Veterinary medicine advisory committee




НазваниеVeterinary medicine advisory committee
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Need for Addressing Issue and Benefits of Establishing

Threshold Levels

DR. BELL: Thank you. The introduction of antibiotics in the 1940's has led to enormous benefits to mankind, and human medicine has led to dramatic reductions of illness and death due to infectious diseases and, by improving animal health, has led to increases in food production. However, the widespread emergence of drug resistance threatens these benefits.

Antimicrobial resistance develops as a consequence of antibiotic use in hospitals, in the community and on farms. Although there is some overlap, the pathogens that acquire resistance and are transmitted in each of these settings tend to be different so that efforts to prolong the useful life of antibiotics must focus on each of these settings. Our focus today is on farms.

CDC recognizes that the use of antibiotics in agriculture is important to enhance food production. However, antibiotic use on farms can pose a risk to human health due to development of resistant bacteria that can infect humans. Resistant bacteria can be transmitted by food, contact with infected or colonized animals, or resistance to genes that emerge in animal strains can be transferred to human pathogens. Judicious use of antibiotics is, therefore, an important preventive and control measure.

I would like to take a minute to pay tribute to the efforts of the American Veterinary Medical Association. I believe that Dr. Vogel is going to speak about their efforts later and I don't want to steal too much of his thunder, but they have really pioneered, over the last year, and have developed an excellent set of general principles to guide the use of therapeutic antibiotics by veterinarians. I am associated with the committee and I can testify to the dedication and commitment of the AVMA and the people who work on this committee, and this is a very impressive contribution.

Much of the difficult work remains to be done as specialty groups take the general principles and develop specific recommendations for their members. This is a pioneering and important effort, but it only applies to the therapeutic use of antibiotics under the control of veterinarians and, as we know, much antibiotic use on the farm is neither therapeutic nor under the control of veterinarians.

Partly to fill these gaps, and partly because compliance with voluntary measures may vary, we very much need a regulatory framework that ensures the availability of safe and effective drugs for treatment of human disease and for food production.

Now, there has been a lot of disagreement over the years between human and animal health communities on these issues. Unfortunately, the controversies have progressed beyond disagreement. There have been a lot of bridges burnt over the years between the animal and human health communities. These bridges need to be repaired. I think in the last year we have seen steps in that direction, and I would mention again that AVMA's efforts in inviting representatives of human medicine to serve as liaison members to their committee has been very helpful. We still do have a long way to go.

Now, it has been very difficult to arrive at a consensus between the human and animal health communities. We all pay homage to the scientific data. However, the problem is that people with different perspectives interpret the same body of information differently. Physicians in human medicine who deal everyday with drug resistant infections may not appreciate the difficult problems in food animal production. People who wrestle everyday with how to produce food economically may never have stood at the bedside of a critically ill patient with invasive Salmonella or other serious infection, hoping that the antibiotics will work and having to deal with the consequences when they did not work. These differences in professional experience and perception inevitable affect how people interpret available information on the issue. In addition, of course, some people with major economic interests at stake may find it difficult to adopt a position contrary to those interests, no matter how much scientific data may be available and what it may show.

So, although more scientific data may help to narrow the gaps, I am starting to wonder if there will ever be a true scientific consensus shared by both the animal and human health communities. I am starting to think that we are reaching the point of diminishing returns from expert committees and scholarly reviews. It seems that if we know the percentage of human versus animal health experts on a particular committee, or writing a particular report, we can often pretty much predict what the report will say. These reports in general have not changed people's minds anyway. They have been basically used by partisans of various positions to wave at each other and selectively quote passages from.

In frustration, some people on both the human and the animal side have given up hopes of truly working together. They have sought to impose solutions through legislation or other types of congressional intervention. These strategies may occasionally produce short term victories. However, these victories just galvanize the opposition to fight harder, and are really not a long term strategy for the long term goals of ensuring safe and effective antibiotics for the treatment of human disease and for food production.

Some may find a stalemate acceptable but ultimately history will pass us all by since it will inevitably be difficult to get approvals for new drugs on the farm if public health concerns are not addressed. Countries that do address public health concerns may well seek to erect trade barriers against products from countries that do not.

So, what is the solution? There really is no substitute for folks in human and animal health communities to roll up their sleeves and figure out an approach that meets the needs of both. We are going to need to look outside the box for solutions.

I just want to reiterate that, you know, I have heard people say that we need more research; if we just wait for this upcoming scholarly review, then everything will become clear; if we have one more meeting or blue ribbon commission, that will lead to consensus. I am starting to hear talk about waiting for scholarly risk assessments. You know, all of these approaches do have some value, but I am not sure that they are going to produce consensus at all. The risk assessment scholarly reviews inevitably depend upon assumptions and weighting factors, and whatever the results are they are going to be challenged by the other side.

I think that what we have to do is figure out an approach that we can all live with even if we don't totally agree with each other. There has been a lot of progress in the last year. I mentioned the AVMA. There was an interesting initiative during the summer in connection with the approval of the cattle fluoroquinolone product, whereby the FDA and the sponsor, the Bayer Company, arrived at an agreement that permitted the licensure of that product. CDC was happy because the public health needs were met. The FDA and the company was happy; the producers were happy. Hopefully, even the cattle were happy. And, this is the kind of pioneering, outside the box thinking that we need.

So, we are now looking at a novel FDA proposal. FDA is really to be congratulated in stepping outside the box to develop this proposal. This is pioneering, innovative thinking. It needs tuning. It will be difficult to implement, but it is a framework offering the hope of the way forward. If it really works it could be offered as an alternative to more draconian measures proposed or undertaken in other countries. If we have a framework in the United States that both the FDA and CDC state meets the needs of protecting the public health, that will be a strong argument in any trade dispute where public health is an issue.

Now, the three options in responding to the FDA proposal that I think folks have available. One option is purely negative; just say, "no, this will never work; it's a bad idea; just say no."

The other is to pay lip service to the approach, to proceed to go along but then basically sabotage the implementation in one way or another. I suspect that might not be too hard to do with a determined effort. I think we all know there are a lot of questions about how this proposal will be implemented. There are going to be difficulties, and I think if a major stakeholder were really determined to block its implementation it might be possible.

Well, if this FDA proposal fails I predict we will all be back here in a few years, looking at each other, in the same predicament but with a dramatically increased level of bitterness as people point fingers as to why it failed.

The third option that people have is to make it work    just make it work. We know there are going to be issues and difficulties, and it needs to be tuned but just make it work because when we all get down to it, you know, aren't we all basically sick and tired of these endless arguments and disputes? Don't we really basically want the FDA to come up with a proposal that we can all live with?

We are going to have to help them. I guess for some folks the idea of helping a regulatory agency might not be something they think of as part of their daily duties but, in this case, we are really helping each other; we are helping ourselves to help the FDA come out with a proposal that works. So, I want to just reiterate a plea that we help them make it work.

I have also been asked to comment on the issue of preestablished thresholds. Using preestablished thresholds to trigger public health interventions is a well established concept. Many people are aware that thresholds are used in mitigating chemical hazards, but also in infectious disease this concept is used. For example, in deciding whether to mount a mass vaccination campaign to interrupt transmission of meningococcal disease in a community CDC uses a threshold level of 30 cases per 100,000 population annualized. For comparison, the background rate of invasive meningococcal disease in the United States is 1 case per 100,000 people per year. If a population such as a school or a community has an annualized rate of 30 per 100,000 in a specific time period, CDC recommends mass vaccination. Sometimes in a small community or college that can only amount to a few cases but the idea of having this threshold saves a lot of time and effort, and streamlines things and provides guidance, and we have found it to be very effective.

Currently, for animal drug approvals the only public health safeguard is the approval process itself. This process can only predict what may happen after a drug is marketed. After approval, if a problem develops the burden is on the FDA to prove that the drug is unsafe. This process can be lengthy and difficult and meanwhile the consequences mount. Therefore, the FDA needs to be cautious in approving new animal antibiotics. If resistance thresholds were established prior to approval in sentinel organisms, for example Salmonella, and if rates exceeding these thresholds more or less automatically resulted in corrective actions, including ultimately withdrawing the approval, CDC would be less concerned about seeing certain antimicrobials approved for food animal use. The AVMA prudent use guidelines would be an essential component part of this framework, providing guidance for veterinarians to use the antibiotics in a way to minimize the likelihood of crossing the thresholds.

Preestablished thresholds are important to focus preventive efforts and to allow prompt mitigation of hazards if the thresholds are exceeded, that is, without an extended period of discussion while resistance rates continue to rise and the antibiotic becomes progressively less effective.

Monitoring thresholds should also be applied to certain currently approved antibiotics, regardless of whether they may be therapeutic or subtherapeutic, with threshold levels requiring corrective action determined by increases in resistance rates for sentinel organisms. The thresholds must be scientifically based and determined on a drug by drug basis.

We are not sure exactly what mechanism the FDA would use to develop these thresholds. They will undoubtedly want outside input, and thresholds would need to be reviewed periodically.

Since CDC is primarily concerned with human disease, we are most concerned about resistance in human isolates. We would advocate that thresholds based on resistance data from human strains derived from animals be a major determinant of regulatory action. For example, CDC estimates about 2,500 cases per year of invasive Salmonella infections in the United States. At the present time, fluoroquinolones are often the drug of choice for invasive Salmonella infections. If the rate of fluoroquinolone resistance in invasive Salmonella from humans rises to 1 percent that will place about 25 patients per year at risk. Treatment failures will be expected. A resistance rate at that level would be of great concern, particularly if the trend was upward. These isolates would be from patients who are not travelers, without pets, not taking antibiotics, and there really wasn't much reason that they could have developed this other than from food animal origin in the U.S.

Now, this would be an example of a threshold that should lead to withdrawal of use from the particular species of animal linked to these infections, and a comprehensive system of surveillance in slaughterhouses would not only confirm that a particular species was associated with the increased human rates but would provide early warning because increases resistance rates at slaughter would precede increased human rates.

In closing, I just want to reiterate one more time the importance of taking the framework proposed by the FDA, making constructive suggestions to improve it and then really rolling up our sleeves to work together to make it work. Thank you.

DR. STERNER: Thank you, David. I will editorialize for just a moment. I hope that panel members were listening very carefully to a very astute insight into the people and politics of what is really a very divisive issue within the professions. Thank you. That was really remarkable, David.

Are there questions for Dr. Bell from the panel?

DR. LANGSTON: I wanted a clarification on that one percent resistance in Salmonella leading to so many human cases. Is that veterinary isolates that you were referring to or human isolates?

DR. BELL: Human isolates.

DR. LANGSTON: Okay. It seems that a key point in this is the fact that there is an association between an increase in the veterinary isolates leading to a human outcome. Do we have a model to do that, and how good is that association? How predictive is it? Do we have any data on that?

DR. BELL: I think my colleague, Dr. Angulo, could speak to the scientific data issues with a greater depth of expertise than I could. We believe that the great majority of Salmonella cases in humans in the United States are attributable to Salmonella derived from food animals. Taking a level of resistance in animals and predicting what would be the human level of resistance, and how to model that, I think might be difficult. But if we start    perhaps not start, if we use as a major determinant the threshold of Salmonella resistance in human cases   and these human cases would not have pets, or have traveled, or have any other realistic explanation    we could be confident in attributing that this was resistance resulting from drug use on the farm. I don't know if Fred wants to add to that.

DR. ANGULO: Well, I think one of the important background statements by the FDA in the framework document, at the bottom of page three, the last sentence, says for foodborne pathogens, especially for those such as Salmonella which are rarely transferred from person to person in the United States    to paraphrase what it says, antimicrobial resistance in those foodborne pathogens, the driving force for that resistance is use of antimicrobials in food animals.

It is true that we cannot say with certainty with a single case where the resistant infection that that person got came from, but when you use epidemiology and look at a population basis, we can say with extreme confidence that the dominant factor contributing to antimicrobial resistance in foodborne pathogens is use of antimicrobials in food animals. That is an important background statement. It is actually not one of the discussion points of this committee but it is an important epidemiological certainty.

DR. BELL: I don't know if this would be better reserved for the discussion part of this, but I can see that for a Class I disease where you are not allowing any increase in resistance, but I don't think I buy into it for a Class II disease where you are having to establish a baseline. I would think you would want some sort of strong association or at least an association on a Class II or a Class III if you are trying to make a quantitative assessment.

DR. ANGULO: I just have one clarification. I understand that except that, of course, the categorization of I, II or III is based upon the antimicrobial not the organism. Salmonella, whether it be tetracycline resistant Salmonella or whether it be fluoroquinolone resistant Salmonella, that assumption of where the resistance comes from is still clear.

DR. STERNER: Dr. Galbraith?

DR. GALBRAITH: David, given some of the regulatory traditions of the federal government, I am curious what you would say about the justification for human indicators and thresholds as opposed to a more conservative approach.

DR. BELL: I am not sure I understand the question. What would be the more conservative approach? I apologize, I just don't    in the background of regulatory tradition, I am not sure what you mean by that.

DR. GALBRAITH: Well, for example, the regulation on pesticide residues in air, food and water    we don't wait for human indicators before taking action, and what you were referring to are some human indicators and thresholds that would trigger action.

DR. BELL: Well, I am not knowledgeable about regulation of pesticides. I think one of the problems that we face here is that we need antibiotics in animals. When antibiotics are approved for use in animals we can't really predict what level of resistance will result; how soon it will result. I support Dr. O'Brien's comments in that regard. So, we would be willing to take a chance, if you will, recognizing the legitimate needs of antibiotics on the farm, as long as there was a good surveillance system that picked up the first signs of adverse human consequences and there was a system already in place to mitigate the hazard. Otherwise, I don't see any other way out of these endless arguments of what would the risk be from approving a drug to be used on the farm. We can't predict it. There is a fair amount of data based on studies in laboratory animals indicating at what level a chemical in the environment would pose a hazard, and so we don't need the human cases to develop; we can monitor the level of chemical in the environment. But in this kind of situation I think it is different.

DR. STERNER: Thank you. That concludes Dr. Bell's remarks. We will move on to this afternoon's first speaker and we will stay on task. Dr. Scott McEwen, from the University of Guelph, is going to talk about risk assessment. We have all heard many comments alluding to the need for good risk assessment. He is going to explain what happens.

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