This past Tuesday, FDA issued a Notice of Opportunity for Hearing (NOOH) proposing to withdraw approval of all new animal drug applications for carbodox that have an indication for use in medicated swine feed. Specifically, FDA is proposing to withdraw approval for this product because it has concluded that certain drug metabolites of the drug are carcinogenic and that the approved withdrawal periods are insufficient to ensure that metabolite residues do not exceed safe levels in the pork produced from pigs administered the drug.
In 2003, the Joint Expert Committee on Food Additives within the World Health Organization (JECFA) issued a report that included data suggesting that residue levels of the carcinogenic metabolites were approximately four times higher than what would be considered safe. A 2014 FDA internal memorandum subsequently concluded that continued approval of the drug would expose humans to between 11 and 30 times the level of metabolites that would be considered safe. FDA also found that this report and internal memorandum are consistent with scientific publications dating back as far as 1990 that suggest that FDA’s earlier conclusions of human food safety were incorrect.
FDA is basing its proposed withdrawal on two distinct legal theories. First, because FDA believes that the metabolites are unsafe for human consumption, FDA asserts that the “new” information regarding the drug and its metabolites renders the product unsafe under the conditions of use described in the approved product labeling. Thus, the product fails to meet what FDA calls the “General Safety Clause” found in section 512 of the FDC Act. There, FDA has the authority to withdraw an approved application if there is data to “show that such drug is unsafe for use under the conditions of use upon the basis of which the application was approved.” FDC Act § 512(e)(1).
Second, and perhaps more interesting, is that FDA bases its proposed withdrawal on a conclusion that carbadox no longer can use the “DES Proviso” exception to the Delaney Clause. We know that for many readers, you are now wondering whether our blog just went haywire and started publishing in a foreign language. So, let’s back up a bit...
In 1968, Congress added a specific subparagraph to the animal drug provisions of the FDC Act. That subparagraph was one of three clauses added to the FDC Act over a ten-year period (from 1958 to 1968) that gave FDA the authority to evaluate and reject food additives, color additives, and animal drugs that are found to induce cancer when ingested by man or animals. Collectively, these provisions are referred to as the Delaney Clauses. The Delaney Clause relevant to animal drug applications, found at section 512(d)(1)(I), however, includes an exception that was included in the statute to cover certain animal drugs such as diethylstilbestrol, often referred to as DES. FDA refers to this exception as the DES Proviso. Via the DES Proviso, a new animal drug that is found to be carcinogenic can, nonetheless, be approved if FDA finds that, under the conditions of use: (1) the drug will not adversely affect animals given the drug; and (2) no residues of the drug are found in the food products derived from treated animals.
It has been known that carbadox was a carcinogen since before it was first approved in 1972. But, because FDA at that time believed that all carcinogenic residues from carbadox would not be detectable in swine tissue after a specified period of time (i.e., the withdrawal period), FDA approved carbadox under the DES Proviso to the Delaney Clause. In 1986, the Center for Science in the Public Interest filed a Citizen Petition asking FDA to withdraw the approval of carbadox due to concerns over carcinogenicity of specified metabolites of the drug. In 1995, FDA denied the petition after finding that, if the product was used according to the approved label, drug residues would not pose a risk to humans consuming the pork from treated animals. In 1998, FDA again found that carbadox residues did not pose a risk to humans consuming pork products. However, based on the 2003 JECFA report and the published literature, FDA has reversed course, finding that the data no longer support a finding that carbadox meets the DES Proviso standard, and, therefore, the general prohibition against approval in the Delaney Clause applies.
To the best of our recollection, this is the first time that FDA has first found that the DES Proviso applies to a drug application, then approved the drug, and later reversed course and sought the withdrawal of the approval based on application of the Delaney Clause. In 1991, FDA withdrew the approval for furazolidone under the same two theories (the Delaney Clause and the General Safety Clause), but in that case furazolidone was approved without any carcinogenicity issues (unlike carbadox, which was initially approved under the DES Proviso).
It is important to note that Phibro Animal Health, the company that manufactures carbadox, stands by the safety of the product. As has been reported by CBS News, the company has stated:
We are disappointed that the FDA would take this action when definitive studies are so close to being completed. Under the FDA's process, we intend to request a hearing and refute the allegations. Phibro will continue to market the product and to vigorously defend [carbadox] based on more than 40 years of science and safe use.
While the safety of carbadox continues to be debated, one thing is for sure: the process for Phibro to seek a hearing and the appeals that such a process may entail will likely mean that this issue is not settled for quite some time.