Rule2024-21616
Microbiology Devices; Reclassification of Cytomegalovirus Deoxyribonucleic Acid Quantitative Assay Devices Intended for Transplant Patient Management
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
September 23, 2024
Effective
October 23, 2024
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
Full Text
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<title>Federal Register, Volume 89 Issue 184 (Monday, September 23, 2024)</title>
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[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 [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-21616]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2016-N-2880]
Microbiology Devices; Reclassification of Cytomegalovirus
Deoxyribonucleic Acid Quantitative Assay Devices Intended for
Transplant Patient Management
AGENCY: Food and Drug Administration (FDA), Department of Health and
Human Services (HHS).
ACTION: Final amendment; final order.
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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
issuing a final order to reclassify cytomegalovirus (CMV)
deoxyribonucleic acid (DNA) quantitative assay devices intended for
transplant patient management, a postamendments class III device
(product code PAB) into class II (general controls and special
controls), subject to premarket notification.
DATES: This order is effective October 23, 2024.
ADDRESSES: For access to the docket to read background documents or the
electronic and-written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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, <a href="/cdn-cgi/l/email-protection#9ecdf7f2f5fbb0cdfdf6f2f1eaeaf3fff0f0def8faffb0f6f6edb0f9f1e8"><span class="__cf_email__" data-cfemail="64370d080f014a37070c080b101009050a0a240200054a0c0c174a030b12">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended, by
the Medical Device Amendments of 1976 (the 1976 amendments) (Pub. L.
94-295), the Safe Medical Devices Act of 1990 (Pub. L. 101-629), the
Food and Drug Administration Modernization Act of 1997 (Pub. L. 105-
115), the Medical Device User Fee and Modernization Act of 2002 (Pub.
L. 107-250), the Medical Devices Technical Corrections Act (Pub. L.
108-214), the Food and Drug Administration Amendments Act of 2007 (Pub.
L. 110-85), and the Food and Drug Administration Safety and Innovation
Act (Pub. L. 112-144), among other amendments, establishes a
comprehensive system for the regulation of medical devices intended for
human use. Section 513 of the FD&C Act (21 U.S.C. 360c) established
three classes of devices, reflecting the regulatory controls needed to
provide reasonable assurance of their safety and effectiveness. The
three classes of devices are class I (general controls), class II
(general controls and special controls), and class III (general
controls and premarket approval).
Devices that were not in commercial distribution prior to May 28,
1976 (generally referred to as postamendments devices) are
automatically classified by section 513(f)(1) of the FD&C Act into
class III without any FDA rulemaking process. Those devices remain in
class III and require premarket approval, unless and until: (1) FDA
reclassifies the device into class I or class II or (2) FDA issues an
order finding the device to be substantially equivalent, in accordance
with section 513(i) of the FD&C Act, to a predicate device that does
not require premarket approval. FDA determines whether new devices are
substantially equivalent to predicate devices by means of premarket
notification procedures in section 510(k) of the FD&C Act (21 U.S.C.
360(k)) and part 807 (21 CFR part 807), subpart E, of FDA's
regulations.
A postamendments device that has been initially classified in class
III under section 513(f)(1) of the FD&C Act may be reclassified into
class I or II under section 513(f)(3) of the FD&C Act. Section
513(f)(3) of the FD&C Act provides that FDA, acting by administrative
order, can reclassify the device into class I or class II on its own
initiative, or in response to a petition from the manufacturer or
importer of the device. To change the classification of the device, the
proposed new class must have sufficient regulatory controls to provide
a reasonable assurance of the safety and effectiveness of the device
for its intended use.
In the Federal Register of September 18, 2020 (85 FR 58300), FDA
published a proposed order to reclassify CMV DNA quantitative assay
devices intended for transplant patient management (``CMV transplant
assays'') from class III into class II (general and special controls),
subject to premarket notification. The comment period on the proposed
order closed on November 17, 2020. FDA received two comments on the
proposed order, both of which were supportive of the reclassification
from Class III to Class II and agreed with FDA
[[Page 77449]]
that CMV transplant assays should be subject to premarket notification.
II. The Final Order
Based on the information discussed in the preamble to the proposed
order (85 FR 58300), the supportive comments received on the proposed
order, and FDA's experience over the years with this device type, FDA
concludes that special controls, in conjunction with general controls,
will provide reasonable assurance of the safety and effectiveness of
CMV transplant assays. Therefore, in accordance with section 513(f)(3)
of the FD&C Act, FDA is issuing this final order to reclassify CMV
transplant assays from class III into class II, subject to premarket
notification. This final order will be codified at 21 CFR 866.3180.\1\
In this final order, FDA has identified special controls under section
513(a)(1)(B) of the FD&C Act, which in addition to general controls,
will provide reasonable assurance of the safety and effectiveness of
the device. FDA is reclassifying these devices and establishing the
special controls as published in the proposed order without change.
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\1\ In December 2019, FDA began adding the term ``Final
amendment'' to the ``ACTION'' caption for these documents, typically
styled ``Final order,'' to indicate an amendment to the Code of
Federal Regulations. This editorial change was made in accordance
with the Office of Federal Register's interpretations of the Federal
Register Act (44 U.S.C. chapter 15), its implementing regulations (1
CFR 5.9 and parts 21 and 22), and the Document Drafting Handbook.
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Section 510(m) of the FD&C Act provides that a class II device may
be exempted from the premarket notification requirements under section
510(k) of the FD&C Act, if the Agency determines that premarket
notification is not necessary to reasonably assure the safety and
effectiveness of the device. FDA has determined that premarket
notification is necessary to reasonably assure the safety and
effectiveness of CMV transplant assays. Therefore, the Agency does not
intend to exempt these class II devices from premarket notification
(510(k)) submission as provided under section 510(m) of the FD&C Act.
The devices that are the subject of this reclassification are
assigned the generic name ``quantitative CMV nucleic acid tests for
transplant patient management.'' These devices are identified as a
quantitative CMV nucleic acid test for transplant patient management, a
device intended for prescription use in the detection of CMV and as an
aid in the management of transplant patients to measure CMV DNA levels
in human plasma and/or whole blood using specified specimen processing,
amplification, and detection instrumentation. The test is intended for
use as an aid in the management of transplant patients with active CMV
infection or at risk for developing CMV infection. The test results are
intended to be interpreted by qualified healthcare professionals in
conjunction with other relevant clinical and laboratory findings.
Under this final order, CMV transplant assays are prescription
devices requiring the supervision of a practitioner licensed by law to
direct the use of the devices in order to ensure accurate
interpretation of results, ensuring the devices provide a reasonable
assurance of safety and effectiveness. As such, the prescription device
must satisfy prescription labeling requirements for in vitro diagnostic
products (see 21 CFR 809.10(a)(4) and (b)(5)(ii)).
In addition, the Agency believes that certain changes could be made
to CMV transplant assays that could significantly affect the safety and
effectiveness of those devices and for which a new 510(k) is likely
required.\2\ Based on FDA's accumulated experience with these devices,
changes that likely could significantly affect the safety and
effectiveness of these devices include, but are not limited to, changes
to critical reagents, changes to final release specifications, and
changes in shelf life of the device. For more information about when to
submit a new 510(k), manufacturers should refer to FDA's guidance
entitled ``Deciding When to Submit at 510(k) for a Change to an
Existing Device'' (Ref. 3).
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\2\ See 21 CFR 807.81(a)(3)(i).
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III. Implementation Strategy
The order is effective 30 days after its date of publication in the
Federal Register.
IV. Analysis of Environmental Impact
The Agency has determined under 21 CFR 25.34(b) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
V. Paperwork Reduction Act of 1995
This final order establishes special controls that refer to
previously approved collections of information found in other FDA
regulations and guidance. Those collections of information are subject
to review by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521). The
collections of information in 21 CFR part 807, subpart E, have been
approved under OMB control number 0910-0120, the collections of
information in 21 CFR part 820 have been approved under OMB control
number 0910-0073, and the collections of information in 21 CFR parts
801 and 809 have been approved under OMB control number 0910-0485.
VI. Codification of Orders
Under section 513(f)(3) of the FD&C Act, FDA may issue final orders
to reclassify devices. FDA will continue to codify classifications and
reclassifications in the Code of Federal Regulations (CFR). Changes
resulting from final orders will appear in the CFR as newly codified
orders. Therefore, under section 513(f)(3), CMV transplant assays are
codified in the new 21 CFR 866.3180 under which CMV transplant assays
are renamed quantitative CMV nucleic acid tests for transplant patient
management and are reclassified from class III into class II.
VII. References
The following references marked with an asterisk (*) are on display
in the Dockets Management Staff (see ADDRESSES; and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they are also available electronically at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. References without asterisks are not on public
display at <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 <a href="https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM514771">https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM514771</a>).
[[Page 77450]]
*4. Transcript of the FDA Microbiology Devices Panel Meeting,
November 9, 2016 (available at <a href="https://www.fda.gov/advisory-committees/microbiology-devices-panel/2016-meeting-materials-microbiology-devices-panel">https://www.fda.gov/advisory-committees/microbiology-devices-panel/2016-meeting-materials-microbiology-devices-panel</a>).
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
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