[Federal Register Volume 89, Number 184 (Monday, September 23, 2024)]
[Rules and Regulations]
[Pages 77448-77451]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2024-21616]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2016-N-2880]


Microbiology Devices; Reclassification of Cytomegalovirus 
Deoxyribonucleic Acid Quantitative Assay Devices Intended for 
Transplant Patient Management

AGENCY: Food and Drug Administration (FDA), Department of Health and 
Human Services (HHS).

ACTION: Final amendment; final order.

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

SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
issuing a final order to reclassify cytomegalovirus (CMV) 
deoxyribonucleic acid (DNA) quantitative assay devices intended for 
transplant patient management, a postamendments class III device 
(product code PAB) into class II (general controls and special 
controls), subject to premarket notification.

DATES: This order is effective October 23, 2024.

ADDRESSES: For access to the docket to read background documents or the 
electronic and-written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: Silke Schlottmann, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, Rm. 3258, Silver Spring, MD 20993-0002, 301-
796-9551, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended, by 
the Medical Device Amendments of 1976 (the 1976 amendments) (Pub. L. 
94-295), the Safe Medical Devices Act of 1990 (Pub. L. 101-629), the 
Food and Drug Administration Modernization Act of 1997 (Pub. L. 105-
115), the Medical Device User Fee and Modernization Act of 2002 (Pub. 
L. 107-250), the Medical Devices Technical Corrections Act (Pub. L. 
108-214), the Food and Drug Administration Amendments Act of 2007 (Pub. 
L. 110-85), and the Food and Drug Administration Safety and Innovation 
Act (Pub. L. 112-144), among other amendments, establishes a 
comprehensive system for the regulation of medical devices intended for 
human use. Section 513 of the FD&C Act (21 U.S.C. 360c) established 
three classes of devices, reflecting the regulatory controls needed to 
provide reasonable assurance of their safety and effectiveness. The 
three classes of devices are class I (general controls), class II 
(general controls and special controls), and class III (general 
controls and premarket approval).
    Devices that were not in commercial distribution prior to May 28, 
1976 (generally referred to as postamendments devices) are 
automatically classified by section 513(f)(1) of the FD&C Act into 
class III without any FDA rulemaking process. Those devices remain in 
class III and require premarket approval, unless and until: (1) FDA 
reclassifies the device into class I or class II or (2) FDA issues an 
order finding the device to be substantially equivalent, in accordance 
with section 513(i) of the FD&C Act, to a predicate device that does 
not require premarket approval. FDA determines whether new devices are 
substantially equivalent to predicate devices by means of premarket 
notification procedures in section 510(k) of the FD&C Act (21 U.S.C. 
360(k)) and part 807 (21 CFR part 807), subpart E, of FDA's 
regulations.
    A postamendments device that has been initially classified in class 
III under section 513(f)(1) of the FD&C Act may be reclassified into 
class I or II under section 513(f)(3) of the FD&C Act. Section 
513(f)(3) of the FD&C Act provides that FDA, acting by administrative 
order, can reclassify the device into class I or class II on its own 
initiative, or in response to a petition from the manufacturer or 
importer of the device. To change the classification of the device, the 
proposed new class must have sufficient regulatory controls to provide 
a reasonable assurance of the safety and effectiveness of the device 
for its intended use.
    In the Federal Register of September 18, 2020 (85 FR 58300), FDA 
published a proposed order to reclassify CMV DNA quantitative assay 
devices intended for transplant patient management (``CMV transplant 
assays'') from class III into class II (general and special controls), 
subject to premarket notification. The comment period on the proposed 
order closed on November 17, 2020. FDA received two comments on the 
proposed order, both of which were supportive of the reclassification 
from Class III to Class II and agreed with FDA

[[Page 77449]]

that CMV transplant assays should be subject to premarket notification.

II. The Final Order

    Based on the information discussed in the preamble to the proposed 
order (85 FR 58300), the supportive comments received on the proposed 
order, and FDA's experience over the years with this device type, FDA 
concludes that special controls, in conjunction with general controls, 
will provide reasonable assurance of the safety and effectiveness of 
CMV transplant assays. Therefore, in accordance with section 513(f)(3) 
of the FD&C Act, FDA is issuing this final order to reclassify CMV 
transplant assays from class III into class II, subject to premarket 
notification. This final order will be codified at 21 CFR 866.3180.\1\ 
In this final order, FDA has identified special controls under section 
513(a)(1)(B) of the FD&C Act, which in addition to general controls, 
will provide reasonable assurance of the safety and effectiveness of 
the device. FDA is reclassifying these devices and establishing the 
special controls as published in the proposed order without change.
---------------------------------------------------------------------------

    \1\ In December 2019, FDA began adding the term ``Final 
amendment'' to the ``ACTION'' caption for these documents, typically 
styled ``Final order,'' to indicate an amendment to the Code of 
Federal Regulations. This editorial change was made in accordance 
with the Office of Federal Register's interpretations of the Federal 
Register Act (44 U.S.C. chapter 15), its implementing regulations (1 
CFR 5.9 and parts 21 and 22), and the Document Drafting Handbook.
---------------------------------------------------------------------------

    Section 510(m) of the FD&C Act provides that a class II device may 
be exempted from the premarket notification requirements under section 
510(k) of the FD&C Act, if the Agency determines that premarket 
notification is not necessary to reasonably assure the safety and 
effectiveness of the device. FDA has determined that premarket 
notification is necessary to reasonably assure the safety and 
effectiveness of CMV transplant assays. Therefore, the Agency does not 
intend to exempt these class II devices from premarket notification 
(510(k)) submission as provided under section 510(m) of the FD&C Act.
    The devices that are the subject of this reclassification are 
assigned the generic name ``quantitative CMV nucleic acid tests for 
transplant patient management.'' These devices are identified as a 
quantitative CMV nucleic acid test for transplant patient management, a 
device intended for prescription use in the detection of CMV and as an 
aid in the management of transplant patients to measure CMV DNA levels 
in human plasma and/or whole blood using specified specimen processing, 
amplification, and detection instrumentation. The test is intended for 
use as an aid in the management of transplant patients with active CMV 
infection or at risk for developing CMV infection. The test results are 
intended to be interpreted by qualified healthcare professionals in 
conjunction with other relevant clinical and laboratory findings.
    Under this final order, CMV transplant assays are prescription 
devices requiring the supervision of a practitioner licensed by law to 
direct the use of the devices in order to ensure accurate 
interpretation of results, ensuring the devices provide a reasonable 
assurance of safety and effectiveness. As such, the prescription device 
must satisfy prescription labeling requirements for in vitro diagnostic 
products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)).
    In addition, the Agency believes that certain changes could be made 
to CMV transplant assays that could significantly affect the safety and 
effectiveness of those devices and for which a new 510(k) is likely 
required.\2\ Based on FDA's accumulated experience with these devices, 
changes that likely could significantly affect the safety and 
effectiveness of these devices include, but are not limited to, changes 
to critical reagents, changes to final release specifications, and 
changes in shelf life of the device. For more information about when to 
submit a new 510(k), manufacturers should refer to FDA's guidance 
entitled ``Deciding When to Submit at 510(k) for a Change to an 
Existing Device'' (Ref. 3).
---------------------------------------------------------------------------

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

III. Implementation Strategy

    The order is effective 30 days after its date of publication in the 
Federal Register.

IV. Analysis of Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. Paperwork Reduction Act of 1995

    This final order establishes special controls that refer to 
previously approved collections of information found in other FDA 
regulations and guidance. Those collections of information are subject 
to review by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521). The 
collections of information in 21 CFR part 807, subpart E, have been 
approved under OMB control number 0910-0120, the collections of 
information in 21 CFR part 820 have been approved under OMB control 
number 0910-0073, and the collections of information in 21 CFR parts 
801 and 809 have been approved under OMB control number 0910-0485.

VI. Codification of Orders

    Under section 513(f)(3) of the FD&C Act, FDA may issue final orders 
to reclassify devices. FDA will continue to codify classifications and 
reclassifications in the Code of Federal Regulations (CFR). Changes 
resulting from final orders will appear in the CFR as newly codified 
orders. Therefore, under section 513(f)(3), CMV transplant assays are 
codified in the new 21 CFR 866.3180 under which CMV transplant assays 
are renamed quantitative CMV nucleic acid tests for transplant patient 
management and are reclassified from class III into class II.

VII. References

    The following references marked with an asterisk (*) are on display 
in the Dockets Management Staff (see ADDRESSES; and are available for 
viewing by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday; they are also available electronically at https://www.regulations.gov. References without asterisks are not on public 
display at https://www.regulations.gov because they have copyright 
restriction. Some may be available at the website address, if listed. 
References without asterisks are available for viewing only at the 
Dockets Management Staff. Although FDA verified the website addresses 
in this document, please note that websites are subject to change over 
time.

1. Ljungman P., M. Boeckh, H.H. Hirsch, et al., ``Definitions of CMV 
Infection and Disease in Transplant Patients for Use in Clinical 
Trials,'' Clinical Infectious Diseases, 64(1):87-91, 2017.
2. Singh, N. and A.P. Limaye, ``Infections in Solid-Organ Transplant 
Recipients,'' Mandell, Douglas, and Bennett's Principles and 
Practice of Infectious Diseases, 7th Edition, Philadelphia 
(PA):Elsevier, pp. 3440-3452, 2015.
*3. ``Deciding When to Submit a 510(k) for a Change to an Existing 
Device--Guidance for Industry and Food and Drug Administration 
Staff,'' issued October 25, 2017 (available at https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM514771).

[[Page 77450]]

*4. Transcript of the FDA Microbiology Devices Panel Meeting, 
November 9, 2016 (available at https://www.fda.gov/advisory-committees/microbiology-devices-panel/2016-meeting-materials-microbiology-devices-panel).
5. Kotton, C.N., D. Kumar, A.M. Caliendo, et al., ``Updated 
International Consensus Guidelines on the Management of 
Cytomegalovirus in Solid-Organ Transplantation,'' Transplantation 
96(4):333-360, 2013.

List of Subjects in 21 CFR Part 866

    Biologics, Laboratories, Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
866 is amended as follows:

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

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

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


0
2. Add Sec.  866.3180 to subpart D to read as follows:


Sec.  866.3180  Quantitative cytomegalovirus nucleic acid tests for 
transplant patient management.

    (a) Identification. A quantitative cytomegalovirus (CMV) nucleic 
acid test for transplant patient management is identified as a device 
intended for prescription use in the detection of CMV and as an aid in 
the management of transplant patients to measure CMV deoxyribonucleic 
acid (DNA) levels in human plasma and/or whole blood using specified 
specimen processing, amplification, and detection instrumentation. The 
test is intended for use as an aid in the management of transplant 
patients with active CMV infection or at risk for developing CMV 
infection. The test results are intended to be interpreted by qualified 
healthcare professionals in conjunction with other relevant clinical 
and laboratory findings.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The labeling required under Sec.  809.10(b) of this chapter 
must include:
    (i) A prominent statement that the device is not intended for use 
as a donor screening test for the presence of CMV DNA in blood or blood 
products.
    (ii) Limitations, which must be updated to reflect current clinical 
practice. The limitations must include, but are not limited to, 
statements that indicate:
    (A) Test results are to be interpreted by qualified licensed 
healthcare professionals in conjunction with clinical signs and 
symptoms and other relevant laboratory results;
    (B) Negative test results do not preclude CMV infection or tissue 
invasive CMV disease, and that CMV test results must not be the sole 
basis for patient management decisions.
    (iii) A detailed explanation of the interpretation of results and 
acceptance criteria must be provided and include specific warnings 
regarding the potential for variability in CMV viral load measurement 
when samples are measured by different devices. Warnings must include 
the following statement, where applicable: ``Due to the potential for 
variability in CMV viral load measurements across different CMV assays, 
it is recommended that the same device be used for the quantitation of 
CMV viral load when managing CMV infection in individual patients.''
    (iv) A detailed explanation of the principles of operation and 
procedures for assay performance.
    (2) Design verification and validation must include the following:
    (i) Detailed documentation of the device description, including all 
parts that make up the device, reagents required for use with the CMV 
assay but not provided, an explanation of the methodology, design of 
the primer/probe sequences, rationale for the selected gene target, and 
specifications for amplicon size, guanine-cytosine content, and degree 
of nucleic acid sequence conservation. The design and nature of all 
primary, secondary, and tertiary quantitation standards used for 
calibration must also be described.
    (ii) A detailed description of the impact of any software, 
including software applications and hardware-based devices that 
incorporate software, on the device's function.
    (iii) Documentation and characterization of all critical reagents 
(e.g., determination of the identity, supplier, purity, and stability) 
and protocols for maintaining product integrity throughout its labeled 
shelf life.
    (iv) Stability data for reagents provided with the device and 
indicated specimen types, in addition to the basis for the stability 
acceptance criteria at all time points chosen across the spectrum of 
the device's indicated life cycle, which must include a time point at 
the end of shelf life.
    (v) All stability protocols, including acceptance criteria.
    (vi) Final lot release criteria, along with documentation of an 
appropriate justification that lots released at the extremes of the 
specifications will meet the claimed analytical and clinical 
performance characteristics as well as the stability claims.
    (vii) Risk analysis and documentation demonstrating how risk 
control measures are implemented to address device system hazards, such 
as Failure Modes Effects Analysis and/or Hazard Analysis. This 
documentation must include a detailed description of a protocol 
(including all procedures and methods) for the continuous monitoring, 
identification, and handling of genetic mutations and/or novel CMV 
stains (e.g., regular review of published literature and annual in 
silico analysis of target sequences to detect possible primer or probe 
mismatches). All results of this protocol, including any findings, must 
be documented.
    (viii) Analytical performance testing that includes:
    (A) Detailed documentation of the following analytical performance 
studies: Limit of detection, upper and lower limits of quantitation, 
inclusivity, precision, reproducibility, interference, cross 
reactivity, carryover, quality control, specimen stability studies, and 
additional studies as applicable to specimen type and intended use for 
the device.
    (B) Identification of the CMV strains selected for use in 
analytical studies, which must be representative of clinically relevant 
circulating strains.
    (C) Inclusivity study results obtained with a variety of CMV 
genotypes as applicable to the specific assay target and supplemented 
by in silico analysis.
    (D) Reproducibility studies that include the testing of three 
independent production lots.
    (E) Documentation of calibration to a standardized reference 
material that FDA has determined is appropriate for the quantification 
of CMV DNA (e.g., a recognized consensus standard).
    (F) Documentation of traceability performed each time a new lot of 
the standardized reference material to which the device is traceable is 
released, or when the field transitions to a new standardized reference 
material.
    (ix) Clinical performance testing that includes:
    (A) Detailed documentation of device performance data from either a 
method comparison study with a comparator that FDA has determined is 
appropriate, or results from a prospective clinical study demonstrating 
clinical validity of the device.
    (B) Data from patient samples, with an acceptable number of the CMV 
positive samples containing an analyte concentration near the lower 
limit of quantitation and any clinically relevant decision points.

[[Page 77451]]

    (C) The method comparison study must include predefined maximum 
acceptable differences between the test and comparator method across 
all primary outcome measures in the clinical study protocol.
    (D) The final release test results for each lot used in the 
clinical study.

    Dated: September 17, 2024.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2024-21616 Filed 9-20-24; 8:45 am]
BILLING CODE 4164-01-P