Notice2023-24548
Phibro Animal Health Corp.; Carbadox in Medicated Swine Feed; Revocation of Approved Method
Primary source
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Published
November 7, 2023
Effective
November 7, 2023
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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.
Full Text
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<title>Federal Register, Volume 88 Issue 214 (Tuesday, November 7, 2023)</title>
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[Federal Register Volume 88, Number 214 (Tuesday, November 7, 2023)]
[Notices]
[Pages 76760-76770]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2023-24548]
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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.
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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 (Sec. 500.82(b) (21 CFR 500.82(b)(defining
``no residue''; Sec. 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.
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\1\ See Sec. 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 S<INF>m</INF> and defining
``S<INF>m</INF>'' 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).
\2\ Consistent with FDA regulations, CVM treats unidentified
residues of a carcinogenic drug as carcinogenic. See Sec. 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).
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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; <a href="https://www.fda.gov/animal-veterinary/workshops-conferences-meetings/part-15-public-hearing-scientific-data-and-information-related-residue-carcinogenic-concern-new">https://www.fda.gov/animal-veterinary/workshops-conferences-meetings/part-15-public-hearing-scientific-data-and-information-related-residue-carcinogenic-concern-new</a>), 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
[[Page 76761]]
concentration of the residue of carcinogenic concern; (3) on additional
information related to the adequacy of the current approved method to
measure QCA as a marker residue for the residue of carcinogenic concern
for the new animal drug carbadox not already contained in Docket No.
FDA-2020-N-0955, ``Phibro Animal Health Corp.; Carbadox in Medicated
Swine Feed; Revocation of Approved Method''; (4) on any method, other
than the current approved method, that demonstrates ``no residue'' for
the new animal drug carbadox in conformance with 21 CFR part 500,
subpart E; and (5) on detailed information on the conduct and quality
of studies providing data to support the points above, including
information on the extraction process and the stability of residues
being analyzed.
In addition to presentations from CVM and from the sponsor of the
carbadox approved applications, several other stakeholders gave
presentations. FDA also opened a docket (Docket No. FDA-2021-N-1326) to
receive additional stakeholder comment on the topics listed above.
After reviewing the comments to this docket (FDA-2020-N-0955), and
presentations and the comments received in the docket for the public
hearing (Docket No. FDA-2021-N-1326), FDA is now finalizing the order
revoking the approved method for detecting residues of carbadox.
Elsewhere in this issue of the Federal Register, FDA is publishing
a notice of opportunity for hearing (NOOH) proposing to withdraw
approval of all new animal drug applications for use of carbadox based
on the lack of an approved method for measuring the residue of
carcinogenic concern. An approved method for measuring the residue of
carcinogenic concern that complies with part 500, subpart E (21 CFR
part 500, subpart E) is required by section 512(d)(1)(I) of the FD&C
Act (21 U.S.C. 360b(d)(1)(I)).
II. Background
A. Regulation of Carcinogenic New Animal Drugs
The Delaney Clause of the FD&C Act generally prohibits the approval
of carcinogenic animal drugs unless the ``Diethylstilbestrol (DES)
Proviso'' applies. See section 512(d)(1)(I) of the FD&C Act. Under the
DES Proviso exception, a carcinogenic new animal drug may be approved
if, among other things, no residue of such drug will be found by
methods of examination prescribed or approved by the Secretary of
Health and Human Services (HHS) by regulations in any edible portion of
such animals after slaughter or in any food yielded by or derived from
the living animals.
As part of a new animal drug application (NADA), the sponsor must
include a description of practicable methods for determining the
quantity, if any, of the new animal drug in or on food and any
substance formed in or on food because of its use, and the proposed
tolerance or withdrawal period or other use restrictions to ensure that
the proposed use of this drug will be safe (Sec. 514.1(b)(7) (21 CFR
514.1(b)(7))). Carcinogenic drugs, such as carbadox, must also meet the
requirements in part 500, subpart E (Sec. 514.1(b)(7)(ii)). These
regulations, known as the sensitivity of the method (SOM) regulations,
set out the requirements to demonstrate that no residues of the drug
will be found by an approved method in any edible tissues of or in any
foods obtained from the animal, as required to comply with the DES
Proviso.
Specifically, the SOM regulations require FDA to determine if any
animal drug or any of its metabolites is a carcinogen (Sec.
500.84(a)). For the drug and each metabolite that FDA decides should be
regulated as a carcinogen, FDA calculates, based on 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 (Sec. 500.84(c)(1)). FDA designates the
lowest concentration (i.e., the concentration of the most potent
carcinogen) thus calculated as the S<INF>o</INF> (Sec. 500.84(c)(1)).
The S<INF>o</INF> 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 (Sec. 500.82(b)).
Because FDA relies on the S<INF>o</INF> from the most potent
carcinogen, 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 human 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 residue of
carcinogenic concern in a specific edible tissue (such as muscle,
liver, kidney, milk, or eggs) 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 the test animals of 1 in 1
million. This value is designated as the S<INF>m</INF> (Sec. Sec.
500.82(b) and 500.84(c)(1)). By limiting the concentration of residue
of carcinogenic concern to a value at or below the S<INF>m</INF>,
consumers can eat a specific edible tissue every day for an entire
lifetime with no significant increase in the risk of cancer.
Based on data submitted by a sponsor, FDA selects a target tissue
\3\ and a marker residue \4\ and designates the concentration of the
marker residue that the method must be able to detect in the target
tissue (Sec. 500.86(a) through (c) (21 CFR 500.86(a) through (c))).
This value, termed the R<INF>m</INF>, is the concentration of a marker
residue in the target tissue when the residue of carcinogenic concern
is equal to S<INF>m</INF> (500.82(b)). When the marker residue is at or
below the R<INF>m</INF>, the residue of carcinogenic concern in the
human diet does not exceed S<INF>o</INF> (Sec. 500.86(c)). This
regulation ensures that when the marker residue is no longer
detectable, the residue of carcinogenic concern does not exceed
S<INF>m</INF> in any of the edible tissues (Sec. Sec. 500.82(b) and
500.86(c)). For any given drug, there may be several different
compounds to consider for use as a marker residue. The R<INF>m</INF>
would be different depending upon the compound selected as the marker
residue.
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\3\ See Sec. 500.82(b) (defining target tissue as the edible
tissue selected to monitor for residues in the target animals,
including, where appropriate, milk or eggs).
\4\ See supra note 1 (defining ``marker residue'').
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A sponsor must submit a method that is able to detect the marker
residue at or below the R<INF>m</INF> (Sec. Sec. 500.88(b) (21 CFR
500.88(b)) and 500.84(c)(2)). There may be multiple methods available
to detect a particular marker residue; however, under the SOM
regulations, a method must be able to confirm the identity of the
marker residue in the target tissue at a minimum concentration
corresponding to the R<INF>m</INF>. The Limit of Detection (LOD) for
the method must be less than or equal to the R<INF>m</INF> (Sec.
500.84(c)(2)). FDA will determine the LOD from the submitted analytical
method validation data (Sec. 500.88(b)).\5\ If
[[Page 76762]]
a method is not developed that can detect the marker residue at or
below the R<INF>m</INF>, the requirements of the SOM regulations are
not satisfied, and FDA cannot approve the drug (see 21 U.S.C.
360b(d)(1)(I); Sec. 500.88).
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\5\ As discussed above, the Delaney Clause prohibits the use of
carcinogenic animal drugs unless the DES Proviso applies (see
section 512(d)(1)(I) of the FD&C Act). The DES Proviso requires
that, among other things, no residue of such drug will be found (by
methods of examination prescribed or approved by the Secretary of
HHS by regulations) in any edible portion of such animals after
slaughter or in any food yielded by or derived from the living
animals. FDA's SOM regulations establish the process by which a
carcinogenic new animal drug may satisfy the DES Proviso. The SOM
regulations were amended in 2002 to revise the operational
definition of the term ``no residue.'' Previously, FDA determined
there was ``no residue'' in edible tissues when the concentration of
the marker residue was at or below R<INF>m</INF>. However, in 1995,
the Department of Justice (DOJ)'s Office of Legal Counsel determined
that FDA's interpretation was not legally supportable. Specifically,
it opined that, if a method detected residue (even if the
concentration of that residue fell below the R<INF>m</INF>) the DES
Proviso requirement for ``no residue'' was not satisfied.
Accordingly, in 2002, FDA revised the definition of ``no residue''
to mean when the concentration of the marker residue is below the
LOD of the method, meaning nondetectable by the method (67 FR 78174;
see also DOJ, Mem. Op. for the Assistant Administrator & Gen.
Counsel EPA & Gen. Counsel DHHS (October 13, 1995), <a href="https://www.justice.gov/d9/olc/opinions/1995/10/31/op-olc-v019-p0247_0.pdf">https://www.justice.gov/d9/olc/opinions/1995/10/31/op-olc-v019-p0247_0.pdf</a>).
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B. History of Carbadox Approvals
Currently, there are three approved NADAs for use of carbadox in
medicated swine feed, either alone or in combination with other
approved new animal drugs. Carbadox, a quinoxaline derivative, is a
synthetic antimicrobial used to manufacture medicated feeds that are
administered ad libitum (available at all times) to swine. Phibro
Animal Health Corp. (Phibro), GlenPointe Centre East, 3d Floor, 300
Frank W. Burr Blvd., Suite 21, Teaneck, NJ 07666, is currently the
sponsor of all three approved NADAs.
1. NADA 041-061
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
at the rate of 10 to 25 grams per ton (g/ton) of feed for increased
rate of weight gain and improved feed efficiency; and at 50 g/ton of
feed for control of swine dysentery (vibrionic dysentery, bloody
scours, or hemorrhagic dysentery), 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 (Ref. 2). However, this
method was not published in the Federal Register as required in Sec.
500.88, and the method that had been published for the 1972 approval
was removed from the Code of Federal Regulations. Nevertheless, since
the January 1998 approval of the supplemental NADA, CVM and the sponsor
have treated the method approved as part of the 1998 supplemental
application as the method of examination prescribed or approved by the
Secretary of HHS by regulations for purposes of applying section
512(d)(1)(I) of the FD&C Act, the Delaney Clause, to carbadox.
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. This supplemental NADA was approved
based on the previous approval of a tolerance of 30 parts per billion
(ppb) for QCA as the marker residue and a residue depletion study using
the approved method that showed residues of QCA in liver depleted below
30 ppb by 42 days (Ref. 3).
2. NADA 092-955
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 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), control of bacterial swine enteritis (salmonellosis or
necrotic enteritis caused by S. 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 (Sec. 558.115(d)(3)(ii)
(21 CFR 558.115(d)(3)(ii))).
3. NADA 141-211
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 at 10 to 25 g/ton of feed
plus oxytetracycline at levels in feed to deliver 10 mg carbadox 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 (Sec. 558.115(d)(4); Sec.
558.450(e)(3)(iii) (21 CFR 558.450(e)(3)(iii)).
C. Statutory Authority To Issue Order
Under 5 U.S.C. 554(e) (section 5(d) of the Administrative Procedure
Act (APA)), an agency, in its sound discretion, may issue a declaratory
order to terminate a controversy or remove uncertainty. The APA defines
``order'' as the whole or a part of a final disposition, whether
affirmative, negative, injunctive, or declaratory in form, of an agency
in a matter other than rulemaking but including licensing (5 U.S.C.
551(6)). The APA defines ``adjudication'' as agency process for the
formulation of an order (5 U.S.C. 551(7)). FDA's regulations,
consistent with the APA, define ``order'' to mean the final Agency
disposition, other than the issuance of a regulation, in a proceeding
concerning any matter (Sec. 10.3(a) (21 CFR 10.3(a)). Our regulations
also define ``proceeding and administrative proceeding'' to mean any
undertaking to issue, amend, or revoke a regulation or order, or to
take or not to take any other form of administrative action, under the
laws administered by FDA (Sec. 10.3(a)). Moreover, our regulations
establish that the Commissioner of Food and Drugs may initiate an
administrative proceeding to issue, amend, or revoke an order (Sec.
10.25(b) (21 CFR 10.25(b)).
On our own initiative, FDA is issuing a 5 U.S.C. 554(e) declaratory
order to remove uncertainty regarding the approved method for carbadox
that measures QCA as a marker residue. An order is the most appropriate
procedure to revoke the approved method because there is no rule to
amend. The approved method is not currently published in the Federal
Register, contrary to Sec. 500.88, and the method that had been
published for the 1972 approval was removed from the Code of Federal
Regulations in 1998 and is no longer the approved method. The FD&C Act
does not provide the procedure we must use to determine whether an
approved method of examination that was never published in the Code of
Federal Regulations satisfies the regulatory requirements of part 500,
subpart E. Thus, we are choosing to issue a declaratory order to remove
uncertainty.
III. Discussion
When CVM approved the supplemental NADA for carbadox in January
1998, it did not require the sponsor to provide data establishing a
known relationship between the concentration of the marker residue
(QCA) and the concentration of the
[[Page 76763]]
residue of carcinogenic concern (Sec. 500.86). At that time, CVM did
not believe that such information was necessary because of previous
conclusions that it had made about the persistence of carcinogenic
residue in the edible tissues of animals administered carbadox. CVM's
understanding, at that time, was that carcinogenic residues, including
desoxycarbadox (DCBX), a known carcinogenic metabolite of carbadox,
depleted quickly (within 72 hours) while QCA residues depleted more
slowly. However, results from subsequent studies led CVM to reexamine
the conclusions it made in 1998 and conclude, based on data from these
studies, that it is necessary to establish a known relationship between
the marker residue and the residue of carcinogenic concern, as required
by regulation.
FDA is revoking the approved method for carbadox that measures QCA
as the marker residue because it is inadequate to monitor the residue
of carcinogenic concern. The approved method cannot adequately monitor
residue of carcinogenic concern because CVM is not aware of any data to
establish a relationship between QCA and the residue of carcinogenic
concern. That means that determining the concentration of QCA in animal
tissue does not allow CVM to determine whether the residue of
carcinogenic concern remains in the edible tissue. Thus, the approved
method does not comply with part 500, subpart E, and therefore does not
satisfy the statutory requirement of section 512(d)(1)(I) of the FD&C
Act.
A. CVM's Conclusions in the January 1998 Approval
In reviewing information for the supplemental NADA for carbadox in
January 1998, CVM relied on studies conducted by the sponsor \6\ and
academic researchers (Ref. 2) to establish an S<INF>o</INF> and an
S<INF>m</INF> for the most potent of the carcinogenic compounds. As
part of the supplemental NADA, the sponsor submitted toxicology
studies, including carcinogenicity bioassays with carbadox, DCBX, and
hydrazine (another carcinogenic metabolite of carbadox). These studies
indicated that DCBX was the most potent of the three identified
carcinogenic residues of carbadox. Based on the carcinogenicity of
DCBX, CVM calculated an S<INF>o</INF> of 0.061 ppb for residue of
carcinogenic concern for carbadox in the total diet. CVM calculated an
S<INF>m</INF> value for the residue of carcinogenic concern in muscle
at 0.305 ppb, in liver at 0.915 ppb, and in kidney and fat at 1.830
ppb. Because liver residues persist the longest, CVM assigned it as the
target tissue. Therefore, 0.915 ppb is the S<INF>m</INF> value for the
residue of carcinogenic concern for carbadox and liver is the target
tissue (Ref. 2).
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\6\ Pfizer, Inc. was the sponsor for carbadox until 2001. The
current sponsor is Phibro.
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Based on information submitted as part of the supplemental NADA
approved in January 1998, CVM made conclusions about how long
carcinogenic residues persist in the edible tissues of swine after
treatment with carbadox and about the appropriate marker residue to
select to monitor carbadox use. As stated in the FOI Summary for the
January 1998 approval of the supplemental NADA, CVM concluded that the
data:
[S]how that carbadox, desoxycarbadox and hydrazine do not
persist in edible tissue as detectable residues beyond 72 hours. The
agency's evaluation of these data, and the new information provided
by the sponsor, demonstrate that following administration, parent
carbadox is rapidly metabolized; that the metabolism of carbadox is
similar among species; that the in vivo metabolism of the compounds
of carcinogenic concern is also rapid and irreversible such that the
resulting metabolic products cannot regenerate compounds of
carcinogenic concern; that the unextractable residues are related to
noncarcinogenic compounds, quinoxaline-2-carboxylic acid (QCA) and
quinoxaline-2-carboxaldehyde; and that QCA is the only residue
detectable in the edible tissues beyond 72 hours post dosing. Thus,
the agency concludes that the unextractable bound residue is not of
carcinogenic concern and that QCA is a reliable marker residue for
carbadox.
CVM made the following conclusions during the review of the
supplemental NADA for carbadox approved in January 1998:
1. Carcinogenic residues do not persist in animal tissue beyond 72
hours postdosing.
2. Extractable QCA is the only residue detectable in edible tissues
72 hours postdosing.
3. Unextractable residues are noncarcinogenic residues related to
QCA.
4. QCA is a reliable marker residue for carbadox and its
metabolites.
5. No residue of carcinogenic concern, even below the
S<INF>o</INF>, is detectable by any method after 72-hours postdosing.
Because of the conclusions made at that time, CVM did not require
the sponsor to submit data to meet the requirements of the part 500,
subpart E, regulations \7\ despite the fact that carbadox is a
carcinogen. CVM instead established a tolerance of 30 ppb for QCA and
granted the supplemental approval for carbadox.
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\7\ These regulations require the sponsor to submit data that
allows FDA to designate an R<INF>m</INF> (the concentration of the
marker residue in the target tissue at which the residue of
carcinogenic concern in the diet of people represents no significant
increase in the risk of cancer to people) based on a known
relationship between the marker residue and the residue of
carcinogenic concern. In addition, the sponsor must provide a method
that can detect the marker residue at or below the R<INF>m</INF>.
Under Sec. 500.86, the necessary steps to meet the operational
definition of ``no residue'' for carbadox are: (1) measure the
depletion of the residue of carcinogenic concern until its
concentration is at or below the S<INF>m</INF> (0.915 ppb) in liver;
(2) measure the depletion of the marker residue until the
concentration of the residue of carcinogenic concern is at or below
the S<INF>m</INF>; (3) use the information in (1) and (2) to
establish an R<INF>m</INF>; and, (4) according to the regulations as
they existed in 1998, develop a method that could detect the marker
residue of the drug, as long as the marker residue would only be
detected at or below the R<INF>m</INF> under the proposed conditions
of use. According to the current regulations, step (4) requires the
development of a method that complies with the operational
definition of no residue (the method's LOD is less than or equal to
the R<INF>m</INF> and the marker residue depletes to a concentration
that cannot be detected by the method).
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B. The Approved Method That Measures QCA as the Marker Residue for
Carbadox Is Inadequate
Under section 512(d)(1)(I) of the FD&C Act, carcinogenic new animal
drugs, such as carbadox, must have a method of detection, prescribed or
approved by regulation, to ensure that no residue of carcinogenic
concern persists in any edible portion of the treated animals after
slaughter or in any food derived from treated animals. FDA has
implemented this statutory requirement through its SOM regulations in
part 500, subpart E, which require that each carcinogenic new animal
drug have a marker residue with a known relationship to the residue of
carcinogenic concern. This relationship is necessary to establish a
concentration of the marker residue (the R<INF>m</INF>) that ensures
any residue of carcinogenic concern in a specific edible tissue is
below the level corresponding to maximum lifetime risk of cancer in the
test animal of 1 in 1 million (the S<INF>m</INF>), based on
calculations that consider the entire human diet (the S<INF>o</INF>).
The approved method must have a limit of detection less than or equal
to the R<INF>m</INF>.
Although CVM approved the method for carbadox as part of the
supplemental NADA in January 1998 and designated the S<INF>m</INF> and
S<INF>o</INF>, it did not require the sponsor to provide data showing
the relationship between QCA and the residue of carcinogenic concern
and therefore could not designate an R<INF>m</INF>. Nor did CVM require
the sponsor to identify
[[Page 76764]]
a method with a limit of detection less than or equal to the
R<INF>m</INF>. Without an R<INF>m</INF> and an appropriate method for
detecting the marker residue (i.e., a method sensitive enough to detect
residues at or below the R<INF>m</INF>), it is impossible to determine
that the residue of carcinogenic concern falls below the S<INF>m</INF>.
Accordingly, based on information currently available to CVM, it is
impossible to use the approved method or any other method to ensure
compliance with the operational definition of no residue.
Furthermore, based on studies conducted since 1998, CVM reevaluated
the conclusions that originally led it to determine that assignment of
a tolerance of 30 ppb for QCA in swine liver would ensure that the
residue of carcinogenic concern would remain at or below its respective
S<INF>o</INF> in all edible tissues (Refs. 4-6). Based on a review of
these data, CVM concluded that: (1) carcinogenic residues persist in
animal tissue more than 72 hours postdosing and (2) QCA is not the only
residue detectable in animal tissue after 72 hours postdosing.
For the 2003 Joint Food and Agriculture Organization (FAO)/World
Health Organization (WHO) Expert Committee on Food Additives (JECFA)
meeting, the sponsor provided data in which it reported that DCBX is
measurable quantitatively (specific concentration measured) at 15 days
postdosing (the last sampling timepoint in the study) (Refs. 4 and 5).
Based on those studies, which showed the persistence of genotoxic,
carcinogenic residues, JECFA recommended withdrawal of the previously
established Codex Alimentarius Commission \8\ (Codex) Maximum Residue
Limit (MRL). Codex subsequently agreed because the amount of residues
of carbadox in human food that would have no adverse health effects in
consumers could not be determined. Following that meeting, the Codex
Committee on Residues of Veterinary Drugs in Foods withdrew the MRL for
carbadox (Ref. 7). Carbadox has been removed from the market in many
foreign jurisdictions, including the European Union (Ref. 8), Canada
(Ref. 9), and Australia (Ref. 10).
---------------------------------------------------------------------------
\8\ For more information about Codex, see <a href="https://www.fao.org/fao-who-codexalimentarius/committees/cac/about/en/">https://www.fao.org/fao-who-codexalimentarius/committees/cac/about/en/</a>.
---------------------------------------------------------------------------
In 2005, the sponsor provided CVM with summary reports for the
studies evaluated by the 2003 JECFA. CVM responded later that year,
informing the sponsor that: (1) because the summaries indicated that
carcinogenic residues persist longer than previously known and there is
no established relationship between QCA and the residue of carcinogenic
concern, CVM was concerned that the use of the 30 ppb tolerance for QCA
and the use of QCA generally as a marker residue may not be appropriate
and (2) accordingly, the sponsor would need to submit existing or new
studies to address the relationship of QCA at 30 ppb and the residue of
carcinogenic concern. CVM also told the sponsor that, if it was
determined that QCA is not appropriate as the marker residue, the
sponsor would need to conduct additional metabolism and residue
depletion studies to identify an appropriate marker residue and
tolerance in order to maintain the carbadox approvals.
Between 2005 and 2011, CVM continued to meet with the sponsor and
to review various submissions from the sponsor, including but not
limited to a study the sponsor conducted in 2008 to 2009 and submitted
in 2009 (hereinafter ``the 2008 study''). None of the submissions,
however, contained reports of studies that were designed to generate
the needed information. Therefore, in 2011, pursuant to section
512(l)(1) of the FD&C Act, FDA ordered the sponsor to provide FDA with
all data, studies, analyses, reviews, reports, or other scientific
evaluations in its possession related to the persistence of DCBX in
edible tissues, the appropriateness of QCA as an analyte for residue
monitoring and for establishing a withdrawal time for the use of
carbadox in pigs, and whether an analytical method for monitoring
carbadox-related carcinogenic residues in edible tissues can be
developed that would comply with part 500, subpart E. The sponsor
responded with, among other submissions, the complete study reports for
the studies evaluated by the 2003 JECFA. CVM reviewed the reports and
determined that the data show qualitatively (specific concentration not
measured) that carbadox and DCBX are present in liver tissue samples at
48 hours and at 15 days withdrawal, respectively. For samples exposed
to enzymes to mimic human digestion, CVM concluded that the mass
spectrometry chromatograms and the reported DCBX concentration data
provide qualitative confirmation of the presence of DCBX at 15 days
withdrawal. These reports show that the known carcinogenic residues
(DCBX) persist beyond 72 hours and that QCA is not the only residue
detectable after 72 hours.
In response to CVM's proposal to withdraw approval of the carbadox
containing new animal drug applications in 2016,\9\ the sponsor
submitted reports from six studies (hereinafter ``the 2016 studies'').
These studies, some of which began in 2012, were initiated without
agreement from CVM that they would provide the necessary data to
address CVM's concerns (specifically, data to demonstrate that the
approved method was adequate to measure the residue of carcinogenic
concern in compliance with FDA's SOM regulations, or that an
alternative method to do so was available).
---------------------------------------------------------------------------
\9\ CVM issued a Notice of Opportunity for Hearing (NOOH) on a
proposal to withdraw approval of the carbadox containing NADAs on
April 12, 2016. [81 FR 21559; (Correction published on April 21,
2016 (81 FR 23499), to correct the telephone number for the
individual to be contacted for further information. The address for
Phibro Animal Health Corp. was also corrected.)] Phibro submitted
data from the 2008 study in its Request for a Hearing in response to
the NOOH. [<a href="https://www.regulations.gov/document/FDA-2016-N-0832-0029">https://www.regulations.gov/document/FDA-2016-N-0832-0029</a>] Phibro also submitted to that same docket reports from
additional studies in July 2016. CVM withdrew the 2016 NOOH on July
20, 2020 (85 FR 43852).
---------------------------------------------------------------------------
Finally, the sponsor and others submitted presentations, documents,
and information in response to the 2020 proposed order, at the March
10, 2022, public hearing, and/or to the docket for the public hearing.
CVM reviewed the presentations, documents, and information, and
determined that they were not sufficient to establish a relationship
between QCA and the residue of carcinogenic concern, which includes
carbadox and DCBX. Additionally, there were no data to establish the
residue level of QCA at which the residue of carcinogenic concern in
the diet of people represents no significant increase in the risk of
cancer to people. Without these data, CVM cannot establish the
R<INF>m</INF> and the sponsor cannot demonstrate ``no residue'' of
carcinogenic concern as required by the SOM regulations in part 500,
subpart E, which implement the FD&C Act at 21 U.S.C. 360b(d)(1)(I).
In sum, based on review of data submitted following the 1998
approval of the method, CVM concludes that: (1) carcinogenic residues
persist in animal tissue more than 72 hours postdosing and (2) QCA is
not the only residue detectable in animal tissue after 72 hours
postdosing. CVM also concludes that data and information submitted
since 1998, including to this docket and to Docket No. FDA-2021-N-1326
by the sponsor and others, do not provide information needed to
establish the relationship between QCA and the residue of carcinogenic
concern. Without knowing this relationship and without a method for
measuring a marker residue with a limit of detection
[[Page 76765]]
at or below the R<INF>m</INF>, the approved method is inadequate for
monitoring compliance with FDA's operational definition of no residue
(see Sec. 500.84(c)(3)). Accordingly, the approved method for carbadox
does not satisfy the statutory or regulatory requirements and is being
revoked.
IV. Comments Received on the Proposed Order and Public Hearing
A. Comments Submitted by the Sponsor
The sponsor of the carbadox NADAs submitted information to the
docket of the proposed order, presented information at the public
hearing, and submitted information to the docket for that hearing.
CVM's scientific review of the sponsor's submitted data, analysis, and
comments prior to the hearing is discussed below and in ``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), which was posted to the public docket
before the hearing (Ref. 6). Information submitted during or after the
hearing is discussed below and in ``CVM's review of documents Phibro
submitted to Docket No. FDA-2021-N-1326 and presentation at the March
10, 2022 Part 15 Hearing'' (October 30, 2023) (Ref. 11), and ``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) (Ref. 12). CVM's review of the sponsor's procedural
and policy objections is reflected below and in the denials of the
sponsor's citizen petition (Docket No. FDA-2020-P-2312) and petition
for stay of action (Docket No. FDA-2020-P-2313), available at <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
In the sponsor's comments and oral presentation, it argued that QCA
is an adequate marker residue and defended the approved method, which
measures QCA. The comments defended the use of the 30 ppb QCA tolerance
and 42-day withdrawal period as sufficient to protect human and animal
safety. The sponsor alternatively suggested use of the U.S. Department
of Agriculture Food Safety and Inspection Service (FSIS) method to
measure QCA. The sponsor also proposed that DCBX could be used as a
marker residue. For measuring DCBX, the sponsor proposed the Canadian
Food inspection Agency (CFIA) method. The sponsor also suggested that
other unnamed methods were available. Finally, the sponsor argued that
a final order was not the appropriate process to revoke an approved
method and that an NOOH is required instead.
Comment on use of QCA as a marker residue. The sponsor states that
an R<INF>m</INF> can be calculated for QCA based on the available data
and submitted an expert opinion about the R<INF>m</INF> for QCA. By
analyzing QCA and DCBX concentrations, the sponsor's expert states that
the R<INF>m</INF> for QCA is either 28.49 ppb (using the 2008 study
data and the approved method) or 28.61 ppb (using the data submitted
for the 1998 supplemental approval and the approved method). The
sponsor also asserted that even if DCBX residues persist longer than
previously known, no residue of carcinogenic concern persists beyond
the current 42-day withdrawal period. The sponsor stated that either
the approved method or FSIS method could be used to measure QCA.
Response to use of QCA as a marker residue. After reviewing the
sponsor's studies submitted to the 2003 JECFA, the 2008 study, the 2016
studies, and other comments and analyses provided by the sponsor, CVM
concludes that it lacks the data to establish an R<INF>m</INF> for QCA
or any other marker residue. The sponsor's expert opinion estimated the
concentration of QCA when DCBX is 0.915 ppb (the S<INF>m</INF> for the
residue of carcinogenic concern in liver for carbadox). This analysis
relied solely on residues of DCBX instead of considering the residue of
carcinogenic concern. DCBX is only one metabolite of carbadox and
therefore just one component of the residue of carcinogenic concern,
which includes all compounds in the total residue of a demonstrated
carcinogen excluding any compounds judged by FDA not to present a
carcinogenic risk (Sec. 500.82). Because QCA and another metabolite,
methyl carbazate, are the only compounds of carbadox that FDA has
judged to not present a carcinogenic risk, the residue of carcinogenic
concern for carbadox includes all carbadox residues except for QCA and
methyl carbazate. The sponsor did not provide an R<INF>m</INF> for the
marker residue QCA that accounted for the residue of carcinogenic
concern, nor is CVM able to calculate one based on the data available.
Without an R<INF>m,</INF> CVM cannot determine if the approved method,
FSIS method, or any other method that measures QCA as the marker
residue is sufficiently sensitive to satisfy the regulatory and
statutory requirements.
Contrary to the sponsor's assertion that the residue of
carcinogenic concern does not persist beyond the 42-day withdrawal
period, data quantifying the residue of carcinogenic concern for
carbadox from the 1998 supplemental approval indicates that a marker
residue would exceed the R<INF>m</INF> (the concentration associated
with no increase in risk to the human consumer) more than 70 days post-
dosing. The data submitted for the 1998 supplemental approval showed
that the total radiolabeled residues have a concentration of 13.3 ppb
at 70 days post-dosing, the last timepoint in the study. After removing
the 9.9 percent QCA residues detected at 70 days,\10\ the remaining
residue has a concentration of 11.98 ppb. This concentration far
exceeds the S<INF>m</INF> value of 0.915 ppb for carbadox and therefore
these data cannot be used to calculate an R<INF>m</INF>. At most, these
data indicate that a marker residue would not reach the R<INF>m</INF>
until more than 70 days post-dosing, well past the current 42-day
withdrawal period.
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\10\ According to the 1998 FOI Summary, QCA and methyl carbazate
are noncarcinogenic metabolites of carbadox (Ref. 2). The sponsor
provided quantitative measurements for QCA, but not for methyl
carbazate.
---------------------------------------------------------------------------
The sponsor's 2008 study and 2016 studies did not provide the
information to determine the residue of carcinogenic concern. The
sponsor's 2008 study does not provide information on the residue of
carcinogenic concern because it measured only QCA and DCBX, not total
residues of carbadox. In addition, CVM concluded that the data from
that study cannot be considered quantitative because of poor method
performance. Likewise, the sponsor's 2016 studies do not provide
quantitative data on the residue of carcinogenic concern. Additionally,
although the sponsor attempted to separate the residues and measure the
presence of each compound individually, it failed to demonstrate that
the analytical procedures used did not cause carcinogenic compounds to
degrade to noncarcinogenic compounds. CVM's review of the method
performance issues and analytical flaws in the sponsor's studies is
discussed in greater detail in Refs. 6 and 11.
CVM also reviewed the information provided by the sponsor during
the public hearing and to the docket following the hearing and
concluded that such information does not allow CVM to determine an
R<INF>m</INF> for the approved method. The new information concerns the
procedures, analysis, and documentation for the 2016 studies; however,
none of the new information
[[Page 76766]]
provides the data necessary to calculate an R<INF>m</INF> because the
studies were not designed to generate the quantitative data necessary
to make these calculations. CVM's review of the new information is
discussed in greater detail in Ref. 11.
Comment on use of DCBX as a marker residue. The sponsor proposed
the use of DCBX as a marker residue and suggested the CFIA method for
detecting DCBX. According to an expert opinion submitted by the
sponsor, DCBX depletes to a concentration of 0.915 ppb at approximately
23 days post-dosing and depletes to the 0.015 ppb detection limit for
the CFIA method at 75 days post-dosing.
Response to use of DCBX as a marker residue. Because DCBX is only
part of the residue of carcinogenic concern, the sponsor's expert
opinion and analysis are insufficient to ensure compliance with the SOM
regulations. The residue of carcinogenic concern for carbadox includes
all carbadox residues excluding residues judged by FDA not to present a
carcinogenic risk (Sec. 500.82(b)). For carbadox, only the compounds
QCA and methyl carbazate have been judged by FDA to be noncarcinogenic.
All other compounds cannot be excluded from the residue of carcinogenic
concern. At most, the expert's opinion indicates that the concentration
of the residue of carcinogenic concern would reach the S<INF>m</INF> at
some point after 23 days (since DCBX is only part of the residue of
carcinogenic concern) and that detectable residues of a carcinogenic
new animal drug are present at 75 days post-dosing, which is 33 days
longer than the current withdrawal period and 72 days longer than was
known in 1998. This information is insufficient to determine an
R<INF>m</INF> for DCBX as a marker residue. Without an R<INF>m</INF>,
CVM cannot determine if the CFIA method or any other method to measure
DCBX is sufficiently sensitive to satisfy the regulatory and statutory
requirements (Sec. 500.88(b)).
Comment on carbadox metabolism. During the public hearing, the
sponsor stated that the metabolism for carbadox is well-known and
asserted that carbadox depletes to DCBX, which in turn depletes to the
noncarcinogenic QCA. The sponsor addressed an April 2022 study (Ref.
13) about the metabolism and residue depletion of carbadox and asserted
that compounds other than DCBX and QCA are intermediates that are
present ``only fleetingly.'' The sponsor also stated during the public
hearing that it would be willing to conduct additional studies.
Response on carbadox metabolism. CVM reviewed the sponsor's
comments regarding a study published in April 2022 that describes
metabolism and residue depletion of carbadox (Ref. 12). The study
identified eight different metabolites of carbadox (DCBX, QCA, and six
others) and proposed two different metabolic pathways for the
degradation of carbadox. The study contradicts the sponsor's claim that
DCBX represents the entirety of the residue of carcinogenic concern.
Although the sponsor states that the six non-QCA, non-DCBX carbadox
residues identified in the April 2022 study are present ``only
fleetingly,'' the method used in that study was not capable of
detecting carbadox metabolites below 20 ppb, a concentration far
greater than the S<INF>m</INF>. Further, FDA regulations prohibit us
from excluding compounds from the residue of carcinogenic concern until
they have been judged to be noncarcinogenic. Only compounds known to be
noncarcinogenic can be subtracted from the total residues for the
determination of residue of carcinogenic concern. Although the 2022
study adds to our knowledge about previously unidentified carbadox
residues, it does not provide total residue data that could be used to
calculate the residue of carcinogenic concern or to determine a
relationship between a marker residue and the residue of carcinogenic
concern for establishment of an R<INF>m</INF>. Finally, although the
sponsor stated that it would be willing to conduct additional studies,
it has not submitted additional studies to date.
Comment on process to revoke the method. The sponsor also argued
that CVM cannot lawfully revoke an approved method using a final order
under the FD&C Act and its implementing regulations, agency precedent,
the Administrative Procedure Act, and the Due Process Clause of the
U.S. Constitution and must rely instead on an NOOH and an evidentiary
hearing before an impartial adjudicator to address the adequacy of the
approved method. Alternatively, the sponsor asserted that revocation of
the method requires rulemaking under the APA instead of a declaratory
order. The sponsor also argued that it is arbitrary and capricious to
revoke an approved method without establishing an alternative method
and that a public hearing is not a substitute for a formal evidentiary
hearing.
Response on process to revoke the method. It is appropriate under
the FD&C Act and its regulations, agency precedent, the Administrative
Procedure Act, and the Due Process Clause of the U.S. Constitution to
address the adequacy of the approved method through a declaratory order
as a threshold matter before proceeding to an NOOH on withdrawal of the
drug's approval. Although the FD&C Act requires an opportunity for a
hearing prior to withdrawing an animal drug approval (which FDA is
providing by issuing an NOOH and considering any request for hearing it
receives), the FD&C Act does not require a specific procedure to
determine whether a particular method of examination satisfies the
statutory and regulatory requirements, nor does it address the
situation when an agency did not follow a regulatory requirement to
publish that method in the Federal Register. A declaratory order is an
appropriate process under the FD&C Act and APA to determine whether a
statutory exclusion applies. See Weinberger v. Hynson, Westcott &
Dunning, Inc., 412 U.S. 609, 626 (1973) (holding that FDA could issue a
declaratory order to terminate controversy and remove uncertainty
regarding whether a new drug and ``me-too'' drugs were exempt from
providing efficacy data).
In Weinberger, the Supreme Court agreed with FDA's conclusion that
efficacy data was required for a class of drugs but held that a hearing
was necessary before withdrawal because the drug sponsor had submitted
substantial evidence of efficacy in line with FDA's regulatory
requirements for well-controlled studies. Id. at 622-23. Here, FDA
concludes that the approved method, which relies on a tolerance of 30
ppb for QCA, does not comply with the statute and implementing
regulations because there is no R<INF>m</INF> for the marker residue
QCA and no determination that the approved method is sufficiently
sensitive to detect the marker residue at or below the R<INF>m.</INF>
Unlike the situation in Weinberger, where the drug sponsor submitted
efficacy data in line with the regulatory and statutory requirements,
the drug sponsor does not assert here that the current tolerance of 30
ppb for QCA has a known relationship with the residue of carcinogenic
concern and therefore has not submitted evidence that the approved
method satisfies the statutory and regulatory requirements. Instead,
the drug sponsor's expert states that the R<INF>m</INF> for QCA is
either 28.49 ppb (using the 2008 data and the approved method) or 28.61
ppb (using the data submitted for the 1998 supplemental approval and
the approved method) based on a calculation that estimates
concentrations of QCA when the estimated concentration of DCBX is 0.915
ppb. DCBX is not the only
[[Page 76767]]
carcinogenic residue that must be considered when determining an
R<INF>m</INF>, so the sponsor's calculations do not account for the
entire residue of carcinogenic concern. However, even if we were to
assume that DCBX is the only carcinogenic residue present, the
sponsor's assertion essentially admits that its own expert does not
think the current tolerance satisfies the regulatory requirements
because the current tolerance of 30 ppb is more than 28.49 ppb or 28.61
ppb (the R<INF>m</INF> identified by the sponsor's expert).
Currently, edible tissues may enter the food supply if they contain
a concentration of QCA at or below 30 ppb. According to the expert's
calculation, when QCA is more than 28.49 ppb or 28.61 ppb, edible
tissues would still contain carcinogenic DCBX above 0.915 ppb, the
level that corresponds to no significant increase in the risk of cancer
to the human consumer. If we accept the expert's calculations as
true,\11\ edible tissues with a QCA concentration of 29 ppb, for
example, could contain carcinogenic residues above 0.915 ppb, yet those
edible tissues could enter the food supply because the QCA tolerance
would be satisfied. The sponsor argues that the current 42-day
withdrawal period provides an additional margin of safety sufficient to
meet the statutory and regulatory requirements because the sponsor's
expert estimates that DCBX depletes to 0.915 ppb at 23 days, 19 days
before the end of the withdrawal period. However, edible tissues are
analyzed for residue concentrations; the length of time since the
animal was treated is not measurable from tissue analysis. Thus, safety
is assured by measuring the concentration of a marker residue that
tracks the residue of carcinogenic concern in edible tissues to
determine whether the concentration is below or above the
R<INF>m</INF>. Regardless of the length of the withdrawal period, the
``no residue'' requirement cannot be met if the marker residue is above
the R<INF>m</INF>. Even if we accepted the sponsor's calculations as
true, a tolerance of 30 ppb for QCA would not be at or below the
R<INF>m</INF> (calculated by the sponsor's expert as 28.49 ppb or 28.61
ppb) in edible tissues of treated swine. Thus, even the sponsor's own
expert opinion supports FDA's conclusion that the approved method does
not satisfy the statutory and regulatory requirements.
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\11\ As discussed above, DCBX is not the only residue of
carcinogenic concern and we have concerns regarding the quality of
data from the 2008 study.
---------------------------------------------------------------------------
CVM spent a decade (2005 to 2015) in discussions with the sponsor
regarding the data necessary to identify an adequate method and did,
and continues to, invite the sponsor to provide that data. At this
time, as discussed above, the sponsor has not submitted that data.
The method revocation and withdrawal of NADA approvals are not so
intertwined as to require a hearing on revocation under the statute or
FDA's regulations. While a sponsor may have an opportunity at a hearing
held on either NADA approvability or NADA withdrawal to show whether
there is an approvable method to meet the DES Proviso, the FD&C Act
does not require an opportunity for a hearing on the interlocutory
revocation of an approved method. 21 U.S.C. 360b(c)(1) and (e)(1)(B).
Furthermore, CVM's decision to revoke the method separately from (and
before) taking action on the NADA is consistent with D.C. Circuit
opinions regarding the DES withdrawal proceedings, which declined to
apply the Delaney Clause when there were currently approved methods
that did not result in detectable levels of residue. In Hess & Clark,
Division of Rhodia, Inc. v. FDA, 495 F.2d 975 (D.C. Cir. 1974), and its
companion case, Chemetron Corp. v. U.S. Dep't of Health, Educ. &
Welfare, 495 F.2d 995 (D.C. Cir. 1974), the court overturned FDA's
withdrawal of approvals of DES because it held that the NOOH preceding
the withdrawals did not adequately provide notice and a meaningful
opportunity to respond to test results that FDA claimed supported
withdrawal. Hess & Clark, 495 F.2d at 983; Chemetron, 495 F.2d at 999.
Notably, the test results were from a method that the U.S. Department
of Agriculture (USDA) utilized that was different from the approved
methods for DES. In discussing the USDA method, the court stated that
``the Delaney Clause is plainly inapplicable'' where ``the only method
by which residues have been detected is [an unapproved method].'' Hess
& Clark, 495 F.2d at 991; see also Chemetron, 495 F.2d at 999 (``The
`DES' exception to the Delaney Clause . . . continues effective unless
the agency detects residues in a slaughtered animal while using an
approved test method. And the residues detected by [USDA] were not
found by an `approved method.' ''). Under this logic, the Delaney
Clause will only apply after the approved method has been revoked or
residue is found by the approved method. Consistent with these cases
(the only court cases that address the applicability of the Delaney
Clause when there is still an approved method), CVM is addressing the
adequacy of the approved method for carbadox before relying on the
Delaney Clause to take action to withdraw the NADAs.\12\ FDA's decision
to revoke the approved method relies on the information submitted to
date by the drug sponsor. This revocation does not prevent the drug
sponsor from providing new or additional data to establish an
R<INF>m</INF> for a marker residue in accordance with the statute and
regulations.
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\12\ While, subsequent to the 1974 DES decisions, FDA proceeded
to a hearing on the withdrawal of DES without revoking the method
first, FDA relied on both the general safety clause and the Delaney
Clause as the basis for withdrawal and, upon subsequent challenge,
the D.C. Circuit declined to address FDA's application of, or
procedure regarding, the Delaney Clause. Rhone-Poulenc, Inc., Hess &
Clark Division v. FDA, 636 F.2d 750, 751-52 & n.2 (D.C. Cir. 1980).
---------------------------------------------------------------------------
On the two previous occasions when FDA withdrew approval for
carcinogenic animal drugs (DES and a class of drugs called
``nitrofurans''), FDA relied on both the Delaney Clause and the general
safety clause, so these prior situations differ significantly from a
withdrawal based solely on the Delaney Clause. Furthermore, both sets
of withdrawal proceedings began before FDA finalized the SOM
regulations in 1987 and therefore provide no guidance on the
appropriate process to determine whether a method complies with the SOM
regulations. The SOM regulations (which implement the DES Proviso) are
a rule of general applicability because they set forth the general
requirements for all regulatory methods for carcinogenic new animal
drugs; by contrast, this final order revoking the method is appropriate
as a declaratory order because it determines whether one specific
method satisfies these general requirements. Notably, FDA does not
approve regulatory methods through notice-and-comment rulemaking under
the APA. See 76 FR 72617, November 25, 2011 (publishing regulatory
method to detect residues of carcinogen without notice-and-comment
rulemaking). Because notice-and-comment rulemaking is not required to
publish a regulatory method, it is not required to revoke a regulatory
method. See Perez v. Mortg. Bankers Ass'n, 575 U.S. 92, 101 (2015).
CVM provided notice of the proposed order and a meaningful
opportunity to be heard. The drug sponsor and other interested parties
had an opportunity to provide comments and other information. The
public hearing served as an additional opportunity for the sponsor and
the public to comment on this matter. The sponsor presented orally and
submitted additional comments to the public hearing docket. In
addition, the sponsor remains able to market carbadox lawfully, so the
[[Page 76768]]
sponsor has not been deprived of a property right.
CVM, as the component of FDA charged with applying the Delaney
Clause and DES Proviso, is appropriately advising on this order and its
involvement does not infect any subsequent proceedings with any bias.
Elsewhere in this issue of the Federal Register, FDA is publishing an
NOOH and, pursuant to FDA regulations, were the sponsor to request a
hearing, the adjudicator of that request would be affiliated with FDA's
Office of the Commissioner and would have had no previous role in the
proceedings to date.
Comment on policy considerations. The sponsor asserts that revoking
the approved method for carbadox and the resulting withdrawal of
carbadox, if it were to occur, would be poor policy because carbadox
supports animal health and serves the public interest in preventing
antimicrobial resistance and because the swine industry and U.S.
economy would face significant costs following revocation of the method
and/or withdrawal of approval of the NADAs. The sponsor also asserts
that carbadox is safe in that it has been used for over 50 years and
has not been linked to a single instance of cancer in pigs or humans.
Response to comment on policy considerations. These comments are
not relevant to whether the approved method meets our regulatory
requirements and is adequate to monitor the residue of carcinogenic
concern in compliance with FDA's operational definition of no residue
or provide information needed to establish the relationship of QCA to
the residue of carcinogenic concern. Without an adequate method, the
drug cannot meet the DES Proviso in section 512(d)(1)(I) of the FD&C
Act that permits the approval of carcinogenic animal drugs under
certain conditions. The carcinogenicity studies of carbadox provided
clear evidence that carbadox caused cancer in mice and rats under
laboratory conditions; therefore, the Delaney Clause applies because
``such drug induces cancer when ingested by man or animal.'' 21 U.S.C.
360b(d)(1)(I).
CVM considered the sponsor's other comments and concluded that they
were not relevant to determining whether the approved method, the CFIA
method, the FSIS method, or any other method complies with the
regulatory and statutory requirements. The comments are discussed in
greater detail in CVM's memoranda regarding carbadox (Refs. 6, 11, and
12) and denials of the sponsor's citizen petition (Docket No. FDA-2020-
P-2312) and petition for stay of action (Docket No. FDA-2020-P-2313).
Based on the available evidence, there currently is no analytical
method for which CVM can conclude that the SOM regulations are met, nor
has the sponsor provided the data to establish an R<INF>m</INF> for any
marker residue. Without this information, CVM is unable to conclude
that there is no residue of carcinogenic concern in swine treated with
carbadox.
B. Comments Submitted by Other Stakeholders
The non-sponsor comments submitted to this docket and to Docket No.
FDA-2021-N-1326, and non-sponsor presentations at the part 15 hearing,
generally concerned the need for carbadox for animal health and
projected economic losses to the swine industry from a decrease in
animal health; the increase in the use of medically important
antimicrobials if carbadox were no longer available; human food safety
and environmental safety; and requests for FDA to work with the sponsor
to develop and approve an adequate method. However, none of the non-
sponsor comments contained any data or information demonstrating that
the approved method meets our regulatory requirements and is adequate
to monitor the residue of carcinogenic concern in compliance with FDA's
operational definition of no residue or that a different method meets
the requirements.
Comments on animal health and projected economic losses to the
swine industry. FDA received several comments stating that carbadox is
the only effective option for stopping swine dysentery and that
alternatives (including vaccines) either do not exist or do not work as
well. Several comments indicated that removing carbadox from the market
would lead to animal suffering and death, and several cited a survey of
veterinarians conducted in 2016 and again in 2020 that estimates the
removal of carbadox would result annually in sickness for 53.5 million
otherwise healthy pigs and cost the nation's hog industry $5.3 billion
over the next decade. Other comments noted that the approved uses of
carbadox are limited to growth promotion, the control of swine
dysentery, and control of salmonellosis caused by Salmonella
choleraesuis. A comment stated that swine dysentery and S. choleraesuis
are rare in U.S. swine herds and can be managed without antibiotics,
pointing to countries that have banned the use of carbadox.
Comments on antimicrobial resistance. Some comments stated that the
only alternatives to carbadox that could be used to treat swine
dysentery are medically important antibiotics for humans, such as
aminoglycosides, and that removing carbadox is contrary to FDA's
strategy with respect to antimicrobial resistance. We also received
comments stating that research has shown that the use of carbadox in
swine increases gene transfer, creating its own resistance problems.
Comments on human food safety and environmental safety issues. We
received several comments defending the human food safety of swine
administered carbadox. One comment pointed out that Salmonella is
zoonotic and could result in food safety issues if not controlled and
that there is an expectation that Salmonella and Brachyspira would make
their way into slaughterhouses, potentially resulting in lower meat
quality and increased contamination if carbadox is no longer available.
We also received comments that asserted that the use of carbadox
creates dangerous residues in food products and results in residues of
carbadox and its metabolites in surface waters in states with large
numbers of pig-producing facilities, and that carbadox poses allergen
and genotoxicity hazards to the farm and feed mill workers who handle
products containing the drug.
Response to comments on animal health, industry economic losses,
antimicrobial resistance, and human food safety. These comments are not
relevant to whether the approved method meets our regulatory
requirements and is adequate to monitor the residue of carcinogenic
concern in compliance with FDA's operational definition of no residue
or provide information needed to establish the relationship of QCA or
any other marker residue to the residue of carcinogenic concern.
Without an adequate method, the drug cannot meet the provisions of
section 512(d)(1)(I) of the FD&C Act.
Comments on process to develop a new method. Several comments
requested that FDA work with the sponsor to develop and approve a new
method. Comments also presented the view that FDA did not provide the
sponsor of carbadox with a clear path forward and that FDA diverged
from its established process, urging that FDA work with the sponsor or
publish an NOOH regarding the adequacy of the approved method.
Response to comments on process to develop a new method. Before
publishing the proposed order, CVM worked with the sponsor for many
years (from 2005 to 2015), during which time it described the steps
needed to be completed to obtain the necessary data
[[Page 76769]]
to establish an R<INF>m</INF>. CVM has repeatedly requested data from
the sponsor to establish the relationship between QCA and the residue
of carcinogenic concern. During this time, the sponsor chose not to
submit protocols for our review under CVM's generally available
protocol review process, except for one study protocol submitted in
2006. That study would have been conducted under FDA's Good Laboratory
Practices and would have provided preliminary information about residue
depletion (although not the data necessary to establish an
R<INF>m</INF>), but the sponsor did not submit a report from this study
and it does not appear this study was ever conducted.
These decade-long communications, along with the clear requirements
of the regulatory text, provided the sponsor with notice of what is
needed to meet the statutory requirements as well as ample time to
carry out the necessary studies. To date, CVM has not received data
demonstrating the approved method is adequate to measure the residue of
carcinogenic concern in compliance with the requirements of FDA
regulations or that an alternative analytical method would meet such
requirements.
CVM, too, has made the swine industry and general public aware of
its concerns with the adequacy of the approved method for carbadox. Its
concern was discussed in the 2016 NOOH, the 2020 Proposed Order, and
during the subsequent public hearing. Indeed, members of the industry
and the general public submitted comments to the dockets and made oral
presentations at the public hearing. While we take seriously the
concept that the sponsor, veterinarians, swine producers, and consumers
have relied on the existence of the approved method for carbadox for
the last 25 years (and the prior approved method for more than two
decades before that) in the form of monetary and physical resource
allocation decisions (including inventory decisions on the part of the
industry), decisions about animal health, and consumer spending and
costs, they have received notice of, and an opportunity to comment on,
CVM's concerns and proposed actions. Additionally, were the sponsor to
request a hearing in response to the NOOH and point to new or
additional data to support the approved method or another approvable
method, it may follow that a hearing is granted on that basis and/or
that the carbadox NADAs are not withdrawn for that or any other
applicable reason. Those considerations together with the
considerations discussed throughout this order--including that the
larger purpose of an approved method is to protect against the presence
of residue of carcinogenic concern in animal tissues consumed by the
public--outweigh any such reliance interests.
V. Conclusion and Order
Although CVM previously determined that carbadox and its
metabolites, including DCBX, induce cancer in animals, in the January
1998 approval of the supplemental NADA for carbadox, CVM determined
that no such residues of the drug would be found in edible tissues
after the preslaughter withdrawal period by the approved method. The
failure to establish an R<INF>m</INF> (which depends on knowing the
relationship between a marker residue and the residue of carcinogenic
concern) during the 1998 process, coupled with analysis of new
information showing that carcinogenic residues persist longer than
previously known, means that the approved method does not meet the
requirements of the FD&C Act and the SOM regulations and is inadequate
to monitor carbadox residues in compliance with FDA's operational
definition of no residue. The new information available since the
approval of the January 1998 supplemental NADA reinforces the
importance of having an approved method that complies with the SOM
regulations.
Nothing submitted to this docket or presented at the public hearing
or submitted to Docket No. FDA-2021-N-1326 demonstrates that the
approved method is adequate to monitor the residue of carcinogenic
concern in compliance with FDA's operational definition of ``no
residue.'' No new information was submitted or presented that
establishes the relationship between QCA and the residue of
carcinogenic concern. Such a relationship must be known in order for
the method to determine that there is no residue of carcinogenic
concern. In addition, no information was submitted or presented that
demonstrates an alternative method is adequate to monitor the residue
of carcinogenic concern in compliance with FDA's regulations.
Therefore, FDA is revoking the approved method.
VI. References
The following references are on display at the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday, and are
available electronically at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. Although FDA
verified the website addresses in this document, please note that
websites are subject to change over time.
1. ``Determination of Carbadox as Quinoxaline-2-Carboxylic Residues
in Swine Liver and Muscle Tissues after Drug Withdrawal.'' Available
at <a href="https://www.fda.gov/media/136267/download">https://www.fda.gov/media/136267/download</a>.
2. FDA, Freedom of Information (FOI) Summary, NADA 041-061, MECADOX
10 (carbadox) Type A medicated article, supplemental approval
January 30, 1998. Available at <a href="https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/308">https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/308</a>.
3. FDA, FOI Summary, NADA 041-061, MECADOX 10 (carbadox) Type A
medicated article, supplemental approval October 5, 1998. Available
at <a href="https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/1673">https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/1673</a>.
4. Su[aacute]rez, A.F. and Arnold, D., Addendum to the carbadox
monograph prepared by the 36th meeting of the Committee and
published in the FAO Food and Nutrition Paper 41/3, Rome 1991,
<a href="http://www.fao.org/fileadmin/user_upload/vetdrug/docs/41-15-carbadox.pdf">http://www.fao.org/fileadmin/user_upload/vetdrug/docs/41-15-carbadox.pdf</a>.
5. Evaluations of the Joint FAO/WHO Expert Committee on Food
Additives (JECFA). Carbadox, <a href="https://apps.who.int/food-additives-contaminants-jecfa-database/chemical.aspx?chemID=2176">https://apps.who.int/food-additives-contaminants-jecfa-database/chemical.aspx?chemID=2176</a>.
6. 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).
7. Report from Codex Alimentarius International Food Standards FAO/
WHO ``Maximum Residue Limits (MRLs) and Risk Management
Recommendations (RMRs) for Residues of Veterinary Drugs in Foods,
CX/MRL 2-2021,'' Carbadox, page 47, <a href="https://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https://workspace.fao.org/sites/codex/Standards/CXM+2/MRL2e.pdf">https://www.fao.org/fao-who-codexalimentarius/sh-proxy/en/?lnk=1&url=https://workspace.fao.org/sites/codex/Standards/CXM+2/MRL2e.pdf</a>.
8. WHO FOOD ADDITIVES SERIES: 51 CARBADOX (addendum),
``Toxicological Evaluation of Certain Veterinary Drug Residues in
Food,'' prepared by the Sixtieth Meeting of the Joint FAO/WHO Expert
Committee on Food Additives (JECFA), WHO, Geneva, 2003, <a href="https://iris.who.int/bitstream/handle/10665/42800/924166051X.pdf?sequence=1">https://iris.who.int/bitstream/handle/10665/42800/924166051X.pdf?sequence=1</a>.
9. Health Canada, Drug and health products, Veterinary drugs, ``List
of Maximum Residue Limits (MRLs) for Veterinary Drugs in Foods,''
<a href="https://www.canada.ca/en/health-canada/services/drugs-health-products/veterinary-drugs/maximum-residue-limits-mrls/list-maximum-residue-limits-mrls-veterinary-drugs-foods.html">https://www.canada.ca/en/health-canada/services/drugs-health-products/veterinary-drugs/maximum-residue-limits-mrls/list-maximum-residue-limits-mrls-veterinary-drugs-foods.html</a> (not listing
carbadox as an approved veterinary drug in food).
10. Australian Pesticides and Veterinary Medicines Authority,
``Substances Not Permitted for Use on Food-Producing Animals in
Australia,'' <a href="https://apvma.gov.au/node/11626">https://apvma.gov.au/node/11626</a>.
[[Page 76770]]
11. Memorandum to File entitled, ``CVM's review of documents Phibro
submitted to Docket No. FDA-2021-N-1326 and presentation at the
March 10, 2022 Part 15 Hearing'' (October 30, 2023).
12. 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).
13. Zhang, J., W. Qu, Z. Wang, and Y. Pan, ``Metabolism and Tissue
Depletion of Carbadox in Swine, Broilers, and Rats,'' ACS
Agricultural Science & Technology 2022 2(3), 477-485. Abstract is
available at <a href="https://pubs.acs.org/doi/abs/10.1021/acsagscitech.1c00260">https://pubs.acs.org/doi/abs/10.1021/acsagscitech.1c00260</a>.
Dated: November 1, 2023.
Kimberlee Trzeciak,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2023-24548 Filed 11-6-23; 8:45 am]
BILLING CODE 4164-01-P
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