[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 [www.gpo.gov]
[FR Doc No: 2022-01156]


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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.

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

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-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 https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday, 240-402-7500.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The

[[Page 3251]]

second copy, which will have the claimed confidential information 
redacted/blacked out, will be available for public viewing and posted 
on https://www.regulations.gov. Submit both copies to the Dockets 
Management Staff. If you do not wish your name and contact information 
to be made publicly available, you can provide this information on the 
cover sheet and not in the body of your comments and you must identify 
this information as ``confidential.'' Any information marked as 
``confidential'' will not be disclosed except in accordance with 21 CFR 
10.20 and other applicable disclosure law. For more information about 
FDA's posting of comments to public dockets, see 80 FR 56469, September 
18, 2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, 240-402-7500.

FOR FURTHER INFORMATION CONTACT: 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

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     Abbreviation/acronym                                        What it means
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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.
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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

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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.
     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.
     HLA antibody detection devices are used to detect 
antibodies to HLA antigens to aid in donor and recipient matching in 
transfusion or transplantation.
     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.
     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.
     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.
     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:
     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.
     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.

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    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 https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

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 https://www.regulations.gov. 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: https://wayback.archive-it.org/7993/20170404105835/https:/www.fda.gov/ohrms/dockets/ac/00/transcripts/3649t2c.pdf.
    2. Blood Products Advisory Committee Meeting transcript--
November 30, 2017, available at: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM590282.pdf .
    3. FDA Executive Summary. Classification of Human Leukocyte, 
Neutrophil and Platelet Antigen or Antibody Tests--November 30, 
2017, available at: https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/UCM586203.pdf.
    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 https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

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


