Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 78265 

Commonwealth of Independent States (CIS). 

The FAA is issuing this AD to address the 

reassessment of these repairs. The unsafe 

condition, if not addressed, could lead to 

damage or failure of the affected parts and 

the NLG, and possible damage to the airplane 

and injury to occupants. 

(f) Compliance 

Comply with this AD within the 

compliance times specified, unless already 

done. 

(g) Requirements 

Except as specified in paragraph (h) of this 

AD: Comply with all required actions and 

compliance times specified in, and in 

accordance with, EASA AD 2024–0022, 

dated January 23, 2024 (EASA AD 2024– 

0022). 

(h) Exceptions to EASA AD 2024–0022 

(1) Where EASA AD 2024–0022 refers to its 

effective date, this AD requires using the 

effective date of this AD. 

(2) This AD does not adopt the ‘‘Remarks’’ 

section of EASA AD 2024–0022. 

(i) Additional AD Provisions 

The following provisions also apply to this 

AD: 

(1) Alternative Methods of Compliance 

(AMOCs): The Manager, International 

Validation Branch, FAA, has the authority to 

approve AMOCs for this AD, if requested 

using the procedures found in 14 CFR 39.19. 

In accordance with 14 CFR 39.19, send your 

request to your principal inspector or 

responsible Flight Standards Office, as 

appropriate. If sending information directly 

to the manager of the International Validation 

Branch, mail it to the address identified in 

paragraph (j) of this AD. Information may be 

emailed to: 9-AVS-AIR-730-AMOC@faa.gov. 

Before using any approved AMOC, notify 

your appropriate principal inspector, or 

lacking a principal inspector, the manager of 

the responsible Flight Standards Office. 

(2) Contacting the Manufacturer: For any 

requirement in this AD to obtain instructions 

from a manufacturer, the instructions must 

be accomplished using a method approved 

by the Manager, International Validation 

Branch, FAA; or EASA; or Airbus SAS’s 

EASA Design Organization Approval (DOA). 

If approved by the DOA, the approval must 

include the DOA-authorized signature. 

(3) Required for Compliance (RC): Except 

as required by paragraph (i)(2) of this AD, if 

any material contains procedures or tests that 

are identified as RC, those procedures and 

tests must be done to comply with this AD; 

any procedures or tests that are not identified 

as RC are recommended. Those procedures 

and tests that are not identified 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 

procedures and tests identified as RC can be 

done and the airplane can be put back in an 

airworthy condition. Any substitutions or 

changes to procedures or tests identified as 

RC require approval of an AMOC. 

(j) Additional Information 

For more information about this AD, 

contact Timothy Dowling, Aviation Safety 

Engineer, FAA, 1600 Stewart Avenue, Suite 

410, Westbury, NY 11590; phone 206–231– 

3667; email Timothy.P.Dowling@faa.gov. 

(k) Material Incorporated by Reference 

(1) The Director of the Federal Register 

approved the incorporation by reference 

(IBR) of the material listed in this paragraph 

under 5 U.S.C. 552(a) and 1 CFR part 51. 

(2) You must use this material as 

applicable to do the actions required by this 

AD, unless this AD specifies otherwise. 

(i) European Union Aviation Safety Agency 

(EASA) AD 2024–0022, dated January 23, 

2024. 

(ii) [Reserved] 

(3) For EASA AD 2024–0022 identified in 

this AD, contact EASA, Konrad-AdenauerUfer 3, 50668 Cologne, Germany; telephone 

+49 221 8999 000; email ADs@

easa.europa.eu; website easa.europa.eu. You 

may find this EASA AD on the EASA website 

at ad.easa.europa.eu. 

(4) You may view this material 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. 

(5) You may view this material at the 

National Archives and Records 

Administration (NARA). For information on 

the availability of this material at NARA, 

visit www.archives.gov/federal-register/cfr/ 

ibr-locations, or email fr.inspection@

nara.gov. 

Issued on September 19, 2024. 

Peter A. White, 

Deputy Director, Integrated Certificate 

Management Division, Aircraft Certification 

Service. 

[FR Doc. 2024–21811 Filed 9–24–24; 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–2024–N–3533] 

Microbiology Devices; Reclassification 

of Antigen, Antibody, and Nucleic 

Acid-Based Hepatitis B Virus Assay 

Devices 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed amendment; proposed 

order; request for comments. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is proposing to reclassify qualitative 

hepatitis B virus (HBV) antigen assays, 

qualitative HBV antibody assays and 

quantitative assays that detect anti-HBs 

(antibodies to HBV surface antigen 

(HBsAg)), and quantitative HBV nucleic 

acid-based assays, all of which are 

postamendments class III devices, into 

class II (general controls and special 

controls), subject to premarket 

notification. FDA is also proposing three 

new device classification regulations 

along with the special controls that the 

Agency believes are necessary to 

provide a reasonable assurance of safety 

and effectiveness for each device. 

DATES: Either electronic or written 

comments on the proposed order must 

be submitted by November 25, 2024. 

Please see section X of this document 

for the proposed effective date when the 

new requirements apply and for the 

proposed effective date of a final order 

based on this proposed order. 

ADDRESSES: You may submit comments 

as follows. Please note that late, 

untimely filed comments will not be 

considered. The https://

www.regulations.gov electronic filing 

system will accept comments until 

11:59 p.m. Eastern Time at the end of 

November 25, 2024. Comments received 

by mail/hand delivery/courier (for 

written/paper submissions) will be 

considered timely if they are received 

on or before that date. 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal Rulemaking 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: 


ddrumheller on DSK120RN23PROD with PROPOSALS1
78266 Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 

• 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– 

2024–N–3533 for ‘‘Microbiology 

Devices; Reclassification of Antigen, 

Antibody, and Nucleic Acid-Based 

Hepatitis B Virus Assay Devices.’’ 

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 

Eastern Time, 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 

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, the plain 

language summary of the proposed 

order of not more than 100 words 

consistent with the ‘‘Providing 

Accountability Through Transparency 

Act,’’ 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: 

Maria Ines Garcia, Center for Devices 

and Radiological Health, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 66, Rm. 3104, Silver Spring, 

MD 20993, 301–796–7017, 

Maria.Garcia@fda.hhs.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background—Regulatory Authorities 

The Federal Food, Drug, and Cosmetic 

Act (FD&C Act), as amended, establishes 

a comprehensive system for the 

regulation of medical devices intended 

for human use. Section 513 of the FD&C 

Act (21 U.S.C. 360c) established three 

categories (classes) of devices, reflecting 

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 (general controls and 

special controls), and class III (general 

controls and premarket approval). 

Section 513(a)(1) of the FD&C Act 

defines the three classes of devices. 

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; 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, 

and for which there is sufficient 

information to establish special controls 

to provide such assurance, including the 

issue 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 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, or present a potential 

unreasonable risk of illness or injury 

(section 513(a)(1)(C) of the FD&C Act). 

Devices that were not in commercial 

distribution before May 28, 1976 

(generally referred to as 

‘‘postamendments devices’’) are 

automatically classified by section 

513(f)(1) of the FD&C Act into class III 

without any FDA rulemaking process. 

Those devices remain in class III and 

require premarket approval, unless, and 

until: (1) FDA reclassifies the device 

into class I or 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 predicate 

devices by means of the premarket 

notification procedures in section 510(k) 

of the FD&C Act and part 807, subpart 

E (21 CFR part 807, subpart E) of FDA’s 

regulations. 

A postamendments device that has 

been initially classified in class III 

under section 513(f)(1) of the FD&C Act 

may be reclassified into class I or class 

II under section 513(f)(3) of the FD&C 

Act. Section 513(f)(3) of the FD&C Act 

provides that FDA, acting by 

administrative order, can reclassify the 

device into class I or class II on its own 

initiative, or in response to a petition 

from the manufacturer or importer of 

the device. To change the classification 

of the device, the proposed new class 

must have sufficient regulatory controls 

to provide reasonable assurance of the 

safety and effectiveness of the device for 

its intended use. 

FDA relies upon ‘‘valid scientific 

evidence’’, as defined in section 

513(a)(3) of the FD&C Act and 21 CFR 

860.7(c)(2), in the classification process 

to determine the level of regulation for 

devices. To be considered in the 

reclassification process, the ‘‘valid 

scientific evidence’’ upon which the 

Agency relies must be publicly available 

(see section 520(c) of the FD&C Act). 


ddrumheller on DSK120RN23PROD with PROPOSALS1
Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 78267 

1FDA notes that the ‘‘ACTION’’ caption for this 

proposed order is styled as ‘‘Proposed amendment; 

proposed order,’’ rather than ‘‘Proposed order.’’ 

Beginning in December 2019, this editorial change 

was made to indicate that the document ‘‘amends’’ 

the Code of Federal Regulations. The change was 

made in accordance with the Office of the Federal 

Register’s (OFR) interpretations of the Federal 

Register Act (44 U.S.C. chapter 15), its 

implementing regulations (1 CFR 5.9 and parts 21 

and 22), and the Document Drafting Handbook. 

2Class I, II, and III recalls are defined in 21 CFR 

7.3(m). 

Publicly available information excludes 

trade secret and/or confidential 

commercial information, e.g., the 

contents of a pending premarket 

approval application (PMA) (see section 

520(c) of the FD&C Act). 

In accordance with section 513(f)(3) of 

the FD&C Act, FDA is issuing this 

proposed order to reclassify qualitative 

HBV antigen assays intended for 

qualitative detection of HBV antigens as 

an aid in the diagnosis of acute or 

chronic HBV infection in specific 

populations, HBV antibody assays 

(including qualitative and quantitative 

anti-HBs) intended for use in the 

detection of antibodies to HBV, and 

quantitative HBV nucleic acid-based 

assays intended for use in the detection 

of HBV nucleic acid in specimens from 

individuals with antibody evidence of 

HBV infection, all of which are 

postamendments class III devices, into 

class II (general controls and special 

controls) subject to premarket 

notification, under three new device 

classification regulations with the 

names ‘‘Qualitative Hepatitis B Virus 

Antigen Assays,’’ ‘‘Hepatitis B Virus 

Antibody Assays,’’ and ‘‘Hepatitis B 

Virus Nucleic Acid-Based Assays.’’ FDA 

believes the standard in section 

513(a)(1)(B) of the FD&C Act is met as 

there is sufficient information to 

establish special controls, which, in 

addition to general controls, will 

provide reasonable assurance of the 

safety and effectiveness of these 

devices.1

Section 510(m) of the FD&C Act 

provides that FDA may exempt a class 

II device from the premarket notification 

requirements under section 510(k) of the 

FD&C Act, if FDA determines that 

premarket notification is not necessary 

to provide reasonable assurance of the 

safety and effectiveness of the device. 

FDA has determined that premarket 

notification is necessary to provide a 

reasonable assurance of the safety and 

effectiveness of HBV antigen assays, 

HBV antibody assays, and HBV nucleic 

acid-based assays for their intended 

uses, therefore, the Agency does not 

intend to exempt these proposed class II 

devices from the requirement for 

premarket notification (510(k)) 

submission as provided under section 

510(m) of the FD&C Act. If this 

proposed order is finalized, persons 

who intend to market this type of device 

must submit to FDA a premarket 

notification under section 510(k) of the 

FD&C Act prior to marketing the device. 

II. Regulatory History of the Devices 

Under section 513(f)(1) of the FD&C 

Act, qualitative HBV antigen assays, 

HBV antibody assays (including 

qualitative and quantitative anti-HBs), 

and quantitative HBV nucleic acidbased assays are automatically classified 

into class III because they were not 

introduced or delivered for introduction 

into interstate commerce for commercial 

distribution before May 28, 1976, and 

have not been found substantially 

equivalent to a device placed in 

commercial distribution after May 28, 

1976, which was subsequently classified 

or reclassified into class II or class I. 

Therefore, they are subject to PMA 

requirements under section 515 of the 

FD&C Act (21 U.S.C. 360e). Qualitative 

HBV antigen assays and HBV antibody 

assays (including qualitative and 

quantitative anti-HBs) are prescription 

devices and assigned product code 

LOM. Quantitative HBV nucleic acidbased assays are prescription devices 

and assigned product code MKT. 

A. Qualitative HBV Antigen Assays 

The first proposed device 

reclassification action applies to 

qualitative HBV antigen assay devices 

that are prescription in vitro diagnostic 

devices intended for qualitative 

detection of HBV antigens as an aid in 

the diagnosis of acute or chronic HBV 

infection in specific populations. On 

February 8, 2001, FDA approved its first 

HBV antigen assay (DiaSorin’s ETI–EBK 

PLUS) for use in the qualitative 

detection of hepatitis Be antigen 

(HBeAg) in human serum or plasma 

(ethylenediaminetetraacetic acid 

(EDTA), citrate, or heparin) as indicative 

of a laboratory diagnosis of HBV 

infection through its PMA process 

under section 515 of the FD&C Act. On 

June 1, 2001, FDA approved its first 

HBV surface antigen (HBsAg) assay 

(Roche Elecsys HBsAg Immunoassay, 

Elecsys HBsAg Confirmatory, and 

Precicontrol HBsAg) for the qualitative 

detection of HBsAg in human serum or 

plasma (heparin, EDTA, sodium citrate) 

in adult pregnant and non-pregnant 

individuals. In a May 22, 2002, Federal 

Register notice (67 FR 36009), FDA 

announced the approval order and the 

availability of the Summary of Safety 

and Effectiveness Data (SSED) for these 

devices. Since the first approval order 

for an HBV antigen assay issued on 

February 8, 2001, FDA has approved 16 

additional original PMAs for qualitative 

HBV antigen assays that are prescription 

devices intended for the detection of 

HBV antigens. These assays are 

intended as an aid in the diagnosis of 

acute or chronic HBV infection in 

conjunction with clinical findings and 

other diagnostic procedures (e.g., HBV 

serology and antigen testing, liver 

function, etc.). These assays are not 

intended for use in screening of blood, 

plasma, cells, or tissue donors. 

A review of the medical device 

reporting (MDR) databases indicates that 

there were 625 reported events for 

qualitative HBV antigen assays as of 

June 2024. Of these reported events, a 

significant majority of these were 

determined to be of no known impact or 

consequence to the patient. Events 

reported included false reactive results, 

false non-reactive results, incorrect or 

inadequate assay results, incorrect/ 

inadequate/imprecise readings, 

improper or incorrect procedure or 

method, device operates differently than 

expected, and adverse event without 

identified device or use problems. 

Where incorrect results were obtained, 

it was not clear what the correct result 

should have been. As of June 2024, 

there have been no class III recalls, six 

class II recalls, and no class I recalls 2

involving qualitative HBV antigen 

assays. The class II recalls occurred 

since 2006 due to defective caps, device 

design, no marketing application, signal 

for reactive results, and biased results 

for biotin concentrations that were 

lower than indicated. No patient harm 

was identified. These facts, coupled 

with the low number of reported events 

that caused patient harm, indicate a 

good safety record for this device class. 

These recall events reflect the risks to 

health identified in section V below, 

and FDA believes the special controls 

proposed herein, in addition to general 

controls, can effectively mitigate the 

risks identified in these recalls. 

B. HBV Antibody Assays (Including 

Qualitative and Quantitative Anti-HBs) 

The second type of devices this 

proposed reclassification order applies 

to are qualitative HBV antibody assays 

and quantitative anti-HBs assays that are 

prescription in vitro diagnostic devices 

intended for use in the detection of 

antibodies to HBV. These devices are 

intended to aid in the diagnosis of HBV 

infection in persons with signs and 

symptoms of hepatitis and in persons at 

risk for HBV infection. On September 

29, 2000, FDA approved its first 

qualitative HBV antibody assay (OrthoClinical Diagnostics, Inc.’s Vitros 


ddrumheller on DSK120RN23PROD with PROPOSALS1
78268 Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 

Immunodiagnostic Products: Anti-HBS 

Reagent Pack/Anti-HBS Calibrators) for 

the qualitative in vitro determination of 

total antibody to hepatitis B surface 

antigen (anti-HBs) in human serum as 

an aid in determining susceptibility to 

HBV infection for individuals prior to or 

following HBV vaccination, or where 

vaccination status is unknown, and for 

use with other HBV serological markers 

for the laboratory diagnosis of HBV 

disease associated with HBV infection, 

through its PMA process under section 

515 of the FD&C Act. In a March 12, 

2001, Federal Register notice (66 FR 

14390), FDA announced the approval 

order and the availability of the SSED 

for this device. On July 22, 2002, FDA 

approved its first quantitative Anti-HBs 

(Siemens Healthcare Diagnostics 

Products Ltd.’s Immulite 2000 XPI AntiHBs) for the quantitative measurement 

of total antibodies to the hepatitis B 

surface antigen (anti-HBs) in human 

serum and plasma (heparinized or 

EDTA) as an aid in the determination of 

susceptibility to HBV infection for 

individuals prior to or following HBV 

vaccination, or where vaccination status 

is unknown, or for use with other HBV 

serological markers for the laboratory 

diagnosis of HBV disease associated 

with HBV infection, through its PMA 

process under section 515 of the FD&C 

Act. 

Since the first approval order of a 

qualitative HBV antibody assay on 

September 29, 2000, FDA has approved 

31 additional original PMAs for 

qualitative HBV antibody assays for the 

detection of antibodies to HBV. FDA has 

also approved six assays for quantitative 

anti-HBs detection. Qualitative HBV 

antibody assays and quantitative antiHBs assays are intended to aid in the 

diagnosis of HBV infection in persons 

with signs and symptoms of hepatitis 

and in persons at risk for HBV infection 

in conjunction with clinical findings 

and other diagnostic procedures (e.g., 

HBV serology and antigen testing, liver 

function, etc.). These assays are not 

intended for use in screening of blood, 

plasma, cells, or tissue donors. 

A review of the MDR databases 

indicates that there were 1,107 reported 

events for HBV antibody assays between 

years 2001 and June 2024. Of these 

reported events, a significant majority of 

these were of no known impact to the 

patient, and only four resulted in impact 

to patients such as misdiagnosis or viral 

infection. Events reported included 

adverse events without identified device 

or use problem, disconnection/low 

assay results, false non-reactive results, 

false reactive results, false high assay 

results (for example, the first assay 

result had a low signal to cutoff (s/co) 

value and repeat testing produced a 

higher s/co value), incorrect assay 

results, inadequate assay results, and 

low assay results (for example, the first 

assay result was in the equivocal zone, 

repeat testing produced a non-reactive 

result, and testing with an alternate 

device produced a reactive result). In 

numerous cases, it was not possible to 

determine what the correct result 

should have been (further testing was 

not performed, insufficient sample 

volume, different assays were used). As 

of June 2024, FDA is aware of 4 class III 

recalls, 12 class II recalls, and no class 

I recalls for these devices. The class II 

recalls occurred in 2007, 2008, 2009, 

2011, 2012, 2013, 2014, 2018, and 2019, 

and were related to issues such as false 

reactive results, false high assay results, 

defective caps, and errors in labeling, 

packaging, or software. No patient harm 

has been identified. These facts, 

coupled with the low number of 

reported events that impacted the 

patient, indicate a good safety record for 

this device class. These recall events 

reflect the risks to health identified in 

section V below, and FDA believes the 

special controls proposed herein, in 

addition to general controls, can 

effectively mitigate the risks identified 

in these recalls. 

C. Quantitative HBV Nucleic AcidBased Assays 

Finally, the third type of device this 

proposed reclassification order applies 

to are quantitative HBV nucleic acidbased assay devices for use as a 

prescription in vitro diagnostic device 

intended for use in the detection of HBV 

nucleic acid in specimens from 

individuals with antibody evidence of 

HBV infection. On September 4, 2008, 

FDA approved its first quantitative HBV 

nucleic assay (Roche Molecular 

Systems, Inc.’s COBAS TaqMan HBV 

Test For Use With The High Pure 

System), an in vitro nucleic acid 

amplification assay for the quantitation 

of HBV deoxyribonucleic acid (DNA) in 

human serum or plasma (EDTA) 

intended for use as an aid in the 

management of patients with chronic 

HBV infection undergoing antiviral 

therapy, through its PMA process under 

section 515 of the FD&C Act. 

Since the first approval order, FDA 

has approved four additional original 

PMAs for quantitative HBV nucleic 

acid-based assays for the quantitative 

detection of HBV DNA. The detection of 

HBV DNA is used for management of 

patients undergoing antiviral therapy for 

assessing response to treatment and not 

as a diagnostic for HBV infection. 

The following section provides 

examples of the different technologies 

used. The different technologies begin 

with specimen lysis and HBV DNA 

through hybridization with magnetic 

particles. The differences in the 

technologies occur with the method of 

amplification: 

• In one technology, the target HBV 

DNA sequence is amplified. The 

presence of HBV amplification products 

is detected by measuring the 

fluorescence of the HBV probe that 

binds to the target. Similarly, the 

presence of the internal control 

amplification product is detected. In the 

absence of HBV or internal control 

target sequences, probe fluorescence is 

quenched. In the presence of HBV or 

internal control target, the HBV or 

internal control probes bind to their 

target. 

• In another technology, target 

amplification occurs via transcriptionbased nucleic acid amplification by 

fluorescent labeled probes (torches). 

More torches hybridize when more 

amplicon is present creating a higher 

fluorescent signal. The time taken for 

the fluorescent signal to reach a 

threshold proportional to the starting 

HBV DNA concentration is measured in 

relation to internal controls. 

A review of the MDR databases 

indicates that as of June 2024 there were 

13 reported events for nucleic acidbased HBV DNA assays since the first 

reported event in 2009. MDRs were for 

the following reasons: (1) incorrect, 

inadequate, or imprecise result or 

readings; (2) high readings; and (3) nonreproducible results. Of these, two had 

no known impact or consequence to the 

patient and two occurred when the 

patient had no signs, symptoms, or 

conditions. As of June 2024, FDA is 

aware of one class III recall, five class 

II recalls, and no class I recalls for these 

devices. The class II recalls occurred 

between 2005 and 2022 and were 

related to issues such as misquantitation 

of high results for negative samples 

(carryover from a high positive sample 

tested adjacent to a negative sample may 

produce an incorrect positive result), 

liquid level detection of reagent 

cassette, under filled and over filled 

enzyme reagent vials in assay kits, 

software, and low level of recombinant 

HBV DNA found in one lot of reagent. 

These facts, coupled with the low 

number of reported events that 

impacted the patient, indicate a good 

safety record for this device class. These 

recall events reflect the risks to health 

identified in section V below, and FDA 

believes the special controls proposed 

herein, in addition to general controls, 

can effectively mitigate the risks 

identified in these recalls. 


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Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 78269 

III. Device Description 

The HBV assays that are the subject of 

this proposed order are 

postamendments prescription in vitro 

diagnostic devices classified into class 

III under section 513(f)(1) of the FD&C 

Act. 

A. Qualitative HBV Antigen Assays 

A qualitative HBV antigen assay is a 

prescription in vitro diagnostic device 

intended for use in the qualitative 

detection of HBV antigens and for use 

as an aid in the diagnosis of HBV 

infection in specific populations. HBV 

antigen assays aid in the diagnosis of 

acute or chronic HBV infection. HBV 

antigen assays typically detect the 

presence of Hepatitis B surface antigen 

(HBsAg) or Hepatitis B e antigen 

(HBeAg). HBV antigens (HBsAg and 

HBeAg), when present in samples, bind 

to anti-HBs or anti-HBe antibodies to 

form a complex that is bound to a solid 

phase (e.g., microparticles, microtiter 

plate or other technology). Detection of 

the complexes can be performed using 

different methods which measure the 

presence/absence of anti-HBs or antiHBe antibodies in the sample. 

Diagnosis of HBV infection should not 

be established based on a single assay 

result but should be determined in 

conjunction with clinical findings and 

other diagnostic procedures (e.g., HBV 

serology and antigen testing, liver 

function, etc.). These assays are not 

intended for use in screening of blood, 

plasma, cells, or tissue donors. 

B. HBV Antibody Assays (Including 

Qualitative and Quantitative Anti-HBs) 

A qualitative HBV antibody assay is a 

prescription in vitro diagnostic device 

intended for use in the qualitative 

detection of antibodies to HBV and for 

use as an aid in the diagnosis of HBV 

infection in specific populations. HBV 

antibody assays aid in the diagnosis of 

HBV infection in persons with signs and 

symptoms of hepatitis and in persons at 

risk for HBV infection. Antibody assays 

typically detect the presence of 

antibodies to HBsAg (anti-HBs), 

Hepatitis B core antigen (anti-HBc), or 

HBeAg (anti-HBe). Diagnosis of HBV 

infection should not be established 

based on a single assay result, but 

should be determined in conjunction 

with clinical findings and other 

diagnostic procedures (e.g., HBV 

serology and antigen testing, liver 

function, etc.). These assays are not 

intended for use in screening of blood, 

plasma, cells, or tissue donors. 

A quantitative assay that detects antiHBs (antibodies to HBV surface antigen 

(HBsAg)) is a prescription in vitro 

diagnostic device that is intended for 

quantitative use to aid in the diagnosis 

of HBV infection in persons with signs 

and symptoms of hepatitis and in 

persons at risk for HBV infection. 

Detection of anti-HBs indicates a 

present or past infection with HBV and 

can be used in conjunction with clinical 

findings such as other HBV serological 

markers (detection of other HBV 

antigens and antibodies to HBV) for 

diagnosis of HBV infection. Anti-HBs 

assay results may be used as an aid in 

the determination of susceptibility to 

HBV infection in individuals prior to 

vaccination or when vaccination status 

is unknown. 

In some device designs, HBV 

antibodies, when present in the sample, 

bind to HBV antigens to form a complex 

that is bound to a solid phase (e.g., 

microparticles, microtiter plate, or other 

technology). Detection of complexes can 

be performed using different methods 

that measure the presence/absence of 

HBV antibodies in the sample. 

C. Quantitative HBV Nucleic AcidBased Assays 

A quantitative HBV nucleic acidbased assay is a prescription in vitro 

diagnostic device intended for use in 

the detection of HBV nucleic acid in 

specimens from individuals with 

antibody evidence of HBV infection. In 

these devices, the detection of HBV 

nucleic acid is used for management of 

patients undergoing antiviral therapy for 

assessing response to treatment and 

NOT as a diagnostic for HBV infection. 

FDA is proposing to reclassify 

qualitative HBV antigen, HBV antibody 

assays (including qualitative and 

quantitative anti-HBs), and quantitative 

HBV nucleic acid-based assays from 

class III (general controls and premarket 

approval) to class II (general controls 

and special controls) and to establish 

new names for the device types that will 

be within the classification regulations. 

FDA proposes to revise 21 CFR part 866 

to create three new device classification 

regulations with the names ‘‘Qualitative 

Hepatitis B Virus Antigen Assays,’’ 

‘‘Hepatitis B Virus Antibody Assays,’’ 

and ‘‘Hepatitis B Virus Nucleic AcidBased Assays.’’ FDA believes that these 

names and proposed identification 

language most accurately describe these 

devices. 

• A Qualitative Hepatitis B Virus 

(HBV) Antigen Assay is tentatively 

identified as an in vitro diagnostic 

device intended for prescription use for 

qualitative use with human serum, 

plasma, or other matrices that aids in 

the diagnosis of chronic or acute HBV 

infection. HBV surface antigen (HBsAg) 

is also used for screening of HBV 

infection in pregnant women to identify 

neonates who are at risk of acquiring 

hepatitis B during perinatal period. The 

assay is not intended for screening of 

blood, plasma, cells, or tissue donors. 

• A Hepatitis B Virus (HBV) Antibody 

Assay is tentatively identified as an in 

vitro diagnostic device intended for 

prescription use in the detection of 

antibodies to HBV in human serum and 

plasma, or other matrices, and or as an 

aid in the diagnosis of HBV infection in 

persons with signs and symptoms of 

hepatitis and in persons at risk for 

hepatitis B infection. In addition, antiHBc IgM (IgM antibodies to core 

antigen) assay is indicative of recent 

HBV infection. Anti-HBs (antibodies to 

surface antigen) assay results may be 

used as an aid in the determination of 

susceptibility to HBV infection in 

individuals prior to or following HBV 

vaccination or when vaccination status 

is unknown. The assay is not intended 

for screening of blood, plasma, cells, or 

tissue donors. The assay is intended as 

an aid in diagnosis in conjunction with 

clinical findings and other diagnostic 

procedures. 

• A Hepatitis B Virus (HBV) Nucleic 

Acid-Based Assay is tentatively 

identified as an in vitro diagnostic 

device intended for prescription use in 

the detection of HBV nucleic acid in 

specimens from individuals with 

antibody evidence of HBV infection. In 

these devices, the detection of HBV 

nucleic acid is used as an aid in the 

management of HBV-infected 

individuals. The assay is intended for 

use with human serum or plasma (and 

other matrices as applicable) from 

individuals with HBV. The assay is not 

intended for use as a donor screening 

assay for the presence of HBV nucleic 

acids in blood, blood products, plasma, 

cells, or tissue donors. 

Based upon our review experience 

and consistent with the FD&C Act and 

FDA’s regulations in 21 CFR 860.134, 

FDA believes that these devices should 

be reclassified from class III into class 

II with special controls because there is 

sufficient information to establish 

special controls that, along with general 

controls, can provide reasonable 

assurance of the devices’ safety and 

effectiveness. 

IV. Proposed Reclassification and 

Summary of Reasons for 

Reclassification 

FDA is proposing to reclassify the 

HBV assays that are the subject of this 

proposed order. On September 7, 2023, 

the Microbiology Devices Panel (Panel) 

of the Medical Devices Advisory 

Committee convened to discuss and 

make recommendations regarding the 


ddrumheller on DSK120RN23PROD with PROPOSALS1
78270 Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 

3https://www.who.int/news-room/fact-sheets/ 

detail/hepatitis-b. Accessed on July 12, 2024. 

4Centers for Disease Control and Prevention— 

Clinical Overview of Hepatitis B (Available at 

https://www.cdc.gov/hepatitis-b/hcp/clinicaloverview/index.html). Accessed on July 12, 2024. 

5 Ibid. 

6 Ibid. 

7https://www.who.int/health-topics/hepatitis/ 

elimination-of-hepatitis-by-2030#tab=tab_1. 

Accessed on July 12, 2024. 

reclassification of HBV assays from class 

III (general controls and premarket 

approval) to class II (general controls 

and special controls) (https://

www.fda.gov/media/173609/download). 

Panel members unanimously agreed that 

special controls, in addition to general 

controls, are necessary and sufficient to 

mitigate the risks to health of patients 

presented by these devices and to 

provide reasonable assurance of the 

safety and effectiveness of these devices 

(Refs. 1 and 2). The Panel agreed with 

FDA-identified risks and identified 

additional risk(s) and benefit(s) to 

include in the overall risk assessment. 

The Panel also discussed potential 

mitigation measure(s)/control(s) FDA 

should consider for each of the 

identified risks and recommended that, 

as part of any reclassification, the 

expected performance for these devices 

should remain the same. Notably, the 

performance of approved HBV antigen 

assays has generally been at least 97 

percent sensitivity and 99 percent 

specificity. For approved anti-HBs, antiHbe, and anti-HBc total assays the 

sensitivity has generally been at least 95 

percent, for approved anti-HBc IgM 

assays the sensitivity has been at least 

86 percent, and for all HBV approved 

antibody assays the specificity has 

generally been above 97 percent. 

FDA believes that at this time, 

sufficient data and information exist 

such that the risks identified in section 

V below can be mitigated by 

establishing special controls, and that 

these special controls, together with 

general controls, are necessary to 

provide a reasonable assurance of the 

safety and effectiveness of these HBV 

assays and therefore proposes these 

devices to be reclassified from class III 

(general controls and premarket 

approval) to class II (general controls 

and special controls). In accordance 

with section 513(f)(3) of the FD&C Act 

and 21 CFR part 860, subpart C, FDA is 

proposing to reclassify qualitative HBV 

antigen assays, HBV antibody assays 

(including qualitative and quantitative 

anti-HBs), and quantitative HBV nucleic 

acid-based assays from class III into 

class II, subject to premarket notification 

(510(k)) requirements. FDA believes that 

there is sufficient information available 

to FDA through FDA’s accumulated 

experience with these devices from 

reviewing the PMAs for these HBV 

assays, and the Panel considerations 

and recommendations regarding the 

proposed special controls that FDA 

believes would effectively mitigate the 

risks to health identified in section V. 

Absent the special controls identified in 

this proposed order, general controls 

applicable to the devices are insufficient 

to provide reasonable assurance of the 

safety and effectiveness of the devices. 

FDA expects that the reclassification of 

these devices would enable more 

manufacturers to develop these assays 

such that patients would benefit from 

increased access to safe and effective 

tests. 

FDA is proposing to create three 

separate classification regulations for 

HBV assays that will be reclassified 

from class III to class II. HBV assays are 

prescription in vitro diagnostic devices, 

and under this proposed order, if 

finalized, these devices will be 

identified as prescription in vitro 

diagnostic devices. As such, the devices 

must satisfy prescription labeling 

requirements for in vitro diagnostic 

products (see 21 CFR 809.10(a)(4) and 

(b)(5)(ii)). In this proposed order, if 

finalized, FDA has identified the special 

controls under section 513(a)(1)(B) of 

the FD&C Act that, together with general 

controls, will provide a reasonable 

assurance of the safety and effectiveness 

of these assays. 

FDA is also proposing to create a new 

product code for HBV antibody assays 

(including qualitative and quantitative 

anti-HBs) that will be assigned upon any 

finalization of this proposed order. 

Qualitative HBV antigen assays will 

continue to be assigned the product 

code LOM upon any finalization of this 

proposed order. 

Section 510(m) of the FD&C Act 

provides that FDA may exempt a class 

II device from the premarket notification 

requirements under section 510(k) of the 

FD&C Act, if FDA determines that 

premarket notification is not necessary 

to provide reasonable assurance of the 

safety and effectiveness of the device. 

For these HBV assays, FDA has 

determined that premarket notification 

is necessary to provide a reasonable 

assurance of the safety and effectiveness 

of these devices. Therefore, the Agency 

does not intend to exempt these 

proposed class II devices from 510(k) 

requirements. If this proposed order is 

finalized, persons who intend to market 

a new HBV assay will no longer need to 

have a PMA for these devices but can 

instead submit to FDA a 510(k) and 

receive clearance prior to marketing the 

device. A 510(k) typically results in a 

shorter premarket review timeline 

compared to a PMA, which ultimately 

provides more timely access of these 

types of devices to patients. 

V. Public Health Benefits and Risks to 

Health 

FDA is providing a substantive 

summary of the valid scientific evidence 

concerning the public health benefits of 

the use of HBV assays (see also https:// 

www.fda.gov/media/171770/download), 

and the nature (and if known, the 

incidence) of the risks of the devices 

(see further discussion of the special 

controls being proposed to mitigate 

these risks in section VII of this 

proposed order). 

HBV infection represents a significant 

global public health burden. According 

to the World Health Organization 

(WHO), in 2019 there were 

approximately 296 million people 

chronically infected people worldwide, 

with 1.5 million new HBV infections 

each year.3 It is estimated by the Centers 

for Disease Control and Prevention 

(CDC) that chronic HBV infection in the 

United States affects at least between 

580,000 to 1.17 million people with 

HBV infection in the United States; twothirds of whom may be unaware of their 

infection.4 HBV infection can be 

asymptomatic, and accordingly, many 

HBV-infected individuals are unaware 

of their HBV infection. Approximately 

95 percent of adult patients with acute 

infection, defined as the first 6 months 

after infection, recover completely, and 

5 percent of adults develop chronic 

HBV.5 Infants born to women who are 

HbsAg-positive are at high risk of HBV 

infection. In absence of treatment, 

infants infected with HBV have a 90 

percent risk of progression to chronic 

HBV and up to 25 percent of infants 

who acquire chronic HBV infection will 

die prematurely from HBV-related 

hepatocellular carcinoma or cirrhosis.6

Patients who are tested and become 

aware that they are HBV infected may 

modify risk behaviors to prevent 

transmission to others and can be 

referred for treatment. Patients with 

chronic HBV infection have a risk of 

developing liver damage, liver cancer, 

or liver failure. They can also spread 

their infection to others. HBV can be 

reactivated in patients receiving 

immunosuppressive therapies, resulting 

in serious risk of liver failure or liverassociated death (Ref. 3). HBV is a 

vaccine-preventable liver infection. 

With the initiation of the WHO Viral 

Hepatitis Elimination Plan 7 and the 

Department of Health and Human 

Services (HHS) Viral Hepatitis National 


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8https://www.hhs.gov/sites/default/files/ViralHepatitis-National-Strategic-Plan-2021-2025.pdf. 

Accessed on July 12, 2024. 

9https://www.cdc.gov/hepatitis/hbv/index.htm. 

Accessed on July 12, 2024. 

Strategic Plan for the United States,8 it 

is important for individuals to know 

their HBV infected status, to link HBV 

infected individuals to care, and to 

eliminate virus transmission. Therefore, 

diagnosis of patients with HBV infection 

through devices such as HBV antibody 

and antigen assays is essential to ensure 

that patients are linked to the 

appropriate care. Current CDC HBV 

Screening and Testing 

Recommendations include testing of the 

following groups: all adults 18 and older 

at least once in their lifetime using a 

triple panel test, pregnant women 

during pregnancy, people who are at 

ongoing risk for exposure, and anyone 

who requests HBV testing.9

FDA considered our accumulated 

experience with the regulation of these 

HBV assays, input from the Panel 

meeting, and postmarket information 

regarding these HBV assays, i.e., 

information from FDA’s publicly 

available MDR, Manufacturer and User 

Facility Device Experience (MAUDE), 

and Medical Device Recall databases. 

These HBV assays provide a benefit to 

the public health by informing 

individuals of their HBV infected status, 

linking HBV infected individuals to 

appropriate care, and aiding in 

eliminating virus transmission. Once an 

individual is tested and diagnosed as 

HBV infected, HBV nucleic acid testing 

is performed to inform treatment 

decisions. While HBV infection is 

treatable, it is not curable, which means 

that most people who start HBV 

antiviral treatment must continue it for 

life. The goal of current treatment is to 

suppress the virus and reduce the 

likelihood of long-term complications 

and transmission (Refs. 3 and 4). Thus, 

identifying individuals who are HBV 

infected, linking them to care, and 

managing their HBV infection to 

alleviate development of liver damage, 

liver cancer, liver failure, and potential 

HBV transmission would not only 

greatly impact public health but also go 

a long way towards helping the United 

States achieve HBV elimination. 

Probable risks to health associated 

with the use of HBV assays include risks 

related to the risk of false results (false 

positives, false negatives, inaccurate low 

assay results, inaccurate high assay 

results, false reactive results, or false 

non-reactive results), failure to correctly 

interpret assay results, and failure to 

correctly operate the device. For HBV 

antigen and antibody assays, false 

positive results are generally referred to 

as false reactive results and false 

negative results are generally referred to 

as false non-reactive results. False 

results can lead to uninfected 

individuals receiving unnecessary 

further testing and treatment or infected 

individuals remaining undiagnosed and 

untreated. Undiagnosed and untreated 

individuals are likely to experience 

increases in morbidity and mortality 

and can spread the infection to others. 

FDA has identified the following 

additional specific risks to health 

associated with each of the HBV assays 

listed below. 

A. Qualitative HBV Antigen Assays 

Factors that may cause decreased 

assay sensitivity and/or an increased 

rate of false non-reactive results include, 

but are not limited to, the presence of 

interfering substances in the sample, 

acute infection at a stage that is too early 

for a device to detect the infection, and 

antigen concentrations that are too low 

to be detected by the device. Factors 

that may lead to false reactive results 

include device contamination from 

reactive samples, cross-reactivity with 

other antigens, or misinterpretation of 

invalid results as reactive. 

• A false reactive assay result for 

HbeAg. Incorrectly interpreting the 

assay results as a reactive assay result or 

failing to correctly operate the assay 

causing a false reactive assay result may 

lead to continued treatment for hepatitis 

B with antiviral medication when it 

otherwise would not be indicated. 

Antiviral medication has risks including 

toxicity and more rarely allergic 

reactions. Over time, viral resistance in 

patients who are co-infected but 

undiagnosed with other viruses that are 

treated with the same antiviral 

medication, such as HIV, can lead to 

viral resistance. 

• A false reactive assay result for 

HbsAg. Incorrectly interpreting the 

assay results as a reactive assay result or 

failing to correctly operate the assay 

causing a false reactive assay result may 

contribute to unnecessary additional 

testing, potentially delaying diagnosis of 

alternative causes of liver disease when 

present and may impact the 

psychological well-being of the patient. 

Factors that may increase the rate of 

false reactive assay reporting include 

cross-reactivity with antigens from other 

microorganisms or other disease 

conditions. 

• A false non-reactive result for 

HbeAg. Incorrectly interpreting the 

assay results as a non-reactive assay 

result or failing to correctly operate the 

assay causing a false non-reactive assay 

result may lead to missing the 

opportunity for treatment of an HBV 

infected individual with antiviral 

medication or premature 

discontinuation of antiviral treatment 

when continuation of treatment is 

otherwise indicated should a clinician 

be falsely led to determine a patient has 

seroconverted HbeAg to anti-Hbe. 

Premature discontinuation of antiviral 

medication could result in adverse 

effects on patient health, such as 

cirrhosis, liver cancer, and liver damage, 

all of which are known to contribute to 

patient morbidity and mortality, or may 

contribute to public health risk by 

leading to virus transmission. 

• A false non-reactive assay result for 

HbsAg. Incorrectly interpreting the 

assay results as a non-reactive assay 

result or failing to correctly operate the 

assay causing a false non-reactive assay 

result may delay or prevent a patient 

with HBV infection from being 

identified and linked to care. Missed 

identification of patients with chronic 

HBV infection could lead to adverse 

effects on patient health such as 

cirrhosis, liver cancer, and liver damage, 

all of which are known to contribute to 

patient morbidity and mortality. A false 

non-reactive HbsAg assay incorrectly 

interpreted as non-reactive also may 

contribute to public health risk by 

leading to virus transmission. 

B. HBV Antibody Assays (Including 

Qualitative and Quantitative Anti-HBs) 

Factors that may cause decreased 

assay sensitivity and/or an increased 

rate of false non-reactive results include, 

but are not limited to, the presence of 

interfering substances in the sample, 

acute infection at a stage that is too early 

for a device to detect the infection, and 

antibody concentrations that are too low 

to be detected by the device. They also 

can be caused by misinterpretation of 

invalid results as non-reactive. Factors 

that may lead to false reactive results 

include device contamination from 

reactive samples, cross-reactivity with 

other antibodies, or misinterpretation of 

invalid results as reactive. 

• A false reactive assay result for 

anti-HBs and anti-HBc. Incorrectly 

interpreting the assay results as a 

reactive assay result or failing to 

correctly operate the assay causing a 

false reactive assay result may lead to 

improper patient management. A false 

reactive antibody assay result could 

result in the unnecessary continuation 

of antiviral treatment. Antiviral 

medication has risks including toxicity 

and more rarely allergic reactions. Over 

time, viral resistance in patients who are 

co-infected but undiagnosed with other 

viruses that are treated with the same 

antiviral medication, such as HIV, can 


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lead to viral resistance. Consequently, 

repeatedly false reactive results have the 

potential to lead to inappropriate 

patient management decisions. 

• A false reactive assay result for 

anti-HBs. Incorrectly interpreting the 

assay results as a reactive assay result or 

failing to correctly operate the assay 

causing a false reactive assay result 

when the device is used as an aid in the 

determination of susceptibility to HBV 

infection in individuals prior to or 

following HBV vaccination or where 

vaccination status is unknown may 

cause a patient to be considered 

previously exposed and therefore 

immune to HBV or that the patient was 

successfully vaccinated. A false reactive 

result may cause the patient to not 

receive a vaccine, vaccine booster, 

hyperimmune globulin, and would be at 

higher risk of infection if exposed to 

HBV. 

• A false reactive assay result for 

anti-Hbe. Incorrectly interpreting the 

assay results as a reactive assay result, 

or failing to correctly operate the assay 

causing a false reactive assay result may 

lead to missing the opportunity for 

treatment of HBV infection with 

antiviral medications in a subset of 

individuals for whom treatment would 

otherwise be indicated, or premature 

discontinuation of antiviral treatment 

when continuation of treatment is 

otherwise indicated should a clinician 

be falsely led to determine a patient has 

seroconverted HbeAg to anti-Hbe. 

Premature discontinuation of antiviral 

medication could result in adverse 

effects on patient health such as 

cirrhosis, liver cancer, and liver damage, 

all of which are known to contribute to 

patient morbidity and mortality, or may 

contribute to public health risk by 

leading to inadvertent transmission of 

virus by an infected individual. 

• A false non-reactive assay result for 

anti-HBc. When the device is used as an 

aid in the diagnosis of HBV infection in 

patients with symptoms of hepatitis or 

who may be at risk for HBV infection, 

incorrectly interpreting the assay results 

as non-reactive assay result, or failing to 

correctly operate the assay causing a 

false non-reactive assay result may lead 

to non-diagnosis or a delay in diagnosis 

of HBV infection with an associated 

delay in therapy and potentially 

increased risk of HBV-related morbidity 

or mortality. Patients with active 

infection may unknowingly continue to 

infect others. False non-reactive results 

can also lead to unnecessary diagnostic 

evaluation if alternative etiologies of 

hepatitis are pursued. False non-reactive 

assay results may occur if the level of 

antibody in a specimen is below the 

limit of detection of the assay. 

• A false non-reactive assay result for 

anti-HBs. When the device is used as an 

aid in the determination of 

susceptibility to HBV infection in 

individuals prior to or following HBV 

vaccination or where vaccination status 

is unknown, incorrectly interpreting the 

assay results as a non-reactive assay 

result or failing to correctly operate the 

assay causing a false non-reactive assay 

result may lead to unnecessary repeated 

vaccination for HBV. 

• A false non-reactive assay result for 

anti-Hbe. Incorrectly interpreting the 

assay results as non-reactive assay result 

or failing to correctly operate the assay 

causing a false non-reactive assay result 

may lead to improper patient 

management, including continued 

treatment for HBV with antiviral 

medication. Antiviral medication has 

risks including toxicity and more rarely 

allergic reactions. Over time, viral 

resistance in patients who are coinfected but undiagnosed with other 

viruses using the same antiviral 

medication, such as HIV, can lead to 

viral resistance. 

C. Quantitative HBV Nucleic AcidBased Assays 

Decreased assay sensitivity and/or an 

increased rate of false negative assay 

reporting may occur with patient 

samples that contain different genotypes 

or rare de novo mutations in HBV 

genomic regions targeted by the device. 

In these situations, HBV viral load can 

transiently decrease and/or become 

undetectable in samples before the virus 

enters chronic replication. 

• A false positive or falsely elevated 

quantitative HBV nucleic acid assay 

result. Incorrectly interpreting the assay 

results as a positive assay result or 

failing to correctly operate the assay 

causing a false positive assay result may 

negatively influence patient 

management decisions. Such decisions 

may include the administration or 

continuation of unnecessary antiviral 

treatment in patients with chronic HBV 

infection with its known toxicities and 

more rarely allergic reactions. Certain 

patients with falsely elevated HBV 

nucleic acid assay results may not 

undergo liver biopsy to investigate other 

causes of liver disease when the biopsy 

would otherwise be indicated for certain 

patients. 

• A false negative or falsely decreased 

quantitative HBV nucleic acid assay 

result. Incorrectly interpreting the assay 

results as a negative assay result, or 

failing to correctly operate the assay 

causing a false negative assay result may 

negatively influence patient 

management decisions for patients with 

chronic HBV infection, including the 

withholding of treatment, failure to 

treat, or premature discontinuation of 

treating HBV infection when antiviral 

treatment is otherwise indicated or the 

choice of an inappropriate treatment. 

This could lead to adverse effects on 

patient health such as progressive liver 

disease, cirrhosis and/or hepatocellular 

carcinoma, and other cancers. Patients 

with active HBV replication also risk 

spreading the virus to others. Certain 

patients with falsely low HBV nucleic 

acid assay results may undergo liver 

biopsy to investigate other causes of 

liver disease. 

VI. Summary of Data Upon Which the 

Reclassification Is Based 

The safety and effectiveness of these 

device types has become well 

established since the initial approval of 

the first qualitative HBV antibody assay 

in 2000, the first HBV antigen assay in 

2001, and the first quantitative HBV 

nucleic acid-based assay in 2008. FDA 

has considered and analyzed the 

following information: (1) accumulated 

experience regulating these HBV assays, 

(2) input from the Panel meeting, and 

(3) postmarket information regarding 

HBV assays, i.e., information from 

FDA’s publicly available MDR, MAUDE, 

and Medical Device Recall databases. 

The available evidence demonstrates 

that there are public health benefits 

derived from the use of HBV assays 

indicated for use to aid in diagnosis of 

HBV infection and/or for use to aid in 

the management of HBV infected 

patients, or as an aid in the 

determination of susceptibility to HBV 

infection (anti-HBs). In addition, the 

nature of the associated risks to health 

are known, and special controls can be 

established to sufficiently mitigate these 

risks. 

Based on our review of the 

information described above, FDA has 

determined that special controls, in 

addition to general controls, are 

necessary to provide a reasonable 

assurance of safety and effectiveness for 

HBV assays, and that sufficient 

information exists to establish such 

special controls. Therefore, FDA, on its 

own initiative, is proposing to reclassify 

these postamendments devices from 

class III (general controls and premarket 

approval) into class II (general controls 

and special controls), subject to 

premarket notification (510(k)) 

requirements. 

VII. Proposed Special Controls 

FDA believes that these devices can 

be classified into class II with the 

establishment of special controls. FDA 

believes that the following proposed 

special controls would mitigate each of 


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Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 78273 

the risks to health described in section 

V and that these special controls, in 

addition to general controls, would 

provide a reasonable assurance of safety 

and effectiveness for HBV assays. Tables 

1 through 3 below demonstrate how 

FDA believes each risk to health 

described in section V would be 

mitigated by the proposed special 

controls for each device type. 

A. Qualitative HBV Antigen Assays 

The risk of inaccurate interpretation 

of assay results can be mitigated by 

special controls requiring certain 

labeling, including providing clearly 

stated warnings and limitations and 

information on principles of operation 

and procedures in performing the assay. 

Risks associated with false results 

(e.g., false non-reactive and false 

reactive assay results) and with the 

failure to correctly operate the device 

can be mitigated through a combination 

of special controls, including certain 

labeling requirements, certain design 

verification and validation information, 

and performance studies. Examples of 

verification and validation information 

to be included in the design of the 

device include documentation of 

performance specifications including 

analytical and clinical performance 

criteria. In addition, design verification 

and validation activities must include 

documentation of a complete device 

description, critical reagents, risk 

analysis strategies, lot release criteria, 

stability studies, and protocols. 

Required statements in labeling can aid 

in mitigating the failure of the device to 

perform as indicated, for example 

including a statement that use of the 

assay with specimen types other than 

those specifically identified for use with 

this device may cause inaccurate assay 

results. Special controls requiring 

additional labeling to provide a brief 

summary of the instructions for use can 

also mitigate these risks. 

TABLE 1—RISKS TO HEALTH AND MITIGATION MEASURES FOR QUALITATIVE HBV ANTIGEN ASSAYS

Identified risks to health Mitigation measures 

False reactive/non-reactive assay result ...................................... Certain labeling information, including limitations, explanation of procedures, 

and results interpretation information. 

Certain design verification and validation information, including certain device 

description information, risk analysis strategies, lot release criteria, stability 

studies and protocols, and performance criteria including analytical studies 

and clinical studies. 

Failure to correctly interpret the assay results ............................. Certain labeling information, including warnings, limitations, results interpretation information, and explanation of procedures. 

Certain design verification and validation information, including certain device 

description information, critical reagent information, risk analysis strategies, 

lot release criteria, and stability studies and protocols. 

Failure to correctly operate the device ......................................... Certain labeling information, including warnings, limitations, results interpretation information, and explanation of procedures. 

Certain design verification and validation information, including certain device 

description, critical reagent information, risk analysis strategies, lot release 

criteria, and stability studies and protocols. 

B. HBV Antibody Assays (Including 

Qualitative and Quantitative Anti-HBs) 

The risk of falsely reactive, nonreactive, elevated, or lowered assay 

results can be mitigated by special 

controls requiring certain labeling, 

including providing clearly stated 

warnings and limitations and 

information on principles of operation 

and procedures in performing the assay. 

Risks associated with the failure of 

the device to perform as indicated (e.g., 

false non-reactive and false reactive 

assay results) can be mitigated through 

a combination of special controls, 

including certain labeling requirements, 

certain design verification and 

validation information, and 

performance studies. Examples of 

verification and validation information 

to be included in the design of the 

device include documentation of 

performance specifications including 

analytical and clinical performance 

criteria. In addition, design verification 

and validation activities must include 

documentation of a complete device 

description, critical reagents, risk 

analysis strategies, lot release criteria, 

stability studies, and protocols. 

Required statements in labeling can aid 

in mitigating the failure of the device to 

perform as indicated; for example, 

including a statement that use of the 

assay with specimen types other than 

those specifically identified for use with 

this device may cause inaccurate assay 

results. 

TABLE 2—RISKS TO HEALTH AND MITIGATION MEASURES FOR HBV ANTIBODY ASSAYS (INCLUDING QUALITATIVE AND

QUANTITATIVE ANTI-HBS) 

Identified risks to health Mitigation measures 

False reactive/false non-reactive assay result. In addition, for 

quantitative assays: Falsely elevated/falsely lowered assay 

result.

Certain labeling information, including limitations, explanation of procedures, 

and results interpretation information. 

Certain design verification and validation information including certain device 

description information, risk analysis strategies, lot release criteria, stability 

studies and protocols, and performance criteria including analytical studies 

and clinical studies. 

Failure to correctly interpret the assay results ............................. Certain labeling information, including warnings, limitations, results interpretation information, and explanation of procedures. 

Certain design verification and validation information including certain device 

description, critical reagent information, risk analysis strategies, lot release 

criteria, and stability studies and protocols. 


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TABLE 2—RISKS TO HEALTH AND MITIGATION MEASURES FOR HBV ANTIBODY ASSAYS (INCLUDING QUALITATIVE AND

QUANTITATIVE ANTI-HBS)—Continued 

Identified risks to health Mitigation measures 

Failure to correctly operate the devices ....................................... Certain labeling information, warnings, limitations, results interpretation information, and explanation of procedures. 

Certain design verification and validation information including certain device 

description, critical reagent information, risk analysis strategies, lot release 

criteria, and stability studies and protocols. 

C. Quantitative HBV Nucleic AcidBased Assays 

The risk of falsely positive, negative, 

elevated, or lowered assay results can be 

mitigated by special controls requiring 

certain labeling, including providing 

clearly stated warnings and limitations, 

device description information, and 

detailed instructions in the device 

labeling regarding the interpretation of 

assay results and principles of operation 

and procedures in performing the assay. 

Risks associated with the failure of 

the device to perform as indicated (e.g., 

inaccurately low or high results, false 

negative results, and false positive assay 

results) can be mitigated through a 

combination of special controls related 

to certain labeling requirements, design 

verification and validation activities, 

and performance studies. Examples of 

verification and validation information 

to be included in the design of the 

device include documentation of a 

complete device description, calibrators, 

critical reagents, traceability, and lot 

release criteria. In addition, design 

verification and validation must include 

documentation of performance 

specifications, including analytical and 

clinical performance criteria. Required 

statements in labeling can aid in 

mitigating the occurrence of inaccurate 

results. The risks of false positive/false 

negative/falsely elevated/falsely 

lowered results due to decreased assay 

sensitivity can be mitigated by special 

controls related to certain labeling, 

design verification and validation 

activities, risk analysis strategies, and 

performance studies. 

TABLE 3—RISKS TO HEALTH AND MITIGATION MEASURES FOR QUANTITATIVE HBV NUCLEIC ACID-BASED ASSAYS

Identified risks to health Mitigation measures 

False positive/false negative/falsely elevated/falsely lowered result.Certain labeling information, including limitations, explanation of procedures, 

and results interpretation information. 

Certain design verification and validation information, including certain device 

description information, risk analysis strategies, lot release criteria, stability 

studies and protocols, and performance criteria including analytical studies 

and clinical studies. 

Failure to correctly interpret the assay results ............................. Certain labeling information, including warnings, limitations, results interpretation information, and explanation of procedures. 

Certain design verification and validation information, including certain device 

description, critical reagent information, risk analysis strategies, lot release 

criteria, and stability studies and protocols. 

Failure to correctly operate the device ......................................... Certain labeling warnings, limitations, results interpretation information, and 

explanation of procedures. 

Certain design verification and validation information including certain device 

description, critical reagent information, risk analysis strategies, lot release 

criteria, and stability studies and protocols. 

If this proposed order is finalized, 

qualitative HBV antigen assays, HBV 

antibody assays (including qualitative 

and quantitative anti-HBs), and 

quantitative HBV nucleic acid-based 

assays will be reclassified into class II 

(general controls and special controls) 

and would be subject to premarket 

notification requirements under section 

510(k) of the FD&C Act. Firms 

submitting a 510(k) of the FD&C Act for 

such devices will be required to comply 

with the particular mitigation measures 

set forth in the special controls. FDA 

believes that adherence to the special 

controls, in addition to the general 

controls, is necessary to provide a 

reasonable assurance of safety and 

effectiveness of HBV assays. 

VIII. 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. 

IX. Paperwork Reduction Act of 1995 

While this proposed order contains no 

new collections of information, it does 

refer to previously approved FDA 

collections of information. The 

previously approved FDA collections of 

information are subject to review by the 

Office of Management and Budget 

(OMB) under the Paperwork Reduction 

Act of 1995 (PRA) (44 U.S.C. 3501– 

3521). The collections of information in 

21 CFR part 820 have been approved 

under OMB control number 0910–0073; 

the collections of information in part 

807, subpart E, have been approved 

under OMB control number 0910–0120; 

and the collections of information in 21 

CFR parts 801 and 809 have been 

approved under OMB control number 

0910–0485. 

X. Proposed Effective Date 

FDA proposes that any final order 

based on this proposed order become 

effective 30 days after the date of its 

publication in the Federal Register. 

XI. Codification of Orders 

Under section 513(f)(3) of the FD&C 

Act, FDA may issue final orders to 

reclassify devices. FDA will continue to 

codify classifications and 


ddrumheller on DSK120RN23PROD with PROPOSALS1
Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 78275 

reclassifications in the Code of Federal 

Regulations (CFR). Changes resulting 

from final orders will appear in the CFR 

as newly codified orders. Therefore, 

under section 513(f)(3) of the FD&C Act, 

in the proposed order, we are proposing 

to codify qualitative hepatitis B virus 

antigen assays in the new § 866.3178, 

hepatitis B virus antibody assays 

(including qualitative and quantitative 

anti-HBs) in the new § 866.3179, and 

quantitative hepatitis B virus nucleic 

acid-based assays in the new § 866.3180, 

under which these HBV assays would 

be reclassified from class III into class 

II. 

XII. References 

The following references marked with 

an asterisk (*) 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 also are available 

electronically at https://

www.regulations.gov. References 

without asterisks are not on public 

display at https://www.regulations.gov 

because they have copyright restriction. 

Some may be available at the website 

address, if listed. References without 

asterisks are available for viewing only 

at the Dockets Management Staff. 

Although FDA verified the website 

addresses in this document, please note 

that websites are subject to change over 

time. 

*1. Summary Minutes Prepared for the 

September 7, 2023, Meeting of the 

Microbiology Devices Panel (available at 

https://www.fda.gov/media/173610/ 

download). 

*2. Meeting Transcript Prepared for the 

September 7, 2023, Meeting of the 

Microbiology Devices Panel (available at 

https://www.fda.gov/media/173609/ 

download). 

3. Terrault, N.A., A.S.F. Lok, B.J. McMahon, 

et al., ‘‘Update on Prevention, Diagnosis, 

and Treatment of Chronic Hepatitis B: 

AASLD 2018 Hepatitis B Guidance.’’ 

Hepatology, 67(4): 1560–1599, 2018. 

4. CDC, ‘‘Clinical Testing and Diagnosis for 

Hepatitis B,’’ https://www.cdc.gov/ 

hepatitis-b/hcp/diagnosis-testing/ 

index.html. Accessed July 11, 2024. 

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, it is proposed 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 § 866.3178 to subpart D to read 

as follows: 

§ 866.3178 Qualitative hepatitis B virus 

antigen assays. 

(a) Identification. A qualitative 

hepatitis B virus (HBV) antigen assay is 

identified as an in vitro diagnostic 

device intended for prescription use for 

qualitative use with human serum, 

plasma, or other matrices that aids in 

the diagnosis of chronic or acute HBV 

infection. HBV surface antigen (HbsAg) 

is also used for screening of HBV 

infection in pregnant women to identify 

neonates who are at risk of acquiring 

hepatitis B during perinatal period. The 

assay is not intended for screening of 

blood, plasma, cells, or tissue donors. 

(b) Classification. Class II (special 

controls). The special controls for this 

device are: 

(1) The labeling required under 

§ 809.10(b) of this chapter must include: 

(i) A prominent statement that the 

assay is not intended for the screening 

of blood, plasma, cells, or tissue donors. 

(ii) A detailed explanation of the 

principles of operation and procedures 

for performing the assay. 

(iii) A detailed explanation of the 

interpretation of results. 

(iv) Limitations, which must be 

updated to reflect current clinical 

practice and disease presentation and 

management. The limitations must 

include statements that indicate: 

(A) The specimen types for which the 

device has been cleared, and that use of 

this assay with specimen types other 

than those specifically cleared for this 

device may result in inaccurate assay 

results. 

(B) When appropriate, performance 

characteristics of the assay have not 

been established in populations of 

immunocompromised or 

immunosuppressed patients or other 

populations where assay performance 

may be affected. 

(C) Diagnosis of hepatitis B infection 

should not be established on the basis 

of a single assay result but should be 

determined by a licensed healthcare 

professional in conjunction with the 

clinical presentation, history, and other 

diagnostic procedures. 

(D) Detection of HBV antigens 

indicates a current infection with 

hepatitis B virus but does not 

differentiate between acute or chronic 

infection. False reactive HbsAg result 

may occur for up to 2 weeks after 

vaccination with HbsAg containing 

vaccine. 

(E) Current methods for the detection 

of hepatitis B antigens may not detect 

all potentially infected individuals. A 

non-reactive assay result does not 

exclude the possibility of exposure to or 

infection with hepatitis B virus. A nonreactive assay result in individuals with 

prior exposure to hepatitis B may be due 

to but not limited to antigen levels 

below the detection limit of this assay 

or lack of antigen reactivity to the 

antibodies in this assay. HBV mutants 

lacking the ability to produce antigens 

have been reported. These may occur as 

‘‘escape’’ mutants in the presence of 

anti-HBV antibodies and such patients 

may be infectious. 

(F) Results obtained with this assay 

may not be used interchangeably with 

results obtained with a different 

manufacturer’s assay. 

(2) Design verification and validation 

must include the following: 

(i) A detailed device description, 

including all parts that make up the 

device, ancillary reagents required but 

not provided, an explanation of the 

device methodology, design of the 

capture antibody(ies), external controls, 

and computational path from collected 

raw data to reported result (e.g., how 

collected raw signals are converted into 

a reported signal and result), as 

applicable to the detection method and 

device design. 

(ii) For devices with assay calibrators, 

the design and composition of all 

primary, secondary, and subsequent 

quantitation standards used for 

calibration as well as their traceability 

to a standardized reference material that 

FDA has determined is appropriate (e.g., 

a recognized consensus standard). In 

addition, analytical testing must be 

performed following the release of a 

new lot of the standard material that 

was used for device clearance or 

approval, or when there is a transition 

to a new calibration standard. 

(iii) Documentation and 

characterization (e.g., supplier, 

determination of identity, purity, and 

stability) of all critical reagents 

(including description of the capture 

antibody(ies)), and protocols for 

maintaining product integrity 

throughout its labeled shelf life. 

(iv) Risk analysis and management 

strategies, such as Failure Modes Effects 

Analysis and/or Hazard Analysis and 

Critical Control Points summaries and 

their impact on assay performance. 

(v) Final release criteria to be used for 

manufactured assay lots with 

appropriate evidence that lots released 


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at the extremes of the specifications will 

meet the identified analytical and 

clinical performance characteristics as 

well as stability. 

(vi) Stability studies for reagents must 

include documentation of an assessment 

of real-time stability for multiple reagent 

lots using the indicated specimen types 

and must use acceptance criteria that 

ensure that analytical and clinical 

performance characteristics are met 

when stability is assigned based on the 

extremes of the acceptance range. 

(vii) All stability protocols, including 

acceptance criteria. 

(viii) Final release assay results for 

each lot used in clinical studies. 

(ix) Reproducibility study data that 

includes the testing of three 

independent production lots. 

(x) Detailed documentation of 

analytical performance studies 

conducted, as appropriate to the 

technology, specimen types tested, and 

intended use of the device, including, 

the limit of blank (LoB), limit of 

detection (LoD), cutoff, precision 

(reproducibility) including lot-to-lot 

and/or instrument-to-instrument 

precision, interference, cross reactivity, 

carryover, hook effect, seroconversion 

panel testing, matrix equivalency, 

prominent mutants/variants detection 

(e.g., for HbsAg), specimen stability, 

reagent stability, and cross-genotype 

antigen detection sensitivity, when 

appropriate. 

(xi) Analytical sensitivity of the assay 

is the same or better than that of other 

cleared or approved assays. 

(xii) For devices with associated 

software or instrumentation, 

documentation must include a detailed 

description of device software, 

including software applications and 

hardware-based devices that incorporate 

software. The detailed description must 

include documentation of verification, 

validation, and hazard analysis and risk 

assessment activities, including an 

assessment of the impact of threats and 

vulnerabilities on device functionality 

and end users/patients as part of 

cybersecurity review. 

(xiii) Detailed documentation and 

results from a clinical study. 

Performance must be analyzed relative 

to an FDA cleared or approved HBV 

antigen assay or a comparator that FDA 

has determined is appropriate. This 

study must be conducted using 

appropriate patient samples, with an 

appropriate number of HBV reactive and 

non-reactive samples in applicable risk 

and disease categories, and any 

applicable confirmatory testing. 

Additional relevant patient groups must 

be validated as appropriate. The 

samples must include prospective 

(sequential) samples for each identified 

specimen type and, as appropriate, 

additional characterized clinical 

samples. Samples must be sourced from 

geographically diverse areas. This study 

must be conducted in the appropriate 

settings by the intended users to 

demonstrate clinical performance. 

■ 3. Add § 866.3179 to subpart D to read 

as follows: 

§ 866.3179 Hepatitis B virus antibody 

assays (including qualitative and 

quantitative anti-HBs). 

(a) Identification. A hepatitis B virus 

(HBV) antibody assay is identified as an 

in vitro diagnostic device intended for 

prescription use in the detection of 

antibodies to HBV in human serum, 

plasma, or other matrices, and as a 

device that aids in the diagnosis of HBV 

infection in persons with signs and 

symptoms of hepatitis and in persons at 

risk for hepatitis B infection. In 

addition, results from an anti-HBc IgM 

(IgM antibodies to core antigen) assay 

indicating the presence of anti-HBc IgM 

are indicative of recent HBV infection. 

Anti-HBs (antibodies to surface antigen) 

assay results may be used as an aid in 

the determination of susceptibility to 

HBV infection in individuals prior to or 

following HBV vaccination or when 

vaccination status is unknown. The 

assay is not intended for screening of 

blood, plasma, cells, or tissue donors. 

The assay is intended as an aid in 

diagnosis in conjunction with clinical 

findings and other diagnostic 

procedures. 

(b) Classification. Class II (special 

controls). The special controls for this 

device are: 

(1) The labeling required under 

§ 809.10(b) of this chapter must include: 

(i) A prominent statement that the 

assay is not intended for the screening 

of blood, plasma, cells, or tissue donors. 

(ii) A detailed explanation of the 

principles of operation and procedures 

for performing the assay. 

(iii) A detailed explanation of the 

interpretation of results. 

(iv) Limitations, which must be 

updated to reflect current clinical 

practice and disease presentation and 

management. The limitations must 

include statements that indicate: 

(A) When appropriate, performance 

characteristics of the assay have not 

been established in populations of 

immunocompromised or 

immunosuppressed patients or other 

special populations where assay 

performance may be affected. 

(B) Detection of HBV antibodies to a 

single viral antigen indicates a present 

or past infection with hepatitis B virus, 

but does not differentiate between acute, 

chronic, or resolved infection. 

(C) The specimen types for which the 

device has been cleared, and that use of 

the assay with specimen types other 

than those specifically cleared for this 

device may result in inaccurate assay 

results. 

(D) Diagnosis of hepatitis B infection 

should not be established on the basis 

of a single assay result but should be 

determined by a licensed healthcare 

professional in conjunction with the 

clinical presentation, history, and other 

diagnostic procedures. 

(E) A non-reactive assay result may 

occur early during acute infection, prior 

to development of a host antibody 

response to infection, or when analyte 

levels are below the limit of detection of 

the assay. 

(F) Results obtained with this assay 

may not be used interchangeably with 

results obtained with a different 

manufacturer’s assay. 

(v) For devices intended for the 

quantitative detection of HBV 

antibodies (anti-HBs), in addition to the 

special controls listed in paragraphs 

(b)(1) and (2) of this section, labeling 

required under § 809.10(b) of this 

chapter must include: 

(A) The assay calibrators’ traceability 

to a standardized reference material that 

FDA has determined is appropriate (e.g., 

a recognized consensus standard) and 

the limit of blank (LoB), limit of 

detection (LoD), limit of quantitation 

(LoQ), linearity, and precision to define 

the analytical measuring interval. 

(B) Performance results of the 

analytical sensitivity study testing a 

standardized reference material that 

FDA has determined is appropriate (e.g., 

a recognized consensus standard). 

(2) Design verification and validation 

must include the following: 

(i) Detailed device description, 

including all parts that make up the 

device, ancillary reagents required but 

not provided, an explanation of the 

device methodology, and design of the 

antigen(s) and capture antibody(ies) 

sequences, rationale for the selected 

epitope(s), degree of amino acid 

sequence conservation of the target, and 

the design and composition of all 

primary, secondary and subsequent 

standards used for calibration. 

(ii) Documentation and 

characterization (e.g., supplier, 

determination of identity, and stability) 

of all critical reagents (including 

description of the antigen(s) and capture 

antibody(ies)), and protocols for 

maintaining product integrity 

throughout its labeled shelf life. 

(iii) Risk analysis and management 

strategies, such as Failure Modes Effects 


ddrumheller on DSK120RN23PROD with PROPOSALS1
Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 78277 

Analysis and/or Hazard Analysis and 

Critical Control Points summaries and 

their impact on assay performance. 

(iv) Final release criteria to be used 

for manufactured assay lots with 

appropriate evidence that lots released 

at the extremes of the specifications will 

meet the identified analytical and 

clinical performance characteristics as 

well as stability. 

(v) Stability studies for reagents must 

include documentation of an assessment 

of real-time stability for multiple reagent 

lots using the indicated specimen types 

and must use acceptance criteria that 

ensure that analytical and clinical 

performance characteristics are met 

when stability is assigned based on the 

extremes of the acceptance range. 

(vi) All stability protocols, including 

acceptance criteria. 

(vii) When applicable, analytical 

sensitivity of the assay is the same or 

better than that of other cleared or 

approved assays. 

(viii) Analytical performance studies 

and results for determining the limit of 

blank (LoB), limit of detection (LoD), 

cutoff, precision (reproducibility), 

including lot-to-lot and/or instrumentto-instrument precision, interference, 

cross reactivity, carryover, hook effect, 

seroconversion panel testing, matrix 

equivalency, specimen stability, reagent 

stability, and cross-genotype antibody 

detection sensitivity, when appropriate. 

(ix) For devices intended for the 

detection of antibodies for which a 

standardized reference material (that 

FDA has determined is appropriate) is 

available, the analytical sensitivity 

study and results testing the 

standardized reference material. 

Detailed documentation of that study 

and its results must be provided, 

including the study protocol, study 

report, testing results, and all statistical 

analyses. 

(x) For devices with associated 

software or instrumentation, 

documentation must include a detailed 

description of device software, 

including software applications and 

hardware-based devices that incorporate 

software. The detailed description must 

include documentation of verification, 

validation, and hazard analysis and risk 

assessment activities, including an 

assessment of the impact of threats and 

vulnerabilities on device functionality 

and end users/patients as part of 

cybersecurity review. 

(xi) Detailed documentation of 

clinical performance testing from a 

clinical study with an appropriate 

number of HBV reactive and nonreactive samples in applicable risk 

categories and conducted in the 

appropriate settings by the intended 

users. Performance must be analyzed 

relative to an FDA cleared or approved 

HBV antibody assay or a comparator 

that FDA has determined is appropriate. 

Additional relevant patient groups must 

be validated as appropriate. The 

samples must include prospective 

(sequential) samples for each identified 

specimen type and, as appropriate, 

additional characterized clinical 

samples. Samples must be sourced from 

geographically diverse areas. 

(3) For any HBV antibody assay 

intended for quantitative detection of 

anti-HBV antibodies, the following 

special controls, in addition to those 

special controls listed in paragraphs 

(b)(1) and (2) of this section, also apply: 

(i) Detailed documentation of the 

metrological calibration traceability 

hierarchy to a standardized reference 

material that FDA has determined is 

appropriate. 

(ii) Detailed documentation of the 

following analytical performance 

studies conducted, as appropriate to the 

technology, specimen types tested, and 

intended use of the device, including 

upper and lower limits of quantitation 

(UloQ and LloQ, respectively), linearity 

using clinical samples, and an accuracy 

study using the recognized international 

standard material. 

4. Add § 866.3180 to subpart D to read 

as follows: 

§ 866.3180 Hepatitis B virus nucleic acidbased assays. 

(a) Identification. A nucleic acidbased hepatitis B virus (HBV) assay is 

identified as an in vitro diagnostic 

device intended for prescription use in 

the detection of HBV nucleic acid in 

specimens from individuals with 

antibody evidence of HBV infection. In 

these devices, the detection of HBV 

nucleic acid is used as an aid in the 

management of HBV-infected 

individuals. The assay is intended for 

use with human serum or plasma (and 

other matrices as applicable) from 

individuals with HBV. The assay is not 

intended for use as a donor screening 

assay for the presence of HBV nucleic 

acids in blood, blood products, plasma, 

cells, or tissue donors, or as a diagnostic 

assay to confirm the presence of HBV 

infection. 

(b) Classification. Class II (special 

controls). The special controls for this 

device are: 

(1) Labeling required under 

§ 809.10(b) of this chapter must include: 

(i) A prominent statement that the 

assay is not intended for use as a 

screening assay for the presence of HBV 

DNA in blood or blood products, 

plasma, cells, or tissue donors, or as a 

diagnostic assay to confirm the presence 

of HBV infection. 

(ii) A detailed explanation of the 

principles of operation and procedures 

for performing the assay. 

(iii) A detailed explanation of the 

interpretation of results. 

(iv) Limitations, which must be 

updated to reflect current clinical 

practice and disease presentation and/or 

management. These limitations must 

include statements that indicate: 

(A) Management of patients 

undergoing hepatitis B virus treatment 

should not be established on the basis 

of a single assay result but should be 

determined by a licensed healthcare 

professional in conjunction with the 

clinical presentation, history, and other 

diagnostic procedures, e.g., HBV 

serologic testing, liver function assays, 

liver elastography, etc. 

(B) The specimen types for which the 

device has been cleared, and that use of 

this assay with specimen types other 

than those specifically cleared for this 

device may result in inaccurate assay 

results. 

(C) The results obtained with this 

assay may not be used interchangeably 

with results obtained with a different 

manufacturer’s assay. 

(2) Design verification and validation 

must include the following: 

(i) Detailed device description, 

including the device components, 

ancillary reagents required but not 

provided, and an explanation of the 

device methodology. Additional 

information appropriate to the 

technology must be included such as 

design of primers and probes, rationale 

for the selected gene targets, 

specifications for amplicon size, and 

degree of nucleic acid sequence 

conservation. 

(ii) For devices with assay calibrators, 

the design and composition of all 

primary, secondary, and subsequent 

quantitation standards used for 

calibration as well as their traceability 

to a standardized reference material that 

FDA has determined is appropriate (e.g., 

a recognized consensus standard). In 

addition, analytical testing must be 

performed following the release of a 

new lot of the standard material that 

was used for device clearance or 

approval, or when there is a transition 

to a new calibration standard. 

(iii) Documentation and 

characterization (e.g., determination of 

the identity, supplier, purity, and 

stability) of all critical reagents 

(including nucleic acid sequences for 

primers and probes) and protocols for 

maintaining product integrity. 

(iv) Risk analysis and management 

strategies demonstrating how risk 


ddrumheller on DSK120RN23PROD with PROPOSALS1
78278 Federal Register / Vol. 89, No. 186 / Wednesday, September 25, 2024 / Proposed Rules 

control measures are implemented to 

address device system hazards, such as 

Failure Modes Effects Analysis and/or 

Hazard Analysis and Critical Control 

Points summaries and their impact on 

assay performance. 

(v) Final release criteria to be used for 

manufactured assay lots with 

appropriate evidence that lots released 

at the extremes of the specification will 

meet the identified analytical and 

clinical performance characteristics as 

well as stability. 

(vi) Stability studies for reagents must 

include documentation of an assessment 

of real-time stability for multiple reagent 

lots using the indicated specimen types 

and must use acceptance criteria that 

ensure that analytical and clinical 

performance characteristics are met 

when stability is assigned based on the 

extremes of the acceptance range. 

(vii) All stability protocols, including 

acceptance criteria. 

(viii) Detailed documentation of 

analytical performance studies 

conducted as appropriate to the 

technology, specimen types tested, and 

intended use of the device, including 

limit of detection (LoD), linearity, 

precision, endogenous and exogenous 

interferences, cross-reactivity, carryover, 

matrix equivalency, sample and 

reagents stability, and as applicable, 

upper and lower limits of quantitation 

(ULoQ and LLoQ, respectively). 

Samples selected for use must be from 

subjects with clinically relevant 

circulating genotypes in the United 

States. Cross-reactivity studies must 

include samples from HBV nucleic acid 

negative subjects with other viral or 

non-viral causes of liver disease, 

including autoimmune hepatitis, 

alcoholic liver disease, chronic hepatitis 

C virus (HCV), primary biliary cirrhosis, 

and nonalcoholic steatohepatitis, when 

applicable. The effect of each identified 

nucleic-acid isolation and purification 

procedure on detection must be 

evaluated. 

(ix) For devices with associated 

software or instrumentation, 

documentation must include a detailed 

description of device software, 

including software applications and 

hardware-based devices that incorporate 

software. The detailed description must 

include documentation of verification, 

validation, and hazard analysis and risk 

assessment activities, including an 

assessment of the impact of threats and 

vulnerabilities on device functionality 

and end users/patients as part of 

cybersecurity review. 

(x) Detailed documentation of 

performance from a clinical study with 

a design and number of clinical samples 

(appropriately statistically powered) 

that is appropriate for the intended use 

of the device as well as conducted in the 

appropriate settings by the intended 

users. The samples must include 

prospective (sequential) samples for 

each claimed specimen type and, as 

appropriate, additional characterized 

clinical samples. Samples must be 

sourced from geographically diverse 

areas. 

Dated: September 20, 2024. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2024–21932 Filed 9–24–24; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF STATE 

22 CFR Parts 120 and 121 

[Public Notice: 12552; DOS–2024–0023] 

RIN 1400–AF29 

International Traffic in Arms 

Regulations: Revisions to Definition 

and Controls Related to Defense 

Services; Extension of Comment 

Period 

AGENCY: Department of State. 

ACTION: Proposed rule; extension of 

comment period. 

SUMMARY: The Department of State is 

extending the comment period for a 

proposed rule published July 29, 2024. 

The original comment period required 

submission of comments on or before 

September 27, 2024. In response to 

requests from the public, the 

Department extends the comment 

period through October 15, 2024. 

DATES: The comment period for the 

proposed rule published July 29, 2024, 

at 89 FR 60980, is extended. Comments 

should be received on or before October 

15, 2024. 

ADDRESSES: Interested parties may 

submit comments by one of the 

following methods: 

• Email: DDTCPublicComments@

state.gov with the subject line: 

‘‘Regulatory Change: Defense Service 

Definition’’. 

• Internet: At www.regulations.gov, 

search for this notice, by docket number 

DOS–2024–0023. Additional 

instructions regarding submission of 

comments can be found in the 

document published at 89 FR 60980, 

July 29, 2024. 

FOR FURTHER INFORMATION CONTACT: 

Sarah Heidema, Director, Office of 

Defense Trade Controls Policy, 

Department of State, telephone (202) 

663–1282; email 

DDTCCustomerService@state.gov. 

ATTN: Revisions to Definition and 

Controls Related to Defense Services. 

SUPPLEMENTARY INFORMATION: On July 

29, 2024, the Department of State 

published a proposed rule proposing 

revisions to the definition of defense 

service at 22 CFR 120.32 of the 

International Traffic in Arms 

Regulations (22 CFR parts 120 through 

130) and to the United States Munitions 

List at 22 CFR 121.1 (89 FR 60980). On 

the same day, the Department of 

Commerce published a complementary 

proposed rule proposing changes to 

existing restrictions under the Export 

Administration Regulations (15 CFR 

parts 730 through 744) on military and 

intelligence end uses and end users and 

related controls on certain activities of 

U.S. persons, as well as the proposed 

addition of a military-support end-user 

control (89 FR 60985). In response to 

requests from the public received by the 

Department of Commerce, and due to 

their plan to extend the comment period 

for their complementary proposed rule 

for 15 more days, as published via 

separate notice, the Department of State 

is similarly extending the comment 

period for its proposed rule for 15 days. 

Stanley L. Brown, 

Acting Assistant Secretary, Bureau of 

Political-Military Affairs, Department of 

State. 

[FR Doc. 2024–22041 Filed 9–23–24; 4:15 pm] 

BILLING CODE 4710–25–P 


ddrumheller on DSK120RN23PROD with PROPOSALS1