3250 Federal Register / Vol. 87, No. 14 / Friday, January 21, 2022 / Proposed Rules 

or lacking a principal inspector, the manager 

of the responsible Flight Standards Office. 

(3) An AMOC that provides an acceptable 

level of safety may be used for any repair, 

modification, or alteration required by this 

AD if it is approved by The Boeing Company 

Organization Designation Authorization 

(ODA) that has been authorized by the 

Manager, Los Angeles ACO Branch, FAA, to 

make those findings. To be approved, the 

repair method, modification deviation, or 

alteration deviation must meet the 

certification basis of the airplane, and the 

approval must specifically refer to this AD. 

(4) AMOCs approved previously for AD 

2017–24–10 are not approved as AMOCs 

with this AD. 

(5) Except as specified by paragraph (i) of 

this AD: For service information that 

contains steps that are labeled as Required 

for Compliance (RC), the provisions of 

paragraphs (m)(5)(i) and (ii) of this AD apply. 

(i) The steps labeled as RC, including 

substeps under an RC step and any figures 

identified in an RC step, must be done to 

comply with the AD. If a step or substep is 

labeled ‘‘RC Exempt,’’ then the RC 

requirement is removed from that step or 

substep. An AMOC is required for any 

deviations to RC steps, including substeps 

and identified figures. 

(ii) Steps not labeled as RC may be 

deviated from using accepted methods in 

accordance with the operator’s maintenance 

or inspection program without obtaining 

approval of an AMOC, provided the RC steps, 

including substeps and identified figures, can 

still be done as specified, and the airplane 

can be put back in an airworthy condition. 

(n) Related Information 

(1) For more information about this AD, 

contact Peter Jarzomb, Aerospace Engineer, 

Airframe Section, FAA, Los Angeles ACO 

Branch, 3960 Paramount Boulevard, 

Lakewood, CA 90712–4137; phone: 562–627– 

5234; email: peter.jarzomb@faa.gov. 

(2) For service information identified in 

this AD, contact Boeing Commercial 

Airplanes, Attention: Contractual & Data 

Services (C&DS), 2600 Westminster Blvd., 

MC 110–SK57, Seal Beach, CA 90740–5600; 

telephone 562–797–1717; internet https://

www.myboeingfleet.com. You may view this 

referenced service information at the FAA, 

Airworthiness Products Section, Operational 

Safety Branch, 2200 South 216th St., Des 

Moines, WA. For information on the 

availability of this material at the FAA, call 

206–231–3195. 

Issued on December 10, 2021. 

Lance T. Gant, 

Director, Compliance & Airworthiness 

Division, Aircraft Certification Service. 

[FR Doc. 2022–01014 Filed 1–20–22; 8:45 am] 

BILLING CODE 4910–13–P 

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 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 


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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 

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. 


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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 deviceassociated 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 positive or false negative results) can result in adverse health 

consequences.

Special controls (1) and (2). 

Failure of software to correctly interpret test results can result in adverse health consequences .... Special controls (1)(e) and (1)(f). 

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 


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Federal Register / Vol. 87, No. 14 / Friday, January 21, 2022 / Proposed Rules 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. 


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3256 Federal Register / Vol. 87, No. 14 / Friday, January 21, 2022 / Proposed Rules 

TABLE 2—SUMMARY OF BENEFITS AND COSTS IN 2020 DOLLARS OVER A 10-YEAR TIME HORIZON

Category Primary 

estimate 

Low 

estimate 

High 

estimate 

Units 

Notes Year 

dollars 

Discount 

rate 

(%) 

Period 

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 $/year ................. .................. .................. .................. .................. 7 ..................

.................. .................. .................. .................. 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-fdaregulations. 

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/CommitteesMeeting

Materials/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/ 


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Federal Register / Vol. 87, No. 14 / Friday, January 21, 2022 / Proposed Rules 3257 

regulatory-information/search-fda-guidancedocuments/recommendations-premarketnotification-510k-submissions-nucleic-acidbased-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 

■ 1. The authority citation for part 866 

continues to read as follows: 

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

360j, 360l, 371. 

■ 2. Add § 866.5960 to subpart F to read 

as follows: 

§ 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 wellcharacterized 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 

DEPARTMENT OF DEFENSE 

Department of the Army, Corps of 

Engineers 

33 CFR Part 334 

[COE–2021–0006] 

Eagle River From Bravo Bridge to 

Eagle Bay in Knik Arm, Richardson 

Training Area on Joint Base 

Elmendorf-Richardson, Alaska; 

Restricted Area 

AGENCY: U.S. Army Corps of Engineers, 

DoD. 

ACTION: Notice of proposed rulemaking 

and request for comments. 

SUMMARY: The U.S. Army Corps of 

Engineers (Corps) is proposing to revise 

its regulations to establish a restricted 

area within the Richardson Training 

Area on Joint Base ElmendorfRichardson (JBER), at Eagle River. The 

United States Army, Alaska (USARAK) 

G3/5/7 Training and Support ActivityAlaska (TSA–AK) requested 

establishment of a restricted area which 

would be located in the area of 

navigable waters extending from the 

span on Bravo Bridge across Eagle River 

to the mouth of Eagle River Knik Arm 

(Eagle River channel). Establishment of 

the restricted area would prevent all 

watercraft navigations and individuals 

from entering an active military range 

munitions impact area at all times, 

except for authorized vessels and 

individuals engaged in support of 

military training and management 

activities. This restricted area is 

necessary to avoid inadvertent entry 

into the impact area during live-fire 

weapons training, exposure to 

hazardous noise, and inadvertent 

encounters with unexploded ordnance. 

DATES: Written comments must be 

submitted on or before February 22, 

2022. 

ADDRESSES: You may submit comments, 

identified by docket number COE– 

2021–0006, by any of the following 

methods: 

Federal eRulemaking Portal: http://

www.regulations.gov. Follow the 

instructions for submitting comments. 

Email: david.b.olson@usace.army.mil. 

Include the docket number, COE–2021– 

0006, in the subject line of the message. 

Mail: U.S. Army Corps of Engineers, 

Attn: CECW–CO–R (David B. Olson), 

441 G Street NW, Washington, DC 

20314–1000. 

Hand Delivery/Courier: Due to 

security requirements, we cannot 

receive comments by hand delivery or 

courier. 


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