Veterinary medicine advisory committee




НазваниеVeterinary medicine advisory committee
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A Proposal Framework for Evaluating and Assuring the Human

Safety of the Microbial Effects of Antimicrobial Mew Animal

Drugs Intended for Use in Food Producing Animals

DR. SUNDLOF: Well, thank you very much, Mr. Chairman. I always said that you stay in this job until you make a critical mass of enemies and then it is goodbye. So, I am not sure that those remarks last night were too comforting.

This is, as most of you are aware, a very, very important meeting for CVM. It lays out a plan for a regulatory framework dealing with some of the very complex issues of antimicrobials. A number of people inside the agency worked very, very hard, through long, arduous, contentious meetings but it never got personal. It was always very much a collegial effort although people held very different views. The resulting framework document, as Dr. Friedman indicated, is more or less the synthesis of many diverse views.

I would also like to reiterate what Dr. Friedman said in that this document represents the best thinking to date out of FDA. It is not a document that is etched in stone. It is out there for broad discussion and broad consideration. It is our first attempt to try and lay out a total package, a framework for dealing with these issues.

The development of resistance of zoonotic enteric organisms, pathogens, is the main subject of concern. We all know that the science clearly supports that exposure of microbes to antimicrobials will select from those populations organisms that have genetically encoded resistance. So, the use of antimicrobials does promote the emergence of resistant organisms. In many of the organisms that we are concerned about from a foodborne pathogen standpoint are normal commensal organisms in food animals. So Salmonella and Campylobacter are normal gut flora of food animals. They don't produce clinical disease most often in those animals but those diseases do occur in humans as foodborne problems.

[Slide]

So, we are going to talk a little bit about that. We will talk about the public health concern. Basically, in the framework document we are concerned about two different types of resistance transfer. One of them is direct transfer, and that would be direct transfer of pathogens from animals to humans, zoonotic transmission.

The second is indirect. That is, the transfer of genetic material from one organism to another organism, which is even a more complex issue. I will say that the issues that we are going to be dealing with are very complex, and we have tried simple answers; simple answers just don't seem to get us very far. So, that is why the framework document looks as complex as it does.

[Slide]

Let's talk about our current regulatory approach. We have fairly stringent pre approval standards. As everybody I think in this room understands, there is strict evaluation of the toxicologic data. We don't want residues in food which are harmful to the public. But until recently, we have only required microbial safety studies for subtherapeutic antimicrobials used in food for more than 14 days. In those cases we did require some safety studies to look at the issues of resistance and pathogen load.

[Slide]

But it wasn't until a few years ago, when we first approved the fluoroquinolone antimicrobial for use in food animals, that it became very apparent that resistance was not just an issue associated with subtherapeutic use of antimicrobials, and we recognized at that point that we would need additional information to be able to evaluate the resistance development to fluoroquinolone and take the appropriate actions.

So, there are approvals now for cattle and poultry. We made sure that those products were available only through veterinary prescription; that it would be illegal to use them in any way that was extra label or off label. We asked the firms to engage in post approval monitoring programs, and we initiated a national antimicrobial resistance monitoring system.

[Slide]

So, FDA's goal then is to protect the public health by preserving long term effectiveness of human antimicrobial drugs while, at the same time, providing for the safe use of antimicrobials in food producing animals.

The purpose of this complex framework is to make sure that we do have a mechanism by which we can still approve these products because they are extremely important in animal agriculture. They are extremely important to the health and welfare of animals, and we just have to make sure that we do it in a way that is protective of the public health.

[Slide]

We have determined that the current regulatory structure for dealing with the approval process doesn't really adequately take into account the issue of antimicrobial resistance. Again, we have strict regulations and requirements for looking at the toxicologic impact of drug residues but, in terms of dealing with the antimicrobial resistance issues, we haven't had a good system for dealing with that.

Earlier this year or late last year, we published a notification of a draft guidance, number 78, and it is in the book that participants have. Basically, it establishes the regulatory authority for FDA to deal with the issue of antimicrobial resistance. That was the first step in going forward with the program, total program, to deal with the antimicrobial resistance issue. From there, the framework document was published last month, in December, and you have that in your package. That is the second part.

Furthermore, we plan to hold workshops to look specifically in detail at what kind of studies would best give us the kind of information that will be necessary to allow decisions of whether or not to approve these products. Throughout this process, we have asked for a lot of input from the public, and we will continue to do so.

[Slide]

The draft guidance for industry, number 78, says FDA now believes that it is necessary to evaluate the human impact of microbial effects associated with all uses of all classes of antimicrobial new animal drugs intended for use in food producing animals.

The two issues that have to be addressed are resistance    what is the potential for the products to cause resistance, and in what organisms? And, what effect does the drug have on the pathogen load that the animal may be carrying at the time it is used for human food?

[Slide]

So, those are the two issues. Now, the draft guidance has been out there since November 18, and the comment period ended on December 18. We only received a few comments on the guidance, and the comments that we did receive did not materially affect the guidance as it stands. So, we will continue to accept comments, and anybody can comment anytime on the guidance. Pretty much, we think we have put the guidance out there; we have listened and received comments, and the comments have not caused us to revise that document.

[Slide]

So, the focus of this meeting will be to determine how the agency should change its requirement for data and information. It is not on whether changes should be made. We have come to the conclusion, and that guidance document, number 78, basically is the position of the FDA that we think this is an issue that must be dealt with. So, it is going to be important to make changes. We want to make the right changes, and that is what we want a lot of input during this meeting for.

[Slide]

The framework document was issued in December, and we will be accepting comments on it until April 6. We are now in the comment period, and we will take all of the information that comes out of this meeting    all the transcripts, go through those, try and sort out the comments, but in addition, if there are additional comments, they can be accepted up until April 6, and we encourage a lot of comments.

The VMAC meeting was called to provide input and to address the specific questions related to the framework document, and the focus of this meeting is the framework document, as was mentioned, and the questions provided to the committee. There are a lot of peripheral issues associated with antimicrobial resistance but we want to keep the focus of this meeting squarely on the framework document.

It articulates FDA's current thinking on how the agency should respond to contemporary information related to the human health impact of the use of antimicrobials in food producing animals.

[Slide]

Now, the framework document lays out a conceptual regulatory construct for addressing the microbiological safety of antimicrobial drugs intended for use in food producing animals. The elements of the document include adequate and well controlled studies in the pre approval phase to provide predictive value on the likelihood and extent to which antimicrobial resistance may develop when the drug is marketed for its intended use.

It also includes monitoring or surveillance in the post approval phase to identify the emergence of resistance if, and when it does, occur.

Finally, it includes regulatory endpoints or thresholds which will trigger specific actions designed to mitigate the continued development of resistance.

These principles will be applied to all antimicrobial drugs intended for use in food producing animals regardless of their intended use. Whether it is therapeutic or subtherapeutic, the same scientific principles apply.

[Slide]

Some of the concepts within the framework    basically there are five components. The first is assessing whether the proposed use will result in increased exposure to pathogenic bacteria. This is referred to as pathogen load. If you use the drug in the animals, will the number of pathogens within the intestinal tract of animals increase? If so, how can this be mitigated?

Secondly, it will assess the safety of the proposed animal uses of drugs according to their importance in human medicine. That is, if you are talking in terms of a risk analysis, this is the hazard analysis. The hazard that we are referring to is the impact on public health that would result if the antimicrobial in question was no longer effective in the treatment of diseases transmitted directly or indirectly through animal derived foods. That is the hazard.

Then, the second part of a risk assessment is the exposure assessment. How likely is it that people will be exposed, that the public will be exposed to resistant organisms that are produced as a result of drug use in animals? So, those are the two components to how we intend to evaluate these.

We also intend to assess pre approval data showing that the level of resistance transfer from proposed uses will be safe. We want some pre approval studies that will give us a predictive value that once the drug is approved the likelihood of resistance development will be manageable.

Then, we also will be talking about establishing resistance and monitoring thresholds. That gives us a target against which to regulate. Without those kinds of targets out there it becomes a very difficult regulatory process to say at some point in time, "well, I think now is the time when it is not safe anymore." So, we want to have a target out there from a regulatory standpoint where we can all declare that actions need to be taken, and those actions may not necessarily mean removal of the product from the market, but to take intervention steps that will mitigate the continued emergence of resistance. Then, establishing pre approval studies and post approval monitoring will be necessary.

The framework document discusses how we intend to categorize these various drugs. There is a two tiered system. The first system looks specifically at the risk to public health    how important are these drugs in human medicine? What would be the impact if they were lost from use? So, we have established a category of 1, 2 and 3. Those will be discussed in much greater detail by others. But it is crucial that the importance of an antimicrobial in human medicine be the first determinant before FDA can assess what effect the development of resistance that drug from food animal use will have on human health. We need to know how important it is in human medicine.

The second part is the human exposure to resistant bacteria. This will include looking at the number of animals that will potentially be exposed or treated by the antimicrobial; the ability of drugs to induce resistance in bacteria of public health significance; and the likelihood that use of the drug in animals will promote resistance.

[Slide]

The pre approval and post approval requirements will vary depending on the evaluation of these two factors: the impact of the drug on human therapy and the potential exposure of humans to pathogenic organisms.

[Slide]

So, establishing the requirements will depend on the category; will depend on the ranking system. The number and type of studies that will be required, and the type of post approval monitoring studies will be determined based on the ranking system that we have proposed in the framework document.

Resistance and monitoring thresholds would be established prior to approval to ensure that resistance does not develop established threshold levels. Resistance thresholds would be set to a defined level of resistance in animals that would result in no or insignificant transfer of resistance to human pathogens.

Monitoring thresholds, on the other hand, would be established so that they can serve as an early warning system, signalling when the loss of susceptibility of resistance prevalence approaches the level of concern.

[Slide]

So, depending upon the category, pre approval studies may be needed. Post approval studies and monitoring, and possibly on farm monitoring studies may be required. We will rely increasingly on the national antimicrobial resistance monitoring system to give us the kind of surveillance information that will be necessary for us to make the right regulatory decisions.

Now, in the presentations to follow, they will provide more of an explanation of the framework document, and presentations will follow on the categorization of antimicrobials by importance in human therapy, the pre approval studies on microbial safety, post approval surveillance issues and the need to set thresholds.

[Slide]

So, I would like to start talking about the framework document and the questions on the framework document to the committee. The framework document sets out, again, a conceptual framework for how we intend to regulate antimicrobial drugs in food animals, and the main focus is on resistance although there are some parts of it that refer to pathogen load.

But we are seeking comments on whether the framework will, indeed, accomplish the goals. Is this conceptual framework that we have laid out going to accomplish the goals of protecting public health, while giving us an avenue for allowing the approval of drugs when they meet the standards that we have set out, and whether it will provide for the safety of these drugs in food animals. So, we are seeking comments.

[Slide]

I will go through the questions. Question one that the committee will be asked to address is FDA's goal is to protect the public health by ensuring that the efficacy of human antimicrobial therapies is not compromised due to use of antimicrobials in food animals, while providing for the safe use of antimicrobials in food animals. Does the framework document, indeed, provide a sound scientific basis for achieving this goal, if implemented?

[Slide]

Question two, categorization of antimicrobials    the agency is proposing that the categorization of antimicrobial drugs for human medicine take into account the usefulness of the drugs in treating both foodborne diseases and non foodborne infectious diseases. What evidence exists that the use of the drug may result in induction of resistant pathogens or the transfer of resistance elements to human pathogens? This approach recognizes not only the well known risk of resistance transfer through classical foodborne pathogens, but also the threat of transfer of resistant bacteria or resistance genes from other intestinal bacteria of food animals resulting in resistant infections of humans with other types of pathogens, for instance, E. coli or Enterococcus. The question to the committee is do you agree with this concept?

[Slide]

Question number three, monitoring thresholds    should multiple monitoring threshold levels be established and should they be based on animal data, human data or both? Should the levels be tied to specific actions, for example, the need for further investigation, the need for mitigation strategies, the need for withdrawal of product from the market, or others?

Secondly, what organisms should be the basis for monitoring thresholds? In the interest of cost containment, should sentinel organisms, and not the pathogens themselves, be designated or should only the foodborne pathogens be used?

[Slide]

The fourth question deals with resistance threshold levels. The agency has proposed the creation of different levels of resistance transfer to humans that would be acceptable based on the importance of the drug or drug class in human medicine. Category I antimicrobial drugs would require that the use in food producing animals results in none or little resistance transfer to humans. Category II antimicrobial drugs would require that a predefined level of maximum resistance transfer be established prior to the approval that would depend on several factors, such as the existence of alternatives to the drug, the human pathogens of concern, etc. The level of resistance transfer must be low enough that there is a reasonable certainty of no harm to humans associated with the use of the product in food animals. What criteria should the agency use to safely define the acceptable level of resistance transfer, if any, for antimicrobial drugs that fall into Categories I and II?

[Slide]

Finally question five, on farm post approval monitoring programs will be necessary for certain antimicrobials in Category II and Category II/high exposure, and some Category II/medium exposures. The question is should those on farm studies be implemented immediately or should they be implemented after there is a for cause concern, once we see resistance starting to develop?

So, those are the five questions that we hope to have answered by the end of tomorrow, and we will have to have answers by the end of tomorrow because most people have flights that are leaving tomorrow afternoon.

So, I commend the advisory committee in advance for what I know is going to be a very lively discussion that is going to occur during the next two days but is of extreme importance to the public and to the Center for Veterinary Medicine. Thank you, Mr. Chairman.

DR. STERNER: Thank you, Dr. Sundlof. Do any members of the VMAC have any questions of Dr. Sundlof at this time?

[No response]

I would like to set the ground rules just a bit. After the break we will begin with our invited speakers, and those are the people seated in the front row, in the reserved seats. We have some housekeeping details that we need to take care of. I understand we are ahead of schedule. The die has been cast for the rest of the speakers and I will hold you scrupulously to the time commitments. You didn't see the trap door over there but it is there!

Setting the ground rules with regard to questions of invited speakers, VMAC members and agency personnel will be extended the opportunity to ask questions. During the public comment period the same applies. If at the end of the public comment period we progress as we have so far, questions from the audience will be entertained of any public speakers that remain.

Along the front table, as I indicated, we have invited speakers. There are three people who are there from USDA who do not have prepared remarks to give, Dr. Kaye Wachsmuth, Deputy Administrator, Office of Public Health and Science at FSIS; Dr. Kenneth Peterson, from the Office of Public Health and Science of Emerging Pathogens; and Dr. William James.

Dick, do you have some additional housekeeping details?

MR. GEYER: Yes, I do. Thank you, Keith. We will handle these administrative announcements now and then take a 20 minute break. We need to do some setup before our first speaker. Keith mentioned the need to stay on schedule because we do have a full day, and to help facilitate that we have a little traffic light. In fact, we have two traffic lights for our speakers. There is one right down in front here and then, in case the speaker is unable to see this one, there is one on the lectern, over there. It will go from green to yellow. The yellow is a two minute warning.

DR. STERNER: And there are no time outs, by the way.

MR. GEYER: No time outs. Then to red. We will set that according to the time that we have agree with all of the speakers that they will actually use for speaking. There will be time beyond that set aside for questions as well, except I think, Keith, as we get into the public speakers this evening we are just going to go right on with one presentation after another and, as Keith said, hold questions until the end.

One of things that I need to do as Executive Secretary is to read a conflict of interest statement. Please bear with me as I do that.

Federal conflict of interest laws preclude the participation of committee members and consultants in advisory committee meetings if they have a conflict of interest unless a waiver of exclusion is granted by the agency.

Based on the submitted agenda for this meeting and the review of all financial interests reported by the committee participants, it has been determined that all interests in the firms regulated by the Center for Veterinary Medicine which have been reported by the participants present no potential for a conflict of interest at this meeting, with the following exceptions:

In accordance with 18 USC 208(b)(3), waivers have been granted to Dr. Steven Barker, Dr. Wanda Haschek Hock, Dr. Robert Holland, Dr. Carl Norden and Dr. Keith Sterner. Under the terms of the waiver Drs. Barker, Haschek Hock, Holland, Norden and Sterner will be permitted to participate fully in discussions and deliberations which will involve human and veterinary medical issues related to antimicrobial resistance associated with drug use in animals.

In regard to FDA's invited guest speakers, Dr. David Bell, Dr. Sherwood Gorbach, Dr. Patricia Lieberman, Dr. Scott McEwen, Dr. J. Michael Rutter, Dr. Abigail Salyers and Dr. Lyle Vogel, the issues to be addressed at the advisory committee meeting will not constitute a conflict of interest for the above names guest speakers.

With respect to all other meeting participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they wish to comment upon. This refers to the speakers in our public speaker session, and we will remind the speakers of that when we begin that session.

Copies of all of the waivers are available through the Freedom of Information Act procedures.

I would like to introduce a couple of staff members for VMAC who are here helping today and who will be able to help out with questions that you all might have: Jackie Pace    if you would stand up, Jackie; John Sheid    John, are you in the back of the room somewhere? I think he is coming in. Michelle Talley. Michelle is back there. Hold your hand up, Michelle. And, is Susan Simmons in the room? She may be outside. Those are the staff members and they and I can answer questions that any of you might have.

Keith, I think those are the only announcements that I have at this point.

DR. STERNER: We are ahead of schedule. We will break for 20 minutes. I have about 9:20 right now. We will meet at 9:40.

[Brief recess]

DR. STERNER: We will start with Dr. Mark Goldberger, from the Center for Drug Evaluation and Research. His subject matter is the importance of antimicrobial drugs for use in human medicine. Dr. Goldberger?

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