Proposed Rule2022-01156
Medical Devices; Immunology and Microbiology Devices; Classification of Human Leukocyte, Neutrophil and Platelet Antigen and Antibody Tests
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
January 21, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, the Agency, or we) is proposing to classify Human Leukocyte Antigen (HLA), Human Platelet Antigen (HPA), and Human Neutrophil Antigen (HNA) devices, a generic type of device, into class II (special controls). FDA is identifying proposed special controls for HLA, HPA, and HNA devices that are necessary to provide a reasonable assurance of safety and effectiveness. FDA is also giving notice that we do not intend to exempt these device types from premarket notification requirements of the Federal Food, Drug, and Cosmetic Act (FD&C Act). FDA is publishing in this document the recommendations of the Blood Products Advisory Committee, serving as a device classification panel, regarding the classification of these devices. After considering public comments on the proposed classification, FDA will publish a final regulation classifying these device types.
Full Text
<html>
<head>
<title>Federal Register, Volume 87 Issue 14 (Friday, January 21, 2022)</title>
</head>
<body><pre>
[Federal Register Volume 87, Number 14 (Friday, January 21, 2022)]
[Proposed Rules]
[Pages 3250-3257]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2022-01156]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2021-N-0851]
Medical Devices; Immunology and Microbiology Devices;
Classification of Human Leukocyte, Neutrophil and Platelet Antigen and
Antibody Tests
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is
proposing to classify Human Leukocyte Antigen (HLA), Human Platelet
Antigen (HPA), and Human Neutrophil Antigen (HNA) devices, a generic
type of device, into class II (special controls). FDA is identifying
proposed special controls for HLA, HPA, and HNA devices that are
necessary to provide a reasonable assurance of safety and
effectiveness. FDA is also giving notice that we do not intend to
exempt these device types from premarket notification requirements of
the Federal Food, Drug, and Cosmetic Act (FD&C Act). FDA is publishing
in this document the recommendations of the Blood Products Advisory
Committee, serving as a device classification panel, regarding the
classification of these devices. After considering public comments on
the proposed classification, FDA will publish a final regulation
classifying these device types.
DATES: Submit either electronic or written comments on the proposed
rule by April 21, 2022.
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 April 21, 2022. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of April 21, 2022. 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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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 (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> 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.
<bullet> 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-2021-N-0851 for ``Medical Devices; Immunology and Microbiology
Classification of Human Leukocyte, Neutrophil and Platelet Antigen and
Antibody Tests.'' Received comments, those filed in a timely manner
(see ADDRESSES), will be placed in the docket and, except for those
submitted as ``Confidential Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> 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
[[Page 3251]]
second copy, which will have the claimed confidential information
redacted/blacked out, will be available for public viewing and posted
on <a href="https://www.regulations.gov">https://www.regulations.gov</a>. 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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: 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: Myrna Hanna, Center for Biologics
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002, 240-
402-7911.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. Statutory and Regulatory Authorities
B. Regulatory History of the Devices
IV. Legal Authority
V. Description of the Proposed Rule and Panel Recommendations
A. Identification
B. Recommended Classification of the Panel
C. Risks to Health and Special Controls
VI. Proposed Classification and FDA's Findings
VII. Proposed Effective Date
VIII. Preliminary Economic Analysis of Impacts
IX. Analysis of Environmental Impact
X. Paperwork Reduction Act of 1995
XI. Federalism
XII. Consultation and Coordination With Indian Tribal Governments
XIII. References
I. Executive Summary
A. Purpose of the Proposed Rule
FDA is proposing to classify HLA, HPA, and HNA devices, a generic
type of device, into class II (special controls). The Agency believes
that the special controls established by this proposed rule, together
with general controls, would provide reasonable assurance of the safety
and effectiveness of these devices. FDA is also giving notice that we
do not intend to exempt HLA, HPA, and HNA devices from premarket
notification requirements of the FD&C Act.
B. Summary of the Major Provisions of the Proposed Rule
FDA is proposing to classify HLA, HPA, and HNA devices, a generic
type of device, into class II with special controls. This proposed rule
provides device descriptions that include indications for use of the
devices and the special controls that will provide reasonable assurance
of the safety and effectiveness of these devices.
C. Legal Authority
FDA is proposing this action under the device provisions of the
FD&C Act including section 513 of the FD&C Act (21 U.S.C. 360c).
D. Costs and Benefits
The benefits of this proposed rule consist of the cost savings
resulting from the reduction in regulatory and economic burden that
accompanies the decrease in the number of information requests and
incomplete submissions submitted by manufacturers and handled by FDA;
however, we lack the information needed that would allow us to quantify
these benefits. The number of requests for additional information
following manufacturers' 510(k) submissions is small and widely
dispersed over the duration of time these devices have been marketed.
The classification procedure and outlined special controls will be
helpful for HLA, HPA, and HNA manufacturers in preparing their
submissions. Further benefits may be derived from the decreased time a
notification submission will need to be reviewed and the subsequent
potential benefits realized by consumers and manufacturers.
The costs of this proposed rule include one-time upfront labeling
redesigns, in addition to initial learning and reading costs. The total
estimated one-time costs of this proposed rule are $434,885 (in 2020
dollars). The present value of these costs is $434,885 because they are
one-time costs that are expected to occur in the first year. The
annualized cost of this proposed rule over 10 years is $54,201 at a
seven percent discount rate and $45,632 at a three percent discount
rate.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
----------------------------------------------------------------------------------------------------------------
Abbreviation/acronym What it means
----------------------------------------------------------------------------------------------------------------
510(k)....................... Premarket Notification.
BPAC......................... Blood Products Advisory Committee.
CFR.......................... Code of Federal Regulations.
FDA.......................... Food and Drug Administration.
FD&C Act..................... Federal Food, Drug, and Cosmetic Act.
HLA.......................... Human Leukocyte Antigen.
HPA.......................... Human Platelet Antigen.
HNA.......................... Human Neutrophil Antigen.
MAUDE........................ Manufacturer and User Facility Device Experience.
MDR.......................... Medical Device Report.
Ref.......................... Reference.
TRALI........................ Transfusion-Related Acute Lung Injury.
U.S.C........................ United States Code.
----------------------------------------------------------------------------------------------------------------
[[Page 3252]]
III. Background
A. Statutory and Regulatory Authorities
The FD&C Act (21 U.S.C. 301 et seq.), as amended by the Medical
Device Amendments of 1976, establishes a comprehensive system for the
regulation of medical devices intended for human use. Section 513 of
the FD&C Act establishes three categories (classes) of devices
depending on the regulatory controls needed to provide reasonable
assurance of their safety and effectiveness. The three categories of
devices are class I (general controls), class II (special controls),
and class III (premarket approval).
Class I devices are those devices for which the general controls of
the FD&C Act (controls authorized by or under sections 501, 502, 510,
516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h, 360i, or
360j) or any combination of such sections) are sufficient to provide
reasonable assurance of safety and effectiveness of the device; or
those devices for which insufficient information exists to determine
that general controls are sufficient to provide reasonable assurance of
safety and effectiveness or to establish special controls to provide
such assurance, but because the devices are not purported or
represented to be for a use in supporting or sustaining human life or
for a use which is of substantial importance in preventing impairment
of human health, and do not present a potential unreasonable risk of
illness or injury, are to be regulated by general controls (section
513(a)(1)(A) of the FD&C Act).
Class II devices are those devices for which general controls by
themselves are insufficient to provide reasonable assurance of safety
and effectiveness, but for which there is sufficient information to
establish special controls to provide such assurance, including the
promulgation of performance standards, postmarket surveillance, patient
registries, development and dissemination of guidelines,
recommendations, and other appropriate actions the Agency deems
necessary to provide such assurance (section 513(a)(1)(B) of the FD&C
Act).
Class III devices are those devices for which insufficient
information exists to determine that general controls and special
controls would provide a reasonable assurance of safety and
effectiveness, and are purported or represented for a use in supporting
or sustaining human life or for a use which is of substantial
importance in preventing impairment of human health, or present a
potential unreasonable risk of illness or injury (section 513(a)(1)(C)
of the FD&C Act).
Under section 513(d)(1) of the FD&C Act, devices that were in
commercial distribution before the enactment of the Medical Device
Amendments of 1976 (1976 amendments) on May 28, 1976 (generally
referred to as ``preamendments devices''), are classified after FDA:
(1) Receives a recommendation from a device classification panel (an
FDA advisory committee); (2) publishes the panel's recommendation,
along with a proposed regulation classifying the device, and provides
an opportunity for interested persons to submit comments; and (3)
publishes a final regulation classifying the device.
FDA has classified most preamendments devices under these
procedures, relying upon valid scientific evidence as described in
section 513(a)(3) of the FD&C Act and 21 CFR 860.7(c), to determine
that there is reasonable assurance of the safety and effectiveness of a
device under its conditions of use.
Devices that were not in commercial distribution before May 28,
1976 (generally referred to as ``postamendments devices''), are
classified automatically by section 513(f) 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
classifies or reclassifies the device into class I or 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.
The Agency determines whether new devices are substantially
equivalent to previously marketed devices by means of premarket
notification procedures in section 510(k) of the FD&C Act and part 807
of the regulations (21 CFR part 807). The 510(k) premarket notification
is a submission made to FDA to demonstrate that the device to be
marketed is at least as safe and effective as (i.e., substantially
equivalent to) a legally U.S. marketed class I or II device of that
same generic type. A generic type of device is a grouping of devices
that do not differ significantly in purpose, design, materials, energy
source, function, or any other feature related to safety and
effectiveness, and for which similar regulatory controls are sufficient
to provide reasonable assurance of safety and effectiveness (21 CFR
860.3(i)). When determined to be substantially equivalent, the subject
device may be legally marketed in the United States. The legally
marketed device to which substantial equivalence is determined is known
as the predicate device. A predicate device can be a preamendments
device or a postamendments device.
A person may market a preamendments device that has been classified
into class III through premarket notification procedures without
submission of a premarket approval application until FDA issues a final
order under section 515(b) of the FD&C Act (21 U.S.C. 360e(b))
requiring premarket approval.
B. Regulatory History of the Devices
The first product license for Leukocyte Typing Serum was issued in
December 1974, by the Bureau of Biologics, FDA. An FDA guideline for
the production, testing, and lot release of Leukocyte Typing Serum was
issued in 1977 and subsequently codified as Additional Standards in the
biologics regulations under 21 CFR 660.10 through 660.15.
In the Federal Register of August 1, 1980 (45 FR 51226), FDA
published a proposed rule recommending that the Additional Standards
for Leukocyte Typing Serum be removed with the subsequent revocation of
the existing product licenses. The proposed rule was prompted by the
realization of the growing complexities of the HLA system and the
difficulty in achieving standardization. The proposed rule was
supported by the argument that the products, while biologics, were also
medical devices that could be appropriately and efficiently regulated
under the FD&C Act as amended by the Medical Device Amendments of 1976
(21 U.S.C 301 et seq). The Agency's intent to classify HLA reagents and
kits was described in the preamble to the 1980 proposed rule.
In the Federal Register of August 10, 1982 (47 FR 34532), FDA
issued a final rule revoking the additional standards for Leukocyte
Typing Serum. The final regulation instructed all manufacturers of
Leukocyte Typing Serum to register and list under part 807. For those
products not currently licensed, manufacturers would be required to
submit premarket notifications (510(k) submissions). The first 510(k)
cleared HLA device used a preamendment HLA device as predicate.
Since 1982, FDA has cleared approximately 100 HLA device premarket
notifications (510(k)) submissions. Since 1993, FDA has cleared seven
HPA assays through the 510(k) premarket notifications pathway. Five
devices were cleared for the detection of antibodies against HPA and
two were cleared for HPA typing. Since 2006, FDA has cleared four HNA
devices through the 510(k) premarket
[[Page 3253]]
notifications pathway. Two devices were cleared for the detection of
antibodies against HNA and two were cleared for HNA typing.
On September 15, 2000, the Blood Products Advisory Committee (BPAC)
(2000 BPAC), serving as a device classification panel, provided
recommendations to FDA regarding the classification of in vitro
diagnostic reagents and kits for use in determining the HLA phenotype
or genotype of an individual, or for detecting antibodies to HLA
antigens (Ref. 1). The scope of the discussion included devices that
are used to support platelet and leukocyte transfusions, or organ and
stem cell transplantation. The classification of HLA kits used to
predict disease was not discussed at the meeting. The 2000 BPAC agreed
unanimously that HLA devices should be classified as class II medical
devices. The panel did not agree that the devices should be exempt from
the requirement to submit a 510(k). Although the 2000 BPAC recommended
classification of the HLA devices as class II, the classification was
not finalized by FDA because of competing priorities.
On November 30, 2017, FDA sought recommendations from the BPAC,
serving as a device classification panel (the Panel) (Refs. 2 and 3),
to discuss the classification of HLA, HPA, and HNA devices. FDA
proposed to the Panel that HLA, HPA, and HNA devices be classified as a
generic device type. The rationale to classify these devices together
was based on the similarities in the biological properties of the three
antigen systems, the use of similar technologies for the detection of
antigens and antibodies, the clinical use of the test results, and the
special controls required to mitigate risks. FDA proposed that these
are devices that do not differ significantly in purpose, design,
materials, energy source, function, or other features related to safety
and effectiveness, and for which similar regulatory controls are
sufficient to provide reasonable assurance of safety and effectiveness.
The Panel recommended that these devices be classified into class II
(special controls) with premarket review. FDA is not aware of new
information that has arisen since the Panel meeting that would provide
a basis for different recommendations or finding. The recommendations
of the Panel are summarized in Section V.
IV. Legal Authority
We are issuing this proposed rule under section 513(a) of the FD&C
Act. FDA has authority under this provision of the FD&C Act to issue a
regulation to establish special controls for class II devices for which
general controls by themselves are insufficient to provide reasonable
assurance of safety and effectiveness of the device, and for which
there is sufficient information to establish special controls to
provide such assurance. Under this authority, FDA is establishing
special controls for HLA, HPA, and HNA devices.
V. Description of the Proposed Rule and Panel Recommendations
This section summarizes the Panel's deliberations on November 30,
2017.
A. Identification
FDA described HLA, HNA, and HPA devices for the Panel's
consideration:
Human Leukocyte, Neutrophil and Platelet antigen and antibody
devices consist of HLA, HNA, and HPA typing and antibody detection
devices.
<bullet> HLA typing devices are used to determine HLA types, to aid
in transfusion or transplantation donor and recipient matching, or to
aid in the diagnosis of diseases.
<bullet> HLA antibody detection devices are used to detect
antibodies to HLA antigens to aid in donor and recipient matching in
transfusion or transplantation.
<bullet> HPA typing devices are used for the detection of human
platelet antigens to aid in donor and recipient matching in blood
transfusion or to aid in the diagnosis of diseases.
<bullet> HPA antibody detection devices are used to detect
autoantibodies and alloantibodies against platelet glycoproteins to aid
in donor and recipient matching in blood transfusion or to aid in the
diagnosis of diseases.
<bullet> HNA typing devices are used for the detection of human
neutrophil antigens to aid in donor and recipient matching in blood
transfusion or to aid in the diagnosis of diseases.
<bullet> HNA antibody detection devices are used to detect
autoantibodies and alloantibodies against neutrophil antigens to aid in
donor and recipient matching in blood transfusion or to aid in the
diagnosis of diseases.
FDA clarified the following devices are not included in the
proposed classification:
<bullet> HLA, HPA, or HNA devices used as a companion diagnostic
device, a device that provides information that is essential for the
safe and effective use of a corresponding therapeutic product.
<bullet> HLA, HPA, or HNA assays that are intended for clinical use
and designed, manufactured, and used within a single laboratory.
B. Recommended Classification of the Panel
The Panel recommended that HLA, HNA, and HPA devices be classified
into class II with special controls with premarket review. The Panel
agreed that general controls were not sufficient to provide reasonable
assurance of safety and effectiveness of HLA, HPA, and HNA devices. The
Panel believed that HLA, HPA, and HNA devices present a potentially
unreasonable risk of illness, injury, or death. Considering these
risks, the Panel agreed that sufficient information exists to establish
special controls for these devices. Consequently, the consensus of the
Panel was that class II classification (special controls) and premarket
review would provide reasonable assurance of safety and effectiveness
of these devices.
The Panel considered the following valid scientific evidence to
make their recommendation regarding the safety and effectiveness of
these devices under its conditions of use. Specifically, the Panel
considered the history of safety and effectiveness of HLA, HPA, and HNA
devices over many years of use; the results of an FDA review of the
scientific literature; medical device reports (MDRs) of adverse events
or malfunctions; device recalls, and FDA's regulatory experiences with
the devices.
C. Risks to Health and Special Controls
As required by section 513(d)(1) of the FD&C Act, FDA provided to
the Panel the following summary of valid scientific evidence regarding
the benefits and risks of HLA, HPA, and HNA devices. A systemic
literature review indicates that the use of these devices has improved
patient care in transfusion and transplantation, and in disease
diagnosis. HLA matching between the donor and recipient is a key
strategy to reduce rejection. The presence of anti-HLA antibodies,
especially donor-specific antibodies, has been associated with worse
outcomes after transplantation or transfusion. Identification of HLA
antibodies allows for informed decisions regarding whether to accept
and transplant an organ for a specific recipient. In similar fashion,
HPA and HLA devices provide a means to detect and identify related
antigens and antibodies facilitating transfusion with compatible blood
(platelet) products. In addition, HNA and HLA devices provide
laboratorians and clinicians tools to investigate transfusion-related
acute lung injury (TRALI) reactions and/or mitigate the risk of future
TRALI reactions associated with implicated blood donors.
[[Page 3254]]
However, available literature, MDRs, and medical device recall data
indicate that HLA, HPA, and HNA devices can malfunction. These devices
may generate false positive, false negative, or inconsistent results
and have the potential to cause adverse health consequences. Suspected
device-associated deaths, serious injuries, and malfunctions are
reported to FDA through the Manufacturer and User Facility Device
Experience (MAUDE) database. Prior to the Panel meeting, FDA conducted
queries of the MAUDE database to identify MDRs related to the use of
HLA, HPA, and HNA devices. The search was restricted to reports that
FDA received and entered into the database before May 1, 2017. There
were 477 MDRs for HLA devices. Most MDRs (464) were reported for HLA
genotyping devices, while 13 MDRs were reported for HLA antibody
detection devices. All MDRs with reportable category information are
malfunctions. The most frequent malfunctions are incorrect reactivity
assignments that lead to mistype or no type HLA results. There have
been no reported deaths or serious injuries related to these
malfunctions. These medical device reports suggest that 510(k)
premarket notification of HLA devices is a necessary means to minimize
adverse health consequences that may result from HLA device
malfunctions. Compared to HLA devices, there are few HPA and HNA
devices in the U.S. market and few reported MDRs. The queries of the
MAUDE database prior to the Panel meeting identified only two MDRs for
HPA devices and no MDRs for HNA devices. However, these devices share
similar technologies and clinical applications to HLA devices and have
the potential for malfunctions that may cause adverse health
consequences. Therefore, 510(k) premarket notification of HPA and HNA
devices is needed to minimize adverse health consequences that may
result from HPA or HNA device malfunction.
Similarly, prior to the Panel meeting, FDA searched the Medical
Device Recalls database for all recalls received before May 1, 2017,
for these devices. Of the total 37 HLA device recalls, none were
classified as class I recalls, in which the violative product could
cause serious adverse health consequences or death. A total of 19
recalls were classified as class II, and 18 were classified as class
III. Most of the recalls (32 of 37) were for products that failed to
provide correct testing results (false negative, false positive,
mistype, or no type). The root causes leading to incorrect HLA typing
results include incorrect reactivity assignments, lack of testing
sample(s) with specific allele before releasing, and manufacturing
errors. The HLA antibody device recalls were due to manufacturing
errors during the production of recombinant HLA proteins, such as
unstable transfectant. No recalls were reported for HPA and HNA
devices. However, these devices share similarities with the HLA devices
and are likely prone to similar malfunctions.
FDA presented the following risks to health associated with HLA,
HPA, and HNA devices: Patient injury or death due to: (1) Poor graft
survival or function due to transplantation of incompatible
hematopoietic cells, tissue, or organ; (2) graft rejection because of
the transplantation of incompatible hematopoietic cells, tissue, or
organ; (3) graft-versus-host disease because of the transplantation of
incompatible immune system cells; (4) incorrect or delayed diagnosis of
medically related conditions or assessment of future risk of adverse
outcomes because of incorrect HLA, HPA, or HNA test results; (5)
transfusion reaction (e.g., transfusion associated lung injury, post
transfusion purpura) due to incorrect HLA, HPA, or HNA test results;
and, (6) platelet refractoriness because of incorrect HLA or HPA typing
or antibody detection results.
FDA next proposed to the Panel measures to mitigate the risks to
health associated with HLA, HNA, and HPA devices. The identified risks
to health and the special controls to mitigate these risks (explained
in the paragraph immediately after the table) are summarized in the
following table:
Table 1--Summary of Risks to Health and Proposed Special Controls
----------------------------------------------------------------------------------------------------------------
Risk to health Method of mitigation (i.e., special control)
----------------------------------------------------------------------------------------------------------------
Inaccurate test results (i.e., false Special controls (1) and (2).
positive or false negative results) can
result in adverse health consequences.
Failure of software to correctly interpret Special controls (1)(e) and (1)(f).
test results can result in adverse health
consequences.
----------------------------------------------------------------------------------------------------------------
FDA proposed the following special controls (cross-referenced in
the table above) to the Panel for HLA, HPA, and HNA devices: (1)
Premarket submissions must include detailed documentation of the
following information: (a) Device accuracy study using well-
characterized samples representing as many targets as possible; (b)
precision studies to evaluate possible sources of variation that may
affect test results; (c) comparison studies to evaluate the device's
performance compared to a predicate; (d) specific information that
addresses or mitigates risks associated with false positive antibody
reactivity e.g., reactivity with denatured/cryptic epitopes, if
applicable; (e) description of how the assay cutoff was established and
validated as well as supporting data; (f) documentation for device
software, including, but not limited to, software requirement
specifications, software design specification, e.g., algorithms, alarms
and device limitations; hazard analysis, traceability matrix,
verification and validation testing, unresolved anomalies, hardware and
software specifications; electromagnetic compatibility and wireless
testing; (g) for multiplex assays in which large numbers of probes and/
or primers are handled during manufacturing process, premarket
submissions should provide the design specifications that are in place
to prevent incorrect reactivity assignment; (h) description of a plan
on how to ensure the performance characteristics of the device remain
unchanged over time when new HLA alleles are identified, and/or
reactivity assignments are changed from the assignments at the time the
device was evaluated; and (2) device labeling must include: (a) A
limitation statement that reads, ``The results should not be used as
the sole basis for making a clinical decision;'' and (b) a warning that
reads ``The device has not been cleared or approved for use as a
companion diagnostic.''
The Panel members agreed with the special controls proposed by FDA.
VI. Proposed Classification and FDA's Findings
After considering the recommendations of the Panel and the valid
scientific evidence, including the
[[Page 3255]]
published literature, MDRs, recall information, and FDA's regulatory
experience with these device types, FDA proposes to classify HLA, HPA,
and HNA devices as class II devices (special controls) with premarket
review. FDA believes general controls by themselves are insufficient to
provide reasonable assurance of safety and effectiveness for these
devices and there is sufficient information to establish special
controls to provide such assurance. FDA believes that special controls,
in addition to general controls, would provide reasonable assurance of
the safety and effectiveness of HLA, HPA, and HNA devices and would,
therefore, mitigate the risks to health associated with their use.
We are proposing to classify the devices as a generic type of
device because of the similarities in the biological properties of the
three antigen systems, the use of similar technologies for the
detection of antigens and antibodies, the clinical use of the test
results, and the special controls required to mitigate risks. The
proposed device identification includes the indications for use of HLA,
HPA, and HNA devices subject to the classification. The following
devices are not included in the proposed classification: HLA, HPA, or
HNA devices used as a companion diagnostic device, a device that
provides information that is essential for the safe and effective use
of a corresponding therapeutic product.
The proposed regulation also includes special controls that are
necessary to provide a reasonable assurance of the safety and efficacy
of the devices. When developing the special controls, we considered the
recommendations provided in the FDA guidance document entitled
``Recommendations for Premarket Notification (510(k)) Submissions for
Nucleic Acid-Based Human Leukocyte Antigen (HLA) Test Kits Used for
Matching of Donors and Recipients in Transfusion and Transplantation''
(Ref. 4).
Section 510(m) of the FD&C Act provides that a class II device may
be exempted from premarket notification requirements under section
510(k) of the FD&C Act, if the Agency determines that premarket
notification is not necessary to assure the safety and effectiveness of
the device. The Agency does not intend to exempt HNA, HPA, and HNA
devices from 510(k) premarket notification as allowed under section
510(m) of the FD&C Act. FDA believes premarket notification is
necessary for these devices to assure their safety and effectiveness.
VII. Proposed Effective Date
FDA proposes that any final regulation based on this proposal
become effective 30 days after its date of publication in the Federal
Register.
VIII. Preliminary Economic Analysis of Impacts
We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct us to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity). We
believe that this proposed rule is not a significant regulatory action
as defined by Executive Order 12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because of the limited impact of this proposed rule, we
propose to certify that the proposed rule will not have a significant
economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $158 million, using the most current (2020) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.
If finalized, the proposed rule would classify HLA, Human HPA, and
HNA devices as a generic group of devices into class II (special
controls). The Agency believes that the special controls included in
this proposed rule, together with general controls, are necessary to
provide reasonable assurance of the safety and effectiveness of these
devices. The special controls in the proposed rule are already
generally practiced by manufacturers of currently cleared devices; the
primary change consists of a labeling update. FDA is also giving notice
that we do not intend to exempt HLA, HPA, and HNA devices from
premarket notification requirements of the FD&C Act.
The proposed rule's costs are summarized in table 2; we are unable
to quantify benefits for this proposed rule. Costs are calculated as
the one-time costs of relabeling affected devices to comply with the
proposed rule and costs associated with reading and understanding the
proposed rule. The total estimated one-time costs of this rule are
$434,885 (in 2020 dollars). The present value of these costs is
$443,885 because they are one-time costs that are expected to occur in
the first year. The annualized cost of this proposed rule over 10 years
is $54,201 at a seven percent discount rate and $45,632 at a three
percent discount rate.
The benefits of this proposed rule consist of the cost savings
resulting from the reduction in regulatory and economic burden that
accompanies the decrease in the number of information requests and
incomplete submissions submitted by manufacturers and handled by FDA;
however, we lack the information needed that would allow us to quantify
these benefits. The number of requests for additional information
following manufacturers' 510(k) submissions is small and widely
dispersed over the duration of time these devices have been marketed.
The classification procedure and outlined special controls would be
helpful for HLA, HPA, and HNA manufacturers in preparing their
submissions. Further benefits may be derived from the decreased time a
notification submission would need to be reviewed and the subsequent
potential benefits realized by consumers and manufacturers. The costs
of this proposed rule include one-time upfront labeling redesigns, in
addition to initial learning and reading costs.
Consistent with Executive Order 12866, table 2 provides the costs
and a description of benefits for this proposed rule.
[[Page 3256]]
Table 2--Summary of Benefits and Costs in 2020 Dollars Over a 10-Year Time Horizon
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
Primary Low High ------------------------------------
Category estimate estimate estimate Year Discount Period Notes
dollars rate (%) covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $/year....... .......... .......... .......... 2020 7 10 ........................................
.......... .......... .......... 2020 3 10 ........................................
Annualized Quantified............. .......... .......... .......... .......... 7 .......... ........................................
.......... .......... .......... .......... 3 .......... ........................................
Qualitative....................... .......... .......... .......... .......... .......... .......... Improved labeling and enhanced certainty
for 510(k) submissions.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized $/year....... $54,201 .......... .......... 2020 7 10 ........................................
$45,632 .......... .......... 2020 3 10 ........................................
Annualized Quantified............. .......... .......... .......... .......... 7 .......... ........................................
.......... .......... .......... .......... 3 .......... ........................................
Qualitative....................... .......... .......... .......... .......... .......... .......... ........................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized $/ .......... .......... .......... .......... 7 .......... ........................................
year.
.......... .......... .......... .......... 3 .......... ........................................
-----------------------------------------------------------------------------------------------------------------
From/To........................... From:
To: ..........
-----------------------------------------------------------------------------------------------------------------
Other Annualized Monetized $/year. .......... .......... .......... .......... 7 .......... ........................................
.......... .......... .......... .......... 3 .......... ........................................
-----------------------------------------------------------------------------------------------------------------
From/To........................... From:
To: ..........
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
State, Local or Tribal Government:
Small Business:
Wages:
Growth:
--------------------------------------------------------------------------------------------------------------------------------------------------------
We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. The full
analysis of economic impacts is available in the docket for this
proposed rule (Ref. 5) and at <a href="https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations">https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations</a>.
IX. Analysis of Environmental Impact
We have 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.
X. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed rule contains no
collection of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.
XI. Federalism
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the proposed rule does not contain policies that have
federalism implications as defined in the Executive Order and,
consequently, a federalism summary impact statement is not required.
XII. Consultation and Coordination With Indian Tribal Governments
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the proposed rule does not contain policies that would
have a substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.
XIII. References
The following references are on display at 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>. 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. Blood Products Advisory Committee Meeting transcript--
September 15, 2000 (pp. 209-220), available at: <a href="https://wayback.archive-it.org/7993/20170404105835/https:/www.fda.gov/ohrms/dockets/ac/00/transcripts/3649t2c.pdf">https://wayback.archive-it.org/7993/20170404105835/https:/www.fda.gov/ohrms/dockets/ac/00/transcripts/3649t2c.pdf</a>.
2. Blood Products Advisory Committee Meeting transcript--
November 30, 2017, available at: <a href="https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM590282.pdf">https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM590282.pdf</a> .
3. FDA Executive Summary. Classification of Human Leukocyte,
Neutrophil and Platelet Antigen or Antibody Tests--November 30,
2017, available at: <a href="https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM586203.pdf">https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM586203.pdf</a>.
4. ``Recommendations for Premarket Notification (510(k))
Submissions for Nucleic Acid-Based Human Leukocyte Antigen (HLA)
Test Kits Used for Matching of Donors and Recipients in Transfusion
and Transplantation: Guidance for Industry,'' July 2015, available
at: https://www.fda.gov/
[[Page 3257]]
regulatory-information/search-fda-guidance-documents/
recommendations-premarket-notification-510k-submissions-nucleic-
acid-based-human-leukocyte-antigen.
5. FDA, ``Medical Devices; Immunology and Microbiology Devices;
Classification of Human Leukocyte, Neutrophil and Platelet Antigen
and Antibody Tests,'' Preliminary Regulatory Impact Analysis Initial
Regulatory Flexibility Analysis Unfunded Mandates Reform Act
Analysis,'' 2019 (available at <a href="https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations">https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations</a>.
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, we
propose 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. 866.5960 to subpart F to read as follows:
Sec. 866.5960 Human Leukocyte, Human Neutrophil, and Human Platelet
antigen and antibody devices.
(a) Identification. Human Leukocyte, Human Neutrophil, and Human
Platelet antigen and antibody devices consist of Human Leukocyte
Antigen (HLA), Human Platelet Antigen (HPA), and Human Neutrophil
Antigen (HNA) typing and antibody detection devices.
(1) HLA typing devices are used to determine HLA types, to aid in
transfusion or transplantation donor and recipient matching, or to aid
in the diagnosis of diseases.
(2) HLA antibody detection devices are used to detect antibodies to
HLA antigens to aid in donor and recipient matching in transfusion or
transplantation.
(3) HPA typing devices are used for the detection of human platelet
antigens to aid in donor and recipient matching in blood transfusion or
to aid in the diagnosis of diseases.
(4) HPA antibody detection devices are used to detect
autoantibodies and alloantibodies against platelet glycoproteins to aid
in donor and recipient matching in blood transfusion or to aid in the
diagnosis of diseases.
(5) HNA typing devices are used for the detection of human
neutrophil antigens to aid in donor and recipient matching in blood
transfusion or to aid in the diagnosis of diseases.
(6) HNA antibody detection devices are used to detect
autoantibodies and alloantibodies against neutrophil antigens to aid in
donor and recipient matching in blood transfusion or to aid in the
diagnosis of diseases.
(b) Classification. Class II (special controls). HLA, HPA, and HNA
typing devices must comply with the following special controls:
(1) Premarket submissions must include detailed documentation of
the following:
(i) Device accuracy study using well-characterized samples
representing as many targets as possible.
(ii) Precision studies to evaluate possible sources of variation
that may affect test results.
(iii) Comparison studies to evaluate the device's performance
compared to a predicate.
(iv) Specific information that addresses or mitigates risks
associated with false positive antibody reactivity, e.g., reactivity
with denatured/cryptic epitopes, if applicable.
(v) Description of how the assay cutoff was established and
validated as well as supporting data.
(vi) Documentation for device software, including, but not limited
to, software requirement specifications, software design
specifications, e.g., algorithms, alarms, and device limitations;
hazard analysis, traceability matrix, verification and validation
testing, unresolved anomalies, hardware and software specifications;
electromagnetic compatibility and wireless testing.
(vii) Design specifications that are in place to prevent incorrect
reactivity assignment or multiplex assays in which large numbers of
probes and/or primers are handled during manufacturing process.
(viii) Description of a plan on how to ensure the performance
characteristics of the device remain unchanged over time when new HLA
alleles are identified and/or reactivity assignments are changed from
the assignments at the time the device was evaluated.
(2) The device labeling must include:
(i) A limitation statement that reads, ``The results should not be
used as the sole basis for making a clinical decision.''
(ii) A warning that reads ``The device has not been cleared or
approved for use as a companion diagnostic.''
Dated: January 11, 2022.
Janet Woodcock,
Acting Commissioner of Food and Drugs.
[FR Doc. 2022-01156 Filed 1-20-22; 8:45 am]
BILLING CODE 4164-01-P
</pre></body>
</html>Indexed from Federal Register on January 21, 2022.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.