Microbiology Devices; Reclassification of Cytomegalovirus Deoxyribonucleic Acid Quantitative Assay Devices Intended for Transplant Patient Management, 77448-77451 [2024-21616]
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Federal Register / Vol. 89, No. 184 / Monday, September 23, 2024 / Rules and Regulations
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Issued on August 1, 2024.
Peter A. White,
Deputy Director, Integrated Certificate
Management Division, Aircraft Certification
Service.
[FR Doc. 2024–21557 Filed 9–20–24; 8:45 am]
BILLING CODE 4910–13–P
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DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA–2016–N–2880]
Microbiology Devices; Reclassification
of Cytomegalovirus Deoxyribonucleic
Acid Quantitative Assay Devices
Intended for Transplant Patient
Management
Food and Drug Administration
(FDA), Department of Health and
Human Services (HHS).
ACTION: Final amendment; final order.
AGENCY:
The Food and Drug
Administration (FDA or the Agency) is
issuing a final order to reclassify
cytomegalovirus (CMV)
deoxyribonucleic acid (DNA)
quantitative assay devices intended for
transplant patient management, a
postamendments class III device
(product code PAB) into class II (general
controls and special controls), subject to
premarket notification.
DATES: This order is effective October
23, 2024.
ADDRESSES: For access to the docket to
read background documents or the
electronic and-written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852, 240–402–7500.
FOR FURTHER INFORMATION CONTACT:
Silke Schlottmann, Center for Devices
and Radiological Health, Food and Drug
Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 3258, Silver Spring,
MD 20993–0002, 301–796–9551,
Silke.Schlottmann@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
SUMMARY:
I. Background—Regulatory Authorities
The Federal Food, Drug, and Cosmetic
Act (FD&C Act), as amended, by the
Medical Device Amendments of 1976
(the 1976 amendments) (Pub. L. 94–
295), the Safe Medical Devices Act of
1990 (Pub. L. 101–629), the Food and
Drug Administration Modernization Act
of 1997 (Pub. L. 105–115), the Medical
Device User Fee and Modernization Act
of 2002 (Pub. L. 107–250), the Medical
Devices Technical Corrections Act (Pub.
L. 108–214), the Food and Drug
Administration Amendments Act of
2007 (Pub. L. 110–85), and the Food and
Drug Administration Safety and
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Innovation Act (Pub. L. 112–144),
among other amendments, establishes a
comprehensive system for the regulation
of medical devices intended for human
use. Section 513 of the FD&C Act (21
U.S.C. 360c) established three classes of
devices, reflecting the regulatory
controls needed to provide reasonable
assurance of their safety and
effectiveness. The three classes of
devices are class I (general controls),
class II (general controls and special
controls), and class III (general controls
and premarket approval).
Devices that were not in commercial
distribution prior to May 28, 1976
(generally referred to as
postamendments devices) are
automatically classified by section
513(f)(1) of the FD&C Act into class III
without any FDA rulemaking process.
Those devices remain in class III and
require premarket approval, unless and
until: (1) FDA reclassifies the device
into class I or class II or (2) FDA issues
an order finding the device to be
substantially equivalent, in accordance
with section 513(i) of the FD&C Act, to
a predicate device that does not require
premarket approval. FDA determines
whether new devices are substantially
equivalent to predicate devices by
means of premarket notification
procedures in section 510(k) of the
FD&C Act (21 U.S.C. 360(k)) and part
807 (21 CFR part 807), subpart E, of
FDA’s regulations.
A postamendments device that has
been initially classified in class III
under section 513(f)(1) of the FD&C Act
may be reclassified into class I or II
under section 513(f)(3) of the FD&C Act.
Section 513(f)(3) of the FD&C Act
provides that FDA, acting by
administrative order, can reclassify the
device into class I or class II on its own
initiative, or in response to a petition
from the manufacturer or importer of
the device. To change the classification
of the device, the proposed new class
must have sufficient regulatory controls
to provide a reasonable assurance of the
safety and effectiveness of the device for
its intended use.
In the Federal Register of September
18, 2020 (85 FR 58300), FDA published
a proposed order to reclassify CMV
DNA quantitative assay devices
intended for transplant patient
management (‘‘CMV transplant assays’’)
from class III into class II (general and
special controls), subject to premarket
notification. The comment period on the
proposed order closed on November 17,
2020. FDA received two comments on
the proposed order, both of which were
supportive of the reclassification from
Class III to Class II and agreed with FDA
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Federal Register / Vol. 89, No. 184 / Monday, September 23, 2024 / Rules and Regulations
that CMV transplant assays should be
subject to premarket notification.
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II. The Final Order
Based on the information discussed in
the preamble to the proposed order (85
FR 58300), the supportive comments
received on the proposed order, and
FDA’s experience over the years with
this device type, FDA concludes that
special controls, in conjunction with
general controls, will provide
reasonable assurance of the safety and
effectiveness of CMV transplant assays.
Therefore, in accordance with section
513(f)(3) of the FD&C Act, FDA is
issuing this final order to reclassify
CMV transplant assays from class III
into class II, subject to premarket
notification. This final order will be
codified at 21 CFR 866.3180.1 In this
final order, FDA has identified special
controls under section 513(a)(1)(B) of
the FD&C Act, which in addition to
general controls, will provide
reasonable assurance of the safety and
effectiveness of the device. FDA is
reclassifying these devices and
establishing the special controls as
published in the proposed order
without change.
Section 510(m) of the FD&C Act
provides that a class II device may be
exempted from the premarket
notification requirements under section
510(k) of the FD&C Act, if the Agency
determines that premarket notification
is not necessary to reasonably assure the
safety and effectiveness of the device.
FDA has determined that premarket
notification is necessary to reasonably
assure the safety and effectiveness of
CMV transplant assays. Therefore, the
Agency does not intend to exempt these
class II devices from premarket
notification (510(k)) submission as
provided under section 510(m) of the
FD&C Act.
The devices that are the subject of this
reclassification are assigned the generic
name ‘‘quantitative CMV nucleic acid
tests for transplant patient
management.’’ These devices are
identified as a quantitative CMV nucleic
acid test for transplant patient
management, a device intended for
prescription use in the detection of
CMV and as an aid in the management
of transplant patients to measure CMV
DNA levels in human plasma and/or
1 In December 2019, FDA began adding the term
‘‘Final amendment’’ to the ‘‘ACTION’’ caption for
these documents, typically styled ‘‘Final order,’’ to
indicate an amendment to the Code of Federal
Regulations. This editorial change was made in
accordance with the Office of Federal Register’s
interpretations of the Federal Register Act (44
U.S.C. chapter 15), its implementing regulations (1
CFR 5.9 and parts 21 and 22), and the Document
Drafting Handbook.
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whole blood using specified specimen
processing, amplification, and detection
instrumentation. The test is intended for
use as an aid in the management of
transplant patients with active CMV
infection or at risk for developing CMV
infection. The test results are intended
to be interpreted by qualified healthcare
professionals in conjunction with other
relevant clinical and laboratory
findings.
Under this final order, CMV
transplant assays are prescription
devices requiring the supervision of a
practitioner licensed by law to direct the
use of the devices in order to ensure
accurate interpretation of results,
ensuring the devices provide a
reasonable assurance of safety and
effectiveness. As such, the prescription
device must satisfy prescription labeling
requirements for in vitro diagnostic
products (see 21 CFR 809.10(a)(4) and
(b)(5)(ii)).
In addition, the Agency believes that
certain changes could be made to CMV
transplant assays that could
significantly affect the safety and
effectiveness of those devices and for
which a new 510(k) is likely required.2
Based on FDA’s accumulated
experience with these devices, changes
that likely could significantly affect the
safety and effectiveness of these devices
include, but are not limited to, changes
to critical reagents, changes to final
release specifications, and changes in
shelf life of the device. For more
information about when to submit a
new 510(k), manufacturers should refer
to FDA’s guidance entitled ‘‘Deciding
When to Submit at 510(k) for a Change
to an Existing Device’’ (Ref. 3).
III. Implementation Strategy
The order is effective 30 days after its
date of publication in the Federal
Register.
IV. 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.
V. Paperwork Reduction Act of 1995
This final order establishes special
controls that refer to previously
approved collections of information
found in other FDA regulations and
guidance. Those collections of
information are subject to review by the
Office of Management and Budget
2 See
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21 CFR 807.81(a)(3)(i).
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77449
(OMB) under the Paperwork Reduction
Act of 1995 (PRA) (44 U.S.C. 3501–
3521). The collections of information in
21 CFR part 807, subpart E, have been
approved under OMB control number
0910–0120, the collections of
information in 21 CFR part 820 have
been approved under OMB control
number 0910–0073, and the collections
of information in 21 CFR parts 801 and
809 have been approved under OMB
control number 0910–0485.
VI. Codification of Orders
Under section 513(f)(3) of the FD&C
Act, FDA may issue final orders to
reclassify devices. FDA will continue to
codify classifications and
reclassifications in the Code of Federal
Regulations (CFR). Changes resulting
from final orders will appear in the CFR
as newly codified orders. Therefore,
under section 513(f)(3), CMV transplant
assays are codified in the new 21 CFR
866.3180 under which CMV transplant
assays are renamed quantitative CMV
nucleic acid tests for transplant patient
management and are reclassified from
class III into class II.
VII. References
The following references marked with
an asterisk (*) 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. References
without asterisks are not on public
display at https://www.regulations.gov
because they have copyright restriction.
Some may be available at the website
address, if listed. References without
asterisks are available for viewing only
at the Dockets Management Staff.
Although FDA verified the website
addresses in this document, please note
that websites are subject to change over
time.
1. Ljungman P., M. Boeckh, H.H. Hirsch, et
al., ‘‘Definitions of CMV Infection and
Disease in Transplant Patients for Use in
Clinical Trials,’’ Clinical Infectious
Diseases, 64(1):87–91, 2017.
2. Singh, N. and A.P. Limaye, ‘‘Infections in
Solid-Organ Transplant Recipients,’’
Mandell, Douglas, and Bennett’s
Principles and Practice of Infectious
Diseases, 7th Edition, Philadelphia
(PA):Elsevier, pp. 3440–3452, 2015.
*3. ‘‘Deciding When to Submit a 510(k) for
a Change to an Existing Device—
Guidance for Industry and Food and
Drug Administration Staff,’’ issued
October 25, 2017 (available at https://
www.fda.gov/MedicalDevices/Device
RegulationandGuidance/Guidance
Documents/UCM514771).
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Federal Register / Vol. 89, No. 184 / Monday, September 23, 2024 / Rules and Regulations
*4. Transcript of the FDA Microbiology
Devices Panel Meeting, November 9,
2016 (available at https://www.fda.gov/
advisory-committees/microbiologydevices-panel/2016-meeting-materialsmicrobiology-devices-panel).
5. Kotton, C.N., D. Kumar, A.M. Caliendo, et
al., ‘‘Updated International Consensus
Guidelines on the Management of
Cytomegalovirus in Solid-Organ
Transplantation,’’ Transplantation
96(4):333–360, 2013.
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 § 866.3180 to subpart D to
read as follows:
■
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§ 866.3180 Quantitative cytomegalovirus
nucleic acid tests for transplant patient
management.
(a) Identification. A quantitative
cytomegalovirus (CMV) nucleic acid test
for transplant patient management is
identified as a device intended for
prescription use in the detection of
CMV and as an aid in the management
of transplant patients to measure CMV
deoxyribonucleic acid (DNA) levels in
human plasma and/or whole blood
using specified specimen processing,
amplification, and detection
instrumentation. The test is intended for
use as an aid in the management of
transplant patients with active CMV
infection or at risk for developing CMV
infection. The test results are intended
to be interpreted by qualified healthcare
professionals in conjunction with other
relevant clinical and laboratory
findings.
(b) Classification. Class II (special
controls). The special controls for this
device are:
(1) The labeling required under
§ 809.10(b) of this chapter must include:
(i) A prominent statement that the
device is not intended for use as a donor
screening test for the presence of CMV
DNA in blood or blood products.
(ii) Limitations, which must be
updated to reflect current clinical
practice. The limitations must include,
but are not limited to, statements that
indicate:
(A) Test results are to be interpreted
by qualified licensed healthcare
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professionals in conjunction with
clinical signs and symptoms and other
relevant laboratory results;
(B) Negative test results do not
preclude CMV infection or tissue
invasive CMV disease, and that CMV
test results must not be the sole basis for
patient management decisions.
(iii) A detailed explanation of the
interpretation of results and acceptance
criteria must be provided and include
specific warnings regarding the
potential for variability in CMV viral
load measurement when samples are
measured by different devices.
Warnings must include the following
statement, where applicable: ‘‘Due to
the potential for variability in CMV viral
load measurements across different
CMV assays, it is recommended that the
same device be used for the quantitation
of CMV viral load when managing CMV
infection in individual patients.’’
(iv) A detailed explanation of the
principles of operation and procedures
for assay performance.
(2) Design verification and validation
must include the following:
(i) Detailed documentation of the
device description, including all parts
that make up the device, reagents
required for use with the CMV assay but
not provided, an explanation of the
methodology, design of the primer/
probe sequences, rationale for the
selected gene target, and specifications
for amplicon size, guanine-cytosine
content, and degree of nucleic acid
sequence conservation. The design and
nature of all primary, secondary, and
tertiary quantitation standards used for
calibration must also be described.
(ii) A detailed description of the
impact of any software, including
software applications and hardwarebased devices that incorporate software,
on the device’s function.
(iii) Documentation and
characterization of all critical reagents
(e.g., determination of the identity,
supplier, purity, and stability) and
protocols for maintaining product
integrity throughout its labeled shelf
life.
(iv) Stability data for reagents
provided with the device and indicated
specimen types, in addition to the basis
for the stability acceptance criteria at all
time points chosen across the spectrum
of the device’s indicated life cycle,
which must include a time point at the
end of shelf life.
(v) All stability protocols, including
acceptance criteria.
(vi) Final lot release criteria, along
with documentation of an appropriate
justification that lots released at the
extremes of the specifications will meet
the claimed analytical and clinical
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performance characteristics as well as
the stability claims.
(vii) Risk analysis and documentation
demonstrating how risk control
measures are implemented to address
device system hazards, such as Failure
Modes Effects Analysis and/or Hazard
Analysis. This documentation must
include a detailed description of a
protocol (including all procedures and
methods) for the continuous monitoring,
identification, and handling of genetic
mutations and/or novel CMV stains
(e.g., regular review of published
literature and annual in silico analysis
of target sequences to detect possible
primer or probe mismatches). All results
of this protocol, including any findings,
must be documented.
(viii) Analytical performance testing
that includes:
(A) Detailed documentation of the
following analytical performance
studies: Limit of detection, upper and
lower limits of quantitation, inclusivity,
precision, reproducibility, interference,
cross reactivity, carryover, quality
control, specimen stability studies, and
additional studies as applicable to
specimen type and intended use for the
device.
(B) Identification of the CMV strains
selected for use in analytical studies,
which must be representative of
clinically relevant circulating strains.
(C) Inclusivity study results obtained
with a variety of CMV genotypes as
applicable to the specific assay target
and supplemented by in silico analysis.
(D) Reproducibility studies that
include the testing of three independent
production lots.
(E) Documentation of calibration to a
standardized reference material that
FDA has determined is appropriate for
the quantification of CMV DNA (e.g., a
recognized consensus standard).
(F) Documentation of traceability
performed each time a new lot of the
standardized reference material to
which the device is traceable is
released, or when the field transitions to
a new standardized reference material.
(ix) Clinical performance testing that
includes:
(A) Detailed documentation of device
performance data from either a method
comparison study with a comparator
that FDA has determined is appropriate,
or results from a prospective clinical
study demonstrating clinical validity of
the device.
(B) Data from patient samples, with an
acceptable number of the CMV positive
samples containing an analyte
concentration near the lower limit of
quantitation and any clinically relevant
decision points.
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(C) The method comparison study
must include predefined maximum
acceptable differences between the test
and comparator method across all
primary outcome measures in the
clinical study protocol.
(D) The final release test results for
each lot used in the clinical study.
Dated: September 17, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
CFR Code of Federal Regulations
COTP Captain of the Port
DHS Department of Homeland Security
FR Federal Register
NPRM Notice of proposed rulemaking
NAD 83 North American Datum 1983
§ Section
U.S.C. United States Code
MASSDOT Massachusetts Department of
Transportation
BILLING CODE 4164–01–P
DEPARTMENT OF HOMELAND
SECURITY
Coast Guard
33 CFR Part 165
[Docket Number USCG–2024–0820]
RIN 1625–AA00
Safety Zone; Kernwood Avenue Bridge
Repairs—Danvers River, Salem, MA,
and Beverly, MA
Coast Guard, DHS.
Temporary Interim Rule and
request for comments.
AGENCY:
ACTION:
The Coast Guard is
establishing a temporary safety zone on
the navigable waters at mile 1.0 Danvers
River, within a 100-yard radius of the
center point of the Kernwood Avenue
Bridge between Salem, MA and Beverly,
MA. The temporary safety zone is
necessary to protect personnel, vessels
and the marine environment from
potential hazards created during bridge
repairs. When enforced, entry of vessels
or persons into this zone is prohibited
unless specifically authorized by the
Captain of the Port Boston or a
designated representative.
DATES:
Effective date: This rule is effective
without actual notice from September
23, 2024 through 11:59 p.m. on
December 31, 2024. For the purposes of
enforcement, actual notice will be used
from September 15, 2024, until
September 23, 2024.
Comments due date: Comments and
related material must be received by the
Coast Guard on or before October 23,
2024.
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SUMMARY:
You may submit comments
identified by docket number USCG–
2024–0820 using the Federal eRulemaking Portal at https://
www.regulations.gov. See the ‘‘Public
Participation and Request for
Comments’’ portion of the
SUPPLEMENTARY INFORMATION section for
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If
you have questions about this
rulemaking, call or email Mr. Timothy
Chase, Waterways Management
Division, U.S. Coast Guard Sector
Boston, telephone 617–447–1620, or
email Timothy.w.chase@uscg.mil.
SUPPLEMENTARY INFORMATION:
FOR FURTHER INFORMATION CONTACT:
I. Table of Abbreviations
[FR Doc. 2024–21616 Filed 9–20–24; 8:45 am]
ADDRESSES:
further instructions on submitting
comments.
II. Background Information and
Regulatory History
On August 28, 2024, the
Massachusetts Department of
Transportation (MassDOT) bridge
division notified the Waterways
Management Division of U. S. Coast
Guard Sector Boston that operations to
make repairs to the Kernwood Avenue
Bridge, spanning the Danvers River
between Salem, MA, and Beverly, MA,
will begin September 15, 2024.
The Coast Guard is issuing this
temporary rule under the authority in 5
U.S.C. 553(b)(B). This statutory
provision authorizes an agency to issue
a rule without prior notice and
opportunity to comment when the
agency for good cause finds that those
procedures are ‘‘impracticable,
unnecessary, or contrary to the public
interest.’’ The Coast Guard finds that
good cause exists for not publishing a
notice of proposed rulemaking (NPRM)
with respect to this rule because the
construction schedule for Kernwood
Avenue Bridge was only recently
finalized and prompt action is needed to
respond to the potential safety hazards
associated with this project. It is
impracticable and contrary to the public
interest to publish an NPRM because
prompt action is needed to establish this
safety zone by September 15, 2024, to
allow for the timely repairs to the
Kernwood Avenue Bridge and ensure
the safety of mariners transiting the area
from the dangers associated with the
operations associated with these repairs.
Also, under 5 U.S.C. 553(d)(3), the
Coast Guard finds that good cause exists
for making this rule effective less than
30 days after publication in the Federal
Register. Delaying the effective date of
this rule would be impracticable
because prompt action is needed to
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77451
ensure public safety during repair
operations to the Kernwood Avenue
Bridge.
Although this regulation is published
as an interim rule without prior notice,
public comment is nevertheless
desirable to ensure that the regulation is
both workable and reasonable.
Accordingly, persons wishing to
comment may do so by submitting
written comments as set out under
ADDRESSES in this preamble.
Commenters should include their names
and addresses, identify the docket
number for the regulation, and give
reasons for their comments. If the Coast
Guard determines that changes to the
temporary interim rule are necessary,
we will publish a temporary final rule
or other appropriate document.
III. Legal Authority and Need for Rule
The Coast Guard is issuing this rule
under authority in 46 U.S.C. 70034. The
Captain of the Port Boston (COTP) has
determined that potential hazards
associated with bridge repair operations
starting September 15, 2024, will be a
safety concern for anyone within a 100yard radius of the center point of the
Kernwood Avenue Bridge. This rule is
needed to protect personnel, vessels,
and the marine environment in the
navigable waters within the safety zone
while bridge repair operations are taking
place.
IV. Discussion of Rule
This rule establishes a safety zone
from September 15, 2024, through 11:59
p.m. on December 31, 2024. While the
safety zone will be effective through this
period, it will only be enforced during
active repair operations, when work
barges and cranes will be placed in the
narrow navigable channel, or other
instances which may create a hazard to
navigation. The active repair operations
will take place during the overnight
hours, from 9 p.m. through 5 a.m.,
Sunday through Thursday, when
boating traffic is minimal.
The safety zone will cover all
navigable waters within a 100-yard
radius of the center point of the
MassDOT Kernwood Avenue Bridge, at
mile 1.0, spanning the Danvers River,
between Salem, MA, and Beverly, MA,
in approximate position 42°32′34.8″ N
70°53′54.2″ W (NAD 83). During times
of enforcement, all persons or vessels
will be prohibited from entering the
safety zone without permission from the
COTP or a designated representative.
The Coast Guard will make notice of
the safety zone via the Local Notice to
Mariners and issue a Broadcast Notice
to Mariners via marine channel 16
(VHF–FM) as soon as practicable in
E:\FR\FM\23SER1.SGM
23SER1
Agencies
[Federal Register Volume 89, Number 184 (Monday, September 23, 2024)]
[Rules and Regulations]
[Pages 77448-77451]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-21616]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2016-N-2880]
Microbiology Devices; Reclassification of Cytomegalovirus
Deoxyribonucleic Acid Quantitative Assay Devices Intended for
Transplant Patient Management
AGENCY: Food and Drug Administration (FDA), Department of Health and
Human Services (HHS).
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
issuing a final order to reclassify cytomegalovirus (CMV)
deoxyribonucleic acid (DNA) quantitative assay devices intended for
transplant patient management, a postamendments class III device
(product code PAB) into class II (general controls and special
controls), subject to premarket notification.
DATES: This order is effective October 23, 2024.
ADDRESSES: For access to the docket to read background documents or the
electronic and-written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Silke Schlottmann, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 3258, Silver Spring, MD 20993-0002, 301-
796-9551, [email protected].
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended, by
the Medical Device Amendments of 1976 (the 1976 amendments) (Pub. L.
94-295), the Safe Medical Devices Act of 1990 (Pub. L. 101-629), the
Food and Drug Administration Modernization Act of 1997 (Pub. L. 105-
115), the Medical Device User Fee and Modernization Act of 2002 (Pub.
L. 107-250), the Medical Devices Technical Corrections Act (Pub. L.
108-214), the Food and Drug Administration Amendments Act of 2007 (Pub.
L. 110-85), and the Food and Drug Administration Safety and Innovation
Act (Pub. L. 112-144), among other amendments, establishes a
comprehensive system for the regulation of medical devices intended for
human use. Section 513 of the FD&C Act (21 U.S.C. 360c) established
three classes of devices, reflecting the regulatory controls needed to
provide reasonable assurance of their safety and effectiveness. The
three classes of devices are class I (general controls), class II
(general controls and special controls), and class III (general
controls and premarket approval).
Devices that were not in commercial distribution prior to May 28,
1976 (generally referred to as postamendments devices) are
automatically classified by section 513(f)(1) of the FD&C Act into
class III without any FDA rulemaking process. Those devices remain in
class III and require premarket approval, unless and until: (1) FDA
reclassifies the device into class I or class II or (2) FDA issues an
order finding the device to be substantially equivalent, in accordance
with section 513(i) of the FD&C Act, to a predicate device that does
not require premarket approval. FDA determines whether new devices are
substantially equivalent to predicate devices by means of premarket
notification procedures in section 510(k) of the FD&C Act (21 U.S.C.
360(k)) and part 807 (21 CFR part 807), subpart E, of FDA's
regulations.
A postamendments device that has been initially classified in class
III under section 513(f)(1) of the FD&C Act may be reclassified into
class I or II under section 513(f)(3) of the FD&C Act. Section
513(f)(3) of the FD&C Act provides that FDA, acting by administrative
order, can reclassify the device into class I or class II on its own
initiative, or in response to a petition from the manufacturer or
importer of the device. To change the classification of the device, the
proposed new class must have sufficient regulatory controls to provide
a reasonable assurance of the safety and effectiveness of the device
for its intended use.
In the Federal Register of September 18, 2020 (85 FR 58300), FDA
published a proposed order to reclassify CMV DNA quantitative assay
devices intended for transplant patient management (``CMV transplant
assays'') from class III into class II (general and special controls),
subject to premarket notification. The comment period on the proposed
order closed on November 17, 2020. FDA received two comments on the
proposed order, both of which were supportive of the reclassification
from Class III to Class II and agreed with FDA
[[Page 77449]]
that CMV transplant assays should be subject to premarket notification.
II. The Final Order
Based on the information discussed in the preamble to the proposed
order (85 FR 58300), the supportive comments received on the proposed
order, and FDA's experience over the years with this device type, FDA
concludes that special controls, in conjunction with general controls,
will provide reasonable assurance of the safety and effectiveness of
CMV transplant assays. Therefore, in accordance with section 513(f)(3)
of the FD&C Act, FDA is issuing this final order to reclassify CMV
transplant assays from class III into class II, subject to premarket
notification. This final order will be codified at 21 CFR 866.3180.\1\
In this final order, FDA has identified special controls under section
513(a)(1)(B) of the FD&C Act, which in addition to general controls,
will provide reasonable assurance of the safety and effectiveness of
the device. FDA is reclassifying these devices and establishing the
special controls as published in the proposed order without change.
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\1\ In December 2019, FDA began adding the term ``Final
amendment'' to the ``ACTION'' caption for these documents, typically
styled ``Final order,'' to indicate an amendment to the Code of
Federal Regulations. This editorial change was made in accordance
with the Office of Federal Register's interpretations of the Federal
Register Act (44 U.S.C. chapter 15), its implementing regulations (1
CFR 5.9 and parts 21 and 22), and the Document Drafting Handbook.
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Section 510(m) of the FD&C Act provides that a class II device may
be exempted from the premarket notification requirements under section
510(k) of the FD&C Act, if the Agency determines that premarket
notification is not necessary to reasonably assure the safety and
effectiveness of the device. FDA has determined that premarket
notification is necessary to reasonably assure the safety and
effectiveness of CMV transplant assays. Therefore, the Agency does not
intend to exempt these class II devices from premarket notification
(510(k)) submission as provided under section 510(m) of the FD&C Act.
The devices that are the subject of this reclassification are
assigned the generic name ``quantitative CMV nucleic acid tests for
transplant patient management.'' These devices are identified as a
quantitative CMV nucleic acid test for transplant patient management, a
device intended for prescription use in the detection of CMV and as an
aid in the management of transplant patients to measure CMV DNA levels
in human plasma and/or whole blood using specified specimen processing,
amplification, and detection instrumentation. The test is intended for
use as an aid in the management of transplant patients with active CMV
infection or at risk for developing CMV infection. The test results are
intended to be interpreted by qualified healthcare professionals in
conjunction with other relevant clinical and laboratory findings.
Under this final order, CMV transplant assays are prescription
devices requiring the supervision of a practitioner licensed by law to
direct the use of the devices in order to ensure accurate
interpretation of results, ensuring the devices provide a reasonable
assurance of safety and effectiveness. As such, the prescription device
must satisfy prescription labeling requirements for in vitro diagnostic
products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)).
In addition, the Agency believes that certain changes could be made
to CMV transplant assays that could significantly affect the safety and
effectiveness of those devices and for which a new 510(k) is likely
required.\2\ Based on FDA's accumulated experience with these devices,
changes that likely could significantly affect the safety and
effectiveness of these devices include, but are not limited to, changes
to critical reagents, changes to final release specifications, and
changes in shelf life of the device. For more information about when to
submit a new 510(k), manufacturers should refer to FDA's guidance
entitled ``Deciding When to Submit at 510(k) for a Change to an
Existing Device'' (Ref. 3).
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\2\ See 21 CFR 807.81(a)(3)(i).
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III. Implementation Strategy
The order is effective 30 days after its date of publication in the
Federal Register.
IV. 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.
V. Paperwork Reduction Act of 1995
This final order establishes special controls that refer to
previously approved collections of information found in other FDA
regulations and guidance. Those collections of information are subject
to review by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521). The
collections of information in 21 CFR part 807, subpart E, have been
approved under OMB control number 0910-0120, the collections of
information in 21 CFR part 820 have been approved under OMB control
number 0910-0073, and the collections of information in 21 CFR parts
801 and 809 have been approved under OMB control number 0910-0485.
VI. Codification of Orders
Under section 513(f)(3) of the FD&C Act, FDA may issue final orders
to reclassify devices. FDA will continue to codify classifications and
reclassifications in the Code of Federal Regulations (CFR). Changes
resulting from final orders will appear in the CFR as newly codified
orders. Therefore, under section 513(f)(3), CMV transplant assays are
codified in the new 21 CFR 866.3180 under which CMV transplant assays
are renamed quantitative CMV nucleic acid tests for transplant patient
management and are reclassified from class III into class II.
VII. References
The following references marked with an asterisk (*) 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. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. Although FDA verified the website addresses
in this document, please note that websites are subject to change over
time.
1. Ljungman P., M. Boeckh, H.H. Hirsch, et al., ``Definitions of CMV
Infection and Disease in Transplant Patients for Use in Clinical
Trials,'' Clinical Infectious Diseases, 64(1):87-91, 2017.
2. Singh, N. and A.P. Limaye, ``Infections in Solid-Organ Transplant
Recipients,'' Mandell, Douglas, and Bennett's Principles and
Practice of Infectious Diseases, 7th Edition, Philadelphia
(PA):Elsevier, pp. 3440-3452, 2015.
*3. ``Deciding When to Submit a 510(k) for a Change to an Existing
Device--Guidance for Industry and Food and Drug Administration
Staff,'' issued October 25, 2017 (available at https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM514771).
[[Page 77450]]
*4. Transcript of the FDA Microbiology Devices Panel Meeting,
November 9, 2016 (available at https://www.fda.gov/advisory-committees/microbiology-devices-panel/2016-meeting-materials-microbiology-devices-panel).
5. Kotton, C.N., D. Kumar, A.M. Caliendo, et al., ``Updated
International Consensus Guidelines on the Management of
Cytomegalovirus in Solid-Organ Transplantation,'' Transplantation
96(4):333-360, 2013.
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. Add Sec. 866.3180 to subpart D to read as follows:
Sec. 866.3180 Quantitative cytomegalovirus nucleic acid tests for
transplant patient management.
(a) Identification. A quantitative cytomegalovirus (CMV) nucleic
acid test for transplant patient management is identified as a device
intended for prescription use in the detection of CMV and as an aid in
the management of transplant patients to measure CMV deoxyribonucleic
acid (DNA) levels in human plasma and/or whole blood using specified
specimen processing, amplification, and detection instrumentation. The
test is intended for use as an aid in the management of transplant
patients with active CMV infection or at risk for developing CMV
infection. The test results are intended to be interpreted by qualified
healthcare professionals in conjunction with other relevant clinical
and laboratory findings.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) The labeling required under Sec. 809.10(b) of this chapter
must include:
(i) A prominent statement that the device is not intended for use
as a donor screening test for the presence of CMV DNA in blood or blood
products.
(ii) Limitations, which must be updated to reflect current clinical
practice. The limitations must include, but are not limited to,
statements that indicate:
(A) Test results are to be interpreted by qualified licensed
healthcare professionals in conjunction with clinical signs and
symptoms and other relevant laboratory results;
(B) Negative test results do not preclude CMV infection or tissue
invasive CMV disease, and that CMV test results must not be the sole
basis for patient management decisions.
(iii) A detailed explanation of the interpretation of results and
acceptance criteria must be provided and include specific warnings
regarding the potential for variability in CMV viral load measurement
when samples are measured by different devices. Warnings must include
the following statement, where applicable: ``Due to the potential for
variability in CMV viral load measurements across different CMV assays,
it is recommended that the same device be used for the quantitation of
CMV viral load when managing CMV infection in individual patients.''
(iv) A detailed explanation of the principles of operation and
procedures for assay performance.
(2) Design verification and validation must include the following:
(i) Detailed documentation of the device description, including all
parts that make up the device, reagents required for use with the CMV
assay but not provided, an explanation of the methodology, design of
the primer/probe sequences, rationale for the selected gene target, and
specifications for amplicon size, guanine-cytosine content, and degree
of nucleic acid sequence conservation. The design and nature of all
primary, secondary, and tertiary quantitation standards used for
calibration must also be described.
(ii) A detailed description of the impact of any software,
including software applications and hardware-based devices that
incorporate software, on the device's function.
(iii) Documentation and characterization of all critical reagents
(e.g., determination of the identity, supplier, purity, and stability)
and protocols for maintaining product integrity throughout its labeled
shelf life.
(iv) Stability data for reagents provided with the device and
indicated specimen types, in addition to the basis for the stability
acceptance criteria at all time points chosen across the spectrum of
the device's indicated life cycle, which must include a time point at
the end of shelf life.
(v) All stability protocols, including acceptance criteria.
(vi) Final lot release criteria, along with documentation of an
appropriate justification that lots released at the extremes of the
specifications will meet the claimed analytical and clinical
performance characteristics as well as the stability claims.
(vii) Risk analysis and documentation demonstrating how risk
control measures are implemented to address device system hazards, such
as Failure Modes Effects Analysis and/or Hazard Analysis. This
documentation must include a detailed description of a protocol
(including all procedures and methods) for the continuous monitoring,
identification, and handling of genetic mutations and/or novel CMV
stains (e.g., regular review of published literature and annual in
silico analysis of target sequences to detect possible primer or probe
mismatches). All results of this protocol, including any findings, must
be documented.
(viii) Analytical performance testing that includes:
(A) Detailed documentation of the following analytical performance
studies: Limit of detection, upper and lower limits of quantitation,
inclusivity, precision, reproducibility, interference, cross
reactivity, carryover, quality control, specimen stability studies, and
additional studies as applicable to specimen type and intended use for
the device.
(B) Identification of the CMV strains selected for use in
analytical studies, which must be representative of clinically relevant
circulating strains.
(C) Inclusivity study results obtained with a variety of CMV
genotypes as applicable to the specific assay target and supplemented
by in silico analysis.
(D) Reproducibility studies that include the testing of three
independent production lots.
(E) Documentation of calibration to a standardized reference
material that FDA has determined is appropriate for the quantification
of CMV DNA (e.g., a recognized consensus standard).
(F) Documentation of traceability performed each time a new lot of
the standardized reference material to which the device is traceable is
released, or when the field transitions to a new standardized reference
material.
(ix) Clinical performance testing that includes:
(A) Detailed documentation of device performance data from either a
method comparison study with a comparator that FDA has determined is
appropriate, or results from a prospective clinical study demonstrating
clinical validity of the device.
(B) Data from patient samples, with an acceptable number of the CMV
positive samples containing an analyte concentration near the lower
limit of quantitation and any clinically relevant decision points.
[[Page 77451]]
(C) The method comparison study must include predefined maximum
acceptable differences between the test and comparator method across
all primary outcome measures in the clinical study protocol.
(D) The final release test results for each lot used in the
clinical study.
Dated: September 17, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-21616 Filed 9-20-24; 8:45 am]
BILLING CODE 4164-01-P