76756 Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 

1. Medicare 

Based on CMS data, we estimate that 

in CY 2024 approximately— 

• 14,232 newly enrolling institutional 

providers will be subject to and pay an 

application fee; and 

• 36,142 revalidating institutional 

providers will be subject to and pay an 

application fee. 

Using a figure of 50,374 (14,232 newly 

enrolling + 36,142 revalidating) 

institutional providers, we estimate an 

increase in the cost of the Medicare 

application fee requirement in CY 2024 

of $1,057,854 (or 50,374 x $21 (or $709 

minus $688)) from our CY 2023 

projections. 

2. Medicaid and CHIP 

Based on CMS and state statistics, we 

estimate that approximately 30,000 

(9,000 newly enrolling + 21,000 

revalidating) Medicaid and CHIP 

institutional providers will be subject to 

an application fee in CY 2024. Using 

this figure, we project an increase in the 

cost of the Medicaid and CHIP 

application fee requirement in CY 2024 

of $630,000 (or 30,000 × $21 (or $709 

minus $688)) from our CY 2023 

projections. 

3. Total 

Based on the foregoing, we estimate 

the total increase in the cost of the 

application fee requirement for 

Medicare, Medicaid, and CHIP 

providers and suppliers in CY 2024 to 

be $1,687,854 ($1,057,854 + $630,000) 

from our CY 2023 projections. 

We do not anticipate any negative 

impact on equity from the increase in 

the application fee amount, which we 

calculated in accordance with the 

requirements specified in statute and 

regulation. Prior application fee 

increases have had no such discernable 

effect, and we reiterate that the fee 

requirement does not apply to 

individual physicians and nonphysician practitioners completing the 

CMS–855I, who represent the 

overwhelming preponderance of the 

more than 2 million Medicare-enrolled 

providers and suppliers. 

The RFA requires agencies to analyze 

options for regulatory relief of small 

businesses. For purposes of the RFA, 

small entities include small businesses, 

nonprofit organizations, and small 

governmental jurisdictions. Most 

hospitals and most other providers and 

suppliers are small entities, either by 

nonprofit status or by having revenues 

of less than $9 million to $47 million in 

any 1 year. Individuals and states are 

not included in the definition of a small 

entity. As we stated in the RIA for the 

February 2, 2011 final rule (76 FR 5952), 

we do not believe that the application 

fee will have a significant impact on 

small entities. 

In addition, section 1102(b) of the Act 

requires us to prepare a regulatory 

impact analysis if a rule may have a 

significant impact on the operations of 

a substantial number of small rural 

hospitals. This analysis must conform to 

the provisions of section 604 of the 

RFA. For purposes of section 1102(b) of 

the Act, we define a small rural hospital 

as a hospital that is located outside of 

a Metropolitan Statistical Area for 

Medicare payment regulations and has 

fewer than 100 beds. We are not 

preparing an analysis for section 1102(b) 

of the Act because we have determined, 

and the Secretary certifies, that this 

notice would not have a significant 

impact on the operations of a substantial 

number of small rural hospitals. 

Section 202 of the Unfunded 

Mandates Reform Act of 1995 (UMRA) 

also requires that agencies assess 

anticipated costs and benefits before 

issuing any rule whose mandates 

require spending in any 1 year of $100 

million in 1995 dollars, updated 

annually for inflation. In 2023, that 

threshold was approximately 

$198million. The Agency has 

determined that there will be minimal 

impact from the costs of this notice, as 

the threshold is not met under the 

UMRA. 

Executive Order 13132 establishes 

certain requirements that an agency 

must meet when it promulgates a 

proposed rule (and subsequent final 

rule) that imposes substantial direct 

requirement costs on state and local 

governments, preempts state law, or 

otherwise has federalism implications. 

Since this notice does not impose 

substantial direct costs on state or local 

governments, the requirements of 

Executive Order 13132 are not 

applicable. 

In accordance with the provisions of 

Executive Order 12866, this notice was 

reviewed by the Office of Management 

and Budget. 

The Administrator of the Centers for 

Medicare & Medicaid Services (CMS), 

Chiquita Brooks-LaSure, having 

reviewed and approved this document, 

authorizes Chyana Woodyard, who is 

the Federal Register Liaison, to 

electronically sign this document for 

purposes of publication in the Federal 

Register. 

Chyana Woodyard, 

Federal Register Liaison, Centers for Medicare 

& Medicaid Services. 

[FR Doc. 2023–24607 Filed 11–6–23; 8:45 am] 

BILLING CODE 4120–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2023–N–4742] 

Phibro Animal Health Corp.; Proposal 

To Withdraw Approval of New Animal 

Drug Applications for Carbadox in 

Medicated Swine Feed; Opportunity for 

a Hearing 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug 

Administration (FDA or the Agency), 

Center for Veterinary Medicine (CVM), 

is proposing to withdraw approval of all 

new animal drug applications (NADAs) 

providing for use of carbadox in 

medicated swine feed, for which Phibro 

Animal Health Corp., Glenpointe Centre 

East, Third Floor, 300 Frank W. Burr 

Blvd., Suite 21, Teaneck, NJ 07666– 

6712, is the sponsor, and is announcing 

an opportunity for the holder of the 

NADAs to request a hearing on this 

proposal. This action is based on CVM’s 

determination that there is no approved 

regulatory method to detect the residue 

of carcinogenic concern in the edible 

tissues of the treated swine. 

DATES: The sponsor of the NADAs may 

submit a written request for a hearing by 

December 7, 2023. Submit all data, 

information, and analyses upon which a 

request for a hearing relies by December 

7, 2023. Either electronic or written 

comments on the notice must be 

submitted by December 7, 2023. 

ADDRESSES: The request for a hearing 

may be submitted by the sponsor of the 

NADAs by either of the following 

methods: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments to 

submit your request for hearing. Your 

request for a hearing submitted 

electronically, including any 

attachments to the request for hearing, 

to https://www.regulations.gov will be 

posted to the docket unchanged. 

Written/Paper Submissions 

Submit written/paper submissions as 

follows: 

• Mail/Hand Delivery/Courier (for 

written/paper request for a hearing): 

Dockets Management Staff (HFA–305), 

Food and Drug Administration, 5630 

Fishers Lane, Rm. 1061, Rockville, MD 

20852. 


khammond on DSKJM1Z7X2PROD with NOTICES
Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 76757 

• Because your request for a hearing 

will be made public, you are solely 

responsible for ensuring that your 

request does not include any 

confidential information that you or a 

third party may not wish to be publicly 

posted, such as confidential business 

information (e.g., a manufacturing 

process). The request for a hearing must 

include the Docket No. FDA–2023–N– 

4742 for ‘‘Phibro Animal Health Corp.; 

Proposal to Withdraw Approval of New 

Animal Drug Applications for Carbadox 

in Medicated Swine Feed; Opportunity 

for a Hearing.’’ The request for a hearing 

will be placed in the docket and 

publicly viewable at https://

www.regulations.gov or at the Dockets 

Management Staff between 9 a.m. and 4 

p.m., Monday through Friday, 240–402– 

7500. 

The sponsor of the NADAs may 

submit all data and analyses upon 

which the request for a hearing relies in 

the same manner as the request for a 

hearing except as follows: 

• Confidential Submissions—To 

submit any data and analyses with 

confidential information that you do not 

wish to be made publicly available, 

submit your data and analyses only as 

a written/paper submission. You should 

submit two copies total of all data and 

analyses. 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 any decisions on 

this matter. 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 

or available at the Dockets Management 

Staff between 9 a.m. and 4 p.m., 

Monday through Friday. Submit both 

copies to the Dockets Management Staff. 

Any information marked as 

‘‘confidential’’ will not be disclosed 

except in accordance with 21 CFR 10.20 

and other applicable disclosure law. 

Comments Submitted by Other 

Interested Parties: For all comments 

submitted by other interested parties, 

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 

December 7, 2023. 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 eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Comments submitted electronically, 

including attachments, to https://

www.regulations.gov will be posted to 

the docket unchanged. Because your 

comment will be made public, you are 

solely responsible for ensuring that your 

comment does not include any 

confidential information that you or a 

third party may not wish to be posted, 

such as medical information, your or 

anyone else’s Social Security number, or 

confidential business information, such 

as a manufacturing process. Please note 

that if you include your name, contact 

information, or other information that 

identifies you in the body of your 

comments, that information will be 

posted on https://www.regulations.gov. 

• If you want to submit a comment 

with confidential information that you 

do not wish to be made available to the 

public, submit the comment as a 

written/paper submission and in the 

manner detailed (see ‘‘Written/Paper 

Submissions’’ and ‘‘Instructions’’). 

Written/Paper Submissions 

Submit written/paper submissions as 

follows: 

• Mail/Hand Delivery/Courier (for 

written/paper submissions): Dockets 

Management Staff (HFA–305), Food and 

Drug Administration, 5630 Fishers 

Lane, Rm. 1061, Rockville, MD 20852. 

• For written/paper comments 

submitted to the Dockets Management 

Staff, FDA will post your comment, as 

well as any attachments, except for 

information submitted, marked and 

identified, as confidential, if submitted 

as detailed in ‘‘Instructions.’’ 

Instructions: All submissions received 

must include the Docket No. FDA– 

2023–N–4742 for ‘‘Phibro Animal 

Health Corp.; Proposal to Withdraw 

Approval of New Animal Drug 

Applications for Carbadox in Medicated 

Swine Feed; Opportunity for a 

Hearing.’’ Received comments, those 

filed in a timely manner (see 

ADDRESSES), will be placed in the docket 

and, except for those submitted as 

‘‘Confidential Submissions,’’ publicly 

viewable at https://www.regulations.gov 

or at the Dockets Management Staff 

between 9 a.m. and 4 p.m., Monday 

through Friday, 240–402–7500. 

• Confidential Submissions—To 

submit a comment with confidential 

information that you do not wish to be 

made publicly available, submit your 

comments only as a written/paper 

submission. You should submit two 

copies total. One copy will include the 

information you claim to be confidential 

with a heading or cover note that states 

‘‘THIS DOCUMENT CONTAINS 

CONFIDENTIAL INFORMATION.’’ The 

Agency will review this copy, including 

the claimed confidential information, in 

its consideration of comments. The 

second copy, which will have the 

claimed confidential information 

redacted/blacked out, will be available 

for public viewing and posted on 

https://www.regulations.gov. Submit 

both copies to the Dockets Management 

Staff. If you do not wish your name and 

contact information to be made publicly 

available, you can provide this 

information on the cover sheet and not 

in the body of your comments and you 

must identify this information as 

‘‘confidential.’’ Any information marked 

as ‘‘confidential’’ will not be disclosed 

except in accordance with 21 CFR 10.20 

and other applicable disclosure law. For 

more information about FDA’s posting 

of comments to public dockets, see 80 

FR 56469, September 18, 2015, or access 

the information at: https://

www.govinfo.gov/content/pkg/FR-2015- 

09-18/pdf/2015-23389.pdf. 

Docket: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852, 240–402–7500. 

FOR FURTHER INFORMATION CONTACT: 

Diane Heinz, Center for Veterinary 

Medicine (HFV–6), Food and Drug 

Administration, 7500 Standish Pl., 

Rockville, MD 20855, 240–402–5692. 

SUPPLEMENTARY INFORMATION: 

I. Approved NADAs for Use of 

Carbadox in Swine Feed 

Carbadox, a quinoxaline derivative, is 

a synthetic organic acid antimicrobial. 

Currently, there are three approved 

NADAs for use of carbadox in 

medicated swine feed, either by itself or 

in combination with other approved 

new animal drugs. Phibro Animal 

Health Corp., Glenpointe Centre East, 

Third Floor, 300 Frank W. Burr Blvd., 

Suite 21, Teaneck, NJ 07666–6712, is 

currently the sponsor of all three 

approved NADAs. 

Carbadox is marketed as a Type A 

medicated article used to manufacture 

complete Type C medicated feeds that 

are administered ad libitum (available at 

all times) to swine. Carbadox is 


khammond on DSKJM1Z7X2PROD with NOTICES
76758 Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 

1 ‘‘Metabolism and Tissue Depletion of Carbadox 

in Swine, Broilers, and Rats,’’ Jie Zhang, Wei Qu, 

Zongchao Wang, and Yuanhu Pan, ACS 

Agricultural Science & Technology 2022 2 (3), 477– 

485. 

indicated for the control of dysentery 

and bacterial enteritis, and for growth 

promotion. A tolerance of 30 parts per 

billion (ppb) has been established for 

residues of quinoxaline-2-carboxylic 

acid (QCA), the marker residue, in liver 

of swine (21 CFR 556.100). The 

combination products containing 

carbadox (carbadox and pyrantel, and 

carbadox and oxytetracycline) are also 

approved for additional indications 

related to the non-carbadox active 

ingredient. 

The following three NADAs are 

approved for the use of carbadox: 

NADA 041–061, originally approved 

in 1972 (37 FR 20683, October 3, 1972), 

provides for the use of MECADOX 10 

(carbadox) Type A medicated article to 

manufacture single-ingredient Type C 

medicated swine feeds for the following 

conditions of use: 

Carbadox at 10 to 25 grams per ton (g/ 

ton) of feed for increased rate of weight 

gain and improved feed efficiency; and 

Carbadox at 50 g/ton of feed for 

control of swine dysentery (vibrionic 

dysentery, bloody scours, or 

hemorrhagic dysentery); for control of 

bacterial swine enteritis (salmonellosis 

or necrotic enteritis caused by 

Salmonella choleraesuis); and for 

increased rate of weight gain and 

improved feed efficiency. 

In January 1998, CVM approved a 

supplemental application to NADA 

041–061, which included the approved 

method. 

In October 1998, CVM approved an 

additional supplemental NADA for 

NADA 041–061, changing the 

withdrawal period for carbadox 

medicated feeds from 70 days to 42 

days. 

Currently, the withdrawal period for 

these uses of carbadox is 42 days 

(§ 558.115(d)(1)(ii) and (d)(2)(ii) (21 CFR 

558.115(d)(1)(ii) and (d)(2)(ii))). 

NADA 092–955, originally approved 

in 1975 (40 FR 45164, October 1, 1975), 

provides for the use of MECADOX 10 

(carbadox) Type A medicated article 

with BANMINTH (pyrantel tartrate) 

Type A medicated article to 

manufacture two-way, combination 

drug Type C medicated swine feeds for 

the following conditions of use: 

Carbadox at 50 g/ton of feed plus 

pyrantel tartrate at 96 g/ton of feed for 

control of swine dysentery (vibrionic 

dysentery, bloody scours, or 

hemorrhagic dysentery); for control of 

bacterial swine enteritis (salmonellosis 

or necrotic enteritis caused by 

Salmonella choleraesuis); as an aid in 

the prevention of migration and 

establishment of large roundworm 

(Ascaris suum) infections; and as an aid 

in the prevention of establishment of 

nodular worm (Oesophagostomum) 

infections. 

The withdrawal period for the use of 

this drug combination is 70 days 

(§ 558.115(d)(3)(ii)). 

NADA 141–211, originally approved 

in 2004 (69 FR 51173, August 18, 2004), 

provides for the use of MECADOX 10 

(carbadox) Type A medicated article 

with TERRAMYCIN 50, TERRAMYCIN 

100, or TERRAMYCIN 200 

(oxytetracycline) Type A medicated 

articles to manufacture two-way, 

combination drug Type C medicated 

swine feeds for the following conditions 

of use: 

Carbadox at 10 to 25 g/ton of feed 

plus oxytetracycline at levels in feed to 

deliver 10 mg oxytetracycline per pound 

of body weight for treatment of bacterial 

enteritis caused by Escherichia coli and 

S. choleraesuis susceptible to 

oxytetracycline; for treatment of 

bacterial pneumonia caused by 

Pasteurella multocida susceptible to 

oxytetracycline; and for increased rate 

of weight gain and improved feed 

efficiency. 

The withdrawal period for the use of 

this animal drug combination is 42 days 

(§ 558.115(d)(4); § 558.450(e)(3)(iii)). 

II. Basis for Withdrawal of Approval 

FDA is providing notice of an 

opportunity for a hearing (NOOH) on 

CVM’s proposal to withdraw approval 

of the NADAs providing for use of 

carbadox in medicated swine feeds. 

New evidence demonstrates that the 

Delaney Clause in section 512(d)(1)(I) of 

the Federal Food, Drug, and Cosmetic 

Act (FD&C Act) (21 U.S.C. 360b(d)(1)(I)), 

which requires that no residue of a 

carcinogenic drug can be found in any 

edible portion of the animal after 

slaughter, applies because the 

Diethylstilbestrol (DES) Proviso 

exception is no longer met (see section 

III). 

Section 512(e)(1)(B) of the FD&C Act 

provides grounds for withdrawal of 

approval of an NADA if new evidence 

not contained in such application or not 

available until after such application 

was approved, tests by new methods, or 

tests by methods not deemed reasonably 

applicable when such application was 

approved, evaluated together with the 

evidence available when the application 

was approved, shows that the Delaney 

Clause, section 512(d)(1)(I) of the FD&C 

Act, applies to the drug. Under the 

Delaney Clause, the Secretary shall not 

approve a new animal drug application 

if ‘‘such drug induces cancer when 

ingested by man or animal or, after tests 

which are appropriate for the evaluation 

of the safety of such drug, induces 

cancer in man or animal’’ (section 512 

(d)(1)(I) of the FD&C Act). An exception 

to this general rule, referred to as the 

‘‘DES Proviso,’’ allows for the approval 

of a carcinogenic new animal drug 

where FDA finds that, under the 

approved conditions of use: (1) The 

drug will not adversely affect the 

animals treated with the drug, and (2) 

no residues of the drug will be found by 

an approved regulatory method in any 

edible tissues of or in any foods yielded 

by the animal (section 512(d)(1)(I)(i) 

through (ii) of the FD&C Act). 

Evidence available at the time of the 

approvals showed that carbadox was 

carcinogenic. At the time of the January 

1998 supplemental approval, CVM 

concluded that carcinogenic residues, 

including desoxycarbadox (DCBX), a 

known carcinogenic metabolite of 

carbadox, depleted quickly (within 72 

hours) while QCA residues depleted 

more slowly (Ref. 1). However, new 

evidence not available at the time of the 

approval, including studies conducted 

by the sponsor and submitted to FDA 

from 2005 to 2016 and a study 

conducted by a third party and 

summarized in a publication in 2022,1

demonstrates that the residue of 

carcinogenic concern persists longer 

than previously known (Refs. 2 to 4). 

Because there is no established 

relationship between concentrations of 

QCA measured by the approved method 

and concentrations of the residue of 

carcinogenic concern, the approved 

regulatory method cannot be used to 

measure the residue of carcinogenic 

concern. 

Elsewhere in today’s Federal Register, 

FDA is publishing a final order (Ref. 5) 

revoking the approved regulatory 

method for carbadox that measures QCA 

as a marker residue to detect the 

presence of any residue of carcinogenic 

concern (Ref. 6). Currently, therefore, 

there is no approved regulatory method 

for carbadox, and the second prong of 

the DES Proviso is not met. 

III. Background Information Regarding 

the Regulation of Carcinogenic New 

Animal Drugs 

Under the Delaney Clause of the 

FD&C Act, the Secretary shall not 

approve a carcinogenic new animal drug 

application unless the DES Proviso 

applies (section 512(d)(1)(I)(i) through 

(ii) of the FD&C Act). FDA has issued 

implementing regulations that set the 

requirements for demonstrating that no 

residues of the drug will be found by an 

approved regulatory method in any 


khammond on DSKJM1Z7X2PROD with NOTICES
Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 76759 

edible tissues of or in any foods yielded 

from the animal (21 CFR part 500, 

subpart E). These regulations, referred to 

as the sensitivity of the method 

regulations (SOM regulations), describe 

how FDA determines whether the 

regulatory method proposed by a 

sponsor is sufficiently sensitive to 

ensure that residues of carcinogenic 

concern in edible tissues will not 

exceed concentrations that represent no 

significant increase in the risk of cancer 

to humans. 

Pursuant to these regulations, FDA 

determines for each drug and each drug 

metabolite (on the basis of the results of 

chronic bioassays and other 

information) whether the drug or any of 

its metabolites are carcinogenic 

(§ 500.84(a) (21 CFR 500.84(a))). For the 

drug and each metabolite determined to 

be carcinogenic, FDA calculates, based 

upon submitted assays, the 

concentration of the test compound in 

the total diet of the test animal that 

corresponds to a maximum lifetime risk 

of cancer in the test animal of 1 in 1 

million (§§ 500.82(b) (21 CFR 500.82(b)) 

and 500.84(c)(1)). FDA designates the 

lowest value thus calculated as the So

(§§ 500.82(b) and 500.84(c)(1)). The So

corresponds to a concentration of 

residue of carcinogenic concern in the 

total human diet that represents no 

significant increase in the risk of cancer 

to people (§ 500.82(b)). Residue of 

carcinogenic concern includes all 

compounds in the total residue of a 

demonstrated carcinogen excluding any 

compound judged by FDA not to 

present a carcinogenic risk (§ 500.82(b)). 

The total residues of carcinogenic 

concern (the drug and all of its 

metabolites less metabolites shown to be 

noncarcinogenic) are regulated based on 

the most potent carcinogenic residue 

(§ 500.84(c)(1)). This approach ensures 

that use of the drug does not present a 

significant increase in the risk of cancer 

when considering all residues in edible 

tissues. 

Because the total diet is not derived 

only from food-producing animals, the 

SOM regulations make adjustments for 

human food intake of edible tissues and 

determine the concentration of residues 

of carcinogenic concern in a specific 

edible tissue that corresponds to no 

significant increase in the risk of cancer 

to the human consumer. FDA assumes 

for purposes of these regulations that 

this value will correspond to the 

concentration of residues in a specific 

edible tissue that corresponds to a 

maximum lifetime risk of cancer in test 

animals of 1 in 1 million. This value is 

termed the Sm (§§ 500.82(b) and 

500.84(c)(1)). 

Based on residue depletion data 

submitted by a sponsor, FDA selects a 

target tissue (the edible tissue selected 

to monitor for residues in the target 

animals) and a marker residue (a residue 

whose concentration is in a known 

relationship to the concentration of the 

residues of carcinogenic concern in the 

last tissue to deplete to the Sm) and 

designates the concentration of the 

marker residue that the regulatory 

method must be capable of detecting in 

the target tissue (§ 500.86(a) through (c) 

(21 CFR 500.86(a) through (c))). This 

value, termed the Rm, is the 

concentration of a marker residue in the 

target tissue when the residue of 

carcinogenic concern is equal to Sm

(§ 500.82(b)). When the marker residue 

is at or below the Rm, the residue of 

carcinogenic concern in the human diet 

does not exceed So (§ 500.86(c)). This 

regulation ensures that when the marker 

residue is no longer detectable, the 

residue of carcinogenic concern does 

not exceed Sm in any of the edible 

tissues (§§ 500.82(b) and 500.86(c)). 

A sponsor must submit a regulatory 

method that is able to detect the marker 

residue at or below the Rm (21 

CFR 500.88(b) and 500.84(c)(2)) (‘‘The 

LOD [Limit of Detection for the 

regulatory method] must be less than or 

equal to Rm.’’)). If a method is not 

developed that can detect the marker 

residue at or below the Rm, the 

requirements of the SOM regulations are 

not satisfied, and FDA cannot approve 

the drug. The DES Proviso and FDA’s 

implementing regulations are satisfied 

where no marker residue is detectable 

using the approved regulatory method 

under the proposed conditions of use of 

the drug, including the proposed 

preslaughter withdrawal period 

(§ 500.84(c)(3)). 

IV. Notice of Opportunity for a Hearing 

CVM is proposing to withdraw 

approval of the three NADAs that 

provide for use of carbadox in swine 

feed because new evidence 

demonstrates that the drug does not 

meet the DES Proviso exception to the 

Delaney Clause. There is currently no 

approved regulatory method for 

carbadox. 

Therefore, notice is given to Phibro 

Animal Health Corp., Glenpointe Centre 

East, Third Floor, 300 Frank W. Burr 

Blvd., Suite 21, Teaneck, NJ 07666– 

6712, and to all other interested 

persons, that the Deputy Commissioner 

for Policy, Legislation, and International 

Affairs, Office of Policy, Legislation, and 

International Affairs proposes to issue 

an order under section 512(e) of the 

FD&C Act withdrawing approval of all 

NADAs providing for use of carbadox in 

medicated swine feed. 

In accordance with section 512 of the 

FD&C Act and 21 CFR part 514 and 

under the authority delegated to the 

Deputy Commissioner for Policy, 

Legislation, and International Affairs, 

Office of Policy, Legislation, and 

International Affairs by the 

Commissioner of Food and Drugs, 

Phibro Animal Health Corp., the 

sponsor, is hereby given an opportunity 

for a hearing to show why approvals of 

NADA 041–061, 092–955, and 141–211 

should not be withdrawn. 

If the sponsor, Phibro Animal Health 

Corp., wishes to request a hearing, the 

sponsor must file the following: (1) a 

written notice of participation and 

request for a hearing (see DATES and 

ADDRESSES) and (2) the data, 

information, and analyses relied on to 

demonstrate that there is a genuine and 

substantial issue of fact that requires a 

hearing (see DATES and ADDRESSES). Any 

other interested person may also submit 

comments on this notice. Procedures 

and requirements governing this NOOH, 

a notice of appearance and request for 

a hearing, submission of data, 

information, and analyses to justify a 

hearing, other comments, and a grant or 

denial of a hearing, are contained in 

§ 514.200 (21 CFR 514.200) and 21 CFR 

part 12. 

The failure of a holder of an approval 

to timely file a request for a hearing as 

required by § 514.200 constitutes an 

election by the holder not to avail itself 

of the opportunity for a hearing and 

constitutes a waiver of any contentions 

concerning the legal status of any such 

drug product, and the Director of CVM 

will summarily enter a final order 

withdrawing the approvals. Any new 

animal drug product marketed without 

an approved NADA is subject to 

regulatory action at any time. 

A request for a hearing may not rest 

upon mere allegations or denials but 

must set forth specific facts showing 

that there is a genuine and substantial 

issue of fact that requires a hearing. If 

it conclusively appears from the face of 

the data, information, and factual 

analyses in the request for hearing that 

there is no genuine and substantial issue 

of fact that precludes the withdrawal of 

approval of the applications, or when a 

request for hearing is not made in the 

required format or with the required 

analyses, the Commissioner of Food and 

Drugs will enter summary judgment 

against the person who requests a 

hearing, making findings and 

conclusions, and denying a hearing. 

If a hearing is requested and is 

justified by the sponsor’s response to 

this NOOH, the issues will be defined, 


khammond on DSKJM1Z7X2PROD with NOTICES
76760 Federal Register / Vol. 88, No. 214 / Tuesday, November 7, 2023 / Notices 

1See § 500.82(b) (defining ‘‘marker residue’’ as 

the residue whose concentration is in a known 

relationship to the concentration of the residue of 

carcinogenic concern in the last tissue to deplete to 

the Sm and defining ‘‘Sm’’ as the concentration of 

a residue of carcinogenic concern in a specific 

edible tissue corresponding to no significant 

increase in the risk of cancer to the human 

consumer). 

2Consistent with FDA regulations, CVM treats 

unidentified residues of a carcinogenic drug as 

carcinogenic. See § 500.82(b) (defining ‘‘residue of 

carcinogenic concern’’ as all compounds in the total 

residue of a demonstrated carcinogen excluding any 

compounds judged by FDA not to present a 

carcinogenic risk). 

a presiding officer will be assigned, and 

a written notice of the time and place at 

which the hearing will commence will 

be issued as soon as practicable. 

This notice is issued under section 

512 of the FD&C Act and under the 

authority delegated to the Deputy 

Commissioner for Policy, Legislation, 

and International Affairs, Office of 

Policy, Legislation, and International 

Affairs. 

V. Environmental Impact 

The Agency has determined under 21 

CFR 25.33(g) that this action is of a type 

that does not individually or 

cumulatively have a significant impact 

on the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

VI. References 

The following references are on 

display in the Dockets Management 

Staff (see ADDRESSES) and are available 

for viewing by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday; they are also available 

electronically at https://

www.regulations.gov. Although FDA 

verified the website addresses in this 

document, please note that websites are 

subject to change over time. 

1. FDA, Freedom of Information Summary, 

NADA 041–061, MECADOX 10 

(carbadox) Type A medicated article, 

supplemental approval January 30, 1998. 

Available at https://

animaldrugsatfda.fda.gov/adafda/app/ 

search/public/document/downloadFoi/ 

308. 

2. Evaluations of the Joint Food and 

Agriculture Organization of the United 

Nations/World Health Organization 

Expert Committee on Food Additives 

(JECFA). Carbadox. 2021. Available at: 

https://apps.who.int/food-additivescontaminants-jecfa-database/Home/ 

Chemical/2176. 

3. Memorandum to File entitled ‘‘CVM 

Response to Phibro Animal Health 

Corporation’s September 18, 2020 

Comments on CVM’s July 20, 2020 

Proposed Order to Revoke the Regulatory 

Method for Carbadox’’ (January 6, 2022). 

4. Memorandum to File entitled ‘‘CVM 

review of comments on the Zhang article 

that Phibro references in the document 

submitted to the Part 15 Hearing docket 

under cover letter dated June 9, 2022, 

and entitled, ‘Phibro Animal Health 

Corporation’s Reply to the January 6, 

2022 ‘CVM Response to Phibro Animal 

Health Corporation’s September 18, 2020 

Comments on CVM’s July 20, 2020 

Proposed Order to Revoke the Regulatory 

Method for Carbadox.’ ’ ’’ (October 30, 

2023). 

5. Phibro Animal Health Corp.; Carbadox in 

Medicated Swine Feed; Revocation of 

Approved Method (November 7, 2023). 

6. ‘‘Determination of Carbadox as 

Quinoxaline-2-carboxylic Residues in 

Swine Liver and Muscle Tissues after 

Drug Withdrawal.’’ Available at https:// 

www.fda.gov/media/136267/download. 

Dated: November 1, 2023. 

Kimberlee Trzeciak, 

Deputy Commissioner for Policy, Legislation, 

and International Affairs. 

[FR Doc. 2023–24547 Filed 11–6–23; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2020–N–0955] 

Phibro Animal Health Corp.; Carbadox 

in Medicated Swine Feed; Revocation 

of Approved Method 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final order. 

SUMMARY: The Food and Drug 

Administration (FDA) is issuing a final 

order to revoke the approved method for 

detecting residues of carbadox, a 

carcinogenic new animal drug used in 

swine feed. An approved method is 

required by the Federal Food, Drug, and 

Cosmetic Act (FD&C Act), as 

implemented by regulation, to show that 

no residue of carcinogenic concern from 

a new animal drug persists in any edible 

tissue or in any food derived from 

treated animals. The approved method 

measures quinoxaline-2-carboxylic acid 

(QCA) as a marker residue to detect the 

presence of any residue of carcinogenic 

concern. QCA is a metabolite of 

carbadox that FDA has judged does not 

present a carcinogenic risk. FDA is 

revoking the approved method for 

carbadox based on its determination 

that the method is inadequate to 

monitor the residue of carcinogenic 

concern in compliance with FDA’s 

operational definition of no residue 

because there is no established 

relationship between the concentration 

of QCA residues as measured by the 

approved method and the concentration 

of the residue of carcinogenic concern. 

DATES: This order is effective November 

7, 2023. 

FOR FURTHER INFORMATION CONTACT: 

Diane Heinz, Center for Veterinary 

Medicine (HFV–6), Food and Drug 

Administration, 7500 Standish Pl., 

Rockville, MD 20855, 240–402–5692. 

SUPPLEMENTARY INFORMATION: 

I. Introduction 

On July 20, 2020, FDA’s Center for 

Veterinary Medicine (CVM), the Center 

within FDA that reviews and approves 

new animal drug applications and 

supplemental applications, proposed to 

revoke the approved method for 

carbadox (Ref. 1), which measures QCA 

as the marker residue 1 to determine 

whether residues of carcinogenic 

concern 2 of carbadox are present (85 FR 

43853, July 20, 2020). QCA is a 

metabolite of carbadox that FDA has 

judged does not present a carcinogenic 

risk. The proposal to revoke the 

approved method was based on FDA’s 

determination that the method does not 

adequately monitor the residue of 

carcinogenic concern in compliance 

with FDA’s operational definition of no 

residue (§ 500.82(b) (21 CFR 

500.82(b)(defining ‘‘no residue’’; 

§ 500.84(c)(3) (21 CFR 500.84(c)(3))). 

That is because the sponsor has not 

established the relationship between the 

concentration of the marker residue 

QCA and the concentration of the 

residue of carcinogenic concern. 

On March 10, 2022, FDA held a 

public hearing under 21 CFR part 15, 

entitled, ‘‘Scientific Data and 

Information Related to the Residue of 

Carcinogenic Concern for the New 

Animal Drug Carbadox’’ to gather 

additional data and information. When 

FDA announced the hearing (87 FR 

2093, January 13, 2022; https://

www.fda.gov/animal-veterinary/ 

workshops-conferences-meetings/part15-public-hearing-scientific-data-andinformation-related-residuecarcinogenic-concern-new), we 

requested public comments and 

presentations at the public hearing, 

particularly: (1) on data to inform our 

knowledge of the residue of 

carcinogenic concern not summarized 

in the FOI Summary for the 1998 

supplemental approvals, including 

additional data regarding the fraction of 

noncarcinogenic residues in the total 

radiolabeled residues of carbadox; (2) 

for any given concentration of a marker 

residue, the corresponding 


khammond on DSKJM1Z7X2PROD with NOTICES