1. What is carbadox?
Carbadox is an animal drug used in swine (hogs and pigs) for production purposes (e.g., increased rate of weight gain and improved feed efficiency) and therapeutic purposes (e.g., to control swine dysentery and bacterial swine enteritis). Carbadox is an animal drug shown to be carcinogenic in laboratory animals. While carbadox is also an antimicrobial, it does not pose the same resistance issues as other antimicrobials and is not considered important to human medicine.
2. What is the current status of the approved animal drug products containing carbadox?
There are three approved New Animal Drug Applications (NADAs) for animal drug products containing carbadox, all held by Phibro Animal Health:
- Mecadox Premix 10 (NADA 041-061); contains carbadox alone
- Banminth/Mecadox (NADA 092-955); contains carbadox plus pyrantel tartrate
- Mecadox/Terramycin (NADA 141-211); contains carbadox plus oxytetracycline
On November 7, 2023, FDA published a final order revoking the regulatory method for carbadox. At the same time, FDA published a Notice of Opportunity for Hearing (NOOH) on a proposal to withdraw approval of these NADAs because there is no longer an approved regulatory method to monitor the residue of carcinogenic concern in compliance with FDA’s regulations in 21 CFR part 500, subpart E. However, unless approval of the NADAs is withdrawn, these drugs remain available for sale and use in the United States.
3. How does the FDA regulate carcinogenic animal drugs?
Under the Delaney Clause in Section 512 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the FDA cannot approve a new animal drug application if it is found to "induce cancer when ingested by man or animal….” An exception to this general rule, referred to as the Diethylstilbestrol "DES" Proviso, allows for the approval of a carcinogenic drug if the FDA finds that, under the approved conditions of use, the drug will not adversely affect treated animals and no residues of the drug will be found by an approved regulatory method in any edible tissues of, or foods from, the animal.
4. Why did FDA revoke the approved method for carbadox?
In 1998, the FDA’s Center for Veterinary Medicine (CVM) approved the most recent testing method for carbadox based on information available to CVM at that time. The method relied on measuring the noncarcinogenic residue quinoxaline-2-carboxylic acid (QCA) as a marker to demonstrate when the residue of carcinogenic concern in the edible tissue of carbadox-treated animals dropped to a level that satisfied the DES Proviso. However, subsequent information showed that carcinogenic residues of carbadox persist longer than previously known. This means that noncarcinogenic QCA is not a reliable marker, as measured by the 1998-approved method, to satisfy the DES Proviso. Specifically, because there is no established relationship between noncarcinogenic QCA measured by the 1998-approved method and the residue of carcinogenic concern, the 1998-approved method does not allow FDA to determine whether the residue of carcinogenic concern can be found in any edible tissue of, or food derived from, the treated animals. Accordingly, in November 2023, FDA revoked the 1998-approved method.
There is currently no approved method for carbadox. Without an approved method, the second prong of the DES Proviso exception to the Delaney Clause, which requires that “no residue of such drug will be found (by methods of examination prescribed or approved by the Secretary by regulations,…), in any edible portion of such animals after slaughter or in any food yielded by or derived from the living animals,” is not met.
5. If there is no longer an approved method to monitor the residue of carcinogenic concern, how will residues of carbadox be monitored?
The revocation of the approved method did not affect the withdrawal and tolerance standards outlined in FDA’s regulations – specifically, the 42-day withdrawal period for Mecadox Premix 10 (NADA 041-061) and Banminth/Mecadox (NADA 092-955) (see 21 CFR 558.115), and the 70-day withdrawal period for Mecadox/Terramycin (NADA 141-211) (see 21 CFR 558.450), as well as the 30 ppb QCA tolerance listed in 21 CFR 556.100.
6. What is the expected impact of this action on the swine industry?
Because the FDA first made public its concern regarding the adequacy of the 1998-approved method with regard to carbadox in 2016, the swine industry has had the opportunity to consider and mitigate potential impacts of this action for several years. In the 2020 proposed order to revoke the carbadox method, the FDA explained that if it finalized the order, it intended to issue a NOOH proposing to withdraw approval of all new animal drug applications containing carbadox because they would no longer satisfy the DES Proviso of the Delaney Clause.
Although carbadox currently remains available for use by the swine industry, if approvals of the applications for carbadox are ultimately withdrawn, carbadox will no longer be available. If this happens, the FDA will work to minimize impacts on the swine industry to the extent possible while ensuring the safety of the food supply.
Should they so choose, pork producers can also work with their veterinarian to identify alternatives to the use of carbadox, such as implementing preventative measures that reduce the need for a drug like carbadox, like vaccination or changes in husbandry practices, and use of other approved drugs.
7. Should consumers stop eating pork products treated with carbadox?
As a general matter, eating a well-balanced diet can facilitate good nutrition and may minimize potential adverse consequences from consuming an excess of any one food.
The agency recognizes that pork is a common protein in American diets. Although the agency is not recommending that people make changes in their food choices during the time that CVM is working to remove the drug from the market, the agency offers the following comment: Pork is a good source of protein; protein can also be found in other meat, poultry, seafood, beans and peas, eggs, processed soy products, nuts and seeds. Selection of a variety of protein foods can improve nutrient intake and health benefits.
8. Does FDA have information about which pork products come from pigs that were treated with carbadox?
No. Producers are not required to report to the FDA which drugs they use.
9. Why did FDA hold a Part 15 public hearing?
FDA regulations provide that the procedures in Part 15 apply when, among other things, the Commissioner concludes that it is in the public interest to permit people to present information and views at a public hearing on any matter pending before the Agency. On March 10, 2022, CVM held a Part 15 public hearing for the public to present scientific data and information related to the residue of carcinogenic concern for carbadox. A transcript of the public hearing can be found at Regulations.gov.
10. Why did the FDA issue an NOOH in November 2023? What are the grounds for the FDA’s new proposal to withdraw the drug?
On November 7, 2023, the FDA published in the Federal Register a notice that CVM is proposing to withdraw the approval of all new animal drug applications containing carbadox because there is no longer an approved regulatory method to monitor the residue of carcinogenic concern in compliance with FDA’s regulations in 21 CFR part 500, subpart E. These regulations set out 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 obtained from, the animal, as required to meet the requirements of the DES Proviso.
The FDA is proposing to withdraw the drug pursuant to Section 512(e)(1)(B) of the FD&C Act because there is now no approved regulatory method. Section 512(e)(1)(B) provides grounds for FDA to propose withdrawal of approval of a new animal drug application when “new evidence not contained in such application or not available to the Secretary 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 … [the Delaney Clause] applies to such drug.”