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Post Approval Surveillance Issues|
DR. TOLLEFSON: Good morning. I am Linda Tollefson. I am Director of the Office of Surveillance and Compliance in the Center for Veterinary Medicine, dealing with all the post marketing issues.
What I want to discuss this morning are the post marketing surveillance issues that are outlined in the framework document.
Because of the human health concerns related to the use of antimicrobials in food animals, FDA developed an antimicrobial resistance surveillance system as a post marketing tool to prospectively monitor the emergence and spread of resistance in enteric pathogens. This system is a collaborative effort among FDA, CDC and USDA, and it became operational in January of 1996, and we have expanded it every year since then.
I will describe this national antimicrobial resistance monitoring system, including its strengths and limitations, and then discuss why the agency is considering on farm studies to monitor antibiotic resistance for Category I and some Category II drugs.
The program monitors changes in susceptibilities to a number of antimicrobials of zoonotic enteric pathogens from human and animal clinical specimens, from healthy farm animals and carcasses of food producing animals at slaughter. We are currently monitoring susceptibilities to 17 antimicrobials among Salmonella, E. coli 057 and Campylobacter. The antimicrobials are either broad spectrum or have a Gram negative spectrum. We have recently begun a pilot study of human Enterococcus isolates using a group of Gram positive drugs but have not done this for the animal isolates.
What we have done is set up a system as two nearly identical parts. The veterinary testing is conducted at USDA Agricultural Research Services, Russell Research Center in Athens, Georgia. Human testing is conducted at the National Center for Infectious Diseases at CDC. Both CDC and USDA use a semi automated system by Sensi Titer for Salmonella and E. coli testing, and the E test for Campylobacter. The labs have comparable methods of isolate handling too.
The goals and objectives of the monitoring program are to provide descriptive data on the extent and temporal trends of antimicrobial susceptibility and enteric organisms from both human and animal populations; facilitate the identification of resistance in humans and animals as it arises because we are interested in the emergence of resistance rather than looking at the absolute prevalence of resistance; provide timely information to all practitioners; prolong the life span of approved drugs by promoting prudent use; identify areas from our detail investigation; and guide research on antibiotic resistance.
Unfortunately, this monitoring system does not provide sufficient information to ensure continued safety of specific food animal antimicrobials after their approval and marketing.
The reason for this the system has a number of inherent limitations. The national antimicrobial resistance monitoring program is only a sentinel system. We can't estimate the magnitude of problems; we can only identify if resistance is emerging. The system cannot tell us how or why the resistance occurred. We do not, and actually are unable on the animal side to collect data related to the resistance findings, such as demographic information and history of drug use. Therefore, we are unable to link the data to particular practices of concern.
Findings from the system then will often require complementary sources of information or more focused analytical studies to be validated. Also, selection biases arise in both the human and animal populations that we are testing and this can severely limit the statistical inferences that can be derived from the data. For example, only a percentage of humans may visit a physician when they do have a foodborne disease. There are questions concerning accurate diagnoses. Samples are not always taken and submitted or reported. Similar problems occur with ill animals.
Now, the program has been expanded as resources permit, as I mentioned previously. For example, with the cooperation of the Food Safety and Inspection Service we have been able to increase the number of Salmonella isolates that are taken at slaughter. However, we are still limited by the cost of supplies and personnel in the number that we can conduct and, of course, we are dealing with Salmonella in this case only.
Post approval monitoring programs would fill many of these gaps for critical drugs. FDA has proposed that these studies be conducted for all Category I drugs and some Category II drugs. They may be necessary for other drugs if the national program, for example, or another source of information found unexpected or unacceptable resistance.
What we are thinking about here is that on farm surveys could be designed to obtain a true prevalence of resistance or decreased susceptibility to specific drugs or drug classes in a food animal production setting. Because we could link the resistance outcome to contextual information surrounding the sample collection, on farm data would provide a strong body of scientific evidence that specific factors, drug related or not related, are leading to resistance outcomes.
We anticipate that these objectives could be accomplished from a broad national on farm program rather than a drug specific study undertaken by each sponsor. Also, they would need to be species specific only since many drug classes could be tested on the same isolates, and many pathogens could potentially be isolated from a single sample.
In addition to other scientific data, the post approval monitoring programs could provide a critical early warning system for detecting and evaluating the emergence of resistance under actual use conditions. On farm studies would allow the agency and the drug sponsor to monitor for established resistance and monitoring thresholds as are described in the framework document.
If, on the other hand, we relied only on the national antimicrobial resistance monitoring system to monitor for established thresholds among the animal data we would have to either greatly expand the veterinary portion of the national system, or lower the threshold to a more conservative value to allow for the uncertainty in the estimates. The national program is not really robust enough in its current form to either establish or monitor thresholds with any kind of confidence.
The on farm studies would be used to collect risk factor information such as drug exposure associated with the collected samples; identify areas to implement mitigation strategies should resistance emerge; and also test effectiveness of on farm intervention strategies. Identification of risk factors for resistance development, such as production practices of drug use practices, will allow mitigation of antimicrobial resistance at the farm level, and should give us a great deal of information on how to do that. Probably very importantly, on farm data would also provide scientifically based evidence for evaluation of effectiveness of intervention or mitigation strategies. That is something that we don't have much information on now.
On farm studies would provide very useful information also if resistance should reach a predetermined threshold. On farm studies could conceivably identify a more precise location where resistance was developing, for example, in a certain geographical location for a specific drug of a class, or in response to use of a particular dosage form. Then, mitigation or regulatory action would have to be taken only on the particular use that is causing the resistance to develop.
Without the information these studies can provide, when resistance reached the predetermined threshold action would need to be taken against all drugs and dosage forms in lieu of information showing that some forms were safe. In other words, we are looking to more focus for on farm studies to provide much more detail about resistance emerging under actual use conditions.
To summarize and I know this is a brief presentation but I will answer questions although the national antimicrobial resistance monitoring system can provide a broad overview of resistance trends for both human and veterinary enteric pathogens and information on several drug classes, it cannot provide demographic and drug related and non related risk factor information on the animal side of the system.
The post approval monitoring programs then are expected to provide data on both resistance and risk factors under actual conditions of use; a means to monitor for established resistance and monitoring thresholds after approval; to help ensure they are not exceeded; and, a means to investigate intervention and mitigation strategies, and implement promising strategies in a timely fashion, and then follow what happens once the mitigation strategies are implemented.
On farm post approval monitoring programs are proposed for certain antimicrobials, Category II, Category II agents, some Category II/M products. The question that we are putting to the committee is one of timing. Should on farm monitoring be instituted by drug sponsors immediately after approval, or be triggered by a change in data generated from other sources, such as the national antimicrobial resistance monitoring system?
The advantages to having these studies instituted immediately post approval are an increased insurance that resistance and monitoring thresholds will not be exceeded; that data from on farm studies will allow us to more precisely determine why and how resistance is emerging; and that mitigation strategies can be implemented in a timely manner. The disadvantage is the cost associated with the studies, potentially in situations where a problem will never arise.
Are there questions?
DR. BARKER: For the on farm type of study, what are the advantages of doing those on farm versus doing them at a stockyard or slaughterhouse?
DR. TOLLEFSON: The main advantage I would consider a stockyard on farm the major advantage is to try to pick up the contextual information surrounding the sample. In the national program when we collect the slaughter isolates, for example, we get species and the sample. We get a broad geographical location but nothing else. So, we don't have any kind of information on the sample that could rule out drug, non drug causes to that resistance development. If you have a program in place where you are monitoring on farm actually, the collection of the sample should probably be close to slaughter because we may not be interested in what happens earlier, conceivably you would have at least a mechanism to collect the information on the risk factors, to find out if, say, a poultry house or the group of animals was treated with drugs what other husbandry practices could be going on; not cleaning up the farm and the environmental concerns that you had mentioned in response to Dr. Miller's presentation. That is what we are thinking of. We don't have any means of doing that in the national program.
DR. STERNER: Yes, Dr. Lein?
DR. LEIN: My concern really in bringing up this fact of on farm versus at slaughterhouse is that we have attempted to do those studies. At least fecal carrying organisms may stay basically pretty stable between leaving the farm and getting to the slaughterhouse. On hide contamination what you brought up, Steve is a big problem. We see changes taking place. Hide is a big sponge that works very nicely as a swab. And, just transportation changes. So, we have to be very definitive, as you start to look at Salmonella, as to typing those and that becomes very expensive because they do change. And, we see a lot of environmental effect in this situation. So, bird contamination, trucks and other things begins to accumulate on these hides as they get to the slaughterhouse.
Also, at slaughterhouse one thing that we have never done that needs to be looked at is what is the environment of the slaughterhouse? What is happening basically as we bring people into this? People become a problem too. So, you have that problem to look at as well.
The on farm studies, as we start to look at these, I think in veterinary medicine and this is probably also true in human medicine we have looked at the individual and as we start to look at herds we certainly can make a diagnosis of the condition. The next thing is how that changes over time is not looked at very easily. And, if you start to look at what is happening with that herd, and that is where it becomes very expensive for the farmer and veterinary medicine over time I think it is necessary but who is going to pick that up? Who is going to pick up the price of monitoring as we go on to following a treatment basically? And, even the laboratories to do herd type work we have to redesign the ability to look at least at a percent of those samples to know what we are looking at and the environment that they are in.
The environment changes so quickly. I was just at a herd the other day doing testing, and if you look at the amount of bird contamination that comes into that herd and I know as we work with the poultry industry, and this would be true of any industry, the amount of rodent contamination it is quite interesting, how that changes. So, the monitoring is going to be something quite interesting to look at.
DR. TOLLEFSON: But I think those are risk factors that you have identified
DR. LEIN: Yes.
DR. TOLLEFSON: You know, the environmental contamination, rodents, birds and so on.
DR. STERNER: Dr. Angulo?
DR. ANGULO: I just wanted, Linda, to make sure you are aware of how much we support your concept. I think there is much detail that has to be worked out for exactly what on farm monitoring might be, but the point is well taken that there are limitations in national surveillance through the NARMS, and if we see increases in resistance, unless there is some work being done on the farm and I am not sure who is going to do it and to what extent it gets done, but unless something is being done on the farm it is unclear how to mitigate what we are detecting in the national system. So, the point is well taken. There are clear limitations in the national system, and unless there is something being done on the farm we are left with uncertainty on how to mitigate the resistance.
DR. STERNER: We have time for just one last question and, Wanda, I saw your hand first.
DR. HASCHEK HOCK: I just wanted to follow up on what Dr. Lein said about on farm surveys versus slaughterhouse surveys because recent studies at the University of Illinois have shown that transportation markedly increases shedding of Salmonella in animals that were not previously shedding. There is also a study showing that food withdrawal can also affect shedding. So, I think that those factors are really important in this discussion.
I also wanted to ask if any other countries have been looking at implementing this type of monitoring and, if they have, if you could give us some details.
DR. TOLLEFSON: In answer to your first point, we are aware of those studies that show transportation effects, but keep in mind that we do have the national program which is heavily weighted towards slaughter samples so we can look at the broad emergence of resistance by species, and we would use the data together. The on farm data would be really more to refine where and how to implement mitigation strategies before it reached a point of no return, if you will, or before resistance would be great enough to impact human public health.
In answer to your other question, there are actually quite a few surveillance programs that are either just beginning to be developed, or in some countries have been in place for a while. One that comes to mind is the Danish system, which is in human and animal and retail food. It is really quite extensive. That does incorporate on farm data. They have limited information collected with those samples and I am not sure how much. I know they do like thousands, 30,000 samples a year. For a very small country it is quite large. Then, there are some European wide ones that are just starting to get into place. Also, the Canadians. Rebecca Irwin is here. They also are starting to do a surveillance program. I don't think, though, that it incorporates an on farm component but she can talk to you. I am sure she would be willing.
DR. STERNER: Excuse me, as Chair I am charged with keeping us on task, and thank you, Dr. Tollefson.
Next, we have from the Centers for Disease Control, Dr. David Bell addressing the issues and the needs for looking at the benefits for establishing threshold levels. Dr. David Bell?
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