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Need for Safe and Effective Antimicrobials for Food Animals|
and AVMA Efforts on Prudent Use
DR. VOGEL: Thank you, Mr. Chairman.
The American Veterinary Medical Association is a professional association with over 62,000 members, which includes 85 percent of the veterinarians in the United States. The objective of the association is to advance the science and art of veterinary medicine including its relationship to public hearth, biological science, and agriculture.
Since its inception in 1863, the AVMA has continuously integrated the objectives of public and animal health. A portion of the veterinarian's oath that is administered to every United States graduate veterinarian reads: "I solemnly swear to use my scientific knowledge and skills for the benefit of society through the protection of animal health, the relief of animal suffering, the conservation of life cycle resources, the promotion of public health, and the advancement of veterinary ethics."
Let me assure that the AVMA takes its responsibility for the protection of public health very seriously.
The American Veterinary Medical Association shares the concerns of the public, governmental agencies, and public health community regarding the broad issue of antimicrobial resistance and specifically the potential risk of resistance developing in animals with subsequent transfer to humans.
We acknowledge that a significant proportion, but not all cases of human Salmonella and Campylobacter infections originate in foods of animal origin. We also acknowledge that the use of antibiotics by veterinarians could possible contribute to antibiotic resistant bacteria developing in animals which can then be transferred to humans.
Because of that concern, the veterinarian profession has invested considerable resources of personnel and money into what we believe will be an effective response to the potential problem.
However, we are also concerned that increased regulation of animal drugs that is not commensurate with the actual public health risk may adversely affect animal health and welfare and may have unexpected adverse human health consequences.
The magnitude of the human health impact of the use of antimicrobials for animals is unknown, and inordinate and unmeasured regulatory actions may unduly contribute to the existing animal drug availability problem. This will have consequences that negatively affect animal health and welfare and ultimately could create other public health risks, such as an increase in the transmission of zoonotic pathogens to humans.
Increased regulation of animal drugs may have significant known and unknown impacts on human and animal health that need to be evaluated.
The issue of antimicrobial resistance has already impeded the approval process for, and usage of, animal drugs especially for food animal drugs. Actual label use of fluoroquinolones in food animals has been banned. Drug approvals of antibiotics, particularly the fluoroquinolones, have been slowed. The number of fluoroquinolones approved for food animals is extremely limited.
In at least one case, a drug sponsor has halted further development of a good animal antibiotic. Who knows how many other promising antibiotics are not being developed because of the increased regulatory requirements?
The use of drugs in animals is fundamental to animal health and well being. Antibiotics are needed for the relief of pain and suffering in animals. For food animals, drugs additionally contribute to the economics of the industry. The gains that have been made in food production capacity will not have been possible were it not for the ability for reliable drugs to contain the threat of disease to animals.
The increased capacity of the American livestock producer has kept high quality protein available for the majority of U.S. consumers and consumers in many other countries.
Other groups also recognize the need for antimicrobials for animals. For example, the report of the 1997 WHO meeting states, "Antimicrobials are vital medicines for the treatment of bacterial infections in both humans and animals. Antimicrobials have also proved to be important for sustainable livestock production and for the control of animal infections that could be passed on to humans.
The recent report of the National Research Council and Institute of Medicine's Committee states, "The benefit to human health and the proper use of antibiotics in food animals is related to the ability for those drugs to combat infectious bacteria that can be transferred to humans by either direct contact with the sick animal, consumption of food contaminated with pathogens from animals, or proliferation into the environment.
We are concerned about the potential human health impact, and we want to maintain the long term effectiveness of antimicrobials for animal and human use. We seek to increase drug approvals for the treatment of animals. Therefore, the AVMA is committed to ensuring judicious use of antimicrobials by veterinarians for the prevention, control, and treatment of animal diseases.
The AVMA has started a profession wide initiative, and we have included companion and food animal practitioner groups and public health representatives to develop and implement judicious use principles.
The approved document which contains the principles is published in the January 15th, 1999 issue of the Journal of the AVMA, and is being distributed in many other ways. I have provided a copy for all of the committee members.
The document states the position of the AVMA as when the decision is reached to use antimicrobials for therapy, veterinarians should strive to optimize therapeutic efficacy and minimize resistance to antimicrobials to protect public and animal health.
The position statement recognizes that veterinarians consider other therapeutic options before using antimicrobial therapy. The statement encourages veterinarians to balance public and animal health in their considerations.
Related to this concept, the objectives of the AVMA are to support development of a scientific knowledge base, support educational efforts, preserve therapeutic efficacy of antimicrobials, and ensure current and future availability of veterinary antimicrobials.
Let me share with you a few of the general principles that will serve as a template from which species guidelines will be customized.
The first principle states that preventive strategies, such as appropriate husbandry and hygiene, routine health monitoring, and immunization should be emphasized.
The second strategy says that other therapeutic options should be considered prior to antimicrobial therapy.
The third point is that antimicrobials considered important in treating refractory infections in human or veterinary medicine should be used in animals only after careful review and reasonable justification. Consider using other antimicrobials for initial therapy.
In this context, the principle takes into account development of resistance or cross resistance to important antimicrobials. Taken together, these three principles state that encourage preventive actions to avoid disease, if disease occurs, consider using other options before using antibiotics, and if antimicrobial therapy is needed, don't use the important ones first.
The next step is to work with species practitioner groups to develop more detailed guidelines appropriate to each species disease and type of client. This will be addressed at the next meeting of the Steering Committee in March.
The AVMA will also work with these groups to develop and deliver a continuing education program to raise the awareness of the profession to the issue and to encourage utilization of the principles.
The profession intends to reach the practitioners with this message at state and national meetings, as well as through publications.
Additionally, the American Academy of Veterinary Pharmacology and Therapeutics has developed an educational proposal for veterinarians and producers. The proposal includes the development of a coalition of veterinary and producer organizations to implement the program. Educational programs will be presented at national, regional, state, and smaller continuing education conferences.
A series of articles will be developed for publication in the Journal of the AVMA. Veterinary schools will be encouraged to incorporate the program into the veterinary school curriculum. This proposal will also be considered further by the AVMA Steering Committee at its next meeting.
We also want to maximize the use of good scientific information as veterinarians use their professional judgment in the drug selection process. The AVMA and the American Association of Bovine Practitioners, the American Association of Swine Practitioners, the Academy of Veterinary consultants, and the National Cattlemen's Beef Association are partnering to fund a project to develop a therapeutically based antimicrobial use informational database. The project's objective is to provide veterinarians with a source of easily assessable information on the therapy of specific diseases to help veterinarians make wise therapeutic decisions.
In the past, therapeutic antimicrobial use has focused on clinical efficacy, but now judicious therapeutic use is being redefined to include the optimization of efficacy and the minimization of resistance.
The database will allow veterinary practitioners to utilize current peer reviewed information when they select treatment regimens. The information will include a full range of therapeutic options including alternatives to antimicrobial therapy.
The pathogen data will included susceptibility profile information. We anticipate that the informational database will be available in book form, but will also be web based and possibly distributed on CD ROM.
We believe that these efforts by the veterinary profession will reduce the development of resistant zoonotic pathogens and commensals in animals, and will lessen the apparently already small risk of a human health impact related to the therapeutic use of antimicrobials in animals.
Are judicious use principles and education enough? Possibly so. We find it curious that the introduction to the FDA framework document states, "FDA, along with other agencies and groups, is actively working to find ways to encourage the prudent use of antimicrobials in human medicine to help address the significant contribution of human use to antimicrobial resistance."
What is curious is that nowhere in the framework document is it mentioned that the FDA, along with the CDC, is working with the AVMA and other groups to encourage the judicious use of antimicrobials in veterinary medicine.
The omission gives the impression that the FDA assigns value to the human prudent use campaign, but has judged the veterinary judicious use efforts to be worthless. The impression is further strengthened by FDA's decision to move forward with a complex and expensive new regulatory initiative without taking the time to evaluate the effectiveness of the veterinary profession's initiative.
The real answer to the question of whether judicious use principles are enough or whether there is a real need for increased regulation depends upon determining the true risk to human health from the use of antimicrobials in animals.
Risk depends not only on the nature and severity of the hazard, but also on the probability of its occurrence, and the probability of the occurrence of an adverse human health effect depends on more than just the prevalence of resistant zoonotic pathogens or commensals in food animals.
Risk is also dependent upon the degree of exposure of people to the resistant organism, the likelihood of causing a disease, the probability of the disease requiring antimicrobial therapy. Remember most cases of food borne diseases do not require antimicrobial therapy, and finally, whether the preferred drug is a specific one for which the pathogen is resistant.
What is the risk of a human health impact of the transfer of antibiotic resistant pathogens from animals to humans? My generation calls that the $64,000 question. However, it will cost more than that now to get the answer, but it would be advantageous if we did know the magnitude of the problem. Then, we would know whether we needed to attack the problem with a bee bee gun, a rifle, a cannon, a cruise missile, or whether an atomic bomb is needed.
What constitutes responsible action? Are judicious use principles enough? Judicious use principles combined with an educational program? Judicious use principles plus an educational program that is supported by an easy to use informational database to support clinical decisions by veterinarians?
We won't know the answers to those questions without a thorough risk assessment. This is a formidable task requiring a significant financial input, as well as scientific manpower, but to proceed forward with increased regulation without an assessment of the beneficial and detrimental effects of that action is unacceptable. Without that information, we are only acting with the hope of favorable results, and we cannot predict the magnitude of the improvement if it does occur.
There are many challenges to conducting microbial risk assessments as was explained to us this morning by Dr. McEwen, but people and organizations are learning how to do microbial risk assessments.
The USDA has recently completed a risk assessment on Salmonella enteritidis. They are starting another on E. coli 0157:H7 in beef. Georgetown University is performing a risk assessment on antimicrobial resistance associated with animal use of antimicrobials.
We are aware that the FDA attempted to perform a risk assessment on fluoroquinolones, which apparently was not completed. At least it has not been shared with the public.
It is interesting to note that the USDA has published their preliminary E. coli document and actively sought public comment and input. Additionally, a draft risk assessment report is expected to be released by USDA for external review in June of 1999. FDA should follow a similar public process.
There are a number of indications that the risk to humans from animal origin resistance organisms does not constitute an imminent public health crisis and that we can take a reasonable amount of time to properly evaluate the risk, the proposed actions, the expected results of those projected actions, and the potential for unexpected adverse events.
For example, Dr. Angulo recently said, "If the same resistance development on food animals should continue in the next 20 years, we would be faced with a major public health problem." This statement implies that we have some time to take responsible action. We do not need to rush forward with experimental regulations.
Let's do a proper analysis to determine the most effective and efficient intervention method or methods, whether it be judicious use principles, alterations in the drug approval process, changed in animal husbandry practices, pathogen reduction activities in slaughter and processing plants, improved transportation and storage of food, and/or improved food handling by food service workers and consumers, or a combination of the above.
The press release resulting from the 1998 WHO meeting states, "To date there has been little documented impact on human health of fluoroquinolones use in livestock, but there is concern over the potential human health consequences if resistance were to increase and spread. Further research and data gathering are thus essential.
The major food borne pathogens of concern for the development of antimicrobial resistance are Salmonella species and Campylobacter jejuni. The incidence of food borne disease caused by those pathogens may actually be decreasing.
As reported by the U.S. Department of Health and Human Services in the Healthy People 2010 draft document, the incidence of disease caused by these pathogens has already decreased to levels below the year 2000 targets established by the Department.
For Salmonella species, the year 2000 target was 16 cases per 100,000 people. The preliminary 1997 data demonstrated 13.8 cases per 100,000. For Campylobacter jejuni, the year 2000 target was 25 cases per 100,000, and the 1997 preliminary data demonstrate 23 cases per 100,000, which is more than a 50 percent reduction from the 1987 baseline figures.
The point is that as the number of human cases of Salmonella and Campylobacter decrease, so do the number of potential cases with decreased susceptibility to antimicrobials.
In addition to a reduction in the number of human cases of salmonellosis, a reduction of Salmonella on animal carcasses has been measured. A preliminary report from the first nine months of Salmonella sampling performed by USDA FSIS on animal carcasses as part of its 1998 pathogen reduction program demonstrates significant reductions in the prevalence of Salmonella on chicken and swine carcasses and in ground beef. There was nearly a 50 percent decline in the prevalence on chicken carcasses, a 40 percent decline in ground beef, and a 25 percent decline on swine carcasses.
These figures indicate that the exposure potential to Salmonella through the food supply is decreasing along with the potential subset of resistant organisms.
Let's turn briefly to addressing the questions posed to the committee. The challenge to VMAC today is to advise on a solution that balances a real drug availability problem with an unquantified potential public health risk.
FDA's stated goal is to protect the public health by ensuring that the efficacy of human antimicrobial therapies is not compromised due to the use of antimicrobials in food animals while providing for the safe use of antimicrobials in food animals.
The first question that the VMAC is asked to consider is whether the framework document provides a sound scientific basis for achieving FDA's goal of protecting the public health while providing for the safe use of antimicrobials in food animals.
The scientific premise of the framework document is that the use of antimicrobials in food animals causes the development of resistance, a hazard, that is or will be a risk to human health; further, that the risk is of the magnitude that justifies the implementation of a complex and expensive drug evaluation and monitoring progress that may have negative animal and human health consequences.
We believe that the agency has demonstrated that a hazard exists, however, the agency has not adequately characterized the risk to humans. We accept the premise that use of antimicrobials, whether in animals or humans, will allow resistance to develop, however, the science has not been presented by the agency that demonstrates the probability of human disease occurrence resulting from that resistance.
Without the necessary science and risk assessment to evaluate the management efforts, the agency's framework document can impede the development and approval of antimicrobials for animals and remove previously approved antibiotics without knowing whether the effects will have a positive effect on human health.
The second question to the committee addresses the categorization of antimicrobial drugs for human medicine. We are concerned because the categories are not well defined. The classification is very subjective which will create uncertainty and will allow controversy for each drug that is being classified.
We also propose for the consideration of FDA that another factor should be included in the categorization scheme, and that is the importance of the drug to animal health and welfare.
Category I contains some eclectic criteria. For example, the first criterion is that the drug is essential for treatment of a serious or life threatening disease in human, but then the second criterion included drugs that are important for treatment of food borne diseases.
The first criterion addresses essential drugs, but the second concerns a lesser group of important drugs. Also, in the vast majority of cases, food borne diseases are not life threatening nor serious, and for some of the few that are, such as E. coli 0157:H7, antimicrobial therapy is contraindicated or at least the need for antimicrobial therapy is controversial.
The third and fourth questions address threshold levels. For both monitoring and resistant threshold levels, a more basic question that needs to be answered first is how do we measure the impact on human health of various threshold levels. The answer can only be determined by risky and costly trial and error or by developing a risk assessment.
The fifth question concerns on farm monitoring. Again, we need to answer the question what is the degree of relationship between resistant levels measured on the farm and the human health impact, what are the outcome measurements.
Until those questions are answered, resources would be more appropriately applied to improvement of the National Antimicrobial Resistance Monitoring System. Questions identified by NARMS could then be investigated with specific research projects.
This can be likened to Food Net, which, based on the results of active surveillance for food borne disease, institutes case control studies to answer questions raised by the surveillance program, but the difference is that Food Nets uses the case control studies for the purpose of research, not regulation.
To summarize, the AVMA is dedicated to the protection of public and animal health. We are very concerned that the use of antimicrobials to treat food animals may cause a public health risk.
Because of that concern, the veterinary profession has invested considerable resources of personnel and money into what we believe will be effective responses to the potential risk, but we are also very concerned that because the human health risk has not been characterized, increased regulation of animal drugs that is not commensurate with the actual public health risk will adversely affect animal health and welfare, and may have unexpected adverse human health consequences.
We recommend that the agency work with other governmental agencies and the public to perform a risk assessment. We believe that the framework document is too complex, uncertain, and possibly too restrictive in comparison to the actual public health risk.
It appears that much of the framework document is designed to gather the scientific information that is needed to measure the risk. Is it appropriate for a governmental regulatory requirement to be used to gather data that rightfully should be obtained through research? We don't think so.
One final thought. Part of the problem may be that the agency is attempting to regulate microbial safety under the rules for food additives instead of as food contaminants.
Food additives are those substances deliberately incorporated into foods which includes, for legal purposes, animal drugs.
The second group, food contaminants, includes anything not specifically approved for food use. Food contaminants are those substances which are unavoidably present and whose presence is tolerated.
According to the Food, Drug, and Cosmetic Act, in general, FDA may not consider values other than safety in approving additives. If a substance is judged reasonably certain to produce no harm when used as intended, FDA is supposed to approve its use.
Conversely, for contaminants, FDA must balance several often competing objectives including safety, food costs, and practicality of the regulatory action. These legal requirements imply very different risk assessment needs. For additives, FDA reaches a judgment on an intake level that will be without effect. For contaminants, FDA needs to know of the likelihood of harm.
We suggest that the agency reevaluate its regulatory approach to consider if microbial safety is more appropriately regulated as a food contaminant.
DR. STERNER: Do any of the Veterinary Medicine Advisory Committee have questions for Dr. Vogel? Dr. Angulo.
DR. ANGULO: Dr. Vogel, I have heard a couple comments about impressions that this new framework might impede new approvals. It is obviously an essential issue, but it might be peripheral to the questions that are asked, but you raised that under the questions about does this framework based upon a sound scientific basis.
So, I am just wrestling with I mean I actually have a converse perspective, that I actually think this framework facilitates new approvals. We don't know exactly how it would move forward, the details we don't know essentially, but I see it a way to facilitate new approvals, not to impede new approvals.
How does it impede new approvals if we lay a framework out that shows how to move forward with approvals? The current system obviously isn't working.
DR. VOGEL: I think the answer to that gets back into the drug approval process and the long time it takes a company to develop a new antibiotic and get it through the system. Which company is going to invest 10 years of time, money, and effort in developing an antibiotic for a food animal when it cannot predict when it's done with its work whether that will be approved by FDA or not?
It just does not make sense for a drug company to invest millions and millions of dollars into an unpredictable system.
DR. STERNER: Further questions or comments? Dr. Angulo.
DR. ANGULO: The second point then on your discussion about the sound scientific basis of achieving of this framework, you mentioned that we haven't quantified the risk, and although you did acknowledge that there is a risk, that it hasn't been fully quantified, which I fully appreciate that it has not been precisely quantified, but the point that should be understood, that the reason why the risk has not been fully quantified is because we have not yet reached antimicrobial resistance that causes treatment failures.
The only way we will fully quantify the risk is if we have treatment failures, and it would reckless for public health to await that point in time. In other words, we should not wait until we have fluoroquinolone resistant Salmonella in this country before we revise the drug approval process in the FDA.
We want to move towards quantified risk assessments, I agree, but we cannot wait until we get those endpoints of clinical treatment failures to answer that question that you are asking.
DR. NORDEN: Dr. Vogel, you raised a lot of points, and your concern about the lack of a quantitative risk assessment, it is correct that it is not there, but what I think is clear, and although I commend your group for judicious use principles and education programs, I think it is very clear from medicine at least, "human medicine," quote, unquote, that that doesn't work, and it hasn't worked, and we have major problems in medicine with prescription of antibiotics and all of the education programs, and the data is very clear on this, really don't make any great difference.
So, I think that it's fine to do it, and I think it's a necessary part of any practice of animal or human medicine, but I think to think that it will make a major difference in the way antibiotics are used is unlikely.
DR. VOGEL: Well, I hope veterinary medicine can prove something to the human medical field, that we can make it work.
DR. STERNER: Thank you, Dr. Vogel.
As has been alluded to earlier, we live in an ever shrinking world, and are more and more influenced by our global economy. To that end, we have an invited speaker from over the Atlantic, from the UK, Dr. Rutter, who is Dr. Steve Sundlof's counterpart in England.
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