exemption be expanded 
to include carrier screening for X-linked conditions. The commenter 
further requested that the exemption be expanded to allow for the 
reporting of diagnostic results.
    (Response) The October 2015 notice and this final order concern the 
exemption from premarket notification of autosomal recessive carrier 
screening gene mutation detection systems in the generic type Sec.  
866.5940. Devices within the scope of the Sec.  866.5940 regulation for 
autosomal recessive carrier screening gene mutation detection systems 
are intended for autosomal recessive carrier screening in adults of 
reproductive age. The requested indications for carrier screening for 
X-linked conditions and for reporting of diagnostic results are outside 
the scope of the Sec.  866.5940 regulation. As this final order 
concerns only exemption of devices within the Sec.  866.5940 
regulation, the request to expand the exemption to include carrier 
screening for X-linked conditions or for the reporting of diagnostic 
results is outside the scope of this action.
    (Comment 4) The three commenters were generally supportive of the 
regulation and special controls established for the device type, 
including for the special controls that relate to genetic counseling 
(e.g., Sec.  866.5940(b)(1) and (b)(4)(iii)(A)). Two commenters 
requested FDA provide additional recommendations that relate to the 
special control requirements related to genetic counseling.
    (Response) FDA appreciates the comments supporting the regulation 
and special controls established for the device type. FDA believes that 
the class II special controls established for the device type, along 
with the applicable general controls, provides reasonable assurance of 
the safety and effectiveness of the device type. FDA notes that while 
the comments received did not propose specific amendments to the 
special control requirements, such discussion is outside the scope of 
the October 2015 notice and this final order, which concerns the 
exemption from premarket notification of autosomal recessive carrier 
screening gene mutation detection systems in the generic type Sec.  
866.5940.

V. Exemption for Autosomal Recessive Carrier Screening Gene Mutation 
Detection System Devices

    FDA has assessed the need for 510(k) clearance for this type of 
device by considering the factors discussed in the January 21, 1998, 
Federal Register notice (63 FR 3142) and subsequently in the Class II 
510(k) Exemption Guidance, as previously discussed in the October 2015 
notice, and has determined they weigh in favor of 510(k) exemption, 
subject to certain limitations discussed later in this order. 
Therefore, for the reasons set forth in the Federal Register of October 
27, 2015, and as informed by the comments received and FDA's 
understanding and experience with autosomal recessive carrier screening 
gene detection systems, FDA has determined that premarket notification 
is not necessary to assure the safety and effectiveness of autosomal 
recessive carrier screening gene detection systems, so long as the 
limitations on exemption described later in this document are not met.

VI. Limitations on Exemption

    This exemption from 510(k) for an autosomal recessive carrier 
screening gene mutation detection system applies only to those devices 
that have existing or reasonably foreseeable characteristics of 
commercially distributed devices within that generic type, or, in the 
case of in vitro diagnostic devices, for which a misdiagnosis, as a 
result of using the device, would not be associated with high morbidity 
or mortality. Therefore, a manufacturer of an autosomal recessive 
carrier screening gene mutation detection system would still be 
required to submit a premarket notification to FDA before introducing a 
device or delivering it for introduction into commercial distribution 
when the device meets any of the conditions described in Sec.  866.9, 
except Sec.  866.9(c)(2) to the extent it may include an autosomal 
recessive carrier screening gene mutation detection system, for the 
reasons explained in the October 2015 notice.
    Specifically, an autosomal recessive carrier screening gene 
mutation detection system is not exempt from the premarket notification 
requirement if such device: (1) Has an intended use that is different 
from the intended use of a legally marketed device in that generic 
type; e.g., the device is intended for a different medical purpose, or 
the device is intended for lay use where the former intended use was by 
health care professionals only; or (2) operates using a different 
fundamental scientific technology than that used by a legally marketed 
device in that generic type; e.g., a surgical instrument cuts tissue 
with a laser beam rather than with a sharpened metal blade, or an in 
vitro diagnostic device detects or identifies infectious agents by 
using a DNA probe or nucleic acid hybridization or amplification 
technology rather than culture or immunoassay technology; or (3) is an 
in vitro device that is intended: for use in the diagnosis, monitoring 
or screening of neoplastic diseases with the exception of 
immunohistochemical devices; for measuring an analyte which serves as a 
surrogate marker for screening, diagnosis, or monitoring of life 
threatening diseases, such as acquired immune deficiency syndrome 
(AIDS), chronic or active hepatitis, tuberculosis, or myocardial 
infarction, or to monitor therapy; for assessing the

[[Page 51570]]

risk of cardiovascular diseases; for use in diabetes management; for 
identifying or inferring the identity of a microorganism directly from 
clinical material; for detection of antibodies to microorganisms other 
than immunoglobulin G (IgG) and IgG assays when the results are not 
qualitative, or are used to determine immunity, or the assay is 
intended for use in matrices other than serum or plasma; for 
noninvasive testing; or for near-patient testing (point of care).
    Exemption from the requirement of premarket notification does not 
exempt a device from other applicable regulatory controls under the 
FD&C Act, including the applicable general and special controls. 
Indeed, FDA's decision to grant 510(k) exemption for these devices is 
based, in part, on the special controls, in combination with general 
controls, providing sufficiently rigorous mitigations for the risks 
identified for this generic type.
    This exemption from 510(k), subject to the limitations described 
above, 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 Federal 
regulation. Specifically, regulated industry will no longer have to 
invest time and resources in premarket notifications, including 
preparation of documents and data for submission to FDA, payment of 
user fees associated with 510(k) submissions, and responding to 
questions and requests for additional information from FDA during 
510(k) review for devices in this exempted type.

VII. Analysis of Environmental Impact

    We have 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.

VIII. Paperwork Reduction Act of 1995

    This notice refers to previously approved collections of 
information found in 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 21 CFR part 807, subpart, E have been 
approved under OMB control number 0910-0120 and the collections of 
information in 21 CFR parts 801 and 809 have been approved under OMB 
control number 0910-0485.

IX. References

    The following references are on display in the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the Web site addresses, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. FDA Guidance, ``Procedures for Class II Device Exemptions from 
Premarket Notification, Guidance for Industry and CDRH Staff,'' 
February 19, 1998, available at https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080199.pdf.
2. FDA Guidance for Industry and FDA Staff ``Class II Special 
Controls Guidance Document: CFTR Gene Mutation Detection Systems,'' 
October 26, 2005, available at: https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071104.pdf.

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

0
1. The authority citation for part 866 continues to read as follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

0
2. In Sec.  866.5940, revise paragraph (b) introductory text to read as 
follows:

Sec.  866.5940  Autosomal recessive carrier screening gene mutation 
detection system.

* * * * *
    (b) Classification. Class II (special controls). The device is 
exempt from the premarket notification procedures in subpart E of part 
807 of this chapter subject to the limitations in Sec.  866.9, except 
Sec.  866.9(c)(2). Autosomal recessive carrier screening gene mutation 
detection system must comply with the following special controls:
* * * * *

    Dated: November 1, 2017.
Lauren Silvis,
Chief of Staff.
[FR Doc. 2017-24162 Filed 11-6-17; 8:45 am]
BILLING CODE 4164-01-P