Cephalosporin Order of Prohibition
Questions and Answers
July 16, 2008
On July 3, 2008, the Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM) issued an order prohibiting the extralabel use of the cephalosporin class of antimicrobial drugs in food-producing animals. A copy of the Federal Register document is available at (http://edocket.access.gpo.gov/2008/E8-15052.htm). CVM recognizes that this action will impact the practice of veterinary medicine in that veterinarians will need to seek alternative therapies for those cases where they previously relied on the extralabel use of cephalosporins. Concerns regarding such impacts of implementing the prohibition have been communicated in a number of comments submitted to the agency to date. CVM is interested in receiving these and any other comments on the implementation of the order of prohibition. Although the basis for the order is fully described in the July 3 final rule, CVM has provided the following questions and answers to help address concerns that may be raised.
When does the order go into effect and is there an opportunity for the public to comment?
The order of prohibition that published as a final rule on July 3, 2008, will go into effect on October 1, 2008. However, the public can submit comments during a 60-day comment period that closes on September 2, 2008. CVM will review all submitted comments and will take into account any relevant information that it had not previously considered.
You may submit written or electronic comments to the Division of Dockets Management. Comments are to be identified with the docket number FDA-2008-N-0326. Received comments may be seen in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday through Friday. Electronic comments or submissions will be accepted by FDA only through the Federal Docket Management System (FDMS) at http://www.regulations.gov/.
More detailed information regarding the submission of comments is contained in the July 3, 2008, Federal Register document. See http://edocket.access.gpo.gov/2008/E8-15052.htm.
Does the new final rule mean that all cephalosporin drug use in food-producing animals is prohibited?
No, the rule only applies to the extralabel use of cephalosporins in food-producing animals. Use of cephalosporin drugs for their approved indications in food animal species is not prohibited under this rule because human food safety issues regarding the approved conditions of use were evaluated during the approval process and found to be safe.
What is extralabel drug use?
The term “extralabel use” refers to use of an approved drug in an animal in a manner that does not follow the approved labeling. Extralabel drug use should only occur in circumstances when an animal’s health is threatened, or suffering or death may occur if treatment is not administered.
Under the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA), extralabel use of drugs in animals is permitted only by, or on the order of, a licensed veterinarian within the context of a valid veterinarian-client-patient relationship. A valid veterinarian-client-patient relationship has several specific components. First, a veterinarian takes responsibility for making medical judgments regarding the animal’s health and the need for medical treatment, and the client (the owner of the animal or animals or other caretaker) agrees to follow the veterinarian’s instructions. Second, the veterinarian is familiar with the animal and can provide a general or preliminary diagnosis for the animal’s medical condition. Third, the veterinarian is available for follow-up in the event of adverse reactions or treatment failure. Therefore, a valid veterinarian-client-patient relationship exists only when the veterinarian has recently seen, and is personally familiar with, how the animal is cared for by virtue of physically examining the animal during medically-appropriate or routine visits to the location where the animal is kept.
Extralabel drug use in food-producing animals carries additional requirements because of the potential for drug residues in edible animal products. The complete extralabel use requirements are found in Title 21 of the U.S. Code of Federal Regulations, Part 530
(http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&sid=089f4038cbe4ebeb439fa31fb6081c81&rgn=div5&view=text&node=21:6.0.1.1.15&idno=21). Some of the requirements for extralabel drug use in food-producing animals include:
*A valid veterinarian-client-patient relationship must exist.
*There is no approved animal drug labeled for the treatment need which has the same active ingredient in the required dosage form and concentration; or, the approved animal drug is clinically ineffective for its approved use and an effective substitute is needed.
*The veterinarian must carefully evaluate and diagnose the condition requiring treatment.
*The veterinarian must establish a scientifically appropriate withdrawal period, based on appropriate scientific information, if available.
*The veterinarian must ensure that the treated animal’s identity is carefully documented and maintained.
*The veterinarian must ensure that the assigned withdrawal times are observed and no illegal drug residues occur in any food-producing animal receiving extralabel drug treatment.
Have other drugs been prohibited from extralabel use in food-producing animals?
Yes. Under AMDUCA, FDA can prohibit the extralabel use of approved animal or human drugs, or an entire class of drugs, in animals if FDA determines that 1) an acceptable analytical method needs to be established and such a method has not or cannot be established; or 2) the extralabel use of the drug or drug class presents a public health risk. FDA can also limit extralabel use to specific species, indications, dosage forms, routes of administration, or a combination of these.
In the case of cephalosporins, FDA is prohibiting extralabel use of the entire class of cephalosporin drugs to avoid risks to public health.
When the Order of Prohibition takes effect, cephalosporins will be added to the current list of drugs and other substances prohibited from extralabel use in all food-producing animals as follows:
Cephalosporins
Chloramphenicol
Clenbuterol
Diethylstilbesterol (DES)
Dimetridazole
Ipronidazole
Other nitroimidazoles
Furazolidone, Nitrofurazone, and other nitrofurans
Sulfonamide drugs in lactating dairy cattle (except approved use of sulfadimethoxine, sulfabromomethazine, and sulfaethoxypyridazine);
Fluoroquinolones
Glycopeptides, and
Phenylbutazone in female dairy cattle 20 months of age or older
In addition, the extralabel use of the following drugs or classes of drugs used to treat or prevent influenza A in humans is prohibited in chickens, turkeys, and ducks: Adamantanes and Neuraminidase inhibitors.
Why did FDA prohibit extralabel use of cephalosporins?
AMDUCA authorized FDA to prohibit the extralabel use of a drug, or class of drugs, in animals if FDA determines that such use presents a risk to public health. The regulations implementing the extralabel use provisions of AMDUCA further defines this to mean that FDA has evidence demonstrating that the use of the drug has caused, or likely will cause an adverse event. In this particular case, FDA considers the relevant “adverse event” to be the increased pressure on the emergence of cephalosporin-resistant zoonotic foodborne pathogens resulting from the extralabel use of cephalosporins.
As explained in the July 3, 2008, final rule, CVM made the decision to prohibit the extralabel use of cephalosporins in food-producing animals based on information supporting the conclusion that such uses are likely contributing to the emergence of cephalosporin-resistant zoonotic foodborne pathogens.
What type of evidence did FDA evaluate to arrive at their decision?
In making its decision to issue the order to prohibit the extralabel use of cephalosporins in food-producing animals, FDA considered a broad set of information, including scientific literature, antimicrobial resistance surveillance data collected as part of the U.S. National Antimicrobial Monitoring System (NARMS), antimicrobial resistance surveillance data collected in other countries, as well as unpublished data collected as part of FDA inspectional activities.
Data collected as part of NARMS has shown a rise in resistance to ceftiofur, a third generation cephalosporin drug approved for use in animals, among Salmonella isolates from both humans and food-producing animals. Although ceftiofur is not used in human medicine, increasing resistance to this drug among animal and human isolates highlights concerns about the movement of foodborne bacteria between animals and humans. Furthermore, increasing resistance to particular cephalosporin drugs is of public health concern in light of evidence of cross-resistance among drugs in the cephalosporin class.
The cephalosporin class of drugs is a critically important class of drug for treating infections in humans. Expanded spectrum cephalosporins (e.g., ceftriaxone and cefotaxime) are the antimicrobial agents of choice for invasive Salmonella infections of pediatric patients.
Does FDA plan to take similar action on other drugs or classes of drugs?
FDA recognizes that it is very important that veterinarians have access to effective therapies for assuring the health and welfare of animals. The ability of veterinarians to use drugs in an extralabel manner, under the provisions of AMDUCA, is a critical mechanism for enabling access to such therapies. With this in mind, FDA carefully considers any decision to exercise its authority to limit extralabel use and, does so only when it believes it is necessary to protect the public health. Given the importance of the cephalosporin class of drugs to human health, FDA felt that action in this particular case was needed to help curb the development of cephalosporin-resistant zoonotic bacteria.
Action by FDA to prohibit the extralabel use of this particular class of antimicrobial drug does not signal that the agency intends to take similar action for other antimicrobial drugs or classes of drugs.
How will this rule impact further antimicrobial drug development for food-producing animals?
The rule does not impede future development of antimicrobial drugs for food-producing animals. The order of prohibition does not preclude drug sponsors from developing and seeking approval for the use of cephalosporins in food-producing animals. During the approval process, drug sponsors are required to provide FDA with data demonstrating the safety and effectiveness of their animal drug. This includes addressing human food safety issues, including the potential for antimicrobial resistance, associated with their drug’s proposed conditions of use. FDA’s final determination of whether a drug can be approved is made when all the components of the drug sponsor’s New Animal Drug Application satisfy the statutory requirements demonstrating that the animal drug is safe and effective.
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