Docket Management
Docket: 98D-1146 - Eval. the Safety of Antimicrobial NADs Re. their Microbiological Effects on Bacteria of Human Health Concern
Comment Number: EC -10

Accepted - Volume 2

Comment Record
Commentor Dr. Thomas Burkgren Date/Time 2002-11-26 17:26:04
Organization American Association of Swine Veterinarians
Category Association

Comments for FDA General
1. General Comments November 26, 2002 Dockets Management Branch (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852 Re: Docket No. 98D-1146; Draft Guidance Document #152: Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern Dear Sir or Madam: The American Association of Swine Veterinarians (AASV) is a professional organization with a membership of approximately 1,000 veterinarians in the United States. AASV’s members have an abiding interest in swine health and production. Swine veterinarians work closely with their clients, the pork producers, to provide the consuming public with safe and wholesome pork. The safe and effective use of antimicrobials is a critical component of maintaining a healthy and safe supply of pork, as well as providing for the health and well-being of the nation’s swine herd. The AASV recognizes and appreciates the efforts of the FDA in assuring the safety and effectiveness of pharmaceuticals used in food animal medicine. The complexity of the issue of antimicrobial resistance does not lend itself to simple solutions. For each solution there may be unintended consequences that are detrimental to animal health and well-being, as well as human health and the public interest. The AASV is pleased to see the FDA’s willingness to employ risk assessment as a part of the approval process. We are encouraged to see that the FDA is moving forward in its efforts to provide guidance to the industry in assessing the safety of antimicrobial new animal drugs. The AASV has significant concerns over the future availability of antimicrobials for use in swine. Today’s swine veterinarian is already forced to practice with a limited armentarium. Any loss of currently approved antimicrobials may severely compromise animal health and welfare. The lack of new approvals for food animals may also complicate and exacerbate resistance problems, both in animals and humans. In general review, the AASV noted a high degree of subjectivity throughout the Draft Guidance Document #152. Pending the practical application of this guidance, this level of subjectivity is disconcerting to veterinary practitioners. The oft-heard suggestion that the precautionary principle be instilled into the drug approval process only increases the concern of those charged with the care and treatment of food animals. There is no room for the precautionary principle in an objective, science-based approval process. The following comments are structured to correspond to specific sections within the Draft Guidance Document #152: Release Assessment The release assessment portion of the proposed qualitative risk assessment is a concept that is very similar to the pre-approval studies proposed and discussed three years ago in the Framework Document. Much of the same apprehension expressed by the AASV in 1999 still applies today. Guidance Document #152 does not cite the scientific process used to establish the validity or relevancy of the seven parameters (listed on page 15 of the Guidance Document) used as predictors of the probability of release of the hazardous agent. The AASV has concern that a lack of scientific technology and subsequent data in the examination of one or more of the listed factors may result in a default ranking of high, even though the said factor(s) may have little significance for the specific new animal drug under consideration. An example might be the relationship of the pharmacokinetics/pharmacodynamics of a drug to the development of resistance. A more thorough and specific citation of the scientific literature on each of these parameters will be useful in determining how factors may be weighted when determining the overall release assessment ranking. Any factor that is clearly lacking the needed science should not be regarded until said science is available. The inclusion of resistance determinants raises questions about the strength of scientific data needed in the release assessment. The scientific understanding of the in-vivo transfer and persistence of genetic material encoding for resistance is limited and not well-defined. The significance of any such transfer is yet to be validated. Basing regulatory decisions on inadequate and inconclusive data could be viewed as an overt application of the precautionary principle. Exposure Assessment The per capita consumption of meat as presented as part of the exposure assessment overestimates the risk. The FDA does not take into account that a fairly large percentage of the per capita consumption is meat that has been further processed or cooked before consumers consume meat. It is a well-accepted fact that cooking decreases the exposure of humans to foodborne pathogens. In light of this, the use of the carcass contamination rates is biased and thus will result in estimating a risk that is too high for those meats that are cooked before reaching the consumer. Consequence Assessment This section of the qualitative risk assessment significantly diverges from the FDA’s prior declaration in the document which states “The FDA believes that human exposure through the ingestion of resistant bacteria from animal-derived foods represents the most significant pathway for human exposure to resistance determinants (or resistant bacteria).” Very few of the human pathogens mentioned in Appendix A have any relationship to foodborne bacteria. It appears that the proposed ranking of antimicrobial drugs according to their importance in human medicine disregards the previous statement and uses a ranking process that ignores the most relevant factor of whether a drug is used to treat foodborne bacterial infections in humans. For example, the relevance of categorizing erythromycin’s importance for treatment of pneumonia caused by Legionella pneumophila is lost when considered in light of foodborne bacteria. To the casual, uninformed reader, it appears that the FDA is linking all resistance problems in human pathogens to the use of antimicrobials in animals. The AASV urges the FDA to narrow the focus of a drug’s importance in human medicine to those related to foodborne bacteria and the antimicrobial treatment thereof. The AASV is also troubled by the apparent lack of transparency in the ranking process used to arrive at the assigned ranks. This lack of transparency could be remedied by simply explaining, on a drug-by-drug basis, the disposition relative to the ten factors identified in Appendix A. As part of this explanation, it is imperative for the FDA to scientifically justify the aforementioned divergence from its own declaration on the significance of animal derived foods. Risk Management Strategies There are several points to consider in the risk management section of the draft document. The first is the limitations placed on marketing status. The AASV suggests that the FDA carefully consider the impacts of eventually requiring most antimicrobials (Category 1 & 2) to be marketed as prescription or veterinary feed directive drugs. This requirement will greatly increase the number of prescriptions and VFDs issued. The current drug distribution system in the United States is not designed for the volume that may be required, nor are there any assurances that there will be increased veterinary supervision on the farms. Such limitations could overextend the current pool of practicing swine veterinarians while placing a significant economic burden on producers. The AASV strongly supports the concept of a veterinarian’s involvement in all antimicrobial use decisions, however it remains to be seen if marketing status limitations will have this effect. Many of the possible use conditions suggested for risk management do not fit into the realities of current swine production. Today’s production systems range in herd size from 1 sow to 700,000 sows. The FDA’s attempts to quantify numbers of animals by labeling groups as “pens” and “herds” does not accomplish any objective measure of a population to be treated. Labeling a building containing 1,000 pigs as a “herd” is not appropriate since the building may very well represent less than 1% of the pigs owned by a large producer. On the other hand a building holding 50 pigs may very well be the entire “herd” owned by a small producer. In addition, not all pigs are reared in “confinement buildings.” A wide range of other production systems such as open lots and pastures will need to be considered. Today’s swine veterinarian relies on the ability to treat populations at risk. In some cases individual animal treatment is efficacious and preserves animal health and welfare. In other cases medication of a larger population of pigs is the best choice. The veterinarian must be allowed to practice medicine by selecting the antimicrobial, the route of administration and the duration of treatment. The modern management of swine production has made tremendous strides in health assurance. However, the need to treat populations of pigs with antimicrobials still remains, much as it did 30 years ago. The medication of a group of pigs through the feed or water is often the most effective and efficient method of therapy for the prevention, control and treatment of a bacterial infection. In many cases, swine veterinarians use clinical decision aids to determine the proper course and scope of therapy for an at-risk population. These decision aids are based on sound clinical science and a practical understanding of the pathogenesis and epidemiology of a specific disease. An example is the treatment of a respiratory infection of pigs with virulent Actinobacillus pleuropneumoniae. This swine pathogen can cause high morbidity as well as high mortality in growing pigs. Using a clinical decision aid, veterinarians will choose to medicate the entire barn of pigs when the individual treatment rate exceeds 5 to 10% of the pigs in the barn. This decision will actually decrease the total amount of antibiotics that may have been used over the entire course of the disease if treatment was only used upon the appearance of clinical signs in individual animals. The benchmark is used as an aid to indicate that this particular disease event is more than sporadic cases and is likely to be an outbreak in a large number of animals. Other factors come into play when deciding on the scope of medication and the duration of treatment. Shared air space certainly enables the rapid dissemination of an airborne pathogen throughout an entire building or lot. Unabated contact with a pathogen (e.g., Erysipelothrix rhusiopathiae) via carrier animals or infected fomites (e.g., soil or bedding) may require an extended period of treatment (longer than 21 days). A clinical history of repeated outbreaks over time in a certain age of pigs (e.g., ileitis due to Lawsonia intracellularis) may require the treatment of the entire group while still incubating a ubiquitous pathogen. All-in, all-out management of a nursery building indicates that the entire building will contain pigs that are all the same age and immune status. The entry of a pathogen into the building will expose all the pigs to infection and will require treatment of the entire barn, not just one room or one pen. It is not unlike the exposure of an entire high school classroom to Bordetella pertussis (“whooping cough”). There may only be a subset of that population who are clinically ill, but anyone with extensive contact with the ill person is treated with erythromycin for the prevention of the disease. Other factors related to limitations on population treatment may involve the logistics of treatment. The treatment of a specific pen within a building may not be logistically possible due to the configuration of the feeding and/or watering system. Feeding and watering systems are typically designed for delivery to an entire building. Dedicated water and feed lines for individual pens are not commonly found in swine production. The retooling of these systems would require a significant outlay of funds. In those cases where an individual pig can be treated, the sick pig will be treated but usually must be left in the pen or lot. The aggressive, dominant nature of swine does not allow sick pigs to be segregated from the healthy population and then upon recovery to be returned to their cohort group. For welfare reasons and to prevent mortality from fighting and aggression, it is important to maintain the integrity of the cohort group and not mix animals. Individual treatment of pigs by injection, especially in large groups, over an extended period of time is extremely stressful to the animal. The exertion of the escape efforts of the pig may exacerbate the illness as well as compromise the welfare of the pigs. In these cases it is prudent to treat the group as unobtrusively as possible through the feed or water. The minimization of stress and suffering during illness is a basic tenet of clinical swine medicine. Swine veterinarians need the ability to treat pigs based on the population at risk. If the FDA wishes to set an arbitrary grouping of pigs as a maximum that can be administered medication, then the AASV strongly recommends that the population at risk be considered to be all of the animals in a building. Selecting a lower denominator as the treatment-eligible group will severely limit the veterinarian in preserving animal health and welfare. Similarly, veterinarians need to be able to medicate groups of animals for the correct duration of time, depending on the pathogenesis and epidemiology of the bacterial disease to set the course of treatment and not on subjective standards with no scientific basis. The last issue to consider under the risk management section is the potential for the FDA to place a “blanket” ban on extra-label drug use (ELDU) of all Category 1 drugs. Without consideration of the specific ELDU considerations of each drug, it seems as though the FDA is embarking on an effort to regulate the practice of veterinary medicine rather than maintain its focus on approving drugs. This position may prove to be counter-productive due to current incomplete knowledge about the exposure and release assessments of future approvals. It is not beyond reason to expect that the ELDU of a future Category 1 drug may be safely employed for certain animals and diseases. In closing, the AASV looks forward to movement towards an improved FDA process for the approval of safe and effective antimicrobials in food-producing animals. However, the AASV remains steadfast in its opposition to any FDA guidance that incorporates or institutionalizes the precautionary principle as part of the approval process. The inclusion of the precautionary principle will do little to truly safeguard human health and will have a devastating impact on animal health and welfare. Sincerely, Thomas J. Burkgren, DVM AASV Executive Director

EC -10