[Federal Register Volume 85, Number 182 (Friday, September 18, 2020)]
[Proposed Rules]
[Pages 58300-58307]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-20716]


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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, 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.

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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

[[Page 58301]]

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, 240-402-7500.
     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, 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 (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

[[Page 58302]]

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\
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    \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.
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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 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

[[Page 58303]]

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

[[Page 58304]]

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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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

[[Page 58305]]

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/

[[Page 58306]]

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.

[[Page 58307]]

    (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