AMDUCA Fluoroquinolone and Glycopeptide Phohibition Analysis of Comments
I. Background
In the Federal Register for May 22, 1997 (62 FR 27944), the Food and Drug Administration (FDA) published as a final rule an order of prohibition against the extralabel use in animals of fluoroquinolones and glycopeptides. The Agency issued this order because of its belief that some extralabel uses of fluoroquinolones and glycopeptides in food-producing animals are capable of increasing the level of drug resistant zoonotic pathogens (pathogens that are infective to humans) in treated animals at the time of slaughter. In issuing the order, FDA made the finding that some extralabel uses of fluoroquinolone and glycopeptide drugs in food-producing animals likely will cause an adverse event, which constitutes a finding under the Animal Medicinal Drug Use Clarification Act of 1994 (the AMDUCA) (Pub. L. 103-396) that extralabel use of these drugs in food animals presents a risk to the public health.
The issuance of the order of prohibition followed the enactment of the AMDUCA and the publication of a final AMDUCA regulation. The AMDUCA was signed into law by the President on October 22, 1994. It amended the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. § 301 et seq.) to allow licensed veterinarians to prescribe extralabel uses of approved animal drugs and human drugs in animals. The implementing regulations for AMDUCA were published in the Federal Register of November 7, 1996 (61 FR 57732) and were codified in the Code of Federal Regulations at 21 CFR part 530.
Section 2(a)(4)(D) of the AMDUCA (21 U.S.C. § 360b(a)(4)(D)) provides that the agency may prohibit an extralabel drug use in animals if, after affording an opportunity for public comment, the agency finds that such use presents a risk to the public health. Sections 530.21 and 530.25 of the implementing regulations describe the basis for issuing an order prohibiting an extralabel drug use in food-producing animals, and the procedure for issuing an order of prohibition is set out in Sec. 530.25. A list of drugs prohibited from extralabel use is set forth in Sec. 530.41.
The AMDUCA requires that opportunity be given for public comment before a prohibition becomes effective. The regulation provides, at Sec. 530.25, for a public comment period of not less than 60 days. It also provides that the order of prohibition will become effective 90 days after the date of publication, unless FDA revokes the order, modifies it or extends the period of public comment. The regulation also states that reasons for the prohibition will be specified.
In accordance with the requirements of the AMDUCA and the implementing regulation, a request for comments was part of the order of prohibition. The request for comments included an address for submission of comments and a requirement that such comments be identified with the docket number for the prohibition (Docket No. 97N-0172). Sixty days from the date of publication were provided for comments. The comments are available for review in the Public Reading Room of the Dockets Management Branch (HFA-305), Room 1-23, 12420 Parklawn Drive, Rockville, MD 20857, between 9 a.m. and 4 p.m., Monday through Friday.
Under its terms, the order of prohibition for fluoroquinolone and glycopeptides was to become effective 90 days from the date of its publication, unless the agency before that time revoked or modified the order, or extended the period for public comment. FDA did not revoke or modify the order, nor did it extend the period for public comment. Accordingly, the prohibition on the extralabel use in food-producing animals of fluoroquinolones and glycopeptides became effective on August 20, 1997.
In a general discussion in the preamble to the order of prohibition, FDA noted that it had responded in the November 7, 1996 final rule to comments from the public on the proposed rule to implement the AMDUCA that expressed concerns about the implications of extralabel use for the development and transfer of antimicrobial resistance. The general discussion added that FDA's response to these comments noted that the agency believes that the selection of resistant human pathogens could be a basis for restricting extralabel drug use provided that the statutory standards for restriction can be met for particular drugs or classes of drugs (61 FR 57732 at 57736 and 57737). The general discussion added that antimicrobial resistant zoonotic enteric microorganisms can be transmitted to humans through consumption of animal products and that certain resistant microorganisms can be transmitted through contact with farm animals and through the environment.
The general discussion also said, in response to comments suggesting that the agency prohibit extralabel use of approved fluoroquinolones and glycopeptides in food-producing animals, that the agency had decided to initiate the process specified by the AMDUCA to implement such prohibition (61 FR 57732 at 57737). It added that the agency's Center for Veterinary Medicine (CVM) has, since the time it first approved a fluoroquinolone for use in food animals (August 1995), informally asked veterinarians to voluntarily refrain from extralabel use of these drugs in food animals and noted that veterinarians' professional associations have actively encouraged their members to refrain from extralabel use of fluoroquinolones in food-producing animals.
FDA received 15 comments relating to the prohibition of extralabel use of fluoroquinolones and glycopeptides in food-producing animals. These comments are discussed below:
1. General Support of the Final Rule Prohibiting Extralabel Use of Fluoroquinolones and Glycopeptides.Eight of the 15 comments expressed general support for the final. These included comments physicians, a microbiologist with expertise in resistance issues, an association of public health veterinarians, a consumer group, the Centers for Disease Control, a governmental entity in the United Kingdom, and an organization advocating "prudent" use of antibiotics. In addition, another group objected to the final rule, but made a statement that they were in agreement with the intent of the order.
Three of the 15 submissions provided general objections to the final rule prohibiting extralabel use of fluoroquinolones and glycopeptides. These objections were registered by two associations representing practitioners of veterinary medicine and one association representing manufacturers of animal drugs.
Two comments stated that the prohibition is not based on adequate scientific evidence. One asked the agency to specify which extralabel uses pose a concern and to provide sound scientific justification as to why these uses present a risk to public health before enacting prohibitions. One comment urged that the prohibition be revoked pending conclusive scientific studies proving that extralabel use presents a risk to public health.
One comment argued that extralabel use of these drugs is necessary for international competition to compete in the "world animal protein market." Another comment suggested that prohibiting the use of the drugs may increase the incidence of food borne salmonellosis disease in the human population.
In passing the AMDUCA, Congress granted FDA broad authority to protect the public health by allowing the agency to restrict or prohibit extralabel uses. A prohibition may be based on a finding that an extralabel use ``presents a risk to the public health.'' FDA has defined the phrase "presents a risk to the public health" in Sec. 530.3(e) as ``likely will cause an adverse event.'' The statutory scheme clearly establishes that prohibiting an extralabel use does not jeopardize an underlying approval or the future approvability of the same active ingredient or class of drug. A total prohibition against extralabel use is an action by the agency which restricts use of the drug to the conditions of use as established through the approval of a new animal drug application.
FDA believes that this prohibition is based on adequate scientific evidence. FDA published as a final rule the order prohibiting the extralabel use of fluoroquinolones and glycopeptides in food-producing animals because, as discussed in the detailed analyses in sections II and III of the preamble to the final rule, the agency determined that use of these drugs other than for the approved label indications in food-producing animals meets the criteria for prohibition in the AMDUCA. The final rule provided detailed scientific analyses of the risks associated with extralabel use of these drugs, supported by 18 references, most in peer-reviewed journals. No evidence to the contrary was provided to FDA in the comments.
Three comments suggested that the prohibition against fluoroquinolones and glycopeptides will result in animal suffering. Two comments requested exemptions for specific species -- beef calves in one comment and catfish in the other. The comment about catfish asserted that there is little danger from extralabel use of fluoroquinolones in catfish because per capita catfish consumption is very low, that catfish are produced in isolated levee ponds, the potential for resistance development for sarafloxacin is low, there are few or no bacteria found in catfish ponds that can infect humans, and there is little threat of resistance transfer from catfish bacteria to humans.
In passing the AMDUCA, Congress affirmed the need to protect the public health as a primary objective of the new statute. The implementing regulations for AMDUCA at 21 CFR part 530 reflect that priority, as does the prohibition of the extralabel use of fluoroquinolones and glycopeptides in food-producing animals. The agency supports drug use that improves animal health or reduces pain and suffering in animals to the extent that such use is consistent with the protection of public health. The agency acknowledges this priority and concludes that it reflects the Congressional intent. The closed nature of aquaculture environments amplifies the likelihood of the development of resistant strains that could present a human health hazard if there is leakage to the outside environment. Similarly, the agency has similar concerns about other extralabel uses, such as fluoroquinolones used to treat dysentery in calves, which is likely to result in the development of resistant bacteria that are likely to be introduced into the environment and possibly into the food supply.
Four comments argued that FDA had not met the requirements for prohibition of an extralabel use of a drug as set forth in the AMDUCA and the implementing regulations had not been met for fluoroquinolones or glycopeptides. These comments suggested that the requirements for prohibition that "present a risk to public health" and "likely will cause an adverse event" have not been met in the order. One comment stated that there is no evidence that zoonotic bacteria have been or will be transmitted from animals to humans.
One comment added that the AMDUCA implementing regulation defines the phrase "a reasonable probability that a drug's use may present a risk to the public health" as meaning that such a use is "likely to cause a potential adverse event," while it defines the phrase "may present a risk to the public health" as meaning that such a "may cause an adverse event." According to the comment, the regulations mean that these phrases are insufficient to support a prohibition of extra-label use. It adds that any order that would prohibit the extralabel use of fluoroquinolones and glycopeptides would have to be based on a finding that such use "presents a risk to the public health" and "likely will cause an adverse event." Thus, according to the comment, FDA must have "evidence that demonstrates" that use of the drug "has caused or likely will cause an adverse event," while the evidence cited in the order of prohibition only suggests that extralabel use of these drugs "may present a risk to the public health."
The order of prohibition included detailed analyses of the science and policy concerns associated with the extralabel use of fluoroquinolones and glycopeptides, including evidence suggesting zoonotic transmission to humans. The two detailed analyses concluded that the "adverse event"' associated with the extralabel use of both fluoroquinolones and glycopeptides in food-producing animals is that such extralabel use likely will lead to increased risk of transfer of resistant organisms to humans and resultant compromise to human therapy. Therefore, the agency concluded that it was acting in the interest of the public health by prohibiting the extralabel use of fluoroquinolones and glycopeptides in food-producing animals.
One comment stated that the May 1994 joint meeting of the Veterinary Medicine Advisory Committee, and the Center for Drug Evaluation and Research's Anti-Infective Drugs Advisory Committee (the joint committee) did not conclude that extralabel use of fluoroquinolones should be prohibited. However, the comments support the view -- and therefore the conclusion of the agency -- that testimony during the hearings identified risks associated with such extralabel use. Furthermore, the agency also testified that it had the authority and will to control the extralabel use of fluoroquinolones in food-producing animals. The comments also agree that suggestions were made during the hearings that prohibition of fluoroquinolones was a supportable option. Therefore, it is FDA's view that data and information presented to the joint committee supports the agency's conclusion that some extralabel uses of fluoroquinolones in food animals meet the AMDUCA regulation's standard of "likely will cause an adverse event."
One comment asserted that insufficient scientific evidence has been provided to support the prohibition of extralabel use of fluoroquinolones and glycopeptides and added that a risk/benefit calculation should be provided. The comment further stated that FDA should specify those uses that are a public health concern and present a "sound scientific justification" as to why these uses present a risk to public health before enacting prohibitions. It is the Agency's view that the references cited in the prohibition provide a sufficient scientific basis to support a prohibition of all extralabel uses of fluoroquinolones and glycopeptides.
One comment noted that the 1995 Report of the American Society for Microbiology Task Force on Antibiotic Resistance states that "many unanswered questions surround the role of animals and the microbiota and the contribution to the problem of antibiotic resistance." It is FDA's view that unanswered questions such as these, along with the evidence developed before and after the issuance of this report, support the agency's determination that use of these drugs other than for the approved label indications in food-producing animals meets the criteria for prohibition in the AMDUCA.
5. General Objections to FDA's Scientific Interpretations.
A. General statements regarding FDA's scientific interpretation
Four comments asserted that FDA's interpretation of the scientific data supporting prohibition of extralabel use of fluoroquinolones and glycopeptides was generally flawed.
One comment asserted that restricting extralabel use of fluoroquinolones and glycopeptides could increase the risk of human food-borne disease, but provided no data in support of this position. It added that the prescription legend and on-going monitoring by veterinarians eliminates the possibility of increased resistance, adding that the cost alone "prohibits" the indiscriminate extralabel use of these drugs. In the absence of supporting data, it is FDA's position, based on its surveillance of the industry, that the level of control currently exercised by veterinarians is not a sufficient guarantee of prevention of increased resistance. Similarly, it is the agency's view that economic factors alone are not sufficient to assure the prevention of increased resistance.
Two comments asserted that the prohibition was not based on adequate scientific evidence that either extralabel uses of these drugs significantly increase the level of antimicrobial resistant zoonotic pathogens in treated animals or that transmission of zoonotic bacteria can occur from animals to humans. These comments were not supported by adequate scientific data, and in the absence of such data, the agency accepts the scientific rationale and supporting studies which demonstrate the transmission of zoonotic bacteria from animals to humans.
One comment said that despite the reports of the increasing incidence of Salmonella typhimurium DT 104 in the United Kingdom (U.K.), a directly causal relationship between the use of fluoroquinolones in food-producing animals and the increase in disease incidence in people has not been established and that reports of increased resistance after licensing of fluoroquinolones in the U.K. are a mere coincidence. FDA believes that coincidence is an insufficient explanation for the data and the agency stands by its belief that, based on the available epidemiologic information, the most likely cause of the increase in Salmonella typhimurium DT 104 resistance in the U.K. results from the use of fluoroquinolones in livestock.
The comment also asserted that a careful examination of the data fails to demonstrate any increase in fluoroquinolone resistance in Salmonella typhimurium DT104 isolates from the U.K. because "nonstandard interpretive criteria" have been "arbitrarily used by the investigators to categorize isolates as resistant...." In the absence of persuasive evidence to the contrary, FDA continues to believe that the U.K. data are accurate and that its conclusions are valid.
B. Objections that call for restrictions on specific drugs, rather than a class of drugs.One comment questions the use of the law to prohibit the extralabel use of an entire class of compounds, when only some uses may present concerns to the agency. The comment quotes a phrase in the order of prohibition which states that "some extralabel uses of fluoroquinolones and glycopeptides in food-producing animals likely will cause an adverse event" (62 FR 27944 at 27946) and asks FDA to specify the uses that meet the criteria for prohibition.
Sec. 530.21 of the AMDUCA implementing regulation permits FDA to prohibit the extralabel use of a drug or class of drugs in food-producing animals if the agency determines that the extralabel use of the drug or class of drugs presents a risk to the public health. The section adds that such a prohibition may be a general ban on the extralabel use of the drug or class of drugs or may be limited to a specific species, indication, dosage form, route of administration, or combination of factors. As stated in the preamble to the final rule, it is the agency's position that the statute authorizes prohibition of an entire class of drugs where the class has one or more common elements that cause a particular risk. This is consistent with situations in which the agency prohibited in the animal drug CPG the extralabel use of the sulfonamide and nitroimidazole drug classes (61 FR 57731 at 57741). The enforceability of a partial prohibition (i.e., a prohibition of certain extralabel uses, but not other extralabel uses) would require allocation of more FDA resources and would be more difficult to accomplish than a prohibition against all extralabel uses of a drug or class of drugs.
As explained in the preamble to the order of prohibition, the agency's finding that some extralabel uses likely will cause an adverse event raises significant concerns about all extralabel uses of these drug classes. Accordingly, FDA has concluded that it is in the interest of public health to prohibit the extralabel use in food-producing animals of all drugs in the fluoroquinolone and glycopeptide classes (62 FR 27944 at 27944-45).
C. Objections asserting that there are no data on glycopeptide use in animals.One objection states that glycopeptides are not being marketed in the U.S., and data from Europe, where a glycopeptide animal drug is approved, do not support an increase in glycopeptide resistance.
As stated in the preamble to the order of prohibition (62 FR 27944 at 27946), there is presently no glycopeptide approved in the United States for use in animals, although vancomycin, a glycopeptide, is approved for use in humans. The order of prohibition thus prohibits the extralabel use in animals of this human drug product. However, the prohibition will apply to any future animal drug approvals of glycopeptides unless the circumstances at the time of such approval cause the agency to reevaluate any part of the prohibition.
As the preamble stated, a number of scientific organizations and individual experts have recommended that the agency prohibit extralabel use of glycopeptides, and these comments were supported by data and information referenced in the order. Among these is a U.K. study that has shown that vancomycin-resistant bacteria may be acquired from animals, while a Danish study has established a connection between feed use of avoparcin, a glycopeptide, and vancomycin-resistant Enterococcus faecium. The study also found identical vancomycin-resistant E. faecium in both pigs and humans, leading the authors to conclude that vancomycin resistant E. faecium can be transmitted to humans through food.
Accordingly, the available data are sufficient to justify a broad prohibition of extralabel uses of glycopeptide drugs in food-producing animals.
Four comments suggested that FDA's prohibition of extralabel uses in food-producing animals of fluoroquinolones and glycopeptides may have a stifling effect on research that might lead to new approvals or that the prohibition against extralabel uses could inhibit future approvals.
It is FDA's position that the agency's action in this order of prohibition does not provide an adequate justification for the apprehension expressed in these comments. As stated in the order of prohibition, "the statutory scheme clearly establishes that prohibiting an extralabel use does not jeopardize an underlying approval or the future approvability of the same active ingredient or class of drug. A total prohibition against extralabel use is an action by the agency which restricts use of the drug to conditions of use established through approval of a new animal drug application. A finding of ``likely will cause an adverse event'' is not a determination regarding the safety of the drug for its approved uses. That determination is made in the approval process, i.e., an approved drug has been determined to be safe for use under labeled conditions." (62 FR 27944 at 27945.)
7. Objection Asserting that Extralabel Use of Drugs is Necessary in Specific Situations.Three comments suggested that use of fluoroquinolones and glycopeptides is necessary in the treatment of specific species and uses. One comment said the poultry industry needed relief; a second sought relief for aquaculture, while a third requested an exception for treatment of diarrhea in beef calves.
As explained in the preamble to the order of prohibition, FDA has concluded that any extralabel uses presents a risk to the public health and, therefore, cannot provide an exemption for specific species or classes at this time.
One comment, which asserted that FDA has justified the prohibition in part because "extralabel use of fluoroquinolones in food-producing animals would interfere with CVM'S ability to interpret the monitoring and surveillance data," noted that several Federal agencies are currently involved in monitoring zoonotic pathogens from a variety of sources, that the sponsors of new animal drug applications are responsible for monitoring target disease organisms, and that fluoroquinolone use can easily be monitored through review of individual veterinarian records.
The partial quote in the comment extracted from a sentence in the preamble to the order of prohibition does not accurately illustrate the focus of FDA's observation that extralabel use makes it harder to obtain surveillance data through the National Antimicrobial Susceptibility Monitoring Program (see 61 FR 57732 at 57736 and 57737) and the postapproval monitoring program for the approved fluoroquinolones. The preamble statement added that these data are critical because early detection of emerging resistance, identified through the monitoring program, will allow the agency to contain any resistance that does occur, thereby limiting its spread.
While it is true that the sponsors of new animal drug applications are responsible for monitoring target disease organisms, this task will become more difficult if there is widespread extralabel use of fluoroquinolones. It is also true that fluoroquinolone use can be monitored through review of individual veterinarian records, but this monitoring would be personnel-intensive, expensive, and intrusive, rather than easy. It is because of the scope and potential seriousness of the problem that several Federal agencies are involved in monitoring zoonotic pathogens from a variety of sources and not as a means of directly controlling extralabel use in food-producing animals.
The basis for the agency's issuance of the order of prohibition for extralabel use in animals of fluoroquinolones and glycopeptides was protection of the public health. The discussion of monitoring was included as an explanation of FDA's efforts to contain resistance for approved uses and not as a justification.
9. More Aggressive Enforcement Necessary
One comment called for more aggressive enforcement actions against persons illegally supplying drugs to the food animal industry.
CVM has been expanding its surveillance and compliance activities to guard against illegal extralabel uses of drugs in animals and protect the public health.
Five comments requested that FDA not approve additional new animal drug applications for fluoroquinolones until further information on resistance becomes available. In addition, three comments requested that existing approvals for fluoroquinolone new animal drugs be revoked.
FDA believes that the scientific data supports a prohibition against extralabel use of fluoroquinolones and glycopeptides, but has not reached the conclusion that the data currently known to the Agency would support a blanket prohibition against new approvals or the revocation of existing approvals.
One comment stated the belief that there are weaknesses in AMDUCA, which permits extralabel use of drugs in animals. The comment asserted that to limit extralabel misuse and overuse of drugs, there should be requirements for: (1) performance of culture and susceptibility testing to determine if the drug chosen for extralabel use will be effective, (2) an "outline" by the practicing veterinarian of the scientific rationale for an extralabel use
As indicated in the preambles to each document, FDA believes that both the Extralabel Drug Use in Animals implementing regulation final rule and the order of prohibition against the extralabel provide an adequate balance between legitimate safety concerns and the statutory right of veterinarians to engage in extralabel use of drugs in animals within the scope of AMDUCA and the regulations.
One comment asserted that the prohibition against extralabel use of fluoroquinolones is necessary in part because AMDUCA and its implementing regulations do not restrict the therapeutic dosing of animals in their water. According to the comment, the prohibition helps to protect the public from the development of antibiotic resistance and subsequent contamination of the environment as a result of administration of fluoroquinolones in drinking water to treat an entire herd or flock, or the administration of these drugs in aquaculture. The concern expressed is that run-off from treated herds or flocks or outflow from ponds of treated animals into open waters or sewage systems could cause these drugs to become widely disseminated environmental contaminants. According to the comment, studies have shown that large percentages of wild fish in close proximity to aquaculture ponds where drugs were administered contained quinolone residues, suggesting that use of fluoroquinolones in water will increase the development of resistance in bacteria in the environment with potential adverse impacts on human health.
The agency believes that the existing prohibition responds adequately to the concerns expressed in this comment. As indicated in the order of prohibition (62 FR 27944 at 27946-47), there are currently two fluoroquinolones approved for use in poultry to be administered via drinking water. However, the drugs are administered as therapeutic agents for short periods of time, such that widespread contamination of the environment does not occur. There are no fluoroquinolones approved for use in aquaculture.
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