[Federal Register Volume 85, Number 182 (Friday, September 18, 2020)]
[Proposed Rules]
[Pages 58300-58307]
[FR Doc No: 2020-20716]

=======================================================================
-----------------------------------------------------------------------

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, To Be Renamed Quantitative
Cytomegalovirus Nucleic Acid Tests for Transplant Patient Management

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed amendment; proposed order; request for comments.

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

SUMMARY: The Food and Drug Administration (FDA or the Agency) is
proposing 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. FDA is also proposing a new device classification

regulation with the name ``quantitative cytomegalovirus (CMV) nucleic
acid tests for transplant patient management'' to identify these
devices along with the special controls that the Agency believes are
necessary to provide a reasonable assurance of safety and effectiveness
for the device. FDA is proposing this reclassification on its own
initiative. If finalized, this order will reclassify these types of
devices from class III (general controls and premarket approval) to
class II (general controls and special controls) and reduce the
regulatory burdens associated with these devices as manufacturers of
these types of devices will no longer be required to submit a premarket
approval application (PMA), but can instead submit a premarket
notification (510(k)) and obtain clearance, before marketing their
device.

DATES: Submit either electronic or written comments on the proposed
order by November 17, 2020. Please see section XII of this document for
the proposed effective date when the new requirements apply and for the
proposed effective date of a final order based on this proposed order.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before November 17, 2020. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of November 17, 2020. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal Rulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed below (see ``Written/Paper Submissions'' and
``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2016-N-2880 for ``Microbiology Devices; Reclassification of
Cytomegalovirus Deoxyribonucleic Acid Quantitative Assay Devices
Intended for Transplant Patient Management, To Be Renamed Quantitative
Cytomegalovirus Nucleic Acid Tests for Transplant Patient Management.''
Received comments, those filed in a timely manner (see ADDRESSSES) will
be placed in the docket and, except for those submitted as
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: 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,<PHONE_NUMBER>.

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_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as
amended, 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.
    FDA relies upon ``valid scientific evidence,'' as defined in
section 513(a)(3) of the FD&C Act and 21 CFR 860.7(c)(2), in the
classification process to determine the level of regulation for
devices. To be considered in the reclassification process, the ``valid
scientific evidence'' upon which the Agency relies must be publicly
available. Publicly available information excludes trade secret and/or
confidential commercial information, e.g., the contents of a pending
PMA application (see section 520(c) of the FD&C Act (21 U.S.C.
360j(c)).
    In accordance with section 513(f)(3) of the FD&C Act, FDA is
issuing this proposed order to reclassify CMV DNA quantitative assay
devices intended for transplant patient management, postamendments
class III devices, into class II (general controls and special
controls), subject to premarket notification because FDA believes the
standard in section 513(a)(1)(B) of the FD&C Act is met as there is
sufficient information to establish special controls, which in addition
to general controls, will provide reasonable assurance of the safety
and effectiveness of the device.\1\
---------------------------------------------------------------------------

    \1\ In December 2019, FDA began adding the term ``Proposed
amendment'' to the ``ACTION'' caption for these documents, typically
styled ``Proposed order'', to indicate that they ``propose to
amend'' 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.
---------------------------------------------------------------------------

    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 DNA quantitative assay devices intended for
transplant patient management. Therefore, the Agency does not intend to
exempt these proposed class II devices from premarket notification
(510(k)) submission as provided under section 510(m) of the FD&C Act.

II. Regulatory History of the Device

    In accordance with section 513(f)(1) of the FD&C Act, CMV DNA
quantitative assay devices intended for transplant patient management
were automatically classified into class III because they were not
introduced or delivered for introduction into interstate commerce for
commercial distribution before May 28, 1976, and have not been found
substantially equivalent to a device placed in commercial distribution
after May 28, 1976, which was subsequently classified or reclassified
into class II or class I. Therefore, the device is subject to PMA
requirements under section 515 of the FD&C Act (21 U.S.C. 360e).
    Accordingly, on July 5, 2012, the Center for Devices and
Radiological Health approved its first CMV DNA quantitative assay for
the quantitative measurement of CMV DNA in human
ethylenediaminetetraacetic acid plasma for use as a prescription device
as an aid in the management of transplant patients, through its PMA
process under section 515 of the FD&C Act. In the January 7, 2013,
Federal Register (78 FR 950) notice, FDA announced the PMA approval
order for the first CMV DNA quantitative device (Roche Molecular
Systems, Inc's COBAS AmpliPrep/COBAS TaqMan CMV Test) and the
availability of the Summary of Safety and Effectiveness Data (SSED) for
the device.
    Since this first approval order, FDA has approved three additional
original PMA applications for CMV DNA quantitative assay devices
intended for transplant patient management that are prescription
devices intended for use, by a qualified licensed healthcare
professional in conjunction with other relevant clinical and laboratory
findings, in the detection of CMV and as an aid in the management of
transplant patients with active CMV infection or at risk of developing
CMV infection by measuring CMV DNA levels in human plasma and/or whole
blood using validated specimen processing, amplification, and detection
instrumentation (hereafter referred to as ``CMV transplant assays.'')
These are prescription devices that are assigned the product code PAB.
As of the date of this proposed order, the Agency has not received any
recalls for these devices and has seen a relatively low incidence of
Medical Device Reports (MDRs).
    Based on a review of the MDR database, five MDRs have been received
for the original Roche Molecular Systems, Inc's COBAS AmpliPrep/COBAS
TaqMan CMV Test. These MDRs included one MedWatch report in 2015
describing a high false positive rate during performance verification,
one adverse event reported to FDA in May of 2014 for the
overquantitation of CMV, and three adverse events reported to FDA
between December 2015 and February 2017 for the underquantitation of
CMV. Evaluation of the patient samples from the 2015 and 2017 adverse
event reports revealed mismatches between the assay primers and patient
CMV sequences. Three additional MDRs were received between 2018 to 2019
for the ABBOTT Realtime CMV. All three adverse events were reports of
overquantification of CMV viral load and none of these reported adverse
events were associated with patient injury.
    These adverse events reflect the risks to health FDA identified in
section VI, and FDA believes the special controls proposed, in addition
to general controls, can effectively mitigate the risks identified in
these adverse event reports.

III. Device Description

    CMV transplant assays are postamendment prescription devices for
transplant patient management and are devices classified into class III
under section 513(f)(1) of the FD&C Act. These devices are described in
FDA SSEDs and in the product code database (assigned product code PAB)
as in vitro nucleic acid assays for the quantitative measurement of CMV
DNA in human plasma or whole blood. The assay can be used to measure
CMV DNA levels serially at baseline and during the course of antiviral
treatment to assess virological response to treatment. The test results
are to be interpreted within the context of all relevant clinical and
laboratory findings.
    FDA is proposing to reclassify CMV transplant assays from class III
(general controls and premarket approval) to class II (general controls
and special controls) and change the device type name to quantitative
CMV nucleic acid tests for transplant patient management. FDA believes
that the following description most accurately describes this device
type and proposes its use for these types of devices. A quantitative
CMV nucleic acid test for transplant patient management is tentatively
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 DNA levels in human plasma and/or whole blood using validated
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 a
qualified licensed healthcare professional in conjunction with other
relevant clinical and laboratory findings. A condition defined as the
isolation of virus or detection of viral proteins or viral nucleic acid
in any body fluid or tissue specimen (Ref. 1). CMV infection in the
setting of solid organ transplant or hematopoietic stem cell
transplantation has previously been associated with significant patient
morbidity, including organ rejection, end organ disease and death (Ref.
2). Currently, CMV transplant assays are used as an aid in the
management of transplant patients with active CMV infection or at risk
of developing CMV infection. The introduction of quantitative CMV
nucleic acid tests for transplant patient management into clinical
practice has helped to reduce the overall rates of CMV-associated
morbidity and mortality post-transplant by enabling detection and
quantification of CMV DNAemia (the presence of CMV DNA in blood or
plasma) in patients, and accordingly, earlier intervention when
necessary. CMV transplant assays are also used to assess patient
response during antiviral treatment in order to guide management
decisions.
    Healthcare professionals managing transplant patients with CMV
DNAemia or CMV infection often have substantial clinical experience
with quantitation of CMV DNA such that patient risks are reduced when
these tests are used for clinical management. Based upon our review
experience and consistent with the FD&C Act and FDA's regulations, FDA
believes that these devices should be reclassified from class III into
class II because there is sufficient information to establish special
controls that, along with general controls, can provide reasonable
assurance of the devices' safety and effectiveness.

IV. Proposed Reclassification

    FDA is proposing to reclassify CMV transplant assay devices. On
November 9, 2016, the Microbiology Devices Panel (Panel) of the Medical
Devices Advisory Committee convened to discuss and make recommendations
regarding the reclassification of CMV transplant assays from class III
(general controls and premarket approval) into class II (general
controls and special controls). Panel members unanimously agreed that
special controls, in addition to general controls, are necessary and
sufficient to mitigate the risks to the health of transplant patients
presented by these devices (Ref. 4).
    FDA agrees and believes that at this time, sufficient data and
information exist such that the risks identified in section VI can be
mitigated by establishing special controls that, together with general
controls, can provide a reasonable assurance of the safety and
effectiveness of these devices and therefore proposes these devices be
reclassified from class III (general controls and premarket approval)
to class II (general controls and special controls).
    In accordance with section 513(f)(3) of the FD&C Act and 21 CFR
part 860, subpart C, FDA is proposing to reclassify postamendments CMV
transplant assays to be renamed ``quantitative CMV nucleic acid tests
for transplant patient management,'' from class III into class II. FDA
believes, at this time, that there is sufficient data and information
available to FDA through FDA's accumulated experience with these
devices from review submissions, recommendations provided by
professional organizations, and from published literature, as well as
the recommendations provided by the Panel, to demonstrate that the
proposed special controls, along with general controls, would
effectively mitigate the risks to health identified in section VI and
provide a reasonable assurance of safety and effectiveness of these
devices. Absent the special controls identified in this proposed order,
general controls applicable to the device type are insufficient to
provide reasonable assurance of the safety and effectiveness of these
devices. FDA expects that the reclassification of these devices would
enable more manufacturers to develop quantitative CMV nucleic acid
tests for transplant patient management such that patients would
benefit from increased access to safe and effective tests.
    FDA is proposing to create a classification regulation for
quantitative CMV nucleic acid tests for transplant patient management
that will be reclassified from class III to class II. Under this
proposed order, if finalized, quantitative CMV nucleic acid tests for
transplant patient management will be identified as a prescription
device as these prescription devices require the supervision of a
practitioner licensed by law to direct the use of the device in order
to ensure accurate interpretation of results and so that these devices
will 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 this proposed order, if finalized, the Agency has
identified the special controls under section 513(a)(1)(B) of the FD&C
Act that, together with general controls, will provide a reasonable
assurance of the safety and effectiveness for quantitative CMV nucleic
acid tests for transplant patient management devices.
    Section 510(m) of the FD&C Act provides that FDA may exempt a class
II device from the premarket notification requirements under section
510(k) of the FD&C Act if FDA determines that premarket notification is
not necessary to provide reasonable assurance of the safety and
effectiveness of the device. For quantitative CMV nucleic acid tests
for transplant patient management, FDA has determined that premarket
notification is necessary to provide a reasonable assurance of the
safety and effectiveness of these devices. Therefore, FDA does not
intend to exempt these proposed class II devices from the 510(k)
requirements. If this proposed order is finalized, persons who intend
to market this type of device must submit a 510(k) to FDA and receive
clearance prior to marketing the device.
    This proposed order, if finalized, will decrease regulatory burden
on industry, as manufacturers will no longer have to submit a PMA
application for these types of devices but can instead submit a 510(k)
to the Agency for review prior to marketing their device. A 510(k)
typically results in a shorter premarket review timeline compared to a
PMA application, which ultimately provides more timely access of these
types of devices to patients.
    In addition, the Agency believes that certain changes could be made
to quantitative CMV nucleic acid tests for transplant patient
management 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).
---------------------------------------------------------------------------

    \2\ See 21 CFR 807.81(a)(3)(i).
---------------------------------------------------------------------------

V. Risks to Health

    The incidence of CMV infection among transplant patients is highly
variable and is dependent upon multiple factors, most importantly the
serostatus of the donor/recipient pair, the type of transplant the
patient received, and the recommended course of immunosuppressive
therapy. If left untreated, transplant patients with CMV infection have
significant risk of developing severe CMV-associated diseases,
including gastroenteritis, pneumonia, hepatitis, pancreatitis, and
myocarditis. However, the risk of CMV-associated morbidity and
mortality has been considerably lowered with effective post-transplant
prophylactic and preemptive antiviral treatments, combined with the use
of quantitative CMV nucleic acid tests for transplant patient
management as part of the current standard monitoring practices.
    After consideration of FDA's accumulated experience with these
devices from review submissions, the recommendations provided by
professional organizations, the recommendations of the Panel for the
classification of these devices (Ref. 4), and published literature, FDA
has identified the following probable risks to health associated with
quantitative CMV nucleic acid tests for transplant patient management:
     Inaccurate interpretation of test results. Inaccurate
interpretation of test results by clinicians may lead to misdiagnosis
with potentially significant impact on patient management.
     Risk of false results (inaccurately low or false negative
test result and inaccurately high or false positive test results). An
inaccurately low or false negative test result may cause withholding or
discontinuation of antiviral therapy which can lead to serious injury,
including death. An inaccurately high or false positive test result
could lead to the unnecessary initiation of treatment, a change in
therapy and/or prolonged duration of therapy, and increased patient
risk to the potential adverse effects of CMV antiviral medications.
     Decreased test sensitivity and/or increased rates of false
negative test reporting. Decreased test sensitivity and/or increased
rates of false negative test reporting may occur with patient samples
containing high CMV strain variability, de novo mutations in genomic
regions of CMV targeted by the device, or undetectable CMV in the
peripheral blood which can occur in CMV infected patients with tissue
invasive disease. Increased rates of false negative test reporting due
to drift in accuracy due to changes in the viral genomic target may
also pose significant risks to patient health.
     Variability in CMV viral load measurement across different
devices. Variability in CMV viral load measurement across different
devices may influence patient management decisions (e.g., a less
sensitive test could lead to earlier discontinuation of treatment),
even if performed appropriately.

VI. Summary of the Reasons for Reclassification

    FDA believes that quantitative CMV nucleic acid tests for
transplant patient management should be reclassified from class III
(general controls and premarket approval) into class II (general
controls and special controls) because special controls, in addition to
general controls, can be established to mitigate the risks to health
identified in section VI and provide a reasonable assurance of the
safety and effectiveness of these devices. The proposed special
controls are identified by FDA in section VII.
    Taking into account the probable health benefits of the use of
these devices and the nature and known incidence of the risks of the
devices, FDA, on its own initiative, is proposing to reclassify these
postamendments class III devices into class II. FDA believes that, when
used as indicated, quantitative CMV nucleic acid tests for transplant
patient management can provide significant benefits to clinicians and
patients, including guiding therapeutic intervention in the setting of
CMV DNAemia and assessment of virological response to anti-CMV therapy.
    FDA's reasons for reclassification are based on the scientific and
medical information available regarding the nature, complexity, and
risks associated with quantitative CMV nucleic acid tests for
transplant patient management. The safety and effectiveness of this
device type has become well established since the initial approval of
the first CMV transplant assay in 2012. Quantitative CMV nucleic acid
tests for transplant patient management have been used for clinical
management of transplant patients nationally and internationally for
many years. The Transplantation Society International CMV Consensus
Group has published recommendations that serve to standardize the
clinical practice for CMV viral load measurement in the context of
transplant patient management (Ref. 5).

VII. Proposed Special Controls

    FDA believes that these devices can be classified into class II
with the establishment of special controls. FDA believes that the
following special controls, together with general controls will provide
reasonable assurance of the safety and effectiveness of the device
type, table 1 demonstrates how these proposed special controls will
mitigate each of the risks to health identified in section VII.
    The risk of inaccurate interpretation of test results can be
mitigated by special controls requiring certain labeling, including
clearly stated warnings and limitations and information on the
principles of operation and procedures in performing the test.
    The risk of false results (e.g., inaccurately low-test result or a
false negative test result and inaccurately high-test result or false
positive test result) can be mitigated through a combination of special
controls including certain labeling requirements, certain design
verification and validation information, and performance studies.
Examples of labeling mitigations include certain warnings and
limitations, as well as a detailed explanation of the interpretation of
results and detailed explanation of principles of operation and
procedures for the device. Required statements in the labeling can aid
in mitigating the failure of the device to perform as indicated.
Examples of verification and validation information to be included in
the design of the devices includes documentation of performance
specifications including analytical and clinical design specifications
and the use of appropriate data analysis methods for method comparison
studies, and documentation of a complete device description,
calibrators, critical reagents, traceability, lot release criteria,
stability studies, and protocols.
    The risk of decreased test sensitivity and/or increased rates of
false negative test reporting can be mitigated by special controls
related to certain labeling, design verification and validation
activities, failure mode analysis, and performance studies.
    Risks associated with test variability in CMV viral load
measurement across different devices may influence patient management
decisions and could lead to adverse effects on patient health. To
mitigate such risks, new devices must be calibrated to an FDA
acceptable standardized reference standard material determined by FDA
to be an appropriate reference material and must

demonstrate continued traceability to appropriate standardized
reference materials. The risk attributable to variability between
different manufacturers' devices may also be mitigated through specific
warnings in the labeling.
    This reclassification order and the identified special controls, if
finalized, would provide sufficient detail regarding FDA's requirements
to reasonably assure safety and effectiveness of quantitative CMV
nucleic acid tests for transplant patient management.

  Table 1--Risks to Health and Mitigation Measures for Quantitative CMV
          Nucleic Acid Tests for Transplant Patient Management
------------------------------------------------------------------------
    Identified risks to health               Mitigation measures
------------------------------------------------------------------------
Inaccurate interpretation of test   Certain labeling warnings,
 results.                            limitations, results interpretation
                                     information, and explanation of
                                     procedures.
Risk of false results.............  Certain labeling warnings,
                                     limitations, results interpretation
                                     information, and explanation of
                                     procedures; Certain design
                                     verification and validation
                                     information, including
                                     documentation of device
                                     descriptions, calibrators, critical
                                     reagents, traceability, lot release
                                     criteria, stability studies and
                                     protocols, and documentation of
                                     analytical and clinical studies.
Decreased test sensitivity and/or   Certain labeling warnings,
 increased rates of false negative   limitations, results interpretation
 test reporting.                     information, and explanation of
                                     procedures; Certain design
                                     verification and validation
                                     information, including
                                     traceability, lot release criteria,
                                     risk analysis, device descriptions
                                     and specifications, analytical
                                     studies, and clinical studies.
Variability in CMV viral load       Certain results interpretation
 measurement across different        information in labeling; Certain
 devices.                            design verification and validation
                                     information, including
                                     documentation of device
                                     descriptions and specifications,
                                     analytical studies, clinical
                                     studies, and traceability studies.
------------------------------------------------------------------------

    If this proposed order is finalized, quantitative CMV nucleic acid
tests for transplant patient management will be reclassified into class
II (general controls and special controls) and would be subject to
premarket notification requirements under section 510(k) of the FD&C
Act. As discussed below, the intent is for the reclassification to be
codified in 21 CFR 866.3180. Firms submitting a premarket notification
under section 510(k) of the FD&C Act for quantitative CMV nucleic acid
tests for transplant patient management will be required to comply with
the particular mitigation measures set forth in the special controls.
Adherence to the special controls, in addition to the general controls,
is necessary to provide a reasonable assurance of the safety and
effectiveness of these devices.

VIII. 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.

IX. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed order contains no new
collections of information. Therefore, clearance by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(PRA) (44 U.S.C. 3501-3521) is not required. However, this proposed
order refers to previously approved collections of information. These
collections of information are subject to review by OMB under the PRA.
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.

X. 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), in the proposed order, we
are proposing to codify CMV transplant assays in the new 21 CFR
866.3180 under which CMV transplant assays will be renamed quantitative
CMV nucleic acid tests for transplant patient management and would be
reclassified from class III into class II.

XI. Proposed Effective Date

    FDA proposes that any final order based on this proposed order
become effective 30 days after its date of publication in the Federal
Register.

XII. 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. FDA has verified the website addresses as of
the date this document publishes in the Federal Register, but 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. p. 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).
*4. Transcript of the FDA Microbiology Devices Panel Meeting,
November 9, 2016 (available at https://www.fda.gov/

downloads/AdvisoryCommittees/CommitteesMeetingMaterials/
MedicalDevices/MedicalDevicesAdvisoryCommittee/
MicrobiologyDevicesPanel/UCM531275.pdf).
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, it is
proposed that 21 CFR part 866 be 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 (CMV) 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.

    (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 15, 2020.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2020-20716 Filed 9-17-20; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register Volume 78, Number 58 (Tuesday, March 26, 2013)]
[Rules and Regulations]
[Pages 18232-18233]
[FR Doc No: 2013-06365]

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

DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 71

[Docket No. FAA-2013-0179; Airspace Docket No. 05-AGL-6]
RIN 2120-AA66

Amendment of VOR Federal Airway V-233, Springfield, IL

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Final rule, technical amendment.

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

SUMMARY: This action amends VHF Omnidirectional Range (VOR) Federal
Airway V-233 in the vicinity of Springfield, IL. The FAA is taking this
action to correct the V-233 description contained in Part 71 to ensure
it matches the information contained in the FAA's aeronautical
database, matches the depiction on the associated charts, and ensures
the safety and efficiency of the National Airspace System (NAS).

DATES: Effective date 0901 UTC March 26, 2013. The Director of the
Federal Register approves this incorporation by reference action under
1 CFR part 51, subject to the annual revision of FAA Order 7400.9 and
publication of conforming amendments.

FOR FURTHER INFORMATION CONTACT: Colby Abbott, Airspace Policy and ATC
Procedures Group, Office of Mission Support Services, Federal Aviation
Administration, 800 Independence Avenue SW., Washington, DC 20591;
telephone:<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

History

    After a recent review of aeronautical data, the Aeronautical
Navigation Products Group identified the VOR Federal airway V-233
description did not match the airway information contained in the FAA's
aeronautical database or the charted depiction of the airway. When V-
233 was amended in the Federal Register of August 8, 2005 (70 FR
45527), the airway was realigned to reflect a radial change due to the
relocation of the Spinner VHF Omnidirectional Range Tactical Air
Navigation (VORTAC) navigation aid. However, the final rule erroneously
used the magnetic radial information from the Spinner VORTAC to
describe the fix between the Spinner VORTAC and the Roberts VOR/
Distance Measuring Equipment (VOR/DME) navigation aids instead of the
true radial information that should have been used. The FAA
aeronautical database contains the correct radial information for
describing the airway fix between the Spinner VORTAC and Roberts VOR/
DME in the airway description and the associated aeronautical charts
remain published correctly. To overcome any confusion or flight safety
issues associated with conflicting airway description information being
published, the FAA is amending the V-233 legal description to reflect
the correct Spinner VORTAC radial information.

The Rule

    The FAA amends Title 14 Code of Federal Regulations (14 CFR) part
71 by amending the legal description of VOR Federal airway V-233 in the
vicinity of Springfield, IL. Specifically, the FAA amends V-233 to
reflect the true radial information from the Spinner VORTAC (061[deg]
radial) to describe the fix between the Spinner VORTAC and Roberts VOR/
DME navigation aids; thus, matching the information currently contained
in the FAA's aeronautical database and the charted depiction of the
airway.
    VOR Federal airways are listed in paragraph 6010 of FAA Order
7400.9W dated August 8, 2012, and effective September 15, 2012, which
is incorporated by reference in 14 CFR 71.1. The VOR Federal airway
listed in this document will be revised subsequently in the Order.
    Accordingly, since this is an administrative correction to update
the V-233 description to be in concert with the FAA's aeronautical
database and charting, notice and public procedures under Title 5
U.S.C. 553(b) are unnecessary.
    The FAA has determined that this regulation only involves an
established body of technical regulations for which frequent and
routine amendments are necessary to keep them operationally current.
Therefore, this regulation: (1) Is not a ``significant regulatory
action'' under Executive Order 12866; (2) is not a ``significant rule''
under Department of Transportation (DOT) Regulatory Policies and
Procedures (44 FR 11034; February 26, 1979); and (3) does not warrant
preparation of a regulatory evaluation as the anticipated impact is so
minimal. Since this is a routine matter that will only affect air
traffic procedures and air navigation, it is certified that this rule,
when promulgated, will not have a significant economic impact on a
substantial number of small entities under the criteria of the
Regulatory Flexibility Act.
    The FAA's authority to issue rules regarding aviation safety is
found in Title 49 of the United States Code. Subtitle I, Section 106
describes the authority of the FAA Administrator. Subtitle VII,
Aviation Programs, describes in more detail the scope of the agency's
authority. This rulemaking is promulgated under the authority described
in Subtitle VII, Part A, Subpart I, Section 40103. Under that section,
the FAA is charged with prescribing regulations to assign the use of
the airspace necessary to ensure the safety of aircraft and the
efficient use of airspace. This regulation is within the scope of that
authority as it amends an existing VOR Federal airway within the NAS.

Environmental Review

    The FAA has determined that this action qualifies for categorical
exclusion under the National Environmental Policy Act in accordance
with 311a, FAA Order 1050.1E, ``Environmental Impacts: Policies and
Procedures.'' This airspace action is not expected to cause any
potentially significant environmental impacts, and no extraordinary
circumstances exist that warrant preparation of an environmental
assessment.

List of Subjects in 14 CFR Part 71

    Airspace, Incorporation by reference, Navigation (air).

Adoption of the Amendment

    In consideration of the foregoing, the Federal Aviation
Administration amends 14 CFR part 71 as follows:

PART 71--DESIGNATION OF CLASS A, B, C, D, AND E AIRSPACE AREAS; AIR
TRAFFIC SERVICE ROUTES; AND REPORTING POINTS

0
1. The authority citation for 14 CFR part 71 continues to read as
follows:

    Authority:  49 U.S.C. 106(g), 40103, 40113, 40120; E.O. 10854,
24 FR 9565, 3 CFR, 1959-1963 Comp., p. 389.

Sec.  71.1  [Amended]

0
2. The incorporation by reference in 14 CFR 71.1 of FAA Order 7400.9W,
Airspace Designations and Reporting Points, signed August 8, 2012, and

effective September 15, 2012, is amended as follows:

Paragraph 6010 VOR Federal Airways.

    (a) Domestic VOR Federal airways.
* * * * *

V-233

    From Spinner, IL; INT Spinner 061[deg] and Roberts, IL, 233[deg]
radials; Roberts; Knox, IN; Goshen, IN; Litchfield, MI; Lansing, MI;
Mount Pleasant, MI; INT Mount Pleasant 351[deg] and Gaylord, MI,
207[deg] radials; Gaylord; to Pellston, MI.
* * * * *

    Issued in Washington, DC, March 13, 2013.
Gary A. Norek,
Manager, Airspace Policy and ATC Procedures Group.
[FR Doc. 2013-06365 Filed 3-25-13; 8:45 am]
BILLING CODE 4910-13-P