81 FR 21559 - Phibro Animal Health Corp.; Carbadox in Medicated Swine Feed; Opportunity for Hearing
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration Federal Register Volume 81, Issue 70 (April 12, 2016)
Food and Drug Administration
Federal Register Volume 81, Issue 70 (April 12, 2016)
| Page Range | 21559-21573 | |
| FR Document | 2016-08327 |
[Federal Register Volume 81, Number 70 (Tuesday, April 12, 2016)] [Notices] [Pages 21559-21573] From the Federal Register Online [www.thefederalregister.org] [FR Doc No: 2016-08327] ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2016-N-0832] Phibro Animal Health Corp.; Carbadox in Medicated Swine Feed; Opportunity for Hearing AGENCY: Food and Drug Administration, HHS. ACTION: Notice of opportunity for hearing. ----------------------------------------------------------------------- SUMMARY: The Food and Drug Administration (FDA), 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. This action is based on CVM's determination that the use of carbadox under the approved conditions of use results in residues of carcinogenic concern in the edible tissues of the treated swine. DATES: Phibro Animal Health Corp. may submit a request for a hearing by May 12, 2016. Submit all data and analysis upon which the request for a hearing relies by July 11, 2016. ADDRESSES: The request for a hearing may be submitted by Phibro Animal Health Corp. by either of the following methods: Electronic SubmissionFederal eRulemaking Portal: http://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 http://www.regulations.gov will be posted to the docket unchanged. Written/Paper Submission Mail/Hand delivery/Courier (for written/paper request for a hearing): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. 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 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- 2016-N-0832 for ``Phibro Animal Health Corp.; Carbadox in Medicated Swine Feed; Opportunity for Hearing.'' The request for a hearing will be placed in the docket and publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday. Phibro Animal Health Corp. may submit all data and analysis 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 analysis. 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 [[Page 21560]] information redacted/blacked out, will be available for public viewing and posted on http://www.regulations.gov or available at the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday. Submit both copies to the Division of Dockets Management. 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 you may submit comments as follows: Electronic Submissions Submit electronic comments in the following way: Federal eRulemaking Portal: http://www.regulations.gov. Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to http://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 http://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): Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. For written/paper comments submitted to the Division of Dockets Management, 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-2016-N-0832 for ``Phibro Animal Health Corp.; Carbadox in Medicated Swine Feed; Opportunity for Hearing.'' Received comments will be placed in the docket and, except for those submitted as ``Confidential Submissions,'' publicly viewable at http://www.regulations.gov or at the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday. 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 http://www.regulations.gov. Submit both copies to the Division of Dockets Management. 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: http://www.fda.gov/regulatoryinformation/dockets/default.htm. Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to http://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 Division of Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: Vernon Toelle, Center for Veterinary Medicine (HFV-230), 7519 Standish Pl., Rockville, MD 20855, 240-276- 9200. 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. (Phibro), 65 Challenger Rd., Ridgefield Park, NJ 07660, 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 to swine. Carbadox is indicated for the control of dysentery and bacterial enteritis, and for growth promotion. A tolerance of 30 parts per billion (ppb) \1\ has been established for residues of quinoxaline-2-carboxylic acid (QCA), the marker residue, in liver of swine (21 CFR 556.100). --------------------------------------------------------------------------- \1\ For consistency and readability throughout this document, concentrations are reported as parts per billion even though original references may report some concentrations as parts per trillion (ppt). --------------------------------------------------------------------------- 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. Currently, the withdrawal period for these uses of carbadox is 42 days (Sec. 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 [[Page 21561]] (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)). 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 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)(ii)). II. Basis for Withdrawal of Approval CVM is providing notice of an opportunity for a hearing (NOOH) on a proposal to withdraw approval of the NADAs providing for use of carbadox in medicated swine feeds. New evidence regarding carcinogenic residues in edible tissues of swine treated with carbadox raises serious questions about the human food safety of the drug. Grounds for withdrawing carbadox are twofold. First, new evidence demonstrates that the Delaney Clause in section 512(d) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 360b), 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.C). Second, new evidence demonstrates that carbadox is not shown to be safe under the General Safety Clause (section 512(e)(1)(B) of the FD&C Act). During the review of a supplemental application to NADA 041-061 approved in January 1998, CVM made the following conclusions about the drug: (1) The parent compound carbadox is rapidly metabolized and carcinogenic residues of the drug are not identifiable in any edible tissues beyond 72 hours post dosing; (2) remaining unextracted residues of carbadox are noncarcinogenic residues related to the noncarcinogenic metabolite QCA; and (3) QCA is a reliable marker residue for carbadox and its metabolites (Ref. 1). Since the evaluation of information submitted by the sponsor in that supplemental application, CVM has become aware of new information that calls into question the basis for its previous conclusions. As described more fully in Section V., this includes new residue depletion data presented to the Joint FAO/WHO Expert Committee on Food Additives (JECFA) \2\ in 2003 that shows that when the marker residue QCA reaches the approved tolerance of 30 ppb in liver, concentrations of the carcinogen desoxycarbadox (DCBX) in the liver would be approximately 4 times higher than the concentration that would be considered safe (Ref. 2 at pp. 16-17). In addition, the new residue depletion data presented to JECFA in 2003 call into question CVM's previously held conclusion that the unextracted residues of carbadox at the withdrawal period are noncarcinogenic compounds related to the QCA metabolite (Ref. 1). The Agency treats the unidentified residues--metabolites of a carcinogenic parent drug with demonstrated carcinogenic metabolites--as carcinogenic. Therefore, the drug is not shown to be safe under the General Safety Clause and the Delaney Clause applies to the drug, because the DES Proviso exception is no longer met. --------------------------------------------------------------------------- \2\ JECFA is an independent committee of international scientific experts administered jointly by the United Nations Food and Agriculture Organization (FAO) and the World Health Organization (WHO) for the purpose of providing independent scientific advice to the FAO, WHO, and member countries. It has been meeting since 1956 specifically to evaluate the safety of food additives, including the animal drug residues in edible tissues. See http://www.codexalimentarius.org/scientific-basis-for-codex/jecfa/en/ and http://www.who.int/foodsafety/areas_work/chemical-risks/jecfa/en/. --------------------------------------------------------------------------- Continued approval of carbadox would expose humans to concentrations of total residues of carcinogenic concern that are approximately 30 times higher (for the approved 42-day withdrawal period) or 11 times higher (for the approved 70-day withdrawal period) than the 0.915 ppb concentration of total residues of carcinogenic concern in liver that would be considered safe (Ref. 3 at p. 17, Table 8). Moreover, the sponsor has not identified an appropriate marker and analytical method to assure that residues of carcinogenic concern are below the level at which the residues present in the total human diet present no significant increase in the risk of cancer to people (the S o ). In addition to the new information presented to JECFA (Ref. 2), publications by Boison, et al., in 2009 (Ref. 4) and Baars, et al., in 1990 (Ref. 5) that were recently provided to CVM by the sponsor call into question the previous conclusion that QCA is an appropriate marker and that all residues of carcinogenic concern deplete within 72 hours after dosing. The new evidence from the 2003 JECFA report (Ref. 2) in conjunction with the publications by Boison, et al., in 2009 (Ref. 4) and Baars, et al., in 1991 (Ref. 6), erode the scientific justification for, and validity of, conclusions previously made about the drug in 1998. Based on this new information, evaluated together with the information available at the time of the approvals, CVM has determined that the drug is not shown to be safe under the General Safety Clause and that the Delaney Clause applies to the drug, because the DES Proviso exception is no longer met. Therefore, CVM proposes to withdraw approval of all NADAs for new animal drugs containing carbadox. III. Legal Context of the Proposed Action and Grounds for Withdrawal A. The Determination of Safety in Section 512 Carbadox, for each of its uses in swine, is a new animal drug as defined in section 201(v) of the FD&C Act (21 U.S.C. 321(v)). As such, under sections 301, 501, 512, 571, and 572 of the FD&C Act (21 U.S.C. 331, 351, 360b, 360ccc, 360ccc-1), the drug cannot be legally introduced or delivered for introduction into interstate commerce in the absence of an NADA approval, a conditional approval, or an animal drug indexing. The requirements for approval of an NADA are set out in section 512(d)(2)(A) of the FD&C Act. Section 512(b)(1)(A) of the FD&C Act requires that a new animal drug must be shown to be safe and effective for its intended uses. Section 201(u) of the FD&C Act provides that ``safe'' as used in section 512 of the FD&C Act ``has reference to the health of man or animal.'' The determination of safety requires CVM to consider, among other relevant factors, ``the probable consumption of such drug and any substance formed in or on food because of the use of such drug . . .'' (section 512(d)(2)(A) of the FD&C Act). Accordingly, CVM must consider not only safety of the new animal drug to the target animal, but also the safety to humans of substances formed in or on food as a result of the use of the new animal drug. [[Page 21562]] ``Safe,'' in the context of human food safety, means a ``reasonable certainty of no harm.'' The definition is derived from language in H. Rep. No. 85-2284, at 4-5 (1958), defining the term ``safe'' as it appears in section 409 of the FD&C Act, which governs food additives (21 U.S.C. 348). Until passage of the Animal Drug Amendments of 1968 (Pub. L. 90-399) (the 1968 amendments), substances formed in or on food due to the use of animal drugs in food-producing animals were regulated under the food additive provisions in section 409 of the FD&C Act. The 1968 amendments consolidated all of the existing statutory authorities related to animal drugs into section 512 of the FD&C Act, and the legislative history shows that the consolidation in no way changed the authorities with respect to the regulation of new animal drugs (S. Rep. No. 90-1308, at 1 (1968)). During the new animal drug application review process, CVM has consistently applied the ``reasonable certainty of no harm'' standard in determining the safety of substances formed in or on food as a result of the use of a new animal drug in a food- producing animal. In order to determine whether a new animal drug meets this standard, section 512(b)(1)(G)-(H) of the FD&C Act requires that whenever a drug may result in residues of the drug or its metabolites in food, an application must include not only full reports of investigations to show that the use of the drug is safe, but also a description of practicable methods for monitoring food to assure that there are no unsafe residues in human food attributable to the drug use, and a demonstration that the conditions of use are adequate to assure there are no unsafe residues. In sum, under section 512(d)(2) of the FD&C Act, the Agency is required, in the evaluation of the supporting safety data, among other things, to consider:The probable consumption of such drug and of any substance formed in or on food because of the use of such drug (i.e., probable human consumption of residues including the parent drug and its metabolites); The cumulative effect on man or animal of such drug, taking into account any chemically or pharmacologically related substance, i.e., toxicological effects of the compounds comprising the residues; and Safety factors which, in the opinion of experts qualified by scientific training and experience to evaluate the safety of such drugs, are appropriate for the use of animal experimentation data (i.e., establishing ``safe'' levels of residues using appropriate safety factors to extrapolate animal data on cumulative effects to humans). When establishing the human food safety of a noncarcinogenic new animal drug used in food-producing animals, CVM establishes a no observed effect level (NOEL) for the residues of that drug in edible tissues--namely, the highest dose of the drug that does not produce the most sensitive treatment-related toxic endpoint in test animals (Ref. 7). From the NOEL, CVM uses safety factors to calculate an acceptable daily intake, and consumption factors to calculate the safe concentration of residues in a particular edible tissue (Ref. 7 at p. 15; section 512(b)(1)(H) of the FD&C Act). Carbadox is both a genotoxic \3\ and mutagenic carcinogen in animals. In the case of a genotoxic carcinogenic drug, establishing the human food safety of the compound via a NOEL is not feasible, therefore human food safety of carcinogenic compounds is ordinarily evaluated by using linear, low-dose extrapolation to evaluate the maximum concentration of total residues of carcinogenic concern that can be present in the total human diet without a significant increase in the risk of cancer to the human consumer (section 512(d)(1)(I) of the FD&C Act; 21 CFR 500.82 and 500.84). In both cases, the safe residue level of the drug is determined through an evaluation of the relevant data relating to the three factors listed above; viz., the probable consumption of the drug residue and its cumulative effect as determined through all relevant safety factors (section 512(d)(2) of the FD&C Act). --------------------------------------------------------------------------- \3\ Genotoxic refers to chemicals that react with DNA or chromosomes to cause damage. When the damage is not repaired and the effect is a heritable change (cell to cell or parent to offspring), it is also termed mutagenic. Thus not all genotoxic chemicals are mutagenic, but all mutagenic chemicals are genotoxic. Uncorrected mutagenesis is thought to be a key step in the development of cancer. ``Mechanisms of Toxicity,'' in Casarett & Doull's Toxicology: The Basic Science of Poisons, edited by Klassen, C.D., 8th Ed., pp. 49-123, 2013. --------------------------------------------------------------------------- B. Grounds for Withdrawal Under the FD&C Act 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 an approved application or not available to the Secretary of Health and Human Services until after such application was approved, or tests by new methods, or tests by methods not deemed reasonably applicable when such application was approved, evaluated together with the evidence available to the Secretary when the application was approved, shows that such drug is not shown to be safe for use under the conditions of use upon the basis of which the application was approved or that subparagraph (I) of paragraph (1) of subsection (d) applies to such drug. The Secretary of Health and Human Services has delegated this authority to the Commissioner of Food and Drugs. See FDA Staff Manual Guide 1410.10 (April 11, 2014). In other words, grounds for withdrawal exist where new evidence shows either that the Delaney Clause applies to the drug (``subparagraph (I) of paragraph (1) of subsection (d)'') or that the drug is not shown to be safe under the approved conditions of use (the General Safety Clause). As explained further, new evidence demonstrates that carbadox meets both grounds for withdrawal. In a proceeding to withdraw the approval of an NADA, the sponsor has the burden of proof to demonstrate that the product is safe and therefore that the NADA approval should remain in effect (21 CFR 12.87(d): (``At a hearing involving issuing, amending, or revoking a regulation or order relating to the safety or effectiveness of a drug . . . the participant who is contending that the product is safe or effective or both and who is . . . contesting withdrawal of approval has the burden of proof in establishing safety or effectiveness or both and thus the right to approval.''); (see also Rhone-Poulenc, Inc. v. FDA, 636 F.2d 750, 752 (D.C. Cir. 1980); Hess & Clark v. FDA, 495 F.2d 975, 992 (D.C. Cir. 1974)). Nevertheless, CVM bears an initial burden of showing that new evidence regarding the new animal drug raises serious questions about the safety of the new animal drug. See Rhone- Poulenc, 636 F.2d at 752. Once CVM has satisfied the initial burden, the burden shifts to the sponsor to establish the safety of the drug: In the Hess & Clark case we held that the ``new evidence'' requirement of the safety clause ``plainly places on the [CVM] an initial burden to adduce the `new evidence' and what that evidence `shows'. Only when the [CVM] has met this initial burden of coming forward with the new evidence is there a burden on the manufacturer to show that the drug is safe.'' Rhone-Poulenc, 636 F.2d at 752 (quoting Hess & Clark, 495 F.2d at 992). To meet its initial burden of proof to withdraw approval of a new animal drug that is ``not shown to be safe,'' CVM must provide ``a reasonable basis from which serious questions about the ultimate safety of [the drug] and the residues that may result from its use may be inferred.'' See Diethylstilbestrol: Withdrawal of Approval of New Animal Drug Applications; Commissioner's Decision (44 FR 54852 at 54861, [[Page 21563]] September 21, 1979) (hereinafter DES Commissioner Decision) (quoting Proposal to Withdraw Approval of New Animal Drug Applications for Diethylstilbestrol, ALJ Initial Decision, Docket No. FDA-1976-N-0028 (formerly 76N-0002), I.D. at 8 (September 21, 1978)), aff'd Rhone- Poulenc, 636 F.2d 750; see also Nitrofurans Commissioner Decision (56 FR 41902 at 41902, August 23, 1991). Serious questions can be raised where the evidence is not conclusive but merely suggestive of an adverse effect. See DES Commissioner Decision. C. Withdrawal Under the Delaney Clause and the DES Proviso Section 512(e)(1)(B) of the FD&C Act provides grounds for withdrawal of approval of an NADA if new evidence, 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 may 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)-(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 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 to detect no residues of the carcinogenic drug 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, CVM 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 should be regulated as a carcinogen (Sec. 500.84(a)). For the drug and each metabolite determined to be carcinogenic, CVM 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 (Sec. 500.84(c)(1)). CVM designates the lowest value thus calculated as the S o (Sec. 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 (Sec. 500.82(b). Residue of carcinogenic concern includes all compounds in the total residue of a demonstrated carcinogen excluding any compound judged by CVM not to present a carcinogenic risk (Sec. 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 (Sec. 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. CVM 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 (Sec. Sec. 500.82(b) and 500.84(c)(1)). Based upon residue depletion data submitted by a sponsor, CVM 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 (Sec. 500.86(a)-(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 , such that the absence of the marker residue in the target tissue above Rm can be taken as confirmation that the residue of carcinogenic concern does not exceed Sm in each of the edible tissues (Sec. Sec. 500.82(b) and 500.86(c)). When the marker residue is at or below the Rm , the residue of carcinogenic concern in the diet of people does not exceed So (Sec. 500.86(c)). A sponsor must submit a regulatory method that is able to detect the marker residue at or below the Rm ((Sec. Sec. 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 cannot be 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 (Sec. 500.84(c)(3)). As stated above, pursuant to section 512(e)(1)(B) of the FD&C Act, the Secretary shall, after due notice and an opportunity for a hearing, withdraw approval of an NADA if the Secretary finds that new evidence, 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 applies to the drug. Evidence that the Delaney Clause applies to a drug exists where the drug has previously been determined to be a carcinogen and the new evidence shows CVM's prior establishment of an analytical method and residue tolerance under the DES proviso exception to the Delaney Clause is inadequate. An analytical method is inadequate where new evidence demonstrates that the method does not accurately detect the marker residue or where new evidence demonstrates that not all residues of carcinogenic concern have depleted at the approved tolerance level of the marker residue (see, e.g., Rhone- Poulenc, 636 F.2d at 752-53.) In establishing that grounds for withdrawal of approval exist under this clause, CVM carries an initial burden to demonstrate that the new animal drug and/or any of its metabolites induces cancer when ingested by man or animals. Proposal to Withdraw New Animal Drug Applications for Furazolidone (NF-180) and Nitrofurazone (NF-7), ALJ Decision, FDA Docket No. FDA-1976-N-0511, at 73 (formerly 76N-0172; November 12, [[Page 21564]] 1986) (hereinafter ALJ Decision, November 12, 1986). Once CVM has satisfied its initial burden, the sponsor bears the burden of showing that the drug satisfies the DES Proviso exception to the Delaney Clause and FDA's implementing regulations. ALJ Decision, November 12, 1986, at 73. (``Since furazolidone is also being challenged under the Delaney Clause, an additional issue . . . is whether new evidence put forth by the Center shows that furazolidone and/or its metabolites induces cancer when ingested by man or animal. If this burden is met, the sponsors must show [that the drug satisfies the DES proviso and FDA's implementing regulations]''); see also 21 CFR 500.92(b) (providing that for those compounds that FDA determines have been shown to induce cancer when ingested by man or animals, Sec. Sec. 500.82 through 500.90 apply). In this case, CVM had previously determined, in the approval and supplemental approvals of new animal drugs containing carbadox, that carbadox and its metabolites, including DCBX, induce cancer in animals, but that the drug could be approved under the DES Proviso exception to the Delaney Clause. See Section IV. However, new evidence raises questions about whether the drug is properly approved under the DES Proviso to the Delaney Clause and FDA's implementing regulations. See Criteria and Procedures for Evaluating Assays for Carcinogenic Residues (44 FR 17070 at 17104, March 20, 1979) (reproposal of rules revoked in accordance with court order). (``[The FD&C Act] defines the new evidence that the Commissioner can consider in determining whether a previously approved compound is safe. [Proper analytical methods establishing residue levels] are necessary to show that a sponsored compound is safe under the FD&C Act. For that reason, the absence of data satisfying the [criteria in 512(e)(1)(B) of the FD&C Act], in conjunction with the evidence already available about a compound, clearly can support the withdrawal of approval of an application.''). In particular, new evidence indicating that an approved regulatory method can no longer be relied upon is sufficient to satisfy the Agency's burden to support withdrawal of approval under section 512(e)(1)(B) of the FD&C Act and the Delaney Clause: In the case of an approved NADA for a carcinogenic compound, if FDA determines based on new information that the approved analytical method for detecting residues is inadequate . . . FDA could withdraw the approval on the basis of the Delaney Clause. Faced with evidence that an approved method was inadequate, FDA could not make a finding that ``no residue'' of the sponsored compound would be found in the edible products of treated animals. The DES Proviso cannot begin to operate without that finding, and, accordingly, the Delaney Clause would preclude continued approval. See Sponsored Compounds in Food Producing Animals; Criteria and Procedures for Evaluating Safety of Carcinogenic Residues; Proposed Rule (50 FR 45530 at 45550, October 31, 1985); \4\ see DES Commissioners' Decision (44 FR 54852 at 54859, September 21, 1979). --------------------------------------------------------------------------- \4\ Under FDA's regulations implementing the Delaney Clause for animal drugs, part 500, subpart E, a carcinogenic drug may not be approved if the regulatory method to test for the compound is not sufficiently sensitive. Sec. Sec. 500.84(c)(2) and 500.88(b). A carcinogenic drug will be withdrawn if new evidence shows that an approved regulatory method is not sufficiently sensitive. In this case, new evidence raises serious questions both about the acceptability of the current method in determining levels of known carcinogenic residues of carbadox, and, further, demonstrates that previously unidentified carcinogenic metabolites exist that are entirely unaccounted for in current approved testing methodology. Because the current analytic method is inadequate to identify the level of known carcinogens and does not identify the residue level of unidentified metabolites of carcinogenic concern, the current method and tolerance are inadequate to satisfy the DES Proviso. D. Withdrawal Under the General Safety Clause The General Safety Clause in section 512(e) of the FD&C Act provides grounds for withdrawal of approval of an NADA if new evidence, 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 drug is ``not shown to be safe for use under the conditions of use upon the basis of which the application was approved'' (section 512(e)(1)(B) of the FD&C Act). CVM has the initial burden to present new evidence that raises serious questions about the safety of the drug. Only upon that showing is there a burden on the manufacturer to demonstrate that the drug is safe. See Rhone-Poulenc, 636 F.2d at 752-53; Hess & Clark, 495 F.2d 975, 992 (D.C. Cir. 1974). When evaluating a drug for withdrawal under the General Safety Clause, for CVM to satisfy its initial burden that new evidence raises serious human food safety questions, it must demonstrate a relationship between the drug residues found in edible tissues and risk to human health. [Without using] the Delaney Clause, it is not enough for the Commissioner merely to show that animal carcasses contain residues and that [the drug] is a carcinogen. Instead, the FDA must show that two different issues are resolved in its favor before it can shift to petitioners the burden of showing safety: (1) whether the detected residues are related to the use of [the drug]; (2) if so, whether the residues, because of their composition, and in the amounts present in the tissue, present some potential hazard to the public health. See Hess & Clark, 495 F.2d at 992 (D.C. Cir. 1974). Applying this test, the D.C. Circuit Court of Appeals has held that new evidence of drug residues in edible tissues in conjunction with evidence that any drug residues of the drug in question present safety concerns is sufficient to satisfy CVM's burden of raising serious questions regarding the safety of the drug. See Rhone-Poulenc, 636 F.2d at 752-53. CVM, acknowledging the Hess & Clark standard and its subsequent application, has withdrawn approval of a new animal drug under the General Safety Clause where new evidence showed that: (1) The new animal drug was carcinogenic; (2) some drug metabolites were mutagenic; and (3) residues left in edible tissues at the withdrawal time were unidentified. See Nitrofurans Commissioners' Decision, 56 FR 41902 at 41910, August 23, 1991 (``Since the nature of these residues and their toxicity were not evaluated, they cannot be regarded as safe . . . Contrary to the sponsors' assertions, the evidence fails to demonstrate that furazolidone's metabolites pose no health risk to the human consumers. Given all the other evidence in the record demonstrating that furazolidone is a carcinogen and that its metabolites are mutagens, I find that, contrary to the sponsors' assertions, the metabolites of furazolidone pose a potential health risk to human consumers.'') see also DES Commissioners' Decision, 44 FR 54852 at 54868 (explaining that, ``[w]here new evidence shows that use of the drug results in residues of unidentified substances,'' CVM must decide whether, despite this lack of knowledge, ``the drug may be considered to be 'shown to be safe[,]' '' as the General Safety Clause requires). In other words, because residues of a mutagenic carcinogen are presumptively carcinogenic, and therefore presumptively unsafe, where new evidence demonstrates that unidentified residues of a mutagenic carcinogen remain at the time of withdrawal, the drug meets the standard set forth in Hess & Clark. [[Page 21565]] Applying the Hess & Clark standard here, the new evidence regarding carbadox clearly meets both prongs of that test. New evidence demonstrates that previously unidentified mutagenic residues of carbadox, a known carcinogen, remain present well after the established withdrawal period. As discussed further in Section V.D., because carbadox is a mutagenic carcinogen and QCA is the only known quantified noncarcinogenic residue of carbadox, all other residues are of carcinogenic concern. The new evidence demonstrates that the total residues of carcinogenic concern at the established 42-day withdrawal period are much higher than previously thought because the residues are no longer shown to be residues related to a noncarcinogenic compound, QCA, as previously believed. See, infra, Section V.D. Thus, the new evidence demonstrates that: (1) The unidentified residues are related to the use of carbadox and (2) the residues pose a potential hazard to public health because of the amount present and because they are residues of carcinogenic concern. IV. Regulation of Residues of Carbadox A. 1972 and 1975 Approvals Carbadox is a carcinogen and was approved as a new animal drug pursuant to the DES Proviso exception to the Delaney Clause. At the time of the initial approval of carbadox in 1972, CVM (then the Bureau of Veterinary Medicine) recognized that carbadox is a carcinogen and therefore required that no residues of carbadox or its metabolite QCA be found in uncooked edible tissues of swine at the time of slaughter, as determined by the approved method of analysis. See 37 FR 20683, October 3, 1972, as amended by 37 FR 23906, November 10, 1972. This approval occurred prior to FDA's 1987 initial issue of regulations implementing the DES Proviso and therefore did not involve the development of a regulatory method sensitive enough to detect a marker residue that corresponded to a lifetime risk of cancer to test animals of 1 in 1 million (as described in Section III.C). In this initial approval, based upon the submission of studies showing the depletion of carbadox residues in edible tissues, CVM determined that ``[a]ll tissues except the liver [were] free of all residues'' of unchanged carbadox at 24 hours after withdrawal of treatment and that unchanged carbadox ``ha[d] disappeared from the liver after 24 hours'' (Ref. 8). CVM also determined from submitted studies that the carcinogenic parent drug was undetectable in liver at 24 hours (Id.). CVM further determined that a ``restriction of use in the labeling provides a withdrawal period long enough [70 days] to assure no hazard to humans consuming residues in meat. In proper use there would be virtually no residues'' of carbadox in tissues at slaughter (Ref. 9). The conclusions CVM made in 1972 regarding the rapid depletion of carcinogenic residues were later independently corroborated by a 1990 evaluation of carbadox by JECFA (Ref. 10 at p. 30). Labeled use restrictions, as the drug was approved in 1972, included an upper weight limit of 75 pounds body weight and a prohibition on mixing into complete feeds containing less than 15 percent crude protein, thus limiting the drug's use to young pigs. These use restrictions provided assurances that the 70-day withdrawal period would likely be followed in practice (Ref. 11). Similarly in 1975, FDA approved NADA 092-955 for the use of carbadox with pyrantel tartrate in Type C medicated swine feed (40 FR 45164, October 1, 1975). At that time, CVM reviewed drug residue studies of carbadox and pyrantel tartrate used in combination. The studies showed that, at 45 and 60 days withdrawal, concentrations of residues of carbadox in all tissues tested were undetectable using the previously approved analytical method with a 30 ppb limit of detection (Ref. 12 at p. 2). B. 1986 Citizen Petition On May 9, 1986, the Center for Science in the Public Interest submitted a citizen petition requesting that FDA withdraw approval of new animal drug applications for ipronidazole, dimetridazole, and carbadox (Ref. 13). The petition asserted that FDA must withdraw the approval of carbadox because carbadox and its metabolites DCBX and hydrazine were found to be carcinogenic, and the approved test method for carbadox residues is ``unsuitable'' (Ref. 13 at p. 20). The asserted unsuitability of the approved test method was based upon the fact that only a small portion of total residues had been positively identified and that the analytical method for carbadox residues was not sensitive enough to ensure that all residues had depleted. FDA responded to the 1986 citizen petition in 1995 after a review of new residue depletion data submitted by (the then sponsor) Pfizer as well as data previously submitted to the Agency as part of the carbadox NADAs. Based upon this review, FDA denied the petition as it related to carbadox because it determined that ``if used according to label directions, residues of carbadox remaining in edible tissues of swine do not pose a human food safety risk to consumers'' (Ref. 14 at p. 2). FDA based this safety determination on the following findings: 1. At 70 days withdrawal, the drug-related residue in swine liver measured 13 ppb. 2. Ten percent of the drug-related residue was extractable and identified to be a noncarcinogenic metabolite, quinoxaline-2-carboxylic acid. 3. The remaining 90% of the drug- related residue was unextractable or bound residues. 4. The bound residues were related to quinoxaline-2-carbodoxaldehyde and quinoxaline-2-carboxylic acid, both of which are of no carcinogenic concern. (Ref. 14 at p. 1). C. Approval of 1998 Supplemental NADAs In 1998, FDA approved two supplemental applications to NADA 041- 061. The first supplement, approved in January 1998, assigned the noncarcinogenic metabolite QCA as the marker residue and set a tolerance of 30 ppb QCA in swine liver (Ref. 1). Toxicology studies, including carcinogenicity bioassays with carbadox, DCBX (a primary metabolite of carbadox), and hydrazine were submitted as part of that supplemental application (Ref. 1 at pp. 1-5). The studies demonstrated the carcinogenicity of carbadox, DCBX, and hydrazine, and indicated that DCBX was the most potent of the three carcinogenic compounds (id.). Consequently, based on DCBX, CVM calculated an So of 0.061 ppb for total residues of carcinogenic concern for carbadox in the total diet (Ref. 1 at p. 5). CVM calculated an Sm value for total residues of carcinogenic concern in muscle at 0.305 ppb, in liver at 0.915 ppb, and in kidney and fat at 1.830 ppb (Ref. 1 at pp. 8-9). The SOM regulations, as they existed in 1998, directed CVM to establish an Rm for carcinogenic compounds used in food- producing animals. CVM did not establish an Rm because CVM concluded the parent carbadox was rapidly metabolized, carcinogenic residues were not detectable beyond 72 hours post dosing, and unextracted residues \5\ were [[Page 21566]] related to noncarcinogenic QCA and not of carcinogenic concern. Because the noncarcinogen QCA was the only detectable metabolite persisting beyond 72 hours post dosing, CVM assigned it as the marker residue (id.). --------------------------------------------------------------------------- \5\ Unextracted residues are residues of the drug that are not released when tissues are exposed to mild aqueous or organic extraction conditions. Guidance on analysis of unextracted total radiolabeled residue is provided in ``Guidance for Industry: General Principles for Evaluating the Safety of Compounds Used in Food- Producing Animals (GFI #3),'' 2006. Unextracted or bound residues can be either: (1) Endogenous components resulting from fragments of the radiolabeled compound being incorporated into naturally occurring molecules such as amino or nucleic acids or (2) covalently bound residues. Covalently bound residues are considered to be of toxicological concern and their availability for absorption into the human gastrointestinal tract is considered during an evaluation of human food safety. Residues incorporated into endogenous molecules are not considered bioavailable or to be of toxicological concern. However, CVM has determined that establishing a potentially carcinogenic compound is bound and not of carcinogenic concern can be complicated by the possibility of gastrointestinal binding and gastrointestinal carcinogenesis and consequently can involve a more comprehensive assessment of the bound compounds as described in GFI #3. Note that while CVM has recognized that carbadox residues have not been fully extracted and characterized, CVM has not made an assessment that the compounds are not carcinogenic because they are bound to endogenous molecules (Ref. 15 at pp. 3-4). Moreover, residue studies presented to JECFA in 2003 suggest that carcinogenic residues that had not been extracted when exposed to organic extraction were released by simulated digestive enzymes (Ref. 2 at pp. 7-8, Table 5). --------------------------------------------------------------------------- At the time it approved the supplement in January 1998, CVM said: The sponsor and academic researchers have conducted numerous studies evaluating the fate of carbadox in animals. These residue depletion data are summarized in FAO Food and Nutrition Paper 41/3 (Food and Agriculture Organization (FAO) of the United Nations, 1991) and show 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 non-carcinogenic compounds, quinoxaline-2-carboxylic acid [QCA] and quinoxaline-2-carboxaldehyde; and that quinoxaline-2-carboxylic acid [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. (Ref. 1 at p. 9). CVM established a tolerance of 30 ppb for residues of QCA in liver, the tissue in which residues persist for the longest time. CVM concluded that the concentration of residues of carcinogenic concern in edible tissues was below the Sm when the concentration of QCA in liver had depleted to 30 ppb.\6\ --------------------------------------------------------------------------- \6\ The SOM regulations, as they existed in 1998, permitted approval of a regulatory method that could detect the marker residue of the drug, as long as the marker residue would only be detected at or below the Rm under the proposed conditions of use. See Sec. 500.86(c) (1998). Under FDA's operational definition of ``no residue,'' a residue of carcinogenic concern, so long as it does not exceed the So , may be detectable by an approved method. The residue data show that carbadox, desoxycarbadox and hydrazine do not persist in edible tissue as detectable residues beyond 72 hours. The in vivo metabolism of the compounds of carcinogenic concern is irreversible. Therefore, in this case, no residue of carcinogenic concern, even below the So, is detectable by any method. The unextracted residues are related to a noncarcinogenic compound, quinoxaline-2-carboxylic acid (QCA), and extractable QCA is the only residue detectable in the edible tissues 72 hours postdosing. Thus, the agency concludes that QCA is a reliable marker residue for carbadox and its metabolites. From these data, FDA has selected liver as the target tissue and quinoxaline-2-carboxylic acid (QCA) as the marker residue. FDA has determined that when QCA, the marker, is at or below 30 ppb in the target tissue, liver, that no residue of carcinogenic concern, above the So , is detectable in each of the edible tissues by any method. The sponsor has submitted a regulatory method capable of measuring QCA at and below 30 ppb in the target tissue. (Ref. 1 at p. 14). As part of their application supporting the January 1998 supplemental approval, the sponsor submitted a regulatory method for residues of QCA in swine liver. The regulatory method relies on a gas chromatograph assay with electron capture detection and has a limit of quantification of 5 ppb (Ref. 1 at p. 13), a 6-fold improvement of the sensitivity from the previously approved regulatory method (Ref 1.) In October 1998, FDA approved an additional supplement to NADA 041- 061 changing the withdrawal period for carbadox medicated feeds from 70 days to 42 days. The supplement was approved based upon the previous approval of a tolerance of 30 ppb for QCA and a residue depletion study that showed that residues of QCA in liver depleted below 30 ppb by 42 days (Ref. 16). To summarize, in 1998, when FDA approved supplements to NADA 041- 061 establishing a drug tolerance and shortening the withdrawal period, the evidence before CVM indicated:A 0.915 ppb concentration of total residues of carcinogenic concern in liver is the concentration that represents no significant increase in the risk of cancer to people--total residues of carcinogenic concern in liver above 0.915 ppb under the drug's approved conditions of use are unsafe. Such residues would preclude continued approval because the drug would not be shown to be safe and because the exception to the Delaney Clause would not apply (Ref. 1 at pp. 8-9, 10, 14). The parent compound carbadox is rapidly metabolized and carcinogenic residues of the drug are not identifiable in any edible tissues beyond 72 hours post dosing (Ref. 1 at p. 9). Remaining unextracted residues of carbadox are noncarcinogenic residues related to the noncarcinogenic metabolite QCA (Ref. 1 at pp. 9, 14). QCA is a reliable marker residue for carbadox and its metabolites; that is, measuring QCA residues in swine liver is a valid method for demonstrating the absence of residues of carcinogenic concern in edible tissues (id.). Based upon these conclusions, CVM found that under the conditions of use the drug did not result in unsafe residues of carcinogenic concern in edible tissues and that the use of carbadox, as approved in the NADA supplements, satisfied the DES Proviso exception to the Delaney Clause prohibition on carcinogenic animal drugs (id.). D. Approval of the 2004 Feed Use Combination In 2004, FDA approved a combination drug medicated feed containing carbadox and oxytetracycline under NADA 141-211 (Ref. 17). In accordance with section 512(d)(4)(A) of the FD&C Act, approval of a combination new animal drug, where the underlying new animal drugs have previously been separately approved for particular uses and conditions of use for which they are intended for use in the combination, will not be refused on human food safety grounds unless the application fails to establish that: (1) None of the animal drugs used in combination, at the longest withdrawal period for any of the drugs in the combination, exceeds its established tolerance or (2) none of the drugs in the combination interferes with the method of analysis for any of the other drugs in the combination (section 512(d)(4)(A)(i)-(ii) of the FD&C Act). In other words, in order to approve a combination new animal drug for a drug product that contains two previously approved new animal drugs, no new information needs to be supplied to establish the safety of either drug. Instead, the application need only demonstrate that use of the drugs in combination will not result in violative [[Page 21567]] residues of any component drug or in drug assay interference. Both carbadox and oxytetracycline had been previously and separately approved by FDA for the same conditions of use proposed for their use in combination. See 21 CFR 558.450 (Oxytetracycline); Sec. 558.115 (Carbadox). The sponsor, Phibro, provided tissue residue depletion data demonstrating that QCA residues did not exceed the tolerance of 30 ppb when carbadox was administered in conjunction with oxytetracycline to swine (Ref. 17). A pharmacokinetic study comparing blood levels of oxytetracycline when administered alone and when administered in conjunction with carbadox satisfied the need to demonstrate that residues of oxytetracycline would not exceed the oxytetracycline tolerance at 42 days (id.). The sponsor further provided data demonstrating noninterference of oxytetracycline with the method of analysis of QCA in liver (id.). Having made the required human food safety demonstrations for combination animal drugs, there was no basis to refuse approval of the product on human food safety grounds. The combination new animal drug was subsequently approved (id.). V. New Information Regarding Carcinogenic Residues in Edible Tissues Three sources provide new information regarding carcinogenic residues in edible tissues: Data submitted to the 2003 JECFA and the subsequent JECFA report (Ref. 2) and two publications in the peer- reviewed literature (Refs. 4 and 6). JECFA is an internationally recognized expert body, providing the scientific evaluations that become the basis for international food standards established by the Codex Alimentarius Commission and supporting international treaties such as the Sanitary Phytosanitary Agreement. JECFA experts are chosen based on expertise, reputation, assurance of lack of conflict of interest, and familiarity with the subject of that particular evaluation. In addition, pursuant to section 512(l)(1) of the FD&C Act,\7\ FDA ordered Phibro to provide it with the same data provided to the 2003 JECFA. CVM evaluated the submitted data and found that it raised questions regarding the safety of food resulting from swine treated with carbadox. Confidence in the information evaluated by the 2003 JECFA that is the basis for CVM's concern about carbadox was increased by the independent findings reported in the two publications discussed further. --------------------------------------------------------------------------- \7\ An order issued pursuant to section 512(l) of the FD&C Act, requires a sponsor to submit such data and information as FDA may find necessary to determine or facilitate a determination whether grounds to withdraw approval of an NADA under section 512(e) of the FD&C Act exist. --------------------------------------------------------------------------- A. New Information Provided to JECFA In 2003, at the request of the Codex Committee on Residues of Veterinary Drugs in Foods (CCRVDF), JECFA reevaluated the recommended Maximum Residue Limits (MRLs) for carbadox that were based upon a 1990 JECFA evaluation of the new animal drug (Ref. 2). CCRVDF, which includes CVM as a participant, determines priorities for the consideration of residues of veterinary drugs in foods and recommends MRLs for veterinary drugs to the Codex Alimentarius Commission of the Food and Agriculture Organization and the World Health Organization of the United Nations. The Codex Alimentarius Commission develops harmonized international food standards, guidelines, and codes of practice to protect the health of the consumers and ensure fair practices in food trade (see footnote 2). Based on studies submitted to JECFA that showed the persistence of genotoxic, carcinogenic residues, JECFA could not determine an amount of residues of carbadox in human food that would have no adverse health effects in consumers. JECFA recommended that the Codex MRLs be withdrawn. CCRVDF concurred with JECFA's recommendation and proposed to the Commission that the MRLs be withdrawn. The Commission subsequently agreed and withdrew the Codex MRLs for carbadox (Ref. 18 at p. 120). As part of the JECFA reevaluation process, Phibro presented two new residue studies to JECFA in 2003. Only one of these studies involved measurement of the depletion of carcinogenic metabolites of carbadox in edible tissues. In that study, animals were fed for 14 days at the approved dose of 55 ppm carbadox in feed (Ref. 2 at pp. 6-10). Animals were euthanized at various time points between 0 hours and 15 days post treatment, and samples of swine muscle, liver, skin, and fat were collected (Ref. 2 at pp. 7-8, Table 5). Prior to analysis for residues, some of the tissue samples were exposed to human digestive enzymes \8\ (Ref. 2 at p. 7). This in vitro model of bioavailability was designed to mimic effects of gastric fluid and intestinal fluid incubation in human stomach and small intestine to evaluate whether residues potentially could be released in the human gastrointestinal tract. To allow comparison, some tissue samples were left untreated while other tissue samples were incubated in simulated gastric fluid (with pepsin) or in simulated intestinal fluid (with pancreatin). Residues of carbadox, DCBX, and QCA were measured in the untreated tissues, in tissues that were incubated with enzymes, and in the supernatant of those tissues that were incubated with enzymes (id.). --------------------------------------------------------------------------- \8\ The use of enzymic preparations to characterize residues is described in section 2.3.4.3.2 of CVM Guidance for Industry (GFI) #205 VICH GL 46, ``Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Animals: Metabolism Study to Determine the Quantity and Identify the Nature of Residues (MRK),'' Sept. 15, 2011 (Ref. 19). --------------------------------------------------------------------------- Residues of carbadox, DCBX, and QCA were measured by liquid chromatography-atmospheric pressure chemical ionization tandem mass spectrometry (LC/APCI-MS/MS). The tissue samples that were not incubated with enzymes were extracted with acetonitrile prior to analysis. The tissue samples that were incubated with enzymes were extracted with ethyl acetate prior to analysis. Supernatants of the enzyme digestion were analyzed directly without extraction. The limits of quantification for LC/APCI-MS/MS were 0.050 ppb for carbadox residues and 0.030 ppb for DCBX residues (id.). The detection capabilities of this methodology were greatly enhanced compared to the previous method for carbadox and DCBX (i.e., the method used for the previous analytical work had a detection limit of 2 ppb) (Ref. 20). The study presented to JECFA showed that residue concentrations of carbadox and DCBX were higher and persisted for a longer period post dosing in liver than in the other sampled tissues. In liver without treatment with simulated digestive fluids, carbadox was detectable (0.050 ppb) as long as 48 hours post dosing and DCBX was detectable (0.138 ppb) at the last sampling time point, which was 15 days post treatment (Ref. 2 at pp. 7-8, Table 5). Treatment of tissues with simulated digestive fluids resulted in measurement of significantly higher concentrations of DCBX. ``Pretreatment of the samples with digestive fluids increased the amounts of carcinogenic residues found in all tissues. In liver the concentration of . . .[DCBX] increased by more than fourfold when the samples were treated with intestinal fluid, and large quantities were present 15 days after withdrawal . . .'' (Ref. 2 at p. 17). [[Page 21568]] In particular, the study showed that concentrations of approximately 35 ppb of DCBX at 0 hours post dosing and approximately 2.7 ppb of DCBX at 15 days post dosing were measured in liver treated with pancreatin (Ref. 2 at p. 8, Table 5). The significantly increased residues found in liver after treatment with intestinal enzymes show that enzymatic treatment was able to release carcinogenic residues that were not extractable by organic solvents, such as those used in tissue residue studies to support the original and supplemental approval of NADAs for use of carbadox. JECFA evaluated the percent recoveries of the analytes. Percent recovery is a measurement of accuracy of the analytical procedure and expresses the closeness of agreement between the true value of the analyte concentration and the mean value obtained by applying the analytical procedure (Ref. 21). JECFA reported that when carbadox, DCBX, and QCA were incubated for 4 hours with digestive enzymes, carbadox and DCBX were unstable (percent recovery decreased) in the samples treated with pepsin, but were stable in pancreatin (Ref. 2 at p. 16). JECFA also reported that the recoveries of the analytes from the liver samples were generally variable and decreased to low levels when digestive enzymes were used prior to extraction (Ref. 2 at pp. 17- 18). After evaluating the residue study, JECFA concluded that the poor recoveries obtained with the enzyme experiments ``showed that the true concentrations of the carcinogenic metabolites in tissues cannot yet be estimated with certainty, since an unknown portion of the releasable residue [of carbadox and DCBX] is destroyed during incubation [of liver tissues] with the [digestive] enzymes'' (Ref. 2 at p. 18). JECFA therefore concluded that the measured values of DCBX and carbadox ``represent[ed] a lower estimate of the total present in the tissue'' (id.). Presented with data demonstrating both the depletion of QCA and depletion of the carcinogenic residue DCBX, JECFA established a relationship between the concentrations of QCA and DCBX in liver (Ref. 2 at p. 14). The statistical analysis of the data showed a linear relationship between the logarithms of the concentrations of QCA and DCBX (Ref. 2 at pp. 14, 18). This relationship allowed JECFA to use regression analysis to assess the concentrations of DCBX when QCA depleted to 30 ppb in liver (the Codex MRL and FDA approved tolerance for carbadox). JECFA determined that ``[a]t the MRL [of 30 ppb] for QCA in liver, the average concentrations of the carcinogenic residue desoxy-carbadox in liver estimated by regression analysis were about 4 [ppb]'' (Ref. 2 at pp. 14, 16-17). JECFA recognized that ``tolerance limits for the concentration of desoxycarbadox were several times higher owing to the wide variation of the data'' and thereby concluded that ``QCA is not a suitable marker for monitoring carcinogenic metabolites of carbadox in liver . . . and QCA does not ensure the absence of carcinogenic residues'' (Ref. 2 at p. 17). In contrast to the previous findings of JECFA, these new data show that carcinogenic residues, in particular DCBX, are present in edible tissues for a significant time during the depletion of parent carbadox (Ref. 2 at p. 18). Moreover, the study shows that treatment with simulated digestive enzymes releases higher levels of the carcinogenic residues DCBX than were recovered using organic extractions in the study. These higher concentrations provide evidence that the carbadox residues that were not extractable or identified in previous studies submitted to the Agency could include carcinogenic residues of carbadox that are releasable with enzymatic treatment of tissues. This evidence calls into question the Agency's previous conclusions that all unextracted and unidentified residues were noncarcinogenic residues related to QCA. After reviewing the new residue data, and considering the previously evaluated genotoxicity and carcinogenicity data, JECFA recommended withdrawal of the previously established Codex MRLs (Ref. 2 at p. 18). Codex subsequently agreed and withdrew the MRLs for carbadox (Ref. 18 at p. 120). In summary, the studies considered by JECFA during its 2003 review of the drug indicated that: Residues of the carcinogenic metabolite of carbadox, DCBX, were measured in edible tissues for 15 days, which was the last sampling time point. DCBX was measured in swine liver after treatment with simulated digestive enzymes at concentrations as high as 2.69 ppb at 15 days post treatment (Ref. 2 at p. 8, Table 5). Analysis of measured concentrations of QCA and DCBX in liver indicated that approximately 4 ppb of DCBX would be present in the liver of treated animals when QCA reached the Codex MRL and the FDA tolerance of 30 ppb in liver (Ref. 2 at pp. 14, 17). This concentration of DCBX alone is more than 4 times higher than the concentration of total residues of carcinogenic concern in liver that would present no significant increase in the risk of cancer to people. Residues of carbadox previously unextracted from edible tissues could be released by gastric and intestinal fluids that mimic the human digestive process (Ref. 2 at p. 16). The enzymatic treatment used in the study significantly increased the recoveries of concentrations of DCBX and carbadox from edible tissues, thereby indicating that some portion of the previously unextracted and unidentified total residues is composed of carcinogenic compounds. B. Additional New Evidence Following the reports of the 2003 JECFA reevaluation of carbadox, CVM requested that Phibro also provide the carcinogenic residue depletion study to CVM. In 2005, in response to CVM's request for information, Phibro submitted a summary of the carcinogenic residue depletion study previously provided to JECFA. Upon review of the summary data, CVM asked Phibro to submit existing studies or provide new and complete studies that address the relationship of QCA at 30 ppb and carbadox and DCBX residues, and about the use of QCA as the marker residue for surveillance purposes. In 2006, CVM asked for and received from Phibro a timeline for submission of complete information that addresses concerns about the relationship of QCA at 30 ppb and carbadox and DCBX residues, and about the use of QCA as the marker residue for surveillance purposes. Between 2006 and 2011, interactions between CVM and Phibro continued, with protocols submitted and reviewed, method validation reports submitted and reviewed, informal communications by email, and informal discussions by telephone. The focus of the interactions was development and validation of methods to measure QCA and DCBX in a tissue residue depletion study. Despite the continued interaction between Phibro and CVM, Phibro has not submitted the requested information. In 2011, pursuant to section 512(l)(1) of the FD&C Act, FDA ordered Phibro to provide all information in its possession with respect to: (1) The persistence of DCBX in edible tissues; (2) the appropriateness of QCA as an analyte for residue monitoring and for establishing a withdrawal time for the use of carbadox in pigs; and (3) whether an analytical method for monitoring carbadox-related carcinogenic residues in edible tissues can be developed that would comply with part 500, subpart E. [[Page 21569]] In response to the 2011 FDA order, Phibro provided CVM with the full study report and appendices, previously provided to JECFA in 2003. CVM has independently evaluated the data from the Phibro study of depletion of carcinogenic residues reviewed by JECFA in 2003, and in particular has reviewed the JECFA conclusion that when QCA reaches 30 ppb in liver, residues of DCBX in liver are ``estimated by regression analysis to be about 4 [ppb]'' (Ref. 2 at p. 18). CVM's statistical analysis of the residue concentrations of DCBX in liver treated with pancreatin (a simulated intestinal fluid) shows that concentrations of DCBX in liver, when QCA reaches the 30 ppb approved tolerance, would average 4 ppb and, based on the data in the JECFA report, could reasonably range from 1.4 ppb to 11 ppb, using a 95 percent prediction range. Based upon this analysis, DCBX alone--leaving aside additional, unidentified residues of carcinogenic concern--significantly exceeds the approved S m when QCA, the approved marker residue, reaches the approved tolerance. The new evidence from the 2003 JECFA re-evaluation of carbadox, along with studies that were later submitted to CVM, undermine the human food safety conclusions that CVM had previously reached when considering the approval of the new animal drug applications for carbadox for its various uses. CVM has engaged with Phibro to evaluate the carbadox-associated safety concerns raised by the new evidence and repeatedly has asked Phibro to submit information that would address these safety concerns. Information provided by Phibro in response to these requests has not resolved CVM's human food safety concerns. 1. Boison, et al., 2009 In addition, a 2009 publication calls into question conclusions made by CVM when it approved the NADAs and supplemental NADAs for carbadox (Ref. 4). Boison, et al., 2009, demonstrates the availability of a sensitive analytical method for DCBX, and provides information from which serious questions about the safety of carbadox can be inferred, specifically whether DCBX may be present in edible tissues of treated swine above the Sm even when the marker residue (QCA) concentration is below the tolerance of 30 ppb (id.). Boison, et al., report: (1) QCA is not a suitable marker for the regulation of carbadox because while QCA is very stable under temperature conditions above 60 [deg]C (i.e., 105 [deg]C), DCBX is not (Ref. 4 at p. 133); (2) the existence of an analytical method capable of detecting DCBX below the Sm for porcine muscle and liver (Ref. 4 at p. 132, Table 5); and (3) detection of DCBX at a concentration greater than 0.050 ppb in the diaphragm (but not the liver) of 2 of 6 hogs fed carbadox, while QCA was not detected in the liver of those same hogs at a limit of quantitation (LOQ) of 0.500 ppb (Ref. 4 at pp. 132-33). The findings of Boison, et al., are significant for two reasons: (1) QCA appears not to be a reliable marker residue and (2) DCBX is reported to be sensitive to the processing temperature used in the analytical method. 2. Baars, et al., 1991 In 2012, in response to FDA's 2011 order under section 512(l) of the FD&C Act, Phibro sent CVM a letter citing Baars, et al., 1990 (Ref. 5), an abstract of a study not previously provided. CVM obtained the study report Baars, et al., 1991 (Ref. 6), which reports an analytical method with a limit of detection of 1 ppb that detects the presence of DCBX in edible tissues for greater than 72 hours after removal of feed containing carbadox. Specifically, Baars, et al., 1991, demonstrated the presence of DCBX for up to 7 days (~168 hours) in the kidney and 14 days (~336 hours) in the liver of swine fed carbadox (Ref. 5 at p. 3, Fig. 3; Ref. 6 at p. 290, Fig. 2). This observation called into question CVM's previous conclusion that all residues of carcinogenic concern deplete within 72 hours. C. New Evidence Calls Into Question Prior CVM Conclusions That Were the Basis of the 1998 Supplemental Approval CVM's prior conclusion that QCA is a reliable marker residue for carbadox and its metabolites was predicated on several underlying conclusions (Ref. 1 at pp. 13-14). These underlying conclusions are reviewed below in light of the new evidence presented above. 1. Previous Conclusion 1: The residue data show that carbadox, DCBX, and hydrazine do not persist in edible tissues as detectable residues beyond 72 hours.\9\ --------------------------------------------------------------------------- \9\ This underlying conclusion is described in the January 30, 1998, summary basis of approval under the Freedom of Information Act (FOI Summary) for NADA 041-061 (Ref. 1 at p. 9) and in the report of the 1990 JECFA meeting (Ref. 10 at p. 30). --------------------------------------------------------------------------- Since the time CVM made this previous conclusion, we have become aware of information that undermines the previous conclusion that carbadox and its carcinogenic metabolites do not persist in edible tissues beyond 72 hours. JECFA, in 2003, reviewed a study detecting DCBX in livers of swine up to 15 days after cessation of carbadox exposure. The study JECFA reviewed was limited to 15 days. The data presented to JECFA in 2003 provide new scientific evidence that DCBX persists in edible tissues of swine as a detectable residue beyond 72 hours (Ref. 2). Further, Baars, et al., 1991, reports detecting DCBX in liver up to Day 14 after cessation of exposure to carbadox using an analytical method with a detection limit of 1 ppb (Ref. 6). Baars, et al., 1991, provides new scientific evidence that DCBX persists as a detectable residue in edible tissues of swine for greater than 72 hours. Scientific evidence from JECFA's 2003 evaluation of submitted information and Baars, et al., 1991, demonstrate that DCBX, one residue of carcinogenic concern for carbadox, persists in edible tissues of swine beyond 72 hours. All of this evidence was first received by CVM after the 1998 approval of the supplemental application to NADA 041- 061. Based on this new scientific evidence, the previous conclusion that DCBX does not persist in edible tissues of swine as a detectable residue beyond 72 hours is no longer justified. 2. Previous Conclusion 2: The unextracted residues are related to a noncarcinogenic compound, QCA, and extractable QCA is the only residue detectable in the edible tissues of swine 72 hours post dosing.\10\ --------------------------------------------------------------------------- \10\ This underlying conclusion is described in the January 30, 1998, summary basis of approval under the Freedom of Information Act (FOI Summary) for NADA 041-061 (Ref. 1 at p. 9) and in the report of the 1990 JECFA meeting (Ref. 10 at p. 30). --------------------------------------------------------------------------- At the time of the 1998 supplemental approval, CVM concluded that that unextracted residues were related to the noncarcinogenic compound, QCA, and that extractable QCA was the only residue detectable in the edible tissues after 72 hours post dosing. However, CVM is now aware of reports of extraction of residues being enhanced by pepsin or pancreatin digestion prior to organic extraction, making non-QCA residues previously thought to be unextractable currently extractable (Ref. 2). JECFA reports that some residues of carbadox previously identified as unextractable can now be extracted (id.). DCBX was found in the newly extractable residues. This scientific evidence demonstrates that some residues previously found to be unextractable are extractable and that the unextractable residues are not all related to QCA. As discussed above, residues of DCBX, a residue of carcinogenic concern, have been detected in edible tissues longer than 72 hours post dosing [[Page 21570]] (Refs. 2, 5, and 6). The previous underlying conclusions that unextracted residues are related to noncarcinogenic compound, QCA, and extractable QCA is the only residue detectable in the edible tissues 72 hours post dosing is no longer justified based on new scientific evidence. 3. Previous Conclusion 3: No residue of carcinogenic concern even below the S0 , is detectable by any method beyond 72 hours.\11\ --------------------------------------------------------------------------- \11\ This underlying conclusion is part of the basis of the January 1998 supplemental approval (FOI Summary) (Ref. 1 at pp. 13- 14). --------------------------------------------------------------------------- Boison, et al., 2009, reports a method capable of detecting DCBX at 0.05 ppb, which is below the 0.061 ppb So and below the Sm of 0.305 ppb in muscle, 0.915 ppb in liver, and 1.83 ppb in kidney and fat. The method is also capable of measuring QCA at 0.500 ppb, below the current tolerance of 30 ppb (Ref. 4 at p. 132, Table 5). Consequently, measurement of the relationship of QCA to at least one residue of carcinogenic concern, DCBX, is now scientifically feasible at the time the last tissue depletes to its Sm . In fact, Boison, et al., 2009, reports the presence of DCBX at a concentration greater than 0.050 ppb in the diaphragm (muscle) of 2 of 6 market- weight hogs fed carbadox, when QCA was not detected, at a limit of quantitation of 0.50 ppb, in the livers of those same hogs (Ref. 4 at pp. 132-133). This evidence raises a serious question about whether QCA at 30 ppb is an appropriate marker residue for carbadox residues of carcinogenic concern. Based on this new scientific evidence, the previous underlying conclusion that no residue of carcinogenic concern, even below the SO , is detectable by any method beyond 72 hours is no longer justified. 4. Previous Conclusion 4: QCA is a reliable marker residue for carbadox and its metabolites.\12\ --------------------------------------------------------------------------- \12\ This underlying conclusion is part of the basis of the January 1998 supplemental approval (FOI Summary) (Ref. 1 at pp. 13- 14). --------------------------------------------------------------------------- In light of the new evidence presented above, the conclusion that QCA is a reliable marker residue for carbadox and its metabolites is no longer justified because: (1) Previous conclusions made by the Agency are no longer scientifically justified and (2) the relationship of QCA to a carbadox residue of carcinogenic concern, DCBX, in the last tissue to deplete to its Sm is not known. D. CVM's Reanalysis of the Human Health Risk From Previously Submitted Residue Data CVM reevaluated the existing carbadox residue data as a result of discussions that took place during meetings in 2011 with Phibro about the composition of total residues of carbadox (Refs. 3 and 22). CVM also reexamined the residue data submitted in support of the 1998 NADA supplements in light of the new understanding from the 2003 JECFA report that carcinogenic residues of carbadox persisted in edible tissues for 15 days, which was the last sampling time point, and that the previously unextractable residues are not necessarily noncarcinogenic residues related to QCA (Ref. 2). Using data in the FOI Summary for the January 30, 1998, supplemental approval, CVM reviewed information on total residue concentrations (measured from total radioactivity present in tissue from swine administered the radiolabeled drug), as well as the percent of total residues represented by QCA--the only noncarcinogenic metabolite of carbadox identified and quantified in the total residues of carbadox (Ref. 1). CVM used the total residue data and the percent of total residues represented by QCA to calculate the total residue of carcinogenic concern present in liver. Under the SOM regulations, ``residues of carcinogenic concern'' in edible tissues are total residues of a carcinogenic drug minus identified residues that are judged by CVM to be noncarcinogenic (Sec. 500.82(b)). CVM previously excluded the unextracted portions of total residues from carcinogenic concern because it believed they were noncarcinogenic, QCA-related residues. The data presented to JECFA in 2003 now refute that conclusion, and CVM has no information, from Phibro or otherwise, that identifies or measures noncarcinogenic residues other than QCA in total residues of carbadox at the withdrawal period. As such, CVM now identifies the total residue of carcinogenic concern by subtracting QCA (identified residues that are confirmed to be noncarcinogenic) from total residues of carbadox. Determining the concentration of residues of carcinogenic concern present in the liver allowed CVM to compare that value with the Sm established for residues of carcinogenic concern in liver. CVM reviewed data regarding concentrations of total residues in swine tissues following 5 days of feeding \14\C-carbadox contained in a residue depletion study (the same study submitted to JECFA for its 1990 evaluation of carbadox (Ref. 10 at p. 31)) submitted by the sponsor in support of the supplemental application to NADA 041-061 approved in January 1998 (Ref. 1, Study No. 1525N-60-87-005). The study measured concentrations of total residues of \14\C-carbadox and residues of QCA. Using these data, the study reported QCA as a mean percentage of the total residues of carbadox. QCA represented 24.4 percent of the total residues at 30 days, 27.5 percent at 45 days, and 9.9 percent at 70 days post dosing (Ref. 1 at p. 13, Table 9). Table 1 presents total carbadox residues and total carbadox residues minus the noncarcinogenic QCA. Column 1 lists the sampling time point when swine were slaughtered following administration of the last dose of carbadox. Column 2 presents mean total residues measured in livers collected from swine slaughtered at each time point. Column 3 lists the mean QCA percentage of total residues at each time point. Column 4 lists the calculated mean total residues of carcinogenic concern based on a subtraction of QCA from the mean total residue values in Column 2. Table 1--Mean Total Residues Measured as \14\C-Carbadox Equivalents, the Mean Percentage of Total Residues Represented by QCA, and Mean Total Residue of Carcinogenic Concern in Liver of Swine (n=3 or 4) Following 5 Days of Feeding \14\C-Carbadox at 55 PPM ---------------------------------------------------------------------------------------------------------------- Total residue of Days post dosing Total residues Percent QCA carcinogenic (ppb) concern (ppb) \1\ ---------------------------------------------------------------------------------------------------------------- 30.............................................................. 74.5 24.4 56.3 45.............................................................. 20.0 27.5 14.5 [[Page 21571]] 70.............................................................. 13.3 9.9 11.98 ---------------------------------------------------------------------------------------------------------------- \1\ Values calculated by subtracting noncarcinogenic QCA portion from total residues. FDA first approved the use of carbadox in 1972 prior to the issuance of the Agency's SOM regulations. CVM did not make a calculation comparing total residues less QCA to the Sm in approving the January 1998 NADA supplement because the data available at the time indicated that DCBX was not detectable beyond 72 hours post dosing (by the analytical method used at the time) and because CVM believed all unextractable residues were noncarcinogenic residues related to QCA (Ref. 1). No residue depletion data presented to the Agency in original or supplemental NADAs showed that carcinogenic residues persisted beyond 72 hours or that the unextractable residues were carcinogenic. As a result, CVM did not, at that time, ask for data regarding the composition of total residues beyond establishing QCA as an appropriate marker residue. New evidence presented to JECFA in 2003 and reported by Boison, et al., 2009, and Baars, et al., 1991, calls CVM's prior conclusions into question and places new significance on the concentrations of total residues of carcinogenic concern for carbadox (Refs. 2, 4, and 6). The individual data shown as mean values in Table 1 were used to predict total residues of carcinogenic concern at the approved 42-day withdrawal period for carbadox in NADAs 041-061 and 141-211, and the approved 70-day withdrawal period for carbadox in NADA 092-955. CVM analyzed the data using the logarithm of the dependent variable (carbadox-equivalents in liver). The logarithmic transformation or ``exponential model'' is consistent with the published JECFA analyses of carbadox and commonly observed elimination behavior of pharmaceuticals (Ref. 22). Using this modeling procedure, the total residues of carcinogenic concern at 42 days are estimated to be 27 ppb with a 95 percent prediction interval of 9 ppb to 80 ppb (Ref. 3 at p. 17, Table 8). These predictions can be compared with the Sm for swine liver of 0.915 ppb. The regression model predicts that swine liver concentrations of total carcinogenic residues will be significantly in excess of the Sm --approximately 30-fold (27 ppb / 0.915 ppb = 29.51) greater residues of carcinogenic concern than the Sm at the approved 42-day withdrawal period for NADAs 041-061 and 141-211 (Ref. 3 at p. 16). Total residues of carcinogenic concern at 70 days are estimated to be 10 ppb with a 95 percent prediction interval of 3 ppb to 32 ppb (Ref. 3 at p. 17, Table 8). The analysis predicts that swine liver concentrations of total carcinogenic residues will be significantly in excess of the Sm -- approximately 11-fold greater residues of carcinogenic concern than the Sm at the approved 70-day withdrawal period for NADA 092- 955. Approval of a carcinogenic new animal drug under the DES Proviso to the Delaney Clause requires development of a sufficiently sensitive regulatory method that detects no residues of carcinogenic concern in the edible tissues of food-producing animals from the use of the animal drug. New evidence raises serious questions about whether the currently approved tolerance for uses of carbadox is adequate under the SOM regulations, and raises serious questions about the continued approval of the compound under the DES Proviso exception to the Delaney Clause due to the lack of a sufficiently sensitive regulatory method. Carbadox is currently approved based upon CVM's previous conclusion that unextractable residues were QCA related and noncarcinogenic. Given this conclusion and the fact that no residues of carcinogenic compounds were detectable by any method beyond 72 hours, CVM determined that QCA was an acceptable marker residue and established the tolerance at 30 ppb. New evidence presented to JECFA in 2003 undermines the conclusion that all unextractable residues at the withdrawal period are QCA related. As a result, under FDA's SOM regulations, all unextractable residues except for measured residues of QCA must be considered residues of carcinogenic concern (Sec. 500.82(b)). Under CVM's analysis (Table 1), concentrations of total residues of carcinogenic concern in liver are approximately 30 times higher than the Sm at the approved 42-day withdrawal period and 11 times higher at the approved 70-day withdrawal period (Ref. 3 at pp. 16-17). CVM would expect that total residues of carcinogenic concern would also exceed the Sm when QCA reaches the approved tolerance of 30 ppb in liver. CVM can no longer conclude that when QCA is at or below 30 ppb, the residues of carcinogenic concern are present at or below a concentration that would present no significant increase in the risk of cancer to humans (Sec. 500.86(c)). The new evidence indicates that QCA is not an appropriate marker residue for residues of carcinogenic concern and that QCA at 30 ppb in swine liver is not an appropriate tolerance. The new evidence also shows that the approved regulatory method for all approved carbadox NADAs is inadequate under the SOM regulations (part 500, subpart E). The inadequacy of the regulatory method is a basis for withdrawal of approval of all carbadox NADAs under section 512(e)(1)(B) of the FD&C Act. See Sponsored Compounds in Food-Producing Animals; Criteria and Procedures for Evaluating the Safety of Carcinogenic Residues, Proposed Rule, preamble to the proposed SOM regulations II (50 FR 45530 at 45550). Similarly, these findings demonstrate that carbadox is no longer shown to be safe under the General Safety Clause because residues of carcinogenic concern remain in swine tissue well past the established withdrawal period. Under the General Safety Clause, drug residues must be determined to be safe based on all available evidence. Where a drug is a known mutagenic carcinogen and new evidence shows that unidentified residues of carcinogenic concern are present at the established withdrawal time, the drug is no longer shown to be safe. See Section III.D. As stated previously, the new evidence presented to JECFA undermines the previously held conclusion that all unextracted residues are QCA related and noncarcinogenic. Because carbadox is a mutagenic carcinogen, all otherwise unidentified [[Page 21572]] residues are treated as carcinogenic. No evidence has been presented to CVM by Phibro or any other source to show that the unidentified residues are noncarcinogenic or that the residues do not otherwise present a threat to public health. As a result, carbadox is not shown to be safe under the General Safety Clause. VI. Notice of Opportunity for a Hearing New evidence regarding carcinogenic residues in edible tissues of swine treated with carbadox raises serious questions about the human food safety of the drug. Therefore, 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 no longer meets the DES Proviso exception to the Delaney Clause and because new evidence demonstrates that carbadox is not shown to be safe under the General Safety Clause. Therefore, notice is given to Phibro Animal Health Corp., 65 Challenger Rd., Ridgefield Park, NJ 07660, and to all other interested persons, that the Director of CVM 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 part 514 (21 CFR part 514) and under the authority delegated to the Director of CVM, Phibro Animal Health Corp., the sponsor, is hereby given an opportunity for hearing to show why approval of NADAs 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: (1) On or before [see DATES], a written notice of appearance and request for a hearing and (2) on or before [see DATES], the data, information, and analyses relied on to demonstrate that there is a genuine and substantial issue of fact to justify a hearing as specified in Sec. 514.200. Any other interested person may also submit comments on this notice (see, ADDRESSES). 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 of denial of a hearing, are contained in Sec. 514.200 and 21 CFR part 12. The failure of a holder of an approval to file timely a written appearance and request for hearing as required by Sec. 514.200 constitutes an election not to avail himself or herself of the opportunity for a hearing and 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 of 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, 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 Director of CVM. VII. 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. VIII. Paperwork Reduction Act of 1995 The collections of information requirements for this document are covered under OMB control numbers 0910-0032 and 0910-0184. IX. References The following references have been placed on display in the Division of Dockets Management (see ADDRESSES) and may be seen by interested persons between 9 a.m. and 4 p.m., Monday through Friday, and are available electronically at http://www.regulations.gov. (FDA has verified the Web site addresses, but FDA is not responsible for any subsequent changes to the Web sites after this document publishes in the Federal Register.) 1. FDA, Freedom of Information (FOI) Summary, NADA 041-061, MECADOX 10 (carbadox) Type A medicated article, supplemental approval January 30, 1998. Available at http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM429999.pdf (accessed on March 19, 2016). 2. JECFA, Report on Carbadox, 2003. Available at ftp://ftp.fao.org/ag/agn/jecfa/vetdrug/41-15-carbadox.pdf (accessed on March 19, 2016). 3. FDA, Memorandum to the File, Claycamp, H.G., ``Preliminary Risk Characterization: Cancer Risk Estimation from Carbadox Residues in Pork from Swine Treated with Carbadox,'' December 16, 2014. 4. Boison, J.O., S.C. Lee, and R.G. Gedir, ``A Determinative and Confirmatory Method for Residues of the Metabolites of Carbadox and Olaquindox in Porcine Tissues,'' Analytica Chimica Acta, 637:128- 134, 2009. 5. Baars, A.J., L.A. van Ginkel, M.M.L. Aerts, et al., ``Kinetics of Carbadox Residues in Pigs,'' In: Proceedings of the EuroResidue Conference, Noorwijkerhout (Haagsma, N., A. Ruiter, and P.B. Czedik- Eysenberg, eds., May 21-23, 1990. 6. Baars, A.J., L.P. Jager, T.J. Spierenberg, et al., ``Residues of Carbadox Metabolites in Edible Pork Products,'' Archives of Toxicology Supplement, 14:288-92, 1991. 7. FDA, CVM Guidance for Industry (GFI) #3, ``General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals,'' July 25, 2006. Available at http://www.fda.gov/downloads/animalveterinary/guidancecomplianceenforcement/guidanceforindustry/ucm052180.pdf (accessed on March 19, 2016). 8. FDA, Memorandum to the File, from Director, Division of New Animal Drugs to Director, Bureau of Veterinary Medicine regarding NADA 41-061--Carbadox for Swine (September 22, 1972). 9. FDA, Memorandum to the File, S.H. Frazier, Jr., Division of Toxicology, to Director, Bureau of Veterinary Medicine, regarding Carbadox for Swine, August 27, 1970. 10. JECFA, Report on Carbadox, 1990. Available at ftp://ftp.fao.org/ag/agn/jecfa/vetdrug/41-3-carbadox.pdf (accessed on March 19, 2016). 11. FDA, Memorandum to the File, from Division of New Animal Drugs to Director, Bureau of Veterinary Medicine, regarding NADA 41-061, Carbadox for Swine (July 7, 1972). 12. FDA, Memorandum to the File, Approval of Original New Animal Drug Application NADA 92-955 (July 29, 1975). 13. Citizen Petition, Center for Science in the Public Interest, Docket No. FDA-1986-P-0299 (formerly 86P-0212), May 9, 1986. 14. FDA, Response to Citizen Petition, Center for Science in the Public Interest, Docket No. FDA-1986-P-0299 (formerly 86P-0212), May 30, 1995. 15. FDA, Memorandum to the File, from Residue Evaluation Branch, Division of Chemistry to Director, Division of [[Page 21573]] Chemistry, regarding Review of Carbadox Metabolism (September 7, 1994). 16. FDA, Freedom of Information (FOI) Summary, NADA 041-061, MECADOX 10 (carbadox) Type A medicated article, supplemental approval October 5, 1998. Available at http://www.fda.gov/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm064223.htm (accessed on March 19, 2016). 17. FDA, Freedom of Information (FOI) Summary, NADA 141-211, MECADOX 10 (carbadox) and TERRAMYCIN 50, 100, or 200 (oxytetracycline) in Type C medicated feed, original approval July 21, 2004. Available at http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118005.pdf (accessed on March 19, 2016). 18. Codex Alimentarius Commission, Twenty-Eighth Session, Headquarters, Food and Agriculture Organization, Rome, Italy, 2005. 19. FDA, CVM Guidance for Industry (GFI) #205, VICH GL 46, ``Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Animals: Metabolism Study to Determine the Quantity and Identify the Nature of Residues (MRK),'' September 15, 2011. Available at http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM207939.pdf (accessed on March 19, 2016). 20. MacIntosh, A.I., G. Lauriault, and G.A. Neville, ``Liquid Chromatographic Monitoring of the Depletion of Carbadox and its Metabolite Desoxycarbadox in Swine Tissues,'' Journal--Association of Official Analytical Chemists, 68:665-71, 1985. 21. FDA, CVM Guidance for Industry (GFI) #208, VICH GL 49, ``Studies to Evaluate the Metabolism and Residue Kinetics of Veterinary Drugs in Food-Producing Animals: Validation of Analytical Methods Used in Residue Depletion Studies,'' September 15, 2011. Available at http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM207942.pdf (accessed on March 19, 2016). 22. FDA, Memorandum to the File, Claycamp, H. G., Verification and Extension of the 2003 JECFA Carbadox Monograph Analyses, July 29, 2012. Dated: April 6, 2016. Tracey Forfa, Acting Director, Center for Veterinary Medicine. [FR Doc. 2016-08327 Filed 4-8-16; 11:15 am] BILLING CODE 4164-01-P
![Federal Register / Vol. 81, No. 70 / Tuesday, April 12, 2016 / Notices 21559
development and the protection of 812.2(c)(3), but FDA’s regulations for Identifiable,’’ issued under the Good
public health, safety, and ethical the protection of human subjects (21 Guidances Practices regulation, 21 CFR
standards, FDA has established human CFR parts 50 and 56) apply to all 10.115, FDA outlines the circumstances
subject protection regulations clinical investigations that are regulated in which it intends to exercise
addressing requirements for informed by FDA (see 21 CFR 50.1, 21 CFR enforcement discretion as to the
consent and institutional review board 56.101, 21 U.S.C. 360j(g)(3)(A), and 21 informed consent regulations for
(IRB) review that apply to all FDA- U.S.C. 360j(g)(3)(D)). clinical investigators, sponsors, and
regulated clinical investigations FDA regulations do not contain IRBs.
involving human subjects. In particular, exceptions from the requirements of The recommendations of the guidance
informed consent requirements further informed consent on the grounds that impose a minimal burden on industry.
both safety and ethical considerations the specimens are not identifiable or FDA estimates that 700 studies will be
by allowing potential subjects to that they are remnants of human affected annually. Each study will result
consider both the physical and privacy specimens collected for routine clinical in one annual record, estimated to take
risks they face if they agree to care or analysis that would otherwise 4 hours to complete. This results in a
participate in a trial. have been discarded. Nor do FDA total recordkeeping burden of 2,800
Under FDA regulations, clinical regulations allow IRBs to decide hours (700 × 4 = 2,800).
investigations using human specimens whether or not to waive informed In the Federal Register of October 23,
conducted in support of premarket consent for research involving leftover 2015 (80 FR 64422), FDA published a
submissions to FDA are considered or unidentifiable specimens. 60-day notice requesting public
human subject investigations (see 21 In a level 1 guidance document, comment on the proposed collection of
CFR 812.3(p)). Many investigational entitled ‘‘Guidance on Informed information. No comments were
device studies are exempt from most Consent for In Vitro Diagnostic Device received.
provisions of part 812, Investigational Studies Using Leftover Human FDA estimates the burden of this
Device Exemptions, under 21 CFR Specimens that are Not Individually collection of information as follows:
TABLE 1—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1
Number of Average
Number of Total annual
The FD&C Act section records per burden per Total hours
recordkeepers records
recordkeeper recordkeeping
520(g) ................................................................................... 700 1 700 4 2,800
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
Dated: April 6, 2016. DATES: Phibro Animal Health Corp. may confidential business information, e.g., a
Leslie Kux, submit a request for a hearing by May manufacturing process. The request for
Associate Commissioner for Policy. 12, 2016. Submit all data and analysis a hearing must include the Docket No.
[FR Doc. 2016–08329 Filed 4–11–16; 8:45 am] upon which the request for a hearing FDA–2016–N–0832 for ‘‘Phibro Animal
BILLING CODE 4164–01–P
relies by July 11, 2016. Health Corp.; Carbadox in Medicated
ADDRESSES: The request for a hearing Swine Feed; Opportunity for Hearing.’’
may be submitted by Phibro Animal The request for a hearing will be placed
DEPARTMENT OF HEALTH AND Health Corp. by either of the following in the docket and publicly viewable at
HUMAN SERVICES methods: http://www.regulations.gov or at the
Division of Dockets Management
Food and Drug Administration Electronic Submission between 9 a.m. and 4 p.m., Monday
• Federal eRulemaking Portal: http:// through Friday.
[Docket No. FDA–2016–N–0832] Phibro Animal Health Corp. may
www.regulations.gov. Follow the
instructions for submitting comments to submit all data and analysis upon which
Phibro Animal Health Corp.; Carbadox
submit your request for hearing. Your the request for a hearing relies in the
in Medicated Swine Feed; Opportunity
request for a hearing submitted same manner as the request for a
for Hearing
electronically, including any hearing except as follows:
AGENCY: Food and Drug Administration, attachments to the request for hearing, • Confidential Submissions—To
HHS. to http://www.regulations.gov will be submit any data and analyses with
ACTION: Notice of opportunity for posted to the docket unchanged. confidential information that you do not
hearing. wish to be made publicly available,
Written/Paper Submission submit your data and analyses only as
SUMMARY: The Food and Drug • Mail/Hand delivery/Courier (for a written/paper submission. You should
Administration (FDA), Center for written/paper request for a hearing): submit two copies total of all data and
Veterinary Medicine (CVM), is Division of Dockets Management (HFA– analysis. One copy will include the
proposing to withdraw approval of all 305), Food and Drug Administration, information you claim to be confidential
asabaliauskas on DSK3SPTVN1PROD with NOTICES
new animal drug applications (NADAs) 5630 Fishers Lane, Rm. 1061, Rockville, with a heading or cover note that states
providing for use of carbadox in MD 20852. ‘‘THIS DOCUMENT CONTAINS
medicated swine feed. This action is Because your request for a hearing CONFIDENTIAL INFORMATION.’’ The
based on CVM’s determination that the will be made public, you are solely Agency will review this copy, including
use of carbadox under the approved responsible for ensuring that your the claimed confidential information, in
conditions of use results in residues of request does not include any its consideration of any decisions on
carcinogenic concern in the edible confidential information that you may this matter. The second copy, which
tissues of the treated swine. not wish to be publicly posted, such as will have the claimed confidential
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![21562 Federal Register / Vol. 81, No. 70 / Tuesday, April 12, 2016 / Notices
‘‘Safe,’’ in the context of human food extrapolate animal data on cumulative safe for use under the conditions of use
safety, means a ‘‘reasonable certainty of effects to humans). upon the basis of which the application
no harm.’’ The definition is derived When establishing the human food was approved or that subparagraph (I) of
from language in H. Rep. No. 85–2284, safety of a noncarcinogenic new animal paragraph (1) of subsection (d) applies
at 4–5 (1958), defining the term ‘‘safe’’ drug used in food-producing animals, to such drug. The Secretary of Health
as it appears in section 409 of the FD&C CVM establishes a no observed effect and Human Services has delegated this
Act, which governs food additives (21 level (NOEL) for the residues of that authority to the Commissioner of Food
U.S.C. 348). Until passage of the Animal drug in edible tissues—namely, the and Drugs. See FDA Staff Manual Guide
Drug Amendments of 1968 (Pub. L. 90– highest dose of the drug that does not 1410.10 (April 11, 2014).
399) (the 1968 amendments), substances produce the most sensitive treatment- In other words, grounds for
formed in or on food due to the use of related toxic endpoint in test animals withdrawal exist where new evidence
animal drugs in food-producing animals (Ref. 7). From the NOEL, CVM uses shows either that the Delaney Clause
were regulated under the food additive safety factors to calculate an acceptable applies to the drug (‘‘subparagraph (I) of
provisions in section 409 of the FD&C daily intake, and consumption factors to paragraph (1) of subsection (d)’’) or that
Act. The 1968 amendments calculate the safe concentration of the drug is not shown to be safe under
consolidated all of the existing statutory residues in a particular edible tissue the approved conditions of use (the
authorities related to animal drugs into (Ref. 7 at p. 15; section 512(b)(1)(H) of General Safety Clause). As explained
section 512 of the FD&C Act, and the the FD&C Act). further, new evidence demonstrates that
legislative history shows that the Carbadox is both a genotoxic 3 and carbadox meets both grounds for
consolidation in no way changed the mutagenic carcinogen in animals. In the withdrawal.
authorities with respect to the case of a genotoxic carcinogenic drug, In a proceeding to withdraw the
regulation of new animal drugs (S. Rep. establishing the human food safety of approval of an NADA, the sponsor has
No. 90–1308, at 1 (1968)). During the the compound via a NOEL is not the burden of proof to demonstrate that
new animal drug application review feasible, therefore human food safety of the product is safe and therefore that the
process, CVM has consistently applied carcinogenic compounds is ordinarily NADA approval should remain in effect
the ‘‘reasonable certainty of no harm’’ evaluated by using linear, low-dose (21 CFR 12.87(d): (‘‘At a hearing
standard in determining the safety of extrapolation to evaluate the maximum involving issuing, amending, or
substances formed in or on food as a concentration of total residues of revoking a regulation or order relating to
result of the use of a new animal drug carcinogenic concern that can be the safety or effectiveness of a drug . . .
in a food-producing animal. present in the total human diet without the participant who is contending that
a significant increase in the risk of the product is safe or effective or both
In order to determine whether a new
cancer to the human consumer (section and who is . . . contesting withdrawal
animal drug meets this standard, section
512(d)(1)(I) of the FD&C Act; 21 CFR of approval has the burden of proof in
512(b)(1)(G)–(H) of the FD&C Act
500.82 and 500.84). In both cases, the establishing safety or effectiveness or
requires that whenever a drug may
safe residue level of the drug is both and thus the right to approval.’’);
result in residues of the drug or its
determined through an evaluation of the (see also Rhone-Poulenc, Inc. v. FDA,
metabolites in food, an application must
relevant data relating to the three factors 636 F.2d 750, 752 (D.C. Cir. 1980); Hess
include not only full reports of
listed above; viz., the probable & Clark v. FDA, 495 F.2d 975, 992 (D.C.
investigations to show that the use of consumption of the drug residue and its
the drug is safe, but also a description Cir. 1974)). Nevertheless, CVM bears an
cumulative effect as determined through initial burden of showing that new
of practicable methods for monitoring all relevant safety factors (section
food to assure that there are no unsafe evidence regarding the new animal drug
512(d)(2) of the FD&C Act). raises serious questions about the safety
residues in human food attributable to
the drug use, and a demonstration that B. Grounds for Withdrawal Under the of the new animal drug. See Rhone-
the conditions of use are adequate to FD&C Act Poulenc, 636 F.2d at 752. Once CVM has
assure there are no unsafe residues. satisfied the initial burden, the burden
Section 512(e)(1)(B) of the FD&C Act
In sum, under section 512(d)(2) of the shifts to the sponsor to establish the
provides grounds for withdrawal of
FD&C Act, the Agency is required, in safety of the drug:
approval of an NADA if new evidence
the evaluation of the supporting safety not contained in an approved In the Hess & Clark case we held that the
data, among other things, to consider: application or not available to the ‘‘new evidence’’ requirement of the safety
• The probable consumption of such Secretary of Health and Human Services clause ‘‘plainly places on the [CVM] an
drug and of any substance formed in or initial burden to adduce the ‘new evidence’
until after such application was and what that evidence ‘shows’. Only when
on food because of the use of such drug approved, or tests by new methods, or the [CVM] has met this initial burden of
(i.e., probable human consumption of tests by methods not deemed reasonably coming forward with the new evidence is
residues including the parent drug and applicable when such application was there a burden on the manufacturer to show
its metabolites); approved, evaluated together with the that the drug is safe.’’ Rhone-Poulenc, 636
• The cumulative effect on man or evidence available to the Secretary F.2d at 752 (quoting Hess & Clark, 495 F.2d
animal of such drug, taking into account when the application was approved, at 992).
any chemically or pharmacologically shows that such drug is not shown to be To meet its initial burden of proof to
related substance, i.e., toxicological withdraw approval of a new animal
effects of the compounds comprising the drug that is ‘‘not shown to be safe,’’
asabaliauskas on DSK3SPTVN1PROD with NOTICES
3 Genotoxic refers to chemicals that react with
residues; and DNA or chromosomes to cause damage. When the CVM must provide ‘‘a reasonable basis
damage is not repaired and the effect is a heritable
• Safety factors which, in the opinion change (cell to cell or parent to offspring), it is also
from which serious questions about the
of experts qualified by scientific training termed mutagenic. Thus not all genotoxic chemicals ultimate safety of [the drug] and the
and experience to evaluate the safety of are mutagenic, but all mutagenic chemicals are residues that may result from its use
such drugs, are appropriate for the use genotoxic. Uncorrected mutagenesis is thought to be may be inferred.’’ See Diethylstilbestrol:
a key step in the development of cancer.
of animal experimentation data (i.e., ‘‘Mechanisms of Toxicity,’’ in Casarett & Doull’s
Withdrawal of Approval of New Animal
establishing ‘‘safe’’ levels of residues Toxicology: The Basic Science of Poisons, edited by Drug Applications; Commissioner’s
using appropriate safety factors to Klassen, C.D., 8th Ed., pp. 49–123, 2013. Decision (44 FR 54852 at 54861,
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![Federal Register / Vol. 81, No. 70 / Tuesday, April 12, 2016 / Notices 21563
September 21, 1979) (hereinafter DES metabolite (on the basis of the results of such that the absence of the marker
Commissioner Decision) (quoting chronic bioassays and other residue in the target tissue above Rm can
Proposal to Withdraw Approval of New information) whether the drug or any of be taken as confirmation that the
Animal Drug Applications for its metabolites should be regulated as a residue of carcinogenic concern does
Diethylstilbestrol, ALJ Initial Decision, carcinogen (§ 500.84(a)). For the drug not exceed Sm in each of the edible
Docket No. FDA–1976–N–0028 and each metabolite determined to be tissues (§§ 500.82(b) and 500.86(c)).
(formerly 76N–0002), I.D. at 8 carcinogenic, CVM calculates, based When the marker residue is at or below
(September 21, 1978)), aff’d Rhone- upon submitted assays, the the Rm, the residue of carcinogenic
Poulenc, 636 F.2d 750; see also concentration of the test compound in concern in the diet of people does not
Nitrofurans Commissioner Decision (56 the total diet of the test animal that exceed So (§ 500.86(c)).
FR 41902 at 41902, August 23, 1991). corresponds to a maximum lifetime risk A sponsor must submit a regulatory
Serious questions can be raised where of cancer in the test animal of 1 in 1 method that is able to detect the marker
the evidence is not conclusive but million (§ 500.84(c)(1)). CVM designates residue at or below the Rm ((§§ 500.88(b)
merely suggestive of an adverse effect. the lowest value thus calculated as the and 500.84(c)(2)) (‘‘The LOD [Limit of
See DES Commissioner Decision. So (§ 500.84(c)(1)). The So corresponds Detection for the regulatory method]
to a concentration of residue of must be less than or equal to Rm.’’)). If
C. Withdrawal Under the Delaney a method cannot be developed that can
carcinogenic concern in the total human
Clause and the DES Proviso detect the marker residue at or below
diet that represents no significant
Section 512(e)(1)(B) of the FD&C Act increase in the risk of cancer to people the Rm, the requirements of the SOM
provides grounds for withdrawal of (§ 500.82(b). Residue of carcinogenic regulations are not satisfied, and FDA
approval of an NADA if new evidence, concern includes all compounds in the cannot approve the drug. The DES
tests by new methods, or tests by total residue of a demonstrated Proviso and FDA’s implementing
methods not deemed reasonably carcinogen excluding any compound regulations are satisfied where no
applicable when such application was judged by CVM not to present a marker residue is detectable using the
approved, evaluated together with the carcinogenic risk (§ 500.82(b)). The total approved regulatory method under the
evidence available when the application residues of carcinogenic concern (the proposed conditions of use of the drug,
was approved shows that the Delaney drug and all of its metabolites less including the proposed preslaughter
Clause, section 512(d)(1)(I) of the FD&C metabolites shown to be withdrawal period (§ 500.84(c)(3)).
Act, applies to the drug. Under the noncarcinogenic) are regulated based on As stated above, pursuant to section
Delaney Clause, the Secretary may not the most potent carcinogenic residue 512(e)(1)(B) of the FD&C Act, the
approve a new animal drug application (§ 500.84(c)(1)). This approach ensures Secretary shall, after due notice and an
if ‘‘such drug induces cancer when that use of the drug does not present a opportunity for a hearing, withdraw
ingested by man or animal or, after tests significant increase in the risk of cancer approval of an NADA if the Secretary
which are appropriate for the evaluation when considering all residues in edible finds that new evidence, tests by new
of the safety of such drug, induces tissues. methods, or tests by methods not
cancer in man or animal’’ (section 512 Because the total diet is not derived deemed reasonably applicable when
(d)(1)(I) of the FD&C Act). An exception only from food-producing animals, the such application was approved,
to this general rule, referred to as the SOM regulations make adjustments for evaluated together with the evidence
DES Proviso, allows for the approval of human food intake of edible tissues, and available when the application was
a carcinogenic new animal drug where determine the concentration of residues approved shows that the Delaney Clause
FDA finds that, under the approved of carcinogenic concern in a specific applies to the drug. Evidence that the
conditions of use: (1) The drug will not edible tissue that corresponds to no Delaney Clause applies to a drug exists
adversely affect the animals treated with significant increase in the risk of cancer where the drug has previously been
the drug and (2) no residues of the drug to the human consumer. CVM assumes determined to be a carcinogen and the
will be found by an approved regulatory for purposes of these regulations that new evidence shows CVM’s prior
method in any edible tissues of or in this value will correspond to the establishment of an analytical method
any foods yielded by the animal (section concentration of residues in a specific and residue tolerance under the DES
512(d)(1)(I)(i)–(ii) of the FD&C Act). edible tissue that corresponds to a proviso exception to the Delaney Clause
FDA has issued implementing maximum lifetime risk of cancer in test is inadequate. An analytical method is
regulations that set the requirements for animals of 1 in 1 million. This value is inadequate where new evidence
demonstrating that no residues of the termed the Sm (§§ 500.82(b) and demonstrates that the method does not
drug will be found by an approved 500.84(c)(1)). accurately detect the marker residue or
regulatory method in any edible tissues Based upon residue depletion data where new evidence demonstrates that
of or in any foods yielded from the submitted by a sponsor, CVM selects a not all residues of carcinogenic concern
animal (21 CFR part 500, subpart E). target tissue (the edible tissue selected have depleted at the approved tolerance
These regulations, referred to as the to monitor for residues in the target level of the marker residue (see, e.g.,
sensitivity of the method regulations animals) and a marker residue (a residue Rhone-Poulenc, 636 F.2d at 752–53.)
(SOM regulations), describe how FDA whose concentration is in a known In establishing that grounds for
determines whether the regulatory relationship to the concentration of the withdrawal of approval exist under this
method proposed by a sponsor to detect residues of carcinogenic concern in the clause, CVM carries an initial burden to
no residues of the carcinogenic drug is last tissue to deplete to the Sm) and demonstrate that the new animal drug
asabaliauskas on DSK3SPTVN1PROD with NOTICES
sufficiently sensitive to ensure that designates the concentration of the and/or any of its metabolites induces
residues of carcinogenic concern in marker residue that the regulatory cancer when ingested by man or
edible tissues will not exceed method must be capable of detecting in animals. Proposal to Withdraw New
concentrations that represent no the target tissue (§ 500.86(a)–(c)). This Animal Drug Applications for
significant increase in the risk of cancer value, termed the Rm, is the Furazolidone (NF–180) and
to humans. concentration of a marker residue in the Nitrofurazone (NF–7), ALJ Decision,
Pursuant to these regulations, CVM target tissue when the residue of FDA Docket No. FDA–1976–N–0511, at
determines for each drug and each drug carcinogenic concern is equal to Sm, 73 (formerly 76N–0172; November 12,
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![21564 Federal Register / Vol. 81, No. 70 / Tuesday, April 12, 2016 / Notices
1986) (hereinafter ALJ Decision, method was inadequate, FDA could not make drug residues found in edible tissues
November 12, 1986). Once CVM has a finding that ‘‘no residue’’ of the sponsored and risk to human health.
satisfied its initial burden, the sponsor compound would be found in the edible
products of treated animals. The DES Proviso [Without using] the Delaney Clause, it is
bears the burden of showing that the not enough for the Commissioner merely to
cannot begin to operate without that finding,
drug satisfies the DES Proviso exception and, accordingly, the Delaney Clause would show that animal carcasses contain residues
to the Delaney Clause and FDA’s preclude continued approval. See Sponsored and that [the drug] is a carcinogen. Instead,
implementing regulations. ALJ Decision, Compounds in Food Producing Animals; the FDA must show that two different issues
November 12, 1986, at 73. (‘‘Since Criteria and Procedures for Evaluating Safety are resolved in its favor before it can shift to
furazolidone is also being challenged of Carcinogenic Residues; Proposed Rule (50 petitioners the burden of showing safety: (1)
under the Delaney Clause, an additional FR 45530 at 45550, October 31, 1985); 4 see whether the detected residues are related to
DES Commissioners’ Decision (44 FR 54852 the use of [the drug]; (2) if so, whether the
issue . . . is whether new evidence put residues, because of their composition, and
forth by the Center shows that at 54859, September 21, 1979).
in the amounts present in the tissue, present
furazolidone and/or its metabolites In this case, new evidence raises some potential hazard to the public health.
induces cancer when ingested by man serious questions both about the See Hess & Clark, 495 F.2d at 992 (D.C. Cir.
or animal. If this burden is met, the acceptability of the current method in 1974).
sponsors must show [that the drug determining levels of known Applying this test, the D.C. Circuit
satisfies the DES proviso and FDA’s carcinogenic residues of carbadox, and, Court of Appeals has held that new
implementing regulations]’’); see also 21 further, demonstrates that previously evidence of drug residues in edible
CFR 500.92(b) (providing that for those unidentified carcinogenic metabolites tissues in conjunction with evidence
compounds that FDA determines have exist that are entirely unaccounted for that any drug residues of the drug in
been shown to induce cancer when in current approved testing question present safety concerns is
ingested by man or animals, §§ 500.82 methodology. Because the current sufficient to satisfy CVM’s burden of
through 500.90 apply). analytic method is inadequate to raising serious questions regarding the
In this case, CVM had previously identify the level of known carcinogens safety of the drug. See Rhone-Poulenc,
determined, in the approval and and does not identify the residue level 636 F.2d at 752–53. CVM,
supplemental approvals of new animal of unidentified metabolites of acknowledging the Hess & Clark
drugs containing carbadox, that carcinogenic concern, the current standard and its subsequent application,
carbadox and its metabolites, including method and tolerance are inadequate to has withdrawn approval of a new
DCBX, induce cancer in animals, but satisfy the DES Proviso.
that the drug could be approved under animal drug under the General Safety
the DES Proviso exception to the D. Withdrawal Under the General Safety Clause where new evidence showed
Delaney Clause. See Section IV. Clause that: (1) The new animal drug was
However, new evidence raises questions carcinogenic; (2) some drug metabolites
The General Safety Clause in section
about whether the drug is properly were mutagenic; and (3) residues left in
512(e) of the FD&C Act provides
approved under the DES Proviso to the edible tissues at the withdrawal time
grounds for withdrawal of approval of
Delaney Clause and FDA’s were unidentified. See Nitrofurans
an NADA if new evidence, tests by new
implementing regulations. See Criteria Commissioners’ Decision, 56 FR 41902
methods, or tests by methods not
and Procedures for Evaluating Assays at 41910, August 23, 1991 (‘‘Since the
deemed reasonably applicable when
for Carcinogenic Residues (44 FR 17070 nature of these residues and their
such application was approved,
at 17104, March 20, 1979) (reproposal of toxicity were not evaluated, they cannot
evaluated together with the evidence
rules revoked in accordance with court be regarded as safe . . . Contrary to the
available when the application was
order). (‘‘[The FD&C Act] defines the sponsors’ assertions, the evidence fails
approved shows that the drug is ‘‘not
new evidence that the Commissioner to demonstrate that furazolidone’s
shown to be safe for use under the
can consider in determining whether a metabolites pose no health risk to the
conditions of use upon the basis of
previously approved compound is safe. human consumers. Given all the other
which the application was approved’’
[Proper analytical methods establishing evidence in the record demonstrating
(section 512(e)(1)(B) of the FD&C Act).
residue levels] are necessary to show that furazolidone is a carcinogen and
CVM has the initial burden to present
that a sponsored compound is safe that its metabolites are mutagens, I find
new evidence that raises serious
under the FD&C Act. For that reason, that, contrary to the sponsors’
questions about the safety of the drug.
the absence of data satisfying the assertions, the metabolites of
Only upon that showing is there a
[criteria in 512(e)(1)(B) of the FD&C furazolidone pose a potential health risk
burden on the manufacturer to
Act], in conjunction with the evidence to human consumers.’’) see also DES
demonstrate that the drug is safe. See
already available about a compound, Commissioners’ Decision, 44 FR 54852
Rhone-Poulenc, 636 F.2d at 752–53;
clearly can support the withdrawal of at 54868 (explaining that, ‘‘[w]here new
Hess & Clark, 495 F.2d 975, 992 (D.C.
approval of an application.’’). In evidence shows that use of the drug
Cir. 1974).
particular, new evidence indicating that results in residues of unidentified
When evaluating a drug for
an approved regulatory method can no substances,’’ CVM must decide whether,
withdrawal under the General Safety
longer be relied upon is sufficient to despite this lack of knowledge, ‘‘the
Clause, for CVM to satisfy its initial
satisfy the Agency’s burden to support drug may be considered to be ’shown to
burden that new evidence raises serious
withdrawal of approval under section be safe[,]’ ’’ as the General Safety Clause
human food safety questions, it must
requires). In other words, because
asabaliauskas on DSK3SPTVN1PROD with NOTICES
512(e)(1)(B) of the FD&C Act and the demonstrate a relationship between the
Delaney Clause: residues of a mutagenic carcinogen are
4 Under FDA’s regulations implementing the presumptively carcinogenic, and
In the case of an approved NADA for a therefore presumptively unsafe, where
Delaney Clause for animal drugs, part 500, subpart
carcinogenic compound, if FDA determines E, a carcinogenic drug may not be approved if the new evidence demonstrates that
based on new information that the approved regulatory method to test for the compound is not
analytical method for detecting residues is unidentified residues of a mutagenic
sufficiently sensitive. §§ 500.84(c)(2) and 500.88(b).
inadequate . . . FDA could withdraw the A carcinogenic drug will be withdrawn if new
carcinogen remain at the time of
approval on the basis of the Delaney Clause. evidence shows that an approved regulatory withdrawal, the drug meets the standard
Faced with evidence that an approved method is not sufficiently sensitive. set forth in Hess & Clark.
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![Federal Register / Vol. 81, No. 70 / Tuesday, April 12, 2016 / Notices 21565
Applying the Hess & Clark standard carcinogenic parent drug was petition as it related to carbadox
here, the new evidence regarding undetectable in liver at 24 hours (Id.). because it determined that ‘‘if used
carbadox clearly meets both prongs of CVM further determined that a according to label directions, residues of
that test. New evidence demonstrates ‘‘restriction of use in the labeling carbadox remaining in edible tissues of
that previously unidentified mutagenic provides a withdrawal period long swine do not pose a human food safety
residues of carbadox, a known enough [70 days] to assure no hazard to risk to consumers’’ (Ref. 14 at p. 2). FDA
carcinogen, remain present well after humans consuming residues in meat. In based this safety determination on the
the established withdrawal period. As proper use there would be virtually no following findings:
discussed further in Section V.D., residues’’ of carbadox in tissues at 1. At 70 days withdrawal, the drug-related
because carbadox is a mutagenic slaughter (Ref. 9). The conclusions CVM residue in swine liver measured 13 ppb. 2.
carcinogen and QCA is the only known made in 1972 regarding the rapid Ten percent of the drug-related residue was
quantified noncarcinogenic residue of depletion of carcinogenic residues were extractable and identified to be a
carbadox, all other residues are of later independently corroborated by a noncarcinogenic metabolite, quinoxaline-2-
carcinogenic concern. The new 1990 evaluation of carbadox by JECFA carboxylic acid. 3. The remaining 90% of the
evidence demonstrates that the total (Ref. 10 at p. 30). drug-related residue was unextractable or
residues of carcinogenic concern at the Labeled use restrictions, as the drug bound residues. 4. The bound residues were
was approved in 1972, included an related to quinoxaline-2-carbodoxaldehyde
established 42-day withdrawal period and quinoxaline-2-carboxylic acid, both of
are much higher than previously upper weight limit of 75 pounds body
which are of no carcinogenic concern. (Ref.
thought because the residues are no weight and a prohibition on mixing into
14 at p. 1).
longer shown to be residues related to complete feeds containing less than 15
a noncarcinogenic compound, QCA, as percent crude protein, thus limiting the C. Approval of 1998 Supplemental
previously believed. See, infra, Section drug’s use to young pigs. These use NADAs
V.D. Thus, the new evidence restrictions provided assurances that the
70-day withdrawal period would likely In 1998, FDA approved two
demonstrates that: (1) The unidentified supplemental applications to NADA
residues are related to the use of be followed in practice (Ref. 11).
Similarly in 1975, FDA approved 041–061. The first supplement,
carbadox and (2) the residues pose a approved in January 1998, assigned the
potential hazard to public health NADA 092–955 for the use of carbadox
with pyrantel tartrate in Type C noncarcinogenic metabolite QCA as the
because of the amount present and marker residue and set a tolerance of 30
because they are residues of medicated swine feed (40 FR 45164,
October 1, 1975). At that time, CVM ppb QCA in swine liver (Ref. 1).
carcinogenic concern. Toxicology studies, including
reviewed drug residue studies of
IV. Regulation of Residues of Carbadox carbadox and pyrantel tartrate used in carcinogenicity bioassays with
combination. The studies showed that, carbadox, DCBX (a primary metabolite
A. 1972 and 1975 Approvals of carbadox), and hydrazine were
at 45 and 60 days withdrawal,
Carbadox is a carcinogen and was concentrations of residues of carbadox submitted as part of that supplemental
approved as a new animal drug in all tissues tested were undetectable application (Ref. 1 at pp. 1–5). The
pursuant to the DES Proviso exception using the previously approved studies demonstrated the
to the Delaney Clause. At the time of the analytical method with a 30 ppb limit carcinogenicity of carbadox, DCBX, and
initial approval of carbadox in 1972, of detection (Ref. 12 at p. 2). hydrazine, and indicated that DCBX was
CVM (then the Bureau of Veterinary the most potent of the three
Medicine) recognized that carbadox is a B. 1986 Citizen Petition carcinogenic compounds (id.).
carcinogen and therefore required that On May 9, 1986, the Center for Consequently, based on DCBX, CVM
no residues of carbadox or its metabolite Science in the Public Interest submitted calculated an So of 0.061 ppb for total
QCA be found in uncooked edible a citizen petition requesting that FDA residues of carcinogenic concern for
tissues of swine at the time of slaughter, withdraw approval of new animal drug carbadox in the total diet (Ref. 1 at p.
as determined by the approved method applications for ipronidazole, 5). CVM calculated an Sm value for total
of analysis. See 37 FR 20683, October 3, dimetridazole, and carbadox (Ref. 13). residues of carcinogenic concern in
1972, as amended by 37 FR 23906, The petition asserted that FDA must muscle at 0.305 ppb, in liver at 0.915
November 10, 1972. This approval withdraw the approval of carbadox ppb, and in kidney and fat at 1.830 ppb
occurred prior to FDA’s 1987 initial because carbadox and its metabolites (Ref. 1 at pp. 8–9).
issue of regulations implementing the DCBX and hydrazine were found to be The SOM regulations, as they existed
DES Proviso and therefore did not carcinogenic, and the approved test in 1998, directed CVM to establish an
involve the development of a regulatory method for carbadox residues is Rm for carcinogenic compounds used in
method sensitive enough to detect a ‘‘unsuitable’’ (Ref. 13 at p. 20). The food-producing animals. CVM did not
marker residue that corresponded to a asserted unsuitability of the approved establish an Rm because CVM concluded
lifetime risk of cancer to test animals of test method was based upon the fact the parent carbadox was rapidly
1 in 1 million (as described in Section that only a small portion of total metabolized, carcinogenic residues were
III.C). residues had been positively identified not detectable beyond 72 hours post
In this initial approval, based upon and that the analytical method for dosing, and unextracted residues 5 were
the submission of studies showing the carbadox residues was not sensitive
depletion of carbadox residues in edible enough to ensure that all residues had
asabaliauskas on DSK3SPTVN1PROD with NOTICES
5 Unextracted residues are residues of the drug
tissues, CVM determined that ‘‘[a]ll depleted. that are not released when tissues are exposed to
mild aqueous or organic extraction conditions.
tissues except the liver [were] free of all FDA responded to the 1986 citizen Guidance on analysis of unextracted total
residues’’ of unchanged carbadox at 24 petition in 1995 after a review of new radiolabeled residue is provided in ‘‘Guidance for
hours after withdrawal of treatment and residue depletion data submitted by (the Industry: General Principles for Evaluating the
that unchanged carbadox ‘‘ha[d] then sponsor) Pfizer as well as data Safety of Compounds Used in Food-Producing
Animals (GFI #3),’’ 2006. Unextracted or bound
disappeared from the liver after 24 previously submitted to the Agency as residues can be either: (1) Endogenous components
hours’’ (Ref. 8). CVM also determined part of the carbadox NADAs. Based resulting from fragments of the radiolabeled
from submitted studies that the upon this review, FDA denied the Continued
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related to noncarcinogenic QCA and not concentration of QCA in liver had to people—total residues of
of carcinogenic concern. Because the depleted to 30 ppb.6 carcinogenic concern in liver above
noncarcinogen QCA was the only Under FDA’s operational definition of ‘‘no 0.915 ppb under the drug’s approved
detectable metabolite persisting beyond residue,’’ a residue of carcinogenic concern, conditions of use are unsafe. Such
72 hours post dosing, CVM assigned it so long as it does not exceed the So, may be residues would preclude continued
as the marker residue (id.). detectable by an approved method. The approval because the drug would not be
residue data show that carbadox, shown to be safe and because the
At the time it approved the desoxycarbadox and hydrazine do not persist
supplement in January 1998, CVM said: exception to the Delaney Clause would
in edible tissue as detectable residues beyond not apply (Ref. 1 at pp. 8–9, 10, 14).
The sponsor and academic researchers 72 hours. The in vivo metabolism of the
compounds of carcinogenic concern is • The parent compound carbadox is
have conducted numerous studies evaluating
irreversible. Therefore, in this case, no rapidly metabolized and carcinogenic
the fate of carbadox in animals. These
residue depletion data are summarized in residue of carcinogenic concern, even below residues of the drug are not identifiable
FAO Food and Nutrition Paper 41/3 (Food the So, is detectable by any method. The in any edible tissues beyond 72 hours
and Agriculture Organization (FAO) of the unextracted residues are related to a post dosing (Ref. 1 at p. 9).
United Nations, 1991) and show that
noncarcinogenic compound, quinoxaline-2- • Remaining unextracted residues of
carboxylic acid (QCA), and extractable QCA carbadox are noncarcinogenic residues
carbadox, desoxycarbadox and hydrazine do
is the only residue detectable in the edible
not persist in edible tissue as detectable related to the noncarcinogenic
tissues 72 hours postdosing. Thus, the agency
residues beyond 72 hours. The agency’s concludes that QCA is a reliable marker metabolite QCA (Ref. 1 at pp. 9, 14).
evaluation of these data, and the new residue for carbadox and its metabolites. • QCA is a reliable marker residue for
information provided by the sponsor, From these data, FDA has selected liver as carbadox and its metabolites; that is,
demonstrate that following administration, the target tissue and quinoxaline-2-carboxylic measuring QCA residues in swine liver
parent carbadox is rapidly metabolized; that acid (QCA) as the marker residue. FDA has is a valid method for demonstrating the
the metabolism of carbadox is similar among determined that when QCA, the marker, is at absence of residues of carcinogenic
species; that the in vivo metabolism of the or below 30 ppb in the target tissue, liver, concern in edible tissues (id.).
compounds of carcinogenic concern is also that no residue of carcinogenic concern,
rapid and irreversible such that the resulting above the So, is detectable in each of the
Based upon these conclusions, CVM
metabolic products cannot regenerate edible tissues by any method. found that under the conditions of use
compounds of carcinogenic concern; that the The sponsor has submitted a regulatory the drug did not result in unsafe
unextractable residues are related to non- method capable of measuring QCA at and residues of carcinogenic concern in
carcinogenic compounds, quinoxaline-2- below 30 ppb in the target tissue. (Ref. 1 at edible tissues and that the use of
carboxylic acid [QCA] and quinoxaline-2- p. 14). carbadox, as approved in the NADA
carboxaldehyde; and that quinoxaline-2- As part of their application supplements, satisfied the DES Proviso
carboxylic acid [QCA] is the only residue supporting the January 1998 exception to the Delaney Clause
detectable in the edible tissues beyond 72 supplemental approval, the sponsor prohibition on carcinogenic animal
hours post dosing. Thus, the agency drugs (id.).
submitted a regulatory method for
concludes that the unextractable bound
residue is not of carcinogenic concern and
residues of QCA in swine liver. The D. Approval of the 2004 Feed Use
that QCA is a reliable marker residue for regulatory method relies on a gas Combination
carbadox. (Ref. 1 at p. 9). chromatograph assay with electron
capture detection and has a limit of In 2004, FDA approved a combination
CVM established a tolerance of 30 ppb quantification of 5 ppb (Ref. 1 at p. 13), drug medicated feed containing
for residues of QCA in liver, the tissue a 6-fold improvement of the sensitivity carbadox and oxytetracycline under
in which residues persist for the longest from the previously approved regulatory NADA 141–211 (Ref. 17). In accordance
time. CVM concluded that the method (Ref 1.) with section 512(d)(4)(A) of the FD&C
concentration of residues of In October 1998, FDA approved an Act, approval of a combination new
carcinogenic concern in edible tissues additional supplement to NADA 041– animal drug, where the underlying new
was below the Sm when the 061 changing the withdrawal period for animal drugs have previously been
carbadox medicated feeds from 70 days separately approved for particular uses
compound being incorporated into naturally to 42 days. The supplement was and conditions of use for which they are
occurring molecules such as amino or nucleic acids approved based upon the previous intended for use in the combination,
or (2) covalently bound residues. Covalently bound will not be refused on human food
residues are considered to be of toxicological
approval of a tolerance of 30 ppb for
concern and their availability for absorption into QCA and a residue depletion study that safety grounds unless the application
the human gastrointestinal tract is considered showed that residues of QCA in liver fails to establish that: (1) None of the
during an evaluation of human food safety. depleted below 30 ppb by 42 days (Ref. animal drugs used in combination, at
Residues incorporated into endogenous molecules the longest withdrawal period for any of
are not considered bioavailable or to be of
16).
toxicological concern. However, CVM has To summarize, in 1998, when FDA the drugs in the combination, exceeds
determined that establishing a potentially approved supplements to NADA 041– its established tolerance or (2) none of
carcinogenic compound is bound and not of 061 establishing a drug tolerance and the drugs in the combination interferes
carcinogenic concern can be complicated by the shortening the withdrawal period, the with the method of analysis for any of
possibility of gastrointestinal binding and
gastrointestinal carcinogenesis and consequently evidence before CVM indicated: the other drugs in the combination
can involve a more comprehensive assessment of • A 0.915 ppb concentration of total (section 512(d)(4)(A)(i)–(ii) of the FD&C
residues of carcinogenic concern in liver Act). In other words, in order to approve
asabaliauskas on DSK3SPTVN1PROD with NOTICES
the bound compounds as described in GFI #3. Note
that while CVM has recognized that carbadox is the concentration that represents no a combination new animal drug for a
residues have not been fully extracted and
characterized, CVM has not made an assessment significant increase in the risk of cancer drug product that contains two
that the compounds are not carcinogenic because previously approved new animal drugs,
they are bound to endogenous molecules (Ref. 15 6 The SOM regulations, as they existed in 1998, no new information needs to be
at pp. 3–4). Moreover, residue studies presented to permitted approval of a regulatory method that supplied to establish the safety of either
JECFA in 2003 suggest that carcinogenic residues could detect the marker residue of the drug, as long
that had not been extracted when exposed to as the marker residue would only be detected at or
drug. Instead, the application need only
organic extraction were released by simulated below the Rm under the proposed conditions of use. demonstrate that use of the drugs in
digestive enzymes (Ref. 2 at pp. 7–8, Table 5). See § 500.86(c) (1998). combination will not result in violative
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residues of any component drug or in that it raised questions regarding the 7). This in vitro model of bioavailability
drug assay interference. safety of food resulting from swine was designed to mimic effects of gastric
Both carbadox and oxytetracycline treated with carbadox. Confidence in fluid and intestinal fluid incubation in
had been previously and separately the information evaluated by the 2003 human stomach and small intestine to
approved by FDA for the same JECFA that is the basis for CVM’s evaluate whether residues potentially
conditions of use proposed for their use concern about carbadox was increased could be released in the human
in combination. See 21 CFR 558.450 by the independent findings reported in gastrointestinal tract. To allow
(Oxytetracycline); § 558.115 (Carbadox). the two publications discussed further. comparison, some tissue samples were
The sponsor, Phibro, provided tissue left untreated while other tissue samples
residue depletion data demonstrating A. New Information Provided to JECFA were incubated in simulated gastric
that QCA residues did not exceed the In 2003, at the request of the Codex fluid (with pepsin) or in simulated
tolerance of 30 ppb when carbadox was Committee on Residues of Veterinary intestinal fluid (with pancreatin).
administered in conjunction with Drugs in Foods (CCRVDF), JECFA Residues of carbadox, DCBX, and QCA
oxytetracycline to swine (Ref. 17). A reevaluated the recommended were measured in the untreated tissues,
pharmacokinetic study comparing blood Maximum Residue Limits (MRLs) for in tissues that were incubated with
levels of oxytetracycline when carbadox that were based upon a 1990 enzymes, and in the supernatant of
administered alone and when JECFA evaluation of the new animal those tissues that were incubated with
administered in conjunction with drug (Ref. 2). CCRVDF, which includes enzymes (id.).
carbadox satisfied the need to CVM as a participant, determines Residues of carbadox, DCBX, and
demonstrate that residues of priorities for the consideration of QCA were measured by liquid
oxytetracycline would not exceed the residues of veterinary drugs in foods chromatography-atmospheric pressure
oxytetracycline tolerance at 42 days and recommends MRLs for veterinary chemical ionization tandem mass
(id.). drugs to the Codex Alimentarius spectrometry (LC/APCI–MS/MS). The
The sponsor further provided data Commission of the Food and tissue samples that were not incubated
demonstrating noninterference of Agriculture Organization and the World with enzymes were extracted with
oxytetracycline with the method of Health Organization of the United acetonitrile prior to analysis. The tissue
analysis of QCA in liver (id.). Having Nations. The Codex Alimentarius samples that were incubated with
made the required human food safety Commission develops harmonized enzymes were extracted with ethyl
demonstrations for combination animal international food standards, guidelines, acetate prior to analysis. Supernatants of
drugs, there was no basis to refuse and codes of practice to protect the the enzyme digestion were analyzed
approval of the product on human food health of the consumers and ensure fair directly without extraction. The limits
safety grounds. The combination new practices in food trade (see footnote 2). of quantification for LC/APCI–MS/MS
animal drug was subsequently approved Based on studies submitted to JECFA were 0.050 ppb for carbadox residues
(id.). that showed the persistence of and 0.030 ppb for DCBX residues (id.).
genotoxic, carcinogenic residues, JECFA The detection capabilities of this
V. New Information Regarding
could not determine an amount of methodology were greatly enhanced
Carcinogenic Residues in Edible
residues of carbadox in human food that compared to the previous method for
Tissues
would have no adverse health effects in carbadox and DCBX (i.e., the method
Three sources provide new consumers. JECFA recommended that used for the previous analytical work
information regarding carcinogenic the Codex MRLs be withdrawn. had a detection limit of 2 ppb) (Ref. 20).
residues in edible tissues: Data CCRVDF concurred with JECFA’s The study presented to JECFA showed
submitted to the 2003 JECFA and the recommendation and proposed to the that residue concentrations of carbadox
subsequent JECFA report (Ref. 2) and Commission that the MRLs be and DCBX were higher and persisted for
two publications in the peer-reviewed withdrawn. The Commission a longer period post dosing in liver than
literature (Refs. 4 and 6). subsequently agreed and withdrew the in the other sampled tissues. In liver
JECFA is an internationally without treatment with simulated
Codex MRLs for carbadox (Ref. 18 at p.
recognized expert body, providing the digestive fluids, carbadox was
120).
scientific evaluations that become the As part of the JECFA reevaluation detectable (0.050 ppb) as long as 48
basis for international food standards process, Phibro presented two new hours post dosing and DCBX was
established by the Codex Alimentarius residue studies to JECFA in 2003. Only detectable (0.138 ppb) at the last
Commission and supporting one of these studies involved sampling time point, which was 15 days
international treaties such as the measurement of the depletion of post treatment (Ref. 2 at pp. 7–8, Table
Sanitary Phytosanitary Agreement. carcinogenic metabolites of carbadox in 5). Treatment of tissues with simulated
JECFA experts are chosen based on edible tissues. In that study, animals digestive fluids resulted in
expertise, reputation, assurance of lack were fed for 14 days at the approved measurement of significantly higher
of conflict of interest, and familiarity dose of 55 ppm carbadox in feed (Ref. concentrations of DCBX. ‘‘Pretreatment
with the subject of that particular 2 at pp. 6–10). Animals were euthanized of the samples with digestive fluids
evaluation. increased the amounts of carcinogenic
at various time points between 0 hours
In addition, pursuant to section residues found in all tissues. In liver the
and 15 days post treatment, and samples
512(l)(1) of the FD&C Act,7 FDA ordered concentration of . . .[DCBX] increased
of swine muscle, liver, skin, and fat
Phibro to provide it with the same data by more than fourfold when the samples
asabaliauskas on DSK3SPTVN1PROD with NOTICES
were collected (Ref. 2 at pp. 7–8, Table
provided to the 2003 JECFA. CVM were treated with intestinal fluid, and
5).
evaluated the submitted data and found large quantities were present 15 days
Prior to analysis for residues, some of
after withdrawal . . .’’ (Ref. 2 at p. 17).
7 An order issued pursuant to section 512(l) of the
the tissue samples were exposed to
FD&C Act, requires a sponsor to submit such data human digestive enzymes 8 (Ref. 2 at p. ‘‘Studies to Evaluate the Metabolism and Residue
and information as FDA may find necessary to Kinetics of Veterinary Drugs in Food-Producing
determine or facilitate a determination whether 8 The use of enzymic preparations to characterize Animals: Metabolism Study to Determine the
grounds to withdraw approval of an NADA under residues is described in section 2.3.4.3.2 of CVM Quantity and Identify the Nature of Residues
section 512(e) of the FD&C Act exist. Guidance for Industry (GFI) #205 VICH GL 46, (MRK),’’ Sept. 15, 2011 (Ref. 19).
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In particular, the study showed that the average concentrations of the carcinogenic concern in liver that would
concentrations of approximately 35 ppb carcinogenic residue desoxy-carbadox present no significant increase in the
of DCBX at 0 hours post dosing and in liver estimated by regression analysis risk of cancer to people.
approximately 2.7 ppb of DCBX at 15 were about 4 [ppb]’’ (Ref. 2 at pp. 14, • Residues of carbadox previously
days post dosing were measured in liver 16–17). JECFA recognized that unextracted from edible tissues could be
treated with pancreatin (Ref. 2 at p. 8, ‘‘tolerance limits for the concentration released by gastric and intestinal fluids
Table 5). The significantly increased of desoxycarbadox were several times that mimic the human digestive process
residues found in liver after treatment higher owing to the wide variation of (Ref. 2 at p. 16). The enzymatic
with intestinal enzymes show that the data’’ and thereby concluded that treatment used in the study significantly
enzymatic treatment was able to release ‘‘QCA is not a suitable marker for increased the recoveries of
carcinogenic residues that were not monitoring carcinogenic metabolites of concentrations of DCBX and carbadox
extractable by organic solvents, such as carbadox in liver . . . and QCA does not from edible tissues, thereby indicating
those used in tissue residue studies to ensure the absence of carcinogenic that some portion of the previously
support the original and supplemental residues’’ (Ref. 2 at p. 17). unextracted and unidentified total
approval of NADAs for use of carbadox. In contrast to the previous findings of residues is composed of carcinogenic
JECFA evaluated the percent JECFA, these new data show that compounds.
recoveries of the analytes. Percent carcinogenic residues, in particular
recovery is a measurement of accuracy DCBX, are present in edible tissues for B. Additional New Evidence
of the analytical procedure and a significant time during the depletion Following the reports of the 2003
expresses the closeness of agreement of parent carbadox (Ref. 2 at p. 18). JECFA reevaluation of carbadox, CVM
between the true value of the analyte Moreover, the study shows that requested that Phibro also provide the
concentration and the mean value treatment with simulated digestive carcinogenic residue depletion study to
obtained by applying the analytical enzymes releases higher levels of the CVM. In 2005, in response to CVM’s
procedure (Ref. 21). JECFA reported that carcinogenic residues DCBX than were request for information, Phibro
when carbadox, DCBX, and QCA were recovered using organic extractions in submitted a summary of the
incubated for 4 hours with digestive the study. These higher concentrations carcinogenic residue depletion study
enzymes, carbadox and DCBX were provide evidence that the carbadox previously provided to JECFA. Upon
unstable (percent recovery decreased) in residues that were not extractable or review of the summary data, CVM asked
the samples treated with pepsin, but identified in previous studies submitted Phibro to submit existing studies or
were stable in pancreatin (Ref. 2 at p. to the Agency could include
provide new and complete studies that
16). JECFA also reported that the carcinogenic residues of carbadox that
address the relationship of QCA at 30
recoveries of the analytes from the liver are releasable with enzymatic treatment
ppb and carbadox and DCBX residues,
samples were generally variable and of tissues. This evidence calls into
and about the use of QCA as the marker
decreased to low levels when digestive question the Agency’s previous
residue for surveillance purposes. In
enzymes were used prior to extraction conclusions that all unextracted and
2006, CVM asked for and received from
(Ref. 2 at pp. 17–18). unidentified residues were
After evaluating the residue study, Phibro a timeline for submission of
noncarcinogenic residues related to
JECFA concluded that the poor complete information that addresses
QCA.
recoveries obtained with the enzyme After reviewing the new residue data, concerns about the relationship of QCA
experiments ‘‘showed that the true and considering the previously at 30 ppb and carbadox and DCBX
concentrations of the carcinogenic evaluated genotoxicity and residues, and about the use of QCA as
metabolites in tissues cannot yet be carcinogenicity data, JECFA the marker residue for surveillance
estimated with certainty, since an recommended withdrawal of the purposes. Between 2006 and 2011,
unknown portion of the releasable previously established Codex MRLs interactions between CVM and Phibro
residue [of carbadox and DCBX] is (Ref. 2 at p. 18). Codex subsequently continued, with protocols submitted
destroyed during incubation [of liver agreed and withdrew the MRLs for and reviewed, method validation
tissues] with the [digestive] enzymes’’ carbadox (Ref. 18 at p. 120). reports submitted and reviewed,
(Ref. 2 at p. 18). JECFA therefore In summary, the studies considered informal communications by email, and
concluded that the measured values of by JECFA during its 2003 review of the informal discussions by telephone. The
DCBX and carbadox ‘‘represent[ed] a drug indicated that: focus of the interactions was
lower estimate of the total present in the • Residues of the carcinogenic development and validation of methods
tissue’’ (id.). metabolite of carbadox, DCBX, were to measure QCA and DCBX in a tissue
Presented with data demonstrating measured in edible tissues for 15 days, residue depletion study. Despite the
both the depletion of QCA and which was the last sampling time point. continued interaction between Phibro
depletion of the carcinogenic residue DCBX was measured in swine liver after and CVM, Phibro has not submitted the
DCBX, JECFA established a relationship treatment with simulated digestive requested information.
between the concentrations of QCA and enzymes at concentrations as high as In 2011, pursuant to section 512(l)(1)
DCBX in liver (Ref. 2 at p. 14). The 2.69 ppb at 15 days post treatment (Ref. of the FD&C Act, FDA ordered Phibro to
statistical analysis of the data showed a 2 at p. 8, Table 5). provide all information in its possession
linear relationship between the • Analysis of measured with respect to: (1) The persistence of
logarithms of the concentrations of QCA concentrations of QCA and DCBX in DCBX in edible tissues; (2) the
asabaliauskas on DSK3SPTVN1PROD with NOTICES
and DCBX (Ref. 2 at pp. 14, 18). This liver indicated that approximately 4 ppb appropriateness of QCA as an analyte
relationship allowed JECFA to use of DCBX would be present in the liver for residue monitoring and for
regression analysis to assess the of treated animals when QCA reached establishing a withdrawal time for the
concentrations of DCBX when QCA the Codex MRL and the FDA tolerance use of carbadox in pigs; and (3) whether
depleted to 30 ppb in liver (the Codex of 30 ppb in liver (Ref. 2 at pp. 14, 17). an analytical method for monitoring
MRL and FDA approved tolerance for This concentration of DCBX alone is carbadox-related carcinogenic residues
carbadox). JECFA determined that ‘‘[a]t more than 4 times higher than the in edible tissues can be developed that
the MRL [of 30 ppb] for QCA in liver, concentration of total residues of would comply with part 500, subpart E.
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In response to the 2011 FDA order, analytical method capable of detecting exposure. The study JECFA reviewed
Phibro provided CVM with the full DCBX below the Sm for porcine muscle was limited to 15 days. The data
study report and appendices, previously and liver (Ref. 4 at p. 132, Table 5); and presented to JECFA in 2003 provide
provided to JECFA in 2003. (3) detection of DCBX at a concentration new scientific evidence that DCBX
CVM has independently evaluated the greater than 0.050 ppb in the diaphragm persists in edible tissues of swine as a
data from the Phibro study of depletion (but not the liver) of 2 of 6 hogs fed detectable residue beyond 72 hours (Ref.
of carcinogenic residues reviewed by carbadox, while QCA was not detected 2).
JECFA in 2003, and in particular has in the liver of those same hogs at a limit Further, Baars, et al., 1991, reports
reviewed the JECFA conclusion that of quantitation (LOQ) of 0.500 ppb (Ref. detecting DCBX in liver up to Day 14
when QCA reaches 30 ppb in liver, 4 at pp. 132–33). The findings of Boison, after cessation of exposure to carbadox
residues of DCBX in liver are ‘‘estimated et al., are significant for two reasons: (1) using an analytical method with a
by regression analysis to be about 4 QCA appears not to be a reliable marker detection limit of 1 ppb (Ref. 6). Baars,
[ppb]’’ (Ref. 2 at p. 18). CVM’s statistical residue and (2) DCBX is reported to be et al., 1991, provides new scientific
analysis of the residue concentrations of sensitive to the processing temperature evidence that DCBX persists as a
DCBX in liver treated with pancreatin (a used in the analytical method. detectable residue in edible tissues of
simulated intestinal fluid) shows that swine for greater than 72 hours.
concentrations of DCBX in liver, when 2. Baars, et al., 1991 Scientific evidence from JECFA’s
QCA reaches the 30 ppb approved In 2012, in response to FDA’s 2011 2003 evaluation of submitted
tolerance, would average 4 ppb and, order under section 512(l) of the FD&C information and Baars, et al., 1991,
based on the data in the JECFA report, Act, Phibro sent CVM a letter citing demonstrate that DCBX, one residue of
could reasonably range from 1.4 ppb to Baars, et al., 1990 (Ref. 5), an abstract of carcinogenic concern for carbadox,
11 ppb, using a 95 percent prediction a study not previously provided. CVM persists in edible tissues of swine
range. Based upon this analysis, DCBX obtained the study report Baars, et al., beyond 72 hours. All of this evidence
alone—leaving aside additional, 1991 (Ref. 6), which reports an was first received by CVM after the 1998
unidentified residues of carcinogenic analytical method with a limit of approval of the supplemental
concern—significantly exceeds the detection of 1 ppb that detects the application to NADA 041–061. Based on
approved Sm when QCA, the approved presence of DCBX in edible tissues for this new scientific evidence, the
marker residue, reaches the approved greater than 72 hours after removal of previous conclusion that DCBX does not
tolerance. The new evidence from the feed containing carbadox. Specifically, persist in edible tissues of swine as a
2003 JECFA re-evaluation of carbadox, Baars, et al., 1991, demonstrated the detectable residue beyond 72 hours is
along with studies that were later presence of DCBX for up to 7 days (∼168 no longer justified.
submitted to CVM, undermine the hours) in the kidney and 14 days (∼336 2. Previous Conclusion 2: The
human food safety conclusions that hours) in the liver of swine fed carbadox unextracted residues are related to a
CVM had previously reached when (Ref. 5 at p. 3, Fig. 3; Ref. 6 at p. 290, noncarcinogenic compound, QCA, and
considering the approval of the new Fig. 2). This observation called into extractable QCA is the only residue
animal drug applications for carbadox question CVM’s previous conclusion detectable in the edible tissues of swine
for its various uses. CVM has engaged that all residues of carcinogenic concern 72 hours post dosing.10
with Phibro to evaluate the carbadox- deplete within 72 hours. At the time of the 1998 supplemental
associated safety concerns raised by the approval, CVM concluded that that
C. New Evidence Calls Into Question unextracted residues were related to the
new evidence and repeatedly has asked Prior CVM Conclusions That Were the
Phibro to submit information that would noncarcinogenic compound, QCA, and
Basis of the 1998 Supplemental that extractable QCA was the only
address these safety concerns. Approval
Information provided by Phibro in residue detectable in the edible tissues
response to these requests has not CVM’s prior conclusion that QCA is a after 72 hours post dosing. However,
resolved CVM’s human food safety reliable marker residue for carbadox and CVM is now aware of reports of
concerns. its metabolites was predicated on extraction of residues being enhanced
several underlying conclusions (Ref. 1 at by pepsin or pancreatin digestion prior
1. Boison, et al., 2009 pp. 13–14). These underlying to organic extraction, making non-QCA
In addition, a 2009 publication calls conclusions are reviewed below in light residues previously thought to be
into question conclusions made by CVM of the new evidence presented above. unextractable currently extractable (Ref.
when it approved the NADAs and 1. Previous Conclusion 1: The residue 2). JECFA reports that some residues of
supplemental NADAs for carbadox (Ref. data show that carbadox, DCBX, and carbadox previously identified as
4). Boison, et al., 2009, demonstrates the hydrazine do not persist in edible unextractable can now be extracted (id.).
availability of a sensitive analytical tissues as detectable residues beyond 72 DCBX was found in the newly
method for DCBX, and provides hours.9 extractable residues. This scientific
information from which serious Since the time CVM made this evidence demonstrates that some
questions about the safety of carbadox previous conclusion, we have become residues previously found to be
can be inferred, specifically whether aware of information that undermines unextractable are extractable and that
DCBX may be present in edible tissues the previous conclusion that carbadox the unextractable residues are not all
of treated swine above the Sm even and its carcinogenic metabolites do not related to QCA.
when the marker residue (QCA) persist in edible tissues beyond 72 As discussed above, residues of
asabaliauskas on DSK3SPTVN1PROD with NOTICES
concentration is below the tolerance of hours. JECFA, in 2003, reviewed a study DCBX, a residue of carcinogenic
30 ppb (id.). detecting DCBX in livers of swine up to concern, have been detected in edible
Boison, et al., report: (1) QCA is not 15 days after cessation of carbadox tissues longer than 72 hours post dosing
a suitable marker for the regulation of
9 This underlying conclusion is described in the 10 This underlying conclusion is described in the
carbadox because while QCA is very
January 30, 1998, summary basis of approval under January 30, 1998, summary basis of approval under
stable under temperature conditions the Freedom of Information Act (FOI Summary) for the Freedom of Information Act (FOI Summary) for
above 60 °C (i.e., 105 °C), DCBX is not NADA 041–061 (Ref. 1 at p. 9) and in the report NADA 041–061 (Ref. 1 at p. 9) and in the report
(Ref. 4 at p. 133); (2) the existence of an of the 1990 JECFA meeting (Ref. 10 at p. 30). of the 1990 JECFA meeting (Ref. 10 at p. 30).
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![21572 Federal Register / Vol. 81, No. 70 / Tuesday, April 12, 2016 / Notices
residues are treated as carcinogenic. No of any contentions concerning the legal supplemental approval January 30, 1998.
evidence has been presented to CVM by status of any such drug product, and the Available at http://www.fda.gov/
Phibro or any other source to show that Director of CVM will summarily enter a downloads/AnimalVeterinary/Products/
ApprovedAnimalDrugProducts/
the unidentified residues are final order withdrawing the approvals.
FOIADrugSummaries/UCM429999.pdf
noncarcinogenic or that the residues do Any new animal drug product marketed (accessed on March 19, 2016).
not otherwise present a threat to public without an approved NADA is subject to 2. JECFA, Report on Carbadox, 2003.
health. As a result, carbadox is not regulatory action at any time. Available at ftp://ftp.fao.org/ag/agn/
shown to be safe under the General A request for a hearing may not rest jecfa/vetdrug/41-15-carbadox.pdf
Safety Clause. upon mere allegations of denials, but (accessed on March 19, 2016).
must set forth specific facts showing 3. FDA, Memorandum to the File, Claycamp,
VI. Notice of Opportunity for a Hearing H.G., ‘‘Preliminary Risk Characterization:
that there is a genuine and substantial
New evidence regarding carcinogenic issue of fact that requires a hearing. If Cancer Risk Estimation from Carbadox
residues in edible tissues of swine Residues in Pork from Swine Treated
it conclusively appears from the face of with Carbadox,’’ December 16, 2014.
treated with carbadox raises serious the data, information, and factual 4. Boison, J.O., S.C. Lee, and R.G. Gedir, ‘‘A
questions about the human food safety analyses in the request for hearing that Determinative and Confirmatory Method
of the drug. Therefore, CVM is there is no genuine and substantial issue for Residues of the Metabolites of
proposing to withdraw approval of the of fact that precludes the withdrawal of Carbadox and Olaquindox in Porcine
three NADAs that provide for use of approval of the applications, or when a Tissues,’’ Analytica Chimica Acta,
carbadox in swine feed because new request for hearing is not made in the 637:128–134, 2009.
evidence demonstrates that the drug no required format or with the required 5. Baars, A.J., L.A. van Ginkel, M.M.L. Aerts,
longer meets the DES Proviso exception et al., ‘‘Kinetics of Carbadox Residues in
analyses, the Commissioner of Food and
to the Delaney Clause and because new Pigs,’’ In: Proceedings of the EuroResidue
Drugs will enter summary judgment Conference, Noorwijkerhout (Haagsma,
evidence demonstrates that carbadox is against the person who requests a N., A. Ruiter, and P.B. Czedik-Eysenberg,
not shown to be safe under the General hearing, making findings and eds., May 21–23, 1990.
Safety Clause. conclusions, and denying a hearing. 6. Baars, A.J., L.P. Jager, T.J. Spierenberg, et
Therefore, notice is given to Phibro If a hearing is requested and is al., ‘‘Residues of Carbadox Metabolites in
Animal Health Corp., 65 Challenger Rd., justified by the sponsor’s response to Edible Pork Products,’’ Archives of
Ridgefield Park, NJ 07660, and to all this NOOH, the issues will be defined, Toxicology Supplement, 14:288–92,
other interested persons, that the a presiding officer will be assigned, and 1991.
Director of CVM proposes to issue an a written notice of the time and place at 7. FDA, CVM Guidance for Industry (GFI) #3,
order under section 512(e) of the FD&C which the hearing will commence will ‘‘General Principles for Evaluating the
Act withdrawing approval of all NADAs Safety of Compounds Used in Food-
be issued as soon as practicable. Producing Animals,’’ July 25, 2006.
providing for use of carbadox in This notice is issued under section
medicated swine feed. Available at http://www.fda.gov/
512 of the FD&C Act and under the downloads/animalveterinary/
In accordance with section 512 of the authority delegated to the Director of guidancecomplianceenforcement/
FD&C Act and part 514 (21 CFR part CVM. guidanceforindustry/ucm052180.pdf
514) and under the authority delegated (accessed on March 19, 2016).
to the Director of CVM, Phibro Animal VII. Environmental Impact 8. FDA, Memorandum to the File, from
Health Corp., the sponsor, is hereby The Agency has determined under 21 Director, Division of New Animal Drugs
given an opportunity for hearing to CFR 25.33(g) that this action is of a type to Director, Bureau of Veterinary
show why approval of NADAs 041–061, that does not individually or Medicine regarding NADA 41–061—
092–955, and 141–211 should not be cumulatively have a significant impact Carbadox for Swine (September 22,
withdrawn. 1972).
on the human environment. Therefore, 9. FDA, Memorandum to the File, S.H.
If the sponsor, Phibro Animal Health neither an environmental assessment
Corp., wishes to request a hearing the Frazier, Jr., Division of Toxicology, to
nor an environmental impact statement Director, Bureau of Veterinary Medicine,
sponsor must file: (1) On or before [see is required. regarding Carbadox for Swine, August
DATES], a written notice of appearance 27, 1970.
and request for a hearing and (2) on or VIII. Paperwork Reduction Act of 1995
10. JECFA, Report on Carbadox, 1990.
before [see DATES], the data, The collections of information Available at ftp://ftp.fao.org/ag/agn/
information, and analyses relied on to requirements for this document are jecfa/vetdrug/41-3-carbadox.pdf
demonstrate that there is a genuine and covered under OMB control numbers (accessed on March 19, 2016).
substantial issue of fact to justify a 0910–0032 and 0910–0184. 11. FDA, Memorandum to the File, from
hearing as specified in § 514.200. Any Division of New Animal Drugs to
other interested person may also submit IX. References Director, Bureau of Veterinary Medicine,
The following references have been regarding NADA 41–061, Carbadox for
comments on this notice (see, Swine (July 7, 1972).
ADDRESSES). Procedures and placed on display in the Division of 12. FDA, Memorandum to the File, Approval
requirements governing this NOOH, a Dockets Management (see ADDRESSES) of Original New Animal Drug
notice of appearance and request for a and may be seen by interested persons Application NADA 92–955 (July 29,
hearing, submission of data, between 9 a.m. and 4 p.m., Monday 1975).
information, and analyses to justify a through Friday, and are available 13. Citizen Petition, Center for Science in the
hearing, other comments, and a grant of electronically at http:// Public Interest, Docket No. FDA–1986–
asabaliauskas on DSK3SPTVN1PROD with NOTICES
denial of a hearing, are contained in www.regulations.gov. (FDA has verified P–0299 (formerly 86P–0212), May 9,
§ 514.200 and 21 CFR part 12. the Web site addresses, but FDA is not 1986.
responsible for any subsequent changes 14. FDA, Response to Citizen Petition, Center
The failure of a holder of an approval
for Science in the Public Interest, Docket
to file timely a written appearance and to the Web sites after this document No. FDA–1986–P–0299 (formerly 86P–
request for hearing as required by publishes in the Federal Register.) 0212), May 30, 1995.
§ 514.200 constitutes an election not to 1. FDA, Freedom of Information (FOI) 15. FDA, Memorandum to the File, from
avail himself or herself of the Summary, NADA 041–061, MECADOX Residue Evaluation Branch, Division of
opportunity for a hearing and a waiver 10 (carbadox) Type A medicated article, Chemistry to Director, Division of
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![Federal Register / Vol. 81, No. 70 / Tuesday, April 12, 2016 / Notices 21573
Chemistry, regarding Review of DEPARTMENT OF HEALTH AND do not wish to be made available to the
Carbadox Metabolism (September 7, HUMAN SERVICES public, submit the comment as a
1994). written/paper submission and in the
16. FDA, Freedom of Information (FOI) Food and Drug Administration manner detailed (see ‘‘Written/Paper
Summary, NADA 041–061, MECADOX Submissions’’ and ‘‘Instructions’’).
[Docket No. FDA–2014–E–1222]
10 (carbadox) Type A medicated article,
supplemental approval October 5, 1998. Written/Paper Submissions
Determination of Regulatory Review
Available at http://www.fda.gov/ Period for Purposes of Patent Submit written/paper submissions as
AnimalVeterinary/Products/ Extension; APOQUEL follows:
ApprovedAnimalDrugProducts/ • Mail/Hand delivery/Courier (for
FOIADrugSummaries/ucm064223.htm AGENCY: Food and Drug Administration, written/paper submissions): Division of
(accessed on March 19, 2016). HHS. Dockets Management (HFA–305), Food
17. FDA, Freedom of Information (FOI) ACTION: Notice. and Drug Administration, 5630 Fishers
Summary, NADA 141–211, MECADOX Lane, Rm. 1061, Rockville, MD 20852.
10 (carbadox) and TERRAMYCIN 50, SUMMARY: The Food and Drug • For written/paper comments
100, or 200 (oxytetracycline) in Type C Administration (FDA) has determined submitted to the Division of Dockets
medicated feed, original approval July the regulatory review period for Management, FDA will post your
21, 2004. Available at http:// APOQUEL and is publishing this notice comment, as well as any attachments,
www.fda.gov/downloads/ of that determination as required by except for information submitted,
AnimalVeterinary/Products/ law. FDA has made the determination marked and identified, as confidential,
ApprovedAnimalDrugProducts/ because of the submission of an if submitted as detailed in
FOIADrugSummaries/ucm118005.pdf application to the Director of U.S. Patent ‘‘Instructions.’’
(accessed on March 19, 2016). and Trademark Office (USPTO), Instructions: All submissions received
18. Codex Alimentarius Commission, Department of Commerce, for the must include the Docket No. FDA–
Twenty-Eighth Session, Headquarters, extension of a patent which claims that 2014–E–1222 for ‘‘Determination of
Food and Agriculture Organization, animal drug product. Regulatory Review Period for Purposes
Rome, Italy, 2005. DATES: Anyone with knowledge that any of Patent Extension; APOQUEL.’’
19. FDA, CVM Guidance for Industry (GFI) of the dates as published (in the Received comments will be placed in
#205, VICH GL 46, ‘‘Studies to Evaluate SUPPLEMENTARY INFORMATION section) are the docket and, except for those
the Metabolism and Residue Kinetics of incorrect may submit either electronic submitted as ‘‘Confidential
Veterinary Drugs in Food-Producing or written comments and ask for a Submissions,’’ publicly viewable at
Animals: Metabolism Study to redetermination by June 13, 2016. http://www.regulations.gov or at the
Determine the Quantity and Identify the Furthermore, any interested person may Division of Dockets Management
Nature of Residues (MRK),’’ September petition FDA for a determination between 9 a.m. and 4 p.m., Monday
15, 2011. Available at http:// regarding whether the applicant for through Friday.
www.fda.gov/downloads/ extension acted with due diligence • Confidential Submissions—To
AnimalVeterinary/ during the regulatory review period by submit a comment with confidential
GuidanceComplianceEnforcement/ October 11, 2016. See ‘‘Petitions’’ in the information that you do not wish to be
GuidanceforIndustry/UCM207939.pdf made publicly available, submit your
SUPPLEMENTARY INFORMATION section for
(accessed on March 19, 2016). comments only as a written/paper
more information.
20. MacIntosh, A.I., G. Lauriault, and G.A. submission. You should submit two
ADDRESSES: You may submit comments
Neville, ‘‘Liquid Chromatographic copies total. One copy will include the
Monitoring of the Depletion of Carbadox as follows:
information you claim to be confidential
and its Metabolite Desoxycarbadox in Electronic Submissions with a heading or cover note that states
Swine Tissues,’’ Journal—Association of ‘‘THIS DOCUMENT CONTAINS
Submit electronic comments in the
Official Analytical Chemists, 68:665–71, CONFIDENTIAL INFORMATION.’’ The
1985.
following way:
• Federal eRulemaking Portal: http:// Agency will review this copy, including
21. FDA, CVM Guidance for Industry (GFI)
www.regulations.gov. Follow the the claimed confidential information, in
#208, VICH GL 49, ‘‘Studies to Evaluate
instructions for submitting comments. its consideration of comments. The
the Metabolism and Residue Kinetics of
Comments submitted electronically, second copy, which will have the
Veterinary Drugs in Food-Producing
Animals: Validation of Analytical including attachments, to http:// claimed confidential information
Methods Used in Residue Depletion www.regulations.gov will be posted to redacted/blacked out, will be available
Studies,’’ September 15, 2011. Available the docket unchanged. Because your for public viewing and posted on http://
at http://www.fda.gov/downloads/ comment will be made public, you are www.regulations.gov. Submit both
AnimalVeterinary/ solely responsible for ensuring that your copies to the Division of Dockets
GuidanceComplianceEnforcement/ comment does not include any Management. If you do not wish your
GuidanceforIndustry/UCM207942.pdf confidential information that you or a name and contact information to be
(accessed on March 19, 2016). third party may not wish to be posted, made publicly available, you can
22. FDA, Memorandum to the File, such as medical information, your or provide this information on the cover
Claycamp, H. G., Verification and anyone else’s Social Security number, or sheet and not in the body of your
confidential business information, such comments and you must identify this
asabaliauskas on DSK3SPTVN1PROD with NOTICES
Extension of the 2003 JECFA Carbadox
Monograph Analyses, July 29, 2012. as a manufacturing process. Please note information as ‘‘confidential.’’ Any
that if you include your name, contact information marked as ‘‘confidential’’
Dated: April 6, 2016.
information, or other information that will not be disclosed except in
Tracey Forfa, accordance with 21 CFR 10.20 and other
identifies you in the body of your
Acting Director, Center for Veterinary comments, that information will be applicable disclosure law. For more
Medicine. posted on http://www.regulations.gov. information about FDA’s posting of
[FR Doc. 2016–08327 Filed 4–8–16; 11:15 am] • If you want to submit a comment comments to public dockets, see 80 FR
BILLING CODE 4164–01–P with confidential information that you 56469, September 18, 2015, or access
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Document Created: 2016-04-12 00:46:48
Document Modified: 2016-04-12 00:46:48
| Category | Regulatory Information | |
| Collection | Federal Register | |
| sudoc Class | AE 2.7: GS 4.107: AE 2.106: | |
| Publisher | Office of the Federal Register, National Archives and Records Administration | |
| Section | Notices | |
| Action | Notice of opportunity for hearing. | |
| Dates | Phibro Animal Health Corp. may submit a request for a hearing by May 12, 2016. Submit all data and analysis upon which the request for a hearing relies by July 11, 2016. | |
| Contact | Vernon Toelle, Center for Veterinary Medicine (HFV-230), 7519 Standish Pl., Rockville, MD 20855, 240-276- 9200. | |
| FR Citation | 81 FR 21559 |
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